144 results on '"Crushell, E."'
Search Results
2. Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: data from the E-HOD registry
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Huemer, Martina, Diodato, Daria, Martinelli, Diego, Olivieri, Giorgia, Blom, Henk, Gleich, Florian, Kölker, Stefan, Kožich, Viktor, Morris, Andrew A., Seifert, Burkhardt, Froese, D. Sean, Baumgartner, Matthias R., Dionisi-Vici, Carlo, the EHOD consortium, Alcalde Martin, C., Baethmann, M., Ballhausen, D., Blasco-Alonso, J., Boy, N., Bueno, M., Burgos Peláez, R., Cerone, R., Chabrol, B., Chapman, K. A., Couce, M. L., Crushell, E., Dalmau Serra, J., Diogo, L., Ficicioglu, C., García Jimenez, M. C., García Silva, M. T., Gaspar, A. M., Gautschi, M., González-Lamuño, D., Gouveia, S., Grünewald, S., Hendriksz, C., Janssen, M. C. H., Jesina, P., Koch, J., Konstantopoulou, V., Lavigne, C., Lund, A. M., Martins, E. G., Meavilla Olivas, S., Mention, K., Mochel, F., Mundy, H., Murphy, E., Paquay, S., Pedrón-Giner, C., Ruiz Gómez, M. A., Santra, S., Schiff, M., Schwartz, I. V., Scholl-Bürgi, S., Servais, A., Skouma, A., Tran, C., Vives Piñera, I., Walter, J., and Weisfeld-Adams, J.
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- 2018
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3. Newborn screening for homocystinurias: recent recommendations versus current practice
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Keller, R., Chrastina, P., Pavlíková, M., Gouveia, S., Ribes, A., Kölker, S., Blom, H. J., Baumgartner, M. R., Bártl, J., Dionisi Vici, C., Gleich, F., Morris, A. A., Kožich, V., Huemer, M., and individual contributors of the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD), Barić, I., Ben-Omran, T., Blasco-Alonso, J., Bueno Delgado, M. A., Carducci, C., Cassanello, M., Cerone, R., Couce, M. L., Crushell, E., Delgado Pecellin, C., Dulin, E., Espada, M., Ferino, G., Fingerhut, R., Garcia Jimenez, I., Gonzalez Gallego, I., González-Irazabal, Y., Gramer, G., Juan Fita, M. J., Karg, E., Klein, J., Konstantopoulou, V., la Marca, G., Leão Teles, E., Leuzzi, V., Lilliu, F., Lopez, R. M., Lund, A. M., Mayne, P., Meavilla, S., Moat, S. J., Okun, J. G., Pasquini, E., Pedron-Giner, C., Racz, G. Z., Ruiz Gomez, M. A., Vilarinho, L., Yahyaoui, R., Zerjav Tansek, M., Zetterström, R. H., and Zeyda, M.
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- 2018
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4. An approach to recognising and identifying metabolic presentations in the paediatric Irish Traveller population
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Forman, E. B., primary, Lynch, S. A., additional, Knerr, I., additional, Monavari, A., additional, Hughes, J., additional, Boruah, R., additional, Green, A., additional, and Crushell, E., additional
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- 2022
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5. A review of anaesthetic outcomes in patients with genetically confirmed mitochondrial disorders
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Smith, A., Dunne, E., Mannion, M., O’Connor, C., Knerr, I., Monavari, A. A., Hughes, J., Eustace, N., and Crushell, E.
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- 2017
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6. Clinical disease characteristics of patients with Niemann-Pick Disease Type C: findings from the International Niemann-Pick Disease Registry (INPDR)
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Bolton SC, Soran V, Pineda M, Imrie J, Gissen P, Jahnova H, Sharma R, Jones S, Santra S, Crushell E, Stampfer M, Coll MJ, Dawson C, Mathieson T, Green J, Dardis A, Bembi B, Patterson MC, Vanier MT, and Geberhiwot T
- Abstract
Background: Niemann-Pick Disease Type C (NPC) is an autosomal recessive rare disease characterised by progressive neurovisceral manifestations. The collection of on-going large-scale NPC clinical data may generate better understandings of the natural history of the disease. Here we report NPC patient data from the International Niemann-Pick Disease Registry (INPDR). Method: The INPDR is a web-based, patient-led independent registry for the collection of prospective and retrospective clinical data from Niemann-Pick Disease patients. Baseline data from NPC patients enrolled into the INPDR from September 2014 to December 2019 was extracted to analyse the demographic, genetic and clinical features of the disease. Results: A total of 203 NPC patients from six European countries were included in this study. The mean age (SD) at diagnosis was 11.2 years (14.2). Among enrolled patients, 168 had known neurological manifestations: 43 (24.2%) had early-infantile onset, 47 (26.4%) had late-infantile onset, 41 (23.0%) had juvenile onset, and 37 (20.8%) had adult onset. 10 (5.6%) patients had the neonatal rapidly fatal systemic form. Among the 97 patients with identified NPC1 variants, the most common variant was the c. 3182T > C variant responsible for the p.lle1061Thr protein change, reported in 35.1% (N = 34) of patients. The frequencies of hepatomegaly and neonatal jaundice were greatest in patients with early-infantile and late-infantile neurological onset. Splenomegaly was the most commonly reported observation, including 80% of adult-onset patients. The most commonly reported neurological manifestations were cognitive impairment (78.5%), dysarthria (75.9%), ataxia (75.9%), vertical supranuclear gaze palsy (70.9%) and dysphagia (69.6%). A 6-domain composite disability scale was used to calculate the overall disability score for each neurological form. Across all with neurological onset, the majority of patients showed moderate to severe impairments in all domains, except for 'swallowing' and 'seizure'. The age at diagnosis and death increased with increased age of neurological symptom onset. Miglustat use was recorded in 62.4% of patients and the most common symptomatic therapies used by patients were antiepileptics (32.9%), antidepressants (11.8%) and antacids (9.4%). Conclusion: The proportion of participants at each age of neurological onset was relatively equal across the cohort. Neurological manifestations, such as ataxia, dysphagia, and dysarthria, were frequently observed across all age categories.
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- 2022
7. Classical Galactosaemia in Ireland: incidence, complications and outcomes of treatment
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Coss, K. P., Doran, P. P., Owoeye, C., Codd, M. B., Hamid, N., Mayne, P. D., Crushell, E., Knerr, I., Monavari, A. A., and Treacy, E. P.
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- 2013
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8. G471 Somatic mosaicism in X-linked PDHA1 gene – a cause of developmental delay and epilepsy
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Kutty, JS, Crushell, E, King, M, and Hughes, JAF
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- 2014
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9. G86(P) Clinical Phenotype associated with recessive mutations in LARS gene
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Slattery, S, Casey, J, Lynam-Lennon, N, Mc Gettigan, P, O’Sullivan, J, Mc Dermott, M, Forde, K, Knerr, I, Treacy, E, Monavari, AA, Hughes, J, Bourke, B, Ennis, S, Lynch, SA, Cotter, M, and Crushell, E
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- 2014
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10. G82(P) Hepato-cerebral mitochondrial DNA depletion: a rare and fatal cause of prolonged neonatal jaundice
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Slattery, S, Broderick, AM, Fraser, B, Hughes, J, Knerr, I, and Crushell, E
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- 2014
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11. Negative screening tests in classical galactosaemia caused by S135L homozygosity
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Crushell, E., Chukwu, J., Mayne, P., Blatny, J., and Treacy, E. P.
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- 2009
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12. S02. TUMOUR RISKS AND GENOTYPE-PHENOTYPE ANALYSIS IN AN IRISH COHORT OF PATIENTS WITH GERMLINE MUTATIONS IN THE SUCCINATE DEHYDROGENASE SUBUNIT GENES SDHB, SDHC AND SDHD
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Hynds, P, Coghlan, D, Purcell, C, Green, A, Ward, A, Lynch, SA, Hough, O, Duff, M, Cody, N, Carroll, C, Bradley, L, Green, Andrew, Lynch, Sally-Ann, Crushell, E, Byrne, N, Gorman, K, King, M, Irvine, A, Monavari, A, Knerr, I, Cotter, M, McConnell, V, Browne, F, Lambert, D, Turner, J, Casey, J, Doyle, S, Nesbitt, IM, Fitzgibbon, M, Pastores, G, Kirk, R, Treacy, EP, Benson, KA, Kennedy, C, Yachnin, K, Cavalleri, G L, Conlon, P, McVeigh, Úna M, McVeigh, Terri P, Miller, Nicola, Morris, Derek W, Kerin, Michael J, Irwin, R., Caffrey, A., McLaughlin, M., McNulty, H., Cassidy, T., Pentieva, K., Walsh, C., Minguzzi, S, MacCooey, A, Brosnan, J, Brosnan, M, Henry, M, Meleady, P, Parle-McDermott, A, Gilbert, EH, O’Reilly, S, Merrigan, M, McGettigan, D, Molloy, AM, Brody, LC, Bodmer, W, Hutnik, K, Ennis, S, Lawson, DJ, Wilson, JF, Cavalleri, GL, Flynn, M, Whitton, L, Gill, M, Corvin, A, Donohoe, G, Morrison, C, Morris, D, Stapleton, CP., Birdwell, KA., Mark, PB., Sanders, ML., Phelan, PJ., Maxwell, AP., McKnight, AJ., Kennedy, C., Jardine, A., Traynor, J.P, Chapman, F., Keating, B., Conlon, PJ., Cavalleri, GL., Gunne, EA, Lambert, DM, Martin, R, Donnelly, DE, Callaghan, MB, Morrison, PJ, McConville, DO, Archbold, GP, Lewis, A, Morrison, P J, Das, S., Kelly, D., Moran, B., Harold, E., Han, K., Mulligan, N., Barrett, C., Buckley, P.G., Mc Mahon, P., McCaffrey, J, Van Essen, H. F., Connor, K., Ylstra, B., Lambrechts, D., Gallagher, W.M., O’Connor, D.P., Kelly, C.M., O’Neill, T, Power, C, de Franco, E, Ellard, S, Antao, B, O’Connell, SM, Dabir, T, Heggarty, S, Dockery, A, Carrigan, M, Wynne, N, Keegan, D, Stevenson, K, Silvestri, G, McCourt, J, Humphries, P, Kenna, PF., Farrar, GJ, Agbahovbe, R, Cohen, ASA, Gibson, WT, Cole, AM, Bohlender, R., Hu, H, Heinrich, E, Ramirez, C, Yu, Y, Powell, F, Gaio, E, Villafuerte, F., Taylor, C, Huff, C, Simonson, T., Cavalleri, G., Scullion, C, Irwin, R, Thakur, A, Walsh, C, Shortall, C, Palfi, A, Chadderton, N, Kenna, PF, Boomkamp, S, Shen, S, Hardcastle, AJ, Maloney, DM, Millington-Ward, S, Mackin, S-J, Irwin, R E., O’Neill, KM., Pollin, G, Apostolova, G, Dechant, G, Mackin, SJ, O’Neill, K, Walsh, CP, Sohedein, MNA, Morris, DW, Chaudhry, M, Segurado, R, Shields, D, Wilson, AG, Watkin, R.L., Piskareva, O., Madden, S., Stallings, R., Kerrigan, S.W., O’Neill, K M., Thursby, SJ, Bertens, C, Masala, L, Loughery, J, McArt, D, Amenyah, S. D., McMahon, A., Deane, J., Ward, M., Strain, J.J., Horigan, G., Purvis, J., Lees-Murdock, D., Lynch, SM., Ward, M, McNulty, H, Horigan, G, Purvis, J, Tackett, M, McKenna, DJ., Angel, Z, and Walsh, CP.
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Abstracts ,Poster Presentations ,Oral Presentations ,Article - Abstract
Neurofibromatosis (NF1) affects 1/2500 people throughout the world. Children with NF1 require a multidisciplinary service ideally, delivered on a single site. NF1 is a very variable condition with children requiring the expertise of genetics, paediatricians, ophthalmologists, dermatologists, neurologists and other specialities as required. Building such a service concentrates expertise, facilitates coordination of care and fosters ideal opportunities for research. Aims: 1) To develop a service ensuring children had access to a multidisciplinary clinic on an annual basis. 2) Hold monthly clinics offering ophthalmology, medical, developmental and dermatology follow up. 3) To create a registry of patients which captures the incidence and prevalence of NF1 in Ireland. To offer best possible care for the children attending the service by following international consensus guidelines. 4) To liaise with NF1 Association, families and research authorities. Methods: 1) Appointment of a CNS/CNM2 in Neurofibromatosis as funded by the NCH Foundation. 2) Visit to the complex NF1 Clinic in Manchester’s Children’s Hospital and learn from their service, MDT and guidelines. 3) Establish links with genetics, oncology, radiology and orthopaedic depts. in OLCHC. 4) Create a referral pathway for HCPs to ensure children with NF1 are referred to most appropriate service in a timely fashion. 5) To register the service on Orphanet and gain entry into an ERN as a multi-site service in conjunction with OLCHC. Results/Conclusion: To date, the service has been running for 9 months. The CNM2 provides telephone service and coordinates clinics. The Clinic has been registered in Orphanet and the process has begun to create a patient registry and enter the service in the ERN., Germline mutations in the succinate dehydrogenase subunit genes SDHB, SDHC and SDHD are the most frequent causes of inherited phaeochromocytomas and paragangliomas. Patients presenting with these tumours are usually offered genetic testing for these and other genes as part of standard clinical investigations. However, the information regarding penetrance and phenotype genotype correlations associated with SDHB/C/D mutations is variable, making it difficult to determine an optimum management strategy for this group. In order to address this issue we undertook a retrospective cohort study of patients who underwent genetic testing for SDHB, SDHC or SDHD. 195 patients were identified through the Irish Genetics laboratory electronic database as having had a genetic test for SDHB, SDHC or SDHD and referral source, referral reason and genetic test outcome were analysed. Analysis of penetrance and phenotype presentation was determined through a Clinical Genetics chart review of 147 patients from 40 separate families. Analysis of age-related tumour risks according to relevant gene and mutation type (for SDHB and SDHD) provided estimates of penetrance and genotype-phenotype correlations. Increased knowledge of the molecular basis of phenotypic variability commonly observed in individuals with germline SDHB/C/D mutations will facilitate the development of age-appropriate management protocols based on gene specific tumour risks., Irish Travellers are an endogamous, ethnically Irish population of ~40,000. Consanguinity is common. Knowledge of Traveller disorders exists but mainly in specialised Irish centres. Most Traveller disorders are published but ethnicity is not explicit, hampering diagnoses, particularly if the patient is overseas where knowledge about this population is poor. Aims: To catalogue inherited Irish Traveller disorders through identifying the disorders, detailing mutations, use of coding, (OMIM, Orphacodes & ICD10), publications, and help develop a database to facilitate diagnoses. Methods: A literature review was undertaken. Key national and international Clinician/scientists were contacted to identify relevant disorders and publications. Laboratory and clinical databases were searched to retrieve disorders & mutations. Annotations were updated. An Excel database was established listing each disorder, its appropriate code, associated mutation and relevant publication. Results: 86 distinct rare genetic disorders resulting in 75 phenotypes were identified; 78/86 were autosomal recessive; 4 of these were dominant disorders presenting only in the recessive state. Seven dominant disorders with no recessive phenotype were included as > one affected individual existed. One common 17q12 duplication was included, presenting in two unrelated families. Homozygous mutations were found in all recessive disorders bar one. The genetic basis of 78/86 was established. A further 2/76 have common haplotypes; the genetic basis of six disorders remains unclear. Linkage disequilibrium was observed in 4 families with co-existing McArdles disease and microcephaly & 11 individuals have co-existing Friedreich’s ataxia & galactosemia. Conclusion: Our work is the first step towards cataloguing inherited Irish Traveller disorders. Future challenges include development of an online mutation database., Primary Trimethylaminuria (TMA)(OMIM 136132), is an autosomal recessive rare disorder which results in diminished capacity to oxidise the dietary derived amine trimethylaminuria to its odourless metabolite Trimethylamine-n-oxide (TMA-n-Oxide). Severe primary TMA has been defined as the percentage of unmetabolised free TMA in urine being >40% and mild/moderate TMA range is 10-39%. More than 30 variants of the Flavin monooxygenase 3 (FMO3) have been reported to cause primary TMA. Diagnosis of primary TMA has implications for management of the patient in relation to treatment and genetic counselling. We sequenced the entire FMO3 gene coding region in 10 patients who had a biochemical diagnosis of TMA made in the past 5 years. Three of the patients had severe TMAU (% TMA range 39.4 to 45), (Group A) and 7 had mild to moderate TMAU (%TMA range 10-30), (Group B). We identified causative (loss of function) in 5/10 individuals. Homozygosity for loss of function mutations was detected for 2/3 cases with severe TMAuria (Group A). 3/7 of the patients with mild to moderate TMAuria biochemically had a genetic diagnosis. Two were homozygous for Glu158Lys/ Glu308Gly and the other was compound heterozygous for P153L and A232T. Primary TMAU is rare in Ireland and mutational analysis should not replace biochemical diagnosis.The rate of detection of pathogenic mutations was low using the recommended biochemical cut-offs. The E305X mutation the first FMO3 mutation described in OMIM (136132.0001) in an Irish Australian family may be an Irish Mutation. Two new apparent FMO3 mutations are described in this Irish population. A cut- off of free TMA levels higher than that suggested on the Gene Utility card may be more beneficial in directing genotyping., Background: As part of the Irish Kidney Gene project, 2000 people with renal disease were surveyed and >30% of participants reported a family history for their condition. This strongly suggests an underlying genetic component for the development of kidney disease. Blood and urine tests as well as kidney biopsies are frequently used to inform on aetiology of the disease. However, in around 10% of cases, aetiology is simply unknown, making it difficult for physicians to provide a clear diagnosis or prognosis to these patients. Aim: This project aims to utilise genomic sequencing to stratify patients with hereditary renal disease (HRD). In doing so we seek to aid clinical diagnosis, provide insight into pathogenesis and in some cases point to specific therapies. Methods: We developed a custom, targeted NGS panel for inherited kidney diseases which we have applied to 48 HRD patients. The panel includes 11 genes which are established causes of polycystic kidney disease, von Hippel Lindau syndrome, renal cysts and diabetes syndrome and Alport syndrome. The NimbleGen Heat-Seq kit was used for library preparation and samples were sequenced using an Illumina MiSeq platform at Beaumont Hospital. Data was analysed using a custom bioinformatics pipeline and variants were classified according to the ACMG guidelines. Results/Conclusions: To date, this panel has identified candidate pathogenic variation in a third of samples studied. Future work in this project will include the development of a larger targeted panel including >100 known renal disease genes., Breast cancer is the most common female malignancy worldwide. Up to 10% of cases are the result of an inherited monogenic mutation, while a further 25% appear in familial clusters. Only 30% of hereditary breast cancers are attributed to mutations in BRCA1 and BRCA2, identified as high-risk genes through linkage analysis. While BRCA mutational status is highly informative, and allows clinicians to modify surveillance, prevention and therapeutic strategies, the risk conferred by mutations in other genes is more difficult to define in light of variable penetrance. Next-generation sequencing has been rapidly evolving to advance testing sensitivity and throughput in a cost-effective manner. This progression has made multi-gene testing a practical option when looking to identify inherited mutation(s) in a clinical setting. However, current clinically available multi-gene panels generate many variants of unknown significance in genes that are presently not considered clinically useful. The aim of our study was to design a multi-gene panel to enable the detection of rare, probably pathogenic variants contributing to the susceptibility of breast cancer in an Irish population. An extensive literature review was conducted in order to generate a list of 282 genes with potential association to breast cancer. Targeted DNA enrichment and multiplexed next-generation sequencing was performed on a cohort of 167 samples from the west of Ireland. 90 breast cancer patients and 77 geographically-matched controls were included in this study. Bioinformatic analysis was performed following GATK best practices workflow. Variant data for our 282 selected genes will be presented and discussed., Increasingly accurate surveys of human health throughout the life course has led experts to propose that stresses on the developing child whilst in the mother’s womb can affect the individual’s health later in life. Such long-term effects on health are thought to be mediated by a semi-permanent trace on the genes called an epigenetic mark, mediated by processes such as DNA methylation. DNA methylation patterns may be altered by the mother’s diet, particularly folate – a key component in the DNA methylation cycle. Currently, mothers are recommended to supplement their diet with 400μg folic acid/day as a preventative measure against neural tube defects prior to/during the first trimester. However, there remains no clinical recommendation as to whether mothers should continue supplementation during the latter two trimesters and the potentially heritable effects. Thus, we analysed cord blood samples (n=93) from the Folic Acid Supplementation in the Second and Third Trimesters (FASSTT) randomised control trial for genome-wide DNA methylation. Offspring exposed to folic acid in later pregnancy had fewer highly methylated genomic regions and more intermediately methylated sites. Upon further interrogation, gene ontology analysis revealed these sites are enriched for genes associated with cognition and neurological system processes, and tissue analysis revealed enrichment of affected genes associated with the brain. Cognitive and psychosocial testing of the children at age 7 years, using standardised tests (WPPSI, TEIQue-CSF, RASP), showed that the children supplemented during pregnancy scored significantly higher for emotional intelligence, resilience and verbal IQ. Thus, this study offers a potential biological mechanism linking maternal folate levels with childhood cognition., Introduction: We previously identified the mitochondrial 10-formyltetrahydrofolate synthase enzyme, MTHFD1L, as a risk factor for human Neural Tube Defects (NTD). This association was further supported by a mouse model of mutant mthfd1l, that exhibited an NTD and was rescued with maternal formate supplementation. The abundance of MTHFD1L is also increased in a range of cancers. MTHFD1L performs the last step in mitochondrial one carbon metabolism to produce formate for transport into the cytoplasm. Aim: Given the pivotal role of MTHFD1L in human disease, we sought to decipher the cellular response to the expression level of MTHFD1L in HEK293 cells. Methods: Human MTHFD1L was overexpressed in a stably transfected line using a pcDNA3.2 vector and knocked down using two inducible shRNA constructs that were clonally selected. Cells were grown and sampled over a five-day period. Expression level was confirmed by RT-qPCR. Intracellular and media formate levels were measured using GC-MS. Proteomics analysis was performed on whole cell lysates using LC-MS/MS on an Ultimate 3000 nano LC system coupled to a LTQ Orbitrap XL. Results: Intracellular and media formate levels directly correlated with expression level of MTHFD1L compared to controls within an approximately 1.5 to 3 fold range. Our proteomics analysis showed that MTHFD1L expression level had an effect on proteins involved in DNA synthesis, replication and repair. Discussion: We have demonstrated that MTHFD1L expression level has a direct impact on both intra- and extra-cellular levels of formate and may act as a signal for uncontrolled cell proliferation., Ireland has remained relatively isolated from mainland Europe, notwithstanding historical migrations including the Norse-Vikings, Anglo-Normans, and the British Plantations. Although previous studies have shown the Irish to have elevated levels of homozygosity compared to mainland Europe, the extent of genetic structure within Ireland, and the genomic impact of historical migrations, is largely unknown. Here we illustrate fine-scale genetic structure across Ireland that follows sociological boundaries and present evidence of admixture events into Ireland. Utilising the ‘Irish DNA Atlas’, a DNA cohort (n = 194) of genealogically described Irish individuals with four generations of ancestry linked to specific regions in Ireland, we analysed in combination with 2,039 individuals of regional British ancestry (the PoBI dataset) and show that the Irish population subdivides into 10 distinct geographically-stratified genetic clusters; three of shared British/Irish ancestry, and seven of predominantly ‘Gaelic’ Irish ancestry. This structure is remarkably homogenous, and is associated with very little gene flow barriers within Ireland. Additionally, using a reference of 6,760 European individuals and two ancient Irish genomes, we quantified the ancestry of these Irish clusters within the context of Europe as well as ancient Ireland. We show high levels of north-west French-like and Norwegian-like ancestry within Ireland, and homogenous levels of ancient Irish ancestry in our ‘Gaelic’ Irish clusters. Finally we detect admixture events into Ireland, coinciding with the Plantations of Ulster, as well as Norse-Viking activity within Ireland. Our work informs both on Irish history, as well as the study of Mendelian and complex disease genetics involving populations of Irish ancestry., Schizophrenia affects 1% of adults and is a major global health problem. I am interested in the potential role of the centrosome in schizophrenia. The centrosome, an organelle within cells, plays a crucial role in brain development where it directs cell shape, polarity and motility. The centrosome also seeds the growth of antenna-like signalling structures called primary cilia. Rare mutations in centrosome genes cause disorders that present with severe cognitive deficits and variable neuropsychiatric phenotypes. GWAS data has implicated many genes in schizophrenia. We have shown that seven schizophrenia risk genes encode proteins with centrosomal functions. Of these, SDCCAG8 is also associated with educational attainment in GWAS and the genome-wide significant SNPs for the two phenotypes are in high linkage disequilibrium indicating a pleiotropic effect. We have found that a schizophrenia risk SNP in SDCCAG8 is significantly associated with poorer performance in a social cognition task, in a large Irish dataset of schizophrenia patients and controls (p=0.001). To analyse the molecular function of SDCCAG8 we have used genome editing to knock it out in neuronal and retinal cells. Preliminary data shows that loss of SDCCAG8 impairs cells’ ability to make primary cilia and that their capacity to repair genome damage is reduced. Current work is addressing whether SDCCAG8 affects activities that may contribute to schizophrenia, including cell migration and cell signalling. This could identify molecular mechanisms by which SDCCAG8 mutations contribute to schizophrenia risk and cognition, and help uncover the processes that implicate centrosome genes in neurodevelopmental phenotypes., Multiple genetic loci have been identified for non-melanoma skin cancer (NMSC) in the general population. Polygenic risk score (PRS) was defined as the sum of all alleles associated with a trait weighted by the effect size of that allele as determined by a previous genome-wide association study (GWAS). We tested whether PRS, calculated using a GWAS of NMSC in a non-transplant population, can be used to determine risk of developing and time to NMSC post-transplant. Post-kidney transplant NMSC cases (n=155) and controls (n=442) were collected from Tennessee, Ireland and Scotland. Genetic variants that reached pre-defined levels of significance were chosen from a squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) GWAS, both conducted in non-transplant populations. Using these GWAS results, BCC and SCC PRSs were calculated at each p-value threshold (pT) for each sample. PRSs were tested as a predictor of case:control status using logistic regression and time to NMSC post-transplant in a survival model. SCC PRS calculated at pT 1x10-6 was the most significant predictor of case: control status of NMSC post-transplant (OR per 1 stdev increase in PRS=2.3; corrected P (Pc)=0.04). When NMSC was subdivided into SCC and BCC, SCC PRS pT 1x10-6 significantly predicted case:control SCC (OR=2.5, Pc=0.02) and BCC status (OR=7.6, Pc=0.02). SCC PRS pT 1x10-5 also significantly predicted time to BCC (Pc=0.007, HR=1.8) and SCC (Pc=0.05, HR=1.4). PRS of non-transplant NMSC can be used to predict case:control status of post-transplant NMSC, SCC and BCC as well as time to developing BCC and SCC post-transplant., Introduction: Rare diseases are diseases, which affect a small number of people compared to the general population. In Europe, a disease is considered rare when it affects no more than 5 per 10,000 individuals. A disease can be rare in one region but common in another. The objective of this study was to derive a proxy estimate the number of childhood onset rare diseases through referrals to the country’s only Genetics center, as the Republic of Ireland does not have a centralized rare disease registry. Methods: A retrospective review of referrals to cytogenetics and clinical genetics for the years 2000-2016 for patients born in the year 2000 was undertaken. Anonymized data was catalogued into rare, common, normal, likely rare & unclassifiable by review of records, and assigned Orphacodes based on diagnosis. Census live birth data was used as the denominator. Results: 54,7891 live births were recorded by the census in 2000. 1872 referrals to Genetics (representing 1749 individuals born in 2000) were retrieved for review. 1007 had cytogenetic testing only, of which 51 had rare chromosomal anomalies. Review of 742 referrals to clinical genetics yielded 581 with a rare disease (78%), 7 with a likely rare disease, 56 with a common disorder, 83 who were normal (at risk relative) & 15 unclassified (hadn’t yet been seen). Of the 53/1749 who had died (3%), 51 had a rare disease with congenital malformations (24) the most common cause., Neurofibromatosis type 1 (NF1) is a relatively common autosomal dominant genetic condition, with an incidence of around 1 in 3000. All NF1 patients attend our regional NF1 clinic intermittently and our departmental database records clinical details. Currently, we have 468 living patients affected with NF1 in Northern Ireland. NF1 is caused by mutations, or occasionally deletions, of the neurofibromin tumour suppressor gene, which leads to over-activation of the RAS-MAPK pathway, and tumour formation. These vary from benign lesions, such as neurofibromas, through to malignant peripheral nerve sheath tumours (MPNSTs) and tumours in other sites, particularly the central nervous system, that can be associated with significant morbidity and mortality. MEK inhibitors have recently been shown to be an effective treatment modality in the tumours associated with NF1. We have studied our population to determine the number of patients with plexiform neurofibromas, who are at risk of MPNSTs, and the proportions of patients with tumours elsewhere. This will allow us to identify which patients could benefit from MEK inhibitors in the future., Tuberous Sclerosis complex (TSC) is an autosomal dominant genetic condition which results, in the majority of patients, from a mutation in the TSC1 or TSC2 genes. Many of the patients are affected by angiomyolipomas and sub-ependymal giant cell astrocytomas. There is evidence that mTOR inhibitors, particularly Everolimus, shrink such tumours. In addition, the recent EXIST-3 study showed that Everolimus led to a significant reduction in seizure frequency in TSC patients whose seizures had previously proved resistant to anti-epileptic drug treatment. Consequently, a European licence has been granted to prescribe Everolimus for this indication. In order to determine the potential number of patients who may be eligible for consideration of this treatment, we undertook a complete population survey of epilepsy in our TSC patients. Information was extracted from our database and descriptive statistics were carried out. We were particularly interested in obtaining numbers of those whose seizures were poorly-controlled, defined as requiring 3 or more anti-epileptic drugs to manage their seizures, or requiring neurosurgical intervention. Many of the TSC patients with a diagnosis of epilepsy were also diagnosed with learning difficulties. The possibility of an association between degree of seizure control and severity of learning difficulties was explored. Finally, the annual cost of prescribing Everolimus to Northern Ireland’s TSC patients with poorly-controlled seizures was estimated., Charcot neuroarthropathy is associated with neurological deficit and is often seen in patients with a history of diabetes. Zygodactyly is a common congenital malformation with cutaneous webbing of the second and third toes. To determine the frequency of Zygodactyly in midfoot (tarso-metatarsal) Charcot neuropathy due to diabetes, we analysed a prospective series of twenty-five patients with Charcot neuropathy referred to podiatry clinics from diabetes and vascular departments. Twenty-nine patients with diabetes (but no Charcot neuropathy) were used as controls. Nineteen of the twenty-five patients with type 2 diabetes, peripheral neuropathy, and midfoot Charcot neuroarthropathy, exhibited Zygodactyly as did one of the twenty-nine controls. There was a significant difference between the two groups (Chi squared test p< 0.001). None of the cases or controls had any dysmorphic features or other limb malformations. Zygodactyly occurred in association with midfoot Charcot neuroarthropathy (diabetic neuropathy) in 76% of cases. No association between Zygodactyly, diabetes and Charcot neuropathy has previously been recognised. Genes such as OPG and RANKL affect foot and bone development and MSX1 and PLA2G6 affect spinal and distal nerve development. The possibility of a genetic contribution in patients who develop type 2 diabetes, peripheral neuropathy and Charcot neuroarthropathy must be considered. Zygodactyly may act as a predictive marker for Charcot neuropathy and further identification of regulatory genes may be possible. Until then, recognition of Zygodactyly may allow early intervention and a reduction of complications in patients with Charcot neuropathy., Development of an unusual clinical phenotype across both common and rare cancer types presents a significant challenge from a diagnostic and therapeutic perspective. We describe two distinct cases involving an Ovarian adenocarcinoma and a Medullary Thyroid cancer (MTC) patient and wherein both patients presented with metastases at highly unusual locations, followed by development of an aggressive disease. In first case involving a patient diagnosed with ovarian adenocarcinoma presented with a rare solitary extracranial brain metastases with no other associated metastases after 2 years post-hysterectomy and chemotherapy. Despite surgical removal of the metastatic lesion and stereotactic radiotherapy, the patient showed a further relapse at the initial as well as two additional extracranial regions. Our current analysis of whole-genome sequencing of primary tumour and extracranial lesion, reveal a remarkable difference in the genomic aberration landscape between the primary tumour and the metastases. In addition, we also identify several structural variants including novel gene fusions as well as gross chromosomal abnormalities, which could be potentially utilized as targets for treating this patient further. In the second case, whole-exome sequencing of primary tumour and bone-marrow metastases in the MTC patient identified three germline single nucleotide polymorphisms (SNPs) within the RET proto-oncogene that remained undetected using routine hospital genetic testing procedures. More importantly, we report for the first time in thyroid cancer on the occurrence of a “chromothripsis-like pattern”, which involved shattering of chromosome 4 leading to complete abrogation of normal chromosomal function, along with dramatic widespread copy number aberrations across both primary tumour and bone marrow samples. These results provide a rationale for the application of comprehensive genomic analysis of cancers presenting with unusual and aggressive phenotypes to facilitate more appropriate therapeutic options and diagnoses., Transient Neonatal Diabetes (TNDM) is characterised by diabetes that develops in the first 6 weeks of life and resolves by 18 months. Approximately 70% of cases are classified as TNDM Type-1 (TNDM1), caused by methylation defects on chromosome 6q24. It is associated with some congenital anomalies, however associated hepatobiliary abnormalities are not described. Choledochal cysts are congenital dilations of part or all of the bile duct, occurring in 100,000-150,000 live births. The 5 major types are classified according to the extent of hepatobiliary involvement. Surgical excision of the cyst is indicated to prevent complications such as stone formation, malignancy, cyst rupture and pancreatitis. We describe a case of TNDM1 due to whole chromosome paternal uniparental disomy 6, with co-existence of a type 1a choledochal cyst in a female born following intrauterine growth retardation. Hyperglycaemia soon after birth led to insulin treatment and a diagnosis of TNDM1, with resolution of the diabetes by 4 months of life. Follow up of antenatal findings of a cystic anomaly demonstrated the presence of a type 1a choledochal cyst on ultrasound and magnetic resonance cholangiopancreatography. Sucessful surgical excision of the cyst and a roux-en-Y hepaticojejunostomy was undertaken at 6 months of age. To our knowledge the co-existence of these disorders has not previously been reported. Further genetic analysis by whole exome sequencing is now in progress to determine if a mutation in the PKHD1 gene, unmasked by the paternal UPD of the entire chromosome 6, explains the associated choledochal cyst in this case., Mosaic mutations can go unnoticed, underlie genetic disease or normal human variation, and may be transmitted as constitutional variants to future generations. Marfan syndrome (MFS) is a clinically variable systemic connective tissue disorder involving ocular, skeletal, and cardiovascular systems. The risk to siblings of an identified de novo variant in a proband remains above population risk but less than the 50% risk attributed probands (~75%) who have an affected parent. This is due to somatic and germline mutations reported in rare cases. We describe the phenotypic variability in three siblings with a confirmed heterozygous pathogenic exon 52 fibrillin1 (FBN1) gene variant with clinically unaffected parents Parental leucocyte DNA was tested and did not identify the FBN1 gene variant. Paternity has been unequivocally confirmed and subsequent testing of parental buccal samples failed to detect the variant. One brother had aortic valve replacement and aortic aneurysm repair at 35 while another brother had surgery of aortic dilatation at the sinuses of Valsalva at 32. The brothers had variable joint hypermobility, patellar dislocations and ophthalmic presentations involving subluxed lenses, myopia and ambylopia. Early onset of varicose veins as a teenager in one and thoracolumbar scolosis in another brother were present. Their 42 year old sister has apparently normal aortic and cardiac imaging and ophthalmology but has mild Marfanoid facial features. To our knowledge this is the first reported family in the literature of 3 siblings as a result of parental mosaicism for a FBN1 gene variant and highlights the impact for genetic counselling., The inherited retinal degeneration (IRD) patient cohort used in the study has been obtained via a collaborative network of opthamoloogists whereby if an IRD is suspected given consent, a DNA sample is taken and provided to a central laboratory for genetic analysis. The study seeks to detect previously identified, together with as yet undiscovered, pathological mutations in a panel of known retinal degeneration genes utilizing target capture next generation sequencing (NGS) for 264 IRD genes. The study to date includes over 700 IRD patients from more than 500 pedigrees. While clinical trials are in progress for patients with IRDs, many such trials require patients to have a known causative mutation to participate in these trials. The Target 5000 research project aims to genetically characterise the estimated 5,000 people in Ireland with IRDs. To date, as part of Target 5000, over 10% of the Irish IRD population has been sequenced providing real insights into the genetic architecture of IRDs in Ireland. Target 5000 offers not only a chance to discover new relevant and pathogenic mutations, but is vital to providing patients with information regarding the underlying genetic pathogenesis of their disease. Thus far, during the course of the study, genetic analysis of IRD patients has helped to resolve ambiguous phenotypes and to identify causative mutations in approximately 60% of IRD cases. The growing body of data from NGS studies of IRDs globally should facilitate better correlations between genotype and phenotype and refine methods for diagnoses and prognoses., Overgrowth syndromes are characterized by tall stature, macrocephaly and other congenital features. These disorders typically arise sporadically through de novo dominant mutations in a growing list of genes. Although whole-exome sequencing (WES) allows us to examine all genes at once in a cost effective manner, we are left with a very large number of possible disease-causing variants to sift through. In addition, we must identify at least two patients with mutations in the same novel gene for the finding to be significant. To address this, we utilized detailed phenotyping of patients with undiagnosed overgrowth to group patients with significant phenotypic overlap and to help us interpret and prioritize the variants identified via WES. We performed WES for 12 undiagnosed patients from our overgrowth cohort. For most patients, there were no obvious causative variants in genes that were previously associated with human overgrowth. Therefore we analysed the participants’ clinical records to look for phenotypic traits that may lead us to new candidate genes. After further mining of the WES data, we prioritized possible disease causing variants based on a number of factors including biological function of the gene, predicted effect on protein function and a minor allele frequency, Living the ‘high life’ presents challenging conditions of extreme cold, hypobaric hypoxia and a restrictive diet that forces populations to adapt to survive. The Quechua are an indigenous high altitude population of Peru and Bolivia. They have resided at altitudes greater than 2500 meters above sea level (m.a.s.l) for the past 10,000 years, following their arrival in South America. Previous studies have characterised their adaptive physiology and identified genes under natural selection (ref). However our understanding of their genetic adaptation to hypoxia is incomplete, as previous studies focused on common genetic variation and applied a limited number of selection tests. To shed further light on genetic adaptation in the Quechua, we established a cohort of 43 Quechua individuals from Cerro de Pasco, Peru (4330 m.a.s.l). We performed whole genome sequencing to a mean depth of 34X. We detailed the demographic history of Quechua using principal components analysis, Admixture and Treemix. We performed five tests of selection, (iHS, XP-EHH, ΔiHH, FST and ΔDAF) on real, and simulated Quechua data incorporating details of the demographic history of the population. We performed a composite of multiple signals (CMS), which aggregates information from the five tests of selection, and identified robust signals of positive selection in high altitude Quechua individuals. The Quechua appear as a relatively homogenous population, with 10% European ancestry. We report the top 1% of genes under selection identified by CMS. We identify putative hypoxia associated genes under selection as well as the previously reported well-characterised hypoxia gene EGLN1., DNA methylation is an important epigenetic mechanism of regulating gene expression that is affected in certain human diseases including imprinting disorders and cancer. In mouse, UHRF1 is an essential cofactor of DNMT1, the enzyme responsible for maintaining methylation patterns. To investigate the effects of loss of UHRF1 on methylation patterns in human cells, UHRF1 levels were decreased in immortalized hTERT fibroblast cell lines using short hairpin RNA. Genome-wide effects on methylation were investigated by the Illumina Infinium HumanMethylation450 BeadChip array. Online bioinformatics software tools were used to identify FDR-significant hypomethylated gene classes, which were then verified by pyrosequencing. Transcriptional effects on these gene classes were investigated by the genome-wide Illumina HumanHT-12 v4 Expression BeadChip array, and verified by RT-qPCR. While UHRF1 depletion caused widespread demethylation, the replication-dependent histone gene cluster and the cancer testis antigen genes were identified as most significantly hypomethylated in UHRF1 knockdown cells. Pyrosequencing confirmed hypomethylation in promoter regions of cancer testis antigen genes TSPY2, MAGEC1, MAGEC2 and MAGEA12, and histone gene HIST2H2AA4 in knockdown cell lines. Hypomethylation in these gene classes correlated with an increase in expression in the knockdown cell line. In addition, cells were rescued using UHRF1 cDNA and showed a return to wild type transcription levels in the rescue cell line. We have shown that these genes are regulated by promoter DNA methylation, confirming the sensitivity of cancer-testis genes to demethylation, supporting possible use of methyltransferase inhibitors to boost antigen presentation in cancers, and the crucial role of UHRF1 in cell cycle regulation., X-linked Retinitis Pigmentosa (XLRP) is a severe, early-onset form of inherited retinal degeneration (IRD). It is estimated that approximately 15% of XLRP cases are due to mutations in RP2 (Retinitis Pigmentosa 2). The ubiquitously expressed RP2 protein is involved in ciliary trafficking of lipid-modified proteins – a process vital for photoreceptor function and survival. Most pathogenic RP2 mutations are suggested to result in truncation or complete loss of the protein. The most common stop mutation, R120X, appears to trigger nonsense-mediated decay of the transcript. RP2 is therefore an excellent candidate for gene augmentation therapy. In recent years, personalised cell models have emerged as invaluable tools for the elucidation of disease pathogeneses and have greatly enhanced pre-clinical proof of concept studies. Through the Target 5000 programme, a project focused on genetic characterisation of the 5,000 IRD patients in Ireland, a male patient harbouring the R120X RP2 mutation was identified. A patient-derived dermal fibroblast cell model of the disease was thus generated and characterised. The transduction efficiencies of AAV vectors of various serotypes in fibroblasts were tested and compared, after which it was decided to proceed with an AAV2/2.CAG.RP2 vector to explore RP2 delivery in this patient-derived cell model. In addition, the effects of RP2 overexpression in vivo in murine photoreceptors and retinal pigment epithelium cells were analysed., Mitochondrial dysfunction leads to a lack of energy production and ultimately the death of the cell. Recently a number of disorders have been shown to have mitochondrial dysfunction including but not limited to; Multiple Sclerosis, Parkinson’s and Leber’s Hereditary Optic Neuropathy (LHON). In LHON, Complex I of the Electron Transport Chain (ETC) is affected which leads to a severe shortage of energy in the cell and eventually cell death. In particular retinal ganglion cells (RGCs) are affected, leading to retinal dysfunction and blindness. These observations have prompted interest in exploring innovative therapeutics to modulate mitochondrial disorders involving complex I deficiency. The team has explored candidate gene therapies for complex I deficiency, which could classically be delivered via Adeno Associated Viruses (AAV) such as AAV serotype 2 (AAV2), among other vectors. As such the team has developed novel in vitro methods for the analysis of complex I deficiency and the evaluation of novel candidate therapies, allowing us to monitor the efficacy of these therapeutics. Assays include a suite of methods to enable evaluation of Complex I activity and oxidative phosphorylation efficiency among other mitochondrial biomarkers. Such assays in principle would be of value for future in vitro and or in vivo studies involving therapies directed towards targeting complex I deficiencies., Background: Imprinted loci are paradigms of epigenetic regulation and are associated with a number of genetic disorders in human. A key characteristic of imprints is the presence of a gametic differentially methylated region (gDMR). Previous studies have indicated that DNA methylation lost from gDMRs could not be restored by DNMT1, or the de novo enzymes DNMT3A or 3B in stem cells, indicating that imprinted regions must instead undergo passage through the germline for reprogramming. However new putative gDMR have recently been described, along with an improved delineation of the existing gDMR locations. We therefore aimed to re-examine the dependence of methylation at gDMRs on the activities of the methyltransferases in mouse embryonic stem cells (ESCs). Method: We examined the most complete current set of imprinted gDMRs that could be assessed using quantitative pyrosequencing assays in two types of ESCs: those lacking DNMT1 (1KO) and cells lacking a combination of DNMT3A and DNMT3B (3abKO). Results: Loss of methylation was approximately equivalent in both cell types. 1KO cells rescued with a cDNA-expressing DNMT1 could not restore methylation at the imprinted gDMRs, confirming previous observations. However, nearly all gDMRs were remethylated in 3abKO cells rescued with a DNMT3A2 expression construct (3abKO + 3a2). Transcriptional activity at the H19/ Igf2 locus also tracked with the methylation pattern, confirming functional reprogramming in the latter. Conclusions: DNMT3A/B plays a vital role in methylation maintenance at imprints as the rescue with DNMT3A2 can restore imprints in these cells. This provides a useful system to explore factors influencing imprint reprogramming., SATB2, BCL11B and GATAD2A map to regions containing genomewide significant SNPs for schizophrenia and regulate key stages of neurodevelopment via epigenetic mechanisms. SATB2 mediates the projection of neurons across the cerebral hemispheres by regulating the activity of BCL11B via the NuRD nucleosome remodelling complex, which contains. GATAD2A. We hypothesized that genes within the NuRD complex and genes regulated by SATB2 in the pre- and post-natal brain may contribute to schizophrenia etiology. To test, we developed three gene-sets. 1.)Genes reported in mouse knockout studies of SATB2 during cortical development (SATB2_ Cortical). 2.)Genes mapping to SATB2 ChIP-seq peaks generated from mouse cortices at E15.5 (SATB2_Pre-natal). 3.)Genes mapping to SATB2 ChIP-seq peaks generated from mouse P0 hippocampal neurons (SATB2_Post-natal). We performed competitive gene set analysis (GSA) using MAGMA to test if genes within a gene-set were more strongly associated with schizophrenia than other genes in the genome. We applied GSA to schizophrenia GWAS (n=150,064). We also investigated these gene-sets for a genetic contribution to educational attainment (EA; proxy for cognition) using GWAS (n=405,072). After multiple test correction, we observed significant associations for (1)SATB2_Cortical with schizophrenia (P=8.65x10-05) and EA (P=0.00049), (2)SATB2_Pre-natal with EA (P=0.0068) and (3)SATB2_Post-natal with schizophrenia (P=0.0069) and EA (P=2.03x10-06). Further GSA established that effect sizes are stronger for these gene-sets when analysis is limited to genes that are highly expressed in neurons or at different key timepoints during neurodevelopment of the cortex or hippocampus. These data support a role for the NuRD complex and genes regulated by SATB2 in schizophrenia and EA, Background: Dacogen (5-aza-2’deoxycitidine) is currently used to treat Acute Myeloid Leukaemia (AML) and is in trials for myeloid dysplastic syndrome and some solid cancers. As a hypomethylating agent it is thought to act by inhibiting the enzymes which add methyl groups to DNA, chief among them DNMT1. Improved targeting has been hindered by a lack of understanding with respect to the exact mechanism of action on DNMT1 and of the gene targets affected by altered methylation following treatment. Methods: We performed a comparative treatment of the same normosomic, non-transformed fibroblast cell line hTERT1604 over three days with either pharmacological 5-aza-2’deoxycitidine (Dacogen) or with SMARTpool siRNA directly targeting DNMT1. DNA was collected for analysis of methylation levels using Illumina 450k BeadChip methylation arrays. Data was analysed in R using the tailored RnBeads pipeline and in-house scripts. Results: Both Dacogen and DNMT1 siRNA caused overall hypomethylation in the treated cells, with the latter proving more efficient at demethylation at genes in particular. Amongst the targets experiencing demethylation, some hypomethylated promoters were unique to Dacogen treatment and therefore off-target with respect to the reduction in DNMT1. However an unexpected phenomenon almost exclusively caused by 5-Aza-2’-deoxycytidine treatment was gain in methylation. Therefore we also compared our findings to an independent published 450k dataset of Dacogen treated AML cells (KG1a). Our results suggest Dacogen is also having an important effect on methylation unrelated to the inhibition of DNMT1 thus suggesting further avenues for therapeutic improvements., Disruptive, damaging ultra-rare variants (dURVs) are more abundant in schizophrenia (SZ) patients than controls and are more concentrated in neuronally-expressed genes with synaptic functions. dURVs in highly constrained genes influence educational attainment (EA; a proxy for cognition) in the general population. We used MAGMA to perform gene set analysis of the largest available GWAS datasets to investigate if association signals for SZ and EA similarly mapped to highly constrained genes and to neuronally-expressed genes with synaptic functions. We investigated if SZ and EA associations were enriched in brain regions at different timepoints from early development through to adulthood. Highly constrained genes (probability of being loss-of-function intolerant; pLI>0.9; n=3,230) are strongly enriched for association with SZ(p=3.14E-08) and EA(p=1.27E-09) in comparison to genes under less constraint (0.1, Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease affecting 45,000 people in Ireland. Prolonged joint inflammation results in tissue damage with consequent reduced functional capacity and quality of life. Damage to the joints of hands and feet, assessed by x-ray, is an important outcome measure that has genetic input of around 60%. Recent studies have identified single nucleotide polymorphisms (SNPs) in immune-related genes that are associated with severity of tissue damage in RA. One of our studies identified an association with C5orf30, a previously uncharacterized regulator of tissue damage and inflammation (1, 2). However a more comprehensive genome wide analysis is required to more fully characterize the genetic basis of RA severity. This project will identify genetic variants, and their synergistic combinations, that are associated with severity of RA. We will analyse genomewide SNP data in 1,007 RA patients using state-of-the-art genetic epidemiology and computational techniques, including negative binomial modelling, to identify variants linked with joint damage severity. The study population is uniquely large and detailed clinical and genetic datasets will be used for validation studies using five European early RA cohorts. Simulations for statistical power indicate excellent power will be achieved for moderately frequent alleles, for effect sizes (IRR) over 1.4. The aim is to develop both a genetic prognostic score for RA, and to identify novel mediators of tissue destruction. The earlier identification of RA patients at risk of poorer outcome would facilitate patient stratification and inform therapeutic targeting with more aggressive regimes whilst avoiding such treatment in patients likely to have a better outcome, Bloodstream infection and sepsis are often instigated by the bacterium Staphylococcus aureus. Upon accessing the bloodstream, S. aureus binds to the endothelium triggering vascular leakage, inflammation and oedema. These characteristics are difficult to treat pharmacologically as the nature of signalling guiding this host response remains unclear. microRNAs (miRNAs) regulate ~60% of the human genome through post-transcriptional silencing/ degradation of target genes. Previously, bacteria were shown to profoundly affect miRNA expression via up-regulation of dendritic miR-99b elicited by M. tuberculosis infection. This study investigates contributions of S. aureus induced endothelial miRNA dysregulation to sustained and excessive host responses in sepsis. Sheared (10dynes/cm2) human endothelial cells were treated with plasma and TNFα to mimic sepsis conditions. Infection induced miRNA alterations were uncovered using Taqman cards to generate miRNA profiles of uninfected and infected cells (RQ = 2-ΔΔCt). Potential mRNA targets were established bioinformatically and confirmed by RNAseq, western blots and qPCR. Following infection, 58 endothelial miRNA were significantly downand 35 significantly up-regulated, including miR-330 (p, DNA methylation is a critical mechanism for regulating gene expression and ensuring genomic stability. However, loss of function mutations of methyltransferase enzymes such as DNMT1 in normal differentiated cells result in a lethal phenotype. Consequently, existing investigations have only assessed DNMT1 knockdowns in embryonic stem cells or cancer cell lines. Here, isogenic lines of hypomorphic, normal, immortalised fibroblasts have instead been generated via stable integration with short hairpin RNA. Enrichment analysis of epigenome-wide methylation arrays indicated widespread demethylation within promoter and gene body regions. In addition, four specific gene categories were highlighted as most affected; protocadherins, genes regulating body mass, olfactory receptors and cancer/testis antigens. Comparison of short-term siRNA and long-term shRNA-mediated depletion of DNMT1 indicated that many regions recover methylation as shRNA-containing cell lines adapt to lowered levels of DNMT1. Interestingly, polycomb-regulated genes are refractory to de novo DNA methylation in these cells following recovery, reinforcing the concept of mutually-exclusive domains that are regulated by these two major epigenetic mechanisms., Background: The MTHFR C677T is a common polymorphism of the folate metabolising enzyme methylene tetrahydrofolate reductase (MTHFR) associated with hypertension. Riboflavin is a cofactor to MTHFR in the one-carbon cycle for generating methyl groups important for biological reactions such as DNA methylation. Supplementation with riboflavin has previously been shown to reduce blood pressure specifically in individuals with the homozygous MTHFR 677TT genotype. The mechanisms underlying the blood pressure lowering effect of riboflavin are currently unknown however aberrant DNA methylation has been implicated in the development of hypertension. The aims of this study were to examine global DNA methylation on hypertension in adults stratified by MTHFR genotype and in response to intervention with 1.6mg/ day of riboflavin in individuals with the MTHFR 677TT genotype. Methods: Stored peripheral blood leukocyte samples from participants who had consented and participated in targeted RCTs at Ulster University’s Nutrition Innovation Centre for food and HEalth (NICHE) and previously screened for the MTHFR C677T polymorphism were accessed for this study. Bisulphite conversion and pyrosequencing was used to analyse global and gene-specific DNA methylation. Results: Preliminary results show that methylation at the repeat element, LINE-1, and imprinted gene, IGF2 was not significantly different between the MTHFR C677T genotypes at baseline. However, subsequent supplementation with riboflavin resulted in a decrease in global methylation and an increase in IGF2 methylation in MTHFR 677TT participants. Conclusion: This is the largest study to date examining the interaction between the MTHFR C677T genotypes, riboflavin supplementation and DNA methylation. Riboflavin supplementation influenced repeat element and imprinted gene methylation in MTHFR 677TT genotype individuals. Further work will provide insights into the mechanism of riboflavin action in lowering blood pressure in these genetically at risk adults., Background: microRNAs are small, non-coding RNAs which are potentially valuable markers of cardiovascular disease (CVD) risk, including hypertension. This novel investigation aims to profile circulating serum concentrations of microRNAs in premature CVD patients to identify microRNAs that correlate best with hypertension. Methods: Serum samples from an existing cohort of 75 premature CVD patients were analysed for expression of 68 CVD-related microRNAs. Patients had been screened for the methylenetetrahydrofolate reductase (MTHFR) gene polymorphism C677T, a risk factor for hypertension. Samples had been collected at baseline and following intervention with riboflavin, co-factor for the MTHFR enzyme, as part of a placebo-controlled double-blind, randomized trial. The associations between miRNA expression and blood pressure at baseline and post-intervention were investigated. Comparisons of data between CC and TT MTHFR genotype groups, and in response to intervention, were assessed using ANOVA, Pearson’s correlation and corrected t-test statistical analyses. Results: microRNA expression was successfully detected and quantified in all samples. At baseline miR-199a-5p expression was inversely correlated (r=-0.51;p, Background: Hypoxia in prostate tumours has been associated with disease progression and metastasis. MicroRNAs are short non-coding RNA molecules which are important in several cell processes, but their role in hypoxic signalling is still poorly understood. miR-210 has been linked with hypoxic mechanisms, but this relationship has not been extensively studied in a prostate cancer setting. Therefore, in this study, we investigate the link between hypoxia and miR-210 in prostate cancer cells. Methods: In this study we have used prostate cancer models of hypoxia to investigate the functionality of miR-210. Expression levels of miR-210 have been measured by qPCR in in vitro and in vivo samples. Functional bioassays were used to examine its effect on prostate cancer cell behaviour. Target genes have been identified and bioinformatic analysis has been employed to investigate a clinical significance for miR-210 in prostate cancer. Results: miR-210 is induced by hypoxia in prostate cancer cells. Over-expression of miR-210 impacts upon target genes which in turn may affect cell proliferation. Data-mining of online repositories of clinical prostate sample data shows that miR-210 is significantly correlated with Gleason grade and other clinical markers of prostate cancer progression. Further in silico analysis of miR-210 cellular networks reveal that miR-210 plays a key role in a number of important cell processes, the dysregulation of which can promote the development of prostate cancer. Conclusions: We propose that miR-210 is an important regulator of cell response to hypoxic stress and may play an important role in the pathogenesis of prostate cancer. Further study will focus on determining its function in prostate cancer and its potential as a biomarker in this disease.
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- 2018
13. Trainee Knowledge and Perceptions of Less Than Full Time Training.
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Howard, C., Golden, M., Gavin, P., and Crushell, E.
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- 2021
14. Biopsychosocial approach to functional abdominal pain
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Crushell, E and Rowland, M
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- 2005
15. Liquid paraffin: a reappraisal of its role in the treatment of constipation
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Sharif, F, Crushell, E, OʼDriscoll, K, and Bourke, B
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- 2001
16. Intussusception associated with bacterial meningitis
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Crushell, E, Flanagan, O, Devins, M, Dunne, K, and Gleeson, J
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- 2001
17. Selected abstracts
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Corkery, P. P., Leek, B. F., Caulfield, B., Garrett, M., Gormley, J. P., OʼDonnell, P. M., Kennedy, N., Sayers, K., Stokes, E., Bresnihan, B., Fitzgerald, O., McGarvey, M. A., Tonra, M., Hooper, A. C. B., Barry, J., Maurer, B., Hussey, J., Gormley, J., Noble, J. G., Alves-Guerreiro, J., Lowe, A. S., Walsh, D. M., NicNiocaill, B., Harte, M., OʼConnor, W. T., OʼHara, A. M., Orren, A., Moran, A. P., Hardiman, D. A., Lee, T. C., Croke, D. T., Tolan, R., McBennett, S., Warmington, S., McGuire, M., Bradford, A., OʼHare, T., MacDermott, M., Lynch, F., OʼRegan, R. G., McLoughlin, P., Quinn, T., Ryan, J. P., Pickering, M., Campion, D. P., Jones, J. F. X., Ryan, S., McNicholas, W. T., Nolan, P., Doyle, F. J., Rackard, S. M., Beddy, P., Campbell, V. A., Bakhle, Y. S., Bell, C., Usher, C., Chan, L., Keenan, A. K., McQuaid, K. E., Cullen, V. C., Smith, E. M., Kelly, A., Lynch, M. A., Freir, D. B., Holscher, C., Herron, C. E., Pearson, H. A., Curran, B. P., OʼConnor, J. J., Quinn, A., McHale, J., Moriarty, D., OʼConnor, J., Glennon, J. C., Van Vliet, B. J., Long, S. K., Kruse, C., Gallagher, H. C., Bacon, C. L., Boland, B., Griffin, A. M., Preisler, J., OʼBrien, L., Regan, C. M., Hurley, S., Kearney, P. J., Slevin, J., Barry-Kinsella, C., Ryan, C. A., Kllleen, O., Glllan, J., Clarke, T., Matthews, T., Corcoran, D., Dunn, E., Geary, M., OʼHerlihy, C., Keane, D., OʼLeary, M. J., Morrison, J. J., Ryan, E., Gorman, W. A., Bourke, A., Larkin, J., Mayes, C., Jenkins, J., Ryan, M., Lalchandani, S., Sheil, O., Lynch, N., Costigan, C., Murphy, J. F., Bhatia, R., Foran, A., Donohue, V., McParland, P., LaSjaunais, P., Rodesch, G., McGinn, M., McAloon, J., OʼLeary, M., Astbury, K., Harmon, D., Sharkey, A., Gaffney, G., OʼRegan, G., McMahon, C., Murray, D., McDermott, C., Woolhead, E., Gillan, J., Cartmill, J. L., Harper, M. A., Al-Shabibi, N., Hanahoe, M., Wingfield, M., Larkin, J. A. M., Bell, A. H., McClure, B. G., Sweeney, L., Martin, D. H., OʼDonoghue, P., Davoren, A., Lucas, G. F., McKiernan, J., Gallagher, D. M. T., Dunne, K. P., Fulena, O., Sheridan, M., Griffin, E., White, M., Deasy, P., OʼRiordan, M., OʼGorman, C., Mongan, C., McCafferkey, M., Henry, G., McKenna, P., OʼMalley, A., Devaney, D., Kelleghan, P., Mooney, E. E., Gillan, J. E., Fitzpatrick, M., McQuillan, K., Heffron, C., Hodnett, P., Curtain, A., OʼConnor, T. C. F., Connell, T. G., Waldron, D., Gorman, W., Bolger, T., OʼKeefe, M., Murphy, J., Dolan, L. M., Traub, A. I., Slattery, M. M., Curley, A. E., Halliday, H. L., Tubman, T. R. J., Kileen, O., Riadha, H., Russell, J., Philips, R., Regan, C., Ali, I., Coughlan, A. C. J., Turner, M. J., Smith, A., OʼFlanagan, D., Igoe, D., Ryan, F., Forde, D., McArdle, E., Ko, D., Bedford, D., Hegarty, M., Dunlevy, B., Corcoran, R., Holohan, T., Feeney, A., McGee, H., Shannon, W., Condon, M., Hyland, C., Sayers, G., Feely, E., Crowley, D., OʼReilly, D., OʼConnell, T., Cronin, M., Johnson, H., Fitzgeraldi, M., Cafferkey, M., Breslin, A., Bonner, C. J., Foley, B., Fitzgerald, M., Wall, P. G., McNamara, E., Costigan, P., Prendergast, T., Foye, K., Cosgrove, C., Keane, A., Murphy, E., OʼDonnell, J., Quinlan, A., Thornton, L., Roch, E. A., Lyons, R. A., Maddocks, A., Barnes, P., Price, L., McCabe, M., Nash, P., Midha, A., Doyle, Y., Kilgallen, A., Wright, P., Ryan, T., De La Harpe, D., Harkins, V., Brennan, C., OʼConnell, V., Evans, D. S., Mhuircheartaigh, Ni J., OʼDonnell, J. M., Rhatigan, A., Shelley, E., Collins, C., Byrne, M., Murphy, A. W., Plunkett, P. K., Murray, A., Bury, G., Lynam, F., McMahon, G., Greally, T., Kane, D., Veale, D., Reece, R., Busteed, S., Bennett, M. W., Stone, M., Molloy, C., OʼConnell, J., Molloy, M. G., Shanahan, F., Guerin, J., Casey, E., Feighery, C., Lin, F., Jackson, J., Pendleton, A., Wright, G. D., Hughes, A. E., OʼGradaigh, D., Debham, I., Compston, J., McEvoy, A., Murphy, E. P., Salonen, D., Payne, P., Lax, M., Lapp, V., Inman, R., OʼRourke, K., Brennan, D., Harty, J., McCarthy, C., OʼByrne, J., Eustace, S., Chirayath, H., Liggett, N. W., Morgan, M. P., Fitzgerald, D. J., McCarthy, C. J., McCarthy, G. M., Lee, R. Z., Wai, K., Nevin, D., Leary, A. O., Lee, R., Casey, E. B., OʼLeary, A., Breen, D., Tuite, D., McInerney, D., Sim, R., Frederic, A. L., Smith, O., White, B., Murphy, M., Silke, C., OʼKeeffe, E., Fanning, N., Spence, L., Parfrey, N. A., McConnell, J. R., Crockard, A. D., Cairns, A. P., Bell, A. L., Kavanagh, O., Moyes, D. A., Finch, M., Rooney, M., Bell, A., Founas, I., El-Magbri, A., Mooney, S., Kennedy, M., Coughlan, R. J., Ramakrishnan, S. A., Gsel, A., Finnerty, O., Burns, M., Yateman, M., Camaco-Hubner, C., Matthews, C. F., Taggart, A., Fuller, K., Murphy, M. S., Phelan, M., Murphy, T. B., Wynne, F., Quane, K., Daly, M., OʼLeary, J., da Silva, I., Bermingham, N., Gogarty, M., Gallagher, L. P., OʼHara, R., Godson, C., Brady, H., Osman, H., El-Rafie, A., Foley-Nolan, D., Kirwan, P., Corcoran, O., Duffy, T., Drummond, F., Madigan, A., Williams, D., Gallagher, P., Hatton, C., Cunningham, S., FitzGerald, O., Minnock, P., Wylie, E., Egan, D., Mc Cormack, J., Shea, M. O., Evans, D., OʼLorcain, P., Comber, H., Evans, A., Jones, J., Garavan, C., Kelleher, K., Boland, M. C., Healy, R., OʼSullivan, M. B., Burke, M., Mc Donald, P., Smithson, R., Glass, J., Mason, C. A., Mullins, N., Nolan, D., McCormick, P., Coughlan, S., Dooley, S., Kelleher, C. C., Hope, A., Murphy, F., Barry, M., Sixsmith, J., MacFarlane, A., MacLeod, C., McElroy, G., OʼLoan, D., Kennedy, F., Kerr, R. M., Lim, J., Allwright, S. P. A., Bradley, F. L., Barry, J. M. G., Long, J., Parry, J. V., Creagh, D., Perry, I. J., Collins, A., Neilson, S., Colwell, N., OʼHalloran, D., OʼNeill, S., McErlain, S., Okasha, M., Gaffney, B., McCarron, P., Hinchion, R., Drew, C., Gavin, A., Fitzpatrick, D., Campbell, R., Wannamethee, S. G., Shaper, A., Friel, S., Kelleher, C., Kee, F., Atterson, C. C., Wilson, E. A., McConnell, J. M., Wheeler, S. M., Watson, J. D., Rahman, Norashikin N., Sheehan, J., Wall, C., Kelleher, B., OʼBroin, S. D., Mullan, R. N., McKeveney, P. J., Hodges, V. M., Winter, P. C., Maxwell, P., Simpson, D. A., Lappin, T. R. J., Maxwell, A. P., Eustace, J. A., Coresh, J., Kutchey, C., Te, P. L., Gimenez, L. F., Scheel, P. J., Walser, M., McMahon, R. A., Clarkson, M., Martin, F., Brady, H. R., Blake, C., OʼMeara, Y. M., Gupta, S., MacKenzie, H., Doyle, S., Fotheringham, T., Haslam, P., Logan, M. P., Conlon, P., Lee, M., Maderna, P., Cottell, D. C., Mitchell, S., Gulmann, C., Østerby, R., Bangstad, H. J., Rljdberg, S., Dempsey, M., Nathwani, S., Ryan, M. P., McMahon, B., Stenson, C., Murtagh, H., Brown, J. H., Doran, P., McGinty, A., Little, M. A., OʼBrien, E., Owens, P., Holian, J., Mee, F., Walshe, J. J., Omer, S. A., Power, D., Diamond, P., Watson, R. W., Shahsafei, A., Jiang, T., Brenner, B. M., Mackenzie, H. S., Neary, J., Dorman, A., Keoghan, M., Campbell, E., Walshe, J., Little, M., Nee, L., OʼCeallaigh, C., McGlynn, H., Bergin, E., Keane, T., Gormley, G., Watson, A., Atta, M. G., Perl, T. M., Song, X., Healy, E., Leonard, M., Lynch, J., Watson, A. J., Lappin, D., Lappin, D. W. P., Hannan, K., Burne, M., Daniels, F., Rabb, H., McBride, B., Kieran, N., Shortt, C., Codd, M., Murray, F., McCormack, A., Brown, C., Wong, C., Dorman, A. M., Keogan, M., Donohue, J., Farrell, J., Donohoe, J., OʼBroin, S., Balfe, A., Mellotte, G. J., Abraham, K. A., McGorrian, C., Wood, A. E., Neligan, M., Kelly, B. D., Finnegan, P., Cormican, M., Callaghan, J., Crean, J. K. G., Moffitt, T. A., Devlin, H. L., Garrett, P. J., Soosay, A., OʼNeill, D., Counihan, A., Hickey, D., Keogan, M. T., Harvey, K., OʼRiordan, E., Waldek, S., Kalra, P. A., OʼDonoghue, D. J., Foley, R. N., Kelliher, D., Mellotte, G., Giblin, L., Keogh, J. A. B., OʼConnell, M., OʼMeara, A., Breatnach, F., Gillick, J., Tazawa, H., Puri, P., Molloy, E., OʼNeill, A. J., Sheridan-Pereira, M., Fitzpatrick, J. M., Webb, D. W., Watson, R. W. G., Linnane, B., OʼDonnell, C., Clarke, T. A., Martin, C., McKay, M., McBrien, J., Glynn, F., OʼDonovan, C., Hall, W. W., Smith, J., Khair, K., Liesner, R., Hann, I. M., Smith, O. P., Gallagher, S., Mahony, M. J., Hilal, A., Cosgrove, J. F., Monaghan, C., Craig, B., Walsh, K., Duff, D., Slizlok, P. O., Halahakoon, C., McMillan, S., Dalzell, E. E., McCaughan, J., Redmond, A. O. B., DeCaluwe, D., Yoneda, A., Akl, U., Dempsey, E., Farrell, M., Webb, D., Elabbas, A., Fox, G., Gormally, S., Grant, B., Corkey, C. W. B., Nicholson, A., Murphy, A., OʼGrady, P., Barry, O., Stewart, M. C., Alderdice, F., Matthews, T. G., McDonnell, M., McGarvey, C., OʼRegan, M., Chróinín, Ní M., Tormey, P., Ennis, S., Green, A. J., Abbas, S., OʼMarcaigh, A., Conran, M., Crushell, E., Saidi, A., Curran, P., Donoghue, V., King, M. D., Elnazir, B., Leonard, J., Kavanagh, C., Brown, D., Corrigan, N., McCord, B., Quinn, M., OʼConnell, L., Mcdonagh, B., Awan, A., Gill, D., Kakkar, R., Warner, J. A., OʼConnor, C., Herzig, M., Twomey, A., White, M. J., Sweeney, B., Surana, R., Hodgson, A., Rafferty, M., Livingstone, W., Peake, D., Wassemer, E., Whitehouse, W., Abdullah, N., Al-Hassan, A., Oslizlok, P., OʼConnell, N., Balding, J., Livingstone, W. J., Healy, M., Mynett-Johnson, L., McAllister, I., Dick, A. C., Herron, B., Boston, V. E., Callaghan, C. O., Brien, D. O., Walsh, A., Philip, M., McShane, D., Hoey, M. C. V., Sharif, F., McDermott, M., Dillon, M., Drumm, B., Rowland, M., Imrie, C., Kelleher, S., Bourke, B., Iqbal, M., Ziedan, Y., OʼNeill, M., OʼRiordan, S., Basheer, S. M. B., OʼCallaghan, S., Chong, A., Kelly, M., Nicholson, A. J., Cooke, R., Sreenan, C., Fallon, M., Denham, B., Dowding, V., Cussen, G., McManus, V., Hensey, O., Monaghan, H., Basheer, S. N., Quinn, E., Hoey, H. M. C. V., Mohamed, S., Ramesh, R. R., Mayne, P., Tracy, E., Gormally, S. M., Curtis, E., McCallion, N., Watson, R., OʼMahony, O., Keegan, M., Ward, K., Barton, D., Poulton, J., Treacy, E., Honour, J., deCaluwe, D., Chróinín, Ni M., Cosgrove, J., Chaudhry, T. S., Long, N. M., Lynch, B., Lasjaunais, P., McDonald, D. G. M., McMenamin, J. B., Farrell, M. J., Roche, E. F., Menon, A., Buckley, C., Mackey, A., Ohlandieck, K., Das, A., Reilly, D., Killeen, O., Harper, J., Roche, E., Hoey, H., Caird, J., OʼBrien, D., Allcutt, D., Farrington, N., Murphy, J. F. A., Savage, J. M., Sands, A. J., Casey, F. A., Craig, B. G., Dornan, J. C., Johnston, J., Patterson, C., Lynch, C., Mulholland, H. C., Watkins, D. C., Young, I., Cran, G., Boreham, C. A. G., McCallion, W. A., Clements, N. F., Stevenson, M. R., Macpherson, C., Jenkins, L., Thompson, A. J., Shields, M. D., Taylor, R. T., Kerr, R., Hughes, J. L., Stewart, M., Jackson, P., Fitzpatrick, C., Rasheed, M., Colhoun, E., Bailie, A. G., Gray, S., Brown, S., Curley, A., Sweet, D. G., MacMahon, K. J., OʼConnor, C. M., Nichelson, A., Lynch, N. E., Finch, D., Foley, M., Scallan, E., Dillon, B., Lyons, S., OʼLoughlin, R., Ward, M., Nally, R., Harkin, A., Kelly, J. P., Leonard, B. E., Magee, P., Connor, T. J., Shen, Y., McCullough, G. R., McDonough, S. M., Niocaill, Nic B., Cramp, A. F. L., Hynes, M., Corkery, P., Carey, M., McGarrigle, D., Higgins, S., Murray, H., Moran, C. J., Dennedy, M. C., Brosnan, J., Morris, L., Sheppard, B. L., Black, A., Wilkins, B., Folan-Curran, J., Skelton, K., Owens, M., Nemeroff, C., Houlihan, D., OʼKeeffe, C., Nolan, N., McCormick, P. A., Baird, A. W., Raducan, I., Corcoran, P., Brennan, R., Molloy, P., Friel, A., Maher, M., Glennon, M., Smith, T., Nolan, A., Houghton, J. A., Carroll, O., Colleran, S., OʼCuinn, G., Snow, H. M., OʼRegan, D., Markos, H. F., Pollock, K., Cannon, D. M., McBean, G., OʼRiordan, A., Quinlan, L. R., Kane, M. T., Higglns, B. D., Moriarty, D. M., Fitzgerald, D., Katkada, A., Canny, G., MacMathuna, P., OʼDonoghue, D., OʼDonovan, M. M., Schuur, A. G., Murphy, K. J., Foley, A. G., ten Bruggencate, S. J. M., and Ireland, L.
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- 2000
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18. Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: data from the E-HOD registry
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Huemer, M. Diodato, D. Martinelli, D. Olivieri, G. Blom, H. Gleich, F. Kölker, S. Kožich, V. Morris, A.A. Seifert, B. Froese, D.S. Baumgartner, M.R. Dionisi-Vici, C. Martin, C.A. Baethmann, M. Ballhausen, D. Blasco-Alonso, J. Boy, N. Bueno, M. Burgos Peláez, R. Cerone, R. Chabrol, B. Chapman, K.A. Couce, M.L. Crushell, E. Dalmau Serra, J. Diogo, L. Ficicioglu, C. García Jimenez, M.C. García Silva, M.T. Gaspar, A.M. Gautschi, M. González-Lamuño, D. Gouveia, S. Grünewald, S. Hendriksz, C. Janssen, M.C.H. Jesina, P. Koch, J. Konstantopoulou, V. Lavigne, C. Lund, A.M. Martins, E.G. Meavilla Olivas, S. Mention, K. Mochel, F. Mundy, H. Murphy, E. Paquay, S. Pedrón-Giner, C. Ruiz Gómez, M.A. Santra, S. Schiff, M. Schwartz, I.V. Scholl-Bürgi, S. Servais, A. Skouma, A. Tran, C. Vives Piñera, I. Walter, J. Weisfeld-Adams, J. the EHOD consortium
- Abstract
Aim: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry. Results: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities. Conclusion: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design. © 2018 SSIEM
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- 2018
19. Consensus clinical management guidelines for Niemann-Pick disease type C
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Geberhiwot T, Moro A, Dardis A, Ramaswami U, Sirrs S, Pineda M, Vanier MT, Walterfang M, Bolton S, Dawson C, Héron B, Stampfer M, Imrie J, Hendriksz C, Gissen P, Crushell E, Coll MJ, Nadjar Y, Klünemann H, Mengel E, Hrebicek M, Jones SA, Ory D, Bembi B, Patterson M, and International Niemann-Pick Disease Registry (INPDR)
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Diagnosis ,NPC ,Management ,Niemann-Pick Type C ,Guidelines - Abstract
Niemann-Pick Type C (NPC) is a progressive and life limiting autosomal recessive disorder caused by mutations in either the NPC1 or NPC2 gene. Mutations in these genes are associated with abnormal endosomal-lysosomal trafficking, resulting in the accumulation of multiple tissue specific lipids in the lysosomes. The clinical spectrum of NPC disease ranges from a neonatal rapidly progressive fatal disorder to an adult-onset chronic neurodegenerative disease. The age of onset of the first (beyond 3 months of life) neurological symptom may predict the severity of the disease and determines life expectancy.NPC has an estimated incidence of ~ 1: 100,000 and the rarity of the disease translate into misdiagnosis, delayed diagnosis and barriers to good care. For these reasons, we have developed clinical guidelines that define standard of care for NPC patients, foster shared care arrangements between expert centres and family physicians, and empower patients. The information contained in these guidelines was obtained through a systematic review of the literature and the experiences of the authors in their care of patients with NPC. We adopted the Appraisal of Guidelines for Research & Evaluation (AGREE II) system as method of choice for the guideline development process. We made a series of conclusive statements and scored them according to level of evidence, strengths of recommendations and expert opinions. These guidelines can inform care providers, care funders, patients and their carers of best practice of care for patients with NPC. In addition, these guidelines have identified gaps in the knowledge that must be filled by future research. It is anticipated that the implementation of these guidelines will lead to a step change in the quality of care for patients with NPC irrespective of their geographical location.
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- 2018
20. S02. The Next Step in Cardiac Genetics: Targeted gene panels and next generation sequencing in inherited cardiac conditions
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Deeny, HA, Murphy, AM, O'Rourke, D, Gallagher, S, Rea, G, Ware, JS, Lightman, EG, Walsh, R, John, S, Homfray, T, Till, J, Prasad, S, Buchan, R, Wilkinson, S, Barton, PJR, Cook, SA, McVeigh, TP, Cody, N, Meany, M, Carroll, C, O'Shea, R, Gallagher, DJ, Clabby, C, Green, AJ, Casey, J, Crushell, E, Hughes, J, Losty, E, Slattery, D, Green, A, Ennis, S, Lynch, SA, Kirk, CW, McKee, S, Project, DDD, Al Shehhi, M, Shen, S, Gallagher, L, Betts, DR, McArdle, L, Quinn, EM, Coleman, C, Molloy, B, Dominguez Castro, P, Trimble, V, Mahmud, N, McManus, R, Jung, S, Salzman, D, Kerin, MJ, Nallur, S, Dookwah, M, Nemec, AA, Sadofsky, J, Paranjape, T, Kelly, O, Chan, E., Miller, N, Sweeney, KJ, Zelterman, D, Sweasy, J, Pilarski, R, Telesca, D, Weidhaas, JB, Stapleton, CP, McCormack, M, Connaughton, D, Phelan, PJ, Cavalleri, GL, Conlon, PJ, Gilbert, E, O'Reilly, S, Merrigan, M, McGettigan, D, Cavalleri, G, Heavin, SB, Slattery, L, Walley, N, Avbersek, A, Novy, J, Sinha, S, Alarts, N, Legros, B, Radtke, R, Doherty, C, Depondt, C, Sisodiya, S, Goldstein, D, Delanty, N, Nesbit, MA, Courtney, DG, Allen, EHA, Atkinson, SD, Maurizi, E, Moore, JE, Pedrioli, DM Leslie, McLean, WHI, Moore, CBT, Petyrka, J, Vieira, M, Donnelly, DE, O'Neill, T, Hardy, R, Morrison, PJ, Hegarty, M, Irvine, M, Dabir, T, Zhang, X, Dineen, T, Flanagan, J, Kovacs, A, Mihart, R, O'Callaghan, J, Culligan, J, Daly, N, McAuliffe, D, Waterstone, J, Owens, P, Guerin, C, Quill, D, Bell, M, Lowery, AJ, Bradley, L, Barton, DE, Matthews, J, Turner, J, O'Byrne, JJ, Fitzsimons, PE, Unger, S, Croft, J, Mayne, PD, Moylette, E, McDonnell, C, Parker, VE, Al-Shehhi, M, Kelly, PM, Costigan, C, Hegarty, A, Knox, R, Byrne, S, Semple, LRK., Irvine, A, McDaid, J, Ryan, H, Dunne, A, Lambert, DM, Treacy, EP, Lynch, SM, McKenna, MM, Walsh, CP, McKenna, DJ, Whitton, L, Cosgrove, D, Clarkson, C, Gill, M, Corvin, A, Rea, S, Donohoe, G, Morris, D, Neville, J, Ryan, AM, Hand, CK, Ryan, E, Ryan, F, Barton, D, O'Dwyer, V, Neylan, D, Nesbitt, H, Byrne, NM, Worthington, J, Mc Keown, SR, Mc Kenna, DJ, Harold, D, Holland, J, Mothershill, O, Allen, EH, Leslie Pedrioli, DM, Courtney, D, Cole, A, Cox, S, Jeong, C, Droma, Y, Hanaoka, M, Ota, M, Gasparini, P, Montgomery, H, Di Rienzo, A, Robbins, P, L. Cavalleri, G, Heavin, S, Buckley, P, Irwin, RE, Thakur, A, O’ Neill, KM, Cummins, Paul, Mackin, SJ, O'Neill, K, Walsh, C, Schiroli, D, Mulligan, R, Sebag, F, Ozaki, M, Molloy, AM, Mills, JL, Fan, R, Wang, Y, Gibney, ER, Shane, B, Brody, LC, Parle-Mcdermott, A, O'Halloran, ET, Ebrahim, A, Meydan, C, Mason, C, and Magalhães, TR
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Poster Presentations ,Abstracts ,Programme ,Spoken Papers - Abstract
Aims The Irish DNA Atlas is a DNA collection being assembled with the aim of describing the fine-scale population structure in Ireland. Understanding such structure can inform on optimal design of clinical genetic studies as well as the history of the Irish population. We will present an overview of and the preliminary findings from the study. Methods We are recruiting individuals with all eight greatgrandparents born in Ireland, within 30 kilometres of each other. Participants are asked to complete a detailed birth-brief, which records place and date of birth of three generations of ancestors. We also collect some basic health-related details. DNA is extracted from a saliva sample. We have genotyped using an Illumina OmniExpressdense SNP genotyping platform. We present a number of analyses designed to visualise genetic structure, including; Principle Component, ADMIXTURE, and Runs of Homozygosity analysis. Results To date we have recruited 162 participants. The mean great-grandparental area is 32 kilometres, with an average greatgrandparental date of birth of 1850. Therefore the individuals in the Atlas provide insight to the genetic landscape of Ireland before significant movement of people from the 20th century onwards. An analysis of dense genotyping data from 142participants shows that the Atlas participants cluster closely with British individuals in a Europe wide PCA, but present different ancestral population components when compared with British, and other European populations. Irish individuals also present slightly higher levels of homozygosity relative to mainland European levels. PCA targeted at specific areas of interest within Ireland also hint at fine-scale substructure. Conclusion Ireland shows typical features of a homogenous population, well suited to the study of rare variation in disease risk., Background Progress in diagnostic and therapeutic strategies in medicine is dependent upon high-quality biomedical research. Translation of research findings into the clinic relies on patient participation in innovative clinical trials. We investigated attitudes to genetic research in Ireland, in particular with respect to commercial and financial implications. Methods A multi-centre cross-sectional survey study was performed. Consecutive patients attending four out-patient clinics were asked to complete paper-based questionnaires. An electronic version of the same questionnaire was created on Survey Monkey with a link made public on a social media website for a period of 24 hours. Data was analysed using SPSS. Results 351 questionnaires were completed (99 paper, 252 electronic). The majority of respondents were female (n = 288, 82%), and highly educated, with 244 (70%) attending college/university. Most participants supported genetic research (267, 76%), more frequently for common diseases (274, 78%) than rare disorders (204, 58%, p < 0.001, x2). 103 (29%) had participated in scientific research, and 57(16%) had donated material to a bio-bank. The majority (n = 213, 61%) would not support research with potential financial/commercial gain. 106(30%) would decline to participate in research if researchers would benefit financially, compared to 49(14%) if the research was supported by a pharmaceutical company, (p < 0.001, x2). Respondents would provide buccal samples (258, 74%) more readily than tissue (225, 64%) or blood (222, 63%). Conclusion A high level of support for genetic research exists among the Irish population, but active participation is dependent upon a number of factors, notably, type of biological material required, frequency of the disease in question, and commercial interest of the researchers., Introduction Although the etiology of schizophrenia (SZ) is largely unknown, it is increasingly clear that genetic and environmental interactions contribute to cognitive deficits associated with this disorder. Recent Genome wide association studies (GWAS) have indicated a link between SZ and immune dysregulation, especially genetic mutations related to the major histocompatibility complex (MHC). Cognitive deficits are core features of Schizophrenia and related disorders, which relate to genetic risk. This study aims to explore the relationship between MHC risk variants for SZ and cognitive deficits, while also relating findings to brain activity. Methods To test if MHC risk variants impair cognition, ANCOVA analysis is performed on genetics data previously collected in a GWAS. Cognition measures are compared in groups with and without MHC genetic risk, in a population of SZ sufferers and healthy controls. Functional MRI imaging will also be performed to test if genetic risk relates to altered neural activity. Results Preliminary analyses suggest that MHC risk variants contribute to impairments in cognition in domains of social cognition, IQ and attention. Further analysis will be performed to test for environmental mediators of this relationship, looking at cannabis use and urbanicity. BOLD fMRI will also be used to test for a relationship between MHC risk and altered neural activity, using MATLAB SPM. Conclusions The MHC genetic variant may serve as a significant risk marker for schizophrenia, and further elucidate etiology of this neurodevelopmental disorder. Future studies on neurobiology of social cognition, and greater knowledge of genetic risk may establish targets for interventions., Aim To create a bioluminescence mouse model which expresses firefly luciferase in the corneal epithelium to assess gene editing and gene silencing for the cornea. Methods A gene targeting vector was generated where the Krt12 coding sequence in and the splice donor site of exon 1 were replaced with a transgene cassette containing a luc2-Multiple Targeting Cassette (MTC) gene fusion. The vector was transfected by electroporation into the Taconic Artemis C57BL/6N Tac ES cell line. Homologous recombinant clones were isolated and validated, and the mice bred with luc2-positive/ PuroR-negative offspring used for colony establishment. To visualise the expression of luc2 within the corneal epithelium, luciferin substrate diluted in viscotears was applied to the front of the eye and then luciferase expression was imaged and assessed using a Xenogen IVIS Lumina Imager and LivingImage 3.2 software. Intrastromal injection of siGlo siRNA was used to determine the localisation of siRNA within the corneal epithelium and then the established mouse model was treated with either native or Accell “self-delivery” siRNA. Results The Accell “self-delivery” siRNA induced potent sustained allele specific silencing for 7 days, while native versions of siRNA resulted in significant knock-down for 1 day only (p < 0.05). We have created and validated a bioluminescence mouse model and have utilised it to assess siRNA in vivo. This mouse model coupled with the Lumina imager will allow us to assess topical delivery of gene therapies to the ocular surface allowing validation for future translation to clinical use., Background Methylation of DNA sequences at promoters, CpG islands and other elements plays a vital role in regulating gene activity. In human, loss of methylation is known to play a causative role in imprinting disorders and in inappropriate germline gene expression in cancers. While in mouse, loss of function mutants have given great insight into the targets of methylation, functional studies in human have been largely limited to cancer cells and more recently stem cells, not normal adult cells. Methods Stable knockdowns of the maintenance methyltransferase DNMT1 were generated in normosomic hTERT-immortalised adult fibroblasts. Genome-wide methylation levels were assayed using the Illumina 450K bead array. Results were analysed using RnBeads and Galaxy. Locusspecific methylation was verified using pyrosequencing and clonal analysis. Validation was achieved using transient siRNA. Results Loss of function was poorly tolerated and all clonally-expanded cell lines had spontaneously restored DNMT1 levels by silencing of the shRNA. Evidence for a genome-wide methylation erasure event followed by a wave of remethylation could be clearly traced. Gene bodies and the shores of CpG islands showed the clearest loss of methylation overall. While most CpG islands are normally unmethylated and so unaffected, both imprints and germline genes fall into the rarer category of normally methylated islands: of these two, lasting loss of methylation was much more common among imprints than germline genes. Conclusions 1: transient loss of methylation is poorly tolerated; 2: a robust mechanism for remethylation exists even in adult cells; 3: aberrant remethylation is frequent on recovery and 4: Imprints are particularly sensitive., Background Dihydrofolate reductase (DHFR) is essential for the conversion of folic acid to active folate needed for one-carbon metabolism. Common genetic variation within DHFR is restricted to the noncoding regions and previous studies have focused on a 19 bp deletion/insertion polymorphism (rs70991108) within intron 1. Reports of an association between this polymorphism and blood folate biomarker concentrations are conflicting. Objective We aimed to evaluate whether the DHFR 19bp deletion/ insertion polymorphism affects circulating folate biomarkers in the largest cohort to address this question to date. Methods Young healthy Irish individuals (n= 2,507) between 19 to 36 years old were recruited between February 2003 and 2004. Folic acid intake from supplements and fortified foods was assessed using a customized food intake questionnaire. Concentrations of serum folate and vitamin B-12, red blood cell (RBC) folate and plasma total homocysteine (tHcy) concentration were measured. Data were analysed using linear regression models. Results Folic acid intake was positively associated with serum (P 326μg folic acid/day; P = 0.96). A non-significant trend towards lower RBC folate by genotype (P = 0.09) was observed in the lowest folic acid intake quintile (0 – 51 μg/day). Conclusion In this cohort of young healthy individuals the DHFR 19bp deletion allele does not significantly affect circulating folate status, irrespective of folic acid intake. Our data rule out a strong functional effect of this polymorphism on blood folate concentrations.
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- 2015
21. S02. Pre-Implantation Genetic Diagnosis (PGD) in Ireland - from validation to introduction of a clinical service
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Morrison, PJ, Campbell, E, Kennedy, F, Russell, A, Smithson, WH, Parsons, L, Liggan, B, Irwin, B, Delanty, N, Hunt, SJ, Craig, J, Morrow, J, Dineen, T, Zhang, X, Flanagan, J, Kovacs, A, Mihart, R, O'Callaghan, J, Culligan, J, Daly, N, Waterstone, J, Magee, AC, Stewart, FJ, Dabir, TA, McConachie, M, McCoubrey, A, McConnell, VPM, Stack, D, O'Meara, E, Phelan, S, McDonagh, N, Kelly, L, Sciot, R, Debiec-Rychter, M, Morris, T, Cochrane, D, Sorensen, P, O'Sullivan, MJ, O'Byrne, JJ, Sweeney, M, Donnelly, D, Lambert, D, Beattie, D, Gervin, C, Graham, CA, Barton, DE, Lynch, SA, Whelan, CD, Hibar, DP, Stein, JL, Speed, D, Sisodiya, S, Ohnson, M, Goldstein, D, Medland, SE, Ranke, B, Thompson, PM, Cavalleri, G, Coleman, C, Quinn, EM, Ryan, AW, Anney, RJL, Trimble, V, Morris, DW, Donohoe, G, Conroy, J, Trynka, G, Wijmenga, C, Ennis, S, McManus, R, O'Halloran, ET, Magalhaes, TR, Cole, A, Cox, S, Jeong, C, Witonsky, D, Robbins, P, Montgomery, H, Ota, M, Hanaoka, M, Droma, Y, Beall, CM, Rienzo, A Di, Casey, J, McGettigan, P, Crushell, E, Hughes, J, Smyth, LJ, Kilner, JK, Benson, KA, Maxwell, AP, McKnight, AJ, Donnelly, DE, Jeffers, L, Hampton, S, Baillie, N, Cooke, S, O'Connell, SM, McDonald, A, O'Toole, N, Bradfield, A, Bradley, M, Hattersley, A, Ellard, S, Proks, P, Mattis, KK, Ashcroft, F, O'Riordan, SMP, Coyle, D, McDermott, M, O'Sullivan, M, Roche, E, Quinn, F, Cody, D, MacMahon, JM, Morrissey, R, Green, A, Thompson, AR, Kulkarni, A, Marks, KJ, Snape, K, Taylor, R, Bradley, L, Ramachandrappa, S, Pinto, CF, Dabir, T, Logan, P, Liew, S., Znaczko, A, Ryan, H., McDevitt, T, Higgins, M, Crowley, A, Rogers, M, Geoghegan, S, Shorto, J, Ramsden, S, O'Riordan, MP, Moore, M, Murphy, M, Irvine, A, Znaczko, Anna, Wilson, A, Stewart, F, Cather, MH, Young, IS, Nicholls, DP, O'Kane, M, Sharpe, P, Hanna, E, Hart, PJ, Savage, N, Humphreys, MW, Shaw-Smith, C, Osio, D, Collinson, MN, McKee, S, McNerlan, S, McGorrian, C, Galvin, J, O'Byrne, J, Stewart, S, Heggarty, SV, Hegarty, SP, McConnell, V, Turner, J, Ward, A, Kelly, R, Joyce, C, ó hIcí, B, Meaney, K, Gibson, L, Kelly, PM, Costigan, C, Gul, R, Byrne, S, Hughes, L, Ozaki, M, O'Sullivan, F, Parle-McDermott, A, Heavin, SB, McCormack, M, Slattery, L, Walley, N, Avbersek, A, Novy, J, Sinha, S, S, Alarts, N, Legros, B, Radtke, R., Sisodiya, Depondt, C, Cavalleri, GL, Connolly, S, Heron, EA, Irvine, MAG, Hughes, AE, Darlow, JM, Darlay, R, Hunziker, M, Kutasy, B, Green, AJ, Cordell, H, Puri, P, Chand, S, McCaughan, JA, Shabir, S, Chan, W, Kilner, J, Borrows, R, Douglas, AP, O'Neill, T, Shepherd, C, Hardy, R, Kenny, Molloy, B, Freeley, M, Quinn, E, McGinn, R, Long, A, Gahan, JM, Connolly, E, Byrne, MM, Gray, SG, Murphy, RT, Gui, H, Heinzen, E, Goldstein, D B, Petrovski, S, O'Brien, TJ, Cherny, S, Sham, PC, Baum, L, Duffy, S, Catherwood, N, McVeigh, TP, Sweeney, KJ, Miller, N, Kerin, MJ, and Weidhaas, JB
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Poster Presentations ,Abstracts ,Spoken Papers - Published
- 2014
22. Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) in the Irish Paediatric Population.
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Mesbah, Z., Ho, K. Sing, Fitzsimons, P., Monavari, A. A., Mayne, P. D., and Crushell, E.
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- 2019
23. A recurrent mitochondrial p.Trp22Arg NDUFB3 variant causes a distinctive facial appearance, short stature and a mild biochemical and clinical phenotype
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Alston, CL, Howard, C, Olahova, M, Hardy, SA, He, L, Murray, PG, O'Sullivan, S, Doherty, G, Shield, JPH, Hargreaves, IP, Monavari, AA, Knerr, I, McCarthy, P, Morris, AAM, Thorburn, DR, Prokisch, H, Clayton, PE, McFarland, R, Hughes, J, Crushell, E, and Taylor, RW
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Male ,RM ,Mitochondrial Diseases ,Dwarfism ,dysmorphic features ,QH301 ,complex I deficiency ,Humans ,Exome ,Child ,QH426 ,Genetic Association Studies ,Electron Transport Complex I ,Genotype-Phenotype Correlations ,Homozygote ,Facies ,Infant ,Mitochondria ,Pedigree ,mitochondrial disease ,Phenotype ,Child, Preschool ,Mutation ,Female ,prognosis - Abstract
BACKGROUND: Isolated Complex I deficiency is the most common paediatric mitochondrial disease presentation, associated with poor prognosis and high mortality. Complex I comprises 44 structural subunits with at least 10 ancillary proteins; mutations in 29 of these have so far been associated with mitochondrial disease but there are limited genotype-phenotype correlations to guide clinicians to the correct genetic diagnosis.METHODS: Patients were analysed by whole-exome sequencing, targeted capture or candidate gene sequencing. Clinical phenotyping of affected individuals was performed.RESULTS: We identified a cohort of 10 patients from 8 families (7 families are of unrelated Irish ancestry) all of whom have short stature (C, p.Trp22Arg NDUFB3 variant. Two sibs presented with primary short stature without obvious metabolic dysfunction. Analysis of skeletal muscle from three patients confirmed a defect in Complex I assembly.CONCLUSIONS: Our report highlights that the long-term prognosis related to the p.Trp22Arg NDUFB3 mutation can be good, even for some patients presenting in acute metabolic crisis with evidence of an isolated Complex I deficiency in muscle. Recognition of the distinctive facial features-particularly when associated with markers of mitochondrial dysfunction and/or Irish ancestry-should suggest screening for the p.Trp22Arg NDUFB3 mutation to establish a genetic diagnosis, circumventing the requirement of muscle biopsy to direct genetic investigations.
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- 2016
24. S1. A prospective study of referrals from the Irish Traveller community to the National Centre for Inherited Metabolic Disorders
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Murphy, AM, Halling, C, Lynch, SA, Monavari, AA, Harty, S, Crushell, E, Treacy, EP, Crawford, H, McKee, SA, Chukwu, J, Taha, A, Stewart, Fiona J, Ryan, Anthony W, Hughes, David, Ryan, Thomas, McManus, Ross, Stoneking, Mark, Ó'Dúshláine, Colm, Dolan, Ciara, Stanton, Alice, Croke, David, Kalviainen, Reetta, Berkovic, Samuel, O'Brien, Terry, Sisodiya, Sanjay, Goldstein, David, Morris, Derek, Delanty, Norman, Cavalleri, Gianpiero, Gilks, William P., Allott, Emma, Donohoe, Gary, Waddington, John L., Gill, Michael, Corvin, Aiden P., Morris, Derek W., McGibbon, D, Benson, C, Meenagh, G, Wright, G, Doherty, M, Hughes, A, McErlean, Seona, Scott, Natalie, Worthington, Jenny, Brown, Gillian, Falchi, Adriana, Berrar, Daniel, Bjourson, Anthony J, McLellan, Andrew, Wynne, Freda, Ball, Melanie, Moore, Tom, Barton, David E., Hastings, Ros J., Berwouts, Sarah, Brady, Christine, Corbisier, Philippe, Corveleyn, Anniek, Elles, Rob, Fowler, Brian, Gancberg, David, Litynski, Piotr, Macek, Milan, Malburg, Ute, Matthijs, Gert, Morris, Michael, Mueller, Clemens, Nagels, Nick, Quellhorst-Pawley, Bettina, Stambergova, Alexandra, Vermeesch, Jan, Vickers, Kate, Dequeker, Elisabeth, Magee, Alex, Lynch, Sally Ann, Offiah, Amaka, Walsh, J, Lambert, D, Baldridge, DM, Morello, R, Eyre, D, Lee, B, Green, AJ, O'Brien, Kirsty, Parle-McDermott, Anne, Langseth, A, Doherty, E, Nestor, T, Lynch, T, Asmus, F, Mary, MD, Mankan, Arun Kumar, Daly, Jacqueline, Caraher, Emma, Kelleher, Dermot, Ó hIcí, Brónagh, Gould, Edith, Kenny, Elaine, Pinto, Carlos, Corvin, Aiden, Schouest, Katherine, Coghlan, Avril, Spillane, Charles, Dash, DP, George, s, Silvestri, G, Jackson, J, Frazer, D, Hughes, AE, Willoughby, C, Donnelly, Deirdre, McKee, Shane, Allott, Emma H., Mitchell, Kevin J., Skehan, EB, Abdulrahim, M, Parfrey, NP, Hand, CK, Colleran, G, Rowan, A, Miller, N, Sawyer, E, Curran, C, Kerin, M, Tomlinson, I, McKay, GJ, Orr, N, Chakravarthy, U, Fitzpatrick, Helen, Clarke, Gillian, Doherty, Aidan, Shepherd, CW, McKee, S, Morrison, PJ, Kelly, Johanna, Conneally, Eibhlin, Vandenburgh, Elizabeth, Meaney, Karen, Hegarty, KG, Daly, M, Shanahan, F, Molloy, MG, Laing, Mary E, Dicker, Patrick, Ho, Wen Lyn, Moloney, Fergal J, Murphy, Gillian M, Conlon, Peter, Whitehead, Alexander S, Shields, Denis C, O'Shea, Rosie, Treacy, Eileen, Murphy, Anne Marie, Lambert, Deborah, Carroll, N, Cahill, S, O'Brien, K, Scott, JM, Parle-McDermott, A, Dabir, Tabib, McCrossan, Brian, Sands, A, Sweeney, L, Magee, A, Graham, Alistair N, McDevitt, Trudi, King, Caitriona, Rogers, Melissa, Roring, Solvig, McQuaid, Shirley, Barton, David E, Smith, G, McManus, D, McConnell, V, Crowley, VEF, Lim, K, Darby, C, Collison, C, Balfe, A, Heggarty, S, Crowley, Vivion EF, Darby, Cindy, Whatley, Sharon, Badminton, Mike, Meng, W, Patterson, CC, Belton, C, Kamaruddin, MS, Horan, PG, Kee, F, McKeown, PP, Cassidy, F, Zhao, C, Badger, J, Delaney, C, Mooney, L, Roche, S, McKeon, P, Dobrin, SE, Butler, Aileen, McManus, David, Jones, June, and Clarkson, Moya
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Poster Presentations ,Abstracts ,Spoken Papers - Published
- 2008
25. A review of anaesthetic outcomes in patients with genetically confirmed mitochondrial disorders
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Smith, A., primary, Dunne, E., additional, Mannion, M., additional, O’Connor, C., additional, Knerr, I., additional, Monavari, A. A., additional, Hughes, J., additional, Eustace, N., additional, and Crushell, E., additional
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- 2016
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26. Management of maple syrup urine disease in the peri-operative period
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McCarron E, McCormack O, Cronin T, McGowan A, Ml, Healy, O'Rourke D, Crushell E, Ravi N, and John V Reynolds
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Young Adult ,Cholecystectomy, Laparoscopic ,Liver Function Tests ,Maple Syrup Urine Disease ,Cholangiopancreatography, Magnetic Resonance ,Humans ,Female ,Gallstones - Abstract
Maple syrup urine disease (MSUD) has an incidence of 1:125,000 newborns in Ireland. Patients, when fasting, or in a catabolic state build up toxic metabolites leading to progressive neurological dysfunction. We describe the necessary peri-operative management of a patient with MSUD who developed symptomatic gallstones requiring a laparoscopic cholecystectomy.
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- 2014
27. Children Growing up in Direct Provision.
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O'Brien, N. and Crushell, E.
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- 2020
28. Genetic landscape of paediatric acute liver failure.
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Lenz, D., D Schlieben, L., Shimura, M., Bianzano, A., Garbade, S., Smirnov, D., Kopajtich, R., Adam, R., Aldrian, D., Baric, I., Baumann, U., Bozbulut, N. E., Bufler, P., Burnyte, B., Calvo, P. L., Crushell, E., Dalgıç, B., Das, A., Dezsofi, A., and Dick, A.
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- 2022
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29. Rotavirus Gastroenteritis is Associated with Increased Morbidity and Mortality in Children with Inherited Metabolic Disorders.
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Smith, A., Mannion, M., O’Reilly, P., Crushell, E., Hughes, J., Knerr, I., Gavin, P., and Monavari, A.
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- 2017
30. A review of anaesthetic outcomes in patients with genetically confirmed mitochondrial disorders.
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Hughes, J., Crushell, E., Smith, A., Mannion, M., Knerr, I., Monavari, A., Dunne, E., Eustace, N., O'Connor, C., and Monavari, A A
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MITOCHONDRIAL pathology , *ANESTHETICS , *METABOLIC disorders , *ANESTHESIA , *PROPOFOL , *ETHERS , *INTRAVENOUS anesthetics , *INTRAVENOUS therapy , *KETAMINE , *RETROSPECTIVE studies , *THIOPENTAL , *GENERAL anesthesia , *INHALATION administration , *PERIOPERATIVE care , *INHALATION anesthetics , *DISEASE complications - Abstract
Mitochondrial disorders are a clinically and biochemically diverse group of disorders which may involve multiple organ systems. General anaesthesia (GA) poses a potential risk of decompensation in children with mitochondrial disorders, and there is little guidance for anaesthetists and other clinicians regarding the optimal anaesthetic agents and perioperative management to provide to patients with mitochondrial disease[15]. The aim of this review was to document adverse events and perioperative complications from GA in patients with genetically confirmed mitochondrial disorders. A retrospective chart review of patients with genetically confirmed mitochondrial disorders who had undergone GA was undertaken. The indication for GA, anaesthetic agents utilised, length of admission and post anaesthetic complications were documented and analysed. Twenty-six patients with genetically proven mitochondrial disease underwent 65 GAs. Thirty-four (52%), received propofol as their induction agent. Thirty-three (51%) patients received sevoflurane for the maintenance of anaesthesia, while 8 (12%) received isoflurane and 24 (37%) received propofol. The duration of most GAs was short with 57 (87%) lasting less than 1 h. Perioperative complications occurred in five patients while under GA including ST segment depression, hypotension and metabolic acidosis in one. All five patients were stabilised successfully and none required ICU admission as a consequence of their perioperative complications. The duration of hospital stay post GA was <24 h in 25 (38%) patients.
Conclusion: No relationship between choice of anaesthetic agent and subsequent perioperative complication was observed. It is likely that individual optimisation on a case-by-case basis is more important overall than choice of any one particular technique. What is Known: • General anaesthesia (GA) poses a potential risk of decompensation in children with mitochondrial disorders. • There is a great diversity in the anaesthetic approaches undertaken in this cohort, and little guidance exists for anaesthetists and other clinicians regarding the optimal anaesthetic agents and perioperative management to provide to patients with mitochondrial disease. What is New: • In this study of 26 patients with genetically confirmed mitochondrial disease who underwent 65 GAs, no relationship between choice of anaesthetic agent and subsequent perioperative complication was observed • It is likely that individual optimisation on a case-by-case basis is more important overall than choice of any one particular technique. [ABSTRACT FROM AUTHOR]- Published
- 2017
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31. Short report: intussusception associated with bacterial meningitis
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Crushell, E
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intussusception ,sepsis ,meningitis - Abstract
Despite its common association with viral illnesses, intussusception has only rarely been found in the presence of bacterial infections. Two infants are described, both of whom were admitted to hospital with bilious vomiting, drowsiness, and dehydration. Both infants required urgent intravenous volume expansion. Intussusception was confirmed, and reduction was achieved by enema in both cases. Recovery was slow, and one infant developed a seizure. Evidence of meningococcal meningitis was found in both, with septicaemia in one. Neurological outcome is normal to date, and there has been no recurrence of intussusception in either case.
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- 2001
32. Classical Galactosaemia in Ireland: incidence, complications and outcomes of treatment
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Coss, K. P., primary, Doran, P. P., additional, Owoeye, C., additional, Codd, M. B., additional, Hamid, N., additional, Mayne, P. D., additional, Crushell, E., additional, Knerr, I., additional, Monavari, A. A., additional, and Treacy, E. P., additional
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- 2012
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33. Selected abstracts
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Corkery, P. P., Leek, B. F., Caulfield, B., Garrett, M., Gormley, J. P., O’Donnell, P. M., Kennedy, N., Sayers, K., Stokes, E., Bresnihan, B., Fitzgerald, O., McGarvey, M. A., Tonra, M., Hooper, A. C. B., Barry, J., Maurer, B., Hussey, J., Gormley, J., Noble, J. G., Alves-Guerreiro, J., Lowe, A. S., Walsh, D. M., NicNiocaill, B., Harte, M., O’Connor, W. T., O’Hara, A. M., Orren, A., Moran, A. P., Hardiman, D. A., Lee, T. C., Croke, D. T., Tolan, R., McBennett, S., Warmington, S., McGuire, M., Bradford, A., O’Hare, T., MacDermott, M., Lynch, F., O’Regan, R. G., McLoughlin, P., Quinn, T., Ryan, J. P., Pickering, M., Campion, D. P., Jones, J. F. X., Ryan, S., McNicholas, W. T., Nolan, P., Doyle, F. J., Rackard, S. M., Beddy, P., Campbell, V. A., Bakhle, Y. S., Bell, C., Usher, C., Chan, L., Keenan, A. K., McQuaid, K. E., Cullen, V. C., Smith, E. M., Kelly, A., Lynch, M. A., Freir, D. B., Holscher, C., Herron, C. E., Pearson, H. A., Curran, B. P., O’Connor, J. J., Quinn, A., McHale, J., Moriarty, D., O’Connor, J., Glennon, J. C., Van Vliet, B. J., Long, S. K., Kruse, C., Gallagher, H. C., Bacon, C. L., Boland, B., Griffin, A. M., Preisler, J., O’Brien, L., Regan, C. M., Hurley, S., Kearney, P. J., Slevin, J., Barry-Kinsella, C., Ryan, C. A., Kllleen, O., Glllan, J., Clarke, T., Matthews, T., Corcoran, D., Dunn, E., Geary, M., O’Herlihy, C., Keane, D., Slattery, M. M., O’Leary, M. J., Morrison, J. J., Ryan, E., Gorman, W. A., Bourke, A., Larkin, J., Mayes, C., Jenkins, J., Ryan, M., Lalchandani, S., Sheil, O., Lynch, N., Costigan, C., Murphy, J. F., Bhatia, R., Foran, A., Donohue, V., McParland, P., LaSjaunais, P., Rodesch, G., McGinn, M., McAloon, J., O’Leary, M., Astbury, K., Harmon, D., Sharkey, A., Gaffney, G., O’Regan, G., McMahon, C., Murray, D., McDermott, C., Woolhead, E., Gillan, J., Cartmill, J. L., Harper, M. A., Al-Shabibi, N., Hanahoe, M., Wingfield, M., Larkin, J. A. M., Bell, A. H., McClure, B. G., Sweeney, L., Martin, D. H., O’Donoghue, P., Davoren, A., Lucas, G. F., McKiernan, J., Gallagher, D. M. T., Dunne, K. P., Fulena, O., Sheridan, M., Griffin, E., White, M., Deasy, P., O’Riordan, M., O’Gorman, C., Mongan, C., McCafferkey, M., Henry, G., McKenna, P., O’Malley, A., Devaney, D., Kelleghan, P., Mooney, E. E., Gillan, J. E., Fitzpatrick, M., McQuillan, K., Heffron, C., Hodnett, P., Curtain, A., O’Connor, T. C. F., Connell, T. G., Waldron, D., Gorman, W., Bolger, T., O’Keefe, M., Murphy, J., Dolan, L. M., Traub, A. I., Slattery, M. M., O’Leary, M. J., Curley, A. E., Halliday, H. L., Tubman, T. R. J., Kileen, O., Riadha, H., Russell, J., Philips, R., Regan, C., Ali, I., Coughlan, A. C. J., Turner, M. J., Smith, A., O’Flanagan, D., Igoe, D., Ryan, F., Forde, D., McArdle, E., Ko, D., Bedford, D., Hegarty, M., Dunlevy, B., Corcoran, R., Holohan, T., Feeney, A., McGee, H., Shannon, W., Condon, M., Hyland, C., Sayers, G., Feely, E., Crowley, D., O’Reilly, D., O’Connell, T., Cronin, M., Johnson, H., Fitzgeraldi, M., Cafferkey, M., Breslin, A., Bonner, C. J., Foley, B., Fitzgerald, M., Wall, P. G., McNamara, E., Costigan, P., Prendergast, T., Foye, K., Cosgrove, C., Keane, A., Murphy, E., O’Donnell, J., Quinlan, A., Thornton, L., Roch, E. A., Lyons, R. A., Maddocks, A., Barnes, P., Price, L., McCabe, M., Nash, P., Midha, A., Doyle, Y., Kilgallen, A., Wright, P., Ryan, T., De La Harpe, D., Harkins, V., Brennan, C., O’Connell, V., Evans, D. S., Ni Mhuircheartaigh, J., O’Donnell, J. M., Rhatigan, A., Shelley, E., Collins, C., Byrne, M., Murphy, A. W., Plunkett, P. K., Murray, A., Bury, G., Lynam, F., McMahon, G., Greally, T., Kane, D., Veale, D., Reece, R., Busteed, S., Bennett, M. W., Stone, M., Molloy, C., O’Connell, J., Molloy, M. G., Shanahan, F., Guerin, J., Casey, E., Feighery, C., Lin, F., Jackson, J., Pendleton, A., Wright, G. D., Hughes, A. E., O’Gradaigh, D., Debham, I., Compston, J., McEvoy, A., Murphy, E. P., Salonen, D., Payne, P., Lax, M., Lapp, V., Inman, R., O’Rourke, K., Brennan, D., Harty, J., McCarthy, C., O’Byrne, J., Eustace, S., Chirayath, H., Liggett, N. W., Morgan, M. P., Fitzgerald, D. J., McCarthy, C. J., McCarthy, G. M., Lee, R. Z., Wai, K., Nevin, D., Leary, A. O., Lee, R., Leary, A. O., Casey, E. B., Leary, A. O., O’Leary, A., Breen, D., Tuite, D., McInerney, D., Sim, R., Frederic, A. L., Smith, O., White, B., Murphy, M., Silke, C., O’Keeffe, E., Fanning, N., Spence, L., Parfrey, N. A., McConnell, J. R., Crockard, A. D., Cairns, A. P., Bell, A. L., Kavanagh, O., Moyes, D. A., Finch, M., Rooney, M., Bell, A., Founas, I., El-Magbri, A., Mooney, S., Kennedy, M., Coughlan, R. J., Ramakrishnan, S. A., Gsel, A., Finnerty, O., Burns, M., Yateman, M., Camaco-Hubner, C., Matthews, C. F., Taggart, A., Fuller, K., Murphy, M. S., Phelan, M., Murphy, T. B., Wynne, F., Quane, K., Daly, M., O’Leary, J., da Silva, I., Bermingham, N., Gogarty, M., Gallagher, L. P., O’Hara, R., Godson, C., Brady, H., Osman, H., El-Rafie, A., Foley-Nolan, D., Kirwan, P., Corcoran, O., Duffy, T., Drummond, F., Madigan, A., Williams, D., Gallagher, P., Hatton, C., Cunningham, S., FitzGerald, O., Minnock, P., Wylie, E., Egan, D., Mc Cormack, J., Shea, M. O., Evans, D., O’Lorcain, P., Comber, H., Evans, A., Jones, J., Garavan, C., Kelleher, K., Boland, M. C., Healy, R., O’Sullivan, M. B., Burke, M., Mc Donald, P., Smithson, R., Glass, J., Mason, C. A., Mullins, N., Nolan, D., McCormick, P., Coughlan, S., Dooley, S., Kelleher, C. C., Hope, A., Murphy, F., Barry, M., Sixsmith, J., MacFarlane, A., MacLeod, C., McElroy, G., O’Loan, D., Kennedy, F., Kerr, R. M., Lim, J., Allwright, S. P. A., Bradley, F. L., Barry, J. M. G., Long, J., Parry, J. V., Creagh, D., Perry, I. J., Collins, A., Neilson, S., Colwell, N., O’Halloran, D., O’Neill, S., McErlain, S., Okasha, M., Gaffney, B., McCarron, P., Hinchion, R., Drew, C., Gavin, A., Fitzpatrick, D., Campbell, R., Wannamethee, S. G., Shaper, A., Friel, S., Kelleher, C., Kee, F., Atterson, C. C., Wilson, E. A., McConnell, J. M., Wheeler, S. M., Watson, J. D., Norashikin Rahman, N., Sheehan, J., Wall, C., Kelleher, B., O’Broin, S. D., Mullan, R. N., McKeveney, P. J., Hodges, V. M., Winter, P. C., Maxwell, P., Simpson, D. A., Lappin, T. R. J., Maxwell, A. P., Eustace, J. A., Coresh, J., Kutchey, C., Te, P. L., Gimenez, L. F., Scheel, P. J., Walser, M., McMahon, R. A., Clarkson, M., Martin, F., Brady, H. R., Blake, C., O’Meara, Y. M., Gupta, S., MacKenzie, H., Doyle, S., Fotheringham, T., Haslam, P., Logan, M. P., Conlon, P., Lee, M., Maderna, P., Cottell, D. C., Mitchell, S., Gulmann, C., Østerby, R., Bangstad, H. J., Rljdberg, S., Dempsey, M., Nathwani, S., Ryan, M. P., McMahon, B., Stenson, C., Murtagh, H., Brown, J. H., Doran, P., McGinty, A., Little, M. A., O’Brien, E., Owens, P., Holian, J., Mee, F., Walshe, J. J., Omer, S. A., Power, D., Diamond, P., Watson, R. W., Shahsafei, A., Jiang, T., Brenner, B. M., Mackenzie, H. S., Neary, J., Dorman, A., Keoghan, M., Campbell, E., Walshe, J., Little, M., Nee, L., O’Ceallaigh, C., McGlynn, H., Bergin, E., Garrett, P. J., Keane, T., Gormley, G., Watson, A., Atta, M. G., Perl, T. M., Song, X., Healy, E., Leonard, M., Lynch, J., Watson, A. J., Lappin, D., Lappin, D. W. P., Hannan, K., Burne, M., Daniels, F., Rabb, H., McBride, B., Kieran, N., Shortt, C., Codd, M., Murray, F., McCormack, A., Brown, C., Wong, C., Dorman, A. M., Keogan, M., Donohue, J., Farrell, J., Donohoe, J., O’Broin, S., Balfe, A., Mellotte, G. J., Abraham, K. A., McGorrian, C., Wood, A. E., Neligan, M., Kelly, B. D., Finnegan, P., Cormican, M., Callaghan, J., Crean, J. K. G., Moffitt, T. A., Devlin, H. L., Garrett, P. J., Soosay, A., O’Neill, D., Counihan, A., Hickey, D., Keogan, M. T., Harvey, K., O’Riordan, E., Waldek, S., Kalra, P. A., O’Donoghue, D. J., Foley, R. N., O’Riordan, A., Kelliher, D., Mellotte, G., Giblin, L., Keogh, J. A. B., O’Connell, M., O’Meara, A., Breatnach, F., Gillick, J., Tazawa, H., Puri, P., Molloy, E., O’Neill, A. J., Sheridan-Pereira, M., Fitzpatrick, J. M., Webb, D. W., Watson, R. W. G., Linnane, B., O’Donnell, C., Clarke, T. A., Martin, C., McKay, M., McBrien, J., Glynn, F., O’Donovan, C., Hall, W. W., Smith, J., Khair, K., Liesner, R., Hann, I. M., Smith, O. P., Gallagher, S., Mahony, M. J., Hilal, A., Cosgrove, J. F., Monaghan, C., Craig, B., Al-Hassan, A., Walsh, K., Duff, D., Slizlok, P. O., Halahakoon, C., MacPherson, C., McMillan, S., Dalzell, E. E., McCaughan, J., Redmond, A. O. B., DeCaluwe, D., Yoneda, A., Akl, U., Dempsey, E., Farrell, M., Webb, D., Elabbas, A., Fox, G., Gormally, S., Grant, B., Corkey, C. W. B., Nicholson, A., Murphy, A., O’Grady, P., Barry, O., Macpherson, C., Stewart, M. C., Alderdice, F., Matthews, T. G., McDonnell, M., McGarvey, C., O’Regan, M., Ní Chróinín, M., Tormey, P., Ennis, S., Green, A. J., Abbas, S., O’Marcaigh, A., Conran, M., Crushell, E., Saidi, A., Curran, P., Donoghue, V., King, M. D., Elnazir, B., Leonard, J., Kavanagh, C., Brown, D., Corrigan, N., McCord, B., Quinn, M., O’Connell, L., Mcdonagh, B., Awan, A., Gill, D., Kakkar, R., Sweet, D. G., Warner, J. A., O’Connor, C., Herzig, M., Twomey, A., White, M. J., Sweeney, B., Surana, R., Hodgson, A., Rafferty, M., Livingstone, W., Peake, D., Wassemer, E., Whitehouse, W., Abdullah, N., Al-Hassan, A., Oslizlok, P., O’Connell, N., Balding, J., Livingstone, W. J., Healy, M., Mynett-Johnson, L., McAllister, I., Dick, A. C., Herron, B., Boston, V. E., Callaghan, C. O., Brien, D. O., Walsh, A., Philip, M., McShane, D., Hoey, M. C. V., Sharif, F., McDermott, M., Dillon, M., Drumm, B., Rowland, M., Imrie, C., Kelleher, S., Bourke, B., Iqbal, M., Ziedan, Y., O’Neill, M., O’Riordan, S., Basheer, S. M. B., O’Callaghan, S., Chong, A., Kelly, M., Nicholson, A. J., Cooke, R., Sreenan, C., Fallon, M., Denham, B., Dowding, V., Cussen, G., McManus, V., Hensey, O., Monaghan, H., Basheer, S. N., Quinn, E., Hoey, H. M. C. V., Mohamed, S., Ramesh, R. R., Mayne, P., Tracy, E., Gormally, S. M., Curtis, E., McCallion, N., Watson, R., O’Mahony, O., Keegan, M., Ward, K., Barton, D., Poulton, J., Treacy, E., Honour, J., deCaluwe, D., Ni Chróinín, M., Cosgrove, J., Chaudhry, T. S., Long, N. M., Lynch, B., Lasjaunais, P., McDonald, D. G. M., McMenamin, J. B., Farrell, M. J., Roche, E. F., Menon, A., Buckley, C., Mackey, A., Ohlandieck, K., Das, A., Reilly, D., Killeen, O., Harper, J., Roche, E., Hoey, H., Caird, J., O’Brien, D., Allcutt, D., Farrington, N., Murphy, J. F. A., Savage, J. M., Sands, A. J., Casey, F. A., Craig, B. G., Dornan, J. C., Johnston, J., Patterson, C., Lynch, C., Mulholland, H. C., Watkins, D. C., Young, I., Cran, G., Boreham, C. A. G., McCallion, W. A., Clements, N. F., Stevenson, M. R., Macpherson, C., O’Donoghue, D., Jenkins, L., Thompson, A. J., Shields, M. D., Taylor, R. T., Kerr, R., Hughes, J. L., Stewart, M., Jackson, P., Fitzpatrick, C., Rasheed, M., Colhoun, E., Bailie, A. G., Gray, S., Brown, S., Curley, A., Sweet, D. G., MacMahon, K. J., O’Connor, C. M., Nichelson, A., Lynch, N. E., Finch, D., Foley, M., Scallan, E., Dillon, B., Lyons, S., O’Loughlin, R., Ward, M., Nally, R., Harkin, A., Kelly, J. P., Leonard, B. E., Nic Niocaill, B., Magee, P., Connor, T. J., Shen, Y., McCullough, G. R., McDonough, S. M., Nic Niocaill, B., Cramp, A. F. L., Hynes, M., Corkery, P., Carey, M., McGarrigle, D., Higgins, S., Murray, H., Moran, C. J., Dennedy, M. C., Brosnan, J., Morris, L., Sheppard, B. L., Black, A., Wilkins, B., Folan-Curran, J., Skelton, K., Owens, M., Nemeroff, C., Houlihan, D., O’Keeffe, C., Nolan, N., McCormick, P. A., Baird, A. W., Raducan, I., Corcoran, P., Brennan, R., Molloy, P., Friel, A., Maher, M., Glennon, M., Smith, T., Nolan, A., Houghton, J. A., Carroll, O., Colleran, S., O’Cuinn, G., Snow, H. M., O’Regan, D., Markos, H. F., Pollock, K., Cannon, D. M., McBean, G., O’Riordan, A., Quinlan, L. R., Kane, M. T., Higglns, B. D., Moriarty, D. M., Fitzgerald, D., Katkada, A., Canny, G., MacMathuna, P., O’Donoghue, D., O’Donovan, M. M., Schuur, A. G., Murphy, K. J., Foley, A. G., ten Bruggencate, S. J. M., and Ireland, L.
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34. Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) in the Irish Population
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Dominguez, M., primary, Crushell, E., additional, Ilmarinen, T., additional, McGovern, E., additional, Collins, S., additional, Chang, B., additional, Fleming, P., additional, Irvine, A.D., additional, Brosnahan, D., additional, Ulmanen, I., additional, Murphy, N., additional, and Costigan, C., additional
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- 2006
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35. A Prospective Study of the Oral Manifestations of Crohn’s Disease
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HARTY, S, primary, FLEMING, P, additional, ROWLAND, M, additional, CRUSHELL, E, additional, MCDERMOTT, M, additional, DRUMM, B, additional, and BOURKE, B, additional
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- 2005
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36. 'Malignant Phenylketonuria' (PKU) Due to Dihydropteridine Reductase (DHPR) Deficiency.
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Ventzke, A, Hoffmann, J, Crushell, E, Monavari, A, Mayne, P D, and Knerr, I
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- 2015
37. The Addition of MCADD to the Newborn Blood Spot Screening Programme.
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Ryan, H., Crushell, E., and Boyle, M. A.
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- 2019
38. Parental experience of enzyme replacement therapy for Hunter syndrome.
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Buraczewska, M, O'Leary, D, Walsh, O, Monavari, A, and Crushell, E
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- 2013
39. Management of maple syrup urine disease in the peri-operative period.
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McCarron, E, McCormack, O, Cronin, T, McGowan, A, Healy, M L, O'Rourke, D, Crushell, E, Ravi, N, and Reynolds, J V
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- 2013
40. A prospective study of referrals from the Irish Traveller community to the National Centre for Inherited Metabolic Disorders.
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Murphy, A. M., Halling, C., Lynch, S. A., Monavari, A. A., Harty, S., Crushell, E., and Treacy, E. P.
- Abstract
Irish Travellers are a nomadic people in whom early marriage, frequent child bearing and consanguinity are cultural norms. They number 22,445, <0.5% of the Irish population, 9.6% of the 1465 patients listed at NCIMD on January 1st 2007 were Travellers. To date 21 different inherited metabolic disorders (IMDs) are reported. Our aim was to prospectively survey all referrals from this community .The study is part of a larger ongoing project to compile a database of "Irish Traveller" genetic disorders to ensure appropriate planning of services and provision of care. All referrals between January 1st and June 30th 2007 were reviewed, those with a Traveller background identified and the following information sought; source, reason & age of referral, diagnosis & outcome. Twenty eight (age range 1 day-16 yrs) of the 84 (33%) patients referred were Travellers. 15 new diagnoses of IMDs were established; of which 3 were genetic disorders not previously noted in this population (MSUD, X linked ALD and Hyperinsulinism). Six patients were diagnosed because of a family member with an IMD. Eight are under investigation for suspected metabolic disorder (mitochondrial). The remaining five are thought to have an undiagnosed autosomal recessive disorder because of the presence of multiple affected siblings. Apart from the patient with mucolipidosis, appropriate treatment was commenced once diagnosis was established with a good outcome to date. This study highlights the huge disease burden imposed by the increased frequency of genetic disorders in consanguinous communities and provides useful epidemiological information for service planning for patients with IMDs with particular reference to the Irish Traveller community [ABSTRACT FROM AUTHOR]
- Published
- 2008
41. MRI in LARS1 deficiency-Spectrum, patterns, and correlation with acute neurological deterioration.
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Hammann N, Lenz D, Bianzano A, Husain RA, Forman E, Bernstein JA, Dattner T, Engelen M, Hanson-Kahn AK, Isidor B, Kotzaeridou U, Tietze A, Trollmann R, Weiß C, Wolffenbuttel BHR, Kölker S, Hoffmann GF, Crushell E, Staufner C, Mohr A, and Harting I
- Abstract
Leucine aminoacyl tRNA-synthetase 1 (LARS1)-deficiency (infantile liver failure syndrome type 1 (ILFS1)) has a multisystemic phenotype including fever-associated acute liver failure (ALF), chronic neurologic abnormalities, and encephalopathic episodes. In order to better characterize encephalopathic episodes and MRI changes, 35 cranial MRIs from 13 individuals with LARS1 deficiency were systematically assessed and neurological phenotype was analyzed. All individuals had developmental delay and 10/13 had seizures. Encephalopathic episodes in 8/13 were typically associated with infections, presented with seizures and reduced consciousness, mostly accompanied by hepatic dysfunction, and recovery in 17/19 episodes. Encephalopathy without hepatic dysfunction occurred in one individual after liver transplantation. On MRI, 5/7 individuals with MRI during acute encephalopathy had deep gray matter and brainstem changes. Supratentorial cortex involvement (6/13) and cerebellar watershed injury (4/13) occurred with seizures and/or encephalopathy. Abnormal brainstem contour on sagittal images (8/13), atrophy (8/13), and myelination delay (8/13) were not clearly associated with encephalopathy. The pattern of deep gray matter and brainstem changes are apparently characteristic of encephalopathy in LARS1-deficiency, differing from patterns of hepatic encephalopathy or metabolic stroke in organic acidurias and mitochondrial diseases. While the pathomechanism remains unclear, fever and energy deficit during infections might be causative; thus, sufficient glucose and protein intake along with pro-active fever management is suggested. As severe episodes were observed during influenza infections, we strongly recommend seasonal vaccination., (© 2024 SSIEM.)
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- 2024
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42. Empagliflozin for treating neutropenia and neutrophil dysfunction in 21 infants with glycogen storage disease 1b.
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Grünert SC, Gautschi M, Baker J, Boyer M, Burlina A, Casswall T, Corpeleijn W, Çıki K, Cotter M, Crushell E, Derks TGJ, Haas D, Kilavuz S, Kingma SDK, Korman SH, Kozek A, de Laet C, Mundy H, Nassogne MC, Quintero V, Rossi A, Spenger J, Spiegel R, Stephenne X, Stojkov D, Tal G, Veiga-da Cunha M, and Wortmann SB
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- Humans, Male, Female, Infant, Retrospective Studies, Sodium-Glucose Transporter 2 Inhibitors therapeutic use, Treatment Outcome, Granulocyte Colony-Stimulating Factor therapeutic use, Glycogen Storage Disease Type I drug therapy, Glycogen Storage Disease Type I complications, Neutropenia drug therapy, Benzhydryl Compounds therapeutic use, Benzhydryl Compounds administration & dosage, Neutrophils drug effects, Glucosides therapeutic use, Glucosides pharmacology, Glucosides administration & dosage
- Abstract
Empagliflozin has been successfully repurposed for treating neutropenia and neutrophil dysfunction in patients with glycogen storage disease type 1b (GSD 1b), however, data in infants are missing. We report on efficacy and safety of empagliflozin in infants with GSD 1b. This is an international retrospective case series on 21 GSD 1b infants treated with empagliflozin (total treatment time 20.6 years). Before starting empagliflozin (at a median age of 8.1 months with a median dose of 0.3 mg/kg/day) 12 patients had clinical signs and symptoms of neutrophil dysfunction. Six of these previously symptomatic patients had no further neutropenia/neutrophil dysfunction-associated findings on empagliflozin. Eight patients had no signs and symptoms of neutropenia/neutrophil dysfunction before start and during empagliflozin treatment. One previously asymptomatic individual with a horseshoe kidney developed a central line infection with pyelonephritis and urosepsis during empagliflozin treatment. Of the 10 patients who were treated with G-CSF before starting empagliflozin, this was stopped in four and decreased in another four. Eleven individuals were never treated with G-CSF. While in 17 patients glucose homeostasis remained stable on empagliflozin, four showed glucose homeostasis instability in the introductory phase. In 17 patients, no other side effects were reported, while genital (n = 2) or oral (n = 1) candidiasis and skin infection (n = 1) were reported in the remaining four. Empagliflozin had a good effect on neutropenia/neutrophil dysfunction-related signs and symptoms and a favourable safety profile in infants with GSD 1b and therefore qualifies for further exploration as first line treatment., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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43. Genetic landscape of pediatric acute liver failure of indeterminate origin.
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Lenz D, Schlieben LD, Shimura M, Bianzano A, Smirnov D, Kopajtich R, Berutti R, Adam R, Aldrian D, Baric I, Baumann U, Bozbulut NE, Brugger M, Brunet T, Bufler P, Burnytė B, Calvo PL, Crushell E, Dalgiç B, Das AM, Dezsőfi A, Distelmaier F, Fichtner A, Freisinger P, Garbade SF, Gaspar H, Goujon L, Hadzic N, Hartleif S, Hegen B, Hempel M, Henning S, Hoerning A, Houwen R, Hughes J, Iorio R, Iwanicka-Pronicka K, Jankofsky M, Junge N, Kanavaki I, Kansu A, Kaspar S, Kathemann S, Kelly D, Kirsaçlioğlu CT, Knoppke B, Kohl M, Kölbel H, Kölker S, Konstantopoulou V, Krylova T, Kuloğlu Z, Kuster A, Laass MW, Lainka E, Lurz E, Mandel H, Mayerhanser K, Mayr JA, McKiernan P, McClean P, McLin V, Mention K, Müller H, Pasquier L, Pavlov M, Pechatnikova N, Peters B, Petković Ramadža D, Piekutowska-Abramczuk D, Pilic D, Rajwal S, Rock N, Roetig A, Santer R, Schenk W, Semenova N, Sokollik C, Sturm E, Taylor RW, Tschiedel E, Urbonas V, Urreizti R, Vermehren J, Vockley J, Vogel GF, Wagner M, van der Woerd W, Wortmann SB, Zakharova E, Hoffmann GF, Meitinger T, Murayama K, Staufner C, and Prokisch H
- Subjects
- Child, Humans, Neoplasm Recurrence, Local, Biomarkers, Europe, Liver Failure, Acute diagnosis, Liver Transplantation adverse effects
- Abstract
Background and Aims: Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, the main causes are viral infections (12%-16%) and inherited metabolic diseases (14%-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition., Approach and Results: With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed., Results: In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF. WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (41%), and in children with recurrent acute liver failure (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8), and DGUOK (n=7) were the most frequent findings. When categorizing, the most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%), and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplantation., Conclusions: This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2024
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44. Impact of genetic and non-genetic factors on phenotypic diversity in NBAS-associated disease.
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Hammann N, Lenz D, Baric I, Crushell E, Vici CD, Distelmaier F, Feillet F, Freisinger P, Hempel M, Khoreva AL, Laass MW, Lacassie Y, Lainka E, Larson-Nath C, Li Z, Lipiński P, Lurz E, Mégarbané A, Nobre S, Olivieri G, Peters B, Prontera P, Schlieben LD, Seroogy CM, Sobacchi C, Suzuki S, Tran C, Vockley J, Wang JS, Wagner M, Prokisch H, Garbade SF, Kölker S, Hoffmann GF, and Staufner C
- Subjects
- Humans, Phenotype, Mutation, Missense, Pelger-Huet Anomaly complications, Pelger-Huet Anomaly genetics, Pelger-Huet Anomaly pathology, Liver Failure, Acute genetics, Neuroblastoma complications
- Abstract
Biallelic pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause a pleiotropic multisystem disorder. Three clinical subgroups have been defined correlating with the localisation of pathogenic variants in the NBAS gene: variants affecting the C-terminal region of NBAS result in SOPH syndrome (short stature, optic atrophy, Pelger-Huët anomaly), variants affecting the Sec 39 domain are associated with infantile liver failure syndrome type 2 (ILFS2) and variants affecting the ß-propeller domain give rise to a combined phenotype. However, there is still unexplained phenotypic diversity across the three subgroups, challenging the current concept of genotype-phenotype correlations in NBAS-associated disease. Therefore, besides examining the genetic influence, we aim to elucidate the potential impact of pre-symptomatic diagnosis, emergency management and other modifying variables on the clinical phenotype. We investigated genotype-phenotype correlations in individuals sharing the same genotypes (n = 30 individuals), and in those sharing the same missense variants with a loss-of-function variant in trans (n = 38 individuals). Effects of a pre-symptomatic diagnosis and emergency management on the severity of acute liver failure (ALF) episodes also were analysed, comparing liver function tests (ALAT, ASAT, INR) and mortality. A strong genotype-phenotype correlation was demonstrated in individuals sharing the same genotype; this was especially true for the ILFS2 subgroup. Genotype-phenotype correlation in patients sharing only one missense variant was still high, though at a lower level. Pre-symptomatic diagnosis in combination with an emergency management protocol leads to a trend of reduced severity of ALF. High genetic impact on clinical phenotype in NBAS-associated disease facilitates monitoring and management of affected patients sharing the same genotype. Pre-symptomatic diagnosis and an emergency management protocol do not prevent ALF but may reduce its clinical severity., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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45. Clinical and biochemical footprints of inherited metabolic disease. XVI. Hematological abnormalities.
- Author
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Dunlea E, Crushell E, Cotter M, Blau N, and Ferreira CR
- Subjects
- Humans, Metabolic Diseases genetics, Anemia
- Abstract
Many classical inherited metabolic diseases (IMDs) are associated with significant hematological complications such as anemia or thrombosis. While these may not be the prominent presenting feature of these conditions, management of these issues is important for optimal outcomes in people with IMDs. Some disorders that are included in the nosology of inherited metabolic disorders, such as inherited disorders of red cell energy metabolism, have purely hematological features, and have typically been cared for by a hematologist. In the 16th issue of the Footprints series, we identified 265 IMDs associated with hematological abnormalities. We review the major hematological manifestations of IMDs, suggest further investigation of hematological findings, and discuss treatment options available for specific hematological complications of IMDs., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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46. Nonsense mutation in the novel PERCC1 gene as a genetic cause of congenital diarrhea and enteropathy.
- Author
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Marek-Yagel D, Stenke E, Pode-Shakked B, Dunne C, Crushell E, Bryce-Smith A, McDermott M, O'Sullivan MJ, Veber A, Krishnamurthy M, Wells JM, Anikster Y, and Bourke B
- Subjects
- Adolescent, Adult, Child, Humans, Male, Young Adult, Diarrhea genetics, Mutation, Phenotype, Codon, Nonsense, Gastrins genetics
- Abstract
Congenital diarrheas and enteropathies (CODEs) constitute a heterogeneous group of individually rare disorders manifesting with infantile-onset chronic diarrhea. Genomic deletions in chromosome 16, encompassing a sequence termed the 'intestine-critical region (ICR)', were recently identified as the cause of an autosomal recessive congenital enteropathy. The regulatory sequence within the ICR is flanked by an unannotated open reading frame termed PERCC1, which plays a role in enteroendocrine cell (EEC) function. We investigated two unrelated children with idiopathic congenital diarrhea requiring home parenteral nutrition attending the Irish Intestinal Failure Program. Currently 12 and 19-years old, these Irish male patients presented with watery diarrhea and hypernatremic dehydration in infancy. Probands were phenotyped by comprehensive clinical investigations, including endoscopic biopsies and serum gastrin level measurements. Following negative exome sequencing, PCR and Sanger sequencing of the entire coding region and intron boundaries of PERCC1 were performed for each proband and their parents. In both patients, serum gastrin levels were low and failed to increase following a meal challenge. While no deletions involving the ICR were detected, targeted sequencing of the PERCC1 gene revealed a shared homozygous c.390C > G stop gain variant. We report clinical and molecular findings in two unrelated patients harboring a shared homozygous variant in PERCC1, comprising the first description of a point mutation in this gene in association with CODE. That both parenteral nutrition dependent children with unexplained diarrhea at our institution harbored a PERCC1 mutation underscores the importance of its inclusion in exome sequencing interpretation., (© 2022. The Author(s).)
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- 2023
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47. Medium Chain Acyl-CoA Dehydrogenase Deficiency: 3 years of Newborn Screening.
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Howard C, Gorman I, Crushell E, Knerr I, Hughes J, Boruah R, O'Grady L, Elsammak MY, Brady JJ, and Monavari AA
- Subjects
- Infant, Newborn, Humans, Acyl-CoA Dehydrogenase, Neonatal Screening, Lipid Metabolism, Inborn Errors diagnosis
- Abstract
Competing Interests: None declared
- Published
- 2023
48. Trainee Knowledge and Perceptions of Less Than Full Time Training.
- Author
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Howard C, Golden M, Gavin P, and Crushell E
- Subjects
- Child, Female, Humans, Ireland, Knowledge, Male, Surveys and Questionnaires, Education, Medical, Graduate, Employment
- Abstract
Background Less than full-time (LTFT) training in Ireland is still unusual. Our aim was to identify perceived barriers to LTFT training amongst paediatric trainees and make recommendations to improve knowledge, uptake, and experience of LTFT training. Methods An email questionnaire was disseminated to RCPI paediatric trainees to assess current awareness of and perceptions of barriers to LTFT training. Results 218 questionnaires were distributed, 59 (29%) responded of whom 50 (85%) were female. 17 planned to apply for LTFT training. Seven had no knowledge of LTFT training. The perceived barriers with the highest rankings (% respondents deeming highest possible relevance) were: LTFT post availability (49%), potential impact on career progression (51%), and availability of only 0.5 whole time equivalency (WTE) - i.e. 19.5 hours/week (54%). Trainees noted lack of flexibility, including availability of the scheme only from July to July, restriction to maximum 2 years. Trainees felt applications would be rejected if they were not a parent. Some reported perceptions from teams that LTFT trainees are less committed and that trainees can find it difficult to integrate. Discussion Training options including >0.5WTE posts should be made available to all trainees, and a cultural shift within training bodies and with trainers should be encouraged to recognise LTFT training as an acceptable pathway for all trainees., Competing Interests: The authors have no conflicts of interest to declare.
- Published
- 2022
49. Parental Perceptions Regarding the Impact of Housing on Child Health.
- Author
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O' Brien N, Quinn N, Joyce B, Hayes AM, Bedford H, and Crushell E
- Subjects
- Humans, Child, Child Health, Cross-Sectional Studies, Parents psychology, Housing, Ill-Housed Persons
- Abstract
Introduction Childhood poverty has life-long adverse impacts. We aimed to assess perceptions of parents of a cohort of children attending a paediatric emergency department regarding the impact of their housing on their child and family Methods From 01/11/2020 - 08/01/2021 a cross-sectional study was performed in a paediatric emergency department in Dublin Results Of 312 parents who completed a questionnaire, 4.5% (n = 14) reported themselves to be homeless. Homeless children were less likely to be registered with general practitioners (78.6% vs. 97.5%, p = .009) or be fully vaccinated (71.4% vs. 92.4%, p = .024). Homeless parents were more likely to feel unsafe at home (35.7% vs. 3.4%, p <.001), and to report that their housing negatively impacted their child's education (58.3% vs 10.7%, p <.001), physical health (45.5% vs 11.7, p = .007), and mental health (61.5% vs 12.6%, p <.001). Ten percent of non-homeless parents were concerned about losing their home. A lack of landlord permission to install child safety measures in the home was reported by 28% of all parents. Conclusion Homeless parents were more likely to report that their living situation negatively impacted their child's play, development, education, safety, and health., Competing Interests: The authors have no conflicts of interest to declare.
- Published
- 2022
50. Glutaric aciduria type 1: Diagnosis, clinical features and long-term outcome in a large cohort of 34 Irish patients.
- Author
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Healy L, O'Shea M, McNulty J, King G, Twomey E, Treacy E, Crushell E, Hughes J, Knerr I, and Monavari AA
- Abstract
Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder that can lead to encephalopathic crises and severe dystonic movement disorders. Adherence to strict dietary restriction, in particular a diet low in lysine, carnitine supplementation and emergency treatment in pre-symptomatic patients diagnosed by high-risk screen (HRS) or newborn screen (NBS) leads to a favourable outcome. We present biochemical and clinical characteristics and long-term outcome data of 34 Irish patients with GA1 aged 1-40 years. Sixteen patients were diagnosed clinically, and 17 patients by HRS, prior to introduction of NBS for GA1 in the Republic of Ireland in 2018. One patient was diagnosed by NBS. Clinical diagnosis was at a median of 1 year (range 1 month to 8 years) and by HRS was at a median of 4 days (range 3 days to 11 years). 14/18 (77.8%) diagnosed by HRS or NBS had neither clinical manifestations nor radiological features of GA1, or had radiological features only, compared to 0/16 (0%) diagnosed clinically ( p < 0.001). Patients diagnosed clinically who survived to school-age were more likely to have significant cerebral palsy and dystonia (7/11; 63.6% vs. 0/13; 0%, p < 0.001). They were less likely to be in mainstream school versus the HRS group (5/10; 50% vs. 12/13; 92.3%; p = 0.012). Clinical events occurring after 6 years of age were unusual, but included spastic diplegia, thalamic haemorrhage, Chiari malformation, pituitary hormone deficiency and epilepsy. The exact aetiology of these events is unclear., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)
- Published
- 2022
- Full Text
- View/download PDF
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