22 results on '"Lianna Kyriakopoulou"'
Search Results
2. Gene mutations as a non-invasive measure of adult cochlear implant performance: Variable outcomes in patients with select TMPRSS3 mutations.
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Justin Cottrell, Peter Dixon, Xingshan Cao, Alex Kiss, Kari Smilsky, Kassandra Kaminskas, Amy Ng, David Shipp, Andrew Dimitrijevic, Joseph Chen, Vincent Lin, Lianna Kyriakopoulou, and Trung Le
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Medicine ,Science - Abstract
BackgroundThe cochlear implant (CI) has proven to be a successful treatment for patients with severe-to-profound sensorineural hearing loss, however outcome variance exists. We sought to evaluate particular mutations discovered in previously established sensory and neural partition genes and compare post-operative CI outcomes.Materials and methodsUtilizing a prospective cohort study design, blood samples collected from adult patients with non-syndromic hearing loss undergoing CI were tested for 54 genes of interest with high-throughput sequencing. Patients were categorized as having a pathogenic variant in the sensory partition, pathogenic variant in the neural partition, pathogenic variant in both sensory and neural partition, or with no variant identified. Speech perception performance was assessed pre- and 12 months post-operatively. Performance measures were compared to genetic mutation and variant status utilizing a Wilcoxon rank sum test, with PResultsThirty-six cochlear implant patients underwent genetic testing and speech understanding measurements. Of the 54 genes that were interrogated, three patients (8.3%) demonstrated a pathogenic mutation in the neural partition (within TMPRSS3 genes), one patient (2.8%) demonstrated a pathogenic mutation in the sensory partition (within the POU4F3 genes). In addition, 3 patients (8.3%) had an isolated neural partition variance of unknown significance (VUS), 5 patients (13.9%) had an isolated sensory partition VUS, 1 patient (2.8%) had a variant in both neural and sensory partition, and 23 patients (63.9%) had no mutation or variant identified. There was no statistically significant difference in speech perception scores between patients with sensory or neural partition pathogenic mutations or VUS. Variable performance was found within patients with TMPRSS3 gene mutations.ConclusionThe impact of genetic mutations on post-operative outcomes in CI patients was heterogenous. Future research and dissemination of mutations and subsequent CI performance is warranted to elucidate exact mutations within target genes providing the best non-invasive prognostic capability.
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- 2023
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3. High diagnostic yield of direct Sanger sequencing in the diagnosis of neuronal ceroid lipofuscinoses
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Abdulhakim Jilani, Diana Matviychuk, Susan Blaser, Sarah Dyack, Jean Mathieu, Asuri N. Prasad, Chitra Prasad, Lianna Kyriakopoulou, and Saadet Mercimek‐Andrews
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CLN genes ,developmental regression ,epilepsy ,neuronal ceroid lipofuscinoses ,visual loss ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 ,Genetics ,QH426-470 - Abstract
Abstract Background Neuronal ceroid lipofuscinoses are neurodegenerative disorders. To investigate the diagnostic yield of direct Sanger sequencing of the CLN genes, we reviewed Molecular Genetics Laboratory Database for molecular genetic test results of the CLN genes from a single clinical molecular diagnostic laboratory. Methods We reviewed electronic patient charts. We used consent forms and Research Electronic Data Capture questionnaires for the patients from outside of our Institution. We reclassified all variants in the CLN genes. Results Six hundred and ninety three individuals underwent the direct Sanger sequencing of the CLN genes for the diagnosis of neuronal ceroid lipofuscinoses. There were 343 symptomatic patients and 350 family members. Ninety‐one symptomatic patients had molecular genetic diagnosis of neuronal ceroid lipofuscinoses including CLN1 (PPT1) (n = 10), CLN2 (TPP1) (n = 33), CLN3 (n = 17), CLN5 (n = 7), CLN6 (n = 10), CLN7 (MFSD8) (n = 10), and CLN8 (n = 4) diseases. The diagnostic yield of direct Sanger sequencing of CLN genes was 27% in symptomatic patients. We report detailed clinical and investigation results of 33 NCL patients. Juvenile onset CLN1 (PPT1) and adult onset CLN6 diseases were nonclassical phenotypes. Conclusion In our study, the diagnostic yield of direct Sanger sequencing was close to diagnostic yield of whole exome sequencing. Developmental regression, cognitive decline, visual impairment and cerebral and/or cerebellar atrophy in brain MRI are significant clinical and neuroimaging denominators to include NCL in the differential diagnosis.
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- 2019
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- View/download PDF
4. Lysine-restricted diet and mild cerebral serotonin deficiency in a patient with pyridoxine-dependent epilepsy caused by ALDH7A1 genetic defect
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Saadet Mercimek-Mahmutoglu, Dawn Corderio, Laura Nagy, Carly Mutch, Melissa Carter, Eduard Struys, and Lianna Kyriakopoulou
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Pyridoxine dependent epilepsy ,Lysine restricted diet ,Alpha-amino adipic acid semialdehyde dehydrogenase deficiency ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Pyridoxine dependent epilepsy (PDE) is caused by mutations in the ALDH7A1 gene (PDE-ALDH7A1) encoding α-aminoadipic-semialdehyde-dehydrogenase enzyme in the lysine catabolic pathway resulting in an accumulation of α-aminoadipic-acid-semialdehyde (α-AASA). We present the one-year treatment outcome of a patient on a lysine-restricted diet. Serial cerebral-spinal-fluid (CSF) α-AASA and CSF pipecolic-acid levels showed decreased levels but did not normalize. He had a normal neurodevelopmental outcome on a lysine-restricted diet. Despite normal CSF and plasma tryptophan levels and normal tryptophan intake, he developed mild CSF serotonin deficiency at one year of therapy. Stricter lysine restriction would be necessary to normalize CSF α-AASA levels, but might increase the risks associated with the diet. Patients are at risk of cerebral serotonin deficiency and should be monitored by CSF neurotransmitter measurements.
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- 2014
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5. Strategies to rescue the consequences of inducible arginase-1 deficiency in mice.
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Laurel L Ballantyne, Yuan Yan Sin, Tim St Amand, Joshua Si, Steven Goossens, Lieven Haenebalcke, Jody J Haigh, Lianna Kyriakopoulou, Andreas Schulze, and Colin D Funk
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Medicine ,Science - Abstract
Arginase-1 catalyzes the conversion of arginine to ornithine and urea, which is the final step of the urea cycle used to remove excess ammonia from the body. Arginase-1 deficiency leads to hyperargininemia in mice and man with severe lethal consequences in the former and progressive neurological impairment to varying degrees in the latter. In a tamoxifen-induced arginase-1 deficient mouse model, mice succumb to the enzyme deficiency within 2 weeks after inducing the knockout and retain
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- 2015
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6. Inducible arginase 1 deficiency in mice leads to hyperargininemia and altered amino acid metabolism.
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Yuan Yan Sin, Laurel L Ballantyne, Kamalika Mukherjee, Tim St Amand, Lianna Kyriakopoulou, Andreas Schulze, and Colin D Funk
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Medicine ,Science - Abstract
Arginase deficiency is a rare autosomal recessive disorder resulting from a loss of the liver arginase isoform, arginase 1 (ARG1), which is the final step in the urea cycle for detoxifying ammonia. ARG1 deficiency leads to hyperargininemia, characterized by progressive neurological impairment, persistent growth retardation and infrequent episodes of hyperammonemia. Using the Cre/loxP-directed conditional gene knockout system, we generated an inducible Arg1-deficient mouse model by crossing "floxed" Arg1 mice with CreER(T2) mice. The resulting mice (Arg-Cre) die about two weeks after tamoxifen administration regardless of the starting age of inducing the knockout. These treated mice were nearly devoid of Arg1 mRNA, protein and liver arginase activity, and exhibited symptoms of hyperammonemia. Plasma amino acid analysis revealed pronounced hyperargininemia and significant alterations in amino acid and guanidino compound metabolism, including increased citrulline and guanidinoacetic acid. Despite no alteration in ornithine levels, concentrations of other amino acids such as proline and the branched-chain amino acids were reduced. In summary, we have generated and characterized an inducible Arg1-deficient mouse model exhibiting several pathologic manifestations of hyperargininemia. This model should prove useful for exploring potential treatment options of ARG1 deficiency.
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- 2013
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7. Trio RNA sequencing in a cohort of medically complex children
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Ashish R. Deshwar, Kyoko E. Yuki, Huayun Hou, Yijing Liang, Tayyaba Khan, Alper Celik, Arun Ramani, Roberto Mendoza-Londono, Christian R. Marshall, Michael Brudno, Adam Shlien, M. Stephen Meyn, Robin Z. Hayeems, Brandon J. McKinlay, Panagiota Klentrou, Michael D. Wilson, Lianna Kyriakopoulou, Gregory Costain, and James J. Dowling
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Genetics ,Genetics (clinical) - Published
- 2023
8. The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations
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Anita Villani, Scott Davidson, Nisha Kanwar, Winnie W. Lo, Yisu Li, Sarah Cohen-Gogo, Fabio Fuligni, Lisa-Monique Edward, Nicholas Light, Mehdi Layeghifard, Ricardo Harripaul, Larissa Waldman, Bailey Gallinger, Federico Comitani, Ledia Brunga, Reid Hayes, Nathaniel D. Anderson, Arun K. Ramani, Kyoko E. Yuki, Sasha Blay, Brittney Johnstone, Cara Inglese, Rawan Hammad, Catherine Goudie, Andrew Shuen, Jonathan D. Wasserman, Rosemarie E. Venier, Marianne Eliou, Miranda Lorenti, Carol Ann Ryan, Michael Braga, Meagan Gloven-Brown, Jianan Han, Maria Montero, Famida Spatare, James A. Whitlock, Stephen W. Scherer, Kathy Chun, Martin J. Somerville, Cynthia Hawkins, Mohamed Abdelhaleem, Vijay Ramaswamy, Gino R. Somers, Lianna Kyriakopoulou, Johann Hitzler, Mary Shago, Daniel A. Morgenstern, Uri Tabori, Stephen Meyn, Meredith S. Irwin, David Malkin, and Adam Shlien
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Cancer Research ,Oncology - Abstract
We conducted integrative somatic–germline analyses by deeply sequencing 864 cancer-associated genes, complete genomes and transcriptomes for 300 mostly previously treated children and adolescents/young adults with cancer of poor prognosis or with rare tumors enrolled in the SickKids Cancer Sequencing (KiCS) program. Clinically actionable variants were identified in 56% of patients. Improved diagnostic accuracy led to modified management in a subset. Therapeutically targetable variants (54% of patients) were of unanticipated timing and type, with over 20% derived from the germline. Corroborating mutational signatures (SBS3/BRCAness) in patients with germline homologous recombination defects demonstrates the potential utility of PARP inhibitors. Mutational burden was significantly elevated in 9% of patients. Sequential sampling identified changes in therapeutically targetable drivers in over one-third of patients, suggesting benefit from rebiopsy for genomic analysis at the time of relapse. Comprehensive cancer genomic profiling is useful at multiple points in the care trajectory for children and adolescents/young adults with cancer, supporting its integration into early clinical management.
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- 2022
9. The CF Canada-Sick Kids Program in individual CF therapy: A resource for the advancement of personalized medicine in CF
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Gengming He, Ling Jun Huan, Karen Ho, Leigh Wellhauser, Julie Avolio, Janet Rossant, Sanja Stanojevic, Lianna Kyriakopoulou, Felix Ratjen, Kai Du, Michelle Klingel, Christine E. Bear, Theo J. Moraes, Tanja Gonska, Claire Bartlett, Hong Ouyang, Jia Xin Jiang, Lisa J. Strug, Paul D. W. Eckford, Amy P. Wong, Jacqueline McCormack, Jin Ye Yang, Sergio L. Pereira, and Lise Munsie
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Whole genome sequencing ,Mutation ,business.industry ,medicine.disease_cause ,medicine.disease ,Precision medicine ,Bioinformatics ,Cystic fibrosis ,03 medical and health sciences ,Drug-naïve ,030104 developmental biology ,0302 clinical medicine ,030228 respiratory system ,Pediatrics, Perinatology and Child Health ,medicine ,Missense mutation ,Personalized medicine ,business ,Induced pluripotent stem cell ,medicine.drug - Abstract
Background Therapies targeting certain CFTR mutants have been approved, yet variations in clinical response highlight the need for in-vitro and genetic tools that predict patient-specific clinical outcomes. Toward this goal, the CF Canada-Sick Kids Program in Individual CF Therapy (CFIT) is generating a "first of its kind", comprehensive resource containing patient-specific cell cultures and data from 100 CF individuals that will enable modeling of therapeutic responses. Methods The CFIT program is generating: 1) nasal cells from drug naive patients suitable for culture and the study of drug responses in vitro , 2) matched gene expression data obtained by sequencing the RNA from the primary nasal tissue, 3) whole genome sequencing of blood derived DNA from each of the 100 participants, 4) induced pluripotent stem cells (iPSCs) generated from each participant's blood sample, 5) CRISPR-edited isogenic control iPSC lines and 6) prospective clinical data from patients treated with CF modulators. Results To date, we have recruited 57 of 100 individuals to CFIT, most of whom are homozygous for F508del (to assess in-vitro: in-vivo correlations with respect to ORKAMBI response) or heterozygous for F508del and a minimal function mutation. In addition, several donors are homozygous for rare nonsense and missense mutations. Nasal epithelial cell cultures and matched iPSC lines are available for many of these donors. Conclusions This accessible resource will enable development of tools that predict individual outcomes to current and emerging modulators targeting F508del-CFTR and facilitate therapy discovery for rare CF causing mutations.
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- 2019
10. High diagnostic yield of direct Sanger sequencing in the diagnosis of neuronal ceroid lipofuscinoses
- Author
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Susan Blaser, Lianna Kyriakopoulou, Saadet Mercimek-Andrews, Chitra Prasad, Sarah Dyack, Diana Matviychuk, Abdulhakim Jilani, Jean Mathieu, and Asuri N. Prasad
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Research Report ,medicine.medical_specialty ,lcsh:QH426-470 ,Endocrinology, Diabetes and Metabolism ,Bioinformatics ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,symbols.namesake ,Molecular genetics ,Internal Medicine ,Medicine ,Cognitive decline ,Exome sequencing ,Sanger sequencing ,lcsh:RC648-665 ,business.industry ,PPT1 ,CLN genes ,Research Reports ,developmental regression ,lcsh:Genetics ,CLN8 ,symbols ,epilepsy ,Differential diagnosis ,business ,Developmental regression ,neuronal ceroid lipofuscinoses ,visual loss - Abstract
Background Neuronal ceroid lipofuscinoses are neurodegenerative disorders. To investigate the diagnostic yield of direct Sanger sequencing of the CLN genes, we reviewed Molecular Genetics Laboratory Database for molecular genetic test results of the CLN genes from a single clinical molecular diagnostic laboratory. Methods We reviewed electronic patient charts. We used consent forms and Research Electronic Data Capture questionnaires for the patients from outside of our Institution. We reclassified all variants in the CLN genes. Results Six hundred and ninety three individuals underwent the direct Sanger sequencing of the CLN genes for the diagnosis of neuronal ceroid lipofuscinoses. There were 343 symptomatic patients and 350 family members. Ninety‐one symptomatic patients had molecular genetic diagnosis of neuronal ceroid lipofuscinoses including CLN1 (PPT1) (n = 10), CLN2 (TPP1) (n = 33), CLN3 (n = 17), CLN5 (n = 7), CLN6 (n = 10), CLN7 (MFSD8) (n = 10), and CLN8 (n = 4) diseases. The diagnostic yield of direct Sanger sequencing of CLN genes was 27% in symptomatic patients. We report detailed clinical and investigation results of 33 NCL patients. Juvenile onset CLN1 (PPT1) and adult onset CLN6 diseases were nonclassical phenotypes. Conclusion In our study, the diagnostic yield of direct Sanger sequencing was close to diagnostic yield of whole exome sequencing. Developmental regression, cognitive decline, visual impairment and cerebral and/or cerebellar atrophy in brain MRI are significant clinical and neuroimaging denominators to include NCL in the differential diagnosis.
- Published
- 2019
11. Continuous Age- and Sex-Adjusted Reference Intervals of Urinary Markers for Cerebral Creatine Deficiency Syndromes: A Novel Approach to the Definition of Reference Intervals
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Mirjam M.C. Wamelink, Andreas Schulze, Jiddeke M. van de Kamp, Lars Mørkrid, Katja Benedikte Prestø Elgstøen, Piero Rinaldo, George J. G. Ruijter, Patricia L. Hall, Lianna Kyriakopoulou, Jess H. Olesen, Alexander D. Rowe, Silvia Tortorelli, Gajja S. Salomons, Laboratory Medicine, Human genetics, NCA - Brain mechanisms in health and disease, and Clinical Genetics
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Male ,Percentile ,Urinary system ,Clinical Biochemistry ,Creatine ,Models, Biological ,chemistry.chemical_compound ,Sex Factors ,Statistics ,Covariate ,Humans ,Medicine ,Polynomial regression ,Brain Diseases ,Creatinine ,business.industry ,Biochemistry (medical) ,Age Factors ,Reference Standards ,Regression ,chemistry ,Female ,Creatine deficiency ,business ,Biomarkers - Abstract
BACKGROUND Urinary concentrations of creatine and guanidinoacetic acid divided by creatinine are informative markers for cerebral creatine deficiency syndromes (CDSs). The renal excretion of these substances varies substantially with age and sex, challenging the sensitivity and specificity of postanalytical interpretation. METHODS Results from 155 patients with CDS and 12 507 reference individuals were contributed by 5 diagnostic laboratories. They were binned into 104 adjacent age intervals and renormalized with Box–Cox transforms (Ξ). Estimates for central tendency (μ) and dispersion (σ) of Ξ were obtained for each bin. Polynomial regression analysis was used to establish the age dependence of both μ[log(age)] and σ[log(age)]. The regression residuals were then calculated as z-scores = {Ξ − μ[log(age)]}/σ[log(age)]. The process was iterated until all z-scores outside Tukey fences ±3.372 were identified and removed. Continuous percentile charts were then calculated and plotted by retransformation. RESULTS Statistically significant and biologically relevant subgroups of z-scores were identified. Significantly higher marker values were seen in females than males, necessitating separate reference intervals in both adolescents and adults. Comparison between our reconstructed reference percentiles and current standard age-matched reference intervals highlights an underlying risk of false-positive and false-negative events at certain ages. CONCLUSIONS Disease markers depending strongly on covariates such as age and sex require large numbers of reference individuals to establish peripheral percentiles with sufficient precision. This is feasible only through collaborative data sharing and the use of appropriate statistical methods. Broad application of this approach can be implemented through freely available Web-based software.
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- 2015
12. In Reply
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Khosrow Adeli, David Colantonio, Mehrdad Yazdanpanah, and Lianna Kyriakopoulou
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Male ,0303 health sciences ,03 medical and health sciences ,0302 clinical medicine ,Biochemistry (medical) ,Clinical Biochemistry ,Humans ,Female ,030204 cardiovascular system & hematology ,Biomarkers ,Blood Chemical Analysis ,030304 developmental biology - Published
- 2014
13. Lysine-restricted diet and mild cerebral serotonin deficiency in a patient with pyridoxine-dependent epilepsy caused by ALDH7A1 genetic defect
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Eduard A. Struys, Laura Nagy, Dawn Corderio, Lianna Kyriakopoulou, Melissa T. Carter, Saadet Mercimek-Mahmutoglu, and Carly Mutch
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medicine.medical_specialty ,Plasma tryptophan ,Lysine ,PDE, pyridoxine dependent epilepsy ,CSF-α-AASA, CSF α-AASA ,Case Report ,Biology ,CNS, central nervous system ,α-AASAD, alpha-aminoadipic acid semialdehyde dehydrogenase ,α AASAS, α-AASA synthase ,CSF, cerebral spinal fluid ,chemistry.chemical_compound ,Endocrinology ,PA, pipecolic acid ,Internal medicine ,Genetics ,medicine ,Alpha-amino adipic acid semialdehyde dehydrogenase deficiency ,Restricted diet ,Neurotransmitter ,MSEL, Mullen Scales of Early Learning ,Molecular Biology ,Pyridoxine-dependent epilepsy ,lcsh:QH301-705.5 ,chemistry.chemical_classification ,HVA, homovanillic acid levels ,P5CR, pyrroline-5-carboxylate reductase ,lcsh:R5-920 ,PDMS-2, Peabody Developmental Motor Scales — 2nd Edition ,Catabolism ,5-HIAA, 5-hydroxyindolacetic acid ,medicine.disease ,P6C, piperidine 6-carboxylic acid ,GA-I, glutaric aciduria type I ,Pyridoxine dependent epilepsy ,Lysine restricted diet ,Enzyme ,chemistry ,lcsh:Biology (General) ,PDE-ALDH7A1, PDE caused by ALDH7A1 genetic defect ,α-AASA, alpha-aminoadipic acid semialdehyde ,CSF-PA, CSF PA ,Serotonin ,lcsh:Medicine (General) - Abstract
Pyridoxine dependent epilepsy (PDE) is caused by mutations in the ALDH7A1 gene (PDE-ALDH7A1) encoding α-aminoadipic-semialdehyde-dehydrogenase enzyme in the lysine catabolic pathway resulting in an accumulation of α-aminoadipic-acid-semialdehyde (α-AASA). We present the one-year treatment outcome of a patient on a lysine-restricted diet. Serial cerebral-spinal-fluid (CSF) α-AASA and CSF pipecolic-acid levels showed decreased levels but did not normalize. He had a normal neurodevelopmental outcome on a lysine-restricted diet. Despite normal CSF and plasma tryptophan levels and normal tryptophan intake, he developed mild CSF serotonin deficiency at one year of therapy. Stricter lysine restriction would be necessary to normalize CSF α-AASA levels, but might increase the risks associated with the diet. Patients are at risk of cerebral serotonin deficiency and should be monitored by CSF neurotransmitter measurements.
- Published
- 2014
- Full Text
- View/download PDF
14. Complex Biological Pattern of Fertility Hormones in Children and Adolescents: A Study of Healthy Children from the CALIPER Cohort and Establishment of Pediatric Reference Intervals
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Julie L.V. Shaw, David Colantonio, Ashley H. Cohen, Man Khun Chan, Dana Bailey, Danijela Konforte, Lianna Kyriakopoulou, Jennifer L. Shea, David Armbruster, and Khosrow Adeli
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Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Peptide Hormones ,media_common.quotation_subject ,Clinical Biochemistry ,Fertility ,030204 cardiovascular system & hematology ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Reference Values ,Sex Hormone-Binding Globulin ,medicine ,Humans ,Testosterone ,Child ,Progesterone ,media_common ,Immunoassay ,Estradiol ,business.industry ,Biochemistry (medical) ,Infant, Newborn ,Infant ,Luteinizing Hormone ,Prolactin ,3. Good health ,Child, Preschool ,030220 oncology & carcinogenesis ,Cohort ,Female ,Follicle Stimulating Hormone ,Parental consent ,business ,Luteinizing hormone ,Gonadal Hormones ,Cohort study ,Hormone - Abstract
BACKGROUND Pediatric endocrinopathies are commonly diagnosed and monitored by measuring hormones of the hypothalamic-pituitary-gonadal axis. Because growth and development can markedly influence normal circulating concentrations of fertility hormones, accurate reference intervals established on the basis of a healthy, nonhospitalized pediatric population and that reflect age-, gender-, and pubertal stage–specific changes are essential for test result interpretation. METHODS Healthy children and adolescents (n = 1234) were recruited from a multiethnic population as part of the CALIPER study. After written informed parental consent was obtained, participants filled out a questionnaire including demographic and pubertal development information (assessed by self-reported Tanner stage) and provided a blood sample. We measured 7 fertility hormones including estradiol, testosterone (second generation), progesterone, sex hormone–binding globulin, prolactin, follicle-stimulating hormone, and luteinizing hormone by use of the Abbott Architect i2000 analyzer. We then used these data to calculate age-, gender-, and Tanner stage–specific reference intervals according to Clinical Laboratory Standards Institute C28-A3 guidelines. RESULTS We observed a complex pattern of change in each analyte concentration from the neonatal period to adolescence. Consequently, many age and sex partitions were required to cover the changes in most fertility hormones over this period. An exception to this was prolactin, for which no sex partition and only 3 age partitions were necessary. CONCLUSIONS This comprehensive database of pediatric reference intervals for fertility hormones will be of global benefit and should lead to improved diagnosis of pediatric endocrinopathies. The new database will need to be validated in local populations and for other immunoassay platforms as recommended by the Clinical Laboratory Standards Institute.
- Published
- 2013
15. Strategies to rescue the consequences of inducible arginase-1 deficiency in mice
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Steven Goossens, Lieven Haenebalcke, Colin D. Funk, Joshua Si, Tim St. Amand, Yuan Yan Sin, Lianna Kyriakopoulou, Jody J. Haigh, Andreas Schulze, and Laurel L. Ballantyne
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Male ,Ornithine ,RNA, Untranslated ,Hyperargininemia ,lcsh:Medicine ,Gene Expression ,MOUSE ,PHENOTYPE ,chemistry.chemical_compound ,Mice ,Genes, Reporter ,Transduction, Genetic ,Transgenes ,lcsh:Science ,Mice, Knockout ,Multidisciplinary ,Sodium phenylbutyrate ,Dependovirus ,Arginase ,Phenotype ,Urea cycle ,Knockout mouse ,Gene Targeting ,VECTORS ,Female ,medicine.drug ,Research Article ,EXPRESSION ,Genetically modified mouse ,medicine.medical_specialty ,Transgene ,Genetic Vectors ,Longevity ,Biology ,Internal medicine ,medicine ,Diet, Protein-Restricted ,Animals ,MUTATIONS ,lcsh:R ,GENE-THERAPY ,Biology and Life Sciences ,HYPERARGININEMIA ,UREA CYCLE DISORDERS ,Molecular biology ,MODEL ,Endocrinology ,chemistry ,Genetic Loci ,Dietary Supplements ,lcsh:Q ,Genes, Lethal - Abstract
Arginase-1 catalyzes the conversion of arginine to ornithine and urea, which is the final step of the urea cycle used to remove excess ammonia from the body. Arginase-1 deficiency leads to hyperargininemia in mice and man with severe lethal consequences in the former and progressive neurological impairment to varying degrees in the latter. In a tamoxifen-induced arginase-1 deficient mouse model, mice succumb to the enzyme deficiency within 2 weeks after inducing the knockout and retain
- Published
- 2015
16. Human Kallikrein Gene 5 (KLK5) Expression by Quantitative PCR: An Independent Indicator of Poor Prognosis in Breast Cancer
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Eleftherios P. Diamandis, Nicoletta Biglia, Piero Sismondi, Lianna Kyriakopoulou, Laura M. Rendl, Maria Diamandis, George M. Yousef, Andreas Scorilas, Maurizia Giai, Riccardo Ponzone, and R. Roagna
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Oncology ,medicine.medical_specialty ,Pathology ,Biochemistry (medical) ,Clinical Biochemistry ,KLK5 ,Kallikrein ,Biology ,medicine.disease ,Reverse transcription polymerase chain reaction ,Prostate cancer ,Breast cancer ,Internal medicine ,medicine ,Breast carcinoma ,Survival analysis ,Tumor marker - Abstract
Background: KLK5 is a newly discovered human kallikrein gene. Many kallikrein genes have been found to be differentially expressed in various malignancies, and prostate-specific antigen (PSA; encoded by the KLK3 gene) is the best tumor marker for prostate cancer. Like the genes that encode PSA and other kallikreins, the KLK5 gene was found to be regulated by steroid hormones in the BT-474 breast cancer cell line.Methods: We studied KLK5 expression in 179 patients with different stages and grades of epithelial breast carcinoma by quantitative reverse transcription-PCR (RT-PCR), using LightCycler® technology. An optimal cutoff point equal to the detection limit (65th percentile) was used. KLK5 values were then compared with other established prognostic factors in terms of disease-free (DFS) and overall survival (OS).Results: High KLK5 expression was found more frequently in pre-/perimenopausal (P = 0.026), node-positive (P = 0.029), and estrogen receptor-negative (P = 0.038) patients. In univariate analysis, KLK5 overexpression was a significant predictor of reduced DFS (P 2 cm) and positive nodes. Hazard ratios derived from Cox analysis and related to DFS and OS were 2.48 (P = 0.005) and 2.37 (P = 0.009), respectively, for the node-positive group and 3.03 (P = 0.002) and 2.94 (P = 0.002), respectively, for patients with tumor sizes >2 cm. KLK5 expression was also associated with statistically significantly shorter DFS (P = 0.006) and OS (P = 0.004) in the subgroup of patients with grade I and II tumors.Conclusions: KLK5 expression as assessed by quantitative RT-PCR is an independent and unfavorable prognostic marker for breast carcinoma.
- Published
- 2002
17. Cloning of a gene (SR-A1), encoding for a new member of the human Ser/Arg-rich family of pre-mRNA splicing factors: overexpression in aggressive ovarian cancer
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Andreas Scorilas, Eleftherios P. Diamandis, Dionyssios Katsaros, and Lianna Kyriakopoulou
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Cancer Research ,Molecular Sequence Data ,Biology ,Gene product ,Exon ,SR protein ,Gene cluster ,RNA Precursors ,Tumor Cells, Cultured ,Humans ,Amino Acid Sequence ,RNA, Messenger ,Cloning, Molecular ,Phylogeny ,Expressed Sequence Tags ,Ovarian Neoplasms ,Sequence Homology, Amino Acid ,Serine-Arginine Splicing Factors ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Alternative splicing ,Chromosome Mapping ,Nuclear Proteins ,RNA-Binding Proteins ,TAF9 ,Regular Article ,gene overexpression in cancer ,Exons ,FOSL1 ,Phosphoproteins ,Molecular biology ,Introns ,SR-A1 ,Alternative Splicing ,ovarian cancer ,Oncology ,GATAD2B ,splicing factors ,RNA polymerase ,serine/arginine-rich proteins ,pre-mRNA splicing ,Female ,Chromosomes, Human, Pair 19 ,SR family - Abstract
By using the positional cloning gene approach, we were able to identify a novel gene encoding for a serine/arginine-rich protein, which appears to be the human homologue of the rat A1 gene. We named this new gene SR-A1. Members of the SR family of proteins have been shown to interact with the C-terminal domain (CTD) of the large subunit of RNA polymerase II and participate in pre-mRNA splicing. We have localized the SR-A1 gene between the known genes IRF3 and RRAS on chromosome 19q13.3. The novel gene spans 16.7 kb of genomic sequence and it is formed of 11 exons and 10 intervening introns. The SR-A1 protein is composed of 1312 amino acids, with a molecular mass of 139.3 kDa and a theoretical isoelectric point of 9.31. The SR-A1 protein contains an SR-rich domain as well as a CTD-binding domain present only in a subset of SR-proteins. Through interactions with the pre-mRNA and the CTD domain of the Polymerase II, SR proteins have been shown to regulate alternative splicing. The SR-A1 gene is expressed in all tissues tested, with highest levels found in fetal brain and fetal liver. Our data suggest that this gene is overexpressed in a subset of ovarian cancers which are clinically more aggressive. Studies with the steroid hormone receptor-positive breast and prostate carcinoma cell lines ZR-75-1, BT-474 and LNCaP, respectively, suggest that SR-A1 is constitutively expressed. Furthermore, the mRNA of the SR-A1 gene in these cell lines appears to increase by estrogens, androgens and glucocorticoids, and to a lesser extend by progestins. © 2001 Cancer Research Campaign http://www.bjcancer.com
- Published
- 2001
18. Marked biological variance in endocrine and biochemical markers in childhood: establishment of pediatric reference intervals using healthy community children from the CALIPER cohort
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Khosrow Adeli, Lianna Kyriakopoulou, Ashley H. Cohen, David Armbruster, Dana Bailey, Man Khun Chan, and David Colantonio
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Percentile ,Homocysteine ,Adolescent ,Clinical Biochemistry ,030209 endocrinology & metabolism ,030204 cardiovascular system & hematology ,Cobalamin ,Body Mass Index ,Cohort Studies ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Sex Factors ,Reference Values ,Medicine ,Humans ,Vitamin B12 ,Child ,2. Zero hunger ,Triiodothyronine ,business.industry ,Biochemistry (medical) ,Age Factors ,Infant, Newborn ,Infant ,3. Good health ,chemistry ,Child, Preschool ,Cohort ,Female ,business ,Body mass index ,Biomarkers ,Blood Chemical Analysis ,Cohort study - Abstract
BACKGROUNDReference intervals are indispensable in evaluating laboratory test results; however, appropriately partitioned pediatric reference values are not readily available. The Canadian Laboratory Initiative for Pediatric Reference Intervals (CALIPER) program is aimed at establishing the influence of age, sex, ethnicity, and body mass index on biochemical markers and developing a comprehensive database of pediatric reference intervals using an a posteriori approach.METHODSA total of 1482 samples were collected from ethnically diverse healthy children ages 2 days to 18 years and analyzed on the Abbott ARCHITECT i2000. Following the CLSI C28-A3 guidelines, age- and sex-specific partitioning was determined for each analyte. Nonparametric and robust methods were used to establish the 2.5th and 97.5th percentiles for the reference intervals as well as the 90% CIs.RESULTSNew pediatric reference intervals were generated for 14 biomarkers, including α-fetoprotein, cobalamin (vitamin B12), folate, homocysteine, ferritin, cortisol, troponin I, 25(OH)-vitamin D [25(OH)D], intact parathyroid hormone (iPTH), thyroid-stimulating hormone, total thyroxine (TT4), total triiodothyronine (TT3), free thyroxine (FT4), and free triiodothyronine. The influence of ethnicity on reference values was also examined, and statistically significant differences were found between ethnic groups for FT4, TT3, TT4, cobalamin, ferritin, iPTH, and 25(OH)D.CONCLUSIONSThis study establishes comprehensive pediatric reference intervals for several common endocrine and immunochemical biomarkers obtained in a large cohort of healthy children. The new database will be of global benefit, ensuring appropriate interpretation of pediatric disease biomarkers, but will need further validation for specific immunoassay platforms and in local populations as recommended by the CLSI.
- Published
- 2013
19. Closing the gaps in pediatric laboratory reference intervals: a CALIPER database of 40 biochemical markers in a healthy and multiethnic population of children
- Author
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Allison A. Venner, David Colantonio, Lianna Kyriakopoulou, David Armbruster, Caitlin H. Daly, Man Khun Chan, Maria D. Pasic, Khosrow Adeli, and Davor Brinc
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Canada ,South asia ,Adolescent ,Databases, Factual ,Patient risk ,Clinical Biochemistry ,030204 cardiovascular system & hematology ,computer.software_genre ,White People ,03 medical and health sciences ,0302 clinical medicine ,Sex Factors ,Asian People ,Reference Values ,Medicine ,Humans ,Child ,Biochemical markers ,Database ,business.industry ,Biochemistry (medical) ,Age Factors ,Infant, Newborn ,Infant ,Multiethnic population ,3. Good health ,Reference intervals ,030220 oncology & carcinogenesis ,Child, Preschool ,Calipers ,Female ,Parental consent ,business ,computer ,Biomarkers ,Pediatric population - Abstract
BACKGROUNDPediatric healthcare is critically dependent on the availability of accurate and precise laboratory biomarkers of pediatric disease, and on the availability of reference intervals to allow appropriate clinical interpretation. The development and growth of children profoundly influence normal circulating concentrations of biochemical markers and thus the respective reference intervals. There are currently substantial gaps in our knowledge of the influences of age, sex, and ethnicity on reference intervals. We report a comprehensive covariate-stratified reference interval database established from a healthy, nonhospitalized, and multiethnic pediatric population.METHODSHealthy children and adolescents (n = 2188, newborn to 18 years of age) were recruited from a multiethnic population with informed parental consent and were assessed from completed questionnaires and according to defined exclusion criteria. Whole-blood samples were collected for establishing age- and sex-stratified reference intervals for 40 serum biochemical markers (serum chemistry, enzymes, lipids, proteins) on the Abbott ARCHITECT c8000 analyzer.RESULTSReference intervals were generated according to CLSI C28-A3 statistical guidelines. Caucasians, East Asians, and South Asian participants were evaluated with respect to the influence of ethnicity, and statistically significant differences were observed for 7 specific biomarkers.CONCLUSIONSThe establishment of a new comprehensive database of pediatric reference intervals is part of the Canadian Laboratory Initiative in Pediatric Reference Intervals (CALIPER). It should assist laboratorians and pediatricians in interpreting test results more accurately and thereby lead to improved diagnosis of childhood diseases and reduced patient risk. The database will also be of global benefit once reference intervals are validated in transference studies with other analytical platforms and local populations, as recommended by the CLSI.
- Published
- 2012
20. Molecular cloning, physical mapping, and expression analysis of a novel gene, BCL2L12, encoding a proline-rich protein with a highly conserved BH2 domain of the Bcl-2 family
- Author
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George M. Yousef, Eleftherios P. Diamandis, Andreas Scorilas, Linda K. Ashworth, Aku Kwamie, and Lianna Kyriakopoulou
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Proline ,Molecular Sequence Data ,Gene Expression ,Muscle Proteins ,Apoptosis ,Biology ,Homology (biology) ,Exon ,Genetics ,Consensus sequence ,Humans ,Amino Acid Sequence ,Cloning, Molecular ,Gene ,Peptide sequence ,Gene map ,Base Sequence ,Sequence Homology, Amino Acid ,Alternative splicing ,DNA ,Physical Chromosome Mapping ,Protein Structure, Tertiary ,Proto-Oncogene Proteins c-bcl-2 ,RNA splicing ,Chromosomes, Human, Pair 19 - Abstract
Members of the Bcl-2 family of apoptosis-regulating proteins contain at least one of the four evolutionarily conserved domains, termed BH1, BH2, BH3, or BH4. Here, we report the identification, cloning, physical mapping, and expression pattern of BCL2L12, a novel gene that encodes a BCL2-like proline-rich protein. Proline-rich sites have been shown to interact with Src homology region 3 (SH3) domains of several tyrosine kinases, mediating their oncogenic potential. This new gene maps to chromosome 19q13.3 and is located between the IRF3 and the PRMT1/HRMT1L2 genes, close to the RRAS gene. BCL2L12 is composed of seven coding exons and six intervening introns, spanning a genomic area of 8.8 kb. All of the exon-intron splice sites conform to the consensus sequence for eukaryotic splice sites. The BCL2L12 protein is composed of 334 amino acids, with a calculated molecular mass of 36.8 kDa and an isoelectric point of 9.45. The BCL2L12 protein contains one BH2 homology domain, one proline-rich region similar to the TC21 protein and, five consensus PXXP tetrapeptide sequences. BCL2L12 is expressed mainly in breast, thymus, prostate, fetal liver, colon, placenta, pancreas, small intestine, spinal cord, kidney, and bone marrow and to a lesser extent in many other tissues. We also identified one splice variant of BCL2L12 that is primarily expressed in skeletal muscle.
- Published
- 2001
21. Characterisation of a novel 49�3�kbG?(A???)0-thalassaemia deletion in seven families of Asian descent
- Author
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John S. Waye, Murray A. Potter, Lianna Kyriakopoulou, Barry Eng, and Lynda Walker
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Genetics ,Delta ,Hematology ,Gene deletion ,Biology ,Beta (finance) - Published
- 2007
22. Prevalence of inherited neurotransmitter disorders in patients with movement disorders and epilepsy: a retrospective cohort study
- Author
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Roberto Mendoza-Londono, Sarah Sidky, Keith Hyland, Elizabeth J. Donner, Jaina Patel, Andreas Schulze, Mahendranath Moharir, Lianna Kyriakopoulou, Komudi Siriwardena, Grace Yoon, Julian Raiman, Saadet Mercimek-Mahmutoglu, and William J. Logan
- Subjects
Male ,medicine.medical_specialty ,Pediatrics ,Movement disorders ,Adolescent ,Cohort Studies ,Epilepsy ,Young Adult ,Internal medicine ,medicine ,Genetics ,Monoamine metabolism ,Humans ,Neurotransmitter metabolism ,Genetics(clinical) ,Pharmacology (medical) ,Child ,Exome ,Pyridoxine-dependent epilepsy ,Genetics (clinical) ,Retrospective Studies ,Inherited neurotransmitter disorders ,Medicine(all) ,Movement Disorders ,business.industry ,Research ,Genetic disorder ,Infant, Newborn ,Infant ,Retrospective cohort study ,General Medicine ,medicine.disease ,Endocrinology ,Pyridoxine metabolism ,Gene Expression Regulation ,Dystonic Disorders ,Child, Preschool ,medicine.symptom ,business ,Metabolism, Inborn Errors ,Cohort study - Abstract
Background Inherited neurotransmitter disorders are primary defects of neurotransmitter metabolism. The main purpose of this retrospective cohort study was to identify prevalence of inherited neurotransmitter disorders. Methods This retrospective cohort study does not have inclusion criteria; rather included all patients who underwent cerebrospinal fluid (CSF) homovanillic and 5-hydroxyindol acetic acid measurements. Patients with CSF neurotransmitter investigations suggestive of an inherited neurotransmitter disorder and patients with normal or non-diagnostic CSF neurotransmitter investigations underwent direct sequencing of single gene disorders. Results There were 154 patients between October 2004 and July 2013. Four patients were excluded due to their diagnosis prior to this study dates. Two major clinical feature categories of patients who underwent lumbar puncture were movement disorders or epilepsy in our institution. Twenty out of the 150 patients (13.3%) were diagnosed with a genetic disorder including inherited neurotransmitter disorders (6 patients) (dihydropteridine reductase, 6-pyruvoyl-tetrahydropterin synthase, guanosine triphosphate cyclohydrolase I, tyrosine hydroxylase, pyridoxine dependent epilepsy due to mutations in the ALDH7A1 gene and pyridoxamine-5-phosphate oxidase deficiencies) and non-neurotransmitter disorders (14 patients). Conclusion Prevalence of inherited neurotransmitter disorders was 4% in our retrospective cohort study. Eight out of the 150 patients (5.3%) had one of the treatable inherited metabolic disorders with favorable short-term neurodevelopmental outcomes, highlighting the importance of an early and specific diagnosis. Whole exome or genome sequencing might shed light to unravel underlying genetic defects of new inherited neurotransmitter disorders in near future.
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