14 results on '"Michelle Farrar"'
Search Results
2. Diagnosis and management of children with McArdle Syndrome (GSD V) in New South Wales
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Louisa Adams, Arthavan Selvanathan, Kiera J. Batten, Nancy vanDoorn, Susan Thompson, Ashleigh Mitchell, Hugo Sampaio, Troy Dalkeith, Jacqui Russell, Carolyn J. Ellaway, Michelle Farrar, Carolyn Broderick, and Kaustuv Bhattacharya
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aerobic ,exercise ,glycogen storage ,McArdle ,rhabdomyolysis ,sports physiology ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 ,Genetics ,QH426-470 - Abstract
Abstract Glycogen storage type V (GSD V—McArdle Syndrome) is a rare neuromuscular disorder characterised by severe pain early after the onset of physical activity. A recent series indicated a diagnostic delay of 29 years; hence reports of children affected by the disorder are uncommon (Lucia et al., 2021, Neuromuscul Disord, 31, 1296–1310). This paper presents eight patients with a median onset age of 5.5 years and diagnosis of 9.5 years. Six patients had episodes of rhabdomyolysis with creatine kinase elevations >50 000 IU/L. Most episodes occurred in relation to eccentric non‐predicted activities rather than regular exercise. One of the patients performed a non‐ischaemic forearm test. One patient was diagnosed subsequent to a skeletal muscle biopsy, and all had confirmatory molecular genetic diagnosis. Three were homozygous for the common PYGM:c.148C > T (p.Arg50*) variant. All but one patient had truncating variants. All patients were managed with structured exercise testing to help them identify ‘second‐wind’, and plan an exercise regimen. In addition all also had an exercise test with 25 g maltodextrin which had statistically significant effect on ameliorating ratings of perceived exertion. GSD V is under‐recognised in paediatric practice. Genetic testing can readily diagnose the condition. Careful identification of second‐wind symptomatology during exercise with the assistance of a multi‐disciplinary team, allows children to manage activities and tolerate exercise. Maltodextrin can be used for structured exercise, but excessive utilisation may lead to weight gain. Early intervention and education may improve outcomes into adult life.
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- 2023
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3. The Carrier Frequency of Two SMN1 Genes in Parents of Symptomatic Children with SMA and the Significance of SMN1 Exon 8 in Carriers
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Joanne E Davidson, Jacqueline S Russell, Noelia Nunez Martinez, David R Mowat, Kristi J Jones, Edwin P Kirk, Didu Kariyawasam, Michelle Farrar, and Arlene D’Silva
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spinal muscular atrophy ,carrier frequency ,silent carrier ,reproductive carrier screening ,Genetics ,QH426-470 - Abstract
Background: Current carrier screening methods do not identify a proportion of carriers that may have children affected by spinal muscular atrophy (SMA). Additional genetic data is essential to inform accurate risk assessment and genetic counselling of SMA carriers. This study aims to quantify the various genotypes among parents of children with SMA. Method: A retrospective cohort study was undertaken at Sydney Children’s Hospital Network, the major SMA referral centre for New South Wales, Australia. Participants included children with genetically confirmed SMA born between 2005 and 2021. Data was collected on parent genotype inclusive of copy number of SMN1 exons 7 and 8. The number of SMN2 exon 7 copies were recorded for the affected children. Descriptive statistics were used to determine the proportion of carriers of 2+0 genotype classified as silent carriers. Chi-square test was used to correlate the association between parents with a heterozygous SMN1 exon 7 deletion and two copies of exon 8 and ≥3 SMN2 copy number in the proband. Results: SMA carrier testing was performed in 118/154 (76.6%) parents, incorporating 59 probands with homozygous SMN1 deletions and one proband with compound heterozygote pathogenic variants. Among parents with a child with SMA, 7.6% had two copies of SMN1 exon 7. When only probands with a homozygous SMN1 exon 7 deletion were included, 6.9% of parents had two copies of SMN1 exon 7. An association was observed between heterozygous deletion of SMN1 exon 7 with two copies of exon 8 in a parent and ≥3 SMN2 copy number in the affected proband (p = 0.07). Conclusions: This study confirmed a small but substantial proportion of silent carriers not identified by conventional screening within an Australian context. Accordingly, the effectiveness of carrier screening for SMA is linked with genetic counselling to enable health literacy regarding high and low risk results and is complemented by new-born screening and maintaining clinical awareness for SMA. Gene conversion events may underpin the associations between parent carrier status and proband SMN2 copy number.
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- 2023
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4. Inherited Paediatric Motor Neuron Disorders: Beyond Spinal Muscular Atrophy
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Hooi Ling Teoh, Kate Carey, Hugo Sampaio, David Mowat, Tony Roscioli, and Michelle Farrar
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Paediatric motor neuron diseases encompass a group of neurodegenerative diseases characterised by the onset of muscle weakness and atrophy before the age of 18 years, attributable to motor neuron loss across various neuronal networks in the brain and spinal cord. While the genetic underpinnings are diverse, advances in next generation sequencing have transformed diagnostic paradigms. This has reinforced the clinical phenotyping and molecular genetic expertise required to navigate the complexities of such diagnoses. In turn, improved genetic technology and subsequent gene identification have enabled further insights into the mechanisms of motor neuron degeneration and how these diseases form part of a neurodegenerative disorder spectrum. Common pathophysiologies include abnormalities in axonal architecture and function, RNA processing, and protein quality control. This review incorporates an overview of the clinical manifestations, genetics, and pathophysiology of inherited paediatric motor neuron disorders beyond classic SMN1-related spinal muscular atrophy and describes recent advances in next generation sequencing and its clinical application. Specific disease-modifying treatment is becoming a clinical reality in some disorders of the motor neuron highlighting the importance of a timely and specific diagnosis.
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- 2017
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5. The Carrier Frequency of Two SMN1 Genes in Parents of Symptomatic Children with SMA and the Significance of SMN1 Exon 8 in Carriers
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D’Silva, Joanne E Davidson, Jacqueline S Russell, Noelia Nunez Martinez, David R Mowat, Kristi J Jones, Edwin P Kirk, Didu Kariyawasam, Michelle Farrar, and Arlene
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spinal muscular atrophy ,carrier frequency ,silent carrier ,reproductive carrier screening - Abstract
Background: Current carrier screening methods do not identify a proportion of carriers that may have children affected by spinal muscular atrophy (SMA). Additional genetic data is essential to inform accurate risk assessment and genetic counselling of SMA carriers. This study aims to quantify the various genotypes among parents of children with SMA. Method: A retrospective cohort study was undertaken at Sydney Children’s Hospital Network, the major SMA referral centre for New South Wales, Australia. Participants included children with genetically confirmed SMA born between 2005 and 2021. Data was collected on parent genotype inclusive of copy number of SMN1 exons 7 and 8. The number of SMN2 exon 7 copies were recorded for the affected children. Descriptive statistics were used to determine the proportion of carriers of 2+0 genotype classified as silent carriers. Chi-square test was used to correlate the association between parents with a heterozygous SMN1 exon 7 deletion and two copies of exon 8 and ≥3 SMN2 copy number in the proband. Results: SMA carrier testing was performed in 118/154 (76.6%) parents, incorporating 59 probands with homozygous SMN1 deletions and one proband with compound heterozygote pathogenic variants. Among parents with a child with SMA, 7.6% had two copies of SMN1 exon 7. When only probands with a homozygous SMN1 exon 7 deletion were included, 6.9% of parents had two copies of SMN1 exon 7. An association was observed between heterozygous deletion of SMN1 exon 7 with two copies of exon 8 in a parent and ≥3 SMN2 copy number in the affected proband (p = 0.07). Conclusions: This study confirmed a small but substantial proportion of silent carriers not identified by conventional screening within an Australian context. Accordingly, the effectiveness of carrier screening for SMA is linked with genetic counselling to enable health literacy regarding high and low risk results and is complemented by new-born screening and maintaining clinical awareness for SMA. Gene conversion events may underpin the associations between parent carrier status and proband SMN2 copy number.
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- 2023
- Full Text
- View/download PDF
6. Incidence of Duchenne muscular dystrophy in the modern era; an Australian study
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Didu Kariyawasam, Arlene D’Silva, David Mowat, Jacqui Russell, Hugo Sampaio, Kristi Jones, Peter Taylor, and Michelle Farrar
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Male ,Muscular Dystrophy, Duchenne ,Cohort Studies ,Pregnancy ,Incidence ,Australia ,Genetics ,Humans ,Female ,Genetics (clinical) ,Retrospective Studies - Abstract
Duchenne muscular dystrophy (DMD), an X-linked recessive condition is maternally inherited in two-thirds of affected boys. It is important to establish carrier status of female relatives to restore reproductive confidence for non-carriers and facilitate reproductive options and cardiac surveillance for carriers. This study investigates disease incidence within an Australian model of cascade screening and evolving genetic diagnostic technologies. A retrospective population-based cohort study of all genetically and/or histopathologically confirmed males with DMD, born in New South Wales and the Australian Capital Territory was undertaken from 2002–2012. Cases were identified using state-wide molecular laboratory and clinical databases. The annual disease incidence and “theoretically” preventable cases were extrapolated over the study period. Proband genotype/phenotype, pedigree analysis, carrier-risk and extent of cascade screening were also determined. The cumulative incidence of disease was 19.7 per 100,000 male live births and 1 in 5076 live born males were diagnosed with DMD. Differences in disease incidence were not statistically different when compared between 2002–2007 and 2008–2012 (incidence rate ratio = 1.13, 95% CI 0.76–1.69, p = 0.52). The incidence rate ratio of theoretically preventable cases did not significantly change between 2002–2007 and 2008–2012 (incidence rate ratio = 2.07, 95% CI 0.58–9.21, p = 0.23). Current diagnostic and cascade screening models have limitations in their impact on disease incidence, due to a spectrum of logistical, patient and condition related factors. Innovative approaches to reduce DMD incidence may be better achieved by preconception or early pregnancy carrier screening, prenatal exome sequencing and newborn screening.
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- 2022
7. Daytime predictors of nocturnal hypercapnic hypoventilation in children with neuromuscular disorders
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Megan Frohlich, John Widger, Ganesh Thambipillay, Arthur Teng, Michelle Farrar, and Sandra Chuang
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Hypercapnia ,Pulmonary and Respiratory Medicine ,Adolescent ,Scoliosis ,Spirometry ,Forced Expiratory Volume ,Vital Capacity ,Pediatrics, Perinatology and Child Health ,Humans ,Hypoventilation ,Neuromuscular Diseases ,Child ,Retrospective Studies - Abstract
To examine objective daytime predictors of nocturnal hypercapnic hypoventilation (NHH) and identify a forced vital capacity (FVC) z-score cut off that predicts NHH using the 2012 Global Lung Function Initiative (GLI) reference equations in pediatric neuromuscular patients.Single-centre retrospective medical record review.Tertiary pediatric hospital in Australia.Children (18 years old) with a neuromuscular disorder (NMD) who had a diagnostic sleep study over a 5-year period.Fifty children were included, median age 11.9 years (interquartile range [IQR]: 4.5-14.3). The majority of children had a diagnosis of Duchenne Muscular Dystrophy (32%). NHH was diagnosed in 18 children (36%). Multivariate logistic regression analysis performed for the entire cohort confirmed a statistically significant association between NHH and scoliosis (odds ratio [OR]: 3.3, p = 0.03), but not age (OR: 1.01, p = 0.26), body mass index z-score (OR: 0.86, p = 0.26) or use of a wheelchair for mobility (OR: 1.25, p = 0.72). For the subset of 29 children who had spirometry testing (median age 12.9 years [IQR: 10.2-14.3]), FVC z-score was the only statistically significant predictor of NHH (OR: 0.45, p = 0.02). NHH was predicted by an FVC z-score-3.24 (sensitivity 78%, specificity 73%), or FVC60% predicted (sensitivity 78%, specificity 73%). There was a strong positive correlation between FVC and forced expiratory volume in 1 s z-scores (rChildren with a NMD and scoliosis or a lower FVC z-score have increased odds of having NHH.
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- 2022
8. Newborn screening programs for spinal muscular atrophy worldwide: Where we stand and where to go
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Tamara Dangouloff, Eva Vrščaj, Laurent Servais, Damjan Osredkar, Thierry Adoukonou, Omid Aryani, Nina Barisic, Fahad Bashiri, Laila Bastaki, Afaf Benitto, Tawfeg Ben Omran, Guenther Bernert, Enrico Bertini, Patricia Borde, Peter Born, Rose-Mary Boustani, Nina Butoianu, Claudia Castiglioni, Feriha Catibusic, Sophelia Chan, Yin Hsiu Chien, Kyproula Christodoulou, Donniphat Dejsuphong, Michelle Farrar, Duma Filip, Nathalie Goemans, Kokou Guinhouya, Jana Haberlova, Kinga Hadzsiev, Kristine Hovhannesyan, Pirjo Isohanni, Nelica Ivanovic Radovic, David Jacquier, Alusine Jalloh, Maria Jedrzejowska, Gwen Kandawasvika, Celestin Kaputu, Nfwama Kawatu, Kristin Kernohan, Jan Kirschner, Barbara Klink, Sherry Kodsy, Ange-Eric Kouame-Assouan, Ruzica Kravljanac, Madara Kreile, Ivan Litvinenko, Hugh McMillan, Sandra Mesa, Inaam Mohamed, Liljana Muaremoska Kanzoska, Yoram Nevo, Seraphin Nguefack, Kafula Nkole, Gina O'Grady, Declan O'Rourke, Maryam Oskoui, Flavia Piazzon, Dimitri Poddighe, Audrone Prasauskiene, Juan Prieto, Magnhild Rasmussen, Santara Razafindrasata, Narayan Saha, Kayoko Saito, Foksouna Sakadi, Modibo Sangare, Mary Schroth, Leanid Shalkevich, Andriy Shatillo, Renu Suthar, Lena Szabo, Nana Tatishvili, Meriem Tazir, Eduardo Tizzano, Haluk Topaloglu, Mar Tulinius, Ludo van der Pol, Gabriel Vazquez, Dimitry Vlodavets, Jithangi Wanigasinghe, Jo Wilmshurst, Hui Xiong, Dimitrios Zafeiriou, and Eleni Zamba
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0301 basic medicine ,medicine.medical_specialty ,Context (language use) ,Disease ,Muscular Atrophy, Spinal ,03 medical and health sciences ,Neonatal Screening ,0302 clinical medicine ,Surveys and Questionnaires ,medicine ,Screening method ,Humans ,Genetics (clinical) ,Newborn screening ,business.industry ,Infant, Newborn ,food and beverages ,Spinal muscular atrophy ,medicine.disease ,SMA ,030104 developmental biology ,Neurology ,Family medicine ,embryonic structures ,Pediatrics, Perinatology and Child Health ,Nusinersen ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Spinal muscular atrophy (SMA) is a rare and devastating disease. New disease-modifying treatments have recently been approved and early treatment has been related to a better outcome. In this context, several newborn screening (NBS) programs have been implemented. The aim of the study was to obtain a global overview on the current situation and perspectives on SMA NBS. We conducted a survey and contacted experts from 152 countries, from which we gathered 87 responses. We identified 9 SMA NBS programs that have so far detected 288 newborns with SMA out of 3,674,277 newborns screened. Funding, screening methods, organisation, and consent process were variable between SMA NBS programs. Many respondents pointed the lack of cost/benefit data as a major obstacle to SMA NBS implementation. In the next four years, our data suggest a 24% coverage of newborns from countries where a disease-modifying drug is available and 8,5% coverage in countries with no diseases-modifying drugs. The annual proportion of newborns to be screened in the coming years is expected to increase steadily. The experts expressed a strong need for the implementation of SMA NBS as means to improve care for patients with SMA.
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- 2021
9. WE-149. Axonal excitability changes in children with spinal muscular atrophy treated with nusinersen
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Didu Kariyawasam, Arlene D'Silva, Michelle Farrar, and Cindy Shin-Yi Lin
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Neurology ,Physiology (medical) ,Neurology (clinical) ,Sensory Systems - Published
- 2022
10. Safety and efficacy of progressive resistance exercise for Charcot-Marie-Tooth disease in children: a randomised, double-blind, sham-controlled trial
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Joshua Burns, Amy D Sman, Kayla M D Cornett, Elizabeth Wojciechowski, Terri Walker, Manoj P Menezes, Melissa R Mandarakas, Kristy J Rose, Paula Bray, Hugo Sampaio, Michelle Farrar, Kathryn M Refshauge, Jacqueline Raymond, Jennifer Baldwin, Marnee J McKay, Anita Mudge, Leanne Purcell, Clare Miller, Kelly Gray, Meghan Harman, Natalie Gabrael, and Robert A Ouvrier
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Weakness ,medicine.medical_specialty ,Intention-to-treat analysis ,business.industry ,030229 sport sciences ,Standard score ,law.invention ,Clinical trial ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,One-repetition maximum ,Pediatrics, Perinatology and Child Health ,Developmental and Educational Psychology ,Physical therapy ,Medicine ,medicine.symptom ,business ,Adverse effect ,030217 neurology & neurosurgery ,Foot (unit) - Abstract
Summary Background Exercise is potentially therapeutic for neuromuscular disorders, but a risk of harm exists due to overwork weakness. We aimed to assess the safety and efficacy of progressive resistance exercise for foot dorsiflexion weakness in children with Charcot-Marie-Tooth disease. Methods We did this randomised, double-blind, sham-controlled trial across the Sydney Children's Hospitals Network (NSW, Australia). Children aged 6–17 years with Charcot-Marie-Tooth disease were eligible if they had foot dorsiflexion weakness (negative Z score based on age-matched and sex-matched normative reference values). We randomly allocated (1:1) children, with random block sizes of 4, 6, and 8 and stratification by age, to receive 6 months (three times per week on non-consecutive days; 72 sessions in total) of progressive resistance training (from 50% to 70% of the most recent one repetition maximum) or sham training (negligible non-progressed intensity), using an adjustable exercise cuff to exercise the dorsiflexors of each foot. The primary efficacy outcome was the between-group difference in dorsiflexion strength assessed by hand-held dynamometry (expressed as a Z score) from baseline to months 6, 12, and 24. The primary safety outcome was the between-group difference in muscle and intramuscular fat volume of the anterior compartment of the lower leg assessed by MRI (expressed as a scaled volume) from baseline to 6 months and 24 months. Participants, parents, outcome evaluators, and investigators other than the treatment team were masked to treatment assignment. Analysis was by intention to treat. The trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12613000552785. Findings From Sept 2, 2013, to Dec 11, 2014, we randomly assigned 60 children to receive progressive resistance exercise (n=30) or sham training (n=30), and 55 (92%) children completed the trial. ANCOVA-adjusted Z score differences in dorsiflexion strength between groups were 0 (95% CI −0·37 to 0·42; p=0·91) at 6 months, 0·3 (−0·23 to 0·81; p=0·27) at 12 months, and 0·6 (95% CI 0·03 to 1·12; p=0·041) at 24 months. Scaled muscle and fat volume was comparable between groups at 6 months (ANCOVA-adjusted muscle volume difference 0, 95% CI −0·03 to 0·10, p=0·24; and fat volume difference 0, 95% CI −0·01 to 0·05, p=0·25) and 24 months (0, −0·08 to 0·12, p=0·67; and 0, −0·05 to 0·03, p=0·58). No serious adverse events were reported. Interpretation 6 months of targeted progressive resistance exercise attenuated long-term progression of dorsiflexion weakness without detrimental effect on muscle morphology or other signs of overwork weakness in paediatric patients with Charcot-Marie-Tooth disease. Funding Muscular Dystrophy Association and Australian National Health and Medical Research Council.
- Published
- 2017
11. Influence of Swab Material on the Detection of Mycoplasma gallisepticum and Mycoplasma synoviae by Real-Time PCR
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V. Laibinis, Naola Ferguson-Noel, and Michelle Farrar
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DNA, Bacterial ,Mycoplasma gallisepticum ,Serial dilution ,Polyesters ,Mycoplasma synoviae ,Real-Time Polymerase Chain Reaction ,Sensitivity and Specificity ,Specimen Handling ,Microbiology ,Food Animals ,TaqMan ,Animals ,Mycoplasma Infections ,Cotton Fiber ,Poultry Diseases ,General Immunology and Microbiology ,biology ,Diagnostic test ,Building and Construction ,biology.organism_classification ,Trachea ,Nylons ,Real-time polymerase chain reaction ,Specimen Quality ,Animal Science and Zoology ,Chickens - Abstract
Recent reports have shown an increased recovery of cells from flocked nylon swabs which may improve the specimen quality and the real sensitivity of diagnostic tests in a clinical setting. In this study, the detection of Mycoplasma gallisepticum (MG) and M. synoviae (MS), using dry swabs of different materials (nylon flocked, cotton, and polyester), was investigated using real-time TaqMan PCR protocols. Different types of samples, including dilutions of pure broth cultures of MG and MS as well as swabs from tracheas of experimentally infected chickens and field cases of infection, were analyzed. There were no statistical differences in real-time PCR results among the different swab types (P < 0.05), indicating that this is not likely to be a significant factor in MG and MS detection by this method.
- Published
- 2012
12. Bone Health in Children with Duchenne Muscular Dystrophy: A Review
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Michelle Farrar, Nadia Perera, primary
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- 2015
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13. What prospective parents need to know about gene tests such as ‘prepair’
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Gianina Ravenscroft, Michelle Farrar, Nigel Laing, and Royston Ong
14. Congenital and childhood myotonic dystrophy: Current aspects of disease and future directions.
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Ho G, Cardamone M, and Farrar M
- Abstract
Myotonic dystrophy type 1 (DM1) is multisystem disease arising from mutant CTG expansion in the non-translating region of the dystrophia myotonica protein kinase gene. While DM1 is the most common adult muscular dystrophy, with a worldwide prevalence of one in eight thousand, age of onset varies from before birth to adulthood. There is a broad spectrum of clinical severity, ranging from mild to severe, which correlates with number of DNA repeats. Importantly, the early clinical manifestations and management in congenital and childhood DM1 differ from classic adult DM1. In neonates and children, DM1 predominantly affects muscle strength, cognition, respiratory, central nervous and gastrointestinal systems. Sleep disorders are often under recognised yet a significant morbidity. No effective disease modifying treatment is currently available and neonates and children with DM1 may experience severe physical and intellectual disability, which may be life limiting in the most severe forms. Management is currently supportive, incorporating regular surveillance and treatment of manifestations. Novel therapies, which target the gene and the pathogenic mechanism of abnormal splicing are emerging. Genetic counselling is critical in this autosomal dominant genetic disease with variable penetrance and potential maternal anticipation, as is assisting with family planning and undertaking cascade testing to instigate health surveillance in affected family members. This review incorporates discussion of the clinical manifestations and management of congenital and childhood DM1, with a particular focus on hypersomnolence and sleep disorders. In addition, the molecular genetics, mechanisms of disease pathogenesis and development of novel treatment strategies in DM1 will be summarised.
- Published
- 2015
- Full Text
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