Genetic Testing in Children with Epilepsy: Report of a Single-Center Experience

Background: Retrospective observational study to determine diagnostic yield and utility of genetic testing in children with epilepsy attending the Epilepsy Clinic at Children\u27s Hospital, London, Ontario, Canada. Methods: Children (birth-18 years) with epilepsy, who were seen in a 10-year period (January 1, 2008-March 31, 2018), were selected using defined inclusion criteria and by combining clinic datasets and laboratory records. Results: In total, 105 children (52.38% male and 47.61% female) with a variety of seizures were included in the analysis. Developmental delay was documented in the majority (83; 79.04%). Overall, a genetic diagnosis was established in 24 (22.85%) children. The diagnostic yield was highest for whole-exome sequencing (WES), at 35.71%. The yield from microarray was 8.33%. Yields of single-gene testing (18.60%) and targeted multigene panel testing (19.23%) were very similar. Several likely pathogenic and pathogenic variants not previously reported were identified and categorized using ACMG criteria. All diagnosed patients underwent a review of anti-seizure medication management and received counseling on natural history of their disease, possible complications, recurrence risks, and possibilities of preimplantation or prenatal genetic diagnosis. Conclusions: Our study confirms the multiple benefits of detecting a genetic etiology in children with epilepsy. Similar yields in single versus multigene testing underscore the importance of accurate clinical phenotyping. Patients with epilepsy and their caregivers in Ontario would undoubtedly benefit from repatriation of multigene panels and WES to the province

Consensus-based care recommendations for congenital and childhood-onset myotonic dystrophy type 1

Purpose of reviewMyotonic dystrophy type 1 is a multisystemic disorder caused by a noncoding triplet repeat. The age of onset is variable across the lifespan, but in its most severe form, the symptoms appear at birth (congenital myotonic dystrophy) or in the pediatric age range (childhood-onset myotonic dystrophy). These children have a range of disabilities that reduce the lifespan and cause significant morbidity. Currently, there are no agreed upon recommendations for caring for these children.Recent findingsThe Myotonic Dystrophy Foundation recruited 11 international clinicians who are experienced with congenital and childhood-onset myotonic dystrophy to create consensus-based care recommendations. The experts used a 2-step methodology using elements of the single text procedure and nominal group technique. Completion of this process has led to the development of clinical care recommendations for this population.SummaryChildren with myotonic dystrophy often require monitoring and interventions to improve the lifespan and quality of life. The resulting recommendations are intended to standardize and improve the care of children with myotonic dystrophy

Distal arthrogryposis type 5 and PIEZO2 novel variant in a Canadian family.

The group of distal arthrogryposis (DA) disorders is characterized by congenital contractures of the distal joints. In most instances, these are genetic disorders are inherited in an autosomal dominant fashion; however, there is wide genetic and phenotypic spectrum. Distal arthrogryposis type 5 (DA5) is clinically characterized by short stature, deep-set eyes, ptosis, ophthalmoplegia, triangular facies, restrictive pulmonary function, and firm muscles. DA5 is produced by a gain-of-function mutations in PIEZO2 gene, encoding for an ion-channel required to convert mechanical stimulus to biological signals in mammals essential to proprioception. Heterozygous mutations in PIEZO2 may lead to other phenotypes like Gordon Syndrome and Marden Walker syndrome. In this report, we present a 3-generation family affected with DA5, who all carry a variant of unknown clinical significance c.8068A\u3eC (p.Ser2690Arg) in the PIEZO2 gene. DA5 is a very rare condition with less than 20 cases previously reported. Our report expands the phenotype and contributes to evidence of this variant\u27s pathogenicity

Body composition in patients with congenital myotonic dystrophy.

INTRODUCTION: Congenital myotonic dystrophy (CDM) is a rare neuromuscular disorder characterized by severe hypotonia and muscle weakness at birth that tends to improve with age. Understanding lean body and bone mass in this population has important research and clinical implications. The main objective of this study was to determine whether older children with CDM had muscle mass similar to healthy controls. METHODS: Thirty-five patients with CDM (3-13 years old) were enrolled. We analyzed lean body mass (LBM) and bone mineral content using the mechanostat framework, which allows calculation of z-scores for sex, age, and height. RESULTS: All patients had low LBM z-scores (muscle mass); however, higher LBM z-score was positively correlated with age (r = 0.45, P = 0.006), showing that it is closer to normal in older patients. DISCUSSION: Unlike other neuromuscular diseases, older children with CDM have a muscle mass closer to age-matched controls, consistent with the clinical profile of increasing strength in childhood. Muscle Nerve 60: 176-179, 2019

Genetic Testing in Children with Epilepsy: Report of a Single-Center Experience

Retrospective observational study to determine diagnostic yield and utility of genetic testing in children with epilepsy attending the Epilepsy Clinic at Children's Hospital, London, Ontario, Canada. Children (birth-18 years) with epilepsy, who were seen in a 10-year period (January 1, 2008-March 31, 2018), were selected using defined inclusion criteria and by combining clinic datasets and laboratory records. In total, 105 children (52.38% male and 47.61% female) with a variety of seizures were included in the analysis. Developmental delay was documented in the majority (83; 79.04%). Overall, a genetic diagnosis was established in 24 (22.85%) children. The diagnostic yield was highest for whole-exome sequencing (WES), at 35.71%. The yield from microarray was 8.33%. Yields of single-gene testing (18.60%) and targeted multigene panel testing (19.23%) were very similar. Several likely pathogenic and pathogenic variants not previously reported were identified and categorized using ACMG criteria. All diagnosed patients underwent a review of anti-seizure medication management and received counseling on natural history of their disease, possible complications, recurrence risks, and possibilities of preimplantation or prenatal genetic diagnosis. Our study confirms the multiple benefits of detecting a genetic etiology in children with epilepsy. Similar yields in single versus multigene testing underscore the importance of accurate clinical phenotyping. Patients with epilepsy and their caregivers in Ontario would undoubtedly benefit from repatriation of multigene panels and WES to the province

Pharmacological Therapy for the Prevention and Management of Cardiomyopathy in Duchenne Muscular Dystrophy: A systematic review

Cardiomyopathy is a major source of morbidity and mortality in Duchenne muscular dystrophy (DMD) patients now that respiratory care has improved. There is currently no definitive evidence guiding the management of DMD-associated cardiomyopathy (DMD-CM). The objective of this systematic review was to evaluate the effectiveness of pharmacotherapies for the prevention and/or management of DMD-CM and to determine the optimal timing to commence these interventions. A systematic search was conducted in January 2016 using MEDLINE, EMBASE and CINAHL databases and grey literature sources for studies evaluating the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, beta-blockers or aldosterone antagonists. Study quality assessment was conducted using the Downs and Black quality assessment checklist. PRISMA reporting guidelines were used. Of the 15 studies included in this review, most were of low methodological quality. Meta-analysis was not possible due to heterogeneity of studies. ACE inhibitors, angiotensin receptor blockers, beta-blockers and/or aldosterone antagonists tended to improve or preserve left ventricular systolic function and delay the progression of DMD-CM. While there is evidence supporting the use of heart failure medication in patients with DMD, data regarding these interventions for delaying the onset of DMD-CM and when to initiate therapy are lacking. PROSPERO registration: CRD42015029555

Further delineation of TBCK - Infantile hypotonia with psychomotor retardation and characteristic facies type 3.

Deleterious homozygous or compound heterozygous mutations in the TBCK (TBC1-domain-containing kinase) gene (implicated in the MTOR pathway) produce profound hypotonia, global developmental delay, facial dysmorphic features, and brain abnormalities. The disorder has been named infantile hypotonia with psychomotor retardation and characteristic facies-3 (IHPRF3). Here we present two sisters with a novel mutation in TBCK (NM_001163435.2: c.753dup; p.(Lys252*)) who have this ultrarare disorder. We have reviewed the literature on the 33 previously reported cases to provide a characterization of this emerging phenotype. Pathogenic mutations in TBCK have a predominant involvement of the Central Nervous System with a progressive pattern, leading to the conclusion where pathogenic mutations of the said gene lead to a progressive neurodegenerative disease. This report adds novel mutation and features to this complex phenotype. Further investigation is required to understand the pathogenesis of TBCK