Genome and RNA sequencing boost neuromuscular diagnoses to 62% from 34% with exome sequencing alone.

OBJECTIVE: Most families with heritable neuromuscular disorders do not receive a molecular diagnosis. Here we evaluate diagnostic utility of exome, genome, RNA sequencing, and protein studies and provide evidence-based recommendations for their integration into practice. METHODS: In total, 247 families with suspected monogenic neuromuscular disorders who remained without a genetic diagnosis after standard diagnostic investigations underwent research-led massively parallel sequencing: neuromuscular disorder gene panel, exome, genome, and/or RNA sequencing to identify causal variants. Protein and RNA studies were also deployed when required. RESULTS: Integration of exome sequencing and auxiliary genome, RNA and/or protein studies identified causal or likely causal variants in 62% (152 out of 247) of families. Exome sequencing alone informed 55% (83 out of 152) of diagnoses, with remaining diagnoses (45%; 69 out of 152) requiring genome sequencing, RNA and/or protein studies to identify variants and/or support pathogenicity. Arrestingly, novel disease genes accounted for <4% (6 out of 152) of diagnoses while 36.2% of solved families (55 out of 152) harbored at least one splice-altering or structural variant in a known neuromuscular disorder gene. We posit that contemporary neuromuscular disorder gene-panel sequencing could likely provide 66% (100 out of 152) of our diagnoses today. INTERPRETATION: Our results emphasize thorough clinical phenotyping to enable deep scrutiny of all rare genetic variation in phenotypically consistent genes. Post-exome auxiliary investigations extended our diagnostic yield by 81% overall (34-62%). We present a diagnostic algorithm that details deployment of genomic and auxiliary investigations to obtain these diagnoses today most effectively. We hope this provides a practical guide for clinicians as they gain greater access to clinical genome and transcriptome sequencing.

Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease.

Purpose: FINCA disease (Fibrosis, Neurodegeneration and Cerebral Angiomatosis, OMIM 618278) is an infantile-onset neurodevelopmental and multiorgan disease. Since our initial report in 2018, additional patients have been described. FINCA is the first human disease caused by recessive variants in the highly conserved NHLRC2 gene. Our previous studies have shown that Nhlrc2-null mouse embryos die during gastrulation, indicating the essential role of the protein in embryonic development. Defect in NHLRC2 leads to cerebral neurodegeneration and severe pulmonary, hepatic and cardiac fibrosis. Despite having a structure suggestive of an enzymatic role and the clinical importance of NHLRC2 in multiple organs, the specific physiological role of the protein is unknown. Methods: The clinical histories of five novel FINCA patients diagnosed with whole exome sequencing were reviewed. Segregation analysis of the biallelic, potentially pathogenic NHLRC2 variants was performed using Sanger sequencing. Studies on neuropathology and NHLRC2 expression in different brain regions were performed on autopsy samples of three previously described deceased FINCA patients. Results: One patient was homozygous for the pathogenic variant c.442G > T, while the other four were compound heterozygous for this variant and two other pathogenic NHLRC2 gene variants. All five patients presented with multiorgan dysfunction with neurodevelopmental delay, recurrent infections and macrocytic anemia as key features. Interstitial lung disease was pronounced in infancy but often stabilized. Autopsy samples revealed widespread, albeit at a lower intensity than the control, NHLRC2 expression in the brain. Conclusion: This report expands on the characteristic clinical features of FINCA disease. Presentation is typically in infancy, and although patients can live to late adulthood, the key clinical and histopathological features are fibrosis, infection susceptibility/immunodeficiency/intellectual disability, neurodevelopmental disorder/neurodegeneration and chronic anemia/cerebral angiomatosis (hence the acronym FINCA) that enable an early diagnosis confirmed by genetic investigations.

Vibration Therapy as an Early Intervention for Children Aged 2-4 Years with Cerebral Palsy: A Feasibility Study.

Aims: To evaluate the feasibility and acceptability of vibration therapy (VT) in preschool children with cerebral palsy (CP) and obtain preliminary data on its potential effectiveness.Methods: Nine children aged 2.5-4.8 years (4 boys) with CP GMFCS levels I-III participated in a single-group feasibility study, undergoing a 12-week control period without intervention, followed by 12 weeks of home-based VT (four times/week, 9 min/day, frequency 20 Hz). We assessed adherence to VT protocol, adverse events, and family acceptability of VT. Clinical assessments included motor function (GMFM-66), body composition (DXA), mobility (10-meter walk/run test), and health-related quality of life (PedsQL).Results: VT was well tolerated and acceptable to families, with high adherence levels reported (mean = 93%). There were no observed between-period differences (ΔControl vs ΔVT) except for an improvement in the PedsQL "Movement & Balance" dimension with VT (p = 0.044). Nonetheless, changes after the VT but not the Control period were suggestive of potential treatment benefits for mobility, gross motor function, and body composition (lean mass and legs bone mineral density).Conclusion: Home-based VT is feasible and acceptable for preschool children with CP. Our preliminary data suggest potential health benefits from VT for these children, supporting larger randomized trials to assess its effectiveness properly. Clinical trial registration number: Australian New Zealand Clinical Trials Registry (ACTRN12618002027291).

Compound heterozygous splicing variants expand the genotypic spectrum of EMC1-related disorders.

EMC1 encodes subunit 1 of the endoplasmic reticulum (ER) membrane protein complex (EMC), a transmembrane domain insertase involved in membrane protein biosynthesis. Variants in EMC1 are described as a cause of global developmental delay, hypotonia, cortical visual impairment, and commonly, cerebral atrophy on MRI scan. We report an individual with severe global developmental delay and progressive cerebellar atrophy in whom exome sequencing identified a heterozygous essential splice-site variant in intron-3 of EMC1 (NM_015047.3:c.287-1G>A). Whole genome sequencing (WGS) identified a deep intronic variant in intron-20 of EMC1 (NM_015047.3:c.2588-771C>G) that was poorly predicted by in silico programs to disrupt pre-mRNA splicing. Reverse Transcription-PCR (RT-PCR) revealed stochastic activation of a pseudo-exon associated with the c.2588-771C>G variant and mis-splicing arising from the c.287-1G>A variant. This case highlights the utility of WGS and RNA studies to identify and assess likely pathogenicity of deep intronic variants and expands the genotypic and phenotypic spectrum of EMC1-related disorders.

Cochlear nerve deficiency in SOX11-related Coffin-Siris syndrome.

The phenotypic spectrum of SOX11-related Coffin-Siris syndrome (CSS) is expanding with reports of new associations. SOX11 is implicated in neurogenesis and inner ear development. Cochlear nerve deficiency, absence or hypoplasia, is commonly associated with cochlear canal stenosis or with CHARGE syndrome, a monogenic condition that affects inner ear development. SOX11 is a transcription factor essential for neuronal identity, highly correlated with the expression of CHD7, which regulates SOX11. We present two unrelated probands, each with novel de novo SOX11 likely pathogenic variants and phenotypic manifestations of CSS including global developmental delay, growth deficiency, and hypoplastic nails. They have unilateral sensorineural hearing loss due to cochlear nerve deficiency confirmed on MRI. SOX11 is implicated in sensory neuron survival and maturation. It is highly expressed in the developing inner ear. Homozygous ablation of SOX11 in a mouse model resulted in a reduction in sensory neuron survival and decreased axonal growth. A heterozygous knockout mice model had hearing impairment with grossly normal inner ear structures like the two probands reported. We propose cochlear nerve deficiency as a new phenotypic feature of SOX11-related CSS. Magnetic resonance imaging is useful in delineating the cochlear nerve deficiency and other CSS-related brain malformations.

PIGN encephalopathy: Characterizing the epileptology.

OBJECTIVE: Epilepsy is common in patients with PIGN diseases due to biallelic variants; however, limited epilepsy phenotyping data have been reported. We describe the epileptology of PIGN encephalopathy. METHODS: We recruited patients with epilepsy due to biallelic PIGN variants and obtained clinical data regarding age at seizure onset/offset and semiology, development, medical history, examination, electroencephalogram, neuroimaging, and treatment. Seizure and epilepsy types were classified. RESULTS: Twenty six patients (13 female) from 26 families were identified, with mean age 7 years (range = 1 month to 21 years; three deceased). Abnormal development at seizure onset was present in 25 of 26. Developmental outcome was most frequently profound (14/26) or severe (11/26). Patients presented with focal motor (12/26), unknown onset motor (5/26), focal impaired awareness (1/26), absence (2/26), myoclonic (2/26), myoclonic-atonic (1/26), and generalized tonic-clonic (2/26) seizures. Twenty of 26 were classified as developmental and epileptic encephalopathy (DEE): 55% (11/20) focal DEE, 30% (6/20) generalized DEE, and 15% (3/20) combined DEE. Six had intellectual disability and epilepsy (ID+E): two generalized and four focal epilepsy. Mean age at seizure onset was 13 months (birth to 10 years), with a lower mean onset in DEE (7 months) compared with ID+E (33 months). Patients with DEE had drug-resistant epilepsy, compared to 4/6 ID+E patients, who were seizure-free. Hyperkinetic movement disorder occurred in 13 of 26 patients. Twenty-seven of 34 variants were novel. Variants were truncating (n = 7), intronic and predicted to affect splicing (n = 7), and missense or inframe indels (n = 20, of which 11 were predicted to affect splicing). Seven variants were recurrent, including p.Leu311Trp in 10 unrelated patients, nine with generalized seizures, accounting for nine of the 11 patients in this cohort with generalized seizures. SIGNIFICANCE: PIGN encephalopathy is a complex autosomal recessive disorder associated with a wide spectrum of epilepsy phenotypes, typically with substantial profound to severe developmental impairment.

Impact and predictors of quality of life in adults diagnosed with a genetic muscle disorder: a nationwide population-based study.

OBJECTIVES: To determine the impact of genetic muscle disorders and identify the sociodemographic, illness, and symptom factors influencing quality of life. METHODS: Adults (aged 16-90 years) with a confirmed clinical or molecular diagnosis of a genetic muscle disorder identified as part of a nationwide prevalence study were invited to complete an assessment of the impact of their condition. Quality of life was measured using the World Health Organization Quality of Life questionnaire. Impact was measured via the prevalence of symptoms and comparisons of quality of life against New Zealand norms. Multivariate regression models were used to identify the most significant predictors of quality of life domains. RESULTS: 490/596 participants completed the assessment (82.2% consent rate). Quality of life was lower than the general population on physical (t = 9.37 p < 0.0001, d = 0.54) social (t = 2.27 p = 0.02, d = 0.13) and environmental domains (t = 2.28 p = 0.02, d = 0.13), although effect sizes were small. No difference was found on the psychological domain (t = - 1.17 p = 0.24, d = 0.07). Multivariate regression models (predicting 42%-64% of the variance) revealed personal factors (younger age, being in employment and in a relationship), symptoms (lower pain, fatigue, and sleep difficulties), physical health (no need for ventilation support, fewer activity limitations and no comorbidities), and psychosocial factors (lower depression, anxiety, behavioural dyscontrol and higher self-efficacy, satisfaction with health care and social support) contributed to improved quality of life. CONCLUSIONS: A range of factors influence the quality of life in adults diagnosed with a genetic muscle disorder and some may serve as targets for multi-faceted intervention.

Coping in Children and Adolescents with a Genetic Muscle Disorder -Findings from a Population-Based Study.

BACKGROUND: The impacts of genetic muscle disorders on quality of life in affected children are well-documented. However, few studies have investigated children's coping strategies and relationships between coping and quality of life. OBJECTIVES: To determine coping strategy use, efficacy, and associations with quality of life in children with a genetic muscle disorder. METHODS: Forty-eight children (6-15 years, 58% male) with a genetic muscle disorder were identified as part of a national prevalence study. Children completed the Kidcope in response to a specific stressor (doctors visits) and the Pediatric Quality of Life Inventory Neuromuscular Module. RESULTS: 'Wishful thinking' (75%, 36/48) and 'cognitive restructuring' (71%, 34/48) were the most frequently used coping strategies. 'Self-criticism' (12%, 6/48), and 'blaming others' and 'resignation' (both 19%, 9/48) were the least used strategies. Coping strategy use did not differ across age and sex groups (p's from 0.08 to 1.00). Positive coping strategies tended to be more effective (medians ranged from 2.00 to 2.75) than negative strategies (medians ranged from 1.38 to 2.50). Using a greater number of different types of positive (F(4, 46) = 5.79, p = 0.001) and/or negative (F(4, 44) = 5.64, p 0.001) coping strategies was linked to poorer health-related quality of life. CONCLUSION: We conclude that children with genetic muscle disorders use a wide range of positive and/or negative coping strategies in response to stressors associated with a doctor visit and may benefit from greater support to improve health-related quality of life. Findings support the value of routine screening of children's coping to identify those who would benefit from support.

A new syndrome of moyamoya disease, kidney dysplasia, aminotransferase elevation, and skin disease associated with de novo variants in RNF213.

Ring-finger protein 213 (RNF213) encodes a protein of unknown function believed to play a role in cellular metabolism and angiogenesis. Gene variants are associated with susceptibility to moyamoya disease. Here, we describe two children with moyamoya disease who also demonstrated kidney disease, elevated aminotransferases, and recurrent skin lesions found by exome sequencing to have de novo missense variants in RNF213. These cases highlight the ability of RNF213 to cause Mendelian moyamoya disease in addition to acting as a genetic susceptibility locus. The cases also suggest a new, multi-organ RNF213-spectrum disease characterized by liver, skin, and kidney pathology in addition to severe moyamoya disease caused by heterozygous, de novo C-terminal RNF213 missense variants.

WGS and RNA Studies Diagnose Noncoding DMD Variants in Males With High Creatine Kinase.

OBJECTIVE: To describe the diagnostic utility of whole-genome sequencing and RNA studies in boys with suspected dystrophinopathy, for whom multiplex ligation-dependent probe amplification and exomic parallel sequencing failed to yield a genetic diagnosis, and to use remnant normal DMD splicing in 3 families to define critical levels of wild-type dystrophin bridging clinical spectrums of Duchenne to myalgia. METHODS: Exome, genome, and/or muscle RNA sequencing was performed for 7 males with elevated creatine kinase. PCR of muscle-derived complementary DNA (cDNA) studied consequences for DMD premessenger RNA (pre-mRNA) splicing. Quantitative Western blot was used to determine levels of dystrophin, relative to control muscle. RESULTS: Splice-altering intronic single nucleotide variants or structural rearrangements in DMD were identified in all 7 families. Four individuals, with abnormal splicing causing a premature stop codon and nonsense-mediated decay, expressed remnant levels of normally spliced DMD mRNA. Quantitative Western blot enabled correlation of wild-type dystrophin and clinical severity, with 0%-5% dystrophin conferring a Duchenne phenotype, 10% ± 2% a Becker phenotype, and 15% ± 2% dystrophin associated with myalgia without manifesting weakness. CONCLUSIONS: Whole-genome sequencing relied heavily on RNA studies to identify DMD splice-altering variants. Short-read RNA sequencing was regularly confounded by the effectiveness of nonsense-mediated mRNA decay and low read depth of the giant DMD mRNA. PCR of muscle cDNA provided a simple, yet informative approach. Highly relevant to genetic therapies for dystrophinopathies, our data align strongly with previous studies of mutant dystrophin in Becker muscular dystrophy, with the collective conclusion that a fractional increase in levels of normal dystrophin between 5% and 20% is clinically significant.

Exercise Cardiac Magnetic Resonance Imaging in Boys With Duchenne Muscular Dystrophy Without Cardiac Disease.

BACKGROUND: Duchenne muscular dystrophy is caused by mutations in the DMD gene, resulting in cardiomyopathy in all affected children by 18 years. Although cardiomyopathy is now the leading cause of mortality in these children, there is ongoing debate regarding timely diagnosis, secondary prevention, and treatment of this condition. The purpose of this study was to use exercise cardiac magnetic resonance imaging in asymptomatic young boys with Duchenne muscular dystrophy to describe their heart function and compare this with healthy controls. METHODS: We studied 11 boys with Duchenne muscular dystrophy aged 8.6 to 13.9 years and 11 healthy age- and sex-matched controls. RESULTS: Compared with the controls, boys with Duchenne muscular dystrophy had lower ejection fraction at rest (57% versus 63%; P = 0.004). During submaximal exercise, they reached similar peak tachycardia but increased their heart rate and cardiac output only half as much as controls (P = 0.003 and P = 0.014, respectively). End-systolic volume remained higher in boys with Duchenne muscular dystrophy both at rest and during exercise. When transthoracic echocardiography was compared with cardiac magnetic resonance imaging, 45% of the echocardiograms had suboptimal or poor views in the Duchenne muscular dystrophy group. CONCLUSIONS: Boys with Duchenne muscular dystrophy had abnormalities in left ventricular systolic function that were exaggerated by exercise stress. Exercise cardiac magnetic resonance imaging is feasible in a select population of children with Duchenne muscular dystrophy, and it has the potential to unmask early signs of cardiomyopathy.

Exercise Training as Part of Musculoskeletal Management for Congenital Myopathy: Where Are We Now?

Congenital myopathy is a heterogeneous group of muscle disorders characterized by muscle weakness and hypotonia. This condition is associated with a range of skeletal, respiratory, and ophthalmologic complications and requires a multidisciplinary therapeutic approach aimed at maximizing the function and independence of patients. One promising direction for therapeutic intervention is physical exercise rehabilitation, given its demonstrated ability to promote muscle and bone health of patients with a variety of neuromuscular conditions. However, there are few data to assist health care professionals identify the optimal physical activity levels and exercise type, including the intensity, frequency, and duration. This lack of empirical evidence is particularly problematic given the fact that inappropriate exercise modes can potentially cause muscle damage in patients with congenital myopathy. In this article, we discuss the rationale behind the incorporation of two types of physical exercises, strength and aerobic training, into the clinical care of patients with congenital myopathy. Given the paucity of literature on the management of congenital myopathy, we review the results of published research on the treatment of both congenital myopathy and other neuromuscular diseases that could provide helpful insights into the physical rehabilitation of patients with congenital myopathy. We also discuss the potential benefits of vibration therapy, which has been studied in patients with other neuromuscular disorders over the last two decades. We conclude by proposing directions for future research on physical rehabilitation of patients with congenital myopathy.

Recurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy.

We present eight families with arthrogryposis multiplex congenita and myopathy bearing a TTN intron 213 extended splice-site variant (NM_001267550.1:c.39974-11T>G), inherited in trans with a second pathogenic TTN variant. Muscle-derived RNA studies of three individuals confirmed mis-splicing induced by the c.39974-11T>G variant; in-frame exon 214 skipping or use of a cryptic 3' splice-site effecting a frameshift. Confounding interpretation of pathogenicity is the absence of exons 213-217 within the described skeletal muscle TTN N2A isoform. However, RNA-sequencing from 365 adult human gastrocnemius samples revealed that 56% specimens predominantly include exons 213-217 in TTN transcripts (inclusion rate ≥66%). Further, RNA-sequencing of five fetal muscle samples confirmed that 4/5 specimens predominantly include exons 213-217 (fifth sample inclusion rate 57%). Contractures improved significantly with age for four individuals, which may be linked to decreased expression of pathogenic fetal transcripts. Our study extends emerging evidence supporting a vital developmental role for TTN isoforms containing metatranscript-only exons.

Clinical presentation and proteomic signature of patients with TANGO2 mutations.

Transport And Golgi Organization protein 2 (TANGO2) deficiency has recently been identified as a rare metabolic disorder with a distinct clinical and biochemical phenotype of recurrent metabolic crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias, and encephalopathy with cognitive decline. We report nine subjects from seven independent families, and we studied muscle histology, respiratory chain enzyme activities in skeletal muscle and proteomic signature of fibroblasts. All nine subjects carried autosomal recessive TANGO2 mutations. Two carried the reported deletion of exons 3 to 9, one homozygous, one heterozygous with a 22q11.21 microdeletion inherited in trans. The other subjects carried three novel homozygous (c.262C>T/p.Arg88*; c.220A>C/p.Thr74Pro; c.380+1G>A), and two further novel heterozygous (c.6_9del/p.Phe6del); c.11-13delTCT/p.Phe5del mutations. Immunoblot analysis detected a significant decrease of TANGO2 protein. Muscle histology showed mild variation of fiber diameter, no ragged-red/cytochrome c oxidase-negative fibers and a defect of multiple respiratory chain enzymes and coenzyme Q10 (CoQ10 ) in two cases, suggesting a possible secondary defect of oxidative phosphorylation. Proteomic analysis in fibroblasts revealed significant changes in components of the mitochondrial fatty acid oxidation, plasma membrane, endoplasmic reticulum-Golgi network and secretory pathways. Clinical presentation of TANGO2 mutations is homogeneous and clinically recognizable. The hemizygous mutations in two patients suggest that some mutations leading to allele loss are difficult to detect. A combined defect of the respiratory chain enzymes and CoQ10 with altered levels of several membrane proteins provides molecular insights into the underlying pathophysiology and may guide rational new therapeutic interventions.

Prevalence of Charcot-Marie-Tooth disease across the lifespan: a population-based epidemiological study.

OBJECTIVES: This population-based study aimed to determine age-standardised prevalence of Charcot-Marie-Tooth disease (CMT) across the lifespan using multiple case ascertainment sources. DESIGN: Point-prevalence epidemiological study in the Auckland Region of New Zealand (NZ). SETTING: Multiple case ascertainment sources including primary care centres, hospital services, neuromuscular disease registry, community-based organisations and self-referral were used to identify potentially eligible participants. PARTICIPANTS: Adults (≥16 years, n=207, 87.7%) and children (<16 years, n=29, 12.3%) with a confirmed clinical or molecular diagnosis of CMT, hereditary sensory neuropathy, hereditary motor neuropathy or hereditary neuropathy with liability to pressure palsies who resided in the Auckland Region of NZ on 1 June 2016. PRIMARY OUTCOME: Prevalence per 100 000 persons with 95% CIs by subtype, age and sex were calculated and standardised to the world population. RESULTS: Age-standardised point prevalence of all CMT cases was 15.7 per 100 000 (95% CI 11.6 to 21.0). Highest prevalence was identified in those aged 50-64 years 25.2 per 100 000 (95% CI 19.4 to 32.6). Males had a higher prevalence (16.6 per 100 000, 95% CI 10.9 to 25.2) than females (14.6 per 100 000, 95% CI 9.6 to 22.4). Prevalence of CMT1A was 6.9 per 100 000 (95% CI 5.6 to 8.4). The majority (93.2%) of cases were identified through medical records, with 6.8% of cases uniquely identified through community sources. CONCLUSIONS: A small but significant proportion of people with CMT are not connected to healthcare services. Epidemiological studies using medical records alone to identify cases may risk underestimating prevalence. Further studies using population-based methods and reporting age-standardised prevalence are needed to improve global understanding of the epidemiology of CMT.

A Nationwide, Population-Based Prevalence Study of Genetic Muscle Disorders.

BACKGROUND: Previous epidemiological studies of genetic muscle disorders have relied on medical records to identify cases and may be at risk of selection biases or have focused on selective population groups. OBJECTIVES: This study aimed to determine age-standardised prevalence of genetic muscle disorders through a nationwide, epidemiological study across the lifespan using the capture-recapture method. METHODS: Adults and children with a confirmed clinical or molecular diagnosis of a genetic muscle disorder, resident in New Zealand on April 1, 2015 were identified using multiple overlapping sources. Genetic muscle disorders included the muscular dystrophies, congenital myopathies, ion channel myopathies, GNE myopathy, and Pompe disease. Prevalence per 100,000 persons by age, sex, disorder, ethnicity and geographical region with 95% CIs was calculated using Poisson distribution. Direct standardisation was applied to age-standardise prevalence to the world population. Completeness of case ascertainment was determined using capture-recapture modelling. RESULTS: Age standardised minimal point prevalence of all genetic muscle disorders was 22.3 per 100,000 (95% CI 19.5-25.6). Prevalence in Europeans of 24.4 per 100,000, (95% CI 21.1-28.3) was twice that observed in NZ's other 3 main ethnic groups; Maori (12.6 per 100,000, 95% CI 7.8-20.5), Pasifika (11.0 per 100,000, 95% CI 5.4-23.3), and Asian (9.13 per 100,000, 95% CI 5.0-17.8). Crude prevalence of myotonic dystrophy was 3 times higher in Europeans (10.5 per 100,000, 9.4-11.8) than Maori and Pasifika (2.5 per 100,000, 95% CI 1.5-4.2 and 0.7 per 100,000, 95% CI 0.1-2.7 respectively). There were considerable regional variations in prevalence, although there was no significant association with social deprivation. The final capture-recapture model, with the least deviance, estimated the study ascertained 99.2% of diagnosed cases. CONCLUSIONS: Ethnic and regional differences in the prevalence of genetic muscle disorders need to be considered in service delivery planning, evaluation, and decision making.

Isolated seizures during the first episode of relapsing myelin oligodendrocyte glycoprotein antibody-associated demyelination in children.

Myelin oligodendrocyte glycoprotein (MOG) antibodies have a strong association with acute disseminated encephalomyelitis (ADEM) in children, and bilateral and recurrent optic neuritis in children and adults. Recent reports suggest that seizures and encephalopathy may occur in children and adults with MOG antibody-associated disease. We describe the clinical, laboratory, and radiological course of four MOG antibody-positive children who first presented with isolated seizures without fulfilling clinical or radiological criteria for ADEM or other central nervous system demyelination syndromes, who months to years later developed more typical demyelination. This case series highlights a novel observation that isolated seizures in the absence of ADEM may be the index presentation for MOG antibody-associated disease, which should therefore be considered a form of autoimmune epilepsy. It would be reasonable to test for MOG antibodies in children with seizures accompanied by subtle inflammatory changes on magnetic resonance imaging or cerebrospinal fluid analyses, particularly if followed by demyelination, given the clinical and therapeutic implications of an expedited diagnosis in minimizing long-term disability. WHAT THIS PAPER ADDS: Isolated seizures in the absence of acute disseminated encephalomyelitis may be the index presentation for myelin oligodendrocyte glycoprotein antibody-associated demyelination.

CONVULSIONES AISLADAS DURANTE UNA PRIMERA RECAÍDA DE UN EVENTO DESMIELINIZANTE ASOCIADA A ANTICUERPOS CONTRA LA GLICOPROTEINA DE LOS OLIGODENDROCITOS DE LA MIELINA: Los anticuerpos contra la Glicoproteina de los Oligodendrocitos de la Mielina (MOG) están fuertemente asociados con la Encefalomielitis Aguda Diseminada (EMAD) en niños, y con la Neuritis Óptica bilateral recurrente en niños y adultos. Recientes reportes sugieren que convulsiones y encefalopatía pueden presentarse con enfermedad asociada a anticuerpos MOG. Describimos la evolución clínica, serologica y radiológica de cuatro niños con anticuerpos positivos para MOG cuya primera presentación fueron convulsiones aisladas sin cumplir todos los criterios cínicos ni radiológicos para EMAD u otro síndrome desmielinizante del sistema nervioso central; y, que luego de meses a años, desarrollaron una desmielinización típica. Esta serie de casos resalta una nueva observación, en la cual, convulsiones aisladas en ausencia de EMAD puede ser la presentación de enfermedad asociada a anticuerpos para MOG; y, por lo tanto, debe ser considerada una forma de epilepsia autoinmune. Sería razonable buscar anticuerpos para MOG en aquellos niños con convulsiones que se acompañan de cambios inflamatorios sutiles en la resonancia magnética y análisis de líquido cefalorraquídeo, en particular, en aquellos que posteriormente desarrollan desmielinización teniendo en cuenta las implicancias clínicas y terapéuticas de realizar un diagnóstico rápido con el fin de minimizar la discapacidad a largo plazo.

CONVULSÕES ISOLADAS DURANTE O PRIMEIRO EPISÓDIO DE DESMIELINIZAÇÃO ASSOCIADA AO ANTICORPO DE GLICOPROTEÍNA DE OLIGODENDRÓCITO DA MIELINA EM CRIANÇAS: Anticorpos de glicoproteína de oligodendrócito da mielina (GOM) têm forte associação com encefalomielite aguda disseminada (EMAD) em crianças, e com neurite óptica bilateral e recorrente em crianças e adultos. Relatos recentes sugerem que convulsões e encefalopatia podem ocorrer em adultos e crianças com doença associada aos anticorpos GOM. Descrevemos o curso clínico, laboratorial, e radiológico de crianças com anticorpos GOM positivos que apresentaram convulsões isoladas pela primeira vez, sem preencher os critérios clínicos e radiológicos para EMAD ou para outras síndromes desmielinizantes do sistema nervoso central, que nos meses ou anos seguintes desenvolveram desmielinização mais típica. Esta série de casos realça uma nova observação de que convulsões isoladas na ausência de EMAD podem ser sinal de doença relacionada ao anticorpo GOM, e deve portanto ser considerada uma forma de epilepsia auto-imune. Seria razoável testar anticorpos GOM em crianças com convulsões acompanhada de doenças inflamatórias sutis à ressonância magnética ou na análise do fluido cérebro-espinhal, particularmente se seguida por desmielinização, dadas as implicações clínicas e terapêuticas do diagnóstico rápido em minimizar incapacidades no longo prazo.

STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility.

SH3 and cysteine-rich domain-containing protein 3 (STAC3) is an essential component of the skeletal muscle excitation-contraction coupling (ECC) machinery, though its role and function are not yet completely understood. Here, we report 18 patients carrying a homozygous p.(Trp284Ser) STAC3 variant in addition to a patient compound heterozygous for the p.(Trp284Ser) and a novel splice site change (c.997-1G > T). Clinical severity ranged from prenatal onset with severe features at birth, to a milder and slowly progressive congenital myopathy phenotype. A malignant hyperthermia (MH)-like reaction had occurred in several patients. The functional analysis demonstrated impaired ECC. In particular, KCl-induced membrane depolarization resulted in significantly reduced sarcoplasmic reticulum Ca2+ release. Co-immunoprecipitation of STAC3 with CaV 1.1 in patients and control muscle samples showed that the protein interaction between STAC3 and CaV 1.1 was not significantly affected by the STAC3 variants. This study demonstrates that STAC3 gene analysis should be included in the diagnostic work up of patients of any ethnicity presenting with congenital myopathy, in particular if a history of MH-like episodes is reported. While the precise pathomechanism remains to be elucidated, our functional characterization of STAC3 variants revealed that defective ECC is not a result of CaV 1.1 sarcolemma mislocalization or impaired STAC3-CaV 1.1 interaction.

Imaging the heart to detect cardiomyopathy in Duchenne muscular dystrophy: A review.

Duchenne Muscular Dystrophy is the most common paediatric neuromuscular disorder. Mutations in the DMD gene on the X-chromosome result in progressive skeletal muscle weakness as the main clinical manifestation. However, cardiac muscle is also affected, with cardiomyopathy becoming an increasingly recognised cause of morbidity, and now the leading cause of mortality in this group. The diagnosis of cardiomyopathy has often been made late due to technical limitations in transthoracic echocardiograms and delayed symptomatology in less mobile patients. Increasingly, evidence supports earlier pharmacological intervention in cardiomyopathy to improve outcomes. However, the optimal timing of initiation remains uncertain, and the benefits of prophylactic therapy are unproven. Current treatment guidelines suggest initiation of therapy once cardiac dysfunction is detected. This review focuses on new and evolving techniques for earlier detection of Duchenne muscular dystrophy-associated cardiomyopathy. Transthoracic echocardiography or cardiac magnetic resonance imaging performed under physiological stress (dobutamine or exercise), can unmask early cardiac dysfunction. Cardiac magnetic resonance imaging can define cardiac function with greater accuracy and reliability than an echocardiogram, and is not limited by body habitus. Improved imaging techniques, used in a timely fashion, offer the potential for early detection of cardiomyopathy and improved long-term outcomes.

Impacts for Children Living with Genetic Muscle Disorders and their Parents - Findings from a Population-Based Study.

BACKGROUND: Genetic muscle disorders, including muscular dystrophies, congenital myopathies, and ion channel muscle diseases can be associated with significant disability. OBJECTIVE: This study aimed to explore child and parent perspectives of the impact of living with a genetic muscle disorder. METHODS: Eighty-three children (<16 years) with a clinical or molecular diagnosis were identified as part of a national prevalence study. Parents' experiences and needs were assessed using a study-specific questionnaire. Additional outcome measures included parent and child self-report versions of the Behavior Assessment System for Children and the Pediatric Quality of Life Inventory. Parents also completed the Hospital Anxiety and Depression Scale and Activlim. RESULTS: Sixty-four percent of families had a combined annual household income below $60,000 NZD ($43,650 USD), being less than the national median income of $73,000 NZD ($53,112 USD). Parents reported needing more support than they were currently receiving (40%), particularly with household chores (23%) and transportation (17%). Few parents (13%) or children (4%) reported significant child behavioral difficulties. Risks of impaired quality of life were high (parent proxy 71%, child report 70%), and associated with co-morbid health conditions (p = 0.008), functional status (p = 0.001), wheelchair use (p = 0.001) and mechanical ventilation (p = 0.01). CONCLUSIONS: Findings are relevant to those involved in the care and support of children, and their families, who are impacted by genetic muscle disorders. Targeted guidelines are required to inform the provision of services, alongside promotion of existing community services to improve access to financial support, and assistance with day-to-day functioning. Future research should examine intervention and treatment options aimed at maximising affected children's quality of life.