For many neuromuscular diseases (NMDs), cardiac disease represents a major cause of morbidity and mortality. The management of cardiac disease in NMDs is made challenging by the broad clinical heterogeneity that exists among many NMDs and by limited knowledge about disease-specific cardiovascular pathogenesis and course-modifying interventions. The overlay of compromise in peripheral muscle function and other organ systems, such as the lungs, also makes the simple application of endorsed adult or pediatric heart failure guidelines to the NMD population problematic. In this statement, we provide background on several NMDs in which there is cardiac involvement, highlighting unique features of NMD-associated myocardial disease that require clinicians to tailor their approach to prevention and treatment of heart failure. Undoubtedly, further investigations are required to best inform future guidelines on NMD-specific cardiovascular health risks, treatments, and outcomes.

Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

CRISPR/Cas9-Induced (CTG⋅CAG) n Repeat Instability in the Myotonic Dystrophy Type 1 Locus: Implications for Therapeutic Genome Editing

CTG repeat expansions in DMPK cause myotonic dystrophy (DM1) with a continuum of severity and ages of onset. Congenital DM1 (CDM1), the most severe form, presents distinct clinical features, large expansions, and almost exclusive maternal transmission. The correlation between CDM1 and expansion size is not absolute, suggesting contributions of other factors. We determined CpG methylation flanking the CTG repeat in 79 blood samples from 20 CDM1-affected individuals; 21, 27, and 11 individuals with DM1 but not CDM1 (henceforth non-CDM1) with maternal, paternal, and unknown inheritance; and collections of maternally and paternally derived chorionic villus samples (7 CVSs) and human embryonic stem cells (4 hESCs). All but two CDM1-affected individuals showed high levels of methylation upstream and downstream of the repeat, greater than non-CDM1 individuals (p = 7.04958 × 10 −12 ). Most non-CDM1 individuals were devoid of methylation, where one in six showed downstream methylation. Only two non-CDM1 individuals showed upstream methylation, and these were maternally derived childhood onset, suggesting a continuum of methylation with age of onset. Only maternally derived hESCs and CVSs showed upstream methylation. In contrast, paternally derived samples (27 blood samples, 3 CVSs, and 2 hESCs) never showed upstream methylation. CTG tract length did not strictly correlate with CDM1 or methylation. Thus, methylation patterns flanking the CTG repeat are stronger indicators of CDM1 than repeat size. Spermatogonia with upstream methylation may not survive due to methylation-induced reduced expression of the adjacent SIX5 , thereby protecting DM1-affected fathers from having CDM1-affected children. Thus, DMPK methylation may account for the maternal bias for CDM1 transmission, larger maternal CTG expansions, age of onset, and clinical continuum, and may serve as a diagnostic indicator.

CpG Methylation, a Parent-of-Origin Effect for Maternal-Biased Transmission of Congenital Myotonic Dystrophy

Objective To genotypically and phenotypically characterize a large pediatric myotonic dystrophy type 1 (DM1) cohort to provide a solid frame of data for future evidence-based health management. Methods Among the 2,697 patients with genetically confirmed DM1 included in the French DM-Scope registry, children were enrolled between January 2010 and February 2016 from 24 centers. Comprehensive cross-sectional analysis of most relevant qualitative and quantitative variables was performed. Results We studied 314 children (52% females, with 55% congenital, 31% infantile, 14% juvenile form). The age at inclusion was inversely correlated with the CTG repeat length. The paternal transmission rate was higher than expected, especially in the congenital form (13%). A continuum of highly prevalent neurodevelopmental alterations was observed, including cognitive slowing (83%), attention deficit (64%), written language (64%), and spoken language (63%) disorders. Five percent exhibited autism spectrum disorders. Overall, musculoskeletal impairment was mild. Despite low prevalence, cardiorespiratory impairment could be life-threatening, and frequently occurred early in the first decade (25.9%). Gastrointestinal symptoms (27%) and cataracts (7%) were more frequent than expected, while endocrine or metabolic disorders were scarce. Conclusions The pedDM-Scope study details the main genotype and phenotype characteristics of the 3 DM1 pediatric subgroups. It highlights striking profiles that could be useful in health care management (including transition into adulthood) and health policy planning.

A large multicenter study of pediatric myotonic dystrophy type 1 for evidence-based management.

Myotonic dystrophy type 1 is the most common form of adult muscular dystrophy and has the world's highest prevalence in the Saguenay-Lac-St-Jean region, due to a founder effect. This autosomal dominant disorder results from an unstable CTG repeat expansion in DMPK. This region of Canada has had a family screening and predictive testing program for this disorder since 1988. Heterozygotes for small expansions (50-100 CTG repeats) can be asymptomatic or minimally affected. The aim of this study was to assess anticipation for these individuals. At the time of this study, the molecular data of 40 individuals and their 76 affected children were available. We compared 76 parent-child pairs. Most offspring (92.1%) had a larger number of repeats than their parent and the median number of repeats in the offspring was 325 (range, 57-2000). The number of CTG repeats was significantly greater when the mutation was transmitted by a father (median, 425 repeats; range, 70-2000), than when it was transmitted by a mother (median, 200 repeats; range, 57-1400). The majority (65.8%) of children also had a more severe phenotype than their parent but the sex of the parent had no significant influence on the severity of the child's phenotype. No congenital phenotype was observed. These results confirm that anticipation is present even when the parent is heterozygous for a small CTG expansion. The parental sex has an impact on the size of the repeat in the next generation, larger increases being transmitted by males with a small expansion.

Annabelle Pratte

Papers

Anticipation in myotonic dystrophy type 1 parents with small CTG expansions