Congenital and childhood myotonic dystrophy: Current aspects of disease and future directions

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.

Keywords: Childhood myotonic dystrophy; Clinical manifestations; Congenital myotonic dystrophy; Management; Myotonic dystrophy type 1; Natural history.

Figure 1

Genogram of family with myotonic dystrophy type 1 illustrating autosomal dominant inheritance. The numbers in brackets indicate the number of CTG triplet repeats in the 3’ untranslated portion of the DMPK gene of affected individuals. Square = male; Circle = female; Black symbol = DM1 affected individuals; Strikethrough symbol = deceased.

Figure 2

The genetic basis of myotonic dystrophy type 1. In DM1 there is an unstable CTG expansion at the DM1 locus, DMPK. Repeat size correlates with phenotype of DM1. DM1: Myotonic dystrophy type 1; DMPK: Dystrophia myotonica protein kinase.

Figure 3

Pathogenic mechanisms in myotonic dystrophy type 1: (A) Normal RNA processing in cell with normal CTG repeats at the myotonic dystrophy type 1 locus; (B) Effects of expanded CTG repeat at the DM1 locus. A: Normal actions of MBNL and CUG BP in regulating alternative splicing within a cell; B: Pathogenic mechanisms involving MBNL and CUG BP, resulting in deregulated alternative splicing. While DM1 mutation is an untranslated CTG expansion, it is expressed at the RNA level and the CUG binds with two RNA binding proteins (CUGBP and MBNL) to disrupt RNA processing and splicing of other genes. For example, altered splicing of chloride channel and insulin receptor transcripts leads to myotonia and insulin resistance, respectively. DM1: Myotonic dystrophy type 1; MBNL: Musclebind-like protein; CUG BP: CUG binding protein.

Figure 4

Novel therapies using RNA-based mechanisms to mediate RNA toxicity in a myotonic dystrophy type 1 cell. Promising trials have shown various means and targets of RNA mediated therapy with the aim of reversing or modifying “spliceopathy” and normalising cellular splice protein levels and actions. MBNL: Musclebind-like protein.