Myotonic dystrophy type 1 (DM1)

DM1 is a multisystem disorder that affects skeletal and smooth muscle as well as the eye, heart, endocrine system, and central nervous system. The clinical findings span a continuum from mild to severe and are commonly categorised into three overlapping phenotypes (mild, classic, and congenital) that generally correlate with CTG trinucleotide repeat in the noncoding region of the DMPK gene. In mild DM1, individuals typically present with cataract and mild myotonia, although diabetes mellitus may also occur. The life span is generaly normal. In classic DM1, predominant distal muscle weakness produces foot drop, gait disturbance, and impaired manual dexterity, while facial and levator palpebrae weakness yields the characteristic facial appearance; grip myotonia interferes with daily activities. Cardiac conduction abnormalities are common and represent a major cause of early mortality and sudden death. Posterior subcapsular cataracts, often with a multicoloured “Christmas tree” appearance on slit-lamp examination, develop in nearly all affected individuals. Endocrine manifestations (including insulin resistance, diabetes mellitus, thyroid dysfunction, and testicular atrophy) and central nervous system involvement are also frequent. Congenital DM1 presents with polyhydramnios, reduced fetal movement, severe neonatal hypotonia, facial diplegia, and respiratory compromise, and is associated with substantial neonatal mortality. Classic-onset disease typically manifests in the second to fourth decade; intra- and interfamilial variability is considerable.

The overall prevalence of DM1 is often estimated at approximately 1/20,000, although substantial geographic variation exists, ranging from about 1/100,000 in parts of Japan to 1/10,000 in Iceland. Founder effects have been documented in regions such as Quebec.

DM1 is caused by a germline unstable CTG trinucleotide repeat expansion (typically ≥ 50 repeats in full-penetrance alleles) located in the 3’ untranslated region of DMPK on chromosome 19q13.32. Expanded CUG-containing transcripts accumulate in the nucleus and form RNA foci that sequester MBNL proteins and alter CELF1/CUG-BP1 activity, resulting in widespread abnormalities of alternative RNA splicing. Mis-splicing of downstream targets, including CLCN1 and the insulin receptor (INSR), contributes to clinical manifestations such as myotonia and insulin resistance. The CTG repeat is highly unstable and may exhibit somatic mosaicism, with repeat length varying among tissues.

DM1 is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% probability of inheriting the expanded DMPK allele. DMPK alleles with more than 34 CTG repeats are unstable and may expand further during meiosis, so offspring may inherit considerably longer repeats than the transmitting parent. This instability underlies anticipation, characterised by earlier disease onset and often greater disease severity in successive generations. Congenital DM1 is almost exclusively associated with maternal transmission. De novo expansions from a normal allele to a disease-causing allele are rare. Once the familial DMPK expansion has been identified, prenatal molecular genetic testing is available.

The diagnosis of DM1 is suspected in individuals with characteristic clinical features and is confirmed by molecular genetic testing demonstrating a pathogenic CTG repeat expansion in DMPK. Electromyography typically shows myotonic discharges, while serum creatine kinase concentrations are normal or only mildly elevated. Muscle biopsy may reveal rows of internal nuclei, ring fibres, sarcoplasmic masses, and type I fibre atrophy, but currently plays only a limited diagnostic role and is generally reserved for unresolved differential diagnostic situations.

Main differential diagnoses include:

• Myotonic dystrophy type 2 (DM2): a multisystem myotonic dystrophy with proximal-predominant weakness, prominent muscle pain, adult onset, no congenital form, and no established anticipation; CNBP
• Myotonia congenita (Thomsen disease, ): a non-dystrophic myotonic disorder without progressive muscle wasting or multisystem involvement; CLCN1
• Paramyotonia congenita and sodium-channel myotonias: cold- and exercise-induced paradoxical myotonia with or without episodic weakness, without dystrophy or multisystem involvement; SCN4A

• Establishing the molecular diagnosis confirms the clinical suspicion, ends the diagnostic odyssey, and provides the basis for informed genetic counselling of the affected individual and their family.
• A confirmed molecular diagnosis of DM1 enables disease-specific management, genetic counselling, and individualized surveillance for systemic complications, particularly cardiac conduction abnormalities, cataracts, and endocrine manifestations including diabetes mellitus. The nature and frequency of surveillance should be tailored to the individual’s clinical status and guided by the treating multidisciplinary team.
• Identification of the familial pathogenic variant enables predictive testing of at-risk relatives, supporting reproductive decision-making and clarification of genetic status within the family.

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