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Proximal myotonic myopathy
A rare myotonic dystrophy of juvenile or adult-onset characterized by mild and fluctuating myotonia, muscle weakness, and rarely cardiac conduction disorders.
ORPHA:606Classification level: Disorder
Prevalence estimates of around 1/100,000 in Germany and 1/600,000 in the United Kingdom have been suggested. Most cases have been reported in ethnic Europeans (mainly in Eastern Europe with a founder effect).
The clinical presentation is marked by significant variability as is the age of onset (juvenile to late adulthood). The primary manifestations include muscle weakness (with early involvement of neck flexors or finger flexors, later involving hip girdle muscles), myotonia, and possibly severe fluctuating or episodic muscle pain, and stiffness. Cataracts, hypogonadism in males/ testicular failure, insulin insensitivity, excessive sweating, cognitive abnormalities are rare features. Cardiac disorders are rare and may include conduction abnormalities (atrioventricular and bundle branch block) and cardiac arrhythmias. Gastrointestinal complications are common and can include constipation, dysphagia, and abdominal pain. Increased risk of cancer involving colon, brain and pancreas has been reported. The phenotype may be particularly mild in a large number of affected individuals.
The disease is caused by a CCTG expansion in the first intron of, nucleic acid binding protein gene (CNBP; 3q21). Mutant alleles have 75 to 11,000 uninterrupted CCTG repeats. The pathogenesis is poorly understood.
There may be considerable difficulty and delay in the diagnosis due to the wide clinical spectrum and non-specific manifestations. The diagnosis is based on molecular genetic testing.
There are several overlapping features with Steinert myotonic dystrophy; whilst the diseases are similar, they are genetically distinct and have different courses and management requirements. The main difference is the absence of congenital form, which is seen in Steinert myotonic dystrophy.
Prenatal diagnosis is possible in affected families with an index patient.
The pattern of inheritance is autosomal dominant. Genetic counselling should be provided to affected families. There is a 50% risk of disease transmission to offspring from an affected parent. A parent with intermediate CCTG repeat expansion is considered to have a premutation and thus there is a risk of transmitting the disorder to their offspring.
Management and treatment
Management primarily involves monitoring of cataracts, insulin metabolism, and cardiac conduction.
The prognosis is generally good with no impact on life expectancy.