Knowledge on rare diseases and orphan drugs

It is the most frequent adult muscular dystrophy and has an estimated prevalence ranging from 1/215,000 in Taiwan to 1/5,500 in Croatia. It appears to be more prevalent in the Saguenay-Lac-St-Jean region-Quebec, Canada (1/600), suggesting a founder effect. The disease occurs worldwide.

The age of onset is highly variable, from prenatal to adulthood. The clinical manifestations also cover a wide range and may differ within and between affected families. Five forms are currently recognized: congenital, early childhood, juvenile, adult-onset and late-onset. Congenital disease (15% of cases) is the most severe form and includes severe generalized weakness at birth with respiratory distress, hypotonia, and feeding difficulty. Patients subsequently develop delayed cognitive and motor milestones intellectual disability, and autism spectrum disorder. The course may be fatal in congenital cases (30-40%). In childhood onset cases (with the age of onset between 1 and 10 years of age), the main clinical manifestations involve muscle weakness (including both proximal and distal muscle group, facial weakness, respiratory and gastrointestinal complications such as respiratory distress, aspiration, dysphagia, constipation and speech disturbances), myotonia, sleep breathing disorders, recurrent infections, cognitive impairment, psychiatric disorders (phobia, depression, anxiety, attention deficit-hyperactivity). The juvenile form with the age of onset between 11 and 20 years of age, is characterized by scholar and behavioral problems and is often under recognized. The classic adult form (75% of cases), which develops between 20 and 40 years of age, is characterized by progressive distal muscle weakness, pain, myotonia and multiorgan involvement (irritable bowel disease, conduction and other cardiac disorders, cataracts, ophthalmoplegia, diabetes mellitus, hypogonadism, hypotestosteronism, and thyroid dysfunction). Intellectual deficit is also present in adult cases. Balding may occur in affected males and females and infertility may be present. Late-onset disease after 40 years of age involves mild myotonia and weakness, daytime sleepiness, and cataracts. A higher cancer risk has been reported in affected patients.

The disease is due to abnormal CTG expansion in the non-translating region of the DMPKgene (19q13.3). Disease severity generally correlates with the number of DNA repeats. More than 2000 CTG repeats may be found. The expansion is unstable, which may explain the clinical variability.

Diagnosis is suspected on the characteristic clinical manifestations and a consistent family history, and confirmed by molecular genetic testing of the causative gene expansion. Muscle biopsy is not anymore necessary for the diagnosis and is has been replaced by genetic testing, which represents the gold standard.

There are several overlapping features with myotonic dystrophy type 2; however, the diseases are distinct genetically and have different courses and management requirements.

Early-onset cases may be identified prenatally with polyhydramnios and reduced fetal movements.

The pattern of inheritance is autosomal dominant. Genetic counselling should be provided to affected families. Whilst there is a 50% risk of disease transmission from an affected parent to their offspring, the disease shows variable penetrance.

No specific targeted treatment is currently available. Management primarily includes monitoring for complications and supportive care (assistive devices, hormone therapy, pain medication).

Some cases are severe and may have an impact on life expectancy, particularly early-onset cases caused by massive gene expansions. The prognosis in adult-onset cases is mainly dependent on the severity of cardiac manifestations. Causes of death include respiratory failure, cardiovascular disease, arrhythmia, and neoplasms.

Last update: August 2020 - Expert reviewer(s): Pr Giovanni MEOLA