Autosomal dominant centronuclear myopathy (ORPHA:169189)
A rare, autosomal dominant congenital myopathy characterized by numerous centrally placed nuclei on muscle biopsy and clinical features of a congenital myopathy (hypotonia, distal/proximal muscle weakness, rib cage deformities (sometimes associated with respiratory insufficiency), ptosis, ophthalmoparesis and weakness of the muscles of facial expression with dysmorphic facial features.
Epidemiology
The exact prevalence remains unknown.
Clinical description
The age of onset is typically in adolescence, although earlier (neonatal to childhood) and later presentations have been reported. Muscle weakness of variable severity is the major clinical manifestation. Distal muscle involvement, particularly in the lower limb, may precede more proximal weakness; the latter finding corresponds to a sequential pattern of involvement on muscle magnetic resonance imaging (MRI) with early involvement of the ankle plantarflexors, namely the medial gastrocnemius, followed by signal changes in the posterior and, eventually, anterior compartment of the thighs. Marked ocular involvement including ptosis and ophthalmoparesis are common, whilst contractures other than those affecting the Achilles tendon and/or long finger flexors are rare. Cardiorespiratory function has been reported as normal in most cases. Patients with early onset may improve in terms of muscle strength but may develop restrictive respiratory impairment over time. Neuropathic signs (absence of tendon reflexes on neurological examination and fibrillations or reduction of the compound muscle action potential on electrophysiological examination) may be present.
Etiology
The disorder is most commonly caused by mutations in the DNM2 (19p13.2). A geno-phenotype has been reported with mutations in the PH domain associated with disease onset in infancy and early childhood, and mutations in the middle-domain associated with presentation in late childhood or early adulthood. DNM2 mutations also cause Charcot-Marie-Tooth (CMT) disease Type B and CMT2M. Other rare causative genes identified include BIN1 (2q14.3) and CCDC78 (16p13.3), which causes a centronuclear myopathy-like phenotype.
Diagnostic methods
Diagnosis is based on typical histopathological findings in combination with suggestive clinical features, and is confirmed by genetic testing. Histological findings include centrally placed nuclei and type 1 predominance; in addition, hypotrophy oxidative stains may reveal radial distribution of sarcoplasmic strands in fibers with central nuclei. Muscle MRI may aid the diagnosis.
Differential diagnosis
The main differential diagnoses include other congenital myopathies with predominant distal involvement, myotonic dystrophy and, if facial involvement is prominent, fascio-scapulo-humeral dystrophy.
Antenatal diagnosis
Prenatal diagnosis is possible where the mutation has previously been identified in a family member.
Genetic counseling
The pattern of inheritance is autosomal dominant. The risk to siblings or offspring of an affected individual inheriting the disease is 50%. Genetic counseling should be offered to all patients and families.
Management and treatment
There is no curative treatment currently available. Management is supportive and based on a multidisciplinary approach.
Prognosis
The disease has usually a slowly progressive course with potential loss of independent ambulation after the sixth decade.

                            Last update: 
                            April 2020


                            - Expert reviewer(s): 
                            Pr Enrico BERTINI  - Dr Adele D'AMICO  - Pr Fabiana FATTORI