Abstract
Centronuclear myopathy (CNM) is an inherited neuromuscular disorder characterised by clinical features of a congenital myopathy and centrally placed nuclei on muscle biopsy.The incidence of X-linked myotubular myopathy is estimated at 2/100000 male births but epidemiological data for other forms are not currently available.The clinical picture is highly variable. The X-linked form usually gives rise to a severe phenotype in males presenting at birth with marked weakness and hypotonia, external ophthalmoplegia and respiratory failure. Signs of antenatal onset comprise reduced foetal movements, polyhydramnios and thinning of the ribs on chest radiographs; birth asphyxia may be the present. Affected infants are often macrosomic, with length above the 90th centile and large head circumference. Testes are frequently undescended. Both autosomal-recessive (AR) and autosomal-dominant (AD) forms differ from the X-linked form regarding age at onset, severity, clinical characteristics and prognosis. In general, AD forms have a later onset and milder course than the X-linked form, and the AR form is intermediate in both respects.Mutations in the myotubularin (MTM1) gene on chromosome Xq28 have been identified in the majority of patients with the X-linked recessive form, whilst AD and AR forms have been associated with mutations in the dynamin 2 (DNM2) gene on chromosome 19p13.2 and the amphiphysin 2 (BIN1) gene on chromosome 2q14, respectively. Single cases with features of CNM have been associated with mutations in the skeletal muscle ryanodine receptor (RYR1) and the hJUMPY (MTMR14) genes.Diagnosis is based on typical histopathological findings on muscle biopsy in combination with suggestive clinical features; muscle magnetic resonance imaging may complement clinical assessment and inform genetic testing in cases with equivocal features. Genetic counselling should be offered to all patients and families in whom a diagnosis of CNM has been made.The main differential diagnoses include congenital myotonic dystrophy and other conditions with severe neonatal hypotonia.Management of CNM is mainly supportive, based on a multidisciplinary approach. Whereas the X-linked form due to MTM1 mutations is often fatal in infancy, dominant forms due to DNM2 mutations and some cases of the recessive BIN1-related form appear to be associated with an overall more favourable prognosis.
Highlights
Management of Centronuclear myopathy (CNM) is mainly supportive, based on a multidisciplinary approach
Additional but inconsistent histopathological features comprise a surrounding central zone either devoid of oxidative enzyme activity or with oxidative enzyme accumulation, and, in patients with mutations in the dynamin 2 (DNM2) gene, radial sarcoplasmic strands surrounding the central area; signs of necrosis or excessive regeneration are usually absent in all forms of CNM
The BIN1 gene is organised in 20 exons, the protein exists in at least 10 different isoforms subject to alternative splicing and, in addition to muscle, the gene is expressed in a number of different tissues including central and peripheral nervous systems [134,135]
Summary
The diagnosis of CNM depends on the presence of typical histopathological findings on muscle biopsy in combination with suggestive clinical features; muscle MR imaging may complement clinical assessment and inform genetic testing in cases with equivocal features. The decision regarding the duration of respiratory support is not an easy one, but as no firm prognostic criteria have yet been established [19], an at least initially proactive stance should be taken and any respiratory management decision should be made on an individual basis rather than on diagnosis alone The latter approach is advisable in cases with neonatal presentation where the X-linked form has been excluded, as recently described patients with recessive mutations in the amphiphysin 2 (BIN1) [59] gene and dominant mutations in the dynamin 2 (DNM2) gene [76] follow a milder course and may even improve over time. Animal models may provide the basis for an advanced understanding of CNM and for future rational therapies of the condition
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