Carina Wallgren-Pettersson

..abstract:..

..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...

..Studies of additional families are needed to localise the as yet unknown causative genes, and to fully elucidate genotype-phenotype correlations...

..At least 1 further gene remains to be identified. Patient care is based on managing the clinical symptoms. Animal models are helping to gain insight into pathogenesis, and a variety of therapeutic approaches are being investigated...

..We conclude that homozygous missense mutations in NEB cause a novel distal myopathy, predominantly involving lower leg extensor muscles, finger extensors and neck flexors...

..Finding the causative mutation(s) determines the mode of inheritance and permits prenatal diagnosis if requested, but will not as such permit prognostication...

..Three had arthrogryposis. In three of the five families, the mutations were located in exon 184. These mutations are predicted to cause absence of the C-terminal part of nebulin...

..Patients with more severe clinical pictures tended to have mutations predicted to be more disruptive than patients with milder forms...

..Missense mutations in TPM2 have previously been found to cause rare cases of nemaline myopathy and distal arthrogryposis. This mutation is one not previously described and the first genetic cause identified for cap disease...

..The use of alternative transcripts might also explain why severe phenotypes are rare among patients with two truncating mutations...

..Both mutations affect conserved amino acids, and in both cases, the mutant allele is expressed. We speculate that the observed mutations affect the formation of the tropomyosin dimer and its actin-binding properties...

..Previously, there had been five reports, only, of NM caused by mutations in TPM3. The mutation reported here is the first deletion to be identified in TPM3, and it is likely to be a founder mutation in the Turkish population...

..Most of the mutations are predicted to result in truncated or internally deleted proteins. Mutations in the differentially expressed exons are expected to reduce the nebulin isoform diversity necessary for normal muscle development...

..In all but two of eight homozygous patients, the clinical picture was more severe than in typical nemaline myopathy...

..Multiple isoforms of nebulin are produced from the 183-exon-containing nebulin gene (NEB). Mutations in NEB cause nemaline myopathy, distal myopathy, and core-rod myopathy...

..The expression patterns did not correlate with fiber-type composition. We speculate that these exons harbor a regulatory function utilized during muscle maturation...

..Nemaline myopathy should be considered as a differential diagnosis in patients presenting with an early-onset predominantly distal myopathy...

..Because of the giant size of the gene, molecular genetic testing methods are difficult to design for routine diagnostic use...

..In the long-term management of patients with nemaline myopathy, respiratory capacity requires regular monitoring for early detection of insidious hypoventilation...

..Our findings have important implications in the diagnosis and management of such families...

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..The high survival rate for this disorder therefore reflects intensive medical intervention without which the majority of these boys would not survive...

..g. actin myopathy. This would suggest that interference with certain actin functions may be more associated with certain phenotypes, though the exact pathophysiology of the actin mutations remains unknown...

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