C.P.1.03 TPM3 is a recurrent cause of congenital fibre type disproportion and is associated with a consistent phenotype.

Abstract

Background: The key diagnostic features of congenital fibre type disproportion (CFTD) are uniform type 1 fibre hypotrophy (without other diagnostic histological abnormalities), together with clinical features of a congenital myopathy. To date, CFTD has been associated with mutations in the ACTA1, SEPN1 and TPM3 genes but the molecular cause in most patients remains uncertain. Objective(s): To investigate the proportion of patients with mutations in TPM3 in a cohort of well-characterised CFTD patients. Method(s): We sequenced all coding exons of the TPM3 gene from either genomic or cDNA in 11 unrelated patients with CFTD. Result(s): In four CFTD families we identified novel missense mutations in TPM3. In one family the mutation (100L > M, previously presented) followed autosomal dominant inheritance. All other mutations (168R > G, 169K > E, 245R > G) affected single patients and were likely de novo mutations (confirmed by parental studies for 169K > E). The changes affect highly conserved amino acids and were not found in 100-200 control chromosomes. All patients had a similar pattern of muscle weakness, with variable severity, that included a waddling gait with foot drop, accentuated lumbar lordosis, weakness of neck movements, facial weakness, and mild ptosis. Four out of 10 patients require nocturnal ventilatory support though all remain ambulant; one from age 3.5 years and three from their mid 30s. Type 1 fibres were 50-70% smaller than type 2 fibres. Both patients biopsied over age 30 years had increased internalized nuclei that were restricted to type 2 fibres. Conclusion(s): Mutations in TPM3 accounted for a quarter of patients in our CFTD cohort, suggesting this gene may a relatively frequent cause. A common phenotype and internalized nuclei in type 2 fibres (in older patients) may be useful indicators of a mutation in TPM3.Copyright © 2007