PT  - JOURNAL ARTICLE
AU  - N Deconinck
AU  - P Richard
AU  - V Allamand
AU  - A Behin
AU  - P Lafôret
AU  - A Ferreiro
AU  - A de Becdelievre
AU  - C Ledeuil
AU  - C Gartioux
AU  - I Nelson
AU  - R Y Carlier
AU  - P Carlier
AU  - K Wahbi
AU  - N Romero
AU  - M T Zabot
AU  - F Bouhour
AU  - V Tiffreau
AU  - A Lacour
AU  - B Eymard
AU  - T Stojkovic
TI  - Bethlem myopathy: long-term follow-up identifies <em>COL6</em> mutations predicting severe clinical evolution
AID  - 10.1136/jnnp-2013-307245
DP  - 2015 Dec 01
TA  - Journal of Neurology, Neurosurgery & Psychiatry
PG  - 1337--1346
VI  - 86
IP  - 12
4099  - http://jnnp.bmj.com/content/86/12/1337.short
4100  - http://jnnp.bmj.com/content/86/12/1337.full
SO  - J Neurol Neurosurg Psychiatry2015 Dec 01; 86
AB  - Objective Mutations in one of the 3 genes encoding collagen VI (COLVI) are responsible for a group of heterogeneous phenotypes of which Bethlem myopathy (BM) represents the milder end of the spectrum. Genotype-phenotype correlations and long-term follow-up description in BM remain scarce.Methods We retrospectively evaluated the long-term clinical evolution, and genotype-phenotype correlations in 35 genetically identified BM patients (23 index cases).Results Nineteen patients showed a typical clinical picture with contractures, proximal weakness and slow disease progression while 11 presented a more severe evolution. Five patients showed an atypical presentation, namely a limb girdle muscle weakness in 2 and a congenital myopathy pattern with either no contractures, or only limited to ankles, in 3 of them. Pathogenic COL6A1-3 mutations were mostly missense or in frame exon-skipping resulting in substitutions or deletions. Twenty one different mutations were identified including 12novel ones. The mode of inheritance was, autosomal dominant in 83% of the index patients (including 17% (N=4) with a de novo mutation), recessive in 13%, and undetermined in one patient. Skipping of exon 14 of COL6A1 was found in 35% of index cases and was mostly associated with a severe clinical evolution. Missense mutations were detected in 39% of index cases and associated with milder forms of the disease.Conclusions Long-term follow-up identified important phenotypic variability in this cohort of 35 BM patients. However, worsening of the functional disability appeared typically after the age of 40 in 47% of our patients, and was frequently associated with COL6A1 exon 14 skipping.