Bethlem myopathy: long-term follow-up identifies COL6 mutations predicting severe clinical evolution

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Bethlem myopathy (BM) is a collagen VI (COLVI) related muscle disorder.
• BM represents the milder end of the COLVI myopathy spectrum.
• Limited data exists on long-term BM patient evolution and genotype-phenotype correlations.

Purpose of the Study:

• To retrospectively evaluate the long-term clinical evolution of Bethlem myopathy patients.
• To investigate genotype-phenotype correlations in a cohort of genetically identified BM patients.

Main Methods:

• Retrospective evaluation of 35 genetically confirmed Bethlem myopathy patients.
• Analysis of clinical data, including disease progression and specific symptoms.
• Genetic analysis to identify mutations in COL6A1, COL6A2, and COL6A3 genes.

Main Results:

• Significant phenotypic variability was observed, with typical, severe, and atypical presentations.
• Common features included contractures and proximal weakness; 11 patients had severe evolution.
• Atypical presentations involved limb girdle weakness or congenital myopathy patterns.
• Novel mutations were identified, with autosomal dominant inheritance being most common (83%).
• COL6A1 exon 14 skipping was associated with severe evolution (35% of index cases).
• Missense mutations were linked to milder BM forms (39% of index cases).

Conclusions:

• Long-term follow-up reveals substantial phenotypic variability in Bethlem myopathy.
• Functional disability commonly worsens after age 40 in nearly half of BM patients.
• COL6A1 exon 14 skipping is frequently associated with disease progression and severity.