Autosomal Recessive COL6A2-Related Bethlem Myopathy in Two Libyan Siblings: A Case Report

الملخص

Background

Bethlem myopathy (BTHLM) is a rare collagen VI-related muscular dystrophy caused by pathogenic variants in COL6A1, COL6A2, or COL6A3. Although the disease is typically inherited in an autosomal dominant manner, autosomal recessive forms have been increasingly recognized and often demonstrate variable clinical severity (1).

Case Presentation

We report two affected siblings from a Libyan family with no reported parental consanguinity, harboring the same homozygous pathogenic splice-site variant in COL6A2 (NM_001849.4: c.1970-9G>A), confirmed by whole-exome sequencing and segregation analysis. Two additional siblings (one male, one female) were clinically unaffected.

Case 1 (16-year-old male): presented with delayed motor milestones (independent walking at 20 months), progressive lower-limb weakness since early childhood, a partial Gowers' sign, exercise-induced calf pain, and proximal muscle weakness. Serum creatine kinase (CK) and tendon reflexes were normal. Examination showed mild elbow flexion weakness (MRC 4/5), pes cavus deformity, and mild gluteal and left calf muscle atrophy, without scoliosis. Respiratory function was preserved.

Case 2 (7-year-old female, younger sibling): exhibited a similar but milder phenotype, with proximal muscle weakness, delayed motor performance, calf discomfort after prolonged walking, and preserved ambulation. Segregation analysis confirmed the identical homozygous COL6A2 variant.

Conclusion

These cases highlight the phenotypic variability of recessive COL6A2-related Bethlem myopathy and emphasize that a normal serum CK does not exclude collagen VI-related dystrophy. Recognition of the characteristic clinical features, combined with molecular confirmation, facilitates accurate diagnosis, multidisciplinary management, and genetic counseling.