Bethlem Myopathy 2

A number sign (#) is used with this entry because of evidence that Bethlem myopathy-2 (BTHLM2), also known as myopathic-type Ehlers-Danlos syndrome, is caused by heterozygous mutation in the COL12A1 gene (120320) on chromosome 6q.

For a discussion of genetic heterogeneity of Bethlem myopathy, see BTHLM1 (158810).

Clinical Features

Zou et al. (2014) reported a boy with features consistent with Bethlem myopathy. Hypotonia, proximal joint contractures, and distal myopathy were noted during his first year of life. Motor development was delayed, and he started to walk shortly before his second birthday. He initially walked with stooped posture, which improved with age. Knee contractures resolved completely, and elbow contractures improved gradually. He had mild kyphosis but no scoliosis. Language development and cognition were normal. Muscle ultrasound of the thigh showed a mild diffuse increase in echogenicity without fasciculations. Nerve conduction studies were normal. Muscle biopsy showed mild variability in fiber diameter without evidence of degeneration or regeneration, consistent with a mild myopathy. The boy's nonconsanguineous parents were unaffected.

Hicks et al. (2014) identified 5 members of 2 families with features of Bethlem myopathy who were found to have mutations in the COL12A1 gene. All 5 patients presented with symptoms of distal hyperlaxity, muscle weakness, skin changes, and joint contractures. The authors noted that the MRI findings in these patients differed from those in Bethlem myopathy patients with a mutation in the collagen VI genes (BTHLM1; 158810). In patients with BTHLM1, the periphery of the muscles is more affected than the central part, and in the calf, one of the first signs is often a 'rim' of fatty infiltration between the soleus and gastrocnemius muscles. In family 1 of Hicks et al. (2014), the only prominent finding on T1-weighted MR images was atrophy of the rectus femoris muscles; in their family 2, the pattern of muscle involvement correlated with disease severity, with the severely affected father showing a more pronounced pathology on MRI compared with his mildly affected sons.

Inheritance

The transmission pattern of Bethlem myopathy-2 in the families reported by Hicks et al. (2014) was consistent with autosomal dominant inheritance.

Molecular Genetics

In a boy with Bethlem myopathy in whom collagen VI was found to be normal, Zou et al. (2014) screened for mutations in the COL12A1 gene and identified a de novo heterozygous missense mutation (I2334T; 120320.0002). Patient muscle and cultured fibroblasts showed decreased extracellular immunostaining for type XII collagen. Extracellular immunostaining for type VI collagen and laminin-gamma-1 (LAMC1; 150290) was preserved.

After excluding mutation in the collagen VI genes and in 12 other candidate genes related to collagen VI processing in 24 patients with a Bethlem myopathy-like phenotype, Hicks et al. (2014) identified 5 members of 2 families with heterozygous mutations in the COL12A1 gene (G2786D, 120320.0003; R1965C, 120320.0004). The mutations segregated with the phenotype in the families.

Animal Model

Izu et al. (2011) generated Col12a1-null mice by targeted deletion of exons 2-5. The knockout mice had fragile bones with a disorganized collagen fiber arrangement, decreased expression of bone matrix proteins, and decreased bone-forming activity associated with delayed terminal differentiation. Zou et al. (2014) showed that the knockout mice had decreased grip strength, a delay in fiber-type transition, and a deficiency in passive force generation, while the muscle seemed more resistant to eccentric contraction-induced force drop, indicating a role for a matrix-based passive force-transducing elastic element in the generation of the weakness.