In a family of British origin with X-linked myopathy with postural muscle atrophy and generalized hypertrophy (XMPMA; 300696), Windpassinger et al. (2008) identified a 3-bp insertion after nucleotide 381 of the FHL1 gene (381_382insATC), leading to the insertion of an isoleucine residue within the second LIM domain (phe127_thr128insile). The mutation affected all 3 FHL1 isoforms.
Sarkozy et al. (2011) reported 2 additional British families with the 381delATC mutation. These 2 families and the family reported by Windpassinger et al. (2008) shared the same haplotype, consistent with a founder effect. The family reported by Windpassinger et al. (2008) included 4 males who presented in their thirties with progressive proximal muscle weakness causing walking difficulties and shoulder weakness. The disorder was progressive with at least 2 patients becoming wheelchair-bound. Other features included spinal rigidity, scapular winging, increased serum creatine kinase, and decreased vital respiratory capacity. One family reported by Sarkozy et al. (2011) included 11 affected individuals (5 women) spanning 5 generations. Three men had onset of symptoms in the second to third decade, with predominant progressive limb girdle weakness, mainly affecting the upper limbs, and scapular winging. They also had spinal rigidity and reduced lung function. An additional 3 deceased male family members were reported as being wheelchair-bound from their thirties, and dying in their late forties/early fifties of cardiorespiratory failure. Female mutation carriers had a slightly later onset of milder symptoms. In the other family reported by Sarkozy et al. (2011), 5 males spanning 4 generations were affected. One had onset in young adulthood of progressive proximal upper and lower limb weakness, foot drop, and restricted neck movements with increased serum creatine kinase. Other family members reportedly had gait difficulties. Sarkozy et al. (2011) noted the heterogeneous phenotypes in these 3 families, although they all had an overall late presentation most consistent with XMPMA. However, the involvement of women in the second family was reminiscent of X-linked dominant scapuloperoneal myopathy (300695).
