G.P.45 A family of autosomal dominant limb-girdle muscular dystrophy with rimmed vacuole

Abstract

Limb-girdle muscular dystrophy (LGMD) is a descriptive term that encompasses childhood- or adult-onset muscular dystrophies, not characterized as dystrophinopathy. While most cases of LGMD follow autosomal recessive inheritance, many families with distinct autosomal dominant (AD) pattern have been reported. Causative genes are known for three of the AD LGMDs, which are myotilin, lamin A/C, and caveolin-3. For the other AD LGMDs, loci by linkage analysis are identified. We found a family of AD LGMD. The affected are 11, both male and female, out of 37 family members through three successive generations without consanguineous marriage. Limb weakness typically starts during childhood. The affected has never been good at sports. They have difficulty lifting heavy objects or climbing stairs, after which pain follows in the used limbs. On examination, mild proximal limb muscle atrophy was noted with moderate calf pseudohypertrophy. Contracture was not evident. They showed Gower’s sign and waddling gait. Distal muscle power was largely preserved compared to proximal parts. Most interestingly, all of the affected had dysphagia that it was a rule to assume chin tuck posture on swallowing. They also had nasal voice with drooping soft palate, but did not have other difficulty in articulation. On muscle biopsy, scattered rimmed vacuoles were noted upon general dystrophic features. Immunohistochemistry of dystrophin, sarcoglycans, dysferlin, and dystroglycans did not reveal abnormality. Distinctive clinical features of previously characterized LGMD like contracture or mounding do not match with this family. Based upon inheritance pattern and pathologic finding, we sequenced myotilin (TTID), but failed to prove any mutation. Very likely this family with unique clinical/pathologic features are due to mutation in a novel gene. Extensive search for the causative gene including exome sequencing and/or linkage analysis is warranted for genetic diagnosis and therapeutic opportunities.