A novel DNAJB6 mutation causing variable phenotypic expression: From distal myopathy to limb girdle muscular dystrophy

Myofibrillar myopathies (MFM) are a heterogeneous group of inherited neuromuscular disorders characterized by myofibrillar dissolution and accumulation of aggregates. The clinical phenotypes of MFM encompass distal myopathies, limb girdle dystrophies, scapuloperoneal syndrome, rigid sine and neuropathy, and cardiomyopathies. Mutations of DNAJB6 gene have been associated with autosomal dominant limb girdle dystrophy and recently with a distal myopathy. We present the clinical, histopathological and muscle imaging features of 2 unrelated autosomal dominant DNAJB6 families, with a novel mutation. The first family is originated from Normandy. Four members of this family present a distal weakness of the lower limb, with onset of the disease between 40 and 60 years of age. They present initially asymmetric weakness and wasting either of the anterior or posterior compartments of the legs. The older case (90 years old) had a distal and proximal weakness of the four limbs and is wheelchair bound. The remaining members of the family are still fully ambulant. The second family is also originated from Normandy. Three members present a proximal weakness predominantly in the lower limbs, with asymmetric involvement in one of them. The onset of the disease ranged from 38 to 55 years of age. All are still ambulant, although one of them aged of 66 years, needed a cane to walk. Cardiac or respiratory involvement was noted detected. Electromyography showed a myogenic pattern. CK were normal or slightly elevated. Muscle biopsy showed in the first family an extensive vacuoles and myofibrillar aggregates, while multiple rimmed vacuoles and cytoplasmic bodies were observed in the second family. Target exome gene panel revealed a novel p.Asn95Leu substitution in the 2 families. This study confirms the causative role of DNAJB6 in distal and limb-girdle muscular dystrophy and the variable histopathological features ranging from rimmed vacuolar pathology to myofibrillar aggregates.