Identification of a desmin gene mutation in scapuloperoneal syndrome

Objective : To delineate the genetic basis of scapuloperoneal syndrome type Kaeser. Background : In 1965, one of the authors reported a kindred with 12 affected members in 5 generations following autosomal dominant inheritance. Age at onset was between 30 and 50 years and followed a slowly progressive course. Histological exmination at autopsy in 1 patient suggested a neurogenic origin, similar to Kugelberg-Welander muscular atrophy. Scapuloperoneal syndrome is a descriptive term comprising various myopathies and muscular atrophies. We examined two affected descendants of the original kindred diagnosed as scapuloperoneal syndrome. The 60-years-old index patient showed pronounced atrophy and weakness of the lower limb and shoulder girdle muscles as well as a slight involvement of the facial muscles and dysphagia, whole body MRI scan showed marked atrophy and fatty degeneration of proximal and distal muscles, only biceps brachii was relatively spared. CK levels were slightly elevated. There was cardiac involvement with mild arrhythmia. Electromyography showed myogenic findings in various muscles as well as subtle neurogenic changes in the distal lower extremities. Methods : DNA was available from 4 affected and from 10 non-affected family members. Linkage analysis was performed for loci known to be associated with autosomal dominant LGMD and myofibrillar myopathies (LGMD1A-1F, IBM3, alpha-B-crystallin, MYH7,ZASP, desmin), followed by direct sequence analysis. Results : Linkage analysis suggested possible linkage to the desmin gene, all other loci were excluded. Mutation screening of the desmin gene revealed a previously described heterozygous R350P mutation in all affected family members, segregating with the disease phenotype. The mutation resides in the evolutionary highly conserved coil 2B domain of the alpha-helical desmin rod domain. Conclusions : Our findings allow reassigning the scapuloperoneal syndrome in the kindred originally described by Kaeser to the group of domiant myopathies, due to the recently described R350P desmin mutation.