G.P.237

Spinal muscular atrophy (SMA) refers to a group of genetic disorders characterized by degeneration of anterior horn cells of the spinal cord. Initially, the disease was considered purely as an autosomal recessive condition caused by deleterious SMN1 mutations in 5q13. Nowadays a growing number of conditions are designated as non-5q forms of SMA. Materials and methods: A four-generation Bulgarian family with 11 affected members and one sporadic patient afflicted with autosomal dominant proximal SMA underwent detailed neurological examination and testing of muscle strength. Evaluation of serum creatine phosphokinase (CPK) levels and electromyography (EMG) were performed in 6 subjects. The molecular-genetic analysis encompassed genome-wide linkage analysis and whole-exome sequencing. The clinical onset was in childhood, varying between 1 and 6 years (mean 3.17 ± 1.70 years). The affected presented with delayed motor milestones, such as walking, difficulties in getting upright from a squatting position and in climbing stairs, a waddling gait, and slow running. The weakness was limited to the lower limbs and did not show significant progression over time, given that the oldest affected individuals still remained ambulatory into the fifth decade. Symmetric wasting was most prominent in the hip muscles, whereas distal leg muscles seemed atrophic in the older family members. EMG analysis proved anterior horn involvement. Serum creatine phosphokinase (CPK) levels were mostly normal. The genome-wide linkage analysis and whole-exome sequencing found a heterozygous de novo c.320C>T (p. Ser107Leu) mutation in bicaudal D homolog 2 (Drosophila) (BICD2) in the 11 affected from the four-generation family and c.2321A>G (p. Glu774Gly) in the sporadic case. Our study identifies BICD2 gene mutations as a cause of the increasing number non-5q linked SMA and highlights its importance in the motor neuron function in humans.