G.P.234: A family with late-onset spinal muscular atrophy with remarkable phenotypic variability, influenced by SMN2 copy number

Abstract

Spinal muscular atrophy (SMA) is a heterogeneous neuromuscular disease of progressive degeneration of anterior horn motor neuron due to homozygous mutation of the survival motor neuron gene (SMN1). Recently, the difference in the SMN2 copy number is considered a critical factor influencing the severity of the disease. We present 2 patients of the same family diagnosed as late onset SMA, genetically confirmed to have homozygous deletion of exon 7 and 8 in SMN1 but showed marked intra-familial variability due to difference in the SMN2 copy number variation. A 43-year old female patient presented with progressive proximal limb weakness which started during high school but did not deteriorate until her age of 40. She visited our clinic at the age of 43 when she started to have difficulty in hiking. Her elder brother was also affected but remarkably more severe in weakness. He had running difficulties during high school but his limb weakness significantly deteriorated to lose independent ambulation since late teen. After nerve conduction study, needle electromyography, muscle imaging and genetic studies, SMN1 revealed the deletion of exon 7 and 8 to make genetic diagnosis of late onset type III SMA. We also measured copy number of SMN2 by MLPA method. Interestingly, SMN2 copy number inversely matched with the severity showing 4 copies with the proband, 3 copies with her brother. We clearly demonstrated the presence of phenotypic variability within the same family, clinically and neuro-radiologically, and it matched with the difference in SMN2 copy numbers. We suggest that SMN2 copy number may be a valuable tool to explain intra-familial variability of SMA severity, and to predict the prognosis with better precision.