Spinal Muscular Atrophy

Abstract

Abstract Spinal muscular atrophy (SMA) is a relatively common neurodegenerative disease marked by muscle weakness and atrophy due to degeneration of motor neurons of the spinal cord and lower brain stem. The most common form of SMA is caused by homozygous disruption of the survival motor neuron 1 ( SMN1 ) gene on chromosome 5q and results in insufficient levels of SMN protein in motor neurons. There is a broad spectrum of clinical severity, which inversely relates to the number of copies of the SMN2 gene. Although advances in the understanding of the disease biology have provided therapeutic targets, no effective disease modifying treatment is currently available. Promising therapeutic strategies include utilising the unique genomic structure of the SMN genes to increase SMN protein transcripts, neuroprotective agents, gene therapy and stem cell transplantation. Key Concepts: The most common form of SMA is secondary to homozygous disruption of the survival motor neuron 1 gene ( SMN1 ) located on chromosome 5q13 and results in insufficient levels of survival motor neuron (SMN) protein in motor neurons. SMA is classified into three common types based on age of onset and maximal motor milestones attained (Munsat and Davies, 1992): SMA type 1 has onset within the first 6 months and patients do not sit without support; SMA type 2 patients manifest weakness after 6 months of age and the maximum motor milestone is the ability to sit; SMA type 3 patients attain the ability to walk. The clinical spectrum of SMA is broad, ranging from early infant death to normal adult life with minimal weakness. The diagnosis of SMA is based on molecular genetic testing. Approximately 95% of individuals with SMA are homozygous for a deletion of SMN1 and 5% may reflect compound heterozygotes. In humans there is an almost identical copy of the gene, SMN2 , which predominantly encodes a truncated form of the SMN protein that is rapidly degraded. Functional ability inversely relates to SMN2 copy number. Current management incorporates multidisciplinary care and focuses on preventing and addressing the complications of weakness and promoting quality of life. Advances in the understanding of molecular pathogenesis of SMA have provided novel therapeutic targets, however translation has held limited success to date.