Chapter 4 - Strategy for the Molecular Testing of Spinal Muscular Atrophy

Abstract

The autosomal recessive disorder proximal spinal muscular atrophy (SMA) is a severe neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, which results in progressive proximal muscle weakness and paralysis. SMA is the most common fatal autosomal recessive disorder, with an estimated incidence of 1 in 6000 to 1 in 10,000 live births. Two almost identical survival motor neuron (SMN) genes are present on 5q13: the SMN1 gene, which is the SMA-determining gene, and the SMN2 gene, which is the modifying gene. The homozygous absence of the SMN1 exon 7 has been observed in the majority of patients and is being utilized as a reliable and sensitive SMA diagnostic test. Although SMN2 produces less full-length transcript than SMN1, the number of SMN2 copies has been shown to modulate the clinical phenotype and is an important prognostic indicator. The goal of population-based SMA carrier screening is to identify couples at risk of having a child with SMA, thus allowing carriers to make informed reproductive choices. Since there is no effective cure for SMA as of 2016, prevention through the identification of carriers becomes an important alternative and has recently been initiated. New treatments are being investigated in clinical trials and may be dependent upon early detection of the disorder, before the irreversible loss of motor neurons. This could potentially be accomplished through a newborn screening program for SMA.