Spinal muscular atrophy: Broad disease spectrum and sex-specific phenotypes

Abstract

Spinal muscular atrophy (SMA) is one of the major genetic disorders associated with infant mortality. More than 90% of cases of SMA result from deletions of or mutations in the Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, does not compensate for the loss of SMN1 due to predominant skipping of exon 7. The spectrum of SMA is broad, ranging from prenatal death to infant mortality to survival into adulthood. All tissues, including brain, spinal cord, bone, skeletal muscle, heart, lung, liver, pancreas, gastrointestinal tract, kidney, spleen, ovary and testis, are directly and/or indirectly affected in SMA. Accumulating evidence on impaired mitochondrial biogenesis and defects in X chromosome-linked modifying factors, coupled with the sexual dimorphic nature of many tissues, point to sex-specific vulnerabilities in SMA. Here we review the role of sex in the pathogenesis of SMA.

Keywords: Intronic splicing silencer N1 (ISS-N1); Male infertility; Mitochondria; Spinal muscular atrophy (SMA); Survival motor neuron (SMN); X chromosome.