A missense mutation in DYNC1H1 gene causing spinal muscular atrophy - Lower extremity, dominant.

Spinal muscular atrophy (SMA) is a hereditary neuromuscular disorder, which causes progressive muscle weakness and in severe cases respiratory failure and death. Although the majority of the SMA cases are autosomal recessive, there is an autosomal dominant variant of SMA that primarily affects the lower extremities, known as 'spinal muscular atrophy - lower extremity, dominant' (SMALED). Mutations in the Dynein Cytoplasmic 1 Heavy Chain 1 (DYNC1H1) gene were the first to be associated with SMALED. Here we report a family with SMALED caused by a pathogenic heterozygous missense c.1809 A>T, p.glu603Asp mutation in DYNC1H1. The main clinical features were congenital hip displacement, talipes, delayed motor development, wasting and weakness in lower limbs with relative sparing of upper extremities and very slow disease progression. SMALED is extremely rare and only a handful of families have been reported. Over the years other phenotypes including Charcot Marie Tooth type 2 and hereditary mental retardation with cortical neural migration defects have also been reported to be caused by DYNC1H1 mutations. This report aims to increase our awareness of SMALED and various other phenotypes associated with mutations in this gene.