A Novel SLC1A4 Mutation (p.Y191*) Causes Spastic Tetraplegia, Thin Corpus Callosum, and Progressive Microcephaly (SPATCCM) With Seizure Disorder

Abstract

Spastic tetraplegia, thin corpus callosum, and progressive microcephaly is a recently described very rare autosomal recessive neurodevelopmental disorder. This disease was first described in 2015 in several families from the Ashkenazi Jewish ancestry with a founder mutation in SLC1A4 (p.E256K) as the underlying genetic cause. SLC1A4 gene encodes for the amino acid transporter ASCT1 that is necessary for serine cellular transport to neurons. We clinically evaluated 2 Pakistani siblings with severe global developmental delay, progressive microcephaly, and seizure disorder. We performed exome sequencing, Sanger sequencing, and segregation analysis to identify the genetic cause of the phenotype followed by in silico analysis to evaluate the pathogenicity of the identified mutation. We identified a novel homozygous variant (c.573T>G) in both patients. The mutation is predicted to cause nonsense mutation (p.Y191*) in the ASCT1 protein. Here, we report the fifth disease causing mutation in SLC1A4 gene and review all previously reported cases.

Keywords: developmental delay; epileptic encephalopathy; infantile spasms; next-generation sequencing; spasticity.

Figure 1.

A, The family pedigree of the affected siblings. B, Magnetic resonance imaging (MRI) findings for the affected male, at 4 years of age. Note the absent corpus callosum, the hypomyelination of the cerebral hemispheres and brain atrophy. C, The SLC1A4 transcript demonstrating the mutation site. D, The protein topological structure and site of the premature stop codon. E, The predicted mutated protein 3D structure modeled by SWISSMODEL/ExPASy prediction tool to the left, compared to the modeled wild-type protein (right).