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.

Cerebrospinal fluid amino acids glycine, serine, and threonine in nonketotic hyperglycinemia

“…Deficiency of the ASCT1 transporter ( SLC1A4 ), which is the main transporter of d ‐serine, as well as for the shuttle of l ‐serine to neurons, resulted in decreased d ‐serine and l ‐serine in mouse brain, and increased threonine, glycine and l ‐alanine, a finding surprisingly similar to what we observed in CSF of human NKH patients 25 . Moreover, human patients with pathogenic variants in SCL1A4 (OMIM# 616657) have a phenotype of progressive severe spastic quadriplegia, thin corpus callosum, and developmental delays, which are also core symptoms of severe NKH, not explained by previous hypotheses on pathophysiology 55–59 . The exact mechanism for these amino acid changes will require further exploration in human brain samples and in cell experiments.…”

“…25 Moreover, human patients with pathogenic variants in SCL1A4 (OMIM# 616657) have a phenotype of progressive severe spastic quadriplegia, thin corpus callosum, and developmental delays, which are also core symptoms of severe NKH, not explained by previous hypotheses on pathophysiology. [55][56][57][58][59] The exact mechanism for these amino acid changes will require further exploration in human brain samples and in cell experiments.…”

Functional and Biochemical Consequences of Disease Variants in Neurotransmitter Transporters: A Special Emphasis on Folding and Trafficking Deficits

“…Of the ASCT1 variants (listed in Table 1 and Fig. 3d ), Y191* ( Abdelrahman, Al-Shamsi, John, Ali, & Al-Gazali, 2019 ), L315Hfs*42 ( Damseh et al, 2015 ) and W453* ( Conroy et al, 2016 ) code for truncated transporters. While no biochemical characterization data is available, the variants are predicted to have folding and/ or trafficking deficits.…”

Comparative Proteome Research in a Zebrafish Model for Vanishing White Matter Disease

“…SLC1A4 mutations were identified in two affected siblings with severe intellectual disability (ID), microcephaly and spasticity, from an Ashkenazi Jewish consanguineous family [ 25 ]. Additional SLC1A4 deficiency was described in patients with neurodevelopmental disorders, presenting with thin corpus callosum, in addition to the phenotypes of developmental delay, microcephaly, and seizures [ 26 , 27 , 28 ]. Glutamate excitotoxicity is associated with neurodegenerative disorders, including demyelination.…”