Progressive encephalopathy due to SLC1A4 mutations in two non Ashkenazi Brazilian siblings.

Objectives: SCL1A4 mutations cause an exceedingly rare neurodevelopmental disorder characterized by intellectual disability, progressive microcephaly, spasticity, epilepsy, and thin corpus callosum. About 20 cases were reported. Most patients are Jewish-Ashkenazi. We report two cases of non Ashkenazi Brazilian siblings. Case 1- This 3-year-old boy, born from first cousins parents, (OFC=35cm.) presented lack of psycho-motor development since the first weeks of life. At 6 months he presented infantile spasms. He never acquired gait or language. The current neurological examination shows microcephaly (OFC=44cm. -3SD), spastic tetraparesis, poor eye contact. MRI showed ventricular ectasy, global reduction of white matter, and thin corpus callosum. Whole exome sequencing showed an homozygous variant in the SLC1A gene, c964C>T. Case 2- This 1y10m old girl is sister of case 1. OFC at birth=34.5cm. She started having clonic seizures at 2 months. Currently, the neurological examination is identical compared to his brother. OFC=40cm (-3DS). Generalized seizures are not well controlled. MRI revealed hypoplasia of white matter and as very thin corpus callosum. Comments: SLC1A4 codes ASCT1 transporter of L-serine from astrocytes to neurons. This amino acid is essential for normal neuronal development , so that impairment of its production causes disruption of neural function. As in our cases, all patients present severe intellectual disability, progressive microcephaly, spastic tetraparesis, and thinning of corpus callosum. Epilepsy is present in most cases. Diagnosis is performed through WES. Several variants are described but there is no clinical-genetic correlation. Albeit most of patients are Ashkenazi-Jewish, few patients like ours lack this ethnic background.
Keywords: SLC1A4 mutation; neurodevelopmental disorders; microcephaly