A rare cause of developmental delay and epilepsy in two siblings: Asparagine synthetase deficiency

Abstract

Objective: Asparagine synthetase deficiency (ASNSD) is a recently described neurometabolic disorder characterized by congenital microcephaly, global developmental delay and variable seizures. Diagnosis is confirmed by findings of low cerebral spinal fluid or plasma asparagine in addition to a mutation in the ASNS gene. Case presentation: We report two siblings at the age of 18 months and 3 years, both presented with global developmental delay, epilepsy, microcephaly, axial hypotonia and lower limb spasticity. Brain magnetic resonance imaging showed marked cerebral atrophy. Numerous metabolic tests including plasma and cerebro-spinal fluid (CSF) amino acid profile did not lead to diagnosis. We identified a novel homozygous missense mutation in the ASNS gene, on position c.1108 C>T (p. Leu370Phe) in both siblings by whole exome sequencing (WES). Conclusion: ASNS deficiency is a very rare disorder; there are a few reported patients in the literature. ASNS deficiency should be kept in mind in any newborn presented with severe congenital microcephaly followed by severe epilepsy and global developmental delay. Plasma or asparagine levels may be nonspecific as in our patient. We would like to highlight the role of WES in the diagnosis of a condition with potential therapeutic option. Our patients showed some improvement in the seizure frequency and motor functions after the administration of asparagine supplementation.