RESUMO
BACKGROUND: Asparagine synthetase deficiency (OMIM# 615574) is a very rare newly described neurometabolic disorder characterized by congenital microcephaly and severe global developmental delay, associated with intractable seizures or hyperekplexia. Brain MRI typically shows cerebral atrophy with simplified gyral pattern and delayed myelination. Only 12 cases have been described to date. The disease is caused by homozygous or compound heterozygous mutations in the ASNS gene on chromosome 7q21. CASE PRESENTATION: Family 1 is a multiplex consanguineous family with five affected members, while Family 2 is simplex. One affected from each family was available for detailed phenotyping. Both patients (Patients 1 and 2) presented at birth with microcephaly and severe hyperekplexia, and were found to have gross brain malformation characterized by simplified gyral pattern, and hypoplastic cerebellum and pons. EEG showed no epileptiform discharge in Patient 2 but multifocal discharges in patient 1. Patient 2 is currently four years old with severe neurodevelopmental delay, quadriplegia and cortical blindness. Whole exome sequencing (WES) revealed a novel homozygous mutation in ASNS (NM_001178076.1) in each patient (c.970C > T:p.(Arg324*) and c.944A > G:p.(Tyr315Cys)). CONCLUSION: Our results expand the mutational spectrum of the recently described asparagine synthetase deficiency and show a remarkable clinical homogeneity among affected individuals, which should facilitate its recognition and molecular confirmation for pertinent and timely genetic counseling.