Asparagine synthetase deficiency: clinical features and experience with asparagine supplementation.

OBJECTIVES: Asparagine synthetase deficiency is a rare autosomal recessive neurometabolic disorder characterized by congenital and progressive microcephaly, severe developmental delay, epilepsy, and progressive cerebral atrophy. Therapeutic experience with L-asparagine supplementation remains limited and heterogeneous. CASE PRESENTATION: We report a preterm female infant born to consanguineous parents who presented with congenital microcephaly and early-onset myoclonic epilepsy. During follow-up, diaphragmatic eventration was identified and contributed to recurrent episodes of respiratory failure. Metabolic screening studies were unremarkable; however, cerebrospinal fluid asparagine concentration was markedly reduced (4.42 μmol/L; reference range 8-34 μmol/L). Brain magnetic resonance imaging demonstrated cerebral atrophy with white matter involvement. Whole-exome sequencing identified a homozygous splice-site variant in the ASNS gene. Oral L-asparagine supplementation was initiated at 5 months of age (50 mg/kg/day and increased to 100 mg/kg/day after one week). A reduction in seizure frequency was observed following treatment initiation; however, this finding should be interpreted cautiously because it coincided with changes in antiepileptic therapy. No meaningful neurodevelopmental progress was observed during follow-up. CONCLUSIONS: ASNSD should be suspected in patients with progressive microcephaly and early-onset epilepsy despite normal metabolic screening, and CSF amino acid analysis is valuable for diagnosis. Although a reduction in seizure frequency was observed following L-asparagine supplementation in our patient, this finding should be interpreted cautiously because phenobarbital was discontinued and topiramate therapy was initiated during the same period. Therefore, the therapeutic efficacy of L-asparagine supplementation remains uncertain, and its impact on neurodevelopment appears limited.