Three New Cases of Asparagine Synthetase Deficiency: Confirmation of a Poor Neurological Outcome and a New Molecular Mechanism

Objective: Asparagine synthetase (AS), encoded by ASNS, catalyzes the synthesis of asparagine from glutamine and aspartate. AS deficiency was recently described as a rare autosomal recessive disorder characterized by severe congenital microcephaly and progressive epileptic encephalopathy. Methods: We report 3 affected patients, one from a French non- consanguineous family and 2 sisters from a consanguineous family. They all presented with severe progressive microcephaly, global developmental delay, central hypotonia, epileptic seizures, spastic quadriplegia, hypereflexia and growth retardation. Brain MRI showed global brain atrophy, simplified gyral pattern and delayed myelination. Biochemical features showed low plasma asparagine level in 2 patients and low CSF asparagine level in one patient. Results: Patient 1 had a deletion of 11Kb involving several exons of ASNS detected by array-CGH and a missense mutation on the second allele, c.144C>A, predicted to change a highly conserved histidine residue, located on a functional domain of the protein (p.His48Gln), absent from control databases and predicted in silico as pathogenic. Whole-exome Sequencing was performed on patient 2 and found a homozygous missense mutation in the ASNS (c.1649G>A / p.Arg550His) reported previously as pathogenic. This mutation was found at the homozygous state in the affected sib and at the heterozygous state in both parents. Conclusion: This report confirms the clinical, biochemical, and radiological features of AS deficiency and the severe neurological outcome. Because of the difficulty to bring out a low level of asparagine in plasma or CSF, genetic screening seems to be the best strategy to diagnose this pathology and secondary, metabolic profile could help to confirm the pathogenicity of variants in ASNS. Moreover, we describe a new pathogenic mutation and a new molecular mechanism in a patient with a compound status (deletion/mutation) detected with array-CGH, which may have been missed using molecular screening strategies, such as Whole-exome Sequencing.