Clinical, molecular, and biochemical delineation of asparagine synthetase deficiency in Saudi cohort

Genet Med. 2020 Dec;22(12):2071-2080. doi: 10.1038/s41436-020-0919-x. Epub 2020 Aug 3.

Abstract

Purpose: Asparagine synthetase deficiency (ASNSD) is a rare neurometabolic disease. Patients may not demonstrate low asparagine levels, which highlights the advantage of molecular over biochemical testing in the initial work-up of ASNSD. We aimed to further delineate the ASNSD variant and phenotypic spectrum and determine the value of biochemical testing as a frontline investigation in ASNSD.

Methods: We retrospectively collected the clinical and molecular information on 13 families with ASNSD from the major metabolic clinics in Saudi Arabia.

Results: The major phenotypes included congenital microcephaly (100%), facial dysmorphism (100%), global developmental delay (100%), brain abnormalities (100%), spasticity (86%), and infantile-onset seizures (93%). Additional unreported phenotypes included umbilical hernia, osteopenia, eczema, lung hypoplasia, and hearing loss. Overall, seven homozygous variants accounted for ASNSD. The p.Tyr398Cys and p.Asn75Ile variants accounted for 54% of the cases. The clinical sensitivity and specificity of the proposed biochemical analysis of cerebrospinal fluid (CSF) for the detection of patients with ASNSD were 83% and 98%, respectively.

Conclusion: Our study describes the largest reported ASNSD cohort with clinical, molecular, and biochemical characterization. Taking into consideration the suboptimal sensitivity of biochemical screening, the delineation of the phenotype variant spectrum is of diagnostic utility for accurate diagnosis, prognosis, counseling, and carrier screening.

Keywords: amino acid analysis; asparagine synthetase deficiency; cerebral atrophy; congenital microcephaly; dysmorphism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aspartate-Ammonia Ligase* / genetics
  • Humans
  • Intellectual Disability* / diagnosis
  • Intellectual Disability* / genetics
  • Microcephaly*
  • Retrospective Studies
  • Saudi Arabia / epidemiology

Substances

  • Aspartate-Ammonia Ligase