Clinical outcomes of two patients with a novel pathogenic variant in ASNS: response to asparagine supplementation and review of the literature

Abstract

Asparagine synthetase deficiency (ASNSD, OMIM #615574) is a rare autosomal recessive neurometabolic inborn error that leads to severe cognitive impairment. It manifests with microcephaly, intractable seizures, and progressive cerebral atrophy. Currently, there is no established treatment for this condition. In our pediatric cohort, we discovered, by whole-exome sequencing in two siblings from Turkey, a novel homozygous missense mutation in asparagine synthetase at NM_133436.3 (ASNS_v001): c.1108C>T that results in an amino acid exchange p.(Leu370Phe), in the C-terminal domain. After identification of the metabolic defect, treatment with oral asparagine supplementation was attempted in both patients for 24 months. Asparagine supplementation was well tolerated, and no further disease progression was observed during treatment. One of our patients showed mild developmental progress with increased levels of attention and improved nonverbal communication. These results support our hypothesis that asparagine supplementation should be further investigated as a treatment option for ASNSD. We further reviewed all previously reported ASNSD cases with regard for their clinical phenotypes and brain imaging findings to provide an essential knowledge base for rapid diagnosis and future clinical studies.Amino acid deficiency: Asparagine supplementation for a neurometabolic disorderStudy of two cases with a rare metabolic disorder, asparagine synthetase deficiency (ASNSD), has identified a new mutation and a potential treatment. Healthy individuals produce the amino acid asparagine, but patients with ASNSD cannot, resulting in severe seizures and cognitive impairment. Sequencing all protein-coding genes, Sebahattin Cirak, University of Cologne, Germany, and co-workers identified a novel mutation in two brothers with ASNSD. Only 31 cases have been reported, and there is no curative treatment available. This disorder can currently only be diagnosed by genetic testing. The disease symptoms seem not to progress once the patients were given an oral asparagine supplementation. The researchers emphasize to be cautios since this is an anectodal experience, and note that newborns with seizures should be genetically tested and further controlled clinical efficacy trials are required.