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

Rosanne Sprute,Anne Koy,Sebahattin Cirak,Turgay Coskun,Anna Malenica-Mandel,Kader Karli Oguz,Haicui Wang,Didem Ardicli,Hülya-Sevcan Daimagüler,Meral Topcu

doi:10.1038/s41439-019-0055-9

Rosanne Sprute, Anne Koy + Show 8 more

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https://doi.org/10.1038/s41439-019-0055-9

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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.

Highlights

Asparagine synthetase deficiency (ASNSD, OMIM#615574) is a rare neurometabolic disorder for which the number of reported cases has recently expanded
Congenital and progressive microcephaly and simplified gyration in children with ASNSD indicate that significant brain damage occurs during embryonic development, suggesting that asparagine synthetase (ASNS) activity is critical for brain development, either due to the accumulation of substrates or a deficiency in its products[3]
Recessive mutations in the ASNS gene have been shown to cause a neurometabolic syndrome with a neurodegenerative disease course[1,2]

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Introduction

#615574) is a rare neurometabolic disorder for which the number of reported cases has recently expanded. This disease can only be diagnosed by genetic testing. Three causative mutations in the gene, which encodes asparagine synthetase (ASNS), were originally reported by Ruzzo et al[1]. The authors discovered that recessive mutations in ASNS are responsible for a severe neurological phenotype characterized by congenital or progressive microcephaly and developmental delay. Congenital and progressive microcephaly and simplified gyration in children with ASNSD indicate that significant brain damage occurs during embryonic development, suggesting that ASNS activity is critical for brain development, either due to the accumulation of substrates or a deficiency in its products[3]

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