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

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

doi:10.1038/s41439-019-0055-9

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

Hum Genome Var. 2019 May 22:6:24. doi: 10.1038/s41439-019-0055-9. eCollection 2019.

Authors

Rosanne Sprute^{1

2}, Didem Ardicli³, Kader Karli Oguz⁴, Anna Malenica-Mandel^{1

2}, Hülya-Sevcan Daimagüler^{1

2}, Anne Koy¹, Turgay Coskun⁵, Haicui Wang^{1

2}, Meral Topcu³, Sebahattin Cirak^{1

2}

Affiliations

¹ 1Faculty of Medicine and University Hospital Cologne, Department of Pediatrics, University of Cologne, 50931 Cologne, Germany.
² 2Faculty of Medicine and the Faculty of Mathematics and Natural Sciences, Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
³ 3Department of Pediatric Neurology, Hacettepe University, 06100 Ankara, Turkey.
⁴ 4Department of Radiology, Hacettepe University, 06100 Ankara, Turkey.
⁵ 5Department of Pediatric Metabolism Unit, Hacettepe University, 06100 Ankara, Turkey.

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.

Keywords: Genetics research; Metabolic disorders; Paediatric neurological disorders.