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Clinical, Laboratory Data and Outcomes of 17 Iranian Citrullinemia Type 1 Patients: Identification of Five Novel Ass1 Gene Mutations Publisher



Moarefian S1, 2 ; Zamani M1, 3 ; Rahmanifar A2 ; Behnam B4, 6 ; Zaman T2, 5
Authors
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Authors Affiliations
  1. 1. Department of Neurogenetics, Iranian Center of Neurological Research (ICNR), Tehran University of Medical Sciences, Tehran, Iran
  2. 2. Clinical and Research Unit, Iranian National Society for the Study of Inborn Errors of Metabolism, Tehran, Iran
  3. 3. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  4. 4. Department of Medical Genetics and Molecular Biology, Iran University of Medical Sciences, Tehran, Iran
  5. 5. Metabolic Unit of the Children's Medical Center, School of Medicine, Tehran University of Medical Science, Tehran, Iran
  6. 6. Amarex Clinical Research, Department of Regulatory Affairs, Germantown, Maryland, United States

Source: JIMD Reports Published:2022


Abstract

Citrullinemia type 1 is an autosomal recessive metabolic disease caused by ASS1 gene mutations encoding argininosuccinic acid synthetase enzyme which is within the pathway of arginine and nitric oxide biosynthesis. Disease confirmation was done by ASS1 gene mutation analysis using next-generation sequencing, DNA Sanger sequencing. The study group was 17 citrullinemia type 1 patients from 10 unrelated families referred to Iranian National Society for Study on Inborn Errors of Metabolism's clinic between 2008 and 2020. Clinical, laboratory, and molecular data were retrospectively evaluated. Eleven different ASS1 gene mutations were detected in 13 (76%) of 17 neonatal, three (18%) of 17 late infantile, and one (6%) of 17 asymptomatic patients. Severe developmental delay and intractable seizures despite metabolic control was outcome of neonatal form survivor. Two late infantile form patients live metabolically controlled with quite normal performance. DNA mutations are as follows: seven missense, one nonsense, and two insertion/deletion mutations in 12, two, and three patients, respectively. Five novel mutations were detected including a homozygous GG deletion in exon 12 (c.790_791delGG;p.Gly264Profs*3) and a homozygous mutation in exon 7 (c.440C>T; p.Met147Thr), both causing infantile (late onset) form; a homozygous mutation in exon 6 (c.1130T>C; p.Met376Thr) causing neonatal form; two compound heterozygote mutations in exon 14 (c.1167_1168insC:p.Gly390Argfs*22& c.1186T>A; p.Ser396Thr) causing asymptomatic form. Five (38%) patients with classic neonatal form had mutation in exon 14 of ASS1 (c.1168G>A; p.Gly390Arg). Classic neonatal was the most common form of disease in Iranian-studied patients and homozygote c.1168G>A was the most frequent ASS1 gene mutation. Global neonatal screening for citrullinemia type 1 in Iran is recommended and certain mutations can be used for screening severe form in this population. © 2022 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.