Clinical, laboratory data and outcomes of 17 Iranian citrullinemia type 1 patients: Identification of five novel ASS1 gene mutations

Shirin Moarefian; Mahdi Zamani; Ali Rahmanifar; Babak Behnam; Talieh Zaman

doi:10.1002/jmd2.12277

Clinical, laboratory data and outcomes of 17 Iranian citrullinemia type 1 patients: Identification of five novel ASS1 gene mutations

JIMD Rep. 2022 Mar 9;63(3):231-239. doi: 10.1002/jmd2.12277. eCollection 2022 May.

Authors

Shirin Moarefian^{1

2}, Mahdi Zamani^{1

3}, Ali Rahmanifar², Babak Behnam^{4

5}, Talieh Zaman^{2

6}

Affiliations

¹ Department of Neurogenetics, Iranian Center of Neurological Research (ICNR) Tehran University of Medical Sciences Tehran Iran.
² Clinical and Research Unit Iranian National Society for the Study of Inborn Errors of Metabolism Tehran Iran.
³ Department of Medical Genetics, School of Medicine Tehran University of Medical Sciences Tehran Iran.
⁴ Department of Medical Genetics and Molecular Biology Iran University of Medical Sciences Tehran Iran.
⁵ Present address: Amarex Clinical Research, Department of Regulatory Affairs, Germantown Maryland USA.
⁶ Metabolic Unit of the Children's Medical Center, School of Medicine Tehran University of Medical Science Tehran Iran.

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.

Keywords: ASS1; Iran; citrullinemia type 1; clinical; novel mutation; outcome.