Clinical, Laboratory Data and Outcomes of 17 Iranian Citrullinemia Type1 Patients: Identification of Five Novel ASS1 Gene Mutations

Background: Citrullinemia type 1 (CTLN1) is an autosomal recessive metabolic disease caused by ASS1 gene mutations encoding argininosuccinic acid synthase enzyme which is within the pathway of arginine and nitric oxide biosynthesis. Methods: Disease confirmation was done by ASS1 gene mutation analysis using Next Generation Sequencing, DNA Sanger sequencing and bioinformatics. The study group members were17 citrullinemia type1 patients from 10 unrelated families referred to Iranian National Society for the Study of Inborn Errors of Metabolism’s clinic between 2008-2020. Clinical, laboratory and molecular data were retrospectively evaluated. Results: Eleven different ASS1 gene mutations were detected. Presentation: 3/17 (76%) neonatal, 3/17 (18%) late infantile, 1/17(6%) asymptomatic. Severe developmental delay and intractable seizures despite metabolic control was the only surviver of neonatal form outcome. Two patients with late infantile form live metabolically and seizure controlled with quite normal performance. DNA mutations: 7 missense, 1 nonsense, and 2 indel mutations in twelve, two, three patients, respectively. Five novel mutations were detected including a homozygous GG deletion in exon 11 (c.790_791delGG; G264Pfs*3) and a homozygous mutation in exon 6 (c.440C>T; p.M147T), both leading to infantile form; a homozygous mutation in exon 14 (c.1130T>C; p.M377T) leading to neonatal form; two compound heterozygote mutations in exon 14 (c.1167_1168insC& c.1186T>A; p.S396T) leading to asymptomatic form. Five patients (38%) with classic neonatal form had mutation in exon14 of ASS1 (c.1168G>A; p.G390R). Conclusions: Classic neonatal form was the most common form of disease in Iranian studied patients and exon 14: c.1168G>A; (p.G390R) was the most frequent ASS1 gene mutation. Global neonatal screening in Iran is recommended for citrullinemia type1 and certain mutations can be used for screening lethal form of disease in this population.