Background: Arginases catalyze the last step in the urea cycle.Hyperargininemia, a rare autosomal-recessive disorder of the urea cycle, presents after the first year of Floor - Equipment age with regression of milestones and evolves gradually into progressive spastic quadriplegia and cognitive dysfunction.Genetic studies reported various mutations in the ARG1 gene that resulted in hyperargininemia due to a complete or partial loss of arginase activity.Case Presentation: Five patients from an extended highly consanguineous Sudanese family presented with regression of the acquired milestones, spastic quadriplegia, and mental retardation.
The disease onset ranged from 1 to 3 years of age.Two patients had epileptic seizures and one patient had stereotypic clapping.Genetic testing using whole-exome sequencing, done for the patients and a healthy parent, confirmed the presence of a homozygous novel missense variant in the ARG1 gene [GRCh37 (NM_001244438.1): exon 4: g.
131902487T>A, c.458T>A, p.(Val153Glu)].The variant was predicted pathogenic by five algorithms Goldenrod and affected a highly conserved amino acid located in the protein domain ureohydrolase, arginase subgroup.
Sanger sequencing of 13 sampled family members revealed complete co-segregation between the variant and the disease distribution in the family in line with an autosomal-recessive mode of inheritance.Biochemical analysis confirmed hyperargininemia in five patients.Conclusion: This study reports the first Sudanese family with ARG1 mutation.The reported variant is a loss-of-function missense mutation.
Its pathogenicity is strongly supported by the clinical phenotype, the computational functional impact prediction, the complete co-segregation with the disease, and the biochemical assessment.