Abstract:
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 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 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.
