Autosomal recessive cerebellar ataxia with spasticity due to a rare mutation in GBA2 gene in a large consanguineous Saudi family.

The nonlysosomal glucosylceramidase β2 ( GBA2 ) gene encode an enzyme that catalyzes the hydrolysis of glucosylceramide to glucose and ceramide. Mutations in the GBA2 gene have been reported to cause hereditary spastic paraplegia, autosomal recessive cerebellar ataxia with spasticity, and Marinescu-Sjögren-Like Syndrome. In this study, we report the clinical features and genetic diagnosis of autosomal recessive cerebellar ataxia with spasticity due to a rare mutation in GBA2 gene in a large consanguineous Saudi family. We included a large consanguineous Saudi family with a presumptive clinical diagnosis of ataxia at King Abdulaziz Medical City in Jeddah, Saudi Arabia. The family included six affected individuals and four unaffected in addition to the parents. Whole exome sequencing (WES) was performed for the proband IV-5, and Sanger sequencing was used to confirm the variant in other family members. Segregation study was performed using DNA from the parents and siblings of the proband. Sequence analysis identified a homozygous variant c.2618G>A, p.(Arg873His) in GBA2 gene. The homozygous variant was identified in affected members of the family while the parents and the other four siblings were heterozygous carriers of the variant. One sibling was not available for genetic testing. The variant identified in our patients is classified as pathogenic considering the current evidence of the variant. Autosomal recessive cerebellar ataxia with spasticity is an extremely rare genetic disorder with very few cases reported in the literature. We conclude that the c.2617G>A mutation in GBA2 gene causes the loss of function with abolishment of the enzymatic activity that causes the disease. This report adds further evidence to support the pathogenicity of this variant. The patients had the classical clinical phenotype of cerebellar ataxia and spasticity consistent with previous reports in the literature.