Alternative titles; symbols
SNOMEDCT: 782721009; ORPHA: 404499; DO: 0080057;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q29 | Spinocerebellar ataxia, autosomal recessive 15 | 615705 | Autosomal recessive | 3 | RUBCN | 613516 |
A number sign (#) is used with this entry because of evidence that autosomal recessive spinocerebellar ataxia-15 (SCAR15) is caused by homozygous mutation in the KIAA0226 gene (RUBCN; 613516) on chromosome 3q29.
Autosomal recessive spinocerebellar ataxia-15 (SCAR15) is characterized by early-onset ataxia, cognitive impairment, dysarthria, and developmental delay. Variable features include seizures, nystagmus, and abnormal reflexes (Seidahmed et al., 2020).
Assoum et al. (2010) reported a consanguineous Saudi Arabian family in which 3 sisters had onset of cerebellar ataxia in early childhood. All showed delayed motor development with delayed walking. Two sisters had a more severe form of the disorder, with an unsteady gait apparent since learning to walk, whereas the third developed unsteady gait around age 7 years. Other features included dysarthria, upper limb involvement, abnormal eye movements, and hyporeflexia. Two patients had increased reflexes in the lower limbs. At age 7 months the 2 sisters who were more severely affected developed epilepsy, which was responsive to treatment with no relapse in either girl since age 3 years; both subsequently showed moderate mental retardation. Brain MRI was normal in the 3 girls at ages 16, 9, and 8 years, respectively, but showed mild cerebellar atrophy and prominent folia in 1 patient at age 18 years, suggesting progression of the disorder. At ages 16 to 25 years, they had limited walking without aid, but were unable to run.
Seidahmed et al. (2020) reported 2 brothers, born of consanguineous Saudi parents, with SCAR15. The sibs (18DG0163) had previously been reported by Maddirevula et al. (2019). The 6.5-year-old proband, who was born at 33 weeks' gestation, sat at age 1 year. He and his 17-year-old brother had delayed walking and always walked with an unsteady gait. They also had delayed speech, which was dysarthric. Cognitive abilities were mildly impaired in the younger sib and borderline in his brother, who was enrolled in special education. The younger brother had no signs of ataxia in the upper or lower limbs. In the older brother, deep tendon reflexes were enhanced in the lower limbs. He had mild upper limb, lower limb, and gait ataxia on tandem walking. Brain auditory evoked response testing revealed increased hearing threshold bilaterally. MRI at age 16 years revealed minimal superior vermian atrophy.
The transmission pattern of spinocerebellar ataxia in the family reported by Assoum et al. (2010) was consistent with autosomal recessive inheritance.
In 3 sisters, born of consanguineous Saudi Arabian parents, with autosomal recessive spinocerebellar ataxia, Assoum et al. (2010) identified a homozygous mutation in the KIAA0226 gene (c.2624delC; 613516.0001). The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in the family. The mutation results in the loss of the highly conserved DAG binding-like motif. Heterozygous carriers were unaffected. No mutations in the KIAA0226 gene were found in 172 additional families with non-Friedreich (FRDA; 229300) ataxia. Assoum et al. (2013) found that transfection of mutant KIAA0226 in COS-1 and HeLa cells resulted in mislocalization of the mutant protein from the late endosome and lysosomes to diffuse cytosolic distribution. The findings suggested that the mutation results in a loss of proper protein function, and that the disorder may relate to defects in endolysosomal machinery.
In 2 brothers, born to first-cousin Saudi parents, with SCAR15, Seidahmed et al. (2020) identified homozygosity for the same c.2624delC mutation in the RUBCN gene that had been described by Assoum et al. (2013) in another Saudi family. The mutation, which was identified by whole-exome sequencing, segregated with the disease in the family. By autozygosity mapping focused on the smallest shared region of homozygosity and mutation age analysis, Seidahmed et al. (2020) showed that the mutation occurred approximately 1,550 years earlier, spanning about 62 generations.
Assoum, M., Salih, M. A., Drouot, N., H'Mida-Ben Brahim, D., Lagier-Tourenne, C., AlDrees, A., Elmalik, S. A., Ahmed, T. S., Seidahmed, M. Z., Kabiraj, M. M., Koenig, M. Rundataxin, a novel protein with RUN and diacylglycerol binding domains, is mutant in a new recessive ataxia. Brain 133: 2439-2447, 2010. [PubMed: 20826435] [Full Text: https://doi.org/10.1093/brain/awq181]
Assoum, M., Salih, M. A., Drouot, N., Hnia, K., Martelli, A., Koenig, M. The Salih ataxia mutation impairs Rubicon endosomal localization. Cerebellum 12: 835-840, 2013. [PubMed: 23728897] [Full Text: https://doi.org/10.1007/s12311-013-0489-4]
Maddirevula, S., Alzahrani, F., Al-Owain, M., Al Muhaizea, M. A., Kayyali, H. R., AlHashem, A., Rahbeeni, Z., Al-Otaibi, M., Alzaidan, H. I., Balobaid, A., El Khashab, H. Y., Bubshait, D. K., and 36 others. Autozygome and high throughput confirmation of disease genes candidacy. Genet. Med. 21: 736-742, 2019. [PubMed: 30237576] [Full Text: https://doi.org/10.1038/s41436-018-0138-x]
Seidahmed, M. Z., Hamad, M. H., AlBakheet, A., Elmalik, S. A., AlDrees, A., Al-Sufayan, J., Alorainy, I., Ghozzi, I. M., Colak, D., Salih, M. A., Kaya, N. Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15). BMC Neurol. 20: 207, 2020. [PubMed: 32450808] [Full Text: https://doi.org/10.1186/s12883-020-01761-w]