Spinocerebellar Ataxia, Autosomal Recessive 20

A number sign (#) is used with this entry because of evidence that autosomal recessive spinocerebellar ataxia-20 (SCAR20) is caused by homozygous mutation in the SNX14 gene (616105) on chromosome 6q14.

Description

Autosomal recessive spinocerebellar ataxia-20 is a neurodevelopmental disorder characterized by severely delayed psychomotor development with poor or absent speech, wide-based or absent gait, coarse facies, and cerebellar atrophy (summary by Thomas et al., 2014).

Clinical Features

Sousa et al. (2014) reported 22- and 19-year-old Portuguese sisters, born of consanguineous parents, with severely delayed psychomotor development and intellectual disability, hypotonia, ataxia, and absent speech. The disorder became apparent in early infancy. Additional neurologic features included hyporeflexia, apraxia, spasticity, and extensor plantar responses. Both patients also had relative macrocephaly, high palate with dental crowding, and coarse facies manifest as short palpebral fissures, broad nasal base, long and broad philtrum, and thick lips. Clinodactyly, camptodactyly, and talipes equinovarus were noted. Brain imaging showed cerebellar hypoplasia and thickening of the cranial vault in both patients; nonspecific white matter abnormalities were found in 1 patient.

Thomas et al. (2014) reported 5 children from 2 unrelated consanguineous families who had developmental delay, severe intellectual disability, and cerebellar ataxia. The patients also had progressive coarsening of facial features, relative macrocephaly, and progressive cerebellar atrophy on brain imaging. Some had sensorineural hearing loss; seizures were not present.

Akizu et al. (2015) reported 12 consanguineous families, all of Arab descent, in which multiple children presented in the first months or years of life with severely delayed psychomotor development, coarse facial features, absent or delayed speech, hypotonia, decreased deep tendon reflexes, and a wide-based, staggering gait or inability to walk. The children were noted to have coarse facial features, including prominent forehead, epicanthal folds, long philtrum, and full lips. More variable features included nystagmus, seizures, hearing loss, kyphoscoliosis, hepatosplenomegaly, macroglossia, hypertrichosis, and autistic features. All patients had cerebellar and cerebral atrophy on brain imaging. Five patients had altered urine oligosaccharides or glycosaminoglycans, but most had normal urinary studies. Neuropathologic examination of 1 child showed almost complete absence of Purkinje cells in the cerebellum and neuronal loss in the cortex.

Inheritance

The transmission pattern of SCAR20 in the families reported by Sousa et al. (2014), Thomas et al. (2014), and Akizu et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected members of 3 unrelated consanguineous families with autosomal recessive SCAR20, including the family reported by Sousa et al. (2014), Thomas et al. (2014) identified 3 different homozygous mutations in the SNX14 gene (616105.0001-616105.0003). Two of the mutations were truncating, and 1 was an intragenic deletion. The mutations, which were found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the families. The findings were consistent with a loss of function. Patient fibroblasts showed cytoplasmic vacuolation with electron-dense material, some reminiscent of lamellar bodies, suggesting a defect in the autophagy pathway. Sequencing of the SNX14 gene in 36 additional patients with pontocerebellar hypoplasia and 168 with idiopathic cerebellar ataxia did not identify any mutations. Thomas et al. (2014) postulated a role for SNX14 in the breakdown and recycling of cellular components in human cerebellar development and maintenance.

In affected members of 12 consanguineous families of Arab descent with SCAR20, Akizu et al. (2015) identified homozygous truncating mutations in the SNX14 gene (see, e.g., 616105.0004-616105.0007). The mutations in 2 families were found by whole-exome sequencing, and mutations in the remaining families were identified by focusing on the SNX14 gene. Overall, SNX14 mutations accounted for 9.9% of the larger cohort of families with cerebellar ataxia who underwent exome sequencing. Patient-derived neuronal cells showed absence of the SNX14 protein, increased lysosomal size, and impaired autophagosome clearance. Akizu et al. (2015) postulated a role for SNX14 in mediating the fusion of lysosomes to autophagosomes.

Animal Model

Akizu et al. (2015) found that morpholino knockdown of the snx14 ortholog in zebrafish resulted in loss of neural tissue volume, reduced cellular area, activation of apoptosis, and impaired autophagic degradation.