Spinocerebellar Ataxia, Autosomal Recessive 23

A number sign (#) is used with this entry because of evidence that autosomal recessive cerebellar ataxia-23 (SCAR23) is caused by homozygous mutation in the TDP2 gene (605764) on chromosome 6p22.

Description

Autosomal recessive spinocerebellar ataxia-23 is a neurologic disorder characterized by epilepsy, intellectual disability, and gait ataxia (summary by Gomez-Herreros et al., 2014).

Clinical Features

Gomez-Herreros et al. (2014) reported 3 brothers, born of consanguineous Irish parents, with intellectual disability, epilepsy, and various levels of ataxia. Age of patients ranged from 23 to 32 years at the time of the report. All had normal early psychomotor development. Two presented in infancy (2 months and 6 months) with seizures. In both of these patients, seizures remitted between ages 4 and 5 years and 10 years, respectively, but thereafter recurred and were difficult to control. One patient had recurrence of seizures after a fall. The third patient developed seizures at age 12 years apparently following a blow to the head; these seizures persisted and were refractory. All had moderate to severe intellectual disability with IQ ranging between 30 and 40. Two had severe ataxia and were wheelchair-bound. The patients had some dysmorphic features that were shared by unaffected family members, including long face, hypotelorism, wide and downslanting palpebral fissures, deep-set eyes with prominent supraorbital ridges, short philtrum, small mouth with prominent lower lip, high palate, and large ears. They also had large hands with short fingernails. An additional patient of Egyptian descent with intellectual disability, fits, and ataxia was also reported, but further clinical details were not provided.

Zagnoli-Vieira et al. (2018) reported a 6-year-old Caucasian boy who presented with developmental delay, microcephaly, and failure to thrive. He was easily fatigued, had difficulty keeping balance, and had an ataxic gait. He had seizures beginning at age 5 months. He also had hypotonia, neutropenia, cardiac arrhythmia, hyponatremia, and gastric dysmotility. Electron transport chain studies on muscle biopsy at age 1 year showed a severe reduction of complex I + III and II + III activity, and his metabolic tests showed high lactate/pyruvate ratio. Following treatment with ubiquinol, carnitine, and leucovorin, the child showed improvement anecdotally in terms of energy and development, with fewer infections and seizures, and a stable gait.

Inheritance

The transmission pattern of SCAR23 in the family reported by Gomez-Herreros et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 Irish brothers, born of consanguineous parents, with SCAR23, Gomez-Herreros et al. (2014) identified a homozygous splice site mutation in the TDP2 gene (605764.0001). The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cell extracts showed absence of the full-length TDP2 protein and absence of 5-prime TDP activity, consistent with a loss of function, although 3-prime TDP activity, conferred by TDP1 (607198), was normal. In addition, patient lymphoblastoid cells were hypersensitive to the TOP2 (126430) poison etoposide. The findings indicated impaired capacity for double-strand break repair. An unrelated Egyptian patient with a similar disorder was homozygous for a truncating mutation in the TDP2 gene (605764.0002).

By whole-exome sequencing in a 6-year-old Caucasian child in the US with SCAR23, Zagnoli-Vieira et al. (2018) identified homozygosity for the same splice site mutation in the TDP2 gene that had been identified by Gomez-Herreros et al. (2014). Western blot analysis did not detect TDP2 protein in patient primary skin fibroblasts. Patient fibroblasts failed to exhibit significant defects in respiratory chain complexes in biochemical assays compared with control human fibroblasts. However, patient fibroblasts showed an inability to rapidly repair topoisomerase-induced DNA double-strand breaks (DSB) in the nucleus and also showed a profound hypersensitivity to this type of DNA damage. Complementation of patient cells with recombinant human TDP2 restored normal rates of nuclear DSB repair.

Animal Model

Gomez-Herreros et al. (2014) found that mice homozygous for a Tdp2 deletion mutation had decreased 5-prime Tdp activity in neural tissues, which was associated with reduced capacity for double-strand break repair in cortical astrocytes and cerebellar granule neurons. Although mutant mice had no detectable neurologic phenotype, histopathologic studies showed a 25 to 30% reduction in the density of interneurons in the molecular layer of the cerebellum, suggesting that Tdp2 is involved in neural development or maintenance.