A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-51 (SCA51) is caused by heterozygous trinucleotide (CAG)n repeat expansion in the THAP11 gene (609119) on chromosome 16q22.

Spinocerebellar ataxia-51 (SCA51) is an autosomal dominant neurologic disorder characterized by progressive gait abnormalities, ataxia, and dysarthria. The age at onset is usually in middle age, but there is phenotypic variability both within and between families. Those with longer expanded repeats tend to have earlier onset and more severe symptoms, consistent with genetic anticipation. Additional features may include dysphagia and nystagmus; brain imaging shows cerebellar atrophy (Tan et al., 2023).

Tan et al. (2023) reported a large multigenerational Chinese family with spinocerebellar ataxia. The median age at symptom onset was 34 years (range 4 to 51), with a trend toward earlier onset in subsequent generations, suggesting genetic anticipation, and the median age at death was 40 years (range 15 to 61). Of the 16 affected family members, only 5 were alive and available for study. The proband, who was the youngest individual in the latest generation, presented at 4 years of age with progressively unsteady gait, hand incoordination, dysarthria, sleep disturbance, and irritability. Within 12 months, she lost ambulation, developed dysphagia, and showed ptosis, esotropia, and slow saccades. Other features included ataxia, pyramidal signs (hyperreflexia, ankle clonus, extensor plantar responses), and mild cognitive impairment. There were no overt seizures, but EEG was consistent with migratory myoclonic seizures. Brain imaging showed mild cerebral and cerebellar atrophy. The other 4 patients had a less severe disorder with later onset (38 to 51 years) of gait ataxia and dysarthria, but no dysphagia, pyramidal signs, cognitive impairment, or ocular movement abnormalities, although 1 had nystagmus. Three patients who were imaged had cerebellar atrophy. Six individuals in this family who were asymptomatic ('preataxic') carried expanded repeats, but were younger than the mean age of onset. A second family (family 2) was also identified. The proband developed progressive ataxic and imbalanced gait at 16 years of age, followed by dysarthria, dysphagia, resting tremor of the upper limbs, and nystagmus. Brain imaging showed cerebellar atrophy. He died in an accident at age 24. His 43-year-old father, who carried the same expanded repeat was asymptomatic ('preataxic').

The transmission pattern of SCA51 in the families reported by Tan et al. (2023) was consistent with autosomal dominant inheritance with age-dependent penetrance and genetic anticipation.

In 5 affected members of a large multigenerational Chinese family (family 1) with SCA51, Tan et al. (2023) identified a heterozygous (CAG)n trinucleotide repeat expansion in exon 1 of the THAP11 gene (609119.0002). The mutation, which was found by a combination of linkage analysis and long-range sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The number of expanded CAG repeats in 4 of the symptomatic patients with onset in adulthood ranged from 45 to 55, whereas the repeat was 100 in the 1 patient with onset at 4 years of age. In addition, there were 6 asymptomatic ('preataxic') individuals in family 1 who carried expanded CAG repeats between 54 to 59, suggesting that they may develop the disease later. A heterozygous expanded repeat of 47 was identified in another family (family 2) in which the symptomatic son (proband) had onset at age 16 years, but his 43-year-old asymptomatic ('preataxic') father also carried an expanded repeat of 47. The repeat number in unaffected individuals ranged from 20 to 34, with the most common size being 28 and 29. There was a strong correlation between the size of the (CAG)n repeat and earlier symptom onset, indicating genetic anticipation. Skin fibroblasts from 3 patients in family 1 and in vitro cellular studies showed abnormal cytoplasmic THAP11-containing polyQ aggregates, intracellular p62 (SQSTM1; 601530) aggregates, and decreased viability compared to controls, illustrating the toxic effects of mutant THAP11 proteins.

Hsiao et al. (2024) did not find expanded trinucleotide repeats in the THAP11 gene among 385 Taiwanese patients of Han Chinese descent with cerebellar ataxia, indicating that the THAP11 repeat expansion is rare. The authors noted they were unable to confirm the findings of Tan et al. (2023).