A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-50 (SCA50) is caused by heterozygous mutation in the NPTX1 gene (602367) on chromosome 17q25.

Spinocerebellar ataxia-50 (SCA50) is an autosomal dominant neurologic disorder characterized by cerebellar ataxia, oculomotor apraxia and other eye movement abnormalities, and cerebellar atrophy on brain imaging. Most patients develop symptoms as adults, although childhood onset has rarely been reported. Additional more variable features may include tremor, dysarthria, dysphagia, and cognitive impairment with executive dysfunction (Coutelier et al., 2022; Schoggl et al., 2022).

Coutelier et al. (2022) reported a large multigenerational family (AAD271) in which 9 individuals had adult-onset cerebellar ataxia. Subsequently, 7 patients from 5 additional families with a similar phenotype were identified. The mean age at symptom onset was 50.7 years (range 34 to 71) and the disorder was slowly progressive. The predominant features were cerebellar ataxia and ocular signs such as horizontal nystagmus, oculomotor apraxia, diplopia, and abnormal saccadic movements. Most patients had variable additional neurologic features, including tremor, myoclonus, chorea, dystonia, hearing loss, and migraine. Pyramidal signs were not observed. Four patients had decreased vibration sense at the ankles, including 2 with electrophysiologic evidence of a peripheral axonal sensorimotor polyneuropathy. A subset of patients studied showed cognitive deficits manifest as dysexecutive syndrome, memory impairment, attention deficit, and apraxia. Brain imaging, when performed, showed mild cerebellar atrophy occasionally complicated by white matter hyperintensities.

Helmchen et al. (2022) studied a 58-year-old woman from one of the families reported by Coutelier et al. (2022) (family LUEB01) who presented with visual symptoms consistent with oculomotor apraxia at 43 years of age. Her visual disturbances were progressive and severe, with an inability to initiate horizontal saccades or smooth pursuit eye movements. She did not have nystagmus or oculomotor cerebellar signs. Functional MRI studies showed abnormally reduced structural connectivity within the defined oculomotor network of each hemisphere (intrahemispheric dysfunction). These studies indicated a bilateral but ipsi-hemispheric oculomotor network disorder involving the frontal eye fields (FEF).

Deppe et al. (2022) reported a man who presented with cerebellar ataxia and dysarthria at 47 years of age. The disorder was slowly progressive, and he developed dysphagia, choreiform dyskinesias, and oculomotor apraxia. He also had moderate cognitive impairment with executive dysfunction, attention deficits, and impaired working memory. Brain imaging showed cerebellar atrophy.

Clinical Variability

Schoggl et al. (2022) reported a 6-year-old girl, born of unrelated parents, who presented with irritability and unsteadiness at 21 months of age after normal early development. At age 2, she had truncal and limb ataxia with an inability to walk and loss of acquired speech. Brain imaging showed cerebellar atrophy. At age 6, she developed generalized epileptic seizures. The authors emphasized the early symptom onset in this patient.

The transmission pattern of SCA50 in the families reported by Coutelier et al. (2022) was consistent with autosomal dominant inheritance.

In affected members of 6 unrelated families with SCA50, Coutelier et al. (2022) identified 2 different heterozygous missense mutations in the NPTX1 gene (G389R, 602367.0001 and E327G, 602367.0002). The mutations, which were found by exome sequencing or targeted sequencing, segregated with the disorder in families with available data. Neither were present in the gnomAD database. Five families carried the G389R mutation, although haplotype analysis excluded a founder effect. The mutant proteins localized to the ER when expressed in COS7 cells, but both caused abnormal and aggregated ER morphologies and hyperplasia of the ER with swollen cisternae, although there were some cytologic differences between the variants. These changes were associated with activation of the ER unfolded protein response (UPR), as evidenced by translocation of ATF6 (605537) to the nucleus and increased cell death. Additional studies indicated that the G389R variant likely resulted in a loss-of-function effect, whereas E327G disrupted NPTX1 secretion and multimerization in a dominant-negative manner. However, both mutations were predicted to result in ER stress, activation of the UPR, and a decrease in cellular viability.

In a man who had onset of SCA50 at age 47 years, Deppe et al. (2022) identified a de novo heterozygous missense mutation in the NPTX1 gene (R143L; 602367.0003). The mutation, which was found by trio-based exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling suggested that the mutation could result in protein misfolding and possible aggregation of dysfunctional multimers.

In a 6-year-old girl, born of unrelated parents, who developed symptoms of SCA50 at 21 months of age, Schoggl et al. (2022) identified a de novo heterozygous missense mutation affecting the pentraxin domain of the NPTX1 gene (Q370R; 602367.0004). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.

See SCA27B (620174) for a form of SCA that had been designated SCA50 in a publication.