Spinocerebellar ataxia type 17 repeat in patients with Huntington's disease‐like and ataxia

We read with interest the report by Toyoshima and colleagues on a patient with spinocerebellar ataxia type 17 (SCA17) homozygous for 48 repeats. The article provides further insight on the heterogeneity of SCA17 and Huntington’s disease-like (HDL) disorders, suggesting that different genotypes could underlie common clinical features and mechanisms of neurodegeneration. Here, we report the distribution analysis of the SCA17 repeat in 98 sporadic Italian HDL patients not carrying pathogenic expansions in the huntingtin and junctophilin-3 genes. Among the HDL patients, 39 were referred to our center with a diagnosis of probable HD, and 59 presented a broader clinical phenotype resembling HDL, including sporadic non-Alzheimer’s dementia associated with involuntary movements, chorea, or dystonia. These latter clinical features are compatible with early-onset HDL forms that do not present clear and specific symptoms of the disease. In addition, we also analyzed 207 sporadic SCA patients, without mutations in the known linked genes, and 106 healthy controls. All patients gave informed consent. A patient affected by dystonia and tics with 43 triplet allele was identified. Sporadic involuntary movements, such as facial grimacing and head jerk, with childhood onset, might depict a HD phenocopy. The patient is now affected by mild symptoms not requiring medical therapy. SCA17 allele frequency distributions (Fig) were similar among the three groups (HDL, ataxia, and controls), and no expansions were found in the entire sample (n 410). It could be debated whether a 43 repeat is possibly pathogenic and responsible for this childhood-onset case, even with mild disease progression. As reported by Toyoshima and colleagues, the double-dose effect of a mutated SCA17 allele does not influence age of onset and would possibly affect the patient’s clinical features. SCA17 expansions with more than 48 repeats have been considered pathogenic; the size of a larger, normal allele ranges from 42 to 44 repeats among various populations. To date, only one allele with 43 repeats has been reported, found in a patient with late-onset ataxia and dementia; otherwise, intermediate repeats ranging between 43 and 48 triplets are considered to be of indeterminate significance or having reduced penetrance. Our observation may support the clinical and genetic heterogeneity of the SCA17 expansion, confirming the rarity of this mutation in ataxic patients. However, further case reports are needed to provide evidence that SCA17 mutations may be responsible for the HDL phenotype, taking into consideration the overlapping clinical features of the disorders.