STUB1‐Related Ataxias: A Challenging Diagnosis

The recent article by Olszewska and Kinsella ¹ adds new information about the genetic and phenotypic complexity of STUB1‐related diseases. The authors describe an ataxic 45‐year‐old woman with 2 compound heterozygous variants in STUB1 and emphasize that dystonia, although rare, may be part of Spinocerebellar Ataxia, Autosomal Recessive 16 (SCAR16), the autosomal recessive disorder caused by biallelic mutations in this gene. However, they also consider the alternative diagnosis of Spinocerebellar Ataxia 48 (SCA48), the counterpart autosomal dominant disorder caused by STUB1 monoallelic mutations. In fact, although c.358 + 1 G > A affects a consensus site for splicing, the missense c.566A > C/p.D189A shows moderate evidence of pathogenicity, satisfying only 2 moderate criteria (PM2, PM3) and a single supporting evidence (PP1) of the American College Medical Genetics and Genomics guidelines for variant interpretation. ²

We recently reviewed the phenotype of 31 SCAR16 and 26 SCA48 patients ³ and share the authors’ concerns about the attribution of this family to one form or another. An argument in favor of the diagnosis of the autosomal recessive form is that the proband’s parents were older than age 70 and asymptomatic. However, a segregation study could not be done and SCA48 can be sporadic, as seen in 4 of the 12 reviewed index cases. On the other side, several findings point to SCA48: mean onset age is 20 ± 14 years in SCAR16 and 42 ± 9 in SCA48; neither the patient nor her sister show features as spasticity, myoclonus, hypogonadism, or abnormal nerve conduction studies, which are distinctive of SCAR16 when compared with SCA48; and dystonia is a rare feature in the autosomal recessive form (10%) and is present in 31% of dominant cases. ³ Finally, the patient’s sister had a mild clinical picture, with dysarthria and memory problems at age 46, which is typical of SCA48 ⁴ and not consistent with SCAR16, which is an early‐onset severe disease.

It is also interesting to note that, although a relatively limited literature is to date available, peculiar magnetic resonance imaging findings could help in distinguishing between the 2 conditions. In particular, although the presence of cerebellar atrophy is significant and constant in both diseases, a T2‐weighted hyperintense signal extending from the dentate nuclei to the middle cerebellar peduncles, coupled to atrophy of the most posterior cerebellar regions, has been recently reported in 90% of SCA48 patients, ⁵ whereas no data on its possible presence are available yet in SCAR16.

A correct diagnosis, of course, is not an academic issue, but is crucial for appropriate genetic counseling and for further research on the topic of STUB1‐related ataxias.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: A. Writing the First Draft, B. Review and Critic

S.C.: 1B, 1C, 2B

F.M.S.: 1B, 1C, 2B

G.D.M.: 1A, 1B, 2A

Disclosures

Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. This paper did not involve human participants and did not need informed consent. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: The authors declare that there are no conflicts of interest.

Financial Disclosures for the Previous 12 Months: The authors have nothing to report.