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Hexanucleotide expansions within the first intron of the C9ORF72 gene are a significant cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), alone or in combination, as well as sporadic ALS worldwide.1–3 Several recent reports have described cases which broaden the clinical phenotype to include behavioral variant FTD with or without early psychiatric presentations and parkinsonian features,4,5 and primary progressive aphasia.6 There is also a report of a patient with a family history of ALS and cerebellar ataxia,5 an intriguing finding as neuroimaging of C9ORF72 patients shows cerebellar atrophy, which is not typically observed with other FTD-related mutations such as MAPT or GRN.7 Cerebellar neuronal cytoplasmic inclusions have also been observed in multiple studies,6,7 yet clinical cerebellar ataxia has not been detected in any large cohorts of C9ORF72 patients with FTD and/or ALS.1–3,7 Since a majority of adult-onset ataxia cases are of unknown etiology, these observations raise the possibility that C9ORF72 may contribute to the development of sporadic spinocerebellar ataxia.
To address this question, we examined 209 adult-onset sporadic ataxia patients for C9ORF7 hexanucleotide expansion (Table I). All patients were screened for common genetic spinocerebellar ataxias including SCA1, SCA2, SCA3, SCA6, SCA7, and/or Friedreich ataxia. Most patients (40%) had pure cerebellar ataxia but, given the known C9ORF72 phenotypes, cases associated with upper motor neuron signs, dementia, and parkinsonism were also included. Approximately one-third of these patients met possible or probable criteria for multiple system atrophy. Testing was performed as previously described3 and only one positive case was identified (1/209, 0.5%).
This patient, currently age 53, developed slowly progressive cerebellar dysfunction in her early 20’s with falls by age 25. Upper motor neuron features of increased lower extremity tone and hyper-reflexia were present but annual assessments have shown no lower motor neuron involvement or cognitive decline. MRI has shown cerebellar atrophy with no frontal or temporal involvement. Evaluation for other genetic causes involving the APTX, ATN1, ATXN1, ATXN2, ATXN3, ATXN7, ATXN8, ATXN10, CACNA1A, FMR1, FXN, KCNC3, PRKCG, PP2R2B, SACS, SETX, SPTBN2, and TBP genes was unremarkable. She is Caucasian with French-Canadian ancestry. As with the prior reported C9ORF72 ataxia case,5 family history was notable for her father and paternal uncle being diagnosed with ALS and dying within 2 years of symptom onset. There were no other affected family members.
We speculate that the clinical findings seen in our patient represent a rare (<1%) C9ORF72 phenotype,5 however, given the lack of other affected family members or unrelated cases, we cannot confirm this. C9ORF72 penetrance varies by age, with full penetrance occurring by the 9th decade,1 and it is possible that our patient will still develop a more classic phenotype. Regardless, this study does not support genetic testing for C9ORF72 expansion in sporadic spinocerebellar ataxia, although, as our study only examined sporadic-onset cases, it remains possible that C9ORF72 may contribute more significantly to dominant familial forms. For now, C9ORF72 testing would only be indicated for ataxia patients with a family history of ALS and/or FTD.
The authors wish to thank all the patients and their families who contributed to this project. Study support provided by NIMH K08MH86297 (BLF), the UCLA Program in Neurogenetics (BLF), and NINDS 5T32NS048004-07 (MP).
BLF has received funding from the National Institutes of Health (NIH) and the National Ataxia Foundation. SLP has received support from Santhera Pharmaceuticals to conduct a phase 3 idebenone study. DHG has received royalty payments from Yale University and Chemicon for antibody sales and funding from the NIH and private foundations. GC has received funding from the NIH, the Muscular Dystrophy Association, and private foundations.
Conflict of Interest statement. None relevant to this work declared.
Author Contributions:BLF and GC were responsible for the conception and design of the research project. MP and SP were responsible for project execution. SLP and DHG supervised the clinical phenotyping and the molecular aspects of the project, respectively. BLF wrote the manuscript and BLF, GC, SLP, and DHG were responsible for its review and critique.
Full Financial Disclosures of All Authors for the Past Year:
MP and SP have nothing to disclose.