Journal
JOURNAL OF HUMAN GENETICS
Volume 63, Issue 4, Pages 417-423Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s10038-017-0408-5
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Funding
- Research on Measures for Intractable Diseases
- Comprehensive Research on Disability Health and Welfare
- Strategic Research Program for Brain Science
- Initiative on Rare and Undiagnosed Diseases in Pediatrics
- Initiative on Rare and Undiagnosed Diseases for Adults from the Japanese Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- fund for Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems from the Japanese Science and Technology Agency
- Ministry of Health, Labor and Welfare
- Takeda Science Foundation
- Ichiro Kanehara Foundation for the Promotion of Medical Science Medical Care
- Grants-in-Aid for Scientific Research [17K16128, 17K19536, 15K09344, 17H00783, 16H05357, 16K15526, 15H05333] Funding Source: KAKEN
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Autosomal recessive cerebellar ataxias (ARCAs) are clinically and genetically heterogeneous neurological disorders. Through whole-exome sequencing of Japanese ARCA patients, we identified three index patients from unrelated families who had biallelic mutations in ERCC4. ERCC4 mutations have been known to cause xeroderma pigmentosum complementation group F (XP-F), Cockayne syndrome, and Fanconi anemia phenotypes. All of the patients described here showed very slowly progressive cerebellar ataxia and cognitive decline with choreiform involuntary movement, with young adolescent or midlife onset. Brain MRI demonstrated atrophy that included the cerebellum and brainstem. Of note, cutaneous symptoms were very mild: there was normal to very mild pigmentation of exposed skin areas and/or an equivocal history of pathological sunburn. However, an unscheduled DNA synthesis assay of fibroblasts from the patient revealed impairment of nucleotide excision repair. A similar phenotype was very recently recognized through genetic analysis of Caucasian cerebellar ataxia patients. Our results confirm that biallelic ERCC4 mutations cause a cerebellar ataxia-dominant phenotype with mild cutaneous symptoms, possibly accounting for a high proportion of the genetic causes of ARCA in Japan, where XP-F is prevalent.
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