Cerebellar ataxia-dominant phenotype in patients with ERCC4 mutations

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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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We thank the patients and their families for their participation in this study. This work was supported by grants from Research on Measures for Intractable Diseases (NM); Comprehensive Research on Disability Health and Welfare (NM); the Strategic Research Program for Brain Science (NM); the Initiative on Rare and Undiagnosed Diseases in Pediatrics (NM); the Initiative on Rare and Undiagnosed Diseases for Adults (NM) from the Japanese Agency for Medical Research and Development; a Grant-in-Aid for Scientific Research on Innovative Areas (Transcription Cycle) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Grants-in-Aid for Scientific Research (A (NM)], B (NMi, HS), and C (HD, SM, MN)); the fund for Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems (NM) from the Japanese Science and Technology Agency; and grants from the Ministry of Health, Labor and Welfare (NM), the Takeda Science Foundation (NMi, HS, NM), and The Ichiro Kanehara Foundation for the Promotion of Medical Science & Medical Care (SM).

Author contributions

HD wrote the main manuscript and prepared the figure and the table. HT, NM, and FT revised the manuscript and gave conceptual advice. HD, SK, SM, SN, MK, AK, RK, and KO collected the clinical data and samples. HD, SM, RF, SI, SK, KT, MT, KT, MN, YT, NMi, and HS conducted the analysis of the genetic data.

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Correspondence to Hiroshi Doi or Fumiaki Tanaka.

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