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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $37.50 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Hammer MB, Eleuch-Fayache G, Schottlaender LV, Nehdi H, Gibbs JR, Arepalli SK, et al. Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity. Am J Hum Genet. 2013;92:245–51.
Pyle A, Griffin H, Yu-Wai-Man P, Duff J, Eglon G, Pickering-Brown S, et al. Prominent sensorimotor neuropathy due to SACS mutations revealed by whole-exome sequencing. Arch Neurol. 2012;69:1351–4.
Doi H, Ohba C, Tsurusaki Y, Miyatake S, Miyake N, Saitsu H, et al. Identification of a novel homozygous SPG7 mutation in a Japanese patient with spastic ataxia: making an efficient diagnosis using exome sequencing for autosomal recessive cerebellar ataxia and spastic paraplegia. Intern Med. 2013;52:1629–33.
Hammer MB, Eleuch-Fayache G, Gibbs JR, Arepalli SK, Chong SB, Sassi C, et al. Exome sequencing: an efficient diagnostic tool for complex neurodegenerative disorders. Eur J Neurol. 2013;20:486–92.
Sijbers AM, de Laat WL, Ariza RR, Biggerstaff M, Wei YF, Moggs JG, et al. Xeroderma pigmentosum group F caused by a defect in a structure-specific DNA repair endonuclease. Cell. 1996;86:811–22.
Kashiyama K, Nakazawa Y, Pilz DT, Guo C, Shimada M, Sasaki K, et al. Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and Fanconi anemia. Am J Hum Genet. 2013;92:807–19.
Bogliolo M, Schuster B, Stoepker C, Derkunt B, Su Y, Raams A, et al. Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia. Am J Hum Genet. 2013;92:800–6.
Tofuku Y, Nobeyama Y, Kamide R, Moriwaki S, Nakagawa H. Xeroderma pigmentosum complementation group F: report of a case and review of Japanese patients. J Dermatol. 2015;42:897–9.
Carre G, Marelli C, Anheim M, Geny C, Renaud M, Rezvani HR, et al. Xeroderma pigmentosum complementation group F: a rare cause of cerebellar ataxia with chorea. J Neurol Sci. 2017;376:198–201.
Miyatake S, Okamoto N, Stark Z, Nabetani M, Tsurusaki Y, Nakashima M, et al. ANKRD11 variants cause variable clinical features associated with KBG syndrome and Coffin-Siris-like syndrome. J Hum Genet. 2017;62:741–6.
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–9.
Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4:1073–81.
Nakazawa Y, Sasaki K, Mitsutake N, Matsuse M, Shimada M, Nardo T, et al. Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair. Nat Genet. 2012;44:586–92.
Sijbers AM, van Voorst Vader PC, Snoek JW, Raams A, Jaspers NG, Kleijer WJ. Homozygous R788W point mutation in the XPF gene of a patient with xeroderma pigmentosum and late-onset neurologic disease. J Invest Dermatol. 1998;110:832–6.
Schwarz JM, Rodelsperger C, Schuelke M, Seelow D. MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods. 2010;7:575–6.
Moriwaki S, Nishigori C, Imamura S, Yagi T, Takahashi C, Fujimoto N, et al. A case of xeroderma pigmentosum complementation group F with neurological abnormalities. Br J Dermatol. 1993;128:91–94.
Marelli C, Guissart C, Hubsch C, Renaud M, Villemin JP, Larrieu L, et al. Mini-exome coupled to read-depth based copy number variation analysis in patients with inherited ataxias. Hum Mutat. 2016;37:1340–53.
Jeppesen DK, Bohr VA, Stevnsner T. DNA repair deficiency in neurodegeneration. Prog Neurobiol. 2011;94:166–200.
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).
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.
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
The Classification of Autosomal Recessive Cerebellar Ataxias: a Consensus Statement from the Society for Research on the Cerebellum and Ataxias Task Force
The Cerebellum (2019)
Characteristics of Xeroderma Pigmentosum in Japan: Lessons From Two Clinical Surveys and Measures for Patient Care
Photochemistry and Photobiology (2019)
The FEBS Journal (2018)