Objective To describe the features of 2 unrelated adults with xeroderma pigmentosum complementation group F (XP-F) ascertained in a neurology care setting. Methods We report the clinical, imaging, molecular, and nucleotide excision repair (NER) capacity of 2 middle-aged women with progressive neurodegeneration ultimately diagnosed with XP-F. Results Both patients presented with adult-onset progressive neurologic deterioration involving chorea, ataxia, hearing loss, cognitive deficits, profound brain atrophy, and a history of skin photosensitivity, skin freckling, and/or skin neoplasms. We identified compound heterozygous pathogenic mutations in ERCC4 and confirmed deficient NER capacity in skin fibroblasts from both patients. Conclusions These cases illustrate the role of NER dysfunction in neurodegeneration and how adult-onset neurodegeneration could be the major symptom bringing XP-F patients to clinical attention. XP-F should be considered by neurologists in the differential diagnosis of patients with adult-onset progressive neurodegeneration accompanied by global brain atrophy and a history of heightened sun sensitivity, excessive freckling, and skin malignancies.
Bibliographical noteFunding Information:
The Article Processing Charge was funded by the NIH.
Intramural Research Program of the National Institutes of Health (NIH) NHGRI and the NCI, Common Fund, Office of the Director; the NIH/NHLBI grant (HHSN268201400058); the NIH/NIA grant (P01AG043376): M.J.Y., E.A.W. and L.J.N.; and the Michael J. Homer Family Fund: M.D.G.
Dr. Shanbhag has received research support from the NIH NINDS and Alzheimer’s Association. Dr. Geschwind has received funding for travel and/or speaker honoraria from Oakstone Publishing, Inc; has served on the editorial board of Dementia & Neuropsychologia; serves or has served as a consultant to Advanced Medical Inc, Best Doctors Inc, Grand Rounds, Gerson Lehrman Group Inc, Guidepoint Global, MEDACorp, LCN Consulting, Optio Biopharma Solutions, various medical-legal consulting, Biohaven Pharmaceuticals Inc, Teva Pharmaceuticals, and Quest Diagnostics; and receives or has received research support from the NIH/NIA (R01 AG031189) PI 2013-2018, Alliance Biosecure, Michael J. Homer Family Fund, CurePSP, and Tau Consortium. Dr.
DiGiovanna serves or has served on scientific sdvisory boards of the Medical and Scientific Advisory Board of the Foundation for Ichthyosis and Related Skin Types; holds patents with regard to the use of synthetic peptides to disrupt the cytoskeleton and therapeutic uses of hmgn1 and hmgn2; consults or has consulted for the US Food and Drug Administration; and is employed by the National Cancer Institute and NIH. Dr. Groden, Dr. Godfrey, and Dr. You-sefzadeh report no disclosures. Dr. Wade is or has been employed by The Scripps Research Institute and The National Institute on Aging. Dr. Niedernhofer holds patents with regard to a rapid test to measure DNA repair capacity of an individual; has received research support from the NIH/ NHLBI, NIH/NIA, and Glenn Award for Aging Research. Dr. Malicdan serves or has served on the editorial board of BMC Musculoskeletal Disorders; holds patents with regard to therapeutic pharmaceutical agent for diseases associated with decrease in function of gne protein, food composition, and food additive, Gne-/-hGNED176VTg as a mouse model for DMRV/HIBM and CANNABINOID RECEPTOR MEDIATING COMPOUNDS; and is employed by the NIH Intramural Research Program. Dr. Kraemer serves or has served on the editorial board of Photodermatology and Pho-toimmunology. Dr. Gahl has received funding for travel and/or speaker honoraria from Cystinosis Research Network; serves or has served on the editorial board of Molecular Genetics and Metabolism; receives or has received licensing royalties from ManNAc; and receives research support from the NIH. Dr. Toro is a full-time employee of the NIH and receives funding from the NIH intramural program. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG.