Adult-Onset Neurodegeneration in Nucleotide Excision Repair Disorders (NERDND): Time to Move Beyond the Skin

Isabell Cordts, Demet Önder, Andreas Traschütz, Xenia Kobeleva, Ivan Karin, Martina Minnerop, Peter Koertvelyessy, Saskia Biskup, Stephan Forchhammer, Johannes Binder, Andreas Tzschach, Frank Meiss, Axel Schmidt, Martina Kreiß, Kirsten Cremer, Martin A. Mensah, Joohyun Park, Maren Rautenberg, Natalie Deininger, Marc SturmPaul Lingor, Thomas Klopstock, Markus Weiler, Franz Marxreiter, Matthis Synofzik, Christian Posch, Judith Sirokay, Thomas Klockgether, Tobias B. Haack, Marcus Deschauer

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Background: Variants in genes of the nucleotide excision repair (NER) pathway have been associated with heterogeneous clinical presentations ranging from xeroderma pigmentosum to Cockayne syndrome and trichothiodystrophy. NER deficiencies manifest with photosensitivity and skin cancer, but also developmental delay and early-onset neurological degeneration. Adult-onset neurological features have been reported in only a few xeroderma pigmentosum cases, all showing at least mild skin manifestations. Objective: The aim of this multicenter study was to investigate the frequency and clinical features of patients with biallelic variants in NER genes who are predominantly presenting with neurological signs. Methods: In-house exome and genome datasets of 14,303 patients, including 3543 neurological cases, were screened for deleterious variants in NER-related genes. Clinical workup included in-depth neurological and dermatological assessments. Results: We identified 13 patients with variants in ERCC4 (n = 8), ERCC2 (n = 4), or XPA (n = 1), mostly proven biallelic, including five different recurrent and six novel variants. All individuals had adult-onset progressive neurological deterioration with ataxia, dementia, and frequently chorea, neuropathy, and spasticity. Brain magnetic resonance imaging showed profound global brain atrophy in all patients. Dermatological examination did not show any skin cancer or pronounced ultraviolet damage. Conclusions: We introduce NERDND as adult-onset neurodegeneration (ND) within the spectrum of autosomal recessive NER disorders (NERD). Our study demonstrates that NERDND is probably an underdiagnosed cause of neurodegeneration in adulthood and should be considered in patients with overlapping cognitive and movement abnormalities.

Original languageEnglish
Pages (from-to)1707-1718
Number of pages12
JournalMovement Disorders
Issue number8
StatePublished - Aug 2022
Externally publishedYes


  • NER
  • UV sensitivity
  • ataxia
  • dementia
  • xeroderma pigmentosum


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