Adult‐Onset Neurodegeneration in Nucleotide Excision Repair Disorders: More Common than Expected

Abstract

Overlap between disorders manifesting with different skin conditions and movement disorders is gaining increased recognition in recent years. 1 Recently, Cordts et al. 2 analyzed prevalence of bilallelic variants in genes of the nucleotide excision repair (NER) pathway in patients presenting primarily with neurological symptoms. In their study, 13 patients with variants in ERCC4 (n = 8), ERCC2 (n = 4), or XPA (n = 1) were identified, which represented 1.0% (n = 12/1206) of their subgroup of patients with ataxia, 3.5% (n = 12/340) of patients with dementia, and 8.6% (n = 12/139) of patients with both ataxia and dementia. All individuals had adultonset progressive neurological deterioration with ataxia, dementia, and frequently chorea, neuropathy, and spasticity. Interestingly, none of these patients presented with skin cancer, and all manifested only minor skin abnormalities. The authors introduced a concept of a novel disease entity-adultonset neurodegeneration within the spectrum of autosomal recessive NER disorders (NERD ND s)-and suggest a novel modular classification system for subtypes of NERD.Here we report a 40-year-old man with a history of adultonset progressive chorea, ataxia, and cognitive impairment. At the age of 28 years he started feeling fatigued and having headaches; at age 33, he noticed mild generalized excessive movements that very slowly progressed, followed by stability problems and cognitive deterioration later on. He was able to work as an electrician until age 36. Objectively, at his first examination at age 38 he presented with mild generalized chorea including face and neck, combined with neocerebellar and paleocerebellar syndrome, cervical dystonia, dystonic posturing of his hands more pronounced on the left (see Supporting Information Video S1), and cognitive impairment, which currently presents his most prominent subjective complaint. His MRI showed a right-side occipital postischemic area, as well as rather marked supratentorial and infratentorial global brain atrophy, which clearly progressed over a 2-year follow-up period (Fig. 1A). In addition, he was