6th Edition of Neurology World Conference 2026

Abstract

Xeroderma pigmentosum type A (XPA) is a rare autosomal recessive disorder caused by defects in the nucleotide excision repair pathway, resulting in marked photosensitivity and progressive neurodegeneration. Neurological manifestations are classically reported in late childhood or early adolescence, typically between 6 and 12 years of age. Early-onset neurological involvement in preschool-aged children remains poorly characterized. We report a case series of five patients from two consanguineous Saudi families, all harboring the same homozygous pathogenic variant in the XPA gene (c.619C>T; p.Arg207*). Neurological symptoms were observed between the ages of 3 and 6 years, significantly earlier than expected. Clinical features included delayed motor milestones, gait instability, spasticity, dysarthria, cognitive impairment, and cutaneous photosensitivity. Disease severity varied within and across families, ranging from mild functional limitation to severe disability requiring wheelchair use and, in one case, death in early adulthood. Neuroimaging consistently demonstrated cerebral volume loss and bilateral white matter hyperintensities, suggesting early central nervous system involvement. Neurophysiological findings were heterogeneous; one patient showed evidence of peripheral neuropathy, while others had normal studies, indicating variable peripheral nervous system involvement. This variability highlights the complex and heterogeneous neurological expression of XPA, even among individuals sharing the same mutation. This case series expands the phenotypic spectrum of XPA by emphasizing that neurodegenerative manifestations may occur much earlier than traditionally recognized. The recurrence of the same pathogenic variant in both families suggests a possible regional founder effect, particularly in populations with high rates of consanguinity. Early recognition of the combination of developmental delay and photosensitivity should prompt consideration of XPA and early genetic testing. Timely diagnosis enables appropriate counselling, family screening, implementation of strict photoprotection, and multidisciplinary management, which may help slow disease progression and improve patient outcomes.