Title : Early-onset neurodegenerative phenotype in xeroderma pigmentosum type A: A two-family case series from Saudi Arabia
Abstract:
Xeroderma pigmentosum type A (XPA) is a rare autosomal recessive disorder caused by defects in the nucleotide excision repair pathway, leading to impaired DNA repair following ultraviolet (UV) damage. Clinically, it is characterized by marked photosensitivity, early cutaneous changes, and progressive neurological deterioration. Neurological manifestations are typically reported in late childhood or early adolescence, most commonly between the ages of 6 and 12 years. Early-onset neurodegenerative presentations in preschool-aged children remain uncommon and are not well described in the literature.
We present 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 evident between the ages of 3 and 6 years, significantly earlier than the classical presentation. Clinical features included delayed motor development, gait instability, spasticity, dysarthria, cognitive impairment, and cutaneous photosensitivity. The clinical course demonstrated notable variability, even among affected siblings, ranging from mild functional impairment to severe disability with wheelchair dependence and, in one case, death in early adulthood.
Neuroimaging findings were consistent across multiple patients, demonstrating cerebral volume loss and bilateral white matter hyperintensities, supporting early central nervous system involvement. Neurophysiological studies revealed heterogeneous findings; while one patient demonstrated peripheral neuropathy, others had normal studies, suggesting variable peripheral nervous system involvement. This highlights the phenotypic heterogeneity of XPA, even in patients sharing the same genetic mutation.
The recurrence of the same pathogenic variant in both families raises the possibility of a regional founder effect, particularly in populations with high rates of consanguinity. This observation has important implications for targeted genetic screening and counseling in similar populations.
This case series expands the recognized clinical spectrum of XPA by demonstrating that neurodegenerative manifestations may occur much earlier than traditionally expected. The presence of early developmental delay in combination with photosensitivity should prompt clinicians to consider XPA and pursue early genetic testing. Timely diagnosis enables appropriate counselling, family screening, implementation of strict photoprotection, and coordinated multidisciplinary care. These measures may help delay disease progression and improve long-term functional outcomes.
