Clinical variability in cerebral tendinous xanthomatosis (CTX): Insights from 16 cases across Gulf Cooperation Council's (GCC's) high consanguineous population.

Background: Cerebrotendinous xanthomatosis (CTX) is a rare neurometabolic disorder characterized by diverse neurological and extra-neurological manifestations. In children, chronic diarrhea, neonatal cholestasis, and cataracts are characteristics and often precede neurological symptoms, while adults typically present with cognitive decline and gait disturbances. This variability contributes to frequent misdiagnosis and delays in diagnosis, leading to significant neurological deterioration.

Objective: To explore the clinical and genetic diversity of CTX cases in the Gulf Cooperation Council (GCC) region, comparing the phenotypic differences between children and adults.

Methods: The retrospective, multicenter, descriptive study included 16 clinically and genetically confirmed CTX cases. Data collected encompassed clinical presentations, diagnostic delays, biochemical markers such as cholestanol levels, neuroimaging findings, and genetic mutations in the CYP27A1 gene. Participants were categorized into pediatric and adult groups.

Results: Common clinical features included cognitive decline (75%), learning difficulties (69%), diarrhea (56%), cataracts (56%), gait issues (50%), and behavioral changes (44%). Notably, childhood diarrhea was strongly associated with earlier diagnosis, with approximately 90% of such cases identified in this age group. Misdiagnosis occurred in 3 patients, with an average diagnostic delay of 6.1 years-shorter for children (2.7 years) compared to adults (11.6 years). Tendon xanthoma was observed in only 1 patient. Genetic testing identified 7 CYP27A1 variants, highlighting genetic heterogeneity in this population.

Conclusion: This study emphasizes the need for increased physician awareness, particularly regarding pediatric presentations, to reduce diagnostic delays and prevent irreversible neurological damage. These findings support integration of targeted genetic testing and early screening programs to improve patient outcomes.