Objective: To develop an algorithm for identifying patients with cerebrotendinous xanthomatosis (CTX) in a cohort of individuals with neurodegenerative disorders.

Background: CTX is a rare autosomal recessive metabolic disorder of bile acid synthesis and lipid-storage caused by biallelic pathogenic variants in the CYP27A1 gene, which encodes the sterol 27-hydroxylase enzyme. Defects in this enzyme lead to abnormal bile acid synthesis and toxic accumulation of cholestanol, bile alcohols and other metabolites in the body resulting in complications like cholestasis, cataracts, tendon xanthomas, ataxia, neuropathy and neuropsychiatric manifestations [1,2]. Movement disorders (MD) in CTX are part of a broader clinical presentation and not the predominant symptom. MD have been reported in ~20-30% of CTX cases, with Parkinsonism being the most frequently reported, followed by dystonia, myoclonus and postural tremor [3,4].

Method: A retrospective review of electronic health records (EHR) from a cohort of ~1000 patients with idiopathic and atypical Parkinsonism, Alzheimer’s disease, and other dementias to identify individuals presenting with cardinal clinical features associated with CTX was conducted. The search criteria included “cataract” (early onset, bilateral, idiopathic, infantile, juvenile, unexplained, unspecified, surgery or lensectomy), “diarrhea” (chronic, idiopathic, and cholestasis, “xanthomas” (tendon and tuberous). Various neuropsychiatric symptoms, signs, and cognitive decline were screened.

Results: We identified 46 individuals with a record of cataracts, 3 with diarrhea and none with xanthomas. Neurological features associated with CTX included 3 individuals with pyramidal signs, 175 with hyperintensities of cerebral white matter, 67 with dystonia, 6 with ataxia, 44 with gait disturbances, 52 with peripheral neuropathy, 5 with atypical behavior, 112 with neuropsychiatric symptoms and 344 with cognitive decline and psychiatric symptoms.

Conclusion: Retrospective EHR reviews in patients with MD provide a valid starting point to identifying individuals with clinical features suggestive of CTX. These preliminary results may help prioritize candidates for further investigations. Genetic testing of the CYP27A1 gene, along with biochemical confirmation, will be essential for definitive diagnosis and could contribute to estimating CTX prevalence in the MD population.

References: 1. Verrips A, Hoefsloot LH, Steenbergen GC, Theelen JP, Wevers RA, Gabreëls FJ, van Engelen BG, van den Heuvel LP. Clinical and molecular genetic characteristics of patients with cerebrotendinous xanthomatosis. Brain. 2000 May;123 ( Pt 5):908-19. doi: 10.1093/brain/123.5.908.
2. Sekijima Y, Koyama S, Yoshinaga T, Koinuma M, Inaba Y. Nationwide survey on cerebrotendinous xanthomatosis in Japan. J Hum Genet. 2018 Mar;63(3):271-280. doi: 10.1038/s10038-017-0389-4.
3. Stelten BML, van de Warrenburg BPC, Wevers RA, Verrips A. Movement disorders in cerebrotendinous xanthomatosis. Parkinsonism Relat Disord. 2019 Jan;58:12-16. doi: 10.1016/j.parkreldis.2018.07.006.
4. Zubarioglu T, Kıykım E, Köse E, Eminoğlu FT, Teke Kısa P, Balcı MC, Özer I, İnci A, Çilesiz K, Canda E, Yazıcı H, Öztürk-Hişmi B, Bulut FD, Dorum S, Akgun A, Yalçın-Çakmaklı G, Kılıç-Yıldırım G, Soyuçen E, Akçalı A, Güneş D, Durmuş A, Gündüz A, Kasapkara ÇS, Göksoy E, Akar HT, Ersoy M, Erdöl Ş, Yıldız Y, Hanağası HA, Arslan N, Aktuğlu-Zeybek Ç. Clinical, biochemical, and molecular insights into Cerebrotendinous Xanthomatosis: A nationwide study of 100 Turkish individuals. Mol Genet Metab. 2024 Jun;142(2):108493. doi: 10.1016/j.ymgme.2024.108493.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/identification-of-cerebrotendinous-xanthomatosis-in-patients-with-neurodegenerative-disorders-from-the-cincinnati-cohort-biomarker-program/