Donders Institute for Brain, Cognition and Behaviour
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Thesis defense Bianca Stelten (Donders series 598)

13 March 2023

Promotor: Prof. dr. R.A. Wevers
Copromotoren: Dr. A. Verrips Canisius Wilhelmina Ziekenhuis. Dr. L.A.J. Kluijtmans.

Cerebrotendinous Xanthomatosis. A treatable inborn error of metabolism

Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive inborn error of metabolism associated with the deficiency of the enzyme sterol 27-hydroxylase, encoded by the CYP27A1 gene. Diagnosis is often delayed by many years, losing a window of opportunity to start early treatment, preventing irreversible symptoms and shorten the diagnostic odyssey for patients and families. The aim of this thesis was to expand the knowledge about the phenotypic heterogeneity in CTX and to describe the long-term follow-up effects of treatment. The thesis starts with describing an expert opinion on best practices for diagnosis, treatment and management of patients with CTX. Different clinical phenotypes have been reported among patients with identical CYP27A1 genotypes, even within families. A better understanding of the phenotypic heterogeneity in CTX hopefully leads to a better and earlier recognition of this disease. We showed that an autism spectrum disorder is an early and probably underestimated frequent feature in CTX. Movement disorders represent a rare clinical feature in CTX, but should be considered, particularly in case of early onset, and when associated with other neurological or systemic features (diarrhea, cataract, tendon xanthomas). Parkinsonism seems to be a treatment-resistant feature. In addition, we described the existence of a 'milder phenotype' in CTX, representing untreated adult patients without neurological involvement at time of diagnosis. It is important to realize that the absence of neurological symptoms at diagnosis does not rule out the development of future neurological symptoms. We showed that start of treatment at an early age, specifically before the age of 24 years, can not only prevent but may even reverse the development of neurological symptoms in CTX. Early start of treatment also prevents brain MRI abnormalities in adult life in CTX. This study emphasizes the importance of early diagnosis in CTX and provides a strong argument to include CTX in newborn screening programs.