Familial variability of cerebrotendinous xanthomatosis lacking typical biochemical findings

JIMD Rep. 2021 Jan 8;59(1):3-9. doi: 10.1002/jmd2.12197. eCollection 2021 May.

PMID: 33977023

Adam J Guenzel, Andrea DeBarber, Kimiyo Raymond, Radhika Dhamija

Summary: In this study reports two siblings who have cerebrotendinous xanthomatosis (CTX). The atypical biochemical presentation of these cases emphasizes the importance of a comprehensive investigation of patients with symptomatology consistent with CTX.

Abstract

Objective: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive bile acid synthesis disorder caused by pathogenic variants in the CYP27A1 gene, which codes for the mitochondrial enzyme sterol 27-hydroxylase. Patients with CTX may have a variety of symptoms, but tendon xanthomas are the most common symptom, along with cataracts, atherosclerosis, and neurological impairment. Regardless of clinical phenotype, CTX patients usually have several times higher levels of cholestanol and bile acid precursors in the bloodstream than healthy controls.

Results: In this study reports two siblings, one with the rare spinal xanthomatosis phenotype and the other with a very mild form of CTX manifesting as minor tendon xanthomatosis and gastrointestinal complaints who both carry compound heterozygous variants in CYP27A1: NM 000784.3: c.410G > A (p.Arg137Gln) and c.1183C > T. (p.Arg395Cys). However, normal levels of serum cholestanol and relatively mild elevations of the bile acid precursors (7α-hydroxy-4-cholesten-3-one and 7α,12α-dihydroxy-4-cholesten-3-one) were found in the biochemical analysis of these patients.

Conclusion: The atypical biochemical presentation of these cases represents a diagnostic challenge for a condition that was once thought to have a sensitive biomarker in cholestanol, and emphasizes the importance of a comprehensive investigation of patients with symptomatology consistent with CTX, which involves bile acid precursor biochemical testing and molecular analysis.

Keywords: cerebrotendinous xanthomatosis (CTX); cholestanol; genotype‐phenotype correlation; spinal xanthomatosis; sterols; xanthomas.