Familial variability of cerebrotendinous xanthomatosis lacking typical biochemical findings

Abstract

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of bile acid synthesis caused by pathogenic variants in the CYP27A1 gene encoding the mitochondrial enzyme sterol 27‐hydroxylase. Patients with CTX can present with a wide range of symptoms, but most often have evidence of tendon xanthomas along with possible cataracts, atherosclerosis, or neurological dysfunction. Regardless of clinical phenotype, CTX patients typically exhibit levels of cholestanol and bile acid precursors in the circulation that are many fold increased over normal control concentrations. Here we report 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, biochemical analysis of these patients revealed 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. The atypical biochemical presentation of these cases represents a diagnostic challenge for a disorder once thought to have a sensitive biomarker in cholestanol and highlight the need for thorough investigation of patients with symptomatology consistent with CTX that includes bile acid precursor biochemical testing and molecular analysis.

Tuberous xanthomatosis is not necessarily associated with increased plasma concentrations of cholestanol in cerebrotendinous xanthomatosis

“…Interestingly, this case diverges from the typical clinical form of CTX by plasma cholestanol in the upper normal range; the absence of neurological disease, cataract or chronic diarrhea; and the severity of the xanthomatosis with development in adulthood [10]. It should be noted that one of the rare reported cases of CTX with normal cholestanol did not present any neurological symptomatology [4].…”

“…In 2018, Sekijima et al proposed inclusion criteria with a high cholestanol level as a required criterion [3]. However, several series have reported a few cases of atypical CTX with normal cholestanol levels but with biallelic CYP27A1 pathogenic variants [4].…”

Allelic prevalence and geographic distribution of cerebrotendinous xanthomatosis

“…Interestingly, such individuals may carry the same variants (eg, p.Arg395Cys) that are found in patients with neurological involvement, suggesting that perhaps additional damaging mechanisms or genetic modifiers other than CYP27A1 loss of function may be at play. Reinforcing this enigmatic picture is the report of a pair of siblings carrying the same pathogenic variants but being at opposite ends of the clinical spectrum, where one sibling developed rare spinal xanthomatosis and the other developed a mild form with minor tendon xanthomas [ 43 ]. In contrast, examples of common clinical manifestation are well documented.…”

Allelic Prevalence and Geographic Distribution of Cerebrotendinous Xanthomatosis

“…Interestingly, such individuals may carry the same variants (eg, p.Arg395Cys) that are found in patients with neurological involvement, suggesting that perhaps additional damaging mechanisms or genetic modi ers other than CYP27A1 loss of function may be at play. Reinforcing this enigmatic picture is the report of a pair of siblings carrying the same pathogenic variants but being at opposite ends of the clinical spectrum, where one sibling developed rare spinal xanthomatosis and the other developed a mild form with minor tendon xanthomas [43]. In contrast, examples of common clinical manifestation are well documented.…”