First case series of Polish patients with cerebrotendinous xanthomatosis and systematic review of cases from the 21st century

Abstract

Cerebrotendinous xanthomatosis (CTX) is an inborn error of metabolism caused by recessive variants in the cytochrome P450 CYP27A1 gene. CTX is said to manifest with childhood-onset chronic diarrhea and the classic triad of juvenile-onset cataracts, Achilles tendons xanthomas, and progressive ataxia. It is currently one of the few inherited neurometabolic disorders amenable to a specific treatment. The diagnosis may be significantly delayed resulting in permanent neurological impairment. A retrospective review of the clinical characteristics and diagnostic findings in case series of six Polish patients with CTX.Additional retrospective review of symptoms and pathogenic variants of 568 CTX available cases and case series from the past 20 years. To the best of our knowledge, this is the widest review of CTX cases reported in years 2000-2021. We report the largest cohort of Polish patients ever published, with the identification of two hot-spot mutations. During the review of available 568 cases, we found significant differences in the clinical phenotypes and the localization of variants within the gene between Asian and non-Asian populations. These findings may facilitate molecular testing in the Polish and Asian populations. Invariably better screening for CTX and wider awareness is needed.

Allelic Prevalence and Geographic Distribution of Cerebrotendinous Xanthomatosis

“…There is scienti c consensus that CTX is clinically not well recognized, frequently has delayed diagnosis [17], and has a prevalence likely underestimated in the general population [20,39], with less than 600 cases reported worldwide [12,28]. In order to facilitate early diagnosis of this disease, we sought to calculate the most updated conservative and accurate estimates for CTX prevalence.…”

“…Finally, we present a map of worldwide geographic estimate disease distribution using a novel approach based on CYP27A1 variant queries performed by clinicians across six continents. The map and CTX prevalence estimate results indicate that the number of individuals with this treatable disorder worldwide should greatly exceed the few hundred currently reported [12,28].…”

“…Neurological dysfunction may be present in childhood with intellectual disability and/or autism spectrum disorder and frequently develops in adulthood with epilepsy, pyramidal and extrapyramidal signs, cerebellar syndrome, peripheral neuropathy and intellectual disability/cognitive decline and progressive neurodegeneration [4][5][6][7][8][9][10]. Because of the pleiotropic phenotypes, accurate diagnosis may be delayed 10-20 years [11,12] and is often achieved only after irreversible neurological involvement has ensued. Treatment with bile acid replacement in the form of CDCA has been successfully used for decades [2,13] and, alternatively, cholic acid treatment has been reported in a modest number of cases.…”

Allelic prevalence and geographic distribution of cerebrotendinous xanthomatosis

“…Neurological dysfunction may be present in childhood with intellectual disability and/or autism spectrum disorder and frequently develops in adulthood with epilepsy, pyramidal and extrapyramidal signs, cerebellar syndrome, peripheral neuropathy and intellectual disability/cognitive decline and progressive neurodegeneration [ 4 – 10 ]. Because of the pleiotropic phenotypes, accurate diagnosis may be delayed 10–20 years [ 11 , 12 ] and is often achieved only after irreversible neurological involvement has ensued. Treatment with bile acid replacement in the form of CDCA has been successfully used for decades [ 2 , 13 ] and, alternatively, cholic acid treatment has been reported in a modest number of cases.…”

“…Finally, we present a map of worldwide geographic estimate disease distribution using a novel approach based on CYP27A1 variant queries performed by clinicians across six continents. The map and CTX prevalence estimate results indicate that the number of individuals with this treatable disorder worldwide should greatly exceed the few hundred currently reported [ 12 , 28 ].…”