Cerebrotendinous Xanthomatosis: A practice review of pathophysiology, diagnosis, and treatment

Abstract

Cerebrotendinous Xanthomatosis represents a rare and underdiagnosed inherited neurometabolic disorder due to homozygous or compound heterozygous variants involving the CYP27A1 gene. This bile acid metabolism disorder represents a key potentially treatable neurogenetic condition due to the wide spectrum of neurological presentations in which it most commonly occurs. Cerebellar ataxia, peripheral neuropathy, spastic paraparesis, epilepsy, parkinsonism, cognitive decline, intellectual disability, and neuropsychiatric disturbances represent some of the most common neurological signs observed in this condition. Despite representing key features to increase diagnostic index suspicion, multisystemic involvement does not represent an obligatory feature and can also be under evaluated during diagnostic work-up. Chenodeoxycholic acid represents a well-known successful therapy for this inherited metabolic disease, however its unavailability in several contexts, high costs and common use in patients at late stages of disease course limit more favorable neurological outcomes for most individuals. This review article aims to discuss and highlight the most recent and updated knowledge regarding clinical, pathophysiological, neuroimaging, genetic and therapeutic aspects related to Cerebrotendinous Xanthomatosis.

Clinical and Imaging Profile of Patients with Cerebrotendinous Xanthomatosis – a Video Case Series from India

“…Early diagnosis is imperative as stabilisation and improvement in disease manifestations are more likely if the treatment starts early. Clinical features of CTX often follow a temporal profile [ 10 ]. The earliest manifestation is the transient and self-limiting neonatal jaundice due to elevated conjugated hyperbilirubinemia and chronic unexplained infantile diarrhoea, both seen in around 75% of the patients.…”

A patient with neuropathy and ataxia: what do I have to consider?

“…Despite some disagreement in the literature, a somatosensory deficit is unlikely to be a feature of SCA6 [31]. Other inherited causes of combined somatosensory and cerebellar impairment include Ataxia with Vitamin E Deficiency (AVED) [32], Cerebrotendinous xanthomatosis [33,34], Polymerase Gamma-Related Ataxia [34], a variant of CMT which is associated with cerebellar disease [35] and Ataxia with Oculomotor Apraxia types 1 and 2 [36 ▪▪ ]. Fragile X-Associated Tremor Ataxia Syndrome (FXTAS) is commonly associated with an axonal neuropathy.…”

Pathophysiology and Treatment of Lipid Abnormalities in Cerebrotendinous Xanthomatosis: An Integrative Review

“…The biochemical effects of CDCA therapy in CTX patients are achieved by inhibiting the classic pathway of cholesterol metabolism via negative feedback over the 7α-hydroxylase enzyme [78,83,94,105], reducing abnormal bile acid synthesis [3,40,83,97,99,106]. With the reduction in bile acid synthesis, the production of intermediate metabolites such as 7αhydroxy-4-cholesten-3-one [49,54,89,90,99] and cholestanol [12,83,94,97,99] is lowered.…”

“…Despite being considered rare, CTX has recently been pointed out as considerably underdiagnosed, which might be related to the high heterogeneity of clinical presentation with a wide range of symptoms, severity and age of onset [3,4]. Typical manifestations Brain Sci.…”

“…The neurologic disturbances comprise peripheral neuropathy, pyramidal signs (such as spastic paraparesis), cerebellar ataxia, cognitive impairment and movement disorders. In childhood and adolescence, the primary findings are bilateral juvenile cataracts, chronic diarrhea and intellectual disability [2,3,5]. It should be noted that one of the earliest manifestations of CTX is neonatal cholestatic jaundice, a condition that, although self-limited and uncomplicated in most cases, occasionally progresses to a severe form with the requirement for liver transplantation and high lethality [2,6].…”