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.

Keywords: CYP27A1; Cerebrotendinous Xanthomatosis; chenodeoxycholic acid; inborn errors of metabolism; inherited metabolic disorders; lipid storage disease.

Figure 1

Biochemical pathways of bile acid metabolism and pathophysiological mechanisms involved in CTX. Both alternative (acidic) and classic (neutral) pathways in liver metabolism are represented in blue color. Primary bile acids (Cholic acid and Chenodeoxycholic acid) are represented in orange. Secondary and tertiary bile salts are showed in red. Brain neurometabolic steps are represented in black squares, as well as molecular targets (receptors) of CDCA and CA (1, 9, 10).

Figure 2

Natural history, disease progression and symptom and sign timeline in each phenotype of CTX (classical, spinal, and “non-neurological” forms), according to the age of symptom-onset (1, 6, 7, 12, 17, 18).

Figure 3

Clinical examination findings in CTX. Note the presence of tendon xanthoma (white arrows) located in the anterior tibial tuberosity (A) and the Achilles tendon (B). Pes cavus (white arrowhead) is also another possible feature (C).

Figure 4

Neuroimaging findings in CTX. (A) Sagittal T1W brain MR imaging (MRI) disclosed mild cerebellar atrophy. (B–G) Axial brain MRI showed hyperintensity involving cerebellar white matter and dentate nuclei (white arrows) in FLAIR (B–E) and T2W imaging (F, G). Axial brain MRI showing mild hypointensity involving cerebellar white matter and dentate nuclei in T1W (H) and SWI sequences (I). Coronal brain MRI showing hyperintensity (white arrow) involving cerebellar white matter and dentate nuclei in T2W imaging (J).

Figure 5

Neuroimaging patterns observed in CTX. (A) Sagittal T1-weighted brain MRI showed hypointense signal in deep cerebellar white matter (white arrow). Axial brain MRI disclosed signal change in deep cerebellar white matter (white arrows) hypointense in T1W (B) and hyperintense in T2W (C) and FLAIR sequences (D). Axial brain MRI disclosed hyperintensity in deep cerebellar white matter in DWI (E) and ADC sequences (F). Coronal brain MRI showed hypointensity in the deep white matter in T1W imaging (G), as well as corresponding hyperintensity (white arrows) in T2W imaging (H).

Figure 6

Neuroradiological features in spinal CTX. (A) Sagittal brain MRI showed normal cerebellar and corpus callosum structure. Axial brain MRI showed mild hyperintensity in dentate nucleus in FLAIR (B) and T2W sequences (C), as well as hyperintensity in dentate nucleus in coronal T2W imaging (D). Sagittal spine MRI showed hyperintense (white arrows) in T2W imaging (E) and isointense change in the dorsal column of the cervical spinal cord in T1-weighted imaging (F). Sagittal thoracic spine MRI showed normal structure (G). Axial cervical spine MRI showed marked hyperintensity of the dorsal column (white arrows) in T1W (H) and T2W imaging (I–K).