Cerebrotendinous Xanthomatosis: Molecular Pathogenesis, Clinical Spectrum, Diagnosis, and Disease-Modifying Treatments

Abstract

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disorder caused by mutations in the CYP27A1 gene, which encodes the mitochondrial enzyme sterol 27-hydroxylase. Decreased sterol 27-hydroxylase activity results in impaired bile acid synthesis, leading to reduced production of bile acids, especially chenodeoxycholic acid (CDCA), as well as elevated serum cholestanol and urine bile alcohols. The accumulation of cholestanol and cholesterol mainly in the brain, lenses, and tendons results in the characteristic clinical manifestations of CTX. Clinical presentation is characterized by systemic symptoms including neonatal jaundice or cholestasis, refractory diarrhea, juvenile cataracts, tendon xanthomas, osteoporosis, coronary heart disease, and a broad range of neuropsychiatric manifestations. The combinations of symptoms vary from patient to patient and the presenting symptoms, especially in the early disease phase, may be nonspecific, which leads to a substantial diagnostic delay or underdiagnosis. Replacement of CDCA has been approved as a first-line treatment for CTX, and can lead to biochemical and clinical improvements. However, the effect of CDCA treatment is limited once significant neuropsychiatric manifestations are established. The age at diagnosis and initiation of CDCA treatment correlate with the prognosis of patients with CTX. Therefore, early diagnosis and subsequent treatment initiation are essential.

Keywords: CTX; CYP27A1; Cerebrotendinous xanthomatosis; Chenodeoxycholic acid; Cholestanol.

Fig.1. Impaired bile acid synthesis in cerebrotendinous xanthomatosis (CTX)

In CTX, mutations in the CYP27A1 gene lead to sterol 27-hydroxylase deficiency, resulting in reduced production of chenodeoxycholic acid and upregulation of the rate-limiting enzyme in the bile acid synthesis pathway, cholesterol 7α-hydroxylase. Increased levels of serum cholestanol and urinary bile alcohols are biological markers in CTX. HMG-CoA: 3-hydroxy-3-methylglutaryl-CoA.

Fig.2. Representative clinical course of classical form CTX

Figure shows typical ages of onset of CTX-related symptoms.

Fig.3. Xanthomas in a patient with CTX

Figure shows xanthoma on the knee (A) and one on the Achilles tendon (B).

Fig.4. Brain magnetic resonance imaging (MRI)

Axial T2-weighted images of the brain showing abnormal hyperintensities in the globus pallidus (arrows in B), internal capsules (arrowheads in B), cerebral peduncles (arrows in C), and dentate nuclei (arrows in D). Diffuse cerebral (A) and cerebellar (D) atrophy are evident. Sagittal T2-weighted image of the spinal cord exhibiting longitudinally extensive hyperintense lesions (arrows in E). Axial T2-weighted image at the C3 level showing involvement of lateral corticospinal tracts (arrowheads in F) and gracile tracts (arrow in F).