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

Abstract

diverse clinical symptoms cause a substantial diagnostic delay [2][3][4]9) . Replacement treatment with chenodeoxycholic acid (CDCA) in the early stage of the disease has been reported to improve or even prevent clinical symptoms of CTX 10,11) ; however, after significant neurological pathology is established, the effect of the treatment is limited and deterioration of clinical manifestations may continue 3,8,12,13) . Therefore, it is crucial to treat CTX patients at the initial stage of the disease. In this article, we provide the current understanding of the underlying pathomechanisms, clinical manifestations, diagnosis, and treatment of CTX. PathophysiologyCTX is caused by mutations in the CYP27A1 gene encoding sterol 27-hydroxylase, a key enzyme in the bile acid synthesis pathway. A schematic 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.

Cerebrotendinous xanthomatosis in a 10-year-old male presenting with Achilles tendon xanthoma and mild intellectual disability: A case report

“…A deficiency of this enzyme leads to reduced production of CDCA and subsequent accumulation of cholestanol in various tissues, resulting in diverse systemic and neurologic clinical manifestations [8]. Systemic symptoms include chronic diarrhea beginning in infancy, childhood-onset cataracts, tendon xanthoma, osteoporosis, and coronary heart disease [9]. When untreated, progressive neurologic dysfunction develops, including intellectual disability, pyramidal and extrapyramidal signs, cerebellar signs, peripheral neuropathy, epilepsy, and psychiatric changes [4,10].…”

CYP27A1 mutation in a case of cerebrotendinous xanthomatosis: A case report

“…The main cause of CTX is sterol 27-hydroxylase deficiency caused by the mutation of CYP27A1 [ 3 ]. CYP27A1 encodes sterol 27-hydroxylase and is the only gene known to be associated with CTX[ 4 ]. Sterol 27-hydroxylase is involved in the biosynthesis of primary bile acids, including cholic acid and CDCA[ 5 ].…”

“…As our patient possesses a known pathogenic mutation in CYP27A1 , we are currently unable to determine whether the new gene mutation is pathogenic; further research is needed to confirm the same. In addition, the biochemical diagnosis of CTX is based on the increase in serum cholestanol and urine bile alcohols levels[ 4 ]. The typical imaging findings indicating the prevalence of CTX include T2-weighted and FLAIR imaging hyperintensity in the dentate nucleus[ 10 ].…”

Emerging cellular themes in leukodystrophies

“…This treatment has shown success when implemented before the age of 25 ( Yahalom et al, 2013 ). However, CDCA is hepatotoxic, prompting some studies to suggest cholic acid as an alternative treatment for patients who tolerate CDCA poorly ( Pierre et al, 2008 ; Koyama et al, 2021 ). In addition, a recent study in a mouse model of CTX used an AAV to express CYP27A1 in the liver and this reestablished bile acid metabolism and restored normal plasma bile acid levels ( Lumbreras et al, 2021 ).…”