Cerebrotendinous xanthomatosis: a comprehensive review of pathogenesis, clinical manifestations, diagnosis, and management.

Shuke Nie,Yunjian Zhang,Guiqin Chen,Xuebing Cao

doi:10.1186/s13023-014-0179-4

Abstract

Cerebrotendinous xanthomatosis (CTX) OMIM#213700 is a rare autosomal-recessive lipid storage disease caused by mutations in the CYP27A1 gene; this gene codes for the mitochondrial enzyme sterol 27-hydroxylase, which is involved in bile acid synthesis. The CYP27A1 gene is located on chromosome 2q33-qter and contains nine exons. A CYP27A1 mutation leads to decreased synthesis of bile acid, excess production of cholestanol, and consequent accumulation of cholestanol in tissues. Currently there is no consensus on the prevalence of CTX, one estimate being <5/100,000 worldwide. The prevalence of CTX due to the CYP27A1 mutation R362C alone is approximately 1/50,000 in Caucasians. Patients with CTX have an average age of 35 years at the time of diagnosis and a diagnostic delay of 16 years. Clinical signs and symptoms include adult-onset progressive neurological dysfunction (i.e., ataxia, dystonia, dementia, epilepsy, psychiatric disorders,peripheral neuropathy, and myopathy) and premature non-neurologic manifestations (i.e., tendon xanthomas, childhood-onset cataracts, infantile-onset diarrhea, premature atherosclerosis, osteoporosis, and respiratory insufficiency). Juvenile cataracts, progressive neurologic dysfunction, and mild pulmonary insufficiency are unique symptoms that distinguish CTX from other lipid storage disorders including familial dysbetalipoproteinemia, homozygous familial hypercholesterolemia, and sitosterolemia, all of which might also present with xanthomas and cardiovascular diseases. Brain magnetic resonance imaging (MRI) shows bilateral lesions in the dentate nucleus of the cerebellum and mild white matter lesions. The classical symptoms and signs, namely elevated levels of cholestanol and bile alcohols in serum and urine, brain MRI, and the mutation in the CYP27A1 gene confirm the diagnosis of CTX. Early diagnosis and long-term treatment with chenodeoxycholic acid (750 mg/d) improve neurological symptoms and contribute to a better prognosis.

Highlights

Definition, history, epidemiology Cerebrotendinous xanthomatosis (CTX; OMIM#213700) is a rare autosomal-recessive inborn disorder of bile acid metabolism due to mutations in the Sterol 27-hydroxylase (CYP27A1) gene (OMIM *606530) located on chromosome 2q33-qter, leading to increased deposition of cholesterol and cholestanol in multiple tissues [1]
There are no consensus data on the prevalence of CTX, the estimated rate being
Based on the results of positron emission tomography (PET), we found a high-density lesion (12 × 14 mm) and a cyst with a gas-fluid level (16 × 20 mm) in the lung of a patient with CTX (Figure 2)

Summary

Introduction

Definition, history, epidemiology Cerebrotendinous xanthomatosis (CTX; OMIM#213700) is a rare autosomal-recessive inborn disorder of bile acid metabolism due to mutations in the CYP27A1 gene (OMIM *606530) located on chromosome 2q33-qter, leading to increased deposition of cholesterol and cholestanol in multiple tissues [1]. CTX can be distinguished from other lipid storage disorders by its specific clinical features such as childhoodonset cataracts, progressive neurologic symptoms, mild pulmonary insufficiency, increased plasma cholestanol levels, and the results of the SSEP assessment [10,22]. The biochemical abnormalities of patients with CTX in the laboratory examination include elevated plasma cholestanol level and increased levels of bile alcohols in urine associated with a diminished biliary concentration of chenodeoxycholic acid [22]. Plasma cholestanol examination with a total score ≥100 is requisite, as is CYP27A1 gene analysis with a total sore ≥200 or the existence of one very strong or four strong indicators Using this efficient diagnostic tool, the investigators achieved a diagnostic age in their study of only 10.6 ± 9.8 years, which compares favorably to the previous average age at diagnosis of 35 years (p

Findings

Conclusion

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