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

Nie S, Chen G, Cao X, Zhang Y - Orphanet J Rare Dis (2014)

Bottom Line: A CYP27A1 mutation leads to decreased synthesis of bile acid, excess production of cholestanol, and consequent accumulation of cholestanol in tissues.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China. nieshuke200554@163.com.

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.

Show MeSH

Related in: MedlinePlus

Metabolic pathway involved in cerebrotendinous xanthomatosis (CTX; modified from Chales and Bjorkhem[10,74]). Due to a mutation in the CYP27A1 gene, cholesterol cannot be converted into bile acids, but is instead converted into cholestanol and bile alcohol. Providing chenodeoxycholic acid exogenously has a negative feedback effect that reduces synthesis of bile acid, thus preventing accumulation of cholestanol.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4264335&req=5

Fig1: Metabolic pathway involved in cerebrotendinous xanthomatosis (CTX; modified from Chales and Bjorkhem[10,74]). Due to a mutation in the CYP27A1 gene, cholesterol cannot be converted into bile acids, but is instead converted into cholestanol and bile alcohol. Providing chenodeoxycholic acid exogenously has a negative feedback effect that reduces synthesis of bile acid, thus preventing accumulation of cholestanol.

Mentions: In 1974, Setoguchi et al. first found that the decrease in bile acid synthesis in patients with CTX resulted from impaired oxidation of the cholesterol side-chain, which suggested that CTX is linked to a disorder of bile acid synthesis [6]. Patients with CTX lack mitochondrial sterol 27-hydroxylase (EC 1.14.13.15). This enzyme is located on the inner membranes of the mitochondria, is expressed in almost all cells of the body, and is an important enzyme in both the alternative and classic bile acid synthesis pathways [7,8]. Cholesterol 7α-hydroxylase (CYP7A1) is the rate-limiting enzyme in the classic pathway. In the alternative pathway, sterol 27-hydroxylase (CYP27A1) oxidizes cholesterol to 27-hydroxycholesterol, which is subsequently hydroxylated by oxysterol 7α-hydroxylase, leading in humans mostly to the formation of chenodeoxycholic acid (CDCA) [8-10]. A deficiency of sterol 27-hydroxylase leads to reduced production of CDCA and subsequently to upregulation of cholesterol 7α-hydroxylase. Upregulation of the rate-limiting enzyme in the classic bile acid pathway results in elevated levels of 7α-hydroxy-4-cholesten-3-one, an efficient precursor to cholestanol [3]. Most of the cholestanol accumulated in patients with CTX is derived from 7α-hydroxylated metabolites of cholesterol, 7α-hydroxy-4-cholesten-3-one being the most important [3,11]. Development and progression of CTX are secondary to the further efficient conversion of 7α-hydroxy-4-cholesten-3-one into cholestanol and bile alcohols by two different pathways [3,12] (Figure 1).Figure 1


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

Nie S, Chen G, Cao X, Zhang Y - Orphanet J Rare Dis (2014)

Metabolic pathway involved in cerebrotendinous xanthomatosis (CTX; modified from Chales and Bjorkhem[10,74]). Due to a mutation in the CYP27A1 gene, cholesterol cannot be converted into bile acids, but is instead converted into cholestanol and bile alcohol. Providing chenodeoxycholic acid exogenously has a negative feedback effect that reduces synthesis of bile acid, thus preventing accumulation of cholestanol.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4264335&req=5

Fig1: Metabolic pathway involved in cerebrotendinous xanthomatosis (CTX; modified from Chales and Bjorkhem[10,74]). Due to a mutation in the CYP27A1 gene, cholesterol cannot be converted into bile acids, but is instead converted into cholestanol and bile alcohol. Providing chenodeoxycholic acid exogenously has a negative feedback effect that reduces synthesis of bile acid, thus preventing accumulation of cholestanol.
Mentions: In 1974, Setoguchi et al. first found that the decrease in bile acid synthesis in patients with CTX resulted from impaired oxidation of the cholesterol side-chain, which suggested that CTX is linked to a disorder of bile acid synthesis [6]. Patients with CTX lack mitochondrial sterol 27-hydroxylase (EC 1.14.13.15). This enzyme is located on the inner membranes of the mitochondria, is expressed in almost all cells of the body, and is an important enzyme in both the alternative and classic bile acid synthesis pathways [7,8]. Cholesterol 7α-hydroxylase (CYP7A1) is the rate-limiting enzyme in the classic pathway. In the alternative pathway, sterol 27-hydroxylase (CYP27A1) oxidizes cholesterol to 27-hydroxycholesterol, which is subsequently hydroxylated by oxysterol 7α-hydroxylase, leading in humans mostly to the formation of chenodeoxycholic acid (CDCA) [8-10]. A deficiency of sterol 27-hydroxylase leads to reduced production of CDCA and subsequently to upregulation of cholesterol 7α-hydroxylase. Upregulation of the rate-limiting enzyme in the classic bile acid pathway results in elevated levels of 7α-hydroxy-4-cholesten-3-one, an efficient precursor to cholestanol [3]. Most of the cholestanol accumulated in patients with CTX is derived from 7α-hydroxylated metabolites of cholesterol, 7α-hydroxy-4-cholesten-3-one being the most important [3,11]. Development and progression of CTX are secondary to the further efficient conversion of 7α-hydroxy-4-cholesten-3-one into cholestanol and bile alcohols by two different pathways [3,12] (Figure 1).Figure 1

Bottom Line: A CYP27A1 mutation leads to decreased synthesis of bile acid, excess production of cholestanol, and consequent accumulation of cholestanol in tissues.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China. nieshuke200554@163.com.

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.

Show MeSH
Related in: MedlinePlus