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Sterol 27-Hydroxylase Deficiency

Sterol 27 Hydroxylase Deficiency

Sterol 27-hydroxylase deficiency, also called cerebrotendinous xanthomatosis, is an uncommon inherited disease where abnormal changes in the sterol 27-hydroxylase gene leads to a disruption in bile acid synthesis. It presents with the following abnormalities: (i) increased plasma concentration of cholestanol and bile alcohols (ii) an excess of bile alcohols in urine (iii) a reduced bile acid concentration in bile.

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Presentation

In about three-quarters of sterol 27-hydroxylase deficiency cases, childhood cataracts are the first manifestation. Some children may have learning disabilities from childhood. However, a majority of them have normal or near normal intelligence till puberty. Neonatal cholestasis, persistent diarrhea,and liver dysfunction may also occur in childhood.

From ages 11 to 30 years, tendons in the hand, elbow, ankle (Achilles ) and neck may begin to develop xanthomas. Neurological symptoms in adulthood include dementia (occurs in more than half the cases between 20-30 years), pyramidal and/or cerebellar ataxia, seizures and polyneuropathy. Peripheral neuropathy and extrapyramidal symptoms like dystonia and atypical parkinsonism may also be present. Some patients may experience behavioral changes, aggressiveness, depression, suicidal thoughts and agitation.

Death in Infancy
  • Some early deaths in infancy have also been reported. The documents contained in this web site are presented for information purposes only.[orpha.net]
Diarrhea
  • Clinical description The initial clinical manifestation may be neonatal cholestasis or chronic diarrhea from infancy. In 75% of cases, cataract is the first finding, often appearing in childhood.[orpha.net]
  • Symptoms in children include childhood cataracts, diarrhea, liver disease and recurrent bone fractures.[symptoma.com]
  • […] and other tissues and with elevated levels of cholesterol in plasma but with normal total cholesterol level; it is characterized by progressive cerebellar ataxia beginning after puberty and by juvenile cataracts, juvenile or infantile onset chronic diarrhea[en.wikipedia.org]
  • Common findings Chronic, sometimes intractable diarrhea occurs, with onset typically in infancy.[emedicine.medscape.com]
Chronic Diarrhea
  • Clinical description The initial clinical manifestation may be neonatal cholestasis or chronic diarrhea from infancy. In 75% of cases, cataract is the first finding, often appearing in childhood.[orpha.net]
  • diarrhea, childhood neurological deficit, and tendineous or tuberous xanthomas.[en.wikipedia.org]
  • Other features of cerebrotendinous xanthomatosis include clouding of the lenses of the eyes ( cataracts ) and chronic diarrhea in childhood; a reduced ability to produce and release a digestive fluid called bile (cholestasis), which can lead to a yellowing[ghr.nlm.nih.gov]
  • The combination of chronic diarrhea and bilateral cataracts in the childhood, described in the case 2, was pathognomonic for the disease 5.[scielo.br]
Liver Dysfunction
  • Infants may present with cholestasis and liver dysfunction. Xanthomata may appear in the 2nd or 3rd decade of life, in the Achilles and other tendons (elbow, hand, patella, neck).[orpha.net]
  • Neonatal cholestasis, persistent diarrhea,and liver dysfunction may also occur in childhood. From ages 11 to 30 years, tendons in the hand, elbow, ankle (Achilles ) and neck may begin to develop xanthomas.[symptoma.com]
  • This infant presented with severe cholestasis (blockage in bile flow from liver) with cirrhosis and liver dysfunction.[themedicalbiochemistrypage.org]
Liver Dysfunction
  • Infants may present with cholestasis and liver dysfunction. Xanthomata may appear in the 2nd or 3rd decade of life, in the Achilles and other tendons (elbow, hand, patella, neck).[orpha.net]
  • Neonatal cholestasis, persistent diarrhea,and liver dysfunction may also occur in childhood. From ages 11 to 30 years, tendons in the hand, elbow, ankle (Achilles ) and neck may begin to develop xanthomas.[symptoma.com]
  • This infant presented with severe cholestasis (blockage in bile flow from liver) with cirrhosis and liver dysfunction.[themedicalbiochemistrypage.org]
Xanthoma
  • These deposits may occur in the tendons, brain, eyes etc. and may present as neonatal cholestasis, tendon xanthomas, brain xanthomas, childhood cataracts and neurological symptoms in adults.[symptoma.com]
  • Abstract Cerebrotendinous xanthomatosis is characterized by the accumulation of cholestanol and cholesterol in xanthomas and brain causing a number of severe symptoms.[ncbi.nlm.nih.gov]
  • Tendon xanthomas may cause discomfort and interfere with tendon flexibility. While many affected people develop tendon xanthomas, these nodules may not be easily visible underneath the skin.[ghr.nlm.nih.gov]
  • Campdelacreu J, Munoz E, Cervera A, Jauma S, Giros M, Tolosa E (2002) Cerebrotendinous xanthomatosis without tendinous xanthomas: presentation of two cases. Neurologia 17:647–650 PubMed Google Scholar 4.[doi.org]
  • Xanthoma of the tendons and lungs were also present but serum cholesterol levels were within normal limits. In 1969 van Bogaert published a 30-year follow-up of one of his original patients. Bibliography L. van Bogaert, H. J. Scherer, E.[whonamedit.com]
Psychiatric Symptoms
  • In addition, psychiatric symptoms and behavioral changes in 73%, osteoporosis in 65%, diarrhea in 47%, and seizures in 24%.[eyewiki.aao.org]
  • Others include intellectual disability, dementia, psychiatric symptoms (i.e., behavioral changes, depression, agitation, hallucination, and suicide attempts), pyramidal signs, progressive ataxia, dystonia, and palatal myoclonus Peripheral Nervous System[flipper.diff.org]
Abnormal Behavior
  • Typical clinical characteristics of CTX may include some combination of infantile-onset chronic diarrhea, bilateral cataracts with juvenile onset, tendon xanthomas, psychiatric and abnormal behavioral symptoms, and cognitive and other neurologic impairments[eyewiki.aao.org]
Aggressive Behavior
  • Conclusion : These findings indicate a possible intervention of cholesterol metabolism in ETN with aggressive behavior.[thyroidworldcongress.com]
Aggressive Behavior
  • Conclusion : These findings indicate a possible intervention of cholesterol metabolism in ETN with aggressive behavior.[thyroidworldcongress.com]
Ataxia
  • Pyramidal signs and/or cerebellar ataxia are present in the 20s or 30s. Patients may experience extrapyramidal manifestations (dystonia and atypical parkinsonism), and peripheral neuropathy.[orpha.net]
  • Genetic testing of the CYP27A1 gene is confirmatory and is increasingly being used as a first line test as part of symptom specific gene panels (genetic eye disease, ataxia, dementia).[en.wikipedia.org]
  • The autosomal recessive cerebellar ataxias. N Engl J Med. 2012 ; 366 (7): 636 –46. Epub 2012/02/18. 2. Pandolfo M. Friedreich ataxia: the clinical picture. J Neurol. 2009 ; 256 Suppl 1: 3 –8. Epub 2009/04/11. 3. Pandolfo M.[cambridge.org]
  • Onset in childhood with dementia; evolving in adolescence with progressive ataxia, spasticity, and cataracts; and finally in adulthood with xanthomas of the tendons, lungs, and brain in the presence of normal or nearly normal blood cholesterol and high[whonamedit.com]
Seizure
  • Adult-onset progressive neurologic dysfunction includes dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, seizures, and neuropathy. Dementia occurs in the 20s in over 50% of cases.[orpha.net]
  • Neurological symptoms in adulthood include dementia (occurs in more than half the cases between 20-30 years), pyramidal and/or cerebellar ataxia, seizures and polyneuropathy.[symptoma.com]
  • These neurological problems include recurrent seizures (epilepsy), movement disorders, impaired speech (dysarthria), loss of sensation in the arms and legs (peripheral neuropathy), decline in intellectual function (dementia), hallucinations, and depression[ghr.nlm.nih.gov]
  • He was taking Phenytoin before presentation for recurrent seizures. He was the third child born out of consanguineous marriage, others being normal.[ijoonline.com]
Peripheral Neuropathy
  • Patients may experience extrapyramidal manifestations (dystonia and atypical parkinsonism), and peripheral neuropathy. Etiology CTX is caused by mutations in the sterol 27-hydroxylase gene ( CYP27A1 ; 2q33-qter).[orpha.net]
  • Peripheral neuropathy and extrapyramidal symptoms like dystonia and atypical parkinsonism may also be present. Some patients may experience behavioral changes, aggressiveness, depression, suicidal thoughts and agitation.[symptoma.com]
  • Exogenous administration reduces high levels of cholesterol and cholestanol in the CSF, tissues, and plasma with improvement in mental function and signs of peripheral neuropathy and cerebellar dysfunction.[disorders.eyes.arizona.edu]
  • These neurological problems include recurrent seizures (epilepsy), movement disorders, impaired speech (dysarthria), loss of sensation in the arms and legs (peripheral neuropathy), decline in intellectual function (dementia), hallucinations, and depression[ghr.nlm.nih.gov]
Dystonia
  • Patients may experience extrapyramidal manifestations (dystonia and atypical parkinsonism), and peripheral neuropathy. Etiology CTX is caused by mutations in the sterol 27-hydroxylase gene ( CYP27A1 ; 2q33-qter).[orpha.net]
  • Peripheral neuropathy and extrapyramidal symptoms like dystonia and atypical parkinsonism may also be present. Some patients may experience behavioral changes, aggressiveness, depression, suicidal thoughts and agitation.[symptoma.com]
  • ., behavioral changes, depression, agitation, hallucination, and suicide attempts), pyramidal signs, progressive ataxia, dystonia, and palatal myoclonus Peripheral Nervous System and muscle involvement: axonal degeneration by demyelination and remyelination[flipper.diff.org]
  • Other findings include extrapyramidal manifestations (dystonia and atypical parkinsonism), seizures, and peripheral neuropathy. Diagnosis/testing.[ctxinfo.org]
Agitation
  • Neuropsychiatric symptoms such as behavioral changes, hallucinations, agitation, aggression, depression, and suicidal tendencies may be prominent. Pyramidal signs and/or cerebellar ataxia are present in the 20s or 30s.[orpha.net]
  • Some patients may experience behavioral changes, aggressiveness, depression, suicidal thoughts and agitation.[symptoma.com]
  • Neuropsychiatric symptoms such as behavioral changes, hallucinations, agitation, aggression, depression, and suicide attempts may be prominent.[ctxinfo.org]
  • ., behavioral changes, depression, agitation, hallucination, and suicide attempts), pyramidal signs, progressive ataxia, dystonia, and palatal myoclonus Peripheral Nervous System and muscle involvement: axonal degeneration by demyelination and remyelination[flipper.diff.org]

Workup

The diagnosis of sterol 27-hydroxylase deficiency can be clinched by the highly elevated plasma cholestanol levels (5-10 times normal) (330 ± 30 μg/dL). A biomarker test for sterol 27-hydroxylase deficiency is increased plasma levels of 5-α-cholestanol, found on gas chromatography-mass spectrometry [20].

Amongst other findings, bile alcohol levels are elevated, with plasma concentrations being 500-1000 times normal (8.48 ± 3.67 nmol/L), while urine bile alcohol levels hover around 14,000 ± 3,500 nmol/L.

Magnetic resonance imaging (MRI) shows a reduction in the total brain volume, affecting both the gray and white matter. This is accompanied by signal alterations in the white matter and hyperintense lesions in the dentate nuclei [16] [21] [22] [23] [24] [25]. Some patients may show cerebellar atrophy. Other tests that may be done to further confirm the above-mentioned findings include diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) [26].

Cerebral atrophy is also seen in gross brain sections, as are yellowish fat deposits in the white matter and choroid plexus [27]. Microscopic examination of the brain shows demyelination and foamy macrophage aggregations in the globus pallidus, granulomas and multiple scattered lipid crystal clefts in the cerebellum and deposition of myelin-like material in the periventricular areas [25] [27] [28] [29].

CYP27A1 gene mutations in introns 2,4,6,7,8 and all the nine exons have been documented [30]. The structure of the human sterol 27-hydroxylase enzyme, consisting of 33 amino acid mitochondrial signal sequence followed by 498 amino acids, was successfully predicted by DNA sequence analysis [31].

Foam Cell
  • Small molecules targeted to mitochondria, capable of sustaining mitochondrial function or improving cholesterol trafficking may aid cholesterol efflux from macrophage ‘foamcells, regressing and stabilizing the atherosclerotic plaque. atherosclerosis[clinsci.org]

Treatment

The mainstay of treatment for sterol 27-hydroxylase deficiency is CDCA therapy which provides symptomatic control along with stabilization of nerve conduction velocities and evoked potentials. CDCA also increases myelin production in the other normal axons. Neurological deficits may however, persist even with CDCA therapy [32]. CDCA therapy, early in the course of the disease, may slow its progression [33].

HMG-CoA reductase inhibitors, co-administered with CDCA or even given alone, may be helpful in ameliorating symptoms and reducing the cholestanol concentration. HMG-CoA reductase inhibitors may however, cause muscle damage as a serious side effect [34] [35] [36].

The neurological manifestations of sterol 27-hydroxylase deficiency are managed symptomatically. Parkinsonism, though unresponsive to levodopa, may be treated by the use of an antihistamine drug, diphenylpyraline hydrochloride [37]. Muscle weakness may be improved by the administration of coenzyme Q10.

Cataract surgery is usually needed in at least one eye, especially by the age of 50 years. Though not conventionally recommended in sterol 27-hydroxylase deficiency, liver transplantation offers hope for disease management.

Prognosis

Most patients are diagnosed with sterol 27-hydroxylase deficiency at the age of 35 on an average, but symptoms begin to appear at 19 years of age, showing a lag of about 16 years between symptoms and actual diagnosis [11]. This can adversely affect prognosis. Survival has been linked in studies to the age at diagnosis [11].

Early diagnosis and treatment with CDCA helps to halt or reverse the neurological or non-neurological symptoms of this disease [16] [17] [18]. Studies have shown that CDCA improved nerve conduction in some patients with polyneuropathy, with the efficacy of therapy determined by the level of irreversible damage [19]. Therefore, children presenting with early signs and symptoms of the disease should be adequately diagnosed and commenced on treatment promptly before progression to the more severe manifestations of this disease.

Etiology

There are two pathways for the synthesis of bile acid, the classic pathway and the alternative pathway. Sterol 27-hydroxylase is an essential enzyme in both these pathways and cholesterol 7α-hydroxylase is the rate-limiting enzyme in the classic pathway [2] [3]. In the alternative pathway, sterol 27-hydroxylase acts on cholesterol to form 27-hydroxycholesterol, which is then hydroxylated by oxysterol 7α-hydroxylase to form CDCA [3] [4] [5].

In cerebrotendinous xanthomatosis, there is a deficiency of the sterol -27 hydroxylase enzyme. Mutations in the CYP27A1 gene, coding for sterol 27-hydrolxylase, thus, adversely affects CDCA synthesis. A low CDCA concentration directs the cholesterol through the cholesterol 7α-hydroxylase enzyme in the classic pathway leading to high levels of cholestanol precursors (7α-hydroxy-4-cholesten-3-one) [6].

Epidemiology

Areas in the world with an increased frequency of sterol 27-hydroxylase deficiency include places where consanguineous relationships are common, such as the Druze community in Israel [7] [8]. There are around 300 documented cases of this disease in the world with a prevalence of about 1 in 50,000 people [9] [10]. This disease is highly prevalent and the affected regions include China, South Africa, Australia, Saudi Arabia, Canada, Belgium, India, and Argentina [11]. In the United States, it is believed that a significant number of cases go undetected and/or misdiagnosed.

Sex distribution
Age distribution

Pathophysiology

Sterol 27-hydroxylase is an enzyme located in the inner part of the mitochondrial membrane; the function of this enzyme is to synthesize bile acid from cholesterol via the classic and alternate pathways.

Due to mutations in the gene for this enzyme, defective sterol 27-hydroxylase is produced. This enzyme deficiency leads to reduced production of CDCA from the breakdown of cholesterol. Physiologically, CDCA is a feedback regulator of the rate-limiting enzyme in the classic pathway of bile acid synthesis, called cholesterol 7-alpha-hydroxylase. A deficiency of sterol 27-hydroxylase leads to reduced CDCA production, leading to a loss of the feedback inhibition of cholesterol 7-alpha-hydroxylase. This results in the excessive formation of 7-alpha-hydroxy-4-cholesten-3-one, a cholestanol precursor [12].

Cholestanol and cholesterol levels thus, build up in various body tissues including the brain, spinal cord, eyes, arteries, veins, muscles, and tendons, thereby causing progressive organ damage.

It is believed that the main effects of sterol 27-hydroxylase deficiency are in the nervous system, with studies on patients showing a decline in total brain volume mainly affecting the gray matter of the cortex [13]. The exact mechanism of how the disease affects the brain remains controversial [14] [15].

Prevention

As the disease is autosomal recessive, each sibling of an affected individual has a 25% chance of disease, a 25% chance of being completely normal and a 50% chance of being a carrier with no symptoms. Prenatal and carrier testing molecular techniques are available for such at-risk families to uncover the genetic variations in the CYP27A1 gene. Maximal mutations occur in the region of exons 6-8 [30] [38].

Summary

Sterol 27-hydroxylase deficiency also called cerebrotendinous xanthomatosis is an inherited rare metabolic disorder wherein bile acid synthesis is disrupted owing to an abnormal alteration in the sterol 27-hydroxylase gene. This disruption leads to elevated cholesterol and cholestanol levels in the body, which may cause progressive damage via their deposition in various body tissues. These deposits may occur in the tendons, brain, eyes etc. and may present as neonatal cholestasis, tendon xanthomas, brain xanthomas, childhood cataracts and neurological symptoms in adults [1].

This disease is quite rare with only about 300 cases documented worldwide. It is inherited in an autosomal recessive fashion, thereby making genetic counseling a necessary part of prevention. Though some children with sterol 27-hydroxylase deficiency may die early, the average life span of untreated cases is around fifty to sixty years.

The diagnostic criteria in adults are any 2 of the following positive findings: early cataracts, persistent diarrhea, high plasma and tendon cholestanol (plasma cholesterol levels may also be reduced or normal), neurological symptoms and tendon xanthomas.

In children with sterol 27-hydroxylase deficiency, the excessive excretion of bile alcohols in urine can be demonstrated using mass spectrophotometry; this is advantageous for early diagnosis. Sterol 27-hydroxylase deficiency can also be diagnosed by molecular testing techniques such as prenatal genetic tests on fetal tissues. On imaging, bilateral hyperintense dentate nuclei and cerebral and cerebellar atrophy can be seen via magnetic resonance imaging (MRI).

Amongst the drugs used for treatment, chenodeoxycholic acid (CDCA) is the therapy of choice to bring bile acid synthesis back to normal. This also controls the rising cholestanol levels and suppresses the neurological symptoms. Hydroxymethyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors are another option for treatment. They may be used concurrently with CDCA. A potential side effect of HMG-CoA inhibitors is rhabdomyolysis. Cholic acid is yet another treatment option that is less hepatotoxic than CDCA, but is not as effective.

Sterol 27-hydroxylase deficiency is a progressive disease and early diagnosis and treatment helps to halt its progression or, in some cases, reverse the damage caused by the buildup of cholestanol and cholesterol in the tissues.

Patient Information

Sterol 27-hydroxylase deficiency also called cerebrotendinous xanthomatosis is an uncommon metabolic disease that disrupts the body’s ability to breakdown various forms of cholesterol due to the deficiency of an enzyme called sterol 27-hydroxylase. This occurs due to a mutation in the gene coding for this enzyme (CYP27A1 gene). As a result of this disease, cholesterol levels begin to accumulate in the body.

It is an inherited disease and for a child to have sterol 27-hydroxylase deficiency, both parents need to pass on a copy of the gene. Carriers only have one copy of the abnormal gene and are usually asymptomatic.

Patients with sterol 27-hydroxylase deficiency experience a broad range of symptoms depending on age and severity. Symptoms in children include childhood cataracts, diarrhea, liver disease and recurrent bone fractures. Adults may present with a variety of neurological symptoms such as memory loss, speech abnormalities, convulsions, depression, hallucinations etc.

Children can be diagnosed by measuring the bile alcohol levels in urine. In adults, the diagnosis is based on positive findings of at least two of the following 5 features:

  • High levels of cholesterol in the tendons of the body
  • Neurological symptoms
  • Fatty deposits in the tendons
  • Cataracts at a young age
  • Long-standing diarrhea

Magnetic resonance imaging (MRI) and computed tomography (CT) scans help provide insights on the level of disease progression, especially in the nervous system. When they obstruct blood flow to the heart or brain, cholesterol accumulations can cause heart disease or stroke. Hence, cerebrovascular and cardiac evaluation, including angiography and echocardiography is also routinely carried out.

Sterol 27-hydroxylase deficiency currently has no cure, but the disease onset can be delayed by the administration of chenodeoxycholic acid (CDCA). In addition, HMG-CoA reductase inhibitors or statins can be used to control the body cholesterol levels. Cataracts usually need to be operated upon by 50 years. Other disease features are managed symptomatically.

References

Article

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Last updated: 2019-07-11 20:06