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Cerebrotendinous Xanthomatosis
A Rare Disease With Diverse Manifestations
Mohammed H. Moghadasian, PhD;
Gerald Salen, MD;
Jiri J. Frohlich, MD;
Charles H. Scudamore, MD
Arch Neurol. 2002;59:527-529.
ABSTRACT
This mini-review deals with a new appraisal of cerebrotendinous xanthomatosis.
In addition to neurologic symptoms, patients with cerebrotendinous xanthomatosis
develop cataracts, diarrhea, Achilles tendon xanthoma, atherosclerotic vascular
disease, and many other abnormalities. Although the pathophysiology of the
disease is not completely understood, excess production and consequent accumulation
of cholestanol in tissues may play a crucial role. Chenodeoxycholic acid is
the most effective therapy. The causative role and detrimental effects (at
a low plasma level) of cholestanol merit further investigation.
INTRODUCTION
Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disease
characterized by formation of xanthomatous lesions in many tissues, in particular
the brain and tendons. The diagnosis of CTX before neurologic deterioration
is crucial to prevent brain damage that leads to severe mental and neurologic
dysfunction and death. In this regard, specific biochemical abnormalities
include elevated plasma and bile cholestanol levels and increased urinary
excretion of bile alcohol glucuronides associated with diminished biliary
concentrations of chenodeoxycholic acid. In children unexplained bilateral
cataracts with chronic diarrhea are the features that suggest this diagnosis
before the onset of neurologic disease.
Cerebrotendinous xanthomatosis is potentially treatable with improvement
in neurologic function. Replacement therapy with chenodeoxycholic acid inhibits
abnormal bile acid synthesis and is most effective in reducing elevated plasma
cholestanol concentrations, and eliminating bile alcohols.
NEW INSIGHTS
Cerebrotendinous xanthomatosis is a rare inborn disorder of bile acid
synthesis in which hepatic conversion of cholesterol to cholic and chenodeoxycholic
acids is impaired.1 A defect in hydroxylation
of the cholesterol side chain that impairs oxidative cleavage has been identified.2 Thus, laboratory findings include elevated plasma
levels of cholestanol and bile alcohols and increased urinary excretion of
bile alcohol glucuronides with diminished biliary concentrations of chenodeoxycholic
acid.3 Clinical signs and symptoms include
cataracts, tendon xanthomas (particularly of the Achilles tendon), neurologic
abnormalities, and premature atherosclerosis. These findings represent the
consequences of the accumulation of cholesterol and cholestanol in affected
tissues. An increase in hepatic cholesterol and bile acid synthesis with up-regulation
of the rate-controlling enzyme activities has been reported in patients with
CTX. Plasma cholesterol levels and lipoprotein profile remain within or below
normal range.
Cerebrotendinous xanthomatosis shares some clinical manifestations such
as xanthomas and coronary atherosclerosis with other lipid storage disorders
including familial hypercholesterolemia and sitosterolemia. However, cataracts,
progressive neurologic symptoms, and mild pulmonary insufficiency are unique
features that distinguish CTX from these 2 xanthomatous disorders. Table 1 summarizes the clinical, biochemical,
and molecular features of these lipid disorders.
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Characteristic Features of Cerebrotendinous Xanthomatosis (CTX) Along
With Those of 2 Other Lipid Disorders With Certain Similarities in Clinical
Course
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It is believed that massive deposition of cholesterol and cholestanol
in affected organs leads to dysfunction and clinical development of the disease
because only trace amounts of cholestanol are normally found in mammalian
tissues.4 Several lines of evidence support
the hypothesis that increased levels of plasma and tissue cholestanol arise
endogenously and that cholestanol is a degradation product of cholesterol.5
Association of bilateral juvenile cataracts with chronic diarrhea may
represent the earliest clinical manifestation of CTX. Tendon xanthomas and
neurologic symptoms lend additional support to the diagnosis of CTX in children.
The presence of bile alcohol glucuronides in plasma and/or urine in association
with elevated cholestanol levels in young individuals confirms CTX. Early
diagnosis and treatment with chendeoxycholic acid contribute to a better prognosis
by preventing the progression of this disabling disease.6 Figure 1 shows the metabolic background of
CTX and the mechanisms for chenodeoxycholic acid therapy.
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Hepatic cholesterol, cholestanol, and bile acid metabolism. CTX indicates
cerebrotendinous xanthomatosis; HMG CoA, 3-hydroxy-3-methylglutaryl coenzyme
A; broken arrow, defective enzyme activity; thick arrows, hyperactive pathways;
plus sign, positive feedback; and minus sign, negative feedback. Chenodeoxycholic
acid therapy (750 mg/d) suppresses the synthesis of cholesterol, cholestanol,
bile alcohol glucuronides, and bile acids and significantly alleviates clinical
symptoms.6 The combined treatment of chenodeoxycholic
acid and pravastatin may also reduce the plasma cholestanol levels and prevent
the progression of CTX.14
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Accumulation of cholestanol in the brain and cerebrospinal fluid is
of particular importance. Cholestanol is exclusively synthesized in the liver
and not in the nervous system. How specifically cholestanol accumulation produces
functional abnormalities is unknown and should be investigated further. The
presence of apolipoprotein B in cerebrospinal fluid indicates penetration
of low-density lipoprotein particles from plasma through the blood-brain barrier.7 These lipoprotein particles may carry cholestanol
as well as cholesterol. Future experimental and/or clinical investigations
may answer the question of whether increased cholestanol biosynthesis and
its accumulation causes neurologic dysfunctions by itself or through other
mechanisms. Because most patients with CTX have brain atrophy, it can be postulated
that the adverse effects of cholestanol may be caused by increased apoptosis
pathways. Treatment with chenodeoxycholic acid reestablished selective permeability
of the blood-brain barrier and normalized cerebrospinal fluid sterol and apolipoprotein
concentrations.7
Most patients with CTX have normal lipoprotein profiles despite increased
cholesterol synthesis. Chenodeoxycholic acid replacement therapy is usually
associated with normalization of cholesterol synthesis and also with the significant
reduction in plasma cholestanol levels which then leads to improvement in
the clinical symptoms of the disease. This plus the absence of neurologic
dysfunction in other lipid disorders such as familial hypercholesterolemia
or sitosterolemia further support the hypothesis that cholestanol itself impairs
brain function.
Several patients with CTX who develop premature atherosclerosis have
been described.8-9 Atherosclerosis
and consequent cardiac events are a serious concern in subjects with CTX.
Segev et al8 reported a myocardial infarction
in a patient who had very low plasma cholesterol levels (138 mg/dL [3.57 mmol/L]).
Another case report described atherosclerotic aneurysms in coronary arteries
of a patient with CTX.9 Whether aneurysmal
rather than obstructive coronary artery disease is more characteristic of
CTX is unknown. Therefore, it is strongly recommended that in all 3 lipid
disorders (familial hypercholesterolemia, sitosterolemia, and CTX) the presence
of cardiovascular disease should be investigated even in asymptomatic patients.
Unlike familial hypercholesterolemia, in both CTX and sitosterolemia there
is an increased low-density lipoprotein receptor activity.10-11
Extensive tendon xanthomas in the presence of low plasma cholesterol levels
are clues for differentiation of CTX from the 2 other disorders.
Osteoporosis and repeated fractures are also features of patients with
CTX.12 The underlying mechanisms for this association
are unexplained. One possibility is that the excess accumulation of cholestanol
and cholesterol may render bones more fragile. Unsteady gait due to neurologic
impairment and subsequent frequent falls may further increase the chance of
bone fracture. Normal serum calcium, phosphate, and vitamin D metabolite levels
are reported in patients with CTX who suffered bone fractures; however, impaired
absorption of radiolabeled calcium in patients with CTX has been reported.
The latter observations raise the question whether cholic acid and chenodeoxycholic
acid can affect calcium absorption? A recent study reported an imbalanced
calcium distribution in advanced atherosclerotic lesions and bone tissues
in individuals with hypercholesterolemia.13
Such a situation may also exist in patients with CTX.
Bile acid therapy is effective, affordable, and safe. A female Canadian
patient with CTX who has been taking chenodeoxycholic acid for many years
is free of CTX symptoms, particularly neurologic signs. While receiving chenodeoxycholic
acid treatment, she gave birth to 2 healthy children (Jean Davignon, MD, oral
communication, October 21, 2000). The major adverse effects of chenodeoxycholic
acid therapy may be diarrhea, restlessness, and impatience. Although statins
have been used,14 their effectiveness is controversial.
One major concern with using statins is the possibility of worsening the condition
owing to increased low-density lipoprotein uptake as the result of augmented
low-density lipoprotein receptor activity. Removal of the Achilles tendon
xanthomas may be considered for cosmetic reasons, but it may worsen the gait
in neurologically affected patients.
CONCLUSIONS
Cerebrotendinous xanthomatosis is a familial disorder of bile acid synthesis.
It may present with chronic diarrhea and bilateral cataracts in early childhood.
Patients usually develop tendon xanthomas and neurologic symptoms after the
second decade of life. Elevated plasma and bile cholestanol levels, increased
urinary excretion of bile alcohol glucuronides associated with diminished
biliary concentrations of chenodeoxycholic acid, plus neurologic impairments
(mental retardation, pyramidal and cerebellar signs along with an abnormal
electroencephalogram, brain computed tomographic scans, or magnetic resonance
images), cataracts, and tendon xanthomas confirm its diagnosis. In most cases
CTX can be effectively treated by the administration of chenodeoxycholic acid
(250 mg, 3 times daily). Early detection and treatment of CTX significantly
reduces the complications of the disease. Laboratory assessment of plasma
cholestanol levels and the urinary excretion of bile alcohol glucuronides
along with sensory evoked potentials can provide a sensitive objective index
of improved neurologic and biochemical function during chenodeoxycholic acid
treatment. This coincides with the normalization of plasma and cerebrospinal
fluid cholestanol levels to normal values during chenodeoxycholic acid treatment.
AUTHOR INFORMATION
Accepted for publication August 23, 2001.
Author contributions: Study concept and design (Dr Moghadasian); acquisition of data (Drs Moghadasian, Salen, and Frohlich); analysis and interpretation (Drs Moghadasian, Salen, Frohlich, and Scudamore); drafting
of the manuscript (Dr Moghadasian); critical revision
of the manuscript for important intellectual content (Drs
Moghadasian, Salen, Frohlich, and Scudamore); obtained funding (Dr Scudamore); administrative, technical, and material
support (Drs Moghadasian, Salen, Frohlich, and Scudamore).
Corresponding author and reprints: Mohammed H. Moghadasian, PhD,
Healthy Heart Program, St Paul's Hospital, Suite 180, 1081 Burrard St, Vancouver,
British Columbia, Canada V6Z 1Y6 (e-mail: mhmoghad{at}interchange.ubc.ca).
From the Departments of Pathology and Laboratory Medicine (Drs Moghadasian
and Frohlich) and Surgery (Dr Scudamore), University of British Columbia,
Vancouver; and Departments of Medicine, University of Medicine and Dentistry
of New Jersey, New Jersey Medical School, Newark (Dr Salen), and Veterans
Affairs Medical Center, East Orange, NJ (Dr Salen).
REFERENCES
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1. Cali JJ, Hsieh CL, Francke U, Russell DW. Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase
underlie cerebrotendinous xanthomatosis. J Biol Chem. 1991;266:7779-7783.
FREE FULL TEXT
2. Salen G, Shefer S, Tint GS. Transformation of 4-cholesten-3-one and 7 -hydroxy-4-cholesten-3-one
into cholestanol and bile acids in cerebrotendinous xanthomatosis. Gastroenterology. 1984;87:276-283.
PUBMED
3. Koopman BJ, Wolthers BG, van der Molen JC, van der Slik W, Waterreus RJ, van Spereeken A. Cerebrotendinous xanthomatosis: a review of biochemical findings of
the patient population in the Netherlands. J Inherit Metab Dis. 1988;11:56-75.
PUBMED
4. Salen G. Cholestanol deposition in cerebrotendinous xanthomatosis: a possible
mechanism. Ann Intern Med. 1971;75:843-851.
5. Salen G, Grundy SM. The metabolism of cholestanol, cholesterol, and bile acids in cerebrotendinous
xanthomatosis. J Clin Invest. 1973;52:2822-2835.
6. Berginer VM, Salen G, Shefer S. Long-term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic
acid. N Engl J Med. 1984;311:1649-1652.
ABSTRACT
7. Salen G, Berginer V, Shore V, et al. Increased concentrations of cholestanol and apolipoprotein B in the
cerebrospinal fluid of patients with cerebrotendinous xanthomatosis: effect
of chenodeoxycholic acid. N Engl J Med. 1987;316:1233-1238.
ABSTRACT
8. Segev H, Reshef A, Clavey V, Delbart C, Routier G, Leitersdorf E. Premature termination codon at the sterol 27-hydroxylase gene causes
cerebrotendinous xanthomatosis in a French family. Hum Genet. 1995;95:238-240.
PUBMED
9. Potkin BN, Hoeg JM, Connor WE, et al. Aneurysmal coronary artery disease in cerebrotendinous xanthomatosis. Am J Cardiol. 1988;61:1150-1152.
FULL TEXT
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ISI
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10. Tint GS, Ginsberg H, Salen G, Le NA, Shefer S. Chenodeoxycholic acid normalizes elevated lipoprotein secretion and
catabolism in cerebrotendinous xanthomatosis. J Lipid Res. 1989;30:633-640.
ABSTRACT
11. Nguyen LB, Shefer S, Salen G. A molecular defect in hepatic cholesterol biosynthesis in sitosterolemia
with xanthomatosis. J Clin Invest. 1990;86:923-931.
12. Federico A, Dotti MT, Lore F, Nuti R. Cerebrotendinous xanthomatosis: pathophysiological study on bone metabolism. J Neurol Sci. 1993;115:67-70.
FULL TEXT
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ISI
| PUBMED
13. Hak AE, Pols HA, van Hemert AM, Hofman A, Witteman JCM. Progression of aortic calcification is associated with metacarpal bone
loss during menopause: a population-based longitudinal study. Arterioscler Thromb Vasc Biol. 2000;20:1926-1931.
FREE FULL TEXT
14. Kuriyama M, Tokimura Y, Fujiyama J, Utatsu Y, Osame M. Treatment of cerebrotendinous xanthomatosis: effects of chenodeoxycholic
acid, pravastatin, and combined use. J Neurol Sci. 1994;125:22-28.
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SECTION EDITOR: DAVID E. PLEASURE, MD
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