DEFINITION AND HISTORICAL NOTES
Cerebrotendinous Xanthomatosis (CTX), also known as cerebral cholesterinosis, 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 involved in bile acid synthesis. Its malfunction leads to increased deposition of cholesterol and cholestanol in multiple tissues., is a rare by a deficiency in enzyme ceramidase which cause a progressive accumulation of fatty material lipids leading to abnormalities in the joints, liver, throat, tissues and central nervous system.
The disease was first described in 1937 by Van Bogaert and colleagues and has since been characterized clinically, biochemically, and genetically. . In 1968, Menkes et al described the accumulation of cholestanol in tissues of the CNS. In 1980, defects in mitochondrial sterol 27-hydroxylase were implicated in the biochemical pathophysiology of the disease by Oftebro et al. In 1991, mutations in the gene CYP27A1 were discovered as causative. . . Since then, more than 50 mutations have been described.
EPIDEMIOLOGY
Currently there is no consensus on the prevalence of CTX, one estimate being <5/100,000 worldwide.
Genetic islands of increased CYP27A1 mutation frequency exist; for example, there is an estimated disease prevalence of 1:440 for the Druze population in Israel.
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.
No sex predilection has been reported for this autosomal recessive disorder, although animal models exhibit sex differences.
ETIOLOGY – GENETICS
CYP27A1 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.
Various mutations in all nine exons and in introns 2,4,6,7, and 8 of the CYP27A1 gene have been described worldwide. Fifty percent of mutations in CYP27A1 have been detected in the region of exons 6–8, 16% in exon 2, and 14% in exon 4. Various mutation types, including missense (approximately 45%), nonsense (approximately 20%), splice site (18%), deletion (14%), and insertion (2%) have been detected in all nine exons of CYP27A1. No genotype-phenotype correlations have been identified in CTX. .
PATHOGENESIS
The primary enzymatic defect in cerebrotendinous xanthomatosis is in mitochondrial sterol 27-hydroxylase, a key enzyme in the complicated process of bile acid synthesis from cholesterol. Defective enzymatic function disrupts bile acid synthesis, the classic and alternative pathway both, as seen in the following figure:
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). . . Defects in the enzyme result in decreased synthesis of CDCA; this, in turn, disrupts feedback regulation on cholesterol 7-alpha-hydroxylase, which is the rate-limiting step in bile acid synthesis. Therefore, bile acid precursors accumulate in tissues.
(EXERPT FROM Chales.) 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.
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.
Deposition of cholestanol, cholesterol and bile alcohols in the CNS (the brain and spinal cord), muscle (including the heart), blood vessels, eye, and tendon results in a degenerative process that worsens over time unless treated.
CLINICAL ONSET
Cerebrotendinous xanthomatosis can present at any age, from the neonatal period to the sixth decade of life or later.
Typically, the disease begins in infancy with chronic diarrhea. Cataracts become evident in childhood or adolescence., and xanthomata develop in the second and third decades of life. Significant neurologic impairment also occurs; this often includes seizures, dementia, and cerebellar and extrapyramidal dysfunction, typically beginning in the third decade of life and progressing until death, often in the sixth decade of life if the condition goes untreated. The presentation and course widely vary, and treatment can dramatically alter the natural history, especially with early initiation.
SYMPTOMS
Patients with CTX present diverse manifestations with multi-organ involvement and a broad range of neurological and non-neurological symptoms. For example, intractable infantile-onset diarrhea and psychomotor retardation are common coexisting clinical features of CTX. .
- Broad Central Nervous System related symptoms: first being epilepsy and Parkinson disease. MRI shows bilateral lesions in the dentate nucleus of the cerebellum and mild white matter lesions (categorizing CTX a leukodistrophia). 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 and muscle involvement: axonal degeneration by demyelination and remyelination. Of note, the presence of tendon xanthomas is not necessary for the diagnosis of CTX because not all patients have visible tendon xanthomas
- Ocular related: childhood-onset cataract is a typical sign of CTX. . and an early symptom preceding neurological signs and tendon xanthoma; it is considered useful for early diagnosis. Cataracts and optic disk paleness are also the common ocular features in adults with CTX
- Cardiovascular related: premature atherosclerosis and cardiovascular disease have been reported in spite of normal serum cholesterol concentrations, due to high levels of 27-hydroxycholesterol and low levels of HDL
- Skeletal system related: often osteoporosis and repeated bone fractures, with no known underlying pathogenesis as to date
- Enterohepatic system related: infantile-onset or adult chronic and intractable diarrhea, with normal gastro-intestinal examinations. Diarrhea in patients with CTX disappears a shortly after the start of CDCA therapy
- Laboratory findings:
- plasma cholestanol concentration five to ten-fold greater than normal (330±30μg/dL);
- urine bile alcohol concentration of 14,000±3,500nmol/L
- plasma bile alcohol concentration more than 500 to 1,000-fold greater than normal (8.48±3.67nmol/L);
- normal-to-low plasma cholesterol concentration, decreased CDCA level, and increased levels of cholestanol and apolipoprotein B in cerebrospinal fluid.
DIAGNOSIS
The diagnosis of CTX is mainly based on clinical findings, biochemical testing, neuroimaging, and molecular genetic analysis. A diagnosis of CTX should be considered for patients with xanthomas and neurological symptoms starting in childhood.
It should be noted that the symptoms might also start in adulthood. As a matter of fact, the mean age at onset of symptoms in patients with CTX is 19 years, but the average age at the time of diagnosis is 35 years (range 23–44), thus representing a diagnostic delay of 16 years (range 2–34).
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. An elevated plasma level of cholestanol is a feature of CTX. .
A new and sensitive multi-analyte blood test with liquid chromatography–electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) methodology can be used to quantify plasma ketostetrol bile acid precursors such as 7-α-hydroxy-4-cholesten-3-one and 5-α-cholestanol.
Mignarri et al. developed an effective suspicion index for early diagnosis composed of weighted scores related to indicators such as family history and systemic and neurological characteristics. Childhood-onset cataracts, diarrhea, and neonatal cholestatic jaundice in combination with neurological features and dentate nucleus abnormalities in MRI were demonstrated to be strong indicators. Tendon xanthomas were considered very strong indicators. 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.
To recap, classical symptoms and signs, namely elevated levels of cholestanol and bile alcohols in serum and urine, cranial magnetic resonance imaging, and mutation in the CYP27A1 gene, confirm the diagnosis.
Brain MRI shows T1-weighted (A, arrow) and T2-weighted (B, arrow) hyperintensities in the dentate nuclei.
DIFFERENTIAL DIAGNOSIS
Both sitosterolemia and familial hypercholesterolemia (FH ) feature similar cardiac syntomps and xanthomatosis. However Juvenile cataracts, progressive neurologic dysfunction, and mild pulmonary insufficiency are unique symptoms that distinguish CTX from other lipid storage disorders; they are non-existent in patients with sitosterolemia or FH.
The biochemical abnormalities that distinguish CTX from other diseases with xanthomas include: high plasma cholestanol concentration, normal-to-low plasma cholesterol concentration, decreased CDCA level, and increased levels of cholestanol and apolipoprotein B in cerebrospinal fluid.
THERAPY
The management of CTX includes replacement therapy, surgery, and other symptomatic therapy.
Early detection and diagnosis of CTX is crucial because early and long-term treatment of CTX with replacement therapy (consisting of CDCA 750 mg/die or cholic acid) improves neurological symptoms and even reverses the progression of the disease. Moreover, the benefits could be enhanced by administration of HMG-CoA reductase inhibitors. However, an obvious delay between symptom onset and diagnosis is prevalent. .
The potential mechanism of bile acid therapy may be exogenous inhibition of bile acid production by activating the bile acid negative feedback mechanism. This would inhibit production of the intermediate 7-α-hydroxy-4-cholesten-3-one, thereby normalizing cholestanol concentration and preventing the accumulation of cholestanol in tissues.
Due to the diverse manifestations and signs of CTX, symptomatic therapy is essential: antidepressant medication in case of depression, antiepileptic therapy in case of convulsive seizures, levodopa in case of parkinsonism, and botulinum toxin in case of dystonia.
FOOTNOTES
Scritto da Fabio Giorgino [fabiogiorgino@gmail.com]
REFERENCES
