Treatment Of Cerebrotendinous Xanthomatosis Research Articles

Treatment of cerebrotendinous xanthomatosis in pregnancy: Patient and physician perspectives

Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive disorder of bile acid synthesis that presents with varied and progressive symptomology. Early treatment with chenodeoxycholic acid (CDCA) improves symptoms and slows degeneration. Patients with CTX are commonly recommended to discontinue CDCA treatment during pregnancy because of theoretical risks to the fetus, but patient and clinician concerns about the risks of stopping treatment cause uncertainty. Herein, we report the experiences and perspectives of two women with CTX from the time of diagnosis through pregnancy, as well as decisions regarding CDCA treatment during pregnancy. Before becoming pregnant, both women were concerned about potential risks to their newborns if they continued or stopped CDCA treatment during pregnancy. Reassurance from their CTX specialist was the primary factor in their decision to continue treatment during pregnancy. After pregnancies complicated by preeclampsia, one gave birth to a healthy infant and the other gave birth to an infant later diagnosed with periventricular leukomalacia. Neither experienced CDCA-related complications.

The safety and effectiveness of chenodeoxycholic acid treatment in patients with cerebrotendinous xanthomatosis: two retrospective cohort studies

ObjectiveTo evaluate the safety and effectiveness of chenodeoxycholic acid (CDCA) treatment in patients with cerebrotendinous xanthomatosis (CTX).MethodsTwo retrospective cohort studies were conducted in CTX patients who underwent CDCA treatment: one in the Netherlands (NL; CDCA-STUK-15-001) and one in Italy (IT; CDCA-STRCH-CR-14-001). Eligible patients were aged 2–75 years, had been diagnosed with CTX, and were treated with CDCA orally for ≥1 year. The impact of CDCA treatment on biochemical markers (including serum cholestanol levels) and disease signs and symptoms were assessed, in addition to the safety and tolerability of CDCA treatment.ResultsA total of 35 patients were screened in the NL study and were diagnosed with CTX at 25.6 (± 13.7 SD) years on average. These patients were treated with CDCA and followed up for a median of 9.00 (range: 0.4–26.3) years. In addition, 28 patients were enrolled in the IT study and were diagnosed at 35.0 (± 11.4 SD) years on average (median duration of CDCA treatment: 5.75 [range: 0.0–25.0] years). Signs and symptoms of disease resolved, improved, or remained stable in many patients, with concomitant improvements in biochemical marker levels (serum cholestanol, p < 0.001; 7α-hydroxy-4-cholesten-3-one, p < 0.001 [IT study]).ConclusionsThe outcomes of these retrospective cohort studies indicate that CDCA is effective in the long-term treatment of CTX, with an acceptable safety profile.

The Diagnosis and Treatment of Cerebrotendinous Xanthomatosis

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The Diagnosis and Treatment of Cerebrotendinous Xanthomatosis

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Cerebrotendinous xanthomatosis: physiopathology, clinical manifestations and genetics

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease, caused by genetic deficiency of the 27-hydroxylase enzyme (encoded by CYP27A1). It plays a key role in cholesterol metabolism, especially in bile acid synthesis and in the 25-hydroxylation of vitamin D3 in the liver. Its deficiency causes reduced bile acid synthesis and tissue accumulation of cholestanol. Clinical manifestations are related to the presence of cholestanol deposits and include tendon xanthomas, premature cataracts, chronic diarrhea, progressive neurologic impairment and less frequently coronary heart disease, early onset osteoporosis and abnormalities in the optic disk and retina. An early diagnosis and treatment with quenodeoxycholic acid may prevent further complications, mainly neurological manifestations. This review summarizes cholesterol metabolism related to bile acid synthesis, physiopathology, biochemistry and treatment of cerebrotendinous xanthomatosis.

A suspicion index for early diagnosis and treatment of cerebrotendinous xanthomatosis

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disorder characterized by a heterogeneous presentation and a broad spectrum of clinical manifestations. Since early diagnosis and replacement therapy with chenodeoxycholic acid can prevent clinical deterioration, our aim was to develop a diagnostic tool to identify and treat CTX patients at an initial stage of the disease. We devised a suspicion index, composed of weighted scores assigned to indicators such as family history characteristics and common systemic and neurological features, on the basis of a pooled analysis of selected international CTX series. The indicators were classified as very strong (score 100), strong (50) or moderate (25). The suspicion index was then applied retrospectively to our CTX population. Early systemic signs such as cataract, diarrhea and neonatal cholestatic jaundice were considered strong indicators, together with neurological features such as intellectual impairment, psychiatric disturbances, ataxia, spastic paraparesis and dentate nuclei abnormalities at MRI. Tendon xanthomas were regarded as very strong indicators, as was an affected sibling. A total score ≥ 100 warranted serum cholestanol assessment. Elevated cholestanol or a total score ≥ 200, with one very strong or four strong indicators, warranted CYP27A1 gene analysis. In our patients, age at diagnosis was 35.5 ± 11.8years (mean ± standard deviation), whereas with the diagnostic tool it became 10.6 ± 9.8years (p < 0.01). Our suspicion index provides a simple and inexpensive diagnostic tool allowing diagnosis and treatment of CTX before neurological disability occurs.

Long-term follow-up on the effect of combined therapy of bile acids and statins in the treatment of cerebrotendinous xanthomatosis: A case report

Cerebrotendinous xanthomatosis (CTX; OMIM 213700) is a rare utosomal recessive inborn error caused by a deficit in bile acid synhesis. A deficiency of the enzyme sterol 27-hydroxylase causes the ccumulation of cholesterol and cholestanol in virtually all tissues. he molecular defect is localized to mutations of the CYP27A1 gene chrom. 2q33-qter), causing a variety of associated symptoms [1]. ystemic and neurological symptoms include intractable diarrhea, uvenile cataracts, tendon xanthomas, and progressive neurologic igns and symptoms. The systemic features typically appear at an arlier age than the neurological manifestations. The principal treatment for CTX is chenodeoxycholic acid CDCA), which inhibits excessive cholesterol and cholestanol ynthesis. Statins are currently thought to be beneficial, when comined with CDCA, yet this remains to be proven. Symptomatic herapies are also important.

Cerebrotendinous Xanthomatosis: A Treatable Disease With Juvenile Cataracts as a Presenting Sign

Cerebrotendinous Xanthomatosis (CTX) is an autosomal recessive disorder of bile acid synthesis1. At least 50 different causative mutations have been identified in the CYP27A1 gene encoding for a sterol 27-hydroxylase important in bile acid synthesis2. Sterol 27-hydroxylase deficiency leads to 5α-cholestanol accumulation in the blood and tissues of affected patients1, including brain, often leading to severe neurological dysfunction that can incapacitate patients by the 4th–5th decade of life1. CTX generally presents clinically in the 2nd–3rd decade; childhood signs and symptoms can include chronic diarrhea, juvenile cataracts, school failure1,3, and potentially xanthomas1. Eighty-five percent of CTX patients develop cataracts of multiple types2, reported to occur as young as age 5–6 years1, with cataracts and chronic diarrhea commonly presenting before neurologic disease3. For this reason, and since diarrhea is non-specific, the clinician may not consider a diagnosis of CTX when cataracts are identified. Treatment for CTX is available in the form of chenodeoxycholic acid (CDCA)1,4. The FDA recently reapproved CDCA (Manchester Pharmaceuticals, Inc). As treatment of CTX from the preclinical stage prevents the onset of disease complications4, the value of early diagnosis for this disorder cannot be overstated. We describe two cases of CTX affected children enrolled in an IRB approved study at OHSU with bilateral cataracts as presenting signs of disease. Case 1 A 9 year old female was referred to an ophthalmologist for decreased vision over several months. Past ocular history was unremarkable; full ocular exam 2 years prior was normal. Family history was unremarkable. Past medical history was significant for diarrhea and nonverbal learning disorder. On examination uncorrected distance visual acuity was 20/80 and uncorrected near acuity was 20/50 in each eye. Manifest refraction was 0.75+0.50X90 in each eye, with corrected distance acuity of 20/60 in the right and 20/80 in the left. Complete dilated exam was remarkable for the presence of cataract in each eye and described as a diffuse nuclear haze on slit lamp examination, with mild posterior capsular opacification (figure 1). Retroillumination highlighted posterior capsular findings (figure 2). Sequential bilateral cataract surgery with intraocular lens placement resulted in a corrected visual acuity of 20/20 in each eye. A metabolic workup indicated plasma 5α-cholestanol was markedly elevated at 3.7 mg/dl (normal < 0.2 mg/dl1), suggestive of CTX. Urine testing confirmed CTX with elevated bile alcohol glucuronides present (30.1 μg/ml). CDCA treatment was initiated and diarrhea resolved within one month, with accompanying weight gain. Plasma cholestanol dropped to 0.5 mg/dl within 7 months and after 6 years of treatment is currently stable at <0.2 mg/dl. No further clinical symptoms of CTX have developed. Figure 1 Diffuse nuclear haze and posterior sub capsular capsule opacification in right (A) and left (B) eye. Figure 2 Posterior sub capsular opacification in right (A) and left (B) eye. Case 2 An 11 year old male was referred to an ophthalmologist for cataract evaluation. High myopia was noted by a previous ophthalmologist at age 4. Family history was significant for high myopia and detached retina in mother and grandmother. Medical history included diarrhea from infancy, delayed language, autism, and seizures. Examination was limited by cooperation; however uncorrected distance visual acuity was at least 20/400 with both eyes open. Dilated examination revealed a refraction of −9.00 +1.00X090 in the right eye, and −9.50+1.25X090 in the left and was remarkable for bilateral cataracts. The lens opacities appeared visually significant with cortical flecks and distorted retinoscopic reflexes. Sequential bilateral cataract surgery was conducted with intraocular lens placement. The corrected visual acuity was 20/30+1 in the right and 20/40 in the left eye. Approximately 5 years later the patient was screened for a cholesterol disorder. Plasma 5α-cholestanol was elevated at 3.1–4.2 mg/dl, consistent with CTX. Elevated bile alcohol glucuronides in urine confirmed CTX. Diarrhea resolved within one month of initiating treatment. Plasma 5α-cholestanol dropped to 0.6 mg/dl within 6–8 months. After 8 months of treatment, the patient remains intellectually impaired, and continues to require an augmentative communication device. Although he still types single words to express wishes and needs, his spoken vocabulary has expanded modestly. His behavioral difficulties (making loud noises/head banging) also appear to be subsiding.

Studies in mice, hamsters, and rats demonstrate that repression of hepatic apoA-I expression by taurocholic acid in mice is not mediated by the farnesoid-X-receptor

It is claimed that apoA-I expression is repressed in mice by cholic acid (CA) and its taurine conjugate, taurocholic acid (TCA) via farnesoid X receptor (FXR) activation. We measured apoA-I expression in mice, hamsters, and rats treated with highly potent and selective synthetic FXR agonists or with TCA. All of the synthetic agonists bound to FXR with high affinity in a scintillation proximity assay. However, TCA did not compete with the radioligand up to the highest concentration used (100 μM). The C-site regulatory region of apoA-I, through which FXR has been reported to regulate its expression, is completely conserved across the species investigated. In both male and female human apoA-I-transgenic mice, we reproduced the previously reported strong inhibition of human apoA-I expression upon treatment with the typical supraphysiological dose of TCA used in such studies. However, in contrast to some previous reports, TCA did not repress murine apoA-I expression in the same mice. Also, more-potent and -selective FXR agonists did not affect human or murine apoA-I expression in this model. In LDL receptor-deficient mice and Golden Syrian hamsters, selective FXR agonists did not affect apoA-I expression, whereas in Wistar rats, some even increased apoA-I expression. In conclusion, selective FXR agonists do not repress apoA-I expression in rodents. Repression of human apoA-I expression by TCA in transgenic mice is probably mediated through FXR-independent mechanisms.

Rifampicin-induced CYP3A4 activation in CTX patients cannot replace chenodeoxycholic acid treatment

Cerebrotendinous xanthomatosis (CTX) is a rare neurodegenerative disorder with cholestanol accumulation resulting from mutations in the sterol 27-hydroxylase gene (CYP27A). Conventional treatment includes chenodeoxycholic acid and HMG-CoA reductase inhibitors. Mice with disrupted Cyp27A (Cyp27 KO) do not show elevated cholestanol levels nor develop CTX manifestations. This phenomenon was proposed to be due to murine CYP3A overexpression leading to an alternative pathway for degradation of bile alcohols including cholestanol. Our objective was to examine the influence of CYP3A4 induction on cholestanol elimination in CTX patients. Rifampicin (600 mg/day×7 days), known to induce the PXR, and thereby to increase CYP3A activity, was used. The degree of CYP3A4 induction was assessed by comparing midazolam pharmacokinetics before and after rifampicin treatment. Cholestanol levels and cholestanol/cholesterol ratios were assayed during the experimental period and compared to a 3 weeks period without treatment. The results show that despite 60% increase in CYP3A4 activity following rifampicin treatment, there is no significant change in cholestanol levels. We conclude that up-regulated expression of CYP3A affects cholestanol elimination in mice differently as compared to its effect in CTX patients. Therefore, CYP3A4 inducers cannot replace chenodeoxycholic acid for the treatment of CTX.

On the mechanism of cerebral accumulation of cholestanol in patients with cerebrotendinous xanthomatosis

The most serious consequence of sterol 27-hydroxylase deficiency in humans [cerebrotendinous xanthomatosis (CTX)] is the development of cholestanol-containing brain xanthomas. The cholestanol in the brain may be derived from the circulation or from 7alpha-hydroxylated intermediates in bile acid synthesis, present at 50- to 250-fold increased levels in plasma. Here, we demonstrate a transfer of 7alpha-hydroxy-4-cholesten-3-one across cultured porcine brain endothelial cells (a model for the blood-brain barrier) that is approximately 100-fold more efficient than the transfer of cholestanol. Furthermore, there was an efficient conversion of 7alpha-hydroxy-4-cholesten-3-one to cholestanol in cultured neuronal and glial cells as well as in monocyte-derived macrophages of human origin. It is concluded that the continuous intracellular production of cholestanol from a bile acid precursor capable of rapidly passing biomembranes, including the blood-brain barrier, is likely to be of major importance for the accumulation of cholestanol in patients with CTX. Such a mechanism also fits well with the observation that treatment with chenodeoxycholic acid, which normalizes the level of the bile acid precursor, results in a reduction of cholestanol-containing xanthomas even in the brain.

Hydrophilic 7β-hydroxy bile acids, lovastatin, and cholestyramine are ineffective in the treatment of cerebrotendinous xanthomatosis

We compared the effect of treatments with hydrophilic bile acids (ursodeoxycholic and ursocholic acids), cholestyramine, and lovastatin versus chenodeoxycholic acid in 4 patients with cerebrotendinous xanthomatosis (CTX). Bile acids and bile alcohols in plasma, bile, and urine before and after treatment were quantitated by gas-liquid chromatography. Untreated, all patients showed abnormal biliary bile acid composition: cholic acid (72.7%) and chenodeoxycholic acid (6.2%), and polyhydroxylated C 27-bile alcohols (10.0%), and elevated plasma cholestanol levels. Treatment with hydrophobic chenodeoxycholic acid inhibited abnormal bile acid synthesis (virtual disappearance of C 27-bile alcohols from plasma, bile, and urine and marked reduction of plasma cholestanol levels). Hydrophilic ursodeoxycholic and ursocholic acids did not inhibit abnormal bile acid synthesis, while cholestyramine increased abnormal bile acid synthesis (continued increased formation of polyhydroxylated C 27-bile alcohols and further elevation of plasma cholestanol levels). Lovastatin did not affect abnormal bile acid synthesis or reduce plasma cholestanol levels. The results demonstrate that impaired side-chain oxidation in bile acid synthesis due to mutations of Cyp27 results in increased formation of polyhydroxylated C 27-bile alcohols and cholestanol in CTX. Hydrophobic chenodeoxycholic acid, but not cholestyramine, lovastatin, or hydrophilic 7β-hydroxy acids, inhibited the abnormal synthetic pathway. The role of chenodeoxycholic acid in downregulating abnormal bile acid synthesis in CTX is emphasized.

Treatment of cerebrotendinous xanthomatosis: effects of chenodeoxycholic acid, pravastatin, and combined use

Treatments by oral administration of chenodeoxycholic acid (CDCA) alone, 3-hydroxy-3-methylglutaryl (HMG) CoA reductase inhibitor (pravastatin) alone, and combination of the two drugs were attempted for 7 patients with cerebrotendinous xanthomatosis (CTX). CDCA treatment at a dose of 300 mg/day reduced serum cholestanol (67.3% reduction), lathosterol (50.8%), campesterol (61.7%) and sitosterol (12.7%). However, the sera of the patients changed to be “atherogenic”; total cholesterol, triglyceride and low-density lipoprotein (LDL)-cholesterol were increased, while high-density lipoprotein (HDL)-cholesterol was decreased. Contrarily, pravastatin at a dose of 10 mg/day improved the sera of the patients to be markedly “anti-atherogenic”, but the reductions of cholestanol (30.4%), lathosterol (44.0%), campesterol (22.9%) and sitosterol (9.6%) were inadequate. Combined treatment with CDCA and pravastatin showed good overlapping of the effects of each drug alone. The sera of the patients were apparently more “anti-atherogenic” than those after CDCA treatment. Serum cholestanol concentration was still 2.7 times higher than in controls, but the serum lathosterol level was within the normal range, indicating that the enhancement of overall cholesterol synthesis in the patients was sufficiently suppressed. Plant sterol levels were also within the normal range. The combination of CDCA and pravastatin was a good treatment for CTX, based on the improvement of serum lipoprotein metabolism, the suppression of cholesterol synthesis, and reductions of cholestanol and plant sterol levels. In all of 7 patients, the progression of disease was arrested, but dramatic effects on clinical manifestations, xanthoma, and electrophysiological findings could not be found after the treatment of these drugs.

Treatment of cerebrotendinous xanthomatosis with low-density lipoprotein (LDL)-apheresis

We studied the effects of LDL-apheresis on the biochemical and clinical abnormalities of 5 patients with cerebrotendinous xanthomatosis (CTX). Levels of both cholestanol and cholesterol decreased to approximately 60% of those of pretreatment after one perfusion and gradually returned to their initial levels within 2 weeks. Improvement of clinical manifestations and regression of Achilles tendon xanthomas were detected after several perfusions, though dramatic changes could not be recognized. EEG abnormalities were improved immediately after LDL-apheresis in one patient. We conclude that LDL-apheresis may affect the serum cholestanol level and clinical manifestations in patients with CTX.

Capillary gas chromatographic determinations of urinary bile acids and bile alcohols in CTX patients proving the ineffectivity of ursodeoxycholic acid treatment

Urine samples and serum samples of a patient with cerebrotendinous xanthomatosis (CTX) were investigated by means of capillary gas chromatography, both before and during oral treatment with ursodeoxycholic acid (UDCA), and the results compared with those obtained during chenodeoxycholic acid (CDCA) therapy. The predominantly excreted bile alcohol, 5β-cholestane-3α,7α,12α,23,25-pentol and two abnormal bile acids, i.e. 23-norcholic acid and 23-hydroxycholic acid were determined. In addition, the serum cholestanol/cholesterol ratio was determined. Whereas previous experiments demonstrated that the urinary excretion of 5β-cholestane-3α, 7α,12α,23,25-pentol and the abnormal bile acids decreased within a few weeks during CDCA therapy, the present study shows that their urinary excretions remain essentially the same during UDCA treatment. In contrast to the decrease in the serum cholestanol/cholesterol ratio during CDCA therapy, this ratio remains essentially the same during UDCA therapy. It is therefore concluded that, in contrast to CDCA therapy, UDCA treatment is not effective in the treatment of CTX.