RARE DISEASE
Cerebrotendinous xanthomatosis
Cerebrotendinous xanthomatosis
Cerebrotendinous xanthomatosis
Synonyms: CTX, Sterol 27-hydroxylase deficiency
Synonyms: CTX, Sterol 27-hydroxylase deficiency
Synonyms: CTX, Sterol 27-hydroxylase deficiency
Drug discovery
3
drugs
With orphan designations
Overview
Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by CYP27A1 mutations disrupting bile acid synthesis, leading to cholestanol accumulation in the brain, tendons, and eyes. Key features include chronic diarrhea, bilateral juvenile cataracts, tendon xanthomas, and progressive neurological deterioration (ataxia, cognitive decline, and neuropathy). Early diagnosis via plasma cholestanol testing and genetic analysis is critical, as treatment with chenodeoxycholic acid (CDCA) halts disease progression [1][3][8][13]. Untreated CTX results in irreversible neurological damage and multisystem complications [9][12].
Burden
Chronic progression causes severe disability (dementia, ataxia) and premature death (untreated life expectancy: 50–60 years) [9][13].
High treatment costs ($300,000+/year for CDCA analogs) and multidisciplinary care requirements create socioeconomic challenges [10][16].
Delayed diagnosis (average 16 years) amplifies irreversible neurological damage [1][13].
Therapies
CDCA (750 mg/day) is first-line, normalizing bile acid synthesis and reducing cholestanol [3][8][13].
Adjunct therapies: Statins (controversial) or LDL apheresis for refractory cases [3][9].
FDA-approved chenodiol (CTEXLI®) in 2025 for adults, showing sustained biochemical and clinical efficacy [8].
Categories: rare endocrine diseases, rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare skin diseases, rare transplant-related disorders
Research Papers
217 drug discovery papers about Cerebrotendinous xanthomatosis, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
217 drug discovery papers about Cerebrotendinous xanthomatosis, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2023-12-16 | Resection of bilateral massive Achilles tendon xanthomata with reconstruction using vascularized iliotibial tract: A case report and literature review.
Cerebrotendinous xanthomatosis is a rare autosomal recessive metabolic disease. Surgical treatment is only indicated when the xanthoma becomes large, painful, and irritable with shoe wear. Reconstruction of the large defect following resection challenging, especially with resection of the entire Achilles tendon. We report a case of bilateral Achilles tendon defects of 16 cm following resection of bilateral Achilles tendon xanthomata, with reconstruction using vascularized iliotibial tract. The patient had a good functional outcome with well-preserved strength and cosmesis. Reconstruction of a total Achilles tendon defect using Vascularized iliotibial tract is safe and effective.
2017-03-08 | Bilateral Achilles Tendon Xanthomas in a Patient with Cerebrotendinous Xanthomatosis
Cerebrotendinous xanthomatosis is a rare, autosomal recessive, lipid storage disease with accumulation of cholestanol in most tissues, particularly in the Achilles tendons. We described a 23-year-old female patient who had progressive painfull swelling of both Achilles tendons due to cerebrotendinous xanthomatosis. We performed surgery on both-side Achilles tendon tumors. Wide degenerative areas of the tendons were resected, and the flexor hallucis longus tendon was harvested and transferred to reconstruct motion function.
2013-11-19 | Reconstruction of bilateral tendoachilles with fascia lata graft
A 19 year old male presented with progressive enlargement of both tendoachilles for 2 years and difficulty in walking for 3 months. The neurological history and examination revealed progressive mental deterioration and ataxia. The blood investigation revealed hypercholesterolemia. We report this rare case of cerebrotendinous xanthomatosis with bilateral tendoachilles enlargement, which was treated by excision of bilateral tendoachilles and reconstruction with fascia lata. The American Orthopedic Foot and Ankle Society hindfoot score was 93/100 bilaterally and the subjective evaluation of the patient showed very good results.
2011-06-13 | Monitoring of 7α-hydroxy-4-cholesten-3-one during therapy of cerebrotendinous xanthomatosis: a case report
Cerebrotendinous xanthomatosis (CTX) is a rare, inherited autosomal-recessive lipid-storage disorder caused by 27-hydroxylase deficiency. In this study, we report of a 30-year old man with this disorder who was treated using chenodeoxycholic acid, simvastatin, and low-density lipoprotein (LDL) apheresis. The LDL apheresis was performed weekly for nine months. The first subjective improvement was reported by the patient after his fourth LDL-apheresis. Spasticity, gait disturbances, and his entire psychomotoric test results had improved tremendously. His fine motoric skills have been regained. The efficacy of LDL-apheresis was monitored using quantitative determination of 7α-OH-4-cholesten-3-one in plasma based on a LC-MS/MS method. The clearance efficacy of 7α-hydroxy-4-cholesten-3-one from the patient's plasma per LDL-apheresis varied between 8% and 53% but returned to the initial high levels after seven days (mean value 241 ng/mL). A slight negative trend in the plasma concentration could be derived over the period of nine months.
2005-02-15 | Normalisation of serum cholestanol concentration in a patient with cerebrotendinous xanthomatosis by combined treatment with chenodeoxycholic acid, simvastatin and LDL apheresis.
The concentrations of serum cholesterol, cholestanol and non-cholesterol sterols were measured in a patient with cerebrotendinous xanthomatosis under different therapeutic regimens. During treatment with chenodeoxycholic acid (CDCA) (750 mg/day) plus simvastatin (20 mg/day) for two years cholesterol and cholestanol concentrations averaged 188+/-10 mg/dl and 0.54+/-0.03 mg/dl. Thereafter treatment with simvastatin was discontinued. During treatment with low-density lipoprotein (LDL)-apheresis plus CDCA for 33 weeks, cholestanol concentrations reached almost normal levels (0.48+/-0.03 mg/dl immediately before and 0.32+/-0.02 mg/dl directly after LDL-apheresis, n=6). A further reduction of cholesterol and cholestanol was achieved by addition of simvastatin (20 mg/day). Cholesterol and cholestanol concentrations before and after LDL-apheresis during this treatment period averaged 122+/-4 mg/dl and 55+/-10 mg/dl, and 0.42+/-0.02 mg/dl and 0.18+/-0.06 mg/dl, respectively. Despite the consistent reduction of cholestanol to normal or even subnormal levels, a definite improvement of clinical symptoms was not noted. Our results suggest caution in the recourse to an aggressive cholestanol lowering therapy.
proteins
2023-12-11 | Cerebrotendinous xanthomatosis presenting with schizophrenia-like disorder: A case report.
Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid-storage disorder caused by mutations in CYP27A1. Psychiatric manifestations in CTX are rare and nonspecific, and they often lead to considerable diagnostic and treatment delay. A 33-year-old female patient admitted to the psychiatric ward for presentation of delusions, hallucinations, and behavioral disturbance is reported. The patient presented with cholestasis, cataract, Achilles tendon xanthoma, and cerebellar signs in adulthood and with intellectual disability and learning difficulties in childhood. After the characteristic CTX findings on imaging were obtained, a pathological examination of the Achilles tendon xanthoma was refined. Re-placement therapy was then initiated after the diagnosis was clarified by genetic analysis. During hospitalization in the psychiatric ward, the nonspecific psychiatric manifestations of the patient posed difficulty in diagnosis. After the patient's history of CTX was identified, the patient was diagnosed with organic schizophrenia-like disorder, and psychotic symptoms were controlled by replacement therapy combined with antipsychotic medication. Psychiatrists should be aware of CTX, its psychiatric manifestations, and clinical features and avoid misdiagnosis of CTX for timely intervention.
2023-03-10 | CYP27A1 deficiency promoted osteoclast differentiation.
The elevating osteoclast differentiation can lead to an imbalance in bone homeostasis, which was responsible for bone loss and bone diseases, such as osteoporosis. Multiple pathways and molecules have been involved in osteoclast formation, but the role of CYP27A1 in osteoclast differentiation has never been explored. CYP27A1 deficient mice were constructed using CRISPR-Cas9 system. Osteoclast differentiation was detected by TRAP staining. Differentially expressed genes (DEGs) were identified using RNA-seq analysis and were confirmed by qRT-PCR and Western blot. The results showed that CYP27A1 knockout (KO) promoted osteoclast differentiation and bone loss. The transcriptomic analysis revealed that CYP27A1 KO led to differential expression of multiple genes, including ELANE, LY6C2, S100A9, GM20708, BGN, SPARC, and COL1A2, which were confirmed by qRT-PCR and Western blot. Enrichment analysis indicated that these differential genes were significantly associated with osteogenesis-related pathways, such as PPAR signaling, IL-17 signaling, and PI3K/AKT signaling, which were confirmed by qRT-PCR and Western blot. These results suggested that CYP27A1 was involved in osteoclast differentiation, providing a novel therapeutic target for osteoclast-related diseases.
2021-04-21 | Metabolic profiling in serum, cerebrospinal fluid, and brain of patients with cerebrotendinous xanthomatosis
Cerebrotendinous xanthomatosis (CTX) is caused by autosomal recessive loss-of-function mutations in CYP27A1, a gene encoding cytochrome p450 oxidase essential for bile acid synthesis, resulting in altered bile acid and lipid metabolism. Here, we aimed to identify metabolic aberrations that drive ongoing neurodegeneration in some patients with CTX despite chenodeoxycholic acid (CDCA) supplementation, the standard treatment in CTX. Using chromatographic separation techniques coupled to mass spectrometry, we analyzed 26 sterol metabolites in serum and cerebrospinal fluid (CSF) of patients with CTX and in one CTX brain. Comparing samples of drug naive patients to patients treated with CDCA and healthy controls, we identified 7α,12α-dihydroxycholest-4-en-3-one as the most prominently elevated metabolite in serum and CSF of drug naive patients. CDCA treatment substantially reduced or even normalized levels of all metabolites increased in untreated patients with CTX. Independent of CDCA treatment, metabolites of the 27-hydroxylation pathway were nearly absent in all patients with CTX. 27-hydroxylated metabolites accounted for ∼45% of total free sterol content in CSF of healthy controls but <2% in patients with CTX. Metabolic changes in brain tissue corresponded well with findings in CSF. Interestingly, 7α,12α-dihydroxycholest-4-en-3-one and 5α-cholestanol did not exert toxicity in neuronal cell culture. In conclusion, we propose that increased 7α,12α-dihydroxycholest-4-en-3-one and lack of 27-hydroxycholesterol may be highly sensitive metabolic biomarkers of CTX. As CDCA cannot reliably prevent disease progression despite reduction of most accumulated metabolites, supplementation of 27-hydroxylated bile acid intermediates or replacement of CYP27A1 might be required to counter neurodegeneration in patients with progressive disease despite CDCA treatment.
2014-08-01 | Cholesterol 24S-Hydroxylase Overexpression Inhibits the Liver X Receptor (LXR) Pathway by Activating Small Guanosine Triphosphate-Binding Proteins (sGTPases) in Neuronal Cells
The neuronal-specific cholesterol 24S-hydroxylase (CYP46A1) is important for brain cholesterol elimination. Cyp46a1 null mice exhibit severe deficiencies in learning and hippocampal long-term potentiation, suggested to be caused by a decrease in isoprenoid intermediates of the mevalonate pathway. Conversely, transgenic mice overexpressing CYP46A1 show an improved cognitive function. These results raised the question of whether CYP46A1 expression can modulate the activity of proteins that are crucial for neuronal function, namely of isoprenylated small guanosine triphosphate-binding proteins (sGTPases). Our results show that CYP46A1 overexpression in SH-SY5Y neuroblastoma cells and in primary cultures of rat cortical neurons leads to an increase in 3-hydroxy-3-methyl-glutaryl-CoA reductase activity and to an overall increase in membrane levels of RhoA, Rac1, Cdc42 and Rab8. This increase is accompanied by a specific increase in RhoA activation. Interestingly, treatment with lovastatin or a geranylgeranyltransferase-I inhibitor abolished the CYP46A1 effect. The CYP46A1-mediated increase in sGTPases membrane abundance was confirmed in vivo, in membrane fractions obtained from transgenic mice overexpressing this enzyme. Moreover, CYP46A1 overexpression leads to a decrease in the liver X receptor (LXR) transcriptional activity and in the mRNA levels of ATP-binding cassette transporter 1, sub-family A, member 1 and apolipoprotein E. This effect was abolished by inhibition of prenylation or by co-transfection of a RhoA dominant-negative mutant. Our results suggest a novel regulatory axis in neurons; under conditions of membrane cholesterol reduction by increased CYP46A1 expression, neurons increase isoprenoid synthesis and sGTPase prenylation. This leads to a reduction in LXR activity, and consequently to a decrease in the expression of LXR target genes.
2003-03-01 | Expression of Sterol 27-Hydroxylase (CYP27A1) Enhances Cholesterol Efflux
Cholesterol efflux from CHOP cells transfected with sterol 27-hydroxylase (CYP27A1) was compared with non-transfected and mock-transfected cells. Transfection caused expression of CYP27A1, formation of 27-hydroxycholesterol, and inhibition of cholesterol biosynthesis. Transfection enhanced cholesterol efflux to apolipoprotein A-I or human plasma by 2–3-fold but did not affect the efflux in the absence of acceptor. The analysis of released sterols revealed that 27-hydroxycholesterol represented only a small proportion of sterols, most of which was non-oxidized cholesterol. Time course and dose dependence studies showed that expression of CYP27A1 in CHOP cells mostly affected the efflux of the "fast" cholesterol pool, and relatively more cholesterol was released with low concentrations of an acceptor. Preincubation of non-transfected cells with exogenous 27-hydroxycholesterol (10−9 and 10−7m) led to the stimulation of cholesterol efflux by 24–60%. Expression of CYP27A1 in CHOP cells did not affect ABCA1 expression and abundance of ABCA1 protein. Thus, introduction of CYP27A1 into cells stimulates cholesterol efflux and therefore may increase protection against atherosclerosis.
small molecules
2026-09-23 | Prevalence and Impact of a Pathogenic CYP27A1 Variant on the Phenotypes Among Patients with Monogenic Heterozygous Familial Hypercholesterolemia.
Cerebrotendinous xanthomatosis (CTX) is a rare inherited metabolic disorder caused by pathogenic variants of cytochrome P450 family 27 subfamily A member 1 (CYP27A1). It remains unclear whether such variants modify the clinical manifestations of familial hypercholesterolemia (FH) caused by defects in the low-density lipoprotein (LDL) receptor or other related genes. We aimed to clarify the impact of the pathogenic variants of CYP27A1 on the clinical phenotypes of patients with FH. We analyzed clinical data from 644 patients with a clinical diagnosis of monogenic FH who underwent genotyping for CYP27A1 and phenotypic assessment, including the serum sterol levels. Multivariate linear regression analyses, adjusted for age and sex, were conducted to assess the impact of pathogenic CYP27A1 variants on the serum cholestanol levels. Among these individuals, 22 (3.4%) carried pathogenic CYP27A1 variants. Patients harboring a pathogenic variant showed significantly higher median cholestanol concentrations than non-carriers (3.7 vs. 2.3 μg/mL, p ＜0.001). A single pathogenic CYP27A1 variant was associated with an increase in serum cholestanol of 2.3 μg/mL (95% confidence interval: 1.4-3.2 μg/mL, p ＜0.001) and an Achilles tendon thickness of 0.4 mm (95% confidence interval: 0.1-0.7 mm, p = 0.02). Furthermore, carriers exhibited significantly greater Achilles tendon thickness than non-carriers (9.6 vs. 8.9 mm, p ＜0.001). We identified a substantial number of patients with pathogenic CYP27A1 variants among the patients with monogenic FH, which influenced their Achilles tendon thickness and serum cholestanol levels.
2026-05-09 | Lipid dysregulation as a central contributor of neurodegenerative diseases: Emerging therapeutic targets and strategies.
Lipid homeostasis is essential for preserving the structural integrity and functional capacity of the brain. A diverse array of lipids, including cholesterol, phospholipids, and sphingolipids, has been identified as playing pivotal roles. Dysregulation of lipid metabolism is increasingly recognized as a central pathological mechanism in neurodegenerative diseases, including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, Huntington's Disease, and Cerebrotendinous Xanthomatosis, though much of the existing evidence comes from associative studies, and causal relationships still need to be further validated through interventional studies. Here we systematically review the metabolic pathways and regulatory networks of major brain lipids, with a focus on delineating disease-specific alterations and summarizing emerging therapeutic strategies targeting lipid metabolism. These strategies encompass the modulation of cholesterol homeostasis, sphingolipid metabolism, phospholipid signaling, and fatty acid oxidation, alongside approaches that enhance lipid clearance and neural repair. Preclinical advances and ongoing clinical trials underscore the translational potential of lipid-targeted interventions. In conclusion, we emphasize the potential of lipid metabolism as a promising avenue for developing novel treatments, offering insights to guide future research and therapeutic innovation in neurodegeneration.
2026-01-13 | Juvenile-Onset Cerebrotendinous Xanthomatosis with Novel Compound Heterozygous CYP27A1 Mutations: Case Series and Literature Review.
Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive neurometabolic disorder characterized by multisystem involvement and marked clinical heterogeneity. Pathogenic variants in the CYP27A1 gene, encoding mitochondrial sterol-27-hydroxylase, disrupt bile acid synthesis, leading to pathological accumulation of cholestanol in neural tissues, tendons, and other organs. This study aimed to characterize two novel CTX cases with compound heterozygous variants in the CYP27A1 gene through integrated clinical-genetic analysis, and to systematically synthesize current evidence on CTX through a literature review. Molecular investigations employed a tiered sequencing strategy: whole-exome sequencing (WES) for variant discovery, third-generation sequencing for variant screening of WES-negative samples, and Sanger sequencing for familial segregation validation. We present two Chinese juvenile-onset CTX cases demonstrating characteristic multisystem involvement, including both extraneural manifestations and progressive neurological deterioration. Genetic investigations revealed three CYP27A1 variants: the previously unreported c.845 - 46_881del83, the splicing variant c.1477-2 A > C, and a novel nonsense variant c.487 C > T in exon 3. Both probands exhibited compound heterozygosity, sharing the c.845 - 46_881del83 variant alongside distinct second alleles (c.1477-2 A > C and c.487 C > T, respectively). Then, a literature review synthesizes current evidence on clinical manifestations, genotypic patterns, and therapeutic approaches in CTX. This study expands the CYP27A1 mutational spectrum with two novel variants and validates the diagnostic utility of long-read sequencing (LRS) in resolving complex autosomal recessive cerebellar ataxia (ARCA) cases. The synthesis of clinical and literature evidence underscores the need for early recognition of CTX's heterogeneous presentations.
2025-12-31 | Cerebrotendinous Xanthomatosis Unmasked by Cutaneous Xanthogranuloma: A Clinicopathological Case Report: A Rare Case Report
Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disorder caused by defective bile acid synthesis, leading to accumulation of cholestanol in multiple tissues. We report a case of a 29-year-old male with intellectual disability and long-standing seizures who presented with multiple painless tendon and cutaneous swellings. Histopathological examination of an excised cutaneous nodule revealed sheets of foamy macrophages, Touton-type giant cells, and cholesterol clefts, suggestive of xanthogranulomatous pathology. Subsequent clinicoradiological correlation demonstrated diffuse cerebral and cerebellar atrophy with chronic white-matter ischemic changes on MRI, along with a history of juvenile cataract, delayed milestones, neonatal jaundice, and chronic diarrhea. Routine lipid profile was within normal limits, excluding common hyperlipidemic xanthomatoses. Based on the characteristic clinical, radiological, and histopathological features, a diagnosis of cerebrotendinous xanthomatosis was established. This case highlights the critical role of pathological vigilance and multidisciplinary evaluation in diagnosing this rare yet treatable metabolic disorder.
2025-12-24 | Cholestanol promotes tau pathology in a mouse model of tauopathy.
Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disease characterized by the accumulation of cholestanol. CTX patients often suffer from cognitive impairment. We found that serum cholestanol levels are higher in Alzheimer's disease (AD) patients than in control subjects. Thus, we tested whether cholestanol regulates the pathogenesis of AD. Cholestanol promotes tau fragmentation and hyperphosphorylation by activating asparagine endopeptidase (AEP). AEP knockdown alleviates cholestanol-induced tau fragmentation and phosphorylation. Feeding cholestanol to tau P301S mice aggravates tau pathology and behavioral defects, while knockout of AEP ameliorates cholestanol-induced tau pathology and behavioral defects in tau P301S mice. These results highlight the role of AEP-mediated tau cleavage in cholestanol-induced tau pathology and cognitive decline. The data also identify the potential therapeutic target of AEP in AD, particularly in AD patients with elevated serum cholestanol levels.
cell therapies
2023-12-16 | Resection of bilateral massive Achilles tendon xanthomata with reconstruction using vascularized iliotibial tract: A case report and literature review.
Cerebrotendinous xanthomatosis is a rare autosomal recessive metabolic disease. Surgical treatment is only indicated when the xanthoma becomes large, painful, and irritable with shoe wear. Reconstruction of the large defect following resection challenging, especially with resection of the entire Achilles tendon. We report a case of bilateral Achilles tendon defects of 16 cm following resection of bilateral Achilles tendon xanthomata, with reconstruction using vascularized iliotibial tract. The patient had a good functional outcome with well-preserved strength and cosmesis. Reconstruction of a total Achilles tendon defect using Vascularized iliotibial tract is safe and effective.
2017-03-08 | Bilateral Achilles Tendon Xanthomas in a Patient with Cerebrotendinous Xanthomatosis
Cerebrotendinous xanthomatosis is a rare, autosomal recessive, lipid storage disease with accumulation of cholestanol in most tissues, particularly in the Achilles tendons. We described a 23-year-old female patient who had progressive painfull swelling of both Achilles tendons due to cerebrotendinous xanthomatosis. We performed surgery on both-side Achilles tendon tumors. Wide degenerative areas of the tendons were resected, and the flexor hallucis longus tendon was harvested and transferred to reconstruct motion function.
2013-11-19 | Reconstruction of bilateral tendoachilles with fascia lata graft
A 19 year old male presented with progressive enlargement of both tendoachilles for 2 years and difficulty in walking for 3 months. The neurological history and examination revealed progressive mental deterioration and ataxia. The blood investigation revealed hypercholesterolemia. We report this rare case of cerebrotendinous xanthomatosis with bilateral tendoachilles enlargement, which was treated by excision of bilateral tendoachilles and reconstruction with fascia lata. The American Orthopedic Foot and Ankle Society hindfoot score was 93/100 bilaterally and the subjective evaluation of the patient showed very good results.
2011-06-13 | Monitoring of 7α-hydroxy-4-cholesten-3-one during therapy of cerebrotendinous xanthomatosis: a case report
Cerebrotendinous xanthomatosis (CTX) is a rare, inherited autosomal-recessive lipid-storage disorder caused by 27-hydroxylase deficiency. In this study, we report of a 30-year old man with this disorder who was treated using chenodeoxycholic acid, simvastatin, and low-density lipoprotein (LDL) apheresis. The LDL apheresis was performed weekly for nine months. The first subjective improvement was reported by the patient after his fourth LDL-apheresis. Spasticity, gait disturbances, and his entire psychomotoric test results had improved tremendously. His fine motoric skills have been regained. The efficacy of LDL-apheresis was monitored using quantitative determination of 7α-OH-4-cholesten-3-one in plasma based on a LC-MS/MS method. The clearance efficacy of 7α-hydroxy-4-cholesten-3-one from the patient's plasma per LDL-apheresis varied between 8% and 53% but returned to the initial high levels after seven days (mean value 241 ng/mL). A slight negative trend in the plasma concentration could be derived over the period of nine months.
2005-02-15 | Normalisation of serum cholestanol concentration in a patient with cerebrotendinous xanthomatosis by combined treatment with chenodeoxycholic acid, simvastatin and LDL apheresis.
The concentrations of serum cholesterol, cholestanol and non-cholesterol sterols were measured in a patient with cerebrotendinous xanthomatosis under different therapeutic regimens. During treatment with chenodeoxycholic acid (CDCA) (750 mg/day) plus simvastatin (20 mg/day) for two years cholesterol and cholestanol concentrations averaged 188+/-10 mg/dl and 0.54+/-0.03 mg/dl. Thereafter treatment with simvastatin was discontinued. During treatment with low-density lipoprotein (LDL)-apheresis plus CDCA for 33 weeks, cholestanol concentrations reached almost normal levels (0.48+/-0.03 mg/dl immediately before and 0.32+/-0.02 mg/dl directly after LDL-apheresis, n=6). A further reduction of cholesterol and cholestanol was achieved by addition of simvastatin (20 mg/day). Cholesterol and cholestanol concentrations before and after LDL-apheresis during this treatment period averaged 122+/-4 mg/dl and 55+/-10 mg/dl, and 0.42+/-0.02 mg/dl and 0.18+/-0.06 mg/dl, respectively. Despite the consistent reduction of cholestanol to normal or even subnormal levels, a definite improvement of clinical symptoms was not noted. Our results suggest caution in the recourse to an aggressive cholestanol lowering therapy.
proteins
2023-12-11 | Cerebrotendinous xanthomatosis presenting with schizophrenia-like disorder: A case report.
Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid-storage disorder caused by mutations in CYP27A1. Psychiatric manifestations in CTX are rare and nonspecific, and they often lead to considerable diagnostic and treatment delay. A 33-year-old female patient admitted to the psychiatric ward for presentation of delusions, hallucinations, and behavioral disturbance is reported. The patient presented with cholestasis, cataract, Achilles tendon xanthoma, and cerebellar signs in adulthood and with intellectual disability and learning difficulties in childhood. After the characteristic CTX findings on imaging were obtained, a pathological examination of the Achilles tendon xanthoma was refined. Re-placement therapy was then initiated after the diagnosis was clarified by genetic analysis. During hospitalization in the psychiatric ward, the nonspecific psychiatric manifestations of the patient posed difficulty in diagnosis. After the patient's history of CTX was identified, the patient was diagnosed with organic schizophrenia-like disorder, and psychotic symptoms were controlled by replacement therapy combined with antipsychotic medication. Psychiatrists should be aware of CTX, its psychiatric manifestations, and clinical features and avoid misdiagnosis of CTX for timely intervention.
2023-03-10 | CYP27A1 deficiency promoted osteoclast differentiation.
The elevating osteoclast differentiation can lead to an imbalance in bone homeostasis, which was responsible for bone loss and bone diseases, such as osteoporosis. Multiple pathways and molecules have been involved in osteoclast formation, but the role of CYP27A1 in osteoclast differentiation has never been explored. CYP27A1 deficient mice were constructed using CRISPR-Cas9 system. Osteoclast differentiation was detected by TRAP staining. Differentially expressed genes (DEGs) were identified using RNA-seq analysis and were confirmed by qRT-PCR and Western blot. The results showed that CYP27A1 knockout (KO) promoted osteoclast differentiation and bone loss. The transcriptomic analysis revealed that CYP27A1 KO led to differential expression of multiple genes, including ELANE, LY6C2, S100A9, GM20708, BGN, SPARC, and COL1A2, which were confirmed by qRT-PCR and Western blot. Enrichment analysis indicated that these differential genes were significantly associated with osteogenesis-related pathways, such as PPAR signaling, IL-17 signaling, and PI3K/AKT signaling, which were confirmed by qRT-PCR and Western blot. These results suggested that CYP27A1 was involved in osteoclast differentiation, providing a novel therapeutic target for osteoclast-related diseases.
2021-04-21 | Metabolic profiling in serum, cerebrospinal fluid, and brain of patients with cerebrotendinous xanthomatosis
Cerebrotendinous xanthomatosis (CTX) is caused by autosomal recessive loss-of-function mutations in CYP27A1, a gene encoding cytochrome p450 oxidase essential for bile acid synthesis, resulting in altered bile acid and lipid metabolism. Here, we aimed to identify metabolic aberrations that drive ongoing neurodegeneration in some patients with CTX despite chenodeoxycholic acid (CDCA) supplementation, the standard treatment in CTX. Using chromatographic separation techniques coupled to mass spectrometry, we analyzed 26 sterol metabolites in serum and cerebrospinal fluid (CSF) of patients with CTX and in one CTX brain. Comparing samples of drug naive patients to patients treated with CDCA and healthy controls, we identified 7α,12α-dihydroxycholest-4-en-3-one as the most prominently elevated metabolite in serum and CSF of drug naive patients. CDCA treatment substantially reduced or even normalized levels of all metabolites increased in untreated patients with CTX. Independent of CDCA treatment, metabolites of the 27-hydroxylation pathway were nearly absent in all patients with CTX. 27-hydroxylated metabolites accounted for ∼45% of total free sterol content in CSF of healthy controls but <2% in patients with CTX. Metabolic changes in brain tissue corresponded well with findings in CSF. Interestingly, 7α,12α-dihydroxycholest-4-en-3-one and 5α-cholestanol did not exert toxicity in neuronal cell culture. In conclusion, we propose that increased 7α,12α-dihydroxycholest-4-en-3-one and lack of 27-hydroxycholesterol may be highly sensitive metabolic biomarkers of CTX. As CDCA cannot reliably prevent disease progression despite reduction of most accumulated metabolites, supplementation of 27-hydroxylated bile acid intermediates or replacement of CYP27A1 might be required to counter neurodegeneration in patients with progressive disease despite CDCA treatment.
2014-08-01 | Cholesterol 24S-Hydroxylase Overexpression Inhibits the Liver X Receptor (LXR) Pathway by Activating Small Guanosine Triphosphate-Binding Proteins (sGTPases) in Neuronal Cells
The neuronal-specific cholesterol 24S-hydroxylase (CYP46A1) is important for brain cholesterol elimination. Cyp46a1 null mice exhibit severe deficiencies in learning and hippocampal long-term potentiation, suggested to be caused by a decrease in isoprenoid intermediates of the mevalonate pathway. Conversely, transgenic mice overexpressing CYP46A1 show an improved cognitive function. These results raised the question of whether CYP46A1 expression can modulate the activity of proteins that are crucial for neuronal function, namely of isoprenylated small guanosine triphosphate-binding proteins (sGTPases). Our results show that CYP46A1 overexpression in SH-SY5Y neuroblastoma cells and in primary cultures of rat cortical neurons leads to an increase in 3-hydroxy-3-methyl-glutaryl-CoA reductase activity and to an overall increase in membrane levels of RhoA, Rac1, Cdc42 and Rab8. This increase is accompanied by a specific increase in RhoA activation. Interestingly, treatment with lovastatin or a geranylgeranyltransferase-I inhibitor abolished the CYP46A1 effect. The CYP46A1-mediated increase in sGTPases membrane abundance was confirmed in vivo, in membrane fractions obtained from transgenic mice overexpressing this enzyme. Moreover, CYP46A1 overexpression leads to a decrease in the liver X receptor (LXR) transcriptional activity and in the mRNA levels of ATP-binding cassette transporter 1, sub-family A, member 1 and apolipoprotein E. This effect was abolished by inhibition of prenylation or by co-transfection of a RhoA dominant-negative mutant. Our results suggest a novel regulatory axis in neurons; under conditions of membrane cholesterol reduction by increased CYP46A1 expression, neurons increase isoprenoid synthesis and sGTPase prenylation. This leads to a reduction in LXR activity, and consequently to a decrease in the expression of LXR target genes.
2003-03-01 | Expression of Sterol 27-Hydroxylase (CYP27A1) Enhances Cholesterol Efflux
Cholesterol efflux from CHOP cells transfected with sterol 27-hydroxylase (CYP27A1) was compared with non-transfected and mock-transfected cells. Transfection caused expression of CYP27A1, formation of 27-hydroxycholesterol, and inhibition of cholesterol biosynthesis. Transfection enhanced cholesterol efflux to apolipoprotein A-I or human plasma by 2–3-fold but did not affect the efflux in the absence of acceptor. The analysis of released sterols revealed that 27-hydroxycholesterol represented only a small proportion of sterols, most of which was non-oxidized cholesterol. Time course and dose dependence studies showed that expression of CYP27A1 in CHOP cells mostly affected the efflux of the "fast" cholesterol pool, and relatively more cholesterol was released with low concentrations of an acceptor. Preincubation of non-transfected cells with exogenous 27-hydroxycholesterol (10−9 and 10−7m) led to the stimulation of cholesterol efflux by 24–60%. Expression of CYP27A1 in CHOP cells did not affect ABCA1 expression and abundance of ABCA1 protein. Thus, introduction of CYP27A1 into cells stimulates cholesterol efflux and therefore may increase protection against atherosclerosis.
small molecules
2026-09-23 | Prevalence and Impact of a Pathogenic CYP27A1 Variant on the Phenotypes Among Patients with Monogenic Heterozygous Familial Hypercholesterolemia.
Cerebrotendinous xanthomatosis (CTX) is a rare inherited metabolic disorder caused by pathogenic variants of cytochrome P450 family 27 subfamily A member 1 (CYP27A1). It remains unclear whether such variants modify the clinical manifestations of familial hypercholesterolemia (FH) caused by defects in the low-density lipoprotein (LDL) receptor or other related genes. We aimed to clarify the impact of the pathogenic variants of CYP27A1 on the clinical phenotypes of patients with FH. We analyzed clinical data from 644 patients with a clinical diagnosis of monogenic FH who underwent genotyping for CYP27A1 and phenotypic assessment, including the serum sterol levels. Multivariate linear regression analyses, adjusted for age and sex, were conducted to assess the impact of pathogenic CYP27A1 variants on the serum cholestanol levels. Among these individuals, 22 (3.4%) carried pathogenic CYP27A1 variants. Patients harboring a pathogenic variant showed significantly higher median cholestanol concentrations than non-carriers (3.7 vs. 2.3 μg/mL, p ＜0.001). A single pathogenic CYP27A1 variant was associated with an increase in serum cholestanol of 2.3 μg/mL (95% confidence interval: 1.4-3.2 μg/mL, p ＜0.001) and an Achilles tendon thickness of 0.4 mm (95% confidence interval: 0.1-0.7 mm, p = 0.02). Furthermore, carriers exhibited significantly greater Achilles tendon thickness than non-carriers (9.6 vs. 8.9 mm, p ＜0.001). We identified a substantial number of patients with pathogenic CYP27A1 variants among the patients with monogenic FH, which influenced their Achilles tendon thickness and serum cholestanol levels.
2026-05-09 | Lipid dysregulation as a central contributor of neurodegenerative diseases: Emerging therapeutic targets and strategies.
Lipid homeostasis is essential for preserving the structural integrity and functional capacity of the brain. A diverse array of lipids, including cholesterol, phospholipids, and sphingolipids, has been identified as playing pivotal roles. Dysregulation of lipid metabolism is increasingly recognized as a central pathological mechanism in neurodegenerative diseases, including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, Huntington's Disease, and Cerebrotendinous Xanthomatosis, though much of the existing evidence comes from associative studies, and causal relationships still need to be further validated through interventional studies. Here we systematically review the metabolic pathways and regulatory networks of major brain lipids, with a focus on delineating disease-specific alterations and summarizing emerging therapeutic strategies targeting lipid metabolism. These strategies encompass the modulation of cholesterol homeostasis, sphingolipid metabolism, phospholipid signaling, and fatty acid oxidation, alongside approaches that enhance lipid clearance and neural repair. Preclinical advances and ongoing clinical trials underscore the translational potential of lipid-targeted interventions. In conclusion, we emphasize the potential of lipid metabolism as a promising avenue for developing novel treatments, offering insights to guide future research and therapeutic innovation in neurodegeneration.
2026-01-13 | Juvenile-Onset Cerebrotendinous Xanthomatosis with Novel Compound Heterozygous CYP27A1 Mutations: Case Series and Literature Review.
Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive neurometabolic disorder characterized by multisystem involvement and marked clinical heterogeneity. Pathogenic variants in the CYP27A1 gene, encoding mitochondrial sterol-27-hydroxylase, disrupt bile acid synthesis, leading to pathological accumulation of cholestanol in neural tissues, tendons, and other organs. This study aimed to characterize two novel CTX cases with compound heterozygous variants in the CYP27A1 gene through integrated clinical-genetic analysis, and to systematically synthesize current evidence on CTX through a literature review. Molecular investigations employed a tiered sequencing strategy: whole-exome sequencing (WES) for variant discovery, third-generation sequencing for variant screening of WES-negative samples, and Sanger sequencing for familial segregation validation. We present two Chinese juvenile-onset CTX cases demonstrating characteristic multisystem involvement, including both extraneural manifestations and progressive neurological deterioration. Genetic investigations revealed three CYP27A1 variants: the previously unreported c.845 - 46_881del83, the splicing variant c.1477-2 A > C, and a novel nonsense variant c.487 C > T in exon 3. Both probands exhibited compound heterozygosity, sharing the c.845 - 46_881del83 variant alongside distinct second alleles (c.1477-2 A > C and c.487 C > T, respectively). Then, a literature review synthesizes current evidence on clinical manifestations, genotypic patterns, and therapeutic approaches in CTX. This study expands the CYP27A1 mutational spectrum with two novel variants and validates the diagnostic utility of long-read sequencing (LRS) in resolving complex autosomal recessive cerebellar ataxia (ARCA) cases. The synthesis of clinical and literature evidence underscores the need for early recognition of CTX's heterogeneous presentations.
2025-12-31 | Cerebrotendinous Xanthomatosis Unmasked by Cutaneous Xanthogranuloma: A Clinicopathological Case Report: A Rare Case Report
Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disorder caused by defective bile acid synthesis, leading to accumulation of cholestanol in multiple tissues. We report a case of a 29-year-old male with intellectual disability and long-standing seizures who presented with multiple painless tendon and cutaneous swellings. Histopathological examination of an excised cutaneous nodule revealed sheets of foamy macrophages, Touton-type giant cells, and cholesterol clefts, suggestive of xanthogranulomatous pathology. Subsequent clinicoradiological correlation demonstrated diffuse cerebral and cerebellar atrophy with chronic white-matter ischemic changes on MRI, along with a history of juvenile cataract, delayed milestones, neonatal jaundice, and chronic diarrhea. Routine lipid profile was within normal limits, excluding common hyperlipidemic xanthomatoses. Based on the characteristic clinical, radiological, and histopathological features, a diagnosis of cerebrotendinous xanthomatosis was established. This case highlights the critical role of pathological vigilance and multidisciplinary evaluation in diagnosing this rare yet treatable metabolic disorder.
2025-12-24 | Cholestanol promotes tau pathology in a mouse model of tauopathy.
Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disease characterized by the accumulation of cholestanol. CTX patients often suffer from cognitive impairment. We found that serum cholestanol levels are higher in Alzheimer's disease (AD) patients than in control subjects. Thus, we tested whether cholestanol regulates the pathogenesis of AD. Cholestanol promotes tau fragmentation and hyperphosphorylation by activating asparagine endopeptidase (AEP). AEP knockdown alleviates cholestanol-induced tau fragmentation and phosphorylation. Feeding cholestanol to tau P301S mice aggravates tau pathology and behavioral defects, while knockout of AEP ameliorates cholestanol-induced tau pathology and behavioral defects in tau P301S mice. These results highlight the role of AEP-mediated tau cleavage in cholestanol-induced tau pathology and cognitive decline. The data also identify the potential therapeutic target of AEP in AD, particularly in AD patients with elevated serum cholestanol levels.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
3 orphan drug designations for Cerebrotendinous xanthomatosis, including 1 approved therapy.
3 orphan drug designations for Cerebrotendinous xanthomatosis, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
chenodiol [Ctexli] | small molecules | FDA | Approved | Mirum Pharmaceuticals, Inc. |
chenodeoxycholic acid | small molecules | FDA | Leadiant Biosciences, Inc. | |
Chenodeoxycholic acid | small molecules | FDA | Dr. Falk Pharma GmbH |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.