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.1477-2A > C, and a novel nonsense variant c.487C > T in exon 3. Both probands exhibited compound heterozygosity, sharing the c.845 - 46_881del83 variant alongside distinct second alleles (c.1477-2A > C and c.487C > 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.

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.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00018-025-05978-1.

Purpose: The Amsterdam UMC pharmacy has been compounding chenodeoxycholic acid (CDCA) capsules for Dutch cerebrotendinous xanthomatosis patients since 2018. However, limited data are available on the pharmacokinetics and bioequivalence of therapeutic CDCA formulations. Methods: An open-label, single-center, randomized, two-period, two-sequence, cross-over study was conducted in 12 healthy volunteers to compare the pharmacokinetic profile of pharmacy-compounded CDCA capsules to that of the authorized CDCA product. Results: Both formulations reached peak plasma concentrations (tmax) at approximately 1 h post-dose. The mean AUC(0–6h) values were 262.4 (±69.4) µmol∙min/L for the compounded capsules and 248.0 (±78.1) µmol∙min/L for the authorized capsules, with a 90% confidence interval (CI) for the AUC(0–6h) ratio of 0.89–1.30, exceeding the accepted bioequivalence range of 0.80–1.25. The mean Cmax for the compounded formulation (2.96 ± 0.91 µmol/L) was significantly lower than that of the comparator product (4.42 ± 1.36 µmol/L; p = 0.0040), with a 90% CI for the Cmax ratio of 0.57–0.80, also outside the bioequivalence range. Conclusions: Overall, the pharmacy-compounded and authorized capsules demonstrate a comparable AUC(0–6h) and tmax. Bioequivalence could not be demonstrated, primarily due to high variation, a significantly lower Cmax, and an AUC(0–6h) ratio outside the accepted limits. These findings indicate that the compounded formulation results in reduced systemic peak exposure compared with the authorized product. However, given the high variation, a larger sample size would be needed to further investigate bioequivalence in future studies.

FDA approves ctexli for cerebrotendinous xanthomatosis: a long-awaited breakthrough

IntroductionHereditary Spastic Paraplegias (HSP) are a group of genetic disorders leading to the degeneration of long motor and sensory tracts in a progressive course. Clinician-reported outcomes (ClinROs) are the most commonly used endpoints for monitoring these diseases, but they have low sensitivity to detect progression. Therefore, identifying new monitoring biomarkers with higher sensitivity to change is crucial. Our objective was to compare the progression of Somatosensory Evoked Potential (SSEP) latencies over time with ClinROs in HSP.MethodsA longitudinal study was conducted on 22 individuals with a genetic diagnosis (13 SPG4, 3 SPG5, 3 SPG7, 2 SPG10, and 1 cerebrotendinous xanthomatosis), with two evaluations over a 4-year interval of upper limb (UL) and lower limb (LL) SSEPs and the Spastic Paraplegia Rating Scale (SPRS) total score and motor items only (mSPRS).ResultsIn the follow-up time analysis, progression after 4 years was observed only for SPRS and mSPRS, with an annual progression of 1.12 points and 1.02 points, respectively. No statistically significant progression was observed for SSEPs. Disease progression modeled according to disease duration showed worsening in all outcomes. For each additional year of disease, the SPRS worsened by 0.834 points (95% CI 0.62 to 1.04, p < 0.001), mSPRS by 0.758 points (95% CI 0.55 to 0.96, p < 0.001), SSEP-UL latency by 0.164 ms (95% CI 0.03 to 0.3, p < 0.001), and SSEP-LL latency by 1.343 ms (95% CI 0.74 to 1.93, p < 0.001). Results for the SPG4 subgroup were similar to those for the overall HSP group.ConclusionThe neurophysiological progression of sensory long tract dysfunction is even slower than the progression of motor findings measured by COAs in HSP. The low sensitivity to change of SSEPs identified suggests that they should not be used as primary endpoints in future clinical trials for disease-modifying drugs.

Hereditary Spastic Paraplegias (HSP) are a group of genetic disorders leading to the degeneration of long motor and sensory tracts in a progressive course. Clinician-reported outcomes (ClinROs) are the most commonly used endpoints for monitoring these diseases, but they have low sensitivity to detect progression. Therefore, identifying new monitoring biomarkers with higher sensitivity to change is crucial. Our objective was to compare the progression of Somatosensory Evoked Potential (SSEP) latencies over time with ClinROs in HSP. A longitudinal study was conducted on 22 individuals with a genetic diagnosis (13 SPG4, 3 SPG5, 3 SPG7, 2 SPG10, and 1 cerebrotendinous xanthomatosis), with two evaluations over a 4-year interval of upper limb (UL) and lower limb (LL) SSEPs and the Spastic Paraplegia Rating Scale (SPRS) total score and motor items only (mSPRS). In the follow-up time analysis, progression after 4 years was observed only for SPRS and mSPRS, with an annual progression of 1.12 points and 1.02 points, respectively. No statistically significant progression was observed for SSEPs. Disease progression modeled according to disease duration showed worsening in all outcomes. For each additional year of disease, the SPRS worsened by 0.834 points (95% CI 0.62 to 1.04, p < 0.001), mSPRS by 0.758 points (95% CI 0.55 to 0.96, p < 0.001), SSEP-UL latency by 0.164 ms (95% CI 0.03 to 0.3, p < 0.001), and SSEP-LL latency by 1.343 ms (95% CI 0.74 to 1.93, p < 0.001). Results for the SPG4 subgroup were similar to those for the overall HSP group. The neurophysiological progression of sensory long tract dysfunction is even slower than the progression of motor findings measured by COAs in HSP. The low sensitivity to change of SSEPs identified suggests that they should not be used as primary endpoints in future clinical trials for disease-modifying drugs.

Cerebrotendinous Xanthomatosis: Unraveling Prominent Neuropsychiatric Symptoms and Mild Cognitive Impairment With Subsequent Clinical Improvement.

Abstract We describe a patient who presented with spastic ataxic syndrome without cataract or xanthomas, and a diagnosis of cerebrotendinous xanthomatosis was made based on imaging and genetic tests. Magnetic resonance imaging of the brain revealed hyperintensities and mineralization of the bilateral dentate nuclei, and clinical exome sequencing showed a homozygous 5’ splice site variation in intron 6 of the CYP27A1 gene (chr2:219678911; G &gt; A). The patient was treated with simvastatin 10 mg/day and ursodeoxycholic acid 300 mg/day. There was objective improvement in the clinical as well as the electrophysiological parameters following treatment. The report highlights the importance of a high index of suspicion, early diagnosis and timely treatment of this potentially reversible condition.

Many inborn errors of metabolism affect pathways involved in the synthesis of a metabolite that has an important biochemical or physiological function, and adverse effects of the disorder can be attributed to the lack of this metabolite. Thus, there is the opportunity for treatment by 'product replacement'. One of the disorders in the pathways for the synthesis of bile acids from cholesterol, 3β-hydroxy-Δ5-C27-steroid dehydrogenase deficiency, causes cholestatic liver disease in infancy that can be treated very effectively with chenodeoxycholic acid (CDCA) and/or cholic acid (CA). There are several other enzyme deficiencies that can cause liver disease in infancy that improve with CDCA or CA or both (alongside a reduction of abnormal bile acids or alcohols); however, individuals with the same gene variant(s) may remain asymptomatic or have transient liver dysfunction that resolves spontaneously. In some disorders, the more usual presentation is with neurological disease later in childhood or in adolescence or adult life, for example, cerebrotendinous xanthomatosis (CTX), α-methylacyl-CoA racemase deficiency, and oxysterol 7α-hydroxylase deficiency. Treatment with CDCA has been dramatically effective in the neurological disease of CTX. In the disorders of peroxisome biogenesis, liver disease is a part of the clinical picture although neurological symptoms tend to be predominant. Treatment with CDCA and CA (or CA alone) leads to a reduction in the levels of C27 bile acids. Some trials suggest this treatment leads to significant improvement in clinical status and liver function tests; others do not. Defects in individual peroxisomal enzymes and transporters vary in their clinical presentations. Treatment of acyl-CoA oxidase 2 deficiency with ursodeoxycholic acid is discussed.

Cerebrotendinous xanthomatosis (CTX) is a rare treatable bile acid disorder caused by homozygous or compound heterozygous variants in CYP27A, a gene that encodes the mitochondrial enzyme sterol 27-hydroxylase (CYP27A1). CYP27A1 facilitates the production of both cholic acid (CA) and chenodeoxycholic acid (CDCA). Deficiencies in CYP27A1 limit the production of both CA and CDCA, leading to multisystemic cholestanol deposition in membranes, including those of neurons, smooth muscle cells, tendons, and the eye. Because of increased concentrations of cholestanol, a byproduct of cholesterol metabolism, in the brain, cognitive decline develops as a hallmark of CTX. First-line treatment approaches for CTX include off-label prescribed CDCA to reduce serum cholestanol levels. Despite its effectiveness, the success of CDCA administration relies on early diagnosis and low disability scores at the time of initiation. Administration when neurological symptoms arise late in the diagnostic process can lead to worse outcomes, including higher mortality. US Food & Drug Administration-approved CA represents an alternative treatment for CTX. CA reduced cholestanol levels in CSF and blood while also reducing bile acid synthesis and excretion of bile alcohols in the urine. Importantly, outcomes with CA therapy are indistinguishable from those mediated by CDCA therapy and are associated with significantly fewer adverse effects. CA is used as an alternative therapy in patients who cannot tolerate CDCA due to its negative effects. Data from studies on CA strongly support the improvement of liver function, which is likely to be at the crux of secondary pathology, including neurological dysfunction. Because no consensus has been published on the treatment of CTX, Stelten et al (Orphanet J Rare Dis 16:353, 2021) a need exists for a direct comparison of the two approaches.

Efficacy, safety, and tolerability of chenodeoxycholic acid (CDCA) in adult patients with cerebrotendinous xanthomatosis (RESTORE): A randomized withdrawal, double-blind, placebo-controlled, crossover phase-3 study.

Cerebrotendinous xanthomatosis (CTX) is a treatable neurometabolic disorder. Chenodeoxycholic acid (CDCA) is the first-line treatment and can potentially halt disease progression if initiated before neurologic symptoms appear. This nationwide, multicenter study evaluates the long-term effects of treatment in 86 genetically confirmed patients with CTX receiving CDCA for ≥ 6 months, focusing on neurologic and extraneurologic outcomes, prognostic factors, and biochemical response. Clinical and biochemical parameters were recorded at baseline and follow-up, and neurological outcomes were assessed using neurological disability scores. Our results indicate a critical age of 28 years for the start of treatment. Patients diagnosed before 28 years showed 100% neurological stabilization or improvement, whereas patients diagnosed later had a higher rate of disease progression (p < 0.05). CDCA effectively stabilized or improved pyramidal and cerebellar symptoms, although myoclonus and parkinsonism remained less responsive. Psychiatric symptoms showed a lower treatment response, with psychosis being the most refractory finding. CDCA resulted in a strong and sustained reduction in cholestanol levels, although biochemical response did not always correlate with clinical improvement. Longer diagnostic delay and presence of anxiety and pyramidal/cerebellar symptoms were associated with poorer outcomes. Notably, a cholestatic child, for whom liver transplantation had initially been considered, recovered completely under CDCA therapy. Our results show that early diagnosis and initiation of CDCA therapy significantly improve neurological outcomes in CTX. However, even in late-diagnosed patients, treatment continues to be beneficial, demonstrating that it is never too late to start therapy. Biochemical response does not always predict clinical improvement; multidisciplinary follow-up is essential.

A Case of Cerebrotendinous Xanthomatosis - Clinical Implications of Delayed Diagnosis

Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive lipid storage disorder caused by mutations in the CYP27A1 gene, leading to sterol 27-hydroxylase deficiency and cholestanol accumulation. Ctexli’s features range from infantile diarrhea to adult-onset neurodegeneration. Early diagnosis and treatment with chenodeoxycholic acid (CDCA) can significantly improve outcomes. Recently, the FDA approved Ctexli (chenodiol), a synthetic form of CDCA, as the first standardized treatment for CTX. Clinical trials demonstrated its efficacy in reducing plasma cholestanol and urinary bile alcohols. Ctexli’s approval represents a significant advancement, enabling more consistent therapy and highlighting the importance of early intervention in managing CTX.

ObjectiveThis study aims to analyze the clinical and genetic characteristics of cerebrotendinous xanthomatosis (CTX) in a Chinese family.MethodsClinical data, including medical history, neurologic and auxiliary examinations, imaging studies, and genetic profiles were collected from a Chinese CTX family at Taiyuan City Central Hospital. The proband underwent whole exome sequencing, which was confirmed via Sanger sequencing in two affected and five unaffected family members.ResultsTwo patients in the pedigree exhibited compound heterozygous missense variants in the CYP27A1 gene: c.379C > T, (pathogenic variants) and c.397 T > C, (a variant of uncertain clinical significance), both located in exon 2. A literature review revealed that c.1263 + 1G > A and C.379C > T are the most common variants in genetically diagnosed Chinese CTX patients, with exon 2 of the CYP27A1 gene.ConclusionThe compound heterozygous variants c.379C > T (p. Arg127Trp) and c.397 T > C (p. Trp133Arg) in the CYP27A1 gene are likely the cause of CTX in this pedigree. This finding expands our understanding of the genetic and clinical spectrum of CTX and provides significant insights for its diagnosis.

Beyond the cataract: Comprehensive ophthalmologic and retinal imaging analysis in cerebrotendinous xanthomatosis.

Cerebrotendinous xanthomatosis (CTX) is a rare neurometabolic disorder characterized by diverse neurological and extra-neurological manifestations. In children, chronic diarrhea, neonatal cholestasis, and cataracts are characteristics and often precede neurological symptoms, while adults typically present with cognitive decline and gait disturbances. This variability contributes to frequent misdiagnosis and delays in diagnosis, leading to significant neurological deterioration. To explore the clinical and genetic diversity of CTX cases in the Gulf Cooperation Council (GCC) region, comparing the phenotypic differences between children and adults. The retrospective, multicenter, descriptive study included 16 clinically and genetically confirmed CTX cases. Data collected encompassed clinical presentations, diagnostic delays, biochemical markers such as cholestanol levels, neuroimaging findings, and genetic mutations in the CYP27A1 gene. Participants were categorized into pediatric and adult groups. Common clinical features included cognitive decline (75%), learning difficulties (69%), diarrhea (56%), cataracts (56%), gait issues (50%), and behavioral changes (44%). Notably, childhood diarrhea was strongly associated with earlier diagnosis, with approximately 90% of such cases identified in this age group. Misdiagnosis occurred in 3 patients, with an average diagnostic delay of 6.1 years-shorter for children (2.7 years) compared to adults (11.6 years). Tendon xanthoma was observed in only 1 patient. Genetic testing identified 7 CYP27A1 variants, highlighting genetic heterogeneity in this population. This study emphasizes the need for increased physician awareness, particularly regarding pediatric presentations, to reduce diagnostic delays and prevent irreversible neurological damage. These findings support integration of targeted genetic testing and early screening programs to improve patient outcomes.

Genetically confirmed atypical cerebrotendinous xanthomatosis with large xanthomas and normal plasma cholestanol in an octogenarian

Diagnosing Cerebrotendinous Xanthomatosis in a Middle-Aged Woman With Cervical Dystonia.

Hereditary ataxia (HA) is a heterogeneous group of complex neurological disorders, which represent a diagnostic challenge due to their diverse phenotypes and genetic etiologies. Next-generation sequencing (NGS) has revolutionized the field of neurogenetics, improving the identification of ataxia-associated genes. Notwithstanding, repeat expansions analysis remains a cornerstone in the diagnostic workflow of these diseases. Here we describe the molecular characterization of a consecutive single-center series of 70 patients with genetically uncharacterized HA. Patients’ samples were analyzed for known HA-associated repeat expansions as first tier and negative ones were analyzed by whole exome sequencing (WES) as second tier. Overall, we identified pathogenic/likely pathogenic variants in 40% (n = 28/70) and variants of unknown significance (VUS) in 20% (n = 14/70) of cases. In particular, 10 patients (14.3%, n = 10/70) presented pathogenic repeat expansions while 18 cases (30%, n = 18/60) harbored at least a single nucleotide variant (SNV) or a copy number variant (CNV) in HA or HSP-related genes. WES allowed assessing complex neurological diseases (i.e., leukodystrophies, cerebrotendinous xanthomatosis and atypical xeroderma pigmentosum), which are not usually referred as pure genetic ataxias. Our data suggests that the combined use of repeat expansion analysis and WES, coupled to detailed clinical phenotyping, is able to detect the molecular alteration underpinning ataxia in almost 50% cases, regardless of the hereditary pattern. Indeed, NGS-based tests are fundamental to acknowledge novel HA-associated genes useful to explain the remaining wide fraction of negative tests. Nowadays, this gap is problematic since these patients could not benefit from an etiological diagnosis of their disease that allows prognostic trajectories and prenatal/preimplantation diagnosis.