Cerebrotendinous Xanthomatosis Patients Research Articles

Cerebrotendinous Xanthomatosis patients with late diagnosed in single orthopedic clinic: two novel variants in the CYP27A1 gene

BackgroundCerebrotendinous Xanthomatosis (CTX) is a rare autosomal recessive lipid storage disorder caused by loss of function variants in the CYP27A1 gene which encodes sterol 27-hydroxylase, on chromosome 2q35. Although the symptoms begin commonly in infancy, CTX diagnosis is often delayed. The aim of this study is to review the orthopedic findings of the disease by providing an overview of the clinical features of the disease. It is to raise awareness of this condition for which early diagnosis and treatment are important.MethodsWe retrospectively evaluated the clinical, laboratory, radiological, and genetic findings of eight patients from four families who were admitted to our Orthopedics and Traumatology Department between 2017 and 2022 due to bilateral Achilles tendon xanthomas, were found to have high cholestanol and CYP27A1 gene mutations.ResultsThe mean age of patients was 37, and five of them were male. The mean age at the onset of symptoms was 9.25 years. The mean age of initial diagnosis was 33.75 years. Between symptom onset and clinical diagnosis, an average delay of 24.5 years was observed. All patients had bilateral Achilles tendon xanthoma. Notably, a novel variant (c.670_671delAA) in CYP27A1 gene was identified in three patients who also presented with peripheral neuropathy and bilateral pes cavus. One patient had osteoporosis and four patients had osteopenia. Five patients had a history of bilateral cataracts. Furthermore, three of the patients had early-onset chronic diarrhea and three of the patients had ataxia. Two of the patients had epilepsy and seven of the patients had behavior-personality disorder. All patients had low intelligence, but none of them had cardiac disease.ConclusionWe present the diagnostic process and clinical features which the largest CTX case series ever reported from single orthopedic clinic. We suggest that patients with normal cholesterol levels presenting with xanthoma being genetically analyzed by testing at their serum cholestanol level, and that all siblings of patients diagnosed with CTX be examined.

Characterization of Postprandial Bile Acid Profiles and Glucose Metabolism in Cerebrotendinous Xanthomatosis.

Cerebrotendinous xanthomatosis (CTX) is a rare inherited disease characterized by sterol 27-hydroxylase (CYP27A1) deficiency and, thus, a lack of bile acid synthesis with a marked accumulation of 7α-hydroxylated bile acid precursors. In addition to their renowned lipid-emulgating role, bile acids have been shown to stimulate secretion of the glucose-lowering and satiety-promoting gut hormone glucagon-like peptide 1 (GLP-1). In this paper, we examined postprandial bile acid, glucose, insulin, GLP-1 and fibroblast growth factor 19 (FGF19) plasma profiles in patients with CTX and matched healthy controls. Seven patients and seven age, gender and body mass index matched controls were included and subjected to a 4 h mixed meal test with regular blood sampling. CTX patients withdrew from chenodeoxycholic acid (CDCA) and statin therapy three weeks prior to the test. Postprandial levels of total bile acids were significantly lower in CTX patients and consisted of residual CDCA with low amounts of ursodeoxycholic acid (UDCA). The postprandial plasma glucose peak concentration occurred later in CTX patients compared to controls, and patients' insulin levels remained elevated for a longer time. Postprandial GLP-1 levels were slightly higher in CTX subjects whereas postprandial FGF19 levels were lower in CTX subjects. This novel characterization of CTX patients reveals very low circulating bile acid levels and FGF19 levels, aberrant postprandial glucose and insulin profiles, and elevated postprandial GLP-1 responses.

Product development and quality of pharmacy compounded chenodeoxycholic acid capsules for Dutch cerebrotendinous xanthomatosis patients.

Introduction: In 2017 the drug chenodeoxycholic acid (CDCA) became unavailable to Dutch patients with the rare inborn error of metabolism cerebrotendinous xanthomatosis (CTX). This was a direct result of a steep price increase after CDCA was authorized in the EU as an orphan drug. As a result, Dutch health insurance companies were unable to reimburse this drug and the availability of CDCA to patients with CTX was directly at risk creating an unmet medical need. CTX is characterized by juvenile cataract, tendon xanthomas, infantile-onset diarrhea, psychomotor retardation and progressive cerebellar ataxia. Treatment with CDCA, when initiated before neurological symptoms are present, can prevent the onset of neurological complications. Methods: To assure continuation of patient treatment with a high quality product, the hospital pharmacy of the Amsterdam UMC developed CDCA capsules as a pharmacy preparation. A simple and robust formulation was developed for capsules in a broad dose range of 35-250mg, ensuring that both pediatric and adult patients can receive an exact dose tailored to their specific needs. Capsules are prepared manually on a small scale for the individual patient. To assure the quality of the product, product validation and stability studies were performed. Results: The results show that the product complies with all specifications based on the requirements of the European Pharmacopoeia. The capsules contain the declared amount of CDCA, no degradation product or other (microbiological) impurities are formed during the production process and the capsules show a quick dissolution profile. Stability studies indicate that it is a stable product and no impurities increase or arise over time. These results show that these pharmacy preparations are of high quality and comply to Good Manufacturing Practice (GMP) requirements. Discussion: Through our research, we have demonstrated that pharmacy compounding can be a viable alternative in situations where immediate access to essential medication is crucial or when certain drugs are temporarily inaccessible. The purpose of this paper is to offer comprehensive guidance to other pharmacies to improve the availability of currently inaccessible drugs through the practice of pharmacy compounding, thereby facilitating improved patient care.

Pathophysiology and Treatment of Lipid Abnormalities in Cerebrotendinous Xanthomatosis: An Integrative Review.

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disorder caused by pathogenic variants in CYP27A1, leading to a deficiency in sterol 27-hydroxylase. This defect results in the accumulation of cholestanol and bile alcohols in various tissues, including the brain, tendons and peripheral nerves. We conducted this review to evaluate lipid profile abnormalities in patients with CTX. A search was conducted in PubMed, Embase and the Virtual Health Library in January 2023 to evaluate studies reporting the lipid profiles of CTX patients, including the levels of cholestanol, cholesterol and other lipids. Elevated levels of cholestanol were consistently observed. Most patients presented normal or low serum cholesterol levels. A decrease in chenodeoxycholic acid (CDCA) leads to increased synthesis of cholesterol metabolites, such as bile alcohols 23S-pentol and 25-tetrol 3-glucuronide, which may serve as surrogate follow-up markers in patients with CTX. Lipid abnormalities in CTX have clinical implications. Cholestanol deposition in tissues contributes to clinical manifestations, including neurological symptoms and tendon xanthomas. Dyslipidemia and abnormal cholesterol metabolism may also contribute to the increased risk of atherosclerosis and cardiovascular complications observed in some CTX patients.

Chenodeoxycholic acid rescues axonal degeneration in induced pluripotent stem cell-derived neurons from spastic paraplegia type 5 and cerebrotendinous xanthomatosis patients

BackgroundBiallelic mutations in CYP27A1 and CYP7B1, two critical genes regulating cholesterol and bile acid metabolism, cause cerebrotendinous xanthomatosis (CTX) and hereditary spastic paraplegia type 5 (SPG5), respectively. These rare diseases are characterized by progressive degeneration of corticospinal motor neuron axons, yet the underlying pathogenic mechanisms and strategies to mitigate axonal degeneration remain elusive.MethodsTo generate induced pluripotent stem cell (iPSC)-based models for CTX and SPG5, we reprogrammed patient skin fibroblasts into iPSCs by transducing fibroblast cells with episomal vectors containing pluripotency factors. These patient-specific iPSCs, as well as control iPSCs, were differentiated into cortical projection neurons (PNs) and examined for biochemical alterations and disease-related phenotypes.ResultsCTX and SPG5 patient iPSC-derived cortical PNs recapitulated several disease-specific biochemical changes and axonal defects of both diseases. Notably, the bile acid chenodeoxycholic acid (CDCA) effectively mitigated the biochemical alterations and rescued axonal degeneration in patient iPSC-derived neurons. To further examine underlying disease mechanisms, we developed CYP7B1 knockout human embryonic stem cell (hESC) lines using CRISPR-cas9-mediated gene editing and, following differentiation, examined hESC-derived cortical PNs. Knockout of CYP7B1 resulted in similar axonal vesiculation and degeneration in human cortical PN axons, confirming a cause-effect relationship between gene deficiency and axonal degeneration. Interestingly, CYP7B1 deficiency led to impaired neurofilament expression and organization as well as axonal degeneration, which could be rescued with CDCA, establishing a new disease mechanism and therapeutic target to mitigate axonal degeneration.ConclusionsOur data demonstrate disease-specific lipid disturbances and axonopathy mechanisms in human pluripotent stem cell-based neuronal models of CTX and SPG5 and identify CDCA, an established treatment of CTX, as a potential pharmacotherapy for SPG5. We propose this novel treatment strategy to rescue axonal degeneration in SPG5, a currently incurable condition.

Features of the metabolic syndrome and subclinical atherosclerosis in patients with cerebrotendinous xanthomatosis: An augmented risk for premature cardiovascular disease.

Background: Cerebrotendinous xanthomatosis (CTX) is a rare lipid storage disease, caused by deficiency of sterol-27-hydroxylase. Xanthomatous lesions in numerous tissues, and an elevation of cholestanol levels, characterize the disease. Its natural course is progressive neurologic deterioration, leading to premature death. Chronic treatment with oral chenodeoxycholic acid (CDCA) reduces cholestanol levels. Occurrence of premature atherosclerosis has been described in CTX in an unknown mechanism. Aim: The aim of the current work was to evaluate the potential metabolic abnormalities and preclinical vascular changes in Israeli CTX patients. Methods: Ten subjects with CTX were studied. Features of the metabolic syndrome were evaluated, and carotid intima media thickness (cIMT) was measured in the common carotid arteries. Results: All patients were diagnosed with CTX, and all received treatment with CDCA, which resulted in normalization of their plasma cholestanol levels. At the conclusion of the follow up, risk factors for CVD and features of MS were present in all the patients and in three patients, cIMT was higher compared to control subjects. Conclusion: Cardiovascular risk factors and premature vascular changes exist in young CTX patients and proper assessment should be implemented with preventive measures to reduce the risk of atherosclerotic cardiovascular disease in CTX patients.

Patents vs patients 1-0: The case of chenodeoxycholic acid.

Profit-driven games with the availability and prices of chenodeoxycholic acid led to the discontinuation of proper treatment for this cerebrotendinous xanthomatosis patient with disastrous consequences to his health.

Prevalence of cerebrotendinous xanthomatosis in cases with idiopathic bilateral juvenile cataract in ophthalmology clinics in Turkey

To determine the prevalence of cerebrotendinous xanthomatosis (CTX) in patients with idiopathic bilateral juvenile cataract in Turkey. In this multicenter, epidemiologic observational study, patients with idiopathic bilateral juvenile cataract (aged ≥1year at study entry) were identified from the records of 31 ophthalmology clinics. The Mignarri suspicion index determined in all potential CTX patients; blood samples were collected, and genetic testing for CYP27A1 gene mutation was performed. Cholestanol levels of the patients were measured, and those with a level of ≥3.75μg/mL (threshold value) underwent genetic testing for mutations in the CYP27A1 gene. CTX was diagnosed in 7 of 452 patients (1.55%) with bilateral juvenile cataract. There was no significant difference between patients with a Mignarri score of <100 (n=8) and those with a score of ≥100 (n=19) with respect to cholestanol levels and genetic test results. Genetic testing was undertaken in 27 patients based on elevated cholestanol levels. Of these 27, 7 (26%) had CYP27A1 gene mutations. Of these 7 patients with genetically confirmed CTX, 5 (71%) were in the group with higher Mignarri score (≥100). CTX is a treatable condition, and early detection is crucial for avoiding irreversible neurological manifestations. Screening using the Mignarri suspicion index and cholestanol blood levels can be helpful in identifying suspected cases of CTX.

Using fiber tractography and diffusion kurtosis imaging to evaluate neuroimaging changes in patients with cerebrotendinous xanthomatosis after stopping chenodeoxycholic acid treatment for three years

BackgroundThe aim of this study was to use tractography and diffusion kurtosis imaging (DKI) to evaluate cerebral white matter (WM) changes in patients with cerebrotendinous xanthomatosis (CTX) after stopping chenodeoxycholic acid (CDCA) treatment. MethodsTwo siblings with CTX aged 40 and 38 years, respectively, who had been diagnosed with CTX for 16 years were enrolled. They had received CDCA treatment from 2005 until 2015, after which CDCA was no longer available in Taiwan. Serial brain magnetic resonance imaging (MRI) studies were used to record brain changes, and a seres of neuropsychiatric tests were used to evaluate cognitive changes 3 years after stopping CDCA treatment. ResultsThe conventional MRI studies revealed progressive changes in dentate nuclei and surrounding cerebellar hemispheres, but no obvious changes in cerebral white matter (WM). Tractography captured in 2018 showed a general reduction in fiber density, especially involving frontal lobe fibers, compared to 2015. In addition, the DKI studies performed in 2018 showed a decreased axonal water fraction in diffuse WM structures and increased RadEAD in frontal WM. Comparisons of the neuropsychiatric test results between 2015 and 2018 showed a marked decline in executive function including design fluency, digit backward span and digit forward span, and this cognitive impairment highly suggested frontal lobe dysfunction. ConclusionsThis study may suggest that cerebral tractography and DKI study results can identify changes in cerebral WM in CTX patients shortly after stopping CDCA treatment, and that they may have a better correlation with the results of neuropsychiatric tests.

Gene supplementation of CYP27A1 in the liver restores bile acid metabolism in a mouse model of cerebrotendinous xanthomatosis

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disease caused by mutations in the CYP27A1 gene, encoding the sterol 27-hydroxylase. Disruption of the bile acid biosynthesis pathway and accumulation of toxic precursors such as cholestanol cause chronic diarrhea, bilateral juvenile cataracts, tissue deposition of cholestanol and cholesterol (xanthomas), and progressive motor/neuropsychiatric alterations. We have evaluated the therapeutic potential of adeno-associated virus (AAV) vectors expressing CYP27A1 in a CTX mouse model. We found that a vector equipped with a strong liver-specific promoter (albumin enhancer fused with the α1 anti-trypsin promoter) is well tolerated and shows therapeutic effect at relatively low doses (1.5 × 1012 viral genomes [vg]/kg), when less than 20% of hepatocytes overexpress the transgene. This vector restored bile acid metabolism and normalized the concentration of most bile acids in plasma. By contrast, standard treatment (oral chenodeoxycholic acid [CDCA]), while reducing cholestanol, did not normalize bile acid composition in plasma and resulted in supra-physiological levels of CDCA and its derivatives. At the transcriptional level, only the vector was able to avoid the induction of xenobiotic-induced pathways in mouse liver. In conclusion, the overexpression of CYP27A1 in a fraction of hepatocytes using AAV vectors is well tolerated and provides full metabolic restoration in Cyp27a1−/− mice. These features make gene therapy a feasible option for the etiological treatment of CTX patients.

Patients with cerebrotendinous xanthomatosis diagnosed with diverse multisystem involvement.

Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease caused by deficiency of sterol 27-hydroxylase enzyme encoded by CYP27A1 gene. This multicenter, cross-sectional descriptive study aimed to document clinical characteristics of CTX patients of different ages, clinical presentations of early-diagnosed patients, and responses to short-term chenodeoxycholic acid (CDCA) treatment. Seven of 11 CTX patients were diagnosed in childhood. Three patients (27%) had neonatal cholestasis, seven (63%) patients had a history of frequent watery defecation started in infantile period, and eight (72.7%) patients had juvenile cataract. Four patients in the adult age group had pyramidal signs and parkinsonism symptoms. The mean Mignarri score at diagnosis was significantly lower in the pediatric patients (267.8 ± 51.4) than in the adult patients (450.0 ± 64.0, p = 0.001). No significant difference was determined between pediatric patients and adult patients regarding plasma cholestanol concentration at diagnosis (p = 0.482). The frequency of defecation decreased with treatment in six children, who had diarrhea at admission. Compared to pretreatment values, patients' body weight and standardized body mass index significantly increased at the 12th month of treatment. In conclusion, Mignarri scores are lower in the pediatric patients than in adult patients since the most determinative signs of the CTX disease are not apparent yet in the childhood. The disease is frequently overlooked in routine practice as the disease presents itself with different clinical combinations both in adults and in children. CTX is potentially a treatable disease; thereby, enhanced awareness is critically important for early diagnosis particularly in children.

Cholestasis as a dominating symptom of patients with CYP27A1 mutations: An analysis of 17 Chinese infants

BackgroundCYP27A1 is the disease-causing gene of cerebrotendinous xanthomatosis (CTX). As a treatable lipid storage disease, early treatment can improve the prognosis. However, CTX patients reported in the literature are mostly adult patients; the phenotype spectrum of CTX in the infantile population remains elusive. ObjectiveWe aimed to investigate the phenotype spectrum of infants who carried pathogenic or likely pathogenic variants in the CYP27A1 gene and were suspected of having CTX. MethodsFrom June 2014 to May 2020, infants with pathogenic or likely pathogenic variants in CYP27A1 gene were enrolled, who underwent next-generation sequencing or Sanger sequencing in Children's Hospital of Fudan University. Patient characteristics, clinical treatments and outcomes were extracted from electronic medical records. ResultsA total of 17 patients with an average onset age of 8 (1–42) days were found. The average diagnosis age was ten months. Cholestasis was the dominant symptom of these infants. Thirteen variants were detected, of which c.379C > T was a hotspot variant (26.5% alleles, 9/34). Cholestatic CTX is usually underestimated, but it could be severe or even fatal in infancy. For outcomes, 5 suffered from liver failure (36%, 5/14), 1 still showed cholestasis (7%, 1/14), 7 were asymptomatic (50%, 7/14), and 1 presented seizure and developmental delay in later childhood (7%, 1/14). ConclusionBased on this infantile cohort, we concluded that it is necessary to consider the possibility of CTX caused by CYP27A1 gene variants for infants with cholestasis.

Cerebrotendinous xanthomatosis with peripheral neuropathy: a clinical and neurophysiological study in Chinese population.

BackgroundCerebrotendinous xanthomatosis (CTX) is an inborn disorder of bile acid metabolism caused by deficiency of sterol 27-hydroxylase (CYP27A1) gene. CTX-related peripheral neuropathy has rarely been discussed in Chinese population. Here, we reported 6 CTX cases and performed a literature review focused on CTX with neuropathy to summarize its clinical and neurophysiological features.MethodsAll clinical data of 6 CTX cases were collected, and 21 reported Chinese CTX patients (including this study) were reviewed and summarized.ResultsClinical manifestations of 6 CTX cases showed great heterogeneity. Cognitive decline, spastic paraplegia, cerebellar ataxia and advanced bulbar palsy were common neurological disorders, often accompanied by non-neurological signs like xanthomas, cataract, diarrhea and pes cavus. Dentate nuclei hyperintensity with or without hyposignal is a valuable MRI hallmark. Pooling our patients and literature review together, peripheral neuropathy was predominant sensorimotor demyelinating type in Chinese population, with an evident length dependent pattern and increased vulnerability in motor nerves. Demyelinating and axonal degeneration tend to exist in severe neuropathy. Three novel mutations including c.1055C>A; c.432T>G; c.472T>G were identified in CYP27A1 and predicted to be pathogenic. Oral CDCA therapy could ameliorate some of the existing symptoms and provide clinical stability, but it could not cease disease progression completely.ConclusionsOur study broadens the phenotype and mutation spectrum of CTX. Patients with cognitive decline, spastic tetraparesis, cerebellar ataxia and bulbar palsy, should be highly suspicious of CTX even no xanthomas disclosed. Peripheral neuropathy was predominant sensorimotor demyelinating type in Chinese population, with mixed axonal and demyelinating type in severe cases. Three novel likely pathogenic mutations including c.1055C>A; c.432T>G; c.472T>G were identified in CYP27A1.

Cerebrotendinous xanthomatosis-associated diarrhea and response to chenodeoxycholic acid treatment.

BackgroundIn patients with cerebrotendinous xanthomatosis (CTX), chronic diarrhea is one of the earliest and main symptoms of the disease. In the current study, we evaluated the characteristics of the diarrhea and its response to chenodeoxycholic acid (CDCA) therapy in a cohort of Dutch CTX patients.MethodsWe performed a retrospective review of medical records for 33 genetically confirmed CTX patients, and abstracted the characteristics of the diarrhea and the response to CDCA therapy (15 mg/kg/day up to 750 mg/day). The Bristol Stool Scale (BSS) was used for qualitative characterization of the stool.ResultsTwenty‐five patients had diarrhea documented at baseline (76%). Of these patients, 10 had diarrhea rated as 6 (fluffy pieces with ragged edges, a mushy stool), and 6 had diarrhea rated as 7 (watery, no solid pieces, entirely liquid) using the BSS. In 10 patients for whom data were recorded, the median stool frequency at baseline was 3 per day (range 2‐6 per day). The response rate with CDCA for diarrhea resolution was 100% based on at least one post‐baseline visit without diarrhea and 95% as assessed at the first post‐baseline visit. In 68% of cases resolution was complete and sustained as no episodes of diarrhea were documented for follow‐up periods as long as 25 years.ConclusionsChronic diarrhea persisting for years without spontaneous remission is a common feature of CTX at diagnosis. Chenodeoxycholic acid is an effective treatment for symptomatic relief of diarrhea in patients with CTX.

Multifocal, hypoechogenic nerve thickening in Cerebrotendinous Xanthomatosis

ObjectiveTo characterize peripheral nerve morphology in cerebrotendinous xanthomatosis (CTX) patients using high-resolution ultrasound (HRUS) in vivo. We hypothesized that nerve enlargements might be present in CTX as a result of accumulation of abnormal lipids with deposition also in peripheral nerves. MethodsFour CTX patients were examined using HRUS to assess morphological abnormalities of peripheral nerves as well as cervical nerve roots 5 and 6. ResultsHRUS revealed mild to moderate, hypoechogenic thickening of sensorimotor nerves (ulnar nerve in 1/4, tibial nerve in 3/4, median nerve 4/4 patients) as well as mild enlargement of pure sensory nerves (sural nerve in 2/3, superficial FN in 2/4 patients). The vagal nerve was moderately enlarged in one patient, cervical roots showed moderate enlargements of C5 in two patients, one of which also showing thickening of C6 as well as in another patient. UPSS score was slightly to moderately abnormal in all patients. The Homogeneity score was not increased suggesting regional to inhomogeneous nerve enlargement. ConclusionsHRUS shows multifocal, hypoechogenic nerve thickening of peripheral nerves and nerve roots in CTX. SignificanceHRUS might serve as a valuable, additive and non-invasive bedside tool to assess peripheral nerve morphology in future clinical studies on CTX patients.

Patients with Lately Diagnosed Cerebrotendinous Xanthomatosis

Objectives: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive inborn lipid storage disorder due to various pathogenic mutations in the CYP27A1 gene. Although the symptoms begin commonly in infancy, CTX diagnosis is often delayed. In this study, we report 7 Turkish CTX patients who had a delayed diagnosis despite early clinical signs and belonged to 6 unrelated families. Methods: We have retrospectively evaluated clinical, laboratory, imaging, and genetic findings of CTX patients, which were collected from 2 centers specialized in movement disorders: the Department of Neurology, Faculty of Medicine, Istanbul University, and the Department of Neurology, Faculty of Medicine, Mersin University. Results: All patients were diagnosed with CTX after neurological symptom development, and their mean age at diagnosis was 38.7 ± 9.6 years, despite a mean onset age of 12.4 ± 10.6 years. The mean follow-up period was 28 months (range: 3–60 months). The most common initial clinical abnormalities in our cohort were unexplained chronic diarrhea (42%), febrile convulsion (42%), juvenile cataract (85%), childhood depression and autism (14%), parkinsonism (14%), and intellectual disability (100%). The most prominent neurological findings were the pyramidal-cerebellar syndrome (85%) and extrapyramidal signs (42%). All patients were genetically confirmed. Serum cholestanol levels were elevated in all patients and decreased after chenodeoxycholic acid (CDCA) treatment in 6 patients. Conclusion: This cohort is the largest CTX case series in Turkey. All cases showed improvement in gastrointestinal symptoms as a response to CDCA treatment and stabilization on neurological symptoms, i.e., no further progression of neurological abnormalities were noted during this treatment. Therefore, early diagnosis and treatment is crucial in preventing clinical deterioration.

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.

Prevalence of oropharyngeal dysphagia in hereditary spastic paraplegias.

Hereditary spastic paraplegias (HSP) are a group of genetic diseases characterized by lower limb spasticity with or without additional neurological features. Swallowing dysfunction is poorly studied in HSP and its presence can lead to significant respiratory and nutritional complications. The aim of this study was to evaluate the frequency and clinical characteristics of dysphagia in different types of HSP. A two-center cross-sectional prevalence study was performed. Genetically confirmed HSP patients were evaluated using the Northwestern Dysphagia Patient Check Sheet and the Functional Oral Intake Scale. In addition, self-perception of dysphagia was assessed by the Eat Assessment Tool-10 and the Swallowing Disturbance Questionnaire. Thirty-six patients with spastic paraplegia type 4 (SPG4), five with SPG11, four with SPG5, four with cerebrotendinous xanthomatosis (CTX), three with SPG7, and two with SPG3A were evaluated. Mild to moderate oropharyngeal dysphagia was present in 3/5 (60%) of SPG11 and 2/4 (50%) of CTX patients. A single SPG4 (2%) and a single SPG7 (33%) patient had mild oropharyngeal dysphagia. All other evaluated patients presented with normal or functional swallowing. Clinically significant oropharyngeal dysphagia was only present in complicated forms of HSP Patients with SPG11 and CTX had the highest risks for dysphagia, suggesting that surveillance of swallowing function should be part of the management of patients with these disorders.

Clinical and molecular genetic features of cerebrotendinous xanthomatosis in Taiwan: Report of a novel CYP27A1 mutation and literature review

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disorder associated with mutations in the CYP27A1 gene, and the genetic features of CTX in Taiwanese have not been examined before. We report a new CTX family with a novel mutation in the CYP27A1 gene and analyze the clinical and molecular genetic features of CTX in Taiwan. The clinical and molecular genetic features of the two siblings from the new CTX family and the other 7 reported Taiwanese CTX patients were included for analysis. The clinical features of the enrolled CTX patients were recorded using the indicators that make up the suspicion index (SI). The age at CTX diagnosis of the two siblings in the new CTX family were in late 30s, and predominantly psychiatric features. Both siblings had compound heterozygous splicing mutations in the CYP27A1 gene, including one mutation in exon 2 (c.435G>T, cryptic splice site) and one mutation in intron 7 (c.1264A>G, canonical splice site). None of the CTX patients in Taiwan were diagnosed during childhood or adolescence, and the most common clinical features of the 9 Taiwanese CTX patients were tendinous xanthomas, followed by ataxia and/or spastic paraparesis, dentate nuclei signal alternation at magnetic resonance imaging, intellectual disability and/or psychiatric disturbance, and polyneuropathy. Mutations in the CYP27A1 gene in the Taiwanese population were most commonly observed in exon 2, followed by exon 8 and intron 7. Except for one CTX patient who had an SI score of 100, the SI scores ranged from 300 to 400 before the study of the CYP27A1 gene and diagnosis. We reported two Taiwanese CTX siblings who had compound heterozygous mutations in CYP27A1. Exons 2 and 8 and intron 7 are the hotspots for Taiwanese CTX mutations. The diagnosis of CTX in Taiwan is usually delayed and is probably under-recognized based on statistical estimations. Early identification and genetic diagnosis may be helpful to CTX patients because early treatment can reduce the accumulation of cholestanol and slow disease progression.

Are Cognitive Changes in Hereditary Spastic Paraplegias Restricted to Complicated Forms?

Background: Little is known about the cognitive profile of Hereditary Spastic Paraplegias (HSP), where most scientific attention has been given to motor features related to corticospinal tract degeneration.Objectives: We aimed to perform a broad characterization of the cognitive functions of patients with pure and complicated HSP as well as to determine the frequency of abnormal cognitive performances in the studied subtypes.Methods: A two-center cross-sectional case-control study was performed. All individuals underwent cognitive assessment through screening tests (Mini Mental State Examination—MEEM and Montreal Cognitive Assessment—MOCA) and tests to assess specific cognitive functions (Verbal fluency with phonological restriction—FAS; Verbal categorical fluency—FAS-cat and Rey's Verbal Auditory Learning Test -RAVLT).Results: Fifty four patients with genetically confirmed HSP diagnosis, 36 with spastic paraplegia type 4 (SPG4), 5 SPG11, 4 SPG5, 4 cerebrotendinous xanthomatosis (CTX), 3 SPG7 and 2 SPG3A, and 10 healthy, unrelated control subjects, with similar age, sex, and education participated in the study. SPG4 patients had worse performances in MOCA, FAS, FAS-cat, and RAVLT when compared to controls. Most SPG4 patients presented cognitive changes not compatible with dementia, performing poorly in memory, attention and executive functions. SPG5 patients scored lower in executive functions and memory, and SPG7 patients performed poorly on memory tasks. All evaluated cognitive functions were markedly altered in CTX and SPG11 patients.Conclusions: Cognitive abnormalities are frequent in HSP, being more severe in complicated forms. However, cognitive impairments of pure HSPs might impact patients' lives, decreasing families' socioeconomic status and contributing to the overall disease burden.