Rare genetic cerebrotendinous xanthomatosis (CTX) cases without cholestanol elevation but with prominent cholesterol-rich tendon xanthomas.

Cerebrotendinous xanthomatosis (CTX) is a rare inherited metabolic disease attributed to the mutation of the gene CYP27A1, resulting in sterol 27-hydroxylase deficiency characterized by deposition of cholestanol and cholesterol in several tissues, like the central nervous system and tendons. Furthermore, cataracts, gallstones, diarrhea and premature atherosclerosis have been reported. Nonetheless, clinical development is extremely heterogeneous in CTX. We report here two cases of CTX genetic alteration in the absence of cholestanol elevation in plasma and tendons but with prominent xanthomas. We propose that CTX may not be characteized by increased plasma cholestanol concentration due to alteration in the sterol 27-hydroxylase gene, but is a more complex pathology where there is significant genetic heterogeneity caused by various CYP27A1 mutations.

Clinical, biochemical, and molecular insights into Cerebrotendinous Xanthomatosis: A nationwide study of 100 Turkish individuals.

OBJECTIVE: Cerebrotendinous xanthomatosis (CTX) is an inherited metabolic disorder characterized by progressive neurologic and extraneurologic findings. The aim of this retrospective, descriptive study was to explore the time of presentation and diagnosis, and to expand the phenotype and genotype of CTX, based on a nationwide and comprehensive series of patients in Turkey. METHODS: The demographic, clinical, biochemical and genotypic characteristics of the CTX patients were reviewed. Data on molecular analysis, age of onset and diagnosis, diagnostic delay, neurologic and extraneurologic symptomatology, results of plasma cholestanol levels, brain magnetic resonance imaging and electromyography at the time of diagnosis were reviewed. RESULTS: 100 confirmed CTX patients from 72 families were included. The mean age at diagnosis was 28.16 ± 14.28 years, and diagnostic delay was 18.39 ± 13.71 years. 36 patients were diagnosed in childhood. Frequency of intention tremor (p = 0.069), peripheral neuropathy (p = 0.234) and psychiatric manifestations (p = 0.396) did not differ between two groups, demonstrating the high rate in pediatric patients. Three adult patients showed a milder phenotype without neurologic involvement. Seven patients had normal plasma cholestanol levels despite neurological impairment. Sequencing of the CYP27A1 gene revealed 25 different variants, with a novel c.671_672del variant not previously described in literature. CONCLUSION: Based on the observations of this Turkish CTX cohort, it is emphasized that the true prevalence of CTX is probably underestimated and that it has a wide spectrum of clinical phenotypes even without neurological impairment. In children, abnormal cerebellar findings, peripheral neuropathy and psychiatric findings associated with intellectual disability have been suggested as warning signs to avoid diagnostic delay. In cases of clinical suspicion, molecular analysis is recommended despite normal plasma cholestanol levels, as severe neurologic involvement may occur in CTX patients without elevated cholestanol levels.

Genetically and clinically confirmed atypical cerebrotendinous xanthomatosis with normal cholestanol and marked elevations of bile acid precursors and bile alcohols.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid disorder. Affected patients often remain undiagnosed until the age of 20-30 years, when they have already developed significant neurologic disease that may not be reversible. An elevated plasma cholestanol concentration has been accepted as a diagnostic criterion for CTX for decades. OBJECTIVE: Full biochemical characterization was performed for three genetically and clinically confirmed atypical CTX cases with normal plasma cholestanol levels. METHODS: Clinical assessment and genetic/biochemical testing for patients with CTX was performed by their physician providing routine standard of care. RESULTS: We report three new atypical CTX cases with large extensor tendon xanthomas but normal plasma cholestanol levels. All three cases had marked elevations of bile acid precursors and bile alcohols in plasma and urine that decreased on treatment with chenodeoxycholic acid. We also review eight published cases of atypical CTX with normal/near normal circulating cholestanol levels. CONCLUSION: The atypical biochemical presentation of these cases provides a diagnostic challenge for CTX, a disorder for which cholestanol has been believed to be a sensitive biomarker. These cases demonstrate measurements of plasma cholestanol alone are insufficient to exclude a diagnosis of CTX. The data presented is consistent with the concept that bile acid precursors and bile alcohols are sensitive biomarkers for atypical CTX with normal cholestanol, and that such testing is indicated, along with CYP27A1 gene analyses, in patients presenting with significant tendon and/or tuberous xanthomas and/or neurologic disease in early adulthood despite normal or near normal cholesterol and cholestanol levels.

Two previously undescribed cholestanol saponins from the rhizomes of Paris fargesii var. petiolata.

Two previously undescribed cholestanol saponins, parpetiosides F - G (1-2), and six known analogs (3-8) were isolated from the rhizomes of Paris fargesii var. petiolata. Their structures were elucidated by extensive spectroscopic data analysis and chemical methods. Compound 1 was a rare 6/6/6/5/5 fused-rings cholestanol saponin with disaccharide moiety linked at C-26 of aglycone which was hardly seen in genus Paris. All of these compounds were discovered in this plant for the first time. In addition, the cytotoxicities of saponins (1-8) against three human cancer cell lines (U87, HepG2 and SGC-7901) were evaluated by CCK-8 method, and saponins 5-8 displayed certain cytotoxicities. The strong interactions between saponins 5-8 and SCUBE3, an oncogene for glioma cells, were displayed by molecular docking.

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

BACKGROUND: Cerebrotendinous 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. METHODS: We 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. RESULTS: The 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. CONCLUSION: We 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.

Urolithin A production drives the effects of pomegranate on the gut microbial metabolism of bile acids and cholesterol in mild dyslipidaemic overweight and obese individuals.

The metabolism of (poly)phenols and some host metabolites, including bile acids (BAs) and cholesterol, varies among individuals depending on their gut microbiota. The gut microbial metabolism of ellagitannins (ETs) and ellagic acid (EA) produces urolithins (Uros), yielding three metabotypes with quantitative and qualitative differences based on dissimilar Uro-producing profiles (UM-A, UM-B, and UM-0, i.e., non-producers). Previous animal studies demonstrated that polyphenols impact BAs and cholesterol microbial metabolism, but data on their effects in humans and data regarding the inter-individual variability of these metabolic conversions are scant. We evaluated whether UMs, as distinctive functional gut-microbiome signatures, could determine the potential effect of a pomegranate extract (PE) rich in ET-EA on the metabolism of BAs and cholesterol in mild dyslipidaemic overweight-obese individuals, with possible consequences on host-lipid homeostasis and gut health. At the baseline, UM-B presented the highest levels of faecal total and secondary BAs and coprostanol, suggesting that the lipid absorption capacity and gut cytotoxic risk could be augmented in UM-B. PE intake significantly reduced faecal coprostanol and BA production, especially secondary BAs, and modulated the gut microbiome, reducing the gut cytotoxic risk, especially in UM-B individuals. The lowering of faecal microbial coprostanol and BAs and some BA-metabolising bacteria was quantitatively correlated with Uro concentrations, mainly faecal Uro-A. This suggests that PE consumption could exert cardiovascular and gut protection through Uro-A production as a direct driver of the effects and indirectly by reducing the Coriobacteriaceae family and BA pool, known factors involved in the gut absorption of lipids.

A case of cerebrotendinous xanthomatosis with massive xanthomas but without a considerable increase in serum cholestanol levels.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by mutations in the sterol 27-hydroxylase gene (CYP27A1). Due to the deficiency of 27-hydroxylase, the synthesis of bile acids from cholesterol is impaired and excessive cholestanol accumulates in various tissues, such as the central nervous system, tendons, and lenses. Patients with CTX typically manifest intellectual decline, pyramidal tract symptoms, cerebellar symptoms, tendon xanthomas, juvenile cataracts, neonatal jaundice, chronic diarrhea, osteoporosis, and premature cardiovascular disease. Here, we report the atypical case of a 35-year-old female with CTX having massive xanthomas but without a considerable increase in serum cholestanol levels (3.9 µg/mL). In the differential diagnosis of xanthoma, CTX should not be ruled out even if the serum levels of cholestanol are not high, and genetic testing is necessary to make the appropriate diagnosis.

Prevalence of cerebrotendinous xanthomatosis among patients diagnosed with early-onset idiopathic bilateral cataracts: final analysis.

Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive bile acid synthesis disorder caused by pathologic variants in CYP27A1, a gene involved in bile acid synthesis. Impaired function in this gene leads to accumulation of plasma cholestanol (PC) in various tissues, often in early childhood, resulting in such clinical signs as infantile diarrhea, early-onset bilateral cataracts, and neurological deterioration. The current study aimed to identify cases of CTX in a population of patients with a greater CTX prevalence than the general population, to facilitate early diagnosis. Patients diagnosed with early-onset, apparently idiopathic, bilateral cataracts between the ages of 2 and 21 years were enrolled. Genetic testing of patients with elevated PC and urinary bile alcohol (UBA) levels was used to confirm CTX diagnosis and determine CTX prevalence. Of 426 patients who completed the study, 26 met genetic testing criteria (PC ≥ 0.4 mg/dL and positive UBA test), and 4 were confirmed to have CTX. Prevalence was found to be 0.9% in enrolled patients, and 15.4% in patients who met the criteria for genetic testing.

Understanding common population markers for SARS-CoV-2 RNA normalization in wastewater - A review.

Wastewater monitoring and epidemiology have seen renewed interest during the recent COVID-19 pandemic. As a result, there is an increasing need to normalize wastewater-derived viral loads in local populations. Chemical tracers, both exogenous and endogenous compounds, have proven to be more stable and reliable for normalization than biological indicators. However, differing instrumentation and extraction methods can make it difficult to compare results. This review examines current extraction and quantification methods for ten common population indicators: creatinine, coprostanol, nicotine, cotinine, sucralose, acesulfame, androstenedione 5-hydroindoleacetic acid (5-HIAA), caffeine, and 1,7-dimethyluric acid. Some wastewater parameters such as ammonia, total nitrogen, total phosphorus, and daily flowrate were also evaluated. The analytical methods included direct injection, dilute and shoot, liquid/liquid, and solid phase extraction (SPE). Creatine, acesulfame, nicotine, 5-HIAA and androstenedione have been analysed by direct injection into LC-MS; however, most authors prefer to include SPE steps to avoid matrix effects. Both LC-MS and GC-MS have been successfully used to quantify coprostanol in wastewater, and the other selected indicators have been quantified successfully with LC-MS. Acidification to stabilize the sample before freezing to maintain the integrity of samples has been reported to be beneficial. However, there are arguments both for and against working at acidic pHs. Wastewater parameters mentioned earlier are quick and easy to quantify, but the data does not always represent the human population effectively. A preference for population indicators originating solely from humans is apparent. This review summarises methods employed for chemical indicators in wastewater, provides a basis for choosing an appropriate extraction and analysis method, and highlights the utility of accurate chemical tracer data for wastewater-based epidemiology.

A Rare Case of Cerebrotendinous Xanthomatosis Associated With a Mutation on COG8 Gene.

Cerebrotendinous xanthomatosis (CTX) is a rare hereditary disease described by a mutation in the CYP27A1 gene, which encodes the sterol 27-hydroxylase enzyme involved in the synthesis of bile acid. Accumulation of cholesterol and its metabolite, cholestanol, in multiple body organs causes the symptoms of this disease. In addition, a mutation in the COG8 gene, which encodes a subunit of conserved oligomeric Golgi (COG) complex, causes another rare disorder attributed to type IIh of congenital disorder of glycosylation (CDG). We described a rare case of CTX disorder associated with a mutation on COG8 gene, which presented by unusual symptoms.

Prospective cholestanol screening of cerebrotendinous xanthomatosis among patients with juvenile-onset unexplained bilateral cataracts.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder related to CYP27A1 biallelic mutations, leading to decreased synthesis of bile acids and increased cholestanol. Juvenile bilateral cataracts are one of the most common findings in the disease, frequently occurring before the onset of neurological manifestations. While early treatment with chenodeoxycholic acid can prevent the onset of neurological impairment, poor awareness of CTX accounts for a markedly delayed diagnosis. The objective of this study was to evaluate the utility of plasma cholestanol analysis at the moment of cataract diagnosis and before the onset of neurological impairment in CTX. METHODS: Multicenter prospective cohort study of patients with juvenile-onset unexplained bilateral cataracts recruited from seven French ophthalmology departments. Plasma cholestanol analysis was performed at diagnosis from January 2018 to January 2020. CYP27A1 genetic testing was performed at the ophthalmologist's discretion. Cholestanol levels were compared with those of a similar population of patients without cataracts (control cohort). RESULTS: 30 patients were finally recruited, with a mean age at cataract diagnosis of 7.1 years (± 4.8 SD, range 1-19 years). One patient had a very high cholestanol level (68 µmol/L, reference < 10) and carried two pathogenic heterozygous mutations in CYP27A1 confirming CTX. This patient was a 19-year-old female, reporting chronic diarrhea only in childhood, and diagnosed with bilateral posterior cataracts with cortical fleck-like opacities. Therefore, the incidence of CTX in our cohort of patients was 3.3%. Five further patients (5/29; 17.2%) had moderate elevations of cholestanol level (between 10.3 and 16.5 µmol/L), compared to 12/286 (4.2%) in the control cohort (p = 0.014) after adjustment for age. CONCLUSION: Our study argue for the relevance of plasma cholestanol CTX screening in all patients with juvenile-onset unexplained cataracts, even without other CTX identified manifestations. Whether moderate elevations of plasma cholestanol unrelated to CTX may be a risk factor for bilateral cataracts occurrence needs further examination.

Serum Phytosterols Are Not Associated with Inflammatory Markers in Two Cross-Sectional, Swiss Population-Based Studies (The CoLaus|PsyCoLaus Study).

BACKGROUND: The association between inflammation and dietary sterols remains poorly assessed at the population level. AIMS: To assess the possible association between serum levels of various phytosterols (PS) and inflammatory markers. METHODS: Serum levels of six PS (campesterol, campestanol, stigmasterol, sitosterol, sitostanol, brassicasterol), four cholesterol synthesis markers (lathosterol, lanosterol, desmosterol, dihydroxylanosterol) and one cholesterol absorption marker (cholestanol) were measured together with levels of CRP, IL-6 and TNF-α in two cross-sectional surveys of a population-based, prospective study. RESULTS: CRP levels were negatively associated with levels of cholestanol and of sterols of plant origin, although some associations were not statistically significant. CRP levels were positively associated with cholesterol synthesis markers in the first but not in the second follow-up. IL-6 levels were negatively associated with cholestanol in both follow-ups. No associations between IL-6 levels and PS were found in the first follow-up, while significant negative associations with campesterol, sitosterol, brassicasterol, sitostanol and campesterol:TC ratio were found in the second follow-up. TNF-α levels were negatively associated with cholestanol in both follow-ups. These associations did not withstand adjusting for sex, age, BMI and statin administration. CONCLUSIONS: In a population-based study, PS serum levels were not significantly associated with inflammatory markers.

Tracking the historical urban and rural sources of fecal pollution in a South American tropical semi-arid region using sterols and endocrine-disrupting chemicals.

Sterols and endocrine-disrupting chemicals were analyzed in two dated sediment cores collected in the Jaguaribe river to determine the recent decades' influence of urbanization and agropastoral activities on the inputs of fecal pollution in a semi-arid region of Brazil. Stigmasterol and sitosterol were the most abundant of the 6 sterols examined in both cores, indicating an important contribution of organic matter from mangrove forests to the study region. Coprostanol presented a continuous increase in concentrations from the 1930s to the 2000s in one core, however, showing higher concentrations (>100 ng g-1) in the upper layers of both cores. The sterols diagnostic ratios indicated fecal pollution through both cores, especially from the 1940s to 1970s. The coprostanol levels followed the variations in population growth in the state of Ceará. Estriol and estrone were the most abundant estrogenic hormones found in both cores. These compounds are probably related to the intense livestock activities in the Ceará state, especially after the 1970s. The baseline levels of fecal sterols and estrogen hormones found in this study possibly represent a previous unimpacted scenario and may be used for future evaluations of fecal pollution from urbanization and livestock activities.

A case of cerebrotendinous xanthomatosis with brain and spinal involvement without tendon xanthomas: Identification of a novel mutation of the CYP27A1 gene.

Cerebrotendinous xanthomatosis (CTX) is a rare inherited disorder of the alternative pathway of bile acid biosynthesis, due to mutation(s) of the gene CYP27A1, leading to sterol 27-hydroxylase deficiency. The latter results in a systematic deposition of cholestanol and cholesterol to the central nervous system and tendons, premature cataract, as well as the manifestation of systematic symptoms, such as chronic diarrhea, osteoporosis, and premature atherosclerosis. Due to its marked clinical heterogeneity, prompt diagnosis of this disorder is challenging. We present a case of a 38-year-old male with gait difficulty, a progressive deterioration in ambulation, several episodes of vertigo and episodic diarrhea. Clinical history revealed neonatal jaundice, juvenile bilateral cataracts, borderline intellectual capacity, hypothyroidism, testicular cancer. Magnetic resonance imaging demonstrated increased T2-weighted signal in internal capsules, midbrain, cerebellum, and spinal cord. Electrodiagnostic study showed mixed polyneuropathy. Genetic analysis revealed a novel, biallelic, most likely pathogenic mutation, in gene CYP2A1 (c.1410_1411del). Plasma sterol profiling confirmed the diagnosis of CTX. Our patient was treated with chenodeoxycholic acid and one year later, he shows a progressive improvement of gait, normalization of plasma sterol biochemistry and electrophysiological parameters. This case highlights the importance of maintaining a high index of suspicion as the key to an early diagnosis of CTX, taking into consideration its clinical variability and, if promptly identified, the good response to treatment.

Cerebrotendinous xanthomatosis with radiological abnormalities of the chest.

A 55-year-old man with mental retardation and calcaneal tendon thickening was referred for a suspected genetic disease. His serum cholestanol was elevated and genetic analysis of his blood cells for CYP27A1 revealed a homozygous missense mutation. We diagnosed him with cerebrotendinous xanthomatosis (CTX). Chest radiography revealed diffuse micronodular and reticular opacities. Histological findings obtained from the transbronchial lung biopsy revealed foamy macrophages and multinucleate giant cells with marked lipid crystal clefts. Although there are few reports of pulmonary lesions in CTX, we concluded from the radiological and histopathological findings that the pulmonary lesions were indeed caused by the CTX. The patient was treated with chenodeoxycholic acid. His neurological findings and calcaneal tendon thickening were unchanged; however, his serum cholestanol and radiological abnormalities of the chest decreased.

Expert opinion on diagnosing, treating and managing patients with cerebrotendinous xanthomatosis (CTX): a modified Delphi study.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare, chronic, progressive, neurodegenerative disorder requiring life-long care. Patients with CTX often experience a diagnostic delay. Although early diagnosis and treatment initiation can improve symptoms and prognosis, a standardised approach to diagnosis, treatment and management of patients is not yet established. AIM: To assess expert opinion on best care practices for patients with CTX using a modified Delphi method. METHODS: A multidisciplinary group of healthcare professionals with expertise in CTX responded to a 3-round online questionnaire (n = 10 in Rounds 1 and 2; n = 9 in Round 3), containing questions relating to the diagnosis, treatment, monitoring, multidisciplinary care and prognosis of patients with CTX. Determination of consensus achievement was based on a pre-defined statistical threshold of ≥ 70% Delphi panellists selecting 1-2 (disagreement) or 5-6 (agreement) for 6-point Likert scale questions, or ≥ 70% Delphi panellists choosing the same option for ranking and proportion questions. RESULTS: Of the Round 1 (n = 22), Round 2 (n = 32) and Round 3 (n = 26) questions for which consensus was assessed, 59.1%, 21.9% and 3.8% reached consensus, respectively. Consensus agreement that genetic analyses and/or determination of serum cholestanol levels should be used to diagnose CTX, and dried bloodspot testing should facilitate detection in newborns, was reached. Age at diagnosis and early treatment initiation (at birth, where possible) were considered to have the biggest impact on treatment outcomes. All panellists agreed that chenodeoxycholic acid (CDCA) is a lifetime replacement therapy which, if initiated early, can considerably improve prognosis as it may be capable of reversing the pathophysiological process in CTX. No consensus was reached on the value of cholic acid therapy alone. Monitoring patients through testing plasma cholestanol levels and neurologic examination was recommended, although further research regarding monitoring treatment and progression of the disease is required. Neurologists and paediatricians/metabolic specialists were highlighted as key clinicians that should be included in the multidisciplinary team involved in patients' care. CONCLUSIONS: The results of this study provide a basis for standardisation of care and highlight key areas where further research is needed to inform best practices for the diagnosis, treatment and management of patients with CTX.

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.

Update on cerebrotendinous xanthomatosis.

PURPOSE OF REVIEW: Cerebrotendinous xanthomatosis (CTX) is a rare genetic lipid storage disorder with highly pleomorphic clinical phenotype. Complications of this disease can be devastating and may include severe cognitive impairment and dementia in later stages. Disease progression can be prevented or stabilized by bile acid replacement therapy, although a subset of patients with advanced disease continue to deteriorate despite therapy. RECENT FINDINGS: Delayed diagnosis of CTX continues to impede effective treatment. A clinical diagnostic algorithm for CTX was developed that can decrease the age of diagnosis of CTX. The strategy of screening children with bilateral juvenile cataracts for CTX also improved diagnosis, as this group had a 500-fold higher-rate of CTX than the general population. Improved diagnosis of CTX is critical, as patients treated early in the course of the disease have significantly better outcomes compared with those treated later. More sensitive and specific biochemical testing for CTX has been developed that is potentially more informative than blood cholestanol to assess treatment efficacy and medication compliance in CTX. SUMMARY: Because we are recognizing more severe presentations of CTX in infants and children, and delayed diagnosis and treatment worsens the prognosis, CTX is an excellent candidate disorder for newborn screening using recently reported methods for newborn dried bloodspot analysis.

A novel synergistic anticancer effect of fungal cholestanol glucoside and paclitaxel: Apoptosis induced by an intrinsic pathway through ROS generation in cervical cancer cell line (HeLa).

In the search for efficient therapeutics with economically viable for cancer treatment, combination therapy has developed as a keystone in the pursuit of novel approaches for drug discovery. In this regard, we confirmed the presence of cholestanol glucoside (CG) in Lasiodiplodia theobromae culture filtrate and its production was estimated to be 20.01 mg/l. The purified fungal CG was obtained with a molecular mass of 550.18 m/z. The combination of CG and paclitaxel (PTX) was found to have potent cytotoxicity against HeLa cells. We revealed that the synergistic effect of CG and PTX induced apoptosis through the formation of nuclear fragments, DNA fragmentation and sub G1 cell cycle arrest. Further, it was proven that apoptosis took place by loss of the mitochondrial membrane potential (MMP) through reactive oxygen species (ROS) production and caspase 3/7 activity. Moreover, the data suggests that the synergistic effect of CG and PTX played a role in a mitochondrial intrinsic pathway through the apoptotic gene expression of Bax, caspase-9 and caspase-3. In addition, the down-regulation of Bcl-2 strongly described the induced apoptosis through an intrinsic pathway using the Western blot analysis. The conclusion of this study is that a combination of CG and PTX has synergistic apoptotic effects in HeLa cells, which provides a possible therapeutic strategy for cancer therapy in the future.