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.

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.

A Late-onset and Relatively Rapidly Progressive Case of Pure Spinal Form Cerebrotendinous Xanthomatosis with a Novel Mutation in the CYP27A1 Gene.

A 61-year-old Japanese man with the pure spinal form of cerebrotendinous xanthomatosis developed dysesthesia of the lower limbs and gait disturbance at 57 years of age. At 61 years old, he was unable to walk without support. A neurological examination showed spasticity and sensory disturbance in the lower limbs. Spinal MRI showed long hyperintense lesions involving the lateral and posterior funiculus in the cervical and thoracic cord on T2-weighted images. His serum cholestanol level was markedly elevated. A CYP27A1 gene analysis identified two missense variants, p.R474W, and a novel p.R262C variant. Combination therapy with chenodeoxycholic acid and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase decreased his serum cholestanol level.

A novel etiologic factor of highly elevated cholestanol levels: progressive familial intrahepatic cholestasis.

Background Progressive familial intrahepatic cholestasis type 3 (PFIC3) is an uncommon cholestatic liver disease caused by mutations in the ATP binding cassette subfamily B member 4 (ABCB4) gene. Although PFIC3 is frequently identified in childhood, ABCB4 disease-causing alleles have been described in adults affected by intrahepatic cholestasis of pregnancy, hormone-induced cholestasis, low-phospholipid-associated cholelithiasis syndrome or juvenile cholelithiasis, cholangiocarcinoma and in sporadic forms of primary biliary cirrhosis. Cholestanol is a biomarker which is elevated especially in cerebrotendinous xanthomatosis and rarely in primary biliary cirrhosis (PBC) and Niemann Pick type C. Case presentation Here we report a Turkish patient with compound heterozygous mutations in the ABCB4 gene, who has hepatosplenomegaly, low level of high-density lipoprotein, cholestasis and high level of cholestanol. Conclusion This is the first PFIC3 case with a high cholestanol level described in the literature. There are very few diseases linked to increased cholestanol levels, two of which are CTX and PBC. From this case, we can conclude that a high cholestanol level might be another indicator of PFIC type 3.

Plasma Metabolomic Changes in Mice With Time-restricted Feeding-attenuated Spontaneous Metastasis of Lewis Lung Carcinoma.

BACKGROUND/AIM: Time-restricted feeding (TRF) during the dark phase of the day restores metabolic homeostasis in mice. MATERIALS AND METHODS: We performed untargeted metabolomic analysis on plasma from mice subjected to TRF that attenuates high-fat diet-enhanced spontaneous metastasis of Lewis lung carcinoma (LLC). RESULTS: Twenty-four of 152 identified metabolites differed among the four dietary groups (non-LLC-bearing mice fed the AIN93G diet and LLC-bearing mice fed the AIN93G, the high-fat diet (HFD), or TRF of the HFD). Component 1 of sparse partial least squares-discriminant analysis showed a clear separation between non-LLC-bearing and LLC-bearing mice. Major metabolites responsible for the changes were elevations in α-tocopherol, docosahexaenoic acid, cholesterol, dihydrocholestrol, isoleucine, leucine, and phenylalanine and decreases in lactic acid and pyruvic acid in LLC-bearing mice particularly those fed the HFD. Time-restricted feeding shifted the metabolic profile of LLC-bearing mice towards that of non-LLC-bearing controls. CONCLUSION: Time-restricted feeding improves metabolic profile of LLC-bearing mice.

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

OBJECTIVE: To evaluate the safety and effectiveness of chenodeoxycholic acid (CDCA) treatment in patients with cerebrotendinous xanthomatosis (CTX). METHODS: Two 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. RESULTS: A 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]). CONCLUSIONS: The outcomes of these retrospective cohort studies indicate that CDCA is effective in the long-term treatment of CTX, with an acceptable safety profile.

[Cerebrotendinous xanthomatosis. Report of one case]. / Xantomatosis cerebrotendinosa sin xantomas tendíneos. Caso clínico.

Cerebrotendinous xanthomatosis (CTX) is an uncommon autosomal recessive disease caused by deficiency of 27-sterol-hydroxylase that results in an accumulation of cholestanol in the central nervous system, eyes, tendons, and blood vessels. We report a 22-year-old woman with a history of cataract surgery at the age of 14, cholecystectomy due to cholelithiasis at the age of 17 and chronic diarrhea, who presented with a six months period of gait instability and frequent falls. Physical examination revealed a bilateral pyramidal and cerebellar syndrome, with no visible tendon xanthomas. Cerebral magnetic resonance imaging showed an increase of the signal intensity on the T2-weighted images in periventricular cerebral white matter, dentate nuclei and spinal cord. With a high suspicion of CXT, a genetic study was conducted identifying a pathogenic variant in the CYP27A1 gene. There is considerable variation in clinical characteristics and age of onset of this disease, including absence of tendon xanthomas, delaying the diagnosis. Early recognition and chronic chenodeoxycholic acid therapy can improve outcome and quality of life.

Chenodeoxycholic Acid: An Update on Its Therapeutic Applications.

Chenodeoxycholic acid (CDCA), 3α,7α-dihydroxy-5ß-cholan-24-oic acid, is a primary bile acid generated in the liver from cholesterol. In liver cells CDCA is conjugated with glycine or taurine to form two bile salts, Glyco-CDCA and Tauro-CDCA, before being released into the bile ducts. In the intestine, CDCA is further metabolized to generate a 7ß epimer, i.e., the ursodeoxycholic acid (UDCA), or dehydroxylate to generate lithocolic acid (LCA). In humans, CDCA is the physiological ligand for the bile acid sensor farnesoid X receptor (FXR), while LCA is a potent agonist for a G protein-coupled receptor, known as GPBAR1 (TGR5). Along with UDCA, CDCA has been clinically used for the dissolution of gallbladder stones at doses ranging from 375 to 750 mg/day, with a success rate of 8 to 18%. Because the efficacy of CDCA was significantly lower than that of UDCA and 18-30% of patients developed significant side effects, the most frequent being diarrhea and a reversible increase in aminotransferases plasma levels, this application has lost its therapeutic relevance. Additionally, the combination of CDCA with UDCA, generally at doses of 5-10 mg/kg each, has failed to provide significant advantages over UDCA alone. In 2017, CDCA has been approved as an orphan indication for the treatment of patients with cerebrotendinous xanthomatosis (CTX), a rare autosomal recessive disorder caused by mutations of sterol 27-hydroxylase (CYP27A1) gene. Since CYP27A1 is essential for cholesterol breakdown, CTX patients develop abnormal lipid storage with increased plasma and tissue levels of cholestanol and very low/absent production of CDCA. CDCA is a potent inhibitor of CYP27A1, and early initiation of CDCA therapy, at doses up to 750 mg/day, is considered the standard medical therapy for CTX resulting in decreased plasma levels of cholestanol and stabilization of neurologic symptoms. Studies in CTX patients have also shown that CDCA might suppress the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in the liver. Furthermore, CDCA promotes the release of glucagon-like peptide-1 (GLP-1) in diabetic patients, likely by activating GPBAR1.