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Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disorder caused by mutations in the CYP27A1 gene, which encodes the mitochondrial enzyme sterol 27-hydroxylase. Decreased sterol 27-hydroxylase activity results in impaired bile acid synthesis, leading to reduced production of bile acids, especially chenodeoxycholic acid (CDCA), as well as elevated serum cholestanol and urine bile alcohols. The accumulation of cholestanol and cholesterol mainly in the brain, lenses, and tendons results in the characteristic clinical manifestations of CTX. Clinical presentation is characterized by systemic symptoms including neonatal jaundice or cholestasis, refractory diarrhea, juvenile cataracts, tendon xanthomas, osteoporosis, coronary heart disease, and a broad range of neuropsychiatric manifestations. The combinations of symptoms vary from patient to patient and the presenting symptoms, especially in the early disease phase, may be nonspecific, which leads to a substantial diagnostic delay or underdiagnosis. Replacement of CDCA has been approved as a first-line treatment for CTX, and can lead to biochemical and clinical improvements. However, the effect of CDCA treatment is limited once significant neuropsychiatric manifestations are established. The age at diagnosis and initiation of CDCA treatment correlate with the prognosis of patients with CTX. Therefore, early diagnosis and subsequent treatment initiation are essential.

There are several hundred single-gene disorders that we classify as inborn errors of metabolism. Inborn errors of metabolism are often rare and highly heterogeneous multisystem diseases with non-neurological and neurological manifestations, commonly with onset during childhood. Movement disorders are among the most common neurological problems in inborn errors of metabolism, but, in many cases, remain poorly defined. Although movement disorders are usually not the only and often not the presenting symptom, their recognition can facilitate a diagnosis. Movement disorders contribute substantially to the morbidity in inborn errors of metabolism and can have a significant impact on quality of life. Common metabolic movement disorders include the monoamine neurotransmitter disorders, disorders of amino and organic acid metabolism, metal storage disorders, lysosomal storage disorders, congenital disorders of autophagy, disorders of creatine metabolism, vitamin-responsive disorders, and disorders of energy metabolism. Importantly, disease-modifying therapies exist for a number of inborn errors of metabolism, and early recognition and treatment can prevent irreversible CNS damage and reduce morbidity and mortality. A phenomenology-based approach, based on the predominant movement disorder, can facilitate a differential diagnosis and can guide biochemical, molecular, and imaging testing. The complexity of metabolic movement disorders demands an interdisciplinary approach and close collaboration of pediatric neurologists, neurologists, geneticists, and experts in metabolism. In this review, we develop a general framework for a phenomenology-based approach to movement disorders in inborn errors of metabolism and discuss an approach to identifying the "top ten" of treatable inborn errors of metabolism that present with movement disorders-diagnoses that should never be missed. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Objective: To evaluate the effect of chenodeoxycholic acid treatment on disease progression in cerebrotendinous xanthomatosis (CTX)., Methods: In this retrospective cohort study, we report the clinical long-term follow-up characteristics of 56 Dutch patients with CTX. Age at diagnosis was correlated with clinical characteristics and with the course of modified Rankin Scale (mRS) and Expanded Disability Status Scale (EDSS) scores at follow-up., Results: Median follow-up time was 8 years (6 months-31.5 years). Patients diagnosed and treated before the age of 24 years had a significantly better outcome at follow-up. When considering only patients with a good treatment adherence (n = 43), neurologic symptoms, if present, disappeared in all patients who were diagnosed before the age of 24 and treated since. Furthermore, treatment prevented the development of new neurologic symptoms during follow-up. In contrast, 61% of the patients diagnosed and treated after the age of 24 showed deterioration of the neurologic symptoms, with parkinsonism as a treatment-resistant feature. There was an improvement or stabilization in favor of patients diagnosed and treated before the age of 24 compared to those treated after the age of 24: 100% vs 58% for mRS scores and 100% vs 50% for EDSS scores, respectively., Conclusions: Treatment start at an early age can reverse and even prevent the development of neurologic symptoms in CTX. This study emphasizes the importance of early diagnosis in CTX and provides a rationale to include CTX in newborn screening programs., (© 2018 American Academy of Neurology.)

Background: Cerebrotendinous xanthomatosis (CTX) is a rare disorder due to defective sterol 27-hydroxylase causing a lack of chenodeoxycholic acid (CDCA) production and high plasma cholestanol levels., Objectives: Our objective was to review the diagnosis and treatment results in 43 CTX cases., Methods: We conducted a careful review of the diagnosis, laboratory values, treatment, and clinical course in 43 CTX cases., Results: The mean age at diagnosis was 32 years; the average follow-up was 8 years. Cases had the following conditions: 53% chronic diarrhea, 74% cognitive impairment, 70% premature cataracts, 77% tendon xanthomas, 81% neurologic disease, and 7% premature cardiovascular disease. The mean serum cholesterol concentration was 190 mg/dL; the mean plasma cholestanol level was 32 mg/L (normal <5.0 mg/L), which decreased to 6.0 mg/L (-81%) with CDCA therapy generally given as 250 mg orally 3 times daily. Of those tested on treatment, 63% achieved cholestanol levels of <5.0 mg/L; 91% had normal liver enzyme levels; none had significant liver problems after dose adjustment. Treatment improved symptoms in 57% at follow-up, but 20% with advanced disease continued to deteriorate. In the United States, CDCA has been approved for gallstone dissolution, but not for CTX despite long-term efficacy and safety data., Conclusions: Health care providers seeing young patients with tendon xanthomas and relatively normal cholesterol levels, especially those with cataracts and learning problems, should consider the diagnosis of CTX so they can receive treatment. CDCA should receive regulatory approval to facilitate therapy for the prevention of the complications of the disease., (Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Cerebrotendinous xanthomatosis (CTX) is likely to be underdiagnosed and precise epidemiological characteristics of CTX are largely unknown as knowledge on the disorder is based mainly on case reports. We conducted a nationwide survey on CTX to elucidate the frequency, clinical picture, and molecular biological background of Japanese CTX patients. In this first Japanese nationwide survey on CTX, 2541 questionnaires were sent to clinical departments across Japan. A total of 1032 (40.6%) responses were returned completed for further analysis. Forty patients with CTX (50.0% male) were identified between September 2012 and August 2015. The mean age of onset was 24.5 ± 13.6 years, mean age at diagnosis was 41.0 ± 11.6 years, and corresponding mean duration of illness from onset to diagnosis was 16.5 ± 13.5 years. The most common initial symptom was tendon xanthoma, followed next by spastic paraplegia, cognitive dysfunction, cataract, ataxia, and epilepsy. The most predominant mutations in the CYP27A1 gene were c.1214G> A (p.R405Q, 31.6%), c.1421G> A (p.R474Q, 26.3%), and c.435G> T (p.G145=, 15.8%). Therapeutic interventions that included chenodeoxycholic acid, HMG-CoA reductase inhibitor, and LDL apheresis reduced serum cholestanol level in all patients and improved clinical symptoms in 40.5% of patients. Although CTX is a treatable neurodegenerative disorder, our nationwide survey revealed an average 16.5-year diagnostic delay. CTX may be underdiagnosed in Japan, especially during childhood. Early diagnosis and treatment are essential to improve the prognosis of CTX.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal-recessive lipid storage disease caused by mutations in the CYP27A1 gene, which lead to deficiency of the mitochondrial enzyme, sterol 27-hydroxylase, resulting in the accumulation of cholestanol in the serum and many affected lesions. To date, more than 50 different CYP27A1 mutations, including missense mutations, frameshifts, and splice site mutations, have been reported worldwide in patients with CTX. Clinical presentation is characterized by neonatal jaundice or cholestasis, refractory diarrhea, juvenile cataracts, tendon xanthomas, osteoporosis, coronary heart disease, and progressive neuropsychiatric disturbances; however, combinations of symptoms vary from patient to patient. Neuropsychiatric abnormalities include mental retardation or dementia, psychiatric symptoms, cerebellar signs, pyramidal signs, progressive myelopathy, peripheral neuropathy, extrapyramidal manifestations, and seizures. Replacement treatment with chenodeoxycholic acid in the early stage of the disease has been reported to improve or even prevent clinical symptoms of CTX. After significant neurological pathology is established, the effect of the treatment is limited and the deterioration of clinical manifestations may continue; therefore, early diagnosis of CTX is crucial.

Cerebrotendinous xanthomatosis (CTX) OMIM#213700 is a rare autosomal-recessive lipid storage disease caused by mutations in the CYP27A1 gene; this gene codes for the mitochondrial enzyme sterol 27-hydroxylase, which is involved in bile acid synthesis. The CYP27A1 gene is located on chromosome 2q33-qter and contains nine exons. A CYP27A1 mutation leads to decreased synthesis of bile acid, excess production of cholestanol, and consequent accumulation of cholestanol in tissues. Currently there is no consensus on the prevalence of CTX, one estimate being <5/100,000 worldwide. The prevalence of CTX due to the CYP27A1 mutation R362C alone is approximately 1/50,000 in Caucasians. Patients with CTX have an average age of 35 years at the time of diagnosis and a diagnostic delay of 16 years. Clinical signs and symptoms include adult-onset progressive neurological dysfunction (i.e., ataxia, dystonia, dementia, epilepsy, psychiatric disorders,peripheral neuropathy, and myopathy) and premature non-neurologic manifestations (i.e., tendon xanthomas, childhood-onset cataracts, infantile-onset diarrhea, premature atherosclerosis, osteoporosis, and respiratory insufficiency). Juvenile cataracts, progressive neurologic dysfunction, and mild pulmonary insufficiency are unique symptoms that distinguish CTX from other lipid storage disorders including familial dysbetalipoproteinemia, homozygous familial hypercholesterolemia, and sitosterolemia, all of which might also present with xanthomas and cardiovascular diseases. Brain magnetic resonance imaging (MRI) shows bilateral lesions in the dentate nucleus of the cerebellum and mild white matter lesions. The classical symptoms and signs, namely elevated levels of cholestanol and bile alcohols in serum and urine, brain MRI, and the mutation in the CYP27A1 gene confirm the diagnosis of CTX. Early diagnosis and long-term treatment with chenodeoxycholic acid (750 mg/d) improve neurological symptoms and contribute to a better prognosis.

Background: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disorder characterized by a heterogeneous presentation and a broad spectrum of clinical manifestations. Since early diagnosis and replacement therapy with chenodeoxycholic acid can prevent clinical deterioration, our aim was to develop a diagnostic tool to identify and treat CTX patients at an initial stage of the disease., Methods: We devised a suspicion index, composed of weighted scores assigned to indicators such as family history characteristics and common systemic and neurological features, on the basis of a pooled analysis of selected international CTX series. The indicators were classified as very strong (score 100), strong (50) or moderate (25). The suspicion index was then applied retrospectively to our CTX population., Results: Early systemic signs such as cataract, diarrhea and neonatal cholestatic jaundice were considered strong indicators, together with neurological features such as intellectual impairment, psychiatric disturbances, ataxia, spastic paraparesis and dentate nuclei abnormalities at MRI. Tendon xanthomas were regarded as very strong indicators, as was an affected sibling. A total score ≥ 100 warranted serum cholestanol assessment. Elevated cholestanol or a total score ≥ 200, with one very strong or four strong indicators, warranted CYP27A1 gene analysis. In our patients, age at diagnosis was 35.5 ± 11.8 years (mean ± standard deviation), whereas with the diagnostic tool it became 10.6 ± 9.8 years (p < 0.01)., Conclusions: Our suspicion index provides a simple and inexpensive diagnostic tool allowing diagnosis and treatment of CTX before neurological disability occurs.

Cerebrotendinous xanthomatosis (CTX) is a rare, inherited autosomal-recessive lipid-storage disorder caused by 27-hydroxylase deficiency. In this study, we report of a 30-year old man with this disorder who was treated using chenodeoxycholic acid, simvastatin, and low-density lipoprotein (LDL) apheresis. The LDL apheresis was performed weekly for nine months. The first subjective improvement was reported by the patient after his fourth LDL-apheresis. Spasticity, gait disturbances, and his entire psychomotoric test results had improved tremendously. His fine motoric skills have been regained. The efficacy of LDL-apheresis was monitored using quantitative determination of 7α-OH-4-cholesten-3-one in plasma based on a LC-MS/MS method. The clearance efficacy of 7α-hydroxy-4-cholesten-3-one from the patient's plasma per LDL-apheresis varied between 8% and 53% but returned to the initial high levels after seven days (mean value 241 ng/mL). A slight negative trend in the plasma concentration could be derived over the period of nine months., (Copyright © 2011. Published by Elsevier Ireland Ltd.)

The concentrations of serum cholesterol, cholestanol and non-cholesterol sterols were measured in a patient with cerebrotendinous xanthomatosis under different therapeutic regimens. During treatment with chenodeoxycholic acid (CDCA) (750 mg/day) plus simvastatin (20 mg/day) for two years cholesterol and cholestanol concentrations averaged 188+/-10 mg/dl and 0.54+/-0.03 mg/dl. Thereafter treatment with simvastatin was discontinued. During treatment with low-density lipoprotein (LDL)-apheresis plus CDCA for 33 weeks, cholestanol concentrations reached almost normal levels (0.48+/-0.03 mg/dl immediately before and 0.32+/-0.02 mg/dl directly after LDL-apheresis, n=6). A further reduction of cholesterol and cholestanol was achieved by addition of simvastatin (20 mg/day). Cholesterol and cholestanol concentrations before and after LDL-apheresis during this treatment period averaged 122+/-4 mg/dl and 55+/-10 mg/dl, and 0.42+/-0.02 mg/dl and 0.18+/-0.06 mg/dl, respectively. Despite the consistent reduction of cholestanol to normal or even subnormal levels, a definite improvement of clinical symptoms was not noted. Our results suggest caution in the recourse to an aggressive cholestanol lowering therapy.

The effects of combined treatment with low-density lipoprotein (LDL)-apheresis, chenodeoxycholic acid (CDCA) and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor were studied in 2 patients with cerebrotendinous xanthomatosis. Patient 1 was initially treated with LDL-apheresis alone: serum cholestanol levels decreased by 50% after each apheresis, but returned to their initial levels within 2 weeks. After an addition of CDCA administration, the serum cholestanol levels steadily decreased, resulting in slight improvement of neurological symptoms. Patient 2 received a combined treatment with LDL-apheresis, CDCA and HMG-CoA reductase inhibitor. This combination showed less LDL-apheresis-dependent fluctuation and more rapid decrease of serum cholestanol levels than those in Patient 1, resulting in improvement and stabilization of the symptoms. Our results suggest that LDL-apheresis in combination with CDCA and HMG-CoA reductase inhibitor may have beneficial effects and can be one of the treatment options.

In this report, we review the clinical, biochemical, pathophysiologic, and therapeutic aspects of cerebrotendinous xanthomatosis. We stress the importance of early diagnosis and treatment. In addition, we describe our experience in treating patients with chenodeoxycholic acid, an essential drug for this disorder that is no longer available.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive sterol storage disease characterised clinically by juvenile bilateral cataracts, progressive neurological dysfunction, and formation of tendon xanthomata. We describe the clinical and biochemical features, molecular diagnosis and long-term management of the first reported Australasian case of CTX. Molecular analysis confirmed the diagnosis of CTX and demonstrated that the patient was homozygous for a G-->A transition in the splice donor site of intron 4 of the sterol 27-hydroxylase gene. Serum cholestanol concentrations were decreased with the HMG-CoA reductase inhibitor simvastatin alone and greater reductions were achieved after the addition of the bile acid chenodeoxycholic acid; suggesting a synergistic effect of this combination. Despite serum cholestanol concentrations remaining within the low-normal range, there has been no significant improvement in mental and physical abilities or in EEG abnormalities with 5 years of treatment. Metabolism of radiolabeled 7-ketocholesterol to aqueous soluble products was absent in CTX-derived macrophages. Consistent with this finding, plasma 7 alpha-hydroxycholesterol, 7 beta-hydroxycholesterol, and 7-ketocholesterol concentrations were increased in the CTX subject compared with controls.

Cerebrotendinous xanthomatosis is characterized by the accumulation of cholestanol and cholesterol in xanthomas and brain causing a number of severe symptoms. More than 20 different mutations have been identified in the gene encoding sterol 27-hydroxylase. Defects in the gene lead to reduced bile acid biosynthesis, with accumulation of 7 alpha-hydroxylated intermediates, one of which is a precursor to cholestanol. The disease can be treated successfully with chenodeoxycholic acid, which reduces the upregulation of cholesterol 7 alpha-hydroxylase and, therefore, the formation of cholestanol. Disruption of the gene encoding sterol 27-hydroxylase in mice does not have the same metabolic consequences as in humans.