Clinical and genetic characteristics of Chinese patients with cerebrotendinous xanthomatosis.
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SUBMITTER: Tao QQ
PROVIDER: S-EPMC6892200 | biostudies-literature | 2019 Dec
REPOSITORIES: biostudies-literature
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Clinical and genetic characteristics of Chinese patients with cerebrotendinous xanthomatosis.
Tao Qing-Qing QQ Zhang Yun Y Lin Hui-Xia HX Dong Hai-Lin HL Ni Wang W Wu Zhi-Ying ZY
Orphanet journal of rare diseases 20191203 1
<h4>Background</h4>Cerebrotendinous xanthomatosis (CTX) is a rare inborn lipid-storage disease caused by mutations in the sterol 27-hydroxylase (CYP27A1) gene with an autosomal recessive pattern of inheritance. To date, only 19 CTX patients from 16 families have been reported in the Chinese population.<h4>Results</h4>Three novel likely pathogenic mutations (c.368_374delCCAGTAC, c.389 T > A and c.571C > T) and 7 previously reported pathogenic mutations (c.379C > T, c.435G > T, c.1016C > T, c.1214 ...[more]
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Project description: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.
| S-EPMC7723652 | biostudies-literature
Project description:BackgroundCerebrotendinous xanthomatosis (CTX) is a treatable autosomal recessive inherited metabolic disorder. It results from a deficiency of sterol 27-hydroxylase (CYP27A1), which is a mitochondrial cytochrome P450 enzyme that catalyzes the hydroxylation of cholesterol and modulates cholesterol homeostasis. Patients with CYP27A1 deficiency show symptoms related to excessive accumulation of cholesterol and cholestanol in lipophilic tissues such as the brain, eyes, tendons, and vessels, resulting in juvenile cataracts, tendon xanthoma, chronic diarrhea, cognitive impairment, ataxia, spastic paraplegia, and peripheral neuropathy. CTX is underdiagnosed as knowledge of the disorder is mainly based on case reports.Case summaryA Chinese family with CTX consisting of one patient and four heterozygous carriers was studied. The patient is a 47-year-old male, who mainly had psychiatric signs but without some cardinal features of CTX such as cataracts, cerebellar ataxia, pyramidal signs and chronic diarrhea. There was a significant increase in the concentration of free fatty acid compared to normal range. Doppler ultrasound of the urinary system showed multiple left kidney stones, a right kidney cyst, and a hypoechoic area in the bladder, which could move with body position. Sagittal and axial magnetic resonance imaging (MRI) of the right ankle joint showed apparent enlargement of the right Achilles tendon and upper medial malleolus flexor tendon, abnormal thickening of the plantar fat, and a small amount of exudation around the fascia in front of the Achilles tendon. Cerebral MRI suggested white matter (WM) demyelination and slight cerebral atrophy. The diagnosis was confirmed by targeted sequencing, which identified compound heterozygous mutations in exon 2 and intron 7 of the CYP27A1 gene (c.435G>T, c.1263+1G>A). Treatment for 3 wk with a combination of lipid-lowering and antipsychotic therapy improved his psychiatric symptoms and normalized the levels of serum free fatty acid. Sediments in the bladder disappeared after therapy.ConclusionCYP27A1 genetic analysis should be the definitive method for CTX diagnosis. This case suggests that urinary system diseases may be neglected in CTX patients. The clinical, biological, radiological, and genetic characteristics of CTX are summarized to promote early diagnosis and treatment of this disease.
| S-EPMC7674721 | biostudies-literature
Project description:Cerebrotendinous xanthomatosis (CTX) is a rare and severe, but treatable, inborn disorder of bile acid biosynthesis and sterol storage with autosomal recessive inheritance and variable clinical presentation. CTX treatment consists of chenodeoxycholic acid and must be started as early as possible to prevent permanent disability. Psychiatric manifestations are rare and non-specific, and often lead to significant diagnostic and treatment delay. Therefore, better recognition of the gamut of psychiatric manifestations in CTX can diminish the risk of misdiagnosis and irreversible neurological deterioration. We hereby describe the psychiatric features in CTX. A complete review of all published cases of CTX in the medical literature was undertaken and the case reports with psychiatric presentation were collected and analyzed. We also describe the psychiatric features in relation to the neurological semeiology in six patients with CTX diagnosed at the La Salpêtrière Hospital. We conclude that psychiatric manifestations in CTX follow a bimodal/bitemporal pattern, appearing early in the disease course in the form of a behavioral/personality disorder associated with learning difficulties or mental retardation, or manifesting in advanced disease in the setting of dementia as rich neuropsychiatric syndromes, such as frontal, orbitofrontal or frontotemporal syndromes of cortico-subcortical dementia encompassing behavioral/personality disturbance, affective/mood disorders or psychotic disorders. Behavioral/personality disturbance in childhood or adolescence, especially when accompanied by learning difficulties, should therefore lead to further investigation to exclude CTX, as early diagnosis and treatment is critical for prognosis.
| S-EPMC3784765 | biostudies-literature
Project description: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.
| S-EPMC8532057 | biostudies-literature
Project description:BackgroundCerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by bi-allelic pathogenic variants in CYP27A1 gene that results in the deposition of cholestanol in the eyes, tendons, soft tissues and nervous system leading to cataracts, xanthomas, and various neuropsychiatric manifestations. The aim of our study is to describe the clinical, radiological and genetic profile of patients with CTX.MethodsThis is a retrospective chart review of patients with CTX diagnosed based on classical clinical and radiological findings. The available clinical details, and investigations, including imaging, electrophysiological, pathological and genetic data, were documented.ResultsFive patients (4 males) were recruited in the study. The median age at presentation was 32 years (range: 21-66 years). Walking difficulty was the most common symptom at presentation. All patients had cataracts, tendon xanthomas, eye movement abnormalities, dysarthria, pyramidal signs, ataxia and gait abnormality. Dystonia was noted in three patients. Palatal tremor and parkinsonism were noted in one patient each. In MRI brain, dentate, and corticospinal tract involvement were the most frequent imaging findings. Bilateral hypertrophic olivary degeneration was noted in one patient and hot cross bun sign in two. Three patients underwent genetic testing and all had pathogenic variants confirming the diagnosis.DiscussionCTX is a rare treatable disorder. Apart from the usual neurological presentation with spastic-ataxia, it can present at a later age with parkinsonism. Typical patterns of imaging findings are helpful in early diagnosis which aids in the treatment to prevent the neurological sequelae of the disease.
| S-EPMC10929277 | biostudies-literature
Project description:Background:Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disorder of bile acid synthesis caused by mutations in the CYP27A1 gene. CTX is an underdiagnosed and potentially treatable disease, thus a detailed appreciation of the phenotypic spectrum and genetic characteristics are crucial for early diagnosis and treatment. Objectives and Methods:Four CTX families with mutations in the CYP27A1 gene were enrolled in our study. We investigated the clinical characteristics and molecular genetic features of the probands with CTX. Genetic analysis was performed for detecting gene variants. Sanger sequencing and segregation analysis were conducted for haplotype analysis. Results:All the four probands were compound heterozygote for two CYP27A1 variants, including one mutation in c.1263+1G>A (intron 7) splice site, two novel likely pathogenic mutations (c.255+1G>T and c.1561dupA) and three pathogenic mutations including c.379C>T, c.1263+1G>A and c.1537C>T previously reported. All of the subjects presented with spastic paraparesis. The other common clinical features included ataxia, childhood-onset diarrhea, cataracts, intellectual disability, tendinous xanthomas and dentate nuclei signal alterations at MRI. Conclusion:Two novel likely pathogenic mutations (c.255+1G>T and c.1561dupA) were reported in our study. The 1263+1G>A mutation was commonly seen in Chinese reported case series (7/25, 28%) and could be a latent hotspot for Chinese CTX mutations. Our study expanded the mutation spectrum of CYP27A1 gene and provide an insightful view of the phenotypic spectrum and genetic characteristics to help early diagnosis and treatment with to improve neurologic dysfunction.
| S-EPMC7342084 | biostudies-literature
Project description: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.
| S-EPMC4264335 | biostudies-literature
Project description:BackgroundCerebrotendinous xanthomatosis (CTX) is a rare recessive genetic disease characterized by disruption of bile acid synthesis due to inactivation of the CYP27A1 gene. Treatment is available in the form of bile acid replacement. CTX is likely underdiagnosed, and prevalence estimates based on case diagnosis are probably inaccurate. Large population-based genomic databases are a valuable resource to estimate prevalence of rare recessive diseases as an orthogonal unbiased approach building upon traditional epidemiological studies.MethodsWe leveraged the Hardy-Weinberg principle and allele frequencies from gnomAD to calculate CTX prevalence. ClinVar and HGMD were used to identify high-confidence pathogenic missense variants and to calculate a disease-specific cutoff. Variant pathogenicity was also assessed by the VarSome implementation of the ACMG/AMP algorithm and the REVEL in silico predictor.ResultsCTX prevalence estimates were highest in Asians (1:44,407-93,084) and lowest in the Finnish population (1:3,388,767). Intermediate estimates were found in Europeans, Americans, and Africans/African Americans (1:70,795-233,597). The REVEL-predicted pathogenic variants accounted for a greater increase in prevalence estimates for Europeans, Americans, and Africans/African Americans compared with Asians. We identified the most frequent alleles designated pathogenic in ClinVar (p.Gly472Ala, p.Arg395Cys), labeled pathogenic based on sequence consequence (p.Met1?), and predicted to be pathogenic by REVEL (p.Met383Lys, p.Arg448His) across populations. Also, we provide a prospective geographic map of estimated disease distribution based on CYP27A1 variation queries performed by healthcare providers from selected specialties.ConclusionsPrevalence estimates calculated herein support and expand upon existing evidence indicating underdiagnosis of CTX, suggesting that improved detection strategies are needed. Increased awareness of CTX is important for early diagnosis, which is essential for patients as early treatment significantly slows or prevents disease progression.
| S-EPMC9843874 | biostudies-literature
Project description:Cerebrotendinous xanthomatosis (CTX) is an inborn error of metabolism leading to progressive multisystem disease. Symptoms often begin in the first decade of life with chronic diarrhea, cataracts, developmental delay, intellectual disability, and cerebellar or pyramidal dysfunction. Later manifestations include tendon xanthomas, polyneuropathy, and abnormal neuroimaging. Pathogenic biallelic variants in CYP27A1 leading to compromised function of sterol 27-hydroxylase result in accumulation of detectable toxic intermediates of bile acid synthesis rendering both genetic and biochemical testing effective diagnostic tools. Effective treatment with chenodeoxycholic acid is available, making early diagnosis critical for patient care. Here we report a new patient with CTX and describe the early signs of disease in this patient. Initial symptoms included infantile spasms, which have not previously been reported in CTX. Developmental delay, mild intellectual disability with measured cognitive decline in childhood, was also observed. These clinical signs do not traditionally compel testing for CTX, and we highlight the need to consider this rare but treatable disorder among the differential diagnosis of children with similar clinical presentation. Increased awareness of early signs of CTX is important for improving time to diagnosis for this patient population.
| S-EPMC5585103 | biostudies-literature
Project description:BackgroundClassic cerebrotendinous xanthomatosis (CTX; OMIM #213700) manifests with chronic diarrhea, juvenile cataracts, tendon xanthomas and neurological symptoms. It is due to biallelic inactivation of CYP27A1 wich leads to cholestanol accumulation in the central nervous system, eyes and tendons. Less commonly, the disease can present in young adults as spastic paraparesis in the absence of xanthomas.Case presentationWe report a 38-year old woman who presented with chronic diarrhea and progressive spastic paraparesis in her twenties. Brain magnetic resonance imaging (MRI) showed cerebral atrophy with diffuse periventricular white matter hyperintensities. Spinal MRI was normal. CYP27A1 gene sequencing confirmed the diagnosis of CTX. Chenodeoxycholic acid (CDCA) treatment was introduced with remission of diarrhea. Unfortunately, the treatment had to be discontinued several times and the patient developed psychosis and an severe ataxospastic gait. Spinal MRI revealed new linear hyperintensities of the corticospinal and gracile tracts. Thirty-three spinal CTX patients were identified by searching in Pubmed, EMBASE™ and Web of Science databases. All patients presented pyramidal signs and 48% had dorsal column signs. Juvenile cataracts were described in 78% of patients, chronic diarrhea in 65%, and tendon xanthomas in 31%. Disease improvement or stabilization with chenodeoxycholic acid was observed in 69% of patients. A higher prevalence of the Arg395Cys allele was observed in patients with spinal CTX as compared to CTX in general (ᵡ2; p < 0.00001).ConclusionsThe diagnosis of spinal CTX can be easily missed or delayed in absence of xanthomas. There is a higher prevalence of the Arg395Cys allele in spinal CTX as compared to classic childhood-onset CTX. CDCA treatment seems to stabilize or improve clinical symptoms in most patients. However, as seen in our patient and in two previously reported cases, sudden interruption of CDCA may lead to irreversible neurological complications.
| S-EPMC7890005 | biostudies-literature