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Cerebrotendinous xanthomatosis (a rare lipid storage disorder): a case report.

ABSTRACT: BACKGROUND:Cerebrotendinous xanthomatosis is a very rare autosomal recessive lipid storage disorder affecting bile acid biosynthesis. It is manifested by subtle neurological and non-neurological symptoms due to abnormal tissue lipid deposition. Diagnosis is usually delayed but early diagnosis and replacement therapy can prevent devastating neurological sequelae. CASE PRESENTATION:We present a case of a 25-year-old Asian Indian woman who presented with gait difficulty, fusiform swellings of bilateral tendo-Achilles and infrapatellar tendons, along with history of bilateral cataract surgery 1 year earlier. The diagnosis was made on the basis of clinical, biochemical, imaging, and histopathological analysis and replacement therapy was started. CONCLUSIONS:The peculiarity of the present case is the absence of any neurological manifestations which are usually the early clues to the diagnosis of cerebrotendinous xanthomatosis. The present case report emphasizes the fact that early age bilateral cataracts along with bilateral tendo-Achilles xanthomas can be early pointers toward the diagnosis of cerebrotendinous xanthomatosis.

SUBMITTER: Razi SM

PROVIDER: S-EPMC4837582 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Cerebrotendinous xanthomatosis (a rare lipid storage disorder): a case report.

Razi Syed Mohd SM Gupta Abhinav Kumar AK Gupta Deepak Chand DC Gutch Manish M Gupta Keshav Kumar KK Usman Syeda Iqra SI

Journal of medical case reports 20160419 1

<h4>Background</h4>Cerebrotendinous xanthomatosis is a very rare autosomal recessive lipid storage disorder affecting bile acid biosynthesis. It is manifested by subtle neurological and non-neurological symptoms due to abnormal tissue lipid deposition. Diagnosis is usually delayed but early diagnosis and replacement therapy can prevent devastating neurological sequelae.<h4>Case presentation</h4>We present a case of a 25-year-old Asian Indian woman who presented with gait difficulty, fusiform swe ...[more]

PMID: 27094915

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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.

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.

Project description:IntroductionCerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disease caused by mutations of the CYP27A1 gene and deficiency of the sterol-27-hydroxylase enzyme in bile acid biosynthesis. It is characterized by the accumulation of cholestanol and bile alcohols in plasma, the formation of xanthomatous lesions in various tissues, and organ degeneration. This disorder is also associated with osteoporosis and increased risk of fracture. To date, only two CTX patients with femoral neck fractures have been reported. Neither was treated by arthroplasties, and the operative outcomes are lacking.Case reportWe report the case of a 46-year-old Thai female who presented with consecutive bilateral femoral neck fractures following minor trauma within a 3-year period and received cementless bipolar hemiarthroplasties. Her phenotypic expression included Achilles tendon masses, childhood-onset cataracts, intellectual disability, and cerebellar ataxia. A brain computed tomography showed non-enhancing hypodense lesions in the bilateral cerebellar hemispheres with mild brain atrophy. Histopathology from an Achilles tendon biopsy revealed tendinous xanthoma and molecular analysis confirmed a homozygous nonsense mutation, c.1072C>T (p.Gln358Ter), in exon 6 of the CYP27A1 gene. The intra-operative crack of a calcar femorale was a major complication during both prosthetic insertion surgeries and warranted cerclage wiring. At the 7-month follow-up of the right hip and the 41-month follow-up of the left hip, postoperative radiographs showed well-fixed and well-aligned prostheses. Independent household ambulation could be resumed with Harris hip scores of 81 points equally.ConclusionCTX is associated with osteoporosis, and middle-aged patients could present with femoral neck fracture following minor trauma. Cementless bipolar hemiarthroplasty for a totally displaced fracture is justified for a patient who has cognitive impairment. Intra-operative fracture is a major complication during prosthetic insertion and warrants cerclage wiring to achieve predictable bone healing and a satisfactory result.

Project description:BackgroundCerebrotendinous xanthomatosis (CTX) is an autosomal-recessive lipid storage disorder caused by mutations in the CYP27A1 gene encoding the key enzyme in the bile acid synthesis, sterol 27-hydroxylase. Here, we report two Japanese CTX siblings with a novel compound heterozygous CYP27A1 mutation, showing different clinical phenotypes and responses to chenodeoxycholic acid (CDCA) therapy.Case presentationThe proband, a 32-year-old man, who had chronic diarrhea, bilateral cataracts, and xanthomas, demonstrated progressive neurological manifestations including ataxia, and spastic paraplegia during a 5-year follow-up period despite normalization of serum cholestanol after initiation of CDCA treatment. He also exhibited cognitive decline although improvement had been observed at the beginning of treatment. Follow-up brain magnetic resonance imaging (MRI) revealed pronounced progressive atrophy in the cerebellum, in addition to expanding hyperintense lesions in the dentate nuclei, posterior limb of the internal capsule, cerebral peduncles, and inferior olives on T2-weighted images. In contrast, the two-year-younger sister of the proband presented with chronic diarrhea, cataracts, xanthomas, and intellectual disability but no other neurological symptoms at the time of diagnosis. CDCA treatment lead to improvement of cognitive function and there were no characteristic CTX-related MRI features during the follow-up period. The siblings shared a paternally inherited c.1420C > T mutation (p.Arg474Trp) and a maternally inherited novel c.1176_1177delGA mutation, predicting p.(Glu392Asp*20).ConclusionsOur cases suggest that early diagnosis and subsequent initiation of CDCA treatment are crucial before the appearance of characteristic MRI findings and severe neurological manifestations related to CTX. Further studies are required to elucidate mechanisms responsible for the clinical diversity of CTX and prognostic factors for long-term outcomes following initiation of CDCA treatment.

Project description:BackgroundCerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disease caused by a mutation in the CYP27A1 gene. Due to the disruption of bile acid synthesis leading to cholesterol and cholestanol accumulation, CTX manifests as premature cataracts, chronic diarrhea, and intellectual disability in childhood and adolescence. This report presents a case of CTX with an unusual phenotype of behavioral variant frontotemporal dementia (bvFTD) in middle age.Case presentationA 60-year-old woman presented with behavioral and personality changes. She showed disinhibition, such as hoarding and becoming aggressive over trifles; compulsive behavior, such as closing doors; apathy; and dietary change. The patient showed a progressive cognitive decline and relatively sparing memory and visuospatial function. She had hyperlipidemia but no family history of neurodegenerative disorders. Initial fluid-attenuated inversion recovery (FLAIR) images showed a high signal in the periventricular area, and brain spectroscopy showed hypoperfusion in the frontal and temporal lobes, mimicking bvFTD. However, on physical examination, xanthomas were found on both the dorsum of the hands and the Achilles tendons. Hyperactive deep tendon reflexes in the bilateral biceps, brachioradialis, and knee and positive Chaddock signs on both sides were observed. Four years later, FLAIR images showed symmetrical high signals in the bilateral dentate nuclei of the cerebellum. Her serum cholestanol (12.4 mg/L; normal value ≤6.0) and 7α,12α-dihydroxycholest-4-en-3-one (0.485 nmol/mL; normal value ≤0.100) levels were elevated. A novel likely pathogenic variant (c.1001T>A, p.Met334Lys) and a known pathogenic variant (c.1420C>T, p.Arg474Trp) of the CYP27A1 gene were found in trans-location. The patient was diagnosed with CTX and prescribed chenodeoxycholic acid (750 mg/day).ConclusionsThis report discusses the case of a middle-aged CTX patient with an unusual phenotype of bvFTD. A novel likely pathogenic variant (c.1001T>A, p.Met334Lys) was identified in the CYP27A1 gene. Early diagnosis is important because supplying chenodeoxycholic acid can prevent CTX progression.

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.

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Cerebrotendinous xanthomatosis (a rare lipid storage disorder): a case report.

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Cerebrotendinous xanthomatosis (a rare lipid storage disorder): a case report.

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