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Axial T2 weighted imaging of patient 1, showing bilateral hyper intense lesions involving the dentate nuclei and the deep cerebellar white matter (a). Supratentorial imaging (Patient 2) shows white matter tract involvement, specifically of the corticospinal tract and optic radiation (b)
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Background
Cerebrotendinous xanthomatosis (CTX) is a rare but treatable neurometabolic disorder of lipid storage and bile acid synthesis. Whilst CTX is said to present with the classic triad of juvenile onset cataracts, tendon xanthomata and progressive ataxia, the diversity of presentation can be such that the diagnosis may be substantially delaye...
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Introduction
Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease that occurs as result of mutation in the CYP27A1 gene. The clinical presentation of the disease is quite wide. We planned to briefly review the literature with this case diagnosed as a CTX.
Case
A 50-year-old male patient was admitted to the neurology outpatien...
Citations
... in the cluster "Miscellaneous" (N = 8), one patient with encephalopathy reported visual impairments [33] and one patient reported several sensory deficits (visual problems, right hearing loss, mild decreased vibration sense) due to cerebrotendinous xanthomatosis [35], which is a neurometabolic disorder of lipid storage and bile acid synthesis [50]. the patient with Systematic lupus erythematosus reported a strength deficits in all four limbs (MMt 4/5) [43], the one with a pontine cavernoma had a right hemiparesis with loss of sensation and proprioception [44] and the case with a charcot-marie-tooth disease had plegia of ankle and foot muscles, hyposensitive feet, impaired vibration sense overall and blindness [45]. ...
Purpose:
Cerebellar impairment (CI) manifests from different etiologies resulting in a heterogenic clinical presentation affecting walking and mobility. Case-reports were reviewed to provide an analytical clinical picture of persons with CI (PwCI) to differentiate cerebellar and non-cerebellar impairments and to identify interventions and assessments used to quantify impact on walking and mobility according to the International Classification of Functioning, Disability and Health (ICF).
Materials and methods:
Literature was searched in PubMed, Web Of Science and Scopus. Case-reports conducting physical rehabilitation and reporting at least one outcome measure of ataxia, gait pattern, walking or mobility were included.
Results:
28 articles with a total of 38 different patients were included. Etiologies were clustered to: spinocerebellar degenerations, traumatic brain injuries, cerebellar tumors, stroke and miscellaneous. The interventions applied were activity-based, including gait and balance training. Participation based activities such as tai chi, climbing and dance-based therapy had positive outcomes on mobility. Outcomes on body function such as ataxia and gait pattern were only reported in 22% of the patients.
Conclusions:
A comprehensive test battery to encompass the key features of a PwCI on different levels of the ICF is needed to manage heterogeneity. Measures on body function level should be included in interventions.
... This downregulation ultimately helps to reduce the accumulation of toxic bile acid intermediates in CTX patients. In patient studies, it was able to reduce cholestanol levels in the cerebral spinal fluid by three-fold and ultimately halt the progression of the disease [7]. ...
Cerebrotendinous xanthomatosis (CTX) is a genetic disorder of the cholesterol metabolic pathway, most often associated with variants in the CYP27A1 gene. The dysregulation of cholesterol metabolism results in the accumulation of metabolites such as cholestanol, which has a predilection for neuronal tissue and tendons. The condition is treatable with chenodeoxycholic acid (CDCA), which halts the production of these metabolites. We present two adult brothers, without diagnosis, suffering from ataxia, general muscle weakness and cognitive deficits. Both brothers suffered from early onset cataracts, watery stools and thoracic kyphoscoliosis. Magnetic resonance imaging revealed hyperintense alterations in the central nervous system and intratendinous xanthomas in the Achilles tendons. A biochemical analysis showed elevated levels of cholestanol, lathosterol and 7-dehydrocholesterol. Their family history was negative for neurological and metabolic disorders. Genetic testing revealed a pathogenic CYP27A1 variant (c.1184+1G>A) in both brothers, confirming the diagnosis. The patients were started on CDCA therapy and have shown significant improvement at their follow-up examinations. Early diagnosis and treatment initiation in CTX patients is of great importance, as the significant reversal of disease progression can be achieved. For this reason, clinical genetic testing is necessary when it comes to patients with an onset of cataracts, chronic diarrhea, and neurological symptoms in early childhood.
... The actual cause of CTX-induced brain injury is unknown. A high quantity of cholestanol in brain tissue is considered to activate apoptotic pathways, resulting in neuronal death [6]. ...
Cerebrotendinous xanthomatosis (CTX), also known as CTX, is an extremely rare bile acid metabolic disorder caused by mutations in the cytochrome P450 family 27 subfamily A member 1 (CYP27A1) gene. This genetic disease is inherited in an autosomal recessive manner, and it affects the enzyme sterol 27-hydroxylase, which is involved in the bile acid metabolic process. It is distinguished by diarrhoea in infancy, early juvenile cataract, tendon xanthomas in adolescence, and progressive neuropsychiatric dysfunction in adulthood. So far, India has reported eight genetically confirmed cases. We present two cases of CTX among siblings in a family. The elder sibling was initially diagnosed, and after reviewing his family history and performing a thorough clinical examination, we discovered a similar manifestation in his younger sibling. Genetic testing on the siblings revealed similar mutations at exon 2 of the CYP27A1 gene. If a pathogenic mutation is discovered in a family member, prenatal and preimplantation genetic testing, as well as childhood screening, are the options. These screening strategies will prevent the onset of neuropsychiatric manifestations and disability.
... CTX is caused by bi-allelic pathogenic variants in CYP27A1 (2q35), which codes sterol 27-hydroxylase, a mitochondrial enzyme of cytochrome P450 oxidase system. Reduction of the activity of this enzyme leads to increased formation and storage of abnormal lipid content in several tissues, especially tendons, lenses and peripheral, and central nervous system (2). ...
... Plasma cholestanol level assessment is indicated in patients with Mignarri scores ≥100. With previous high levels of plasma cholestanol or a Mignarri score ≥200 (including at least 1 "very strong indicator" or 4 "strong indicator"), there is a formal indication for genetic analysis of CYP27A1 gene (2,37,39,40). The clinical use of the Mignarri score should not limit the early investigation of patients with clinical features highly suggestive of CTX diagnosis (i.e., juvenile cataracts, childhoodonset chronic diarrhea), even in the absence of score values higher than 100 or 200 points or other clinical signs. ...
Cerebrotendinous Xanthomatosis represents a rare and underdiagnosed inherited neurometabolic disorder due to homozygous or compound heterozygous variants involving the CYP27A1 gene. This bile acid metabolism disorder represents a key potentially treatable neurogenetic condition due to the wide spectrum of neurological presentations in which it most commonly occurs. Cerebellar ataxia, peripheral neuropathy, spastic paraparesis, epilepsy, parkinsonism, cognitive decline, intellectual disability, and neuropsychiatric disturbances represent some of the most common neurological signs observed in this condition. Despite representing key features to increase diagnostic index suspicion, multisystemic involvement does not represent an obligatory feature and can also be under evaluated during diagnostic work-up. Chenodeoxycholic acid represents a well-known successful therapy for this inherited metabolic disease, however its unavailability in several contexts, high costs and common use in patients at late stages of disease course limit more favorable neurological outcomes for most individuals. This review article aims to discuss and highlight the most recent and updated knowledge regarding clinical, pathophysiological, neuroimaging, genetic and therapeutic aspects related to Cerebrotendinous Xanthomatosis.
... Other symptoms include osteoporosis, arterial disease, and early atherosclerosis. The rarest symptoms include Parkinson's disease and xanthoma of the spine [2]. CTX is easily misdiagnosed as a treatable disease. ...
Background:
Cerebrotendinous xanthomatosis is an autosomal recessive disorder of lipid metabolism caused by the mutation of the CYP27A1 gene encoding sterol 27-hydroxylase, an essential enzyme for the conversion of cholesterol to chenodeoxycholic and cholic acids. Cerebrotendinous xanthomatosis is a rare neurological disease with a wide range of clinical symptoms that are easily misdiagnosed.
Case summary:
Here we report the clinical, biochemical, and molecular characterization of a 33-year-old female patient with cerebrotendinous xanthomatosis. The patient developed ataxia and had the typical symptoms of juvenile cataracts, tendon xanthomata, and progressive nervous system dysfunction. Magnetic resonance imaging of the brain revealed bilateral dentate nucleus lesions and white matter abnormalities. This patient was misdiagnosed for 2 years resulting in severe neurological complications. After 2 years of chenodeoxycholic acid treatment, she still presented with ataxia and dysarthria. The pathogenic sites of CYP27A1 were identified as c.255+1G>T and c.1263+1G>T, which were both caused by shear denaturation.
Conclusion:
Cerebrotendinous xanthomatosis requires a multidisciplinary diagnosis that must be made early to avoid progressive neurological degeneration. c.1263+1G>T is a known mutation, but c.255+1G>T is a rare mutation site.
Introduction
Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid metabolism disorder. It is caused by a defect in the sterol-27-hydroxylase gene, leading to the deposition of cholesteryl and bile alcohol in large amounts, causing a variety of clinical manifestations; however, tremor as the main manifestation of CTX has not been reported.
Patient’s concerns and clinical findings
Herein, we report a 27-year-old woman, who developed head and body tremors at the age of 12 years. Many hospitals misdiagnosed her condition as idiopathic tremor and Parkinson disease, with a poor curative effect.
Primary diagnosis and intervention
We diagnosed her with CTX and treated with chenodeoxycholic acid and clonazepam.
Conclusion
The patient’s condition considerably improved. This case could help avoid misdiagnosis and mistreatment in clinical practice.
Purpose/aim of the study:
Cerebrotendinous xanthomatosis is a disease with important clinical and molecular heterogeneity. CYP27A1 gene was described as the cause of these defects, with more than 50 mutations involved in the disease. The objective of this study was to carry out a genetic study and a clinical description of a patient with unusual clinical manifestation of the disease.
Materials and methods:
DNA sequencing was used for the evaluation of CYP27A1 exon sequences and their intron/exon boundaries. Copy number variants were calculated using a method based on depth of sequencing coverage. In addition, the potential effects of the missense variants were analyzed, and an in-silico protein modeling tool was used. Finally, a patient case description was performed in order to evaluate patient phenotype according to genetic results.
Results:
Patient clinical features indicate the possible presence of a disease milder phenotype. When analyzing the CYP27A1 gene, patient presents a pathogenic variant (p.Arg474Trp) and a variant of unknown significance (p.Met130Ile) that causes a slight modification of the protein functional structure. This variant in homozygosis or double or compound heterozygosis together with other biallelic pathological mutations may be the cause of the clinical phenotype observed in the reported patient.
Conclusions:
Clinical manifestations of cerebrotendinous xanthomatosis are heterogeneous, and sometimes wrongly suggest the presence of other diseases. Some patients seem to present an "incomplete" phenotype, which could be redefined as a variant of the disease with further studies. The evaluation of new mutations allows for earlier diagnosis and greater effectiveness in its treatment.
Δ ⁴ -3-Oxosteroid 5β-reductase ( AKR1D1 ) deficiency typically causes severe cholestasis occurs in newborns, leading to death unless patients are treated with primary bile acids. However, we encountered an AKR1D1 deficiency patient treated with only ursodeoxycholic acid who had cholestasis until about 1 year of age but then grew up healthy without further treatment. We also have been following other healthy patients with AKR1D1 mutation who have never developed cholestasis and have not been treated. However, reports are few, involving 3 patients. To better understand and clinically manage a diverse group of patients with AKR1D1 mutation who do not develop potentially fatal cholestasis in the neonatal period, ongoing accumulation and study of informative cases is needed.
Cerebrotendinous xanthomatosis (CTX) is an inborn error of metabolism caused by recessive variants in the cytochrome P450 CYP27A1 gene. CTX is said to manifest with childhood‐onset chronic diarrhea and the classic triad of juvenile‐onset cataracts, Achilles tendons xanthomas, and progressive ataxia. It is currently one of the few inherited neurometabolic disorders amenable to a specific treatment. The diagnosis may be significantly delayed resulting in permanent neurological impairment. A retrospective review of the clinical characteristics and diagnostic findings in case series of six Polish patients with CTX. Additional retrospective review of symptoms and pathogenic variants of 568 CTX available cases and case series from the past 20 years. To the best of our knowledge, this is the widest review of CTX cases reported in years 2000–2021. We report the largest cohort of Polish patients ever published, with the identification of two hot‐spot mutations. During the review of available 568 cases, we found significant differences in the clinical phenotypes and the localization of variants within the gene between Asian and non‐Asian populations. These findings may facilitate molecular testing in the Polish and Asian populations. Invariably better screening for CTX and wider awareness is needed.
