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A summary of the main MRI findings in CTX. a Axial FLAIR image shows cortical atrophy (patient 37). b Coronal T2W image demonstrates cortical atrophy, marked cerebellar atrophy, and hyperintensity of dentate nuclei and surrounding white matter (patient 19). c Axial FLAIR image shows posterior periventricular white matter lesions (patient 23). d Axial FLAIR image shows bilateral hyperintense lesions of the midbrain (patient 16). e Axial FLAIR image shows bilateral small hypointense lesions (vacuoles) in the medulla oblongata (patient 16). f Axial FLAIR image demonstrates white matter lesions in the subcortical white matter (patient 8). g Axial FLAIR image demonstrates bilateral dentate nuclei hyperintensity (patient 10). h Axial FLAIR image shows areas of low signal intensity consistent with cerebellar vacuolation (patient 38). i Axial and l sagittal T2W images show cervical spinal cord involvement with white matter abnormalities in the lateral and dorsal columns (patient 38)
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Cerebrotendinous xanthomatosis (CTX) is a metabolic disease characterized by systemic signs and neurological impairment, which can be prevented if chenodeoxycholic acid (CDCA) treatment is started early. Despite brain MRI represents an essential diagnostic tool, the spectrum of findings is worth to be reappraised, and follow-up data are needed. We...
Citations
... In the context of this heterogeneity, Magnetic Resonance Imaging (MRI) plays a key role in the evaluation of these conditions, being crucial in the differential diagnosis process not only to exclude other underlying conditions possibly explaining the clinical phenotype, but also in the determination of the pattern of cerebellar involvement. From a neuroradiological standpoint, atrophy of the cerebellum is often the common denominator, and can represent sometimes the only imaging change detectable with conventional imaging in many of these conditions [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Indeed, in many cases the neuroradiological evaluation of these patients is primarily focused on the detection of this feature, often reported as a vague "cerebellar atrophy" and without a specific evaluation, detection and reporting of the possible selective involvement of the main structures of the cerebellum (e.g. ...
... In particular, if any infratentorial T2-weighted changes are found, these can be divided in three major patterns of signal changes: the presence of a bilateral hyperintensity of the DN, the presence of a HCB sign, and other signal changes affecting the infratentorial compartment. The presence of a bilateral DN T2-weighted involvement ( Fig. 4) can direct the diagnosis toward a relatively smaller group of conditions, which in terms of prevalence mostly should suggest Cerebrotendinous Xanthomatosis (CTX), Ataxia with Oculomotor Apraxia Type 1 (AOA1) and 2 (AOA2), Spastic Paraplegia Type 7 (SPG7), and the autosomal recessive Spinocerebellar Ataxia Type 10 (SCAR10) [4,5,8,10,25,26]. In the case of the presence of associated signal changes (i.e., a low signal in Susceptibility Weighted Imaging -SWI-surrounding the DN) a diagnosis of CTX can be suggested [8], while the evaluation of the age of onset can help distinguishing between AOA Type 1 and 2 (usually presenting with an onset before the 2nd decade) [27] and SPG7 or SCAR10 (usually presenting with an onset after the 2nd decade) [5,9,28]. ...
... The presence of a bilateral DN T2-weighted involvement ( Fig. 4) can direct the diagnosis toward a relatively smaller group of conditions, which in terms of prevalence mostly should suggest Cerebrotendinous Xanthomatosis (CTX), Ataxia with Oculomotor Apraxia Type 1 (AOA1) and 2 (AOA2), Spastic Paraplegia Type 7 (SPG7), and the autosomal recessive Spinocerebellar Ataxia Type 10 (SCAR10) [4,5,8,10,25,26]. In the case of the presence of associated signal changes (i.e., a low signal in Susceptibility Weighted Imaging -SWI-surrounding the DN) a diagnosis of CTX can be suggested [8], while the evaluation of the age of onset can help distinguishing between AOA Type 1 and 2 (usually presenting with an onset before the 2nd decade) [27] and SPG7 or SCAR10 (usually presenting with an onset after the 2nd decade) [5,9,28]. In the first case, the presence of Alpha-Fetoprotein (AFP) levels below 15 μg/L can orient the diagnosis towards AOA1 rather than AOA2 [29], while the occurrence of spastic paraplegia should suggest SPG7 above SCAR10 [30], that furthermore typically shows low Coenzyme Q10 (CoQ10) values [9]. ...
The complexity in diagnosing hereditary degenerative ataxias lies not only in their rarity, but also in the variety of different genetic conditions that can determine sometimes similar and overlapping clinical findings. In this light, Magnetic Resonance Imaging (MRI) plays a key role in the evaluation of these conditions, being a fundamental diagnostic tool needed not only to exclude other causes determining the observed clinical phenotype, but also to proper guide to an adequate genetic testing. Here, we propose an MRI-based diagnostic algorithm named CHARON (Characterization of Hereditary Ataxias Relying On Neuroimaging), to help in disentangling among the numerous, and apparently very similar, hereditary degenerative ataxias. Being conceived from a neuroradiological standpoint, it is based primarily on an accurate evaluation of the observed MRI findings, with the first and most important being the pattern of cerebellar atrophy. Along with the evaluation of the presence, or absence, of additional signal changes and/or supratentorial involvement, CHARON allows for the identification of a small groups of ataxias sharing similar imaging features. The integration of additional MRI findings, demographic, clinical and laboratory data allow then for the identification of typical, and in some cases pathognomonic, phenotypes of hereditary ataxias.
... Recently, some studies have shown that the cerebellar vacuolation on MRI could be a marker related to the poor prognosis of CTX patients. 19,20 Because of the positive effects of long-term consumption of CDCA in patients with CTX, as detailed in a study by Berginer in 1984, CDCA has been approved for use as a firstline treatment for CTX. 21 According to studies, the prognosis of CTX patients is affected by the age at diagnosis and the initiation of CDCA treatment. ...
Cerebrotendinous xanthomatosis (CTX) is a rare hereditary disease described by a mutation in the CYP27A1 gene, which encodes the sterol 27-hydroxylase enzyme involved in the synthesis of bile acid. Accumulation of cholesterol and its metabolite, cholestanol, in multiple body organs causes the symptoms of this disease. In addition, a mutation in the COG8 gene, which encodes a subunit of conserved oligomeric Golgi (COG) complex, causes another rare disorder attributed to type IIh of congenital disorder of glycosylation (CDG). We described a rare case of CTX disorder associated with a mutation on COG8 gene, which presented by unusual symptoms.
... Recently, some studies have shown that the cerebellar vacuolation on MRI could be a marker related to the poor prognosis of CTX patients. 19,20 Because of the positive effects of long-term consumption of CDCA in patients with CTX, as detailed in a study by Berginer in 1984, CDCA has been approved for use as a firstline treatment for CTX. 21 According to studies, the prognosis of CTX patients is affected by the age at diagnosis and the initiation of CDCA treatment. ...
Cerebrotendinous xanthomatosis (CTX) is a rare hereditary disease described by a mutation in the CYP27A1 gene, which encodes the sterol 27-hydroxylase enzyme involved in the synthesis of bile acid. Accumulation of cholesterol and its metabolite, cholestanol, in multiple body organs causes the symptoms of this disease. In addition, a mutation in the COG8 gene, which encodes a subunit of conserved oligomeric Golgi (COG) complex, causes another rare disorder attributed to type IIh of congenital disorder of glycosylation (CDG). We described a rare case of CTX disorder associated with a mutation on COG8 gene, which presented by unusual symptoms.
... MRI also gives an idea of the prognosis. Cerebellar vacuolation has been recently indicated as a marker of a poor prognosis in CTX, while the absence of dentate nuclei signal alteration is considered an indicator of a better prognosis [26]. The fact that imaging examinations were normal in our case may explain why the prognosis was better than that of his brothers. ...
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 outpatient clinic complaining of progressive worsening of his walking, and swelling in his legs. Mild mental retardation was detected in our patient. In addition to the visual impairment that would be explained by cataracts, he had xanthomas in both lower extremities. Signs related to bilateral cataract surgery and intraocular lens were detected during an eye examination. There were no abnormal findings in electroencephalography, electroneuromyography, and brain magnetic resonance imaging of the patient, whom we learned that her visual impairment started in childhood. The Mignarri Suscipion Index index was calculated as 275. A genetic examination was requested and the CYP27A1 gene was p.A216P (c.The mutation 646G>C) (CM044609) was detected as homozygous.
Conclusion
Due to the low awareness of CTX and the variability of its clinical findings, its diagnosis may be delayed for years, as in our patient. When diagnosed, most patients may have severe, often irreversible neurological damage. With the early recognition of the CTX and the start of treatment, patients can have a chance to quality life.
... CTX is also known to involve the central nervous system. Conventional MRI shows both supratentorial and infratentorial lesions with cortical and cerebellar atrophy, as well as nonspecific white matter hyperintensities in the subcortical, periventricular, and cerebellar white matter, brainstem, and dentate nucleus (Mignarri et al., 2017). Interestingly, CTX patients with cerebellar vacuolation showed detrimental outcomes. ...
Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disorder caused by 27-hydroxylase deficiency. We report the clinical characteristics of six Korean CTX patients. The median age of onset was 22.5 years, the median age at diagnosis was 42 years, and the diagnostic delay was 18.1 years. The most common clinical symptoms were tendon xanthoma and spastic paraplegia. Four of five patients exhibited latent central conduction dysfunction. All patients carried the same mutation in CYP27A1 (c.1214 G>A [p.R405Q]). CTX is a treatable neurodegenerative disorder; however, our results revealed that patients with CTX in Korea might receive the diagnosis after a prolonged delay.
... Outros achados da RMI incluem lesões hiperintensas em T2 e FLAIR na substância branca periventricular, cápsula interna, mesencéfalo, região anterior da ponte e no parênquima cerebelar, consistente com os achados da literatura comuns da RMI de pacientes com XCT 3 . Esses sinais ocorrem devido ao acúmulo de lipídio em células nervosas com desmielinização e degeneração axonal, especialmente nos estágios mais tardios da doença 3,9,10 . ...
Xantomatose cerebrotendínea (XCT) é uma doença congênita autossômica recessiva rara multissistêmica do metabolismo do ácido biliar que leva ao acúmulo de intermediários do colesterol em diversos tecidos. A principal manifestação da doença é o acometimento neurológico progressivo e irreversível, que inicia na infância e evolui com disfunção neurológica grave na fase adulta. Sintomas não neurológicos característicos como xantomas tendíneos, cataratas de início na infância e diarreia crônica infantil também podem estar presentes. No Brasil, não existe terapia medicamentosa para a doença. A principal abordagem terapêutica para retardar a progressão do quadro é o acompanhamento multidisciplinar com o objetivo de melhorar a qualidade de vida. Apesar dos sintomas iniciarem na infância, a maioria dos pacientes demora em média 16 anos para receber o diagnóstico, fase na qual o dano neurológico já é extenso e as abordagens terapêuticas não são mais eficazes. Neste estudo é relatado o caso de paciente de 47 anos com XCT que iniciou os sintomas na infância, com piora neurológica aos 38 anos e diagnóstico aos 44 anos, fase na qual a neurodegeneração já era grave e irreversível. Os testes laboratoriais e Imagem de Ressonância Magnética indicaram alterações características da doença. Ressalta-se a importância de ter a XTC como diagnóstico diferencial na presença de um quadro neurológico progressivo, amplo e variado, associado com xantomas tendíneos e outros sinais e sintomas específicos. Por tratar-se de doença crônica e degenerativa, o diagnóstico precoce é essencial para que se possa instituir medidas que melhorem a qualidade de vida.
... Our patient's gene sequencing results showed two mutation sites in CYP27A1: c.380G>A located on exon 2 and c.1563dupA located on exon 9. Among these, the mutation site c.380G>A has been reported previously [9], but the c.1563dupA mutation is novel and yet to be reported. As our patient possesses a known pathogenic mutation in CYP27A1, we are currently unable to determine whether the new gene mutation is pathogenic; further research is needed to confirm the same. ...
Background:
Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive metabolic disease caused by mutations in CYP27A1. It has a low incidence rate, insidious onset, and diverse clinical manifestations. It can be easily misdiagnosed and can go unrecognized by clinicians, leading to delayed treatment and worsened patient outcomes.
Case summary:
A 38-year-old male was admitted to our hospital with a history of unabating unstable posture and difficulty in walking for more than 30 years. Subsequently based on the patient's medical history, clinical symptoms, magnetic resonance imaging and gene sequencing results, he was finally diagnosed with CTX. Due to the low incidence rate of the disease, clinicians have insufficient knowledge of it, which makes the diagnosis process more tortuous and prolongs the diagnosis time.
Conclusion:
Prompt diagnosis and treatment of CTX improve patient outcomes.
... It was found that presence of significant neurological manifestations at the time of diagnosis was associated with a poor prognosis in CTX patients who were 25 years of age or older [8]. On MRI, cerebellar vacuolation has been recently indicated as a poor prognostic marker in CTX [19,20], while absence of dentate nuclei signal changes is associated with a better prognosis [20]. In the present siblings, CDCA treatment lead to a similar gradual decline in serum cholestanol, but the clinical courses were markedly different. ...
... It was found that presence of significant neurological manifestations at the time of diagnosis was associated with a poor prognosis in CTX patients who were 25 years of age or older [8]. On MRI, cerebellar vacuolation has been recently indicated as a poor prognostic marker in CTX [19,20], while absence of dentate nuclei signal changes is associated with a better prognosis [20]. In the present siblings, CDCA treatment lead to a similar gradual decline in serum cholestanol, but the clinical courses were markedly different. ...
Background
Cerebrotendinous 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 presentation
The 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).
Conclusions
Our 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.
... Other licensed and unlicensed therapies that have been used alone or in combination include cholic acid [14], 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) [14][15][16][17][18][19][20], low-density lipoprotein (LDL) apheresis [21][22][23], and ursodeoxycholic acid (despite not being effective in CTX) [24][25][26][27][28]. Treatment is therefore inconsistent and more specific guidelines on best treatment practices are required. Furthermore, the most appropriate tests for monitoring treatment efficacy and timing for these, is yet to be confirmed [4,29,30]. ...
... Whilst the value of MRI biomarkers toward revealing disease prognosis was indicated, their use for measuring clinical improvement compared with clinical scales requires further investigation, e.g. benefits during presymptomatic stages or during slow disease evolution [29]. Further research also needs to identify what follow-up tests/ examinations are appropriate based on the heterogenous clinical presentation of patients. ...
Background
Cerebrotendinous xanthomatosis (CTX) is a rare, chronic, progressive, neurodegenerative disorder requiring life-long care. Patients with CTX often experience a diagnostic delay. Although early diagnosis and treatment initiation can improve symptoms and prognosis, a standardised approach to diagnosis, treatment and management of patients is not yet established.
Aim
To assess expert opinion on best care practices for patients with CTX using a modified Delphi method.
Methods
A multidisciplinary group of healthcare professionals with expertise in CTX responded to a 3-round online questionnaire (n = 10 in Rounds 1 and 2; n = 9 in Round 3), containing questions relating to the diagnosis, treatment, monitoring, multidisciplinary care and prognosis of patients with CTX. Determination of consensus achievement was based on a pre-defined statistical threshold of ≥ 70% Delphi panellists selecting 1–2 (disagreement) or 5–6 (agreement) for 6-point Likert scale questions, or ≥ 70% Delphi panellists choosing the same option for ranking and proportion questions.
Results
Of the Round 1 (n = 22), Round 2 (n = 32) and Round 3 (n = 26) questions for which consensus was assessed, 59.1%, 21.9% and 3.8% reached consensus, respectively. Consensus agreement that genetic analyses and/or determination of serum cholestanol levels should be used to diagnose CTX, and dried bloodspot testing should facilitate detection in newborns, was reached. Age at diagnosis and early treatment initiation (at birth, where possible) were considered to have the biggest impact on treatment outcomes. All panellists agreed that chenodeoxycholic acid (CDCA) is a lifetime replacement therapy which, if initiated early, can considerably improve prognosis as it may be capable of reversing the pathophysiological process in CTX. No consensus was reached on the value of cholic acid therapy alone. Monitoring patients through testing plasma cholestanol levels and neurologic examination was recommended, although further research regarding monitoring treatment and progression of the disease is required. Neurologists and paediatricians/metabolic specialists were highlighted as key clinicians that should be included in the multidisciplinary team involved in patients’ care.
Conclusions
The results of this study provide a basis for standardisation of care and highlight key areas where further research is needed to inform best practices for the diagnosis, treatment and management of patients with CTX.
... 205 In line with this hypothesis, a correlation of dentate nuclei hyperintensity with cognitive impairment was reported. 28 Moreover, in various studies, we found that patients with cerebellum changes detected in MRI as a part of cognitive impairment presented with dysthymia, depression, behavioral changes, irritability, emotional lability, and anxiety. 13,21,22,28 However, such psychiatric and cognitive manifestations were also present in cases without evident cerebellar involvement. ...
... 28 Moreover, in various studies, we found that patients with cerebellum changes detected in MRI as a part of cognitive impairment presented with dysthymia, depression, behavioral changes, irritability, emotional lability, and anxiety. 13,21,22,28 However, such psychiatric and cognitive manifestations were also present in cases without evident cerebellar involvement. 28 Ultimately, in some cases, developmental defects of the nervous system could have a decisive influence on cognitive functions. ...
... 13,21,22,28 However, such psychiatric and cognitive manifestations were also present in cases without evident cerebellar involvement. 28 Ultimately, in some cases, developmental defects of the nervous system could have a decisive influence on cognitive functions. ...
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.
