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Aad Verrips - One of the best experts on this subject based on the ideXlab platform.

  • Cerebrotendinous Xanthomatosis associated diarrhea and response to chenodeoxycholic acid treatment
    JIMD reports, 2020
    Co-Authors: Eric P Brass, Bianca M. L. Stelten, Aad Verrips
    Abstract:

    Background In patients with Cerebrotendinous Xanthomatosis (CTX), chronic diarrhea is one of the earliest and main symptoms of the disease. In the current study, we evaluated the characteristics of the diarrhea and its response to chenodeoxycholic acid (CDCA) therapy in a cohort of Dutch CTX patients. Methods We performed a retrospective review of medical records for 33 genetically confirmed CTX patients, and abstracted the characteristics of the diarrhea and the response to CDCA therapy (15 mg/kg/day up to 750 mg/day). The Bristol Stool Scale (BSS) was used for qualitative characterization of the stool. Results Twenty-five patients had diarrhea documented at baseline (76%). Of these patients, 10 had diarrhea rated as 6 (fluffy pieces with ragged edges, a mushy stool), and 6 had diarrhea rated as 7 (watery, no solid pieces, entirely liquid) using the BSS. In 10 patients for whom data were recorded, the median stool frequency at baseline was 3 per day (range 2-6 per day). The response rate with CDCA for diarrhea resolution was 100% based on at least one post-baseline visit without diarrhea and 95% as assessed at the first post-baseline visit. In 68% of cases resolution was complete and sustained as no episodes of diarrhea were documented for follow-up periods as long as 25 years. Conclusions Chronic diarrhea persisting for years without spontaneous remission is a common feature of CTX at diagnosis. Chenodeoxycholic acid is an effective treatment for symptomatic relief of diarrhea in patients with CTX.

  • Cerebellar Disease Mimicking Cerebrotendinous Xanthomatosis: Langerhans Cell Histiocytosis
    Pediatric Neurology, 2017
    Co-Authors: Bianca M. L. Stelten, Ron A Wevers, Marjo S. Van Der Knaap, Aad Verrips
    Abstract:

    Abstract Background This report highlights the differential diagnosis of predominant cerebellar white matter abnormalities with dentate nuclei involvement. Patient description We describe two individuals with Langerhans cell histiocytosis in whom the diagnosis of Cerebrotendinous Xanthomatosis was initially considered. The clinical picture consisted of a progressive cerebellar syndrome with typical magnetic resonance imaging abnormalities. In both individuals, the cerebellar syndrome preceded the diagnosis of Langerhans cell histiocytosis. Conclusions The magnetic resonance imaging abnormalities and neurological features in patients with Langerhans cell histiocytosis can be strikingly similar to those with Cerebrotendinous Xanthomatosis. In Cerebrotendinous Xanthomatosis, the cerebellar symptoms and cerebellar white matter abnormalities are usually seen in adult patients. In a pediatric patient with a cerebellar syndrome, showing these cerebellar white matter abnormalities a diagnosis of Langerhans cell histiocytosis is more likely.

  • hepatotoxicity due to chenodeoxycholic acid supplementation in an infant with Cerebrotendinous Xanthomatosis implications for treatment
    European Journal of Pediatrics, 2016
    Co-Authors: Aad Verrips, Hidde H Huidekoper, Annet M Bosch
    Abstract:

    We present a two-week old girl who was diagnosed with Cerebrotendinous Xanthomatosis (CTX), an inborn error of bile acid synthesis, after a diagnostic workup for convulsions which were shown to be caused by a parechovirus encephalitis. The diagnosis of CTX was confirmed with CYP27A1 mutation analysis. She was started on chenodeoxycholic acid (CDCA) supplementation, which inhibits cholestanol production through a feedback mechanism, at the advised dosage of 15 mg/kg/day. Within 6 weeks, she developed jaundice with hepatomegaly. CDCA supplementation was stopped after which liver size and function rapidly normalised. CDCA supplementation was then restarted and maintained at 5 mg/kg/day. Cholestanol, liver enzymes and total bilirubin were frequently monitored in the patient, who is now 2.8 years of age, and have remained within normal range. Her psychomotor development has been normal.

  • unusual Cerebrotendinous Xanthomatosis with fronto temporal dementia phenotype
    American Journal of Medical Genetics Part A, 2005
    Co-Authors: L Guyantmarechal, Aad Verrips, Ron A Wevers, Carole Girard, Fokje Zijlstra, Erik A Sistermans, Pierre Vera, Dominique Campion, Didier Hannequin
    Abstract:

    Cerebrotendinous Xanthomatosis (CTX) is an autosomal recessive lipid storage disease caused by a deficiency of the mitochondrial enzyme 27-sterol hydroxylase (CYP27). We report a 53-year-old man, with an unusual phenotype of CTX. He had xanthomas since adolescence. He had no mental retardation and developed at 44 years a progressive neuropsychiatric phenotype, suggestive of fronto-temporal dementia according to clinical Neary criteria. Cataract and ataxia were absent. Cerebral MRI revealed diffuse hyperintense T2 abnormalities in the supratentorial white matter without cerebellar atrophy or lesions, while Technetium-99m-ECD brain SPECT revealed a severe cerebellar hypoperfusion. Serum cholestanol level was elevated with excessive urinary bile alcohols excretion. Mutation analysis revealed that he was compound heterozygous for two mutations in the CYP27A1 gene: 1016 C > T (exon 5) on one allele and a novel mutation, 1435C > G (exon 8) on the other allele. A follow-up study was conducted to evaluate the effects of chenodeoxycholic acid (CDCA) and simvastatin treatment during 3 years. In spite of this treatment, cognitive functions declined but no other signs of neurological deterioration appeared.

  • Cerebrotendinous Xanthomatosis the spectrum of imaging findings and the correlation with neuropathologic findings
    Radiology, 2000
    Co-Authors: Frederik Barkhof, Aad Verrips, Ron A Wevers, B G M Van Engelen, Pieter Wesseling, M S Van Der Knaap, F J M Gabreels, A J M Keyser, J Valk
    Abstract:

    PURPOSE: To describe imaging findings and their neuropathologic correlate in patients with Cerebrotendinous Xanthomatosis (CTX). MATERIALS AND METHODS: Computed tomographic (CT) and magnetic resonance (MR) images in 24 patients with symptoms (mean age at time of imaging, 37 years; mean disease duration, 18 years) were reviewed for site and frequency of brain, spinal cord, and Achilles tendon involvement. Two patients died, and imaging findings were compared with postmortem neuropathologic findings. RESULTS: Apart from nonspecific supratentorial atrophy and deep white matter changes, more typical hyperintense lesions were seen on T2-weighted images in the dentate nucleus (in 79% of patients), globus pallidus, substantia nigra, and inferior olive and extended into adjacent white matter as disease progressed. In these locations, lipid crystal clefts and perivascular macrophages, neuronal loss, demyelination, fibrosis, and reactive astrocytosis were found at microscopic examination. Hypointensity was sometime...

Ron A Wevers - One of the best experts on this subject based on the ideXlab platform.

  • Cerebrotendinous Xanthomatosis without neurological involvement
    Journal of Internal Medicine, 2021
    Co-Authors: Bianca M. L. Stelten, Ron A Wevers, Frederick J Raal, A D Marais, Niels P Riksen, J Roeters E Van Lennep, P B Duell, M Van Der Graaf, Leo A J Kluijtmans, A Verrips
    Abstract:

    Background Cerebrotendinous Xanthomatosis (CTX) is an autosomal recessively inherited inborn error of metabolism. Neurological symptoms are considered to be a clinical hallmark of untreated adult patients. We describe a 'milder CTX phenotype', without neurological involvement. Methods We performed a retrospective patient file study in 79 genetically confirmed Dutch patients with CTX (55 patients aged ≥ 21 years) to study the clinical heterogeneity of CTX. We studied the frequency of adult patients with CTX without neurological involvement at diagnosis, in our Dutch cohort, and included a family from South Africa and patients from Italy, USA, Chile and Asia from the literature. Results In total, we describe 19 adult patients with CTX from 16 independent families, without neurological symptoms at diagnosis. A relatively small percentage (21%, n = 4) had a history of cataract. The majority, 84% (n = 16), presented with tendon xanthomas as the sole or predominant feature. The majority of patients showed increased plasma cholesterol levels. No correlation was found between this 'milder phenotype', the cholestanol levels and the CYP27A1 genotype. In addition, we describe three novel mutations in the CYP27A1 gene. Conclusions This study shows the clinical heterogeneity of CTX, highlighting the existence of a 'milder phenotype', that is without neurological involvement at diagnosis. Adult patients with CTX may present with tendon xanthomas as the sole or predominant feature, mimicking familial hypercholesterolemia. It is important to realize that the absence of neurological symptoms does not rule out the development of future neurological symptoms. As CTX is a treatable disorder, early diagnosis and initiation of treatment when additional clinical signs occur is therefore essential.

  • Cerebellar Disease Mimicking Cerebrotendinous Xanthomatosis: Langerhans Cell Histiocytosis
    Pediatric Neurology, 2017
    Co-Authors: Bianca M. L. Stelten, Ron A Wevers, Marjo S. Van Der Knaap, Aad Verrips
    Abstract:

    Abstract Background This report highlights the differential diagnosis of predominant cerebellar white matter abnormalities with dentate nuclei involvement. Patient description We describe two individuals with Langerhans cell histiocytosis in whom the diagnosis of Cerebrotendinous Xanthomatosis was initially considered. The clinical picture consisted of a progressive cerebellar syndrome with typical magnetic resonance imaging abnormalities. In both individuals, the cerebellar syndrome preceded the diagnosis of Langerhans cell histiocytosis. Conclusions The magnetic resonance imaging abnormalities and neurological features in patients with Langerhans cell histiocytosis can be strikingly similar to those with Cerebrotendinous Xanthomatosis. In Cerebrotendinous Xanthomatosis, the cerebellar symptoms and cerebellar white matter abnormalities are usually seen in adult patients. In a pediatric patient with a cerebellar syndrome, showing these cerebellar white matter abnormalities a diagnosis of Langerhans cell histiocytosis is more likely.

  • unusual Cerebrotendinous Xanthomatosis with fronto temporal dementia phenotype
    American Journal of Medical Genetics Part A, 2005
    Co-Authors: L Guyantmarechal, Aad Verrips, Ron A Wevers, Carole Girard, Fokje Zijlstra, Erik A Sistermans, Pierre Vera, Dominique Campion, Didier Hannequin
    Abstract:

    Cerebrotendinous Xanthomatosis (CTX) is an autosomal recessive lipid storage disease caused by a deficiency of the mitochondrial enzyme 27-sterol hydroxylase (CYP27). We report a 53-year-old man, with an unusual phenotype of CTX. He had xanthomas since adolescence. He had no mental retardation and developed at 44 years a progressive neuropsychiatric phenotype, suggestive of fronto-temporal dementia according to clinical Neary criteria. Cataract and ataxia were absent. Cerebral MRI revealed diffuse hyperintense T2 abnormalities in the supratentorial white matter without cerebellar atrophy or lesions, while Technetium-99m-ECD brain SPECT revealed a severe cerebellar hypoperfusion. Serum cholestanol level was elevated with excessive urinary bile alcohols excretion. Mutation analysis revealed that he was compound heterozygous for two mutations in the CYP27A1 gene: 1016 C > T (exon 5) on one allele and a novel mutation, 1435C > G (exon 8) on the other allele. A follow-up study was conducted to evaluate the effects of chenodeoxycholic acid (CDCA) and simvastatin treatment during 3 years. In spite of this treatment, cognitive functions declined but no other signs of neurological deterioration appeared.

  • Cerebrotendinous Xanthomatosis the spectrum of imaging findings and the correlation with neuropathologic findings
    Radiology, 2000
    Co-Authors: Frederik Barkhof, Aad Verrips, Ron A Wevers, B G M Van Engelen, Pieter Wesseling, M S Van Der Knaap, F J M Gabreels, A J M Keyser, J Valk
    Abstract:

    PURPOSE: To describe imaging findings and their neuropathologic correlate in patients with Cerebrotendinous Xanthomatosis (CTX). MATERIALS AND METHODS: Computed tomographic (CT) and magnetic resonance (MR) images in 24 patients with symptoms (mean age at time of imaging, 37 years; mean disease duration, 18 years) were reviewed for site and frequency of brain, spinal cord, and Achilles tendon involvement. Two patients died, and imaging findings were compared with postmortem neuropathologic findings. RESULTS: Apart from nonspecific supratentorial atrophy and deep white matter changes, more typical hyperintense lesions were seen on T2-weighted images in the dentate nucleus (in 79% of patients), globus pallidus, substantia nigra, and inferior olive and extended into adjacent white matter as disease progressed. In these locations, lipid crystal clefts and perivascular macrophages, neuronal loss, demyelination, fibrosis, and reactive astrocytosis were found at microscopic examination. Hypointensity was sometime...

  • clinical and molecular genetic characteristics of patients with Cerebrotendinous Xanthomatosis
    Brain, 2000
    Co-Authors: Aad Verrips, Ron A Wevers, F J M Gabreels, Lies H Hoefsloot, Gerry Steenbergen, Joop P Theelen, Baziel G M Van Engelen, Lambert P Van Den Heuvel
    Abstract:

    Cerebrotendinous Xanthomatosis (CTX) is a lipid storage disease caused by a deficiency of the mitochondrial enzyme 27-sterol hydroxylase (CYP 27), due to mutations in its gene. In this study we report on mutations in 58 patients with CTX out of 32 unrelated families. Eight of these were novel mutations, two of which were found together with two already known pathogenic mutations. Twelve mutations found in this patient group have been described in the literature. In the patients from 31 families, mutations were found in both alleles. In the literature, 28 mutations in 67 patients with CTX out of 44 families have been described. Pooling our patient group and the patients from the literature together, 37 different mutations in 125 patients out of 74 families were obtained. Identical mutations have been found in families from different ethnic backgrounds. In 41% of all the patients, CYP 27 gene mutations are found in the region of exons 6-8. This region encodes for adrenodoxin and haem binding sites of the protein. Of these 125 patients, a genotype-phenotype analysis was done for 79 homozygous patients harbouring 23 different mutations, out of 45 families. The patients with compound heterozygous mutations were left out of the genotype-phenotype analysis. The genotype-phenotype analysis did not reveal any correlation.

Hoshita Takahiko - One of the best experts on this subject based on the ideXlab platform.

Une Mizuho - One of the best experts on this subject based on the ideXlab platform.

Ingemar Bjorkhem - One of the best experts on this subject based on the ideXlab platform.

  • unique case of Cerebrotendinous Xanthomatosis revisited all the mutations responsible for this disease are present in the cyp27a1 gene
    Journal of Internal Medicine, 2018
    Co-Authors: H Jiao, M Hansson, Maria Olin, Gosta Eggertsen, Mats Eriksson, Bo Angelin, Ingemar Bjorkhem
    Abstract:

    Cerebrotendinous Xanthomatosis (CTX) is a rare recessive disorder believed to be exclusively caused by mutations in the CYP27A1 gene coding for the enzyme sterol 27-hydroxylase. The disease is characterized by tendon xanthomas, juvenile cataract, progressive dementia, chronic diarrhea, osteoporosis, ataxia and premature atherosclerosis. Xanthomas also often occur in the brain, in particular in cerebellum (1). This article is protected by copyright. All rights reserved.

  • evaluation of cholesterol metabolism in Cerebrotendinous Xanthomatosis
    Journal of Inherited Metabolic Disease, 2016
    Co-Authors: Andrea Mignarri, Ingemar Bjorkhem, Marina Del Puppo, Antonio Federico, Gian Nicola Gallus, Alessandro Magni, Maria Teresa Dotti
    Abstract:

    Cerebrotendinous Xanthomatosis (CTX) is a treatable bile acid disorder caused by mutations of CYP27A1. The pathogenesis of neurological damage has not been completely explained. Oral chenodeoxycholic acid (CDCA) can lead to clinical stabilization, but in a subgroup of patients the disease progresses despite treatment. In the present study, we aimed at clarifying cholesterol metabolism abnormalities and their response to CDCA treatment, in order to identify reliable diagnostic and prognostic markers and understand if differences exist between stable patients and those with neurological progression. We enrolled 19 untreated CTX patients and assessed serum profile of bile acids intermediates, oxysterols, cholesterol, lathosterol, and plant sterols. Then we performed a long-term follow up during CDCA therapy, and compared biochemical data with neurological outcome. We observed increase of cholestanol, 7α-hydroxy-4-cholesten-3-one (7αC4), lathosterol, and plant sterols, whereas 27-hydroxycholesterol (27-OHC) was extremely low or absent. CDCA treatment at a daily dose of 750 mg normalized all biochemical parameters except for 7αC4 which persisted slightly higher than normal in most patients, and 27-OHC which was not modified by therapy. Biochemical evaluation did not reveal significant differences between stable and worsening patients. Cholestanol and 7αC4 represent important markers for CTX diagnosis and monitoring of therapy. Treatment with CDCA should aim at normalizing serum 7αC4 as well as cholestanol, since 7αC4 better mirrors 7α-hydroxylation rate and is thought to be correlated with cholestanol accumulation in the brain. Assessment of serum 27-OHC is a very good tool for biochemical diagnosis at any stage of disease. Lathosterol and plant sterols should be considered as additional markers for diagnosis and monitoring of therapy. Further studies including long-term assessment of bile acid intermediates in cerebrospinal fluid are needed in patients who show clinical progression despite treatment.

  • on the mechanism of cerebral accumulation of cholestanol in patients with Cerebrotendinous Xanthomatosis
    Journal of Lipid Research, 2007
    Co-Authors: Ute Panzenboeck, Magnus Hansson, Ulla Andersson, Wolfgang Sattler, Steve Meaney, Ingemar Bjorkhem
    Abstract:

    The most serious consequence of sterol 27-hydroxylase deficiency in humans [Cerebrotendinous Xanthomatosis (CTX)] is the development of cholestanol-containing brain xanthomas. The cholestanol in the brain may be derived from the circulation or from 7alpha-hydroxylated intermediates in bile acid synthesis, present at 50- to 250-fold increased levels in plasma. Here, we demonstrate a transfer of 7alpha-hydroxy-4-cholesten-3-one across cultured porcine brain endothelial cells (a model for the blood-brain barrier) that is approximately 100-fold more efficient than the transfer of cholestanol. Furthermore, there was an efficient conversion of 7alpha-hydroxy-4-cholesten-3-one to cholestanol in cultured neuronal and glial cells as well as in monocyte-derived macrophages of human origin. It is concluded that the continuous intracellular production of cholestanol from a bile acid precursor capable of rapidly passing biomembranes, including the blood-brain barrier, is likely to be of major importance for the accumulation of cholestanol in patients with CTX. Such a mechanism also fits well with the observation that treatment with chenodeoxycholic acid, which normalizes the level of the bile acid precursor, results in a reduction of cholestanol-containing xanthomas even in the brain.

  • Cerebrotendinous Xanthomatosis in the israeli druze molecular genetics and phenotypic characteristics
    American Journal of Human Genetics, 1994
    Co-Authors: Eran Leitersdorf, Ingemar Bjorkhem, Siman Morkos, Ayeleth Reshef, Vardiella Meiner, R Safadi, Yechiel Friedlander, V M Berginer
    Abstract:

    Cerebrotendinous Xanthomatosis (CTX) is an autosomal recessive lipid-storage disease caused by mutations in the sterol 27 hydroxylase gene (CYP27). Clinically, a multitude of neurological, skeletal, and vascular manifestions are usually present. Premature atherosclerosis has been reported in CTX and may be related to the metabolic derangement caused by the deficiency of the enzyme. A CYP27 nonsense mutation created by the deletion of cytosine{sub 376} has been identified in four Israeli Druze CTX patients residing in the same village. Molecular screening for this mutation in families of two probands revealed a total of 10 homozygotes and 28 heterozygotes whose clinical and biochemical characteristics are described. Overall, except for tendon xanthomas, most of the clinical manifestions progress with age. The CYP27 mutation was associated with modest differences in the levels of plasma total cholesterol (TC) and LDL cholesterol (LDL-C). The distribution of plasma concentrations of TC and LDL-C in the CTX families was consistent with a polygenic model. A similar model that includes also the effects of the CYP27 genotypes was not better supported by the data. It may be concluded that, in CTX, the presence of a CYP27 mutation does not significantly affect the plasma concentrations of lipids and lipoproteins. Therefore,more » the reported increased prevalence of atherosclerosis in this disease must be related to other factors. 34 refs., 3 figs., 4 tabs.« less