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Viktor Kožich - One of the best experts on this subject based on the ideXlab platform.
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Homocystinuria patient and caregiver survey experiences of diagnosis and patient satisfaction
Orphanet Journal of Rare Diseases, 2021Co-Authors: T Morrison, Viktor Kožich, F Bosch, Markus A Landolt, Martina Huemer, Andrew A M MorrisAbstract:The main genetic causes of Homocystinuria are cystathionine beta-synthase (CBS) deficiency and the remethylation defects. Many patients present in childhood but milder forms may present later in life. Some countries have newborn screening programs for the Homocystinurias but these do not detect all patients. HCU Network Australia is one of the very few support groups for patients with Homocystinurias. Here we report the results of its survey of 143 patients and caregivers from 22 countries, evaluating current diagnostic pathways and management for the Homocystinurias. Most (110) of the responses related to patients with CBS deficiency. The diagnosis was made by newborn screening in 20% of patients and in 50% of the others within 1 year of the initial symptom but in 12.5% it took over 15 years. The delay was attributed mainly to ignorance of the disease. Physicians need to learn to measure homocysteine concentrations in children with neurodevelopmental problems, and in patients with heterogeneous symptoms such as thromboembolism, dislocation of the optic lens, haemolytic uraemic syndrome, and psychiatric disease. Even when the diagnosis is made, the way it is communicated is sometimes poor. Early-onset CBS deficiency usually requires a low-protein diet with amino acid supplements. More than a third of the participants reported problems with the availability or cost of treatment. Only half of the patients always took their amino acid mixture. In contrast, good adherence to the protein restriction was reported in 98% but 80% said it was hard, time-consuming and caused unhappiness. There is often a long delay in diagnosing the Homocystinurias unless this is achieved by newborn screening; this survey also highlights problems with the availability and cost of treatment and the palatability of protein substitutes.
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enzyme replacement with pegylated cystathionine β synthase ameliorates Homocystinuria in murine model
Journal of Clinical Investigation, 2016Co-Authors: Erez M Bublil, Tomas Majtan, Viktor Kožich, Insun Park, Jakub Krijt, Richard S Carrillo, Helena Hůlkova, Jan P. KrausAbstract:Homocystinuria, which typically results from cystathionine β-synthase (CBS) deficiency, is the most common defect of sulfur amino acid metabolism. CBS condenses homocysteine and serine to cystathionine that is then converted to cysteine. Individuals with Homocystinuria have markedly elevated plasma levels of homocysteine and methionine and reduced concentrations of cystathionine and cysteine. Clinical disease manifestations include thromboembolism and neuropsychiatric, ocular, and skeletal complications. Here, we have shown that administration of PEGylated CBS into the circulation of Homocystinuria model mice alters the extra- and intracellular equilibrium of sulfur amino acids, resulting in a decrease of approximately 75% in plasma total homocysteine (tHcy) and normalization of cysteine concentrations. Moreover, the decrease in homocysteine and the normalization of cysteine in PEGylated CBS-treated model mice were accompanied by improvement of histopathological liver symptoms and increased survival. Together, these data suggest that CBS enzyme replacement therapy (ERT) is a promising approach for the treatment of Homocystinuria and that ERT for metabolic diseases may not necessitate introduction of the deficient enzyme into its natural intracellular compartment.
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Vascular presentation of cystathionine beta-synthase deficiency in adulthood
Journal of Inherited Metabolic Disease, 2011Co-Authors: Martin Magner, Josef Hyánek, Lucie Krupková, Tomáš Honzík, Jiří Zeman, Viktor KožichAbstract:Several recent studies describing a solely vascular presentation of cystathionine beta-synthase (CBS) deficiency in adulthood prompted us to analyze the frequency of patients manifesting with vascular complications in the Czech Republic. Between 1980 and 2009, a total of 20 Czech patients with CBS deficiency have been diagnosed yielding an incidence of 1:311,000. These patients were divided into three groups based on symptoms leading to diagnosis: those with vascular complications, with connective tissue manifestation and with neurological presentation. A vascular event such as a clinical feature leading to diagnosis of Homocystinuria was present in five patients, while two of them had no other symptoms typical for CBS deficiency at the time of diagnosis. All patients with the vascular manifestation were diagnosed only during the past decade. The median age of diagnosis was 29 years in the vascular, 11.5 years in the connective tissue and 4.5 years in the neurological group. The ratio of pyridoxine responsive to nonresponsive patients was higher in the vascular (4 of 5 patients) and connective tissue groups (6 of 7 patients) than in the neurological group (2 of 8 patients). Mutation c.833T>C (p.I278T) was frequent in patients with vascular (6/10 alleles) and connective tissue presentation (8/14 alleles), while it was not present in patients with neurological involvement (0/16 alleles). During the last decade, we have observed patients with Homocystinuria diagnosed solely due to vascular events; this milder form of Homocystinuria usually manifests at greater ages, has a high ratio of pyridoxine responsiveness/nonresponsiveness, and the mutation c.833T>C (p.I278T) is often present.
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cystathionine beta synthase null homocystinuric mice fail to exhibit altered hemostasis or lowering of plasma homocysteine in response to betaine treatment
Molecular Genetics and Metabolism, 2010Co-Authors: Kenneth N Maclean, Viktor Kožich, Jakub Sikora, Hua Jiang, Lori S Greiner, Eva Kraus, Jakub Krijt, Linda S Crnic, Robert H Allen, Sally P StablerAbstract:Cystathionine beta-synthase (CBS) deficient Homocystinuria is an inherited metabolic defect that if untreated typically results in mental retardation, thromboembolism and a range of connective tissue disturbances. A knockout mouse model has previously been used to investigate pathogenic mechanisms in classical Homocystinuria (Watanabe et al., PNAS 92 (1995) 1585–1589). This mouse model exhibits a semi-lethal phenotype and the majority of mice do not survive the early neonatal period. We report here that the birth incidence of cbs (−/−) mice produced from heterozygous crosses is non-Mendelian and not significantly improved by treatment with either the Hcy lowering compound betaine or the cysteine donor N-acetylcysteine. Betaine treatment did improve survival of cbs (−/−) mice and restored fertility to female cbs (−/−) mice but did so without significantly lowering Hcy levels. Surviving cbs (−/−) mice failed to show any alteration in coagulation parameters compared to wild-type controls. Moribund cbs (−/−) mice exhibited severe liver injury and hepatic fibrosis while surviving cbs (−/−) mice although less severely affected, still exhibited a level of severe liver injury that is not found in the human disease. The hepatopathy observed in this model may offer an explanation for the failure of cbs (−/−) mice to respond to betaine or exhibit a hypercoagulative phenotype. We conclude that although this model provides useful data on the biochemical sequelae of classical Homocystinuria, it does not successfully recapitulate a number of important features of the human disease and its use for studying mechanisms in Homocystinuria should be treated with caution as the hepatopathy produces changes which could influence the results.
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a novel transgenic mouse model of cbs deficient Homocystinuria does not incur hepatic steatosis or fibrosis and exhibits a hypercoagulative phenotype that is ameliorated by betaine treatment
Molecular Genetics and Metabolism, 2010Co-Authors: Kenneth N Maclean, Viktor Kožich, Jakub Sikora, Hua Jiang, Lori S Greiner, Eva Kraus, Jakub Krijt, Katherine H Overdier, Renata Collard, Gary BrodskyAbstract:Cystathionine beta-synthase (CBS) catalyzes the condensation of homocysteine (Hcy) and serine to cystathionine, which is then hydrolyzed to cysteine by cystathionine gamma-lyase. Inactivation of CBS results in CBS-deficient Homocystinuria more commonly referred to as classical Homocystinuria, which, if untreated, results in mental retardation, thromboembolic complications, and a range of connective tissue disorders. The molecular mechanisms that underlie the pathology of this disease are poorly understood. We report here the generation of a new mouse model of classical Homocystinuria in which the mouse cbs gene is inactivated and that exhibits low-level expression of the human CBS transgene under the control of the human CBS promoter. This mouse model, designated “human only” (HO), exhibits severe elevations in both plasma and tissue levels of Hcy, methionine, S-adenosylmethionine, and S-adenosylhomocysteine and a concomitant decrease in plasma and hepatic levels of cysteine. HO mice exhibit mild hepatopathy but, in contrast to previous models of classical Homocystinuria, do not incur hepatic steatosis, fibrosis, or neonatal death with approximately 90% of HO mice living for at least 6 months. Tail bleeding determinations indicate that HO mice are in a hypercoagulative state that is significantly ameliorated by betaine treatment in a manner that recapitulates the disease as it occurs in humans. Our findings indicate that this mouse model will be a valuable tool in the study of pathogenesis in classical Homocystinuria and the rational design of novel treatments.
Bernard A. Cooper - One of the best experts on this subject based on the ideXlab platform.
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thermolability of residual methylene tetrahydrofolate reductase mr activity methionine synthase activity and methyl cobalamin levels in cultured fibroblasts from patients with mr deficiency
Advances in Experimental Medicine and Biology, 1993Co-Authors: David S Rosenblatt, H Lueshing, Nora V Matiaszuk, L Lownang, A Arzoumanian, Bernard A. CooperAbstract:The clinical findings in patients with MR deficiency, the most common inborn error of folate metabolism, range from death in infancy to asymptomatic Homocystinuria in adulthood (1–8). Patients may have developmental delay, psychiatric manifestations, and gait abnormalities. The biochemical manifestations include moderate Homocystinuria and homocystinemia. Plasma methionine levels are usually low or normal. In contrast to patients with functional deficiencies of methionine synthase (cblE, cblG), megaloblastic anemia is not found. There is a correlation between the proportion of methyltetrahydrofolate in extracts of cultured fibroblasts, the residual MR activity, and the clinical severity of the disease (9–11). Genetic heterogeneity of MR deficiency was suggested when we observed varying patterns of thermostability at 55° in fibroblast extracts (9).
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thermolability of residual methylenetetrahydrofolate reductase mr activity methionine synthase activity and methyl cobalamin levels in cultured fibroblasts from patients with mr deficiency
Advances in Experimental Medicine and Biology, 1993Co-Authors: David S Rosenblatt, H Lueshing, Nora V Matiaszuk, L Lownang, A Arzoumanian, Bernard A. CooperAbstract:The clinical findings in patients with MR deficiency, the most common inborn error of folate metabolism, range from death in infancy to asymptomatic Homocystinuria in adulthood (1–8). Patients may have developmental delay, psychiatric manifestations, and gait abnormalities. The biochemical manifestations include moderate Homocystinuria and homocystinemia. Plasma methionine levels are usually low or normal. In contrast to patients with functional deficiencies of methionine synthase (cblE, cblG), megaloblastic anemia is not found. There is a correlation between the proportion of methyltetrahydrofolate in extracts of cultured fibroblasts, the residual MR activity, and the clinical severity of the disease (9–11). Genetic heterogeneity of MR deficiency was suggested when we observed varying patterns of thermostability at 55° in fibroblast extracts (9).
David Watkins - One of the best experts on this subject based on the ideXlab platform.
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clinical biochemical and molecular presentation in a patient with the cbld Homocystinuria inborn error of cobalamin metabolism
JIMD reports, 2014Co-Authors: David Watkins, David S Rosenblatt, Isabelle R Miousse, Celia Atkinson, Julian RaimanAbstract:Disorders of intracellular cobalamin (vitamin B12) metabolism result from deficient synthesis of the coenzymes derived from vitamin B12: adenosylcobalamin and methylcobalamin. Disturbances of cobalamin-cofactor synthesis result in elevated levels of homocysteine and/or methylmalonic acid. Nine defects of intracellular cobalamin metabolism have been defined. The most common of these disorders is cblC (combined methylmalonic aciduria and Homocystinuria). The cblD disorder is rare with fewer than twenty cases reported in the literature. Some cblD patients have combined methylmalonic aciduria and Homocystinuria (referred to as “cblD original,” “cblD-combined,” or herein “cblD-MMA/HC”); some have isolated Homocystinuria (referred to as “cblD-variant 1” or herein “cblD-HC”); and others have isolated methylmalonic aciduria (called “cblD-variant 2” or herein “cblD-MMA”). Only six cases of cblD-HC have been defined thus far. We report the 7th case of cblD-HC. The clinical manifestations, biochemical profile, genetic mutation, and plausible ancestry are discussed.
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clinical and molecular heterogeneity in patients with the cbld inborn error of cobalamin metabolism
The Journal of Pediatrics, 2009Co-Authors: Isabelle R Miousse, David Watkins, David Coelho, Tony Rupar, Eric Crombez, Eric Vilain, Jonathan A Bernstein, Tina M Cowan, Christopher Leemesser, Gregory M EnnsAbstract:Objectives To describe 3 patients with the cblD disorder, a rare inborn error of cobalamin metabolism caused by mutations in the MMADHC gene that can result in isolated Homocystinuria, isolated methylmalonic aciduria, or combined Homocystinuria and methylmalonic aciduria. Study design Patient clinical records were reviewed. Biochemical and somatic cell genetic studies were performed on cultured fibroblasts. Sequence analysis of the MMADHC gene was performed on patient DNA. Results Patient 1 presented with isolated methylmalonic aciduria, patient 3 with isolated Homocystinuria, and patient 2 with combined methylmalonic aciduria and Homocystinuria. Studies of cultured fibroblasts confirmed decreased synthesis of adenosylcobalamin in patient 1, decreased synthesis of methylcobalamin in patient 3, and decreased synthesis of both cobalamin derivatives in patient 2. The diagnosis of cblD was established in each patient by complementation analysis. Mutations in the MMADHC gene were identified in all patients. Conclusions The results emphasize the heterogeneous clinical, cellular and molecular phenotype of the cblD disorder. The results of molecular analysis of the MMADHC gene are consistent with the hypothesis that mutations affecting the N terminus of the MMADHC protein are associated with methylmalonic aciduria, and mutations affecting the C terminus are associated with Homocystinuria.
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identification of the gene responsible for methylmalonic aciduria and Homocystinuria cblc type
Nature Genetics, 2006Co-Authors: Jordan P Lernerellis, Jamie C Tirone, Janet L Atkinson, Carole Dore, David Watkins, Peter D Pawelek, Chantal F. MorelAbstract:Identification of the gene responsible for methylmalonic aciduria and Homocystinuria, cblC type
Christian Denier - One of the best experts on this subject based on the ideXlab platform.
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a case of Homocystinuria due to cbs gene mutations revealed by cerebral venous thrombosis
Journal of the Neurological Sciences, 2014Co-Authors: Mariana Sarov, Adeline Not, Helene Ogier De Baulny, Pascal Masnou, K Vahedi, M G Bousser, Christian DenierAbstract:Abstract Background Homocystinuria caused by cystathionine beta synthase (CBS) deficiency is most often diagnosed in childhood and has a variable expressivity. The most frequent abnormalities include intellectual disability, ectopia lentis, myopia, skeletal abnormalities or thromboembolism. Objective To report a case of Homocystinuria unraveled by cerebral venous thrombosis (CVT). Observation A 17 year old female was admitted in our department of neurology for subacute headache and presented seizures in the emergency room. Cerebral imaging revealed CVT. Severe hyperhomocysteinemia was found and led to the diagnosis of Homocystinuria due to composite heterozygous mutations in the CBS gene. Further investigations disclosed lens subluxation in association with myopia, mild scoliosis and osteopenia. The patient was treated by heparin followed by warfarin, vitamin therapy and dietary methionine restriction. Total homocysteine and methionine levels became normal in a few weeks and the patient had a complete recovery. Conclusion In patients with CVT, plasma total homocysteine measurement as part of the etiologic work up may reveal severe hyperhomocysteinemia due to CBS or remethylation defects that require specific treatment and management including perhaps protein-restricted diet and/or vitamin therapy for life.
David S Rosenblatt - One of the best experts on this subject based on the ideXlab platform.
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clinical biochemical and molecular presentation in a patient with the cbld Homocystinuria inborn error of cobalamin metabolism
JIMD reports, 2014Co-Authors: David Watkins, David S Rosenblatt, Isabelle R Miousse, Celia Atkinson, Julian RaimanAbstract:Disorders of intracellular cobalamin (vitamin B12) metabolism result from deficient synthesis of the coenzymes derived from vitamin B12: adenosylcobalamin and methylcobalamin. Disturbances of cobalamin-cofactor synthesis result in elevated levels of homocysteine and/or methylmalonic acid. Nine defects of intracellular cobalamin metabolism have been defined. The most common of these disorders is cblC (combined methylmalonic aciduria and Homocystinuria). The cblD disorder is rare with fewer than twenty cases reported in the literature. Some cblD patients have combined methylmalonic aciduria and Homocystinuria (referred to as “cblD original,” “cblD-combined,” or herein “cblD-MMA/HC”); some have isolated Homocystinuria (referred to as “cblD-variant 1” or herein “cblD-HC”); and others have isolated methylmalonic aciduria (called “cblD-variant 2” or herein “cblD-MMA”). Only six cases of cblD-HC have been defined thus far. We report the 7th case of cblD-HC. The clinical manifestations, biochemical profile, genetic mutation, and plausible ancestry are discussed.
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thermolability of residual methylene tetrahydrofolate reductase mr activity methionine synthase activity and methyl cobalamin levels in cultured fibroblasts from patients with mr deficiency
Advances in Experimental Medicine and Biology, 1993Co-Authors: David S Rosenblatt, H Lueshing, Nora V Matiaszuk, L Lownang, A Arzoumanian, Bernard A. CooperAbstract:The clinical findings in patients with MR deficiency, the most common inborn error of folate metabolism, range from death in infancy to asymptomatic Homocystinuria in adulthood (1–8). Patients may have developmental delay, psychiatric manifestations, and gait abnormalities. The biochemical manifestations include moderate Homocystinuria and homocystinemia. Plasma methionine levels are usually low or normal. In contrast to patients with functional deficiencies of methionine synthase (cblE, cblG), megaloblastic anemia is not found. There is a correlation between the proportion of methyltetrahydrofolate in extracts of cultured fibroblasts, the residual MR activity, and the clinical severity of the disease (9–11). Genetic heterogeneity of MR deficiency was suggested when we observed varying patterns of thermostability at 55° in fibroblast extracts (9).
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thermolability of residual methylenetetrahydrofolate reductase mr activity methionine synthase activity and methyl cobalamin levels in cultured fibroblasts from patients with mr deficiency
Advances in Experimental Medicine and Biology, 1993Co-Authors: David S Rosenblatt, H Lueshing, Nora V Matiaszuk, L Lownang, A Arzoumanian, Bernard A. CooperAbstract:The clinical findings in patients with MR deficiency, the most common inborn error of folate metabolism, range from death in infancy to asymptomatic Homocystinuria in adulthood (1–8). Patients may have developmental delay, psychiatric manifestations, and gait abnormalities. The biochemical manifestations include moderate Homocystinuria and homocystinemia. Plasma methionine levels are usually low or normal. In contrast to patients with functional deficiencies of methionine synthase (cblE, cblG), megaloblastic anemia is not found. There is a correlation between the proportion of methyltetrahydrofolate in extracts of cultured fibroblasts, the residual MR activity, and the clinical severity of the disease (9–11). Genetic heterogeneity of MR deficiency was suggested when we observed varying patterns of thermostability at 55° in fibroblast extracts (9).