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1.
Mol Genet Metab ; 127(1): 1-11, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31103398

RESUMO

Phenylketonuria (PKU) is an inherited metabolic disease caused by phenylalanine hydroxylase (PAH) deficiency. As the resulting high blood phenylalanine (Phe) concentration can have detrimental effects on brain development and function, international guidelines recommend lifelong control of blood Phe concentration with dietary and/or medical therapy. Sapropterin dihydrochloride is a synthetic preparation of tetrahydrobiopterin (6R-BH4), the naturally occurring cofactor of PAH. It acts as a pharmacological chaperone, reducing blood Phe concentration and increasing dietary Phe tolerance in BH4-responsive patients with PAH deficiency. Protocols to establish responsiveness to sapropterin dihydrochloride vary widely. Two meetings were held with an international panel of clinical experts in PKU management to develop recommendations for sapropterin dihydrochloride response testing. At the first meeting, regional differences and similarities in testing practices were discussed based on guidelines, a literature review, outcomes of a global physician survey, and case reports. Statements developed based on the discussions were sent to all participants for consensus (>70% of participants) evaluation using a 7-level rating system, and further discussed during the second meeting. The experts recommend sapropterin dihydrochloride response testing in patients with untreated blood Phe concentrations of 360-2000 µmol/L, except in those with two null mutations. For neonates, a 24-h sapropterin dihydrochloride loading test is recommended; responsiveness is defined as a decrease in blood Phe ≥30%. For older infants, children, adolescents, and adults, a test duration of ≥48 h or a 4-week trial is recommended. The main endpoint for a 48-h to 7-day trial is a decrease in blood Phe, while improved Phe tolerance is the endpoint to be assessed during a longer trial. Longer trials may not be feasible in some locations due to lack of reimbursement for hospitalization, while a 4-week trial may not be possible due to limited access to sapropterin dihydrochloride or public health regulation. A 48-h response test should be considered in pregnant patients who cannot achieve blood Phe ≤360 µmol/L with a Phe-restricted diet. Durability of response and clinical benefits of sapropterin dihydrochloride should be assessed over the long term. Harmonization of protocols is expected to improve identification of responders and comparability of test results worldwide.

2.
J Inherit Metab Dis ; 42(1): 128-139, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30740731

RESUMO

PURPOSE: To assess how the current practice of newborn screening (NBS) for homocystinurias compares with published recommendations. METHODS: Twenty-two of 32 NBS programmes from 18 countries screened for at least one form of homocystinuria. Centres provided pseudonymised NBS data from patients with cystathionine beta-synthase deficiency (CBSD, n = 19), methionine adenosyltransferase I/III deficiency (MATI/IIID, n = 28), combined remethylation disorder (cRMD, n = 56) and isolated remethylation disorder (iRMD), including methylenetetrahydrofolate reductase deficiency (MTHFRD) (n = 8). Markers and decision limits were converted to multiples of the median (MoM) to allow comparison between centres. RESULTS: NBS programmes, algorithms and decision limits varied considerably. Only nine centres used the recommended second-tier marker total homocysteine (tHcy). The median decision limits of all centres were ≥ 2.35 for high and ≤ 0.44 MoM for low methionine, ≥ 1.95 for high and ≤ 0.47 MoM for low methionine/phenylalanine, ≥ 2.54 for high propionylcarnitine and ≥ 2.78 MoM for propionylcarnitine/acetylcarnitine. These decision limits alone had a 100%, 100%, 86% and 84% sensitivity for the detection of CBSD, MATI/IIID, iRMD and cRMD, respectively, but failed to detect six individuals with cRMD. To enhance sensitivity and decrease second-tier testing costs, we further adapted these decision limits using the data of 15 000 healthy newborns. CONCLUSIONS: Due to the favorable outcome of early treated patients, NBS for homocystinurias is recommended. To improve NBS, decision limits should be revised considering the population median. Relevant markers should be combined; use of the postanalytical tools offered by the CLIR project (Collaborative Laboratory Integrated Reports, which considers, for example, birth weight and gestational age) is recommended. tHcy and methylmalonic acid should be implemented as second-tier markers.

3.
J Inherit Metab Dis ; 42(2): 333-352, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30773687

RESUMO

AIM: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry. RESULTS: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities. CONCLUSION: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design.

4.
J Inherit Metab Dis ; 40(1): 21-48, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27905001

RESUMO

BACKGROUND: Remethylation defects are rare inherited disorders in which impaired remethylation of homocysteine to methionine leads to accumulation of homocysteine and perturbation of numerous methylation reactions. OBJECTIVE: To summarise clinical and biochemical characteristics of these severe disorders and to provide guidelines on diagnosis and management. DATA SOURCES: Review, evaluation and discussion of the medical literature (Medline, Cochrane databases) by a panel of experts on these rare diseases following the GRADE approach. KEY RECOMMENDATIONS: We strongly recommend measuring plasma total homocysteine in any patient presenting with the combination of neurological and/or visual and/or haematological symptoms, subacute spinal cord degeneration, atypical haemolytic uraemic syndrome or unexplained vascular thrombosis. We strongly recommend to initiate treatment with parenteral hydroxocobalamin without delay in any suspected remethylation disorder; it significantly improves survival and incidence of severe complications. We strongly recommend betaine treatment in individuals with MTHFR deficiency; it improves the outcome and prevents disease when given early.


Assuntos
Metilação/efeitos dos fármacos , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Proteínas Proto-Oncogênicas c-cbl/deficiência , Vitamina B 12/farmacologia , Vitamina B 12/uso terapêutico , Animais , Homocisteína/genética , Humanos , Metionina/genética
5.
Med Hypotheses ; 90: 53-6, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27063086

RESUMO

Our preliminary data show high levels of adenosine in the blood of very low birth weight (VLBW) infants, positively correlating to their prematurity (i.e. body weight class). This prompted us to look for a mechanism promoting such impressive adenosine increase. We hypothesized a correlation with oxygen challenge. In fact, it is recognized that either oxygen lack or its excess contribute to the pathogenesis of the injuries of prematurity, such as retinopathy (ROP) and periventricular white matter lesions (PWMI). The optimal concentration of oxygen for resuscitation of VLBW infants is currently under revision. We propose that the elevated adenosine blood concentrations of VLBW infants recognizes two sources. The first could be its activity-dependent release from unmyelinated brain axons. Adenosine in this respect would be an end-product of the hypometabolic VLBW newborn unmyelinated axon intensely firing in response to the environmental stimuli consequent to premature birth. Adenosine would be eventually found in the blood due to blood-brain barrier immaturity. In fact, adenosine is the primary activity-dependent signal promoting differentiation of premyelinating oligodendrocyte progenitor cells (OPC) into myelinating cells in the Central Nervous System, while inhibiting their proliferation and inhibiting synaptic function. The second, would be the ecto-cellular ATP synthesized by the endothelial cell plasmalemma exposed to ambient oxygen concentrations due to premature breathing, especially in lung. ATP would be rapidly transformed into adenosine by the ectonucleotidase activities such as NTPDase I (CD39), and NT5E (CD73). An ectopic extra-mitochondrial aerobic ATP synthetic ability was reported in many cell plasma-membranes, among which endothelial cells. The potential implications of the cited hypotheses for the neonatology area would be great. The amount of oxygen administration for reviving of newborns would find a molecular basis for its assessment. VLBW infants may be regarded as those in which premature exposure to ambient oxygen concentrations and oxidative stress causes a premature functioning of the extra-mitochondrial oxidative phosphorylation primarily in axons and endothelium. Adenosine may become a biomarker of prematurity risk, whose implications further studies may assess.


Assuntos
Adenosina/sangue , Recém-Nascido Prematuro/sangue , Recém-Nascido de muito Baixo Peso/sangue , Modelos Biológicos , Potenciais de Ação , Trifosfato de Adenosina/biossíntese , Axônios/metabolismo , Barreira Hematoencefálica , Membrana Celular/metabolismo , Relação Dose-Resposta a Droga , Células Endoteliais/metabolismo , Humanos , Recém-Nascido , Bainha de Mielina/fisiologia , Neurogênese , Oligodendroglia/citologia , Fosforilação Oxidativa , Estresse Oxidativo , Oxigênio/administração & dosagem , Oxigênio/efeitos adversos , Oxigênio/sangue , Oxigenoterapia/efeitos adversos
6.
J Inherit Metab Dis ; 37(5): 831-40, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24599607

RESUMO

UNLABELLED: The cblC defect is the most common inborn error of vitamin B12 metabolism. Despite therapeutic measures, the long-term outcome is often unsatisfactory. This retrospective multicentre study evaluates clinical, biochemical and genetic findings in 88 cblC patients. The questionnaire designed for the study evaluates clinical and biochemical features at both initial presentation and during follow up. Also the development of severity scores allows investigation of individual disease load, statistical evaluation of parameters between the different age of presentation groups, as well as a search for correlations between clinical endpoints and potential modifying factors. RESULTS: No major differences were found between neonatal and early onset patients so that these groups were combined as an infantile-onset group representing 88 % of all cases. Hypotonia, lethargy, feeding problems and developmental delay were predominant in this group, while late-onset patients frequently presented with psychiatric/behaviour problems and myelopathy. Plasma total homocysteine was higher and methionine lower in infantile-onset patients. Plasma methionine levels correlated with "overall impression" as judged by treating physicians. Physician's impression of patient's well-being correlated with assessed disease load. We confirmed the association between homozygosity for the c.271dupA mutation and infantile-onset but not between homozygosity for c.394C>T and late-onset. Patients were treated with parenteral hydroxocobalamin, betaine, folate/folinic acid and carnitine resulting in improvement of biochemical abnormalities, non-neurological signs and mortality. However the long-term neurological and ophthalmological outcome is not significantly influenced. In summary the survey points to the need for prospective studies in a large cohort using agreed treatment modalities and monitoring criteria.


Assuntos
Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Proteínas Proto-Oncogênicas c-cbl/genética , Vitamina B 12/metabolismo , Idade de Início , Encéfalo/patologia , Proteínas de Transporte/genética , Criança , Pré-Escolar , Progressão da Doença , Grupos Étnicos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/terapia , Prognóstico , Inquéritos e Questionários
7.
Pediatrics ; 131(6): e1881-8, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23690520

RESUMO

OBJECTIVE: Sapropterin dihydrochloride, the synthetic form of 6R-tetrahydrobiopterin (BH4), is an approved drug for the treatment of patients with BH4-responsive phenylketonuria (PKU). The purpose of this study was to assess genotypes and data on the long-term effects of BH4/sapropterin on metabolic control and patient-related outcomes in 6 large European countries. METHODS: A questionnaire was developed to assess phenotype, genotype, blood phenylalanine (Phe) levels, Phe tolerance, quality of life, mood changes, and adherence to diet in PKU patients from 16 medical centers. RESULTS: One hundred forty-seven patients, of whom 41.9% had mild hyperphenylalaninemia, 50.7% mild PKU, and 7.4% classic PKU, were followed up over ≤12 years. A total of 85 different genotypes were reported. With the exception of two splice variants, all of the most common mutations were reported to be associated with substantial residual Phe hydroxylase activity. Median Phe tolerance increased 3.9 times with BH4/sapropterin therapy, compared with dietary treatment, and median Phe blood concentrations were within the therapeutic range in all patients. Compared with diet alone, improvement in quality of life was reported in 49.6% of patients, improvement in adherence to diet was reported in 47% of patients, and improvement in adherence to treatment was reported in 63.3% of patients. No severe adverse events were reported. CONCLUSIONS: Our data document a long-term beneficial effect of orally administered BH4/sapropterin in responsive PKU patients by improving the metabolic control, increasing daily tolerance for dietary Phe intake, and for some, by improving dietary adherence and quality of life. Patient genotypes help in predicting BH4 responsiveness.


Assuntos
Biopterina/análogos & derivados , Fenilalanina/sangue , Fenilcetonúrias/tratamento farmacológico , Adolescente , Adulto , Biopterina/uso terapêutico , Criança , Pré-Escolar , Dieta , Europa (Continente) , Seguimentos , Genótipo , Humanos , Lactente , Pessoa de Meia-Idade , Mutação , Fenótipo , Fenilcetonúrias/sangue , Estudos Retrospectivos , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
8.
Adv Ther ; 30(3): 212-28, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23436109

RESUMO

INTRODUCTION: Pharmacological levels of the phenylalanine hydroxylase enzyme cofactor, tetrahydrobiopterin (BH4), reduce plasma phenylalanine levels in some patients with phenylketonuria (PKU), providing the first pharmacological therapy for PKU. Responsiveness to this therapy must be determined empirically through a BH4 loading test or trial. The authors have analyzed the loading tests currently in use in light of the numerous factors that can influence their results. Sapropterin dihydrochloride is a stable, synthetic form of BH4 approved for treatment of PKU in responsive patients. METHODS: An expert panel identified evidence from published reports of clinical experience. Reports of research involving at least 25 patients and published in English were considered. RESULTS: In all, 14 studies met both criteria; eight employing the sapropterin dihydrochloride preparation from Schircks Laboratories and six the sapropterin dihydrochloride preparation from Biomarin/Merck Serono. CONCLUSION: The arbitrary responsiveness definition of a >30% reduction in blood phenylalanine appears to be a good compromise between sensitivity and specificity for the initial screening test. However, individual patient characteristics should be considered when interpreting results, especially in patients with low baseline phenylalanine levels.


Assuntos
Biopterina/análogos & derivados , Seleção de Pacientes , Fenilalanina/sangue , Fenilcetonúrias/tratamento farmacológico , Biopterina/uso terapêutico , Humanos
9.
Ann Ist Super Sanita ; 48(2): 119-21, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22751553

RESUMO

Biological samples collected in biobanks are a resource with significant research potential. The Italian Joint Group CNB - CNBBSV (National Committee of Bioethics - National Committee for Biosecurity, Biotechnologies and Life Sciences) published a document reporting recommendations on storage and use of dried blood spot (DBS) and on the development of a National Network of Regional Newborn Screening Repositories for collection of residual DBS. Several ethical questions (about consent, possible use of genetic information, unanticipated possible usages for research purposes) rise from residual newborn screening specimens collections. Moreover, legal and ethical controversies are accentuated by the conflicts between the interests of sample donors, biobank holders, researchers and the public. To overcome these difficulties the identification of a few criteria for storage and research usage of DBS is crucial.


Assuntos
Bancos de Espécimes Biológicos/normas , Preservação de Sangue/normas , Coleta de Amostras Sanguíneas/normas , Privacidade Genética/normas , Testes Genéticos , Testes Obrigatórios , Triagem Neonatal , Academias e Institutos/organização & administração , Bancos de Espécimes Biológicos/ética , Bancos de Espécimes Biológicos/organização & administração , Preservação de Sangue/ética , Preservação de Sangue/métodos , Coleta de Amostras Sanguíneas/ética , Coleta de Amostras Sanguíneas/métodos , Dessecação , Testes Genéticos/ética , Testes Genéticos/métodos , Humanos , Recém-Nascido , Itália , Testes Obrigatórios/ética , Testes Obrigatórios/métodos , Minnesota , Triagem Neonatal/ética , Triagem Neonatal/métodos , Consentimento dos Pais , Relações Profissional-Família , Manejo de Espécimes/normas
10.
Mol Genet Metab ; 106(4): 439-41, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22658692

RESUMO

INTRODUCTION: 3-Methyl CoA carboxylase (3-MCC) deficiency is an inborn error of metabolism in the catabolism of the amino acid leucine. Original reports suggested this disorder was associated with significant neurological and biochemical effects. However newborn screening has identified a higher than expected incidence of this disorder with apparent normal outcome in most cases. METHOD: A retrospective analysis of thirty-five cases of 3-MCC deficiency identified by newborn screening and diagnosed by enzyme or molecular analysis. RESULTS: There was a strong inverse correlation between initial C5OH level and residual enzyme activity. A few reports of hypoglycemia, ketosis, poor feeding/failure to thrive or fasting intolerance were reported, but there was no clear relationship between symptoms and residual enzyme activity. Developmental outcome included several children with mental retardation (including one with Down syndrome and one with schizencephaly) and two with Autism Spectrum disorders but there was no apparent relationship to residual enzyme activity. Free carnitine deficiency was relatively common. DISCUSSION: Although residual enzyme activity was clearly related to metabolite elevation, there was no apparent relationship with other measures of outcome. The number of reports of neurologic abnormalities or metabolic symptoms (poor feeding, hypoglycemia, fasting intolerance, etc.) is concerning, but the significance is unclear in this retrospective sample.


Assuntos
Carbono-Carbono Ligases/deficiência , Triagem Neonatal/métodos , Distúrbios Congênitos do Ciclo da Ureia/diagnóstico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Distúrbios Congênitos do Ciclo da Ureia/enzimologia
12.
Genet Med ; 12(7): 431-9, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20531206

RESUMO

PURPOSE: Nail-Patella syndrome (MIM 161200) is a rare autosomal dominant disorder characterized by hypoplastic or absent patellae, dystrophic nails, dysplasia of the elbows, and iliac horn. In 40% of cases, a glomerular defect is present and, less frequently, ocular damage is observed. Inter- and intrafamilial variable expressivity of the clinical phenotype is a common finding. Mutations in the human LMX1B gene have been demonstrated to be responsible for Nail-Patella syndrome in around 80% of cases. METHODS: Standard polymerase chain reaction and sequencing methods were used for mutation and single nucleotide polymorphism identification and control of cloned sequences. Array-CGH (Agilent, 244A Kit) was used for detection of deletions. Standard cloning techniques and the Snapshot method were used for analysis of mosaicism. RESULTS: In this study, we present the results of LMX1B screening of 20 Nail-Patella syndrome patients. The molecular defect was found in 17 patients. We report five novel mutations and a approximately 2 Mb deletion in chromosome 9q encompassing the entire LMX1B gene in a patient with a complex phenotype. We present evidence of somatic mosaicism in unaffected parents in two cases, which, to our knowledge, are the first reported cases of inheritance of a mutated LMX1B allele in Nail-Patella syndrome patients from a mosaic parent. CONCLUSION: The study of the described case series provides some original observations in an "old" genetic disorder.


Assuntos
Deleção Cromossômica , Proteínas de Homeodomínio/genética , Mosaicismo , Síndrome da Unha-Patela/genética , Mutação Puntual/genética , Fatores de Transcrição/genética , Criança , Cromossomos Humanos Par 9/genética , Hibridização Genômica Comparativa , Feminino , Humanos , Proteínas com Homeodomínio LIM , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Pais , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Prognóstico
13.
Mol Genet Metab ; 93(4): 475-80, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18164228

RESUMO

Methylmalonic aciduria (MMA) and homocystinuria, cblC type (MIM 277400) is the most frequent inborn error of vitamin B(12). The recent identification of the disease gene, MMACHC, has permitted preliminary genotype-phenotype correlations. We studied 24 Italian and 17 Portuguese patients with cblC defect to illustrate the spectrum of mutations in a southern European population and discuss the impact that mutation identification has on routine diagnostic procedures. Since the metabolic defect raises the serum levels of homocysteine, we also tested if variants in MTHFR-playing a key role in homocysteine remethylation pathway-could act as genetic modifier in cblC defect. We found that the c.271dupA (accounting for 55% of the MMACH alleles in our cohort) followed by c.394C>T (16%) and c.331C>T (9%) were the most frequent mutations. In our study we also identified a novel mutation (c.544T>C). On the other hand, the MTHFR genotype did not appear to influence age at onset, the clinical phenotype and outcome of patients with cblC defect. This study shows that mutation screening for the most common MMACH mutations occurring in early-onset forms (c.271dupA and c.331C>T) seems to have a high diagnostic yield in a southern European population with cblC defect. Although the identification of the gene defect per se does not predict completely time and severity of disease appearance, our data corroborate the importance of a molecular testing to offer accurate prenatal diagnosis to couples at high risk of having affected children.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Proteínas de Transporte/genética , Homocistinúria/genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Itália , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Ácido Metilmalônico/urina , Fenótipo , Portugal
14.
Pediatr Nephrol ; 22(5): 727-33, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17277954

RESUMO

We prospectively evaluated the effects of L-carnitine supplementation on plasma free carnitine (FC) levels, serum lipid profile, and erythropoietin (rhEPO) requirement in 24 children treated with peritoneal dialysis (PD; n=16) or hemodialysis (HD; n=8). The study was divided into a 3-month observation period, and a 3-month treatment period during which patients received 20 mg/kg per day of L-carnitine given orally. Clinical, biochemical, and hematological data were collected every 3 months. FC levels were measured in plasma and peritoneal dialysate by tandem mass spectrometry. There were no statistically significant changes in lipid levels, hemoglobin, or rhEPO requirements during the course of the study. Fifteen patients (13 PD, 2 HD) had plasma FC levels measured before and after treatment; FC levels increased from 32.1 +/- 14.1 micromol/l to 80.9 +/- 38.7 micromol/l (P<0.001). In PD patients, dialysate FC losses increased from 106 +/- 78 micromol/day at baseline to 178 +/- 119 micromol/day after supplementation. Positive correlations between FC plasma levels and dialysate levels (R=0.507) or daily excretion (R=0.603) were found after treatment. In our case series, an oral dose of 20 mg/kg per day of L-carnitine restored FC levels and produced a positive carnitine balance with no significant effects on hematological parameters or lipid profile over a 3-month period. Prolonged treatment duration may be required to obtain significant results.


Assuntos
Anemia/sangue , Carnitina/uso terapêutico , Lipídeos/sangue , Diálise Peritoneal , Diálise Renal , Adolescente , Anemia/tratamento farmacológico , Carnitina/administração & dosagem , Carnitina/sangue , Criança , Suplementos Nutricionais , Eritropoetina/uso terapêutico , Hematócrito , Humanos , Seleção de Pacientes , Estudos Prospectivos
15.
Blood Coagul Fibrinolysis ; 16(4): 267-73, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15870546

RESUMO

Hyperhomocysteinemia is associated with an increased risk of venous and arterial thrombosis, probably by inducing endothelial damage. Von Willebrand factor (VWF) is an endothelial marker protein. It is a plasma multimeric molecule that plays a thrombophilic role. Our purpose was to investigate VWF changes in patients with thrombosis following oral methionine load. We evaluated homocysteine levels and VWF parameters (plasma levels, activity, proteolysis fragments, and multimer composition) before and after methionine load in 42 women with venous or arterial thrombosis and in 36 healthy women. Methionine load induced mild hyperhomocysteinemia in 10 patients and two controls. No changes in VWF levels and activity were observed, but an increased amount of VWF proteolysis fragments was found post-load in patients and controls. VWF multimer composition was unaffected in controls, while a decrease of the largest VWF multimers was found in women with thrombosis. Homocysteine levels inversely correlated with the amount of the largest multimers in hyperhomocysteinemic patients. Large VWF molecules were probably released from endothelial cells following load, and rapidly cleaved by the specific VWF-cleaving protease. VWF proteolysis was enhanced in mild hyperhomocysteinemic patients, thus leading to downregulation of VWF size to smaller multimers.


Assuntos
Metionina/farmacologia , Trombose/sangue , Fator de von Willebrand/análise , Adulto , Estudos de Casos e Controles , Dimerização , Feminino , Homocisteína/sangue , Humanos , Hiper-Homocisteinemia/induzido quimicamente , Metionina/administração & dosagem , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Peptídeo Hidrolases/metabolismo , Fator de von Willebrand/efeitos dos fármacos , Fator de von Willebrand/metabolismo
16.
Pediatr Nephrol ; 18(3): 225-9, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12644913

RESUMO

Hyperhomocysteinemia is well documented in chronic renal failure (CRF) and premature and progressive occlusive vascular disease is common in CRF. The combined effects of renal failure, folate and vitamin B(12) levels, and a common mutation (C677T) in the methylenetetrahydrofolate reductase (MTHFR) gene that leads to total plasma homocysteine (tHcy) elevation in CRF children were investigated. Forty-two children (15 females) with CRF, mean age 10.3+/-4.7 years, were included. The mean glomerular filtration rate (GFR) was 37.3+/-16.9 ml/min per 1.73 m(2). The control group comprised 33 children (18 females) with a mean age of 8.6+/-3.4 years. There were 40% of CRF patients with hyperhomocysteinemia. Folate and vitamin B(12) deficiencies were identified in 14% (n=6) and 5% (n=2), respectively, of all patients. On univariate analysis, the tHcy serum concentration was negatively correlated with the plasma folate concentration (P<0.05) in controls, and with GFR (P<0.05) in patients. On multiple regression analysis for the predictors of tHcy serum concentrations, folic and vitamin B(12 )were significant in controls, whereas only GFR was significant in CRF children. In our patients no effect of the MTHFR polymorphism on tHcy levels was seen This result, in addition to the limited number of patients, may partially be explained by the low prevalence of folate deficiency in our patients.


Assuntos
Ácido Fólico/sangue , Homocisteína/sangue , Falência Renal Crônica/sangue , Falência Renal Crônica/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Vitamina B 12/sangue , Adolescente , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/epidemiologia , Hiper-Homocisteinemia/genética , Falência Renal Crônica/epidemiologia , Masculino , Mutação Puntual , Valor Preditivo dos Testes , Prevalência , Análise de Regressão
17.
Epilepsia ; 43(6): 616-22, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12060021

RESUMO

PURPOSE: To describe epilepsy and EEG findings in the early-onset cobalamin (Cbl) C/D deficiency, an inborn error of intracellular Cbl metabolism characterized by high plasma levels of methylmalonic acid, homocystine, and homocysteine. METHODS: Type and frequency of seizures were studied in 10 patients (six boys and four girls) who underwent waking and sleep EEG. RESULTS: Half of patients had seizures in the first year of life (either concurrent with the other symptoms of disease or some months after the onset of disease); seizures occurred after 2 years in the other half of patients. Convulsive status epilepticus was the initial manifestation in three patients. During the follow-up, nine patients had seizures (mainly partial) despite specific treatment for Cbl C/D deficiency and antiepileptic drugs. Focal or multifocal epileptiform abnormalities during waking EEG that increased during sleep EEG were recorded in the majority of patients. Plasma levels of homocystine and homocysteine were constantly higher than normal, despite therapy institution. CONCLUSIONS: Epilepsy and EEG abnormalities are prominent features in the early-onset type of combined methylmalonic aciduria and homocystinuria due to Cbl C/D deficiency, possibly related to the pathologically and persistently high levels of homocysteine, experimentally proven to induce seizures. Plasma amino acids evaluation and urinary acid organic analysis should be performed in any infant showing seizures associated with feeding difficulties and failure to thrive, at onset during the first year of life, as well as in any child with convulsive status epilepticus and a history of psychomotor developmental delay of unknown origin.


Assuntos
Eletroencefalografia/estatística & dados numéricos , Epilepsia/diagnóstico , Homocistinúria/diagnóstico , Ácido Metilmalônico/urina , Deficiência de Vitamina B 12/diagnóstico , Idade de Início , Encéfalo/patologia , Encéfalo/fisiopatologia , Epilepsia/etiologia , Epilepsia/metabolismo , Feminino , Seguimentos , Homocisteína/sangue , Homocistina/sangue , Homocistinúria/complicações , Homocistinúria/metabolismo , Humanos , Lactente , Recém-Nascido , Imagem por Ressonância Magnética , Masculino , Ácido Metilmalônico/sangue , Sono/fisiologia , Vitamina B 12/metabolismo , Deficiência de Vitamina B 12/complicações , Deficiência de Vitamina B 12/metabolismo , Vigília/fisiologia
18.
Hum Genet ; 110(1): 68-74, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11810299

RESUMO

Methylation is an essential process in the body. Methyl groups in the form of S-adenosylmethionine are used for the synthesis of many essential compounds (e.g., creatine, phosphatidylcholine, and the methylation of DNA in gene expression). Glycine N-methyltransferase (GNMT) is an abundant enzyme in liver. It catalyzes the methylation of glycine by using S-adenosylmethionine (AdoMet) to form N-methylglycine (sarcosine) with the concommitant production of S-adenosylhomocysteine (AdoHcy). It plays an important role in the economy of methyl groups in the body. The function of GNMT has been hypothesized to provide an alternative route for the conversion of excess AdoMet to AdoHcy in order to preserve the AdoMet/AdoHcy ratio. GNMT is also inhibited by a specific form of folate, 5-methyltetrahydrofolate pentaglutamate. As such, GNMT participates in a regulatory scheme that links the de novo synthesis of methyl groups to the availability of dietary methionine. This hypothesis can now be tested in man. We report here for the first time two Italian sibs who are compound heterzygotes in the gene that encodes GNMT. Both have evidence of mild liver disease. Each bears the same two missense mutations, one in exon 1 (Leu49Pro) and the second in exon 4 (His176Asn). Restriction enzyme analysis of panels of diverse DNA samples indicates that these mutations are not attributable to a common polymorphism.


Assuntos
Metionina/metabolismo , Metiltransferases/genética , Substituição de Aminoácidos , Sítios de Ligação , Proteínas de Transporte/genética , Primers do DNA , Éxons , Glicina N-Metiltransferase , Humanos , Metiltransferases/química , Modelos Moleculares , Mutação de Sentido Incorreto , Reação em Cadeia da Polimerase , Conformação Proteica , Subunidades Proteicas , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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