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1.
Mol Genet Metab ; 102(1): 44-8, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20947400

RESUMO

Derivatives of 4-methylumbelliferone (4MU) are favorite substrates for the measurement of lysosomal enzyme activities in a wide variety of cell and tissue specimens. Hydrolysis of these artificial substrates at acidic pH leads to the formation of 4-methylumbelliferone, which is highly fluorescent at a pH above 10. When used for the assay of enzyme activities in dried blood spots the light emission signal can be very low due to the small sample size so that the patient and control ranges are not widely separated. We have investigated the hypothesis that quenching of the fluorescence by hemoglobin leads to appreciable loss of signal and we show that the precipitation of hemoglobin with trichloroacetic acid prior to the measurement of 4-methylumbelliferone increases the height of the output signal up to eight fold. The modified method provides a clear separation of patients' and controls' ranges for ten different lysosomal enzyme assays in dried blood spots, and approaches the conventional leukocyte assays in outcome quality.


Assuntos
Hemoglobinas/análise , Himecromona/análogos & derivados , Doenças por Armazenamento dos Lisossomos/diagnóstico , Adolescente , Adulto , Estudos de Casos e Controles , Ensaios Enzimáticos Clínicos , Ensaios Enzimáticos , Enzimas/sangue , Fluorescência , Precipitação Fracionada , Humanos , Himecromona/sangue , Himecromona/química , Indicadores e Reagentes , Lactente , Leucócitos/enzimologia , Doenças por Armazenamento dos Lisossomos/sangue , Ácido Tricloroacético/química
2.
J Inherit Metab Dis ; 32(5): 630, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19642010

RESUMO

Objectives Isolated methylmalonic acidurias (MMAurias) are caused by deficiency of methylmalonyl-CoA mutase or by defects in the synthesis of its cofactor 5'-deoxyadenosylcobalamin. The aim of this study was to evaluate which parameters best predicted the long-term outcome. Methods Standardized questionnaires were sent to 20 European metabolic centres asking for age at diagnosis, birth decade, diagnostic work-up, cobalamin responsiveness, enzymatic subgroup (mut(0), mut(-), cblA, cblB) and different aspects of long-term outcome. Results 273 patients were included. Neonatal onset of the disease was associated with increased mortality rate, high frequency of developmental delay, and severe handicap. Cobalamin non-responsive patients with neonatal onset born in the 1970s and 1980s had a particularly poor outcome. A more favourable outcome was found in patients with late onset of symptoms, especially when cobalamin responsive or classified as mut(-). Prevention of neonatal crises in pre-symptomatically diagnosed newborns was identified as a protective factor concerning handicap. Chronic renal failure manifested earlier in mut(0) patients than in other enzymatic subgroups. Conclusion Outcome in MMAurias is best predicted by the enzymatic subgroup, cobalamin responsiveness, age at onset and birth decade. The prognosis is still unfavourable in patients with neonatal metabolic crises and non-responsiveness to cobalamin, in particular mut(0) patients.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Biomarcadores/análise , Metilmalonil-CoA Mutase/deficiência , Adolescente , Adulto , Idade de Início , Erros Inatos do Metabolismo dos Aminoácidos/epidemiologia , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/mortalidade , Criança , Pré-Escolar , Cobamidas/deficiência , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Metilmalonil-CoA Mutase/genética , Avaliação de Resultados em Cuidados de Saúde , Prognóstico , Análise de Sobrevida , Adulto Jovem
3.
J Inherit Metab Dis ; 32(1): 27-31, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19130289

RESUMO

BACKGROUND: The clinical severity of phenylalanine hydroxylase deficiency is usually defined by either pre-treatment phenylalanine (Phe) concentration or Phe tolerance at 5 years of age. So far, little is known about the course of Phe tolerance or the ability of both pre-treatment Phe and Phe tolerance at early age to predict Phe tolerance at later age. AIM: This study was conducted to investigate the course of the individual Phe tolerance and to assess the predictive value of both the pre-treatment Phe concentration and Phe tolerance at 1 and 6 months and 1, 2, 3 and 5 years for Phe tolerance at 10 years of age. METHOD: Data on blood Phe concentration, prescribed Phe intake and weight of 213 early and continuously treated Dutch PKU patients up to 10 years of age were collected. Data acquired under good metabolic control were used in the study. Tolerance was expressed in mg/day and mg/kg per day. RESULTS: Data at 1 and 6 months and at 1, 2, 3 and 5 years of 61, 58, 59, 57, 56 and 59 patients were included for comparison with the Phe tolerance at 10 years. Phe tolerances (mg/kg per day) at 2, 3 and 5 years showed a clear correlation with the tolerance at 10 years of age (r = 0.608, r = 0.725 and r = 0.661). Results for tolerance expressed as mg/day were comparable. Pre-treatment Phe concentrations did not correlate significantly with the tolerance. CONCLUSION: Pre-treatment Phe is unreliable but Phe tolerance is a reliable predictor of the tolerance at 10 years of age, starting at 2 years of age.


Assuntos
Tolerância a Medicamentos , Fenilalanina/farmacologia , Fenilcetonúrias/diagnóstico , Fatores Etários , Criança , Pré-Escolar , Tolerância a Medicamentos/fisiologia , Seguimentos , Humanos , Recém-Nascido , Triagem Neonatal , Fenilalanina/sangue , Fenilalanina Hidroxilase/genética , Fenilcetonúrias/sangue , Fenilcetonúrias/genética , Prognóstico
4.
J Am Diet Assoc ; 108(10): 1704-7, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18926138

RESUMO

This study investigated which methods patients and parents used to determine phenylalanine (Phe) intake and the relationship between the methods applied, age, and blood Phe concentration, as this practice had not been studied before in relation to metabolic control. A questionnaire was sent to 327 Dutch phenylketonuria patients (age 0-29 years) to investigate the method used to determine Phe intake (either by estimation, exact measurement, or a combination of both). Mean blood Phe concentration of each individual patient was related to the method reported to be used. Three different age groups (<10 years, > or =10-15 years, and > or =16 years) were distinguished. The response rate for the questionnaires was 73%. In these 188 patients, data for both Phe concentrations and questionnaires could be used. Of these, 75 used exact measurement, 75 used estimation, and 38 used both methods. The number of patients that estimated Phe intake clearly increased with age. Whatever method was used, an increase in Phe concentrations was seen with age. During childhood, exact measurement was used more frequently, and from adolescence on estimation was used more frequently. The method (exact measurement and/or estimation) did not result in statistically different Phe concentrations in any of the three age groups, although blood Phe concentration tended to be lower in adolescence using exact measurement. Data suggest that estimation and exact measurement of Phe intake are both reliable methods. Therefore, in addition to exact measurement, patients should be instructed in both methods at an early age, so that both methods can be used adequately.


Assuntos
Dieta com Restrição de Proteínas , Proteínas Alimentares/administração & dosagem , Fenilalanina/administração & dosagem , Fenilalanina/sangue , Fenilcetonúrias/dietoterapia , Adolescente , Adulto , Distribuição por Idade , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Países Baixos , Necessidades Nutricionais , Fenilcetonúrias/sangue , Inquéritos e Questionários
5.
Ned Tijdschr Geneeskd ; 151(21): 1191-6, 2007 May 26.
Artigo em Holandês | MEDLINE | ID: mdl-17557760

RESUMO

The data from 5 clinics concerning 8 infants, who had developed severe lactic acidosis and hyperglutamic acidaemia were reviewed. Blood-lactate levels were up to 15 mmol/l (reference level: < 2) and plasma-glutamate levels up to 1632 pmol/l (reference level: 14-78), and there was no concomitant hyperglutaminaemia (levels up to 1032 micromol/l (reference level: 333-809)). A positive correlation between the amount of calcium levulinate administered and the degree of hyperglutamic acidaemia was found. Replacement of the calcium levulinate by another calcium salt caused a reversal of the biochemical abnormalities of the patients. Two of the infants had a 22q11 microdeletion. This development of severe acidosis in infants who had been given a calcium supplement in the form of calcium levulinate may be related to genetic predisposition. The paradoxal hyperketonaemia and generalized aminoaciduria in 4 other patients suggested disturbed function ofthe mitochondrial respiratory chain. The hypothesis of the occurrence of an underlying defect of the mitochondrial respiratory chain was tested in the muscle tissue of one 22q11 patient, but this showed no abnormalities. Excessive accumulation of glutamate because of dysfunction ofglutamine synthetase, which forms glutamate from glutamine seems unlikely because of the relatively low values of plasma glutamate compared to the glutamine plasma levels. Calcium levulinate should no longer be used in neonates as it may lead to lactic acidosis.


Assuntos
Acidose Láctica/induzido quimicamente , Inibidores Enzimáticos/efeitos adversos , Ácido Glutâmico/sangue , Hipocalcemia/tratamento farmacológico , Ácidos Levulínicos/efeitos adversos , Acidose Láctica/sangue , Acidose Láctica/genética , Deleção Cromossômica , Cromossomos Humanos Par 22 , Inibidores Enzimáticos/uso terapêutico , Feminino , Predisposição Genética para Doença , Humanos , Recém-Nascido , Lactatos/sangue , Ácidos Levulínicos/uso terapêutico , Masculino
6.
Mol Genet Metab ; 87(2): 102-6, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16275149

RESUMO

Malonyl-CoA decarboxylase (MCD) deficiency is an extremely rare inborn error of metabolism that presents with metabolic acidosis, hypoglycemia, and/or cardiomyopathy. Patients also show neurological signs and symptoms that have been infrequently reported. We describe a girl with MCD deficiency, whose brain MRI shows white matter abnormalities and additionally diffuse pachygyria and periventricular heterotopia, consistent with a malformation of cortical development. MLYCD-gene sequence analysis shows normal genomic sequence but no messenger product, suggesting an abnormality of transcription regulation. Our patient has strikingly low appetite, which is interesting in the light of the proposed role of malonyl-CoA in the regulation of feeding control, but this remains to be confirmed in other patients. Considering the incomplete understanding of the role of metabolic pathways in brain development, patients with MCD deficiency should be evaluated with brain MRI and unexplained malformations of cortical development should be reason for metabolic screening.


Assuntos
Encefalopatias Metabólicas/genética , Encéfalo/anormalidades , Carboxiliases/deficiência , Agenesia do Corpo Caloso , Encefalopatias Metabólicas/enzimologia , Tronco Encefálico/anormalidades , Carboxiliases/genética , Células Cultivadas , Cerebelo/anormalidades , Córtex Cerebral/anormalidades , Pré-Escolar , Análise Mutacional de DNA , Ingestão de Alimentos/genética , Feminino , Fibroblastos/enzimologia , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Pele/citologia , Pele/enzimologia
7.
J Inherit Metab Dis ; 28(1): 95-8, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15702410

RESUMO

Four myopathic patients with complex I deficiency followed diets containing 55 energy per cent (En%) as fat or 25 En% as fat, both for three weeks. Maximal workload and muscle force were not different on either diet. Exercise endurance time, oxygen consumption and lactate levels were also not different, but one patient had diminished endurance time on 25 En% as fat. Our observations do not support the use of increasing the fat in the diet of patients with mitochondrial complex I deficiency.


Assuntos
Gorduras na Dieta/uso terapêutico , Miopatias Mitocondriais/sangue , Miopatias Mitocondriais/patologia , Músculos/patologia , Adolescente , Adulto , Citosol/metabolismo , Exercício Físico , Feminino , Humanos , NAD/metabolismo , Oxigênio/metabolismo , Consumo de Oxigênio , Fatores de Tempo
8.
J Inherit Metab Dis ; 28(6): 845-54, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16435176

RESUMO

In a previous study, Dutch children with phenylketonuria (PKU) were found to be slightly shorter than their healthy counterparts. In the literature, it has been hypothesized that a higher protein intake is necessary to optimize growth in PKU patients. The study aimed to investigate whether protein intake (total, natural and protein substitute) in this group might be an explanatory factor for the observed growth. Growth of height and head circumference and dietary data on protein intake (total, natural and protein substitute) from 174 Dutch PKU patients born between 1974 and 1996 were analysed retrospectively for the patients' first 3 years of life. Analyses were corrected for energy intake during the first year of life and for the clinical severity of the deficiency of phenylalanine hydroxylase by means of plasma phenylalanine concentration at birth. Neither protein nor energy intake correlated with height growth. A positive, statistically significant relation between head circumference growth and natural protein and total protein intake was found, but not with the intake of the protein substitute or energy. Therefore, this study suggests that improvement of the protein substitute rather than an increase of total protein intake may be important in optimizing head circumference growth in PKU patients.


Assuntos
Fenilcetonúrias/metabolismo , Proteínas/metabolismo , Estatura , Cefalometria , Pré-Escolar , Proteínas Alimentares , Ingestão de Energia , Crescimento , Cabeça/anatomia & histologia , Humanos , Lactente , Recém-Nascido , Modelos Estatísticos , Países Baixos , Necessidades Nutricionais , Fenilalanina/metabolismo , Análise de Regressão , Estudos Retrospectivos , Fatores de Tempo
9.
J Inherit Metab Dis ; 27(1): 47-55, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-14970745

RESUMO

Pearson syndrome is an often fatal multisystem disease associated with mitochondrial DNA rearrangements. Here we report a patient with a novel mtDNA deletion of 3.4 kb ranging from nucleotides 6097 to 9541 in combination with deletion dimers. The mutation percentage in different tissues (blood, muscle and liver) varied between 64% and 95%. After a remission period of about a year, the patient suddenly died at the age of 3 years owing to a severe lactic acidosis. A second patient with a previously reported deletion of 8 kb and a milder phenotype was found to have mitochondrial duplications and died at the age of 10 years. From these data and data from previous reports, we hypothesize that duplications might be beneficial in the clinical course of the disease and in life expectancy.


Assuntos
Anemia/genética , Doenças da Medula Óssea/genética , DNA Mitocondrial/genética , Deleção de Genes , Duplicação Gênica , Rearranjo Gênico , Pancreatopatias/genética , Criança , Pré-Escolar , Dimerização , Evolução Fatal , Feminino , Fibrose , Genótipo , Humanos , Pancreatopatias/patologia , Fenótipo , Síndrome
10.
Neurology ; 62(3): 439-44, 2004 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-14872027

RESUMO

OBJECTIVE: To define neuroimaging characteristics of peroxisome biogenesis disorders (PBD) with prolonged survival belonging to the Zellweger spectrum (ZeS). METHODS: The authors studied MR images of 25 patients surviving the first year. Neuroimages were compared to neurologic profiles, PBD-ZeS specific compound developmental scores, and two common PEX1 mutations. RESULTS: Three groups are defined based on normal findings, developmental anomalies, and regressive changes. Regressive changes consisting of leukoencephalopathy were identified in patients who had either stable clinical course or progressive deterioration. Concomitant neocortical atrophy was encountered in a minority. Leukoencephalopathy with stable clinical course represents the largest subgroup (48%). The authors found the central cerebellar white matter a focus for early changes in both asymptomatic and symptomatic leukoencephalopathy. A relationship between white matter involvement in clinically stable leukoencephalopathy and degree of developmental failure could not be established. The common homozygous PEX1 G843D mutation is represented in the three main outcome groups. This result points to variable phenotypic expression of the most common PEX1 mutation. CONCLUSIONS: MR findings in ZeS patients surviving the first year differ from Zellweger syndrome in predominance of regressive over developmental changes. Distribution pattern suggests identical pathomechanisms for symptomatic and asymptomatic leukoencephalopathy.


Assuntos
Ventrículos Cerebrais/patologia , Neocórtex/patologia , Síndrome de Zellweger/patologia , ATPases Associadas a Diversas Atividades Celulares , Adolescente , Adulto , Substituição de Aminoácidos , Atrofia , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Lactente , Masculino , Proteínas de Membrana/genética , Mutação de Sentido Incorreto , Bainha de Mielina/patologia , Fenótipo , Análise de Sobrevida , Síndrome de Zellweger/classificação , Síndrome de Zellweger/genética , Síndrome de Zellweger/mortalidade
11.
J Pediatr Surg ; 38(9): 1407-8, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-14523833

RESUMO

An 11-year-old girl with lipoprotein lipase deficiency experienced recurring episodes of abdominal pain. She initially underwent appendectomy for suspected appendicitis; however, the appendix was normal. Pancreatitis was subsequently identified as the cause of her pain.


Assuntos
Apendicite/diagnóstico , Hiperlipoproteinemia Tipo I/complicações , Pancreatite Necrosante Aguda/diagnóstico , Pancreatite Necrosante Aguda/etiologia , Abdome Agudo/etiologia , Amilases/sangue , Criança , Erros de Diagnóstico , Feminino , Humanos , Hiperlipoproteinemia Tipo I/metabolismo , Lipase/sangue , Pancreatite Necrosante Aguda/metabolismo
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