RESUMO
We describe a 16-year old boy with glycogen storage disease type Ib, homozygous for the common 1211-1212delCT mutation, who never experienced neutropenia, and did not suffer from frequent infections or inflammatory bowel disease. In addition, neutrophil function tests showed no abnormalities.
Assuntos
Doença de Depósito de Glicogênio Tipo I/genética , Mutação , Neutropenia/diagnóstico , Neutropenia/genética , Neutrófilos/patologia , Adolescente , Antiporters/genética , Homozigoto , Humanos , Fígado/enzimologia , Masculino , Proteínas de Transporte de Monossacarídeos/genética , Neutrófilos/metabolismo , FenótipoRESUMO
MR spectroscopy results in a mild case of guanidinoacetate methyltransferase (GAMT) deficiency are presented. The approach differs from previous MRS studies in the acquisition of a chemical shift imaging spectral map showing gray and white matter with the corresponding spectra in one overview. MR spectroscopy revealed guanidinoacetate (GAA) in the absence of creatine. New is that GAA signals are more prominent in gray matter than in white. In the prevailing view, that enzyme deficiency is localized in liver and pancreas and that all GAA is transported into the brain from the blood and the cerebrospinal fluid, this would be compatible with a more limited uptake and/or better clearance of GAA from the white matter compared to the grey matter.
Assuntos
Química Encefálica , Creatina/deficiência , Glicina/análogos & derivados , Guanidinoacetato N-Metiltransferase/deficiência , Imageamento por Ressonância Magnética/métodos , Ácido Aspártico/análogos & derivados , Ácido Aspártico/análise , Pré-Escolar , Colina/análise , Creatina/análise , Creatina/sangue , Ácido Glutâmico/análise , Glicina/análise , Glicina/sangue , Glicina/líquido cefalorraquidiano , Humanos , Hidrogênio , Espectroscopia de Ressonância Magnética/métodos , Masculino , SíndromeRESUMO
We present a relatively mild case of peroxisomal D-bifunctional protein deficiency with inconsistent screening results in plasma for peroxisomal disorders.
Assuntos
17-Hidroxiesteroide Desidrogenases/deficiência , Análise Química do Sangue/métodos , Ácidos Graxos/análise , Hidroliases/deficiência , Erros Inatos do Metabolismo/diagnóstico , Transtornos Peroxissômicos/diagnóstico , Peroxissomos/metabolismo , Encéfalo/patologia , Consanguinidade , Fácies , Ácidos Graxos/metabolismo , Feminino , Fibroblastos/metabolismo , Homozigoto , Humanos , Lactente , Imageamento por Ressonância Magnética , Mutação , Proteína Multifuncional do Peroxissomo-2RESUMO
The occurrence of (symptoms related to) osteopenia is a known complication in glycogen storage disease type Ia (GSD Ia) patients. However, only limited information is available about bone mineral density (BMD). Using dual energy x-ray absorptiometry, we studied both cross-sectional and longitudinal lumbar spine areal BMD (BMD(areal) in g/cm2), areal BMD corrected for delayed bone maturation (BMD(bone age) in g/cm2), and volumetric BMD (BMD(vol) in g/cm3). Prepubertal GSD Ia patients (n = 8) had normal BMD (median z-scores BMD(areal) -0.6, BMD(bone age) -0.5 and BMD(vol) -0.5), whereas adolescent patients (n = 12) and adult patients (n = 9) had significantly reduced BMD (BMD(areal) -2.3, BMD(bone age) -1.6, BMD(vol) -2.0, and BMD(areal) -1.9, BMD(vol) -1.5, respectively). Our longitudinal study, showing a stable BMD(areal) but a trend to a decrease in BMD(vol) in prepubertal patients during follow-up, did not clarify whether the difference in BMD between prepubertal and adolescent/adult patients reflects a diminished accretion of BMD during childhood or reflects historical differences in treatment. In adolescent and adult GSD Ia patients, BMD(areal) and BMD(vol) were reduced but stable during follow-up. Especially patients with delayed bone maturation were at risk for reduced BMD. No correlation between parameters of metabolic control and BMD could be detected. Daily calcium intake was within recommended allowances ranges. Abnormal biochemical results included hypomagnesaemia (29%), hypercalciuria (34%) and reduced tubular resorption of phosphate (21%). Although the underlying pathophysiology of reduced BMD in GSD Ia remains unsolved, metabolic control should be optimized to correct as much as possible metabolic and endocrine abnormalities that may influence both bone matrix formation and bone mineral accretion.
Assuntos
Densidade Óssea , Doença de Depósito de Glicogênio Tipo I/metabolismo , Absorciometria de Fóton , Adolescente , Adulto , Envelhecimento/metabolismo , Criança , Pré-Escolar , Estudos Transversais , Feminino , Doença de Depósito de Glicogênio Tipo I/fisiopatologia , Humanos , Estudos Longitudinais , Vértebras Lombares/metabolismo , Masculino , PuberdadeRESUMO
Growth retardation is one of the clinical characteristics of glycogen storage disease (GSD) type IX. Initial growth retardation has been described in a few case reports, followed by a complete catch-up in growth. This study aimed to determine the growth pattern of patients with GSD IX. Growth charts of 51 male Dutch patients with GSD IX (age 0-33 years, median follow-up time 8.3 years (range 0-30.5 years)) were studied retrospectively and compared with Dutch standard growth charts. Patients had a normal height at birth, significant growth retardation between the ages of 2 and 10 years (mean z-score -1.96), delayed growth spurt in puberty and catch-up towards quite normal final height (mean z-score -0.55). We conclude that GSD IX patients have a specific growth pattern characterized by initial growth retardation, a late growth spurt and complete catch-up in final height. Intervention for growth retardation is therefore in general not warranted. It is speculated that mild hypoglycaemia related to the disorder may cause endocrine changes. Because the glucose need per kg bodyweight decreases with age, the enzyme defect becomes less important with ageing and the effect on growth diminishes.
Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/genética , Doença de Depósito de Glicogênio/genética , Transtornos do Crescimento/genética , Fosforilase Quinase/deficiência , Fosforilase Quinase/genética , Adolescente , Adulto , Envelhecimento/fisiologia , Estatura/genética , Criança , Pré-Escolar , Seguimentos , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Doença de Depósito de Glicogênio/enzimologia , Transtornos do Crescimento/patologia , Humanos , Lactente , Masculino , Estudos RetrospectivosRESUMO
Glycogen storage disease type I (GSD I) (McKusick 232200) is caused by inherited defects of the glucose-6-phosphatase complex. Patients with GSD Ia as well as patients with GSD lb may suffer from intermittent diarrhoea, which seems to worsen with age. The cause of this diarrhoea is unknown. This study describes the results of investigations of intestinal functions and morphology in patients with GSD Ia and GSD lb, which were performed to detect a common cause for chronic diarrhoea in GSD I. The following were investigated: faecal fat excretion, faecal alpha1-antitrypsin and faecal chymotrypsin, expiratory H2 concentrations, persorption of cornstarch in urine and colonic biopsies. With the investigations presented in this study, no common cause for diarrhoea in GSD I was found. In GSD lb loss of mucosal barrier function due to inflammation, documented by increased faecal alpha1-antitrypsin excretion (3.5-9.6 mg/g dry faeces) and inflammation in the colonic biopsies, seems to be the main cause. The inflammation is most likely related to disturbed neutrophil function, which is often found in GSD lb. Whether another cause is involved in GSD Ia and in GSD Ib, related to the disturbed function of glucose-6-phosphatase in the enterocyte, remains to be investigated.
Assuntos
Doença de Depósito de Glicogênio Tipo I/fisiopatologia , Intestinos/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Doença Crônica , Quimotripsina/metabolismo , Colo/metabolismo , Colo/patologia , Diarreia/etiologia , Gorduras na Dieta/metabolismo , Fezes/enzimologia , Feminino , Doença de Depósito de Glicogênio Tipo I/complicações , Doença de Depósito de Glicogênio Tipo I/patologia , Humanos , Hidrogênio/metabolismo , Lactente , Absorção Intestinal , Intestinos/patologia , Masculino , Amido/metabolismo , alfa 1-Antitripsina/metabolismoRESUMO
OBJECTIVE: To investigate the incidence, the severity, and the course of neutropenia, neutrophil dysfunction, and inflammatory bowel disease (IBD) in glycogen storage disease (GSD) type Ib. METHOD: As part of a collaborative European Study on GSD type I, a retrospective registry was established in 12 European countries that included all patients with GSD-I who were known at the centers and were born from 1960 to 1995. Of a total of 288 patients with GSD-I, 57 who had GSD-Ib form the basis of this study. RESULTS: Neutropenia (defined as an absolute neutrophil count <1 x 10(9)/L) was found in 54 patients. In 64% of the patients neutropenia was documented before the age of 1 year, but in 18% of the patients neutropenia was first noted between the ages of 6 and 9 years. Neutropenia was persistent in 5 patients and intermittent without any clear cyclical course in 45. Neutrophil function was investigated in 18 patients with neutropenia and was abnormal in all. Perioral infections were reported in 37 patients, perianal infections in 27 patients, and protracted diarrhea in 23 patients. Findings on colonoscopy and radiologic studies in 10 of 20 patients suspected to have IBD were abnormal in all. All patients with IBD, perioral infections, and perianal infections had neutropenia. CONCLUSIONS: Intermittent severe neutropenia is frequently found in patients with GSD-Ib. The study also indicates that IBD in GSD-Ib is underdiagnosed; up to 77% of the patients studied had evidence of IBD, all of whom had neutropenia. IBD was not detected in those with normal neutrophil counts. These findings support the notion that neutropenia and/or neutrophil dysfunction in GSD-Ib and IBD are causally related.
Assuntos
Doença de Depósito de Glicogênio Tipo I/epidemiologia , Doenças Inflamatórias Intestinais/epidemiologia , Neutropenia/epidemiologia , Neutrófilos/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Comorbidade , Progressão da Doença , Europa (Continente)/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Doenças Inflamatórias Intestinais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Neutropenia/fisiopatologia , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
UNLABELLED: The prerequisite for liver transplantation as a therapeutic option for inherited metabolic diseases should be that the enzyme defect, being responsible for the major clinical (hepatic and/or extra-hepatic) abnormalities, is localised in the liver. Furthermore, no adequate dietary or pharmacological treatment should be available or such treatment should have an unacceptable influence on the quality of life. We report an infant, who developed end-stage liver disease with persistent lactic acidaemia in his first months of life. Analysis of the mitochondrial respiratory chain in liver tissue revealed a combined partial complex I and IV deficiency. No extra-hepatic involvement could be demonstrated by careful screening for multiple organ involvement, including analysis of the mitochondrial respiratory chain in muscle tissue and cultured skin fibroblasts. The boy received a reduced size liver graft at the age of 8 months. He recovered successfully. Almost 5 years after transplantation he is in good clinical condition. No clinical or biochemical signs of any organ dysfunction have been demonstrated. The considerations on which basis it was decided that there was no contra-indication to perform liver transplantation in this patient are discussed. CONCLUSION: The possibility of a mitochondrial respiratory chain deficiency should be considered in liver disease of unknown origin prior to liver transplantation. Liver transplantation is a therapeutic option in mitochondrial respiratory chain deficiency-based end-stage liver disease provided that extra-hepatic involvement is carefully excluded.
Assuntos
Deficiência de Citocromo-c Oxidase , Falência Hepática/genética , Transplante de Fígado , Miopatias Mitocondriais/genética , NADH NADPH Oxirredutases/deficiência , Pré-Escolar , Contraindicações , Complexo I de Transporte de Elétrons , Seguimentos , Humanos , Lactente , Falência Hepática/cirurgia , Testes de Função Hepática , Masculino , Miopatias Mitocondriais/cirurgiaRESUMO
UNLABELLED: We studied the glucose-6-phosphatase (G6Pase) gene of 30 unrelated glycogen storage disease type Ia (GSD Ia) patients using single strand conformational polymorphism (SSCP) prior to automated sequencing of exons revealing an aberrant SSCP pattern. In all patients we could identify mutations on both alleles of the G6Pase gene, indicating that this method is a reliable procedure. A total of 14 different mutations were identified. R83C (16/60), 158delC (12/60), Q347X (7/60), R170X (6/60) and deltaF327 (4/60) were found most frequently. Nine other mutations accounted for the other 15 mutant alleles. Two DNA-based prenatal diagnoses were performed successfully. At present, 56 mutations in the G6Pase gene have been reported in 300 unrelated GSD Ia patients and an overview of these mutations is presented. Evidence for a clear genotype-phenotype correlation could be established neither from our data nor from those in the literature. With increased knowledge about the genetic basis of GSD Ia and GSD Ib and the high detection rate of mutations, it is our opinion that the diagnoses GSD Ia and GSD Ib can usually be based on clinical and biochemical abnormalities combined with mutation analysis instead of enzyme assays in liver tissue obtained by biopsy. A newly developed flowchart for the diagnosis of GSD I is presented. CONCLUSION: Increased knowledge of the genetic basis of glycogen storage disease type I provides a DNA-based diagnosis, prenatal DNA-based diagnosis in chorionic villus samples and carrier detection.
Assuntos
Doença de Depósito de Glicogênio Tipo I/genética , Mutação , Amostra da Vilosidade Coriônica , DNA/análise , Feminino , Glucose-6-Fosfatase/genética , Doença de Depósito de Glicogênio Tipo I/classificação , Doença de Depósito de Glicogênio Tipo I/diagnóstico , Humanos , Masculino , Polimorfismo Conformacional de Fita Simples , GravidezRESUMO
We identified a novel mutation (867delA) in the glucose-6-phosphatase gene of two siblings with glycogen storage disease type Ia. Although both siblings share the same mutations, their phenotype regarding adult height and hepatomegaly differs. In glycogen storage disease type Ia, substantial heterogeneity in phenotype is observed. So far, no evidence for a clear genotype-phenotype correlation has been found. Hum Mutat 15:381, 2000.
Assuntos
Mutação da Fase de Leitura , Glucose-6-Fosfatase/genética , Doença de Depósito de Glicogênio/enzimologia , Doença de Depósito de Glicogênio/genética , Adulto , Éxons/genética , Feminino , Genótipo , Humanos , Masculino , Núcleo Familiar , Fenótipo , Polimorfismo Conformacional de Fita SimplesRESUMO
Deficient activity of glucose-6-phosphatase (G6Pase) causes glycogen storage disease type Ia (GSD Ia). We analysed the G6Pase gene of 16 GSD Ia patients using single strand conformation polymorphism (SSCP) analysis prior to automated sequencing of exon(s) revealing an aberrant SSCP pattern. In all GSD Ia patients we were able to identify mutations on both alleles of the G6Pase gene, indicating that this method is a reliable procedure to identify mutations. Four novel mutations (175delGG, R170X, G266V and V338F) were identified.