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1.
J Pharm Biomed Anal ; 176: 112798, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31394303

RESUMO

PURPOSE: Salts of phenylacetic acid (PAA) and phenylbutyric acid (PBA) have been used for nitrogen elimination as a treatment for hyperammonaemia caused by urea cycle disorders (UCD). A new analytical method for PBA measurement in urine which helps to evaluate the drug adherence has been implemented. METHODS: Urine specimens from UCD patients receiving PBA were analysed by tandem mass spectrometry to measure urine phenylacetylglutamine (PAGln). Some clinical and biochemical data for each patient were collected. RESULTS: Our study included 87 samples from 40 UCD patients. The PAGln levels did not correlate with height, weight or age. However, the PAGln values showed correlation with PBA dose (r = 0.383, P = 0.015). Plasma glutamine and ammonia levels presented a positive correlation (r = 0.537, P < 0.001). The stability for PAGln in urine was determined at different storage temperatures. CONCLUSIONS: We have developed a simple method for the determination of PAGln in urine, which acts as useful biomarker of effective drug delivery. PAGln in urine is stable at room temperature at least for 15 days, and for several months when frozen at -20 °C. This procedure is useful for the optimization and monitorization of the drug dose allowing the use of spot urine samples.

2.
Front Immunol ; 10: 1264, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31214199

RESUMO

The lysosome has a key role in the presentation of lipid antigens by CD1 molecules. While defects in lipid antigen presentation and in invariant Natural Killer T (iNKT) cell response were detected in several mouse models of lysosomal storage diseases (LSD), the impact of lysosomal engorgement in human lipid antigen presentation is poorly characterized. Here, we analyzed the capacity of monocyte-derived dendritic cells (Mo-DCs) from Fabry, Gaucher, Niemann Pick type C and Mucopolysaccharidosis type VI disease patients to present exogenous antigens to lipid-specific T cells. The CD1b- and CD1d-restricted presentation of lipid antigens by Mo-DCs revealed an ability of LSD patients to induce CD1-restricted T cell responses within the control range. Similarly, freshly isolated monocytes from Fabry and Gaucher disease patients had a normal ability to present α-Galactosylceramide (α-GalCer) antigen by CD1d. Gaucher disease patients' monocytes had an increased capacity to present α-Gal-(1-2)-αGalCer, an antigen that needs internalization and processing to become antigenic. In summary, our results show that Fabry, Gaucher, Niemann Pick type C, and Mucopolysaccharidosis type VI disease patients do not present a decreased capacity to present CD1d-restricted lipid antigens. These observations are in contrast to what was observed in mouse models of LSD. The percentage of total iNKT cells in the peripheral blood of these patients is also similar to control individuals. In addition, we show that the presentation of exogenous lipids that directly bind CD1b, the human CD1 isoform with an intracellular trafficking to the lysosome, is normal in these patients.

3.
Mitochondrion ; 47: 309-317, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30831263

RESUMO

Mitochondrial diseases (MD) are a group of rare inherited disorders, characterized by phenotypic heterogeneity, with hitherto no effective therapeutic options. The aim of this study was to develop a next generation sequencing (NGS) strategy, by using a custom gene panel and whole mitochondrial genome, to identify the disease causing pathogenic variants in 146 patients suspicious of MD. The molecular analysis of this cohort revealed six novel and 15 described pathogenic variants, as well as 26 variants of unknown significance. Our findings are expanding the mutational landscape of these disorders and support the use of a NGS strategy for a higher diagnostic yield.

5.
Rev Port Cardiol ; 37(7): 625.e1-625.e5, 2018 Jul.
Artigo em Inglês, Português | MEDLINE | ID: mdl-29789210

RESUMO

Dilated cardiomyopathy is the most common form of cardiomyopathy and the main cause of cardiac transplantation in children and in adults. Infants and children have a wider spectrum of etiologies, hampering their identification. The most frequent initial manifestation of dilated cardiomyopathy is symptomatic heart failure during exercise or at rest (although many patients are asymptomatic). Some causes are potentially reversible, therefore the investigation should be carefully planned and immediately performed after diagnosis. In most children no cause is identified, which limits the targeted therapeutic approach and therefore the effectiveness of the treatment. The authors present a case of dilated cardiomyopathy secondary to renovascular hypertension diagnosed in an infant with 3.5 month-old, highlighting the etiological investigation, treatment and evolution. The authors present this case emphasising the fact that the arterial hypertension diagnose in infants is not always easy, questioning the current recommendations relating to an initial evaluation on blood pressure. We postulate that the assessment of blood pressure in newborns can detect early renovascular hypertension (and even other cardiovascular diseases) and help prevent the development of deleterious effects, including fatal episodes.

6.
JIMD Rep ; 42: 113-119, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29478218

RESUMO

INTRODUCTION: Combined oxidative phosphorylation deficiency 20 (COXPD20) is a mitochondrial respiratory chain complex (RC) disorder, caused by disease-causing variants in the VARS2 gene, which encodes a mitochondrial aminoacyl-tRNA synthetase. Here we describe a patient with fatal mitochondrial encephalopathy caused by a homozygous VARS2 gene missense variant. CASE REPORT: We report the case of a girl, the first child of non-consanguineous and healthy parents, born from an uneventful term pregnancy, who presented, in the neonatal period, major hypotonia and microcephaly. At 4 months of age she showed poor eye contact, nystagmus, global psychomotor development delay and failure to thrive, without dysmorphic features. Focal seizures started at 24 months which evolved to a severe epileptic encephalopathy and finally to super refractory status epilepticus, leading to her death at 28 months of age. Etiologic investigation encompassing metabolic and genetic causes failed to disclose a diagnosis. Post-mortem exome sequencing allowed the identification of a pathogenic variant in VARS2 gene in the homozygous state (c.1100C > T, p.Thr367Ile) in the patient, inherited from her heterozygous parents, leading to the diagnosis of COXPD2. CONCLUSION: To the best of our knowledge, this is the fifth case described in the literature of a child with disease-causing variant in VARS2. With this report we expand the knowledge about the phenotype associated with this very rare mitochondrial defect, further emphasizing the use of exome sequencing as a very powerful diagnostic tool.

9.
J Inherit Metab Dis ; 38(6): 1041-57, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25875215

RESUMO

BACKGROUND: The clinical presentation of patients with organic acidurias (OAD) and urea cycle disorders (UCD) is variable; symptoms are often non-specific. AIMS/METHODS: To improve the knowledge about OAD and UCD the E-IMD consortium established a web-based patient registry. RESULTS: We registered 795 patients with OAD (n = 452) and UCD (n = 343), with ornithine transcarbamylase (OTC) deficiency (n = 196), glutaric aciduria type 1 (GA1; n = 150) and methylmalonic aciduria (MMA; n = 149) being the most frequent diseases. Overall, 548 patients (69 %) were symptomatic. The majority of them (n = 463) presented with acute metabolic crisis during (n = 220) or after the newborn period (n = 243) frequently demonstrating impaired consciousness, vomiting and/or muscular hypotonia. Neonatal onset of symptoms was most frequent in argininosuccinic synthetase and lyase deficiency and carbamylphosphate 1 synthetase deficiency, unexpectedly low in male OTC deficiency, and least frequently in GA1 and female OTC deficiency. For patients with MMA, propionic aciduria (PA) and OTC deficiency (male and female), hyperammonemia was more severe in metabolic crises during than after the newborn period, whereas metabolic acidosis tended to be more severe in MMA and PA patients with late onset of symptoms. Symptomatic patients without metabolic crises (n = 94) often presented with a movement disorder, mental retardation, epilepsy and psychiatric disorders (the latter in UCD only). CONCLUSIONS: The initial presentation varies widely in OAD and UCD patients. This is a challenge for rapid diagnosis and early start of treatment. Patients with a sepsis-like neonatal crisis and those with late-onset of symptoms are both at risk of delayed or missed diagnosis.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Encefalopatias Metabólicas/diagnóstico , Glutaril-CoA Desidrogenase/deficiência , Hiperamonemia/diagnóstico , Doença da Deficiência de Ornitina Carbomoiltransferase/diagnóstico , Distúrbios Congênitos do Ciclo da Ureia/diagnóstico , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Europa (Continente) , Feminino , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Vômito , Adulto Jovem
10.
J Inherit Metab Dis ; 38(6): 1059-74, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25875216

RESUMO

BACKGROUND: The disease course and long-term outcome of patients with organic acidurias (OAD) and urea cycle disorders (UCD) are incompletely understood. AIMS: To evaluate the complex clinical phenotype of OAD and UCD patients at different ages. RESULTS: Acquired microcephaly and movement disorders were common in OAD and UCD highlighting that the brain is the major organ involved in these diseases. Cardiomyopathy [methylmalonic (MMA) and propionic aciduria (PA)], prolonged QTc interval (PA), optic nerve atrophy [MMA, isovaleric aciduria (IVA)], pancytopenia (PA), and macrocephaly [glutaric aciduria type 1 (GA1)] were exclusively found in OAD patients, whereas hepatic involvement was more frequent in UCD patients, in particular in argininosuccinate lyase (ASL) deficiency. Chronic renal failure was often found in MMA, with highest frequency in mut(0) patients. Unexpectedly, chronic renal failure was also observed in adolescent and adult patients with GA1 and ASL deficiency. It had a similar frequency in patients with or without a movement disorder suggesting different pathophysiology. Thirteen patients (classic OAD: 3, UCD: 10) died during the study interval, ten of them during the initial metabolic crisis in the newborn period. Male patients with late-onset ornithine transcarbamylase deficiency were presumably overrepresented in the study population. CONCLUSIONS: Neurologic impairment is common in OAD and UCD, whereas the involvement of other organs (heart, liver, kidneys, eyes) follows a disease-specific pattern. The identification of unexpected chronic renal failure in GA1 and ASL deficiency emphasizes the importance of a systematic follow-up in patients with rare diseases.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Acidúria Argininossuccínica/diagnóstico , Encefalopatias Metabólicas/diagnóstico , Glutaril-CoA Desidrogenase/deficiência , Doença da Deficiência de Ornitina Carbomoiltransferase/diagnóstico , Acidemia Propiônica/diagnóstico , Distúrbios Congênitos do Ciclo da Ureia/diagnóstico , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Europa (Continente) , Feminino , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Falência Renal Crônica/complicações , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Triagem Neonatal , Fenótipo , Sistema de Registros , Adulto Jovem
11.
Cardiol Young ; 25(2): 333-7, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24423967

RESUMO

Dilated cardiomyopathy is the most common form of cardiomyopathy in the paediatric population and an important cause of heart transplantation in children. The clinical profile and course of dilated cardiomyopathy in children have been poorly characterised. A retrospective review of 61 patients (37 female; 24 male) diagnosed with dilated cardiomyopathy from January, 2005 to June, 2012 at a single institution was performed. The median age at diagnosis was 15 months. Heart failure was present in 83.6% of patients and 44.3% required intensive care. The most prevalent causes were idiopathic (47.5%), viral myocarditis (18.0%) and inherited metabolic diseases (11.5%). In viral myocarditis, Parvovirus B19 was the most common identified agent, in concurrence with the increasing incidence documented recently. Inherited metabolic diseases were responsible for 11.5% of dilated cardiomyopathy cases compared with the 4-6% described in the literature, which reinforces the importance of considering this aetiology in differential diagnosis of paediatric dilated cardiomyopathy. The overall mortality rate was 16.1% and five patients underwent heart transplantation. In our series, age at diagnosis and aetiology were the most important prognosis factors. We report no mortality in the five patients who underwent heart transplantation, after 2 years of follow-up.


Assuntos
Cardiomiopatia Dilatada/etiologia , Infecções por Citomegalovirus/complicações , Insuficiência Cardíaca/etiologia , Influenza Humana/complicações , Erros Inatos do Metabolismo/complicações , Distrofia Muscular de Duchenne/complicações , Miocardite/complicações , Infecções por Parvoviridae/complicações , Antagonistas Adrenérgicos beta/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Cardiomiopatia Dilatada/mortalidade , Cardiomiopatia Dilatada/terapia , Cardiotônicos/uso terapêutico , Pré-Escolar , Estudos de Coortes , Cuidados Críticos , Diuréticos/uso terapêutico , Feminino , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/terapia , Transplante de Coração , Humanos , Lactente , Masculino , Miocardite/virologia , Infecções por Parvoviridae/virologia , Parvovirus B19 Humano , Inibidores da Agregação de Plaquetas/uso terapêutico , Estudos Retrospectivos , Centros de Atenção Terciária
12.
J Inherit Metab Dis ; 37(1): 43-52, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23749220

RESUMO

Classic galactosemia is an autosomal recessive disorder caused by deficient galactose-1-phosphate uridylyltransferase (GALT) activity. Patients develop symptoms in the neonatal period, which can be ameliorated by dietary restriction of galactose. Many patients develop long-term complications, with a broad range of clinical symptoms whose pathophysiology is poorly understood. The high allelic heterogeneity of GALT gene that characterizes this disorder is thought to play a determinant role in biochemical and clinical phenotypes. We aimed to characterize the mutational spectrum of GALT deficiency in Portugal and to assess potential genotype-phenotype correlations. Direct sequencing of the GALT gene and in silico analyses were employed to evaluate the impact of uncharacterized mutations upon GALT functionality. Molecular characterization of 42 galactosemic Portuguese patients revealed a mutational spectrum comprising 14 nucleotide substitutions: ten missense, two nonsense and two putative splicing mutations. Sixteen different genotypic combinations were detected, half of the patients being p.Q188R homozygotes. Notably, the second most frequent variation is a splicing mutation. In silico predictions complemented by a close-up on the mutations in the protein structure suggest that uncharacterized missense mutations have cumulative point effects on protein stability, oligomeric state, or substrate binding. One splicing mutation is predicted to cause an alternative splicing event. This study reinforces the difficulty in establishing a genotype-phenotype correlation in classic galactosemia, a monogenic disease whose complex pathogenesis and clinical features emphasize the need to expand the knowledge on this "cloudy" disorder.


Assuntos
Galactosemias/genética , Mutação de Sentido Incorreto , Processamento de RNA , UTP-Hexose-1-Fosfato Uridililtransferase/genética , Adolescente , Adulto , Alelos , Análise Mutacional de DNA , Feminino , Galactose/sangue , Galactosefosfatos/sangue , Frequência do Gene , Estudos de Associação Genética , Homozigoto , Humanos , Masculino , Fenótipo , Portugal , UTP-Hexose-1-Fosfato Uridililtransferase/metabolismo , Adulto Jovem
13.
Eur J Paediatr Neurol ; 16(3): 292-300, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-21925911

RESUMO

Three related infants of Roma ancestry, two of them siblings, showed hypotonia, predominantly axial, from birth, difficulty swallowing, myoclonic seizures, and respiratory difficulty. Dysmorphic features, principally micrognathia were present. EEGs showed focal epileptiform abnormalities. All three died in their 5th month from respiratory insufficiency complicated by pneumonia. Autopsy showed small brains without malformation. Microscopy revealed numerous axonal spheroids involving particularly the brain stem and spinal cord, with especial prominence in the middle cerebellar peduncle, the anterior part of the thalamic reticular nuclei, and the anterior horns and columns of the spinal cord. Spheroids that appeared to be on axons of lower motor neurons were especially large. No spheroids were seen in peripheral nerves; electron microscopy did not show spheroids in skin. By electron microscopy spheroids contained neurofilaments, sparse mitochondria, and electron dense granules. The material did not allow identification of microtubules. Closely packed vesicles excluded neurofilamanets from the center of many spheroids, especially in the middle cerebellar peduncle. Sprouting of axons from the surface of many spheroids was seen. This disease is distinct from the well described type of infantile neuroaxonal dystrophy (Seitelberger's disease) in view of the distribution of spheroids, presence of spheroids on proximal rather than distal parts of axons, sparing of the peripheral nerves, lack of staining for synuclein, presence of sprouting, and lack of membranous profiles in the spheroids. A review of reported types of axonal dystrophy has not shown identical cases.


Assuntos
Encéfalo/patologia , Distrofias Neuroaxonais/patologia , Medula Espinal/patologia , Evolução Fatal , Feminino , Humanos , Recém-Nascido , Masculino , Microscopia Eletrônica , Distrofias Neuroaxonais/fisiopatologia , Linhagem , Roma , Irmãos
14.
J Inherit Metab Dis ; 34(3): 835-42, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21347589

RESUMO

Short-chain 3-hydroxyacyl-CoA dehydrogenase (HADH, SCHAD) deficiency (OMIM #231530) represents a recently described disorder of mitochondrial fatty acid beta-oxidation, with less than ten cases described worldwide. The main clinical presentation of this metabolic disease is different from other inherited defects of fatty acid ß-oxidation as the hypoglycemia is associated with hyperinsulinism. We present the clinical, biochemical and molecular findings of four new Caucasian patients with HADH deficiency. These new cases contribute to a more comprehensive description of the phenotype, diagnostic biomarkers and treatment options for this poorly defined disease.


Assuntos
Diagnóstico Precoce , Erros Inatos do Metabolismo/diagnóstico , 3-Hidroxiacil-CoA Desidrogenases/deficiência , 3-Hidroxiacil-CoA Desidrogenases/genética , Adolescente , Criança , Consanguinidade , Feminino , Humanos , Lactente , Masculino , Erros Inatos do Metabolismo/genética , Linhagem , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Adulto Jovem
15.
Mol Genet Metab ; 100(4): 385-7, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20466570

RESUMO

Maple syrup urine disease is an autosomal recessive disorder of branched-chain amino acids metabolism with a worldwide frequency of 1/185,000 live newborns. In Portugal, the incidence of the disease has not been assessed. Based on the review of the cases diagnosed by tandem mass spectrometry an incidence of 1/86,800 live newborns was estimated in Portugal, indicating that the disease is more frequent in this country than reported in most populations.


Assuntos
Doença da Urina de Xarope de Bordo/epidemiologia , Adolescente , Adulto , Criança , Humanos , Incidência , Recém-Nascido , Doença da Urina de Xarope de Bordo/diagnóstico , Triagem Neonatal , Portugal/epidemiologia , Adulto Jovem
16.
Mol Genet Metab ; 94(2): 148-56, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18378174

RESUMO

Maple syrup urine disease (MSUD) is an autosomal recessive disorder, caused by the defective function of the branched-chain alpha-ketoacid dehydrogenase complex (BCKD). BCKD is a mitochondrial complex, encoded by four nuclear genes (BCKDHA, BCKDHB, DBT and DLD), involved in the metabolism of branched-chain amino acids (BCAAs). Since the MSUD mutational spectrum has not been previously assessed in Portugal, in this study we present the molecular characterization of 30 MSUD Portuguese patients. Seventeen putative mutations have been identified (six in BCKDHA, five in BCKDHB and six in DBT); seven of them are here described for the first time. The most common mutation identified was a C deletion in BCKDHA gene (c.117delC; p.R40GfsX23), already reported in the Spanish population. Interestingly, it was found in all patients of a Gypsy community from South of the country, so a founder effect is probably responsible for the high incidence of the disease in this community. Structural models of MSUD missense mutations have been performed to understand their pathogenic effect, in order to elucidate and often to predict the severity of a mutation clinical consequence.


Assuntos
3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/química , 3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/genética , Doença da Urina de Xarope de Bordo/genética , Mutação de Sentido Incorreto , Roma/genética , 3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/metabolismo , Aminoácidos de Cadeia Ramificada/sangue , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Complexos Multienzimáticos/química , Complexos Multienzimáticos/genética , Complexos Multienzimáticos/metabolismo , Portugal , Espectrometria de Massas em Tandem
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