Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 24
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mol Genet Metab ; 127(4): 336-345, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31326288

RESUMO

INTRODUCTION: Glycerol phenylbutyrate (GPB) is currently approved for use in the US and Europe for patients of all ages with urea cycle disorders (UCD) who cannot be managed with protein restriction and/or amino acid supplementation alone. Currently available data on GPB is limited to 12 months exposure. Here, we present long-term experience with GPB. METHODS: This was an open-label, long-term safety study of GPB conducted in the US (17 sites) and Canada (1 site) monitoring the use of GPB in UCD patients who had previously completed 12 months of treatment in the previous safety extension studies. Ninety patients completed the previous studies with 88 of these continuing into the long-term evaluation. The duration of therapy was open ended until GPB was commercially available. The primary endpoint was the rate of adverse events (AEs). Secondary endpoints were venous ammonia levels, number and causes of hyperammonemic crises (HACs) and neuropsychological testing. RESULTS: A total of 45 pediatric patients between the ages of 1 to 17 years (median 7 years) and 43 adult patients between the ages of 19 and 61 years (median 30 years) were enrolled. The treatment emergent adverse events (TEAE) reported in ≥10% of adult or pediatric patients were consistent with the TEAEs reported in the previous safety extension studies with no increase in the overall incidence of TEAEs and no new TEAEs that indicated a new safety signal. Mean ammonia levels remained stable and below the adult upper limit of normal (<35 µmol/L) through 24 months of treatment in both the pediatric and adult population. Over time, glutamine levels decreased in the overall population. The mean annualized rate of HACs (0.29) established in the previously reported 12-month follow-up study was maintained with continued GPB exposure. CONCLUSION: Following the completion of 12-month follow-up studies with GPB treatment, UCD patients were followed for an additional median of 1.85 (range 0 to 5.86) years in the present study with continued maintenance of ammonia control, similar rates of adverse events, and no new adverse events identified.

2.
Pediatrics ; 144(2)2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31350360

RESUMO

In 2016, the American Academy of Pediatrics published a clinical practice guideline that more specifically defined apparent life-threatening events as brief resolved unexplained events (BRUEs) and provided evidence-based recommendations for the evaluation of infants who meet lower-risk criteria for a subsequent event or serious underlying disorder. The clinical practice guideline did not provide recommendations for infants meeting higher-risk criteria, an important and common population of patients. Therefore, we propose a tiered approach for clinical evaluation and management of higher-risk infants who have experienced a BRUE. Because of a vast array of potential causes, the initial evaluation prioritizes the diagnosis of time-sensitive conditions for which delayed diagnosis or treatment could impact outcomes, such as child maltreatment, feeding problems, cardiac arrhythmias, infections, and congenital abnormalities. The secondary evaluation addresses problems that are less sensitive to delayed diagnosis or treatment, such as dysphagia, intermittent partial airway obstruction, and epilepsy. The authors recommend a tailored, family-centered, multidisciplinary approach to evaluation and management of all higher-risk infants with a BRUE, whether accomplished during hospital admission or through coordinated outpatient care. The proposed framework was developed by using available evidence and expert consensus.

4.
Genet Med ; 2018 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-30245509

RESUMO

PURPOSE: TANGO2-related disorders were first described in 2016 and prior to this publication, only 15 individuals with TANGO2-related disorder were described in the literature. Primary features include metabolic crisis with rhabdomyolysis, encephalopathy, intellectual disability, seizures, and cardiac arrhythmias. We assess whether genotype and phenotype of TANGO2-related disorder has expanded since the initial discovery and determine the efficacy of exome sequencing (ES) as a diagnostic tool for detecting variants. METHODS: We present a series of 14 individuals from 11 unrelated families with complex medical and developmental histories, in whom ES or microarray identified compound heterozygous or homozygous variants in TANGO2. RESULTS: The initial presentation of patients with TANGO2-related disorders can be variable, including primarily neurological presentations. We expand the phenotype and genotype for TANGO2, highlighting the variability of the disorder. CONCLUSION: TANGO2-related disorders can have a more diverse clinical presentation than previously anticipated. We illustrate the utility of routine ES data reanalysis whereby discovery of novel disease genes can lead to a diagnosis in previously unsolved cases and the need for additional copy-number variation analysis when ES is performed.

5.
Mol Genet Metab ; 124(2): 109-113, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29703588

RESUMO

Current newborn screening (NBS) for urea cycle disorders (UCD) is incomplete as only distal UCDs are included in most NBS programs by measuring elevated amino acid concentrations. NBS for the proximal UCDs involves the detection in NBS spots of low citrulline values, a finding which is often overlooked because it is considered to be inadequate. We retrospectively analyzed NBS blood spots from known UCD patients comparing the utility of the Region 4 Stork (R4S) interpretive tools to conventional cutoff based interpretation. This study shows the utility of R4S tools in detecting all UCDs, and provides evidence to support the nomination to add proximal UCDs to the recommended uniform screening panel.

6.
Epilepsia ; 59(2): 389-402, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29315614

RESUMO

OBJECTIVE: Pathogenic SLC6A1 variants were recently described in patients with myoclonic atonic epilepsy (MAE) and intellectual disability (ID). We set out to define the phenotypic spectrum in a larger cohort of SCL6A1-mutated patients. METHODS: We collected 24 SLC6A1 probands and 6 affected family members. Four previously published cases were included for further electroclinical description. In total, we reviewed the electroclinical data of 34 subjects. RESULTS: Cognitive development was impaired in 33/34 (97%) subjects; 28/34 had mild to moderate ID, with language impairment being the most common feature. Epilepsy was diagnosed in 31/34 cases with mean onset at 3.7 years. Cognitive assessment before epilepsy onset was available in 24/31 subjects and was normal in 25% (6/24), and consistent with mild ID in 46% (11/24) or moderate ID in 17% (4/24). Two patients had speech delay only, and 1 had severe ID. After epilepsy onset, cognition deteriorated in 46% (11/24) of cases. The most common seizure types were absence, myoclonic, and atonic seizures. Sixteen cases fulfilled the diagnostic criteria for MAE. Seven further patients had different forms of generalized epilepsy and 2 had focal epilepsy. Twenty of 31 patients became seizure-free, with valproic acid being the most effective drug. There was no clear-cut correlation between seizure control and cognitive outcome. Electroencephalography (EEG) findings were available in 27/31 patients showing irregular bursts of diffuse 2.5-3.5 Hz spikes/polyspikes-and-slow waves in 25/31. Two patients developed an EEG pattern resembling electrical status epilepticus during sleep. Ataxia was observed in 7/34 cases. We describe 7 truncating and 18 missense variants, including 4 recurrent variants (Gly232Val, Ala288Val, Val342Met, and Gly362Arg). SIGNIFICANCE: Most patients carrying pathogenic SLC6A1 variants have an MAE phenotype with language delay and mild/moderate ID before epilepsy onset. However, ID alone or associated with focal epilepsy can also be observed.


Assuntos
Epilepsias Mioclônicas/fisiopatologia , Proteínas da Membrana Plasmática de Transporte de GABA/genética , Deficiência Intelectual/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Adolescente , Adulto , Anticonvulsivantes/uso terapêutico , Ataxia/complicações , Ataxia/genética , Ataxia/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Eletroencefalografia , Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/genética , Epilepsias Parciais/complicações , Epilepsias Parciais/tratamento farmacológico , Epilepsias Parciais/genética , Epilepsias Parciais/fisiopatologia , Epilepsia Generalizada/complicações , Epilepsia Generalizada/tratamento farmacológico , Epilepsia Generalizada/genética , Epilepsia Generalizada/fisiopatologia , Feminino , Estudos de Associação Genética , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/complicações , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , Mutação , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/complicações , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Resultado do Tratamento , Ácido Valproico/uso terapêutico , Adulto Jovem
7.
Pediatrics ; 137(5)2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27244835

RESUMO

This is the first clinical practice guideline from the American Academy of Pediatrics that specifically applies to patients who have experienced an apparent life-threatening event (ALTE). This clinical practice guideline has 3 objectives. First, it recommends the replacement of the term ALTE with a new term, brief resolved unexplained event (BRUE). Second, it provides an approach to patient evaluation that is based on the risk that the infant will have a repeat event or has a serious underlying disorder. Finally, it provides management recommendations, or key action statements, for lower-risk infants. The term BRUE is defined as an event occurring in an infant younger than 1 year when the observer reports a sudden, brief, and now resolved episode of ≥1 of the following: (1) cyanosis or pallor; (2) absent, decreased, or irregular breathing; (3) marked change in tone (hyper- or hypotonia); and (4) altered level of responsiveness. A BRUE is diagnosed only when there is no explanation for a qualifying event after conducting an appropriate history and physical examination. By using this definition and framework, infants younger than 1 year who present with a BRUE are categorized either as (1) a lower-risk patient on the basis of history and physical examination for whom evidence-based recommendations for evaluation and management are offered or (2) a higher-risk patient whose history and physical examination suggest the need for further investigation and treatment but for whom recommendations are not offered. This clinical practice guideline is intended to foster a patient- and family-centered approach to care, reduce unnecessary and costly medical interventions, improve patient outcomes, support implementation, and provide direction for future research. Each key action statement indicates a level of evidence, the benefit-harm relationship, and the strength of recommendation.


Assuntos
Apneia/diagnóstico , Cianose/diagnóstico , Hipotonia Muscular/diagnóstico , Terminologia como Assunto , Emergências , Humanos , Lactente , Fatores de Risco , Morte Súbita do Lactente/diagnóstico
9.
Mol Genet Metab ; 116(1-2): 29-34, 2015 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26296711

RESUMO

BACKGROUND: Health care outcomes have been increasingly assessed through health-related quality of life (HRQoL) measures. While the introduction of nitrogen-scavenging medications has improved survival in patients with urea cycle disorders (UCDs), they are often associated with side effects that may affect patient compliance and outcomes. METHODS: Symptoms commonly associated with nitrogen-scavenging medications were evaluated in 100 adult and pediatric participants using a non-validated UCD-specific questionnaire. Patients or their caregivers responded to a pre-defined list of symptoms known to be associated with the use of these medications. Responses were collected at baseline (while patients were receiving sodium phenylbutyrate [NaPBA]) and during treatment with glycerol phenylbutyrate (GPB). RESULTS: After 3 months of GPB dosing, there were significant reductions in the proportion of patients with treatment-associated symptoms (69% vs. 46%; p<0.0001), the number of symptoms per patient (2.5 vs. 1.1; p<0.0001), and frequency of the more commonly reported individual symptoms such as body odor, abdominal pain, nausea, burning sensation in mouth, vomiting, and heartburn (p<0.05). The reduction in symptoms was observed in both pediatric and adult patients. The presence or absence of symptoms or change in severity did not correlate with plasma ammonia levels or NaPBA dose. CONCLUSIONS: The reduction in symptoms following 3 months of open-label GPB dosing was similar in pediatric and adult patients and may be related to chemical structure and intrinsic characteristics of the product rather than its effect on ammonia control.


Assuntos
Glicerol/análogos & derivados , Fenilbutiratos/efeitos adversos , Qualidade de Vida , Autorrelato , Distúrbios Congênitos do Ciclo da Ureia/tratamento farmacológico , Adolescente , Adulto , Idoso , Amônia/sangue , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Feminino , Glicerol/efeitos adversos , Glicerol/química , Glicerol/uso terapêutico , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fenilbutiratos/química , Fenilbutiratos/uso terapêutico , Inquéritos e Questionários , Distúrbios Congênitos do Ciclo da Ureia/sangue , Distúrbios Congênitos do Ciclo da Ureia/psicologia , Adulto Jovem
10.
Genet Med ; 17(7): 561-8, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25503497

RESUMO

PURPOSE: The aim of this study was to examine predictors of ammonia exposure and hyperammonemic crises in patients with urea cycle disorders. METHODS: The relationships between fasting ammonia, daily ammonia exposure, and hyperammonemic crises were analyzed in >100 patients with urea cycle disorders. RESULTS: Fasting ammonia correlated strongly with daily ammonia exposure (r = 0.764; P < 0.001). For patients with fasting ammonia concentrations <0.5 upper limit of normal (ULN), 0.5 to <1.0 ULN, and ≥1.0 ULN, the probability of a normal average daily ammonia value was 87, 60, and 39%, respectively, and 10.3, 14.1, and 37.0% of these patients, respectively, experienced ≥1 hyperammonemic crisis over 12 months. Time to first hyperammonemic crisis was shorter (P = 0.008) and relative risk (4.5×; P = 0.011) and rate (~5×, P = 0.006) of hyperammonemic crises were higher in patients with fasting ammonia ≥1.0 ULN vs. <0.5ULN; relative risk was even greater (20×; P = 0.009) in patients ≥6 years old. A 10- or 25-µmol/l increase in ammonia exposure increased the relative risk of a hyperammonemic crisis by 50 and >200% (P < 0.0001), respectively. The relationship between ammonia and hyperammonemic crisis risk seemed to be independent of treatment, age, urea cycle disorder subtype, dietary protein intake, or blood urea nitrogen. Fasting glutamine correlated weakly with daily ammonia exposure assessed as 24-hour area under the curve and was not a significant predictor of hyperammonemic crisis. CONCLUSION: Fasting ammonia correlates strongly and positively with daily ammonia exposure and with the risk and rate of hyperammonemic crises, suggesting that patients with urea cycle disorder may benefit from tight ammonia control.


Assuntos
Amônia/sangue , Glutamina/sangue , Hiperamonemia/sangue , Distúrbios Congênitos do Ciclo da Ureia/sangue , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Adulto Jovem
11.
Mol Genet Metab ; 111(4): 484-92, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24503138

RESUMO

Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a fatty acid oxidation disorder with widely varying presentations that has presented a significant challenge to newborn screening (NBS). The Western States Regional Genetics Services Collaborative developed a workgroup to study infants with NBS positive for VLCADD. We performed retrospective analysis of newborns with elevated C14:1-acylcarnitine on NBS in California, Oregon, Washington, and Hawai'i including available confirmatory testing and clinical information. Overall, from 2,802,504 children screened, there were 242 cases screen-positive for VLCADD. There were 34 symptomatic true positive cases, 18 asymptomatic true positives, 112 false positives, 55 heterozygotes, 11 lost to follow-up, and 12 other disorders. One in 11,581 newborns had an abnormal NBS for suspected VLCADD. Comparison of analytes and analyte ratios from the NBS demonstrated statistically significant differences between true positive and false positive groups for C14:1, C14, C14:1/C2, and C14:1/C16. The positive predictive value for all true positive cases was 94%, 54%, and 23% when C14:1 was ≥2.0 µM, ≥1.0 µM, and ≥0.7 µM, respectively. Sequential post-analytical analysis could reduce the referral rate in 25.8% of cases. This study is the largest reported follow-up of infants with NBS screen-positive results for suspected VLCADD and demonstrates the necessity of developing comprehensive and consistent long-term follow-up NBS systems. Application of clinical information revealed differences between symptomatic and asymptomatic children with VLCADD. Comparison of NBS analytes and analyte ratios may be valuable in developing more effective diagnostic algorithms.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Erros Inatos do Metabolismo Lipídico/diagnóstico , Doenças Mitocondriais/diagnóstico , Doenças Musculares/diagnóstico , Triagem Neonatal/métodos , Carnitina/análogos & derivados , Carnitina/metabolismo , Análise Mutacional de DNA , Demografia , Ácidos Graxos/metabolismo , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Reprodutibilidade dos Testes
12.
Pediatr Neurol ; 50(1): 108-11, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24138954

RESUMO

BACKGROUND: Elevated plasma homocysteine is a risk factor for arterial and venous thromboses in adults. Homocysteine is increased in cystathionine beta-synthase deficiency, a treatable amino acid metabolic disorder that may be missed on newborn screening placing children at risk of thrombosis and strokes. PATIENT: We present a 3-year-old girl with normal newborn screening for cystathionine beta-synthase deficiency who developed a symptomatic cerebral venous sinus thrombosis. Subsequent testing revealed marked hyperhomocystinemia and genetic testing confirmed cystathionine beta-synthase deficiency. CONCLUSIONS: Current newborn screening is limited in its ability to detect cystathionine beta-synthase deficiency and although postanalytical interpretation may provide increased sensitivity, a normal newborn screening result should not replace the importance of physician surveillance.


Assuntos
Trombose do Corpo Cavernoso/complicações , Homocistinúria/etiologia , Acidente Vascular Cerebral/complicações , Trombose do Corpo Cavernoso/diagnóstico , Pré-Escolar , Feminino , Homocistinúria/diagnóstico , Humanos , Angiografia por Ressonância Magnética , Imagem por Ressonância Magnética
13.
Pediatr Int ; 55(6): e156-8, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24330302

RESUMO

Deficiency in methylmalonyl-coenzyme A mutase (MCM) is associated with accumulation of methylmalonic acid (MMA) and clinical outcomes that include early death and neurological impairment. Reported here are two unrelated patients with a homozygous p.P86L mutation in the MUT gene, which encodes MCM, diagnosed following newborn screening. This is the first description of a homozygous mutation in the N-terminal extended segment of the MCM apoenzyme. Both in vitro and in vivo testing did not find a response to supplemental hydroxocobalamin. After discontinuation of hydroxocobalamin in one patient, serum MMA level remained elevated but stable, while urine MMA increased. Both patients have remained asymptomatic with normal development. The observed homozygous p.P86L mutation in the N-terminal extended segment may yield reduced MCM activity and is refractory to hydroxocobalamin supplementation, while not inducing a metabolically unstable phenotype. These genotype-phenotype associations further enhance the understanding of methylmalonic acidemia, which will continue to improve patient care.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Metilmalonil-CoA Mutase/genética , Mutação , Doenças Assintomáticas , Pré-Escolar , Feminino , Homozigoto , Humanos , Recém-Nascido , Masculino
14.
Hepatology ; 57(6): 2171-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22961727

RESUMO

UNLABELLED: Glycerol phenylbutyrate is under development for treatment of urea cycle disorders (UCDs), rare inherited metabolic disorders manifested by hyperammonemia and neurological impairment. We report the results of a pivotal Phase 3, randomized, double-blind, crossover trial comparing ammonia control, assessed as 24-hour area under the curve (NH3 -AUC0-24hr ), and pharmacokinetics during treatment with glycerol phenylbutyrate versus sodium phenylbutyrate (NaPBA) in adult UCD patients and the combined results of four studies involving short- and long-term glycerol phenylbutyrate treatment of UCD patients ages 6 and above. Glycerol phenylbutyrate was noninferior to NaPBA with respect to ammonia control in the pivotal study, with mean (standard deviation, SD) NH3 -AUC0-24hr of 866 (661) versus 977 (865) µmol·h/L for glycerol phenylbutyrate and NaPBA, respectively. Among 65 adult and pediatric patients completing three similarly designed short-term comparisons of glycerol phenylbutyrate versus NaPBA, NH3 -AUC0-24hr was directionally lower on glycerol phenylbutyrate in each study, similar among all subgroups, and significantly lower (P < 0.05) in the pooled analysis, as was plasma glutamine. The 24-hour ammonia profiles were consistent with the slow-release behavior of glycerol phenylbutyrate and better overnight ammonia control. During 12 months of open-label glycerol phenylbutyrate treatment, average ammonia was normal in adult and pediatric patients and executive function among pediatric patients, including behavioral regulation, goal setting, planning, and self-monitoring, was significantly improved. CONCLUSION: Glycerol phenylbutyrate exhibits favorable pharmacokinetics and ammonia control relative to NaPBA in UCD patients, and long-term glycerol phenylbutyrate treatment in pediatric UCD patients was associated with improved executive function (ClinicalTrials.gov NCT00551200, NCT00947544, NCT00992459, NCT00947297). (HEPATOLOGY 2012).


Assuntos
Amônia/sangue , Glicerol/análogos & derivados , Fenilbutiratos/uso terapêutico , Distúrbios Congênitos do Ciclo da Ureia/tratamento farmacológico , Adolescente , Adulto , Criança , Estudos Cross-Over , Método Duplo-Cego , Feminino , Glutamina/sangue , Glicerol/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Distúrbios Congênitos do Ciclo da Ureia/sangue , Adulto Jovem
15.
Pediatr Int ; 54(5): 585-601, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22494076

RESUMO

BACKGROUND: The current diagnostic approach for mitochondrial disorders requires invasive procedures such as muscle biopsy and multiple biochemical testing but the results are often inconclusive. Clinical sequencing tests are available only for a limited number of genes. Recently, massively parallel sequencing has become a powerful tool for testing genetically heterogeneous conditions such as mitochondrial disorders. METHODS: Targeted next-generation sequencing was performed on 26 patients with known or suspected mitochondrial disorders using in-solution capture for the exons of 908 known and candidate nuclear genes and an Illumina genome analyzer. RESULTS: None of the 18 patients with various abnormal respiratory chain complex (RCC) activities had molecular defects in either subunits or assembly factors of mitochondrial RCC enzymes except a reference control sample with known mutations in SURF1. Instead, several variants in known pathogenic genes including CPT2, POLG, PDSS1, UBE3A, SDHD, and a few potentially pathogenic variants in candidate genes such as MTO1 or SCL7A13 were identified. CONCLUSIONS: Sequencing only nuclear genes for RCC subunits and assembly factors may not provide the diagnostic answers for suspected patients with mitochondrial disorders. The present findings indicate that the diagnostic spectrum of mitochondrial disorders is much broader than previously thought, which could potentially lead to misdiagnosis and/or inappropriate treatment. Overall analytic sensitivity and precision appear acceptable for clinical testing. Despite the limitations in finding mutations in all patients, the present findings underscore the considerable clinical benefits of targeted next-generation sequencing and serve as a prototype for extending the clinical evaluation in this clinically heterogeneous patient group.


Assuntos
Transporte de Elétrons/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Doenças Mitocondriais/diagnóstico , Análise de Sequência de DNA/métodos , Sequência de Bases , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Doenças Mitocondriais/genética , Mutação
16.
Pediatr Nephrol ; 27(9): 1453-64, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21947256

RESUMO

Newborn screening (NBS) has rapidly changed since its origins in the 1960s. Beginning with a single condition, then a handful in the 1990 s, NBS has expanded in the past decade to allow the detection of many disorders of amino-acid, organic-acid, and fatty-acid metabolism. These conditions often present with recurrent acute attacks of metabolic acidosis, hypoglycemia, liver failure, and hyperammonemia that may be prevented with initiation of early treatment. Renal disease is an important component of these disorders and is a frequent source of morbidity. Hemodialysis is often required for hyperammonemia in the organic acidemias and urea-cycle disorders. Rhabdomyolysis with renal failure is a frequent complication in fatty-acid oxidation disorders. Newer screening methods are under investigation to detect lysosomal storage diseases, primary immunodeficiencies, and primary renal disorders. These advances will present many challenges to nephrologists and pediatricians with respect to closely monitoring and caring for children with such disorders.


Assuntos
Diagnóstico Precoce , Nefropatias/diagnóstico , Erros Inatos do Metabolismo/diagnóstico , Triagem Neonatal/métodos , Triagem Neonatal/tendências , Humanos , Recém-Nascido , Nefropatias/etiologia , Erros Inatos do Metabolismo/etiologia
17.
Mol Genet Metab ; 100 Suppl 1: S97-105, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20188616

RESUMO

The Urea Cycle Disorders Consortium (UCDC) was created as part of a larger network established by the National Institutes of Health to study rare diseases. This paper reviews the UCDC's accomplishments over the first 6years, including how the Consortium was developed and organized, clinical research studies initiated, and the importance of creating partnerships with patient advocacy groups, philanthropic foundations and biotech and pharmaceutical companies.


Assuntos
Comportamento Cooperativo , Doenças Raras/terapia , Distúrbios Congênitos do Ciclo da Ureia/terapia , Humanos , Relações Interinstitucionais , Estudos Longitudinais , Sistema de Registros
18.
J Inherit Metab Dis ; 32 Suppl 12009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19639391

RESUMO

Pyruvate dehydrogenase (PDH) is a crucial multienzyme system linking glycolysis to the tricarboxylic acid cycle by catalysing the decarboxylation of pyruvate to acetyl-CoA. Deficiency in pyruvate dehydrogenase is most commonly secondary to mutations in the X-linked PDHA1 gene encoding the E1 alpha subunit. There is a wide range of clinical presentations from severe neonatal lactic acidosis to chronic encephalopathy (Leigh syndrome). In recent years, a small subset of patients was recognized with less severe involvement, presenting initially only with intermittent symptoms, mainly of ataxia. Most of these patients remain stable for a number of years before developing progressive neurological deterioration around puberty at the latest. There does not appear to be a reliable correlation between genotype, phenotype, or enzyme activity. This makes counselling in a clinical setting challenging. We report a case with a previously known common mutation in PDHA1 (R263G) with an excellent outcome at 18 years of age. Previous patients with this mutation have presented with mental retardation and/or Leigh syndrome, while our patient's clinical outcome is exceptional. He is cognitively normal and has normal brain MRI. His management includes a stringent carbohydrate-free diet, as well as supplementation with thiamine, carnitine and vitamin E. This case further broadens the clinical spectrum, including now an example of a cognitively normal adult with PDH deficiency.


Assuntos
Cognição , Mutação , Piruvato Desidrogenase (Lipoamida)/genética , Doença da Deficiência do Complexo de Piruvato Desidrogenase/genética , Adolescente , Análise Mutacional de DNA , Dieta com Restrição de Carboidratos , Suplementos Nutricionais , Predisposição Genética para Doença , Humanos , Imagem por Ressonância Magnética , Masculino , Fenótipo , Doença da Deficiência do Complexo de Piruvato Desidrogenase/diagnóstico , Doença da Deficiência do Complexo de Piruvato Desidrogenase/enzimologia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/psicologia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/terapia , Resultado do Tratamento
19.
Mol Ther ; 17(3): 425-9, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19156135

RESUMO

We report the development of a gene replacement strategy for very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. VLCAD is a mitochondrial enzyme involved in fatty acid beta-oxidation, a key step in energy production during times of fasting or stress. Deficiency of VLCAD classically presents as hepatic dysfunction, hypoglycemia, cardiomyopathy, rhabdomyolysis, and/or sudden death. While dietary therapy for VLCAD deficiency has proven beneficial in preventing some symptoms, a risk of metabolic catastrophic decompensation remains throughout life during times of increased energy demand. We designed a recombinant adeno-associated virus (AAV) expressing the human VLCAD gene (AAV8-hVLCAD). To demonstrate its in vivo activity, AAV8-hVLCAD was administered via the tail vein to VLCAD-knockout mice. A reduction in accumulated serum long-chain acylcarnitines and increased fasting tolerance judged on blood glucose concentrations were observed as of 11 days postinjections through >100 days. Western analysis of liver, skeletal muscle, and heart extracts using PEP1 anti-hVLCAD antibody revealed short-term hVLCAD expression in the liver and muscle and longer-term expression in heart. This demonstrates the ability of human VLCAD to correct the biochemical phenotype of VLCAD-deficient mice.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Dependovirus/genética , Terapia Genética , Acil-CoA Desidrogenase de Cadeia Longa/genética , Animais , Jejum , Humanos , Hipoglicemia/sangue , Hipoglicemia/enzimologia , Hipoglicemia/genética , Camundongos , Especificidade de Órgãos
20.
Am J Med Genet A ; 143A(6): 599-603, 2007 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-17304549

RESUMO

The 1qter microdeletion is often reported in the literature as a part of a complex chromosome rearrangement. We describe a patient with a normal initial cytogenetic analysis later found by subtelomeric FISH to have a de novo isolated 1qter microdeletion. Further characterization was completed through microarray comparative genomic hybridization (CGH) and specific bacterial artificial chromosomes (BACs) to a region of 5.2-5.3 Mbp. Six additional cases were reviewed from a literature search. While no particular feature is specifically unique, the most frequently associated features include short stature, developmental delay and mental retardation, microcephaly, seizures, abnormal corpus callosum, and abnormal ear shape. This further delineates the phenotype and further narrows the chromosomal region responsible for a 1qter microdeletion phenotype.


Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 1 , Deficiências do Desenvolvimento/patologia , Face/anormalidades , Microcefalia/patologia , Anormalidades Múltiplas/patologia , Pré-Escolar , Bandeamento Cromossômico , Feminino , Genoma Humano , Humanos , Hibridização in Situ Fluorescente , Lactente , Cariotipagem , Hibridização de Ácido Nucleico/métodos , Fenótipo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA