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1.
J Community Genet ; 14(6): 613-620, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37847346

RESUMO

Newborn screening in Alaska includes screening for carnitine palmitoyltransferase 1A (CPT1A) deficiency. The CPT1A Arctic variant is a variant highly prevalent among Indigenous peoples in the Arctic. In this study, we sought to elicit Alaska Native (AN) community member and AN-serving healthcare providers' knowledge and perspectives on the CPT1A Arctic variant. Focus groups with community members and healthcare providers were held in two regions of Alaska between October 2018 and January 2019. Thematic analysis was used to identify recurring constructs. Knowledge and understanding about the CPT1A Arctic variant and its health impact varied, and participants were interested in learning more about it. Additional education for healthcare professionals was recommended to improve providers' ability to communicate with family caregivers about the Arctic variant. Engagement with AN community members identified opportunities to improve educational outreach via multiple modalities for providers and caregivers on the Arctic variant, which could help to increase culturally relevant guidance and avoid stigmatization, undue worry, and unnecessary intervention. Education and guidance on the care of infants and children homozygous for the CPT1A Arctic variant could improve care and reduce negative psychosocial effects.

2.
Sci Data ; 8(1): 114, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33883556

RESUMO

Every year individuals experience symptoms that remain undiagnosed by healthcare providers. In the United States, these rare diseases are defined as a condition that affects fewer than 200,000 individuals. However, there are an estimated 7000 rare diseases, and there are an estimated 25-30 million Americans in total (7.6-9.2% of the population as of 2018) affected by such disorders. The NIH Common Fund Undiagnosed Diseases Network (UDN) seeks to provide diagnoses for individuals with undiagnosed disease. Mass spectrometry-based metabolomics and lipidomics analyses could advance the collective understanding of individual symptoms and advance diagnoses for individuals with heretofore undiagnosed disease. Here, we report the mass spectrometry-based metabolomics and lipidomics analyses of blood plasma, urine, and cerebrospinal fluid from 148 patients within the UDN and their families, as well as from a reference population of over 100 individuals with no known metabolic diseases. The raw and processed data are available to the research community so that they might be useful in the diagnoses of current or future patients suffering from undiagnosed disorders.


Assuntos
Lipidômica , Doenças Metabólicas/diagnóstico , Metabolômica , Doenças não Diagnosticadas/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Conjuntos de Dados como Assunto , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Espectrometria de Massas , Doenças Metabólicas/sangue , Doenças Metabólicas/líquido cefalorraquidiano , Doenças Metabólicas/urina , Pessoa de Meia-Idade , Doenças não Diagnosticadas/sangue , Doenças não Diagnosticadas/líquido cefalorraquidiano , Doenças não Diagnosticadas/urina , Adulto Jovem
4.
PLoS Genet ; 16(6): e1008841, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32544203

RESUMO

Hypomyelination, a neurological condition characterized by decreased production of myelin sheets by glial cells, often has no known etiology. Elucidating the genetic causes of hypomyelination provides a better understanding of myelination, as well as means to diagnose, council, and treat patients. Here, we present evidence that YIPPEE LIKE 3 (YPEL3), a gene whose developmental role was previously unknown, is required for central and peripheral glial cell development. We identified a child with a constellation of clinical features including cerebral hypomyelination, abnormal peripheral nerve conduction, hypotonia, areflexia, and hypertrophic peripheral nerves. Exome and genome sequencing revealed a de novo mutation that creates a frameshift in the open reading frame of YPEL3, leading to an early stop codon. We used zebrafish as a model system to validate that YPEL3 mutations are causative of neuropathy. We found that ypel3 is expressed in the zebrafish central and peripheral nervous system. Using CRISPR/Cas9 technology, we created zebrafish mutants carrying a genomic lesion similar to that of the patient. Our analysis revealed that Ypel3 is required for development of oligodendrocyte precursor cells, timely exit of the perineurial glial precursors from the central nervous system (CNS), formation of the perineurium, and Schwann cell maturation. Consistent with these observations, zebrafish ypel3 mutants have metabolomic signatures characteristic of oligodendrocyte and Schwann cell differentiation defects, show decreased levels of Myelin basic protein in the central and peripheral nervous system, and develop defasciculated peripheral nerves. Locomotion defects were observed in adult zebrafish ypel3 mutants. These studies demonstrate that Ypel3 is a novel gene required for perineurial cell development and glial myelination.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Bainha de Mielina/patologia , Neurogênese/genética , Proteínas Supressoras de Tumor/genética , Animais , Plexo Braquial/diagnóstico por imagem , Criança , Análise Mutacional de DNA , Modelos Animais de Doenças , Embrião não Mamífero , Feminino , Mutação da Fase de Leitura , Substância Cinzenta/diagnóstico por imagem , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico por imagem , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Humanos , Imageamento por Ressonância Magnética , Neuroglia/patologia , Oligodendroglia , Nervo Isquiático/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Sequenciamento do Exoma , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
5.
Anal Chem ; 92(2): 1796-1803, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31742994

RESUMO

Advancements in molecular separations coupled with mass spectrometry have enabled metabolome analyses for clinical cohorts. A population of interest for metabolome profiling is patients with rare disease for which abnormal metabolic signatures may yield clues into the genetic basis, as well as mechanistic drivers of the disease and possible treatment options. We undertook the metabolome profiling of a large cohort of patients with mysterious conditions characterized through the Undiagnosed Diseases Network (UDN). Due to the size and enrollment procedures, collection of the metabolomes for UDN patients took place over 2 years. We describe the study designed to adjust for measurements collected over a long time scale and how this enabled statistical analyses to summarize the metabolome of individual patients. We demonstrate the removal of time-based batch effects, overall statistical characteristics of the UDN population, and two case studies of interest that demonstrate the utility of metabolome profiling for rare diseases.


Assuntos
Lipídeos/análise , Modelos Estatísticos , Doenças não Diagnosticadas/diagnóstico , Estudos de Coortes , Humanos , Metabolômica , Doenças não Diagnosticadas/metabolismo
6.
N Engl J Med ; 379(22): 2131-2139, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30304647

RESUMO

BACKGROUND: Many patients remain without a diagnosis despite extensive medical evaluation. The Undiagnosed Diseases Network (UDN) was established to apply a multidisciplinary model in the evaluation of the most challenging cases and to identify the biologic characteristics of newly discovered diseases. The UDN, which is funded by the National Institutes of Health, was formed in 2014 as a network of seven clinical sites, two sequencing cores, and a coordinating center. Later, a central biorepository, a metabolomics core, and a model organisms screening center were added. METHODS: We evaluated patients who were referred to the UDN over a period of 20 months. The patients were required to have an undiagnosed condition despite thorough evaluation by a health care provider. We determined the rate of diagnosis among patients who subsequently had a complete evaluation, and we observed the effect of diagnosis on medical care. RESULTS: A total of 1519 patients (53% female) were referred to the UDN, of whom 601 (40%) were accepted for evaluation. Of the accepted patients, 192 (32%) had previously undergone exome sequencing. Symptoms were neurologic in 40% of the applicants, musculoskeletal in 10%, immunologic in 7%, gastrointestinal in 7%, and rheumatologic in 6%. Of the 382 patients who had a complete evaluation, 132 received a diagnosis, yielding a rate of diagnosis of 35%. A total of 15 diagnoses (11%) were made by clinical review alone, and 98 (74%) were made by exome or genome sequencing. Of the diagnoses, 21% led to recommendations regarding changes in therapy, 37% led to changes in diagnostic testing, and 36% led to variant-specific genetic counseling. We defined 31 new syndromes. CONCLUSIONS: The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35%. (Funded by the National Institutes of Health Common Fund.).


Assuntos
Testes Genéticos , Doenças Raras/genética , Análise de Sequência de DNA , Adulto , Animais , Criança , Diagnóstico Diferencial , Drosophila , Exoma , Feminino , Testes Genéticos/economia , Custos de Cuidados de Saúde/estatística & dados numéricos , Humanos , Masculino , Modelos Animais , National Institutes of Health (U.S.) , Doenças Raras/diagnóstico , Síndrome , Estados Unidos
7.
Am J Ophthalmol Case Rep ; 10: 244-248, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29780943

RESUMO

PURPOSE: We present the first detailed ophthalmic description of a child with Helsmoortel-Van der Aa Syndrome (HVDAS), including longitudinal follow-up and analysis. OBSERVATIONS: After extensive workup, a young child with poor visual behavior, hypotonic cerebral palsy, intellectual disability, and global developmental delay was found to have a heterozygous de novo mutation in the ADNP gene and diagnosed with HVDAS. Ophthalmic findings were remarkable for progressive nystagmus, macular pigment mottling, mild foveal hypoplasia with abnormal macular laminations, persistent rod dysfunction with electronegative waveform, and progressive cone degeneration. CONCLUSIONS AND IMPORTANCE: Patients with HVDAS are known to have abnormal visual behavior due to refractive or cortical impairment. However, we present the first description, to our knowledge, of an association with retinal mal-development and degeneration. Thus, patients with HVDAS should be referred for ophthalmic genetics evaluation, and HVDAS should be on the differential diagnosis for young children with global developmental delay who present with nystagmus, rod and cone dysfunction with electronegative waveform, and relative lack of severe structural degeneration on optical coherence tomography.

8.
Am J Hum Genet ; 102(3): 494-504, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29478781

RESUMO

ATP synthase, H+ transporting, mitochondrial F1 complex, δ subunit (ATP5F1D; formerly ATP5D) is a subunit of mitochondrial ATP synthase and plays an important role in coupling proton translocation and ATP production. Here, we describe two individuals, each with homozygous missense variants in ATP5F1D, who presented with episodic lethargy, metabolic acidosis, 3-methylglutaconic aciduria, and hyperammonemia. Subject 1, homozygous for c.245C>T (p.Pro82Leu), presented with recurrent metabolic decompensation starting in the neonatal period, and subject 2, homozygous for c.317T>G (p.Val106Gly), presented with acute encephalopathy in childhood. Cultured skin fibroblasts from these individuals exhibited impaired assembly of F1FO ATP synthase and subsequent reduced complex V activity. Cells from subject 1 also exhibited a significant decrease in mitochondrial cristae. Knockdown of Drosophila ATPsynδ, the ATP5F1D homolog, in developing eyes and brains caused a near complete loss of the fly head, a phenotype that was fully rescued by wild-type human ATP5F1D. In contrast, expression of the ATP5F1D c.245C>T and c.317T>G variants rescued the head-size phenotype but recapitulated the eye and antennae defects seen in other genetic models of mitochondrial oxidative phosphorylation deficiency. Our data establish c.245C>T (p.Pro82Leu) and c.317T>G (p.Val106Gly) in ATP5F1D as pathogenic variants leading to a Mendelian mitochondrial disease featuring episodic metabolic decompensation.


Assuntos
Alelos , Doenças Metabólicas/genética , ATPases Mitocondriais Próton-Translocadoras/genética , Mutação/genética , Subunidades Proteicas/genética , Sequência de Aminoácidos , Sequência de Bases , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Mutação com Perda de Função/genética , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , ATPases Mitocondriais Próton-Translocadoras/química , Subunidades Proteicas/química
9.
Epilepsia ; 58(10): 1771-1781, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28762469

RESUMO

OBJECTIVES: Glutaric acidemia type I (GA-I) is an inherited neurometabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase (GCDH) and characterized by increased levels of glutaric, 3-OH-glutaric, and glutaconic acids in the brain parenchyma. The increment of these organic acids inhibits glutamate decarboxylase (GAD) and consequently lowers the γ-aminobutyric acid (GABA) synthesis. Untreated patients exhibit severe neurologic deficits during development, including epilepsy, especially following an acute encephalopathy outbreak. In this work, we evaluated the role of the GABAergic system on epileptogenesis in GA-I using the Gcdh-/- mice exposed to a high lysine diet (Gcdh-/- -Lys). METHODS: Spontaneous recurrent seizures (SRS), seizure susceptibility, and changes in brain oscillations were evaluated by video-electroencephalography (EEG). Cortical GABAergic synaptic transmission was evaluated using electrophysiologic and neurochemical approaches. RESULTS: SRS were observed in 72% of Gcdh-/- -Lys mice, whereas no seizures were detected in age-matched controls (Gcdh+/+ or Gcdh-/- receiving normal diet). The severity and number of PTZ-induced seizures were higher in Gcdh-/- -Lys mice. EEG spectral analysis showed a significant decrease in theta and gamma oscillations and predominant delta waves in Gcdh-/- -Lys mice, associated with increased EEG left index. Analysis of cortical synaptosomes revealed a significantly increased percentage of glutamate release and decreased GABA release in Gcdh-/- -Lys mice that were associated with a decrease in cortical GAD immunocontent and activity and confirmed by reduced frequency of inhibitory events in cortical pyramidal cells. SIGNIFICANCE: Using an experimental model with a phenotype similar to that of GA-I in humans-the Gcdh-/- mice under high lysine diet (Gcdh-/- -Lys)-we provide evidence that a reduction in cortical inhibition of Gcdh-/- -Lys mice, probably induced by GAD dysfunction, leads to hyperexcitability and increased slow oscillations associated with neurologic abnormalities in GA-I. Our findings offer a new perspective on the pathophysiology of brain damage in GA-I.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Encefalopatias Metabólicas/genética , Encéfalo/efeitos dos fármacos , Epilepsia/genética , Glutaril-CoA Desidrogenase/deficiência , Glutaril-CoA Desidrogenase/genética , Ácido gama-Aminobutírico/efeitos dos fármacos , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Animais , Western Blotting , Encefalopatias Metabólicas/metabolismo , Cromatografia Líquida de Alta Pressão , Epilepsia/metabolismo , Antagonistas GABAérgicos/farmacologia , Glutamato Descarboxilase , Ácido Glutâmico/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Glutaril-CoA Desidrogenase/metabolismo , Camundongos , Camundongos Knockout , Pentilenotetrazol/farmacologia , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Ácido gama-Aminobutírico/metabolismo
11.
Am J Med Genet A ; 173(9): 2500-2504, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28657663

RESUMO

Pompe disease is a rare inherited metabolic disorder of glycogen metabolism caused by mutations in the GAA gene, encoding the acid α-1,4 glucosidase. Successful diagnosis of Pompe disease is achieved by clinical and biochemical evaluation followed by confirmation with DNA testing. Here, we report a male infant with a prenatal onset of cardiac symptoms and enzyme testing consistent with Pompe disease, but DNA testing by Sanger sequencing revealed no pathogenic variants. Due to the strong indication from clinical, enzymatic, and histological studies (despite the absence of molecular confirmation by traditional Sanger sequencing), enzyme replacement therapy (ERT) for Pompe disease was initiated. Reanalysis of the patient's DNA sample using next generation sequencing (NGS) of a panel of target genes causing glycogen storage disorders demonstrated compound heterozygosity for a point mutation and an exonic deletion in the GAA gene. This case illustrates the value of astute clinical judgement in patient management as well as the power of target capture deep NGS in the simultaneous detection of both a point mutation and a heterozygous exonic deletion by correcting pitfalls of the traditional PCR based sequencing, namely; allele dropout and the inability to detect exonic deletions.


Assuntos
Doença de Depósito de Glicogênio Tipo II/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Patologia Molecular/métodos , alfa-Glucosidases/genética , Éxons/genética , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Heterozigoto , Humanos , Lactente , Masculino , Mutação Puntual/genética
12.
J Inherit Metab Dis ; 40(1): 75-101, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27853989

RESUMO

Glutaric aciduria type I (GA-I; synonym, glutaric acidemia type I) is a rare inherited metabolic disease caused by deficiency of glutaryl-CoA dehydrogenase located in the catabolic pathways of L-lysine, L-hydroxylysine, and L-tryptophan. The enzymatic defect results in elevated concentrations of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutaryl carnitine in body tissues, which can be reliably detected by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Most untreated individuals with GA-I experience acute encephalopathic crises during the first 6 years of life that are triggered by infectious diseases, febrile reaction to vaccinations, and surgery. These crises result in striatal injury and consequent dystonic movement disorder; thus, significant mortality and morbidity results. In some patients, neurologic disease may also develop without clinically apparent crises at any age. Neonatal screening for GA-I us being used in a growing number of countries worldwide and is cost effective. Metabolic treatment, consisting of low lysine diet, carnitine supplementation, and intensified emergency treatment during catabolism, is effective treatment and improves neurologic outcome in those individuals diagnosed early; treatment after symptom onset, however, is less effective. Dietary treatment is relaxed after age 6 years and should be supervised by specialized metabolic centers. The major aim of this second revision of proposed recommendations is to re-evaluate the previous recommendations (Kölker et al. J Inherit Metab Dis 30:5-22, 2007b; J Inherit Metab Dis 34:677-694, 2011) and add new research findings, relevant clinical aspects, and the perspective of affected individuals.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Encefalopatias Metabólicas/diagnóstico , Encefalopatias Metabólicas/tratamento farmacológico , Glutaril-CoA Desidrogenase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Encefalopatias Metabólicas/metabolismo , Suplementos Nutricionais , Glutaratos/metabolismo , Glutaril-CoA Desidrogenase/metabolismo , Humanos , Lisina/metabolismo
13.
Nutr Res ; 36(1): 101-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26773786

RESUMO

A higher incidence of osteopenia is observed among children with inherited metabolic disorders (inborn errors of metabolism, or IEMs) who consume medical food-based diets that restrict natural vitamin D-containing food sources. We evaluated the vitamin D status of children with IEMs who live in the Pacific Northwest with limited sun exposure and determined whether bone mineral density (BMD) in children with phenylketonuria (PKU), the most common IEM, correlated with diet or biochemical markers of bone metabolism. We hypothesized that children with IEMs would have lower serum vitamin D concentrations than controls and that some children with PKU would have reduced bone mineralization. A retrospective record review of 88 patients with IEMs, and 445 children on unrestricted diets (controls) found the 25-hydroxyvitamin D concentrations were normal and not significantly different between groups (IEM patients, 27.1 ± 10.9; controls, 27.6 ± 11.2). Normal BMD at the hip or spine (-2

Assuntos
25-Hidroxivitamina D 2/sangue , Densidade Óssea , Doenças do Desenvolvimento Ósseo/prevenção & controle , Calcifediol/sangue , Alimentos Formulados , Erros Inatos do Metabolismo/dietoterapia , Deficiência de Vitamina D/prevenção & controle , Centros Médicos Acadêmicos , Adolescente , Adulto , Biomarcadores/sangue , Doenças do Desenvolvimento Ósseo/epidemiologia , Doenças do Desenvolvimento Ósseo/etiologia , Criança , Estudos de Coortes , Estudos Transversais , Registros Eletrônicos de Saúde , Alimentos Formulados/efeitos adversos , Humanos , Incidência , Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/fisiopatologia , Oregon/epidemiologia , Fenilcetonúrias/sangue , Fenilcetonúrias/dietoterapia , Fenilcetonúrias/fisiopatologia , Estudos Retrospectivos , Risco , Deficiência de Vitamina D/epidemiologia , Deficiência de Vitamina D/etiologia , Adulto Jovem
14.
Parasit Vectors ; 9: 7, 2016 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-26728034

RESUMO

BACKGROUND: Mitochondria play essential biological functions including the synthesis and trafficking of porphyrins and iron/sulfur clusters (ISC), processes that in mammals involve the mitochondrial ATP-Binding Cassette (ABC) transporters ABCB6 and ABCB7, respectively. The mitochondrion of pathogenic protozoan parasites such as Leishmania is a promising goal for new therapeutic approaches. Leishmania infects human macrophages producing the neglected tropical disease known as leishmaniasis. Like most trypanosomatid parasites, Leishmania is auxotrophous for heme and must acquire porphyrins from the host. METHODS: LmABCB3, a new Leishmania major protein with significant sequence similarity to human ABCB6/ABCB7, was identified and characterized using bioinformatic tools. Fluorescent microscopy was used to determine its cellular localization, and its level of expression was modulated by molecular genetic techniques. Intracellular in vitro assays were used to demonstrate its role in amastigotes replication, and an in vivo mouse model was used to analyze its role in virulence. Functional characterization of LmABCB3 was carried out in Leishmania promastigotes and Saccharomyces cerevisiae. Structural analysis of LmABCB3 was performed using molecular modeling software. RESULTS: LmABCB3 is an atypical ABC half-transporter that has a unique N-terminal extension not found in any other known ABC protein. This extension is required to target LmABCB3 to the mitochondrion and includes a potential metal-binding domain. We have shown that LmABCB3 interacts with porphyrins and is required for the mitochondrial synthesis of heme from a host precursor. We also present data supporting a role for LmABCB3 in the biogenesis of cytosolic ISC, essential cofactors for cell viability in all three kingdoms of life. LmABCB3 fully complemented the severe growth defect shown in yeast lacking ATM1, an orthologue of human ABCB7 involved in exporting from the mitochondria a gluthatione-containing compound required for the generation of cytosolic ISC. Indeed, docking analyzes performed with a LmABCB3 structural model using trypanothione, the main thiol in this parasite, as a ligand showed how both, LmABCB3 and yeast ATM1, contain a similar thiol-binding pocket. Additionally, we show solid evidence suggesting that LmABCB3 is an essential gene as dominant negative inhibition of LmABCB3 is lethal for the parasite. Moreover, the abrogation of only one allele of the gene did not impede promastigote growth in axenic culture but prevented the replication of intracellular amastigotes and the virulence of the parasites in a mouse model of cutaneous leishmaniasis. CONCLUSIONS: Altogether our results present the previously undescribed LmABCB3 as an unusual mitochondrial ABC transporter essential for Leishmania survival through its role in the generation of heme and cytosolic ISC. Hence, LmABCB3 could represent a novel target to combat leishmaniasis.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Leishmania major/genética , Leishmaniose/parasitologia , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Heme/metabolismo , Humanos , Ferro/metabolismo , Leishmania major/metabolismo , Leishmania major/patogenicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Modelos Moleculares , Transporte Proteico , Enxofre/metabolismo , Virulência
15.
Genet Med ; 18(9): 933-9, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26820065

RESUMO

PURPOSE: Infant mortality in Alaska is highest among Alaska Native people from western/northern Alaska, a population with a high prevalence of a genetic variant (c.1436C>T; the arctic variant) of carnitine palmitoyltransferase 1A (CPT1A). METHODS: We performed an unmatched case-control study to determine the relationship between the arctic variant and infant mortality. The cases were 110 Alaska Native infant deaths from 2006 to 2010 and the controls were 395 Alaska Native births from the same time period. In addition to the overall analysis, we conducted two subanalyses, one limited to subjects from western/northern Alaska and one limited to infants heterozygous or homozygous for the arctic variant. RESULTS: Among western/northern Alaska residents, 66% of cases and 61% of controls were homozygous (adjusted odds ratio (aOR): 2.5; 95% confidence interval (CI): 1.3, 5.0). Among homozygous or heterozygous infants, 58% of cases and 44% of controls were homozygous (aOR: 2.3; 95% CI: 1.3, 4.0). Deaths associated with infection were more likely to be homozygous (OR: 2.9; 95% CI: 1.0-8.0). Homozygosity was strongly associated with a premorbid history of pneumonia, sepsis, or meningitis. CONCLUSION: Homozygosity for the arctic variant is associated with increased risk of infant mortality, which may be mediated in part by an increase in infectious disease risk. Further studies are needed to determine whether the association we report represents a causal association between the CPT1A arctic variant and infectious disease-specific mortality.Genet Med 18 9, 933-939.


Assuntos
Carnitina O-Palmitoiltransferase/genética , Doenças Transmissíveis/genética , Mortalidade Infantil , Triagem Neonatal , Alaska , Nativos do Alasca/genética , Doenças Transmissíveis/mortalidade , Doenças Transmissíveis/patologia , Feminino , Estudos de Associação Genética , Variação Genética , Homozigoto , Humanos , Índios Norte-Americanos , Lactente , Recém-Nascido , Masculino , Meningite/genética , Meningite/mortalidade , Pneumonia/genética , Pneumonia/mortalidade , Fatores de Risco , Sepse/genética , Sepse/mortalidade
16.
Mol Genet Metab ; 116(4): 252-9, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26490222

RESUMO

BACKGROUND: Arginine:glycine aminotransferase (AGAT) (GATM) deficiency is an autosomal recessive inborn error of creative synthesis. OBJECTIVE: We performed an international survey among physicians known to treat patients with AGAT deficiency, to assess clinical characteristics and long-term outcomes of this ultra-rare condition. RESULTS: 16 patients from 8 families of 8 different ethnic backgrounds were included. 1 patient was asymptomatic when diagnosed at age 3 weeks. 15 patients diagnosed between 16 months and 25 years of life had intellectual disability/developmental delay (IDD). 8 patients also had myopathy/proximal muscle weakness. Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels. 3 families had protein truncation/null mutations. The rest had missense and splice mutations. Treatment with creatine monohydrate (100-800 mg/kg/day) resulted in almost complete restoration of brain creatine levels and significant improvement of myopathy. The 2 patients treated since age 4 and 16 months had normal cognitive and behavioral development at age 10 and 11 years. Late treated patients had limited improvement of cognitive functions. CONCLUSION: AGAT deficiency is a treatable intellectual disability. Early diagnosis may prevent IDD and myopathy. Patients with unexplained IDD with and without myopathy should be assessed for AGAT deficiency by determination of urine/plasma GAA and cerebral creatine levels (via brain MRS), and by GATM gene sequencing.


Assuntos
Amidinotransferases/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Creatina/uso terapêutico , Deficiência Intelectual/tratamento farmacológico , Doenças Musculares/tratamento farmacológico , Distúrbios da Fala/tratamento farmacológico , Adolescente , Amidinotransferases/química , Amidinotransferases/genética , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Criança , Pré-Escolar , Creatina/deficiência , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/tratamento farmacológico , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Expressão Gênica , Genes Recessivos , Glicina/análogos & derivados , Glicina/sangue , Glicina/deficiência , Glicina/urina , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Espectroscopia de Ressonância Magnética , Masculino , Modelos Moleculares , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Doenças Musculares/fisiopatologia , Mutação , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Análise de Sequência de DNA , Distúrbios da Fala/diagnóstico , Distúrbios da Fala/genética , Distúrbios da Fala/fisiopatologia , Resultado do Tratamento , Adulto Jovem
17.
J Neurol Sci ; 344(1-2): 105-13, 2014 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-24996493

RESUMO

We evaluated the antioxidant defense system and protein oxidative damage in the brain and liver of 15-day-old GCDH deficient knockout (Gcdh(-/-)) mice following an acute intraperitoneal administration of Lys (8 µmol/g). We determined reduced glutathione (GSH) concentrations, sulfhydryl content, carbonyl formation and the activities of the antioxidant enzymes glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT) and glutathione reductase (GR) in the brain and liver of these animals. 2',7'-dihydrodichlorofluorescein (DCFH) oxidation was also measured as an index of free radical formation. The only parameters altered in Gcdh(-/-) compared to wild type (Gcdh(+/+)) mice were a reduction of liver GSH concentrations and of brain sulfhydryl content. Acute Lys injection provoked a decrease of GSH concentration in the brain and sulfhydryl content in the liver, and an increase in carbonyl formation in the brain and liver of Gcdh(-/-) mice. Lys administration also induced a decrease of all antioxidant enzyme activities in the brain, as well as an increase of the activities of SOD and CAT in the liver of Gcdh(-/-) mice. Finally, Lys elicited a marked increase of DCFH oxidation in the brain and liver. It is concluded that Lys overload compromises the brain antioxidant defenses and induces protein oxidation probably secondary to reactive species generation in infant Gcdh(+/+) mice.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/patologia , Encefalopatias Metabólicas/patologia , Encéfalo/metabolismo , Glutaril-CoA Desidrogenase/deficiência , Lisina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Análise de Variância , Animais , Animais Recém-Nascidos , Encefalopatias Metabólicas/complicações , Lesões Encefálicas/etiologia , Lesões Encefálicas/prevenção & controle , Catalase , Modelos Animais de Doenças , Glutaril-CoA Desidrogenase/efeitos dos fármacos , Glutaril-CoA Desidrogenase/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase , Lisina/farmacologia , Camundongos , Camundongos Transgênicos , Fármacos Neuroprotetores/farmacologia , Oxirredução , Superóxido Dismutase
20.
PLoS One ; 9(3): e90477, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24594605

RESUMO

We determined mRNA expression of the ionotropic glutamate receptors NMDA (NR1, NR2A and NR2B subunits), AMPA (GluR2 subunit) and kainate (GluR6 subunit), as well as of the glutamate transporters GLAST and GLT1 in cerebral cortex and striatum of wild type (WT) and glutaryl-CoA dehydrogenase deficient (Gchh-/-) mice aged 7, 30 and 60 days. The protein expression levels of some of these membrane proteins were also measured. Overexpression of NR2A and NR2B in striatum and of GluR2 and GluR6 in cerebral cortex was observed in 7-day-old Gcdh-/-. There was also an increase of mRNA expression of all NMDA subunits in cerebral cortex and of NR2A and NR2B in striatum of 30-day-old Gcdh-/- mice. At 60 days of life, all ionotropic receptors were overexpressed in cerebral cortex and striatum of Gcdh-/- mice. Higher expression of GLAST and GLT1 transporters was also verified in cerebral cortex and striatum of Gcdh-/- mice aged 30 and 60 days, whereas at 7 days of life GLAST was overexpressed only in striatum from this mutant mice. Furthermore, high lysine intake induced mRNA overexpression of NR2A, NR2B and GLAST transcripts in striatum, as well as of GluR2 and GluR6 in both striatum and cerebral cortex of Gcdh-/- mice. Finally, we found that the protein expression of NR2A, NR2B, GLT1 and GLAST were significantly greater in cerebral cortex of Gcdh-/- mice, whereas NR2B and GLT1 was similarly enhanced in striatum, implying that these transcripts were translated into their products. These results provide evidence that glutamate receptor and transporter expression is higher in Gcdh-/- mice and that these alterations may be involved in the pathophysiology of GA I and possibly explain, at least in part, the vulnerability of striatum and cerebral cortex to injury in patients affected by GA I.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/patologia , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Encefalopatias Metabólicas/patologia , Córtex Cerebral/metabolismo , Glutaril-CoA Desidrogenase/deficiência , Neostriado/metabolismo , Receptores de Glutamato/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/enzimologia , Sistema X-AG de Transporte de Aminoácidos/genética , Animais , Encefalopatias Metabólicas/enzimologia , Córtex Cerebral/patologia , Dieta , Feminino , Regulação da Expressão Gênica , Glutaril-CoA Desidrogenase/metabolismo , Lisina/metabolismo , Masculino , Camundongos , Neostriado/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Glutamato/genética
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