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1.
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.).

2.
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.

3.
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.

4.
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
6.
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
7.
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
8.
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
9.
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
10.
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
11.
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
12.
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
15.
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
16.
Acta Neuropathol Commun ; 2: 13, 2014 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-24468193

RESUMO

BACKGROUND: Metabolic stroke is the rapid onset of lasting central neurological deficit associated with decompensation of an underlying metabolic disorder. Glutaric aciduria type I (GA1) is an inherited disorder of lysine and tryptophan metabolism presenting with metabolic stroke in infancy. The clinical presentation includes bilateral striatal necrosis and spontaneous subdural and retinal hemorrhages, which has been frequently misdiagnosed as non-accidental head trauma. The mechanisms underlying metabolic stroke and spontaneous hemorrhage are poorly understood. RESULTS: Using a mouse model of GA1, we show that metabolic stroke progresses in the opposite sequence of ischemic stroke, with initial neuronal swelling and vacuole formation leading to cerebral capillary occlusion. Focal regions of cortical followed by striatal capillaries are occluded with shunting to larger non-exchange vessels leading to early filling and dilation of deep cerebral veins. Blood-brain barrier breakdown was associated with displacement of tight-junction protein Occludin. CONCLUSION: Together the current findings illuminate the pathophysiology of metabolic stroke and vascular compromise in GA1, which may translate to other neurometabolic disorders presenting with stroke.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/complicações , Encefalopatias Metabólicas/complicações , Hemorragia Cerebral/etiologia , Glutaril-CoA Desidrogenase/deficiência , Acidente Vascular Cerebral/etiologia , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/ultraestrutura , Encefalopatias Metabólicas/genética , Encefalopatias Metabólicas/patologia , Capilares/patologia , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Glutaril-CoA Desidrogenase/genética , Angiografia por Ressonância Magnética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Eletrônica , Ocludina/metabolismo , Estatísticas não Paramétricas
17.
J Pediatr ; 163(6): 1716-21, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23992672

RESUMO

OBJECTIVE: To evaluate whether the arctic variant (c.1436C→T) of carnitine palmitoyltransferase type 1A (CPT1A) is associated with a higher incidence of adverse health outcomes in Alaska Native infants and children. STUDY DESIGN: We evaluated health measures from birth certificates (n = 605) and Alaska Medicaid billing claims (n = 427) collected from birth to 2.5 years of age for a cohort of Alaska Native infants with known CPT1A genotype. To account for geographic variations in gene distribution and other variables, data also were evaluated in cohorts. RESULTS: When analysis was restricted to residents of nonhub communities in Western and Northern Alaska, children homozygous for the arctic variant experienced more episodes of lower respiratory tract infection than did heterozygous or noncarrier children (5.5 vs 3.7, P = .067) and were more likely to have had otitis media (86% vs 69%, 95% CI 1.4-8.9). Associations were weaker for more homogeneous cohorts. CONCLUSIONS: The association of the arctic variant of CPT1A with infectious disease outcomes in children between birth and 2.5 years of age suggests that this variant may play a role in the historically high incidence of these health outcomes among indigenous Arctic populations; further studies will need to assess if this association was confounded by other risk factors.


Assuntos
Carnitina O-Palmitoiltransferase/genética , Índios Norte-Americanos/genética , Infecção/enzimologia , Infecção/genética , Alaska , Variação Genética , Humanos , Lactente , Recém-Nascido
18.
Biochim Biophys Acta ; 1832(10): 1463-72, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23623985

RESUMO

The metabolic disorder glutaric aciduria type 1 (GA1) is caused by deficiency of the mitochondrial glutaryl-CoA dehydrogenase (GCDH), leading to accumulation of the pathologic metabolites glutaric acid (GA) and 3-hydroxyglutaric acid (3OHGA) in blood, urine and tissues. Affected patients are prone to metabolic crises developing during catabolic conditions, with an irreversible destruction of striatal neurons and a subsequent dystonic-dyskinetic movement disorder. The pathogenetic mechanisms mediated by GA and 3OHGA have not been fully characterized. Recently, we have shown that GA and 3OHGA are translocated through membranes via sodium-dependent dicarboxylate cotransporter (NaC) 3, and organic anion transporters (OATs) 1 and 4. Here, we show that induced metabolic crises in Gcdh(-/-) mice lead to an altered renal expression pattern of NaC3 and OATs, and the subsequent intracellular GA and 3OHGA accumulation. Furthermore, OAT1 transporters are mislocalized to the apical membrane during metabolic crises accompanied by a pronounced thinning of proximal tubule brush border membranes. Moreover, mitochondrial swelling and increased excretion of low molecular weight proteins indicate functional tubulopathy. As the data clearly demonstrate renal proximal tubule alterations in this GA1 mouse model during induced metabolic crises, we propose careful evaluation of renal function in GA1 patients, particularly during acute crises. Further studies are needed to investigate if these findings can be confirmed in humans, especially in the long-term outcome of affected patients.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/patologia , Encefalopatias Metabólicas/patologia , Modelos Animais de Doenças , Túbulos Renais Proximais/patologia , Animais , Glutaratos/metabolismo , Glutaril-CoA Desidrogenase/deficiência , Glutaril-CoA Desidrogenase/genética , Túbulos Renais Proximais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais
19.
Mol Genet Metab ; 108(1): 30-9, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23218171

RESUMO

Deficiency of glutaryl-CoA dehydrogenase (GCDH) activity or glutaric aciduria type I (GA I) is an inherited neurometabolic disorder biochemically characterized by predominant accumulation of glutaric acid and 3-hydroxyglutaric acid in the brain and other tissues. Affected patients usually present acute striatum necrosis during encephalopathic crises triggered by metabolic stress situations, as well as chronic leukodystrophy and delayed myelination. Considering that the mechanisms underlying the brain injury in this disease are not yet fully established, in the present study we investigated important parameters of oxidative stress in the brain (cerebral cortex, striatum and hippocampus), liver and heart of 30-day-old GCDH deficient knockout (Gcdh(-/-)) and wild type (WT) mice submitted to a normal lysine (Lys) (0.9% Lys), or high Lys diets (2.8% or 4.7% Lys) for 60 h. It was observed that the dietary supplementation of 2.8% and 4.7% Lys elicited noticeable oxidative stress, as verified by an increase of malondialdehyde concentrations (lipid oxidative damage) and 2-7-dihydrodichlorofluorescein (DCFH) oxidation (free radical production), as well as a decrease of reduced glutathione levels and alteration of various antioxidant enzyme activities (antioxidant defenses) in the cerebral cortex and the striatum, but not in the hippocampus, the liver and the heart of Gcdh(-/-) mice, as compared to WT mice receiving the same diets. Furthermore, alterations of oxidative stress parameters in the cerebral cortex and striatum were more accentuated in symptomatic, as compared to asymptomatic Gcdh(-/-) mice exposed to 4.7% Lys overload. Histopathological studies performed in the cerebral cortex and striatum of these animals exposed to high dietary Lys revealed increased expression of oxidative stress markers despite the absence of significant structural damage. The results indicate that a disruption of redox homeostasis in the cerebral cortex and striatum of young Gcdh(-/-) mice exposed to increased Lys diet may possibly represent an important pathomechanism of brain injury in GA I patients under metabolic stress.


Assuntos
Encéfalo/metabolismo , Glutaril-CoA Desidrogenase/metabolismo , Homeostase , Lisina/administração & dosagem , Animais , Suplementos Nutricionais , Glutaril-CoA Desidrogenase/genética , Camundongos , Camundongos Knockout , Oxirredução , Estresse Oxidativo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
20.
Mol Genet Metab ; 107(3): 375-82, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22999741

RESUMO

Mitochondrial dysfunction has been proposed to play an important role in the neuropathology of glutaric acidemia type I (GA I). However, the relevance of bioenergetics disruption and the exact mechanisms responsible for the cortical leukodystrophy and the striatum degeneration presented by GA I patients are not yet fully understood. Therefore, in the present work we measured the respiratory chain complexes activities I-IV, mitochondrial respiratory parameters state 3, state 4, the respiratory control ratio and dinitrophenol (DNP)-stimulated respiration (uncoupled state), as well as the activities of α-ketoglutarate dehydrogenase (α-KGDH), creatine kinase (CK) and Na+, K+-ATPase in cerebral cortex, striatum and hippocampus from 30-day-old Gcdh-/- and wild type (WT) mice fed with a normal or a high Lys (4.7%) diet. When a baseline (0.9% Lys) diet was given, we verified mild alterations of the activities of some respiratory chain complexes in cerebral cortex and hippocampus, but not in striatum from Gcdh-/- mice as compared to WT animals. Furthermore, the mitochondrial respiratory parameters and the activities of α-KGDH and CK were not modified in all brain structures from Gcdh-/- mice. In contrast, we found a significant reduction of Na(+), K(+)-ATPase activity associated with a lower degree of its expression in cerebral cortex from Gcdh-/- mice. Furthermore, a high Lys (4.7%) diet did not accentuate the biochemical alterations observed in Gcdh-/- mice fed with a normal diet. Since Na(+), K(+)-ATPase activity is required for cell volume regulation and to maintain the membrane potential necessary for a normal neurotransmission, it is presumed that reduction of this enzyme activity may represent a potential underlying mechanism involved in the brain swelling and cortical abnormalities (cortical atrophy with leukodystrophy) observed in patients affected by GA I.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Encefalopatias Metabólicas/genética , Encefalopatias Metabólicas/patologia , Córtex Cerebral/patologia , Corpo Estriado/patologia , Glutaril-CoA Desidrogenase/deficiência , Hipocampo/patologia , ATPase Trocadora de Sódio-Potássio/genética , Erros Inatos do Metabolismo dos Aminoácidos/enzimologia , Animais , Encefalopatias Metabólicas/enzimologia , Córtex Cerebral/enzimologia , Corpo Estriado/enzimologia , Creatina Quinase/genética , Creatina Quinase/metabolismo , Regulação para Baixo , Transporte de Elétrons/genética , Alimentos Formulados , Expressão Gênica , Glutaril-CoA Desidrogenase/genética , Hipocampo/enzimologia , Humanos , Complexo Cetoglutarato Desidrogenase/genética , Complexo Cetoglutarato Desidrogenase/metabolismo , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/metabolismo , Fosforilação Oxidativa , ATPase Trocadora de Sódio-Potássio/metabolismo
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