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1.
Revista Digital de Postgrado ; 9(2): 214, ago. 2020.
Artigo em Espanhol | LILACS, LIVECS | ID: biblio-1103446

RESUMO

El término Origen Temprano de las Enfermedades del Adulto explica la aparición temprana de las condiciones anormales cardiovasculares y metabólicas en la vida adulta, mayor riesgo de morbilidad y muerte asociados a factores ambientales, especialmente nutricionales, que actúan en las primeras etapas de la vida. Estas respuestas programadas dependen de la naturaleza del estímulo o noxa, del tiempo de exposición y del momento de ocurrencia de la noxa, pudiendo un solo genotipo original varios fenotipos y estarían condicionadas por criterios críticos en los cuales se desarrollarían cambios a largo plazo pudiendo ser reversibles o no. La Programación Fetal explica que respuestas adaptativas embrionarias y fetales en un ambiente subóptimo genera consecuencias adversas permanentes. La desnutrición, así como la sobrenutrición fetal aumenta el riesgo de desarrollar alteraciones en el peso y composición corporal fetal, y posteriormente obesidad, síndrome metabólico, incremento en la adiposidad, alteración en el metabolismo de la glucosa y / o insulina, alteración del metabolismo lipídico, alteraciones hepáticas y de las cifras tensionales. La impronta genómica es esencial para el desarrollo y defectos en la misma puede originar alteraciones de la identidad parental transmisibles a las siguientes generaciones. Esta programación fetal puede ser explicada por la epigenética, definida como la serie de alteraciones hereditarias de la expresión genética a través de modificaciones del ADN y las histonas centrales sin cambios en la secuencia de ADN. Estas modificaciones epigenéticas alteran la estructura y condensación de la cromatina, afectando la expresión del genotipo y fenotipo. Este artículo desarrolla los aspectos involucrados en la Programación Fetal y los posibles mecanismos sobre la misma(AU)


The term Early Origin of Adult Diseases explains the early onset of abnormal cardiovascular and metabolic conditions in adult life, increased risk of morbidity and death associated with environmental factors, especially nutritional factors, that act in the early stages of life. These programmed responses depend on the nature of the stimulus or noxa, the time of exposure and the moment of occurrence of the noxa, with a single original genotype being able to have several phenotypes and would be conditioned by critical criteria in which long-term changes could develop, reversibles or not. Fetal Programming explains that embryonic and fetal adaptive responses in a suboptimal environment generate permanent adverse consequences. Fetal malnutrition as overnutrition increases the risk of developing alterations in fetal body weight and composition, and subsequently obesity, metabolic syndrome, increased adiposity, impaired glucose and / or insulin metabolism, impaired lipid metabolism, liver disorders and altered blood pressure. The genomic imprint is essential for development and defects in it can cause alterations of the parental identity and are transmitted to the following generations. This fetal programming can be explained by epigenetics, defined as the series of inherited alterations of genetic expression through modifications of DNA and central histones without changes in the DNA sequence. These epigenetic modifications alter the structure and condensation of chromatin, affecting the expression of the genotype and phenotype. This article develops the aspects involved in Fetal Programming and the possible mechanisms on it(AU)


Assuntos
Humanos , Transtornos da Nutrição Fetal , Desenvolvimento Fetal , Noxas , Doenças Nutricionais e Metabólicas , Composição Corporal , Hipotálamo/anatomia & histologia , Erros Inatos do Metabolismo
2.
Revista Digital de Postgrado ; 9(2): 205, ago. 2020. tab
Artigo em Espanhol | LILACS, LIVECS | ID: biblio-1102879

RESUMO

La Parálisis Cerebral (PC) es un conjunto de alteraciones motrices no progresivas en la población infantojuvenil, ocasionadas por lesión ­a nivel cerebral- de neuronas o fibras de esa vía, de sus aferencias o de las que la modulan; para su diagnóstico deben conocerse otras patologías también frecuentes y que pueden incidir simultánea o causalmente en la motricidad del paciente; la resultante sería disfunción motora tanto voluntaria como involuntaria, refleja o con propósito, de la postura y/o del tono muscular. Objetivo: detectar errores innatos metabólicos (EIM) que causan o se asocian con PC en una serie significativa. Métodos: Estudio descriptivo-interpretativo, se revisaron los expedientes clínicos del Centro de Parálisis Cerebral de Caracas, en cuyos diagnósticos se presentaron ambas alteraciones, entre los años 1988 y 2018. Resultados: De las 2.000 historias clínicas revisadas, el exámen clínico y las pruebas de laboratorio permitieron seleccionar 174 casos de EIM. Conclusiones: Se tipificaron los errores innatos metabólicos en diez formas clínicas distintas, se evidenciaron en pacientes con PC atendidos en un centro público de Caracas, es posible que la casuística sea varias veces mayor en Venezuela dado que ya no se aplica la pesquisa en los centros de atención pública(AU)


Cerebral Palsy (CP) is a set of non-progressive motor alterations in the child and youth population, caused by injury - at the brain level - of neurons or fibers of that pathway, their afferences or those that modulate it; for its diagnosis, other pathologies that are also frequent and that can simultaneously or causally affect the motor skills of the same patient must be known; The result would be both voluntary and involuntary motor dysfunction, reflected or with purpose, of posture and / or muscle tone. Objective: to detect inborn metabolic errors (EIM) that cause or are associated with CP in a significant series. Methods: Descriptive-interpretive study, we reviewed the clinical records of the Cerebral Palsy Center of Caracas, in whose diagnoses both alterations were presented, between the years 1988 and 2018. Results: Of the 2,000 clinical histories reviewed, the clinical examination and tests Laboratory tests allowed the selection of 174 cases of IMD. Conclusions: Inborn metabolic errors were typified in ten different clinical forms, they were evidenced in patients with CP treated in a public center in Caracas, it is possible that the casuistry is several times greater in Venezuela since the investigation is no longer applied in the centers of public attention(AU)


Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Paralisia Cerebral/patologia , Erros Inatos do Metabolismo , Neurônios/metabolismo , Pediatria , Doenças do Sistema Nervoso
3.
Wiad Lek ; 73(6): 1211-1216, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32723955

RESUMO

OBJECTIVE: The aim: To compose an applicable diagnostic checklist for neonatologists, pediatricians, and general practitioners who refer newborns with certain inherited metabolic diseases (IMDs) suspicion to confirmatory testing laboratories. PATIENTS AND METHODS: Materials and methods: Analyzed international and generally, known national clinical guides and recommendations devoted to IMDs diagnostics, treatment and follow up. RESULTS: Results: Considering integral character of the diagnostic work-up of inborn errors of metabolism, authors of this article composed an applicable checklist that comprises set of data necessary for interpretation the positive results of expanded newborn screening and making decision of appropriate biochemical and molecular tests are required for confirmatory follow-up testing to establish the diagnosis and prescribe pathogenetic therapy. CONCLUSION: Conclusions: Properly filled checklist allow metabolic professionals to select appropriate confirmatory tests and interpret results obtained. Early IMDs diagnosis and prompt treatment initiation are crucial for positive outcomes and proved to be an effective tool to decrease levels of child disability and infant mortality.


Assuntos
Doenças Metabólicas/diagnóstico , Erros Inatos do Metabolismo/diagnóstico , Criança , Diagnóstico Diferencial , Humanos , Lactente , Recém-Nascido , Triagem Neonatal , Pediatras
4.
Artigo em Alemão | MEDLINE | ID: mdl-32542434

RESUMO

For many inborn metabolic diseases, a lifelong diet is a crucial part of the therapy since pharmacological therapy is available for only a few conditions and patients. The implementation of a low natural protein diet with a reduced intake of natural protein and the complementary use of synthetic amino acid mixtures is described using the examples of phenylketonuria and urea cycle disorders focusing on children and adolescents. For phenylketonuria, the amino acid supplement is free of phenylalanine whereas for urea cycle disorders, it exclusively consists of essential amino acids. The dietary treatment aims to maintain metabolic stability and to prevent accumulation of toxic metabolites. At the same time, the nutritional requirements to ensure growth and development must be met. Therefore, patients need to follow strict rules regarding the choice of food products. This restrictive therapy interferes with the desire for autonomy and the joy of eating and often results in a reduced quality of life.Following the diet is crucial for a favorable outcome. To meet its requirements, patients and their families are provided with training. It is a great challenge not only to support the patients and their families in all practical aspects of dietary management, but also to motivate them to lifelong adherence in order to ensure the best possible outcome.


Assuntos
Erros Inatos do Metabolismo , Adolescente , Criança , Dieta , Alemanha , Humanos , Fenilcetonúrias , Qualidade de Vida
5.
Rev Med Liege ; 75(5-6): 420-425, 2020 May.
Artigo em Francês | MEDLINE | ID: mdl-32496691

RESUMO

Inborn errors of metabolism (IEM) represent a vast group of orphan genetic disorders associated with enzyme deficiencies, substrates accumulation and products depletion. For several decades, the cornerstone of life-saving therapies in IEM was based on extreme manipulations of the nutritional intakes. Such outstanding dietary engineering is still relevant today, but new therapeutic avenues have emerged last years, based on better pathophysiological understanding and technological advances. In this paper, we summarize current and new therapeutic options in the field of IEM.


Assuntos
Erros Inatos do Metabolismo , Humanos , Erros Inatos do Metabolismo/terapia , Doenças Raras
6.
Rev Med Suisse ; 16(695): 1120-1122, 2020 May 27.
Artigo em Francês | MEDLINE | ID: mdl-32462842

RESUMO

Patients come in consultation with a variety of complaints, some of which are unusual. We present here the case of a patient consulting for nauseating body odors for whom a diagnosis of trimethylaminuria could be found. This pathology, not very well known, may have important psychiatric and social repercussions. Genetics play a major role in diagnosis, while treatment consists essentially of various palliative measures.


Assuntos
Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/terapia , Metilaminas/urina , Humanos , Erros Inatos do Metabolismo/genética , Odorantes/análise
7.
Ann Endocrinol (Paris) ; 81(2-3): 110-117, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32409005

RESUMO

Hypoglycemia is defined by a low blood glucose level associated to clinical symptoms. Hypoglycemia may be related to treatment of diabetes, but also to drugs, alcohol, critical illness, cortisol insufficiency including hypopituitarism, insulinoma, bariatric or gastric surgery, pancreas transplantation or glucagon deficiency, or may be surreptitious. Some hypoglycemic episodes remain unexplained, and genetic, paraneoplastic and immune causes should be considered. Genetic causes may be related to endogenous hyperinsulinism and to inborn errors of metabolism (IEM). Endogenous hyperinsulinism is related to monogenic congenital hyperinsulinism, and especially to mutations of the glucokinase-activating gene or of insulin receptors, both characterised by postprandial hypoglycemia with major hyperinsulinism. In adulthood, IEM-related hypoglycemia can persist in a previously diagnosed childhood disease or may be a presenting sign. It is suggested by systemic involvement (rhabdomyolysis after fasting or exercising, heart disease, hepatomegaly), sometimes associated to a family history of hypoglycemia. The timing of hypoglycemic episodes with respect to the last meal also helps to orientate diagnosis. Fasting hypoglycemia may be related to type 0, I or III glycogen synthesis disorder, fatty acid oxidation or gluconeogenesis disorder. Postprandial hypoglycemia may be related to inherited fructose intolerance. Exercise-induced hyperinsulinism is mainly related to activating mutation of the SLC16A1 gene. Besides exceptional ectopic insulin secretion, paraneoplastic causes involve NICTH (Non-Islet-Cell Tumour Hypoglycemia), caused by Big-IGF2 secretion by a large tumour, with low blood levels of insulin, C-peptide and IGF1. Autoimmune causes involve antibodies against insulin (HIRATA syndrome), especially in case of Graves' disease, or against the insulin receptor. Medical history, timing, and insulin level orientate the diagnosis.


Assuntos
Hipoglicemia/epidemiologia , Hipoglicemia/etiologia , Adulto , Idade de Início , Antígenos CD/genética , Criança , Complicações do Diabetes/sangue , Complicações do Diabetes/epidemiologia , Jejum/sangue , Humanos , Hiperinsulinismo/sangue , Hiperinsulinismo/complicações , Hiperinsulinismo/epidemiologia , Insulinoma/sangue , Insulinoma/complicações , Insulinoma/epidemiologia , Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/epidemiologia , Erros Inatos do Metabolismo/genética , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/epidemiologia , Receptor de Insulina/genética , Fatores de Risco
9.
Adv Exp Med Biol ; 1236: 225-244, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32304075

RESUMO

Genetic model systems allow researchers to probe and decipher aspects of human disease, and animal models of disease are frequently specifically engineered and have been identified serendipitously as well. Animal models are useful for probing the etiology and pathophysiology of disease and are critical for effective discovery and development of novel therapeutics for rare diseases. Here we review the impact of animal model organism research in three examples of congenital metabolic disorders to highlight distinct advantages of model system research. First, we discuss phenylketonuria research where a wide variety of research fields and models came together to make impressive progress and where a nearly ideal mouse model has been central to therapeutic advancements. Second, we review advancements in Lesch-Nyhan syndrome research to illustrate the role of models that do not perfectly recapitulate human disease as well as the need for multiple models of the same disease to fully investigate human disease aspects. Finally, we highlight research on the GM2 gangliosidoses Tay-Sachs and Sandhoff disease to illustrate the important role of both engineered traditional laboratory animal models and serendipitously identified atypical models in congenital metabolic disorder research. We close with perspectives for the future for animal model research in congenital metabolic disorders.


Assuntos
Modelos Animais de Doenças , Erros Inatos do Metabolismo , Animais , Gangliosidoses GM2 , Humanos , Doenças Raras/congênito , Doença de Sandhoff , Doença de Tay-Sachs
10.
Clin Sci (Lond) ; 134(8): 941-953, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32227118

RESUMO

The sodium-hydrogen exchanger isoform 3 (NHE3, SLC9A3) is abundantly expressed in the gastrointestinal tract and is proposed to play essential roles in Na+ and fluid absorption as well as acid-base homeostasis. Mutations in the SLC9A3 gene can cause congenital sodium diarrhea (CSD). However, understanding the precise role of intestinal NHE3 has been severely hampered due to the lack of a suitable animal model. To navigate this problem and better understand the role of intestinal NHE3, we generated a tamoxifen-inducible intestinal epithelial cell-specific NHE3 knockout mouse model (NHE3IEC-KO). Before tamoxifen administration, the phenotype and blood parameters of NHE3IEC-KO were unremarkable compared with control mice. After tamoxifen administration, NHE3IEC-KO mice have undetectable levels of NHE3 in the intestine. NHE3IEC-KO mice develop watery, alkaline diarrhea in combination with a swollen small intestine, cecum and colon. The persistent diarrhea results in higher fluid intake. After 3 weeks, NHE3IEC-KO mice show a ∼25% mortality rate. The contribution of intestinal NHE3 to acid-base and Na+ homeostasis under normal conditions becomes evident in NHE3IEC-KO mice that have metabolic acidosis, lower blood bicarbonate levels, hyponatremia and hyperkalemia associated with drastically elevated plasma aldosterone levels. These results demonstrate that intestinal NHE3 has a significant contribution to acid-base, Na+ and volume homeostasis, and lack of intestinal NHE3 has consequences on intestinal structural integrity. This mouse model mimics and explains the phenotype of individuals with CSD carrying SLC9A3 mutations.


Assuntos
Anormalidades Múltiplas/genética , Diarreia/congênito , Células Epiteliais/metabolismo , Erros Inatos do Metabolismo/genética , Trocador 3 de Sódio-Hidrogênio/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/mortalidade , Anormalidades Múltiplas/patologia , Animais , Diarreia/genética , Diarreia/metabolismo , Diarreia/mortalidade , Diarreia/patologia , Modelos Animais de Doenças , Feminino , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Erros Inatos do Metabolismo/metabolismo , Erros Inatos do Metabolismo/mortalidade , Erros Inatos do Metabolismo/patologia , Camundongos , Camundongos Knockout , Mutação , Trocador 3 de Sódio-Hidrogênio/metabolismo
11.
BMC Med Genet ; 21(1): 79, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32295532

RESUMO

BACKGROUND: Congenital chloride diarrhea (CLD; OMIM 214700) is a rare autosomal recessive disorder caused by pathogenic variations in the solute carrier family 26 member A3 (SLC26A3) gene. Without salt substitution, this chronic diarrheal disorder causes severe dehydration and electrolyte disturbances. Homozygous variants in the nearby gene SLC26A4 disrupt anion exchange in the inner ear and the thyroid, causing Pendred syndrome (PDS; OMIM 274600), which is the most frequent form of syndromic deafness. CASE PRESENTATION: We report an unusual co-occurrence of two rare homozygous mutations in both the SLC26A3 and SLC26A4 genes, causing a rare combination of both CLD and PDS in two siblings. Although the clinical pictures were typical, the combined loss of these anion transporters might modulate the risk of renal injury associated with CLD. CONCLUSIONS: Familial presentation of two rare autosomal recessive disorders with loss of function of different SLC26 anion transporters is described. Independent homozygous variants in the SLC26A3 and SLC26A4 genes cause CLD and PDS in siblings, shedding light on co-occurrence of rare recessive traits in the progeny of consanguineous couples.


Assuntos
Antiportadores de Cloreto-Bicarbonato/genética , Diarreia/congênito , Bócio Nodular/genética , Perda Auditiva Neurossensorial/genética , Erros Inatos do Metabolismo/genética , Transportadores de Sulfato/genética , Diarreia/diagnóstico , Diarreia/genética , Diarreia/patologia , Feminino , Genes Recessivos/genética , Testes Genéticos , Bócio Nodular/diagnóstico , Bócio Nodular/patologia , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Humanos , Lactente , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/patologia , Mutação , Linhagem , Gravidez , Doenças Raras/diagnóstico , Doenças Raras/genética , Doenças Raras/patologia , Irmãos
12.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(4): 423-426, 2020 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-32219827

RESUMO

OBJECTIVE: To analyze the clinical and genetic characteristics of an infant girl featuring comprehensive developmental backwardness. METHODS: The patient was subjected to clinical examination, gas chromatography mass spectrometry and next-generation sequencing (NGS). RESULTS: The child was insensitive to sound, could not turn over, raise head, laugh or recognize his mother. Laboratory tests were all normal, but metabolic analysis suggested 3-methylglutaconic aciduria due to elevated 3-methylglutaconic acid and 3-methylglutaric acid. NGS has detected two compound heterozygous CLPB variants in the child, namely c.1085G>A and c.1700A>C, which were respectively inherited from her father and mother. Bioinformatic analysis predicted both variants to be pathogenic. The patient was diagnosed with 3-methylglutaconic aciduria type VII (MGCA7). CONCLUSION: The MGCA7 in the child was probably caused by CLPB gene variants. NGS has provided a powerful diagnostic tool for this rare disorder.


Assuntos
Endopeptidase Clp/genética , Erros Inatos do Metabolismo/genética , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente
13.
Endocr Pract ; 26(6): 651-659, 2020 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-32045292

RESUMO

Objective: Primary generalized glucocorticoid resistance (PGGR) is a rare hereditary disease characterized by generalized partial target-tissue insensitivity to glucocorticoids. To date, few cases have been reported, and more cases, especially involving other races, are needed to fully understand this disease. Methods: This study presented a novel glucocorticoid receptor mutation in a PGGR pedigree. The index patient was a 14-year-old male with fatigue, hypokalemia, hypertension, and polyuria. Eleven family members were available for the genetic screen. Next-generation sequencing and Sanger sequencing were used to identify the mutation. We systematically investigated the molecular mechanism through which the mutation impaired glucocorticoid signal transduction in COS-7 cells. Results: The index patient carried a de novo homo-zygous mutation within exon 6 (c.1652C>A, p.551S>Y), whereas eight family members carrying a heterozygous mutation were all phenotypically silent. The affinity of the human glucocorticoid receptor (hGR) for the ligand was 1.97-fold lower in the patient than in the family members. Mutant hGRα (551Y) displayed a 3.2-fold reduction in its ability to transactivate glucocorticoid-responsive genes. When exposed to the same concentration of dexamethasone, hGRα (551Y) displayed a reduced ability to trans-locate into the nucleus and decreased levels of hGR dimer formation and could not effectively induce the glucocorticoid response element to regulate the transcription of related genes. After 2 years of dexamethasone treatment, the volume of the left and right adrenal glands of the index subject decreased by 55.6% and 32.4%, respectively. The pituitary volume decreased by 18.9%. During the 2-year follow-up, none of the heterozygous carriers developed hypertension or hypokalemia. Conclusion: We described a novel homozygous glucocorticoid receptor mutation causing PGGR. This homozygous mutation leads to hypertension and hypokalemia, but its heterozygous mutation has no relevant clinical symptoms. Abbreviations: ACTH = adrenocorticotropic hormone; DBD = DNA-binding domain; GR = glucocorticoid receptor; GRE = glucocorticoid response element; hGR = human glucocorticoid receptor; LBD = ligand-binding domain; PGGR = primary generalized glucocorticoid resistance.


Assuntos
Erros Inatos do Metabolismo , Receptores de Glucocorticoides/genética , Adolescente , Animais , Chlorocebus aethiops , Dexametasona , Glucocorticoides , Humanos , Masculino , Erros Inatos do Metabolismo/genética , Mutação
14.
Nat Commun ; 11(1): 970, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080200

RESUMO

Deregulation of mitochondrial network in terminally differentiated cells contributes to a broad spectrum of disorders. Methylmalonic acidemia (MMA) is one of the most common inherited metabolic disorders, due to deficiency of the mitochondrial methylmalonyl-coenzyme A mutase (MMUT). How MMUT deficiency triggers cell damage remains unknown, preventing the development of disease-modifying therapies. Here we combine genetic and pharmacological approaches to demonstrate that MMUT deficiency induces metabolic and mitochondrial alterations that are exacerbated by anomalies in PINK1/Parkin-mediated mitophagy, causing the accumulation of dysfunctional mitochondria that trigger epithelial stress and ultimately cell damage. Using drug-disease network perturbation modelling, we predict targetable pathways, whose modulation repairs mitochondrial dysfunctions in patient-derived cells and alleviate phenotype changes in mmut-deficient zebrafish. These results suggest a link between primary MMUT deficiency, diseased mitochondria, mitophagy dysfunction and epithelial stress, and provide potential therapeutic perspectives for MMA.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Erros Inatos do Metabolismo/metabolismo , Erros Inatos do Metabolismo/patologia , Metilmalonil-CoA Mutase/deficiência , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Mitofagia/fisiologia , Alquil e Aril Transferases/deficiência , Alquil e Aril Transferases/genética , Erros Inatos do Metabolismo dos Aminoácidos/genética , Animais , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Técnicas de Inativação de Genes , Humanos , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Erros Inatos do Metabolismo/genética , Metilmalonil-CoA Mutase/genética , Metilmalonil-CoA Mutase/metabolismo , Camundongos , Camundongos Knockout , Doenças Mitocondriais/genética , Mitofagia/genética , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Estresse Fisiológico , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Peixe-Zebra
15.
Pediatrics ; 145(3)2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32034080

RESUMO

Successful intervention for inborn errors of metabolism (IEMs) is a triumph of modern medicine. For many of these conditions, medical foods are the cornerstone of therapy and the only effective interventions preventing disability or death. Medical foods are designed for patients with limited or impaired capacity to ingest, digest, absorb, or metabolize ordinary foods or nutrients, whereby dietary management cannot be achieved by modification of the normal diet alone. In the United States today, access to medical foods is not ensured for many individuals who are affected despite their proven efficacy in the treatment of IEMs, their universal use as the mainstay of IEM management, the endorsement of their use by professional medical organizations, and the obvious desire of families for effective care. Medical foods are not sufficiently covered by many health insurance plans in the United States and, without insurance coverage, many families cannot afford their high cost. In this review, we outline the history of medical foods, define their medical necessity, discuss the barriers to access and reimbursement resulting from the regulatory status of medical foods, and summarize previous efforts to improve access. The Advisory Committee on Heritable Disorders in Newborns and Children asserts that it is time to provide stable and affordable access to the effective management required for optimal outcomes through the life span of patients affected with IEMs. Medical foods as defined by the US Food and Drug Administration should be covered as required medical benefits for persons of all ages diagnosed with an IEM.


Assuntos
Dieta , Suplementos Nutricionais , Erros Inatos do Metabolismo/dietoterapia , Suplementos Nutricionais/economia , Acesso aos Serviços de Saúde , Humanos , Recém-Nascido , Cobertura do Seguro/legislação & jurisprudência , Erros Inatos do Metabolismo/diagnóstico , Triagem Neonatal , Estados Unidos
16.
Adv Clin Chem ; 94: 85-153, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31952575

RESUMO

Metabolomics is an intriguing field of study providing a new readout of the biochemical activities taking place at the moment of sampling within a subject's biofluid or tissue. Metabolite concentrations are influenced by several factors including disease, environment, drugs, diet and, importantly, genetics. Metabolomics signatures, which describe a subject's phenotype, are useful for disease diagnosis and prognosis, as well as for predicting and monitoring the effectiveness of treatments. Metabolomics is conventionally divided into targeted (i.e., the quantitative analysis of a predetermined group of metabolites) and untargeted studies (i.e., analysis of the complete set of small-molecule metabolites contained in a biofluid without a pre-imposed metabolites-selection). Both approaches have demonstrated high value in the investigation and understanding of several monogenic and multigenic conditions. Due to low costs per sample and relatively short analysis times, metabolomics can be a useful and robust complement to genetic sequencing.


Assuntos
Testes Genéticos , Metabolômica , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Fenótipo
18.
Eur J Endocrinol ; 182(2): R15-R27, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31995340

RESUMO

Glucocorticoids (GC) such as cortisol regulate multiple physiological functions, notably those involved in development, metabolism, inflammatory processes and stress, and exert their effects upon binding to the glucocorticoid receptor (GR, encoded by NR3C1 gene in humans). GC signaling follows several consecutive steps leading to target gene transactivation, including ligand binding, nuclear translocation of ligand-activated GR complexes, DNA binding, and recruitment of functional transcriptional machinery. Generalized glucocorticoid resistance syndrome, due to GR loss-of-function mutations, may be related to the impairment of one of the GC signaling steps. To date, 31 NR3C1 loss-of-function mutations have been reported in patients presenting with various clinical signs such as hypertension, adrenal hyperplasia, hirsutism or metabolic disorders associated with biological hypercortisolism but without Cushing syndrome signs and no negative regulatory feedback loop on the hypothalamic-pituitary-adrenal axis. Functional characterization of GR loss-of-function mutations often demonstrates GR haploinsufficiency and a decrease of GR target gene induction in relevant cell types. The main signs at presentation are very variable from resistant hypertension, bilateral adrenal hyperplasia likely related to increased ACTH levels but not exclusively, hirsutism to isolated renin-angiotensin-aldosterone system abnormalities in a context of 11ßHSD2 deficiency. Some mutated GR patients are obese or overweight together with a healthier metabolic profile that remains to be further explored in future studies. Deciphering the molecular mechanisms altered by GR mutations should enhance our knowledge on GR signaling and ultimately facilitate management of GC-resistant patients. This review also focuses on the criteria facilitating identification of novel NR3C1 mutations in selected patients.


Assuntos
Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Receptores de Glucocorticoides/deficiência , Hormônio Adrenocorticotrópico/sangue , Hormônio Adrenocorticotrópico/genética , Glucocorticoides/sangue , Glucocorticoides/genética , Humanos , Hidrocortisona/sangue , Hidrocortisona/genética , Erros Inatos do Metabolismo/sangue , Receptores de Glucocorticoides/sangue , Receptores de Glucocorticoides/genética
19.
Nat Commun ; 11(1): 322, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949167

RESUMO

We previously observed an unexpected fivefold (35 vs. 200 days) difference in the survival of respiratory chain complex III (CIII) deficient Bcs1lp.S78G mice between two congenic backgrounds. Here, we identify a spontaneous homoplasmic mtDNA variant (m.G14904A, mt-Cybp.D254N), affecting the CIII subunit cytochrome b (MT-CYB), in the background with short survival. We utilize maternal inheritance of mtDNA to confirm this as the causative variant and show that it further decreases the low CIII activity in Bcs1lp.S78G tissues to below survival threshold by 35 days of age. Molecular dynamics simulations predict D254N to restrict the flexibility of MT-CYB ef loop, potentially affecting RISP dynamics. In Rhodobacter cytochrome bc1 complex the equivalent substitution causes a kinetics defect with longer occupancy of RISP head domain towards the quinol oxidation site. These findings represent a unique case of spontaneous mitonuclear epistasis and highlight the role of mtDNA variation as modifier of mitochondrial disease phenotypes.


Assuntos
Complexo III da Cadeia de Transporte de Elétrons/genética , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Epistasia Genética/genética , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Mitocôndrias/genética , Doenças Mitocondriais/genética , ATPases Associadas a Diversas Atividades Celulares/genética , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Animais , Grupo dos Citocromos b/química , Grupo dos Citocromos b/genética , Citocromos b , DNA Mitocondrial , Complexo III da Cadeia de Transporte de Elétrons/química , Metabolismo Energético , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Simulação de Dinâmica Molecular , Oxirredução
20.
Xenobiotica ; 50(1): 19-33, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31317802

RESUMO

The review focuses on genetic variants of human flavin-containing monooxygenase 3 (FMO3) and their impact on enzyme activity, drug metabolism and disease.The majority of FMO-mediated metabolism in adult human liver is catalyzed by FMO3. Some drugs are metabolized in human liver predominantly by FMO3, but most drug substrates of FMO3 are metabolized also by other enzymes, particularly cytochromes P-450, and the FMO3-catalyzed reaction is not the major route of metabolism.Rare variants that severely affect production or activity of FMO3 cause the disorder trimethylaminuria and impair metabolism of drug substrates of FMO3. More common variants, particularly p.[(Glu158Lys);(Glu308Gly)], can moderately affect activity of FMO3 in vitro and reduce metabolism of drug substrates in vivo, in some cases increasing drug efficacy or toxicity.Common variants of FMO3 have been associated with a number of disorders, but additional studies are needed to confirm or refute such associations.Elevated plasma concentrations of trimethylamine N-oxide, a product of an FMO3-catalyzed reaction, have been implicated in certain diseases, particularly cardiovascular disease. However, the evidence is often contradictory and additional work is required to establish whether trimethylamine N-oxide is a cause, effect or biomarker of the disease.Genetic variants of other FMOs are also briefly discussed.


Assuntos
Inativação Metabólica/genética , Oxigenases/genética , Adulto , Humanos , Erros Inatos do Metabolismo , Metilaminas/urina , Oxigenases/metabolismo , Polimorfismo Genético
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