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1.
Hinyokika Kiyo ; 67(9): 419-421, 2021 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-34610707

RESUMO

We report a case of 2,8-dihydroxyadenine (DHA) urolithiasis in a 65-year-old male. He initially visited another institution because right hydronephrosis was revealed in a medical checkup. Computed tomography demonstrated radiolucent right renal stones. We performed percutaneous nephrolithotripsy and flexible transurethral lithotripsy and removed the stones successfully. An analysis of the stone fragments revealed 2,8-DHA urolithiasis. 2,8-DHA stones are relatively rare and caused by adenine phosphoribosyltransferase deficiency.


Assuntos
Cálculos Renais , Litotripsia , Urolitíase , Adenina , Adenina Fosforribosiltransferase/deficiência , Idoso , Humanos , Cálculos Renais/terapia , Masculino , Erros Inatos do Metabolismo , Urolitíase/diagnóstico por imagem
2.
Zhonghua Gan Zang Bing Za Zhi ; 29(8): 740-742, 2021 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-34517453

RESUMO

Inherited metabolic liver disease is a wide-range of diseases that cause abnormal metabolism, resulting from genetic defects. Notably, some inherited metabolic liver diseases are closely associated to infection on account of specific substances abnormal metabolism or key enzyme activities deficiency. Therefore, understanding the inherited metabolic liver disease-associated infection would be helpful to clinical practice and improve patient prognosis.


Assuntos
Hepatopatias , Doenças Metabólicas , Erros Inatos do Metabolismo , Humanos , Hepatopatias/etiologia
3.
Orphanet J Rare Dis ; 16(1): 383, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34503561

RESUMO

BACKGROUND: Infants with neonatal-onset diarrhea present with intractable diarrhea in the first few weeks of life. A monogenic mutation is one of the disease etiologies and the use of next-generation sequencing (NGS) has made it possible to screen patients for their mutations. MAIN BODY: We retrospectively reviewed the clinical data of four children from unrelated families, who presented with neonatal-onset, chronic, watery, non-bloody diarrhea. After genetic whole-exome sequencing, novel mutations were identified in the EPCAM gene of two children. Congenital chloride diarrhea was diagnosed in one case, which was associated with an SLC26A3 mutation, in which the patient presented with watery diarrhea, malnutrition, and hypochloremic alkalosis. Patient 4 was diagnosed with microvillus inclusion disease and possessed novel compound heterozygous mutations in the MYO5B gene. A review of the genetic variants of SLC26A3 reported in East Asia revealed that c.269_270 dupAA (p.G91Kfs*3) is the most frequent SLC26A3 mutation in China, compared with c.2063-1 G > T in Japan and Korea. EPCAM and MYO5B genetic variants were only sporadically reported in East Asia. CONCLUSION: This study expands our knowledge of the clinical manifestations and molecular genetics of neonatal-onset watery diarrhea. Early diagnosis could be achieved by genomic analysis in those infants whose histology features are not typical. The discovery of four novel mutations in the EPCAM gene and two novel mutations in the MYO5B gene provides further etiological evidence for the association of genetic mutations with neonatal-onset diarrhea. To date, c.269_270 dupAA is the most frequent SLC26A3 mutation in China.


Assuntos
Antiportadores de Cloreto-Bicarbonato , Diarreia , Erros Inatos do Metabolismo , Cadeias Pesadas de Miosina/genética , Miosina Tipo V/genética , Transportadores de Sulfato , Antiportadores de Cloreto-Bicarbonato/genética , Diarreia/genética , Extremo Oriente , Humanos , Recém-Nascido , Erros Inatos do Metabolismo/genética , Mutação/genética , Estudos Retrospectivos , Transportadores de Sulfato/genética
4.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360727

RESUMO

Hereditary leiomyomatosis and renal cell carcinoma (HL (RCC)) entails cutaneous and uterine leiomyomatosis with aggressive type 2 papillary RCC-like histology. HLRCC is caused by pathogenic variants in the FH gene, which encodes fumarate hydratase (FH). Here, we describe an episode of young-onset RCC caused by a genomic FH deletion that was diagnosed via clinical sequencing. A 35-year-old woman was diagnosed with RCC and multiple metastases: histopathological analyses supported a diagnosis of FH-deficient RCC. Although the patient had neither skin tumors nor a family history of HLRCC, an aggressive clinical course at her age and pathological diagnosis of FH-deficient RCC suggested a germline FH variant. After counseling, the patient provided written informed consent for germline genetic testing. She was simultaneously subjected to paired tumor profiling tests targeting the exome to identify a therapeutic target. Although conventional germline sequencing did not detect FH variants, exome sequencing revealed a heterozygous germline FH deletion. As such, paired tumor profiling, not conventional sequencing, was required to identify this genetic deletion. RCC caused by a germline FH deletion has hitherto not been described in Japan, and the FH deletion detected in this patient was presumed to be of maternal European origin. Although the genotype-phenotype correlation in HLRCC-related tumors is unclear, the patient's family was advised to undergo genetic counseling to consider additional RCC screening.


Assuntos
Fumarato Hidratase/deficiência , Deleção de Genes , Mutação em Linhagem Germinativa , Leiomiomatose/genética , Erros Inatos do Metabolismo/genética , Hipotonia Muscular/genética , Síndromes Neoplásicas Hereditárias/genética , Transtornos Psicomotores/genética , Neoplasias Cutâneas/genética , Neoplasias Uterinas/genética , Adulto , Feminino , Fumarato Hidratase/genética , Testes Genéticos , Humanos
5.
Zhonghua Er Ke Za Zhi ; 59(8): 695-699, 2021 Aug 02.
Artigo em Chinês | MEDLINE | ID: mdl-34333924

RESUMO

Objective: To explore the clinical characteristics, genotypes and long-term outcomes of individuals with 3-methylglutaconic aciduria. Methods: The clinical features, biochemical data, genetic test results and treatment outcomes of six children with 3-methylglutaconic aciduria admitted to the Department of Endocrinology, Genetics and Metabolism, Xinhua Hospital from February 2017 to February 2019 were retrospectively analyzed and the Gesell developmental diagnosis schedule was performed to evaluate the development of four patients. Results: Among 6 children with 3-methylglutaconic aciduria 2 were males and 4 were females.Four cases had 3-methylglutaconic aciduria type Ⅰ and 2 cases had 3-methylglutaconic aciduria with deafness,encephalopathy, and Leigh-like syndrome. Five of 6 patients were detected by newborn screening among whom 4 remained asymptomatic, and only one had a postmortem diagnosis. Among them, 4 patients remained asymptomatic, while two presented with clinical symptoms such as jaundice and dyspnea and the age of disease onset was 1 and 2 days respectively. The concentration of 3-methylglutaconic acid in urine of all affected individuals was between 22.38 and 77.09 mmol/molCr, which was above the normal value. Genetic tests were performed for all patients. Eleven variants were identified in 2 genes, of which 10 variants were novel and only c.442C>T p.(R148X) has been previously reported; Seven variants (c.656-2delA, EX5-EX6 Del, c.942+3A>G, c.373C>T p.(R125W), c.895-3C>G, c.667C>T p.(R223X) and c.894+5G>A) were in AUH gene. The others (c.548G>A p.(R138Q), c.442C>T p.(R148X), c.1339C>T p.(R447X) and c.973dupA p.(M325Nfs*5) were in SERAC1 gene. After being treated with leucine diet restriction and L-carnitine, 4 patients with AUH gene variation who were from asymptomatic phase developed normally, whereas those 2 patients with SERAC1 gene variation had a poor prognosis. During the follow-up, 2 patients exhibited varying degrees of psychomotor retardation, the rest had normal course of development. Conclusions: There are significant clinical heterogeneities among individuals with 3-methylglutaconic aciduria. The most common pathogenic variants are splicing variations, followed by nonsense, missense and frameshift mutations. Leucine-free diet and oral L-carnitine therapy are effective for some patients. Newborn screening is essential for early diagnosis and improvement of prognosis.


Assuntos
Encefalopatias , Erros Inatos do Metabolismo , Criança , Feminino , Glutaratos , Humanos , Recém-Nascido , Masculino , Mutação , Triagem Neonatal , Estudos Retrospectivos
6.
J Clin Pathol ; 74(10): 615-619, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34353877

RESUMO

Fumarate hydratase (FH), encoded by the FH gene, is an enzyme which catalyses the conversion of fumarate to L-malate as part of the tricarboxylic acid cycle. Biallelic germline mutations in FH result in fumaric aciduria, a metabolic disorder resulting in severe neurological and developmental abnormalities. Heterozygous germline mutations in FH result in hereditary leiomyomatosis and renal cell carcinoma, a cancer predisposition syndrome. FH deficiency has multiple oncogenic mechanisms including through promotion of aerobic glycolysis, induction of pseudohypoxia, post-translational protein modification and impairment of DNA damage repair by homologous recombination. FH-deficient neoplasms can present with characteristic morphological features that raise suspicion for FH alterations and also frequently demonstrate loss of FH immunoreactivity and intracellular accumulation of 2-succinocysteine, also detected by immunohistochemistry.


Assuntos
Fumarato Hidratase/deficiência , Fumarato Hidratase/metabolismo , Erros Inatos do Metabolismo/enzimologia , Hipotonia Muscular/enzimologia , Neoplasias/enzimologia , Transtornos Psicomotores/enzimologia , Animais , Fumarato Hidratase/genética , Regulação Enzimológica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Leiomiomatose/enzimologia , Leiomiomatose/genética , Leiomiomatose/patologia , Erros Inatos do Metabolismo/genética , Hipotonia Muscular/genética , Mutação , Neoplasias/genética , Neoplasias/patologia , Síndromes Neoplásicas Hereditárias/enzimologia , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Fenótipo , Transtornos Psicomotores/genética , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Uterinas/enzimologia , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia
7.
Clin Chim Acta ; 522: 96-104, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34411555

RESUMO

A growing number of inborn errors of metabolism (IEM) associated with compromised mitochondrial energy metabolism manifest an unusual phenotypic feature: 3-methylglutaconic (3MGC) aciduria. Two major categories of 3MGC aciduria, primary and secondary, have been described. In primary 3MGC aciduria, IEMs in 3MGC CoA hydratase (AUH) or HMG CoA lyase block leucine catabolism, resulting in a buildup of pathway intermediates, including 3MGC CoA. Subsequent thioester hydrolysis yields 3MGC acid, which is excreted in urine. In secondary 3MGC aciduria, no deficiencies in leucine catabolism enzymes exist and 3MGC CoA is formed de novo from acetyl CoA. In the "acetyl CoA diversion pathway", when IEMs directly, or indirectly, interfere with TCA cycle activity, acetyl CoA accumulates in the matrix space. This leads to condensation of two acetyl CoA to form acetoacetyl CoA, followed by another condensation between acetyl CoA and acetoacetyl CoA to form 3-hydroxy, 3-methylglutaryl (HMG) CoA. Once formed, HMG CoA serves as a substrate for AUH, producing trans-3MGC CoA. Non enzymatic isomerization of trans-3MGC CoA to cis-3MGC CoA precedes intramolecular cyclization to cis-3MGC anhydride plus CoA. Subsequent hydrolysis of cis-3MGC anhydride gives rise to cis-3MGC acid, which is excreted in urine. In reviewing 20 discrete IEMs that manifest secondary 3MGC aciduria, evidence supporting the acetyl CoA diversion pathway was obtained. This biochemical pathway serves as an "overflow valve" in muscle / brain tissue to redirect acetyl CoA to 3MGC CoA when entry to the TCA cycle is impeded.


Assuntos
Glutaratos , Erros Inatos do Metabolismo , Metabolismo Energético , Glutaratos/metabolismo , Humanos , Erros Inatos do Metabolismo/metabolismo , Mitocôndrias/metabolismo
8.
Nutrients ; 13(6)2021 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-34202936

RESUMO

Children with inborn errors of intermediary metabolism (IEiM) must follow special diets that restrict their intake of essential nutrients and may compromise normal growth and development. We evaluated body composition, bone mineral density, physical activity, and food intake in IEiM patients undergoing dietary treatment. IEiM patients (n = 99) aged 5-19 years and healthy age- and sex-matched controls (n = 98) were recruited and underwent dual-energy X-ray absorptiometry to evaluate anthropometric characteristics and body composition. Data on food intake and physical activity were also collected using validated questionnaires. The height z-score was significantly lower in IEiM patients than controls (-0.28 vs. 0.15; p = 0.008), particularly in those with carbohydrate and amino acid metabolism disorders. Significant differences in adiposity were observed between patients and controls for the waist circumference z-score (-0.08 vs. -0.58; p = 0.005), but not the body mass index z-score (0.56 vs. 0.42; p = 0.279). IEiM patients had a significantly lower total bone mineral density (BMD) than controls (0.89 vs. 1.6; p = 0.001) and a higher risk of osteopenia (z-score < -2, 33.3% vs. 20.4%) and osteoporosis (z-score < -2.5, 7.1% vs. 0%), but none presented fractures. There was a significant positive correlation between natural protein intake and BMD. Our results indicate that patients with IEiM undergoing dietary treatment, especially those with amino acid and carbohydrate metabolism disorders, present alterations in body composition, including a reduced height, a tendency towards overweight and obesity, and a reduced BMD.


Assuntos
Composição Corporal , Ingestão de Alimentos , Exercício Físico , Erros Inatos do Metabolismo/fisiopatologia , Adiposidade , Adolescente , Índice de Massa Corporal , Densidade Óssea , Doenças Ósseas Metabólicas/etiologia , Criança , Pré-Escolar , Estudos Transversais , Dieta , Carboidratos da Dieta/administração & dosagem , Proteínas na Dieta/administração & dosagem , Feminino , Humanos , Masculino , Erros Inatos do Metabolismo/dietoterapia , Osteoporose/etiologia , Adulto Jovem
9.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202771

RESUMO

In this article, we review the biological and clinical implication of the Recruitment-Secretory Block ("R-SB") phenomenon. The phenomenon refers to the reaction of the liver with regard to protein secretion in conditions of clinical stimulation. Our basic knowledge of the process is due to the experimental work in animal models. Under basal conditions, the protein synthesis is mainly carried out by periportal (zone 1) hepatocytes that are considered the "professional" synthesizing protein cells. Under stimulation, midlobular and centrolobular (zones 2 and 3) hepatocytes, are progressively recruited according to lobular gradients and contribute to the increase of synthesis and secretion. The block of secretion, operated by exogenous agents, causes intracellular retention of all secretory proteins. The Pi MZ phenotype of Alpha-1-antitrypsin deficiency (AATD) has turned out to be the key for in vivo studies of the reaction of the liver, as synthesis and block of secretion are concomitant. Indeed, the M fraction of AAT is stimulated for synthesis and regularly exported while the Z fraction is mostly retained within the cell. For that reason, the phenomenon has been designated "Recruitment-Secretory Block" ("R-SB"). The "R-SB" phenomenon explains why: (a) the MZ individuals can correct the serum deficiency; (b) the resulting immonohistochemical and electron microscopic (EM) patterns are very peculiar and specific for the diagnosis of the Z mutation in tissue sections in the absence of genotyping; (c) the term carrier is no longer applicable for the heterozygous condition as all Pi MZ individuals undergo storage and the storage predisposes to liver damage. The storage represents the true elementary lesion and consequently reflects the phenotype-genotype correlation; (d) the site and function of the extrahepatic AAT and the relationship between intra and extracellular AAT; (e) last but not least, the concept of Endoplasmic Reticulum Storage Disease (ERSD) and of a new disease, hereditary hypofibrinogenemia with hepatic storage (HHHS). In the light of the emerging phenomenon, described in vitro, namely that M and Z AAT can form heteropolymers within hepatocytes as well as in circulation, we have reviewed the whole clinical and experimental material collected during forty years, in order to evaluate to what extent the polymerization phenomenon occurs in vivo. The paper summarizes similarities and differences between AAT and Fibrinogen as well as between the related diseases, AATD and HHHS. Indeed, fibrinogen gamma chain mutations undergo an aggregation process within the RER of hepatocytes similar to AATD. In addition, this work has clarified the intriguing phenomenon underlying a new syndrome, hereditary hypofibrinogenemia and hypo-APO-B-lipoproteinemia with hepatic storage of fibrinogen and APO-B lipoproteins. It is hoped that these studies could contribute to future research and select strategies aimed to simultaneously correct the hepatocytic storage, thus preventing the liver damage and the plasma deficiency of the two proteins.


Assuntos
Suscetibilidade a Doenças , Retículo Endoplasmático/metabolismo , Sistemas de Translocação de Proteínas/metabolismo , Animais , Animais Geneticamente Modificados , Biomarcadores , Modelos Animais de Doenças , Predisposição Genética para Doença , Humanos , Fígado/metabolismo , Fígado/patologia , Fígado/ultraestrutura , Redes e Vias Metabólicas , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Transporte Proteico , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismo , Deficiência de alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/metabolismo
10.
Laryngoscope ; 131 Suppl 6: S1-S25, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34142720

RESUMO

OBJECTIVES/HYPOTHESIS: To document the history of hearing seeing in children and adults. STUDY DESIGN: A literature search in all languages was carried out with the terms of hearing screening from the following sources: Pub Med, Science Direct, World Catalog, Index Medicus, Google scholar, Google Books, National Library of Medicine, Welcome historical library and The Library of Congress. METHODS: The primary sources consisting of books, scientific reports, public documents, governmental reports, and other written material were analyzed to document the history of hearing screening. RESULTS: The concept of screening for medical conditions that, when found, could influence some form of the outcome of the malady came about during the end of 19th century. The first applications of screening were to circumscribe populations, schoolchildren, military personnel, and railroad employees. During the first half of the 20th century, screening programs were extended to similar populations and were able to be expanded on the basis of the improved technology of hearing testing. The concept of universal screening was first applied to the inborn errors of metabolism of newborn infants and particularly the assessment of phenylketonuria in 1963 by Guthrie and Susi. A limited use of this technique has been the detection of genes resulting in hearing loss. The use of a form of hearing testing either observational or physiological as a screen for all newborns was first articulated by Larry Fisch in 1957 and by the end of the 20th century newborn infant screening for hearing loss became the standard almost every nation worldwide. CONCLUSIONS: Hearing screening for newborn infants is utilized worldwide, schoolchildren less so and for adults many industrial workers and military service undergo hearing screening, but this is not a general practice for screening the elderly. LEVEL OF EVIDENCE: NA Laryngoscope, 131:S1-S25, 2021.


Assuntos
Testes Auditivos/história , Triagem Neonatal/história , Adulto , Fatores Etários , Audiometria/história , Audiometria/instrumentação , Criança , Cristianismo/história , Perda Auditiva/diagnóstico , Perda Auditiva/história , História do Século XIX , História do Século XX , História do Século XXI , História Antiga , Humanos , Lactente , Recém-Nascido , Judaísmo/história , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/história , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/história
11.
Indian J Pediatr ; 88(7): 679-689, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34097229

RESUMO

Inborn errors of metabolism (IEM), otherwise known as inherited metabolic disorders (IMD), are individually rare, but collectively common. IEM pose a challenge to diagnosis, as neonates present with nonspecific signs. A high index of suspicion is essential. Knowledge on clinical presentation may be life saving, especially for conditions that are treatable. It is important for the first-line physicians not to miss treatable disorders. Simplified classification and algorithmic approach help in the clinical setting. This article describes the classification of IEM into three groups, namely group 1 - intoxication disorders, group 2 - energy defects, and group 3 - storage disorders. Clinical presentations of IEM in the neonatal period, a quick guide to the diagnosis with the help of baseline investigations (glucose, arterial blood gas, lactate, ammonia, and ketone abbreviated as GALAK), a tabulated guide to the diagnosis with the help of tandem mass spectrometry (TMS), and gas chromatography and mass spectrometry (GCMS) are summarized in this article. Four principles of therapy that include substrate reduction, provision of deficient metabolites, disposal of toxic metabolites, and increase in enzyme activity are elaborated with particular stress to the diet management. In addition, a list of medications used in the treatment of different disorders classified according to Society for the Study of IEM (SSIEM) is presented.


Assuntos
Erros Inatos do Metabolismo , Gasometria , Humanos , Recém-Nascido , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/terapia , Triagem Neonatal , Espectrometria de Massas em Tandem
14.
J Coll Physicians Surg Pak ; 30(6): 663-667, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34102777

RESUMO

OBJECTIVE: To determine the relationship of oxidative stress status with follow-up parameters, metabolic control status, and treatment compliance evaluation in patients diagnosed within toxication type inherited metabolic disease (IMDs). STUDY DESIGN: Descriptive, analytical study. PLACE AND DURATION OF STUDY: Dr. Sami Ulus, Maternity and Child Health, Training and Research Hospital, Ankara, Turkey, between September 2019 and March 2020. METHODOLOGY: Sixty-seven patients, who were followed up with a diagnosis of IMDs in the pediatric metabolism outpatient clinic, and 41 healthy volunteers who applied to the social pediatrics outpatient clinic, were evaluated. ​Disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios of the patient and control group were calculated. P <0.05 (*) value was considered significant in statistical analysis. RESULTS: The mean native thiol / total thiol ratio of the patient group was significantly lower when compared to the control group (92.0±3.3 vs 94.1±2.7, p=0.001). The median disulfide level [19.8 (11.6-25) vs 14(10.1-18.8), p=0.004], the mean disulfide / native thiol (4.5±2.0 vs 3.2±1.6, p<0.001) and the mean disulfide / total thiol ratios (4.0±1.7 vs 2.9±1.4, p=0.001) were higher in the patient group compared to the control group.The findings showed that oxidative stress status was increased during metabolic attacks. Poor metabolic control and non-compliance to treatment was found to be associated with increased oxidative stress. Oxidative stress parameters were found to be correlated with metabolic chemicals such as ammonia, leucine, and citrulline. There was no correlation between phenylalanine and lactate levels and oxidative stress parameters. CONCLUSION:  Metabolic control status and compliance with treatment are related to oxidative stress level, showing thiol/disulfide balance in urea cycle defects, phenylketonuria, and galactosemia patients. Key Words: Thiol / disulfide, Metabolic diseases, MSUD, Galactosemia, Hyperammonemia.


Assuntos
Dissulfetos , Erros Inatos do Metabolismo , Criança , Feminino , Homeostase , Humanos , Estresse Oxidativo , Gravidez , Compostos de Sulfidrila , Turquia
16.
Int J Mol Sci ; 22(9)2021 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-34063237

RESUMO

Muscle carnitine palmitoyltransferase II (CPT II) deficiency is associated with various mutations in CPT2 gene. In the present study, the impact of the two CPT II variants P50H and Y479F were characterized in terms of stability and activity in vitro in comparison to wildtype (WT) and the well investigated variant S113L. While the initial enzyme activity of all variants showed wild-type-like behavior, the activity half-lives of the variants at different temperatures were severely reduced. This finding was validated by the investigation of thermostability of the enzymes using nano differential scanning fluorimetry (nanoDSF). Further, it was studied whether the protein stabilizing diphosphatidylglycerol cardiolipin (CL) has an effect on the variants. CL indeed had a positive effect on the stability. This effect was strongest for WT and least pronounced for variant P50H. Additionally, CL improved the catalytic efficiency for CPT II WT and the investigated variants by twofold when carnitine was the varied substrate due to a decrease in KM. However, there was no influence detected for the variation of substrate palmitoyl-CoA. The functional consequences of the stabilization by CL in vivo remain open.


Assuntos
Cardiolipinas/metabolismo , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Músculos/metabolismo , Carnitina , Carnitina O-Palmitoiltransferase/deficiência , Humanos , Cinética , Erros Inatos do Metabolismo Lipídico , Erros Inatos do Metabolismo , Mutação
18.
Mol Genet Metab ; 133(2): 182-184, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34020866

RESUMO

Carnitine palmitoyl transferase II (CPT II) catalyzes the release of activated long-chain fatty acids from acylcarnitines into mitochondria for subsequent fatty acid oxidation. Depending on residual enzyme activity, deficiency of this enzyme leads to a spectrum of symptoms from early onset hypoglycemia, hyperammonemia, cardiomyopathy and death to onset of recurrent rhabdomyolysis in adolescents and young adults. We present a case of successful orthotopic heart transplantation in a patient with severe infantile onset cardiomyopathy due to CPT II deficiency identified through newborn screening. Excellent cardiac function is preserved 12 years post-transplantation; however, the patient has developed intermittent episodes of hyperammonemia and rhabdomyolysis later in childhood and early adolescence readily resolved with intravenous glucose. Successful heart transplant in this patient demonstrates the feasibility of this management option in patients with even severe forms of long chain fatty acid oxidation disorders.


Assuntos
Carnitina O-Palmitoiltransferase/deficiência , Carnitina O-Palmitoiltransferase/genética , Transplante de Coração/métodos , Coração/fisiopatologia , Erros Inatos do Metabolismo/terapia , Adolescente , Adulto , Idade de Início , Cardiomiopatias/genética , Cardiomiopatias/patologia , Cardiomiopatias/terapia , Carnitina O-Palmitoiltransferase/metabolismo , Ácidos Graxos/metabolismo , Humanos , Hiperamonemia/genética , Hiperamonemia/patologia , Hiperamonemia/terapia , Hipoglicemia/genética , Hipoglicemia/patologia , Hipoglicemia/terapia , Recém-Nascido , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Erros Inatos do Metabolismo/patologia , Triagem Neonatal , Rabdomiólise/genética , Rabdomiólise/patologia , Rabdomiólise/terapia , Adulto Jovem
19.
FEBS J ; 288(17): 5021-5041, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33971084

RESUMO

Inborn errors of immunity (IEIs) are a group of genetically defined disorders leading to defective immunity. Some IEIs have been linked to mutations of immune receptors or signaling molecules, resulting in defective signaling of respective cascades essential for combating specific pathogens. However, it remains incompletely understood why in selected IEIs, such as X-linked lymphoproliferative syndrome type 2 (XLP-2), hypo-immune response to specific pathogens results in persistent inflammation. Moreover, mechanisms underlying the generation of anticytokine autoantibodies are mostly unknown. Recently, IEIs have been associated with coronavirus disease 2019 (COVID-19), with a small proportion of patients that contract severe COVID-19 displaying loss-of-function mutations in genes associated with type I interferons (IFNs). Moreover, approximately 10% of patients with severe COVID-19 possess anti-type I IFN-neutralizing autoantibodies. Apart from IEIs that impair immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV-2 encodes several proteins that suppress early type I IFN production. One primary consequence of the lack of type I IFNs during early SARS-CoV-2 infection is the increased inflammation associated with COVID-19. In XLP-2, resolution of inflammation rescued experimental subjects from infection-induced mortality. Recent studies also indicate that targeting inflammation could alleviate COVID-19. In this review, we discuss infection-induced inflammation in IEIs, using XLP-2 and COVID-19 as examples. We suggest that resolving inflammation may represent an effective therapeutic approach to these diseases.


Assuntos
COVID-19/genética , Interferon Tipo I/genética , Erros Inatos do Metabolismo/genética , SARS-CoV-2/patogenicidade , COVID-19/imunologia , COVID-19/virologia , Humanos , Imunidade/genética , Inflamação/genética , Inflamação/imunologia , Inflamação/virologia , Erros Inatos do Metabolismo/imunologia , SARS-CoV-2/imunologia , Viroses/genética , Viroses/imunologia , Viroses/virologia
20.
Mol Genet Metab ; 133(2): 157-181, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33965309

RESUMO

Glutaric aciduria type I (GA-I, OMIM # 231670) is an inborn error of metabolism caused by a deficiency of glutaryl-CoA dehydrogenase (GCDH). Patients develop acute encephalopathic crises (AEC) with striatal injury most often triggered by catabolic stress. The pathophysiology of GA-I, particularly in brain, is still not fully understood. We generated the first knock-in rat model for GA-I by introduction of the mutation p.R411W, the rat sequence homologue of the most common Caucasian mutation p.R402W, into the Gcdh gene of Sprague Dawley rats by CRISPR/CAS9 technology. Homozygous Gcdhki/ki rats revealed a high excretor phenotype, but did not present any signs of AEC under normal diet (ND). Exposure to a high lysine diet (HLD, 4.7%) after weaning resulted in clinical and biochemical signs of AEC. A significant increase of plasmatic ammonium concentrations was found in Gcdhki/ki rats under HLD, accompanied by a decrease of urea concentrations and a concomitant increase of arginine excretion. This might indicate an inhibition of the urea cycle. Gcdhki/ki rats exposed to HLD showed highly diminished food intake resulting in severely decreased weight gain and moderate reduction of body mass index (BMI). This constellation suggests a loss of appetite. Under HLD, pipecolic acid increased significantly in cerebral and extra-cerebral liquids and tissues of Gcdhki/ki rats, but not in WT rats. It seems that Gcdhki/ki rats under HLD activate the pipecolate pathway for lysine degradation. Gcdhki/ki rat brains revealed depletion of free carnitine, microglial activation, astroglyosis, astrocytic death by apoptosis, increased vacuole numbers, impaired OXPHOS activities and neuronal damage. Under HLD, Gcdhki/ki rats showed imbalance of intra- and extracellular creatine concentrations and indirect signs of an intracerebral ammonium accumulation. We successfully created the first rat model for GA-I. Characterization of this Gcdhki/ki strain confirmed that it is a suitable model not only for the study of pathophysiological processes, but also for the development of new therapeutic interventions. We further brought up interesting new insights into the pathophysiology of GA-I in brain and periphery.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Encefalopatias Metabólicas/genética , Encéfalo/metabolismo , Gliose/genética , Glutaril-CoA Desidrogenase/deficiência , Glutaril-CoA Desidrogenase/genética , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Animais , Arginina/metabolismo , Encéfalo/patologia , Encefalopatias Metabólicas/metabolismo , Encefalopatias Metabólicas/patologia , Creatina/sangue , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Gliose/metabolismo , Gliose/patologia , Glutaril-CoA Desidrogenase/metabolismo , Humanos , Lisina/metabolismo , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Ratos
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