RESUMO
The current German newborn screening (NBS) panel includes 13 inherited metabolic diseases (IMDs). In addition, a NBS pilot study in Southwest Germany identifies individuals with propionic acidemia (PA), methylmalonic acidemia (MMA), combined and isolated remethylation disorders (e.g., cobalamin [cbl] C and methylenetetrahydrofolate reductase [MTHFR] deficiency), cystathionine ß-synthase (CBS) deficiency, and neonatal cbl deficiency through one multiple-tier algorithm. The long-term health benefits of screened individuals are evaluated in a multicenter observational study. Twenty seven screened individuals with IMDs (PA [N = 13], MMA [N = 6], cblC deficiency [N = 5], MTHFR deficiency [N = 2] and CBS deficiency [N = 1]), and 42 with neonatal cbl deficiency were followed for a median of 3.6 years. Seventeen screened IMD patients (63%) experienced at least one metabolic decompensation, 14 of them neonatally and six even before the NBS report (PA, cbl-nonresponsive MMA). Three PA patients died despite NBS and immediate treatment. Fifteen individuals (79%) with PA or MMA and all with cblC deficiency developed permanent, mostly neurological symptoms, while individuals with MTHFR, CBS, and neonatal cbl deficiency had a favorable clinical outcome. Utilizing a combined multiple-tier algorithm, we demonstrate that NBS and specialized metabolic care result in substantial benefits for individuals with MTHFR deficiency, CBS deficiency, neonatal cbl deficiency, and to some extent, cbl-responsive MMA and cblC deficiency. However, its advantage is less evident for individuals with PA and cbl-nonresponsive MMA. SYNOPSIS: Early detection through newborn screening and subsequent specialized metabolic care improve clinical outcomes and survival in individuals with MTHFR deficiency and cystathionine-ß-synthase deficiency, and to some extent in cobalamin-responsive methylmalonic acidemia (MMA) and cblC deficiency while the benefit for individuals with propionic acidemia and cobalamin-nonresponsive MMA is less evident due to the high (neonatal) decompensation rate, mortality, and long-term complications.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Homocistinúria , Triagem Neonatal , Acidemia Propiônica , Humanos , Triagem Neonatal/métodos , Homocistinúria/diagnóstico , Recém-Nascido , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Acidemia Propiônica/diagnóstico , Feminino , Masculino , Alemanha , Lactente , Projetos Piloto , Pré-Escolar , Vitamina B 12/sangue , Criança , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Espasticidade Muscular , Transtornos PsicóticosRESUMO
Organic acidemias (OA) are a group of rare autosomal recessive disorders of intermediary metabolism that result in a systemic elevation of organic acid. Despite optimal dietary and cofactor therapy, OA patients still suffer from potentially lethal metabolic instability and experience long-term multisystemic complications. Severely affected patients can benefit from elective liver transplantation, which restores hepatic enzymatic activity, improves metabolic stability, and provides the theoretical basis for the pursuit of gene therapy as a new treatment for patients. Because of the poor outcomes reported in those with OA, especially methylmalonic and propionic acidemia, multiple gene therapy approaches have been explored in relevant animal models. Here, we review the results of gene therapy experiments performed using MMA and PA mouse models to illustrate experimental paradigms that could be applicable for all forms of OA.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Transplante de Fígado , Acidemia Propiônica , Animais , Camundongos , Humanos , Acidemia Propiônica/genética , Acidemia Propiônica/terapia , Acidemia Propiônica/complicações , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Transplante de Fígado/efeitos adversos , Terapia Genética , Modelos Animais de Doenças , Ácido MetilmalônicoRESUMO
Newborn screening (NBS) programs are effective measures of secondary prevention and have been successively extended. We aimed to evaluate NBS for methylmalonic acidurias, propionic acidemia, homocystinuria, remethylation disorders and neonatal vitamin B12 deficiency, and report on the identification of cofactor-responsive disease variants. This evaluation of the previously established combined multiple-tier NBS algorithm is part of the prospective pilot study "NGS2025" from August 2016 to September 2022. In 548,707 newborns, the combined algorithm was applied and led to positive NBS results in 458 of them. Overall, 166 newborns (prevalence 1: 3305) were confirmed (positive predictive value: 0.36); specifically, methylmalonic acidurias (N = 5), propionic acidemia (N = 4), remethylation disorders (N = 4), cystathionine beta-synthase (CBS) deficiency (N = 1) and neonatal vitamin B12 deficiency (N = 153). The majority of the identified newborns were asymptomatic at the time of the first NBS report (total: 161/166, inherited metabolic diseases: 9/14, vitamin B12 deficiency: 153/153). Three individuals were cofactor-responsive (methylmalonic acidurias: 2, CBS deficiency: 1), and could be treated by vitamin B12, vitamin B6 respectively, only. In conclusion, the combined NBS algorithm is technically feasible, allows the identification of attenuated and severe disease courses and can be considered to be evaluated for inclusion in national NBS panels.
Assuntos
Homocistinúria , Acidemia Propiônica , Deficiência de Vitamina B 12 , Humanos , Recém-Nascido , Homocistinúria/diagnóstico , Estudos Prospectivos , Triagem Neonatal/métodos , Projetos Piloto , Vitamina B 12 , Deficiência de Vitamina B 12/diagnóstico , Fenótipo , Ácido Metilmalônico/metabolismo , VitaminasRESUMO
INTRODUCTION: Tandem mass spectrometry (TMS) has emerged an important screening tool for various metabolic disorders in newborns. However, there is inherent risk of false positive outcomes. Objective To establish analyte-specific cutoffs in TMS by integrating metabolomics and genomics data to avoid false positivity and false negativity and improve its clinical utility. METHODS: TMS was performed on 572 healthy and 3000 referred newborns. Urine organic acid analysis identified 23 types of inborn errors in 99 referred newborns. Whole exome sequencing was performed in 30 positive cases. The impact of physiological changes such as age, gender, and birthweight on various analytes was explored in healthy newborns. Machine learning tools were used to integrate demographic data with metabolomics and genomics data to establish disease-specific cut-offs; identify primary and secondary markers; build classification and regression trees (CART) for better differential diagnosis; for pathway modeling. RESULTS: This integration helped in differentiating B12 deficiency from methylmalonic acidemia (MMA) and propionic acidemia (Phi coefficient=0.93); differentiating transient tyrosinemia from tyrosinemia type 1 (Phi coefficient=1.00); getting clues about the possible molecular defect in MMA to initiate appropriate intervention (Phi coefficient=1.00); to link pathogenicity scores with metabolomics profile in tyrosinemia (r2=0.92). CART model helped in establishing differential diagnosis of urea cycle disorders (Phi coefficient=1.00). CONCLUSION: Calibrated cut-offs of different analytes in TMS and machine learning-based establishment of disease-specific thresholds of these markers through integrated OMICS have helped in improved differential diagnosis with significant reduction of the false positivity and false negativity rates.
Assuntos
Acidemia Propiônica , Tirosinemias , Recém-Nascido , Humanos , Triagem Neonatal/métodos , Metabolômica , Aprendizado de MáquinaRESUMO
Orphan drug designation (ODD) is an important program intended to facilitate the development of orphan drugs in the United States. An orphan drug benefiting pediatric patients can qualify as a drug for a Rare Pediatric Disease Designation (RPDD) as well. The ODD and RPDD programs provide financial incentives for development of diagnostic drugs, preventive measures, and treatment of diseases affecting small patient populations (adult and pediatric) for which commercial development would otherwise be very challenging. In 2019, a multidisciplinary group of collaborators at National Institutes of Health (NIH) embarked upon a gene therapy platform program called Platform Vector Gene Therapy (PaVe-GT) intended to develop gene therapies for four such rare disorders. An important part of PaVe-GT is to publicly share scientific and regulatory experience gained at different stages during the implementation of the PaVe-GT platform utilizing illustrative examples. The PaVe-GT team recently obtained ODD and RPDD for an adeno-associated virus gene therapy to treat propionic acidemia. Given an increasing interest in obtaining ODD for gene therapy, especially by small companies, research investigators, and patient groups, we overview the submission process and subsequently provide examples of our ODD and RPDD applications. Our ODD and RPDD applications and templates can also be found on the PaVe-GT website. Shared reference documents will have great utility to assist parties who may have limited experience with the preparation of similar applications for their orphan product.
Assuntos
Produção de Droga sem Interesse Comercial , Acidemia Propiônica , Humanos , Estados Unidos , Criança , United States Food and Drug Administration , Aprovação de Drogas , Doenças Raras/genética , Doenças Raras/terapia , Terapia Genética , National Institutes of Health (U.S.)RESUMO
Propionic acidemia (PA) is a rare inherited metabolic disease due to inborn errors of metabolism. PA results in the accumulation of abnormal organic acid metabolites in multiple systems, mainly the central nervous system and the heart. Cardiac complications include dilated cardiomyopathy (DCM) and carry a 40-50% increased mortality risk. Liver transplantation (LT) is required in PA patients when medical treatment fails and may prevent or slow down the cardiomyopathy progression. However, severe heart disease may be a serious contraindication to LT. We present a complicated case of a PA patient, supported with a Left Ventricular Assist Device, who underwent a heart and Liver transplant. PA patients are at increased risk for metabolic acidosis during surgery, with increased anion gap and hyperammonemia. A strict multi-disciplinary approach is needed to prevent and treat metabolic decompensation. The patient had a successful heart and liver transplant after a strict treatment protocol in the pre, intra, and post-operative periods. His case highlights the complexity of PA patients and the increased risk for metabolic decompensation during surgery and provides an insight into how to manage such complicated patients.
Assuntos
Cardiomiopatias , Coração Auxiliar , Transplante de Fígado , Acidemia Propiônica , Humanos , Cardiomiopatias/etiologia , Cardiomiopatias/cirurgia , Transplante de Fígado/efeitos adversos , Acidemia Propiônica/complicações , Acidemia Propiônica/diagnóstico , Acidemia Propiônica/terapia , Resultado do Tratamento , MasculinoRESUMO
Propionic acid (PA) predominantly accumulates in tissues and biological fluids of patients affected by propionic acidemia that may manifest chronic renal failure along development. High urinary excretion of maleic acid (MA) has also been described. Considering that the underlying mechanisms of renal dysfunction in this disorder are poorly known, the present work investigated the effects of PA and MA (1-5 mM) on mitochondrial functions and cellular viability in rat kidney and cultured human embryonic kidney (HEK-293) cells. Mitochondrial membrane potential (∆ψm), NAD(P)H content, swelling and ATP production were measured in rat kidney mitochondrial preparations supported by glutamate or glutamate plus malate, in the presence or absence of Ca2+. MTT reduction and propidium iodide (PI) incorporation were also determined in intact renal cells pre-incubated with MA or PA for 24 h. MA decreased Δψm and NAD(P)H content and induced swelling in Ca2+-loaded mitochondria either respiring with glutamate or glutamate plus malate. Noteworthy, these alterations were fully prevented by cyclosporin A plus ADP, suggesting the involvement of mitochondrial permeability transition (mPT). MA also markedly inhibited ATP synthesis in kidney mitochondria using the same substrates, implying a strong bioenergetics impairment. In contrast, PA only caused milder changes in these parameters. Finally, MA decreased MTT reduction and increased PI incorporation in intact HEK-293 cells, indicating a possible association between mitochondrial dysfunction and cell death in an intact cell system. It is therefore presumed that the MA-induced disruption of mitochondrial functions involving mPT pore opening may be involved in the chronic renal failure occurring in propionic acidemia.
Assuntos
Falência Renal Crônica , Acidemia Propiônica , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Cálcio/metabolismo , Ciclosporina/metabolismo , Ciclosporina/farmacologia , Ácido Glutâmico/farmacologia , Células HEK293 , Humanos , Rim , Falência Renal Crônica/metabolismo , Malatos/metabolismo , Malatos/farmacologia , Maleatos , Potencial da Membrana Mitocondrial , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , NAD/metabolismo , Permeabilidade , Propídio/metabolismo , Propídio/farmacologia , Acidemia Propiônica/metabolismo , Ratos , Ratos WistarRESUMO
INTRODUCTION: A growing number of epidemiological evidence reveals that electronic cigarettes (E-cigs) were associated with pneumonia, hypertension and atherosclerosis, but the toxicological evaluation and mechanism of E-cigs were largely unknown. OBJECTIVE: Our study was aimed to explore the adverse effects on organs and metabolomics changes in C57BL/6J mice after acute exposure to E-cigs. METHODS AND RESULTS: Hematoxylin and eosin (H&E) staining found pathological changes in tissues after acute exposure to E-cigs, such as inflammatory cell infiltration, nuclear pyknosis, and intercellular interstitial enlargement. E-cigs could increase apoptosis-positive cells in a time-dependent way using Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. Oxidative damage indicators of reactive oxygen species (ROS), malondialdehyde (MDA) and 4-hydroxynonena (4-HNE) were also elevated after E-cigs exposure. There was an increasing trend of total glycerol and cholesterol in serum, while the glucose and liver enzymes including alanine aminotransferase (ALT), aspartate transaminase (AST), gamma-glutamyltranspeptidase (γ-GT) had no significant change compared to that of control. Further, Q Exactive high field (HF) mass spectrometer was used to conduct metabolomics, which revealed that differential metabolites including l-carnitine, Capryloyl glycine, etc. Trend analysis showed the type of compounds that change over time. Pathway enrichment analysis indicated that E-cigs affected 24 metabolic pathways, which were mainly regulated amino acid metabolism, further affected the tricarboxylic acid (TCA) cycle. Additionally, metabolites-diseases network analysis found that the type 2 diabetes mellitus, propionic acidemia, defect in long-chain fatty acids transport and lung cancer may be related to E-cigs exposure. CONCLUSIONS: Our findings provided important clues for metabolites biomarkers of E-cigs acute exposure and are beneficial for disease prevention.
Assuntos
Diabetes Mellitus Tipo 2 , Sistemas Eletrônicos de Liberação de Nicotina , Acidemia Propiônica , Animais , Metabolômica , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Objective: To investigate the spectrum of amino acid, organic acid, and fatty acid oxidative metabolic diseases in children diagnosed by detecting urinary organic acid levels using gas chromatography-mass spectrometry. Methods: From January 2005 to December 2021, clinical data of 2 461 children diagnosed with inherited metabolic diseases (IMD) by gas chromatography-mass spectrometry, in combination with tandem mass spectrometry and genetic testing in Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine were retrospectively analyzed. Results: Among 2 461 children, 1 446 were male and 1 051 were female. A total of 32 types of IMD were detected among 2 461 patients, which included 10 amino acid disorders in 662 cases (26.9%), 6 common diseases were hyperphenylalaninemia, citrin deficiency, ornithine carbamoyltransferase deficiency, maple syrup urine disease, alkaptonuria, and tyrosinemia-I, 17 types of organic acidemias in 1 683 cases (68.4%), 6 common diseases were methylmalonic acidemia, propionic acidemia, valeric acidemia-type â , isovaleric acidemia, 3-methylcrotonyl-CoA carboxylase deficiency and multiple carboxylase deficiency and 5 fatty acid ß oxidative defects in 116 cases (4.7%), 2 common diseases were multiple acyl-CoA dehydrogenase deficiency and short-chain acyl-CoA dehydrogenase deficiency). Conclusion: Among the diseases diagnosed by analyzing urinary organic acid profiling with gas chromatography-mass spectrometry, the most common are organic acidemias, followed by amino acid disorders and fatty acid oxidation defects.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Doenças Metabólicas , Acidemia Propiônica , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Aminoácidos , Criança , China , Ácidos Graxos/metabolismo , Feminino , Cromatografia Gasosa-Espectrometria de Massas/métodos , Humanos , Masculino , Doenças Metabólicas/diagnóstico , Acidemia Propiônica/diagnóstico , Estudos Retrospectivos , Análise EspectralRESUMO
BACKGROUND: Current world experience regarding living donor liver transplantation (LDLT) in the treatment of propionic acidemia (PA) is limited, especially in terms of using obligate heterozygous carriers as donors. This study aimed to evaluate the clinical outcomes of LDLT in children with PA. METHODS: From November 2017 to January 2020, 7 of the 192 children who underwent LDLT at our institution had been diagnosed with PA (median age, 2.1 years; range, 1.1-5.8 years). The primary indication for transplantation was frequent metabolic decompensations in 6 patients and preventative treatment in 1 patient. Of the seven parental living donors, six were genetically proven obligate heterozygous carriers. RESULTS: During a median follow-up of 23.9 months (range, 13.9-40.2 months), all patients were alive with 100% allograft survival, and no severe transplant-related complications occurred. In the case of liberalized protein intake, they did not suffer metabolic decompensation or disease-related complications and made progress in neurodevelopmental delay and body growth, as well as blood and urinary metabolite levels. In one patient with pre-existing mild dilated cardiomyopathy, her echocardiogram results completely normalized 13.8 months post-transplant. All living donors recovered well after surgery, with no metabolic decompensations or procedure-related complications. Western blotting revealed that the hepatic expressions of PCCA and PCCB in one of the heterozygous donors were comparable to those of the normal healthy control at the protein level. CONCLUSIONS: LDLT using partial liver grafts from asymptomatic obligate heterozygous carrier donors is a viable therapeutic option for selected PA patients, with no negative impact on donors' and recipients' clinical courses.
Assuntos
Transplante de Fígado , Acidemia Propiônica , Criança , Pré-Escolar , Feminino , Heterozigoto , Humanos , Fígado , Transplante de Fígado/métodos , Doadores Vivos , Acidemia Propiônica/genética , Acidemia Propiônica/cirurgiaRESUMO
Presentación del caso: se reporta un paciente pediátrico con diagnóstico de hiperglicinemia no cetósica (HNC), enfermedad neurometabólica poco frecuente ocasionada por una deficiencia en el sistema de segmentación de la glicina, codificada por los genes GLDC, GCSH, AMT y GCSL que conduce a niveles elevados de glicina en la sinapsis generando un efecto agonista prolongado en los receptores N-metil-D-aspartato (NMDA). Discusión y conclusiones: se asocia con hipotonía, convulsiones y trastornos de la deglución, los cuales dependerán de la edad de presentación. Se revisa la literatura actual para el abordaje perioperatorio.
Case presentation: we report a child with a diagnosis of non-ketotic hyperglycinemia (NKGH), a rare neurometabolic disease caused by a defect in the glycine cleavage system, encoded by the GLDC, GCSH, AMT and GCSL genes resulting in elevated synaptic glycine levels generating a prolonged agonist effect on N-methyl-D-aspartate (NMDA) receptors. Discussion and conclusions: it is associated with hypotonia, seizures and swallowing disorders, which will depend on the age at presentation. A literature review was conducted to tailor perioperative approach.
Assuntos
Humanos , Masculino , Lactente , Hiperglicinemia não Cetótica , Acidemia Propiônica , Período Perioperatório , Transtornos de Deglutição , Fundoplicatura , Hipotonia MuscularRESUMO
Propionic aciduria (PA) is caused by deficiency of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). Due to inefficient propionate catabolism patients are endangered by life-threatening ketoacidotic crisis. Protein and amino acid restriction are major therapeutic pillars. However, long-term complications like neurological deterioration and cardiac abnormalities cannot be prevented. Chronic kidney disease (CKD), which is a well-known characteristic of methylmalonic aciduria two enzymatic steps downstream from PCC, has been recognized as a novel late-onset complication in PA. The pathophysiology of CKD in PA is unclear. We investigated mitochondrial structure and metabolism in human renal tubular cells of healthy controls and PA patients. The cells were exposed to either standard cell culture conditions (NT), high protein (HP) or high concentrations of isoleucine and valine (I/V). Mitochondrial morphology changed to condensed, fractured morphology in PA cells irrespective of the cell culture medium. HP and I/V exposure, however, potentiated oxidative stress in PA cells. Mitochondrial mass was enriched in PA cells, and further increased by HP and I/V exposure suggesting a need for compensation. Alterations in the tricarboxylic acid cycle intermediates and accumulation of medium- and long-chain acylcarnitines pointed to altered mitochondrial energy metabolism. Mitophagy was silenced while autophagy as cellular defense mechanisms was highly active in PA cells. The data demonstrate that PA is associated with renal mitochondrial damage which is aggravated by protein and I/V load. Preservation of mitochondrial energy homeostasis in renal cells may be a potential future therapeutic target.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/patologia , Metilmalonil-CoA Descarboxilase/genética , Mitocôndrias/metabolismo , Acidemia Propiônica/genética , Insuficiência Renal Crônica/patologia , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Estudos de Casos e Controles , Linhagem Celular , Ciclo do Ácido Cítrico , Metabolismo Energético/genética , Células Epiteliais/metabolismo , Humanos , Metilmalonil-CoA Descarboxilase/metabolismo , Mitocôndrias/patologia , Estresse Oxidativo/genética , Acidemia Propiônica/enzimologia , Insuficiência Renal Crônica/complicaçõesRESUMO
OBJECTIVE: To detect pathogenic variants in a pedigree affected with propionic acidemia (PA). METHODS: The proband was subjected to high-throughput next-generation sequencing. Suspected variants were validated by Sanger sequencing of his family members. mRNA was extracted from peripheral blood lymphocytes from the proband's father in order to verify the impact of the splicing variant by RT-PCR combined with Sanger sequencing. The pathogenicity of the missense variant was predicted by using PolyPhen-2, Mutation Taster, SIFT, COBALT and HOPE software. RESULTS: The proband was found to harbor compound heterozygous variants of the PCCB gene, namely c.184-2A>G and c.733G>A (p.G245S), which were respectively inherited from his father and mother. RT-PCR combined with Sanger sequencing confirmed skipping of exon 2 during transcription. Bioinformatic analysis indicated the c.733G>A (p.G245S) variant to be damaging. CONCLUSION: The two variants of the PCCB gene probably underlay the disease in this patient. Above findings have enriched the spectrum of PCCB gene variants.
Assuntos
Mutação de Sentido Incorreto , Acidemia Propiônica , Éxons , Humanos , Mutação , Linhagem , Acidemia Propiônica/genéticaRESUMO
BACKGROUND: Propionate inborn errors of metabolism (PIEM), including propionic (PA) and methylmalonic (MMA) acidemias, are inherited metabolic diseases characterized by toxic accumulation of propionic, 3-hydroxypropionic, methylcitric, and methylmalonic organic acids in biological fluids, causing recurrent acute metabolic acidosis events and encephalopathy, which can lead to fatal outcomes if managed inadequately. PIEM patients can develop hematological abnormalities and immunodeficiency, either as part of the initial clinical presentation or as chronic complications. The origin and characteristics of these abnormalities have been studied poorly. Thus, the aim of the present work was to evaluate and describe lymphoid, myeloid, and erythroid cell population profiles in a group of clinically stable PIEM patients. METHODS: This was a retrospective study of 11 nonrelated Mexican PIEM patients. Clinical, biochemical, nutritional, hematological, and lymphocyte subsets were analyzed. RESULTS: Despite being considered clinically stable, 91% of patients had hematological or immunological abnormalities. The absolute lymphocyte subset counts were low in all patients but one, with CD4+ T-cell lymphopenia, being the most common one. Furthermore, of the 11 studied subjects, nine presented with a low CD4/CD8 ratio. Among the observed hematological alterations, bicytopenia was the most common (82%) one, followed by anemia (27%). CONCLUSION: Our results contribute to the landscape of immunological abnormalities observed previously in PIEM patients; these abnormalities can become a life-threatening chronic complications because of the increased risk of opportunistic diseases. These findings allow us to propose the inclusion of monitoring immune biomarkers, such as subsets of lymphocytes in the follow up of PIEM patients.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/sangue , Linfócitos B/patologia , Subpopulações de Linfócitos/patologia , Linfócitos T/patologia , Erros Inatos do Metabolismo dos Aminoácidos/imunologia , Antígenos de Diferenciação/metabolismo , Linfócitos B/metabolismo , Biomarcadores/sangue , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Subpopulações de Linfócitos/metabolismo , Masculino , Acidemia Propiônica/sangue , Acidemia Propiônica/imunologia , Estudos Retrospectivos , Linfócitos T/metabolismoRESUMO
OBJECTIVES: To determine the incidence of newborn screening (NBS) disorders and to study the key performance indicators of the program. METHODS: This retrospective single-center study enrolled all infants who underwent NBS from January 2012 to December 2017 at Prince Sultan Military Medical City, Riyadh, Saudi Arabia. We screened 17 NBS disorders. Blood samples were collected 24 hours after birth. If the initial result was positive, a second sample was collected. True positive cases were immediately referred for medical management. Data were extracted from laboratory computerized and non-computerized records using case report forms. RESULTS: During the study period, 56632 infants underwent NBS with a coverage rate of 100%. Thirty-eight cases were confirmed. The incidence of congenital hypothyroidism was 1:3775. The positive predictive value for the detection of congenital hypothyroidism was 11.8%. Propionic aciduria was the most common metabolic disorder, with an incidence of 1:14158. Very long-chain acyl CoA dehydrogenase deficiency and glutaric aciduria type 1 had an incidence of 1:18877 each. Phenylketonuria, biotinidase deficiency, maple syrup urine disease, and citrullinemia had an incidence of 1:28316 each. However, galactosemia and 3-methyl crotonyl carboxylase deficiency had the lowest incidence of 1:56632. CONCLUSION: The NBS coverage rate at our facility was 100%. Congenital hypothyroidism was the most frequently detected disorder with an incidence that matches worldwide figures. The incidence of other inherited disorders was consistent with regional figures.
Assuntos
Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/epidemiologia , Triagem Neonatal , Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/epidemiologia , Biomarcadores/sangue , Encefalopatias Metabólicas/diagnóstico , Encefalopatias Metabólicas/epidemiologia , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Síndrome Congênita de Insuficiência da Medula Óssea/epidemiologia , Glutaril-CoA Desidrogenase/deficiência , Humanos , Hipotireoidismo/diagnóstico , Hipotireoidismo/epidemiologia , Incidência , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/epidemiologia , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/epidemiologia , Doenças Musculares/diagnóstico , Doenças Musculares/epidemiologia , Valor Preditivo dos Testes , Acidemia Propiônica/diagnóstico , Acidemia Propiônica/epidemiologia , Estudos Retrospectivos , Arábia Saudita/epidemiologia , Fatores de TempoRESUMO
La linfohistiocitosis hemofagocítica (LHH) puede ser primaria (hereditaria) o secundaria a infecciones, tumores malignos, trastornos reumatológicos, síndromes de inmunodeficiencia y metabolopatías. Se informaron casos de intolerancia a la proteína lisinúrica, deficiencia de múltiples sulfatasas, galactosemia, enfermedad de Gaucher, síndrome de Pearson y galactosialidosis. No se sabe cómo se desencadena la LHH en las metabolopatías. Se diagnosticó LHH en un lactante de 2 meses con letargo, palidez, alimentación deficiente, hepatoesplenomegalia, fiebre y pancitopenia, y se instauró el protocolo HLH-2004. Se realizaron, en conjunto, análisis para detectar mutaciones genéticas y pruebas metabólicas; los resultados fueron negativos para las mutaciones genéticas de LHH primaria, pero se detectaron hiperamoniemia y concentración elevada de metilcitrato. Se diagnosticó acidemia propiónica. Aquí informamos sobre un caso de LHH secundaria a acidemia propiónica. Es posible la realización simultánea de pruebas de detección de trastornos metabólicos y de mutaciones genéticas para el diagnóstico temprano en los lactantes con LHH
Hemophagocytic lymphohystiocytosis (HLH) may be primary (inherited/familial) or secondary to infections, malignancies, rheumatologic disorders, immune deficiency syndromes and metabolic diseases. Cases including lysinuric protein intolerance, multiple sulfatase deficiency, galactosemia, Gaucher disease, Pearson syndrome, and galactosialidosis have previously been reported. It is unclear how the metabolites trigger HLH in metabolic diseases. A 2-month-old infant with lethargy, pallor, poor feeding, hepatosplenomegaly, fever and pancytopenia, was diagnosed with HLH and the HLH-2004 treatment protocol was initiated. Analysis for primary HLH gene mutations and metabolic screening tests were performed together; primary HLH gene mutations were negative, but hyperammonemia and elevated methyl citrate were detected. Propionic acidemia was diagnosed with tandem mass spectrometry in neonatal dried blood spot. We report this case of HLH secondary to propionic acidemia. Both metabolic disorder screening tests and gene mutation analysis may be performed simultaneously especially for early diagnosis in infants presenting with HLH.
Assuntos
Humanos , Masculino , Lactente , Linfo-Histiocitose Hemofagocítica/diagnóstico , Acidemia Propiônica/diagnóstico , Pancitopenia , Esplenomegalia , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Acidemia Propiônica/tratamento farmacológico , Torpor , Terapia de Substituição Renal Contínua , HepatomegaliaRESUMO
Hemophagocytic lymphohystiocytosis (HLH) may be primary (inherited/familial) or secondary to infections, malignancies, rheumatologic disorders, immune deficiency syndromes and metabolic diseases. Cases including lysinuric protein intolerance, multiple sulfatase deficiency, galactosemia, Gaucher disease, Pearson syndrome, and galactosialidosis have previously been reported. It is unclear how the metabolites trigger HLH in metabolic diseases. A 2-month-old infant with lethargy, pallor, poor feeding, hepatosplenomegaly, fever and pancytopenia, was diagnosed with HLH and the HLH-2004 treatment protocol was initiated. Analysis for primary HLH gene mutations and metabolic screening tests were performed together; primary HLH gene mutations were negative, but hyperammonemia and elevated methyl citrate were detected. Propionic acidemia was diagnosed with tandem mass spectrometry in neonatal dried blood spot. We report this case of HLH secondary to propionic acidemia. Both metabolic disorder screening tests and gene mutation analysis may be performed simultaneously especially for early diagnosis in infants presenting with HLH.
La linfohistiocitosis hemofagocítica (LHH) puede ser primaria (hereditaria) o secundaria a infecciones, tumores malignos, trastornos reumatológicos, síndromes de inmunodeficiencia y metabolopatías. Se informaron casos de intolerancia a la proteína lisinúrica, deficiencia de múltiples sulfatasas, galactosemia, enfermedad de Gaucher, síndrome de Pearson y galactosialidosis. No se sabe cómo se desencadena la LHH en las metabolopatías. Se diagnosticó LHH en un lactante de 2 meses con letargo, palidez, alimentación deficiente, hepatoesplenomegalia, fiebre y pancitopenia, y se instauró el protocolo HLH-2004. Se realizaron, en conjunto, análisis para detectar mutaciones genéticas y pruebas metabólicas; los resultados fueron negativos para las mutaciones genéticas de LHH primaria, pero se detectaron hiperamoniemia y concentración elevada de metilcitrato. Se diagnosticó acidemia propiónica. Aquí informamos sobre un caso de LHH secundaria a acidemia propiónica. Es posible la realización simultánea de pruebas de detección de trastornos metabólicos y de mutaciones genéticas para el diagnóstico temprano en los lactantes con LHH.
Assuntos
Linfo-Histiocitose Hemofagocítica/etiologia , Acidemia Propiônica/diagnóstico , Humanos , Lactente , Linfo-Histiocitose Hemofagocítica/diagnóstico , Masculino , Acidemia Propiônica/complicaçõesRESUMO
La acidemia propiónica es una rara enfermedad metabólica (prevalencia: 1/100 000), cuya detección puede hacerse de forma precoz mediante el cribado neonatal en las primeras 72 horas de vida. Puede tener una presentación neonatal grave, tardía intermitente o crónica progresiva. El tratamiento de las crisis consiste en la inversión del catabolismo que detiene la ingesta proteica con aporte intravenoso de calorías no proteicas. La mortalidad depende, fundamentalmente, de los episodios de descompensación aguda, mientras que la evolución asocia una alta tasa de secuelas neurológicas y déficits cognitivos.Se presenta el caso de una recién nacida de 11 días de vida con clínica de estancamiento ponderal, letargia, acidosis metabólica e hiperamonemia, que, debido a una falla en el proceso de cribado, no se benefició del diagnóstico precoz.A pesar de la ya existente detección por cribado, es vital mantener un alto índice de sospecha en casos sugestivos de metabolopatías.
Propionic acidemia is a rare metabolic disease (prevalence 1/100,000) that can be early detected with the newborn metabolic screening within the first 72 hours of life. It can have a severe neonatal presentation, a late intermittent onset or a chronic and progressive course. The treatment in the crisis consists in inverting the catabolism by pausing the protein intake and giving intravenous non-protein calories. Mortality depends mainly on acute episodes of decompensation, while evolution and prognosis associate a high rate of neurological sequelae and cognitive deficiencies.We present the case of an 11-day-old female newborn with failure to thrive, lethargy, metabolic acidosis and hyperammonemia that, because of a failed newborn screening process, could not be early diagnosed.In spite of the existence of early detection with the newborn metabolic screening, it is very important to keep a high suspicion in cases that suggest metabolic disorders.
Assuntos
Humanos , Feminino , Recém-Nascido , Triagem Neonatal , Acidemia Propiônica/diagnóstico , Acidemia Propiônica/tratamento farmacológico , Sepse , HiperamonemiaRESUMO
Liver transplantation (LT) for patients with propionic acidemia (PA) is an emerging therapeutic option. We present a retrospective review of patients with PA who underwent LT at a tertiary liver center between 1995 and 2015. A total of 14 children were identified (8 males) with median age at initial presentation of 3 days (range, 0-77 days). Pretransplant median protein restriction was 1 g/kg/day (range, 0.63-1.75 g/kg/day), 71% required supportive feeding, and 86% had developmental delay. Frequent metabolic decompensations (MDs) were the main indication for LT with a median age at transplantation of 2.4 years (range, 0.8-7.1 years). Only 1 graft was from a living donor, and 13 were from deceased donors (4 auxiliary). The 2-year patient survival was 86%, and overall study and graft survival was 79% and 69%, respectively. Three patients died after LT: at 43 days (biliary peritonitis), 225 days (acute-on-chronic rejection with multiorgan failure), and 13.5 years (posttransplant lymphoproliferative disease). Plasma glycine and propionylcarnitine remained elevated but reduced after transplant. Of 11 survivors, 5 had at least 1 episode of acute cellular rejection, 2 sustained a metabolic stroke (with full recovery), and 3 developed mild cardiomyopathy after LT. All have liberalized protein intake, and 9 had no further MDs: median episodes before transplant, 4 (range, 1-30); and median episodes after transplant, 0 (range, 0-5). All survivors made some developmental progress after LT, and none worsened at a median follow-up of 5.8 years (range, 2-23 years). LT in PA significantly reduces the frequency of MDs, can liberalize protein intake and improve quality of life, and should continue to be considered in selected cases.
Assuntos
Transplante de Fígado , Acidemia Propiônica , Criança , Pré-Escolar , Humanos , Lactente , Transplante de Fígado/efeitos adversos , Doadores Vivos , Masculino , Acidemia Propiônica/diagnóstico , Acidemia Propiônica/cirurgia , Qualidade de Vida , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Methylmalonic acidemia (MMA) and propionic acidemia (PA) are related disorders of mitochondrial propionate metabolism, caused by defects in methylmalonyl-CoA mutase (MUT) and propionyl-CoA carboxylase (PCC), respectively. These biochemical defects lead to a complex cascade of downstream metabolic abnormalities, and identification of these abnormal pathways has important implications for understanding disease pathophysiology. Using a multi-omics approach in cellular models of MMA and PA, we identified serine and thiol metabolism as important areas of metabolic dysregulation. METHODS: We performed global proteomic analysis of fibroblasts and untargeted metabolomics analysis of plasma from individuals with MMA to identify novel pathways of dysfunction. We probed these novel pathways in CRISPR-edited, MUT and PCCA null HEK293 cell lines via targeted metabolomics, gene expression analysis, and flux metabolomics tracing utilization of 13C-glucose. RESULTS: Proteomic analysis of fibroblasts identified upregulation of multiple proteins involved in serine synthesis and thiol metabolism including: phosphoserine amino transferase (PSAT1), cystathionine beta synthase (CBS), and mercaptopyruvate sulfurtransferase (MPST). Metabolomics analysis of plasma revealed significantly increased levels of cystathionine and glutathione, central metabolites in thiol metabolism. CRISPR-edited MUT and PCCA HEK293 cells recapitulate primary defects of MMA and PA and have upregulation of transcripts associated with serine and thiol metabolism including PSAT1. 13C-glucose flux metabolomics in MUT and PCCA null HEK293 cells identified increases in serine de novo biosynthesis, serine transport, and abnormal downstream TCA cycle utilization. CONCLUSION: We identified abnormal serine metabolism as a novel area of cellular dysfunction in MMA and PA, thus introducing a potential new target for therapeutic investigation.