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1.
Orphanet J Rare Dis ; 14(1): 73, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940196

RESUMO

BACKGROUND: Most patients with isolated methylmalonic acidemia (MMA) /propionic acidemia (PA) presenting during the neonatal period with acute metabolic distress are at risk for death and significant neurodevelopmental disability. The nationwide newborn screening for MMA/PA has been in place in Taiwan from January, 2000 and data was collected until December, 2016. RESULTS: During the study period, 3,155,263 newborns were screened. The overall incidence of MMA mutase type cases was 1/121,356 (n = 26), 1 cobalamin B was detected and that for PA cases (n = 4) was 1/788,816. The time of referral is 8.8 days for MMA patients, and 7.5 days for PA patients. The MMA mutase type patients have higher AST, ALT, and NH3 values as well as a lower pH value (p < 0.05). The mean age for liver transplantation (LT) is 402 days (range from 0.6-6.7 yr) with 16 out of 20 cases (80.0%) using living donors. The mean admission length shortened from 90.6 days/year (pre-LT) to 5.3 days/year (at 3rd year post-LT) (p < 0.0005). Similarly, the tube feeding ratio decreased from 67.8 to 0.50% (p < 0.00005). The anxiety level of the caregiver was reduced from 33.4 to 27.2 after LT (p = 0.001) and the DQ/IQ performance of the patients was improved after LT from 50 to 60.1 (p = 0.07). CONCLUSION: MMA/PA patients with LT do survive and have reduced admission time, reduced tube feeding and the caregiver is less anxious.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Transplante de Fígado/normas , Acidemia Propiônica/fisiopatologia , Acidemia Propiônica/terapia , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/mortalidade , Cuidadores/psicologia , Cuidadores/estatística & dados numéricos , Nutrição Enteral/estatística & dados numéricos , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Recém-Nascido , Transplante de Fígado/mortalidade , Masculino , Mutação , Triagem Neonatal , Acidemia Propiônica/genética , Acidemia Propiônica/mortalidade , Taiwan , Resultado do Tratamento
2.
J Extra Corpor Technol ; 49(1): 64-66, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28298669

RESUMO

The usual indications for extra corporeal membrane oxygenation (ECMO) are for respiratory or cardiac failure. Although continuous renal replacement therapy (CRRT) is frequently used when patients are on ECMO, the need for CRRT as the primary indication for ECMO is rare. A case of a neonate placed onto veno-venous ECMO for the use of CRRT to treat hyperammonemia from propionic acidemia is presented.


Assuntos
Anastomose Cirúrgica/métodos , Oxigenação por Membrana Extracorpórea/métodos , Acidemia Propiônica/terapia , Terapia de Substituição Renal/métodos , Feminino , Humanos , Recém-Nascido , Resultado do Tratamento
3.
Pediatr Emerg Care ; 33(2): 142-146, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28141776

RESUMO

Inborn errors of metabolism (IEM) are genetic disorders that disrupt enzyme activity, cellular transport, or energy production. They are individually rare, but collectively have an incidence of 1:1000. Most patients with IEMs are followed by a physician with expertise in Biochemical Genetics (Metabolism), but may present outside of this setting. Because IEMs can present acutely with life-threatening crises that require specific interventions, it is critical for the emergency medicine physicians, pediatricians, internists, and critical care physicians as well as biochemical geneticists to be familiar with the initial assessment and management of patients with these disorders. Appropriate early care can be lifesaving. This protocol is not designed to replace the expert consultation of a biochemical geneticist but rather to improve early care and increase the level of comfort of the acute care physician with initial management of organic acidemias until specialty consultation is obtained.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/terapia , Acidemia Propiônica/terapia , Doença Aguda , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Gerenciamento Clínico , Humanos , Acidemia Propiônica/diagnóstico
4.
Liver Transpl ; 21(9): 1208-18, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25990417

RESUMO

Propionic acidemia (PA) and classical methylmalonic acidemia (MMA) are rare inborn errors of metabolism that can cause early mortality and significant morbidity. The mainstay of disease management is lifelong protein restriction. As an alternative, liver transplantation (LT) may improve survival, quality of life, and prevent further neurological deterioration. The aim of our study was to estimate the incremental costs and outcomes of LT versus nutritional support in patients with early-onset MMA or PA. We constructed a Markov model to simulate and compare life expectancies, quality-adjusted life years (QALYs), and lifetime direct and indirect costs for a cohort of newborns with MMA or PA who could either receive LT or be maintained on conventional nutritional support. We conducted a series of 1-way and probabilistic sensitivity analyses. In the base case, LT on average resulted in 1.5 more life years lived, 7.9 more QALYs, and a savings of $582,369 for lifetime societal cost per individual compared to nutritional support. LT remained more effective and less costly in all 1-way sensitivity analyses. In the probabilistic sensitivity analysis, LT was cost-effective at the $100,000/QALY threshold in more than 90% of the simulations and cost-saving in over half of the simulations. LT is likely a dominant treatment strategy compared to nutritional support in newborns with classical MMA or PA.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/economia , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Dieta com Restrição de Proteínas/economia , Transplante de Fígado/economia , Apoio Nutricional/economia , Acidemia Propiônica/economia , Acidemia Propiônica/terapia , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/mortalidade , Análise Custo-Benefício , Árvores de Decisões , Dieta com Restrição de Proteínas/efeitos adversos , Custos de Cuidados de Saúde , Humanos , Recém-Nascido , Transplante de Fígado/efeitos adversos , Transplante de Fígado/mortalidade , Cadeias de Markov , Modelos Econômicos , Apoio Nutricional/efeitos adversos , Acidemia Propiônica/diagnóstico , Acidemia Propiônica/mortalidade , Qualidade de Vida , Anos de Vida Ajustados por Qualidade de Vida , Fatores de Risco , Sobreviventes , Fatores de Tempo , Resultado do Tratamento
5.
Hum Gene Ther ; 26(3): 153-60, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25654275

RESUMO

Propionic academia (PA) occurs because of mutations in the PCCA or PCCB genes encoding the two subunits of propionyl-CoA carboxylase, a pivotal enzyme in the breakdown of certain amino acids and odd-chain fatty acids. There is no cure for PA, but dietary protein restriction and liver transplantation can attenuate its symptoms. We show here that a single intravenous injection of adeno-associated virus 2/8 (AAV8) or AAVrh10 expressing PCCA into PA hypomorphic mice decreased systemic propionylcarnitine and methyl citrate for up to 1.5 years. However, long-term phenotypic correction was always better in male mice. AAV-mediated PCCA expression was similar in most tissues in males and females at early time points and differed only in the liver. Over 1.5 years, luciferase and PCCA expression remained elevated in cardiac tissue for both sexes. In contrast, transgene expression in the liver and skeletal muscles of female, but not male, mice waned­suggesting that these tissues were major sinks for systemic phenotypic correction. These data indicate that single systemic intravenous therapy by AAV vectors can mediate long-term phenotype correction for PA. However, tissue-specific loss of expression in females reduces efficacy when compared with males. Whether similar sex-biased AAV effects occur in human gene therapy remains to be determined.


Assuntos
Biomarcadores/sangue , Terapia Genética/métodos , Vetores Genéticos/genética , Metilmalonil-CoA Descarboxilase/metabolismo , Acidemia Propiônica/genética , Acidemia Propiônica/terapia , Caracteres Sexuais , Animais , Carnitina/análogos & derivados , Carnitina/sangue , Citratos/sangue , Dependovirus , Feminino , Injeções Intravenosas , Fígado/metabolismo , Luciferases , Masculino , Metilmalonil-CoA Descarboxilase/genética , Camundongos , Músculo Esquelético/metabolismo , Acidemia Propiônica/sangue , Reação em Cadeia da Polimerase em Tempo Real
6.
Orphanet J Rare Dis ; 9: 130, 2014 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-25205257

RESUMO

Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC). MMA has an estimated incidence of ~ 1: 50,000 and PA of ~ 1:100'000 -150,000. Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture, leading to early death or to severe neurological handicap in many survivors. Mental outcome tends to be worse in PA and late complications include chronic kidney disease almost exclusively in MMA and cardiomyopathy mainly in PA. Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine. This may be related to under recognition and delayed diagnosis due to nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Acidemia Propiônica/diagnóstico , Acidemia Propiônica/terapia , Humanos , Guias de Prática Clínica como Assunto
7.
Hum Gene Ther ; 25(9): 837-43, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25046265

RESUMO

Propionic acidemia (PA) is an autosomal recessive inborn error of metabolism caused by deficiency of propionyl-CoA carboxylase (PCC). This enzyme is composed of six PCCA and six PCCB subunits and mediates a critical step in catabolism of odd chain fatty acids and certain amino acids. Current treatment options for PA are limited to stringent dietary restriction of protein consumption and some patients undergo elective liver transplantation. We previously generated a hypomorphic model of PA, designated Pcca(-/-)(A138T), with 2% of wild-type enzyme activity that mimics many aspects of the human disease. In this study, we used the differing tissue tropisms of adeno-associated virus (AAV) to probe the ability of liver or muscle-directed gene therapy to treat systemic aspects of this disease that affects many cell types. Systemic therapy with muscle-biased AAV1, liver-biased AAV8, and broadly tropic AAVrh10 mediated significant biochemical corrections in circulating propionylcarnitine (C3) and methyl citrate by all vectors. The innate tissue bias of AAV1 and AAV8 gene expression was made more specific by the use of muscle-specific muscle creatine kinase (specifically MCK6) and hepatocyte-specific transthyretin (TTR) promoters, respectively. Under these targeted conditions, both vectors mediated significant long-term correction of circulating metabolites, demonstrating that correction of muscle and likely other tissue types in addition to liver is necessary to fully correct pathology caused by PA. Liver-specific AAV8-TTR-PCCA mediated better correction than AAV1-MCK-PCCA. These data suggest that targeted gene therapy may be a viable alternative to liver transplantation for PA. They also demonstrate the effects of tissue-specific and broad gene therapy on a cell autonomous systemic genetic disease.


Assuntos
Biomarcadores/sangue , Dependovirus/genética , Terapia Genética/métodos , Vetores Genéticos/genética , Metilmalonil-CoA Descarboxilase/genética , Acidemia Propiônica/terapia , Tropismo Viral/fisiologia , Clonagem Molecular , Creatina Quinase/genética , Creatina Quinase/metabolismo , Dependovirus/fisiologia , Vetores Genéticos/administração & dosagem , Humanos , Fígado/metabolismo , Microscopia Confocal , Músculo Esquelético/enzimologia , Músculo Esquelético/metabolismo , Acidemia Propiônica/sangue , Acidemia Propiônica/genética , Tropismo Viral/genética
8.
Arq Bras Endocrinol Metabol ; 58(3): 237-42, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24863085

RESUMO

OBJETIVO: To evaluate the therapeutic agents used during metabolic crises and in long-term management of patients with propionic acidemia (PA). MATERIALS AND METHODS: The records of PA patients were retrospectively evaluated. RESULTS: The study group consisted of 30 patients with 141 admissions. During metabolic crises, hyperammonemia was found in 130 (92%) admissions and almost all patients were managed with normal saline, ≥ 10% dextrose, and restriction of protein intake. In 56 (40%) admissions, management was done in intensive care unit, 31 (22%) with mechanical ventilation, 10 (7%) with haemodialysis, 16 (11%) with vasopressor agents, and 12 (9%) with insulin. In the rescue procedure, L-carnitine was used in 135 (96%) patients, sodium bicarbonate in 116 (82%), sodium benzoate in 76 (54%), and metronidazole in 10 (7%), biotin in about one-quarter, L-arginine in one third, and antibiotics in three-quarter of the admissions. Blood/packed RBCs were used in 28 (20%) patients, platelets in 26 (18%), fresh frozen plasma in 8 (6%), and granulocyte-colony stimulating factors in 10 (7%) admissions. All patients were managed completely/partially with medical nutrition formula plus amino acid mixture, vitamins and minerals. For long-term management 24 (80%) patients were on L-carnitine, 22 (73%) on sodium benzoate, 6 (20%) on biotin, one half on alkaline therapy and 4 (13%) on regular metronidazole use. Almost all patients were on medical formula and regular follow-up. CONCLUSION: Aggressive and adequate management of acute metabolic crises with restriction of protein intake, stabilization of patient, reversal of catabolism, and removal of toxic metabolites are essential steps. Concerted efforts to ensure adequate nutrition, to minimize the risk of acute decompensation and additional therapeutic advances are imperative to improve the outcome of PA patients.


Assuntos
Acidemia Propiônica/terapia , Adolescente , Anti-Infecciosos/uso terapêutico , Biotina/uso terapêutico , Carnitina/uso terapêutico , Criança , Pré-Escolar , Dieta com Restrição de Proteínas , Feminino , Humanos , Hiperamonemia/sangue , Hiperamonemia/tratamento farmacológico , Lactente , Recém-Nascido , Assistência de Longa Duração , Masculino , Metronidazol/uso terapêutico , Terapia Nutricional , Acidemia Propiônica/diagnóstico , Estudos Retrospectivos , Benzoato de Sódio/uso terapêutico , Bicarbonato de Sódio/uso terapêutico , Complexo Vitamínico B/uso terapêutico
10.
Arq. bras. endocrinol. metab ; 58(3): 237-242, abr. 2014. tab
Artigo em Inglês | LILACS | ID: lil-709352

RESUMO

Objetivo : To evaluate the therapeutic agents used during metabolic crises and in long-term management of patients with propionic acidemia (PA).Materials and methods : The records of PA patients were retrospectively evaluated.Results : The study group consisted of 30 patients with 141 admissions. During metabolic crises, hyperammonemia was found in 130 (92%) admissions and almost all patients were managed with normal saline, ≥ 10% dextrose, and restriction of protein intake. In 56 (40%) admissions, management was done in intensive care unit, 31 (22%) with mechanical ventilation, 10 (7%) with haemodialysis, 16 (11%) with vasopressor agents, and 12 (9%) with insulin. In the rescue procedure, L-carnitine was used in 135 (96%) patients, sodium bicarbonate in 116 (82%), sodium benzoate in 76 (54%), and metronidazole in 10 (7%), biotin in about one-quarter, L-arginine in one third, and antibiotics in three-quarter of the admissions. Blood/packed RBCs were used in 28 (20%) patients, platelets in 26 (18%), fresh frozen plasma in 8 (6%), and granulocyte-colony stimulating factors in 10 (7%) admissions. All patients were managed completely/partially with medical nutrition formula plus amino acid mixture, vitamins and minerals. For long-term management 24 (80%) patients were on L-carnitine, 22 (73%) on sodium benzoate, 6 (20%) on biotin, one half on alkaline therapy and 4 (13%) on regular metronidazole use. Almost all patients were on medical formula and regular follow-up.Conclusion : Aggressive and adequate management of acute metabolic crises with restriction of protein intake, stabilization of patient, reversal of catabolism, and removal of toxic metabolites are essential steps. Concerted efforts to ensure adequate nutrition, to minimize the risk of acute decompensation and additional therapeutic advances are imperative to improve the outcome of PA patients. Arq Bras Endocrinol Metab. 2014;58(3):237-42.


Objetivo : Avaliar os agentes terapêuticos usados durante as crises metabólicas e para o manejo de longo prazo de pacientes com academia propiônica (AP).Materiais e métodos : Avaliação retrospectiva das fichas médicas de pacientes com AP.Resultados : O grupo estudado consistiu de 30 pacientes com 141 hospitalizações. Durante as crises metabólicas, a hiperamonemia foi observada em 130 (92%) pacientes hospitalizados e quase todos foram tratados com solução salina regular, ≥ 10% dextrose e restrição da ingestão de proteína. Em 56 (40%) das hospitalizações, o manejo foi feito na unidade de terapia intensiva, 31(22%) com ventilação mecânica, 10 (7%) com hemodiálise, 16 (11%) com vasopressores e 12 (9%) com insulina. Para o resgate, a L-carnitina foi usada em 135 (96%) pacientes, o bicarbonato de sódio em 116 (82%), o benzoato de sódio em 76 (54%), o metronidazole em 10 (7%), a biotina em cerca de um quarto, a L-arginina em um quarto e antibióticos em três quartos dos pacientes hospitalizados. Sangue/concentrado de hemácias foram usados em 28 (20%), plaquetas em 26 (18%), plasma fresco congelado em 8 (6%) e fatores estimulantes de colônias de granulócitos em 10 (7%) pacientes hospitalizados. Todos os pacientes foram manejados completamente/parcialmente com fórmula de nutrição hospitalar mais uma mistura de aminoácidos, vitaminas e minerais. Para o manejo de longo prazo, 24 (80%) dos pacientes foram tratados com L-carnitina, 22 (73%) com benzoato de sódio, 6 (20%) com biotina, a metade com tratamento alcalino e 4 (13%) com uso regular de metronidazole. Quase todos os pacientes foram tratados com fórmulas médicas e acompanhamento regular.Conclusão : O manejo adequado e agressivo de crises metabólicas com restrição da ingestão de proteína, ...


Assuntos
Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Acidemia Propiônica/terapia , Anti-Infecciosos/uso terapêutico , Biotina/uso terapêutico , Carnitina/uso terapêutico , Dieta com Restrição de Proteínas , Hiperamonemia/sangue , Hiperamonemia/tratamento farmacológico , Assistência de Longa Duração , Metronidazol/uso terapêutico , Terapia Nutricional , Acidemia Propiônica/diagnóstico , Estudos Retrospectivos , Benzoato de Sódio/uso terapêutico , Bicarbonato de Sódio/uso terapêutico , Complexo Vitamínico B/uso terapêutico
11.
J Inherit Metab Dis ; 37(1): 31-7, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23797949

RESUMO

BACKGROUND: Recurrent acute and life-threatening metabolic decompensations are thought to be the major cause of mortality and morbidity in patients with propionic acidemia (PA). Since metabolic decompensations in these patients usually develop gradually, there is considerable uncertainty about the beginning and when emergency treatment should be initiated. The major aim of this study was to evaluate the usefulness of biochemical parameters for improving decision-making on the start of emergency treatment. METHODS: We analysed data of 16 PA patients continuously followed in our centre. Metabolic decompensation was defined clinically by the occurrence of at least one of three alarming symptoms: vomiting, food refusal or impaired consciousness. Thirty-eight biochemical parameters were analysed. RESULTS: A total of 259 metabolic decompensations were documented and compared with 625 routine visits. Among the symptoms used to clinically define metabolic decompensations, vomiting was most frequent (87 %). In total, 19 biochemical parameters differentiated between metabolic decompensations and routine visits. Among them ammonia, acid-base balance and anion gap were most reliable to identify a metabolic decompensation, and to estimate its severity. A comparative analysis of patients with PA and methylmalonic acidemia during metabolic decompensation showed similar results. CONCLUSIONS: Ammonia, acid-base balance and anion gap are important biochemical parameters to identify an (impending) metabolic decompensation and to assess its severity in PA patients. The identified biochemical parameters should be integrated in an algorithm for clinical decision-making on emergency treatment and should be tested in a prospective trial.


Assuntos
Tomada de Decisões , Tratamento de Emergência , Acidemia Propiônica/sangue , Acidemia Propiônica/terapia , Equilíbrio Ácido-Base , Adolescente , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/sangue , Amônia/química , Apetite , Criança , Pré-Escolar , Técnicas de Apoio para a Decisão , Humanos , Propionatos/química , Acidemia Propiônica/diagnóstico , Inconsciência , Vômito , Adulto Jovem
12.
Ren Fail ; 36(3): 451-2, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24329397

RESUMO

Neonatal-onset propionic acidemia (PA), the most common form, is characterized by poor feeding, vomiting, and somnolence in the first days of life in a previously healthy infant, followed by lethargy, seizures, and can progress to coma if not identified and treated appropriately. It is frequently accompanied by metabolic acidosis with anion gap, ketonuria, hypoglycemia, hyperammonemia, and cytopenias. PA is caused by deficiency of propionyl-CoA carboxylase (PCC), the enzyme that catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA. Herein, we report a case of 3-day-old neonate with PA presented with acute renal failure and metabolic acidosis was effectively treated by peritoneal dialysis and conventional methods.


Assuntos
Lesão Renal Aguda/etiologia , Lesão Renal Aguda/terapia , Hiperamonemia/etiologia , Hiperamonemia/terapia , Acidemia Propiônica/complicações , Acidemia Propiônica/terapia , Terapia Combinada , Feminino , Humanos , Recém-Nascido , Diálise Peritoneal , Acidemia Propiônica/diagnóstico
13.
Mol Ther ; 21(7): 1316-23, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23648696

RESUMO

Propionic acidemia (PA) is a recessive genetic disease that results in an inability to metabolize certain amino acids and odd-chain fatty acids. Current treatment involves restricting consumption of these substrates or liver transplantation. Deletion of the Pcca gene in mice mimics the most severe forms of the human disease. Pcca(-) mice die within 36 hours of birth, making it difficult to test intravenous systemic therapies in them. We generated an adult hypomorphic model of PA in Pcca(-) mice using a transgene bearing an A138T mutant of the human PCCA protein. Pcca(-/-)(A138T) mice have 2% of wild-type PCC activity, survive to adulthood, and have elevations in propionyl-carnitine, methylcitrate, glycine, alanine, lysine, ammonia, and markers associated with cardiomyopathy similar to those in patients with PA. This adult model allowed gene therapy testing by intravenous injection with adenovirus serotype 5 (Ad5) and adeno-associated virus 2/8 (AAV8) vectors. Ad5-mediated more rapid increases in PCCA protein and propionyl-CoA carboxylase (PCC) activity in the liver than AAV8 and both vectors reduced propionylcarnitine and methylcitrate levels. Phenotypic correction was transient with first generation Ad whereas AAV8-mediated long-lasting effects. These data suggest that this PA model may be a useful platform for optimizing systemic intravenous therapies for PA.


Assuntos
Terapia Genética/métodos , Acidemia Propiônica/terapia , Animais , Dependovirus/genética , Modelos Animais de Doenças , Humanos , Metilmalonil-CoA Descarboxilase/genética , Metilmalonil-CoA Descarboxilase/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos
14.
Orphanet J Rare Dis ; 8: 6, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-23305374

RESUMO

BACKGROUND: Propionic acidemia is an inherited disorder caused by deficiency of propionyl-CoA carboxylase. Although it is one of the most frequent organic acidurias, information on the outcome of affected individuals is still limited. STUDY DESIGN/METHODS: Clinical and outcome data of 55 patients with propionic acidemia from 16 European metabolic centers were evaluated retrospectively. 35 patients were diagnosed by selective metabolic screening while 20 patients were identified by newborn screening. Endocrine parameters and bone age were evaluated. In addition, IQ testing was performed and the patients' and their families' quality of life was assessed. RESULTS: The vast majority of patients (>85%) presented with metabolic decompensation in the neonatal period. Asymptomatic individuals were the exception. About three quarters of the study population was mentally retarded, median IQ was 55. Apart from neurologic symptoms, complications comprised hematologic abnormalities, cardiac diseases, feeding problems and impaired growth. Most patients considered their quality of life high. However, according to the parents' point of view psychic problems were four times more common in propionic acidemia patients than in healthy controls. CONCLUSION: Our data show that the outcome of propionic acidemia is still unfavourable, in spite of improved clinical management. Many patients develop long-term complications affecting different organ systems. Impairment of neurocognitive development is of special concern. Nevertheless, self-assessment of quality of life of the patients and their parents yielded rather positive results.


Assuntos
Acidemia Propiônica/patologia , Adolescente , Criança , Pré-Escolar , Cognição , Feminino , Humanos , Lactente , Deficiência Intelectual , Masculino , Acidemia Propiônica/psicologia , Acidemia Propiônica/terapia , Desempenho Psicomotor , Qualidade de Vida , Estudos Retrospectivos , Resultado do Tratamento
16.
Ophthalmologe ; 109(12): 1211-3, 2012 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-22733289

RESUMO

Propionic acidemia (PA) is a rare autosomal recessive disorder resulting from deficiency of the biotin-dependent enzyme propionyl-CoA carboxylase, which is necessary for the catabolism of branched chain amino acids and odd-chain fatty acids. Although optic atrophy was documented in four cases, no glaucomatous optic atrophy has yet been described. This article describes the first case of a 12-year-old boy with PA showing bilateral glaucomatous optic disc atrophy due to dysgenetic changes of the angle of the anterior chamber.


Assuntos
Glaucoma/diagnóstico , Glaucoma/terapia , Procedimentos Cirúrgicos Oftalmológicos/métodos , Acidemia Propiônica/diagnóstico , Acidemia Propiônica/terapia , Procedimentos Cirúrgicos Reconstrutivos/métodos , Criança , Diagnóstico Diferencial , Glaucoma/congênito , Humanos , Masculino , Acidemia Propiônica/genética , Resultado do Tratamento
17.
Hum Mutat ; 33(6): 973-80, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22334403

RESUMO

Aminoglycosides and other compounds can promote premature termination codon (PTC) readthrough constituting a potential therapy for patients with nonsense mutations. In a cohort of 190 propionic acidemia (PA) patients, we have identified 12 different nonsense mutations, six of them novel, accounting for 10% of the mutant alleles. Using an in vitro system, we establish the proof-of-principle that nonsense mutations in the PCCA and PCCB genes encoding both subunits of the propionyl-CoA carboxylase (PCC) enzyme can be partially suppressed by aminoglycosides, with different efficiencies depending on the sequence context. To correct the metabolic defect, the amino acid incorporated at the PTC should support protein function, and this has been evaluated in silico and by in vitro expression analysis of the predicted missense changes, most of which retain partial activity, confirming the feasibility of the approach. In patients' fibroblasts cultured with readthrough drugs, we observe a fourfold to 50-fold increase in the PCC activity, reaching up to 10-15% level of treated control cells. The ability to partially correct nonsense PCCA and PCCB alleles represents a potential therapy or supplementary treatment for a number of propionic acidemia (PA) patients, encouraging further clinical trials with readthrough drugs without toxic effects such as PTC124 or other newly developed compounds. Hum Mutat 33:973-980, 2012. © 2012 Wiley Periodicals, Inc.


Assuntos
Códon sem Sentido , Metilmalonil-CoA Descarboxilase/genética , Acidemia Propiônica/genética , Aminoglicosídeos/farmacologia , Códon , Estudos de Coortes , Éxons , Fibroblastos/metabolismo , Humanos , Metilmalonil-CoA Descarboxilase/metabolismo , Mutação de Sentido Incorreto/efeitos dos fármacos , Acidemia Propiônica/metabolismo , Acidemia Propiônica/terapia
19.
Mol Genet Metab ; 105(1): 3-4, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21908219

RESUMO

In January 2011, Children's National Medical Center in Washington, D.C. hosted a consensus conference to discuss and develop recommendations for the diagnosis and management of propionic acidemia. Several resulting manuscripts from this conference are included in this issue. Topics covered include recommendations for acute management of metabolic decompensations, recommendations for chronic management and health monitoring, natural history of disease in patients with propionic acidemia, and neurologic complications in propionic acidemia.


Assuntos
Conferências de Consenso como Assunto , Acidemia Propiônica/terapia , Diretrizes para o Planejamento em Saúde , Humanos , Estudos Longitudinais , Acidemia Propiônica/diagnóstico
20.
Mol Genet Metab ; 105(1): 16-25, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22000903

RESUMO

Propionic acidemia or aciduria is an intoxication-type disorder of organic metabolism. Patients deteriorate in times of increased metabolic demand and subsequent catabolism. Metabolic decompensation can manifest with lethargy, vomiting, coma and death if not appropriately treated. On January 28-30, 2011 in Washington, D.C., Children's National Medical Center hosted a group of clinicians, scientists and parental group representatives to design recommendations for acute management of individuals with propionic acidemia. Although many of the recommendations are geared toward the previously undiagnosed neonate, the recommendations for a severely metabolically decompensated individual are applicable to any known patient as well. Initial management is critical for prevention of morbidity and mortality. The following manuscript provides recommendations for initial treatment and evaluation, a discussion of issues concerning transport to a metabolic center (if patient presents to a non-metabolic center), acceleration of management and preparation for discharge.


Assuntos
Acidemia Propiônica/terapia , Diretrizes para o Planejamento em Saúde , Humanos , Acidemia Propiônica/dietoterapia
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