RESUMO
Pyruvate carboxylase (PC) deficiency is a rare autosomal recessive disease and provides clinics in three essential phenotypes. Type B PC deficiency is characterized by lactic acidosis and hyperammonemia. We report a Turkish patient who was diagnosed with type B PC deficiency. Despite the application of anaplerotic treatment with biotin, citrate and arginine-aspartate, continuous veno-venous hemodialysis (CVVHD) treatments were applied due to the failure to keep hyperammonemia and lactic acidosis under control. Ammonia values increasing to 860 µmol/L were observed. A homozygous novel variant was detected in PC gene analyses containing a 12-base pair deletion on exon 8. Although the mutation found was not reported previously, it was accepted as a pathogenic variant due to its presence in a functional region of the protein. In type B PC deficiency, although a high level of ammonia is expected, it rarely exceeds 200 µmol/L. As far as we know, the present case has the highest ammonia values in the literature. This paper has been shared to highlight to keep PC deficiency in mind regarding the differential diagnosis of hyperammonemia, particularly in the presence of lactic acidosis, and to serve as a model for the use of different modalities in the management process of PC deficiency.
Assuntos
Encefalopatias Metabólicas/tratamento farmacológico , Hiperamonemia/tratamento farmacológico , Mutação , Doença da Deficiência de Piruvato Carboxilase/complicações , Piruvato Carboxilase/genética , Encefalopatias Metabólicas/etiologia , Encefalopatias Metabólicas/patologia , Gerenciamento Clínico , Humanos , Hiperamonemia/etiologia , Hiperamonemia/patologia , Recém-Nascido , Masculino , Apoio Nutricional , Prognóstico , Piruvato Carboxilase/metabolismo , Diálise RenalRESUMO
Pyruvate carboxylase (PC) is a biotin-containing enzyme that is responsible for the adenosine triphosphate-dependent carboxylation of pyruvate to oxaloacetate, a key intermediate in the tricarboxylic acid cycle. PC deficiency (OMIM 266150) is a rare autosomal recessive metabolic disease, causing elevation of pyruvate, lactate, and alanine. Three types of PC deficiency have been described in the literature; A, B, and C. Type A PC deficiency, also called infantile or North American type, is characterized by infantile onset acidosis, failure to thrive, and developmental delay. The second subtype or type B, the neonatal or French form, presents usually in the neonatal period, mostly in the first 72 hours of life with severe lactic acidosis, truncal hypotonia, and seizures. The third type is called type C, is extremely rare with few cases published in the literature. In this case report, we present an 11-month-old girl who presented with acute flaccid paralysis, lethargy, and constipation with elevated ketones and lactate. She was confirmed genetically and biochemically to have PC deficiency type C. The patient's unusual presentation expands the clinical phenotype of this extremely rare disease.
Assuntos
Acidose Láctica/diagnóstico , Cetose/diagnóstico , Paraplegia/diagnóstico , Doença da Deficiência de Piruvato Carboxilase/diagnóstico , Acidose Láctica/etiologia , Constipação Intestinal/diagnóstico , Constipação Intestinal/etiologia , Feminino , Humanos , Lactente , Cetose/etiologia , Letargia/diagnóstico , Letargia/etiologia , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/etiologia , Paraplegia/etiologia , Fenótipo , Doença da Deficiência de Piruvato Carboxilase/complicaçõesRESUMO
OBJECTIVE: Pyruvate carboxylase (PC) deficiency is a rare metabolic disease. Recently, therapeutic possibilities have been introduced. We aimed to report the largest series of the B type of PC deficiency, focusing on some neurological aspects that have not yet been documented. METHODS: We retrospectively studied nine patients with the severe neonatal form of PC deficiency diagnosed in our hospital. Detailed clinical features, brain imaging, biochemical characteristics, and global outcome are reported. RESULTS: All patients had axial hypotonia and tachypnea during the first hours of life. The initial level of consciousness was preserved in most patients. Abnormal movements (high-amplitude tremor and hypokinesia) and bizarre ocular behavior were the most common findings, whereas epilepsy was infrequent. Brain magnetic resonance imaging mostly disclosed cystic periventricular leukomalacia. Hypoglycemia, lactic acidosis, and hypercitrullinemia were invariably found. Hyperammoniemia, hypernatremia, and high proline and lysine were frequently detected. A rapid fatal outcome was observed in most patients. INTERPRETATION: Clinical and biochemical characteristics of this deficiency are highly suggestive. Abnormal movements such as rigidity and hypokinesia (hypokinetic-rigid syndrome) are an important hallmark and may orientate to PC deficiency when associated with severe lactic acidosis.
Assuntos
Doenças do Sistema Nervoso , Doença da Deficiência de Piruvato Carboxilase , Aminoácidos/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/fisiopatologia , Doença da Deficiência de Piruvato Carboxilase/complicações , Doença da Deficiência de Piruvato Carboxilase/fisiopatologia , Estudos Retrospectivos , Convulsões/fisiopatologiaAssuntos
Erros Inatos do Metabolismo/complicações , Espasmos Infantis/etiologia , Diagnóstico Diferencial , Humanos , Hiperglicinemia não Cetótica/complicações , Lactente , Recém-Nascido , Síndrome dos Cabelos Torcidos/complicações , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/terapia , Doenças Mitocondriais/complicações , Fenilcetonúrias/complicações , Prognóstico , Doença da Deficiência de Piruvato Carboxilase/complicações , Piruvato Desidrogenase (Lipoamida)/deficiência , Espasmos Infantis/diagnóstico , Espasmos Infantis/terapiaRESUMO
Pyruvate carboxylase deficiency, complex form, presents in early infancy with lethal metabolic acidosis, resulting from ketoacidosis and lactic acidemia. Renal tubular acidosis, hyperammonemia, and citrullinemia complete the picture. In an infant with this disease, large amounts of glucose ameliorated the ketoacidosis, but worsened the lactic acidosis. Orthotopic hepatic transplantation completely reversed the ketoacidosis and the renal tubular abnormality and ameliorated the lactic acidemia. Concentrations of glutamine in cerebrospinal fluid were low and did not improve with liver transplantation.
Assuntos
Transplante de Fígado , Doença da Deficiência de Piruvato Carboxilase/metabolismo , Doença da Deficiência de Piruvato Carboxilase/cirurgia , Acidose Tubular Renal/etiologia , Citrulinemia/etiologia , Glucose/administração & dosagem , Glutamina/líquido cefalorraquidiano , Humanos , Hiperamonemia/etiologia , Lactente , Ácido Láctico/sangue , Masculino , Doença da Deficiência de Piruvato Carboxilase/complicações , Doença da Deficiência de Piruvato Carboxilase/tratamento farmacológicoRESUMO
Seizures and metabolic disease are frequently associated, either indirectly as a consequence of the metabolically caused brain dysgenesis or directly by the metabolic derangement. This article describes defects in pyruvate metabolism (pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency) and Krebs cycle defects such as fumarase deficiency. Clinical characterizations and diagnostic strategies have been developed for each of these diseases. In contrast, very little is known about the specific epileptic features in these disorders. In females with a pyruvate dehydrogenase deficiency E1alpha owing to the mutation in the subunit E1alpha of the pyruvate dehydrogenase complex West's syndrome associated with large ventricles and corpus callosum agenesis on magnetic resonance imaging can be the main feature of the disease. In fumarase deficiency, prenatal brain dysgenesis is the most prominent feature of the disease. Diagnosis of these disorders requires measurements of lactate and pyruvate in plasma and cerebrospinal fluid, analysis of amino acids in plasma and organic acids in urine, and neuroradiologic investigations. Further biochemical and molecular analysis leads to a definitive diagnosis and opens the way to adequate treatment, genetic counseling, and prenatal diagnosis.
Assuntos
Encéfalo/anormalidades , Ciclo do Ácido Cítrico/fisiologia , Fumarato Hidratase/deficiência , Doença da Deficiência de Piruvato Carboxilase/diagnóstico , Doença da Deficiência do Complexo de Piruvato Desidrogenase/diagnóstico , Ácido Pirúvico/metabolismo , Diagnóstico Diferencial , Humanos , Imageamento por Ressonância Magnética , Doença da Deficiência de Piruvato Carboxilase/complicações , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Doença da Deficiência do Complexo de Piruvato Desidrogenase/dietoterapia , Convulsões/etiologia , Fatores SexuaisRESUMO
OBJECTIVE: To report the clinical history and laboratory evaluation of a patient presenting with lactic acidosis secondary to pyruvate carboxylase deficiency. METHODS AND RESULTS: Enzyme analysis of cultured skin fibroblasts revealed 2-5% of normal pyruvate carboxylase activity. Although most patients with this condition die in early infancy, this child has survived to age 8-1/2 years, with only occasional episodes of metabolic acidosis, usually responding rapidly to intravenous hydration and bicarbonate. Despite having a seizure disorder and moderate mental retardation, he continues to thrive and make progress in his acquisition of motor and language skills. Of the 35 patients described in the literature with pyruvate carboxylase deficiency, only two other patients have lived beyond 5 years of age. CONCLUSION: There does not seem to be a correlation of prolonged survival with residual pyruvate carboxylase activity on assay of cultured fibroblasts. Possible explanations for this patient's prolonged survival include tissue heterogeneity, increased residual enzyme activity in vivo, or partial stabilization of the enzyme by supplemental biotin.
Assuntos
Fibroblastos/enzimologia , Doença da Deficiência de Piruvato Carboxilase/enzimologia , Acidose Láctica/complicações , Adulto , Alanina/sangue , Células Cultivadas , Criança , Pré-Escolar , Feminino , Fibroblastos/patologia , Humanos , Lactatos/análise , Ácido Láctico , Masculino , Doença da Deficiência de Piruvato Carboxilase/complicações , Doença da Deficiência de Piruvato Carboxilase/diagnósticoAssuntos
Acidose Láctica/etiologia , Lactatos/sangue , Erros Inatos do Metabolismo/complicações , Acidose Láctica/sangue , Adulto , Criança , Ciclo do Ácido Cítrico , Feminino , Gluconeogênese , Glicogênio/metabolismo , Humanos , Recém-Nascido , Ácido Láctico , Masculino , Mitocôndrias/metabolismo , Doença da Deficiência de Piruvato Carboxilase/complicações , Piruvatos/metabolismoRESUMO
Pyruvate carboxylase deficiency results in congenital lactic acidosis. We report the significant finding in a child with infantile spasms controlled with adrenocorticotrophin hormone (ACTH) but who then developed severe lactic acidosis; pyruvate carboxylase deficiency was subsequently diagnosed. Blood lactate, pyruvate, and alanine levels were elevated, as well as cerebrospinal fluid alanine. Plasma alanine concentration was doubled by ACTH therapy. Fibroblasts contained extremely low pyruvate carboxylase activity. The patient died at 12 weeks of age after recurrent episodes of profound acidosis. At autopsy, the brain manifested cystic degeneration and demyelination. Pyruvate carboxylase deficiency is associated with neonatal onset of acidosis, delayed development, seizures, hypotonia, recurrent profound acidosis, and early death. The dramatic rise in plasma alanine content coincident with ACTH therapy suggest that ACTH played a role in precipitating the catastrophic metabolic acidosis.