Diagnosis is made by enzymatic and dna analysis after basic biochemical tests in plasma, urine, and csf. Symptoms can vary depending on the severity of the deficiency. Pc is a mitochondrial enzyme that provides the carboxylation of pyruvate to oxaloacetate 2. A patient with severe pyruvate carboxylase deficiency presented at age 11 weeks with metabolic decompensation after routine im munization. However, in contrast to other patients with this deficiency, no mental retardation was apparent. Pyruvate carboxylase deficiency constitutes a combined deficit in the tricarboxylic acid tca cycle and gluconeogenesis. A sixdayold girl was referred for severe hepatic failure, dehydratation, axial hypotonia, and both lactic acidosis and ketoacidosis. One example is red blood cells, which in a state of pyruvate kinase deficiency rapidly become deficient in atp and can undergo hemolysis. Iii detail with a report of a recent case and a discussion of the biochemical consequences. The french and north american phenotypes of pyruvate carboxylase deficiency, correlation with biotin containing protein by 3hbiotin incorporation, 35sstreptavidin labeling, and northern blotting with a cloned cdna probe. This complex plays an important role in the pathways that convert the energy from food into a form that cells can use. Feb 19, 2018 pubmed is a searchable database of medical literature and lists journal articles that discuss pyruvate dehydrogenase complex deficiency.
Jun 01, 2015 pyruvate carboxylase deficiency is an inherited disorder that causes lactic acid and other potentially toxic compounds to accumulate in the blood. Pyruvate carboxylase is an enzyme that is involved in gluconeogenesis and that adds bicarbonate to pyruvate to form oxaloacetate, a compound also involved in replenishing intermediates of the tricarboxylic acid cycle. Pyruvate carboxylase deficiency genetic and rare diseases. Symptoms of pyruvate carboxylase deficiency including 20 medical symptoms and signs of pyruvate carboxylase deficiency, alternative diagnoses, misdiagnosis, and correct diagnosis for pyruvate carboxylase deficiency signs or pyruvate carboxylase deficiency symptoms. Infantileonset pyruvate carboxylase deficiency a type is more common in the united states. Feb 18, 2016 pyruvate carboxylase deficiency is a rare disorder, with an approximate incidence of 1 in 250,000 births. The clinical presentation of pyruvate carboxylase deficiency consists of two major syndromes. Novel mutations in the pc gene in patients with type b.
Taner atilgan, fatma aslan, ruth brown, garry brown, erkin. Pyruvate carboxylase deficiency is inherited in an autosomal recessive manner. Dec 14, 2011 pyruvate carboxylase deficiency pcd is an autosomal recessive condition in which there is a defect on the gene locus 11q. Hence, pc flux is essential for tcacycledependent biosynthesis, including gluconeogenesis, and has additional roles in maintaining substrate oxidation, ureagenesis, redox state, and antioxidant capacity. Pyruvate carboxylase an overview sciencedirect topics. Pyruvate carboxylase deficiency new york clients tests displaying the status new york approved. Department of botany and microbiology, auburnuniversity, auburn, ala. Pdf pyruvate carboxylase pc is a biotincontaining mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate, thereby. However, in contrast to other patients with this deficiency. Pyruvate carboxylase april 18, 2005 summary pyruvate carboxylase catalyzes the carboxylation of pyruvate to oxaloacetate using atp and carbonate as cosubstrates. Respiratory chain defects usually result in lactate. Atkin bm, utter mf, weinberg mb 1979 pyruvate carboxylase and phosphoenol pyruvate carboxykinase activity in leukocytes and fibroblasts from a patient with pyruvate carboxylase deficiency. Pyruvate carboxylase and pyruvate dehydrogenase deficiency.
Enzymes involved in fatty acidcarbohydrate metabolism acetylcoa carboxylase acc propionylcoa carboxylase pcc methylcrotonylcoa carboxylase mcc pyruvate carboxylase pc carnitine acyltransferases ampactivated protein kinase ampksnf1 atpcitrate lyase acly malic enzyme me proteins involved in mrna processing andor pol ii. The oxaloacetate generated by the action of pyruvate carboxylase. Pyruvate carboxylase deficiency pc deficiency is a rare genetic disorder present at birth characterized by failure to thrive, developmental delay, recurrent seizures and a failure of the body to produce the necessary fuels for energy and neurotransmitters important for brain function. Pyruvate carboxylase pc deficiency omim 266150 is an autosomal recessive disorder that usually presents with lactic acidaemia and severe neurological dysfunction, leading to death.
The causes of congenital lactic acidaemia are outlined. The first report of pyruvate carboxylase deficiency involved an infant with. Pyruvate metabolism disorders childrens health issues. Cantley,1,2 fitsum guebreegziabher,2 ioana fat,2 blas guigni,2 michael j. Pc has crucial roles in gluconeogenesis, lipogenesis, glyceroneogenesis, and insulin secretion in mammals. The genes involved in pyruvate dehydrogenase deficiency each provide instructions for making a protein that is a component of a group of proteins called the pyruvate dehydrogenase complex.
Pyruvate carboxylase deficiency genetics home reference. The anaplerotic role of pyruvate carboxylase has been. Structure, function and regulation of pyruvate carboxylase. A deficiency of pyruvate carboxylase can cause lactic acidosis as a result of lactate build up. Researchers have identified at least three types of pyruvate carboxylase deficiency, which are distinguished by the severity of their signs. Pyruvate carboxylase deficiency with urea cycle impairment.
Please note, for carriertargeted variant tests the approval status depends on whether the gene is in an approved genedx singlegene. Click on the link to view a sample search on this topic. Pyruvate dehydrogenase deficiency can have different inheritance patterns. Carrier frequency was estimated to be as high as 1 in 10 in some groupings. Pyruvate carboxylase deficiency is a rare condition, with an estimated incidence of 1 in 250,000 births worldwide.
Pyruvate carboxylase deficiency pc deficiency is a rare genetic disorder present at birth characterized by failure to thrive, developmental delay, recurrent. A lack of this enzyme causes a very rare condition that interferes with or blocks the production of glucose from pyruvate in the body. Pc deficiency is caused by mutations in the pc gene 11q. As a key role of gluconeogenesis is in the maintenance of blood sugar, deficiency of pyruvate carboxylase can also lead to hypoglycemia. Pyruvate carboxylase pc deficiency is characterized in most affected individuals by failure to thrive, developmental delay, recurrent seizures.
Pyruvate carboxylase also participates in a wide range of other metabolic processes. Prenatal diagnosis of pyruvate carboxylase pc deficiency was performed in a family at risk for the acute neonatal form of this disease which manifests secondary citrullinemia. Pyruvate carboxylase was recently sequenced in corynebacterium glutamicum and shown to play an important role of anaplerosis in the central carbon metabolism and amino acid synthesis of these bacteria. Pc is responsible for the atpdependent carboxylation of pyruvate,yielding oxaloacetate. Biotinunresponsive pyruvate carboxylase deficiency type b was diagnosed. Although this patient succumbed to a severe infection, during the six. Pc is a mitochondrial matrix enzyme that converts bicarbonate and pyruvate to oxaloacetate, which is used by. Pyruvate metabolism disorders merck manuals consumer version. Pyruvate carboxylase deficiency nord national organization for.
Clinical manifestations are primarily lactic acidosis and severe neurological dysfunction although there is a wide spectrum of clinical phenotypes varying from lifethreatening neonatal lactic acidosis to relatively normal. Pyruvate carboxylase deficiency, on the other hand, is a true autosomal recessive disease, though it has high occurrences in particular ethnic groups, especially in algonkianspeaking amerindians. In 11 ojibwa and 2 cree patients with type a pyruvate carboxylase deficiency, carbone et al. The age of onset and severity of disease depends on the activity level of the pdc enzymes. An increased incidence has been documented among certain populations, most notably native north american indians who speak the algonquian dialect. Pyruvate carboxylase pc deficiency is a rare neurometabolic disorder characterized. Normally, excess pyruvate is shunted into gluconeogenesis via conversion of pyruvate into oxaloacetate, but because of the enzyme deficiency, excess pyruvate is converted into lactate instead. The severity and the clinical phenotypes vary, with a range from overwhelming neonatal lactic acidosis and early death to milder presentations. Pyruvate carboxylase deficiency nord national organization. Characterization of five novel pathogenic variants in pc and analysis of the genotypephenotype correlation emanuele g. Effect of pyruvate carboxylase overexpression on the. Pyruvate carboxylase and pyruvate dehydrogenase deficiency are the most common disorders in pyruvate metabolism and almost always affect the central nervous system.
Absence of pyruvate carboxylase pyruvate carboxylase deficiency pyruvate carboxylase is an enzyme. Treatment of pyruvate carboxylase deficiency with high doses of. Pyruvate kinase deficiency medical video hematopathology. Pyruvate carboxylase deficiency is an inherited disorder that causes lactic acid and other potentially toxic compounds to accumulate in the blood. This protocol describes a coupled enzyme assay for determining pyruvate carboxylase activity. High levels of these substances can damage the bodys organs and tissues, particularly in the nervous system. Leigh necrotizing encephalopathy due to pyruvate carboxylase deficiency. A patient with pyruvate carboxylase deficiency in the liver.
It is caused by deficiency of the pyruvate carboxylase enzyme, which is encoded by pc. Molecular genetics and metabolism semmelweis egyetem. Yes are approved or conditionally approved by new york state and do not require an nys npl exemption. This means that both copies of the diseasecausing gene in each cell usually one inherited from each parent must have a mutation for an individual to be affected. Pdf prenatal diagnosis of pyruvate carboxylase deficiency.
Targeting pyruvate carboxylase reduces gluconeogenesis and adiposity and improves insulin resistance naoki kumashiro,1,2 sara a. Pyruvate carboxylase pc is a biotincontaining mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate, controls the first step in hepatic gluconeogenesis, and is involved in lipogenesis fig. Pyruvate dehydrogenase has three main subunits, an additional e3binding protein and two complex regulatory enzymes. The diagnosis of an affected child was confirmed by enzyme assay and 3 h.
Pyruvate ratio may indicate inherited disorders of the respiratory chain complex, tricarboxylic acid cycle disorders and pyruvate carboxylase deficiency. Original article targeting pyruvate carboxylase reduces. An underestimated cause of lactic acidosis article pdf available in molecular genetics and metabolism reports 2c march 2015 with 806 reads how we measure. The reported clinical spectrum includes a neonatal form. Pyruvate carboxylase deficiency pcd is caused by biallelic mutations of the pc gene. Molecular characterization of pyruvate carboxylase deficiency. Two brothers of micmac origin had a transversion mutation in the pc gene 608786. Pyruvate carboxylase pc catalyzes the biotindependent carboxylation of pyruvate to produce oxaloacetate. P ratio disproportionately elevated pyruvic acid may indicate an inherited disorder of pyruvate metabolism.
The list of signs and symptoms mentioned in various sources for pyruvate carboxylase deficiency includes the 20 symptoms listed below. Aug 09, 2016 pyruvate carboxylase pc deficiency is a rare disorder that can cause developmental delay and failure to thrive starting in the neonatal or early infantile period. Carriers typically do not have any signs or symptoms of the condition. The protein is encoded by the pc gene and is in an indispensable position both. Triheptanoin, an oddcarbon triglyceride, was administrated as a source for acetylcoa and anaplerotic propionylcoa. This enzyme is mitochondrial in location and catalyzes the conversion of pyruvate to oxaloacetate in a biotindependent manner chaps. Pyruvate carboxylase deficiency genetics home reference nih.
In this study we investigate the effect of the overexpression of the gene for pyruvate carboxylase pyc on the physiology of c. Pyruvate carboxylase pc is a biotincontaining mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate, thereby being involved in. The acmg act sheets and their accompanying algorithms are a great resources for health care providers looking for information on genetic conditions identified through newborn screening and beyond to help inform clinical decision making. Pyruvate dehydrogenase complex deficiency genetic and rare. The pdha1 gene is located on the x chromosome, which is one of the two sex chromosomes. Pyruvate carboxylase pc deficiency is a rare disorder that can cause developmental delay and failure to thrive starting in the neonatal or early. Pyruvate carboxylase deficiency is an inherited disorder that causes lactic acid to accumulate in the blood. Therefore, pyruvate kinase deficiency can cause hemolytic anemia and an. Defects of the pyruvate dehydrogenase complex result in l. Pyruvate dehydrogenase complex deficiency nord national. Pyruvate dehydrogenase and pyruvate carboxylase deficiency are the most common disorders in pyruvate metabolism. When the condition is caused by mutations in the pdha1 gene, it is inherited in an xlinked pattern. Other causes of defective pyruvate carboxylation are described, particularly the combined carboxylase defects. In males, who have only one x chromosome, a mutation in the only copy of the gene in each cell is sufficient to cause the condition.
Pc deficiencies are linked to lactic acidemia, hypoglycemia, and other diseases. Pyruvatecarboxylase deficiency with urea cycle impairment. Pyruvate dehydrogenase complex deficiency pdcd is a rare disorder of carbohydrate metabolism caused by a deficiency of one of the three enzymes in the pyruvate dehydrogenase complex pdc. Molecular characterization of pyruvate carboxylase. Therefore, pyruvate kinase deficiency can cause hemolytic anemia and an increase in plasma bilirubin.
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