Pyruvate carboxylase deficiency

Barry Wolf MD PhD

Neurogenetic Disorders

Updated 11.09.2024
Released 03.30.1995
Expires For CME 11.09.2027

Pyruvate carboxylase deficiency

Author: Barry Wolf MD PhD

See Contributor Disclosures

Pyruvate carboxylase deficiency

In This Article

Quick Link

Introduction

Overview

The author explains that a child with type B pyruvate carboxylase deficiency exhibited infantile parkinsonism and GABAergic hypotransmission.

Key points

	• Pyruvate carboxylase deficiency, an inherited metabolic disorder, usually presents during infancy or early childhood with metabolic acidosis and hypoglycemia.
	• Some individuals with pyruvate carboxylase deficiency can exhibit mild symptoms, whereas others have severe symptoms; the variability in symptoms appears to be based on the nature of their enzyme defect.
	• Although pyruvate carboxylase is a biotin-dependent enzyme, individuals with the disorder do not usually respond to biotin therapy.
	• Pyruvate carboxylase deficiency may be treated with thiamine and increased glucose, especially when experiencing severe metabolic crises. Various other supplements and interventions are used to treat the disorder with varying success.

Historical note and terminology

Hommes and colleagues reported a patient with pyruvate carboxylase deficiency and Leigh syndrome (34). This association, however, was not confirmed by later studies.

A child with intermittent lactic acidosis, profound mental and motor retardation, hypoglycemia, hyperpyruvic acidemia, and hyperalaninemia was the first to be reported with the North American phenotype (12). In 1976, two siblings with neonatal congenital lactic acidosis and pyruvate carboxylase deficiency were described (62). They were the first patients reported with the French phenotype of pyruvate carboxylase deficiency. Since then, more than 30 children with pyruvate carboxylase deficiency have been reported.

Clinical manifestations

Presentation and course

The various clinical features and treatments of individuals with pyruvate carboxylase have been reviewed (79). Approximately half of the patients with pyruvate carboxylase deficiency were severely ill in the neonatal period and died within the first 4 months of life (French phenotype or Type A) (62; 17; 77; 07; 58; 60; 28; 55; 84; 46; 61; 20). The other half of the patients had clinical symptoms during infancy (North American phenotype or Type B) (12; 42; 21; 74; 67; 05; 04; 59; 58; 30; 50; 69; 53). Several children with a mild or benign variant of pyruvate carboxylase deficiency have been reported (75; 29; 33; 03). These children have mild clinical and metabolic problems, and one child even had normal development.

Patients with the Type B or French phenotype are usually normal at birth. After 3 to 48 hours they become acutely ill with hypothermia, hypotonia, lethargy, and vomiting. The majority of them die in the neonatal period. Some survive for several weeks. They are, however, unresponsive and severely hypotonic and die before the age of 5 months, usually from respiratory abnormalities. However, one child who survived the neonatal period with lactic acidemia is now 9 years old and has only mild developmental delay (63). One affected child exhibited infantile parkinsonism and GABAergic hypotransmission (51). An individual with type B disease was under poor control, and his ammonia increased to 860 µmol/L (37). He was homozygous for a novel 12-base pair deletion in exon 8.

Patients with the North American phenotype become severely ill between 2 and 5 months of age. In some of these patients, symptoms are noticed at birth and include hypotonia, feeding difficulties, failure to thrive, convulsions, and respiratory difficulties. Initially, development is normal, but delays soon become obvious. Patients become progressively hypotonic, unaware of their surroundings, and unable to smile or support their head. They consistently have numerous episodes of acute vomiting, dehydration, tachypnea, facial pallor, and cold cyanotic extremities, characteristically precipitated by metabolic acidosis or infectious stress. Pyramidal tract signs, ataxia, and nystagmus are observed. Mental retardation is evident in all patients. Convulsions complicate the clinical picture in several patients. Funduscopic examination reveals no abnormalities. The course of the disease is generally progressive, and most patients die in infancy.

Several children with pyruvate carboxylase deficiency have had milder clinical courses (75; 66; 29; 33; 03). The oldest of these children is about 10 years old. Some have exhibited neurologic symptoms, whereas others have shown normal development with few metabolic abnormalities. These patients will probably be found to have missense gene mutations.

In the largest series of nine children with pyruvate carboxylase deficiency (Type B), all exhibited axial hypotonia and tachypnea at birth. Tremors and hypokinesis were observed in most children, whereas seizures were uncommon. Hypoglycemia, lactic acidosis, hyperammonemia, hypernatremia, and elevated concentrations of citrulline, proline, and lysine were common (78). These children had cystic periventricular leukomalacia. Most of these children died despite rigorous therapy (27). A child who was initially diagnosed as having hypoxic-ischemic encephalopathy in the newborn period was subsequently diagnosed as having pyruvate carboxylase deficiency (87).

Individuals with pyruvate carboxylase deficiency were classified by their clinical phenotypes as having the infantile form (Type A), the neonatal form (Type B), and the benign form (Type C) (80; 79). These patients, one with Type A, five with Type B, and two with Type C, had a variety of mutations, including eight novel complex mutations. These phenotypic designations correlated poorly with outcomes. Moreover, mosaicism was found in five of these patients; four of them had prolonged survival, and the fifth died of medical complications. This report further emphasizes that the clinical phenotype classifications are probably of little practical value. The clinical characteristics of these various types of pyruvate carboxylase deficiencies have been reviewed (43). Novel variants in individuals with type A and type C, together with previously reported individuals, were studied to evaluate genotype-phenotype correlations and found some possible explanations for their differences (15). A 4-year-old female presented with what appeared to be diabetic ketoacidosis with metabolic acidosis, Kussmaul breathing, hyperglycemia, and ketonemia and was subsequently shown to have pyruvate carboxylase deficiency type C (22). An infant with Type B pyruvate carboxylase deficiency was delivered after exhibiting widened posterior horns of lateral ventricles, huge subependymal cysts, and increased biparietal diameter and head circumference prenatally (86).

Prognosis and complications

Pyruvate carboxylase deficiency is associated with invariably fatal outcomes in patients with the French phenotype and the North American phenotype. In the former, patients usually die in the neonatal period, whereas in the latter, during infancy. Two patients, initially symptomatic at 2 and 5 months, survived until 5 years of age (58), and another was 7 years and 9 months old when he died (67). A patient with a benign variant had normal mental and motor development. Despite several episodes of metabolic acidosis, she continues to be in good general health at the age of 7 years. The outcome of children with pyruvate carboxylase deficiency is variable and may positively correlate with the severity of the initial clinical presentation (18). A patient with Type C exhibited transient flaccid paralysis with ketoacidosis (02).

Clinical vignette

A 3-day-old male infant exhibited respiratory distress, lethargy, hypotonia, and myoclonic seizures. He had severe ketolactic acidosis, hyperammonemia, and hypoglycemia. He also had a markedly elevated plasma lactate and lactate-pyruvate ratio. Urinary organic acids showed elevated lactate, pyruvate, and 3-OH-butyrate as well as increased excretion of alpha-ketoglutarate. Plasma 3-OH-butyrate was increased, and the ratio of 3-OH-butyrate to acetoacetate was decreased. Plasma amino acid analysis was normal except for a mild elevation of alanine. Based on these results, a diagnosis of pyruvate carboxylase deficiency was considered, and the child was treated with biotin and glucose infusions. However, he continued to deteriorate rapidly and exhibit seizures that failed to respond to anticonvulsive medications. He died at 10 days of age. A liver sample obtained at autopsy had undetectable pyruvate carboxylase activity, thereby confirming the diagnosis of pyruvate carboxylase deficiency.

Biological basis

Etiology and pathogenesis

The disease is caused by defects in pyruvate carboxylase. The disorder is inherited as an autosomal recessive trait.

Pyruvate carboxylase (pyruvate:CO² ligase; E.C. 6.4.1.1) catalyzes the formation of oxaloacetate from pyruvate and bicarbonate at the expense of ATP (72). The molecular mechanism of this multifunctional enzyme has been elucidated (45). Pyruvate carboxylase is localized in the mitochondrial matrix (83; 09). Pyruvate carboxylase and the other mitochondrial carboxylases are rapidly biotinylated in the cytosol before transfer into mitochondria (35). It has an important gluconeogenic, anaplerotic, and lipogenetic role. In the last step of glycolysis, phosphoenolpyruvate is converted to pyruvate, but the reverse reaction cannot be used for gluconeogenesis. Pyruvate must first be carboxylated with the formation of oxaloacetate. Because the latter cannot diffuse freely out of the mitochondrion, oxaloacetate is reduced to malate, which reaches the cytoplasm using the malate/aspartate shuttle. Malate is reoxidized to oxaloacetate, which now can be converted to phosphoenolpyruvate by phosphoenolpyruvate carboxykinase and can be used for further gluconeogenesis. Pyruvate carboxylase controlling the first step of gluconeogenesis has an important regulating role (24). Important organs for gluconeogenesis are the liver and kidney. The anaplerotic role of pyruvate carboxylase is even more important than the gluconeogenic role. The cell can increase the capacity of the Krebs cycle by increasing the concentration of Krebs cycle intermediates that function as carrier molecules. By converting pyruvate, an easily available substrate, to oxaloacetate, pyruvate carboxylase becomes the most important anaplerotic enzyme. Acetyl-CoA functions as the signal. When Krebs cycle capacity is too low, acetyl-CoA will accumulate and activate pyruvate carboxylase, which increases production of oxaloacetate. In case of severe pyruvate carboxylase deficiency, there will be a lack of Krebs cycle intermediates, resulting in a low concentration of reducing equivalents in the mitochondrial matrix. This will cause a shift of the redox equilibrium between 3-OH-butyrate and acetoacetate into the direction of the latter, and the ratio of 3-OH-butyrate to acetoacetate will be decreased (21). There also will be a shortage of aspartate because aspartate is formed in the mitochondrial matrix from oxaloacetate by a transamination reaction. As a consequence, the malate/aspartate shuttle, which normally serves as an import mechanism of reducing equivalents from the cytoplasm into the mitochondrial matrix, will be impaired. The result is that in the cytoplasm the redox equilibrium between lactate and pyruvate will be driven into the direction of the former. The ratio of lactate to pyruvate will be increased.

Pyruvate carboxylase is also important for lipogenesis (40). Fatty acids are synthesized in the cytoplasm from acetyl-CoA. Intramitochondrially produced acetyl-CoA cannot freely diffuse to the cytoplasm. By the action of citrate synthase, acetyl-CoA is ligated to oxaloacetate with formation of citrate that can be translocated to the cytoplasm where it is cleaved to oxaloacetate and acetyl-CoA. Intramitochondrially formed oxaloacetate can also be converted to malate, which shuttles to the cytoplasm where it generates reducing equivalents necessary for lipid synthesis. The lipogenetic role of pyruvate carboxylase, thus, consists in producing oxaloacetate. The increased demand of lipogenesis is associated with increasing concentration of pyruvate carboxylase mRNA (26). Important lipogenetic tissues are liver, adipose tissue, lactating mammary gland, adrenal gland, and brain.

Pyruvate carboxylase has been purified from liver (64). The complex has a molecular weight of 500 kDa. It is a tetramer composed of four identical subunits (72). The molecular weight of the subunit is 130 kDa (06). The subunit protein is encoded in the nucleus. Following its synthesis in the cytoplasm it is imported into the mitochondrial matrix. To be catalytically active the pyruvate carboxylase subunits must form a tetramer. More than half of the patients with the French phenotype had absence of pyruvate carboxylase protein and of the corresponding mRNA. Patients with the North American phenotype generally had cross-reacting material (CRM-positive) (58; 57), as did the patient with the benign variant of pyruvate carboxylase deficiency (75).

The full-length cDNA of human pyruvate carboxylase has been cloned and sequenced by two groups (41; 81). The coding sequence is 3534 bp and is flanked by an 82 bp 5’ untranslated sequence and a 389 bp 3’ untranslated sequence excluding the poly-A tail. The translated amino acid sequence is 1178 residues and contains a biotin attachment site and ATP and pyruvate binding sites. The full-length mature protein is 127,370 Da. The first 20 residues constitute the mitochondrial signal peptide sequence that is cleaved off after translocation of the protein into the mitochondrial matrix. The sequence 198–203 is probably part of the ATP-binding site and the 618-626 sequence is located at or near the pyruvate-binding site of the enzyme. Biotin is covalently attached to an epsilon amino group of a lysine located 35 residues from the carboxyl terminus of the protein (25; 38). Twenty-six amino acids more proximal from this lysine residue is a "Pro-Met-Pro" sequence, important for the "flip-flop" movement of the biotin-bearing arm, necessary for transferring the CO2-group toward pyruvate (85). The highest level of carboxylase mRNA is in liver (81). The gene for pyruvate carboxylase is located on the long arm of human chromosome 11 (25).

Multiple different mutations have been identified in the pyruvate carboxylase gene that causes pyruvate carboxylase deficiency (57; 81; 82; 14; 13; 48; 52; 31; 65; 68; 88). Mutations in the Type A form appear to be more severe, with deletions resulting essentially in no enzyme activity (82), and those in the Type B form are missense mutations resulting in residual enzyme activity (14; 13). There is a diverse spectrum of variants, including intronic variants, that have been found to cause pyruvate carboxylase deficiency (70). However, a study described an individual homozygous for a missense mutation that causes a severe form of type B deficiency (52). In addition, their studies did not find recurrent mutations among individuals from Turkey where there is a high degree of consanguinity.

An individual with pyruvate carboxylase deficiency was shown to have nemaline rods on muscle biopsy (71). This was speculated to be due to cellular energy shortage and altered energy metabolism of pyruvate.

A report summarizes the neurologic findings in pyruvate carboxylase deficiency and compares them to those of pyruvate dehydrogenase deficiency and disorders of the Krebs cycle (19). Only a few detailed neuropathological descriptions were reported in the literature. The brain of one patient with the French phenotype was examined by G Lyon (62). Widespread diffuse and symmetrical demyelination of the cerebral and cerebellar white matter and symmetrical periventricular cavities around the frontal and temporal horns of the lateral ventricles and between the dentate nuclei and the fourth ventricle were found. Gray structures were normal. One patient with the North American phenotype had mildly enlarged lateral ventricles and a reduction in the amount of the cerebral white matter, particularly in the corpus callosum (04). Microscopic examination disclosed a severe depletion of neurons in the cerebral cortex, numerous ectopic neurons in the white matter, and ectopic glia in the subarachnoid space. Myelin was poorly formed in a bilaterally symmetrical distribution in the cerebral and cerebellar hemisphere. In addition, there were accumulations of macrophages in the perivascular spaces of white matter, subependymal gliosis, and hyperplasia of protoplasmatic astrocytes in cortical structures. Microscopic examination of the liver revealed steatosis with preserved hepatic lobular architecture (04). Examination of the kidney showed diffuse vacuolation of the distal renal tubules.

Magnetic resonance imaging of a 20-month-old boy revealed leukodystrophy of the brainstem and the subcortical white matter (32). A brother and sister with the disorder were both born with macrocephaly and severe ischemic-like lesions of the brain (11). Periventricular leukomalacia was found on fetal ultrasonography. Both died in the first week of life. Another child with the French-type disease had periventricular cysts and diffuse hypomyelination (54). He died at 6 months of age. In a subsequent pregnancy, periventricular cysts were seen on fetal ultrasonography. Finding periventricular cysts on fetal ultrasonography of at-risk pregnancy may be a useful prenatal indicator of an affected fetus.

Diagnostic workup

Blood analyses of individuals with the French phenotype of pyruvate carboxylase deficiency showed metabolic acidosis, hyperlactacidemia, and hypoglycemia in some patients. Serum lactate concentrations varied between 10 and 20 mmol (normal less than 2.2), with a ratio of lactate to pyruvate between 50 and 100 (normal less than 28). Blood 3-OH-butyrate was increased (0.5 to 2.7 mmol, normal less than 0.1). The ratio of 3-OH-butyrate to acetoacetate was decreased (less than 2, normal 2.5 to 3). Hyperammonemia was a constant finding (100 to 600 mg/dL, normal less than 60) as was a striking increase of plasma citrulline (300 to 400 mmol, normal less than 40). Plasma amino acid profiles showed an increase of lysine and proline, which is a nonspecific finding. Hyperalaninemia, usually accompanying hyperlactacidemia, was not found in several patients with the French phenotype of pyruvate carboxylase deficiency. Plasma aspartate was normal. Only one patient had a significant decrease in plasma aspartate (77).

Serum lactate in patients with the North American phenotype was increased but less than in patients with the French phenotype. It varied between 2 and 10 mmol. Lactate-to-pyruvate ratios were normal or moderately increased (less than 50, normal less than 28). Plasma ammonia concentration was normal as was citrulline concentration. Plasma alanine concentration was increased in all patients (0.5 to 1.4 mmol, normal less than 0.455). An increase of plasma 3-OH-butyrate and free fatty acids was found, and the ratio of 3-OH-butyrate to acetoacetate was normal or decreased. Serum lactate concentration, lactate-to-pyruvate ratio, and plasma alanine concentrations were increased in cerebrospinal fluid. Glutamine was decreased in cerebrospinal fluid and in postmortem brain (53). Urinary organic acids showed elevated lactate, pyruvate, and 3-OH-butyrate as well as increased excretion of alpha-ketoglutarate. Overnight serum glucose concentrations usually were normal but decreased after a 24-hour fast (04). Hypoglycemia was present, especially during acute episodes of metabolic acidosis. During these episodes, serum lactate concentrations generally were above 10 mmol.

Fetuses of six pregnancies with pyruvate carboxylase deficiency revealed ventriculomegaly, frontal horn impairment associated with subependymal, and paraventricular cysts (23). These findings may provide a clue that an at-risk pregnancy has the disorder.

The patient with the benign variant had several acute episodes of metabolic acidosis with elevated blood lactate, pyruvate, alanine, 3-OH-butyrate, acetoacetate, and lysine and undetectable low aspartate.

Cultured skin fibroblasts are used preferentially to assay catalytic activity of pyruvate carboxylase (21). A radiometric method provides the most reliable results (73). The activity is 10-fold higher in liver than in cultured skin fibroblasts, but the need for a liver biopsy limits the use of this tissue. Enzyme activity can be determined in postmortem liver, although results have to be interpreted with caution because of rapid postmortem degradation of the enzyme. Kerr and colleagues updated a method for assaying pyruvate carboxylase activity in crude homogenates of cultured skin fibroblasts, lymphocytes, and frozen liver (36).

Pyruvate carboxylase has low activity in skeletal muscle, which makes this tissue unsuitable for assay. Pyruvate carboxylase activity was severely decreased in all patients with the French phenotype (less than 5% of normal). In patients with the North American phenotype, it varied from less than 5% to 23% of controls. A patient with the benign variant had less than 2% of activity in her cultured skin fibroblasts as compared with controls.

Pyruvate carboxylase deficiency should be considered in the differential diagnosis of fetal abortions or terminated pregnancies when an inherited metabolic disorder is suspected (16).

Management

Patients with isolated pyruvate carboxylase deficiency did not respond to biotin therapy (62; 21; 04; 07). Daily administration of thiamine was used to lower the concentration of lactate by stimulating pyruvate dehydrogenase complex, but this was without significant clinical effect. Oral administration of other cofactors and medications (eg, dichloroacetate) did not influence the lactic acidemia or improve the clinical condition. A comatose child with severe ketolactic acidemia with low aspartate and glutamine and elevated citrulline and proline was treated with high doses of citrate and aspartate to provide oxaloacetate (01). The ketolactic acidosis improved, and the plasma amino acids became normal, with the exception of arginine. Glutamine continued to be low in the cerebrospinal fluid. Although the child has experienced milder metabolic compromise during infections or fasting, she is profoundly retarded, has spasticity, and only partially controlled myoclonic seizures. Treatment with adrenocorticotropic hormone in two patients with pyruvate carboxylase deficiency and infantile spasms induced severe metabolic acidosis with greatly increased blood lactate, pyruvate, and alanine concentrations (61). Neither high-fat nor high-carbohydrate diets were beneficial. Administration of substrates, including aspartic and glutamic acids, had no consistent effect on blood lactate concentrations. Acute metabolic crises can be detrimental both physically and mentally. Prompt treatment with oral or intravenous glucose-containing fluids and bicarbonate is advised during these episodes. Orthotopic liver transplantation has been performed in one child with pyruvate carboxylase deficiency (49). Ketolactic acidosis markedly improved, but the low glutamine concentration in the cerebrospinal fluid did not correct following transplantation. Oral triheptanoin, an odd carbon triglyceride that is a source of acetyl CoA and anaplerotic propionyl CoA, has been used to treat an infant with the disorder (47). The child exhibited rapid reversal of hepatic failure but died of at 6 months of age from sepsis. Further trials of this therapy are necessary to draw any conclusions about its efficacy. Various novel interventions that enhance anaplerosis or replenish the citric acid intermediates for the treatment of the disorder have been reviewed (43).

It is important to avoid fasting and a ketogenic diet in individuals with pyruvate carboxylase deficiency (79).

Several children with pyruvate carboxylase deficiency have been treated with triheptanoin, a triglyceride that provides anaplerotic substrates for the TCA cycle, in addition to citrate and 2-chloropropionate (10). Although the medication was well tolerated, it did not alter the clinical course. In another study, triheptanion was used in the treatment of 12 individuals with pyruvate carboxylase deficiency with mixed results; some exhibited no change, some improved, and some became worse (39). In another case of pyruvate carboxylase deficiency with Type C, triheptanoin was well-tolerated and effective for 2 years by potentially restoring energy homeostasis and myelin synthesis (08). The authors suggested alternatively designed trials were needed to determine the efficacy of this anaplerotic agent in individuals with pyruvate carboxylase deficiency.

References

01: Ahmad A, Kahler SG, Kishnani PS, et al. Treatment of pyruvate carboxylase deficiency with high doses of citrate and aspartate. Am J Med Genet 1999;87(4):331-8. PMID 10588840
02: Almomen M, Sinclair G, Stockler-Ipsiroglu SG, Horvath GA. Pyruvate carboxylase deficiency type C: a rare cause of acute transient flaccid paralysis with ketoacidosis. Neuropediatrics 2018;49(6):369-72. PMID 30045381
03: Arnold GL, Griebel ML, Porterfield M, Brewster M. Pyruvate carboxylase deficiency. Report of a case and additional evidence for the "mild" phenotype. Clin Pediatr (Phila) 2001;40(9):519-21. PMID 11583052
04: Atkin BM, Buist NR, Utter MF, Leiter AB, Banker BQ. Pyruvate carboxylase deficiency and lactic acidosis in a retarded child without Leigh's disease. Pediatr Res 1979b;13:109-16. PMID 219411
05: Atkin BM, Utter MF, Weinberg MB. Pyruvate carboxylase and phosphoenolpyruvate carboxykinase activity in leucocytes and fibroblasts from a patient with pyruvate carboxylase deficiency. Pediatr Res 1979a;13:38-43. PMID 107509
06: Barden RE, Taylor BL, Isohashi F, et al. Structural properties of pyruvate carboxylases from chicken liver and other sources. Proc Natl Acad Sci U S A 1975;72:4308-12. PMID 1105579
07: Bartlett K, Ghneim HK, Stirk JH, Dale G, Alberti KG. Pyruvate carboxylase deficiency. J Inherit Metab Dis 1984;7(Suppl):74-8. PMID 6434849
08: Bernhardt I, Van Dorp L, Dixon M, et al. Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin. JIMD Rep 2023;65(1):10-16. PMID 38186850
09: Brech W, Shrago E, Wilken D. Studies on pyruvate carboxylase in rat and human liver. Biochem Biophys Acta 1970;201:145-54. PMID 5418716
10: Breen C, White FJ, Scott CA, et al. Unsuccessful treatment of severe pyruvate carboxylase deficiency with triheptanoin. Eur J Pediatr 2014;173(3):361-6. PMID 24114256
11: Brun N, Robitaille Y, Grignon A, Robinson BH, Mitchell GA, Lambert M. Pyruvate carboxylase deficiency: prenatal onset of ischemia-like brain lesions in two sibs with the acute neonatal form. Am J Med Genet 1999;84(2):94-101. PMID 10323732
12: Brunette MG, Delvin E, Hazel B, Scriver CR. Thiamine responsive lactic acidosis in a patient with deficient low Km pyruvate carboxylase activity in liver. Pediatrics 1972;50:702-11. PMID 4343503
13: Carbone MA, Applegarth DA, Robinson BH. Intron retention and frameshift mutations result in severe pyruvate carboxylase deficiency in two male siblings. Hum Mutat 2002;20(1):48-56. PMID 12112657
14: Carbone MA, MacKay N, Ling M, et al. Amerindian pyruvate carboxylase deficiency is associated with two distinct missense mutations. Am J Hum Genet 1998;62(6):1312-9. PMID 9585612
15: Coci EG, Gapsys V, Shur N, et al. Pyruvate carboxylase deficiency type A and type C: characterization of five novel pathogenic variants in PC and analysis of the genotype-phenotype correlation. Hum Mutat 2019;40(6):816-27. PMID 30870574
16: Collardeau-Frachon S, Cordier MP, Rossi M, Guibaud L, Vianey-Saban C. Antenatal manifestations of inborn errors of metabolism: autopsy findings suggestive of a metabolic disorder. J Inherit Metab Dis 2016;39(5):597-610. PMID 27106218
17: Coude FX, Ogier H, Marsac C, Munnich A, Charpentier C, Saudubray JM. Secondary citrullinemia with hyperammonemia in four neonatal cases of pyruvate carboxylase deficiency. Pediatrics 1981;68:914. PMID 6798542
18: Debray FG, Lambert M, Chevalier I, et al. Long-term outcome and clinical spectrum of 73 pediatric patients with mitochondrial diseases. Pediatrics 2007;119:722-33. PMID 17403843
19: De Meirleir L. Defects of pyruvate metabolism and the Krebs cycle. J Child Neurol 2002;17(Suppl 3):3S26-33; discussion 3S33-4. PMID 12597053
20: De Meirleir L. Disorders of pyruvate metabolism. Handb Clin Neurol 2013;113:1667-73. PMID 23622387
21: De Vivo DC, Haymond MW, Leckie MP, Bussmann YL, McDougal DB Jr, Pagliara AS. The clinical and biochemical implications of pyruvate carboxylase deficiency. J Clin Endocrinol Metab 1977;45:1281-96. PMID 412860
22: Dogulu N, Öncül Ü, Köse E, Aycan Z, Eminoğlu FT. Pyruvate carboxylase deficiency type C as a differential diagnosis of diabetic ketoacidosis. J Pediatr Endocrinol Metab 2021;34:947-50. PMID 33860652
23: Egloff C, Eldin de Pecoulas A, Mechler C, et al. Prenatal sonographic description of fetuses affected by pyruvate dehydrogenase or pyruvate carboxylase deficiency. Prenat Diagn 2018. [Epub ahead of print] PMID 29752808
24: Exton JH, Park CR. Control of gluconeogenesis in liver. II Effects of glucagon, catecholamines, and adenosine 3',5'-monophosphate on gluconeogenesis in the perfused rat liver. J Biol Chem 1968;243:4189-96. PMID 5679958
25: Freytag SO, Collier KJ. Molecular cloning of a cDNA for human pyruvate carboxylase. J Biol Chem 1984;259:12831-7. PMID 6548474
26: Freytag SO, Utter MF. Induction of pyruvate carboxylase apoenzyme and holoenzyme in 3T3-L1 cells during differentiation. Proc Natl Acad Sci U S A 1980;77(3):1321-5. PMID 6929488
27: Garcia-Cazorla A, Rabier D, Touati G, et al. Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects. Ann Neurol 2006;59:121-7. PMID 16278852
28: Greter J, Gustafsson J, Holme E. Pyruvate carboxylase deficiency with urea cycle impairment. Acta Paediatr Scand 1985;74:982-6. PMID 3937431
29: Hamilton J, Rae MD, Logan RW, Robinson PH. A case of benign pyruvate carboxylase deficiency with normal development. J Inherit Metab Dis 1997;20(3):401-3. PMID 9266366
30: Haworth JC, Robinson BH, Perry TL. Lactic acidosis due to pyruvate carboxylase deficiency. J Inherit Metab Dis 1981;4:57-8. PMID 6790846
31: Hidalgo J, Campoverde L, Ortiz JF, Ruxmohan S, Eissa-Garcés A. A unique case of pyruvate carboxylase deficiency. Cureus 2021;13:e15042. PMID 34150393
32: Higgins JJ, Glasgow AM, Lusk M, Kerr DS. MRI, clinical, and biochemical features of partial pyruvate carboxylase deficiency. J Child Neurol 1994;9(4):436-9. PMID 7822739
33: Higgins JJ, Ide SE, Oghalai JS, Polymeropoulos MH. Lack of mutations in the biotin-binding region of the pyruvate carboxylase (PC) gene in a family with partial PC deficiency. Clin Biochem 1997;30(1):79-81. PMID 9056115
34: Hommes FA, Polman HA, Reerink JD. Leigh's encephalomyelopathy: an inborn error of gluconeogenesis. Arch Dis Child 1968;43:423-6. PMID 4873809
35: Ingaramo M, Beckett D. Selectivity in post-translational biotin addition to five human carboxylases. J Biol Chem 2012;287:1813-22. PMID 22123817
36: Kerr D, Grahame G, Nakouzi G. Assays of pyruvate dehydrogenase complex and pyruvate carboxylase activity. Methods Mol Biol 2012;837:93-119. PMID 22215543
37: Kose MD, Colak R, Ergon EY, et al. Challenges in the management of an ignored cause of hyperammonemic encephalopathy: pyruvate carboxylase deficiency. J Pediatr Endocrinol Metab 2020;33(4):569-74. PMID 32145058
38: Lamhonwah AM, Quan F, Gravel RA. Sequence homology around the biotin-binding site of human propionyl-CoA carboxylase and pyruvate carboxylase. Arch Biochem Biophys 1987;254:631-6. PMID 3555348
39: Lasio ML, Leshinski AC, Ducich NH, et al. Clinical, biochemical and molecular characterization of 12 patients with pyruvate carboxylase deficiency treated with triheptanoin. Mol Genet Metab 2023;139(2):107605. PMID 37207470
40: Mackall JC, Lane MD. Role of pyruvate carboxylase in fatty acid synthesis: alterations during preadipocyte differentiation. Biochem Biophys Res Commun 1977;79(3):720-5. PMID 597301
41: MacKay N, Rigat B, Douglas C, Chen HS, Robinson BH. cDNA cloning of human kidney pyruvate carboxylase. Biochem Biophys Res Commun 1994;202(2):1009-14. PMID 8048912
42: Maesaka H, Komiya K, Misugi K, Tada K. Hyperalaninemia, hyperpyruvicemia and lactic acidosis due to pyruvate carboxylase deficiency of the liver; treatment with thiamine and lipoic acid. Eur J Pediatr 1976;122:159-68. PMID 817914
43: Marin-Valencia I, Roe CR, Pascual JM. Pyruvate carboxylase deficiency: mechanisms, mimics and anaplerosis. Mol Genet Metab 2010;101(1):9-17. PMID 20598931
44: Marsac C, Augereau Ch, Feldman G, Wolf B, Hansen TL, Berger R. Prenatal diagnosis of pyruvate carboxylase deficiency. Clin Chim Acta 1982;119:121-7. PMID 6800673
45: Menefee AL, Zeczycki TN. Nearly 50 years in the making: defining the catalytic mechanism of the multifunctional enzyme, pyruvate carboxylase. FEBS J 2014;281:1333-54. PMID 24476417
46: Merinero Cortes B, Del Valle Martinez J, Perez-Cerda Silvestre C, et al. Acidosis lactica neonatal debida a deficiencia aislada de piruvato carboxilasa. An Esp Pediatr 1988;29:57-60. PMID 3142324
47: Mochel F, DeLonlay P, Touati G, et al. Pyruvate carboxylase deficiency: clinical and biochemical response to anaplerotic diet therapy. Mol Genet Metab 2005 84:305-12. PMID 15781190
48: Monnot S, Serre V, Chadefaux-Vekemans B, et al. Structural insights on pathogenic effects of novel mutations causing pyruvate carboxylase deficiency. Hum Mutat 2009;30(5):734-40. PMID 19306334
49: Nyhan WL, Khanna A, Barshop BA, et al. Pyruvate carboxylase deficiency--insights from liver transplantation. Mol Genet Metab 2002;77(1-2):143-9. PMID 12359142
50: Oizumi J, Shaw KNF, Giudici TA, Carter M, Donnell N, Ng WG. Neonatal pyruvate carboxylase deficiency with renal tubular acidosis and cystinuria. J Inherit Metab Dis 1983;6:89-93. PMID 6422151
51: Ortez C, Jou C, Cortès-Saladelafont E, et al. Infantile parkinsonism and GABAergic hypotransmission in a patient with pyruvate carboxylase deficiency. Gene 2013;532(2):302-6. PMID 23973720
52: Ostergaard E, Duno M, Møller LB, et al. Novel mutations in the PC gene in patients with type B pyruvate carboxylase deficiency. JIMD Rep 2013;9:1-5. PMID 23430542
53: Perry TL, Haworth JC, Robinson BH. Brain amino acid abnormalities in pyruvate carboxylase deficiency. J Inherit Metab Dis 1985;8:63-6. PMID 2878111
54: Pineda M, Campistol J, Vilaseca MA, et al. An atypical French form of pyruvate carboxylase deficiency. Brain Dev 1995;17(4):276-9. PMID 7503391
55: Pollock MA, Cumberbatch M, Bennet MJ, et al. Pyruvate carboxylase deficiency in twins. J Inherit Metab Dis 1986;9(1):29-30. PMID 3088322
56: Rajakumar A, Kaliamoorthy I, Reddy MS, Rela M. Anaesthetic considerations for liver transplantation in propionic acidemia. Indian J Anaesth 2016;60(1):50-4. PMID 26962256
57: Robinson BH, Oei J, Saudubray JM, et al. The French and North American phenotypes of pyruvate carboxylase deficiency. Correlation with biotin-containing protein by 3H-biotin incorporation, 35S-streptavidin labeling, and northern blotting with a cloned cDNA probe. Am J Hum Genet 1987;40:50-9. PMID 3101494
58: Robinson BH, Oei J, Sherwood WG, et al. The molecular basis for the two different clinical presentations of classical pyruvate carboxylase deficiency. Am J Hum Genet 1984;36(2):283-94. PMID 6424438
59: Robinson BH, Taylor J, Sherwood WG. The genetic heterogeneity of lactic acidosis: occurrence of recognizable inborn errors of metabolism in a pediatric population with lactic acidosis. Pediatr Res 1980;14:956-62. PMID 6775276
60: Robinson BH, Toone J, Petrova-Benedict R, Dimmick JE, Oei J, Applegarth DA. Prenatal diagnosis of pyruvate carboxylase deficiency. Prenat Diagn 1985;5:67-71. PMID 3919380
61: Rutledge SL, Snead OC, Kelly DR, et al. Pyruvate carboxylase deficiency: acute exacerbation after ACTH treatment of infantile spasms. Pediatr Neurol 1989;5:249-52. PMID 2553027
62: Saudubray JM, Marsac C, Charpentier C, Cathelineau L, Besson Leaud M, Leroux JP. Neonatal congenital lactic acidosis with pyruvate carboxylase deficiency in two siblings. Acta Paediatr Scand 1976;65:717-24. PMID 826106
63: Schiff M, Levrat V, Acquaviva C, Vianey-Saban C, Rolland MO, Guffon N. A case of pyruvate carboxylase deficiency with atypical clinical and neuroradiological presentation. Mol Genet Metab 2006;87(2):175-7. PMID 16325442
64: Scrutton MC, Olmsted MR, Utter MF. Pyruvate carboxylase from chicken liver. Meth Enzymol 1968;13:235.
65: Sharif S, Velumula PK, Boddu PK, Altinok D, Fernandes N. A rare case of Type B neonatal pyruvate carboxylase enzyme deficiency presenting with refractory lactic acidosis in the early neonatal period. Cureus 2022;14(10):e29903. PMID 36348915
66: Stern HJ, Nayar R, Depalma L, Rifai N. Prolonged survival in pyruvate carboxylase deficiency: lack of correlation with enzyme activity in cultured fibroblasts. Clin Biochem 1995;28(1):85-9. PMID 7720232
67: Tada K, Takada G, Omura K, Itokawa Y. Congenital lactic acidosis due to pyruvate carboxylase deficiency: absence of an inhibitor of TPP-ATP phosphoryl transferase. Eur J Pediatr 1978;127(2):141-7. PMID 203466
68: Tao D, Zhang H, Yang J, et al. PC splice-site variant c.1825+5G>A caused intron retention in a patient with pyruvate carboxylase deficiency: A case report. Front Pediatr 2022;10:825515. PMID 35573952
69: Tsuchiyama A, Oyanagi K, Hirano S, et al. A case of pyruvate carboxylase deficiency with later prenatal diagnosis of an unaffected sibling. J Inherit Metab Dis 1983;6:85-8. PMID 6422150
70: Tsygankova P, Bychkov I, Minzhenkova M, et al. Expanding the genetic spectrum of the pyruvate carboxylase deficiency with novel missense, deep intronic and structural variants. Mol Genet Metab Rep 2022;32:100889. PMID 35782291
71: Unal O, Orhan D, Ostergaard E, et al. A patient with pyruvate carboxylase deficiency and nemaline rods on muscle biopsy. J Child Neurol 2013;28(11):1505-8. PMID 22965558
72: Utter MF, Barden RE, Taylor BL. Pyruvate carboxylase: an evaluation of the relationships between structure and mechanisms and between structure and catalytic activity. Adv Enzymol 1975;42:1-72. PMID 1093362
73: Utter MF, Keech DB. Formation of oxaloacetate from pyruvate and CO2. J Biol Chem 1960;235:17-8. PMID 13840551
74: Van Biervliet JP, Bruinvis L, van der Heiden C, et al. Report of a patient with severe, chronic lactic acidaemia and pyruvate carboxylase deficiency. Dev Med Child Neurol 1977;19(3):392-401. PMID 407120
75: Van Coster RN, Fernhoff PM, De Vivo DC. Pyruvate carboxylase deficiency: a benign variant with normal development. Pediatr Res 1991;30(1):1-4. PMID 1909777
76: Van Coster RN, Janssens S, Misson JP, Verloes A, Leroy JG. Prenatal diagnosis of pyruvate carboxylase deficiency by direct measurement of catalytic activity on chorionic villi samples. Prenat Diagn 1998;18(10):1041-4. PMID 9826895
77: Vidailhet M, Lebebvre E, Beley G, Marsac C. Neonatal lactic acidosis with pyruvate carboxylase inactivity. J Inherit Metab Dis 1981;4:131-2.
78: Walker V. Ammonia metabolism and hyperammonemic disorders. Adv Clin Chem 2014;67:73-150. PMID 25735860
79: Wang D, De Vivo D. Pyruvate carboxylase deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews® [Internet]. Seattle: University of Washington, 2018.
80: Wang D, Yang H, De Braganca KC, et al. The molecular basis of pyruvate carboxylase deficiency: mosaicism correlates with prolonged survival. Mol Genet Metab 2008;95(1-2):31-8. PMID 18676167
81: Wexler ID, Du Y, Lisgaris MV, et al. Primary amino acid sequence and structure of human pyruvate carboxylase. Biochim Biophys Acta 1994;1227(1-2):46-52. PMID 7918683
82: Wexler ID, Kerr DS, Du Y, et al. Molecular characterization of pyruvate carboxylase deficiency in two consanguineous families. Pediatr Res 1998;43(5):579-84. PMID 9585002
83: Wieland O, Evertz-Prusse E, Stukowski B. Distribution of pyruvate carboxylase and phosphoenol-pyruvate carboxykinase in human liver. FEBS Lett 1968;2:26-8. PMID 11946259
84: Wong LT, Davidson AG, Applegarth DA, et al. Biochemical and histologic pathology in an infant with cross-reacting material (negative) pyruvate carboxylase deficiency. Pediatr Res 1986;20:274-9. PMID 3085060
85: Wood HG, Barden RE. Biotin enzymes. Annu Rev Biochem 1977;46:385-413. PMID 20039
86: Xue M. Case report: prenatal neurological injury in a neonate with pyruvate carboxylase deficiency type B. Front Endocrinol (Lausanne) 2023;14:1199590. PMID 37484962
87: Zahid M, Khan AH, Yunus ZM, et al. Inherited metabolic disorders presenting as hypoxic ischaemic encephalopathy: a case series of patients presenting at a tertiary care hospital in Pakistan. J Pak Med Assoc 2019;69(3):432-6. PMID 30890842
88: Zhao X, Ding J, Jin D. Analysis of child with pyruvate carboxylase deficiency type A due to compound heterozygous variants of the PC gene. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2022;39(9):996-1000. PMID 36082573

Patient Profile

Age range of presentation: 0 to 23 months
Sex preponderance: male=female
Heredity: heredity typical

heredity may be a factor

autosomal recessive
Population groups selectively affected: Native Americans
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Disorders of pyruvate metabolism and gluconeogenesis: E74.4
ICD-11: Pyruvate carboxylase deficiency: 5C53.03
OMIM: Pyruvate carboxylase deficiency: #266150

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Pyruvate carboxylase deficiency

Differential Diagnosis

hyperlactacidemia
pyruvate dehydrogenase complex
defects of enzyme complexes of respiratory chain
defects of enzymes of gluconeogenesis
glucose-6-phosphatase defect
- phosphoenolpyruvate carboxykinase defect
- fructose-1,6-diphosphatase defect
- defects of Krebs cycle enzymes
- fumarase deficiency
- defects in enzymes involved in mitochondrial beta-oxidation of fatty acids
- defects of enzymes involved in metabolism of several organic acids

Also Relevant

Agenesis of the corpus callosum
Biotin holocarboxylase synthetase deficiency
Biotinidase deficiency
Isolated beta-methylcrotonyl-CoA carboxylase deficiency
Leigh syndrome

Clinical Categories

Neurogenetic Disorders

Web References

Testing

Pyruvate Carboxylase Deficiency

Pyruvate carboxylase deficiency

Pyruvate carboxylase deficiency

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Anesthesia

References

Contributors

Author

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Carnitine palmitoyltransferase II deficiency

Pelizaeus-Merzbacher disease

Vanishing white matter disease

Wilson disease

Aromatic L-amino acid decarboxylase deficiency

White matter abnormalities in the brain

Hypermethioninemia

POLG-related mitochondrial disorders

Pyruvate carboxylase deficiency

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Anesthesia

References

Contributors

Author

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Carnitine palmitoyltransferase II deficiency

Pelizaeus-Merzbacher disease

Vanishing white matter disease

Wilson disease

Aromatic L-amino acid decarboxylase deficiency

White matter abnormalities in the brain

Hypermethioninemia

POLG-related mitochondrial disorders

This is an article preview.
Start a Free Account
to access the full version.