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Pyruvate Carboxylase Deficiency

, MD and , MD.

Author Information
, MD
Department of Neurology
Columbia University
New York, New York
, MD
Department of Pediatric and Neurology
Columbia University
Neurological Institute of New York
New York, New York

Initial Posting: ; Last Update: July 21, 2011.

Summary

Disease characteristics. Pyruvate carboxylase (PC) deficiency is characterized in most affected individuals by failure to thrive, developmental delay, recurrent seizures, and metabolic acidosis. Three clinical types are recognized: type A (infantile form), in which most affected children die in infancy or early childhood; type B (severe neonatal form), in which affected infants have hepatomegaly, pyramidal tract signs, and abnormal movement and die within the first three months of life; and type C (intermittent/benign form), in which affected individuals have normal or mildly delayed neurologic development and episodic metabolic acidosis.

Diagnosis/testing. The diagnosis of PC deficiency rests on analysis of amino acids and organic acids and detection of deficiency of PC enzyme activity measured in fibroblasts. PC is the only gene known to be associated with PC deficiency.

Management. Treatment of manifestations: Intravenous glucose-containing fluids, hydration, and correction of the metabolic acidosis are the mainstays of acute management. Correction of biochemical abnormalities and supplementation with citrate, aspartic acid, and biotin may improve somatic findings but not neurologic manifestations. Orthotopic liver transplantation may be indicated in some patients. Anaplerotic therapies such as triheptanoin show some promise, especially regarding the neurologic manifestations, but need to be further evaluated.

Prevention of primary manifestations: Use of a high-carbohydrate and high-protein diet to prevent activation of gluconeogenesis.

Surveillance: Regular monitoring of serum lactate concentrations.

Agents/circumstances to avoid: Fasting; the ketogenic diet.

Genetic counseling. PC deficiency is inherited in an autosomal recessive manner. De novo somatic mutations have been reported. If both parents are carriers, sibs of an individual with PC deficiency have a 25% chance of inheriting both mutations and being affected, a 50% chance of inheriting one mutated gene and being carriers, and a 25% chance of inheriting both normal genes and not being carriers. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk is possible by molecular genetic testing if both disease-causing alleles have been identified in an affected family member.

Diagnosis

Clinical Diagnosis

Pyruvate carboxylase (PC) deficiency is suspected in individuals with failure to thrive, developmental delay, recurrent seizures, and metabolic acidosis.

The three clinical presentations of PC deficiency:

  • Type A: infantile or North American form
  • Type B: severe neonatal or French form
  • Type C: intermittent/benign form

Testing

Biochemical testing abnormalities by PC deficiency type

  • Type A. Infantile-onset mild to moderate lactic acidemia; normal lactate-to-pyruvate ratio despite acidemia [Robinson 2000, Wang et al 2008]
  • Type B. Increased lactate-to-pyruvate ratio; increased acetoacetate to 3-hydroxybutyrate ratio; elevated blood concentrations of citrulline, proline, lysine, and ammonia; low concentration of glutamine [Nelson et al 2000, García-Cazorla et al 2006, Wang et al 2008]
  • Type C. Episodic metabolic acidosis with normal citrulline plasma concentrations and elevated lysine and proline plasma concentrations [Wang et al 2008]

Abnormalities by analyte

Note: For each of the following analytes the abnormal values overlap among types A, B, and C. Normal values differ by laboratory.

  • Lactate and pyruvate. The lack of PC enzyme activity causes the accumulation of pyruvate in the plasma, which is subsequently converted into lactate by the enzyme lactate dehydrogenase, causing an elevated plasma concentration of lactic acid. Elevated blood lactate concentrations (5.5-27.8 mmol/L; normal range 0.5-2.2) are characteristically found in PC deficiency type A (2-10 mmol/L), type B (>10 mmol/L), and type C (2-5 mmol/L). Blood pyruvate concentrations are usually elevated in PC deficiency type B (0.14-0.90 mmol/L; normal range 0.04-0.13), resulting in an elevated lactate-to-pyruvate ratio (>20). The ratio is usually normal in PC deficiency type A and C (<20).
  • Amino acids. In serum and urine: high alanine, citrulline, and lysine; low aspartic acid and glutamine. Amino acid concentrations vary with the general metabolic state of the individual.
    • Hyperalaninemia as a result of pyruvate shunting
    • Hypercitrullinemia and hyperlysinemia caused by the block in the urea cycle secondary to a low aspartic acid
    • Low aspartic acid and glutamine as a result of deficiency in the oxaloacetate precursor
  • Ketonemia. 3-hydroxybutyrate and acetoacetate concentrations are increased in blood. In PC deficiency type B, the ratio of acetoacetate to 3-hydroxybutyrate is increased, reflecting a low NADH-to-NAD ratio inside the mitochondria. Lack of oxaloacetate prevents the liver from oxidizing acetyl-CoA derived from pyruvate and fatty acids. The expanded acetyl-CoA pool results in hepatic ketone body synthesis [De Vivo et al 1977].
  • Hypoglycemia. Oxaloacetate deficiency limits gluconeogenesis. Note: Hypoglycemia is not a consistent finding despite the fact that PC is the first rate-limiting step in gluconeogenesis.
  • Hyperammonemia results from poor ammonia disposal and decreased urea cycle function.
  • Cerebrospinal fluid (CSF)
    • Elevated lactate and pyruvate concentrations
    • Markedly reduced glutamine concentration
    • Elevated glutamic acid and proline concentrations
  • PC enzyme assay. In PC deficiency, fibroblast PC enzyme activity is usually less than 5% of that observed in controls [Wang et al 2008]. Similar abnormalities are noted in lymphoblasts. Muscle PC activity is quite low in control tissue.

Molecular Genetic Testing

Gene. PC is the only gene in which mutations are known to cause PC deficiency.

Clinical testing

  • Sequence analysis of PC promoters and coding region detects mutations in 95% of affected individuals including the most common PC mutations (p.Ala610Thr, p.Arg631Gln, and p.Ala847Val).
  • Deletion/duplication analysis. The usefulness of deletion/duplication testing has not been demonstrated, as no deletions or duplications of PC have been reported to cause pyruvate carboxylase deficiency.

Table 1. Summary of Molecular Genetic Testing Used in Pyruvate Carboxylase Deficiency

Gene SymbolTest MethodMutations Detected 1Mutation Detection Frequency by Test Method 2
PCSequence analysisSequence variants 395%
Deletion/ duplication analysis 4Deletion/ duplication of one or more exons or the whole gene 5Unknown

1. The presence of mosaicism may complicate molecular testing; see Genotype Phenotype Correlations, Table 2, and Wang et al [2008].

2. The ability of the test method used to detect a mutation that is present in the indicated gene

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.

5. No deletions or duplications involving PC have been reported to cause pyruvate carboxylase deficiency. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis of PC deficiency rests on the following:

  • Detection of characteristic abnormalities in serum concentrations of amino acids, organic acids, glucose, and ammonia
  • Deficiency of PC enzyme activity assayed in fibroblasts and other tissues
  • Identification of PC mutations by sequence analysis

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Most individuals with pyruvate carboxylase (PC) deficiency present with failure to thrive, developmental delay, recurrent seizures, and metabolic acidosis. Hypoglycemia is an inconsistent finding.

Three types of PC deficiency have been recognized, based on clinical presentation.

Type A (infantile form) is characterized by infantile onset with mild metabolic acidosis, delayed motor development, intellectual disability, failure to thrive, apathy, hypotonia, pyramidal tract signs, ataxia, nystagmus, and convulsions.

Episodes of acute vomiting, tachypnea, and acidosis are usually precipitated by metabolic or infectious stress.

Most affected children die in infancy or early childhood, although some may survive to maturity. Older individuals function at a lower-than-average level and need special care and schooling [Carbone et al 1998, Wang et al 2008].

Type B (severe neonatal form) was first described in France by Saudubray et al [1976]. Affected infants present with biochemical abnormalities, hypoglycemia, hyperammonemia, hypernatremia, anorexia, hepatomegaly, convulsions, stupor, hypotonia, pyramidal tract signs, abnormal movements (including high-amplitude tremor and dyskinesia), and bizarre ocular behavior.

Motor development is severely retarded and affected individuals have intellectual disability [García-Cazorla et al 2006, Wang et al 2008].

Although the majority of affected infants die within the first three months of life [García-Cazorla et al 2006], two are alive at ages nine and 20 years, likely because of mosaicism [Wang et al 2008] (see Genotype-Phenotype Correlations).

Type C (intermittent/benign form) is characterized by normal or mildly delayed neurologic development and episodic metabolic acidosis. Five affected individuals have been reported [Van Coster et al 1991, Stern et al 1995, Vaquerizo Madrid et al 1997, Arnold et al 2001, Wang et al 2008]. The first individual described had normal mental and motor development at age 12 years despite several earlier episodes of metabolic acidosis [Van Coster et al 1991].

Brain MRI. Symmetric cystic lesions and gliosis in the cortex, basal ganglia, brain stem, or cerebellum; generalized hypomyelination; and hyperintensity of the subcortical fronto-parietal white matter were described in some individuals with type A.

Ventricular dilation, cerebrocortical and white matter atrophy, or periventricular white matter cysts have been reported in some individuals with type B [García-Cazorla et al 2006].

Magnetic resonance spectroscopy (MRS). Brain MRS shows high levels for lactate and choline, and low levels for N-acetylaspartate.

Pathophysiology. The glutamine-glutamate cycle in astrocytes requires a continuous supply of oxaloacetate provided by the reaction catalyzed by PC enzyme activity.

Genotype-Phenotype Correlations

Type A. Seven mutations (p.Arg62Cys, p.Arg631Gln, p.Ala847Val, p.Val145Ala, p.Arg451Cys, p.Ala610Thr, and p.Met743Ile) have been identified in five individuals [Wang et al 2008].

Type B. Complex missense mutations, deletions, and splice donor site mutations occur in homozygotes, compound heterozygotes, and individuals with mosaicism (see Table 2) [Wang et al 2008].

Type C. A heterozygous mutation (p.Ser266Ala) and somatic mosaic mutation (p.Ser705X) were observed in the first individual described [Wang et al 2008], and compound heterozygosity for the mutations p.Thr569Ala and Leu1137Valfs*1170 was observed in the second individual described [Wang et al 2008].

Mosaicism was found in five individuals [Wang et al 2008, Table 3 (type A: #6; type B: #2, #5, and #7; type C: #1)]. Four had prolonged survival; the fifth (type B: #7) died from unrelated medical complications.

Homozygous mutations. The deaths of the more severely affected individuals with type B correlated with homozygous mutations, which produced very low amounts (2% and 3%) of fibroblast PC protein [Wang et al 2008, Table 3].

Prevalence

In most populations, the incidence of PC deficiency is low (1:250,000).

PC deficiency is more prevalent in particular ethnic groups:

  • Type A. Incidence is increased among the native North American Ojibwa, Cree, and Micmac tribes of the Algonquin-speaking peoples. The A610T mutation was identified in all 13 affected individuals of Ojibwa and Cree origin. In those populations the carrier frequency may be as high as 1:10 [Carbone et al 1998].
  • Type B. Incidence is increased in Europe (France especially, but also Germany and England).

Differential Diagnosis

Biotinidase deficiency results from the inability to recycle endogenous biotin and to use protein-bound biotin from the diet. Biotin binds to propionyl-coenzyme A-carboxylase, pyruvate carboxylase (PC), beta-methylcrotonyl-CoA carboxylase, and acetyl-CoA carboxylase. Deficiency affects all biotinylated enzymes and can present in the neonatal period or later in infancy with neurologic symptoms such as lethargy, seizures with metabolic acidosis, hearing loss, alopecia, and perioral/facial dermatitis. It can be effectively treated with biotin.

In the untreated state, profound biotinidase deficiency during infancy is usually characterized by neurologic and cutaneous findings that include seizures, hypotonia, and rash, often accompanied by hyperventilation, laryngeal stridor, and apnea. Older children may also have alopecia, ataxia, developmental delay, sensorineural hearing loss, optic atrophy, and recurrent infections. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.

Biotinidase deficiency is caused by mutations in BTD. Individuals with profound biotinidase deficiency have lower than 10% of mean normal serum biotinidase activity; individuals with partial biotinidase deficiency have 10%-30% of mean normal serum biotinidase activity.

Biotinidase deficiency is inherited in an autosomal recessive manner.

Pyruvate dehydrogenase complex (PDHC) deficiency results from deficiency of either one of three catalytic components (E1, E2, and E3) or the regulatory component of PDHC (pyruvate dehydrogenase phosphate phosphatase). The diagnosis of PDHC deficiency is suspected in individuals with lactic acidemia who have a progressive or intermittent neurologic syndrome including: poor acquisition or loss of motor milestones, poor muscle tone, new onset seizures, periods of incoordination (i.e., ataxia), abnormal eye movements, poor response to visual stimuli, and episodic dystonia. Blood and CSF lactate concentrations are elevated and are associated with elevations of blood and CSF concentrations of pyruvate and alanine. Unlike PC deficiency, PDH deficiency usually presents with a normal lactate-to-pyruvate ratio in plasma. Typically, the CSF lactate elevations are higher than those in the blood, giving rise to the term “cerebral lactic acidosis.”

Brain MRI may show varying combinations of ventricular dilatation; cerebral atrophy; hydrocephaly; partial or complete absence of the corpus callosum; absence of the medullary pyramids; abnormal and ectopic inferior olives; symmetric cystic lesions; gliosis in the cortex, basal ganglia, brain stem, or cerebellum; or generalized hypomyelination.

Brain MRS shows:

  • High lactate concentrations, giving rise to the term “cerebral lactic acidosis”
  • N-acetylaspartate and choline concentrations consistent with hypomyelination

PDHC enzyme activity assay, immunoblotting analysis, and sequence analysis of two of the genes known to be associated with this disorder (PDHA1 [pyruvate dehydrogenase E1 deficiency] and DLAT [pyruvate dehydrogenase E2 deficiency]) can help make the diagnosis [DiMauro & De Vivo 1999]. Most pathogenic mutations involve the X-linked gene PDHA1, which encodes the E1 alpha subunit.

Respiratory chain disorder may result from mutations in nuclear genes or mitochondrial genes that encode any one of the five enzyme complexes. Lactate and pyruvate concentrations are elevated, and the lactate/pyruvate ratio is elevated, often above 20. Biopsied skeletal muscle may reveal ragged-red fibers, cytochrome c-oxidase negative fibers, and succinate dehydrogenase intensely positive fibers. These histologic abnormalities are commonly seen with nuclear DNA mutations causing intergenomic signaling defects and mitochondrial DNA mutations affecting protein synthesis genes. Brain MRI may reveal distinctive abnormalities, as described with Leigh disease or mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) [DiMauro & Schon 2007]. Nuclear gene mutations are inherited in an autosomal recessive or dominant manner; mitochondrial DNA mutations are inherited as maternal, non-Mendelian traits.

Krebs cycle disorders are rare and the enzymyopathies are partial. Lactate and pyruvate concentrations are elevated and the lactate/pyruvate ratio is normal. Urine organic acid profile may reveal distinctive elevation of fumaric acid or other Krebs cycle intermediates, reflecting the site of the enzyme deficiency (see Organic Acidemias).

Gluconeogenic defects may be aggravated clinically by fasting. Blood lactate, pyruvate, and alanine concentrations are classically elevated with clinical symptoms, and blood glucose concentration is low, indicating glycogen depletion and gluconeogenic pathway block. Ketone bodies are elevated, reflecting a physiologic response to fasting, stress, and hypoglycemia.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with pyruvate carboxylase (PC) deficiency, the following are recommended:

  • Blood, urine, and CSF measures of organic and amino acids; brain MRI and MRS analysis
  • Evaluation by a pediatric neurologist skilled in metabolic and genetic disorders to confirm the diagnosis, guide the treatment, and determine the prognosis
  • Genetic counseling for the parents regarding the risk of recurrence in future pregnancies

Treatment of Manifestations

Treatment focuses on providing alternative energy sources, hydration, and correction of the metabolic acidosis during acute decompensation. Stimulating residual PC enzyme activity is an important goal for long-term stable metabolic status. Correction of the biochemical abnormality can reverse some symptoms, but central nervous system damage progresses regardless of treatment [DiMauro & De Vivo 1999].

“Anaplerotic therapy” is based on the concept that an energy deficit in these diseases could be improved by providing alternative substrate for both the citric acid cycle and the electron transport chain for enhanced ATP production [Roe & Mochel 2006].

  • Citrate supplementation reduces the acidosis and provides substrate for the citric acid cycle [Ahmad et al 1999].
  • Aspartic acid supplementation allows the urea cycle to proceed and reduces the plasma and urine ammonia concentrations but has no effect on the neurologic disturbances as the aspartate does not enter the brain freely [Ahmad et al 1999].
  • Biotin supplementation is given to help optimize the residual PC enzyme activity but is usually of little use.
  • Triheptanoin, an odd-carbon triglyceride, providing a source for acetyl-CoA and anaplerotic propionyl-CoA, has been tried in one individual with biotin-unresponsive PC deficiency type B with immediate reversal (<48 h) of major hepatic failure and full correction of all biochemical abnormalities [Mochel et al 2005]. Triheptanoin provides C5-ketone bodies that can cross the blood-brain barrier, therefore providing substrates for the brain. Dietary intervention with triheptanoin is the only therapeutic approach that showed improvement of brain metabolism. However, this observation needs to be confirmed in additional patients.
  • Orthotopic liver transplantation has reversed the biochemical abnormalities in two patients [Nyhan et al 2002].

Prevention of Primary Manifestations

Educate parents about the factors that elicit a crisis and the early signs of decompensation.

Carry an informational statement regarding the child's disorder and the appropriate treatment in an emergency setting.

Minimize intercurrent infections as environmental stressors.

Surveillance

Monitor lactate levels regularly.

Agents/Circumstances to Avoid

Avoid the following:

  • Fasting
  • The ketogenic diet, which precipitates life-threatening metabolic acidosis

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy in a woman with PC deficiency has not been reported. However, women with the benign form (Type C) could become pregnant; such a pregnancy should be closely monitored for any metabolic derangements including dehydration and acidosis.

Therapies Under Investigation

Thiamine and lipoic acid could optimize PDHC activity, which could help reduce the plasma and urine pyruvate and lactate concentrations through an alternate route of pyruvate metabolism. Theoretically, this intervention could increase the acetyl-CoA pool and worsen the ketonemia.

  • Thiamine was tried in an individual with PC deficiency who was found to be responsive.
  • Two sisters with PC deficiency, severe intellectual disability and motor retardation, and Leigh syndrome improved clinically and biochemically after treatment with thiamine and lipoic acid. The precise molecular diagnosis in these cases is uncertain.

Based on reports from the literature [Nyhan et al 2002, Mochel et al 2005], it has been suggested that a combination of orthotopic liver transplantation and anaplerotic diet be used in order to obtain both (i) long-term metabolic stability and (ii) improvement/correction of brain energy metabolism, myelination, and neurotransmission.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Pyruvate carboxylase (PC) deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • In most instances, the parents of a proband are heterozygotes and, therefore, carry a single copy of a disease-causing mutation in PC.
  • De novo somatic mutations have been reported [Wang et al 2008] and may influence the phenotype and result in prolonged survival of the proband.
  • Heterozygotes are asymptomatic.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
    • If both parents are carriers, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
    • If only one parent is a carrier (i.e., the PC deficiency occurred as the result of de novo somatic mutation in the proband in one allele and an inherited mutation in another allele), the sibs of a proband have a 50% chance of being asymptomatic carriers and a 50% chance of being unaffected and not carriers.
  • Heterozygotes are asymptomatic.

Offspring of a proband. The offspring of a proband are obligate heterozygotes for a disease-causing mutation.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family have been identified.

Biochemical genetic testing for carrier status is not reliable.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • United Mitochondrial Disease Foundation (UMDF)
    8085 Saltsburg Road
    Suite 201
    Pittsburg PA 15239
    Phone: 888-317-8633 (toll-free); 412-793-8077
    Fax: 412-793-6477
    Email: info@umdf.org
  • Association for Neuro-Metabolic Disorders (ANMD)
    5223 Brookfield Lane
    Sylvania OH 43560-1809
    Phone: 419-885-1809; 419-885-1497
    Email: volk4olks@aol.com
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Pyruvate Carboxylase Deficiency: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
PC11q13​.2Pyruvate carboxylase, mitochondrialPC homepage - Mendelian genesPC

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Pyruvate Carboxylase Deficiency (View All in OMIM)

266150PYRUVATE CARBOXYLASE DEFICIENCY
608786PYRUVATE CARBOXYLASE; PC

Molecular Genetic Pathogenesis

Pyruvate carboxylase (PC) [EC 6.4.1.1] is a biotin-dependent mitochondrial enzyme that plays an important role in energy production and anaplerotic pathways. PC catalyzes the conversion of pyruvate to oxaloacetate (Figure 1).

Figure 1

Figure

Figure 1. Diagrammatic representation of metabolic pathway affected by PC deficiency. The PC enzyme is indicated by the red oval; the dotted arrow lines represent absent pathways.

Normal allelic variants. Many normal allelic variants have been reported. Most are in the untranslated regions (UTR) and introns. Three normal allelic variants are in the coding region (see Table 2).

PC contains 20 coding exons and four non-coding exons at the 5’-UTR [Wang et al 2008]. All four non-coding exons are involved in alternative splicing, resulting in three tissue-specific PC transcripts carrying the same coding region: variant 1 (4004bp, NM_000920.3), variant 2 (3959 bp, NM_022172.2), and variant 3 (4192bp, NM_001040716.1) (Figure 2). Southern blotting of human genomic DNA showed that PC exists in a single copy and no pseudogenes are detected.

Figure 2

Figure

Figure 2. PC structure and three transcript variants. The coding exons of PC are represented by rectangles with different symbols and Arabic numbers on the top. The four untranslated exons (UEs) are labeled UE1-UE4 (top left). The arrows before UE1, UE2, (more...)

Pathologic allelic variants

Table 2. Selected PC Allelic Variants

Class of Variant AlleleDNA Nucleotide Change Protein Amino Acid Change
(Alias 1)
Reference Sequences
Normalc.2286C>Gp.= 2
(Arg762Arg)
NM_000920​.3
NP_000911​.2
c.2619C>Tp.= 2
(Asn873Asn)
c.2874G>Tp.= 2
(Gly958Gly)
c.227A>Tp.His76Leu 3
c.1054G>Tp.Ala352Ser 3
Pathologicc.184C>Tp.Arg62Cys
c.796T>Ap.Ser266Ala
c.434T>Cp.Val145Ala
c.1351C>Tp.Arg451Cys
c.1705A>Gp.Thr569Ala
c.1828G>Ap.Ala610Thr
c.1892G>Ap.Arg631Gln
c.2114C>Ap.Ser705X 4
c.2229G>Tp.Met743Ile
c.2540C>Tp.Ala847Val
3499-3500delCTp.Leu1137ValfxX1170 5

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. p.= designates that protein has not been analyzed, but no change is expected

3. Presumed normal allelic variants, but not yet reported in individuals with PC deficiency.

4. Indicates the mosaic state of this allele

5. Wang et al [2008]

Table 3. PC Genotypes and PC Level and Activity

Case
ID#
PC
Type
DNA Nucleotide 1 ChangeProtein Amino Acid Change 2PC Amount 3PC Activity 4
1Cc.[796T>G; =] +
[=; 2114C>A, =]
p.[S266A; =] +
[=; S705X, =]
86%1.9%
2Bc.[1892G>A, =; =] +
[=; 2493_2494delGT, =]
p.[R631Q, =; =] +
[=; V831Vfs*832,=]
8%0
3Bc.[321+1G>T] + [321+1G>T]p.[V105_K107del] +
[V105_K107del]
3%0
4Bc.[806G>A] + [806G>A] p.[R269Q] + [R269Q]2%5%
5Bc.[467G>A; 496G>A; 1892G>A, =; 2540C>T, =] +
[467G>A; 496G>A; =; =]
p.[R156Q; V166I; R631Q, =; A847V, =] +
[R156Q; V166I; =; =]
44%1.9%
6Ac.[184C>T; 1892G>A ; 2540C>T] + [=; 1892G> A, =; 2540C> T, =] p.[R62C; R631Q; 847V] + [=; R631Q, =; A847V, =]49%6%
7Bc.[1892G>A; 2540C>T] +
[1892G>A, =; 2540C>T, =] 6
p.[R631Q; A847V] +
[R631Q, =; A847V, =]
17%17%
8Cc.[1705A>G; =] +
[=; 3409-3410delCT]
p.[T569A; =] +
[=; L1137Vfs*1170]
N/A1%
5Ac.[434T>C] + [434T>C]p.[V145A] + [V145A]Barely detectable7%-25%
10 5Ac.[1351C>T] + [1351C>T]p.[R451C] + [R451C]~100%7%
11 5Ac.[1828G>A] + [1828G>A]p.[A610>T] + [A610T]~100%1%-4%
12 5Ac.[2229G>T] + [2229G>T]p.[M743I] + [M743I]~100%1%-4%
13 5Bc.[2493_2494delGT] +
[2473+2-2473+5delTGCA]
p.[V831Vfs*832] +
[E825Gfs*846]
~01%-4%

Adapted from Wang et al [2008]

1. Nomenclature follows the recommendations for the description of sequence variants [www​.hgvs.org/mutnomen/recs.html, www​.hgvs.org/mutnomen, www​.hgvs.org/mutnomen/checklist.html [den Dunnen & Antonarakis 2000, den Dunnen & Paalman 2003]. The coding sequence is NM_000920​.3. Nucleotide +1 is the A of the ATG translation initiation codon. In brief, nucleotide changes in a single allele are listed between brackets as c.[434T>C] and changes in each allele as c.[434T>C] + [434T>C]. Nomenclature for mosaic cases is complex. Two different nucleotides found at one position on one chromosome are described as c.[2114C>A, =] (where “=” indicates the normal variant); more than two different substitutions are separated by a semicolon as c.[796T>G; =] + [=; 2114C>A, =]. Refer to www​.hgvs.org/mutnomen/examplesDNA.html for more information.

2. Note: Changes are deduced based on the findings in DNA level. “0” indicates no protein; “=” indicates WT protein synthesized. The single-letter abbreviation for amino acids is used in this table; see Quick Reference for an explanation. Nomenclature for amino acid changes follows the same general format as described above for nucleotide changes.

3. The PC /MCC +PCC ratios in individuals with PC are normalized to the ratio in normal control.

4. The PC activity is expressed as the ratio of patient/control.

5. #10 and #13 were reported by Carbone et al [1998] and Carbone et al [2002]; #11 and #12 were reported by Wexler et al [1998].

6. Nomenclature indicates the mosaic state of the two substitutions 1892G>A and 2549C>T in this allele. Together, with the other allele, these substitutions are more abundant than the ‘=’ (wild-type) in this individual.

Normal gene product. The protein consists of 1178 amino acids with a molecular weight of approximately 125 kd. It consists of a homotetramer of polypeptides, each covalently bound to a biotin molecule and processing both the catalytic and regulatory functions.

PC (EC 6.4.1.1, PC) normally serves an anaplerotic function by replenishing the Krebs cycle and intermediates the conversion of pyruvate into oxaloacetate in response to elevated acetyl-coenzyme A levels (Figure 1). The anaplerotic function of PC is important for the biosynthesis of neurotransmitters in the central nervous system, as well as energy metabolism. PC also controls the first step of hepatic gluconeogenesis and is important in lipogenesis.

The enzyme is localized within the mitochondrial matrix in many tissues. Expression is highest in the liver, kidney, adipose tissue, pancreatic islets, and lactating mammary gland. Expression is moderate in brain, heart, and adrenal gland, and least in white blood cells and skin fibroblasts [Jitrapakdee & Wallace 1999].

Abnormal gene product. In some individuals with missense mutations, the protein is expressed but lacks activity or has only residual activity. Nonsense, splice-site, and frameshift mutations identified to date result in quick degradation of mRNA. The mutagenesis studies of p.Ala610Thr, identified in Ojibwa with type A PC deficiency in a retroviral expression system have shown that the mutation may affect the stability of the protein, resulting in decreased steady-state levels of expression, and affect the secondary structure of the protein during the import process, thereby inhibiting proper translocation into the mitochondria.

References

Literature Cited

  1. Ahmad A, Kahler SG, Kishnani PS, Artigas-Lopez M, Pappu AS, Steiner R, Millington DS, Van Hove JL. Treatment of pyruvate carboxylase deficiency with high doses of citrate and aspartate. Am J Med Genet. 1999;87:331–8. [PubMed: 10588840]
  2. 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;40:519–21. [PubMed: 11583052]
  3. Carbone MA, Applegarth DA, Robinson BH. Intron retention and frameshift mutations result in severe pyruvate carboxylase deficiency in two male siblings. Hum Mutat. 2002;20:48–56. [PubMed: 12112657]
  4. Carbone MA, MacKay N, Ling M, Cole DE, Douglas C, Rigat B, Feigenbaum A, Clarke JT, Haworth JC, Greenberg CR, Seargeant L, Robinson BH. Amerindian pyruvate carboxylase deficiency is associated with two distinct missense mutations. Am J Hum Genet. 1998;62:1312–9. [PMC free article: PMC1377163] [PubMed: 9585612]
  5. De Vivo DC, Haymond MW, Leckie MP, Bussman YL, McDougal DB, Pagliara AS. The clinical and biochemical implications of pyruvate carboxylase deficiency. J Clin Endocrinol Metab. 1977;45:1281–96. [PubMed: 412860]
  6. den Dunnen JT, Antonarakis SE. Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat. 2000;15:7–12. [PubMed: 10612815]
  7. den Dunnen JT, Paalman MH. Standardizing mutation nomenclature: why bother? Hum Mutat. 2003;22:181–2. [PubMed: 12938082]
  8. DiMauro S, De Vivo DC. Diseases of carbohydrate, fatty acid and mitochondrial metabolism. In: Siegel J, ed. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. Philadelphia, PA: Lippincott-Raven Publishers; 1999:841-63.
  9. DiMauro S, Schon EA. Mitochondrial disorders in the nervous system. Annu Rev Neurosci. 2007;31:91–123. [PubMed: 18333761]
  10. García-Cazorla A, Rabier D, Touati G, Chadefaux-Vekemans B, Marsac C, de Lonlay P, Saudubray JM. Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects. Ann Neurol. 2006;59:121–7. [PubMed: 16278852]
  11. Jitrapakdee S, Wallace JC. Structure, function and regulation of pyruvate carboxylase. Biochem J. 1999;340:1–16. [PMC free article: PMC1220216] [PubMed: 10229653]
  12. Mochel F, DeLonlay P, Touati G, Brunengraber H, Kinman RP, Rabier D, Roe CR, Saudubray JM. Pyruvate carboxylase deficiency: clinical and biochemical response to anaplerotic diet therapy. Mol Genet Metab. 2005;84:305–12. [PubMed: 15781190]
  13. Nelson BA, Robinson KA, Buse MG. High glucose and glucosamine induce insulin resistance via different mechanisms in 3T3-L1 adipocytes. Diabetes. 2000;49:981–91. [PubMed: 10866051]
  14. Nyhan WL, Khanna A, Barshop BA, Naviaux RK, Precht AF, Lavine JE, Hart MA, Hainline BE, Wappner RS, Nichols S, Haas RH. Pyruvate carboxylase deficiency--insights from liver transplantation. Mol Genet Metab. 2002;77:143–9. [PubMed: 12359142]
  15. Robinson BH. Lactic Acidemia: Disorders of Pyruvate Carboxylase and Pyruvate Dehydrogenase. New York, NY: McGraw-Hill; 2000.
  16. Roe CR, Mochel F. Anaplerotic diet therapy in inherited metabolic disease: therapeutic potential. J Inherit Metab Dis. 2006;29:332–40. [PubMed: 16763896]
  17. Saudubray JM, Marsac C, Cathelineau CL, Besson Leaud M, Leroux JP. Neonatal congenital lactic acidosis with pyruvate carboxylase deficiency in two siblings. Acta Paediatr Scand. 1976;65:717–24. [PubMed: 826106]
  18. 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;28:85–9. [PubMed: 7720232]
  19. Van Coster RN, Fernhoff PM, De Vivo DC. Pyruvate carboxylase deficiency: a benign variant with normal development. Pediatr Res. 1991;30:1–4. [PubMed: 1909777]
  20. Vaquerizo Madrid J, Val Sanchez de Leon JM, Sanchez Alarcon J, Remon Alvarez-Arenas J. Congenital oculomotor apraxia and partial deficiency of pyruvate carboxylase. An Esp Pediatr. 1997;47:663–4. [PubMed: 9575131]
  21. Wang D, Yang H, De Braganca KC, Lu J, Yu Shih L, Briones P, Lang T, De Vivo DC. The molecular basis of pyruvate carboxylase deficiency: mosaicism correlates with prolonged survival. Mol Genet Metab. 2008;95:31–8. [PMC free article: PMC2572257] [PubMed: 18676167]
  22. Wexler ID, Kerr DS, Du Y, Kaung MM, Stephenson W, Lusk MM, Wappner RS, Higgins JJ. Molecular characterization of pyruvate carboxylase deficiency in two consanguineous families. Pediatr Res. 1998;43:579–84. [PubMed: 9585002]

Chapter Notes

Revision History

  • 21 July 2011 (me) Comprehensive update posted live
  • 2 June 2009 (et) Review posted live
  • 7 March 2005 (ddv) Original submission
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