Summary
Clinical 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
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 is established in a proband by identification of PC enzyme deficiency in fibroblasts or lymphoblasts. In individuals with PC deficiency, fibroblast PC enzyme activity is usually less than 5% of that observed in controls. The diagnosis of PC deficiency can also be established in a proband by identification of biallelic pathogenic variants in PC on molecular genetic testing.
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 affected individuals. Anaplerotic therapies such as triheptanoin show some promise, especially regarding the neurologic manifestations, but need to be further evaluated.
Prevention of primary manifestations: Parental education regarding factors that elicit a crisis and early signs of decompensation; written information on the child's disorder and appropriate emergency treatment to be carried at all times; minimization of intercurrent infections and environmental stressors; high-carbohydrate and high-protein diet with frequent feedings to prevent dependence on gluconeogenesis.
Prevention of secondary complications: Hospitalization for the management of fever, infection, dehydration, or trauma; intensive proactive medical support to prevent dehydration, hypotension, hypoglycemia, and increasing metabolic acidosis.
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 pathogenic variants have been reported. If both parents are carriers, sibs of an individual with PC deficiency have a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being carriers, and a 25% chance of inheriting both normal genes and not being carriers. Carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible by molecular genetic testing if both pathogenic variants have been identified in an affected family member.
Clinical Characteristics
Clinical Description
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 [Wang et al 2008].
Type B (severe neonatal form). 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 abnormal ocular behavior.
Motor development is severely retarded and affected individuals have intellectual disability [Wang et al 2008].
The majority of affected infants die within the first three months of life [García-Cazorla et al 2006]; however, two affected individuals were 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 frontoparietal white matter were described in some individuals with type A.
Ventricular dilatation, 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 pathogenic variants (p.Arg62Cys, p.Val145Ala, p.Arg451Cys, p.Ala610Thr, p.Arg631Gln, p.Met743Ile, and p.Ala847Val) have been identified in five individuals [Wang et al 2008].
Type B. Missense variants, deletions, and splice donor site pathogenic variants occur in homozygotes, compound heterozygotes, and individuals with mosaicism (see Table 2) [Wang et al 2008].
Type C. A heterozygous variant (p.Ser266Ala) and somatic mosaic variant (p.Ser705Ter) were observed in the first individual described [Wang et al 2008]; compound heterozygosity for the pathogenic variants p.Thr569Ala and p.Leu1137ValfsTer34 was observed in the second individual described [Wang et al 2008].
Mosaicism (see Molecular Genetics) was found in five individuals [Wang et al 2008: Table 2 (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 pathogenic variants. The deaths of the more severely affected individuals with type B correlated with homozygous variants, which produced very low amounts (2% and 3%) of fibroblast PC protein [Wang et al 2008: Table 2].
Prevalence
In most populations, the birth incidence of PC deficiency is low (1:250,000).
PC deficiency is more prevalent in particular ethnic groups:
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 pathogenic variants in BTD. Individuals with profound biotinidase deficiency have less 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. Blood glucose values are normal and decline only slowly with fasting because of increased pyruvate carboxylation and gluconeogenesis. Blood ketone bodies are usually not detectable, unlike PC deficiency. Also, unlike PC deficiency, PDHC 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; and generalized hypomyelination.
Brain MRS shows high lactate concentrations (giving rise to the term "cerebral lactic acidosis") and low N-acetylaspartate and choline concentrations consistent with hypomyelination.
PDHC enzyme assay, immunoblotting analysis, and molecular genetic testing of the genes known to be associated with this disorder (see Primary Pyruvate Dehydrogenase Complex Deficiency Overview) can help establish the diagnosis.
Respiratory chain disorder may result from pathogenic variants in nuclear genes or mitochondrial genes that encode any one of the five respiratory chain 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 pathogenic nuclear DNA variants causing intergenomic signaling defects and pathogenic mitochondrial DNA variants affecting protein synthesis genes. Brain MRI may reveal distinctive abnormalities, as described with Leigh syndrome or mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) [DiMauro & Schon 2008]. Nuclear gene variants are inherited in an autosomal recessive or dominant manner; mitochondrial DNA variants 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.
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.
Carbonic anhydrase VA deficiency is suspected in children with neonatal, infantile, or early-childhood metabolic hyperammonemic encephalopathy combined with hyperlactatemia and metabolites suggestive of multiple carboxylase deficiency. The diagnosis is established in a proband with these metabolic findings and biallelic pathogenic variants in CA5A.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with pyruvate carboxylase (PC) deficiency, the evaluations summarized in this section are recommended (if not performed as part of the evaluation that led to the diagnosis):
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
Consultation with a clinical geneticist and/or genetic counselor
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].
Prevention of Primary Manifestations
Educate parents about the factors that elicit a crisis and the early signs of decompensation.
Carry written information regarding the child's disorder and appropriate treatment in an emergency setting.
Minimize intercurrent infections and environmental stressors.
Provide a high-carbohydrate and high-protein diet with frequent feedings to help prevent dependence on gluconeogenesis.
Prevention of Secondary Complications
Individuals with PC deficiency are very brittle metabolically. Intensive medical support is indicated proactively to prevent dehydration, hypotension, hypoglycemia, and increasing metabolic acidosis. Hospitalization is indicated for the management of fever, infection, dehydration, or trauma. The ketogenic diet is an absolute contraindication, shown to worsen the acidosis into a life-threatening range.
Surveillance
Monitor lactate levels regularly.
Agents/Circumstances to Avoid
Avoid the following:
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 pyruvate dehydrogenase complex (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.
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 in the US and EU Clinical Trials Register in Europe for 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, mode(s) of 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; it is not meant to address all personal, cultural, or
ethical issues that may arise 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
Sibs of a proband
If both parents are carriers, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants, a 50% chance of inheriting one
pathogenic variant, and a 25% chance of inheriting neither pathogenic variant.
Sibs who inherit two pathogenic variants will be affected. Sibs who inherit one
pathogenic variant (heterozygotes) are expected to be asymptomatic. A sib who is
heterozygous for an inherited pathogenic variant could be affected if the sib has a
de novo somatic
PC pathogenic variant.
Offspring of a proband. The offspring of a proband are typically heterozygous for a pathogenic variant.
Other family members. Each sib of a heterozygous parent is at a 50% risk of being a carrier.
Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the PC pathogenic variants in the family.
Biochemical genetic testing for carrier status is not reliable.
Prenatal Testing and Preimplantation Genetic Testing
Molecular genetic testing. Once the PC pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk for PC and preimplantation genetic testing are possible.
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
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Gene | Chromosome Locus | Protein | Locus-Specific Databases | HGMD | ClinVar |
---|
PC
| | Pyruvate carboxylase, mitochondrial |
PC database
|
PC
|
PC
|
Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Molecular 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 (see ).
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.
Gene structure.
PC contains 20 coding exons and four noncoding exons at the 5'-UTR [Wang et al 2008]. All four noncoding exons are involved in alternative splicing, resulting in three tissue-specific PC transcripts carrying the same coding region: variant 1 (4004 bp, NM_000920.3), variant 2 (3959 bp, NM_022172.2), and variant 3 (4192 bp, NM_001040716.1) (). Southern blotting of human genomic DNA showed that PC exists in a single copy and no pseudogenes are detected. For a detailed summary of gene and protein information, see Table A, Gene.
PC structure and three transcript variants. The coding exons of PC are represented by rectangles with different patterns and Arabic numbers on the top. The four untranslated exons (UEs) are labeled UE1-UE4 (top left). The arrows before UE1, UE2, and UE4 (more...)
Pathogenic variants. Missense, nonsense, frameshift, and splice site variants in PC are associated with PCD. Mosaicism, in which the abnormal allele was typically present in a greater proportion than the normal allele, was found in five individuals [Wang et al 2008]. Four had prolonged survival.
Of note, two substitutions – c.1892G>A (p.Arg631Gln) and c.2549C>T (p.Ala847Val) – were found in a mosaic state on the same allele in three individuals [Wang et al 2008].
Table 2.
PC Variants Discussed in This GeneReview
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DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
---|
c.184C>T | p.Arg62Cys |
NM_000920.4
NP_000911.2
|
c.434T>C | p.Val145Ala |
c.796T>A | p.Ser266Ala |
c.1351C>T | p.Arg451Cys |
c.1705A>G | p.Thr569Ala |
c.1828G>A | p.Ala610Thr |
c.1892G>A | p.Arg631Gln 1, 2 |
c.2114C>A | p.Ser705Ter 1 |
c.2229G>T | p.Met743Ile |
c.2540C>T | p.Ala847Val 1, 2 |
c.3409_3410delCT | p.Leu1137ValfsTer34 |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Indicates the mosaic state of this allele
- 2.
These variants have been observed in cis.
Normal gene product. The protein consists of 1,178 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 intermediates. PC catalyzes the conversion of pyruvate to oxaloacetate; this reaction is allosterically activated by elevated acetyl-coenzyme A levels (). 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 lowest in white blood cells and skin fibroblasts [Jitrapakdee & Wallace 1999].
Abnormal gene product. Loss of protein function may occur from loss of mRNA expression or loss or reduction of functional activity of PC. Individuals with mosaic pathogenic variants retained greater enzyme activity than those with non-mosaic pathogenic variants [Wang et al 2008].