Pyruvate Carboxylase Deficiency

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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.

Diagnosis

There are three clinical presentations of pyruvate carboxylase (PC) deficiency:

  • Type A. Infantile or North American form
  • Type B. Severe neonatal or French form
  • Type C. Intermittent/benign form

Suggestive Findings

PC deficiency should be suspected in individuals with the following clinical features and biochemical findings.

Clinical features

  • Failure to thrive
  • Developmental delay
  • Recurrent seizures

Biochemical findings by PC deficiency type [Wang et al 2008]

  • Type A. Infantile-onset mild to moderate lactic acidemia; normal lactate-to-pyruvate ratio despite acidemia
  • Type B. Increased lactate-to-pyruvate ratio; decreased 3-hydroxybutyrate-to-acetoacetate ratio; elevated blood concentrations of citrulline, proline, lysine, and ammonia; low concentration of glutamine
  • Type C. Episodic metabolic acidosis with normal plasma citrulline concentrations and elevated plasma lysine and proline concentrations

Biochemical abnormalities by analyte. Note: For each of the following analytes the abnormal values overlap among PC deficiency 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 to 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

Establishing the Diagnosis

The diagnosis of PC deficiency is established in a proband by identification of PC enzyme deficiency in fibroblasts or lymphoblasts by PC enzyme assay. In individuals with PC deficiency, fibroblast PC enzyme activity is usually less than 5% of that observed in controls [Wang et al 2008]. Note: Muscle PC activity is quite low in control tissue. Therefore, PC enzyme assay on muscle tissue is not recommended.

The diagnosis of PC deficiency can also be established in a proband by identification of biallelic pathogenic variants in PC on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

  • Single-gene testing. Sequence analysis of PC is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
    Note: (1) Pathogenic variants have been found to be mosaic, an unusual occurrence in an autosomal recessive disorder (see Genotype-Phenotype Correlations and Molecular Genetics). (2) Since PC deficiency occurs through a loss-of-function mechanism, testing for intragenic deletions or duplication could identify a disease-causing variant; such a variant has not been reported.
  • A multigene panel that includes PC and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing, mitochondrial sequencing, and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Pyruvate Carboxylase Deficiency

Gene 1Method 2Proportion of Probands with Pathogenic Variants 3 Detectable by Method
PCSequence analysis 495% 5
Gene-targeted deletion/duplication analysis 6Unknown 7
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

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

3.

See Molecular Genetics for information on allelic variants detected in this gene.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Sequence analysis of the PC coding region and promoter detects pathogenic variants in 95% of affected individuals, including the most common pathogenic variants: p.Ala610Thr, p.Arg631Gln, and p.Ala847Val.

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

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 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 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 Leu1137ValfsTer1170 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:

  • Type A. Incidence is increased among the native North American Ojibwa, Cree, and Micmac tribes of the Algonquin-speaking peoples. The p.Ala610Thr pathogenic variant 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 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 (OMIM PS312170) 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 sequence analysis of two of the genes known to be associated with this disorder, PDHA1 and DLAT, 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].

  • 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 little effect on the neurologic disturbances as the aspartate does not enter the brain freely [Ahmad et al 1999]. Lowering the body ammonia burden may mitigate the neurologic insult.
  • Biotin supplementation is given to help optimize the residual PC enzyme activity but is usually of little efficacy.
  • 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, Mochel 2017]. 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 affected individuals.
  • Orthotopic liver transplantation has reversed the biochemical abnormalities in two affected individuals [Nyhan et al 2002].

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:

  • Fasting
  • The ketogenic diet, which aggravates 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 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.

  • An individual with PC deficiency was responsive to treatment with thiamine.
  • 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 individuals 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.

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