Genetics of Pyruvate Carboxylase Deficiency 

Updated: Mar 15, 2019
Author: Richard E Frye, MD, PhD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG 

Overview

Background

Pyruvate carboxylase deficiency (PCD) is a rare disorder that can cause developmental delay and failure to thrive starting in the neonatal or early infantile period. Pyruvate carboxylase deficiency results in malfunction of the citric acid cycle and gluconeogenesis, thereby depriving the body of energy; the former biochemical process derives energy from carbohydrates, whereas the latter produces carbohydrate fuel for the body when carbohydrate intake is low. See the image below.

This is a diagrammatic representation of the citri This is a diagrammatic representation of the citric acid cycle and the abnormalities found in pyruvate carboxylase deficiency. The dotted line represents absent pathways. Pyruvate cannot produce oxaloacetate and is shunted to alternative pathways that produce lactic acid and alanine. The lack of oxaloacetate prevents gluconeogenesis and urea cycle function.

Metabolic acidosis caused by an abnormal lactate production is associated with nonspecific symptoms such as severe lethargy, poor feeding, vomiting, and seizures, especially during periods of illness and metabolic stress. In the most severe form, pyruvate carboxylase deficiency results in progressive neurologic symptoms, starting in the neonatal or early infantile period, include developmental delay, poor muscle tone, abnormal eye movements, or seizures. Therapies can ameliorate the biochemical abnormalities but cannot undo the progressive neurologic damage.[1]

Pathophysiology

Pyruvate carboxylase (PC) is a biotin-dependent mitochondrial enzyme that plays an important role in energy production and anaplerotic pathways.[2, 3] PC catalyzes the conversion of pyruvate to oxaloacetate. Oxaloacetate is 1 of 2 essential substrates needed to produce citrate, the first substrate in gluconeogenesis (see the image below).

This is a diagrammatic representation of the citri This is a diagrammatic representation of the citric acid cycle and the abnormalities found in pyruvate carboxylase deficiency. The dotted line represents absent pathways. Pyruvate cannot produce oxaloacetate and is shunted to alternative pathways that produce lactic acid and alanine. The lack of oxaloacetate prevents gluconeogenesis and urea cycle function.

Pyruvate carboxylase deficiency affects metabolism in several major ways, including the following[4, 5] :

  • The production of citrate, the first substrate in the citric acid cycle, is limited, thus preventing the citric acid cycle from proceeding.

  • The precursor of oxaloacetate, pyruvate, is shunted towards alternate metabolic pathways, leading to an increase in lactic acid, alanine, and acetylcoenzyme A (acetyl-CoA). Acetyl-CoA cannot produce citrate without oxaloacetate and is shunted to produce ketone bodies.

  • Gluconeogenesis cannot proceed without oxaloacetate, resulting in hypoglycemia during times of prolonged fasting. Tissues that are solely dependent on glucose for fuel, such as the brain, are severely compromised during fasting states. Because cells cannot use the citric acid cycle to produce energy, energy is extracted from glucose exclusively through glycolysis. The highly inefficient process of glycolysis causes glucose to be degraded at a very high rate, resulting in a glucose deficit, thereby compounding the problem.[6, 7]

  • Aspartic acid, which is derived from oxaloacetate, is required for the urea cycle. A decrease in aspartic acid production reduces ammonia disposal and leads to increased serum ammonia levels.

  • PC produces intermediates of the citric acid cycle that are important for nervous system function. Alpha-ketoglutarate is a precursor for the major CNS excitatory neurotransmitter, glutamate. It also has a role in producing myelin, the key substance involved in transmission of neuronal signals

  • PC also has a role in lipogenesis in adipose tissue.

The following 3 types of pyruvate carboxylase deficiency have been defined:

  • Type A: The North American phenotype is characterized by infantile onset, moderate lactate level elevation, normal lactate-to-pyruvate ratio, global developmental delay with mental retardation, and survival until adulthood.

  • Type B: The French phenotype is characterized by neonatal onset, high lactate and ammonia levels, abnormal lactate-to-pyruvate ratio, and death within the first few months of life.

  • Type C: The benign phenotype is characterized by recurrent episodes of mild-to-moderate lactate elevation without any neurological or cognitive symptoms.

Epidemiology

Frequency

United States

Pyruvate carboxylase deficiency is a rare disorder, with an approximate incidence of 1 in 250,000 births. Infantile-onset pyruvate carboxylase deficiency (A type) is more common in the United States. An increased incidence has been documented among certain populations, most notably native North American Indians who speak the Algonquian dialect. A founder effect has been postulated.

International

Neonatal onset pyruvate carboxylase deficiency (B type) has a higher incidence in France.

Mortality/Morbidity

Most patients with type B pyruvate carboxylase deficiency die within the first 6 months of life. Some therapies may reduce the biochemical dysfunction. However, progressive neurologic deterioration results in significant morbidity. Severe energy deficit in the CNS causes neurologic symptoms and congenital brain malformations due to a lack of energy during neurogenesis. In neonates with apparently normal brains, progressive neurologic deterioration varies. Hypomyelination, cystic lesions, and gliosis of the cortex or cerebellum with gray matter degeneration or necrotizing encephalopathy occur in some infants. Others develop Leigh syndrome, which is a gliosis of the brainstem and basal ganglia with capillary proliferation and characteristic changes on CT scanning and MRI. Most patients with the type A pyruvate carboxylase deficiency live into adulthood but have global neurological and cognitive dysfunction.

Age

The age of presentation for the most serious forms varies from the prenatal period to early infancy. Severe disease has prenatal onset and is associated with congenital brain abnormalities. Type A pyruvate carboxylase deficiency manifests in early infancy. The benign form manifests as periods of lactic acidosis anytime during life.

 

Presentation

History

The following are important aspects in the history of patients with pyruvate carboxylase deficiency (PCD):

  • Birth: Low Apgar scores and small size for gestational age are nonspecific symptoms of metabolic disturbance during gestation.

  • General: The development of poor feeding, vomiting, and lethargy are nonspecific but common symptoms of metabolic illnesses. If these symptoms are instigated by a mild viral illness and are more severe than would be expected, a metabolic disturbance should be considered, especially after a bacterial infection has been ruled out.

  • Development: Mental, psychomotor, and/or growth retardation are nonspecific symptoms of metabolic disease.

  • Neurologic: Poor acquisition or loss of motor milestones, new-onset seizures, episodic incoordination, abnormal eye movements, and poor response to visual stimuli are signs of poor neurologic development or degenerative disease.

  • Respiratory: A history of apnea, dyspnea, or respiratory depression is consistent with neurologic disease or severe lactic acidosis.

Physical

Neurologic findings include the following:

  • Hypotonia, ataxia, tremors, and choreoathetosis are consistent with pyruvate carboxylase deficiency.

  • Progressive motor pathway degeneration results in a present Babinski sign and spastic diplegia or quadriplegia.

  • Ophthalmologic examination may reveal poor visual tracking, grossly dysconjugate eye movements, poor pupillary response, and blindness.

  • Prenatal microcephaly or postnatal microcephaly also may be evident on physical examination.

Intermittent hyperpnea at rest, apnea, dyspnea, Cheyne-Stokes respiration, and respiratory failure are nonspecific signs of metabolic and neurologic disease or severe acidosis.

Hepatomegaly is also noted.

Causes

The gene that encodes pyruvate carboxylase (PC) has been localized to bands 11q13.4-q13.5.

An autosomal recessive inheritance pattern is characteristic.

Neonatal pyruvate carboxylase deficiency is associated with complete absence of messenger ribonucleic acid (mRNA) and the PC enzyme protein.

Infantile-onset pyruvate carboxylase deficiency is associated with a residual enzyme activity less than 2% of normal levels.

 

DDx

 

Workup

Laboratory Studies

The following should be assessed in patients with pyruvate carboxylase deficiency (PCD):

Lactate and pyruvate levels

High blood lactate and pyruvate levels with or without a lactic aciduria suggests an inborn error of energy metabolism.

An increased lactate-to-pyruvate ratio is characteristic of citric acid cycle disorders.

This ratio may be particularly elevated during periods of crisis, such as illness or metabolic stress.

Hypoglycemia

Hypoglycemia during fasting results from greatly reduced gluconeogenesis.

Period of fasting required to produce symptoms is much shorter in pyruvate carboxylase deficiency than other disorders.

Amino acid levels

Measurement of serum amino acids reveals hyperalaninemia, hypercitrullinemia, hyperlysinemia, and low aspartic acid levels.

Hyperalaninemia is due to the pyruvate shunting.

Hypercitrullinuria and hyperlysinemia result from a metabolic block in the urea cycle due to a low aspartic acid.

Low aspartic acid is due to the deficiency in the oxaloacetate precursor.

Amino acid levels vary with the general metabolic state of the patient. If the patient is in a catabolic state, proteins are degraded, resulting in the elevation of many amino acids and a nonspecific amino acid profile.

Other studies

Hyperammonemia results from poor ammonia disposal and decreased urea cycle function.

Abnormal enzyme function can be detected by functional assays performed on leukocytes, fibroblasts, or properly preserved tissue samples.

The severe form of pyruvate carboxylase deficiency can be diagnosed by demonstrating the absence of pyruvate carboxylase (PC) mRNA or specific cross-reacting material.

Cerebrospinal fluid (CSF) shows an elevation of lactate and pyruvate.

CSF glutamine is markedly reduced, whereas glutamic acid and proline levels are elevated.

Imaging Studies

MRI

Type B pyruvate carboxylase deficiency is associated with ventricular dilation, cerebrocortical and white matter atrophy, or periventricular white matter cysts.

Type A pyruvate carboxylase deficiency is associated with symmetric cystic lesions and gliosis in the cortex, basal ganglia, brainstem, or cerebellum and/or generalized hypomyelination, as well as hyperintensity of the subcortical fronto-parietal white matter.

Magnetic resonance spectroscopy (MRS)

Brain MRS shows high lactate levels, as well as levels of N -acetylaspartate and choline consistent with hypomyelination.

Histologic Findings

Histologic examination of the liver may reveal lipid droplet accumulation.

CNS neuropathology may include poor myelination, paucity of cerebral cortex neurons, gliosis, and proliferation of astrocytes.

 

Treatment

Medical Care

Treatments in patients with pyruvate carboxylase deficiency (PCD) are aimed at stimulating the pyruvate dehydrogenase complex (PDC) and providing alternative fuels. Correction of the biochemical abnormality can reverse some symptoms, but central nervous system damage progresses regardless of treatment.

The PDC can provide an alternative pathway for pyruvate metabolism PDC activity can be optimized by cofactor supplementation with thiamine and lipoic acid and administration of dichloroacetate. Increased pyruvate metabolism through this pathway can help reduce the pyruvate and lactate levels.

Biotin supplementation is given to help optimize the residual enzyme activity but is usually of little use.

Citrate supplementation reduces the acidosis and provides the needed substrate in the citric acid cycle.

Aspartic acid supplementation allows the urea cycle to proceed and reduces the ammonia level.

One patient reportedly was successfully treated with a continuous nocturnal gastric drip feeding of uncooked cornstarch.

Triheptanoin has reportedly reversed hepatic failure and biochemical abnormalities in one case by presumably providing a source of acetyl-CoA and anaplerotic propionyl-CoA. However, life expectancy was not prolonged.

Orthotopic liver transplantation has reversed the biochemical abnormalities in one patient.[8]

Consultations

Evaluation by an expert in metabolic and genetic disorders is necessary to confirm the diagnosis, guide the appropriate treatment, and determine the prognosis.

Genetic counseling for the parents is important in order to determine the risk of recurrence in future pregnancies.

Diet

Diet has a small effect on outcome.

A high-carbohydrate, high-protein diet may help to maintain an anabolic state and prevent activation of gluconeogenesis.

 

Medication

Medication Summary

Sodium dichloroacetate is a compound that is believed to activate the PDC by inhibiting the inactivating kinase, resulting in decreased lactate production and promotion of pyruvate oxidation.

Acute decompensation during illness in patients with PCD requires management of the acidosis with hydration and intravenous bicarbonate.

Enzyme activator

Class Summary

Dichloroacetate (DCA) sodium is the only drug found to activate the enzyme complex.

Sodium dichloroacetate

Designated as an orphan drug in the United States. Used to treat lactic acidosis. This is a compound that is believed to activate the PDC by inhibiting the inactivating kinase, resulting in decreased lactate production and promotion of pyruvate oxidation.

Alkalinizing agents

Class Summary

Sodium bicarbonate is used as a gastric, systemic, and urinary alkalinizer and has been used in the treatment of acidosis resulting from metabolic and respiratory causes, including diabetic coma, diarrhea, kidney disturbances, and shock. Sodium bicarbonate also increases renal clearance of acidic drugs.

Sodium bicarbonate

Bicarbonate can be used to correct the acidosis in chronic and acute settings.

Citrate solutions (Bicitra, Polycitra)

Several solutions containing citrate with sodium or potassium or both are available as alkalinizing agents. With normal hepatic function, 1 mEq of citrate is converted to 1 mEq of bicarbonate.

 

Follow-up

Further Outpatient Care

Lactate levels should be closely monitored.

A dietary log should be completed to help evaluate dietary manipulations and to ensure compliance.

An informational statement that describes the child's disorder and the appropriate medical treatment for the disorder in an emergency setting should be carried by the parents at all times.

Further Inpatient Care

Acute decompensation during illness in patients with pyruvate carboxylase deficiency (PCD) requires admission and management of the acidosis with hydration and intravenous bicarbonate.

The patient must be supplied with adequate carbohydrates.

Prognosis

Although diet manipulation and supplementation of substrates and cofactors can reverse some of the biochemical abnormalities, neurologic abnormalities typically progress, and demise within the first 6 months of life is the rule.

Enzyme activity of cultured chorionic villus cells can be determined in time to allow for early prenatal diagnosis.

Patient Education

The patient and the parents should be well educated on the factors that elicit a crisis and the early signs of decompensation.

For excellent patient education resources, please refer to eMedicinehealth.