Pyruvate carboxylase (PC) deficiency is a rare disorder that can cause developmental delay and failure to thrive starting in the neonatal or early infantile period. All patients who develop symptoms in the first weeks and months of life have lactic acidosis.
PC 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. Oxaloacetate is 1 of 2 essential substrates needed to produce citrate, the first substrate in gluconeogenesis.[1]
PC deficiency results in malfunction of the citric acid cycle and of gluconeogenesis (as seen in the diagram below), thereby depriving the body of energy. The citric acid cycle derives energy from carbohydrates, while gluconeogenesis produces carbohydrate fuel for the body when carbohydrate intake is low. Loss of PC activity and the citric acid (Krebs) cycle lead to decreased glutamate production, important in the nervous system. See the figure below.
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Diagrammatic representation of the citric acid cycle and the abnormalities found in pyruvate carboxylase deficiency (PCD). The dotted line represents ....
Metabolic acidosis caused by 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, including developmental delay, poor muscle tone, abnormal eye movements, and seizures. Therapies such as alkalinization can ameliorate the biochemical abnormalities, but cannot prevent the progressive neurologic damage that occurs. PC also has a role in lipogenesis in adipose tissue.
Types of pyruvate carboxylase deficiency
The following types of PC deficiency have been defined[2] :
Type A - The North American phenotype; characterized by infantile onset, moderate lactate elevation, normal lactate-to-pyruvate ratio, global developmental delay with mental retardation, and survival until adulthood
Type B - The French phenotype; characterized by neonatal onset, high lactate and ammonia elevation, abnormal lactate-to-pyruvate ratio, and death within the first few months of life
Type C - The benign phenotype; characterized by recurrent episodes of mild to moderate lactate elevation without any neurologic or cognitive symptoms.
Consultations
Evaluation of the patient by an expert in metabolic and genetic disease is necessary to confirm the diagnosis, guide appropriate treatment, and determine prognosis. Enzyme testing and DNA confirmation are available. Genetic counseling for parents is important in order to discuss the 1 in 4 recurrence risk for future pregnancies.
Patient education
The patient and the parents should be well educated on the factors that elicit a crisis and the early signs of decompensation.
Pyruvate carboxylase (PC) deficiency affects metabolism in several major ways. The production of citrate, the first substrate in the citric acid cycle, is limited, thus preventing the citric acid cycle from functioning, shown in the figure below.
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Diagrammatic representation of the citric acid cycle and the abnormalities found in pyruvate carboxylase deficiency (PCD). The dotted line represents ....
The precursor of oxaloacetate, pyruvate, is shunted toward 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 also 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,[3] 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 high rate, resulting in a glucose deficit, thereby compounding the problem.
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 central nervous system excitatory neurotransmitter, glutamate. PC also has a role in producing myelin, the key substance involved in transmission of neuronal signals.
The gene that encodes pyruvate carboxylase (PC) has been localized to chromosome band 11q13.4-q13.5. PC deficiency is inherited from parents by an autosomal recessive inheritance pattern. Neonatal PC deficiency is associated with a complete absence of PC messenger ribonucleic acid (mRNA) and the PC enzyme protein. Infantile-onset PC deficiency is associated with residual enzyme activity that is less than 2% of normal.
In a study by Monnot et al, the authors concluded that their results, along with data already culled from previously identified PC mutations, indicated that type A PC deficiency is caused by the association of 2 missense mutations found in either the biotin carboxylase or carboxyltransferase (N-terminal part) domain of the PC molecule, while type B consistently arises from at least 1 truncating mutation, which in most cases occurs in PC's carboxyltransferase (C-terminal part) or biotin carboxyl carrier protein domain. The investigators examined 9 novel mutations of the PC gene in 5 unrelated patients, 2 of whom had type A and 3 of whom had type B PC deficiency.[4, 5]
Pyruvate carboxylase (PC) deficiency is a rare disorder, with an approximate incidence of 1 in 250,000 births. Infantile-onset type A PC deficiency is more common in the United States. An increased incidence has been documented among certain populations, most notably native North Americans who speak the Algonquin dialect. A founder effect has been postulated.
The neonatal onset type B pyruvate carboxylase deficiency has a greater incidence in France, although it has been described in Canada, Egypt, and Saudi Arabia.
Age of presentation for the most serious forms varies from the prenatal period to early infancy. Severe disease has prenatal onset with congenital brain abnormalities. Type A cases manifest in early infancy. The benign form manifests as periods of lactic acidosis anytime during life.
Although dietary manipulation and supplementation of substrates and cofactors can reverse some of the biochemical abnormalities in type B PC deficiency, neurologic abnormalities progress and most patients die within the first 6 months of life.[6] The severe energy deficit in the central nervous system causes neurologic symptoms and congenital brain malformation due to a lack of energy during neurogenesis.
In neonates with apparently normal brains, progressive neurologic deterioration is variable. 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 computed tomography (CT) and magnetic resonance imaging (MRI) scans.
Most patients with the type A pyruvate carboxylase deficiency live into adulthood but have global neurologic and cognitive dysfunction.
Patient history in pyruvate carboxylase (PC) deficiency is characterized as follows:
Birth - Low Apgar scores and an infant small for dates are nonspecific signs of a metabolic disturbance during gestation
General - Development of poor feeding, vomiting, and lethargy are nonspecific, but common, symptoms of metabolic illnesses; symptoms can be initiated by a mild viral illness and are out of proportion to the severity of the illness
Developmental - Mental, psychomotor, and/or growth retardation are nonspecific signs 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[7]
Respiratory - A history of apnea, dyspnea, or respiratory depression is consistent with neurologic disease or severe lactic acidosis.
Physical examination findings in pyruvate carboxylase (PC) deficiency are neurologic, respiratory, and abdominal. Hypotonia, ataxia, tremors, and choreoathetosis are consistent with PC deficiency. Progressive motor pathway degeneration results in positive Babinski sign and spastic diplegia or quadriplegia. Ophthalmologic examination may reveal poor visual tracking, grossly disconjugate eye movements, poor pupillary response, and/or blindness. Prenatal 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. Abdominally, hepatosplenomegaly may be appreciated.
High blood lactate and pyruvate levels with or without 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.
Cerebrospinal fluid shows an elevation of lactate and pyruvate. Cerebrospinal fluid glutamine is markedly reduced, while glutamic acid and proline levels are elevated.
Hypoglycemia
Hypoglycemia may occur during fasting because of reduced gluconeogenesis. The period of fasting required to produce symptoms is much shorter in pyruvate carboxylase (PC) deficiency than in other disorders.
Hyperammonemia
Hyperammonemia results from the poor ammonia disposal and decreased urea cycle function.
Abnormal enzyme function
Abnormal enzyme function can be detected by a functional assay performed on leukocytes, fibroblasts, or properly preserved tissue samples. PC deficiency is inherited in an autosomal recessive manner. Enzyme activity of cultured chorionic villus cells can be determined in time for early termination of the pregnancy.
Absence of mRNA
The severe form of PC deficiency can be diagnosed by demonstrating the absence of PC messenger ribonucleic acid (mRNA) or specific cross-reacting material.
Histologic findings
Histologic examination of the liver may reveal lipid droplet accumulation. Central nervous system neuropathology may include poor myelination, paucity of cerebral cortex neurons, gliosis, and proliferation of astrocytes. Some patients demonstrate nemaline rods on muscle biopsy.[8]
Measurement of serum amino acids may reveal the following:
Hyperalaninemia - Due to pyruvate shunting
Low aspartic acid - Due to the deficiency of the oxaloacetate precursor
Hypercitrullinuria and hyperlysinemia - Result from a metabolic block in the urea cycle due to low aspartic acid
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.
Type B pyruvate carboxylase (PC) deficiency is associated with ventricular dilation, cerebrocortical and white matter atrophy, or periventricular white matter cysts.
Type A is associated with symmetrical cystic lesions and gliosis in the cortex, basal ganglia, brainstem, or cerebellum and/or generalized hypomyelination, as well as hyperintensity of the subcortical frontoparietal white matter.
Magnetic resonance spectroscopy
Brain MR spectroscopy shows high lactate levels, as well as levels of N -acetylaspartate and choline consistent with hypomyelination.
Treatments are aimed at stimulating the pyruvate dehydrogenase complex and providing alternative fuels. Correction of the biochemical abnormality can reverse some symptoms, but central nervous system damage progresses regardless of treatment. (Orthotopic liver transplantation reversed the biochemical abnormalities in one patient.)
The pyruvate dehydrogenase complex can provide an alternative pathway for pyruvate metabolism. Pyruvate dehydrogenase complex activity can be optimized by cofactor supplementation with thiamine and lipoic acid and administration of dichloroacetate. Increased pyruvate metabolism through this pathway can help to reduce the pyruvate and lactate levels.
Other pharmacologic treatments include the following:
Biotin supplementation - Administered to help optimize residual enzyme activity, but it is usually of little use except potentially in a mildly affected type 3 patient
Citrate supplementation - Reduces 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
Cornstarch - One patient was reportedly treated successfully with continuous, nocturnal gastric-drip feeding with uncooked cornstarch
Triheptanoin - Triheptanoin - Has reportedly reversed hepatic failure and biochemical abnormalities in 1 case, presumably by providing a source of acetyl-CoA and anaplerotic propionyl-CoA; however, life expectancy was not prolonged and recent evidence suggests triheptanoin is ineffective[9]
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.[10] A dietary log should be completed to help evaluate dietary manipulations and to ensure compliance.
Acute decompensation during illness requires admission to the hospital and management of the acidosis with hydration and intravenous bicarbonate. The patient must be supplied with adequate carbohydrates.
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 patient’s parents at all times.
Richard E Frye, MD, PhD, Professor of Child Health, University of Arizona College of Medicine at Phoenix; Chief of Neurodevelopmental Disorders, Director of Autism and Down Syndrome and Fragile X Programs, Barrow Neurological Institute at Phoenix Children's Hospital
Disclosure: Nothing to disclose.
Coauthor(s)
Paul J Benke, MD, PhD, Director of Clinical Genetics, Joe DiMaggio Children's Hospital
Disclosure: Nothing to disclose.
Chief Editor
George T Griffing, MD, Professor Emeritus of Medicine, St Louis University School of Medicine
Disclosure: Nothing to disclose.
Acknowledgements
Elena Citkowitz, MD, PhD, FACP Clinical Professor of Medicine, Yale University School of Medicine; Director, Cholesterol Management Center, Director, Cardiac Rehabilitation, Department of Medicine, Hospital of St Raphael
Elena Citkowitz, MD, PhD, FACP is a member of the following medical societies: American College of Physicians, American Heart Association, National Lipid Association, and Sigma Xi
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Reference Salary Employment
Kent Wehmeier, MD Professor, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, St Louis University School of Medicine
Kent Wehmeier, MD is a member of the following medical societies: American Society of Hypertension, Endocrine Society, and International Society for Clinical Densitometry
Diagrammatic representation of the citric acid cycle and the abnormalities found in pyruvate carboxylase deficiency (PCD). 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 limits gluconeogenesis and urea cycle function.
Diagrammatic representation of the citric acid cycle and the abnormalities found in pyruvate carboxylase deficiency (PCD). 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 limits gluconeogenesis and urea cycle function.
Diagrammatic representation of the citric acid cycle and the abnormalities found in pyruvate carboxylase deficiency (PCD). 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 limits gluconeogenesis and urea cycle function.
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