eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Pyruvate Carboxylase Deficiency

Author: Richard E Frye, MD, PhD, Assistant Professor, Departments of Pediatrics and Neurology, University of Texas Health Science Center at Houston
Coauthor(s): Paul J Benke, MD, PhD, Director of Clinical Genetics, Joe DiMaggio Children's Hospital
Contributor Information and Disclosures

Updated: Nov 6, 2009

Introduction

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.

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.

Pathophysiology

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

Pyruvate carboxylase deficiency affects metabolism in several major ways, including the following:

• 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.
• 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.

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.

Clinical

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

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.

• Search for CME/CE on This Topic »

• Pyruvate Carboxylase Deficiency (Endocrinology)
• Hyperammonemia (Neurology)
• Lactic Acidosis (Emergency Medicine)
• Ataxia with Identified Genetic and Biochemical Defects (Neurology)