Pyruvate carboxylase deficiency

Alternate names

PC deficiency; Ataxia with lactic acidosis 2; Leigh necrotizing encephalopathy due to pyruvate carboxylase deficiency; Leigh syndrome due to pyruvate carboxylase deficiency.

Definition

Pyruvate carboxylase deficiency is an inherited disorder that causes lactic acid and other potentially toxic compounds to accumulate in the blood. High levels of these substances can damage the body's organs and tissues, particularly in the nervous system.

Types

Researchers have identified at least three types of pyruvate carboxylase deficiency, types A, B, and C, which are distinguished by the severity of their signs and symptoms.

Epidemiology

Pyruvate carboxylase deficiency is a rare condition, with an estimated incidence of 1 in 250,000 births worldwide. Type A appears to be much more common in some Algonkian Indian tribes in eastern Canada.

Cause

• Mutations in the PC gene cause pyruvate carboxylase deficiency. This gene provides instructions for making an enzyme called pyruvate carboxylase. This enzyme is active in mitochondria, which are the energy-producing centers within cells. It is involved in several important cellular functions, including the generation of glucose, a simple sugar that is the body's main energy source.
• Pyruvate carboxylase also plays a role in the formation of the protective sheath that surrounds certain nerve cells (myelin) and the production of brain chemicals called neurotransmitters that allow nerve cells to communicate with one another.
• Mutations in the PC gene reduce the amount of pyruvate carboxylase in cells or disrupt the enzyme's activity. The missing or altered enzyme cannot carry out its essential role in generating glucose, which impairs the body's ability to make energy in mitochondria.
• Additionally, a loss of pyruvate carboxylase allows compounds such as lactic acid and ammonia to build up and damage organs and tissues. Researchers suggest that the loss of pyruvate carboxylase function in the nervous system, particularly the role of the enzyme in myelin formation and neurotransmitter production, also contributes to the neurologic features of pyruvate carboxylase deficiency.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

TypeA Type A, which has been identified mostly in people from North America, has severe symptoms that begin in infancy.

• Characteristic features include developmental delay and a buildup of lactic acid in the blood (lactic acidosis). Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, and difficulty breathing.
• In some cases, episodes of lactic acidosis are triggered by an illness or periods without food (fasting). Children with pyruvate carboxylase deficiency type A typically survive only into infancy or early childhood.

TypeB Pyruvate carboxylase deficiency type B has life-threatening signs and symptoms that become apparent shortly after birth. This form of the condition has been reported mostly in Europe, particularly France. Affected infants have severe lactic acidosis, a buildup of ammonia in the blood (hyperammonemia), and liver failure. They experience neurological problems including weak muscle tone (hypotonia), abnormal movements, seizures, and coma. Infants with this form of the condition usually survive for less than 3 months after birth.

TypeC A milder form of pyruvate carboxylase deficiency, sometimes called type C, has also been described. This type is characterized by slightly increased levels of lactic acid in the blood and minimal signs and symptoms affecting the nervous system.

Diagnosis

• 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.

Treatment

Intravenous glucose-containing fluids, hydration, and correction of the metabolic acidosis are the mainstays of acute management.[1].

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.

NIH genetic and rare disease info

• NIH info on Pyruvate carboxylase deficiency

Pyruvate carboxylase deficiency is a rare disease.

Pyruvate carboxylase deficiency Resources
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