Pyruvate dehydrogenase deficiency
Pyruvate dehydrogenase deficiency is a rare condition characterized by the buildup of lactic acid in the body and a variety of neurological problems that typically appear shortly after birth.
Overview
Pyruvate dehydrogenase deficiency is a rare condition where the body cannot properly convert energy from food into a usable form for cells. This leads to a buildup of a chemical called lactic acid (lactic acidosis) and significant neurological impairment. Signs and symptoms vary widely but often include nausea, vomiting, breathing difficulties, and abnormal heartbeats. Because of the severity of these health effects, many individuals do not survive past childhood, though some may live into adolescence or adulthood.
Symptoms
Neurological and physical symptoms often manifest shortly after birth and may include:
- Delayed development of mental abilities and motor skills (such as sitting and walking)
- Intellectual disability
- Seizures
- Weak muscle tone (hypotonia)
- Poor coordination and difficulty walking
- Abnormal brain structures, such as underdevelopment of the corpus callosum, atrophy of the cerebral cortex, or lesions on the brain
- Lactic acidosis, which can cause nausea, vomiting, severe breathing problems, and abnormal heartbeat
Causes
The condition is caused by mutations in genes that provide instructions for the pyruvate dehydrogenase complex. This complex is essential for converting pyruvate into acetyl-CoA, a critical step in cellular energy production. When this complex functions poorly, pyruvate builds up and is converted into lactic acid, while cellular energy production is diminished. The brain, which requires high amounts of energy, is particularly affected.
Associated Genes
- DLAT
- PDHA1
- PDHB
- PDHX
- PDP1
Inheritance
Inheritance patterns depend on the specific gene involved:
- X-linked inheritance: Mutations in the PDHA1 gene follow this pattern. In males, one mutated copy is sufficient to cause the condition. In females, the condition can be variable due to X-inactivation, where one X chromosome is turned off in each cell. Females with this condition often exhibit skewed X-inactivation, where the chromosome with the normal gene copy is inactivated in most cells.
- Autosomal recessive inheritance: Mutations in other associated genes follow this pattern, meaning both copies of the gene in each cell must have mutations for the condition to occur. Parents of an affected individual typically do not show symptoms.