Pyruvate Dehydrogenase Complex Deficiency

Synonyms

PDHD, PDH Deficiency, PDHC Deficiency, Pyruvate Dehydrogenase Complex Deficiency Disease, PDCDD, Pyruvate Dehydrogenase Deficiency, PDCD,

Overview

Pyruvate dehydrogenase complex deficiency (PDCD) is a rare disorder of carbohydrate metabolism caused by a deficiency of one of the three enzymes in the pyruvate dehydrogenase complex (PDC). The age of onset and severity of disease symptoms vary widely. Individuals with PDCD symptom onset in the prenatal period or in infancy usually die in early childhood. Those who develop PDCD later in childhood may have neurological symptoms but usually survive into adulthood. Most individuals with PDCD have an abnormality in the PDHA1 gene located on the X chromosome. A smaller percentage of affected individuals have forms of the disorder that follow autosomal recessive inheritance.

Symptoms

Individuals with PDCD are affected by a broad spectrum of symptoms ranging from fatal lactic acidosis in infancy to chronic neurological dysfunction. Not all individuals with PDCD are affected at birth, but almost all show signs of the disease during their first year of life. The most common presenting features of PDCD, including poor feeding, lethargy and rapid breathing (tachypnea), are due to increased blood levels of lactic acid. Other early symptoms include neurological function impairments, such as motor delays, poor muscle tone (hypotonia) and seizures, as well as brain structural abnormalities on neuroimaging. Many individuals with PDCD also have developmental delays, incoordination (ataxia) and respiratory infections/distress. When symptoms begin during the prenatal period or soon after birth, neurological development can be severely impacted leading to major deficits. However, individuals with symptom onset well after birth may have normal neurologic development with intermittent displays of symptoms such as ataxia.

Causes

PDCD is caused by abnormalities in the genes that encode the components of the pyruvate dehydrogenase complex. The pyruvate dehydrogenase complex contains three enzymes, E1, E2, and E3, and multiple coenzymes. The E1 enzyme is comprised of an alpha and a beta subunit. PDCD is most commonly caused by abnormalities in the gene that encodes the E1 alpha subunit, E1-alpha subunit pyruvate dehydrogenase gene or PDHA1. There are many different abnormalities in the PDHA1 gene, also called PDHA1 variants, which are known to cause PDCD. Most PDHA1 variants are sporadic meaning they are new changes to the PDHA1 gene and were not inherited. However, because this gene is located on the X chromosome, when it is inherited, it follows an X-linked recessive pattern of inheritance.

X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working gene he will develop the disease.

Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.

If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.

Sometimes, PDCD is caused by abnormalities in genes that encode different subunits of the pyruvate dehydrogenase complex. These genes include PDHX, PDHB, DLAT, PDP1 and DLD. Abnormalities in these genes follow an autosomal recessive inheritance pattern.

Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.

Diagnosis

Biochemical abnormalities vary from severe acidosis (abnormally high blood levels of lactic acid) shortly after birth to mildly elevated levels, oftentimes following a meal high in carbohydrates. In some patients, elevation of blood lactate levels is seen only during the acute episodes. Excretion of abnormally large amounts of the amino acid alanine (alaninuria) may occur only during acute episodes. Imaging studies such as magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) may reveal structural brain abnormalities associated with severe disease. A definitive clinical diagnosis can be made by measuring abnormal PDC enzyme levels or function in leukocytes, fibroblasts or from a tissue biopsy.

Genetic diagnosis can be made by the identification of pathogenic variants in the PDHA1, PDHX, PDHB, DLAT, PDP1 or DLD genes.

Treatment

There are no treatments available that are specific to PDCD. Dichloroacetate may be administered to treat lactic acidosis, either intravenously during acute episodes or orally on a regular basis. Many affected individuals benefit from maintaining a ketogenic (low carb, high fat) diet and taking antiepileptic drugs to prevent seizures. Some affected individuals respond to treatment with thiamine, a cofactor for the E1 subunit of the pyruvate dehydrogenase complex. Individuals with mutations that affect this binding site specifically may require higher doses of thiamine supplementation.

Genetic counseling is recommended for families of children with pyruvate dehydrogenase complex deficiency.