Pyruvate Dehydrogenase Complex Deficiency (PDCD/PDH)

Pyruvate dehydrogenase complex deficiency (PDCD) (formerly known as PDH deficiency) is an inherited inborn error of metabolism. This means that children born with this disorder can’t convert some of the food they eat into energy.

In a normal metabolic cycle, carbohydrates are broken down into energy by certain enzymes called the pyruvate dehydrogenase complex. Children with PDCD have fewer enzymes than those without the disorder, so they are less able to break down carbohydrates and sugars into energy.

This energy is used not only for children to run, play, and learn, but also for cell formation, growth, and throughout the lifetime of a cell. Without energy for the cells to maintain healthy functioning, they can not function correctly, become damaged, and possibly die. Without healthy functioning cells in all parts of the body, children with PDCD can experience poor muscle tone, neurological damage (brain cell injury, cognitive delays, and seizures), and other problems like poor feeding and lethargy.

The inability of the body to break down carbohydrates into energy produces a potentially dangerous chemical called lactic acid. High lactic acid can make symptoms worse, as well as cause low blood pressure, vomiting, high heart rate, and rapid breathing .

Each child is affected a little differently, and severity levels vary from mild to fatal. It is thought that for children with low enzyme complex activities in the brain and nervous system, symptoms can be the most severe. Enzyme complex activities in brain and the nervous system cannot be directly measured at this time, so enzyme levels are measured in blood, skin (fibroblasts), or muscle using a blood test or biopsy as part of the process of diagnosing PDCD.

Boys are often considered to be affected more severely. However, many girls are severely affected as well and boys can sometimes be only mildly affected. One of the genes responsible for creating an enzyme in the PDC complex resides on the X chromosome. Boys have one X chromosome and one Y chromosome, while girls have two X chromosomes. This means that, in general, girls are able to produce more of the enzyme than boys. This particular gene, called PDHA1 (see below), is linked with the most common form of PDCD. Other genes associated with PDCD are not on the X chromosome and affect boys and girls equally.

While most children with PDCD display some or all of these symptoms, the levels of severity vary and can not be predicted based soley on diagnostic tests. Each child is different and responds to the defect a little differently. Each child will also respond differently to treatments and medications. These medications and treatments should be tailored to your childs specific needs and followed closely under the supervision of a doctor.

 

How is Pyruvate Dehydrogenase Complex Deficency inherited?

More than half of cases of PDCD are associated with a gene called PDHA1 and most (about 75%) of the changes in this gene occur spontaneously. This means that neither parent is a carrier, so the chance of having another affected child is low. However, in about 25% of families with a child with a PHDA1 gene change, the child’s mother is a carrier of the gene change and the chances of having another affected child are higher. When the problem lies in other genes besides PDHA1, it is possible for both parents to carry the gene change. In these cases of “recessive inheritance,” the carrier parents are generally healthy but have a 25% chance of having a child with PDCD with each pregnancy. Only genetic testing can determine which mutation your child has. Your doctor can give you more information on this testing.

 

 

SIGNS & SYMPTOMS OF PDCD/PDH

Newborns

Infants/Toddlers

Older

Lactic Acidosis (excessive blood lactate level)

X

Respiratory Failure (ventilator dependence)

X

Lethargy or Coma

X

Developmental Delay leading to intellectual disability

X (most)

Seizures

X (many)

Brain Malformations (enlarged ventricles, atrophy of brain, corpus callosum malformations)

X (many, especially girls)

Small head circumference

X (many)

Leigh’s Syndrome (lesions in brainstem or basal ganglia of brain, with loss of motor skills, eye movement problems, breathing problems, etc.)

X (many boys, some girls)

Ataxia (loss of balance)

X (most boys, many girls)

Dystonia (abnormal posture of limbs)

X (many)

Peripheral Neuropathy (nerve damage, numbness/tingling)

X (many)

Also seen (infants and older):

  • Hypotonia (low muscle tone, especially trunk – seen in most individuals)
  • Hypertonia (increased muscle tone, especially arms and legs – seen in many, and may accompany hypotonia of trunk)

 


Medical Therapy

Sodium dicholoroacetate (DCA) helps to activate the enzyme complex and decreases the lactic acidosis in individuals with E1 alpha enzyme deficiency (i.e. in individuals with PDCD caused by changes in PDHA1 or PDHB genes). This drug is still currently undergoing investigational studies and may not be appropriate for all children. As with all medication regimens, your doctor and you will decide the best medication course for your child.

Acidic Episodes

Sodium bicarbonate
-may be used for acute acidosis to alkalize metabolic acidosis

Diet

Ketogenic Diet
– the main treatment for PDCD currently. The diet is high fat, low protein and low carbohydrate. The diet forces the body to create ketones to use as energy, instead of glucose. The ketones are then used to fuel the brain and body. The diet is initiated under a doctor’s supervision and is tailored to your child’s specific needs. The diet can be initiated under a 4:1, 3:1, or a 2:1 ratio. This means, for example, four parts of fat to a combined one part protein and carbohydrate.

Seizure Control

About half of children with PDCD will experience seizures. Because children present differently with different types and severity of seizures, anti-epileptic (anti-seizure) medications are tailored to each individual child. Your doctor will work with you and your child to determine the best medication course to control your child’s seizures.

 

 


RESEARCH STUDIES AND CLINICAL TRIALS

Physicians at University Hospitals Case Medical Center in Cleveland, Ohio are currently recruiting children and adults with pyruvate dehydrogenase complex (PDC) deficiency and other disorders of pyruvate metabolism for a research study seeking to better understand the genetic causes, symptoms, usefulness of current treatments, and outcomes for these disorders. The research project involves completing a questionnaire about the individual or family’s medical history and experiences with PDC deficiency or other disorder of pyruvate metabolism, review of medical records by the researchers, and in some cases, genetic testing. No experimental treatments will be given as part of the study, and travel is not necessary. If you are interested in learning more about this research study, please contact Audrey Lynn, study coordinator, at 216-844-3936 option 2.


ADDITIONAL RESOURCES

 

Social Media
Link to Facebook and our group is called PDCD Parents & Friends https://www.facebook.com/groups/pdcdkids/

Mystery Diagnosis Episode: “Lethal Diet” (aired in 2005)
http://www.youtube.com/watch?v=mrFb3v1SUSQ&feature=youtu.be
http://www.youtube.com/watch?v=UxQ_3z6SK9M&feature=youtu.be