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Simple Introduction

Pyruvate dehydrogenase complex

Consists of 3 subunit enzyme:

Enzyme	Abbreviated	Prosthetic Group
Pyruvate Dehydrogenase	E1	Thiamine pyrophosphate (TPP)
Dihydrolipoyl Transacetylase	E2	Lipoamide
Dihydrolipoyl Dehydrogenase	E3	FAD

How is it linked to the disease?

Pyruvate dehydrogenase complex is required to convert pyruvate(produced from glycolysis) to acetyl coA. Acetyl CoA then act as a precursor to undergo Krebs Cycle.

In aerobic respiration, Krebs cycle and Glycolysis are IMPORTANT because they produce ATP(chemical energy) from our diet(glucose)

What is Pyruvate dehydrogenase complex deficiency (PDHA)?

Pyruvate dehydrogenase complex deficiency (PDHA) is a genetic disorder that results in a malfunctioning of the Krebs, or tricarboxylic acid (TCA), cycle. It is sex-linked and appears to be a dominant trait.

Further details are shown in the video below:

Source: Diwan, Joyce J. Pyruvate Dehydrogenase & Krebs Cycle. 1998-2007. Web. <http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb1/part2/krebs.htm>.

Videos featuring patients suffering from the disease

Interesting article on PDH structure

"Massive Enzyme Footballs Control Sugar Metabolism

ScienceDaily (July 18, 2011) — Neutron scattering has revealed how massive enzyme complexes inside cells might determine whether sugar is burnt for energy or stored as fat. The findings promise to improve understanding of diabetes and a range of metabolic diseases."

Read the full article here:  http://www.sciencedaily.com/releases/2011/07/110718091823.htm

Institut Laue-Langevin (ILL) (2011, July 18). Massive enzyme footballs control sugar metabolism. ScienceDaily. Retrieved July 9, 2012, from http://www.sciencedaily.com­/releases/2011/07/110718091823.htm

Blogpost about a young girl who is confirmed with Pyruvate dehydrogenase complex deficiency

The parents thoughts on their daughter who is confirmed suffering from PDCD

Main causes of the pyruvate dehydrogenase complex deficiency

Pyruvate dehydrogenase complex deficiency is usually caused by a deficiency of one or more enzymes or cofactors (such as thiamine) that are needed for an important chemical reaction in the cells of the body.


These enzymes or cofactors are part of the pyruvate dehydrogenase complex and normally convert (or aid in converting) a chemical called pyruvate to another chemical called acetyl-coenzyme A (CoA), which is one of two important chemicals the body needs to make citrate for the cells.


Because pyruvate cannot be converted to acetyl-CoA, there is too much pyruvate in the cells, which then undergoes lactic fermentation instead of Kreb's cycle. Hence lactic acid, instead of citrate, is produced from the pyruvate. Without the body undergoing Kreb cycle, there is insufficient amount of energy being produced.


The condition is sometimes referred to as pyruvate dehydrogenase complex (PDHC) deficiency because there is a "complex" of three enzymes normally used in the reaction; when any one or more of the enzymes needed for the above-described reaction are deficient, the condition results. 


Genetic Cause:

 mutations in the X-linked E1 alpha gene


Chances of each gender being affected:
Almost equal numbers of affected males and females have been identified However, there is a difference in the distribution of the type of mutations between both sexes.


Modes of inheritance of mutation:
X-linked dominant( Abnormal gene on the X chromosome-sex chromosome, dominates the other normal gene from another parent)

It may seem that the mode of inheritance is autosomal recessive mode of inheritance of the disease (Both parents are carriers of the mutation) since there is an almost equal chance of males or females being infected. This is because studies have shown that there is presence of  developmental lethality in males as the effect of mutation is more severe as compared to pattern of X-inactivation in females.



Mutations in the X-linked E1 alpha subunit gene:


missense/nonsense (found in all exons)
insertion/deletion mutations( found mostly in exon 10 and 11)
Mutations were never present in the somatic cells of the father



Sources
Non-scientific articles:
1.Frye, R. (2012, March 12). Medscape reference. Retrieved from http://emedicine.medscape.com/article/948360-overview
2.Genetic and rare diseases information center (gard). In (2011). National Institutes of Health. Retrieved from http://rarediseases.info.nih.gov/GARD/QnASelected.aspx?diseaseID=7513
Scientific article:
3.Lissens W. (2000). Retrieved from website: http://www.ncbi.nlm.nih.gov/pubmed/10679936

Diagnosis of PDCD

The diagnosis of pyruvate dehydrogenase (PDH) deficiency may be considered in any individual with early-onset neurological disease, especially if it appears to be associated with structural abnormalities in the brain and unexplained lactic acidosis.

When it seems that lactic acid (also called lactate) and pyruvate are not significantly high in the blood , an important clue to the diagnosis may be high concentrations of lactate and/or pyruvate in the cerebrospinal fluid (the fluid that surrounds the brain and spinal cord).

Magnetic resonance spectroscopy (MRS), a radiology medical imaging technique which helps to determine level of metabolites, may be used for diagnosis.
It can help to discover lactate concentration in our central nervous system.  Serum and urine amino acids tested usually shows hyperalaninemia. When lactic acidosis is present, other disorders involving pyruvate abnormalities are part of the differential diagnosis.

However, in all of these conditions, the diagnosis is based on specific laboratory tests. Detailed tests are being implemented to determine the enzymatic activity of the PDH complex and also the different components of the complex ( cofactors such as thiamine). Most of the patients that suffers from PDCD usually are being discovered to have lack of E1 enzyme.



Source:
National Institues of Health (NIH), Office of Rare Disease Research. (2011). Pyruvate dehydrogenase deficiency. Retrieved from Genetic and Rare Diseases Information Center website: http://rarediseases.info.nih.gov/GARD/Condition/7513/QnA/29055/Pyruvate_dehydrogenase_deficiency.aspx

Signs and symptoms

The enzymatic activity of the PDC is the determining factor of the serverity of disease and the age where the patients are confirmed suffering from PDCD. The earlier patients are suffering from PDCD the higher mortality they face. That is, patients suffering from PDCD during their prenatal period usually face death in early childhood. On the other hand, those who suffers from the disease at a later period will instead face spastic conditions and poor motor coordination but usually survive till they reach adulthood.

Categories of symptoms: neurological and metabolic.


Individuals with neurological onset of PDCD typically exhibit poor muscle tone, lethargy, seizures, and may develop severe mental retardation, blindness, microcephaly, and spastic damage to muscles and tendons.

Individuals with metabolic symptoms of PDCD usually have extremely high levels of lactic acid within the bloodstreams. Hence, causing high amounts of ammonia. This type of onset typically does not respond to medical treatment, thus, causing many patients to die in infancy.

Common signs include a complicated, difficult delivery, low birth weight, low Apgar scores, short neck, shortened limbs, bent fingers, club foot and ventricular septal defect. Unusual, dysmorphic facial features are sometimes associated with this disorder, such as an upturned nose, drooping eyelids, low-set ears, and a squinting appearance.

• Low birth weight.
• Abnormal appearance of the face.
• Short neck, short hands
• Poor muscle tone.
• Lethargy.
• Seizures.
• Mental retardation.
• Abnormal muscle movement.
• Poor food intake.
• Spastic condition.

Sources: 

1. Joseph Pritchard. (2011, May 04). Livestrong.com. Retrieved from http://www.livestrong.com/article/434370-a-pyruvate-dehydrogenase-deficiency/

2. A R. (2011, January 20). Simple remedies. Retrieved from http://www.simple-remedies.com/health-tips-3/pyruvate-dehydrogenase-deficiency.html

Images from:

http://www.livingwithcerebralpalsy.com/images/hypotonia.jpg

http://www.umm.edu/graphics/images/en/19076.jpg

How the illness affect individuals?

Malfunction of the Krebs Cycle will lead the cell to undergo anaerobic respiration where by lactate fermentation occurs after glycolysis. This may cause accumulation of lactate resulting in lactic acidosis.

This results in the following symptoms:

• Poor feeding
• Lethargy
• Rapid breathing (ie, tachypnea)
  
  

Neurological damages

•  affect neuronal migration
•  affect axonal growth
• affected  cell-cell interactions
•  disordered neuronal cytoarchitecture
•  neuropil fibers in grey matter
•  reduced size of bundles
•  disorganization of fibers in white matter.
• myelin sheath insulating some nerves may be missing entirely
  

Poor neurological development results in following symptoms:

• Poor acquisition or loss of motor milestones
• Poor muscle tone
• New onset seizures
• Periods of incoordination (ie, ataxia)
• Abnormal eye movements
• Poor response to visual stimuli
  
  
  
  
  
  
  Sources:
  1.Richard E Frye. (2012). Medscape reference. In Retrieved from http://emedicine.medscape.com/article/948360-clinical
  2. Pritchard, J. (2011, May 04). A pyruvate dehydrogenase deficiency. Retrieved from http://www.livestrong.com/article/434370-a-pyruvate-dehydrogenase-deficiency/
  3. Pliss , L. State University of New York at Buffalo, School of Medicine and Biomedical Sciences. (2004).Biochemical and structural brain alterations in female mice with cerebral pyruvate dehydrogenase deficiency (15569252). Retrieved from NCBI PubMed website: http://www.ncbi.nlm.nih.gov/pubmed/15569252
  4.Casto, J. (2002). Pyruvate dehydrogenase complex deficiency disease. Retrieved from http://www.ehow.com/facts_5984398_pyruvate-dehydrogenase-complex-deficiency-disease.html
  
  Images are extracted from Google Images
  
  

  
  

Treatment

Treatment of PDHA is on a case-by-case basis depending on the observed symptoms.
Reduction of acidosis
Lowering of lactic acid level does not reverse the damage done to the Central Nervous System of the patient and all the symptoms.

1.Ketogenic diet
-low carbohydrate but high in protein and fat
-treatment for E1 subunit deficiency of the complex

How it works?

Though the ketogenic diet has been used for a long period of time to treat PDCD,

how the ketogenic diet works treat the disease is still unknown.

The following are proposed mechanistic theories of chronic ketosis action:

• modification of the tricarboxylic acid cycle which increase γ-aminobutyric acid synthesis in the brain
• limit reactive oxygen species generation
• boost energy production in brain tissue.

As a result of the above actions, hyperpolarization of neurons occurs, stabilizing synaptic function and increasing resistance to seizures throughout the brain.

2.Oral citrate

3. Sodium Bicarbonate



Targeting the pyruvate dehydrogenase complex
(supplementation of cofactors to the enzyme)
optimizing the ability of the enzyme
Most PCD are responsive towards these cofactors

Dietary supplements
1.high doses of thiamine
-protect against neuropathy


















2. lipoic acid


3. L-carnitine


4.Dichloroacetate



- reduces the inhibitory phosphorylation of pyruvate dehydrogenase complex
- studies shown effectiveness differs in the type of gene deletion that cause the mutation in the gene

After administration of 6 months:
-reduces lactic level after meals

Long-term use associated with:
reversible peripheral neuropathy( may reverse damage of peripheral nervous system)
elevation in liver transaminases(enzymes that indicate liver damage).

Sources
1.Richard E, F. (2012). Pyruvate dehydrogenase complex deficiency treatment & management. In MedScape Reference. Retrieved from http://emedicine.medscape.com/article/948360-treatment
2.Alexander L. Rogovik. (2010). Retrieved from website: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902940/

Treatments (continued)

Early and Continuing intervention programs for developmental delays and mental retardation


Anti-convulsants to control seizures
suppress the rapid and excessive firing of neurons that initiate a seizure


Muscle relaxants to control spasticity

-The signals in motor neurons that cause muscle contractions are dependent on the balance of synaptic excitation and inhibition the motor neuron receives.

-Spasmolytic agents (muscle relaxants)  work by either enhancing the level of inhibition, or decreasing the level of excitation. Inhibition is enhanced by mimicking the actions of endogenous inhibitory substances, such as gamma-aminobutyric acid (GABA)

Surgery


to release the permanent muscle, tendon, and ligament tightening (contracture) at the joints that is characteristic of longer term spasticity.












Alternative source of acetyl-CoA that is not produced in enough quantities
a high-fat diet including beer




Sources:
1. Wikipedia. (2011, November 17). Anticonvulsant. Retrieved from http://en.wikipedia.org/wiki/Anticonvulsant
2. Johnson, P. A. (2002). Health line. Gale Encyclopedia of Genetic Disorders Part I.  Retrieved from http://www.healthline.com/galecontent/pyruvate-dehydrogenase-complex-deficiency
3. Skeletal muscle relaxant. (2012, January 19). Retrieved from http://en.wikipedia.org/wiki/Muscle_relaxant


Images retrieved from Google Images