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Hello!

We warmly welcome you to our blog Ketogenic Solution! 

We will be writing blog posts about this rare metabolic disorder called Pyruvate Dehydrogenase Complex Deficiency (PDCD) Be sure to stick around as we address questions such as the main causes of PDCD, the biochemistry behind PDCD, current cures and many more! Do feel free to drop us a question! 

Are you at risk of Pyruvate Dehydrogenase Complex Deficiency?

Who is at Risk? What causes Pyruvate Dehydrogenase Complex Deficiency?

Scientist believe that Pyruvate Dehydrogenase Complex Deficiency(PDCD) is hereditary; It is a metabolic disorder caused by  mutation in the PDHA1 gene. The mutation is a type of X-linked recessive inheritance. Usually X-linked diseases occurs in males, however, PDCD affects a equal number of male and female. This is because males only have one X chromosome and will not form barr bodies in order to inactivate the mutated PDHA1 gene found on the X chromosome.

Why are females Affected although it is a X-linked disease?

Reason 1

Females have two X-chromosomes, therefore one of the X chromosome will from barr bodies in order to inactivate one of the X chromosome. This can occur randomly(X-inactivation) or not randomly(skewed X-inactivation). Unfortunately in PDCD, scientist  found that skewed X-inactivation occurs, this means that the X chromosome containing the normal PDHA1 gene is inactivated instead through the formation of barr bodies. This skewed X-inactivation results in the  expression of mutated PDHA1 gene resulting in PDCD. However it is possible for skewed X-chromsome to inactivate mutated PHDA1 gene instead resulting in the female just becoming a carrier of the mutated PHDA1 gene that she can pass on to her offspring. 

Reason 2

The father and mother of the child passes on both X-Chromsome containing mutated PDHA1 gene resulting in homozygous expression. However, the most common cause of PDCD in females is due to skewed X-inactivation because many of those born with PDCD do not usually survive past childhood in order to reproduce. There is currently no cure for PDCD, however, there is treatment in the form of a Ketogenic diet. 

Metabolic disorder: A inherited genetic disease that causes a defect in a single gene that codes for a single enzyme that converts substrate (e.g glucose)  thus the substrate cannot be broken down.

PDHA1: Pyruvate dehydrogenase (lipoamide) alpha 1

X-linked recessive inheritance: a mutation in the gene of the X chromosome which results in the expression of the mutated phenotype

Ketogenic diet: Is a diet rich in fat but low in carbohydrates (more on the Ketogenic diet will be found in a later post)

The story of Alex:

                                             

Alex was diagnosed with Pyruvate Dehydrogenase Complex Deficiency(PDCD) shortly before his 2nd birthday. Although PDHC is deadly, being put on a Ketogenic Diet since saved his life!

How does PDCD affect the individual?

Glucose is the primary source of energy for cells in the body. Normally, glucose is broken down in cells by aerobic respiration to produce large amounts of ATP. However, individuals suffering from PDCD lack Pyruvate dehydrogenase Complex (PDC) forces the body to break down glucose anaerobically to produce large amounts of Latic acid and 2 ATP instead of just 36 ATP.  

Pyruvate dehydrogenase Complex (PDC) is involved in converting pyruvate into Acetyl-CoA in the body after glycolysis in aerobic respiration. Acetyl-CoA is essential to kick start the kerb cycle and eventually electron transport chain in order  to produce large amount of ATP for the body. (more on the biochemistry behind PDCD and PDC in another post)  

Overview of the glucose metabolic process in cells of a person without Pyruvate Dehydrogenase Complex Deficiency
(Taken from Caveats when considering ketogenic diets for the treatment of pyruvate dehydrogenase complex deficiency  written by Timothy A Weber, BS, M.Rita Antognetti, MS, RD and Peter W, Stacpoole, Phd, MD)

Those who suffer from PDCD are unable to convert pyruvate to Acetyl-CoA through oxidative decarboxylation.

Puruvate -----------x-------------> Acetyl-CoA

Pyruvate Dehydrogenase Complex

Taken from page 87 of Medical Biochemistry written by Dr Zhu CongJu Ngee Ann Polytechnic School of Life Science and Chemical Technology

As seen in the image above, shows that weather glucose is aerobically or anaerobically broken down, glycolysis occurs to produce pyruvate.

  

The severity of Pyruvate dehydrogenase complex deficiency can be categorised into type A, B and C.

Type A: Begins in infancy. They have mild lactic acidosis resulting in developmental delay (e.g learning to sit up or lift their neck) vomiting, muscle weakness, abdominal pain and tiredness.

Type B: Begins shortly after birth. Serious lactic acidosis and Hyperammonemia is also a common symptom. THisresults in liver failure, abnormal eye movements, weak muscle tone, coma and seizures. These children usually only manage to survive for several months.

Type C: Benign form of the disease. The elevation of latic acid concentration in their blood is mild and only occurs periodically. Such individuals manage to lead a normal life.

ATP: Adenosine Triphosphate- The only form of energy used by the body

Lactic acidosis: The build up of lactic acid in the blood which results in PH of the blood to fall to below PH7.35-7.45 (e.g PH5)

Hyperammonemia: excess ammonia in the blood (although hyperammonemia is not caused by PDCD, is has been observed people who suffer from PDCD often have hyperammonemia coupled with PDCD. The cause of hyperammonemia in those with PDCD is still unknown)

What is the biochemistry behind the disease?

Pyruvate dehydrogenase complex (PDC) deficiency (PDCD) is one of the most common neurodegenerative disorders associated with abnormal mitochondrial metabolism. The citric acid cycle is a major biochemical process that derives energy from carbohydrates. Malfunction of this cycle deprives the body of energy. An abnormal lactate buildup results in nonspecific symptoms (e.g., severe lethargy, poor feeding, tachypnea), especially during times of illness, stress, or high carbohydrate intake.
                                    
Pyruvate dehydrogenase (PDH) deficiency (PDHD) is caused by a deficiency of one or more enzymes or cofactors(e.g. thiamine) that are needed for an important chemical reaction in the cells of the body. These enzymes or cofactors belong to the pyruvate dehydrogenase complex and is used to convert a chemical named pyruvate to acetyl-coenzyme A (widely known as acetyl-CoA). Acetyl-CoA is an important chemical which the body requires to make citrate for the cells. Without the enzyme or cofactor, pyruvate cannot be converted to acetyl-CoA. As such, there will be too much pyruvate in the cells. The absence of enzymes will cause reaction of pyruvate to be directed to production of lactate.Citrate is the first step in another important group of chemical reactions called the citric acid cycle (also known as Electron Transport Chain(ETC)), which then cannot proceed. The body tries to make alternate pathways to produce more acetyl-CoA, but there is still not enough energy made in the body, especially in the central nervous system (CNS). The amount of energy that is deficient depends on the amount of the enzyme that is deficient. 

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. Glucose in the body will be converted into pyruvate. In a healthy human, pyruvate can be converted into Acetyl-CoA, which is used in the ETC, and lactate. Conversion to Acetyl-CoA is more favoured and will happen more than it being converted to lactate. However, people who suffers from PDHD lacks the pyruvate dehydrogenase complex, hence are unable to metabolise pyruvate to Acetyl-CoA, and can only convert pyruvate to lactate, also known as lactic acid. Lactic acid in high concentration in the body is harmful as it causes lactic acidosis which is life-threatening as it might cause shock and organ failures.
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What are the current cures?

There are no cures for pyruvate dehydrogenase deficiency (PDHD). However, there are a few treatments available, with goals to include stimulating the pyruvate dehydrogenase complex (PDHC). Treatments serves to provide alternative sources of energy and preventing immediate, acute worsening of the condition. However, even with treatment, damage to the central nervous system is prevailing.

The lack of pyruvate dehydrogenase complex forces the glucose to only go one pathway, which is to produce lactic acid, which is harmful to the body if in high concentration. Lactic acid accumulation may be lessened by giving a high fat/low carbohydrate (ketogenic) diet. Scientists are still researching on ways to cure PDHD. There is some evidence that a medication called dichloroacetate may reduce the metabolic issues in some patients. 

The standard of care is to supplement cofactors, which are substances in the body that help the chemical reactions in the cells to occur; these include thiamine, carnitine, and lipoid acid. The individuals with PDH deficiency that respond to these cofactors usually have a better outcome. However, giving all of these cofactors to all patients with PDH deficiency is typical in order to optimise pyruvate dehydrogenase complex function. Oral citrate is often used to treat acidosis, which is a condition where excessive acid is present in the body.

Supplement alone will not be able to reduce and sustain an acceptable amount of lactic acid in the body. People who suffer from PDHD are required to live with a ketogenic diet. A ketogenic diet refers to a diet that is high in fat and low in carbohydrate. It is low in carbohydrate as to avoid having glucose, the most common carbohydrate, in the systems of people suffering from PDHD. Since people who suffers from PDHD lack the pyruvate dehydrogenase complex, they are unable to metabolise glucose into another compound. As such, the glucose is converted to lactate, which is also known as lactic acid, and will build up in the body. Examples of food with high fat and low carbohydrate contents are oils, cheese, beef, pork, egg, coconut and avocados.

More on the Ketogenic diet

WHY?

As we now know, Ketogenic diet is a diet high in fat and low in carbohydrate. Those suffering from PDCD cannot use glucose as a primary source of acetyl-CoA thus they have to use Fats as an alternate source of Acetyl Co-A instead. Which is why the Ketogenic diet is usually recommended for those suffering with PDCD to help keep them alive and keep the lactic acid level in their blood low.

What kind of foods should they consume? 

avocados, olive oils, walnuts, olives 

Sources of fats and oils: Although their diet is high in fats, they should try to consume the goof types of fats that promote good cholesterol. Examples of such foods are 

1. omega 3 and omega 6 that can be taken from food like walnuts, tuna, salmon, Shellfish or even supplements like krill oil that is high in omega 3 content   

Tuna and Salmon fish 

2. Saturated and monounsaturated fats from foods such as avocados, eggs, coconut oil, olive oil, walnuts

Although the diets is high in fats, they should always consume the corrects types of fats and not foods that is high in trans fats(a type of unsaturated fat) as this would significantly increase their risk of coronary heart disease.This is because trans fats raises bad cholesterol, which would defeat the purpose to trying to increase their life expectancy through the practice of the Ketogenic diet.  

Foods high in Trans fat include margarine, deep-fried food like donuts, fast foods like McDonald's hamburgers, processed food like microwavable popcorn 

Fibre is essential to helping maintain colon health while prevent constipations. Especially with a high fat diet, constipations is to be expected. Consuming vegetable such as broccoli, spinach are good sources of calcium, fibre, vitamin A and C etc The vitamins found in these vegetables can be an alternative source of fibre and vitamins to fruits that are sweet and contain glucose that cannot be cannot be broken down by those with PDCD

Good sources of calcium can be obtained from non dairy sources that isn't from the e,g cows milk that if often high in sugar or added sugar. While foods like yoghurt is high in calcium, they also often contain added sugar and also lactic acid. Because we want to minimise lactic acid levels in the blood of those with PDCD yoghurt should be avoided  food like  Examples of non dairy food high in calcium is kale, sesame seeds, firm tofu, almonds, bok choy, spinach are good sources of calcium without the added sugar that those with PDCD are unable to process.  

Although the ketogenic diet is often recommended by doctors as a form of treatment, there is very little to no control measures put in place for a standardised Ketogenic diet to treat PDCD due to the lack of research and the rare occurrence of this mitochondria metabolic disease. 

Food for thought

A KETOGENIC DIET RECIPE OF : 

poached salmon with home made mayonnaise, half boiled egg and a side of salad 

Serves 1

Ingredients: 

-200g of Salmon with skin (bones removed)

-two eggs

-Salt 

-olive oil

-mustard

-ice in a bowl water

-1/4 reddish 

-1/4 cucumber 

-Balsamic vinegar 

-Olive oil

-1/4 carrot

-A cup of baby romaine lettuce (purple and green)

Instructions: 

1. Bring a pot of water enough to cover the salmon when salmon is lowered into the pot 

2. Season salmon into boiling water and cook for 6-7 minutes (depending on the thickness of your salmon) or until salmon turn light pink and remove from water and plate 

3. Lower the one egg into the same pot of water and set a timer for 7 minutes 

make sure that the water is not at a rolling boil but a gentle simmer as a rolling boil might crack the shell of the egg before the eggs is cooked

4. Prepare a boil of water with ice, make sure water is ice cold

4. Remove egg from the pot of simmering water and put directly into a the bowl of ice cold water 

5. Cool the egg down to the temperature of the water before pealing the shell off and cutting the half boiled egg to reveal this(as seen in image below) plate egg next to salmon

6. To make homemade mayonnaise, separate egg yolk from egg white, then whisk the egg yolk with a table spoon of mustard. Then add oil olive slowly while whisking. Add olive oil until it becomes a thick vicious mixture. Add salt to taste. 

7. Put a few dollops of mayonnaise over the salmon, 

8. Next, cut carrots into strips, slides the radish to get thin slices and dice cucumbers

9. Prepare salad dressing by putting 2 table spoon of olive oil into a small container and a table spoon of balsamic vinegar. Shake up the two liquids in the container.

10.Toss the romaine baby lettuce with the prepared carrots radish and cucumber and prepared salad dressing

11. Plate salad next to poached salmon glazed with mayonnaise and half boiled eggs. 

Enjoy!