Three types of this disorder have been identified and each type has been categorized based on the severity of their signs and symptoms and they are called Type A, Type B, and Type C pyruvate carboxylase deficiency.
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Pyruvate Carboxylase Deficiency
Diagnosis
Molecular Genetic Testing
Identifying Pyruvate Carboxylase enzyme in fibroblasts
Pyruvate Carboxylase deficiency is a rare autosomal recessive disorder that results in the buildup of lactic acid and other toxic compounds in the blood, while depriving the body of energy. The increase in lactic acid can cause internal damage to organs and tissues in the body. Pyruvate Carboxylase deficiency also impacts the nervous system in ways that can cause developmental delays in the early stages of life. In addition, pyruvate carboxylase catalyzes the conversion of pyruvate molecules into oxaloacetate, an essential substrate needed in the Krebs cycle and gluconeogenesis. A deficiency of this enzyme causes disruptions to these cycles and result in lower amounts of energy being produced for the body and pyruvate molecules being shuttered into ulternate pathways that produce lactic acid.
A molecular technology that can be used to perform DNA testing is called polymerase chain reaction-based assays or PCR.
Fibroblasts are cells that are most commonly found in all forms of connective tissue.
PCR amplifies targeted segments of DNA and the amplified product can then be tested to detect any presence of a mutation.
PCR
DNA tests require minimal sample amounts and can be done on any tissue sample.
5%
Carrier testing of relatives and parents for the abnormal gene that causes pyruvate carboxylase deficiency can be done to show the chances of parents having a child with the disorder.
The fibroblast pyruvate carboxylase enzyme activity can be tested to indicate pyruvate carboxylase deficiency, as this disorder can be indicated when this enzyme activity is usually less than 5%.
25%
If both parents are shown to be carriers, there is a 25% chance that the child can obtain both abnormal genes and acquire the disorder.
Ethical Implications
Genetic Testing
Privacy Concerns
Does not always provide sufficient information
Some genetic tests may not identify all the possible gene mutations that cause a specific condition. Not being able to obtain full and sufficient information can result in parents making difficult decisions based on keeping a child. If both parents were tested positive as carriers for pyruvate carboxylase and the fetus was tested to have inherited both mutated genes, the severity of the disorder in the baby is still unknown. This arises the ethical situation where the parents must decide whether to continue or end pregnancy without having sufficient information on the severity of the disorder that their child might have.
When genetic testing is completed, the privacy of this information is constantly questioned. Individuals may always wonder who has control of distributing and examining this information. Several situations may take place where a family member is tested positive for a certain mutation but chooses to keep this information private from her family members due to personal reasons. Doctors are then faced with the ethical situation of either honouring the patients desire’s or warning any family members of their potential risk of carrying the mutation as well.
Viewing Symptoms
The signs and symptoms for each type of this disorder has different levels of severity, which can help diagnose them.
In the nervous system, pyruvate carboxylase has the important role of replenishing certain components needed for making neurotransmitters that are used for nerve cell communication. This means that a deficiency in this enzyme effects the production of neurotransmitters which can cause developmental delays.
Pyruvate carboxylase also has an important role in the creation of myelin, a protective sheath that surrounds nerve cells. Having pyruvate carboxylase deficiency can negatively affect nerve cells which can also lead to developmental delays.
Type A
If symptoms are shown as early as infancy, Type A Pyruvate Carboxylase deficiency can be diagnosed.
Type B
If symptoms are shown shortly after child birth, Type B Pyruvate Carboxylase deficiency can be diagnosed.
Type C
If symptoms are very mild and minimal, Type C Pyruvate Carboxylase deficiency can be diagnosed.
Type A Pyruvate carboxylase deficiency is shown as early as infancy. Children with this deficiency typically only survive up until infancy or early childhood, but may survive until adulthood.
Type B Pyruvate carboxylase becomes apparent shortly after birth. This type is very severe as the life expectancy with this disorder is usually less than 3 months after birth.
Type C Pyruvate carboxylase is the least harmful and individuals can still be expected to live a normal life with the disorder. Individuals still experience mild symptoms of the disorder.
Treatments
As of now, no complete cure for pyruvate carboxylase deficiency has been discovered.
An estimated 1 in 250,000 births worldwide can have this rare disorder.
Treatment of this disorder is aimed to provide alternative sources of energy for the body by alternative methods to metabolizing pyruvate.
Stimulating the Pyruvate
Dehydrogenase complex
Citrate Supplementation
Biotin supplementation
This complex can be used as another way to metabolize pyruvate.
Citrate is an important molecule needed for the Krebs cycle to take place and produce energy for the body.
Biotin is a cofactor of pyruvate carboxylase and taking biotin supplements will increase enzyme activity, but it is usually of little use except potentially in a mildly affected type C patient.
The activity of pyruvate dehydrogenase can be increased by specific cofactor supplements that consist of thiamine and lipoic acid and dichloroacetate.
Citrate is limited in the body with this disorder as there is a deficiency in pyruvate carboxylase, which is an enzyme that aids in producing oxaloacetate, a molecule needed to create citrate.
As pyruvate metabolism increases through using this technique, pyruvate and lactate levels decrease which overall decreases the amount of lactic acid present in the blood.
More pyruvate is metabolized by pyruvate dehydrogenase instead of going through this reaction.
Citrate supplementation helps reduce lactic acid levels and supply's the body with an increased amount of citrate levels to carry through the Krebs cycle and eventually produce energy for the body.
High Carbohydrate Diet
Nervous System Treatment
Unfortunately, there is no treatment currently available to improve the neurological symptoms of pyruvate carboxylase deficiency.
Type B is most common in France, but has been recorded in parts of Canada, Egypt and Saudi Arabia.
Type A most common in North America, particularly Algonkian tribes near eastern Canada.
History
The pyruvate carboxylase enzyme was discovered in 1959 at Case Western Reserve University by M.F. Utter and D.B. Keech. Their discoveries included identifying the function of the enzyme and finding that it was a biotin-containing mitochondrial enzyme.
If it wasn't for these individuals, the extent to which this deficiency could be identified would not be as effective, as they were able to find how and where this enzyme works in the body.
Even now, a treatment method for pyruvate carboxylase deficiency includes biotin supplementation, as both Utter and Keech were able to find that biotin is a cofactor of the pyruvate carboxylase, which shows that taking biotin supplements would increase enzymatic activity.
A high-carbohydrate and high protein diet can help maintain energy levels as not enough energy is being produced by the body.
Researchers
How does it get passed down?
Pyruvate Carboxylase deficiency is autosomal recessive
This means when both the mother and father are carriers of the mutated gene that causes this disorder, their future child has a 25% chance of getting this disorder.
The Krebs Cycle
The pyruvate carboxylase enzyme is used in the mitochondria in the Krebs cycle to catalyze the chemical reaction that converts a pyruvate molecule into a molecule known as oxaloacetate.
This reaction is essential, as oxaloacetate is used in the Krebs cycle which is a process that contributes towards energy production for the body.
Pyruvate carboxylase deficiency results in lower amounts oxaloacetae molecules being produced. This restricts the Krebs cycle from taking place and causes the body to be deprived of energy.
Since pyruvate is not converted to oxaloacetate through the Krebs cycle and gluconeogenesis, the pyruvate molecule is shuttered into alternative pathways that produce lactic acid with the help of the lactate dehydrogenase enzyme.
LACTIC ACID BUILDUP LEADS TO LACTIC ACIDOSIS!!
Pyruvate Carboxylase Enzyme
Pyruvate Carboxylase Gene
Mitochondria
Pyruvate Carboxylase Deficiency is caused by mutations in the pyruvate carboxylase gene, which is a gene that provides the instructions for creating an enzyme known as pyruvate carboxylase.
Years of practice: 21+ years
Specialty: Neurology
Dr. Dong is affiliated with the Gwinnett Medical Center as a neurologist in Duluth, Georgia. He has been practicing medicine for over 20 years after graduating and receiving his medical degree from Shandong Medical University.
Pyruvate Cabroxylase deficiency causes developmental delay, deprivation of energy and an accumulation of lactic acid in the blood, which is known as lactic acidosis.
Dong Wang, MD
With Type A, there is moderate lactic acid build up that can lead to:
With Type B, there is severe lactic acidosis, ammonia accumulation in the blood, and liver failure. Symptoms include:
Dr. Dong has also completed research on pyruvate carboxylase deficiency and his findings has helped make it clearer to identify individuals who may have this disorder. His findings included how pyruvate carboxylase deficiency should be suspected in individuals with the following clinical features: failure to thrive, developmental delay and recurrent seizures. He was also able to find that the different types of this disorder included a different amount of lactic acid buildup in the blood. For type A, lactic acid concentrations were between 2-10 mmol/L. In type B, lactic acid concentrations were greater than 10mmol/L. Finally in type C, lactic acid concentrations were between 2-5 mmol/L. The normal range would be around 0.5-2.2 mmol/L and based on Dr. Dong’s research, it is effectively shown that type B is the most severe, type C is the least sever and type A is in the middle in terms of lactic acid buildup caused by an accumulation of the pyruvate molecule.
Type C involves a small increase of lactic acid in the blood and few signs and symptoms affecting the nervous system. Symptoms are similar to symptoms of Type A, but are much more milder.
Seizures and possibly coma
Gluconeogenesis
With pyruvate carboxylase difficiency,
there is less glucose generation, resulting in the body also being deprived of energy.
Gluconeogenesis generates glucose (the bodys main energy source), when carbohydrate intake is low.
Pyruvate Carboxylase catalyzes the conversion of pyruvate molecules into oxaloacetate in the first step of gluconeogenesis in the kidneys and liver.
Liver
The Gauvin Family
Walk through of the lives of these people dealing with pyruvate carboxylase deficiency.
Alison and Ben were a couple that gave birth to two children who were diagnosed with pyruvate carboxylase deficiency.
Pyruvate carboxylase deficiency is known to be autosomal recessive. A recessive genetic disorder can occur when both parents are carriers of an abnormal gene for a specific trait.
Shortly after, Alison was pregnant with another child, Clementine, who was born at 38 weeks and she was also diagnosed with type A pyruvate carboxylase deficiency.
In 2010, the couple had their first son Beckett at 38 weeks and they immediately noticed that their son was a little sleepy, cold and three pounds lighter than their oldest child. Beckett was kept in the neonatal intensive care unit to be constantly monitored by doctors and the couple hoped for everything to be okay.
Not soon after, Beckett started to struggle with breathing and seemed to be dying. After a day in Boston Children’s Hospital, Beckett was diagnosed with type A pyruvate carboxylase deficiency. The doctors had explained to the couple that this rare disorder results in the buildup of lactic acid and a decrease in energy production. Even if Beckett did survive, the doctors explained that he will be severely retarded as a deficiency in this enzyme strongly effects the nervous system as well. With this condition, Beckett had to be closely monitored and treated by pediatricians. Although, Beckett made good improvement and the couple was able to take him home after 10 weeks in the hospital.
Child has a 50% chance of inheriting one abnormal gene and one normal gene for the trait, making them carriers, but unaffected by the symptoms and signs of pyruvate carboxylase deficiency.
Child has a 25% chance of inheriting both abnormal genes from each parent and being effected by pyruvate carboxylase deficiency.
Unfortunately, Clementine died in July 2012 at 2 years old and Beckett died eight weeks later at 3 years old.
Although both these children were unable to survive, their parents still provided them with full lives and their condition has greatly helped further research on this extremely rare disorder.
Both Beckett and Clementine experienced two years without any extreme emergencies. As this disorder impacts the nervous system, both children still had developmental delays. Ben and Alison still tried their best to give everything they could to Beckett and Clementine by putting them in speech therapy to learn how to communicate. Both Alison and Ben had to deal with several rude comments on the condition of their children, but never failed to provide them with an amazing life.
Child has a 25% chance of inheriting both abnormal genes from each parent and being effected by pyruvate carboxylase deficiency.