Pyruvate Carboxylase Deficiency

What else is it called?

  • Ataxia with Lactic Acidosis, type II
  • Leigh Necrotizing Encephalopathy due to Pyruvate Carboxylase Deficiency
  • Leigh Syndrome Due to Pyruvate Carboxylase Deficiency
  • PC Deficiency
  • Type II Ataxia with Lactic Acidosis

Get in touch

Contact our caring team on 08452 412 173 for help and support. Our phone lines open 10am-4pm, Monday to Friday.

Prefer to email? Our email address is contact@metabolicsupportuk.org.

What causes it?

Pyruvate Carboxylase Deficiency is a rare neurometabolic disorder. This disorder is caused by problems in the PC gene which provides instructions for producing the pyruvate carboxylase enzyme.  The enzyme is found in a part of the body’s cells called the mitochondria. Often referred to as the cell’s battery, this part of the cell is responsible for producing energy. The enzyme has several main purposes including:

  • Making glucose – the body’s main energy source.
  • Forming myelin – a protective sheath surrounding certain nerve cells.
  • Producing neurotransmitters – chemicals that enable nerve cells to transmit messages to each-other.

Problems in the PC gene mean that not enough of the pyruvate carboxylase enzyme is made and this affects the production of energy in the mitochondria. It also allows toxic substances such as lactic acid and ammonia to accumulate and this becomes progressively harmful to the organs and tissues, especially in the nervous system. A deficiency also means the enzyme does not produce enough neurotransmitters which are important for brain function and this contributes to the neurological symptoms seen in this disorder.

How common is it?

This disorder is estimated to affect approximately 1 in 250,000 births worldwide. There is a much higher incidence of Type A in North America and some Algonkian Indian tribes in eastern Canada. Type B has been most commonly reported in Europe, and especially in France. There have only been 5 cases of Type B recorded.

What are the signs and symptoms?

There are 3 forms of this disorder:

  • Type A (Infantile form)
  • Type B (Severe neonatal form)
  • Type C (intermittent/benign form)

Common symptoms in all types include:

  • Failure to thrive
  • Developmental delay
  • Recurrent seizures
  • Metabolic acidosis

Low blood sugar (hypoglycaemia) can be a symptom in any of the forms but is not always seen.

Pyruvate Carboxylase Deficiency Type A

Type A has symptoms beginning in infancy. Symptoms include:

  • Mildly elevated levels of acid in the blood caused by a chemical imbalance (metabolic acidosis)/high levels of lactic acid in the blood (lactic acidosis)
  • Delays in mental and motor developmental milestones are common which affects skills such as sitting, crawling, standing, walking and holding/grasping objects
  • Intellectual disability
  • Lack of emotion, feeling, or concern (apathy)
  • Failure to grow or gain weight (failure to thrive)
  • Low muscle tone (hypotonia)
  • Pyramidal tract signs e.g. continuous contraction of the muscles, muscle weakness, and over-responsive reflexes
  • Problems with co-ordination, balance and speech (ataxia)
  • Crossed eyes (nystagmus)
  • Seizures
  • Tiredness (fatigue)
  • Episodes of rapid, shallow breathing (tachypnea), vomiting, abdominal pain and high levels of acid in the blood (crises) are usually triggered by infection, illness, or long periods without food.

This type has a severe course and most children die in infancy or early childhood. However, some may survive to adulthood, and will require special care and education.

Pyruvate Carboxylase Deficiency Type B

Symptoms are either present at birth or are found shortly after. Symptoms are severe and progressive. They may include:

  • Low blood sugar (hypoglycaemia)
  • Mildly elevated levels of acid in the blood caused by a chemical imbalance (metabolic acidosis)/high levels of lactic acid in the blood (lactic acidosis)
  • High ammonia levels in the blood (hyperammonaemia)
  • High levels of sodium in the blood (hypernatremia)
  • Anorexia
  • Enlarged liver (hepatomegaly) progressing to liver failure
  • Seizures
  • Low muscle tone (hypotonia)
  • Pyramidal tract signs e.g. continuous contraction of the muscles, muscle weakness, and over-responsive reflexes
  • Abnormal movements
  • Abnormal eye movements
  • Severe delays in mental and motor developmental milestones are common which affects skills such as sitting, crawling, standing, walking and holding/grasping objects
  • Intellectual disability
  • Coma

Most infants with this type die within the first 3 months of life. 2 have survived longer.

Pyruvate Carboxylase Deficiency Type C

Symptoms of type C are much milder. This form is known as the intermittent or benign form. The main symptom is episodes of elevated levels of acid in the blood caused by a chemical imbalance (metabolic acidosis)/mildly elevated levels of lactic acid in the blood (lactic acidosis). Development is either normal, or there may be mild delays in reaching developmental milestones such as sitting, crawling, standing, and walking.

Type C is a mostly benign form of the disorder. It is unlikely to have any effect on life-expectancy.

How is it diagnosed?

This disorder should be suspected following the onset of the key symptoms. It can be diagnosed through a range of blood tests, an enzyme essay or via genetic testing.

Can it be treated?

There is no cure for Pyruvate Carboxylase Deficiency. Treatment is primarily aimed at correcting the chemical imbalance in the body and reducing the build-up of acids i.e. metabolic acidosis/lactic acidosis. Some symptoms may be improved with supplements such as citrate, aspartic acid and biotin. However, this will not correct any neurological symptoms.  Treatment options explore ways of providing alternative sources of energy for the body and alternative means of metabolising pyruvate (anaplerotic therapy). The drug tripheptanoin has shown some promise in correcting certain symptoms, however further studies are needed. A low fat/high carbohydrate diet may be recommended.

All children and adults with this disorder should have a written information on the disorder and an emergency regimen plan which has been provided by a specialist, which must be followed in the event of a crisis. Avoidance of these crises are key, and parents/carers will be educated in avoidance and early recognition of the onset of a crisis.  Triggers include infections, illness and long periods without food. A ketogenic diet (high fat/low carbohydrate) must be avoided as it is proven to precipitate symptoms to a life-threatening stage.

Any emergency regimen must be followed, and this may result in being admitted to hospital to manage any illness or infection, preventing dehydration, and preventing the further onset of symptoms such as acidosis.

Do my family need to be tested?

Humans have chromosomes composed of DNA. Genes are pieces of DNA that carry the genetic instruction. Each chromosome may have several thousand genes. We inherit particular chromosomes from the egg of the mother and sperm of the father. The genes on those chromosomes carry the instructions that determine a person’s characteristics, which are a combination of the parents.

In most cases, this is an inherited condition. However, sometimes it can occur sporadically. There is nothing that could have been done to prevent it.

Everyone has a pair of genes that make the pyruvate carboxylase enzyme. In children with Pyruvate Carboxylase Deficiency, neither of these genes works correctly. These children inherit one non-working gene from each parent.

Parents of children with Pyruvate Carboxylase Deficiency are carriers of the condition. Carriers do not have the disorder because the other gene of this pair is working correctly.

When both parents are carriers, in each pregnancy the risk to the baby is as follows:

  • 25% chance (1 in 4) of Pyruvate Carboxylase Deficiency
  • 50% chance (1 in 2) for the baby to be a carrier of Pyruvate Carboxylase Deficiency
  • 25% chance (1 in 4) for the baby to have two working genes and neither have Pyruvate Carboxylase Deficiency or be a carrier

Relevant Organisations

References

References are available on request. Please contact Helen Morris by phoning 0845 241 2173 or emailing helen@metabolicsupportuk.org [Resource Library No: PCM010].

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