Propionic Acidaemia (PPA)

What is propionic acidaemia?

Propionic acidaemia is a rare genetic disease characterised by incomplete metabolism of certain amino acids and, to a lesser degree, fats and cholesterol. The processing error causes propionic acid and other toxic substances to accumulate in the blood. Left untreated, these toxins damage the body’s organs especially the brain.

Propionic acidaemia varies in severity. Some individuals show only mild symptoms, while in others life-threatening complications such as stroke and coma occur. Progressive brain damage is a characteristic feature.

The amino acids that cause a problem in propionic acidaemia are isoleucine, valine, threonine and methionine. Amino acids are the building blocks of proteins. After eating proteins, the body ‘metabolises’ or breaks them down into amino acids. Animal proteins include dairy products, meat, eggs and fish. Proteins are also found in plants including soy, legumes, grains and nuts. The body uses the amino acids to make its own proteins essential for life – for example enzymes; structural proteins in muscles, hair, skin, cells and cartilage; proteins that generate movement in muscles; or those involved in cell functioning or immune responses. In periods of fasting or illness, the body often switches to use its own proteins, and stored fats, to generate energy. Leucine, isoleucine, valine and threonine are essential amino acids meaning that the body cannot make them. Therefore, these amino acids come from ingested protein or from the breakdown of previously ingested and stored proteins.

Propionic acidaemia has several other names. These include ‘propionic aciduria’ since high levels of propionic acid are also seen in the urine (-uria = in the urine); ‘propionyl-CoA carboxylase deficiency’ after the characteristic enzyme abnormality or ‘ketotic hyperglycinaemia’ describing the presence of keto acids and glycine in the blood (hyper = high; -aemia = in the blood). The disease shows many similarities to methylmalonic acidaemia.

How common is propionic acidaemia?

Overall, propionic acidaemia occurs in approximately 1 in 100,000 individuals globally. It is more common in the Arab population of Saudi Arabia (1 in 2000-5000) and the Inuits of Greenland (1 in 1000). The disease may also be more prevalent in Amish and Mennonite communities in the USA.

What causes propionic acidaemia?

In propionic acidaemia, a mutation in one of two genes causes a deficiency in an enzyme called propionyl-CoA carboxylase. This enzyme is needed for the correct processing of isoleucine, valine, threonine and methionine amino acids and certain fats and cholesterol. When the enzyme is missing or shows reduced activity, these substances remain incompletely metabolised. This results in the production of propionic acid and other toxic substances. Keto acids are also generated, which are metabolic by-products created when the body resorts to using its own protein and fat stores for energy. 

Propionic acidaemia is a recessively inherited genetic disorder, meaning that a child would only have the condition if both parents ‘carry’ the genetic mutation. Genes are arranged in structures called chromosomes that contain two strings or ‘alleles’. Offspring inherit one allele from their father and one from their mother. Carrying one copy of the mutated gene does not affect health, but when two mutated copies come together, the linked enzyme is deficient either in quantity or effect and the disease is expressed. For each and every pregnancy, there is a 1 in 4 chance of two carriers of the genetic mutation having a child with the disease. 

What are the symptoms and signs of propionic acidaemia?

Commonly, symptoms of propionic acidaemia develop in the first months of life. Infants fail to thrive due to feeding problems and vomiting. Their muscle tone is abnormally weak and they may show signs of extreme tiredness. Pronounced accumulation of metabolic by-products causes the blood and tissues become abnormally acidic (a condition known as metabolic acidosis). Keto acids also build up in the blood and tissues (known as ketoacidosis) and high levels are also seen in the urine. Blood levels of ammonia, a waste product of protein breakdown, and the amino acid glycine rise significantly. This early-onset form of the disease is often associated with rapid decline, culminating in severe dehydration, shock, heart abnormalities, brain damage, stroke, seizure and coma. Untreated, few infants survive such events.

Alternatively, propionic acidaemia may not manifest until later in childhood. In this case, individuals suffer intermittent metabolic ‘crises’, characterised by metabolic acidosis, ketoacidosis, extreme tiredness, vomiting, seizures and low muscle tone. The crises are triggered by infections, fever and periods without food, and are due to the body breaking down stored proteins and fats and releasing the toxic substances into the blood. Although children can be relatively healthy between attacks, for the majority there are long-term consequences. These include intellectual and learning disability, delayed development, abnormal movements due to a stroke, rigid muscle tone, poor growth/short height, seizures, osteoporosis, inflammation of the pancreas and an increased susceptibility to infection.

How is propionic acidaemia diagnosed?

Blood and urine tests are the primary methods of diagnosis, evaluating levels of propionic acid, keto acids, ammonia and glycine. Enzyme analysis can be used to identify abnormal levels of propionyl-CoA carboxylase activity. Genetic tests are sometimes carried out to confirm a mutation in the genes linked to the disease. In certain countries, newborn screening programmes help detect the condition early.

How is propionic acidaemia treated?

Treatment of propionic acidaemia involves dietary restriction of protein generally and of methionine, threonine, valine and isoleucine specifically. The diet needs to be continued indefinitely and must be initiated only after consultation with a dietician. As with any restrictive diet, it is important to ensure optimal nutrition. While natural protein intake is limited, a formula free of methionine, threonine, valine and isoleucine is prescribed. A range of such formulas is available, designed specifically to meet the nutritional needs of children at different ages. These specially formulated powders contain a balanced mix of essential and non-essential amino acids, vitamins, minerals and carbohydrates to avoid malnutrition of other amino acids and to sustain normal growth and development in children. Several low-protein food products are also available.

During periods of illness, fasting and infection, aggressive treatment is initiated to prevent the body breaking down its own energy stores. This includes limiting protein intake, giving glucose and additional fluids, increasing carnitine supplementation plus, in some cases, using dialysis to reduce ammonia levels and correct metabolic acidosis.

Supplementation with carnitine, an enzyme involved in fatty acid metabolism, helps to neutralise the toxic metabolic by-products. Antibiotics may help reduce the production of propionic acid by the intestine and help reduce the frequency of infections. Biotin (vitamin B7) supplements may also prove useful in some individuals. Biotin is a co-factor that helps the enzyme propionyl-CoA carboxylase function.

Sufferers are advised to avoid long periods of fasting, especially during periods of illness. For example, eating a snack at bedtime reduces the duration of overnight fasting.

Early and appropriate intervention helps to reduce the risk of complications in propionic acidaemia. However, even with treatment individuals can develop permanent learning difficulties and movement disorders. Also, sufferers are often prone to infections, which require careful management to avoid triggering metabolic crises.