Propionic Acidaemia

Propionic acidaemia is a rare inherited disorder where the body cannot properly break down certain proteins and fats, leading to a dangerous buildup of toxic acids that can cause serious health problems from the first days of life.

Table of contents

• What is propionic acidaemia?
• Signs and symptoms
• Causes and inheritance
• How common is it?
• Diagnosis
• Treatment and management
• Long-term complications
• Medical classification codes
• Other names for this condition

What is propionic acidaemia?

Propionic acidaemia is an inherited disorder in which the body is unable to process certain parts of proteins and fats properly. It is classified as an organic acid disorder, which means it leads to an abnormal buildup of particular acids known as organic acids. When these acids accumulate in abnormal levels in the blood, urine, and tissues, they can be toxic and cause serious health problems^[1].

The disorder is caused by a defect in an enzyme called propionyl-CoA carboxylase. This enzyme normally helps the body break down certain amino acids (the building blocks of proteins), specifically valine, isoleucine, methionine, and threonine. It also helps break down certain types of fat and cholesterol. Without this enzyme working properly, a substance called propionyl-CoA and other potentially harmful compounds build up to toxic levels in the body^[1].

Signs and symptoms

Propionic acidaemia can vary in severity. In most cases, the features become apparent within a few days after birth. This severe form, called neonatal-onset propionic acidaemia, is characterized by a healthy-appearing newborn who then develops poor feeding and decreased alertness in the first few days of life^[1][2].

The initial symptoms of the neonatal form include poor feeding, vomiting, loss of appetite, weak muscle tone (called hypotonia), and lack of energy (called lethargy). Without prompt diagnosis and management, these symptoms can progress to more serious medical problems, including heart abnormalities, seizures, coma, and possibly death. The condition is frequently accompanied by metabolic acidosis (a dangerous buildup of acid in the blood), low blood sugar, high ammonia levels in the blood (called hyperammonemia), and abnormalities in blood cells^[1][2].

Less commonly, the signs and symptoms appear during childhood and may come and go over time. This is called late-onset propionic acidaemia. Some affected children experience intellectual disability or delayed development. In children with this later-onset form, episodes of more serious health problems can be triggered by prolonged periods without food (fasting), fever, or infections^[1][2].

The symptoms during an acute episode or metabolic crisis can include lethargy, altered mental status, nausea, vomiting, and in severe cases, swelling of the liver. Laboratory findings typically show low blood sugar, metabolic acidosis, and high ammonia levels^[8].

Causes and inheritance

Propionic acidaemia is caused by mutations in either the PCCA or PCCB genes. These genes provide instructions for making two parts (subunits) of the enzyme propionyl-CoA carboxylase. Mutations in either gene disrupt the function of this enzyme and prevent the normal breakdown of certain amino acids and fats^[1].

The disorder is inherited in an autosomal recessive pattern. This means both copies of the gene in each cell have mutations. Every person receives two copies of each gene—one from their mother and one from their father. In order to be affected with propionic acidaemia, an individual needs to have two disease-causing genetic variants in the same gene. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition^[1][4].

When acute illness occurs in propionic acidaemia, propionic acid accumulates, leading to profound metabolic acidosis, low blood sugar, and high ammonia levels. Catabolic stress—such as normal newborn metabolism, or an acute illness from infection, injury, surgery, or fever—produces breakdown of the body’s own proteins, leading to an increase in the involved amino acids. When excessive protein is eaten, a similar increase in these amino acids occurs^[8].

How common is it?

Propionic acidaemia affects about 1 in 100,000 people in the United States. The condition appears to be more common in several populations worldwide, including the Inuit population of Greenland, some Amish communities, and Saudi Arabians^[1][6].

Diagnosis

Newborns with propionic acidaemia can be identified through expanded newborn screening tests, which are now available in many states and countries. The newborn screening test detects an elevated level of a substance called propionylcarnitine (C3)^[2][3].

In symptomatic individuals or those detected by newborn screening, testing of urine organic acids reveals elevated 3-hydroxypropionate and the presence of methylcitrate, tiglylglycine, propionylglycine, and lactic acid. Testing of plasma amino acids generally reveals elevated glycine^[2].

Confirmation of the diagnosis relies on detection of mutations in the PCCA or PCCB genes through molecular genetic testing, or detection of deficient enzyme activity. In individuals with unclear molecular genetic test results, a combination of enzymatic and molecular diagnostics may be necessary^[2].

In families with a known mutation, prenatal diagnosis can be made by measuring specific substances in the amniotic fluid or by genetic testing^[6].

Treatment and management

There is no cure for propionic acidaemia, but it can be managed with a modified diet, medication, and special medical formulas. The treatment of individuals with acutely decompensated propionic acidaemia is a medical emergency. Healthcare professionals must treat precipitating factors such as infection, dehydration, and vomiting, and work to reverse the breakdown of the body’s own proteins^[2][9].

One of the most common treatments is restriction of natural protein in foods and formula. The specifics of the diet are followed by a dietician and are monitored with growth, development, and laboratory tests. Because not enough protein may be taken in through diet due to protein restriction, special formulas are used to increase the amount of protein in the diet. These formulas do not contain or have very little of the amino acids valine, isoleucine, threonine, and methionine^[14].

Many individuals take a medication called L-carnitine (also known as levocarnitine), as those with propionic acidaemia often have carnitine deficiency. Carnitine helps bind to propionic acid in the body. Some individuals also take antibiotics to reduce the amount of bacteria in the gut that produces propionic acid^[14].

Individuals diagnosed early and who begin proper treatment promptly have the best outcomes. It is important for families to recognize early signs of dehydration, poor feeding, seizures, and breathing difficulties, as metabolic crises play a major role in the neurological problems observed in patients with propionic acidaemia^[3].

In some cases with severe symptoms, liver transplants or multi-organ transplants may be considered. This can be discussed with healthcare providers on a case-by-case basis^[14].

Long-term complications

Manifestations of propionic acidaemia over time can include growth impairment, intellectual disability, seizures, damage to areas of the brain called the basal ganglia, inflammation of the pancreas (called pancreatitis), heart muscle disease (called cardiomyopathy), and chronic kidney disease. Other rarely reported complications include damage to the optic nerve, hearing loss, and in females, premature ovarian insufficiency^[2][5].

Clinical and imaging evidence suggests that propionic acidaemia predisposes patients to damage in the basal ganglia, which are structures deep in the brain involved in movement control. This damage can occur even in the absence of clear low oxygen levels during a crisis^[3].

Heart problems are also a concern. Some patients develop prolonged QTc intervals (an abnormality on heart monitoring) and decreased heart pumping ability^[1].

Medical classification codes

E71.1
D056693

Other names for this condition

Hyperglycinemia with ketoacidosis and leukopenia, Ketotic glycinemia, Ketotic hyperglycinemia, PCC deficiency, PROP, Propionicacidemia, Propionyl-CoA carboxylase deficiency, Propionic aciduria, Propionyl-CoA carboxylase deficiency