Propionic acidemia is a rare inherited metabolic disorder where the body cannot properly break down certain proteins and fats. This inability stems from a deficiency in the enzyme propionyl-CoA carboxylase. As a result, harmful substances accumulate in the blood and urine, leading to a range of health problems. The disorder usually becomes apparent shortly after birth but can present later in life, requiring lifelong management.
Clinical Presentation and Symptoms
Neonatal-Onset
The most common form of propionic acidemia presents in the first few days or weeks of life, often after protein feeding begins. Newborns who appeared healthy at birth may develop symptoms like poor feeding, vomiting, and lethargy. Without intervention, affected infants can experience diminished muscle tone (hypotonia), dehydration, and seizures.
This rapid onset of symptoms is an acute metabolic crisis, or decompensation. The accumulation of toxic substances leads to an excess of acid in the blood and tissues (metabolic acidosis). This can escalate to a progressive encephalopathy (brain disease), which may result in a coma and can be fatal if not treated promptly. The initial presentation can be mistaken for other common neonatal issues, making accurate diagnosis a time-sensitive matter.
Late-Onset
Propionic acidemia can also manifest later in childhood or, rarely, in adulthood. These individuals may have a milder enzyme deficiency and appear healthy for years. Symptoms are often triggered by metabolic stress, such as an illness, infection, or a significant dietary change. The presentation can be varied and may not be immediately recognized as a metabolic disorder.
Symptoms in late-onset propionic acidemia can include a failure to grow and gain weight at the expected rate, a condition known as failure to thrive. Individuals may also experience developmental regression, losing previously acquired skills. Other features include movement disorders like dystonia (involuntary muscle contractions) and psychiatric issues such as behavioral problems.
Genetic Basis and Inheritance
Propionic acidemia is caused by mutations in the PCCA or PCCB genes. These genes provide instructions for creating the alpha and beta subunits of the enzyme propionyl-CoA carboxylase (PCC). Both subunits must join to form a functional enzyme, and a mutation in either gene results in a defective or deficient enzyme.
The PCC enzyme processes propionyl-CoA, a substance produced during the breakdown of certain amino acids. The enzyme also plays a role in the metabolism of certain odd-chain fatty acids and cholesterol. When the PCC enzyme is not working correctly, propionyl-CoA and related toxic compounds build up in the body, leading to the clinical signs of the disorder.
The inheritance pattern is autosomal recessive, meaning an individual must inherit a mutated copy of the PCCA or PCCB gene from both parents. A person with only one mutated copy is a carrier. Carriers are healthy because their one functional gene produces enough PCC enzyme.
When two carriers have a child, there is a 25% chance with each pregnancy that the child will be affected by propionic acidemia. There is a 50% chance the child will be a carrier, and a 25% chance the child will be unaffected.
Diagnosis and Testing
Diagnosis often begins with newborn screening, where a blood test from a heel prick can identify elevated levels of propionylcarnitine (C3). This substance is an indicator of propionic acidemia. A positive screen indicates that further confirmatory testing is necessary.
Confirmatory tests include a urine organic acid analysis, which looks for characteristic organic acids like methylcitrate and propionylglycine. Plasma acylcarnitine analysis is also used to confirm the elevated C3 levels and search for other related compounds.
Molecular genetic testing is the standard approach for a definitive diagnosis, analyzing the PCCA and PCCB genes to identify disease-causing mutations. This confirms the diagnosis and can sometimes provide information about the condition’s potential severity. An enzyme assay to directly measure enzyme activity may be performed, but this is less common than genetic testing.
Management and Treatment Strategies
Managing propionic acidemia is a lifelong process focused on preventing the buildup of toxic metabolites. The primary treatment is a low-protein diet that restricts the amino acids isoleucine, valine, methionine, and threonine. This diet must be tailored and monitored by a metabolic physician and dietitian to provide enough protein for growth without causing metabolic instability.
Individuals with propionic acidemia rely on medical formulas for adequate nutrition. These formulas provide calories, vitamins, and minerals with a balanced mix of amino acids, but are low in the problematic ones. Medical foods are a primary source of nutrition throughout life.
Medication also supports management. L-carnitine supplementation helps the body remove toxic organic acids by facilitating their excretion in the urine. Antibiotics like metronidazole are sometimes used to reduce propionic acid produced by gut bacteria. During illness or metabolic stress, hospital intervention is often required to prevent a metabolic crisis.
For individuals with severe, difficult-to-manage propionic acidemia, a liver transplant is a treatment option. Because the enzyme deficiency is primarily in the liver, a transplant provides a source of the functional PCC enzyme. This can reduce the risk of metabolic decompensation and allow for a more liberal diet. However, a liver transplant is a major surgery with risks, including the need for lifelong immunosuppressant medications.
Long-Term Outlook and Complications
Propionic acidemia is a condition with potential long-term complications affecting multiple organ systems. The neurologic outcome is a primary concern, as many individuals experience some degree of intellectual disability or developmental delay. Early diagnosis and consistent metabolic management can improve cognitive outcomes, but the risk remains.
Other organs can be affected over time. Potential long-term issues include:
- Cardiomyopathy, a disease of the heart muscle.
- Pancreatitis, or inflammation of the pancreas.
- Optic neuropathy, which is damage to the optic nerve.
- A persistent seizure disorder.
- Chronic kidney disease.
The buildup of toxic metabolites contributes to these long-term problems. Even with diligent management, individuals may experience recurrent metabolic crises during illness, which can cause further damage. Lifelong follow-up with a team of specialists is required to monitor and manage these complications. The condition requires continuous care to optimize quality of life and long-term health.