Propionic Acidemia, Metabolic Disorder,Organic acid condition Screening -Infant

Summary of Recommendation and Evidence

Population	Recommendation	Grade (What's This?)
Screening of both Genders	The genetic screening for Propionic Acidemia is recommended.	B

Propionic acidemia, also known as propionic aciduria, propionyl-CoA carboxylase deficiency and ketotic glycinemia, is an autosomal recessive metabolic disorder, classified as a branched-chain organic acidemia. The disorder presents in the early neonatal period with progressive encephalopathy.

OVERVIEW

Propionic acidemia is caused by a defect in the mitochondrial enzyme propionyl-CoA carboxylase, which is responsible for converting propionyl-CoA to methylmalonyl-CoA and subsequently to succinyl-CoA that enters the Krebs cycle. Propionyl-CoA carboxylase is involved in the catabolism of isoleucine, valine, methionine, and threonine, odd-chain fatty acids, cholesterol and nucleotides. The defect results in the accumulation of propionic acid and its metabolites, and a deficiency of Krebs cycle with impaired energy production. Propionic acidemia is caused by a defect in either of two genes (PCCA and PCCB) that code for the alpha and beta subunits of the enzyme. Affected patients can present at a few days of life with progressive lethargy progressing to coma with severe metabolic acidosis and hyperammonemia. Some patients with milder mutations can present later in life with failure to thrive, vomiting, neurological symptoms (abnormal movements, seizures), and delays in development.

SCREENING

Finding

Elevated C3 (propionyl carnitine)

Tested By

Tandem mass spectrometry (MS/MS); sensitivity: NA; specificity: NA

PREVALENCE

The incidence is about 1:238,346.

INHERITANCE

PA is inherited in an autosomal recessive manner. It affects both boys and girls equally.

PRENATAL TESTING

DNA testing by amniocentesis

OTHER TESTING

If the familial mutation is known, DNA testing is possible.

CLINICAL CHARACTERISTICS

With treatment, normal development and IQ are possible for patients with milder variants and symptomatic improvement may be seen in individuals already affected. Without treatment, metabolic crises (severe metabolic acidosis with hyperammonemia) may lead to progressive neurologic injury and death. Symptoms generally begin within the first few days after birth, though in variant forms they may not begin until after 6 weeks of age. Symptoms may be triggered by fasting and illness and children may appear healthy between metabolic crisis episodes. Children with milder variants can present with neurological symptoms or cardiomyopathy, without acute metabolic acidosis. The typical facies of infants with propionic acidemia includes: frontal bossing, widened depressed nasal bridge, epicanthal folds, long philtrum, upturned curvature of the lips.

Initial signs/symptoms may include:

Poor feeding
Vomiting
Seizures
Lethargy progressing to coma
Lab findings:
Metabolic acidosis
Hyperammonemia
Ketonuria
Neutropenia and thrombocytopenia
Elevated glycine (usually after the newborn period) in blood and presence of methylcitric acid in urine organic acids

If not treated promptly, recurrent metabolic crises may lead to:

Mental retardation
Movement disorders
Dystonia
Spasticity
Stroke
Brain damage
Death

EARLY SIGNS

Signs of propionic acidemia (PROP) usually start within a few days after birth. In some cases, signs may not appear until childhood or later. This is why early screening and identification is so important.

Early signs of PROP include:

Poor feeding
Vomiting
Loss of appetite
Weak muscle tone (known as hypotonia)
Sleeping longer or more often
Tiredness

Many of these signs may occur when your baby eats foods that his or her body cannot break down. They can be triggered by long periods of time without eating, illnesses, and infections.

CAUSES

When we eat food, enzymes help break it down. Some enzymes break down proteins into their building blocks, called amino acids. Other enzymes break down the amino acids. In propionic acidemia (PROP), the enzyme propionyl-CoA carboxylase (PCC) is not working correctly.

PCC’s job is to break down the amino acids isoleucine, valine, methionine, and threonine and a type of fat called odd chain fats.

If your baby has PROP, then his or her body either does not make enough or makes non-working PCC enzymes. When PCC is not working correctly, isoleucine, valine, methionine, threonine and odd-chained fats cannot be broken down. This causes other toxins in the body to build up.

PROP is an autosomal recessive genetic condition. This means that a child must inherit two copies of the non-working gene for PROP, one from each parent, in order to have the condition. The parents of a child with an autosomal recessive condition each carry one copy of the non-working gene, but they typically do not show signs and symptoms of the condition. While having a child with PROP is rare, when both parents are carriers, they can have more than one child with the condition.

TREATMENT

Children with propionic acidemia (PROP) need to limit certain proteins and fats in their diets because their bodies cannot break down these substances. From birth, your baby will need to be on a carefully planned diet. There are special formulas available for children with PROP (see Accessing Care below). These formulas will likely need to be continued through adulthood.

Your baby will also need to eat often. Long periods without food, as well as fever and infections, can trigger many of the signs mentioned in the Early Signs section.

Supplements and Medications

Your baby might also need to take supplements for L-carnitine and biotin. These are natural compounds that help break down fats and proteins, but they may not be naturally occurring in your baby’s body. Your doctor will need to write you a prescription for these supplements.

Your doctor may also prescribe antibiotics to help reduce the levels of propionic acid in your baby’s body.

EXPECTED OUTCOMES

Treatment for can help reduce some of the Propionic Acidemia (PROP) complications of the condition. It is possible for children receiving treatment for PROP to have learning disabilities or developmental delays. It is important to screen for and treat PROP because, if left untreated, babies can die within their first year of life.