3-Methylcrotonyl-CoA Carboxylase Deficiency, Metabolic Disorder, Organic acid condition Screening -Infant

3-Methylcrotonyl-CoA Carboxylase Deficiency, Metabolic Disorder, Organic acid condition Screening -Infant

3-Methylcrotonyl-CoA Carboxylase Deficiency, Metabolic Disorder, Organic acid condition Screening

Summary of Recommendation and Evidence

Population

Recommendation

Grade
(What's This?)

Screening of both Genders

The genetic screening for 3-Methylcrotonyl-CoA Carboxylase Deficiency (3MCC) is recommended.

B

Methylcrotonyl CoA carboxylase (MCC) (3-methylcrotonyl CoA carboxylase, methylcrotonoyl-CoA carboxylase) is a biotin-requiring enzyme located in the mitochondria. MCC uses bicarbonate as a carboxyl group source to catalyze the carboxylation of a carbon adjacent to a carbonyl group performing the fourth step in processing leucine, an essential amino acid. 

OVERVIEW

Lack of the enzyme (usually present in liver, fibroblasts, and leukocytes) impairs the break down of leucine resulting in metabolic acidosis and occasional hypoglycemia. The phenotype is extremely variable, ranging from patients presenting in infancy with severe neurological involvement and developmental delays to patients with recurrent attacks of metabolic decompensation followed by complete recovery to asymptomatic adults. This enzyme requires biotin and elevated C5-OH can be seen in biotinidase deficiency.

SCREENING

Finding

Elevated C5-OH (acylcarnitine)

Tested By

Tandem mass spectrometry (MS/MS); sensitivity: 100%; specificity: NA

PREVALENCE

Approximately 1 in 50,000

INHERITANCE

3MCC is inherited in an autosomal recessive manner. It affects both boys and girls equally.

PRENATAL TESTING

DNA testing possible by amniocentesis if both disease causing mutations of an affected family member have been identified.

OTHER TESTING

Genetic testing is possible for at-risk family members if both disease causing mutations of an affected family member have been identified.

CLINICAL CHARACTERISTICS

With treatment, normal development and IQ are possible. However, severe episodes of hypoglycemia may still result in seizures and/or mental retardation. Without treatment, recurring metabolic crises, associated with illness, may result in developmental delay/mental retardation, seizures, coma, or death. Symptoms generally begin after three months and before three years of age. Affected children may be healthy between metabolic crises. Some people remain completely asymptomatic. 

Initial signs/symptoms may include:

  • Poor feeding
  • Vomiting
  • Irritability
  • Spasticity
  • Lethargy
  • Lab findings:
  1. Hyperammonemia
  2. Low carnitine levels
  3. Ketoacidosis
  4. Hypoglycemia

If not treated promptly and consistently, patients may experience:

  • Failure to thrive
  • Fasting intolerance
  • Hypotonia
  • Reye-like illness
  • Seizures
  • Coma
  • Developmental delay/mental retardation
  • Death

EARLY SIGNS

Each child with 3-methylcrotonyl-CoA carboxylase deficiency (3-MCC) has a different experience. Your child might start showing signs of 3-MCC around three to six months, three years, or even in adulthood. Some babies can have this condition and never show any signs.

Signs of 3-MCC include:

  • Poor appetite
  • Sleeping longer or more often 
  • Tiredness
  • Behavior changes
  • Irritability
  • Muscle weakness (known as hypotonia)
  • Vomiting
  • Muscle tightness (also called spasticity)
  • Delayed growth
  • Developmental delays

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.

If your baby shows any of these signs, be sure to contact your baby’s doctor immediately.

CAUSES

When we eat food, enzymes help break it down. Some enzymes help break down proteins into their building blocks, called amino acids. Other enzymes break down these amino acids. In babies with 3-methylcrotonyl-CoA carboxylase deficiency (3-MCC), the enzyme 3-methylcrotonyl-CoA carboxylase (MCC) is not working correctly.

This enzyme’s job is to break down the amino acid leucine. If your baby has 3-MCC, he or she either does not make enough or makes non-working MCC enzymes. When MCC does not work correctly, your baby’s body cannot break down leucine, which causes the build-up of harmful organic acids.

3-MCC is an autosomal recessive genetic condition. This means that a child must inherit two copies of the non-working gene for 3-MCC, 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 3-MCC is rare, when both parents are carriers, they can have more than one child with the condition. 

TREATMENT

Treatments vary among children with 3-methylcrotonyl-CoA carboxylase deficiency (3-MCC). Some children never need any treatment. Your baby’s doctor will be able to determine which treatments your baby needs.

Dietary Treatment

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

Your baby will also need to follow a very specific diet because he or she cannot break down a substance in proteins called leucine. Your baby’s doctor might recommend a special leucine-free baby formula or other foods made for children with 3-MCC. These formulas will likely need to be continued through adulthood.

Supplements and Medications

L-carnitine supplements can also be helpful. L-carnitine is a natural substance that helps remove harmful waste products from the body. Your baby’s doctor can determine how much L-carnitine your child needs and write an appropriate prescription.

EXPECTED OUTCOMES

Most children who are diagnosed with 3-methylcrotonyl-CoA carboxylase deficiency (3-MCC) at birth never need any special treatment. They can live healthy lives. Even children with signs of 3-MCC have typical growth and development with early and careful treatment.

If 3-MCC is not treated, babies can develop breathing problems, seizures, liver failure, and coma. This can result in brain damage or even death.