3-Hydroxy-3-Methyglutaric Aciduria, Metabolic Disorder, Organic acid condition Screening -Infant

3-Hydroxy-3-Methyglutaric Aciduria, Metabolic Disorder, Organic acid condition Screening -Infant

3-Hydroxy-3-Methyglutaric Aciduria, 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-Hydroxy-3-Methyglutaric Aciduria is recommended.

B

3-hydroxy-3-methylglutaric aciduria (HMG) is a condition in which the body is unable to break down certain proteins. People with the condition are also unable to produce ketone bodies, substances that help the body store energy.  HMG is considered an organic acid condition because it can lead to a harmful amount of organic acids and toxins in the body.  

OVERVIEW

The lack of the enzyme 3-hydroxy-3-methylglutaryl-CoA lyase (usually expressed at high levels in the liver) impairs the formation of ketone bodies from fat and the break down of leucine. This results in increased utilization of glucose with hypoglycemia and accumulation of toxic metabolites. The lack of energy causes seizures and lethargy, accompanied by metabolic acidosis and hypoketotic hypoglycemia. Mutations in the HMGCL gene cause HMG-CoA lyase deficiency.

SCREENING

Finding

Elevated C5-OH (acylcarnitine)

Tested By

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

PREVALENCE

Rare.

INHERITANCE

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

PRENATAL TESTING

DNA testing by amniocentesis or chorionic villus sampling (CVS) if both disease causing mutations of an affected family member have been identified; enzyme testing by maternal urine analysis possible at >23 weeks gestational age.

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 or fasting, will likely result in developmental delay/mental retardation or death. Symptoms generally begin from infancy up to 3 years of age. Affected children may be healthy between metabolic crises.

Initial signs/symptoms may include:

  • Poor feeding
  • Vomiting
  • Irritability
  • Lethargy
  • Lab findings:
  1. Metabolic acidosis
  2. Non-ketotic hypoglycemia 

 

If not treated promptly and consistently, patients may experience:

  • Failure to thrive
  • Hepatomegaly
  • Seizures
  • Apnea
  • Developmental delay/mental retardation
  • Death

EARLY SIGNS

Each child with 3-hydroxy-3-methylglutaric aciduria (HMG) has a slightly different experience. Most affected children start to show signs of HMG between 3 months and 2 years of age.  In a few cases, babies start to show signs of the condition just a few days after birth.

Signs of HMG include:

  • Poor appetite
  • Sleeping longer or more often
  • Tiredness
  • Irritability
  • Weak muscle tone (known as hypotonia)
  • Fever
  • Vomiting
  • Diarrhea
  • Low blood sugar (hypoglycemia)
  • Behavior changes

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 help break down protein into its building blocks (called amino acids). In 3-hydroxy-3-methylglutaric aciduria (HMG), the enzyme “HMG CoA lyase” is not working correctly.

This enzyme has two jobs. First, it breaks down leucine, an amino acid, to make energy. Second, it helps make ketone bodies from fat. Ketone bodies are substances used for energy. 

When this enzyme doesn’t work,  organic acids build up in the body which can be harmful in large amounts. Generally, if your body starts to run low on the ketone bodies needed for your brain, you can use stored fat from other areas to make the ketone bodies. If there is not enough sugar in your body (such as between meals) then your body is unable to turn the fat into the needed ketone bodies and you may begin to experience symptoms.

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

TREATMENT

Dietary Treatment

Your baby will need to be on a strict diet to avoid certain proteins and fats. When your baby eats fats and proteins that he or she cannot break down, it may cause many of the signs mentioned in the Early Signs section.  A metabolic doctor or a dietician can help you plan a well-balanced diet for your child.

Your baby’s doctor might recommend special baby formulas and foods made especially for children with 3-hydroxy-3-methylglutaric aciduria (HMG). These formulas will likely be needed through adulthood.

Your baby will also need to eat often. Long periods of time without food, illnesses, and infections can trigger signs of HMG.

Supplements and Medication

Your baby’s doctor might write a prescription for L-carnitine supplements. L-carnitine is a naturally occurring substance in the body, but your baby’s body might not make enough of it. Prescription L-carnitine supplements can help get rid of toxic waste products in the body.

EXPECTED OUTCOMES

If your baby receives early and careful treatment, he or she will most likely have a healthy life with normal growth and development.

It is possible, even with treatment, for babies with 3-hydroxy-3-methylglutaric aciduria (HMG) to have low blood sugar and other signs of HMG.

Early screening and treatment are very important. Babies who do not receive treatment usually die or develop permanent brain damage.