GA2/MADD

Introduction

Glutaric Acidemia Type II/Multiple Acyl-CoA Dehydrogenase Deficiency or GA2/MADD is a rare but serious fatty acid oxidation disorder (FAOD). At International Network for Fatty Acid Oxidation Research and Management (INFORM), Jerry Vockley has made it his mission to teach the public, especially those affected by these disorders, more about FAODs.

What is GA2/MADD Deficiency?

GA2/MADD is an inherited disorder that reduces the body’s ability to obtain energy from most proteins and fats. The mitochondria, known as “powerhouses of the cell,” cannot process the energy from fats and amino acids because of a defect in electron transfer flavoproten (ETF) or electron transfer flavoprotein dehydrogenase (ETFDH). Without these proteins, a patient with GA2/MADD may have a range of symptoms from lethargy to life-threatening organ failure, since the unused fats and amino acids can grow to toxic levels in the body.

Genetics

Like other FAODs, Glutaric Acidemia Type II/Multiple Acyl-CoA Dehydrogenase Deficiency is a genetic disorder. Specifically, GA2/MADD occurs where there are genetic defects in any of three genes: ETFa, ETFB, or ETFDH. When a child inherits a mutation for one of these genes from each carrier parent, they will have this fatty acid oxidation disorder. When both parents are carriers, there is a 25% chance that every child they bear together could have this genetic disorder.

Signs and Symptoms of GA2/MADD Deficiency

GA2/MADD can be apparent as a serious condition at birth or as a mild disease in adolescence or young adulthood. Symptoms also vary by age and severity. Fatty acid oxidation research suggests that in newborns, the most common symptoms include:

Low muscle tone (hypotonic)
Abnormal facial and body features
A large liver
Characteristic smell like sweaty feet
Brain abnormalities
Weak and enlarged hearts (cardiomyopathy)
Kidneys with fluid filled sacs (cystic)

Infants and children with milder forms of the disease may only show symptoms after an ear infection, gastrointestinal distress, or another relatively minor health problem. At that time, a child may exhibit signs of GA2/MADD like:

Difficulty waking (lethargy)
Vomiting
Limpness
Irritability

The mildest cases of GA2/MADD may only become evident in adolescence or young adulthood as muscle pain and weakness.

Diagnosis

Like other fatty acid oxidation disorders, newborn screening is one way to diagnose this problem. Newborn screening by tandem mass spectrometry of blood spots can identify the most severe cases of GA2/MADD in early infancy. An organic acid analysis of urine samples is also used for diagnostic purposes. If necessary, further studies on the analysis of cellular activity can determine whether the defect is in the ETF or ETFDH protein. Molecular testing for these defects is usually more readily available than protein diagnostics.

Severe forms of GA2/MADD can be diagnosed before birth by using organic acid analysis to identify increased glutaric acid in amniotic fluid. In some cases, an ultrasound examination of the fetus will show cysts in the kidneys.

Treatment

Without immediate treatment, infants with the most severe GA2/MADD defects often die during the first weeks of life, usually from heart-associated problems. Fortunately, most newborns who receive early treatment can survive well into adulthood. Like other fatty acid oxidation disorders, the primary form of treatment is frequent feedings. Patients must eat every 2-3 hours to start to avoid going without food (fasting). In some cases, continuous feeding of carbohydrates through a stomach tube may be necessary to prevent low blood sugar, especially at night. A riboflavin supplement may help some patients by stabilizing the defective protein. Pharmacologic doses of carnitine (50-100 mg/kg/day) are given as well to help remove unused fats and amino acids.

Mildly ill children with MADD should be given liquids that contain glucose or sugars frequently. Parents should call their health care provider immediately whenever these infants show signs of lethargy, vomiting, diarrhea, fever, poor appetite, or an infection. Once in the hospital, these children will be given sugar intravenously to provide energy and correct the issues.

Investigative Therapies and Fatty Acid Oxidation Research

Information on current clinical trials for fatty acid oxidation disorders likes Glutaric Acidemia Type II/Multiple Acyl-CoA Dehydrogenase Deficiency are posted at ClinicalTrials.gov. At INFORM Network, we work to provide you with the latest research and news regarding these disorders. You can also learn more information about FAODs support groups from our annual conference.