GA2/MADD

Introduction

Glutaric Acidemia Type II/Multiple Acyl-CoA Dehydrogenase 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.

Signs and symptoms

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. Newborns may have low muscle tone (hypotonic), abnormal facial and body features, a large liver, and a characteristic smell like sweaty feet. Upon closer observation, they may have brain abnormalities, weak and enlarged hearts (cardiomyopathy), and 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 can be difficult to awaken (lethargic), vomiting, limp, or irritable.  The mildest cases of GA2/MADD may only become evident in adolescence or young adulthood as muscle pain and weakness.

Diagnosis

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 can determine whether the defect is in the ETF or ETFDH protein. Both can be identified by analysis of cellular activity. 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.

Genetics

GA2/MADD is a genetic disorder that can result from defects in any of three genes: ETFa, ETFB or ETFDH. It occurs when a child inherits a mutation in the gene for one of the ETFs or ETFDH from each carrier parent. When both parents are carriers, there is a 25% chance with each pregnancy of having another child with this genetic disorder .

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. The primary form of treatment is frequent feedings, 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 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 become excessively sleepy, are vomiting, have diarrhea, a fever, poor appetite, or an infection. In hospital, these children will be given sugar intravenously to provide energy.

Investigational Therapies

Information on current clinical trials is posted at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

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