Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is a rare, inherited metabolic condition affecting the body’s ability to convert fats and proteins into energy. This process powers cells, especially during fasting or illness. In individuals with MADD, this system is faulty, leading to a potential energy crisis and a harmful buildup of unused metabolic substances. The condition is also known as Glutaric Aciduria Type II (GA-II).
Genetic Origins of MADD
MADD is an autosomal recessive genetic disorder, meaning an individual must inherit a non-working gene from both parents. Parents who carry one mutated copy are considered carriers but do not show symptoms. For each pregnancy, a carrier couple has a 25% chance of having a child with MADD.
The condition arises from mutations in the ETFA, ETFB, or ETFDH genes. These genes provide instructions for proteins in the mitochondria, the energy-producing centers of cells. The ETFA and ETFB genes code for electron transfer flavoprotein (ETF), while ETFDH codes for ETF-ubiquinone oxidoreductase (ETF:QO). Mutations in these genes create a dysfunctional enzyme system, impairing energy production and causing the toxic buildup seen in MADD.
Clinical Presentation and Symptoms
The clinical signs of MADD exist on a spectrum, categorized by age of onset and severity. The most severe form is the neonatal-onset type, appearing within the first few days of life. Newborns present with profound hypotonia (weak muscle tone), poor feeding, and severe, non-ketotic hypoglycemia (low blood sugar without ketone production). Affected infants may have an enlarged liver (hepatomegaly), cardiomyopathy, and a distinctive “sweaty feet” odor from isovaleric acid accumulation.
The neonatal-onset form has two sub-types: one with congenital anomalies and one without. Those with anomalies may have distinct facial features, structural brain abnormalities, or cystic kidneys. The prognosis for neonatal-onset MADD is poor, with many infants succumbing to the disease within the first few months of life.
The late-onset form of MADD can manifest from infancy through adulthood and is milder. Symptoms appear episodically and include recurrent vomiting, lethargy, and muscle weakness, particularly after illness, fasting, or exercise. Chronic muscle pain and exercise intolerance are also complaints for these individuals.
Regardless of the type, MADD carries the risk of a metabolic crisis. This is a life-threatening episode where the body’s energy demands overwhelm its capacity, causing a rapid worsening of symptoms. Crises are triggered by stressors like fever, infection, or prolonged fasting. During a crisis, an individual can experience extreme hypoglycemia, metabolic acidosis (a buildup of acid in the blood), and hyperammonemia (high ammonia levels), which can progress to coma or death if not treated urgently.
The Diagnostic Process
Diagnosing MADD begins with newborn screening programs. A blood sample from a heel prick is analyzed using tandem mass spectrometry to screen for metabolic disorders by detecting abnormal substance levels. For MADD, the screening looks for elevated concentrations of various acylcarnitines. An abnormal screen flags the infant for further investigation.
If screening is abnormal or symptoms develop later, physicians order specific lab tests. A plasma acylcarnitine profile analyzes fats in the blood, showing elevations in short-, medium-, and long-chain acylcarnitines in MADD. A urine organic acid analysis can also reveal high levels of acids like glutaric and ethylmalonic, indicating a blockage in metabolism.
Confirmation of MADD comes from genetic testing, which involves sequencing DNA to find mutations in the ETFA, ETFB, and ETFDH genes. Identifying mutations on both copies of one of these genes confirms the diagnosis. This genetic information is also important for family counseling and predicting disease severity and treatment response.
Management and Treatment Strategies
Managing MADD focuses on preventing metabolic crises and minimizing toxic buildup through careful dietary management. Patients require a diet low in fat and protein to reduce the nutrients their bodies cannot process. To provide adequate energy, the diet is high in carbohydrates.
A primary dietary rule is the strict avoidance of fasting, as going too long without food can trigger a metabolic crisis. This means patients must eat frequent meals and snacks. Some may require continuous overnight feeding through a gastrostomy tube or use uncooked cornstarch for a slow release of glucose.
Supplementation is another part of MADD treatment. High doses of Riboflavin (Vitamin B2) are prescribed, as it is a precursor to a helper molecule for the deficient enzymes. In some individuals, high-dose riboflavin can improve enzyme function, known as riboflavin-responsive MADD. L-carnitine is used to help remove toxic fatty acids from the body, and Coenzyme Q10 (CoQ10) may be recommended to support energy production.
A clear emergency protocol is important, as common illnesses can precipitate a metabolic crisis. During these times, patients need prompt medical intervention, which involves hospitalization for intravenous (IV) fluids with a high glucose concentration. This IV glucose provides a direct energy source, bypassing the faulty metabolic pathways. Families are provided with an emergency letter for healthcare providers that outlines the immediate steps for management.