Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is a rare, inherited metabolic disorder that significantly impairs the body’s ability to convert fats and proteins into energy. It is also known as Glutaric Acidemia Type II (GA2) because glutaric acid is present in the urine of affected individuals. The disorder has a wide clinical spectrum, ranging from life-threatening illness in newborns to a milder, later-onset presentation in adults. Early detection through screening is important for prompt treatment, as the disorder can rapidly lead to severe complications.
The Metabolic Basis of Multiple Acyl-CoA Dehydrogenase Deficiency
This disorder fundamentally involves a failure in fatty acid beta-oxidation, the primary way the body breaks down fats for energy during fasting or illness. This process requires acyl-CoA dehydrogenases, which work on different lengths of fatty acid chains (SCAD, MCAD, LCAD, and VLCAD). These enzymes must transfer electrons to a critical co-factor system: the Electron Transfer Flavoprotein (ETF) and the Electron Transfer Flavoprotein Dehydrogenase (ETFDH).
MADD occurs due to a defect in either the ETF or the ETFDH protein, which accept electrons from all acyl-CoA dehydrogenases. Because the ETF/ETFDH system is a common component for multiple pathways, its failure impairs the function of all FAD-dependent acyl-CoA dehydrogenases simultaneously. This widespread metabolic blockade prevents the body from fully breaking down fats and some amino acids for energy.
The resulting energy deficit is compounded by the buildup of partially processed fatty acids and amino acid metabolites, which become toxic. These accumulated substances, including various acyl-CoA compounds, are shunted into alternative pathways. This leads to the characteristic excretion of multiple organic acids in the urine, such as glutaric acid. The inability to utilize fat stores for energy also leads to non-ketotic hypoglycemia, a dangerous drop in blood sugar without the compensatory production of ketones.
Clinical Presentation and Severity
The clinical manifestations of MADD are highly variable, categorized into two main groups: a severe neonatal-onset form and a milder, late-onset form. The severe neonatal-onset form typically presents within the first 48 hours of life with life-threatening symptoms. Newborns may experience profound hypoglycemia, metabolic acidosis, enlarged liver (hepatomegaly), and weak muscle tone (hypotonia).
In the most severe cases, the disorder can involve congenital anomalies, including dysmorphic facial features and cystic kidneys. Without prompt intervention, the neonatal-onset form often leads to severe complications such as hypertrophic cardiomyopathy and death within the first weeks or months of life. A characteristic “sweaty feet” odor may sometimes be present due to the buildup of specific metabolites.
The milder, late-onset form has a variable presentation, with symptoms appearing from infancy to adulthood. This form is often characterized by chronic or intermittent episodes of muscle weakness, exercise intolerance, and muscle pain (myalgia). Metabolic crises are frequently triggered by stressors like prolonged fasting, illness, or fever. These crises can manifest as recurrent episodes of vomiting, lethargy, and metabolic decompensation resembling Reye syndrome.
Identifying the Disorder Through Screening and Testing
Early diagnosis of MADD is frequently accomplished through Newborn Screening (NBS) programs utilizing tandem mass spectrometry (MS/MS) on dried blood spots. This screening tool measures the levels of various acylcarnitine species in the blood, which are compounds formed when the body attempts to excrete toxic metabolites. A positive screen shows characteristic elevations of multiple acylcarnitines of varying chain lengths, reflecting the widespread block in fatty acid oxidation:
- C4
- C5
- C6
- C8
- C10
- C14
If the newborn screen suggests MADD, confirmatory biochemical tests establish the diagnosis. Urine organic acid analysis is a key follow-up test, revealing the presence of multiple dicarboxylic acids, including glutaric acid and ethylmalonic acid. A plasma acylcarnitine profile further quantifies the elevated acylcarnitine species, which may also show low free carnitine due to its consumption during the excretion process.
The diagnosis is ultimately confirmed through molecular genetic testing, which analyzes the genes responsible for the ETF and ETFDH proteins. Pathogenic variations in the ETFA, ETFB, or ETFDH genes confirm the diagnosis. Genetic testing is particularly valuable for milder, late-onset cases, where biochemical markers may sometimes appear normal during asymptomatic periods.
Treatment and Long-Term Management Strategies
The primary goal of MADD management is to prevent metabolic crises by minimizing the body’s reliance on fat metabolism for energy. A specialized dietary regimen is implemented, focusing on a high-carbohydrate and low-fat, low-protein intake to reduce the substrates that cannot be processed. The avoidance of prolonged fasting is a fundamental rule for all individuals with MADD, as fasting forces the body into fat metabolism.
Infants and children require frequent feedings. For older individuals, overnight fasting limits are strictly enforced, sometimes requiring uncooked cornstarch at bedtime to provide a slow-releasing source of glucose. Supplementation with L-Carnitine is routinely prescribed to help remove toxic acyl-CoA compounds. Carnitine binds to the accumulating fatty acid intermediates, forming acylcarnitines that are safely excreted, replenishing the body’s free carnitine stores.
A highly effective treatment, especially for those with the late-onset form, is pharmacological doses of Riboflavin (Vitamin B2). Riboflavin is a precursor to the flavin adenine dinucleotide (FAD) co-factor, which is necessary for the function of the defective ETF and ETFDH proteins. Riboflavin supplementation (100–300 mg per day) can stabilize the faulty enzyme complex and enhance its residual activity, leading to significant clinical improvement in those with the riboflavin-responsive form.
Emergency protocols are a fundamental part of management, providing a plan for illness or metabolic stress. During fever, vomiting, or other illnesses, immediate medical intervention is necessary, typically involving the administration of intravenous (IV) glucose. Providing high-dose IV dextrose halts the body’s catabolic state, supplies energy, and prevents the toxic buildup of metabolites until the crisis has passed.
Understanding Genetic Inheritance
Multiple Acyl-CoA Dehydrogenase Deficiency is inherited in an autosomal recessive pattern. This means an individual must inherit a non-working copy of the gene from each parent to be affected by the disorder. The genes involved are typically ETFA, ETFB, or ETFDH, which code for the Electron Transfer Flavoprotein complex components.
A person who carries only one copy of the non-working gene is called a carrier and typically does not show symptoms. When both parents are carriers, they have a 25% chance with each pregnancy of having a child affected by MADD. Because of this inheritance pattern, genetic counseling is often recommended for families, providing information on recurrence risk and testing options for other family members.