Glutaric aciduria type 2 (GA-II), also known as multiple acyl-CoA dehydrogenase deficiency (MADD), is a rare, inherited metabolic disorder. It interferes with the body’s ability to process fats and certain proteins for energy. This prevents proper nutrient breakdown, leading to a buildup of harmful substances and a wide range of signs varying in severity.
Understanding Glutaric Aciduria Type 2
Glutaric aciduria type 2 stems from a deficiency in specific enzymes involved in the body’s metabolic pathways. These enzymes, electron transfer flavoprotein (ETF) and electron transfer flavoprotein dehydrogenase (ETFDH), are found in the mitochondria, the energy-producing centers within cells. Their role is to help break down fats and certain amino acids from proteins to generate energy.
The genetic basis of GA-II is autosomal recessive inheritance. This means an individual must inherit two copies of a non-working gene, one from each parent, to develop the condition. Mutations in the ETFA, ETFB, or ETFDH genes cause this enzyme deficiency. When these enzymes are either missing or not functioning correctly, partially broken-down proteins and fats accumulate within the cells. This accumulation can lead to a dangerous chemical imbalance, such as high levels of acids in the blood, known as metabolic acidosis.
Recognizing the Signs
GA-II presents with diverse signs, from severe forms appearing shortly after birth to milder forms later in life. These include neonatal-onset forms and a late-onset form.
The severe neonatal-onset forms appear within the first few days of life and can include physical abnormalities. Infants may present with poor feeding, lethargy, weak muscle tone (hypotonia), and low blood sugar (hypoglycemia). Some may also have brain malformations, an enlarged liver, kidney malformations, or unusual facial features. A distinctive “sweaty feet” odor can also be a sign.
The late-onset form, appearing in infancy, childhood, or adulthood, involves less severe symptoms. Individuals might experience episodes of weakness, behavioral changes, nausea, vomiting, and low blood sugar. Muscle fatigue, weakness, and pain are also common. These episodes, called metabolic crises, can be triggered by common illnesses or prolonged periods without food.
Diagnosis and Management
Diagnosis often begins with newborn screening programs. If results are abnormal, further tests are performed, including analyzing organic acids in urine and acylcarnitine profiles in blood, which show elevated levels of substances like C4 and C5 acylcarnitines. Confirmatory genetic testing provides a definitive diagnosis.
Management of GA-II focuses on dietary modifications and specific nutrient supplementation to minimize the accumulation of harmful substances and support energy production. A primary strategy involves a diet that is low in fat and protein but high in carbohydrates. This dietary approach helps reduce the body’s reliance on the impaired fat and protein breakdown pathways for energy.
Nutrient supplementation is also a common part of the management plan. Carnitine supplementation helps transport fatty acids for metabolism and prevents deficiency. Riboflavin (vitamin B2) is given as it is a precursor to flavin adenine dinucleotide (FAD), a cofactor for the deficient enzymes. Coenzyme Q10 may also be supplemented. During illness or metabolic crisis, emergency protocols include administering intravenous glucose to provide an immediate energy source and prevent severe hypoglycemia and metabolic acidosis.