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  • Updated 05.05.2023
  • Released 05.15.2010
  • Expires For CME 05.05.2026

Multiple acyl-CoA dehydrogenase deficiency



Multiple acyl-CoA dehydrogenase deficiency, also known as glutaric aciduria type II, is an inborn error of metabolism with a spectrum of clinical presentations that range from a severe, life-threatening neonatal-onset form with profound metabolic acidosis, hypoketotic hypoglycemia, hyperammonemia, cardiomyopathy, and liver disease to a later-onset form predominantly characterized by chronic musculoskeletal symptoms, exercise intolerance, and recurrent episodes of rhabdomyolysis as well as episodes of metabolic decompensation with acidosis and hypoglycemia in the setting of precipitating stressors (11). Patients with the early-onset form may also present with congenital anomalies.

Key points

• Multiple acyl-CoA dehydrogenase deficiency is a disorder of fatty acid, amino acid, and choline metabolism caused by defects in the ETF–ETF:QO complex that impair the transfer of electrons to the mitochondrial respiratory chain.

• The disease course is highly variable, ranging from a severe neonatal-onset presentation with or without congenital malformations to later-onset forms with intercurrent metabolic decompensations and chronic musculoskeletal symptoms.

• Plasma acylcarnitine profile and urine organic acids are diagnostic but may be normal in asymptomatic patients with later-onset forms. Glutaric aciduria type II is also detected by newborn screening.

• Diets low in fat and protein, supplementation with riboflavin and carnitine, and avoidance of catabolism are the therapeutic strategies in milder or late-onset disease. Severe neonatal forms are mostly lethal.

• Disorders of riboflavin metabolism can also present with clinical features and biochemical abnormalities suggestive of MADD.

Historical note and terminology

MADD was initially described in 1976 in a male neonate of Turkish descent who was born via vaginal delivery at term following an uncomplicated pregnancy (30). The family’s first child had died within a few hours of life of an undetermined cause. The next child developed tachypnea at 2 hours of life and was found to have metabolic acidosis and profound hypoglycemia at 16 hours of life (24 mg/dl). He was given dextrose 10% and sodium bicarbonate; however, he developed worsening hypoglycemia (5 mg/dl) and cardiorespiratory arrest at 32 hours of life that required intubation. He subsequently developed hypothermia, seizures, and persistent hypoglycemia despite infusion of dextrose 20%. He died at 70 hours of life. His skin, urine, and blood had a sweaty feet odor. Metabolic studies in blood, urine, and fibroblasts revealed abnormal metabolites suggestive of a pathway affecting multiple acyl-CoA dehydrogenases. Due to an abundance of glutaric acid, the authors proposed the designation “glutaric aciduria II,” to differentiate this disease from glutaric aciduria I, which had been described the year before.

MADD represents a clinical spectrum classically described as type I, associated with neonatal presentation and congenital anomalies; type II, associated with neonatal presentation without congenital anomalies; and type III, associated with late-onset disease (29). Milder, later-onset disease forms are also referred to as “ethylmalonic-adipic aciduria” (25). In reality, it is a clinical spectrum ranging from mild to severe disease.

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