3-methylcrotonyl-CoA carboxylase deficiency

3-Methylcrotonyl-CoA carboxylase (MCC) deficiency, also known as 3-MCC deficiency or 3-methylcrotonylglycinuria, is an inherited disorder of leucine (branched-chain amino acid) metabolism. It is caused by a deficiency of the mitochondrial enzyme 3-methylcrotonyl-CoA carboxylase, which is essential for the fourth step in leucine catabolism. This enzyme is a biotin-dependent carboxylase composed of alpha (MCCC1 gene) and beta (MCCC2 gene) subunits. When the enzyme is deficient, toxic metabolites including 3-methylcrotonylglycine and 3-hydroxyisovaleric acid accumulate in the body. The clinical presentation of MCC deficiency is highly variable. Many individuals identified through newborn screening remain asymptomatic throughout life, while others may develop symptoms ranging from mild to severe. Symptomatic individuals, particularly during infancy or early childhood, may present with metabolic crises triggered by illness, fasting, or physiological stress. These crises can include hypoglycemia, metabolic acidosis, hyperammonemia, lethargy, vomiting, poor feeding, hypotonia (low muscle tone), and seizures. In severe cases, metabolic decompensation can lead to coma or death if untreated. Some affected individuals develop developmental delay or neurological problems. The condition primarily affects the nervous system and metabolic processes. Treatment focuses on preventing metabolic crises through dietary management, including avoidance of prolonged fasting and, in some cases, leucine restriction. Supplementation with L-carnitine may be recommended to prevent secondary carnitine deficiency, which is commonly observed in affected individuals. During acute metabolic crises, emergency management includes intravenous glucose and correction of metabolic abnormalities. Biotin supplementation has been tried but is generally not effective since MCC deficiency is typically not biotin-responsive. With the widespread adoption of expanded newborn screening using tandem mass spectrometry, MCC deficiency has been identified as one of the most common organic acidurias detected, though the majority of identified individuals appear to remain clinically unaffected.

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