General description

3-Methylcrotonyl-CoA carboxylase deficiency (3-MCCD) is a rare inherited disorder of leucine metabolism characterized by a highly variable clinical phenotype.

The clinical presentation of 3-MCCD is characterized by extraordinary heterogeneity, ranging from asymptomatic individuals to those with severe, life-threatening symptoms. The vast majority of patients identified through newborn screening remain asymptomatic, indicating the disorder's very low clinical penetrance. For symptomatic patients, the age of onset varies considerably, from the neonatal period to adulthood, with most symptomatic cases presenting between 2-33 months of age.

Most symptomatic patients exhibit normal growth and development until experiencing an acute metabolic crisis. These crises are typically precipitated by specific triggers, including minor infections, fasting, introduction of protein-rich diets, or strenuous physical activity. During these episodes, patients may present with vomiting, lethargy, coma, apnea, hypotonia, and seizures. Laboratory findings during acute decompensation often include metabolic acidosis, hypoglycemia, mild hyperammonemia, elevated liver transaminases, and ketonuria.

Between episodes of metabolic crisis, patients are typically asymptomatic. However, repeated crises without proper management can lead to more severe complications, including developmental delay, seizures, weakness, muscular hypotonia, and rarely, neurological abnormalities such as metabolic stroke, hemiparesis, and encephalopathy.

References

1. Reddy, Nihaal, et al. "Neuroimaging findings of organic acidemias and aminoacidopathies." Radiographics 38.3 (2018): 912-931.
2. Alshumrani, Ghazi Adlan, and Zoltan Patay. "Brain magnetic resonance imaging and proton MR spectroscopic findings after metabolic crisis in 3-methylcrotonylglycinuria." Annals of Saudi Medicine 35.1 (2015): 64-68.