3-Methylcrotonyl-CoA carboxylase deficiency

Signs and symptoms

Those with 3-Methylcrotonyl-CoA carboxylase deficiency typically display normal development until 6 months to 3 years old, when patients present with an acute episode. These acute episodes are typically brought on by increased protein load or intercurrent infections. During metabolic crisis, moderate hyperammonemia, hypoglycemia, and metabolic acidosis have been noted. There is a broad spectrum of clinical manifestations ranging from cardiomyopathy, developmental delays, leukodystrophy, necrotizing encephalopathy, respiratory failure, hypotonia, cerebral palsy and failure to thrive. Carnitine deficiency is found in about 50% of cases.

Over 90% of those diagnosed with 3-Methylcrotonyl-CoA carboxylase deficiency by newborn screening remain asymptomatic. The medical abnormalities that present in the few who do show symptoms are not always clearly related to 3-Methylcrotonyl-CoA carboxylase deficiency. Manifestations of 3-Methylcrotonyl-CoA carboxylase deficiency vary even among family members who share a common environment and genetics.

Genetics

The MCCC1 and MCCC2 genes make protein subunits that come together to form an enzyme called 3-methylcrotonyl-CoA carboxylase. This enzyme plays an essential role in breaking down proteins from the diet. Specifically, the enzyme is responsible for the fourth step in processing leucine. If a mutation in the MCCC1 or MCCC2 gene reduces or eliminates the activity of 3-methylcrotonyl-CoA carboxylase, the body is unable to process leucine properly. As a result, toxic byproducts of leucine processing build up to harmful levels, damaging the brain and nervous system. This condition is inherited in an autosomal recessive pattern.

Diagnosis

3-Methylcrotonyl-CoA carboxylase deficiency is diagnosed by the detection of organic acids in urine using gas chromatography or mass spectrometry and analysis of the blood by liquid chromatography-tandem mass spectrometry. 3-Methylcrotonyl-CoA carboxylase deficiency is characterized by increased 3-hydroxyisovaleric acid and 3-methylcrotonylglycine levels in the urine. The acylcarnitines profile shows elevated concentrations of 3-hydroxyisovalerylcarnitine as well as an increased ratio of 3-hydroxyisovalerylcarnitine to propionylcarnitine.

Since genotype isn't predictive of phenotype, DNA testing isn't necessary. However, DNA analysis may help confirm 3-Methylcrotonyl-CoA carboxylase deficiency when the diagnosis is uncertain.

3-hydroxyisovalerylcarnitine is also elevated in other metabolism disorders such as 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency, biotinidase deficiency, multiple carboxylase deficiency, mitochondrial acetoacetyl-CoA thiolase deficiency and malonic aciduria. 3-Methylcrotonyl-CoA carboxylase deficiency is differentiated by the lack of other urine metabolites and by measuring the activity of 3-methylcrotonyl-CoA carboxylase, biotinidase, and other biotin-dependent carboxylases.

Screening

It is one of the 29 conditions currently recommended for newborn screening by the American College of Medical Genetics.

Treatment

Symptoms can be reduced by avoiding leucine, an amino acid. Leucine is a component of most protein-rich foods; therefore, a low-protein diet is recommended. Some isolated cases of this disorder have responded to supplemental biotin; this is not altogether surprising, consider that other biotin-related genetic disorders (such as biotinidase deficiency and holocarboxylase synthetase deficiency) can be treated solely with biotin. Individuals with these multiple carboxylase disorders have the same problem with leucine catabolism as those with 3-methylcrotonyl-CoA carboxylase deficiency.

References

This article incorporates public domain text from The U.S. National Library of Medicine

References

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