3-methylcrotonyl-CoA carboxylase deficiency (ORPHA:6)
A rare inherited disorder of leucine metabolism characterized by a highly variable clinical picture ranging from metabolic crisis in infancy to asymptomatic adults.
Epidemiology
The birth prevalence in Europe is estimated at 1/50,000-1/30,000. The introduction of neonatal screening programs based on tandem mass spectrometry has revealed a high frequency of this disorder, and it now appears to be the most common organic aciduria in some populations.
Clinical description
Patients with 3-methylcrotonyl-CoA carboxylase deficiency (3-MCCD) have a variable clinical phenotype with the vast majority of patients being asymptomatic and a small subgroup displaying symptoms of an organic aciduria, usually in association with environmental triggering factors. Many newborns now diagnosed through expanded newborn screening tests remain asymptomatic, indicating that the disease has a very low clinical penetrance. Most symptomatic patients have normal growth and development until presenting with an acute metabolic crisis, usually following a minor infection, fasting or introduction of a protein-rich diet, between the ages of 2-33 months. Symptoms include vomiting, coma and apnea. Rarely, neurological abnormalities (i.e. metabolic stroke, hemiparesis, and encephalopathy), weakness, muscular hypotonia and developmental delay have been reported. Between episodes of metabolic crisis patients are usually asymptomatic. Some patients with 3-MCCD may not develop symptoms until adulthood, manifesting with weakness and fatigue, while others may never show symptoms.
Etiology
3-MCCD is due to mutations in the MCCC1 (3q27.1) or MCCC2 (5q12-q13) genes. These two genes encode MCCase subunit alpha and MCCase subunit beta, which together catalyze the fourth step in the leucine catabolic pathway. Mutations in these genes lead to reduced or absent 3-MCC activity, thereby allowing the toxic byproducts of leucine processing to build up and cause clinical symptoms. Evidence is emerging that consanguinity with homozygosity for damaging mutations in a second rare disease gene may be associated with non-specific severe phenotypes of 3-MCCD.
Diagnostic methods
Newborn screening using tandem mass spectrometry reveals an elevation of C5-hydroxy acylcarnitine on blood spots. Urine organic acid analysis shows elevation of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine. Carnitine serum levels can be decreased. Lymphocyte and fibroblast assays show low to absent 3-MCC activity while other carboxylase enzymes have normal activity. Laboratory findings during an acute metabolic crisis include metabolic acidosis, hypoglycemia, and in some cases, mild hyperammonemia. Molecular genetic testing identifying two disease causing alleles confirms diagnosis. Newborn screening programs are available in the U.S. and some European countries.
Differential diagnosis
The differential diagnosis includes other organic acidurias such as multiple carboxylase deficiency as well as Reye's syndrome.
Antenatal diagnosis
Antenatal diagnosis is possible in families with known disease causing mutations.
Genetic counseling
3-MCCD is inherited autosomal recessively and genetic counseling is recommended.
Management and treatment
Early diagnosis may help in properly managing 3-MCCD and reducing the risk of severe metabolic crisis. Treatment is often not necessary in asymptomatic individuals. Some patients may require oral L-carnitine supplementation. A diet restricted in leucine is usually not warranted. Avoidance of fasting and of other precipitating stresses is recommended (mainly in infants and young children), as is the regular monitoring of free carnitine concentrations. An emergency regimen (IV glucose and the correction of acidosis) is recommended during intercurrent illness.
Prognosis
The prognosis is usually good but depends on the severity of symptoms experienced.

                            Last update: 
                            September 2020


                            - Expert reviewer(s): 
                            Pr Matthias BAUMGARTNER