Final Diagnosis -- 3-MethylCrotonyl-CoA Carboxylase ( 3-MCC) Deficiency



3-MCC deficiency is one of the defects that effect degradation pathway of Leucine. This disorder follows an autosomal recessive inheritance pattern. In situations in which there is increase in the cellular energy requirements (e.g. in infections) especially if accompanied by reduced glucose intake, the body tries to generate energy from proteins (amino acids) and fat. Amino acids including Leucine degradation produce energy in the form of ketones bodies. In patients with 3-MCC is deficiency Leucine degradation results in accumulation of a 3-methylcrotonyl-CoA. The accumulated substrate produces metabolic acidosis, 3-hydroxyisovaleric acid, and 3-methylcrotonylglycine.

The clinical presentation is quite variable. It varies from relatively asymptomatic to sever manifestations including vomiting, lethargy, apnea, hypotonia, or hyperreflexia and seizures. The age of onset of symptoms is usually during the first several years of life, but later onset has been reported. Symptoms often have onset with an infection, illness, or prolonged fasting. Other patients may present with failure to thrive beginning in the neonatal period or developmental delay.

The development of expanded newborn screening (NBS) has shed considerable new insight into this disorder. Recent evidence suggests that, behind medium chain acyl CoA dehydrogenase deficiency and phenylketonuria, isolated 3-MCC deficiency may be the most common of the inherited organic/amino-acidurias. Patients detected by NBS screening of blood spots have uniformly shown an absence of symptomatology. Newborn Screening using tandem mass spectrometry reveals an elevation of C5-hydroxy acylcarnitine from the dried blood spot of an affected patient. The diagnosis of 3-MCC deficiency then requires further testing. Urine organic acid analysis shows elevation of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine. An important differential diagnosis is multiple carboxylase deficiency. The diagnosis is established by acylcarnitine profile using tandem mass spectrometry following carnitine supplementation. In cases with 3-MCC, 3-hydroxyisovalerylcarnitine is usually elevated. If C3 acylcarnitine is elevated, the disorder is most likely multiple carboxylase deficiency. To further confirm isolated 3-MCC deficiency, the enzyme activity should be assayed in fibroblasts or leukocytes, along with at least one other carboxylase having normal enzyme activity. Many neonates testing positive on blood acylcarnitine profiling have been later shown to have an affected mother, and the elevations associate with elevations in maternal circulation

During the episodes patients may have profound hypoglycemia, mild metabolic acidosis, hyperammonemia, elevated liver transaminases. Plasma free carnitine levels may be very low

Treatment of 3-MCC deficiency involves reducing dietary Leucine intake using a special Leucine-depleted formula or a protein restricted diet. With the onset of illness special care including IV glucose and the correction of acidosis might be needed. Carnitine and glycine supplementation have proven beneficial.


  1. Gibson, K.M., Bennett, M.J., Naylor, E.W., et al. 3-MethylCrotonyl-CoA Carboxylase Deficiency in Amish/Mennonite adults identified by detection of increased acylcarnitines in blood spots of their children. J Pediatrics 132:519, 1998.
  2. Tuchman, M., Berry, S.A., Thuy, L.P., et al. Partial MethylCrotonyl-CoA Carboxylase Deficiency in an infant with failure to thrive, gastrointestinal dysfunction and hypertonia. Pediatrics 91:664, 1993.
  3. Elpeleg, O.N., Havkin, S., Barash, V., et al. Familial hypotonia of childhood caused by isolated 3-MethylCrotonyl-CoA Carboxylase Deficiency. J Pediatrics 121:407, 1992.
  4. Koeberl, D.D., Millington, D.S., Smith, W.E., et al. Evaluation of 3-Methylcrotoonyl-CoA Carboxylase Deficiency Detected by Tandem Mass Spectrometry Newborn Screening. J Inherit Metab Dis 26:25, 2003.

Contributed by Ahmed Bedeir MD and K Michael Gibson, PhD, FACMG

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