NeurometPlus

Incidence

Autosomal recessive. Until recently it was considered very rare if it exists. Its isolated occurrence was disputed. Reported cases may be Holocarboxylase sinthetase deficiency. It is a disorder of leucine degradation pathway. Until recently isolated MCC deficiency has been considered to be a rare inborn error of metabolism. Tandem MS, recently introduced to newborn screening in an increasing number of screening centers, allows for the first time detection of a large variety of organic acidurias including isolated MCC deficiency. First results show that isolated MCC deficiency appears to be the most frequent organic aciduria detected in tandem MS-based screening programs in North America, Europe and Australia with an overall frequency of approximately 1 in 40,000 to 1 in 50,000. At least 40 cases of isolated biotin-resistant MCC deficiency have been described.

Clinical Characteristics

Isolated 3-methylcrotonyl-CoA carboxylase (MCC) deficiency is an autosomal recessive disorder of leucine catabolism. MCC is a heteromeric mitochondrial enzyme comprised of biotin-containing alpha-subunits and smaller beta-subunits. The recent introduction of neonatal screening programs based on tandem mass spectrometry has revealed an unexpectedly high frequency of this disorder, which appears to be the most common organic aciduria in some populations. The phenotype is variable, ranging from neonatal onset with severe neurological involvement to asymptomatic adults. Most patients however have normal growth and development until presenting with an acute metabolic decompensation between 2 and 33 months of age. Such an episode usually follows a minor infection or introduction of a protein-rich diet. Symptoms include vomiting, opisthotonus, involuntary movements, seizures, coma and apnoea. The major abnormal metabolites are 3-methylcrotonylglycine and 3-hydroxyisovaleric acid in urine, and 3-hydroxisovalerylcarnitine in plasma. The patients usually respond to intraveinous fluids and cessation of protein feeding and are asymptomatic between acute episodes. Long term treatment with modest leucine restriction and oral L-carnitine supplementation appears to be sufficient for normal growth and development. Has been reported a cat urine odor. Onset early infancy to childhood. Episodes of metabolic acidosis precipitated by high protein intake or febrile disease. Hypotonia, myoclonic seizures, choreoathetosis and alopecia may be present. Apnea & unexpected death might occur. Patients typically present with acute metabolic acidosis following intercurrent illness. The possibility of isolated MCC deficiency should be considered in patients with typical signs of an organic aciduria and especially those with hypoglycemia or Reye-like syndrome. It should also be considered in patients with hypotonia, seizures, or developmental delay. After the recent introduction of tandem Mass Spectrometry (MS) newborn screening in an increasing number of screening centres, the range of clinical symptoms has become even wider ranging from neonatal onset to asymptomatic newborns and adults

Precipitants

High protein intake or febrile disease.

Provocation Tests

High-protein feeding may induce attack of acidosis later during childhood.

Diagnostic Procedures

EB-F, EB-W, GC/MS, Tandem MS/MS. The major abnormal metabolites are 3-methylcrotonylglycine and 3-hydroxyisovaleric acid in urine, and 3-hydroxisovalerylcarnitine in plasma. Urinary organic acid analysis usually enables the physician to make the diagnosis of isolated MCC deficiency. There is a characteristic organic aciduria with massive excretion of 3-hydroxyisovaleric acid (3-HIVA) and 3-methylcrotonylglycine (3-MCG), usually in combination with a severe secondary carnitine deficiency. In addition, accumulated acyl-CoA compounds are trans-esterified to acylcarnitine esters. The major abnormal metabolite, 3-hydroxyisovalerylcarnitine, is found in blood and urine. It should be noted that modest elevations of 3-HIVA and 3-hydroxyisovalerylcarnitine are not specific for isolated MCC deficiency. Enzymatic assay of MCC and at least one other mitochondrial carboxylase to exclude multiple carboxylase deficiencies is essential for confirmation of isolated MCC deficiency. If a patient is clinically or biochemically suspected to have isolated MCC deficiency, confirmation by direct enzyme assay is highly recommended.