Beta-ketothiolase deficiency. (2-Methyl acetoacetyl-CoA 3-ketothiolase deficiency) (mitochondrial 3-ketothiolase or beta-ketothiolase deficiency). 3-oxothiolase deficiency.
Incidence
This condition is inherited in an autosomal recessive pattern and is extremely rare having only been reported in 50 to 60 individuals throughout the world. Disorder of isoleucine catabolism.
Clinical Characteristics
This disorder, initially called alpha-methylacetoacetic aciduria, and more recently 3-oxothiolase deficiency, is an inborn error of isoleucine catabolism characterized by urinary excretion of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, tiglylglycine, and 2-butanone. Periodic severe ketoacidosis, usually trigered by intercurrent illness. Mild neurological signs such as mild developmental delay may be present. This rare disorder is characterized by normal early development followed by a progressive loss of mental and motor skills. It is clinically characterized by intermittent ketoacidotic episodes, with no clinical symptoms between episodes. Ketoacidotic episodes are usually severe and sometimes accompanied by lethargy/coma. Some patients may have neurological impairments as a sequela of these episodes. The disorder is caused by a mutation in a gene localized to chromosome region 11q and is transmitted in an autosomal recessive manner. More than 20 mutations have been identified. T2 deficiency is characterized by urinary excretion of 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate, and tiglylglycine but its extent is variable. Acylcarnitine analysis is also useful for the diagnosis. However, the diagnosis should be confirmed by enzyme assay. Treatments of acute episodes include infusion of sufficient glucose and correction of acidosis. Motor and mental development are generally normal.
Precipitants
Attacks are often triggered by an infection, fasting (not eating), or in some cases, other types of stress.
Provocation Tests
Mitochondrial 3-ketothiolase deficiency: Isoleucine loading (75 mg/kg that can be repeated on consecutive days or 100 mg/kg single dose) leads to increased excretion of metabolites; identical doses of valine and leucine serve as control. Since the disease is easily diagnosed in between the attacks by the characteristic acylcarnitine profile in tandem MS, provocation tests are rarely needed.
Diagnostic Procedures
EB-F, OB-F. Tandem MS or acyl-carnitine profile. Acylcarnitine analysis is useful for the diagnosis. However, the diagnosis should be confirmed by enzyme assay.