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At a glance

It is an inherited mitochondrial disease (inborn error of metabolism) affecting the isoleucine catabolism resulting in recurrent episodes of ketoacidosis. This medical condition belongs to a spectrum of disease called organic acidemias. Clinically, it is associated with severe ketosis, acidosis, hypoglycemia, causing severe vomiting, poor feeding, seizures, muscular hypotonia, lethargy leading progressively to coma as a result of toxic encephalopathy. The onset of the disease is at birth and if the diagnosis is made in the first 10 days of life, there is potential for good outcome.

Synonyms

Beta-Ketothiolase Deficiency (note that beta-ketothiolase describes a group of enzymes, and patients with defects of different thiolases are known to have a different clinical picture); T2 Deficiency; Alpha-Methyl-Acetoacetic Aciduria; Methionine S-Adenosyltransferase (MAT) Deficiency; 2-Alpha Methyl-3-Hydroxybutyricacidemia; 3-Alpha-Oxothiolase Deficiency; 3-Alpha Ketothiolase Deficiency; 3-Alpha KTD Deficiency.

Incidence

The exact incidence remains unknown. There are approximately 60 cases that have been described in the literature.

Genetic inheritance

It is believed inherited as an autosomal recessive mode. The responsible acetoacetyl-CoA thiolase (ACAT) gene has been mapped to chromosome 11q22.3-23.1. The severity of the clinical features and the penetrance within families are variable.

Pathophysiology

Mitochondrial ACAT is responsible for cleavage of acetyl-CoA from acetoacetyl-CoA and 2-methylacetoacetyl-CoA, which is an intermediate in the isoleucine metabolism, but also for acetoacetyl-CoA formation in ketogenesis and acetoacetyl-CoA cleavage in ketolysis.

Diagnosis

Based on recurrent episodes of severe ketosis and acidosis without chronic ketosis. Urine analysis before and after an isoleucine challenge (showing 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, butanone, and tiglylglycine) is helpful for diagnosis. Demonstration of the enzyme defect in fibroblasts or leukocytes confirms the definite diagnosis.

Clinical aspects

Children with this defect commonly present with failure to thrive, recurrent episodes of severe ketoacidosis with hyperventilation (caused by metabolic acidosis), vomiting, diarrhea (often bloody), and coma during the course of intercurrent infections or after excessive protein intake. Onset is rarely before age 4 months. Most patients (approximately 60%) can have normal mental development if severe metabolic decompensations can be prevented. However, ataxia and frequent headaches have been reported. One case with congestive cardiomyopathy has been described. Mainstay of therapy is moderate restriction of isoleucine intake, intravenous glucose, and sodium bicarbonate during decompensations and avoidance of fasting.

Precautions before anesthesia

Most importantly, hypoglycemia during preoperative fasting must be prevented. A dextrose-containing intravenous solution should be started before the preoperative fasting period and kept intraoperatively and postoperatively until regular oral feeds are tolerated again. Cardiomyopathy has been described, so cardiac assessment of the patient is recommended.

Anesthetic considerations

Regional anesthesia allows better monitoring of central nervous function. Lactated Ringer solution should be avoided in patients with mitochondrial diseases because ...

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