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Beta-ketothiolase deficiency

Synonym(s) 3-ketothiolase deficiency
3-oxothiolase deficiency
Alpha methylacetoacetic aciduria
Alpha-methyl-acetoacetyl-CoA thiolase deficiency
Mitochondrial acetoacetyl-coenzyme A thiolase deficiency
T2 deficiency
Prevalence <1 / 1 000 000
Inheritance Autosomal recessive
Age of onset Infancy
  • E71.1
MeSH -
MedDRA -


Disease definition

Beta-ketothiolase (T2) deficiency is a rare organic aciduria (see this term) affecting ketone body metabolism and the catabolism of isoleucine and characterized by intermittent ketoacidotic episodes associated with vomiting, dyspnea, tachypnoea, hypotonia, lethargy and coma, with an onset during infancy or toddlerhood and usually ceasing by adolescence.


The birth prevalence (from newborn screening) has been estimated at 1/137,120 newborns in Australia and 1/232,000 newborns in the U.S.A.

Clinical description

Neonates and infants often appear normal at birth as the disease does not usually present until the ages of 5 months to 2 years. The onset of symptoms usually occurs in the form of a ketoacidotic crisis, most often brought on by stress, fasting, increased dietary protein intake, acute illness and/or infections (i.e. gastroenteritis). An acetone or fruity odor on the breath often signals ketoacidosis. These episodes are associated with vomiting, dyspnea, lethargy and unconsciousness, and can lead to coma and death if not treated. Neurological sequelae (such as developmental delay) following severe episodes are common. Rarely, patients present with signs of metabolic encephalopathy (hypotonia, dysarthria, cholea, developmental delay). The occurrence of developmental delay or neurological manifestations before a first ketoacidotic crisis, however, is very rare. The frequency of episodes decreases with age, eventually stopping before adolescence. In between episodes, patients are often asymptomatic.


This disease is caused by mutations (at least 50 described) in the acetyl-CoA acetyltransferase1 (ACAT1) gene located on chromosome11q22.3. This gene encodes the ACAT1 enzyme, which when its activity is reduced or absent, impairs the breakdown of isoleucine and acetoacetyl- Co A, hampering the utilization of ketone bodies and leading to toxic accumulations of isoleucine derived acyl-CoA esters in the body.

Diagnostic methods

Most patients are diagnosed by demonstrating metabolic acidosis and ketosis, by urinary organic acid analysis (2-methyl-3-hydroxybutyrate (the most reliable marker), 2- methylacetoacetate and tiglylglycine), or by acylcarnitine analysis during metabolic decompensation. Diagnosis can be confirmed by cultured fibroblast enzyme assays (reduced potassium-dependent acetoacetyl-CoA thiolase activity) and molecular genetic testing. Computed tomography of the brain may reveal basal ganglia lesions that have been reported in some patients. Newborn screening programs are available in certain countries like the U.S. and Australia.

Differential diagnosis

The differential diagnosis includes sepsis, other organic acidurias such as HSD10 disease and succinyl-CoA:3-ketoacid CoA transferase deficiency (see these terms), other conditions that cause ketoacidosis in childhood, and glycogen storage disease due to glycogen synthase deficiency (see this term).

Antenatal diagnosis

Prenatal testing is possible in families with a known disease causing mutation by mutation analysis or enzyme activity assays using cultured amniocytes.

Genetic counseling

T2 deficiency is inherited autosomal recessively. Genetic counseling is possible.

Management and treatment

During a ketoacidotic crisis, intravenous fluids with glucose and electrolytes should be administered immediately. Bicarbonate (initially as 1mmol/kg over 10 minutes followed by continuous infusion) should equally be given to treat acidosis. Carnitine supplementation may be helpful. Dialysis is effective but usually not necessary. Unconscious patients and those with severe dyspnea may require mechanical ventilation. Long-term management involves avoidance of fasting (and IV glucose in cases of fever or vomiting) and, in children, a mildly restricted protein intake (1.5-2g/kg/day), avoidance of fat-rich (ketogenic) diet, and L-carnitine therapy in those with low carnitine levels.


The prognosis is often good if detected early and treated properly so as to prevent ketoacidotic attacks.

Expert reviewer(s)

  • Dr Toshiyuki FUKAO

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