What is a deficiency of acetyl-CoA (Acetyl-Coenzyme A) acetyltransferase?

Deficiency of Acetyl-CoA Acetyltransferase (ACAT1)

Acetyl-CoA acetyltransferase deficiency, also known as beta-ketothiolase deficiency or mitochondrial acetoacetyl-CoA thiolase (T2) deficiency, is an autosomal recessive inborn error of metabolism affecting isoleucine and ketone body metabolism, characterized by recurrent episodes of severe ketoacidosis that can be life-threatening if not properly diagnosed and treated. 1, 2

Pathophysiology

• Deficiency of mitochondrial acetoacetyl-CoA thiolase (encoded by the ACAT1 gene) disrupts two metabolic pathways: isoleucine catabolism and ketone body metabolism (ketolysis) 1, 2
• The enzyme normally catalyzes the reversible formation of acetoacetyl-CoA from two molecules of acetyl-CoA during ketogenesis and ketolysis 3
• This deficiency leads to the accumulation of toxic metabolites and inability to properly utilize ketone bodies during periods of metabolic stress 4
• Recent research has identified additional functions of ACAT1 beyond its classical activity, including acetylation of Pyruvate Dehydrogenase (PDH), suggesting broader metabolic implications 3

Clinical Presentation

• Typically presents between 6-24 months of age, though presentation can vary significantly 2
• Characterized by recurrent episodes of severe ketoacidosis triggered by:
  • Protein-rich meals 1
  • Fasting 4
  • Intercurrent illness 5
• Acute episodes typically present with:
  • Vomiting and dehydration 1
  • Tachypnea 1
  • Lethargy and potential progression to coma 4
• Unlike other metabolic disorders, blood glucose is often normal or high during ketoacidotic episodes 4
• Between episodes, patients may be asymptomatic 2

Diagnostic Evaluation

• Diagnosis requires comprehensive laboratory evaluation including 5, 6:

  • Plasma acylcarnitine profile
  • Urine organic acid analysis
  • Plasma carnitine levels (free and total)
  • Genetic testing for ACAT1 mutations

• Characteristic laboratory findings include:

  • Urine organic acid analysis showing increased excretion of:
    • 2-methyl-3-hydroxybutyric acid 2
    • Tiglylglycine 1, 2
    • 2-methyl-acetoacetic acid (in some cases) 2
    • 3-hydroxybutyric acid and acetoacetic acid 1
  • Severe metabolic acidosis with low lactate and ammonia levels 4

• Diagnostic pitfalls:

  • May be misdiagnosed as diabetic ketoacidosis, salicylism, "fasting ketoacidosis" or "idiopathic ketotic hypoglycemia" 4
  • Some patients with "mild" mutations may be misinterpreted as normal by certain enzymatic assays (coupled assay with tiglyl-CoA) 7

Genetic Aspects

• Inherited as an autosomal recessive trait 2
• Caused by mutations in the ACAT1 gene 1, 7
• Significant genetic heterogeneity exists with various mutations identified:
  • Some mutations (e.g., A132G, D339-V340insD) result in residual enzyme activity ("mild" mutations) 7
  • Others (e.g., c.52-53insC, G152A, H397D, IVS8+1g>t) are "null" mutations with no residual activity 7

Management

• Acute management of ketoacidotic episodes:

  • Aggressive hydration and correction of acidosis 4, 2
  • Provision of adequate calories to reverse catabolism 8
  • Close monitoring of electrolytes and acid-base status 4

• Long-term management:

  • Avoidance of prolonged fasting 8
  • Dietary modifications may be necessary, particularly during illness 8
  • Emergency protocols for early intervention during catabolic stress 2

• Prognosis is relatively good if acute episodes are adequately treated 2

Differential Diagnosis

• Other organic acidemias 5
• Fatty acid oxidation disorders 5
• Diabetic ketoacidosis 4
• Salicylate poisoning 4

Laboratory Considerations

• Preferred sample type for testing is plasma or serum 5
• Samples should be frozen immediately and shipped on dry ice 5
• Acylcarnitine profile analysis is a key diagnostic test 5, 6
• Genetic testing is required for definitive diagnosis 1, 7