Beta-ketothiolase deficiency (T2)

Baby Detect > Metabology > Beta-ketothiolase deficiency (T2)

ACAT1 gene

Also known as: T2 deficiency; 2-methyl-3-hydroxybutyric acidemia; mitochondrial acetoacetyl-coa thiolase deficiency – MAT deficiency; 3-oxothiolase deficiency

OMIM#203750 https://omim.org/entry/203750

1. The disease

Beta-ketothiolase deficiency is a rare, genetic organic aciduria affecting ketone body metabolism and the catabolism of isoleucine. This condition is caused by mutations in the ACAT1 gene – a mutation must be present in the copies inherited from both the mother and the father – for the disease to manifest itself. If, however, patients are properly diagnosed, inexpensive preventive measures as avoid fasting can be effective, and normal development is expected.

2. The Symptoms

Babies are expected to be asymptomatic at birth and in the first weeks of life. Symptoms often appear between the fifth months to the second year of life, but onset as early as 2 days has been reported. Lack of early signs or symptoms does not exclude the diagnosis.

  • Infants can present with vomiting, lethargy, rapid respiration, metabolic acidosis with normal glucose and intermittent ketoacidosis. Hyperglycemia or hypoglycemia may be present in almost 30% of the patients (Nguyen et al. 2017). Severe crisis can lead to coma.
  • Some patients who experience severe ketoacidosis can develop psychomotor retardation or fatal outcomes.
  • Hyperglycemia or hypoglycemia may be observed (glucose levels range from 15-260mg/dL) during ketoacidotic episodes during neonatal periods or infancy and ammonia is expected to be normal or slightly high with no need for hemodialysis (just rare cases). It is vital to avoid an initial misdiagnosis of diabetic ketoacidosis.

3. Actions to take in case of early diagnosis

  • Babies with a positive genetic test (having 2 mutations or 2 copies of a single mutation in the ACAT1 gene) should continue breastfeeding. Early treatment is essential in preventing chronic symptoms.
  • Early treatment, avoidance of prolonged periods of fasting, is crucial in preventing metabolic crises and chronic symptoms, such as neurologic impairment.
  • Biochemical diagnosis is essential for confirming diagnosis with acylcarnitine analysis or urinary organic acid analysis. Be aware that mild forms of the disorder (mild genotype also) can present no biochemical abnormalities.
  • T2 is a lifelong disease that requires lifetime compliance to dietary management (specially fasting avoidance) and regular follow-up with a metabolic disease specialist and a multidisciplinary approach to care, including pediatrics, genetics and nutrition.
  • The prognosis for T2 is very favorable with lifetime compliance to fractionated meals.
  • Genetic counseling is highly recommended for family planning and evaluation of at-risk family members such as siblings.

4. For more information

Orphanet: https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=713&Disease_Disease_Search_diseaseGroup=Beta-ketothiolase-deficiency&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Beta-ketothiolase-deficiency&title=Beta-ketothiolase%20deficiency&search=Disease_Search_Simple

Biblio: Grünert SC, Schmitt RN, Schlatter SM, et al. Clinical presentation and outcome in a series of 32 patients with 2-methylacetoacetyl-coenzyme A thiolase (MAT) deficiency. Mol Genet Metab. 2017;122(1-2):67-75. doi:10.1016/j.ymgme.2017.06.012. PMID: 28689740.