Organic Acid Disorders

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Disease Name Beta-ketothiolase deficiency
Alternate name(s) Alpha-methylacetoacetic aciduria, 2-methyl-3-hydroxybutyric academi, Mitochondrial acetoacetyl-CoA thiolase deficiency, MAT deficiency, T2 deficiency, 3-oxothiolase deficiency, 3-ketothiolase deficiency, 3-KTD deficiency
Acronym BKD
Disease Classification Organic Acid Disorder
Variants No, but there is considerable clinical heterogeneity
Variant name N/A
Symptom onset Late infancy or childhood. Mean age at presentation is 15 months (range 3 days to 48 months). There are documented cases of asymptomatic patients with enzyme deficiency. Frequency of decompensation attacks falls with age and is uncommon after the age of 10.
Symptoms Symptoms include intermittent episodes of severe metabolic acidosis and ketosis accompanied by vomiting (often hematemesis), diarrhea and coma that may progress to death. There is great clinical heterogeneity between patients. Infancy is the period of highest risk for decompensation. Death or neurologic complications can occur. Neurologic damage includes striatal necrosis of the basal ganglia, dystonia and/or mental retardation. Other symptoms include cardiomyopathy, prolonged QT interval, neutropenia, thrombocytopenia, poor weight gain, renal failure and short stature. If neurologically intact, patients are normal between episodes.
Natural history without treatment Clinical outcome varies widely with a few patients suffering severe psychomotor retardation or death as a result of their initial attack and others with normal development and no episodes of acidosis.
Natural history with treatment Despite severe recurrent attacks, appropriate supportive care can result in normal development.
Treatment Avoidance of fasting. Bicarbonate therapy and intravenous glucose in acute crises. Possible protein restriction. Consider carnitine supplementation.
Other N/A
Physical phenotype No dysmorphisms
Inheritance Autosomal recessive
General population incidence unknown
Ethnic differences None known
Population N/A
Ethnic incidence N/A
Enzyme location Converts 2-methylacetoacetyl-CoA to propionyl-CoA and acetyl-CoA.
Enzyme Function Catalyzes the decarboxylation of oxoacids.
Missing Enzyme Mitochondrial acetoacetyl-CoA thiolase enzyme
Metabolite changes Increased urinary excretion of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, tiglylglycine, 2-butanone, and ketone bodies (acetoacetic acid, 3-hydroxybutyric acid).
Gene ACAT1
Gene location 11q22.3-q23.1
DNA testing available Not in US. Sequencing of gene on a research basis.
DNA testing detail No common mutation known
Prenatal testing Enzyme analysis in amniocytes or CVS tissue. If mutations have been identified, DNA testing is possible.
MS/MS Profile C5:1 tiglycarnitine – elevated
OMIM Link www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=203750
Genetests Link www.genetests.org
Support Group

Organic Acidemia Association
www.oaanews.org

Save Babies through Screening Foundation
www.savebabies.org

Genetic Alliance
www.geneticalliance.org

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