Paula and Bobby
Parents of Lillie
What is Alpha-Methylacetoacetic Aciduria?
Alpha-Methylacetoacetic Aciduria is a rare disease. It is also known as 2-methyl-3-hydroxybutyric Acidemia 2-methylacetoacetyl-CoA thiolase deficiency 3-keto-thiolase deficiency 3-ketothiolase Deficiency 3-ktd Deficiency 3-oxothiolase Deficiency Beta-ketothiolase Deficiency Mat Deficiency Mitochondrial Acetoacetyl-coa Thiolase Deficiency T2 Deficiency.
This condition usually presents with lethargy, vomiting, seizures, and a ketoacidosis. Other children present with an extrapyramidal syndrome with an onset at 3 years, progressing later to become both rigid and spastic with swallowing difficulties at a late stage. In the patients described by Ozand et al., (1994) there were two other modes of presentation, one being similar to an immune deficiency and the other as a chronic progressive encephalopathy.
Beta-ketothiolase deficiency is a defect in the catabolism of isoleucine, a step which precedes the formation of proprionate. Beta-thiolase is responsible for the breakdown of alpha-methylacetoacetyl CoA to acetyl CoA and propionyl CoA, hence the accumulation of alpha-methylacetoacetate and its product alpha-methyl-beta-hydroxybutyrate.
There are 5 thiolases. One is cytosolic (ACAT2) and one is mitochondrial (ACAT1). There is no direct enzyme assay but the gene for ACAT1 has been mapped (11q22-23) and cloned (Kuwahara et al., 1992). To date 17 mutations have been found (Fukao et al., 1995, 1997), and prenatal diagnosis at gene level has been achieved (Fukao et al., 1995).
The gene for ACAT2 is on chromosome 6q25.3-q26 (Masuno et al., 1996). There is also a mild phenotype (transient ketoacidosis with normal development) with residual enzyme activity (Fukao et al., 1996, Gibson and Feigenbaum, 1997).
Nguyen et al. (2017) described the clinical, biochemical, and molecular characteristics of 41 patients with ß-ketothiolase deficiency. The disease in 66% patients was caused by p.Arg208* mutation. Patients were 23 males, and 18 females, all from northern Vietnam. At the first episode, most frequent symptoms included altered mental status, tachypnea, dehydration, fever, vomiting, and diarrhea. Laboratory findings at the first episode included metabolic acidosis and ketonuria.
* This information is courtesy of the L M D.
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What gene changes cause Alpha-Methylacetoacetic Aciduria?
The syndrome is inherited in the following inheritance pattern/s:
Autosomal Recessive - Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms but have a 25% chance of passing the copies of the gene mutations onto each of their children.
In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation that occurs during the reproductive process.
OMIM Number - 203750 (please check the OMIM page for updated information)
The syndrome can be caused by mutations in the following gene/s location/s:
ACAT1 - 11q22.3
What are the main symptoms of Alpha-Methylacetoacetic Aciduria?
The typical symptoms of the syndrome are:
Intellectual disability, Episodic ketoacidosis, Dehydration, Autosomal recessive inheritance, Vomiting
How does someone get tested for Alpha-Methylacetoacetic Aciduria?
The initial testing for Alpha-Methylacetoacetic Aciduria can begin with facial genetic analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the type of genetic testing needed. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
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