Beta-ketothiolase deficiency is a rare,

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and ...

metabolic disorder A metabolic disorder is a disorder that negatively alters the body's processing and distribution of macronutrients, such as proteins, fats, and carbohydrates. Metabolic disorders can happen when abnormal chemical reactions in the body alter the ...

in which the body cannot properly process the

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

isoleucine or the products of

lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids incl ...

breakdown. Along with

SCOT deficiency Succinyl-CoA:3-oxoacid CoA transferase deficiency is an inborn error of ketone body utilization. Succinyl-CoA:3-oxoacid CoA transferase catalyzes the transfer of coenzyme A from succinyl-coenzyme A to acetoacetate. It can be caused by mutatio ...

, it belongs to a group of disorders called ketone utilisation disorders. The typical age of onset for this disorder is between 6 months and 24 months.

Symptoms and signs

The signs and symptoms of beta-ketothiolase deficiency include

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteri ...

dehydration In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mi ...

, trouble breathing, extreme tiredness, and occasionally

convulsion A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is sometimes used as a ...

s. These episodes are called ketoacidotic attacks and can sometimes lead to

coma A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to respond normally to painful stimuli, light, or sound, lacks a normal wake-sleep cycle and does not initiate voluntary actions. Coma patients exhi ...

. Attacks occur when compounds called

organic acids An organic acid is an organic compound with acidic properties. The most common organic acids are the carboxylic acids, whose acidity is associated with their carboxyl group –COOH. Sulfonic acids, containing the group –SO2OH, are ...

(which are formed as products of amino acid and fat breakdown) build up to toxic levels in the blood. These attacks are often triggered by an infection, fasting (not eating), or in some cases, other types of stress.

Genetic

This condition is inherited in an

pattern and is extremely rare having only been reported in 50 to 60 individuals throughout the world.

Mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...

s in the ''

ACAT1 Acetyl-CoA acetyltransferase, mitochondrial, also known as acetoacetyl-CoA thiolase, is an enzyme that in humans is encoded by the ''ACAT1'' (Acetyl-Coenzyme A acetyltransferase 1) gene. Acetyl-Coenzyme A acetyltransferase 1 is an acetyl-CoA C-a ...

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

cause beta-ketothiolase deficiency. The

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

made by the ''ACAT1'' gene plays an essential role in breaking down proteins and fats in the diet. Specifically, the enzyme is responsible for processing isoleucine, an amino acid that is part of many proteins. This enzyme also processes

ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bon ...

s, which are produced during the breakdown of fats. If a mutation in the ''ACAT1'' gene reduces or eliminates the activity of this enzyme, the body is unable to process isoleucine and ketones properly. As a result, harmful compounds can build up and cause the blood to become too acidic (

ketoacidosis Ketoacidosis is a metabolic state caused by uncontrolled production of ketone bodies that cause a metabolic acidosis. While ketosis refers to any elevation of blood ketones, ketoacidosis is a specific pathologic condition that results in changes in ...

), which impairs tissue function, especially in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

Diagnosis

In beta-ketothiolase deficiency, alpha-methyl-beta-keto-butyrate, alpha-methyl-beta-OH-butyrate and tiglyl glycine (upstream metabolites of the affected enzyme) may accumulate and may be detected on urine organic acid analysis by GC-MS. This may aid in the diagnosis, but for a more definitive diagnosis genetic confirmation needs to be done.

Treatment

During a ketoacidotic crisis, intravenous fluids with glucose and electrolytes should be administered immediately. Bicarbonate (initially as 1 mmol/kg over 10 minutes followed by continuous infusion) should 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 intravenous 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. Avoidance of isoleucine overload might prevent neurological complications, but currently there is no evidence to support this

References

''This article incorporates public domain text fro
The U.S. National Library of Medicine
'

External links

{{Amino acid metabolic pathology Amino acid metabolism disorders Autosomal recessive disorders Rare diseases