Beta-Ketothiolase Deficiency

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Beta-ketothiolase deficiency is an autosomal recessive inherited disorder in which the body is impaired due to the body’s inability to process ketones, which are molecules produced during the breakdown of fats from diet. Recent evidence also suggests that accumulated isoleucine catabolic intermediates also have harmful effects independent of ketoacidosis. Mutations in the ACAT1 gene cause beta-ketothiolase deficiency.

The signs and symptoms of beta-ketothiolase deficiency typically appear between the ages of 6 months and 24 months. Affected children experience episodes of vomiting, dehydration, difficulty breathing, extreme tiredness (lethargy), and, occasionally, seizures. These episodes, which are called ketoacidotic attacks, sometimes lead to coma. Ketoacidotic attacks are frequently triggered by infections, prolonged periods without food (fasting), or increased intake of protein-rich foods.

BKT is believed to be extremely rare, affecting less than 1 million new-borns worldwide, with neither preference over sex nor country.

Dehydration is one of the symptoms that may occur with this condition, other symptoms may include:

• Vomiting
• Dehydration
• Difficulty breathing
• Extreme tiredness [lethargy]
• Occasionally seizures

These episodes, which are called ketoacidotic attacks, sometimes lead to coma. Patients may remain asymptotic for long periods of time until a severe episode occurs, this may then produce serious neurotological damage to the child or individual.

In addition, recent evidence suggests that BKT deficiency may cause chronic neurological complications even without obvious episodes of ketoacidosis

• High or low blood sugars
• Hyperammonia [high levels of ammonia]
• Diarrhoea may be a part of triggering this condition
• Fever
• Poor appetite
• Trouble breathing
• Tiredness

Diagnosis of this condition is often very quick, which benefits the patient as there is a reduced risk of acute and chronic health complications. This condition is usually suspected in the case of severe metabolic acidosis (detected by blood gases analysis) and ketosis (in analysis of urine or blood) out of proportion to the associated diseases. More specific biochemical markers can be detected by analysis of urinary organic acids and/or blood acylcarnitine.

Diagnosis is usually made by determination of metabolic acidosis and ketosis by urinary organic acid analysis. Diagnosis may also be made by cultured enzyme assays, cultured patient`s tissues and/or genetic analysis by a hospital that provides this testing

In some countries the newborn screening can determine whether your son or daughter has a specific metabolic condition however it is unclear as to which countries offer this for this metabolic condition.

In terms of management, it is important to avoid prolonged bouts of fasting as this may lead to a high level of ketones in the body, thus causing ketoacidosis.

Reducing protein intake to 1.5g/kg/day helps to avoid a high intake of isoleucine from protein-based foods and thereby avoiding subsequent health complications.

Low doses of insulin infusion, with glucose infusion and monitoring of blood glucose may be effective to reduce ketosis.

During a ketoacidotic crisis, intravenous fluids with glucose and electrolytes should be administered immediately. Carnitine supplementation may be helpful. Dialysis is effective but usually not necessary. Unconscious patients and those with severe dyspnoea may require mechanical ventilation. Long-term management involves avoidance of fasting [and IV 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.

BKT deficiency only be passed on to a child if both parents have a copy of the faulty gene. This is called autosomal recessive inheritance. A person who has a copy of the faulty gene is known as a carrier.

If both parents are carriers, their child has a one in four (25%) chance of inheriting the disorder, and a one in two chance (50%) of being a carrier. This is the same for each child the parents have.

If the child only inherits one copy of the faulty gene, they will be a carrier but will not have the disorder. In some rare cases, carriers have had mild symptoms of the disorder for which they carry the faulty gene.

Once you are diagnosed, you can speak to a genetic counsellor. They can explain how you may have inherited BKT. They can also tell you about genetic testing for the rest of your family. They can provide advice and support if you go on to have children of your own.

References are available on request. Please contact Helen Morris by phoning 0845 241 2173 or emailing contact@metabolicsupportuk.org [Resource Library No: BAP031].