Beta ketothiolase deficiency

Alternate Names

Alpha-methylacetoaceticaciduria; 2-methyl-3-hydroxybutyricacidemia; Mitochondrial acetoacetyl-CoA Thiolase deficiency; 3-oxothiolase deficiency; 3-ketothiolase deficiency

Definition

Beta-ketothiolase deficiency is an inherited disorder in which the body cannot effectively process a protein building block (amino acid) called isoleucine. This condition also impairs the body's ability to process ketones, which are molecules produced during the breakdown of fats.

Epidemiology

Beta-ketothiolase deficiency appears to be very rare. Fewer than 250 affected individuals have been reported in the medical literature.

Cause

Mutations in the ACAT1 gene cause beta-ketothiolase deficiency. This gene provides instructions for making an enzyme that is found in the energy-producing centers within cells (mitochondria). This enzyme plays an essential role in breaking down proteins and fats from the diet. Specifically, the ACAT1 enzyme helps process isoleucine, which is a building block of many proteins, and ketones, which are produced during the breakdown of fats.

Mutations in the ACAT1 gene reduce or eliminate the activity of the ACAT1 enzyme. A shortage of this enzyme prevents the body from processing proteins and fats properly. As a result, related compounds can build up to toxic levels in the blood. These substances may cause the blood to become too acidic (ketoacidosis) and can damage the body's tissues and organs, particularly in the nervous system.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

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 or periods without food (fasting), and increased intake of protein-rich foods can also play a role.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Fever
• Hyperuricemia(High blood uric acid level)
• Ketonuria
• Metabolic acidosis
• Tachypnea(Increased respiratory rate or depth of breathing)
• Vomiting(Throwing up)

30%-79% of people have these symptoms

• Apathy(Lack of feeling, emotion, interest)
• Coma
• Cough(Coughing)
• Dehydration
• Diarrhea(Watery stool)
• Excessive daytime somnolence(Excessive daytime sleepiness)
• Hyperammonemia(High blood ammonia levels)
• Ketoacidosis
• Leukocytosis(Elevated white blood count)
• Thrombocytosis(Increased number of platelets in blood)

5%-29% of people have these symptoms

• Abnormal metabolic brain imaging by MRS
• Agitation
• Anorexia
• Ataxia
• Body odor
• Edema(Fluid retention)
• Extrapyramidal dyskinesia
• Hepatomegaly(Enlarged liver)
• Hyperglycemia(High blood sugar)
• Hypertension
• Hypoglycemia(Low blood sugar)
• Hyporeflexia(Decreased reflex response)
• Hypotension(Low blood pressure)
• Increased serum lactate
• Motor delay
• Muscular hypotonia(Low or weak muscle tone)
• Oral aversion
• Pallor
• Seizure
• Spasticity(Involuntary muscle stiffness, contraction, or spasm)
• Weight loss

1%-4% of people have these symptoms

• Intellectual disability, mild(Mental retardation, borderline-mild)
• Intellectual disability, severe(Early and severe mental retardation)

Diagnosis

Most patients are diagnosed by demonstrating metabolic acidosis and ketosis, by urinary organic acid analysis (2-methyl-3-hydroxybutyrate (the most reliable marker), 2- methylacetoacetate and tiglylglycine), or by acylcarnitine analysis during metabolic decompensation.

Diagnosis can be confirmed by cultured fibroblast enzyme assays (reduced potassium-dependent acetoacetyl-CoA thiolase activity) and molecular genetic testing. Computed tomography of the brain may reveal basal ganglia lesions that have been reported in some patients. Newborn screening programs are available in certain countries including the U.S. and Australia.

Differential diagnosisThe differential diagnosis includes sepsis, other organic acidurias, HSD10 disease and succinyl-CoA:3-ketoacid CoA transferase deficiency, and other conditions that cause ketoacidosis in childhood.

Antenatal diagnosisIn families with a known disease causing mutation, prenatal testing is possible by molecular genetic testing or enzyme activity assays using cultured amniocytes.

Treatment

Treatment involves managing acute crises with intravenous (IV) fluids, glucose, and electrolytes along with bicarbonate. Long-term management involves eating frequently, following a reduced-protein diet, avoidance of high-fat foods, and, in some cases, carnitine supplementation.