What Is Cytosolic Acetoacetyl CoA Thiolase Deficiency?
Cytosolic Acetoacetyl CoA Thiolase Deficiency is an inherited disorder in which the body is unable to process the amino acid (building blocks of proteins) isoleucine. The body’s ability to process ketones is also affected. The affected child experiences intermittent ketoacidosis episodes characterized by breathing difficulty, dehydration, vomiting, lethargy, and seizures. The ketoacidotic attacks are usually triggered by increased protein-rich food intake, fasting, and infections. Severe cases may even lead to comas.
The condition is inherited in an autosomal recessive manner. The clinical signs and symptoms usually appear between the ages of six and twenty-four months. The condition is rare, with fewer cases reported in the medical literature. There is no ethnic predisposition for the condition.
Other names for the condition are:
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2-methy-3-hydroxybutyriacidemia.
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Alpha-methyl-acetoacetic aciduria.
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3- keto thiolase deficiency.
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3-oxo thiolase deficiency.
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Beta-keto thiolase deficiency.
How Does the Condition Present Clinically?
The condition is characterized by intermittent ketoacidotic episodes with no clinical symptoms present between the episodes.
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Clinical symptoms are usually not seen in the neonatal period or early infancy.
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The severity and frequency of symptoms vary from person to person.
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The first ketoacidotic attacks are usually seen between five months and two years of age. Neonatal onset is uncommon.
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The ketoacidotic attacks are followed by gastroenteritis or infections like measles, otitis media, or upper respiratory tract infections.
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The symptoms of ketoacidotic attacks are:
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Dehydration.
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Vomiting.
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Lethargy.
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Breathing difficulty.
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Hypotonus.
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Convulsions in some.
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At times, this may result in a coma.
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Hypotonia, mental developmental delay, and truncal ataxia in some cases.
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Other frequent symptoms are:
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Lack of emotions (apathy).
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Diarrhea.
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Increased daytime sleepiness.
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Elevated white blood cell count (leukocytosis).
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Reduced consciousness.
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Increased platelet count.
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Less frequent symptoms are:
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Anorexia (lack of appetite for food).
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Unpleasant body odor.
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Restlessness.
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hypertension/ hypotension.
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Pallor.
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Weight loss.
What Are the Causes?
The condition is caused by mutations in the acetyl-CoA acetyltransferase 1 gene (ACAT1 gene). This gene provides information essential for producing an enzyme in the mitochondria. This enzyme plays a vital role in the diet's breakdown of proteins and fat. Specifically, these are important for processing an amino acid called isoleucine. Isoleucine is the building block of various proteins and ketones.
A mutation in the ACAT1 gene lowers the activity of the ACAT1 enzyme, and as a result, the body cannot properly process proteins and fat. Hence, the blood becomes acidic, which causes damage to the body’s tissues and organs. The condition is inherited in an autosomal recessive manner, which means both copies of the mutated gene are present. The affected child's parents may be asymptomatic as they carry a single copy of the mutated gene.
What Are the Diagnostic Tests?
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Urinary Organic Acid Analysis:
A urinary organic acid analysis of acute episodes shows increased excretion of dicarboxylic acid and ketone bodies.
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Acylcarnitine Analysis:
Acylcarnitine analysis of dried blood spotted on Guthrie paper or in urine is a good diagnostic tool for different types of organic acidemia.
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Enzyme Assay:
The enzymatic assay is essential for confirming the diagnosis. There are two types- indirect assays and direct in-vitro assays.
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Molecular Diagnosis:
Mitochondrial acetoacetyl-CoA thiolase (T2) protein detection is done by immunoblot analysis. If T2 protein cannot be detected in a test or is extremely decreased, the observation suggests T2 deficiency. In some cases, only the enzyme activity is affected by a genetic mutation, and the protein is not destabilized. Immunoblot is used as a complementary test following an enzyme assay.
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Prenatal Diagnosis:
Cytosolic acetoacetyl CoA thiolase deficiency is an autosomal recessive condition. The parents of the affected child are heterozygous carriers without any clinical symptoms. Asymptomatic T2-deficient siblings can be identified by family analysis. Prenatal diagnosis is made by measuring T2 activity in cultured chorionic villi cells, or amniocytes.
What Is the Differential Diagnosis?
The differential diagnosis of the condition includes all conditions that produce ketoacidosis. Therefore, an assessment of ketosis with blood glucose levels should be carried out. Increased blood glucose levels in ketosis suggest diabetes.
The two major differential diagnoses are:
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Ketotic Hypoglycemia:
Recurrent ketosis in childhood and ketotic hypoglycemia are frequent causes of ketosis in children. However, if ketosis is more severe than in recurrent ketosis in childhood and ketotic hypoglycemia, then cytosolic acetoacetyl CoA thiolase deficiency should be considered. Enzymatic confirmation should be carried out in such cases.
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SCOT Deficiency:
Succinyl-Co A:3-ketoacid CoA transferase (SCOT) deficiency is another important differential diagnosis. This condition is also characterized by intermittent ketoacidotic attacks with no symptoms between the episodes. More than half of the affected have a neonatal onset of SCOT deficiency, contrary to cytosolic acetoacetyl CoA thiolase deficiency. The condition is characterized by permanent ketosis in most cases.
How Is the Condition Managed?
General Management Measures:
The general management measures aim to avoid severe ketoacidosis and include the following:
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Diet plan- to reduce the isoleucine load, a mild restriction in protein intake is recommended. A fat-rich diet should also be avoided, as it induces ketogenesis.
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Carnitine supplementation- L- carnitine supplementation) should be considered in patients with low carnitine levels.
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Prophylactic glucose infusion is recommended to avoid prolonged fasting in the affected. Intravenous glucose infusion is considered in vomiting patients.
Management of Acute Episodes:
In the case of acute episodes, acidosis should be corrected, and ketogenesis should be reduced. It is treated similarly to ketoacidosis.
Even in normoglycemic patients, glucose infusion is done for maintaining blood glucose levels and thereby suppressing ketoacidosis. Electrolytes are administered to keep the urine output sufficient.
Conclusion:
Cytosolic acetoacetyl CoA thiolase deficiency is a rare inherited disorder characterized by the inability of the body to process isoleucine. Neonatal onsets are rare in this condition. The affected person presents with intermittent ketoacidosis episodes. It is a genetic condition inherited in an autosomal recessive manner. Genetic mutations that occur in the ACAT1 gene are responsible for the condition. Enzymatic assays are done to confirm the diagnosis. Management options include acute episodes and general management. The condition mostly has a favorable prognosis.
