For the public
For the public (Non-medical staff).
Original writing was in Japanese. Authors translated it into English. So, some expressions should be revised.
What are ketone bodies?
We always keep blood glucose level to provide glucose to the brain. Failure of this mechanism results in hypoglycemia (low glucose level). Hypoglycemia causes severe symptoms of unconsciousness and convulsion. Food intake supplies glucose and excess glucose is converted into glycogen in the liver. Also lipids are accumulated in adipose(fat) tissues. After a period of glucose supply from food intake (~3hr after meal), glucose is produced by degradation of glycogen first (until 6~8hrs after meal). Then fatty acids are produced from adipose tissues and are beta-oxidized in the liver (after 6-8hrs after meal). Ketones (acetoacetate and 3-hydroxybutyrate) are products via beta-oxidation and HMG-CoA pathway in the liver. Ketones are substitute energy sources for glucose and functions to keep blood glucose level.
In healthy children, ketone are produced to some extent after a period of fast, but ketone production is enhanced in a longer fasting and/or under stress conditions such as febrile or infected conditions. Ketones are produced during stress conditions. Hence production of ketones is physiologically important but massive production may mean signs of unfavorite conditions.
When you take your kid with symptoms of fever and appetite loss to a clinic or hospital, a doctor may tell you that his (her) urine is strongly positive for ketones and that he (she )had better have intravenous fluids. Overproduction of ketones means he (she) has strong stress or shortage of glucose, so supplement of glucose reduces a risk of hypoglycemia or ketoacidosis.
There are rare disorders in which ketones can not be efficiently produced. Patients with such disorders develop hypoglycemia under stresses such as fasting and febrile condition.
There are rare disorders in which ketones can not be efficiently utilized in extrahepatic tissues. Beta-ketothiolase deficiency and succinyl-CoA: 3-ketoacid CoA transferase deficiency belong to ketolytic defects. In these disorders, ketone producion is enhanced under ketogenic stresses such as fasting and/or febrile conditions, but extrahepatic tissues can not incorporate and use ketones as energy source. It results in accumulation of ketones in blood (ketoacidosis). This condition is out of homeostasis and causes polypneas and unconsciousness
Beta-ketothiolase deficiency
What is this disorder?
This disorder was first reported in Lancet by Daum and Scriver et al in 1971. This disorder is caused by the defect of mitochondrial acetoacetyl-CoA thiolase which plays roles in isoleucine catabolism and ketone body metabolism. Patients with this disorder develop metabolic acidosis due to accumulation of ketone bodies (3-hydroxybutyrate and acetoacetate) and intermediate acids in isoleucine catabolic pathway, and become a dangerous condition with symptoms such as dyspnea (polypnea) and unconsciousness.
They looks completely well except for such crises. Hence nobody can notice the presence of the disease before the first crisis.
Even one crisis with severe acidosis and long unconsciousness may result in death or developmental delay. On the other hand, one can recover from severe ketoacidosis without any sequelae..
In general, chemical diagnosis can be made by urinary organic acid analysis and blood acylcarnitine analysis. General pediatricians (physicians) do not know this rare disorder well, so patients may have such special tests, after multiple ketoacidotic crises.
If your child is suspected as having this disorder?
Skin biopsy will be necessary to confirm the diagnosis. Enzyme assay using cultured skin cells (fibroblasts) is a golden standard. Alternative is DNA diagnosis. Confirmation of the diagnosis leads to good management and treatment.
If your child is diagnosed as having beta-ketothiolase deficiency?
After confirmation of the diagnosis, it is very important to give glucose (carbohydrate) to your child promptly not to enhance ketone body production when he or she has ketogenic conditions such as a febrile condition, fasting, and/or vomiting. Adequate glucose infusion prevent him or her from developing crisis. Over intake of protein results in overload of isoleucine and could evoke ketoacidosis. So, mild protein restriction is one reasonable management. Oral carnitine supplementation is another possible management. Prevention of severe ketoacidotic crises is the essental matter. After childhood (over 12years), frequency and severity of ketoacidotic crises are reduced. Normal growth and development are expected in this disorder if patients recovered from the first ketoacidotic crisis without severe complication and they have not had further severe ketoacidotic crises.
Some female patients successfully delivered her babies without any complication.
Succinyl-CoA:3-ketoacid CoA transferase deficiency
What is this disorder?
This disorder was first reported by Tildon et al in 1972. This disorder is caused by the defect of succinyl-CoA:3-ketoacid CoA transferase which catalizes an important step of ketone body utilization. Patients with this disorder develop metabolic acidosis due to accumulation of ketone bodies (3-hydroxybutyrate and acetoacetate) and become a dangerous condition with symptoms such as dyspnea (polypnea) and unconsciousness. They looks completely well except for such crises. Hence nobody can notice the presence of the disease before the first crisis. However, if tested, patients had higher blood ketone levels and positive urinary ketone even when patients look completely well.
Even one crisis with severe acidosis and long unconsciousness may result in death or developmental delay. On the other hand, one can recover from severe ketoacidosis without any sequelae..
In general, urinary organic acid analysis and blood acylcarnitine analysis are only useful for differential diagnosis. So, enzyme assay is essential for the diagnosis. General pediatricians (physicians) do not know this rare disorder well, so patients may have diagnostic enzyme assay, after multiple ketoacidotic crises. In other words, physician is excellent if they consider this disorder in ketoacidotic conditions.
If your child is suspected as having this disorder?
Enzyme assay can be done using blood samples. Skin biopsy mayl be necessary to confirm the diagnosis in some cases. Enzyme assay using cultured skin cells (fibroblasts) is a golden standard. Alternative is DNA diagnosis. Confirmation of the diagnosis leads to good management and treatment.
If your child is diagnosed as having SCOT deficiency?
After confirmation of the diagnosis, it is very important to give glucose (carbohydrate) to your child promptly not to enhance ketone body production when he or she has ketogenic conditions such as a febrile condition, fasting, and/or vomiting. Adequate glucose infusion prevent him or her from developing crisis. Prevention of severe ketoacidotic crises is the essental matter. After childhood (over 12years), frequency and severity of ketoacidotic crises are reduced. Normal growth and development are expected in this disorder if patients recovered from the first ketoacidotic crisis without severe complication and they have not had further severe ketoacidotic crises. Some female patients successfully delivered her babies without any complication.