QUESTION OF THE DAY
A 3-month-old girl is brought to the pediatrician due to fussiness and lethargy. According to the parents, the baby was just fine until the mother needed to return to work, and the baby was being switched from breast milk to baby foods, formula, and fruit juices. At that time, the child cried while feeding, sometimes vomited, and had been lethargic. The baby’s appetite seemed to have worsened. The parents thought that if only formula was used, the baby was better, but they really could not remember. Which possible enzyme defect might lead to this case presentation?
The right answer is Aldolase. The child is most probably suffering from ‘Hereditary fructose Intolerance’. The onset of symptoms after ingestion of fructose or fructose containing diet (fruit juices in the given case) is a sign of hereditary fructose Intolerance.
Hereditary fructose intolerance is caused by mutation in the gene encoding Aldolase B enzyme. These patients are healthy and asymptomatic until fructose or sucrose (table sugar) is ingested (usually from fruit, sweetened cereal, or sucrose-containing formula).
Much of the ingested fructose is metabolized by the liver, using the fructose 1-phosphate pathway (Figure). The first step is the phosphorylation of fructose to fructose 1-phosphate by fructokinase. Fructose 1-phosphate is then split into glyceraldehyde and Dihydroxyacetone phosphate, an intermediate in glycolysis. This aldol cleavage is catalyzed by a specific fructose 1-phosphate aldolase (aldolase B). Glyceraldehyde is then phosphorylated to glyceraldehyde 3-phosphate, a glycolytic intermediate, by triose kinase.
Figure- Metabolism of fructose by fructose-1-P pathway
Alternatively, fructose can be phosphorylated to fructose 6-phosphate by hexokinase. However, the affinity of hexokinase for glucose is 20 times as great as it is for fructose. In extra hepatic tissues, hexokinase catalyzes the phosphorylation of most hexose sugars, including fructose, but glucose inhibits the phosphorylation of fructose, since it is a better substrate for hexokinase.Little fructose 6- phosphate is formed in the liver because glucose is so much more abundant in this organ.
Fructose-6-p is phosphorylated by PFK-1 and is subsequently cleaved to form the two triose phosphates. The two triose phosphates, Dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, may be degraded by glycolysis or may be substrates for aldolase and hence gluconeogenesis, which is the fate of much of the fructose metabolized in the liver.
A defect in the Aldolase B gene results in a decrease in activity that is 15 percent or less than that of normal. This results in a buildup of F1P levels in the hepatocytes. Because the maximal rate of fructose phosphorylation by fructokinase is so high (almost an order of magnitude greater than that of glucokinase), intracellular levels of both ATP and inorganic phosphate (Pi) are significantly decreased. The drop in ATP concentration adversely affects a number of cellular events.
Clinical features include-Recurrent vomiting, abdominal pain, and hypoglycemia that may be fatal. Older patients who survive infancy develop a natural avoidance of sweets and fruits early in life and as a result frequently are without any dental caries.
Long-term exposure to fructose can result in liver failure, renal tubulopathy and growth retardation.
The option Galactokinase is incorrect, since Galactokinase is an enzyme for phosphorylation of galactose, a constituent of milk sugar -lactose. Since milk is well tolerated, the Galactokinase deficiency is ruled out.
Fructokinase deficiency is a benign defect manifested by fructosuria (excretion of excessive fructose in urine) .In the given study the child has clear manifestations of hereditary fructose intolerance, thus fructokinase deficiency is ruled out.
Hexokinase and glucokinase are the enzymes for phosphorylation of glucose. Since the child is tolerating milk (lactose has glucose and galactose), the deficiency of these enzymes is also ruled out. Thus the right option is Aldolase deficiency.
For further reading of fructose metabolism and hereditary fructose intolerance, follow the links-
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