eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Fructose 1-Phosphate Aldolase Deficiency (Fructose Intolerance)

Author: Karl S Roth, MD, Professor and Chair, Department of Pediatrics, Creighton University School of Medicine
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Updated: Mar 24, 2009

Introduction

Background

Clinical intolerance to fructose was initially described in 1956. The following year, researchers reported a familial incidence of the disorder in several family members, postulating that the defect was a deficiency of hepatic fructose 1-aldolase. Within the next 4-5 years, the enzyme defect in aldolase B isozyme in the liver was demonstrated, and hereditary fructose intolerance (HFI) became recognized as a distinct clinical entity. The rapid early progress in the understanding of this disorder may have occurred because of the fairly dramatic and difficult-to-miss symptoms associated with fructose ingestion. These symptoms include vomiting, hypoglycemia, failure to thrive, cachexia, hepatomegaly, jaundice, coagulopathy, coma, renal Fanconi syndrome, and severe metabolic acidosis (in part due to lactic acidosis).

Pathophysiology

Affected individuals are completely asymptomatic until they ingest fructose. Thus, homozygous neonates remain clinically well until confronted with dietary sources of fructose. Although lactose is the carbohydrate base in most infant formulas, some (eg, soy formulas) contain sucrose, a fructose-glucose disaccharide that may cause symptoms. The biochemistry of hereditary fructose intolerance is complex for 2 reasons: (1) 3 isozymes of aldolase (A, B, C) exist, of which aldolase B is expressed exclusively in the liver, kidney, and intestine, and (2) aldolase B mediates 3 separate reactions (ie, cleavage of fructose 1-phosphate [F-1-P]; cleavage of fructose 1,6-diphosphate; and condensation of the triose phosphates, glyceraldehyde phosphate, and dihydroxyacetone phosphate to form fructose 1,6-diphosphate).

In normal cellular conditions, the primary enzymatic activity of aldolase B is to cleave fructose diphosphate (FDP), which forms rather than condenses the triose phosphate compounds. Here, the enzyme is central to the glycolytic pathway. Because the reaction is reversible, aldolase B is an essential enzyme in the process of gluconeogenesis (which is, in some respects, a reversal of glycolysis). The absence of the latter function readily explains the clinical hypoglycemia in individuals with hereditary fructose intolerance.

Reduced cleavage of F-1-P leads to its cellular accumulation and fructokinase inhibition, causing free fructose accumulation in the blood. A generally accepted consequence of this sequence is a dramatic change in the ATP-adenosine monophosphate (AMP) cellular ratio, with a resultant acceleration in production of uric acid. This accounts for the hyperuricemia observed during an acute episode. Competition between urate and lactate for renal tubule excretion accounts for the lactic acidemia.

The cause of severe hepatic dysfunction remains unknown but may be a manifestation of focal cytoplasmic degeneration and cellular fructose toxicity. The cause of renal tubular dysfunction also remains unclear; patients with renal tubular dysfunction primarily present with a proximal tubular acidosis complicated by aminoaciduria, glucosuria, and phosphaturia. Thus, in an infant who is homozygous for fructose 1-aldolase deficiency, fructose ingestion triggers a cascade of biochemical events that result in severe clinical disease.  

Frequency

United States

Although the true prevalence has not been established, hereditary fructose intolerance may be more common than originally believed; many asymptomatic affected people may simply avoid the ingestion of most or all sweets. The prevalence has been estimated to be as high as 1 case per 20,000 individuals.

International

The prevalence of hereditary fructose intolerance in central Europe has been reported to be 1 case per 26,100 individuals.¹

Mortality/Morbidity

Morbidity is implicit in untreated patients. Hypoglycemia and acidosis may act together to cause organ shock or coma. Ongoing hepatocellular insult may result in cirrhosis and eventual hepatic failure. Failure to thrive progressing to cachexia is the rule. Mortality may result from any or all of the above conditions.

Sex

Hereditary fructose intolerance is an autosomal recessive trait that is equally distributed between the sexes.

Age

In many infants, the age at symptom onset leads to the diagnosis. An accurate dietary history can indicate a link between the introduction of fruits into the diet and symptom onset.²

Clinical

History

• As in other autosomal recessive disorders, a pedigree is unlikely to reveal other family members with fructose 1-phosphate aldolase deficiency. Individuals who are obligate heterozygotes do not demonstrate the symptoms of hereditary fructose intolerance (HFI).
• Because the history may be vital to the diagnosis, the importance of taking an extensive dietary history, especially in individuals with hereditary fructose intolerance, cannot be overemphasized. Many soy formulas contain sucrose as a carbohydrate source that may supply enough fructose to cause clinical symptoms.
• Some affected infants refuse all sweets after becoming ill early in life; thus, a history of food rejection is also important.

Physical

• A clinically well patient demonstrates no abnormal physical findings.
• Acutely ill children are often tachypneic because of acidosis. They have enlarged liver and are slightly-to-moderately icteric. Accompanying hypoglycemia may cause tremors or seizures, as well as diaphoresis.
• Abdominal pain may be observed.³
• Exceptionally good dental hygiene is a common feature among children with hereditary fructose intolerance, presumably because of diminished carbohydrate intake.

Causes

• Hereditary fructose intolerance is inherited as an autosomal recessive trait. The gene has been mapped to one locus, band 9q22.3.
• As of 1995, 21 mutations had been reported at this locus, most of them single-base substitutions.⁴

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