Fructose-1-Phosphate Aldolase Deficiency

Etiology

HFI is caused by a deficiency of aldolase B, an isoenzyme expressed in the liver, kidney, and intestinal tissue that is important in fructose metabolism. The enzyme catalyzes various reactions, including the cleavage of fructose-1-phosphate and the reversible cleavage of fructose-1,6-bisphosphate (FBP) into glyceraldehyde phosphate (glyceraldehyde-P) and dihydroxyacetone phosphate (DHAP). The aldolase B gene (ALDOB) is located at 9q31.1, and more than 40 causative mutations have been identified.[1][2] Mutational variants include missense substitutions, deletions, frameshift alterations, and splice-site mutations.[3]The most frequent mutations are A150P, A149P, and A174D.[4][5] The severity of the disease depends on the residual aldolase B activity, and HFI is not diagnosed in some individuals due to self-imposed dietary restriction.[6]

Epidemiology

Hereditary fructose intolerance has an autosomal recessive inheritance pattern and affects males and females equally. The prevalence of the disease is estimated to be approximately 1 in 20,000 births in the US and 1 in 26,100 live births in Europe.[7][8]

Pathophysiology

Aldolase B is the key enzyme in fructose metabolism, and its deficiency can lead to toxic accumulation of fructose 1-phosphate. Fructose is rapidly converted to fructose 1-phosphate by fructokinase; without further metabolism, fructose 1-phosphate leads to depletion of inorganic phosphate and adenosine triphosphate (ATP). Phosphate and ATP depletion are responsible for acute symptoms and long-term organ injury in this condition. Moreover, this cascade leads to increased uric acid production because of increased adenine nucleotide degradation by adenosine deaminase (ADA), similar to the process seen in glucose-6-phosphatase and fructose 1,6-diphosphatase deficiencies.[9] Accumulation of fructose 1-phosphate leads to activation of pyruvate kinase and subsequent accumulation of Krebs cycle precursors, alanine, lactate, and pyruvate, producing a suggestive metabolic picture of this condition. These compounds also contribute to acidosis in this condition, in addition to proximal renal tubular dysfunction. 

As noted previously, products of aldolase B activity on fructose 1,6-bisphosphate (FBP) are glyceraldehyde phosphate and dihydroxyacetone phosphate (DHAP). These molecules are substrates for gluconeogenesis and glycolysis via fructose 1,6-diphosphate, and for oxidation via conversion to pyruvate, respectively. Aldolase B also converts fructose 1-phosphate to glyceraldehyde and DHAP. Deficiency of aldolase B activity leads to accumulation of fructose 1-phosphate and phosphate depletion, thereby inhibiting both gluconeogenesis and glycolysis and resulting in hypoglycemia in affected individuals.

Symptoms typically start in infancy, when complementary feeding begins, and foods containing fructose or sucrose are introduced. Hypoglycemia associated with HFI occurs immediately after fructose ingestion. Fructose ingestion causes bloating, nausea, vomiting, abdominal pain, diarrhea, and hypoglycemia. Gastrointestinal symptoms are due to deficiency of fructose 1-phosphate aldolase in the cells of the small intestine. Consequently, this unpleasant experience may lead to an aversion to sweet foods. Affected individuals may develop symptoms of irritable bowel syndrome after chronic exposure to fructose or related substances. Phosphate depletion also causes hypermagnesemia. The severity of symptoms depends on the fructose load, and clinical manifestations also occur after administration of 2 sucrose-containing oral vaccines: RotaTeq (Merck and Co., Inc.) and Rotarix (GSK Biologicals). A sucrose solution given to infants for a minor procedure can also lead to severe symptoms of HFI. In early infancy, large amounts of fructose-containing food (eg, milk or formula) may produce shock or acute hepatic failure and may even lead to death.[10]

Chronic fructose ingestion causes failure to thrive and progressive liver dysfunction. The early renal effect is damage to the proximal tubules, leading to glucosuria and phosphaturia, and even overt Fanconi syndrome; repeated and prolonged exposure to fructose can lead to renal failure. The pathogenesis of renal tubular dysfunction is believed to be related to decreased activity of vacuolar ATPase, which is responsible for endosomal acidification and proton secretion, due to aldolase deficiency.[11]

 Characteristic Metabolic Disturbances

• Hypoglycemia
• Lactic acidosis
• Hypophosphatemia
• Hyperuricemia
• Hypermagnesemia
• Hyperalaninemia
• Glucosuria, aminoaciduria, phosphaturia, bicarbonaturia, and kaliuresis [12] 

Histopathology

Histological Findings on Liver Biopsy

• Giant cell transformation along with steatosis, fibrosis, and cirrhosis [13]

Electron Microscopy and Ultrastructural Findings on Liver Biopsy

• Concentric and irregularly disposed membranous arrays are present in the glycogen-rich areas of most hepatocytes
• Marked rarefaction of the cytoplasm (fructose holes)
• Formation of cytolysosomes and damage to the endoplasmic reticulum [14]

History and Physical

Clinicians should evaluate the patient's dietary history. As noted previously, symptoms typically start in infancy, when complementary feeding begins, and foods containing fructose or sucrose are introduced. Hypoglycemia associated with HFI occurs immediately after fructose ingestion during the immediate postprandial state. Clinically, symptoms can include recurrent vomiting, abdominal bloating, diarrhea, yellow discoloration of the eyes (icterus), hepatomegaly, and failure to thrive in infants (see Pathophysiology section). Depending on the activity of aldolase B, symptoms may vary, and affected individuals often develop an aversion to foods high in fructose and sucrose. Some patients remain undiagnosed for many years. Heterozygous individuals (carriers) are generally asymptomatic, but hyperuricemia is observed in some patients, with a predisposition to gouty arthritis.[15][16]

Characteristic Clinical Findings

• Nausea, vomiting, bloating, and diarrhea after consuming fructose-containing food or drink
• Symptoms of hypoglycemia: sympathetic and neuroglycopenic
• Hepatomegaly, jaundice, and features of hepatic decompensation
• Polyuria
• Chronic growth restriction and failure to thrive [12]

Clinicians should suspect HFI in any infant or child with recurrent hypoglycemia episodes with acidosis, hepatomegaly, gastrointestinal tract symptoms, and hepatic and renal dysfunction.

Evaluation

The diagnosis of HFI is primarily based on clinical findings and metabolic disturbances observed in individuals after ingestion of fructose-, sucrose-, or sorbitol-containing foods. The fructose tolerance test (FTT) can identify the disorder in individuals with suspected HFI, but it is not recommended due to the associated metabolic risks. In a child with episodes of hypoglycemia, hepatomegaly, and liver dysfunction, urine should be tested for reducing substances. The type of urine carbohydrate, including fructose, can be tested by thin-layer chromatography to help establish the diagnosis.[2] An invasive test for HFI is liver biopsy with assessment of aldolase B activity, which is a sensitive test for diagnosing this entity and can be used in cases with a high index of suspicion and negative molecular genetics. Other supportive laboratory evaluations include urine electrolytes and amino acids consistent with a proximal renal tubule defect and elevated carbohydrate-deficient transferrin levels.

Molecular genetics: Biallelic pathogenic or likely pathogenic variants in ALDOB can confirm the diagnosis. More than three-fourths of cases are due to sequence variation, and the remaining are due to copy number variation. Beyond diagnostic confirmation, baseline evaluation and follow-up surveillance for complications are integral parts of the assessment. Hepatic function, renal function, ophthalmic assessment for lenticular opacities, and metabolic complications of renal tubulopathies should be assessed at diagnosis and periodically thereafter. Carbohydrate-deficient transferrin or N-glycan assay by tandem mass spectrometry and/or monitoring of plasma lysosomal enzymes (aspartylglucosaminidase and α-mannosidase) can reflect adherence to the recommended diet in HFI.

Treatment / Management

Acute Treatment

In an emergency, patients may present with lethargy, seizures, coma, or hepatic and renal failure. Acute treatment includes intravenous glucose (dextrose) administration, correction of potential metabolic acidosis, and supportive care for other metabolic abnormalities. Treatment of acute renal or hepatic decompensation is part of acute management in this situation. Patients with acute decompensation require active treatment and an interdisciplinary team approach.

Chronic Treatment

The mainstay of treatment for HFI) is dietary adherence and prevention of acute manifestations. The only effective treatment is a fructose- and sucrose-free diet. Sorbitol present in medicines and sugar-free products should also be excluded.[2] Sucralose, used as a noncaloric sweetener, should also be avoided. Clinicians should take care to avoid medicines, formulas, and fluids that may not list sucrose or sorbitol as the primary ingredients but may contain small amounts. Sucrose-containing oral vaccines, such as RotaTeq and Rotarix, should also be avoided. Because patients with HFI adhere to a specific diet, micronutrient deficiencies can occur and may be prevented by daily supplementation with multivitamins (folate and vitamin C).(A1)

Readers should review curated lists of foods and sugars that can be used in this condition. Resources include HFI Treatment:[Boston University. HFI Treatment] and [Boston University. Sugar and Sweeteners] Another useful resource on HFI food options is from their support group, the HFI discussion board [Home | HFI-INFO Discussion Board]. Ketohexokinase inhibitor therapy was recently assessed to mitigate symptoms and end-organ damage in patients with HFI. [ClinicalTrials.gov.Ketohexokinase Inhibition in Hereditary Fructose Intolerance] 

Differential Diagnosis

In the setting of hypoglycemia and a varied combination of liver dysfunction, acidosis, with or without lactic acidosis, renal tubulopathy or renal decompensation, and gastrointestinal tract symptoms, the following are the possibilities: 

• Infectious hepatitis, sepsis, or disseminated intravascular coagulation
• Autoimmune liver disease
• Neonatal hemochromatosis
• Toxic ingestion
• α1-Antitrypsin deficiency
• Tyrosinemia
• Galactosemia
• Urea cycle disorders
• Citrin deficiency
• Fatty acid oxidation disorders including medium-chain acyl-coenzyme A dehydrogenase deficiency, long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency, and very long-chain acyl-coenzyme A dehydrogenase deficiency
• Maple syrup urine disease
• Wilson disease
• Glycogen storage disease 
• Disorders of mitochondrial DNA depletion
• Transaldolase deficiency
• Congenital disorders of glycosylation
• Fructose 1,6-bisphosphatase deficiency (FBP1)
• Primary pyruvate dehydrogenase complex deficiency
• Organic acidemias
• Cystinosis 
• Fanconi-Bickel syndrome

Prognosis

Fructose intolerance has an excellent prognosis, provided the individual follows strict dietary compliance. If the disorder is diagnosed early in its course and management is initiated promptly, the individual can achieve normal cognitive development and lifespan. Conversely, if individuals with HFI do not adhere to recommended dietary restrictions, chronic liver or renal disease is a common consequence.

Complications

If dietary restrictions are not followed, serious complications can occur, including the following:

• Growth restriction
• Episodes of recurrent severe hypoglycemia may lead to coma on occasions
• Lactic acidosis
• Hepatomegaly, hepatic dysfunction, hepatic adenoma, and fibrosis
• Renal proximal tubular dysfunction, metabolic abnormalities, nephrocalcinosis, and chronic kidney disease
• Lenticular cataracts
• Coagulopathy

Because patients adhere to a fructose-, sucrose-, and sorbitol-restricted diet for life, hepatic steatosis has recently been described.[17]