Chapter 155. Disorders of Galactose and Fructose Metabolism and Gluconeogenesis

Galactosemia denotes the elevated level of galactose in the blood and is found in three distinct inborn errors of galactose metabolism (Chapter 154, Fig. 154-1) in one of the following enzymes: galactose-1-phosphate uridyl transferase, galactokinase, and uridine diphosphate galactose-4-epimerase. The term galactosemia, although adequate for the deficiencies for any of these three disorders, generally designates the transferase deficiency, which is by far the most prevalent and is called classical galactosemia.1

Classic galactosemia due to a complete galactose-1-phosphate uridyl transferase deficiency is a serious disease, with an incidence of approximately 1 in 60,000. Symptoms typically appear by the second half of the first week of life. The newborn receives high amounts of lactose (up to 40% in breast milk and certain formulas), which consists of equal parts of glucose and galactose. Without the transferase, the infant is unable to metabolize galactose-1-phosphate (see Chapter 154, Fig. 154-1), the accumulation of which results in injury to parenchymal cells of the kidney, liver, and brain.

Clinical Presentation and Laboratory Findings

The diagnosis of uridyl transferase deficiency should be considered in newborns, older infants, or children with any of these clinical manifestations: jaundice, hepatomegaly, vomiting, hypoglycemia, convulsions, lethargy, irritability, feeding difficulties, poor weight gain, aminoaciduria, nuclear cataracts, vitreous hemorrhage, hepatic cirrhosis, ascites, splenomegaly, or mental retardation. Patients with galactosemia are at increased risk for Escherichia coli neonatal sepsis; the onset of sepsis often precedes the diagnosis of galactosemia. Pseudotumor cerebri may occur and may cause a bulging fontanel.

When the diagnosis is not made at birth, damage to the liver (cirrhosis) and brain (mental retardation) becomes increasingly severe and irreversible. Symptoms are milder and improve when milk is temporarily withdrawn and replaced by lactose-free nutrition.

Partial transferase deficiency due to Duarte variant is generally asymptomatic. It is more frequent than classic galactosemia and is often diagnosed in mass newborn screening because of moderately elevated blood galactose or low transferase activity.

Genetics

Transferase deficiency galactosemia (OMIM 230400) is inherited as an autosomal recessive disorder. There are several enzymatic variants of galactosemia. Duarte variant is the most common and has a carrier frequency of 12% in the general population. Individuals with Duarte variant homozygote have diminished red cell enzyme activity (50% of normal) but usually no clinical manifestations. Individuals with Duarte galactosemia (D/G) compound heterozygosity have 25% of the enzyme activity, and galactose-1-phosphate levels are often elevated. These children are usually asymptomatic, but most physicians restrict lactose intake if the erythrocyte galactose-1-phosphate levels are elevated. Some African American patients have milder symptoms despite absence of measurable transferase activity in erythrocytes; these patients retain 10% enzyme activity in liver and intestinal mucosa, while most white patients have no detectable activity in any of these tissues. The gene for galactose-1-phosphate uridyl transferase is located on chromosome 9p13. In African Americans, 48% of alleles are represented by the S135L mutation; a mutation may be responsible for the milder disease. In the white population, 70% of alleles are represented by the Q188R missense mutation. Carrier testing and prenatal diagnosis can be carried out by direct enzyme analysis of amniocytes or chorionic villi. Also, testing can be DNA-based.

Diagnosis

The preliminary diagnosis of galactosemia is made by demonstrating a reducing substance in urine specimens collected while the patient is receiving human or cow’s milk or another formula containing lactose. The reducing substance found in urine by Clinitest can be identified by chromatography or by an enzymatic test specific for galactose. Galactosuria is present provided the last milk feed does not date back more than a few hours and the child is not vomiting excessively. Caution is needed in choosing the kind of test used for reducing substances. Clinistix urine test results are negative, because the test materials rely on the action of glucose oxidase, which is specific for glucose and is nonreactive with galactose. However, owing to a proximal renal tubular syndrome, the acutely ill baby may also excrete glucose together with amino acids. In the past, diagnostic challenge tests dependent on administering galactose orally or intravenously were used. These should be avoided because galactose is injurious to persons with galactosemia. Light and electron microscopy of hepatic tissue reveals fatty infiltration, the formation of pseudoacini, and eventual macronodular cirrhosis. These changes are consistent with a metabolic disease but do not indicate the precise defect.

Definitive diagnosis can be made by direct enzyme assay using erythrocytes or other tissues that also exhibit increased concentrations of galactose-1-phosphate (Paigen assay). The gold standard for diagnosing classical galactosemia is measuring galactose-1-phosphate uridyltransferase activity in erythrocytes (isolated from either heparin or EDTA whole blood; Beutler assay). It is important to confirm that the patient did not receive a blood transfusion prior to collecting the blood sample, as a diagnosis of galactosemia could be missed.

Treatment

Because of widespread newborn screening for galactosemia, patients are being identified early and treated early (see Chapter 134). The most important step in the initial management of patients with classical galactosemia is immediately removing all galactose from the diet as soon as the condition is suspected. Additional therapies may be indicated in the case of complications such as sepsis, liver failure with clotting abnormalities, or hyperbilirubinemia. For long-term management, individuals need to be on a soy formula and a formula based on casein hydrolysates and dextrin maltose, as these are carbohydrate sources with very little galactose. However, some galactose will inevitably be introduced into the diet, as many foods, such as fruits and vegetables, bread, and legumes, contain trace amounts of galactose. There are controversies concerning the daily allowance of galactose during long-term treatment with a very strict diet; one extreme restricts galactose-containing fruits and vegetables, and the other extreme advises only a lactose-free diet. Calcium and vitamin D supplements are needed due to the restricted diet to reduce the risk of osteopenia and osteoporosis.

Elimination of galactose from the diet reverses growth failure and renal and hepatic dysfunctions. Cataracts regress, and most patients have no impairment of eyesight. Early diagnosis and treatment have improved the prognosis of galactosemia; on long-term follow-up, however, patients still manifest ovarian failure with primary or secondary amenorrhea, developmental delay, and learning disabilities, which increase in severity with age. In addition, most will manifest speech disorders, such as speech apraxia, while a smaller number demonstrate poor growth and impaired motor function and balance (with or without overt ataxia). The relative control of galactose-1-phosphate levels does not always correlate with long-term outcome, leading to the belief that other factors, such as UDP-galactose deficiency (a donor for galactolipids and proteins), may be responsible. Other factors could include ongoing damage due to endogenous galactose synthesis, with some damage occurring in utero. However, it appears that a substantial part of the long-term complications originate from continuous toxicity during life.2,3

Galactokinase deficiency is generally considered to be rare when compared to classical galactosemia.

Clinical Presentation and Laboratory Diagnosis

In contrast to the multiple systems that are affected in transferase-deficiency galactosemia, cataract and, rarely, pseudotumor cerebri caused by galactitol accumulation are the only consistently reported abnormalities in this disorder. The affected infant is otherwise asymptomatic. A high incidence of this disorder is found among an endogamous Gypsy population coming from some regions of East Europe. The high incidence is attributable to a founder effect, as demonstrated by the segregation of a single nucleotide mutation (P28T) that is present in about 5% of the Gypsy population.

Affected patients have an increased concentration of blood galactose levels, provided they have been fed a lactose-containing formula. Final diagnosis is made by demonstrating normal transferase activity and an absence of galactokinase activity in erythrocytes.

Genetics

Two genes have been reported to encode galactokinase: GK1 on chromosome 17q24 and GK2 on chromosome 15. Mutations causing GK deficiency (OMIM 230200) have been identified only in GK1. A majority of these mutations are of missense type and cause amino acid changes of conserved residues, which have an active role in the enzyme’s stability and activity. It is now known that human GK2 is a highly efficient GalNAc kinase with galactokinase activity when this sugar is present at high concentrations. Thus, galactokinase (galK) deficiency is not genetically heterogeneous.

Treatment

Treatment is dietary restriction of galactose intake. As patients with galactokinase deficiency have minimal complications aside from cataracts, inhibition of galactokinase activity by a selective inhibitor might be a promising approach for controlling damage in classical galactosemia in GALT-deficient patients.4

The abnormally accumulated metabolites are very much like those seen in transferase deficiency; however, there is also an increase in cellular UDP galactose.

Clinical Presentation and Laboratory Diagnosis

In general, there are two forms of epimerase deficiency. A benign, peripheral form is discovered incidentally through a neonatal screening program. Affected persons in this case are healthy and without problems; The enzyme deficiency is limited to leukocytes and erythrocytes, without deranged metabolism in other tissues. No treatment is required. The second form of epimerase deficiency is more severe and generalized, with clinical manifestations that resemble transferase deficiency. Patients typically develop cataracts within the first few months of life; these are followed by liver, kidney, and brain damage. Affected individuals have additional symptoms of hypotonia and nerve deafness. The enzyme deficiency is generalized, and clinical symptoms respond to restriction of dietary galactose.5

Genetics

The gene for epimerase is located on chromosome 1p35-36; mutations responsible for both forms of the epimerase deficiency (OMIM *606953) have been identified.

Diagnosis

Although this form of galactosemia is rare, it must be considered in a symptomatic patient with measurable galactose-1-phosphate who has normal transferase activity. Diagnosis is confirmed by the assay of epimerase in erythrocytes.

Treatment

Infants with the benign form of epimerase deficiency do not require treatment. Patients with the severe form of epimerase deficiency cannot synthesize galactose from glucose and are therefore galactose dependent. Because galactose is an essential component of many nervous system structural proteins, patients are placed on a galactose-restricted diet rather than a galactose-free diet.

Deficiency of Fructokinase (Benign Fructosuria)

Benign fructosuria (OMIM 229800) is not associated with any clinical manifestations. It is an accidental finding usually made through the detection of fructose as the reducing substance in the urine. No treatment is necessary.6

Deficiency of Fructose-1-Phosphate or Fructose 1,6-Bisphosphate Aldolase (Aldolase B, or Hereditary Fructose Intolerance)

This severe disease of infants appears with the ingestion of fructose-containing food and is caused by deficiency of aldolase B (fructose 1,6-bisphosphate aldolase) activity in the liver, kidney, and intestine. The same enzyme catalyzes the hydrolysis of fructose-1-phosphate and fructose 1,6-bisphosphate into the 3-carbon sugars dihydroxyacetone phosphate, glyceraldehyde 3-phosphate, and glyceraldehyde. Deficiency of this enzyme activity causes a rapid accumulation of fructose-1-phosphate and initiates severe toxic symptoms when exposed to fructose.

Clinical Presentation and Laboratory Findings

Patients with fructose intolerance are perfectly healthy and asymptomatic until fructose or sucrose (table sugar) is ingested (usually from fruit, fruit juice, or sweetened cereal). Clinical manifestations may resemble those of galactosemia and include jaundice, hepatomegaly, vomiting, lethargy, irritability, and convulsions. Laboratory findings include prolonged clotting time, hypoalbuminemia, elevation of bilirubin and liver transaminase levels, and proximal tubular dysfunction (Fanconi type with hyperphosphaturia). If the disease is not diagnosed and intake of the noxious sugar persists, postprandial hypoglycemic episodes recur, and liver and kidney failure progress, eventually leading to death.

Older patients usually develop an aversion to fructose-containing foods after experiencing recurrent abdominal pain, anorexia, and nausea while consuming these foods. Despite their self-imposed dietary restriction, some patients develop chronic fructose intoxication and present with growth failure and hepatomegaly. Others may be asymptomatic into adulthood, with significant absence of dental caries and a positive family history as the only indicators of disease. Some patients have suffered iatrogenic death or life-threatening events during fructose infusions.

Genetics

The true incidence of hereditary fructose intolerance (OMIM 229600) is not known but may be as high as 1 in 23,000. The gene for aldolase B is on chromosome 9q22.3. Several mutations causing hereditary fructose intolerance have been identified. A single missense mutation, a G-to-C transversion in exon 5, which results in the normal alanine at position 149 being replaced by a proline (A149P), is the most common mutation identified in northern Europeans. This mutation plus two other mutations, A174D and N334K, account for approximately 80% to 85% of hereditary fructose intolerance in Europe and the United States. Diagnosis of hereditary fructose intolerance can thus be made by screening these mutations in the majority of patients. Prenatal diagnosis should be possible from both amniocentesis and chorionic villi, utilizing DNA mutational or linkage analysis.

Diagnosis

Suspicion of the enzyme deficiency is fostered by the presence of a reducing substance in the urine during an attack. Laboratory studies show evidence of hepatic impairment, with increased blood bilirubin, methionine, and tyrosine, and abnormal coagulation tests. A proximal renal tubular acidosis develops with renal Fanconi syndrome, producing aminoaciduria and hypokalemia. Metabolic abnormalities include hypoglycemia, hypophosphatemia from inorganic phosphate trapping and renal tubular loss, metabolic acidosis from increased lactate and renal bicarbonate losses, and hyperuricemia due to inhibition of AMP deaminase. Anemia and thrombocytopenia are also common.

Definitive diagnosis is first made by mutation analysis.6 If no mutation is found, and when the clinical diagnosis is highly probable, one can perform an intravenous fructose tolerance load, which is more reliable and less dangerous than an oral load. It results in a rapid fall, first of serum phosphate, then of blood glucose, and a subsequent rise of uric acid and magnesium concentrations. Alternatively, aldolase B can be measured on a liver biopsy sample.

Treatment

Treatment consists of completely eliminating all sources of sucrose, fructose, and sorbitol from the diet, preferably with the help of a dietician familiar with metabolic disorders, as many foods contain these ingredients. Formula-fed infants with hereditary fructose intolerance who cannot tolerate lactose-based formulas must be given sucrose-free soy or elemental formulas. Whereas commonly used formulas that contain corn syrup (glucose polymer) solids are safe for HFI patients, foods with “high fructose corn syrup solids” must be avoided. Medications must be carefully screened for the presence of sorbitol and sucrose sweeteners, and water-soluble vitamin supplements should be given.

With treatment, liver and kidney dysfunction improve and catch-up growth is common. Intellectual development is usually unimpaired. As the patient matures, symptoms become milder even after fructose ingestion, and the long-term prognosis is good. Owing to dietary avoidance of sucrose, affected patients have few dental caries.7

Fructose 1,6-Diphosphatase Deficiency

Fructose 1,6-diphosphatase deficiency (OMIM 229700) is a defect in gluconeogenesis.

Clinical Presentation and Laboratory Diagnosis

The disease is characterized by life-threatening fasting episodes of lactic acidosis, hypoglycemia, hyperventilation, convulsions, and coma. Hepatomegaly is present during acute episodes. These episodes are triggered by a decrease in oral food intake during febrile illness or gastroenteritis. Laboratory findings include low blood glucose, high lactate and uric acid concentrations, and metabolic acidosis. In contrast to hereditary fructose intolerance, there is usually no aversion to sweets, and renal tubular and liver functions are normal. Treatment of acute attacks consists of correcting hypoglycemia and acidosis by IV infusion, and the response is usually rapid. Later, avoiding fasting and eliminating fructose and sucrose from the diet prevent further episodes. For long-term prevention of hypoglycemia, a slowly released carbohydrate such as cornstarch is useful. Patients who survive childhood seem to develop normally. In some women managed with appropriate diets, successful pregnancies have been reported.

Diagnosis

The diagnosis is established by demonstrating an enzyme deficiency in either the liver or an intestinal biopsy specimen. The enzyme defect may sometimes be demonstrated in leukocytes. The gene coding for fructose 1,6-diphosphatase is located on chromosome 9q22. In patients with known mutations, carrier detection and prenatal diagnosis are possible using the DNA-based test.