Galactosemia

Biochemical background

In this disorder, individuals are unable to metabolize the sugar galactose, a sugar commonly derived from the disaccharide lactose. The common results of this defect are the formation of cataracts, mental retardation, poor growth, and even death from liver damage. The most common biochemical defects are a deficiency either in galactokinase or in galactose 1-phosphate uridyl-transferase.



Case description

ID/CC

Newborn female, 7 days old, breast-fed. Jaundiced and slow to respond to stimuli. Convulsions earlier that day.

HPI

Normal delivery, normal body weight. Indolence from day 3; jaundice apparent from day 5. Neither parent reported any family history of galactosemia; the mother, however, was adopted and had no direct knowledge of her biological parents.

PE

10% below normal body weight. Noticeable muscular tonus.

Labs

 

Test Lab results - this patient Normal values or range
Serum bilirubin 12 mg/dL 0.2 - 1.0 mg/dL
Hb 185 g/L 110 - 170 g/L
Serum AST 50 U/L 7.0 - 20 U/L
Serum ALT 45 U/L 6.0 - 21 U/L

Galactose 1-P uridyltransferase (in erythrocytes)

0 2 - 31 units per g of Hb
Urinary reducing sugars Positive Negative
Urinary glucose Negative < 250 mg/dL






Questions

1. What is the most common enzyme deficiency that causes galactosemia?

2. What are the common biochemical consequences of a defect in this enzyme?

3. What is the significance of the tests for urinary glucose and for reducing sugars in the urine?

4. What s the significance of the tests for Hb, AST, ALT, and bilirubin?

5. Considering that galactosemia is a hereditary recessive disease, how do you explain the parents not reporting any family history of the disease?

6. Could a galactosemic mother produce galactose in her breast milk? Explain.

7. What therapy would you recommend in this case?

8. Would you recommend a galactose tolerance test for this patient? Why or why not?





Answers/Discussion

1. What is the most common enzyme deficiency that causes galactosemia?

Usually the cause is a lack of activity of galactose 1-phosphate uridyltransferase.

2. What are the common biochemical consequences of a defect in this enzyme?

The immediate consequence is the inability to convert galactose to glucose. This leads to accumulation of galactose 1-phosphate and then free galactose in tissues. This can cause depletion of inorganic phosphate, and interfere with normal cell function. Cells that are especially vulnerable appear to be those of the liver and of the nervous system.

3. What is the significance of the tests for urinary glucose and for reducing sugars in the urine?

The reducing sugar in the urine is galactose. The glucose oxidase test shows that it is not glucose. The unusual excretion of galactose is a good diagnostic here.

4. What is the significance of the tests for Hb, AST, ALT, and bilirubin?

The high bilirubin test values show some interference with heme group metabolism. The normal values for hemoglobin show that this is not occurring in the red blood cells (i.e., no hemolysis). The high values for AST and ALT indicate tissue damage in the liver, the major site for bilirubin metabolism. The lab test on erythrocytes for the particular enzyme galactose 1-phosphate uridyltransferase is confirmatory for the disease.

5. Considering that galactosemia is a hereditary recessive disease, how do you explain the parents not reporting any family history of the disease?

Classical galactosemia is an inherited autosomal recessive disease. The incidence in the general population is about 1 in 40,000 newborns. Both parents could be heterozygous and not have overt symptoms, but their offspring would have a 1 in 4 chance of being homozygous for the recessive allele and so developing the disease. The mother's family history is unknown, since she was adopted. It is not clear why the father's family showed no history of the disease; perhaps his is a new mutation, or perhaps his knowledge of family history is imperfect.

6. Could a galactosemic mother produce galactose in her breast milk? Explain.

Lactose of course contains galactose. This sugar could be synthesized from glucose, without the mother ever having to ingest galactose, by first converting glucose to glucose 1-phosphate, then to UDP-glucose, then epimerizing the sugar to galactose, and finally releasing galactose 1-phosphate, which can then be used for lactose synthesis.

7. What therapy would you recommend in this case?

The main therapy is to restrict the patient's intake of lactose, the main dietary source of galactose. Thus the patient should be put on a milk-free diet.

8. Would you recommend a galactose tolerance test for this patient? Why or why not?

While a galactose tolerance test would certainly show a much higher than normal level of galactose in the blood after administration of galactose, it would be dangerous to the patient (the galactose is toxic here) and so the test is unethical.

 


Biochemical details

Biochemical role of galactose: Galactose is an aldohexose, a six-carbon sugar with an aldehydic carbon. The aldehyde group normally reacts with a hydroxyl group in the same chain, to form a ring structure. In the case of galactose, this ring has six members, five of which are carbons and one member being oxygen. Galactose is one of the two simple sugars that make up milk sugar, lactose. Galactose is also used in glycolipids and glycoproteins, and it may be converted to galactosamine, then N-acetylated and further modified (by, e.g., sulfation). These derivatized forms of galactose are used as constituents of mucopolysaccharides like chondroitin sulfate and keratan sulfate.

Normal metabolism: The conversion of galactose to glucose takes place in the liver quite rapidly. Galactose is first phosphorylated by the enzyme galactokinase, at the expense of a molecule of ATP:

The phosphorylated galactose is then uridylated, with the UDP derived from a molecule of UDP-glucose:



Notice how this releases glucose 1-phosphate, which is then readily metabolized to glucose 6-phosphate, for entry to the glycolytic pathway, etc.

The UDP-galactose is then epimerized to UDP-glucose, which can then act as a donor of the UDP moiety to an incoming molecule of galactose 1-phosphate. The epimerization involves the formation of the 4-keto intermediate, using NAD+ as a hydrogen acceptor, then donor:

 

Notice that there is no net oxidation or reduction here. The reaction is reversible, so that UDP-glucose and UDP-galactose are freely interconvertible. This in fact permits the biosynthesis of galactose from glucose, even when galactose is excluded from the diet, so that glycolipids and glycoproteins can continue to be made.

Overall, the reaction can be diagrammed as:



Enzymatic defects: Notice that a deficiency in galactokinase will immediately block the synthesis of galactose 1-phosphate, resulting in the accumulation of galactose. As galactose builds up in the circulation, more of it can enter the lens of the eye. There part of it is converted to galactitol (dulcitol) by aldose reductase; the galactitol initiates the formation of cataracts, a characteristic of the disease.

A deficiency in galactose 1-phosphate uridyl transferase will block the interconversion of UDP-glucose and UDP-galactose. This will result in accumulation of galactose 1-phosphate, and eventually of galactose as well. In fact, this latter enzymatic deficiency is more serious than a deficiency in galactokinase. The accumulation of galactose 1-phosphate in the liver depletes inorganic phosphate stores, and so leads to liver damage (there can be cataract formation as well, due to the abnormally high levels of galactose). The incidence of deficiency in the uridyl transferase is about 1 in 40,000 live births.

 

References

S. Segal, A. Blair, & H. Roth (1965), "The metabolism of galactose by patients with congenital galactosemia", Am. J. Med. 83, 62

A. Dahlquist, R. Jagenburg, & A. Mark (1969), "A patient with hereditary galactosemia", Acta Pediatr. Scand. 58, 237

 

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