GALACTOSEMIA

OBJECTIVES:
1. Identify the metabolic reactions that galactose undergo: as it is converted to
glucose; as it becomes part of lactose and other galactolipids
2. Identify the reason behind some patients failure to metabolize galactose and
develop galactosemia. Determine the enzymes deficient
3. Identify the biochemical effects of galactosemia and their corresponding clinical
manifestations and their molecular explanation
4. Identify the laboratory procedures that can be done to diagnose galactosemia
and their corresponding rationale
5. Discuss the treatment of galactosemia
6. Determine reason why galactosemic patients can tolerate milk and other
galactose-containing products once they are adults

The metabolic reactions that galactose undergo:

As it is converted to glucose
In the first step, galactose is phosphorylated by galactokinase to galactose 1phosphate.
In the third step, D-galactose-1-phosphate uridylyltransferase converts
galactose 1-phosphate to UDP-galactose using UDP-glucose as theuridine
diphosphate source.
Finally, UDP-galactose 4-epimerase recycles
glucose for the transferase reaction.

the

UDP-galactose

to

UDP-

Additionally, phosphoglucomutase converts the D-glucose 1-phosphate to Dglucose 6-phosphate.

Figure 1.1 Conversion of Galactose to Glucose

as it is becomes part of lactose and other galactolipids

UDP-galactose can serve as the donor of galactose units in a number of
synthetic pathways, including synthesis of lactose, glycoproteins, glycolipids,
and glycosaminoglycans.
Lactose is synthesized in Golgi by lactose synthase (UDP-galactose:glucose
galactosyltransferace), which transfers galactose from UDP-galactose to
glucose, releasing UDP. This enzyme is composed of two proteins, A and B.
Protein A is a B-D-galactosyltransferace, and is found in number of body
tissues. In tissues other than the lactating mammary gland, this enzyme
transfers galactose from UDP-galactose to N-acetyl-D-glucosamine, forming
the same B(1-4)linkage found in lactose, and producing N-acetyllactosamine
a component of the structurally important N-linked glycoproteins.
Protein B is found in lactating mammary glands. It is a-lactalbumin, and its
synthesis is stimulated by the peptide hormone, prolactin. Protein B forms a
complex with the enzyme, protein A, changing specificity of that transferase
so that lactose, rather than N-acetyllactosamine, is produced.

Figure 1.2 Conversion of UDP-Galactose to Lactose

Figure 1.3 Lactose synthesis

as it is oxidized as source of energy

For galactose to be utilized for energy, it must be transformed into something

that can enter the metabolic pathway that converts glucose into energy (plus
water and carbon dioxide)
The glycolytic pathway begins with the breakdown of glucose, but other
sugars simple or complex, if converted to any of the glycolytic intermediates
can be used in glycolytic pathway for the production of energy. The sugars
like fructose, Galactose, Mannose and even Glycerol produced from hydrolysis
of tryglycerides or obtained diet or other sources can be oxidized through
glycolysis.

Figure 1.4 Feeder Pathways for Glycolysis

Reason why some patients fail to metabolize galactose and develop

galactosemia and the enzymes that are deficient:

Inability to metabolize galactose occurs in galactosemia, which may be caused

by inherited defects in galactokinase, uridyl transferase or 4-epimerase. It is an
inborn error of metabolism. This is caused by a deficiency in any of the following
enzymes:

Galactose-1-phosphate uridyl transferase (GALT): GALT deficiency results

in tissue accumulation of Galactose-1-phosphate and galactose.
Galactokinase: Galactose accumulates in the blood and tissues.
Uridyl-diphosphogalactose-4-epimerase (GALE): a rare condition.

Types of Galactosemia

Galactose 1-phosphate uridyl transferase deficiency galactosemia

Classic galactosemia is a serious disease with an early onset of symptoms
The incidence is 1 in 60,000, therefore, it is a quite rare disease
The newborn infant normally receives up to 20% of caloric intake as lactose
(from milk), which consists of glucose and galactose
Without uridyl transferase, the infant is unable to metabolize galactose 1phosphatethe accumulation of galactose 1-phosphate results in injury to
parenchymal cells to the kidney, liver, and brain
Galactose 1-phosphate uridyl transferase deficiency galactosemia
Galactosemia caused by uridyl transferase deficiency is inherited as an
autosomal recessive trait, therefore, it is a hereditary disease of the newborn
The gene for galactose-1-phosphate uridyl transferase is located on
chromosome 9p13.
African-American patients have milder symptoms (despite the absence of
measurable transferase activity in erythrocytes) and retain 10% of enzyme
activity in the liver and intestinal mucosa
Caucasian patients have no detectable enzyme activity in any of these
tissues
Galactokinase Deficiency
In contrast to the multiple systems that are affected in uridyl transferase
deficiency, cataracts are usually the sole manifestation of galactokinase
deficiency.
The affected infant is otherwise asymptomatic.
This disorder is characterized by elevated blood galactose levels with normal
uridyl transferase activity and an absence of galactokinase activity in
erythrocytes.
Treatment is dietary restriction of galactose intake.
Mutations leading to galactokinase deficiency have been identified in the
gene coding for galactokinase (located on chromosome 17q24).
Uridine diphosphate galactose 4-epimerase (UDP Gal 4-epimerase) deficiency
Aside from the accumulated metabolites in uridyl transferase deficiency, this
type of galactosemia shows an increase in cellular UDP galactose.

2 forms of epimerase deficiency:

1. A benign form wherein the patients are healthy; the enzyme
deficiency is limited to leukocytes and erythrocytes, without
deranged metabolism in other tissues, and no treatment is
required.
2. A rare and severe form with clinical manifestations resembling
uridyl transferase deficiency with hypotonia and nerve deafness
The gene for epimerase is located in chromosome 1p35-36; mutations
responsible for both forms of the epimerase deficiency have been identified.

Galactosemia Metabolism

Biochemical effects of galactosemia and their corresponding clinical

manifestations and their molecular explanation:

Inability to metabolize galactose occurs in galactosemia which can be caused

by inherited defects of galactokinase, uridyl transferase or 4-epimerase,
though deficiency of uridyl transferase is the best known.
The symptoms usually manifest within days to weeks after birth. The infant
usually is reluctant to ingest breast milk or milk formulas, develops vomiting,
shows poor nutrition and fails to thrive. In galactosemia, it is more severe if it
is the result of a defect in the uridyl transferase, since galactose 1-phosphate
accumulates and depletes the liver of inorganic phosphate. This accumulation
will then lead to jaundice, hepatomegaly and cirrhosis. If left untreated, this
can ultimately lead to liver failure and mental deterioration. Another
symptom of galactosemia is cataract which is due to the accumulation of
galacticol in the lens of the eye. In the lens, galactose is converted by aldose
reductase to galatitol which will cause excessive hydration together with a
decrease in gluthathione in the lens leading to cataract formation. In the
kidney and intestines, the accumulation of galactose and galactose 1phosphate may lead to an inhibition of amino acid transport. In uridyl
transferase deficiency, the epimerase is present in adequate amounts, so
that the galactosemic individual can still form UDPGal from glucose. This
explains how it is possible for normal growth and development of affected
children to occur despite the galactose-free diets used to control the
symptoms of the disease.

Laboratory procedures that can be done to diagnose galactosemia and

rationale behind the use of each test:
Urine test
To test for galactose in the urine sample, taping of a plastic collection bag to
the baby's genital area would be done. After the baby urinates, the collection
bag is removed.
Blood test
Since galactosemia test is done a baby, a heel stick test would be done and if
the test shows the baby is positive for galactosemia, it would be confirmed on
a blood sample taken from a vein.
Sample of a Lab Result of a Patient with Galactosemia
Test
Serum bilirubin
Hb
Serum AST
Serum ALT

Lab results - this

patient
12 mg/dL
185 g/L
50 U/L
45 U/L

Normal
values
or range
0.2 - 1.0 mg/dL
110 - 170 g/L
7.0 - 20 U/L
6.0 - 21 U/L

2 - 31 units per g
of Hb

Positive

Negative

Negative

< 250 mg/dL

Galactose
1-P
uridyltransferase (in
erythrocytes)
Urinary
reducing
sugars
Urinary glucose

The common enzyme deficiency for galactosemia is galactose 1-phosphate

uridyltransferase. Lacking the of activity of the enzyme would result to the
presence of reducing sugar in the urine, galactose. Using the glucose oxidase
test shows that it is not glucose. The unusual excretion of galactose is used to
be a good diagnostic of galactosemia.
The significance of high bilirubin test values shows 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.
Other tests:
Galactose Tolerance test is the administration of galactose to the patient
that would determine a higher than normal level of galactose in the blood.
This method is not used since galactose in toxic for the patient that would be
fatal.
Signs include:
Amino acids in the urine and/or blood plasma (aminoaciduria)
Enlarged liver (hepatomegaly)
Fluid in the abdomen (ascites)
Low blood sugar (hypoglycemia)
Newborn screening in many states will test for this condition.
Tests include:
Blood culture for bacterial infection (E. coli sepsis)
Enzyme activity in the red blood cells
Ketones in the urine
Prenatal diagnosis by directly measuring the enzyme galactose-1-phosphate
uridyl transferase
"Reducing substances" in the infant's urine, and normal or low blood sugar
while the infant is being fed breast milk or a formula containing lactose
Treatment for Galactosemia

Galactosemia is an inherited disorder characterized by an inability of the

body to utilize galactose. Galactosemia means "galactose in the blood ".
Galactose is a type of food sugar found mainly in dairy products, and is
produced within the body as well. The main source of galactose in the diet is
milk products. Milk contains a sugar called lactose, and during digestion,
lactose is broken down into the sugars glucose and galactose. Glucose can be
used as a source of energy by the body, but galactose needs to be further
broken down by a specific chemical (enzyme) before it can be utilized.
Persons with galactosemia have very little or entirely lack an enzyme that
helps the body break down galactose. There are three different enzyme
problems that can lead to galactosemia. This information will focus on the
most common type of galactosemia, often called "classic galactosemia". The
enzyme that is reduced or missing in classic galactosemia is called galactose1-phosphate uridyl transferase (GALT). The GALT enzyme enables the body to
break down galactose into glucose for energy. Because some individuals with
galactosemia have more enzyme than others, the severity and treatment of
the disorder can vary.
Galactosemia is treated by removing foods that contain galactose from the
diet. Any foods containing lactose, thereby containing galactose, should be
avoided. Untreated galactosemia will result in a harmful build-up of galactose
and galactose-1-phosphate (a form of galactose) in the bloodstream and body
tissues. Infants with unrecognized galactosemia usually have problems with
feeding and do not grow as they should. If galactosemia is not treated,
infants can develop cataracts, liver disease and kidney problems. In addition,
the build-up of galactose and galactose-1-phosphate can cause brain
damage, and in some cases, can lead to death. Even with treatment, some
children may develop learning disabilities, and girls with galactosemia may
have problems with their ovaries. With continued dietary management,
however, many individuals with galactosemia enjoy good health, and are able
to lead independent lives.
Dietary Management of Galactosemia
The main goal of dietary treatment of galactosemia is to remove any foods
containing galactose from the diet. Because milk and milk products are the
most common food source of galactose, persons with galactosemia should
avoid these foods. In the past, there was some controversy about how long a
person with galactosemia should remain on a galactose-restricted diet. It is
now recommended that persons with galactosemia should avoid eating foods
with galactose throughout life.
DIET

Ideally, a person with galactosemia should have a blood gal-1-p level below 3
to 4 mg/100 ml. A galactose-restricted diet should keep blood gal-1-p at this
level, while containing enough nutrients for normal body function. The diet
allows most protein-containing foods other than milk and milk products.
Fruits, vegetables, grains, breads, fats and sugars are acceptable, as long as
they do not have ingredients that contain galactose. Some fruits and
vegetables do contain small amounts of galactose. However, the form of
galactose (bound galactose) found in fruits and vegetables is not usable by
the body, and may not contribute to elevated blood gal-1-p. Recent research
has shown that bound galactose may in fact be usable by the body, but
further studies are needed to confirm this.
FOOD LABELS
The labels of all processed foods must be read carefully for ingredients which
are milk products. The milk products to be avoided in processed foods are
milk, casein, dry milk solids, lactose, curds and whey. The milk proteins
casein and caseinate must be limited in the diet. They can provide large
amounts of galactose if many foods or large amounts of any food containing
casein are eaten. The following products may be used because they do not
contain lactose: lactate, lactic acid, lactylates and calcium compounds. Food
labels should be checked every time, since the ingredients in food products
can change without notice.
MEDICINE
Lactose is often used as a filler or inactive ingredient in medicines, and might
not be listed on the package. The best way to ensure that a medication does
not contain fillers with galactose is to ask a pharmacist. They should have
access to information about medication ingredients. If possible, have a
pharmacist be aware of what medication ingredients are unacceptable to you.
This is the most effective way of avoiding galactose-containing medications.
DIETARY SUPPLEMENTS
Dietary supplements should be taken only when recommended by your
doctor or health care professional. Federal regulations require that these
products be labeled for the percentage of US RDA nutrients; fillers or inactive
ingredients are not listed. Because lactose may be used as a filler in some
dietary supplements, it is important to check with a pharmacist to ensure a
supplement does not contain any hidden sources of galactose.
Milk and milk products are the usual dietary source of calcium. Because
persons with galactosemia remove milk products from their diet, they need to

add calcium back into their diet through supplements. All people with
galactosemia should have a regular daily supplement of calcium either from a
soy formula or tablets. Consult your doctor or nutritionist to find out how
much calcium supplementation is right for you.
Dietary Treatment of Galactosemia
The goal of dietary treatment for galactosemia is to minimize galactose
intake which in turn minimizes galactose-1-phosphate production. Galactose1-phosphate levels are determined by: 1) individual internal galactose
production, 2) the specific allele for galactosemia, and 3) galactose intake
from foods. It is not possible for a person with galactosemia to have a
galactose-free diet. However, all persons with galactosemia should limit
galactose intake from foods to a very low level. The galactose-1-phosphate
levels of the individual determine the degree of dietary restriction necessary.
Why can galactosemic patients tolerate milk & other galactose containing
products once they are adults?
Galactose disposal by oxidation from 13C-label enrichment in plasma
galactose and expired carbon dioxide accounts for about 99% of body
galactose disposal. Less then 2% of endogenous galactose were found
disposed by the Kidneys.
In patients exhibiting GALT activity in RBC of less than 1% of control, the
release of galactose from endogenous intracellular sources ranged from 10 to
20 mg/kg body weight.
In addition, about 3 to 10 mg/kg body weight of galactose was obviously
converted intracellular to yield galactitol prior to release into the plasma
compartment and subsequent excretion by the kidneys.
Thus estimates for total endogenous galactose production ranged from 12 to
25 mg/kg body weight. Free galactose is produced from endogenous sources
at a physiologically relevant rate in galactosemia. Endogenous galactose
production decreases significantly with age. Normal galactose turnover rates
can be achieved at low residual GALT activities.

REFERENCES:

AMERICAN MEDICAL ASSOCIATION. (2004). Family Medical Guide. John Wiley

& Sons. Canada. pp. 1184.
BONCI, L. (2003). American Dietetic Association Guide to Better Digestion.
John Wiley & Sons. Canada. pp. 143.
FIEBACH, N. H. (2007). Principles of Ambulatory Medicine. Lippincott Williams
& Wilkins. Philadelphia. pp. 957.

GLEW, R.H. (1997). Clinical Studies in Medical Biochemistry. Oxford University

Press. United Kingdom. pp. 380.
N.A. (2008). Diagnostic Tests Made Incredibly Easy! Lippincott Williams &
Wilkins. Philadelphia. pp. 442.
SHERWOOD, L. (2010). Fundamentals of Human Physiology. 4th ed. Cengage
Learning. Asia. pp.928.
HARVEY, R.A. & FERRIER, D.R. (2011). Lippincotts Illustrated Reviews:
Biochemistry. 5th ed. Wolters Kluwer Lippincotts Williams & Wilkins. New York.
pp. 520.
MURRAY, R.K, BENDER, D.A., BOTHAM, K.M., KENNELLY, P.J., RODWELL, V.W. &
WEIL, P.A. (2009). Harpers Illustrated Biochemistry. 28th ed. Mc-Graw Hill.
New York. pp. 693.
http://www.biocarta.com/pathfiles/feederpathway.asp
http://www.nichd.nih.gov/publications/pubs/upload/NICHD_MM_Lactose_FS.pdf
http://www.efsa.europa.eu/en/efsajournal/pub/1777.htm
http://www.nationaldairycouncil.org/Research/DairyCouncilDigestArchives/Pag
es/dcd79-5Page3.aspx
http://www.livestrong.com/article/499386-types-of-lactose-intolerance/
http://emedicine.medscape.com/article/187249-overview