Far Eastern University Dr.

Nicanor Reyes Memorial Foundation

Institute of Medicine

Biochemistry Laboratory Conference

Galactosemia

Section 1B1 Medicine Group 6

Members:
EGANA, Alyssa Jane C.
ESCOTO, Monique Ann Theresse A.
ESGUERRA, Toni Camille T.
ESPINO, Joseph Daniel S.
ESTAVILLO, Karen G.
FABIAN, Trixia Anne B.

GALACTOSEMIA
Learning Objectives:
1. Discuss the metabolic reactions that galactose undergo after absorption
2. Define Galactosemia
3. Differentiate the different types of galactosemia as to the enzymes that are
deficient, clinical manifestations.
4. Explain the different laboratory procedures that can be done to diagnose
galactosemia
5. Discuss the treatment of galactosemia
I.

Introduction
Galactosemia
Also known as galactose diabetes. It is an inherited condition in
which the body is unable to use or metabolize the simple sugar galactose
(Medline Plus, 2015). This means that it is passed down through families.
It came from the words, galactose which is a type of sugar in food and
emia which means blood. There is elevated galactose in the blood in
patients suffering from this illness. A small amount of galactose is present
in many foods. It is primarily part of a larger sugar called lactose, which is
found in all dairy products and many baby formulas (Genetics Home
Reference, 2016). Thus, it is the main source of galactose in the diet. The
signs and symptoms of galactosemia result from an inability to produce
energy or glucose for the body to use.
Since galactosemic patients cannot breakdown galactose, the
following foods should be avoided:
Butter
Margarine
Cheese - cottage cheese, cream cheese and other cheese-based
products (Note: some hard mature cheeses are allowed)
Cream
Ice cream
Milk - milk chocolate, non-fat milk, human breast milk, goats milk,
cows milk
Offal meats (liver, kidney, brains, pate)
Legumes (dried peas, beans, lentils)
Fermented soybean products (miso, soy sauce)
Sour cream
Yogurt
Galactose
Sometimes abbreviated as Gal, is a monosaccharide, a hexose and it
is the C4 epimer of glucose. It means that these isomers are differing as a

result of variations in configuration of the OH on atom 4 (Harpers, 30 th

Edition).

Figure 1. Fischers and Hayworths Projection of Galactose and Glucose

D Galactose
Source: hydrolysis of lactose
Biochemical Importance:
Readily metabolized to glucose
Synthesized in the mammary gland for synthesis of lactose in milk
Clinical Significance: hereditary of galactosemia as a result of failure to
metabolize galactose leads to cataract
Lactose
Like what was discussed earlier, the main source of galactose is
lactose. Since lactose is a disaccharide and a relatively large molecule, they
cannot be absorbed by the small intestine. Before it can be absorbed, it must
be broken down into smaller monosaccharide. In order to do this, the small
intestine produces an enzyme called lactase. This will attach itself to the
lactose molecule and hydrolyze it into glucose and galactose. These smaller
molecules can now easily be absorbed by the intestine and enter the blood
stream.

Figure 2. Breakdown of Lactose to Galactose and Glucose via The Lactase Enzyme

It is mainly found in milk (and many pharmaceutical preparations as a

filler) and lack of lactase (alactasia) will also lead to a disorder known as

II.

lactose intolerance diarrhea and flatulence. This may also be excreted in

the urine in pregnancy
Galactose Metabolism
Galactose is derived from the intestinal hydrolysis of the disaccharide
lactose; the sugar found in milk (a disaccharide of glucose and galactose) and
it is needed for the synthesis of lactose, glycolipids, proteoglycans, and
glycoproteins. It is readily converted in the liver to glucose. This occurs
through a series of steps or metabolic pathway for the catabolism of Dgalactose that is referred to as the Leloir pathway, named after Luis
Federico Leloir who determined the overall process of galactose utilization. It
can also be converted to lactose in the lactating mammary gland. Lastly, it
can be oxidized as a source of energy.
A. Conversion of Galactose to Glucose
Galactose exists in two different sterioisomeric forms namely, -Dgalactose and -D-galactose. The -form is the one that is readily
metabolized in the Leloir pathway since it is the active form of the pathway.
On the other hand, the -form is converted to the -form via the enzyme
galactose mutarotase which is encoded by the galactose mutarotase (GALM)
or also known as aldose 1 epimerase)

Figure 3. Sterioisomeric Forms of Galactose

Figure 4. Pathway of conversion of galactose to glucose in the liver

The first step of the reaction, galactokinase catalyzes the
phosphorylation of -D-galactose, using ATP as a phosphate donor to yield
galactose-1-phosphate (phosphorylation at C-1, Figure 4). Galactose 1phosphate reacts with UDPGlc to form urinidine diphosphate galactose

(UGPGal) and glucose 1-phosphate, in a reaction catalyzed by galactose-1phosphate uridyl transferase (GALT). The conversion of UDPGal to
UDPGlc is catalyzed by UDPGal 4-epimerase (GALE). The reaction involves
oxidation, and then reduction, at carbon 4, with NAD+ as a coenzyme. The
UDPGlc is then incorporated into glycogen. The UDP portion is exchanged for
phosphate for phosphate generating glucose-1-phosphate, which then is
converted to glucose-6-phosphate (G6P) by phosphoglucose mutase. It will
then enter glycolysis to be able to generate energy. In addition, glucose-6phosphate can be converted to glucose in the liver through the enzyme
glucose-6-phosphate.
The epimerase reaction is freely reversible, so glucose can be converted
to galactose, and galactose is not a dietary essential.
B. Becomes Part of Lactose and Other Galactolipids
Lactose synthesis pathway is found in the mammary glands of the
mammalians. Lactose is a disaccharide composed of D-galactose and Dglucose link through 1-4 glycosidic linkage. It is a reducing sugar because
of its free hydroxy group at anomeric carbon (carbon number 2) and can be
oxidized to sugar acids. It is a soluble and least sweet ugar.

Figure 5. Lactose

Figure 6. Pathway of conversion of glucose to lactose in the lactating mammary

gland.

Like what was mentioned earlier, UDP galactose can serve as the donor
of galactose units in the synthesis of lactose, glycolipids, proteoglycans,
glycoproteins, and glycosaminoglycans.
Lactose synthase is located in the lumen of the Golgi complex of the
mammary gland, which is the one, involved in the lactose synthesis pathway.
It is a galactosyl tranferase catalyzing the condensation of UDP-galactose
and D-glucose to form lactose. This comprises of a two-protein complex that
is attached to the membranes of the Golgi membranes. These proteins are
called -galactosyl transferase (GT catalytic protein) and -lactalbmin
(auxillary protein). The latter is the only one expressed in the mammary gland
and involved in lactose synthesis together with -galactosyl transferase.
Another enzyme called Nucleotide Diphosphate (NDPase), which is also
attached to the membrane of the Golgi membrane, is involved in the
regeneration of Pi from UDP cleavage. To be able to form lactose, glucose
and UDP-galactose is needed and both which come form the cytosol.
In the lactose synthesis pathway, glucose is transported into the Golgi
lumen by passive transport via GLUT 1. On the other hand, UDP-galactose is
transported actively. This pathway is neither influenced by the glucose nor
product produced (lactose). However, it may be inhibited if theres excess
amount of UDP galactose.
The lactose formed in this pathway cannot be carried out of the Golgi
vesicles because there is no transporter for this sugar. Thus, it remains in the
lumen of the Golgi complex and creates osmotic pressure. This osmotic
pressure is remained via draining of water out into the vesicles.
In the absence of -lactalbmin, -galactosyl transferase, which is found in
number of body tissues (other than the lactating mammary gland), catalyzes
the transfer of galactose from UDP galactose to terminal Nacetylglucosamine of oligosaccarides in glycoproteins, forming the same (1
4) linkage found in lactose, and producing N-acetyl-D-glucosamine, a
component of the structurally important N-linked glycoprotein. Thus, it is
involved in glycoprotein biosyntheis like in tissues other than mammary gland.

Figure 7. Lactose Synthesis

C. Is Oxidized as Source of Energy
The glucose 6 phosphate that is formed in the conversion of galactose
in the liver can already be used in glycolysis, which would eventually produce
energy. Also, for galactose to be utilized for energy, it needs to be converted
first to be able to enter the metabolic pathway that convert glucose into
energy, water and carbon dioxide.
The glycolytic pathway comprises of 10 enzyme-catalyzed steps. During
glycolysis, glucose, a six-carbon carbohydrate, is oxidized to form two
molecules of pyruvate, a three-carbon molecule. For each glucose molecule
metabolized, the pathway produces two molecules of ATP and two molecules
of NADH. Other than glucose, many carbohydrates meet their catabolic fate
in Glycolysis, after being transformed into one of the Glycolytic intermediates.
The most significant are the storage polysaccharides Glycogen and Starch;
the disaccharides Maltose, Lactose, Trehalose and Sucrose; and the
monosaccharides Fructose, Mannose, Galactose.

Figure 8. Feeder Pathways for Glycolysis

III.
IV.
V.

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III- Differentiate the different types of galactosemia as to the enzymes that are
deficient, clinical manifestations
A. Classic and Clinical Variant Galactosemia

Classic and clinical variant galactosemia are rare genetic metabolic disorders. The
patient with classic galactosemia carries deleterious mutations in both copies of their
GALT gene so that their blood shows essentially no detectable residual GALT activity.
The patient with clinical variant galactosemia also carries deleterious mutations in both
copies of their GALT gene, but one or both mutations leave a small amount of residual
GALT activity. In the vast majority of cases, the GALT mutations in classic and clinical
variant galactosemia are inherited so that both parents of an affected child are carriers.
Rare exceptions occur. Patients with classic galactosemia are sometimes described as
having the genetic makeup "G/G." When a person who does not have galactosemia
consumes food containing lactose (e.g., dairy products such as milk, cheese, butter),
their body breaks down the lactose into galactose and glucose, and then further
metabolizes both of these sugars. The human body also is able to make endogenous
galactose. When a person with galactosemia consumes food containing lactose or
galactose they are not able to fully metabolize the galactose, so it can build up in their
cells and tissues. Galactose that is synthesized in the body may also build up. Other
molecules derived from galactose, such as galactose-1-phosphate (Gal-1P), galactitol,
and galactonate, may also build up in the cells and tissues of patients with
galactosemia, especially if they are consuming high levels of dietary lactose or
galactose. Untreated, classic and clinical variant galactosemia are potentially lethal
disorders. If an affected infant continues to drink milk the baby may develop symptoms

that progress in days from jaundice, vomiting, and diarrhea, to liver disease and failure
to thrive, and eventually to E. coli sepsis, which can be fatal.
Diagnosis is made usually within the first weeks of life in follow-up to newborn
screening, which is a blood test from a heel prick offered to all newborns in the United
States and many other countries.
Treatment for classic or clinical variant galactosemia requires the immediate and
strict exclusion of lactose/galactose from the babys diet. This is usually
accomplished by switching the baby from drinking breast milk or a milk-based formula to
drinking a low galactose formula, such as soy or elemental formula. Even with early
diagnosis and careful restriction of lactose/galactose from the diet, however, patients
with classic and clinical variant galactosemia remain at increased risk for long-term
complications that include speech and language, fine and gross motor skill delays and
specific learning or cognitive and behavioral disabilities. Some patients experience
many of these complications; others do not. Primary or premature ovarian insufficiency
is also very common among girls and women with classic and clinical variant
galactosemia. Prenatal diagnosis by genetic or biochemical testing is available.

Duarte Variant Galactosemia

Duarte variant galactosemia, sometimes called just Duarte galactosemia or DG, is
much more common than classic or clinical variant galactosemia in many populations
and also results from mutations in the GALT gene. However, instead of carrying severe
mutations in both copies of their GALT gene, patients with Duarte variant galactosemia
carry one GALT copy with a severe (G) mutation and a second GALT copy that is only
very mildly impaired and that shows a collection of characteristic sequence changes
that classify it as Duarte (also called D or D2). A child with Duarte variant galactosemia
therefore generally has one parent who is a carrier for a severe (G) GALT mutation, and
one parent who is a carrier for the Duarte variant. Patients with Duarte variant
galactosemia usually show about 25% the normal level of GALT activity in red blood
cells. Newborns with Duarte variant galactosemia may not show any symptoms, such
as jaundice, while drinking milk. Experts therefore disagree about whether infants with
Duarte variant galactosemia should be put on a lactose/galactose restricted diet, and no
one knows whether older children or adults with Duarte variant galactosemia are at
increased risk for long-term complications. Reported studies give mixed or inconclusive
results, so that more research is needed to answer the question. If long-term
developmental complications do occur in patients with Duarte variant galactosemia they
are generally believed to be milder than those experienced by patients with classic
galactosemia.
Type I: Classic Galactosemia or Galactose-1-phosphate uridylyltransferase (GALT)
deficiency is the most common and most severe form of the condition. Duarte
Galactosemia is a variant of classic galactosemia. The complications associated with

classic galactosemia have not been associated with Duarte galactosemia. The child
with Duarte galactosemia inherits a gene for classic galactosemia (G) from one parent,
and a Duarte variant gene (D) from the other parent. Patients with this genetic make-up
are frequently referred to as D/G galactosemics. Genotypes involving the Duarte variant
gene include:
D/N = carrier of Duarte galactosemia (about 75% enzyme activity)
D/D = homozygous carrier of Duarte galactosemia (about 50% enzyme
activity)
D/G = Duarte galactosemia (about 25 - 50% enzyme activity)
B. Galactokinase Deficiency Galactosemia
Galactokinase deficiency results from inheritance of deleterious mutations in the human
GALK1 gene leading to loss of galactokinase (GALK) enzyme activity. Like patients with
loss of GALT activity, patients missing GALK activity cannot fully metabolize galactose
so that if they consume a diet high in lactose/galactose they will accumulate high levels
of galactose and galactose metabolites including galactitol and presumably galactonate,
though this metabolite is rarely measured. Unlike patients who are missing GALT
activity, patients with galactokinase deficiency do not accumulate high levels of Gal-1P
because GALK is the enzyme that synthesizes Gal-1P.
Galactokinase deficiency is very rare in many populations and is not detected by many
newborn screening programs so that long-term follow-up studies of large numbers of
patients diagnosed with galactokinase deficiency have been difficult to conduct.
Because those patients with galactokinase deficiency studied were ostensibly well as
infants, except for cataracts that self-resolved following dietary galactose restriction,
loss of galactokinase was believed to be relatively benign regardless of diet. Babies
born with galactosemia II will develop cataracts at an early age unless they are given a
galactose-free diet.
.

C. Epimerase Deficiency Galactosemia

Epimerase deficiency results from inheritance of deleterious mutations in the human

GALE gene leading to partial loss of UDP-galactose 4-epimerase (GALE) enzyme
activity. Like patients with loss of GALT or GALK activity, patients with impaired GALE
activity cannot fully metabolize galactose. Galactoepimerase deficiency is also known
as galactosemia type III. Sign and symptoms vary from mild to severe and include
catatracts, delayed growth and development, intellectual disability, liver disease, and
kidney problems.

Patients with impaired GALE activity may be categorized as having one of three forms
of epimerase deficiency: (1) generalized epimerase deficiency which results from
profound but not complete loss of GALE activity, (2) intermediate epimerase deficiency
which results from partial but not profound loss of epimerase activity in multiple tissues,
and (3) peripheral epimerase deficiency which results from loss of epimerase activity
only in some cell types (e.g. red blood cells) but not in others (e.g. lymphoblasts or
liver). In terms of clinical severity, generalized epimerase deficiency is similar to classic
galactosemia, peripheral epimerase deficiency is generally considered benign, and
intermediate epimerase deficiency is of unknown clinical significance.

IV.

CLINICAL MANIFESTATIONS

Symptoms of galactosemia usually begins within days to weeks after birth. The
infant usually is reluctant to ingest breast milk or milk formulas, developing
vomiting, shows poor nutrition, and fails to thrive (inadequate weight gain and
physical growth in children). Elevated galactose levels lead to decrease hepatic
output of glucose and hence to hypoglycaemia.
Jaundice, hepatomegaly, and evidence of liver disease may develop. Cirrhosis
and mental retardation of classic galactosemia are related to increased amounts
of galactose-1-phosphate in the liver and in the brain. Mental retardation
becomes evident after 6-12 months and is usually not reversible.

In the lens, galactose is converted by aldose reductase to galactitol. As a

consequence, excessive hydration occurs which, together with a decrease in
glutathione in the lens, leads to cataract formation. The only consistent feature of
galactokinase deficiency is cataract formation. Cataracts are usually not present
at birth but develop gradually over weeks to months.

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