MANNOSIDOSIS AND GALACTOSEMIA: SOMETHING TO WATCH OUT

FOR
Galactosemia is an autosomal recessive disorder where people who
have this disease cannot produce the enzyme to breakdown galactose into
simpler compounds. This is different from lactose intolerant people. Lactose
intolerance is the disorder where in the infected is not bale to breakdown
lactose into glucose and galactose. Galactosemia, however, deals with the
further degredation of galactose.
The lelior pathway is a metabolic process in the body that deals with
the breakdown of galactose. It was named after Luis Leoior. The Leloir
pathway is comprised of four steps. The first step is the conversion of -Dgalactose to -D-galactose by galactose mutarotase; this step is the key step
for this process. The next is the conversion of -D-galactose to galactose-1phosphate through the phosphorylization by galactokinase. After, Galactose1-phosphate is converted into UDP-galactose by D-galactose-1-phosphate
uridyl transferase with UDP-Glucose as the source of uridyl. And lastly, a
tranferase reaction occurs between D-glucose and UDP-Galactose by UDPgalactose-4-epimerase.
There are three types of galactosemic disease: (1) the most common
yet deadliest is the type that lacks the enzyme Galactose-1-phosphate uridyl
transferase (GALT) This enzyme catalyzes the second step of the Leloir
pathway of galactose metabolism. The FOXO3 gene expresses GALT. The
inexistence of this enzyme can result in what is normally called as the
classic galactosemia. This can be fatal especially to babies because lactose,
or milk, is their primary source of food. If there is nothing to brakdown
galactose then there will be an accumulation of this and eventually the cells
become dysfunctional and they eventually die. (2) the second type is due to
the deficiency of galactokinase which does not convert galactose to
galactose-1-phosphate, which increases the concentrations of galactose and
galactitol. This disorder is expressed by the mutation of the GALK1 gene
located on chromosome 17; this is an autosomal recessive disorder.
Autosomal means that it is inborn; one can get it through inheritance. The

major side effect is the formation of cataract because of the accumulation of

galactitol in the lens during the first couple of months during childhood. This is
can be prevented by restricting galactose in the diet. (3) the last type is the
GALE deficiency which is due to the deficiency of galactose epimerase which
is a rare autosomal disease. There are two types of this disease: one is
benign RBC deficiency and the other is severe liver deficiency. GALE
deficiency prevents the formation of glucose-1-phosphate. Once this
compound is accumulated in the body, it interferes with a group of enzymes
(phosphoglucomutase, glycogen phosphorylase, UDP-glycopyrophoshorylase
and inositol monophosphatase) that causes a blockage in the Leloir pathway
and it activates other pathways of glucose metabolism, which leads to the
formation of galactonate and galactitol. The first is metabolized through the
pentose phosphate pathway while the latter may accumulate in the lens of the
eye which causes cataract formation and lead to cell death.
One of the organelles in the cell, called the lysosome, contains
enzymes called mannosidases; these perform the major functions of a
lysosome. These functions define the lysosome as both a refrigerator and a
dump site. Weird huh? This is because the lysosome is able to use waste
products of the cell. The lysosomes degrade these waste products and use
them to synthesize new compounds that are ready to be used for other
metabolic processes in the cell. An example could be glycolysis or the citric
acid cycle. One of the enzymes that are used to degrade carbohydrates, or
mannose in particular is called mannosidase. When the gene that is used to
express the release of mannose is not working, a lysosomal disorder is
contracted; this is called mannosidosis. Mannosidosis is a recessive
autosomal idisorder wherein the gene that expresses the release of
mannosidase is either defective or is not working at all.
Mannosidosis is inherited in an autosomal recessive pattern. This
means that parents of a person have this trait. It probably was not expressed
by the parents gene due to its recessive property, but it could be expressed in
their child due to both recessive traits being in the child. Figure 1 shows the
Punnet Square of two heterozygous parents based on the gene for the
expression of alpha-mannosidase. The dominant trait, M, is the absence of

mannosidase, while the recessive trait, m is the presence of mannosidase.

This is always true because mannosidase is not a normal occurrence. It is a
genetic disorder, thus it is recessive trait. There are two homozygous
expressions of the trait that each occur 25% of the time, these are MM and
mm. The first is expressed as a person with a functioning mannosidase, while
the latter is expressed as a person who has a defect with their production of
the mannosidase enzyme. The other 50% is due to Mm, which is a
heterozygous trait but it is expressed as the dominant trait, which means that
the person will have a normal production of the enzyme.
Trait

MM

Mm

Mm

mm

There are two types of mannosidosis, both

of which are found in different gene locations.

Figure 1. Punnet Square of

the Mannosidosis Gene

The alpha and the beta mannosidosis: The first is

contracted due to a mutation in the MANB gene
on chromosome 19. This means that the alpha
sub-unit of the mannosidase is lacking. The
MANB gene is the one that signals the cell to
produce the enzyme alpha-mannosidase to be

able to breakdown complex sugar molecules. These sugar molecules are

attached to glycoproteins that the cells receptors readily identify it and let it
enter the cell to be able to perform its functions. This enzyme breaks down
large sugar molecules (oligosaccharides) that contain mannose, which is a C#2 epimer of glucose. When alpha-mannosidase is not able to perform its
role, then there will be an accumulation of complex sugars in the lysosome.
This is not favorable because it causes the cell to malfunction and eventually
die due to self-digestion. The second is contracted when the beta sub-unit is
missing. This is seen when there is mutation on the MANB1 gene on
chromosome 4. The latter kind is mostly expressed in animals.
Both Mannosidosis and Galactosemia are autosomal recessive
disorders that occur because there is a lack of an enzyme that is used to
break down sugars into simpler molecules. Mannosidosis is a disorder
wherein the infected is not able to break down mannose; this is true for
galactosemia except the sugar that it cannot break down is galactose. Both
are also present as the recessive gene and are inherited. Symptoms of which

are hepatomegaly or enlarged liver. These diseases give one quite the scare
because carbohydrates are an important factor in ones diet.

References:
http://www.health.am/encyclopedia/more/galactose_6_phosphate_epimerase
_deficiency/
http://en.wikipedia.org/wiki/Galactokinase_deficiency
http://en.wikipedia.org/wiki/Galactokinase
http://en.wikipedia.org/wiki/Galactose_epimerase_deficiency
http://en.wikipedia.org/wiki/Galactose_epimerase
http://www.healthline.com/galecontent/mannosidosis#4
http://ghr.nlm.nih.gov/Resources/health
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515294/
http://www.ojrd.com/content/3/1/21
http://en.wikipedia.org/wiki/Metabolism
http://en.wikipedia.org/wiki/Leloir_Pathway
http://www.ncbi.nlm.nih.gov/books/NBK1518/
http://en.wikipedia.org/wiki/Galactosemia
http://medical-dictionary.thefreedictionary.com/galactosemia
http://www.nlm.nih.gov/medlineplus/ency/article/000366.htm
http://ghr.nlm.nih.gov/condition=galactosemia