Download Key Medical Terms Associated with Enzymes and Body Chemistry

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Key Medical Terms Associated with Enzymes and Body Chemistry
Metabolism is the sum of all the chemical reactions that take place in the cells and the fluids of the
body. This includes the absorption of nutrients and minerals, the breakdown and buildup of large
molecules, the interconversion of small molecules, and the production of energy from these chemical
reactions. Virtually every chemical step of metabolism is catalyzed by an enzyme. Disorders of
these enzymes that result from abnormalities in their genes are known as inborn errors of
metabolism.
Tay-Sachs Disease (TSD) is a
autosomal recessive neurodegenerative
disease caused by a defective enzyme
(hexosaminidase A (Hex-A)) for the
breakdown of lipids, particularly the fatty
acid derivative called a ganglioside.
Hexasaminidase A is a vital hydrolytic
enzyme, found in the lysosomes, that
breaks down lipids. Babies born with
Neuronal lysosomes: Accumulate
TSD do not produce the HEX A enzyme
lipids due to reduction in breakdown
and so harmful quantities of the ganglioside fatty substance
of gangliosides
accumulates in the liposome’s of their brain cells. The excess
accumulation causes nerve cells to bulge, function poorly and die. Usually, the child with this problem
appears to be developing normally in the first few months but after about 6 months,
it gets worse. Children with this disorder eventually become blind, deaf, mentally
retarded and paralyzed, occurring within a year or two and usually die before age 5.
Those with less severe forms can affect people into their 20s and 30s. Currently
there is no cure or effective way to delay the progression of the disease. TSD is an
autosomal recessive genetic disorder, meaning that both parents must be
carriers in order to give birth to an affected child. Then, there is a 25% chance with
each pregnancy of having a child with TSD. One of the most common initial
symptoms is a red spot in the eyes described as a 'cherry-red spot' due to change in the retina at
the back of the eye. All babies in the United States and Canada are tested for TSD right after birth.
Each year in the U.S. about 1 in 10,000 children are diagnosed with TSD.A review of basic gene
transmission can be found at the end of this document.
Phenylketonuria (PKU): An autosomal recessive genetic disorder characterized by a mutation in
the gene for the liver (hepatic) enzyme phenylalanine hydroxylase (PAH), rendering it
nonfunctional. This disorder is the most common genetic disorder of amino acid metabolism affecting
about 1 in 10,000 people. This enzyme is necessary to metabolize the amino acid phenylalanine to
the amino acid tyrosine. When PAH activity is reduced, phenylalanine accumulates and is converted
into phenylketone (hens the name phenylketonuria), which can be detected in the blood and urine.
Phenylketone is also known as phenylpyruvate (phenylpyruvic acid). Phenylalanine is an essential
amino acid (meaning that it cannot be synthesized in the body and must be taken in through the diet)
that is needed for normal growth and development. A blood test is performed to check if a newborn
has the PAH enzyme needed to use
phenylalanine in his or her body. High
blood phenylalanine and
phenylketone levels can cause brain
damage, seizures, and severe mental
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retardation. The artificial sweetener aspartame (Equal,
NutraSweet), which is added to many diet foods and diet
sodas, contains phenylalanine. Federal regulations require that
any food that contains aspartame bear this warning:
"Phenylketonurics: Contains phenylalanine." This warning
helps people with PKU avoid products that are a source of
phenylalanine.
Symptoms can include mental retardation, hyperactivity,
stunted growth, small head size (microcephaly), and fair skin
and blue eyes. Reasons for symptoms: Phenylalanine is
converted into tyrosine and then to melanin, the pigment
responsible for skin and hair color. Therefore, infants with the
condition often have lighter skin, hair, and eyes than brothers
or sisters without the disease. Tyrosine is the precursor to
the neurotransmitters dopamine and norepinephrine
(noradrenaline), and to the hormone epinephrine
(adrenaline). Dopamine is a major brain neurotransmitter. PKU patients who
do not consume enough tyrosine in their diet cannot produce sufficient amounts of
dopamine. Low dopamine levels in the brain
disrupt normal communication between nerve
cells, which results in impaired cognitive
(mental) function. Other symptoms may include:
Delayed mental and social skills; Head size
significantly below normal (microcephaly);
Hyperactivity; Jerking movements of the arms or
legs; Mental retardation and seizures.
The damage caused by PKU can begin weeks after the baby has started drinking
breast milk or formula. Babies with PKU need foods low in phenylalanine to prevent severe brain
damage. Phenylalanine is found in most foods that have protein, such as milk, cheese, and meats.
Albinism: An autosomal recessive genetic disorder that
results in a lack of pigment in the skin, hair and eyes. It is
caused by a defective gene that provides instructions to
make the enzyme called tyrosinase that produces
melanin. This enzyme is located in melanocytes, which
are specialized cells that produce a pigment called
melanin. Tyrosinase is responsible for the first step in melanin production.
Through a series of chemical reactions the amino acid tyrosine is
converted to melanin in the skin, hair follicles, the colored part of the eye
(the iris), and the retina. There is no cure for albinism. One person in
17,000 in the U.S.A. has some type of albinism. Albinism is an autosomal
recessive disorder, meaning that both parents must be carriers in order to
give birth to an affected child. Then, there is a 25% chance with each
pregnancy of having a child with albinism.
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Galactosemia: A genetic disorder (autosomal recessive) caused by
a deficiency in the enzyme that metabolizes galactose. Milk
contains various sugars including the disaccharide lactose (glucose
attached to galactose) and the monosaccharide galactose. An
infant with galactosemia is unable to use (metabolize) the simple
sugar galactose, which reaches high levels in the body, causing
damage to the liver, central nervous system and various other body
systems. An infant with galactosemia may develop jaundice,
vomiting, lethargy, irritability and convulsions. The classic form of
galactosemia is due to a deficiency of the enzyme galactose-1phosphate uridyl transferase, and, if untreated, it presents in the infant with fatal liver failure.
Screening for Galactosemia by blood sample in the first few days of life has been very successful in
identifying the disorder, and simple alteration of the diet (replacing milk with formulas that do not
contain galactose or lactose) has permitted a generation of individuals to survive with quite normal
lives and, in general, normal intellect.
Familial Hypercholesterolemia (FH): A genetic disorder resulting
is a reduced ability to remove cholesterol from the bloodstream.
FH is characterized by high cholesterol levels, specifically very high
levels of low-density lipoproteins (LDL, "bad cholesterol"), in the
blood and early cardiovascular disease. Lipids, which include
cholesterol, are insoluble in water; therefore, they are
transported as complexes of lipoproteins. These proteins also
serve as ligands (binding groups) to specific receptors that help
move the lipoprotein into the cell. If the cells do not make the
receptors or have a reduced number of receptors on their
surface then the lipid containing lipoproteins are not
transported into the cell very well and remain in the blood
stream. Familial
hypercholesterolemia (FH) is an
autosomal dominant pattern of
inheritance meaning that one copy of
an altered gene in each cell is
sufficient to cause the disorder.
However this type of expression is
considered to be an incomplete
dominant or a semidominant trait,
which means there are two forms of
the disease - the disease exhibits a
gene dosage effect. Homozygous
individuals (2 bad gene copies) are
more severely affected than are
heterozygotes (1 bad gene copy).
Heterozygotes for FH occur with a
frequency of 1 in 500 which makes
this disease one of the most
common inherited disorders in
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metabolism. Heterozygous for the FH gene, means they've inherited one defective gene and one
healthy gene. Specifically, patients have mutations in the low-density lipoprotein receptor
(LDLR) gene that encodes the low density lipoprotein (LDL) receptor protein, which normally
removes LDL from the circulation, or apolipoprotein B (ApoB), which is the part of LDL that binds
with the receptor. Heterozygotes will have reduced numbers of Low Density Lipoprotein
receptors (LDLR) on their cell surfaces and higher-than-normal levels of blood cholesterol. Although
they are at increased risk for atherosclerosis and heart disease, symptoms may not develop at
all, or not until later in life. Having two abnormal copies (being homozygous) may cause severe
atherosclerosis cardiovascular disease in childhood. A child of two heterozygous parents may be
homozygous for the disease form of the FH gene. With two defective genes, a homozygous child has
a very severe form of the disease and produces few or no LDL receptors. About 1 in 1 million people
have this form of the disease. They may have heart attacks as early as age 2 and seldom live to
be 20 years old.
As circulating levels of lipids rise
(hyperlipidemia), cholesterol nodules
accumulate around tendons and beneath the
skin creating yellow deposits called
xanthomas. Specifically, xanthomas are
lesions characterized by accumulations of
lipid-laden macrophages. Xanthomas can
occur in persons of any age, but usually occur
in people older than 50 years. They appear anywhere on the body, but are
most often seen on the elbows, joints, tendons, knees, hands,
feet, or buttocks. Xanthomas may be a sign of a medical condition
that involves an increase in blood lipids. Such conditions include
diabetes, hyperlipidemia and of course, inherited metabolic
disorders such as familial hypercholesterolemia. If you have a
disease that causes increased blood lipids, treating the condition
may help reduce the development of xanthomas. They can be
surgically removed but will return if blood lipid levels remain high.
There's so much cholesterol
in the blood of FH people
that they can develop
cholesterol nodules called
xanthomas in their skin and
tendons. Hyperlipidemia can
also result in xanthomas.
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Genetic Review: Since many of the metabolic disorders are autosomal recessive it is important to
have a basic understanding about how this type of inheritance pattern works. The following is a brief
review about genes and how they are passed on. We will cover genes and inheritance patterns in
more detail during the genetic portion of the class. For now, use this information to help clarify what
an autosomal disorder is and then focus primarily on the disorders which you are expected to
understand for the upcoming quizzes and exams.
The cells of the body contain information, in the form of genes, for the
body to make all the necessary structural components and chemicals
to ensure normal function. If a gene is changed so that it does not
work properly, it is described as defective or faulty. The information
contained in the defective gene, and its product, is impaired. The
information for our cells to make a specific enzyme is contained
within a specific gene(s). To illustrate the inheritance pattern I will use
Tay Sach Disease (TSD) as an example which is due to a defective
gene for the enzyme called hexosaminidase A (Hex-A). The
information for our cells to make the HEX A enzyme is contained in a
gene, called the HEX A gene, located on chromosome number 15.
We all have two copies of chromosome number 15 in all our body
cells which you received from each of your parents, and therefore two copies of the gene that codes
for the HEX A enzyme. As there are two copies of each gene, if a person has a change in one copy of
their HEX A gene, and the other copy is working, they will still produce sufficient amounts of the HEX
A enzyme for normal body function. People who have one working copy of the HEX A gene and one
that is defective are called 'carriers' of the change that makes the gene defective or genetic carriers
for TSD. Genetic carriers for TSD do not have Tay-Sachs disease and are not affected in any way
because they can still produce enough HEX A enzyme. People with TSD have both copies of their
HEX A gene as defective: they cannot produce the important HEX A enzyme.
Important note about Genetic carriers. Individuals who are genetic carriers for TSD have one
working copy of their HEX A gene and one copy that is faulty in every cell. Being a genetic carrier for
TSD or any other genetic disorder is not like being a carrier of an infectious virus like hepatitis.
Genetic carriers for TSD cannot pass it on to others like a virus. They can, however pass the
defective gene on to their children. The effect of the change in the gene is 'recessive' or hidden by
the presence of the working copy of the gene. The pattern of inheritance in families of the defective
gene causing TSD is therefore described as autosomal recessive inheritance. In Figures 1 and 2
which illustrate the pattern of inheritance, the faulty HEX A gene is represented by 'r'; the working
copy by 'R'. There are four possibilities, in every pregnancy, for the combinations of genes passed
from the parents.
As shown in Figure 1, if a couple are both carriers of the defective HEX A gene, in every pregnancy
there is a 1 in 4 chance, or 25%, that they will have a child who inherits both copies of the defective
gene from his/her parents. In this case, no working gene product will be produced and their child will
be affected by TSD. There is a 1 in 4 chance, or 25%, that their child will inherit both copies of the
working gene and will be unaffected by TSD and cannot pass the faulty gene on to their children.
There is a 1 in 2 chance (2 in 4 chances), or 50%, that their child will inherit one faulty copy of the
gene and one working copy of the gene from each parent and he/she will be an unaffected genetic
carrier for TSD, just like the parents.
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Figure 1: Autosomal recessive inheritance where both parents are carriers of the faulty
HEX A gene. The faulty HEX A gene copy is represented by 'r'; the working copy by 'R'.
Figure 2: Autosomal recessive inheritance where only one parent is a carrier of the faulty
HEX A gene. The faulty HEX A gene copy is represented by 'r'; the working copy by 'R'.
If only one parent is a carrier of the faulty HEX A gene (Figure 2), in every pregnancy there is no
chance that the couple will have a baby affected with TSD. There is a 1 chance in 2 (2 chances in 4)
or 50% that the baby will be an unaffected genetic carrier for TSD, just like his/her parents. We will be
going over these types of inheritance patterns in detail during our lab on genetics. However, if you
have any questions please let me know.