Genetic Disorder

A genetic disorder is an illness caused by abnormalities

in genes or chromosomes, especially a condition that is
present from before birth. Most genetic disorders are quite
rare and affect one person in every several thousands or
millions.
A genetic disorder may or may not be a heritable disorder.
Some genetic disorders are passed down from the parents'
genes, but others are always or almost always caused by
new mutations or changes to the DNA. In other cases, the
same disease, such as some forms of cancer, may be caused
by an inherited genetic condition in some people, by new
mutations in other people, and by nongenetic causes in still
other people.
Some types of recessive gene disorders confer an advantage
in certain environments when only one copy of the gene is
present.
The four different types of genetic disorders are
(1) single-gene,
(2) multifactorial,
(3) chromosomal, and
(4) mitochondrial.
Single Gene Disorder
A single gene disorder is the result of a single mutated gene.
Over 4000 human diseases are caused by single gene
defects. Single gene disorders can be passed on to
subsequent generations in several ways. Genomic
imprintingand uniparental disomy, however, may affect
inheritance patterns. The divisions between recessive and
dominant types are not "hard and fast", although the
divisions between autosomal and X-linked types are (since
the latter types are distinguished purely based on the
chromosomal location of the gene). For
example, achondroplasia is typically considered a dominant
disorder, but children with two genes for achondroplasia
have a severe skeletal disorder of which achondroplasics
could be viewed as carriers. Sickle-cell anemia is also
considered a recessive condition, but heterozygous carriers
have increased resistance to malaria in early childhood,
which could be described as a related dominant
condition. When a couple where one partner or both are
sufferers or carriers of a single gene disorder and wish to
have a child, they can do so through in vitro fertilization,
which means they can then have a preimplantation genetic
diagnosis to check whether the embryo has the genetic
disorder.
Autosomal dominant
Only one mutated copy of the gene will be necessary for a
person to be affected by an autosomal dominant disorder.
Each affected person usually has one affected parent. The
chance a child will inherit the mutated gene is 50%.
Autosomal dominant conditions sometimes have
reduced penetrance, which means although only one
mutated copy is needed, not all individuals who inherit that
mutation go on to develop the disease. Examples of this
type of disorder are Huntington's
disease, neurofibromatosis type 1, neurofibromatosis type
2,Marfan syndrome, hereditary nonpolyposis colorectal
cancer, and hereditary multiple exostoses, which is a highly
penetrant autosomal dominant disorder. Birth defects are
also called congenital anomalies.

Autosomal recessive
Two copies of the gene must be mutated for a person to be
affected by an autosomal recessive disorder. An affected
person usually has unaffected parents who each carry a
single copy of the mutated gene (and are referred to as
carriers). Two unaffected people who each carry one copy
of the mutated gene have a 25% chance with each
pregnancy of having a child affected by the disorder.
Examples of this type of disorder are cystic fibrosis, sickle-
cell disease, Tay-Sachs disease, Niemann-Pick
disease, spinal muscular atrophy, and Roberts syndrome.
Certain other phenotypes, such as wet versus dry earwax,
are also determined in an autosomal recessive fashion.

X-linked dominant
X-linked dominant disorders are caused by mutations in
genes on the X chromosome. Only a few disorders have this
inheritance pattern, with a prime example being X-linked
hypophosphatemic rickets. Males and females are both
affected in these disorders, with males typically being more
severely affected than females. Some X-linked dominant
conditions, such as Rett syndrome, incontinentia
pigmenti type 2 and Aicardi syndrome, are usually fatal in
males either in utero or shortly after birth, and are
therefore predominantly seen in females. Exceptions to this
finding are extremely rare cases in which boys
with Klinefelter syndrome (47,XXY) also inherit an X-linked
dominant condition and exhibit symptoms more similar to
those of a female in terms of disease severity. The chance of
passing on an X-linked dominant disorder differs between
men and women. The sons of a man with an X-linked
dominant disorder will all be unaffected (since they receive
their father's Y chromosome), and his daughters will all
inherit the condition. A woman with an X-linked dominant
disorder has a 50% chance of having an affected fetus with
each pregnancy, although it should be noted that in cases
such as incontinentia pigmenti, only female offspring are
generally viable. In addition, although these conditions do
not alter fertility per se, individuals with Rett syndrome or
Aicardi syndrome rarely reproduce.

X-linked recessive
X-linked recessive conditions are also caused by mutations
in genes on the X chromosome. Males are more frequently
affected than females, and the chance of passing on the
disorder differs between men and women. The sons of a
man with an X-linked recessive disorder will not be
affected, and his daughters will carry one copy of the
mutated gene. A woman who is a carrier of an X-linked
recessive disorder (XRXr) has a 50% chance of having sons
who are affected and a 50% chance of having daughters
who carry one copy of the mutated gene and are therefore
carriers. X-linked recessive conditions include the serious
diseases hemophilia A, Duchenne muscular dystrophy,
and Lesch-Nyhan syndrome, as well as common and less
serious conditions such as male pattern baldness and red-
green color blindness. X-linked recessive conditions can
sometimes manifest in females due to skewed X-
inactivation or monosomy X (Turner syndrome).
Y-linked
Y-linked disorders are caused by mutations on the Y
chromosome. Because males inherit a Y chromosome from
their fathers, every son of an affected father will be
affected. Because females only inherit an X chromosome
from their fathers, and never a Y chromosome, female
offspring of affected fathers are never affected.
Since the Y chromosome is relatively small and contains
very few genes, relatively few Y-linked disorders
occur. Often, the symptoms include infertility, which may
be circumvented with the help of some fertility treatments.
Examples are male infertility.
Cystic fibrosis

Cystic fibrosis is a genetic disorder that affects the

respiratory and digestive systems.

People with cystic fibrosis inherit a defective gene on chromosome 7

called CFTR (cystic fibrosis transmembrane conductance regulator).
The protein produced by this gene normally helps salt (sodium chloride)
move in and out of cells. If the protein doesn't work correctly, that
movement is blocked and an abnormally thick sticky mucus is produced
on the outside of the cell. The cells most seriously affected by this are
the lung cells. This mucus clogs the airways in the lungs, and increases
the risk of infection by bacteria.

The thick mucus also blocks ducts in the pancreas, so digestive

enzymes can't get into the intestines. Without these enzymes, the
intestines cannot properly digest food. People who have the disorder
often do not get the nutrition they need to grow normally.
 Finally, cystic fibrosis affects the
sweat glands. Too much salt is lost through sweat, which can disrupt the
delicate balance of minerals in the body.

How do people get cystic fibrosis?

Cystic fibrosis is a recessive disorder, which means that both parents

must pass on the defective gene for any of their children to get the
disease. If a child inherits only one copy of the faulty gene, he or she will
be a carrier. Carriers don't actually have the disease, but they can pass
it on to their children.

What are the symptoms of cystic fibrosis?

Symptoms of cystic fibrosis can include: coughing or wheezing,

respiratory illnesses (such as pneumonia or bronchitis), weight loss,
salty-tasting skin, and greasy stools. Because the lungs are clogged and
repeatedly infected, lung cells don't last as long as they should.
Therefore, most cystic fibrosis patients only live to be slightly more than
thirty years old.

How do doctors diagnose cystic fibrosis?

People with cystic fibrosis have between 2 and 5 times the normal
amount of salt in their sweat. Thus, doctors can use a sweat test to
measure the amount of salt (sodium chloride) in a person's sweat.
Sweat is collected from the person's arm or leg and taken to a laboratory
to be analyzed.

In newborns, doctors can measure the amount of a protein called

trypsinogen in the blood. The level of this protein is higher than normal
in people with cystic fibrosis.
Finally, genetic tests can identify a faulty CFTR gene using a sample of
the patient's blood.

How is cystic fibrosis treated?

Although there is no cure for cystic fibrosis,

new treatments are helping people with the disease live longer than
before. Most treatments work by clearing mucus from the lungs and
preventing lung infections. The common treatments include:

Chest physical therapy, in which the patient is repeatedly clapped

on the back to free up mucus in the chest

Inhaled antibiotics to kill the bacteria that cause lung infections

Bronchodilators (also used by people with asthma) that help keep the
airways open

Pancreatic enzyme replacement therapy to allow proper food digestion

 Gene therapy (a treatment currently in clinical trials), in which the
healthy CFTR gene is inserted into the lung cells of a patient to correct
the defective gene.

Interesting facts about cystic fibrosis

More than 1,000 different mutations in the CFTR gene have been
identified in cystic fibrosis patients. The most common mutation
(observed in 70% of cystic fibrosis patients) is a three-base deletion in
the DNA sequence, causing an absence of a single amino acid in the
protein product.

About 2,500 babies are born with cystic fibrosis in the U.S. each year.

More than 10 million Americans carry the cystic fibrosis gene but don't
know it.
Sickle Cell Disease

Sickle cell disease is a disorder that affects the red

blood cells, which use a protein called hemoglobin to transport oxygen
from the lungs to the rest of the body. Normally, red blood cells are
round and flexible so they can travel freely through the narrow blood
vessels.

The hemoglobin molecule has two parts: an alpha and a beta. Patients
with sickle cell disease have a mutation in a gene on chromosome 11
that codes for the beta subunit of the hemoglobin protein. As a result,
hemoglobin molecules don't form properly, causing red blood cells to
be rigid and have a concave shape (like a sickle used to cut wheat).
These irregularly shaped cells get stuck in the blood vessels and are
unable to transport oxygen effectively, causing pain and damage to
the organs.

How do people get sickle cell disease?

 Sickle cell disease is inherited in
an autosomal recessive pattern.
This means that a child will not
inherit the disease unless both
parents pass down a defective
copy of the gene. People who
inherit one good copy of the
gene and one mutated copy are
carriers. They are clinically
normal, but can still pass the
defective gene to their children.

What are the symptoms of

sickle cell disease?

Sickle cell disease prevents

oxygen from reaching the
spleen, liver, kidneys, lungs,
heart, or other organs, causing a
lot of damage. Without oxygen,
the cells that make up these
organs will begin to die. For
example, the spleen is often
destroyed in these patients
resulting in some loss of immune function. As a result, these patients
often experience frequent infections.

The red blood cells of patients with sickle cell disease don't live as
long as healthy red blood cells. As a result, people with this disorder
often have low red blood cell counts (anemia), which is why this
disease is commonly referred to as sickle cell anemia.

When sickle-shaped red blood cells get stuck in blood vessels this can
cause episodes of pain called crises. Other symptoms include:
delayed growth, strokes, and jaundice (yellowish hue to the skin and
eyes because of liver damage).

Because of these complications, people with this disorder are likely to

have their life span reduced by about 30 years.
How do doctors diagnose sickle cell disease?

Most states routinely screen newborns for sickle cell disease with a
simple blood test.

If the disorder is not detected at birth, a blood sample can be used in a

test called hemoglobin electrophoresis. This test will determine
whether a person has sickle cell disease, or whether he or she is a
carrier of the faulty hemoglobin gene.

How is sickle cell disease treated?

Babies and young children with sickle cell disease must take a daily
dose of penicillin to prevent potentially deadly infections. Patients also
take folic acid, which helps build new red blood cells.

Doctors advise people with sickle cell disease to get plenty of rest,
drink lots of water, and avoid too much physical activity.

Blood transfusions that provide a patient with healthy red blood cells
are a common treatment.

People with more severe cases of the disease can be treated with a
bone marrow transplant. This procedure provides the patient with
healthy red blood cells from a donor, ideally from a sibling.

Interesting facts about sickle cell disease

Unlike normal red blood cells, which can live for 120 days, sickle-
shaped cells live only 10 to 20 days.

In the United States, the disease most commonly affects African-

Americans. About 1 out of every 500 African-American babies born in
the United States has sickle cell anemia.

Sickle cell disease is most common among people from Africa, India,
the Caribbean, the Middle East, and the Mediterranean. The high
prevalence of the defective gene in these regions may be due to the
fact that carriers of a mutation in the beta-subunit of hemoglobin are
more resistant to malaria. Malaria is a disease caused by a parasite
that is transmitted to a person when they are bitten by an infected
mosquito.
Multifactorial and polygenic (complex)
disorders
Genetic disorders may also be complex, multifactorial, or
polygenic, meaning they are likely associated with the
effects of multiple genes in combination with lifestyles and
environmental factors. Multifactorial disorders
include heart disease and diabetes. Although complex
disorders often cluster in families, they do not have a clear-
cut pattern of inheritance. This makes it difficult to
determine a person’s risk of inheriting or passing on these
disorders. Complex disorders are also difficult to study and
treat because the specific factors that cause most of these
disorders have not yet been identified.
On a pedigree, polygenic diseases do tend to "run in
families", but the inheritance does not fit simple patterns as
with Mendelian diseases. But this does not mean that the
genes cannot eventually be located and studied. There is
also a strong environmental component to many of them
(e.g., blood pressure).
 Alzheimer's disease

Alzheimer's is a disease that causes dementia, or loss of

brain function. It affects the parts of the brain that deal with memory,
thought, and language.

The brain of a person with Alzheimer's

contains abnormal clumps of cellular
debris and protein(plaques) and
collapsed microtubules (support
structures of the cell). Microtubule
disintegration is caused by a
malfunctioning protein called tau, which
normally stabalizes the microtubules. In
Alzheimer's patients, tau proteins
instead cluster together to form disabling
tangles. These plaques and tangles
damage the healthy cells around them.
The brain also produces smaller amounts of neurotransmitters
(acetylcholine, serotonin, and norepinephrine), chemicals that allow
nerve cells to talk to one another.
 The most common form of the disease,
which strikes after age 65, is linked to the apolipoprotein E (apoE) gene
on chromosome 19. Scientists don't know how apoE4 increases the risk
of developing Alzheimer's. They do know that everyone has apoE, which
comes in three forms. One of the forms (apoE4) increases a person's
risk of developing Alzheimer's. The other two forms seem to protect
against the disease. While people who inherit the apoE4 form of the
gene are at increased risk for the disease, they will not necessarily
develop it.

Mutations in genes found on chromosomes 1, 14, and 21 are linked to

rarer forms of the disease, which strike earlier in life.

How do people get Alzheimer's disease?

Scientists don't know exactly how people develop Alzheimer's, but they
believe it is caused by a combination of genes and environmental factors
(multifactorial disorder).

The early-onset forms of Alzheimer's are inherited in an autosomal

dominant pattern, which means that only one parent has to pass down a
defective copy of the gene for their child to develop the disorder.

What are the symptoms of Alzheimer's disease?

Because Alzheimer's destroys brain cells, people who have the disorder
slowly lose their ability to think clearly. At first, they may forget words or
names, or have trouble finding things. As the disorder worsens, they
may forget how to do simple tasks (such as walking to a friend's house
or brushing their hair). Some people with Alzheimer's also feel nervous
or sad.

How do doctors diagnose Alzheimer's disease?

There is no one test for Alzheimer's. Doctors use several different tests
to check a patient's memory, language skills, and problem solving
abilities. These tests don't diagnose Alzheimer's, but they can rule out
other disorders that have similar symptoms.

How is Alzheimer's disease treated?

There is no cure for Alzheimer's, but a few medicines can slow its
symptoms. A drug called Aricept increases the amount of the
neurotransmitter acetylcholine in the brain. A new medicine, Namenda,
protects brain cells from a chemical called glutamate, which can damage
nerve cells. Doctors may also give their Alzheimer's patients
antidepressants or anti-anxiety medicines to ease some of their
symptoms.

People with Alzheimer's often need a caregiver - someone to help

them get around and do the things they were once able to do
themselves.

Interesting facts about Alzheimer's disease

Alzheimer's was named after the German doctor, Alois Alzheimer, who
first named the disorder in 1906.

The older a person gets, the higher his or her risk of getting Alzheimer's.
Only about 1 or 2 people out of 100 have Alzheimer's at age 65;
whereas, one out of every five people has the disorder by age 80.

As many as 4 million Americans have Alzheimer's disease.

Hypothyroidism

The thyroid is the largest endocrine gland in the body. It sits just below
the larynx (voice box) and wraps around the trachea (windpipe). The
thyroid gland produces thyroid hormone, which helps the body grow and
develop. It also plays an important role in the body's metabolism (the
processes in the body that use energy, such as eating, breathing, and
regulating heat).

Hypothyroidism (or underactive thyroid) is a common condition in which

the thyroid gland produces too little thyroid hormone. About 1 in 5,000
babies is born with congenital hypothyroidism, in which the thyroid fails
to grow normally and cannot produce enough of its hormone. There is
no known cause for most cases of congenital hypothyroidism. But about
10 to 20 percent of the time, the condition is caused by an inherited
defect that alters the production of thyroid hormone.

The most common inherited form of hypothyroidism is a defect of the

TPO (thyroid peroxidase) gene on chromosome 2. This gene plays an
important role in thyroid hormone production.

How do people get hypothyroidism?

 Hypothyroidism may be caused by 1) an
autoimmune disease that attacks the thyroid gland, 2) surgery or
radiation to treat thyroid cancer and other conditions, or 3) rare and
random genetic events in which a mutation is acquired during early
development.

What are the symptoms of hypothyroidism?

In babies with the inherited form of hypothyroidism, the condition affects

growth and cognitive development. It may cause mental retardation,
delayed puberty, stunted growth, and ataxia (inability to coordinate
muscle movements).

In adults, hypothyroidism slows the body's metabolism, making the

patient feel mentally and physically sluggish. Symptoms may include
weakness, fatigue, muscle aches, mood swings, hair loss, memory loss,
or slow speech. A person's symptoms will depend upon how little thyroid
hormone they produce, and for how long they have had the disorder.

When the body is deprived of thyroid hormone, the pituitary gland works
overtime, producing extra thyroid-stimulating hormone (TSH). This glut
of TSH may enlarge the thyroid into a condition called a goiter.

How do doctors diagnose hypothyroidism?

Babies are normally screened for hypothyroidism 24 hours after birth. A

tiny sample of blood taken from the baby's heel is tested for low thyroid
hormone levels or high thyroid-stimulating hormone (TSH) levels.

How is hypothyroidism treated?

Hormone replacement therapy: people with hypothyroidism must take a

synthetic form of thyroid hormone every day to reduce their symptoms.

Interesting facts about hypothyroidism

One in 5,000 people has hypothyroidism.

Chromosome Abnormalities
A chromosome anomaly, abnormality or aberration reflects
an atypical number ofchromosomes or a structural
abnormality in one or more chromosomes.
A karyotype refers to a full set of chromosomes from an
individual which can be compared to a "normal" karyotype
for the species via genetic testing. A chromosome anomaly
may be detected or confirmed in this manner. Chromosome
anomalies usually occur when there is an error incell
division following meiosis or mitosis. There are many types
of chromosome anomalies. They can be organized into two
basic groups, numerical and structural anomalies.

Numerical disorders
This is called aneuploidy (an abnormal number of
chromosomes), and occurs when an individual is missing
either a chromosome from a pair (monosomy) or has more
than two chromosomes of a pair (trisomy, tetrasomy, etc.).
In humans an example of a condition caused by a numerical
anomaly is Down Syndrome, also known as Trisomy 21 (an
individual with Down Syndrome has three copies of
chromosome 21, rather than two). Trisomy has been
determined to be a function of maternal age.
An example of monosomy is Turner Syndrome, where the
individual is born with only one sex chromosome, an X.

Structural abnormalities
When the chromosome's structure is altered, this can take
several forms:
 Deletions: A portion of the chromosome is missing or
deleted. Known disorders in humans include Wolf-
Hirschhorn syndrome, which is caused by partial
deletion of the short arm of chromosome 4;
and Jacobsen syndrome, also called the terminal 11q
deletion disorder.
 Duplications: A portion of the chromosome is
duplicated, resulting in extra genetic material. Known
human disorders includeCharcot-Marie-Tooth disease
type 1A which may be caused by duplication of the
gene encoding peripheral myelin protein 22(PMP22) on
chromosome 17.
 Translocations: A portion of one chromosome is
transferred to another chromosome. There are two
main types of translocations:
 Reciprocal translocation: Segments from two
different chromosomes have been exchanged.
 Robertsonian translocation: An entire
chromosome has attached to another at the
 centromere - in humans these only occur with
chromosomes 13, 14, 15, 21 and 22.
 Inversions: A portion of the chromosome has broken
off, turned upside down and reattached, therefore the
genetic material is inverted.
 Insertions: A portion of one chromosome has been
deleted from its normal place and inserted into
another chromosome.
 Rings: A portion of a chromosome has broken off and
formed a circle or ring. This can happen with or
without loss of genetic material.
 Isochromosome: Formed by the mirror image copy of a
chromosome segment including the centromere.
Chromosome instability syndromes are a group of disorders
characterized by chromosomal instability and breakage.
They often lead to an increased tendency to develop certain
types of malignancies.

Inheritance
Most chromosome abnormalities occur as an accident in the
egg or sperm, and therefore the anomaly is present in every
cell of the body. Some anomalies, however, can happen
after conception, resulting in Mosaicism (where some cells
have the anomaly and some do not). Chromosome
anomalies can be inherited from a parent or be "de novo".
This is why chromosome studies are often performed on
parents when a child is found to have an anomaly. If the
parents do not possess the abnormality it was not
initially inherited; however it may be transmitted to
subsequent generations.
Williams Syndrome

Williams syndrome is a rare genetic disorder that

affects a child's growth, physical appearance, and
cognitive development. People who have
Williams syndrome are missing genetic material
from chromosome 7, including the gene elastin.
This gene's protein product gives blood vessels
the stretchiness and strength required to
withstand a lifetime of use. The elastin protein is
made only during embryonic development and
childhood, when blood vessels are formed.
Because they lack the elastin protein, people with Williams Syndrome
have disorders of the circulatory system and heart defects.

How do people get Williams syndrome?

A deletion is caused by a break in the DNA molecule that makes up a

chromosome. In most cases, the chromosome break occurs while the
sperm or egg cell (the male or female gamete) is developing. When this
gamete is fertilized, the child will develop Williams syndrome. The
parent, however, does not have the break in any other cells of the body
and does not have the syndrome. In fact, the break is usually such a
rare event that it is very unlikely to happen again if the parent has
another child.

It is possible for a child to inherit a broken chromosome from a parent

who also had the disorder. But this is rare because most people with
Williams syndrome do not have children.

What are the symptoms of Williams syndrome?

The most common symptoms of Williams syndrome are mental

retardation, heart defects, and unusual facial features (small upturned
nose, wide mouth, full lips, small chin, widely spaced teeth).
Other symptoms include: low birth weight, failure to gain weight
appropriately, kidney abnormalities, and low muscle tone.

People with this syndrome also exhibit characteristic behaviors, such as

hypersensitivity to loud noises and an overly outgoing personality.

How do doctors diagnose Williams syndrome?

Doctors can identify the syndrome by its distinctive physical

characteristics. They can confirm the diagnosis by using a special
technique called FISH (fluorescent in situ hybridization).

The chromosomal deletion that causes Williams Syndrome is so small

that it cannot be seen in a karyotype. The deletion can be observed,
however, with FISH. This technique allows DNA sequences to be
labeled with a fluorescent chemical (called a probe) that lights up when
exposed to ultraviolet (UV) light. The Williams Syndrome deletion can be
detected by labeling the elastin gene with a fluorescent probe. The gene
will light up under a UV light only if it is present; a lack of signal indicates
a deletion.

How is Williams syndrome treated?

There is no cure for Williams syndrome. Patients must be continually

monitored and treated for symptoms throughout their lives.

Interesting facts about Williams syndrome

One out of every 10,000 babies is born with Williams syndrome.

Williams syndrome is considered a microdeletion syndrome because the

deletion is too small to be observed microscopically (less than 5 million
bases of DNA are deleted).

When deletions occur during the formation of the egg and sperm, it is
caused by unequal recombination during meiosis. Recombination
normally occurs between pairs of chromosomes during meiosis while
they are lined up at the metaphase plate. If the pairs of chromosomes
don't line up correctly, or if the chromosome breaks aren't repaired
properly, the structure of the chromosome can be altered. Unequal
recombination occurs more often than usual at this location on
chromosome 7, causing Williams syndrome. This is likely due to some
highly repetitive DNA sequence that flanks the commonly deleted region.
Cri-du-Chat syndrome
The name of this syndrome is French for "cry of the cat," referring to the
distinctive cry of children with this disorder. The cry is caused by
abnormal larynx development, one of the many symptoms associated
with this disorder. It usually becomes less noticeable as the baby gets
older, making it difficult for doctors to diagnose cri-du-chat after age two.
Cri-du-chat is caused by a deletion (the length of which may vary) on the
short arm of chromosome 5. Multiple genes are missing as a result of
this deletion, and each may contribute to the symptoms of the disorder.
One of the deleted genes known to be involved is TERT (telomerase
reverse transcriptase). This gene is important during cell division
because it helps to keep the tips of chromosomes (telomeres) in tact.

How do people get Cri-du-Chat syndrome?

A deletion is caused by a break in the DNA

molecule that makes up a chromosome. In most cases, the chromosome
break occurs while the sperm or egg cell (the male or female gamete) is
developing. When this gamete is fertilized, the child will develop cri-du-
chat syndrome. The parent, however, does not have the break in any
other cells of the body and does not have the syndrome. In fact, the
break is usually such a rare event that it is very unlikely to happen again
if the parent has another child.

It is possible for a child to inherit a broken chromosome from a parent

who also had the disorder.

What are the symptoms of Cri-du-Chat syndrome?

 Babies with cri-du-chat are usually small at birth,
and may have respiratory problems. Often, the
larynx doesn't develop correctly, which causes the
signature cat-like cry.

People who have cri-du-chat have very distinctive

features. They may have a small head
(microcephaly), an unusually round face, a small
chin, widely set eyes, folds of skin over their eyes,
and a small bridge of the nose.

Several problems occur inside the body, as well. A

small number of children have heart defects, muscular or skeletal
problems, hearing or sight problems, or poor muscle tone. As they grow,
people with cri-du-chat usually have difficulty walking and talking
correctly. They may have behavior problems (such as hyperactivity or
aggression), and severe mental retardation. If no major organ defects or
other critical medical conditions exist, life expectancy is normal.

How do doctors diagnose cri-du-chat syndrome?

Doctors most often identify cri-du-chat by the infant's cat-like cry. Other
signs are microcephaly, poor muscle tone, and mental retardation.

It is also possible to test for cri-

du-chat (and other chromosomal
abnormalitites) while the baby is
still in its mother's womb. They
can either test a tiny sample of
tissue from outside the sac where
the baby develops (chorionic
villus sampling (CVS)), or they
can test a sample of the amniotic
fluid (amniocentesis).

How is cri-du-chat syndrome treated?

Although there is no real treatment for cri-du-chat syndrome, children

with the disorder can go through therapy to improve their language skills,
motor skills, and to help them develop as normally as possible.
Interesting facts about cri-du-chat syndrome

The geneticist Jerome Lejeune identified cri-du-chat syndrome in 1963.

He also discovered the genetic abnormality that causes Down
syndrome.

Cri-du-chat is one of the most common syndromes caused by a

chromosomal deletion. It affects between 1 in 20,000 and 1 in 50,000
babies.

In 80 percent of the cases, the chromosome carrying the deletion comes

from the father's sperm rather than the mother's egg.

When deletions occur during the formation of an egg or sperm, it is

caused by unequal recombination during meiosis. Recombination
normally occurs between pairs of chromosomes during meiosis while
they are lined up at the metaphase plate. If the pairs of chromosomes
don't line up correctly, or if the chromosome breaks aren't repaired
properly, the structure of the chromosome can be altered. When unequal
recombination occurs at this location on chromosome 5, it causes cri-du-
chat syndrome.
Mitochondrial Disorders
Mitochondrial diseases are a group of disorders caused by
dysfunctional mitochondria, the organelles that generate
energy for the cell. Mitochondria are found in every cell of
the human body except red blood cells. Mitochondria
convert the energy of food molecules into the ATP that
powers most cell functions.
Mitochondrial diseases are often caused by genetics or
mutations to the mitochondrial DNA that affect
mitochondria function. Mitochondrial diseases take on
unique characteristics both because of the way the diseases
are often inherited and because mitochondria are so critical
to cell function. The subclass of these diseases that have
neuromuscular disease symptoms are often called
a mitochondrial myopathy.

Classification
In addition to the mitochondrial myopathies, other
examples include:
 Diabetes mellitus and deafness (DAD)
 this combination at an early age can be due to
mitochondrial disease
  Diabetes mellitus and deafness can also be found
together for other reasons
 Leber's hereditary optic neuropathy (LHON)
 visual loss beginning in young adulthood
 eye disorder characterized by progressive loss of
central vision due to degeneration of the optic
nerves and retina
 Wolff-Parkinson-White syndrome
 multiple sclerosis-type disease
 affects 1 in 50,000 people in Finland
 Leigh syndrome, subacute sclerosing encephalopathy
 after normal development the disease usually
begins late in the first year of life, although onset
may occur in adulthood
 a rapid decline in function occurs and is marked by
seizures, altered states of consciousness,
dementia, ventilatory failure
 Neuropathy, ataxia, retinitis pigmentosa, and
ptosis (NARP)
 progressive symptoms as described in the
acronym
 dementia
 Myoneurogenic gastrointestinal
encephalopathy (MNGIE)
 gastrointestinal pseudo-obstruction
 neuropathy
 Myoclonic Epilepsy with Ragged Red Fibers (MERRF)
 progressive myoclonic epilepsy
 "Ragged Red Fibers" – clumps of diseased
mitochondria accumulate in the
subsarcolemmal region of the muscle fiber and
appear as "Ragged Red Fibers" when muscle is
stained with modified Gömöri trichrome stain
 short stature
 hearing loss
 lactic acidosis
 exercise intolerance
 Mitochondrial myopathy, encephalomyopathy, lactic
acidosis, stroke-like symptoms (MELAS)
 mtDNA depletion
 mitochondrial neurogastrointestinal
encephalomyopathy (MNGIE)
Treatment of Genetic Disorders

Most genetic disorders, unfortunately,

cannot be cured. The available
treatments help manage the diseases
caused by abnormal genes, while the
treatment itself and its efficacy vary
from one type of disorder to another.
Genetic researchers, however, are very
optimistic about gene therapy which has shown promising
results in clinical trials. However, it remains unavailable to
the wider population and at the moment of writing, gene
therapy is used only for clinical trials.
Gene therapy is hoped to cure or improve treatment of
genetic disorders by replacing the mutated or
malfunctioned gene, manipulating or turning off the gene
causing the disease or stimulate other bodily functions to
fight the disease. The most common method is replacement
of a malfunctioned or sometimes a missed gene with a
healthy one. However, gene therapy poses a risk of
potentially serious complications, in the first place due to
the method that is used to insert the “new“ genes – the use
of viruses. These have the ability to identify certain cells as
well as to transmit the genetic material into the cells
containing malfunctioned or missed gene. For that reason
modified viruses are used as vectors or carriers of the
healthy genes. This method of insertion of healthy genes
may not seem problematic at a first glance but it can cause
cause potentially serious complications as already
mentioned earlier.

The inserted virus can be

perceived as a foreign invader by
the immune system. As a result,
the immune system triggers a
release of antibodies to destroy the virus similar when
catching a flu for instance. However, the reaction of the
immune system could be more severe to the genetically
modified virus than the one causing flu and can even lead to
organ failure. In addition to the immune system factor, the
use of viruses as vectors poses a risk of viral spread in the
body resulting in development of other diseases including
cancer, transformation of the inserted virus into its original
disease-causing form and genetic changes in the
reproductive cells which can be passed to offspring if having
children after gene therapy. Due to the mentioned potential
side effects and inadequate proof for efficacy of gene
therapy it may take some time before it will become
available to patients.
As already mentioned earlier, the available treatments for
most genetic disorders provide only relief from the
symptoms of the disease and delay its progress. Genetic
testing, on the other hand, is used to evaluate the risk of an
individual for diseases related to genetic factors and
prenatal diagnostic testing for genetic disorders. Individuals
who are at high risk of developing a potentially serious
disease due to the presence of certain genes are sometimes
able to prevent it from occurring with early preventive
measures which may be sometimes very radical. For
example, women who have the so-called autosomal
dominant genetic disorder are sometimes recommended
total mastectomy (surgical removal of both breast) to
prevent breast cancer. Prenatal diagnostic testing, on the
other hand, shows if the foetus has a potentially serious
genetic disorder in order to enable the parents to decide
whether they want to continue or end the pregnancy.
Gene therapy

Gene therapy using an Adenovirus vector. A new gene is

inserted into a cell using an adenovirus. If the treatment is
successful, the new gene will make functional protein to
treat a disease.
Gene therapy is the use of DNA as a pharmaceutical agent
to treat disease. It derives its name from the idea that DNA
can be used to supplement or altergenes within an
individual's cells as a therapy to treat disease. The most
common form of gene therapy involves using DNA that
encodes a functional, therapeutic gene in order to replace
a mutated gene. Other forms involve directly correcting a
mutation, or using DNA that encodes a therapeutic protein
drug (rather than a natural human gene) to provide
treatment. In gene therapy, DNA that encodes a therapeutic
protein is packaged within a "vector", which is used to get
the DNA inside cells within the body. Once inside, the DNA
becomes expressed by the cell machinery, resulting in the
production of therapeutic protein, which in turn treats the
patient's disease.
Gene therapy was first conceptualized in 1972, with the
authors urging caution before commencing gene therapy
studies in humans. The first FDA-approved gene therapy
experiment in the United States occurred in 1990, when
Ashanti DeSilva was treated for ADA-SCID. Since then, over
1,700 clinical trials have been conducted using a number of
techniques for gene therapy.
Although early clinical failures led many to dismiss gene
therapy as over-hyped, clinical successes in 2006-2011 have
bolstered new optimism in the promise of gene therapy.
These include successful treatment of patients with the
retinal disease Leber's congenital amaurosis, X-linked
SCID, ADA-SCID, adrenoleukodystrophy, chronic
myelogenous leukemia (CML),and Parkinson's
disease. These recent clinical successes have led to a
renewed interest in gene therapy, with several articles in
scientific and popular publications calling for continued
investment in the field.
Types of gene therapy
Gene therapy may be classified into the two following
types:

Somatic gene therapy

In somatic gene therapy, the therapeutic genes are
transferred into the somatic cells, or body, of a patient. Any
modifications and effects will be restricted to the individual
patient only, and will not be inherited by the patient's
offspring or later generations. Somatic gene therapy
represents the mainstream line of current basic and clinical
research, where the therapeutic DNA transgene (either
integrated in the genome or as an external episome or
plasmid) is used to treat a disease in an individual.
Germ line gene therapy
In germ line gene therapy, Germ cells, i.e., sperm or eggs,
are modified by the introduction of functional genes, which
are integrated into their genomes. This would allow the
therapy to be heritable and passed on to later generations.
Although this should, in theory, be highly effective in
counteracting genetic disorders and hereditary diseases,
many jurisdictions prohibit this for application in human
beings, at least for the present, for a variety of technical and
ethical reasons.
RNAi
RNA interference (RNAi) is a biological process in
which RNAmolecules inhibit gene expression, typically by
causing the destruction of specific mRNA molecules.
Historically, it was known by other names, including co-
suppression, post transcriptional gene silencing (PTGS),
andquelling. Only after these apparently unrelated
processes were fully understood did it become clear that
they all described the RNAi phenomenon. In 2006, Andrew
Fire and Craig C. Mello shared the Nobel Prize in Physiology
or Medicine for their work on RNA interference in the
nematode worm C. elegans, which they published in 1998.
Two types of small ribonucleic acid (RNA) molecules –
microRNA(miRNA) and small interfering RNA (siRNA) – are
central to RNA interference. RNAs are the direct products of
genes, and these small RNAs can bind to other
specific messenger RNA (mRNA) molecules and either
increase or decrease their activity, for example by
preventing an mRNA from producing a protein. RNA
interference has an important role in defending cells against
parasitic nucleotide sequences – viruses andtransposons –
but also in directing development as well as gene
expression in general.
The RNAi pathway is found in many eukaryotes including
animals and is initiated by the enzyme Dicer, which cleaves
long double-stranded RNA(dsRNA) molecules into short
double stranded fragments of ~20nucleotides that are
called siRNAs. Each siRNA is unwound into two single-
stranded (ss) ssRNAs, namely the passenger strand and the
guide strand. The passenger strand is degraded, and the
guide strand is incorporated into the RNA-induced silencing
complex (RISC). The most well-studied outcome is post-
transcriptional gene silencing, which occurs when the guide
strand base pairs with a complementary sequence in a
messenger RNA molecule and induces cleavage
by Argonaute, the catalytic component of the RISC complex.
In some organisms, this process is known to spread
systemically, despite the initially limited molar
concentrations of siRNA.
RNAi has become a valuable research tool, both in cell
culture and in living organisms, because synthetic dsRNA
introduced into cells can selectively and robustly induce
suppression of specific genes of interest. RNAi may be used
for large-scale screens that systematically shut down each
gene in the cell, which can help identify the components
necessary for a particular cellular process or an event such
as cell division. The pathway is also used as a practical tool
in biotechnology and medicine.
Macular Degeneration
The first RNAi therapy to reach patients in clinical trials is a
treatment that aims at a debilitating eye disease called
macular degeneration. Biotech firms had focused on the
disease for many reasons: Most critically, RNAi drugs can be
delivered directly to the diseased tissue—literally injected
into the eye. This direct delivery helps ensure that "naked"
RNAi drugs—short strands of RNA that aren't packaged and
protected in membranes and which quickly break down in
the bloodstream—can reach their target intact. Local
delivery also makes it less likely that the drugs will have
unanticipated, harmful effects elsewhere in the body.
What's more, the disease is triggered by a well-known
culprit—a protein called VEGF that promotes blood vessel
growth. In patients with macular degeneration, too much of
this protein leads to the sprouting of excess blood vessels
behind the retina. The blood vessels leak, clouding and
often entirely destroying vision. The new RNAi drugs shut
down genes that produce VEGF.
The first clinical trial, involving about two dozen patients,
launched in the fall of 2004. While intended primarily to
assess safety issues, this ongoing trial shows promising
results. Two months after being injected with the drug, a
quarter of the patients had significantly clearer vision, and
the other patients' vision had at least stabilized. If
subsequent trials prove they are effective, RNAi drugs for
this condition could hit the market by 2009.
To test their RNAi treatment,
Stanford researchers used mice
infected with a specially crafted,
"glowing" version of a hepatitis C
gene (left). The treatment effectively
turned off the glowing gene (right).
HEPATITIS C
The RNA interference system that cells naturally possess
likely evolved millions of years ago, as organisms survived
the onslaught of dangerous invading viruses. So it makes
sense that researchers are now trying to harness the cell's
RNAi machinery to fight a wide range of viruses. One of the
most noteworthy is hepatitis C, which infects roughly 200
million people worldwide and causes an often fatal disease
of the liver.
In 2002, geneticists Anton McCaffrey and Mark Kay at
Stanford University announced that their RNAi treatment
had controlled the virus in laboratory mice. It was the first
time an RNAi approach had worked not just in lab cell
cultures but in living animals. In their initial experiments,
the researchers injected "naked" RNA strands into the tail
veins of mice using a high-pressure, rapid-transfusion
method to ensure that the RNA strands were taken up in
the liver.
But the delivery method McCaffrey and Kay used, which
doubled the mice's blood volume within eight seconds, isn't
feasible for humans. And even if it were, the effects of
naked RNA are likely to wear off in a matter of days. So
these researchers are exploring ways to use viral vectors—
viruses stripped of their harmful genes—to ferry RNA-
making molecules into liver cells. It's a technique that has
been refined over a decade of gene therapy research and, if
successful, would provide long-term protection.

A brain devastated by
Huntington's disease, a genetic
disorder for which there is now
no effective treatment or cure .
To defeat hereditary diseases like
Huntington's, doctors ideally want to shut down the
operation of a harmful gene over the lifetime of an
individual. It's another case where, rather than repeatedly
administer "naked" RNAi drugs, researchers hope to employ
safe, stripped-down viruses to transport RNA-making
molecules to target cells. Once embedded in the cell's
machinery, these RNA-making molecules could continuously
silence the troublesome gene.
In 2004, Beverly Davidson and colleagues at the University
of Iowa used this technique to treat mice with
spinocerebellar ataxia, a neurological disorder akin to
Huntington's. It was a landmark—the first time that an
actively troublesome gene was put out of commission in
such a way. Soon after, Davidson treated mice with
Huntington's, a disease that affects more than 30,000
people in the U.S. alone.
But in the Huntington's experiments, there was a critical
catch: in addition to silencing the harmful gene, the
treatment also shut down the healthy version of the
Huntington's gene. (Patients carry both.) While Davidson
and other researchers are optimistic that they can tweak
the design of RNAi drugs to overcome this obstacle, such
"off-target" affects could hinder many RNAi therapies.
As with the best current HIV
drug regimes, new RNAi
therapies must attack the virus
on multiple fronts at once to
counter the problem of drug
resistance.
HIV
Almost as soon as RNA interference was discovered in
human cells, scientists began exploring how it could be
recruited to battle HIV. By late 2002, Phillip Sharp and
colleagues at MIT announced they could interrupt various
steps in the HIV life cycle with RNAi molecules. But these
and other experiments were largely "proof-of-principle"
studies, stopping the virus in cell cultures, not human
patients.
HIV mutates and evolves resistance so rapidly that any
single target for an RNAi therapy won't be sufficient.
Molecular biologist John Rossi of City of Hope Medical
Center and colleagues at Colorado State University have
engineered an RNAi therapy aiming at multiple HIV genes.
And to build up the multipronged attack even more, Rossi
combines this RNAi therapy with two other RNA
technologies (called ribozymes and RNA decoys) to block
HIV's replication and invasion of the immune system.
Rossi's group is tackling the critical issue of drug delivery in
yet another way. If it works, doctors might one day extract
stem cells from a patient's bone marrow, genetically alter
these cells with the RNA therapy, then transfuse them back
into the patient, where they would develop into healthy
immune-system cells safeguarded against HIV. Rossi has
established the therapy with mice and rhesus monkeys, and
hopes to move into clinical trials in 2006.

A child's lungs, infected with

RSV. The virus prompts as
many as 125,000 pediatric
hospitalizations in the U.S.
each year.
RESPIRATORY INFECTIONS
For biotech firms aiming to bring RNAi therapies to market
quickly, diseases of the lung, like those of the eye, are prime
candidates. It's relatively simple to deliver RNAi drugs
directly to the respiratory system—patients can inhale
them. One day, we may breathe in RNAi drugs for a host of
different viruses, including SARS and influenza. The first
virus to be defeated in this way, though, will likely be
respiratory syncytial virus, or RSV.
RSV, while not commonly known by name, infects almost
every child in the U.S. by the age of two. Infection typically
leads just to cold-like symptoms, but it can have far graver
consequences, including croup, pneumonia, and respiratory
failure. RSV also endangers the elderly and people with
weak immune systems.
By early 2005, biochemist Sailen Barik at the University of
South Alabama had engineered RNAi molecules to shut
down various RSV genes. Like the treatment for macular
degeneration, these molecules were short strands of
"naked" RNA that would rapidly break down in the
bloodstream. When inhaled by mice, though, the short RNA
strands reached their targets intact and controlled the virus.
Clinical trials for RSV are slated to begin in the first half of
2006.
 Because diseased cells of the
blood system are relatively
accessible, leukemia may be
among the first forms of cancer
treated with RNAi drugs.
CANCER
Cancer often involves mutant genes that promote
uncontrolled cell growth. In the last few years, researchers
have silenced more than a dozen known cancer-causing
genes with RNAi. Yet, once again, most of this success has
been with cell cultures in the lab, and delivery poses the key
hurdle in moving from the lab to the bedside of patients.
Researchers are just beginning, for instance, to sort through
how RNAi therapies might reach and penetrate tumors.
Rather than take a leading role, some RNAi therapies may
help defeat cancers by supporting chemotherapy. Drug
resistance is a major problem in chemotherapy, thwarting
between 20 and 50 percent of all current treatments. In
many of these failures, the guilty agent is a protein called P-
glycoprotein. Like a misguided housekeeper, this protein
sweeps drugs out of diseased cells. In 2004, a team of
scientists at Imperial College London showed that RNAi can
stop production of the protein in multidrug-resistant
leukemia cells, restoring their sensitivity to existing drugs.
RNAi also provides a powerful new way for scientists to
discover and learn more about genes that trigger or inhibit
cancer. Greg Hannon and his group at Cold Spring Harbor
Laboratory are part of an effort to decipher the function of
15,000 genes in a variety of human cancer cell lines. Such
efforts might pinpoint genes never before linked to
cancer and generate novel ideas for treatments.
Challenges for the Future of Genetic Medicine
The future of genetic medicine will be marked by social,
ethical, and legal challenges, especially for the disability
community. Some of the most important challenges include
the diagnosis/therapy gap, confidentiality, and prenatal
screening--each of which is briefly addressed below.

The Diagnosis/Therapy Gap

While the ability to diagnose genetic conditions continues
to grow almost exponentially, there remains a profound
time gap between the capacity to diagnose and the capacity
to treat. Sadly, to date there are very few effective
therapies for genetically linked conditions. It is likely that
for some time there will be many more genetic diseases
diagnosed than can be treated.

This phenomenon has resulted in the emergence of a new

class of patient: the presymptomatic ill. These are persons
who have been diagnosed with a genetic disease for which
there is no treatment. In many cases they may not show
symptoms of the disease for a number of years, sometimes
never. Yet they carry the knowledge that they have a
genetic condition that may one day lead to their disability
or death.

No one knows what the psychological and social

implications of the diagnostic/therapy gap will be. What
might it be like for a young girl to know at eight years of age
that she has the gene for Huntington's, a disease whose
debilitating symptoms do not appear until about 40-50
years of age? How will that knowledge affect her life's
choices? More importantly, how will that knowledge affect
the choices of her parents as they nurture her? Will they be
over-protective and smothering? Will they discourage long-
term life planning?

Genetic knowledge indeed carries the power to shape lives

for good or ill. The challenge of genetic knowledge is
knowing what to do with that information. For instance,
women diagnosed with one of the breast cancer genes,
BRCA-1 or BRCA-2, sometimes undergo prophylactic
mastectomy because of their fear of getting cancer. In some
cases, though, these patients were either misdiagnosed or
they misunderstood the meaning of the tests. Tragically,
this results in unnecessary physical and psychological
trauma associated with mastectomy. On the other hand,
many women have doubtless dodged breast cancer by
having the procedure. How do we balance the benefits and
harms of genetic knowledge? This is a question with which
we are only beginning to grapple.

Confidentiality
Information about one's possible disease conditions is
highly personal information. Individuals may or may not
want to know that information. Clearly there are others
who might wish to have your personal genetic information--
namely, your employer and your insurance company. After
all, they, too, stand to gain or lose if you become ill.

In 1982, only 1.6% of companies reported that they were

using genetic tests for employment purposes. By 1997, the
American Management Association found that the number
had grown to about 10% of companies. Increasing numbers
of persons are reporting genetic discrimination in the
workplace. They may be denied employment or promotions
based on their genetic information. At the same time, only
about 21 states have enacted laws to prevent workplace
genetic discrimination, and only 42 states have even
minimal protections against insurance discrimination based
on genetic conditions.
Poll after poll shows that overwhelming numbers of
Americans want genetic privacy protected. Yet, there is no
national comprehensive genetic privacy/anti-discrimination
legislation.

What will the future hold for those with genetic conditions?
Will they be able to get jobs? Will they be able to secure
insurance? We should all contact our elected officials to let
them know our concerns about our national genetic future.
Prenatal Screening
Another example of the power of genetic knowledge is its
link to prenatal (before birth) genetic screening. Prenatal
screening may be performed either before implantation
or in utero. In pre-implantation screening, embryos who
have been created in the laboratory are tested for certain
genetic conditions and are either implanted or destroyed
depending on the results and wishes of the prospective
parents. In post-implantation screening, unborn children
are tested in the womb to see if they are carrying
deleterious genes, and then a decision is made either to
carry them to term or abort them. Some parents who are
morally opposed to embryo selection or abortion may
refuse prenatal genetic testing, since they intend to bring a
child to term regardless of genetic condition. Others may
find the information important as they prepare for a child
who may have disabilities.

For a Truly Human Future

Most people in the disability community already know that
"disease" and "illness" are not value-free labels. Disabilities
(like abilities) are largely social constructs rather than clear-
cut categories. Unfortunately, many healthy persons and
many in the scientific community seem unaware that this is
the case. Discrimination against persons because of their
race, gender, or disability is an ugly reality. Discrimination
based on genetic identity is uglier still. If we are to attain a
truly human future for ourselves and for our children, we
must value individuals for who they are--not for what they
can do. As imagers of God, every person should receive
respect and be treated with dignity, regardless of their
genetic condition.

To be sure, the genetic revolution will lead to great

advances in the relief of human suffering and the treatment
of human diseases. We may even witness the emergence of
genetic cures. Our laudable goal of treating human disease
and relieving human suffering must not be allowed to
become a tool for eliminating the persons who are
suffering. To do so would be to use the good gift of genetic
knowledge for evil ends. Only vigilance on the part of us all
can prevent a bleak genetic future from unfolding. Contrary
to what many people may believe, the social, ethical, and
legal implications of the new genetics are not merely the
domain of the scientist, philosopher, theologian, or lawyer.
We all have a stake in our genetic future.