The Gale Genetic Disorders of encyclopedia vol 1 - part 9 ppt

HSP is “complicated” if other complex problems are
present such as seizures, dementia, loss of muscle mass,
mental delays, dry and thick skin (ichthyosis), vision
problems or loss, and ataxia.
Problems with gait may progress over years or
decades in uncomplicated HSP. This finding may begin at
any age, from early childhood through late adulthood.
The problems are usually limited to the lower extremities
(legs and feet). Occasionally, urinary bladder distur-
bances may develop over time. People with complicated
HSP have other associated health problems including
mental delays and dementia.
Alternate names for HSP include hereditary spastic
paraparesis, familial spastic paraplegia, familial spastic
paralysis, and Stumpell-Lorrain syndrome.
Genetic profile
HSP is a genetically diverse group of disorders. It
can be inherited in autosomal dominant or autosomal
recessive manners; these are further divided into uncom-
plicated and complicated groups. An X-linked recessive
form also exists for complicated HSP. The genes for HSP
are designated “spastic gait” (SPG) genes, and are num-
bered 1–13 in order of their discovery. Determination of
the exact type of HSP in a family is usually done by a
detailed family history, rather than genetic testing.
In autosomal recessive HSP, individuals may be car-
riers, meaning that they carry a copy of an altered gene.
However, carriers often do not usually have symptoms of
HSP. Those affected with autosomal recessive HSP have
two copies of an altered gene, having inherited one copy
from their mother, and the other from their father. Thus,

only two carrier parents can have an affected child. For
each pregnancy that two carriers have together, there is a
25% chance for them to have an affected child, regardless
of the child’s gender. In families with autosomal reces-
sive HSP, one would not expect to find other affected
family members in past generations.
Autosomal recessive uncomplicated HSP is thought
to represent about 25% of inherited spastic paraplegia.
The SPG5 gene (found on chromosome 8 at 8p11–8q13)
and SPG11 gene (on the long arm of chromosome 15 at
15q13–q15) appear to be responsible for this group of
HSP. Autosomal recessive complicated HSP has been
associated with alterations in the SPG7 gene (on the long
arm of chromosome 16 at 16q24.3). Additionally, a gene
named the paraplegin gene has been identified at the
SPG7 locus. Although its function is not well understood,
alterations in this gene appear to be responsible for auto-
somal recessive complicated HSP.
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
547
Hereditary spastic paraplegia
In autosomal dominant HSP, an affected individual
has one copy of a genetic alteration that causes HSP. The
individual has a 50% chance to pass the alteration on to
each of his or her children, regardless of that child’s gen-
der. There are often other affected family members in
prior generations, and often a parent is affected.
As of 2000, seven genes have been attributed to
autosomal dominant uncomplicated HSP. The uncompli-
cated form comprises about 80% of families with autoso-

mal dominant HSP. They are: SPG3 (found on the long
arm of chromosome 14 at 14q11–q21), SPG4 or spastin
(short arm of chromosome 2 at 2p22), SPG6 (long arm of
chromosome 15 at 15q11.1), SPG8 (long arm of chro-
mosome 8 at 8q23–q24), SPG10 (long arm of chromo-
some 12 at 12q13), SPG12 (long arm of chromosome 12
at 19q13), and SPG13 (long arm of chromosome 2 at
2q24–q34). Of this group, about 45% of families have
SPG4 or spastin alterations.
Autosomal dominant complicated HSP has been
attributed to alterations in the SPG9 gene (on the long
arm of chromosome 10 at 10q23.3–q24.2).
In X-linked recessive HSP, only males are affected
with the condition, because the genetic alterations are
found on the X-chromosome. Males have only one X-
chromosome, and females have two. Males with an X-
linked condition have the genetic alteration on their
single X-chromosome, and they develop symptoms of the
condition. Females are carriers, and typically do not have
symptoms. However, when carrier females have sons,
they have a 50% chance of having an affected son. In
families with X-linked HSP, males are affected and it is
passed through women in the family.
X-linked forms of HSP are complicated HSP. The
SPG1 gene on the long arm of chromosome X at Xq28
(also known as the L1 cell adhesion molecule) and SPG2
gene on Xq28 (also known as the proteolipid protein)
have been associated with this form of HSP. Specifically,
proteolipid protein alterations cause a condition known
as Pelizaeus-Merzbacher disease.

Demographics
HSP is relatively rare; through 1996 more than
eighty unrelated families had been studied throughout the
world. Hereditary spastic paraplegia appears to affect
individuals and various age groups around the world.
With the exception of X-linked recessive HSP, it affects
men and women equally.
Signs and symptoms
The symptoms of uncomplicated HSP may appear at
any age. It may progress very slowly, without any obvi-
ous changes to bring symptoms to medical attention, pos-
sibly appearing as general “clumsiness.” Individuals with
uncomplicated HSP often have no problems with
strength in their upper extremities and no problems with
speech, chewing, or swallowing. They may notice their
leg muscles becoming very stiff, and may stumble when
climbing stairs or crossing curbs. These symptoms can
progress and worsen with time.
Each family with HSP is unique, with varying symp-
toms. Additionally, affected individuals within the same
family may have varying presentations of the disease. In
1999, a family was reported in which individuals in suc-
cessive generations had increasingly severe symptoms of
pure HSP, a phenomenon known as “genetic anticipa-
tion.” People with pure HSP may experience difficulty
walking and often eventually require canes, walkers, or
wheelchairs. As a later symptom, people may experience
an urgency to urinate, or may have problems with urinary
control. Generally, the lower extremities experience
increased reflexes, and may become stiff.

Individuals with complicated HSP still have spastic
paraplegia of the lower extremities as a common finding,
but may also experience other associated health prob-
lems. These may include seizures, mental delays, vision
loss, and loss of muscle mass. Cataracts, gastric reflux,
abnormal eye movements, severe general muscle weak-
ness, and ataxia can also be present.
For some forms of complicated HSP, specific syn-
dromes have been identified. Silver syndrome is an auto-
somal dominant condition involving progressive spastic
paraplegia and loss of muscle mass, particularly in the
hands. Pelizaeus-Merzbacher disease is an X-linked
recessive form of complicated HSP. It usually develops in
infancy or early childhood with abnormal eye move-
ments, severe muscle weakness, feeding problems, and
developmental delays. These findings can progress to
include severe muscle spasticity and ataxia.
Diagnosis
HSP has classically been diagnosed by a careful
physical examination, as well as obtaining a detailed per-
sonal and family medical history. Other similar disorders
often need to be ruled out before considering HSP.
Uncomplicated HSP is diagnosed by four clinical criteria:
• Clinical symptoms: Progressive spastic muscle weak-
ness of both lower extremities, often with urinary
urgency or lower extremity paresthesia.
• Neurologic examination: Increased muscle tone/
reflexes at the hamstrings, quadriceps, and ankles; mus-
cle weakness at hamstrings and lower limbs; decreased
ability to sense vibrations in the lower limbs; abnormal

gait with an uneven drop of the foot. (Mental delays or
dementia are not expected in pure HSP.)
• Family history: Similar to an autosomal dominant pat-
tern (several affected family members in different gen-
erations), autosomal recessive pattern (siblings may be
affected but little or no history of affected family mem-
bers in prior generations), or X-linked recessive pattern
(primarily affected males who are related to each other
through their mothers).
• Exclusion of other conditions.
548
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
Hereditary spastic paraplegia
KEY TERMS
Amniocentesis—A procedure performed at 16-18
weeks of pregnancy in which a needle is inserted
through a woman’s abdomen into her uterus to
draw out a small sample of the amniotic fluid from
around the baby. Either the fluid itself or cells from
the fluid can be used for a variety of tests to obtain
information about genetic disorders and other
medical conditions in the fetus.
Ataxia—A deficiency of muscular coordination,
especially when voluntary movements are
attempted, such as grasping or walking.
Chorionic villus sampling (CVS)—A procedure
used for prenatal diagnosis at 10-12 weeks gesta-
tion. Under ultrasound guidance a needle is
inserted either through the mother’s vagina or
abdominal wall and a sample of cells is collected

from around the fetus. These cells are then tested
for chromosome abnormalities or other genetic
diseases.
Dementia—A condition of deteriorated mental
ability characterized by a marked decline of intel-
lect and often by emotional apathy.
Gait—A manner of walking.
Magnetic resonance imaging (MRI)—A technique
that employs magnetic fields and radio waves to
create detailed images of internal body structures
and organs, including the brain.
Paraplegia—Loss of voluntary movement and sen-
sation of both lower extremities.
Paresthesia—An abnormal sensation resembling
burning, pricking, tickling, or tingling.
Spasticity—Increased mucle tone, or stiffness,
which leads to uncontrolled, awkward move-
ments.
Magnetic resonance imaging (MRI) of the brain and
spinal cord are usually normal in people with uncompli-
cated HSP. It is a difficult task to eliminate other neuro-
logic disorders with symptoms similar to HSP, such as
structural abnormalities of the brain or spinal cord.
Multiple sclerosis often includes gait incoordination, but
it does not always progress or worsen with time. Some
other genetic conditions involving muscle weakness
include various forms of leukodystrophy; however, these
neurological problems may progress rapidly, and may
even result in death. Some infectious diseases may in
some ways mimic HSP, such as AIDS or syphilis.

Genetic testing for some forms of both pure and
complicated HSP is available on a research basis. In these
cases, testing is usually performed on a blood sample,
and the genes are analyzed. Because the testing is con-
sidered experimental research, testing may be cost-free
but results may not always be available to the family.
For Pelizaeus-Merzbacher disease, genetic testing is
available on a clinical basis at a limited number of labo-
ratories, and families receive their results. In this case,
results would be considered abnormal if alterations in the
proteolipid gene were identified. Because Pelizaeus-
Merzbacher disease is an X-linked recessive disorder,
any male with the alteration would always have carrier
daughters and unaffected sons. The affected person’s
mother would then be a carrier, and risks to her family
members could be predicted by the same form of testing.
An exception to this would be in the case of some moth-
ers of boys with PLP mutations who are not carriers
because their sons have new mutations.
Prenatal testing for Pelizaeus-Merzbacher disease
can be performed on DNA extracted from fetal cells
obtained through amniocentesis or chorionic villus sam-
pling (CVS).
Treatment and management
There is no specific treatment to prevent, slow, or
reverse the progressive symptoms in HSP. Some treat-
ment approaches for other patients with paraplegia have
been useful. This includes oral and muscle injections of a
medication known as Baclofen, which can be used in
early stages of muscle weakness. A medication known as

Oxybutynin has been helpful for the urinary distur-
bances. Physical therapy and exercise are considered
important elements in maintaining muscle strength and
range of motion. However, it is still unclear whether
physical therapy promotes muscle improvement or
reduces the rate of muscle weakness and decline.
Prognosis
Complicated HSP may be associated with a short-
ened lifespan, because involvement of other health prob-
lems can worsen an individual’s prognosis. For example,
in Pelizaeus-Merzbacher disease, lifespan is shortened
because the associated severe muscle weakness and feed-
ing problems for a young child may lead to early death.
Though it is usually very physically disabling, uncompli-
cated or pure HSP does not typically shorten lifespan.
Resources
PERIODICALS
Fink, J.K., et al. “Hereditary Spastic Paraplegia: Advances in
Genetic Research.” Neurology 46 (1996): 1507–14.
ORGANIZATIONS
HSPinfo.org. 2107 Worchester Drive, Salt Lake City, UT
84121. Phone: (801) 944-6295. Fax: (801) 328-7348.
ϽϾ.
National Ataxia Foundation. 2600 Fernbrook Lane, Suite 119,
Minneapolis, MN 55447. Phone: (763) 553-0020. Fax:
(763) 553-0167. ϽϾ.
National Organization for Rare Disorders (NORD). PO Box
8923, New Fairfield, CT 06812-8923. (800) 999-6673 or
(203) 746-6518. Fax: (203) 746-6481. Ͻhttp://www
.rarediseases.orgϾ.

WEBSITES
The Familial Spastic Paraplegia Support Group (England).
Ͻ />Fink, John K. “Hereditary Spastic Paraplegia Overview.”
GeneClinics. Ͻ />details.htmlϾ. (August 11, 2000).
HealthLINK.
Ͻ />Hereditary Spastic Paraplegia Home Page.
Ͻ />NINDS Hereditary Spastic Paraplegia Information Page.
Ͻ />hereditarysp.htmϾ.
Deepti Babu, MS
I
Hermansky-Pudlak syndrome
Definition
Hermansky-Pudlak syndrome (HPS) is a rare inher-
ited disorder of melanin production. Melanin is the pig-
ment that gives color to the skin, hair, and eyes. A lack or
decrease of pigment in the skin and eyes is called oculo-
cutaneous albinism. HPS is a specific type of oculocuta-
neous albinism that also includes a bleeding tendency
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
549
Hermansky-Pudlak syndrome
and have typical skin pigmentation. However, each time
they have a child, the chance for the child to have HPS is
25%, or 1 in 4. Unless someone in the family has HPS,
most couples are unaware of their risk.
Researchers mapped the HPS1 gene to the long arm
of chromosome 10 in 1995, and later identified its exact
location in 1996. The protein produced by the HPS gene
helps organelles (specialized parts) of the cell’s cyto-
plasm (portion of the cell between the membrane and

nucleus) to develop and function normally.
In 1999, another group of researchers identified a
mutation, or gene change, in the AP3B1 gene located on
chromosome 5 as another cause of HPS. This gene makes
AP3, a molecule that helps to sort proteins within the
body’s cells.
Demographics
In northwest Puerto Rico, HPS is a common inher-
ited disorder. More than 300 persons are affected. The
carrier rate is about one in 21. Intermarriage accounts for
the high frequency. Researchers have traced the origin of
HPS to southern Spain. Cases have also been reported in
the Dutch, Swiss, and Japanese. Both sexes are equally
affected. However, females will have more lung symp-
toms than males.
Signs and symptoms
People with HPS have a broad range of skin color
from tan to white, reflecting the partial absence of pig-
mentation. Hair color ranges from brown to white, also
reflecting how much pigmentation is present.
Poor vision and eye abnormalities are common in
people with HPS. Visual acuity can approach 20/200.
Nystagmus, an irregular rapid back and forth movement
of the eyes, is also common. The eyes can have an
improper muscle balance called strabismus. Sensitivity to
bright light and glare, known as photophobia, is a fre-
quent complaint of people with HPS. These visual prob-
lems all result from abnormal development of the eye due
to the lack of pigment. Just as skin and hair color vary, so
will eye color. Red, brown, hazel, and violet eyes have

been reported.
A bleeding tendency distinguishes HPS from other
types of albinism. People with HPS will bruise easily and
bleed for an extended time after dental extractions and
surgical procedures. Platelets are the disc-shaped struc-
tures in the blood that cause clotting. In people with HPS,
the platelets are missing certain internal components that
cause them to clump together during the clotting process.
The third finding of HPS is the accumulation of
ceroid in certain cells of the body such as bone marrow
550
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
Hermansky-Pudlak syndrome
KEY TERMS
Bioptics—Glasses that have small telescopes fitted
in the lens.
Ceroid—The byproduct of cell membrane break-
down.
Colitis—Inflammation of the colon.
Cytoplasm—The substance within a cell including
the organelles and the fluid surrounding the
nucleus.
Diarrhea—Loose, watery stool.
Melanin—Pigments normally produced by the
body that give color to the skin and hair.
Mutation—A permanent change in the genetic
material that may alter a trait or characteristic of
an individual, or manifest as disease, and can be
transmitted to offspring.
Nystagmus—Involuntary, rhythmic movement of

the eye.
Oculocutaneous albinism—Inherited loss of pig-
ment in the skin, eyes, and hair.
Organelle—Small, sub-cellular structures that
carry out different functions necessary for cellular
survival and proper cellular functioning.
Photophobia—An extreme sensitivity to light.
Sputum—A mixture of saliva and mucus from the
lungs.
Strabismus—An improper muscle balance of the
ocular muscles resulting in crossed or divergent
eyes.
and the storage of ceroid, the byproduct of cell mem-
brane breakdown, in the body’s cells.
Description
In 1959, Drs. F. Hermansky and P. Pudlak reported
two unrelated people with oculocutaneous albinism who
had lifelong bleeding problems. The female died at age
33, and at that time large amounts of pigment were dis-
covered in the walls of her small blood vessels.
Genetic profile
HPS is an autosomal recessive disorder. This means
that the disease manifests itself when a person has inher-
ited one nonworking copy of the HPS gene from each
parent. Parents who carry the gene for HPS are healthy
and the lung. As ceroid collects in the lungs, it makes the
affected individual prone to respiratory infections and
progressive lung disease that restricts breathing. Some
people also complain of colitis (an inflammation of the
colon) and diarrhea (loose, watery stools).

Diagnosis
Diagnosis of HPS can be made by specialized
platelet testing and molecular testing for the known gene
mutations. Very few laboratories are equipped to perform
these tests. A person who is suspected to have HPS
should consult with a geneticist or genetic counselor to
arrange for the appropriate tests. Molecular testing is
available for Puerto Rican families who usually have a
specific detectable gene alteration, which is a duplication
of a small segment of the gene.
Analysis of the person’s platelets will determine if
they are lacking the critical internal parts, called dense
bodies, that help to clot blood. If dense bodies are not
present, then HPS is the diagnosis.
For affected people of Puerto Rican ancestry, one
unique gene mutation is present. Several other muta-
tions can also be detected, but the lack of a gene mutation
does not mean a person does not have HPS, since all
mutations have not been identified.
For some families with an affected child, prenatal
diagnosis may be possible for future pregnancies. Parents
should consult with a genetics specialist when planning a
pregnancy.
Treatment and management
For the individual with HPS, vision problems are
always present. Many people will meet the legal defini-
tion of blindness, but still have enough vision for reading
and other activities. Other affected people may be far-
sighted or near-sighted.
An ophthalmologist, a specialist for the eyes, will

help those individuals who have strabismus, a muscle
imbalance in the eyes. They can have corrective surgery
that will not only improve their physical appearance but
also expand their visual field. Surgery, however, cannot
restore pigment to the eyes nor correct the optic nerve
pathways leading from the brain to the eyes.
Many optical aids can help a person with HPS func-
tion better in daily life. Aids like hand-held magnifiers,
strong reading glasses, and glasses that have small tele-
scopes fitted in the lens called bioptics can make hobbies,
jobs, and other activities easier.
Protection from excessive sunlight is crucial for peo-
ple with HPS. Sunscreens of the highest rating should be
used to decrease the chance for fatal skin cancers. By
wearing clothing that blocks as much sunlight as possi-
ble, people with HPS can enjoy outdoor activities. A der-
matologist, a specialist in skin disorders, can examine the
affected person if any changes in skin color or appear-
ance occur. Annual skin check-ups are important.
As people with HPS reach their 30s, they begin to
have lung disease. The first sign is difficulty in breathing,
followed by a cough that does not bring up sputum, a
mixture of saliva and mucus, from the lungs. Gradually,
the lungs develop a tough, fibrous tissue that further lim-
its breathing. The inability to breathe is the most com-
mon cause of death for people with HPS.
Prolonged bleeding after tooth extraction, nosebleed,
or surgery occurs regularly in people with HPS. Before
any surgery, treatment with desmopressin, a drug that
stimulates clotting activity, can be effective. Also, indi-

viduals with HPS should avoid aspirin, because it makes
blood less likely to clot.
Prognosis
Many people with HPS may have concerns about
their physical appearance and decreased vision.
Education about the disorder is important to prevent iso-
lation and stigmatization. Once the visual difficulties are
addressed, people with albinism can participate in most
activities.
Although many preventive efforts can improve the
quality of life for a person with HPS, the progressive lung
disease cannot be halted. The inability to breathe gener-
ally becomes fatal when the affected person is 40–50
years old.
Resources
BOOKS
Kanski, Jack J. Clinical Ophthalmology: A Systematic
Approach. Woburn, MA: Butterworth-Heinemann
Medical, 1999.
Landau, Elaine. Living with Albinism (First Book). New York,
NY: Franklin Watts, 1998.
PERIODICALS
Dell’Angelica, E.C., et al. “Altered Trafficking of Lysosomal
Proteins in Hermansky-Pudlak Syndrome Due to
Mutations in the Beta-3A Subunit of the AP-3 Adaptor.”
Molec. Cell 3 (1999): 11-21.
Depinho, R.A., and K.L. Kaplan. “The Hermansky-Pudlak
Syndrome, Report of Three Cases and Review of
Pathophysiology and Management Considerations.”
Medicine 64 (1985): 192-202.

Gahl, W.A., et al. “Genetic Defects and Clinical Characteristics
of Patients with a Form of Oculocutaneous Albinism
(Hermansky-Pudlak Syndrome).” New England Journal of
Medicine 338 (1998): 1258-1264.
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
551
Hermansky-Pudlak syndrome
Sandberg-Gertzen, H., R. Eid, and G. Jarnerot. “Hermansky-
Pudlak Syndrome with Colitis and Pulmonary Fibrosis.”
Scandinavian Journal of Gastroentology 34 (1999): 1055-
1056.
Wijermans, P. W., and D. B. van Dorp. “Hermansky-Pudlak
Syndrome, Correction of Bleeding Time by 1-Desamino-
8D-Arginine Vasopressin.” American Journal of
Hematology 30 (1989): 154-157.
Wildenberg, S. C., W. S. Oetting, and C. Almodovar. “Gene
Causing Hermansky-Pudlak Syndrome in a Puerto Rican
Population Maps to Chromosome 10q2.” Human Genetics
57 (1995): 755-765.
ORGANIZATIONS
Hermansky-Pudlak Syndrome Network. 39 Riveria Court,
Malverne, NY 11565-1602. (800) 789-9477 or (516) 599-
2077. Ͻ />National Organization for Albinism and Hypopigmentation.
1530 Locust St. #29, Philadelphia, PA 19102-4415. (215)
545-2322 or (800) 473-2310. Ͻ />infobulletins/hermansky-pudlak-syndrome.htmlϾ.
WEBSITES
FriendshipCenter.com. ϽϾ.
NORD—National Organization for Rare Disorders.
ϽϾ.
Suzanne M. Carter, MS, CGC

I
Hermaphroditism
Definition
Hermaphroditism is a rare condition in which ovar-
ian and testicular tissue exist in the same person. The tes-
ticular tissue contains seminiferous tubules or
spermatozoa. The ovarian tissue contains follicles or cor-
pora albicantia. The condition is the result of a chromo-
some anomaly.
Description
Among human beings, hermaphroditism is an
extremely rare anomaly in which gonads for both sexes
are present. External genitalia may show traits of both
sexes, and in which the chromosomes show male-
female mosaicism (where one individual possesses both
the male XY and female XX chromosome pairs). There
are two different variants of hermaphroditism: true her-
maphroditism and pseudohermaphroditism. There are
female and male pseudohermaphrodites. True hermaph-
roditism refers to the presence of both testicular and
ovarian tissue in the same individual. The external geni-
talia in these individuals may range from normal male to
normal female. However, most phenotypic males have
hypospadias. Pseudohermaphroditism refers to gonadal
dysgenesis.
Genetic profile
The most common karyotype for a true hermaphro-
dite is 46XX. DNA from the Y chromosome is translo-
cated to one of the X-chromosomes. The karyotype for
male pseudohermaphrodites is 46XY. Female pseudoher-

maphroditism is more complicated. The condition is
caused by deficiencies in the activity of enzymes. The
genetic basis for three enzyme deficiencies have been
identified. Deficiency of 3B hydroxysteroid dehydroge-
nase—Type 2 is due to an abnormality on chromosome
1p13.1. Deficiency of 21-Hydroxylase is due to an abnor-
mality on chromosome 6p21.3. Deficiency of 11B-
Hydroxylase—Type 1 is due to an abnormality on
chromosome 8q21.
Demographics
True hermaphrodites are extremely rare.
Approximately 500 individuals have been identified in
the world to date. Because of the ambiguity of genitalia
and difficulties in making an accurate diagnosis, the inci-
dence of pseudohermaphroditism is not well established.
The incidence of male pseudohermaphroditism has been
estimated at between 3 and 15 per 100,000 people. The
incidence of female pseudohermaphroditism has been
estimated at between 1 and 8 per 100,000 people.
552
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
Hermaphroditism
KEY TERMS
Corpora albicantia—Plural of corpus albicans. A
corpus albicans is the scar tissue that remains on
an ovarian follicle after ovulation.
Dysgenesis—Defective or abnormal formation of
an organ or part usually occuring during embry-
onic development.
Follicle—A pouch-like depression.

Mosaicism—A genetic condition resulting from a
mutation, crossing over, or nondisjunction of chro-
mosomes during cell division, causing a variation
in the number of chromosomes in the cells.
Semineferous tubules—Long, threadlike tubes that
are packed in areolar tissue in the lobes of the
testes.
Spermatozoa—Mature male germ cells that
develop in the seminiferous tubules of the testes.
Signs and symptoms
True hermaphroditism is characterized by ambigu-
ous internal and external genitalia. On internal examina-
tion (most often using laparoscopy), there is microscopic
evidence of both ovaries and testes. Male pseudoher-
maphroditism is also characterized by ambiguous inter-
nal and external genitalia. However, gonads are often (but
not always) recognizable as testes. These are frequently
softer than normal. An affected person is often incom-
pletely masculinized. Female pseudohermaphroditism is
characterized by female internal genitals. External geni-
tals tend to appear as masculine. This is most commonly
characterized by clitoral hypertrophy. Most hermaphro-
dites are infertile although a small number of pregnancies
have been reported.
Diagnosis
True hermaphroditism is often diagnosed after
laparoscopic investigation. An initial suspicion of male
pseudohermaphroditism is often made by inspection of
external genitals. This is confirmed by chromosomal
analysis and assays of hormones such as testosterone.

Initial suspicion of female pseudohermaphroditism is
also made by inspection of external genitals. This is con-
firmed by analysis of chromosomes and hormonal assay.
Laparoscopic examination usually reveals nearly normal
female internal genitals.
Treatment and management
Early assignment of gender is important for the emo-
tional well being of any person with ambiguous genitalia.
A decision to select a gender of rearing is based on the
corrective potential of the ambiguous genitalia, rather
than using chromosome analysis. Once the decision is
made regarding gender, there should be no question in
the family’s mind regarding the gender of the child from
that point on.
Corrective surgery is used to reconstruct the external
genitalia. In general, it is easier to reconstruct female
genitalia than male genitalia, and the ease of reconstruc-
tion will play a role in selecting the gender of rearing.
Treating professionals must be alert for stress in persons
with any form of hermaphroditism and their families.
Prognosis
With appropriate corrective surgery, the appearance
of external genitalia may appear normal. However, other
problems such as virilization may appear later in life. As
of 2001, there is some interest among persons with
ambiguous genitalia at birth to reverse their gender of
rearing.
Resources
BOOKS
Rappaport, Robert. “Female Pseudohermaphroditism.” In

Nelson Textbook of Pediatrics. Edited by Richard E.
Behrman et al. 16th ed. Philadelphia, W.B. Saunders,
2000, p. 1760.
Rappaport, Robert. “Male Pseudohermaphroditism.” In Nelson
Textbook of Pediatrics, edited by Richard E. Behrman et
al. 16th ed. Philadelphia, W.B. Saunders, 2000, pp. 1761-
1764.
Rappaport, Robert. “True Hermaphroditism.” In Nelson Textbook
of Pediatrics, edited by Richard E. Behrman et al. 16th ed.
Philadelphia, PA: W.B. Saunders, 2000, pp. 1765-1766.
Wilson, Jean D., and James E. Griffin. “Disorders of Sexual
Differentiation.” In Harrison’s Principles of Internal
Medicine. Edited by Anthony S. Fauci, et al. 14th ed. New
York: McGraw-Hill, 1998, pp. 2119-2131.
PERIODICALS
Denes F. T., B.B. Mendonca, and S. Arap. “Laparoscopic
Management of Intersexual States.” Urology Clinics of
North America 28, no. 1 (2001): 31-42.
Krstic Z. D., et al. “True Hermaphroditism: 10 Years’
Experience.” Pediatric Surgery International 16, no. 8
(2000): 580-583.
Wiersma, R. “Management of the African Child With True
Hermaphroditism.” Journal of Pediatric Surgery 36, no. 2
(2001): 397-399.
Zuker, K. J. “Intersexuality and Gender Identity Differenti-
ation.” Annual Review of Sexual Research 10 (1999): 1-69.
ORGANIZATIONS
Genetic Alliance. 4301 Connecticut Ave. NW, #404, Washing-
ton, DC 20008-2304. (800) 336-GENE (Helpline) or (202)
966-5557. Fax: (888) 394-3937. info@geneticalliance.

ϽϾ.
Hermaphrodite Education and Listening Post. PO Box 26292,
Jacksonville, NY 32226. Ͻhttp://users
.southeast.net/~help/Ͼ.
Intersex Society of North America. PO Box 301, Petaluma, CA
94953-0301. ϽϾ.
March of Dimes Birth Defects Foundation. 1275 Mamaro-
neck Ave., White Plains, NY 10605. (888) 663-4637.
ϽϾ.
WEBSITES
Born True Hermaphrodite
Ͻ />Columbia Electronic Encyclopedia.
Ͻ />Hermaphrodite Education and Listening Post.
Ͻ />Loyola University Stritch School of Medicine.
Ͻ />Developmental_genetic_diseases/hermaphroditism.htmϾ.
National Library of Medicine.
Ͻ />UK Intersex Association. Ͻ />L. Fleming Fallon, Jr., MD, DrPH
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
553
Hermaphroditism
High density hypoprotein deficiency see
Tangier disease
I
Hirschsprung’s disease
Definition
Hirschsprung’s disease, also known as congenital
megacolon or aganglionic megacolon, is an abnormality
in which certain nerve fibers are absent in segments of
the bowel, resulting in severe bowel obstruction.
Description

Hirschsprung’s disease is caused when certain nerve
cells (called parasympathetic ganglion cells) in the wall
of the large intestine (colon) do not develop before birth.
Without these nerves, the affected segment of the colon
lacks the ability to relax and move bowel contents along.
This causes a constriction and as a result, the bowel
above the constricted area dilates due to stool becoming
trapped, producing megacolon (dilation of the colon).
The disease can affect varying lengths of bowel segment,
most often involving the region around the rectum. In up
to 10% of children, however, the entire colon and part of
the small intestine are involved.
Genetic profile
Hirschsprung’s disease occurs early in fetal develop-
ment when, for unknown reasons, there is either failure
of nerve cell development, failure of nerve cell migration,
or arrest in nerve cell development in a segment of bowel.
The absence of these nerve fibers, which help control the
movement of bowel contents, is what results in intestinal
obstruction accompanied by other symptoms.
There is a genetic basis to Hirschsprung’s disease,
and it is believed that it may be caused by different
genetic factors in different subsets of families. Proof that
genetic factors contribute to Hirschsprung’s disease is
that it is known to run in families, and it has been seen in
association with some chromosome abnormalities. For
example, about 10% of children with the disease have
Down syndrome (the most common chromosome
abnormality). Molecular diagnostic techniques have
identified many genes that cause susceptibility to

Hirschsprung’s disease. As of 200l, there are a total of six
genes: the RET gene, the glial cell line-derived neu-
rotrophic factor gene, the endothelin-B receptor gene,
endothelin converting enzyme, the endothelin-3 gene,
and the Sry-related transcription factor SOX10.
Mutations that inactivate the RET gene are the most fre-
quent, occurring in 50% of familial cases (cases which
run in families) and 15-20% of sporadic (non-familial)
cases. Mutations in these genes do not cause the disease,
but they make the chance of developing it more likely.
Mutations in other genes or environmental factors are
required to develop the disease, and these other factors
are not understood.
For persons with a ganglion growth beyond the sig-
moid segment of the colon, the inheritance pattern is
autosomal dominant with reduced penetrance (risk closer
to 50%). For persons with smaller segments involved, the
inheritance pattern is multifactorial (caused by an inter-
action of more than one gene and environmental factors,
risk lower than 50%) or autosomal recessive (one disease
gene inherited from each parent, risk closer to 25%) with
low penetrance.
Demographics
Hirschsprung’s disease occurs once in every 5,000
live births, and it is about four times more common in
males than females. Between 4% and 50% of siblings are
also afflicted. The wide range for recurrence is due to the
fact that the recurrence risk depends on the gender of the
affected individual in the family (i.e., if a female is
affected, the recurrence risk is higher) and the length of

the aganglionic segment of the colon (i.e., the longer the
segment that is affected, the higher the recurrence risk).
Signs and symptoms
The initial symptom is usually severe, continuous
constipation. A newborn may fail to pass meconium (the
first stool) within 24 hours of birth, may repeatedly vomit
yellow or green colored bile and may have a distended
(swollen, uncomfortable) abdomen. Occasionally, infants
may have only mild or intermittent constipation, often
with diarrhea.
While two-thirds of cases are diagnosed in the first
three months of life, Hirschsprung’s disease may also be
diagnosed later in infancy or childhood. Occasionally,
even adults are diagnosed with a variation of the disease.
In older infants, symptoms and signs may include
anorexia (lack of appetite or inability to eat), lack of the
urge to move the bowels or empty the rectum on physical
examination, distended abdomen, and a mass in the colon
that can be felt by the physician during examination. It
should be suspected in older children with abnormal
bowel habits, especially a history of constipation dating
back to infancy and ribbon-like stools.
Occasionally, the presenting symptom may be a
severe intestinal infection called enterocolitis, which is
life threatening. The symptoms are usually explosive,
554
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
Hirschsprung’s disease
watery stools and fever in a very ill-appearing infant. It is
important to diagnose the condition before the intestinal

obstruction causes an overgrowth of bacteria that evolves
into a medical emergency. Enterocolitis can lead to
severe diarrhea and massive fluid loss, which can cause
death from dehydration unless surgery is done immedi-
ately to relieve the obstruction.
Diagnosis
Hirschsprung’s disease in the newborn must be dis-
tinguished from other causes of intestinal obstruction.
The diagnosis is suspected by the child’s medical history
and physical examination, especially the rectal exam.
The diagnosis is confirmed by a barium enema x ray,
which shows a picture of the bowel. The x ray will indi-
cate if a segment of bowel is constricted, causing dilation
and obstruction. A biopsy of rectal tissue will reveal the
absence of the nerve fibers. Adults may also undergo
manometry, a balloon study (device used to enlarge the
anus for the procedure) of internal anal sphincter pressure
and relaxation.
Treatment and management
Hirschsprung’s disease is treated surgically. The goal
is to remove the diseased, nonfunctioning segment of the
bowel and restore bowel function. This is often done in
two stages. The first stage relieves the intestinal obstruc-
tion by performing a colostomy. This is the creation of an
opening in the abdomen (stoma) through which bowel
contents can be discharged into a waste bag. When the
child’s weight, age, or condition is deemed appropriate,
surgeons close the stoma, remove the diseased portion of
bowel, and perform a “pull-through” procedure, which
repairs the colon by connecting functional bowel to the

anus. This usually establishes fairly normal bowel
function.
Prognosis
Overall, prognosis is very good. Most infants with
Hirschsprung’s disease achieve good bowel control after
surgery, but a small percentage of children may have lin-
gering problems with soilage or constipation. These
infants are also at higher risk for an overgrowth of bacte-
ria in the intestines, including subsequent episodes of
enterocolitis, and should be closely followed by a physi-
cian. Mortality from enterocolitis or surgical complica-
tions in infancy is 20%.
Prevention
Hirschsprung’s disease is a congenital abnormality
that has no known means of prevention. It is important to
diagnose the condition early in order to prevent the
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
555
Hirschsprung’s disease
KEY TERMS
Anus—The opening at the end of the intestine that
carries waste out of the body.
Barium enema x ray—A procedure that involves
the administration of barium into the intestines by
a tube inserted into the rectum. Barium is a chalky
substance that enhances the visualization of the
gastrointestinal tract on x-ray.
Colostomy—The creation of an artificial opening
into the colon through the skin for the purpose of
removing bodily waste. Colostomies are usually

required because key portions of the intestine
have been removed.
Enterocolitis—Severe inflammation of the intes-
tines that affects the intestinal lining, muscle,
nerves and blood vessels.
Manometry—A balloon study of internal anal
sphincter pressure and relaxation.
Meconium—The first waste products to be dis-
charged from the body in a newborn infant, usu-
ally greenish in color and consisting of mucus, bile
and so forth.
Megacolon—Dilation of the colon.
Parasympathetic ganglion cell—Type of nerve cell
normally found in the wall of the colon.
development of enterocolitis. Genetic counseling can
be offered to a couple with a previous child with the dis-
ease or to an affected individual considering pregnancy to
discuss recurrence risks and treatment options. Prenatal
diagnosis is not available.
Resources
BOOKS
Buyse, Mary Louise, MD., ed. “Colon, Aganglionosis.” In Birth
Defects Encyclopedia. Oxford: Blackwell Scientific
Publications, 1990.
Phillips, Sidney F., and John H. Pemberton. “Megacolon:
Congenital and Acquired.” In Sleisenger & Fordtran’s
Gastrointestinal and Liver Disease. Edited by Mark
Feldman, et al. Philadelphia: W.B. Saunders Co., 1998.
PERIODICALS
Kusafuka, T., and P. Puri. “Genetic Aspects of Hirschsprung’s

Disease.” Seminars in Pediatric Surgery 7 (1998): 148-55.
Martucciello, G., et al. “Pathogenesis of Hirschsprung’s
Disease.” Journal of Pediatric Surgery 35 (2000): 1017-
25.
Munnes, M., et al. “Familial Form of Hirschsprung Disease:
Nucleotide Sequence Studies Reveal Point Mutations in
the RET Proto-oncogene in Two of Six Families But Not
in Other Candidate Genes.” American Journal of Medical
Genetics 94 (2000): 19-27.
Puri, P., K. Ohshiro, and T. Wester. “Hirschsprung’s Disease: A
Search for Etiology.” Seminars in Pediatric Surgery 7
(1998): 140-7.
Salomon, R., et al. “From Monogenic to Polygenic: Model of
Hirschsprung Disease.” Pathol Biol (Paris) 46 (1998):
705-7.
ORGANIZATIONS
American Pseudo-Obstruction & Hirschsprung’s Society. 158
Pleasant St., North Andover, MA 01845. (978) 685-4477.
Pull-thru Network. 316 Thomas St., Bessemer, AL 35020. (205)
428-5953.
Amy Vance MS, CGC
HLA region see Major histocompatibility
complex
I
Holoprosencephaly
Definition
Holoprosencephaly is a disorder in which there is a
failure of the front part of the brain to properly separate
into what is commonly know as the right and left halves
of the brain. This lack of separation is often accompanied

by abnormalities of the face and skull. Holoprosen-
cephaly may occur individually or as a component of a
larger disorder.
Description
Types of holoprosencephaly
Holoprosencephaly comes in three different types:
alobar, semilobar, and lobar. Each of these classifications
is based on the amount of separation between what is
commonly known as the left and right halves of the brain.
Alobar holoprosencephaly is considered to be the most
severe form of the disease, in which the separation
between the two halves, or hemispheres, completely fails
to develop. Semilobar holoprosencephaly represents
holoprosencephaly of the moderate type, where some
separation between the hemispheres has occurred. Lobar
holoprosencephaly represents the least severe type of
holoprosencephaly in which the hemispheres are almost,
but not completely, divided.
The severity of the effect of the disease on the brain
is often reflected in craniofacial abnormalities (abnormal-
ities of the face and skull). This has led to many health
care professionals utilizing the phrase “the face predicts
the brain.” This phrase is generally but not always accu-
rate. Children may have severe craniofacial abnormalities
with mild (lobar) holoprosencephaly, or children may
have severe (alobar) holoprosencephaly with mild facial
changes. Since the development of the face, skull, and the
front of the brain are interconnected, the changes in the
face often, but do not always, correspond with changes in
the brain. Finally, the designation of these disorders from

least severe to most severe can be mildly misleading,
since the best predictor of the severity of the disease,
according to Barr and Cohen, is how well the brain func-
tions, not its appearance. However, the alobar, semilobar,
and lobar categories are universally utilized and give an
indication of the severity of the disease, so knowledge of
these categories and what they represent is useful.
Other brain abnormalities in holoprosencephaly
All patients with holoprosencephaly lack a sense of
smell through the first cranial nerve (the olfactory nerve).
Interestingly enough, one has a partial sense of smell
through the sense of taste, which is governed by the sev-
enth cranial nerve. The term “smell” and what it means in
a conventional and strictly neurological sense differ, so it
may be useful to think of persons with holoprosen-
cephaly as lacking a portion of what is in common usage
referred to as smell. This deficiency in smell can be
detected by testing. One other important structural abnor-
mality should be mentioned. The corpus callosum, which
is the part of the brain that connects the right and left
hemispheres with each other, is absent or deficient in per-
sons with holoprosencephaly.
Synonyms for holoprosencephaly
Arrhinencephaly and familial alobar holoprosen-
cephaly are synonyms for this disorder.
Genetic profile
Genetic causes of holoprosencephaly
Holoprosencephaly is a feature frequently found in
many different syndromes including, but not limited to:
trisomy 13, trisomy 18, tripoloidy, pseudotrisomy 13,

Smith-Lemli-Opitz syndrome, Pallister-Hall syn-
drome, Fryns syndrome, CHARGE association,
Goldenhar syndrome, frontonasal dysplasia, Meckel-
Gruber syndrome, velocardiofacial syndrome, Genoa
syndrome, Lambotte syndrome, Martin syndrome, and
Steinfeld syndrome, as well as several teratogenic syn-
dromes such as diabetic embryopathy, accutane embry-
opathy, and fetal alcohol syndrome. Holoprosencephaly
has been linked to at least 12 different loci on 11 different
chromosomes. Some candidate genes are Sonic hedge-
556
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
Holoprosencephaly
hog (abbreviated Shh, and located at 7q36), SIX3 (located
at 2p21), and the ZIC2 gene (located on chromosome 13).
The gene causing Smith-Lemli-Opitz syndrome, which
affects cholesterol synthesis, also is interesting, since it is
also obviously a candidate to cause holoprosencephaly.
Shh, cholesterol, the prechordal plate, and the
cause of holoprosencephaly
Holoprosencephaly probably arises in one of two
ways (suggested by experiments in animal models).
Early in the life of an embryo, an area called the pre-
chordal plate forms. The prechordal plate is an area of the
embryo which is important for the formation of the brain.
The prechordal plate is said to induce brain formation.
One can think of the induction process in the following
way. If you take a sponge, wet it, and then place a paper
towel on top of it, the paper towel will absorb some of the
water. In the same way, a signal (the water) goes from the

sponge (prechordal plate) to the paper towel (future brain
tissue). If the water doesn’t hit the paper towel, brain tis-
sue will not form. This is an extremely simplified version
of how the process works, for many reasons. One is that
the prechordal plate is not the only “sponge.” The noto-
chord is another sponge, which sends out the signal
(water) of Shh to form brain and spinal cord and other
nervous tissue. Of course, Shh has already been men-
tioned as a candidate for a gene which causes holopros-
encephaly. It turns out it is better than a candidate,
because mutations in Shh have been found in some famil-
ial forms of holoprosencephaly. Further evidence that
Shh plays a role in holoprosencephaly comes from Shh in
mice and fish, which both result in holoprosencephaly.
Thus, it would be a nice, clear-cut picture if mutations in
Shh and Shh alone led to holoprosencephaly, because
Shh mutations lead to holoprosencephaly in other ani-
mals and Shh is already known to be involved in the for-
mation of neural tissue.
However, Shh is not the only answer. Many persons
with holoprosencephaly have perfectly normal Shh
genes, and, as previously mentioned, a number of genes
have been linked to holoprosencephaly, including genes
involved in cholesterol synthesis. So why are so many
genes involved?
One possible answer stems from the connection
between cholesterol and the Shh signaling pathway.
When Shh travels from one tissue to another tissue, there
are a number of other genes involved before Shh has its
final effect. This process is called signal transduction,

and the genes that make it up are part of a signaling path-
way. Signal transduction can be compared to a shot in the
game of pool. When shooting pool, one must take the cue
(Shh), hit the cue ball (another gene; for Shh this would
be the gene Patched), and the cue ball goes on to hit the
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
557
Holoprosencephaly
KEY TERMS
Corpus callosum—A thick bundle of nerve fibers
deep in the center of the forebrain that provides
communications between the right and left cere-
bral hemispheres.
Craniofacial—Relating to or involving both the
head and the face.
Induction—Process where one tissue (the pre-
chordal plate, for example) changes another tissue
(for example, changes tissue into neural tissue).
Neural—Regarding any tissue with nerves, includ-
ing the brain, the spinal cord, and other nerves.
ball that one is interested in sinking (in this case sinking
the ball means making a normal brain). Thus, each step
depends on the last step and the next step. If one doesn’t
have the stick or the cue ball one cannot sink the ball in
the pocket. Thus, a number of mutations in genes in the
Shh signaling pathway, and not just Shh, could cause
holoprosencephaly. Not just that, but other genes
involved in cholesterol biosynthesis can have effects on
genes in the Shh signaling pathway. Cholesterol appears
to affect the function of the gene Patched. In the pool

example, a lack of cholesterol would not mean the cue
ball is gone, but maybe that the cue ball has a big lump
on one side, so the shot is likely to miss.
Another possible answer comes from studies on
bone morphogenetic proteins (BMPs) in chickens. Up
until now, the problem of holoprosencephaly has been
addressed as if it occurs when neural tissue is formed.
However, the presence of too much BMP in a chick
embryo after the time neural tissue is formed can cause
holoprosencephaly. It appears there are two stages that
can be interfered with: one that occurs at the time of neu-
ral tissue formation involving Shh, and another that
occurs later involving BMPs. Increased levels of BMPs
may cause important neural cells to die. It has been spec-
ulated that holoprosencephaly is either a failure to grow
neural cells due to failure in Shh pathway, or an excess of
neural cells dying possibly due to increased levels of
BMPs. Both may end up being true, with some Shh sig-
naling defects early, and BMP mutations later.
Teratogens also cause holoprosencephaly
A teratogen is any environmental influence that
adversely affects the normal development of the fetus.
Teratogens can be skin creams, drugs, or alcohol.
Alcohol, when ingested in sufficient amounts during the
second week of pregnancy, is thought to lead to some
cases of holoprosencephaly. Cytomegalovirus infections
in the mother during pregnancy have also been associated
with holoprosencephaly. Additionally, in animals, drugs
inhibiting cholesterol synthesis have been shown to cause
cases of holoprosencephaly. Finally, the drug cyclopa-

mine, which affects the Shh pathway, also causes holo-
prosencephaly in animals. Cyclopamine was discovered
when an abnormally large number of sheep were found to
have holoprosencephaly. A local shepherd and scientists
determined the drug was found in a fungus called
Veratrum californicum.
Demographics
Holoprosencephaly affects males and females at the
same rate. Estimates vary on the frequency of the disor-
der in children with normal chromosomes. The estimates
range from one case in every 11,363 births to one case in
53,394 births. It is important to note that this rate of inci-
dence excludes those cases which are caused by chro-
mosomal abnormalities, like trisomy 13.
Signs and symptoms
In holoprosencephaly alone, symptoms involve the
brain and/or the face and bones of the face and skull.
Facial abnormalities exhibit a wide range. In the most
severe cases, persons with holoprosencephaly lack eyes
and may lack a nose. Less severe is cyclopia, or the pres-
ence of a single eye in the middle of the face above the
possibly deformed or absent nose. Even less severe are
ethmocephaly and cebocephaly, in which the eyes are set
close together and the nose is abnormal. In premaxillary
agenesis the patient has a midline cleft lip and cleft palate
and close-set eyes. If the face is very abnormal, the patient
is likely to have alobar holoprosencephaly, the most severe
type. In addition to abnormalities of the face, children with
alobar holoprosencephaly also have small brains (less than
100g). These children also have small heads unless they

have excess cerebrospinal fluid. Excess cerebrospinal
fluid can cause the head to be abnormally large.
Persons with holoprosencephaly experience many
problems due to brain malformations including in utero
or neonatal death. Survivors may experience seizures,
problems with muscle control and muscle tone, a delay in
growth, problems feeding (choking and gagging or slow-
ness, pauses, and a lack of interest), intestinal gas, con-
stipation, hormone deficiencies from the pituitary,
breathing irregularities, and heart rhythm and heart rate
abnormalities. These problems are usually least severe in
lobar holoprosencephaly and most severe in alobar.
Children with holoprosencephaly also experience severe
deficiencies in their ability to speak and in their motor
skills. An ominous sign that children with holoprosen-
cephaly may exhibit is a sustained (lasting many hours or
days) period of irregular breathing and heart rate. This
may precede death. However, episodes lasting only min-
utes are usually followed by a full recovery.
Diagnosis
Prenatal ultrasound and computerized tomography
can be used to determine whether the fetus has holopros-
encephaly and its severity. After birth, physical appear-
ance and/or imaging of the brain can determine a
diagnosis of holoprosencephaly. Once a diagnosis of
holoprosencephaly has been made, syndromes of which
holoprosencephaly is a part must be considered. Forty-
one percent of holoprosencephaly cases are thought to
have a chromosomal abnormality as the primary cause.
Holoprosencephaly is estimated to be found in the con-

text of a larger syndrome in 25% of the remaining cases.
Treatment and management
Although no treatment exists for the underlying dis-
ease, symptomatic treatment can reduce the amount of
fluid surrounding the brain and assist in feeding. Medical
intervention can reduce or eliminate seizures and hor-
monal deficiencies. However, few treatments exist for the
most serious aspects of the disease—breathing and heart
arrhythmias (irregular heart rate)—or for the problems
associated with developmental delay and poor muscle
control. One important aspect of treatment is to help par-
ents understand the effects of the disease and what may
558
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
Holoprosencephaly
The most severe form of holoprosencephaly, alobar
holoprosencephaly, results when the brain fails to separate
into the right and left lobes.
(Greenwood Genetic Center)
be expected from the child. Support groups, like the one
listed at the end of this entry, may be important for this
purpose. Parents should also be prepared to deal with a
large number of health care professionals based on their
child’s particular needs.
Prognosis
About half of the children born with alobar holo-
prosencephaly die before the age of four to five months,
but a much longer survival time is possible, up to at least
11 years. Children with semilobar and lobar holoprosen-
cephaly may live for any length of time. Depending on

the severity of the holoprosencephaly, however, parents
should be prepared for differences in their child. For
example, children with alobar holoprosencephaly and
semilobar holoprosencephaly learn to speak very little, if
at all, and children with alobar holoprosencephaly have
difficulty even mastering the simple task of reaching and
grasping an object. On the other end of the spectrum,
children may develop much more normally. It is very
important to understand the severity of the disorder to
understand the child’s abilities and possibilities.
Resources
BOOKS
Sadler, T. W. Langman’s Medical Embryology. Baltimore:
Williams and Williams, 1995, pp. 53-60.
PERIODICALS
Barr, M., and M. Cohen. “Holoprosencephaly survival and per-
formance.” American Journal of Medical Genetics 89
(1999): 116-120.
ORGANIZATIONS
National Organization for Rare Disorders (NORD). PO Box
8923, New Fairfield, CT 06812-8923. (203) 746-6518 or
(800) 999-6673. Fax: (203) 746-6481. Ͻhttp://www
.rarediseases.orgϾ.
Michael V. Zuck, PhD
I
Holt-Oram syndrome
Definition
Holt-Oram syndrome (HOS) is one of several hered-
itary conditions characterized by abnormalities of the
heart and hands at birth.

Description
HOS involves variable abnormalities of the heart and
the hands, or hands and arms. The heart abnormalities
may range from disturbances in the electrical conduction
pattern of the heart to severe structural defects requiring
surgical intervention for survival. The abnormalities of
the upper limbs are usually bilateral (occurring on both
sides) and asymmetric (not identical from side to side).
The severity of the upper limb changes may range from
minor signs, such as clinodactyly (inward curvature of
the fingers) to disabling defects, such as small or missing
bones resulting in very short arms.
Some individuals with HOS are so mildly affected,
they do not require any special care or treatment. Other
individuals are severely affected and may have signifi-
cant disability resulting from abnormalities of the arms,
or may have limited lifespans due to serious heart abnor-
malities. The signs of HOS are usually limited to the
heart and skeleton. HOS does not cause mental
retardation.
Some references may use the alternative name of
hand-heart syndrome. However, Holt-Oram syndrome is
one of many hereditary hand-heart syndromes, so the two
names are not truly interchangeable.
Genetic profile
HOS is inherited as an autosomal dominant condi-
tion, with variable expressivity (meaning that different
individuals with HOS may have very different signs of
the condition) and complete penetrance (meaning that
every individual that has the genetic change causing the

condition has some physical symptoms). An autosomal
dominant condition only requires the presence of one
abnormal gene on a non-sex-linked chromosome for the
disorder to occur. Some researchers have observed fami-
lies with incomplete penetrance (meaning that not every
individual with the gene abnormality shows symptoms)
as well.
In some individuals and families, HOS is caused by
mutations in the TBX5 gene located on the long arm of
chromosome 12. The TBX5 gene encodes a transcription
factor that helps regulate DNA expression. Other fami-
lies with HOS do not show mutations in the TBX5 gene,
indicating that mutations in other genes can also cause
HOS. HOS families that have TBX5 mutations do not
appear to differ significantly from those which do not.
Some patients with HOS have inherited it from an
affected parent, whereas others have it as the result of a
new change in a gene. The proportion of patients with
HOS resulting from new mutations ranges from 8% to
85%. Regardless of where the gene came from, an
affected individual has a 50% chance of passing on the
gene and the condition to each child. It is difficult to pre-
determine the severity of symptoms a child may have.
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
559
Holt-Oram syndrome
Demographics
Since HOS was first described in 1960, more than
200 cases have been reported in individuals of diverse
ethnicity. The incidence of the condition has been esti-

mated as 1/100,000 live births.
Signs and symptoms
All individuals with HOS have some degree of upper
limb abnormality, and most (approximately 95% in
familial cases) have defects or dysfunction of the heart.
Other body parts and systems are usually not signifi-
cantly affected by HOS.
Defects of the upper limbs
The limb abnormalities in HOS primarily affect the
radial side (the inner or thumb side of the arm/hand).
Involvement of the ulnar side (the outer side of the
arm/hand, opposite the thumb) may also occur to a lesser
degree. In some individuals, the abnormality of the upper
limb may be very mild, such as hypoplasia (underdevel-
opment) of the muscle at the base of the thumb, limited
rotation of the arm, or narrow, sloping shoulders. Rarely,
severe abnormalities of the upper limbs may be present,
resulting in extremely short, “flipper-like” arms.
Abnormalities of the upper limb are always bilateral and
usually asymmetric. In 90% of patients, the left side is
more severely affected.
The thumb is the most commonly affected part of the
upper limb in HOS, and is affected in some way in 84%
of patients. Some individuals have three phalanges (or
bones) in the thumb, resulting in a thumb that can bend
in three places, like a finger. In other cases, the thumb
may be hypoplastic (underdeveloped). Syndactyly (or
skin webbing) may occur between the thumb and index
finger.
Abnormalities of the fingers may include hypopla-

sia, underdevelopment, or absence of one or more fin-
gers. Clinodactyly (inward curvature) of the fifth or
“pinky” finger is also common. In some patients, poly-
dactyly (extra fingers) has been reported.
The bones of the arms may also be affected by HOS.
The radius (the inner bone of the forearm, adjacent to the
thumb) may be hypoplastic or even missing. Such
patients may have a lesser degree of hypoplasia of the
ulna (outer bone of the forearm, opposite the thumb). The
upper arm may be short. In rare cases, as noted above, the
bones of the arm are dramatically shortened, resulting in
a tiny arm.
Individuals with HOS often appear to have narrow,
sloping shoulders. This likely results from some degree
of hypoplasia of the clavicles (collarbones), as well as
decreased musculature which occurs secondarily to bone
hypoplasia.
Defects and dysfunction of the heart
The vast majority (95%) of individuals with HOS
who have inherited it from an affected parent have heart
involvement. Most have a defect in the structure of the
heart. In some patients, there is no structural defect in the
heart, but abnormalities are present in the pattern of elec-
trical conduction in the heart.
The most common heart abnormalities in people
with HOS are septal defects, or holes in the heart. A hole
may occur in the wall separating the atria of the heart
(atrioseptal defect or ASD), or the wall separating the
ventricles of the heart (ventriculoseptal defect or VSD).
In rare cases, more severe and complex heart defects may

occur, such as hypoplastic left heart (in which the cham-
bers of the left side of the heart are too small to function
normally) or tetralogy of fallot (a specific combination of
four heart defects). In the case of severe defects, surgical
correction is necessary for survival. However, most per-
sons with HOS do not require surgical intervention.
Some individuals with HOS have a cardiac conduc-
tion defect, or an abnormal electrical pattern in the heart.
The complex motion of the heart requires a system of
electrical impulses for coordinated contraction of the
muscle fibers. In people with cardiac conduction defects,
these electrical impulses may not occur in the normal pat-
tern, resulting in an abnormal heartbeat. In rare cases,
this can result in sudden death.
Other defects
Additional skeletal abnormalities occasionally
reported in patients with HOS include scoliosis,verte-
bral abnormalities, and minor deformities of the rib cage.
Some patients may have abnormalities unrelated to the
cardiac or skeletal systems, such as minor eye defects and
various birthmarks. It is not clear whether these addi-
tional findings are coincidental or part of HOS.
Diagnosis
The diagnosis of HOS is made on the basis of the
clinical judgment by a specialist physician, usually a
geneticist, following physical examination and review of
pertinent tests or studies. Diagnostic criteria may be
employed to guide this decision. One commonly used set
of criteria for the diagnosis of HOS require that there be
1) defect(s) of the radial side of the hand/arm, as well as

2) septal defect(s) or conduction abnormality of the heart,
within one individual or family.
X rays may be necessary to determine involvement
of the bones of the upper limb. Diagnosis of structural
560
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
Holt-Oram syndrome
defects of the heart requires echocardiography, or ultra-
sound visualization of the heart. Conduction defects of
the heart are identified via electrocardiography (EKG).
This test involves measuring the electrical activity of the
heart and charting the electrical impulses associated with
each heartbeat.
Testing to identify changes in the TBX5 gene may be
offered, but is not necessary for a diagnosis of HOS.
Identification of a change or alteration in the TBX5 gene
could provide confirmation of the clinical diagnosis, pre-
natal diagnosis, or assist in the diagnosis of at-risk family
members who are minimally affected. Prenatal screening
in a pregnancy at risk for HOS may also be attempted by
fetal ultrasonography targeted toward the fetal arms and
heart. However, a normal ultrasound examination does
not eliminate the possibility of HOS in the unborn baby.
Treatment and management
There is no specific treatment for HOS. Surgery or
other treatment may be recommended for cardiac abnor-
malities. Referral for genetic counseling should be con-
sidered for families in which HOS has been diagnosed.
Some patients with HOS have life-threatening heart
defects that require surgical correction for survival. The

most complex heart defects may require multiple surger-
ies. However, many individuals have asymptomatic or no
heart abnormalities. When life-threatening irregularities
are present in the heartbeat, a pacemaker device is
inserted. These devices correct the abnormal electrical
patterns which cause the irregularities and stimulate the
heart to beat normally.
Because eye abnormalities have been occasionally
reported in HOS, an eye examination may be recom-
mended at the time of diagnosis.
Prognosis
The prognosis for individuals with HOS depends on
the severity of associated birth defects, which varies con-
siderably. Positive correlation has been reported between
the severity of upper limb and heart defects. In other
words, individuals who have more severe hand or arm
involvement may be more likely to have a symptomatic
heart defect. People who have HOS resulting from new
mutations are more likely to have severe defects than
those who have inherited it from a parent.
In some cases, HOS may lead to death in early
infancy due to multiple septal defects or other complex
structural abnormalities of the heart. Severe and unrecog-
nized disturbances of the cardiac conduction system can
lead to sudden death. In other cases, heart involvement is
limited to asymptomatic irregular heartbeat requiring no
treatment.
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
561
Homocystinuria

KEY TERMS
Atria—The two chambers at the top of the heart,
where blood from the lungs or body pools before
entering one of the ventricles.
Polydactyly—The presence of extra fingers or toes.
Radius—One of the two bones of the forearm, the
one adjacent to the base of the thumb.
Septal defect—A hole in the heart.
Syndactyly—Abnormal webbing of the skin
between the fingers or toes.
Ulna—One of the two bones of the forearm, the
one opposite the thumb.
Ventricles—One of the chambers (small cavities)
of the heart through which blood circulates. The
heart is divided into the right and left ventricles.
Several unusual findings have been described with
respect to the severity of HOS in families. Affected
women have been reported to have a higher chance of
having a severely affected child than do affected men. The
severity of defects associated with HOS has also been
reported to increase with successive generations. The pos-
sible explanations for these observations are not known.
Resources
BOOKS
Jones, Kenneth L. Smith’s Recognizable Patterns of Human
Malformation. Philadelphia, PA: W.B. Saunders
Company, 1997.
PERIODICALS
Newbury, R.A., R. Leanage, J.A. Raeburn, and I.D. Young.
“Holt-Oram Syndrome: A clinical genetic study.” Journal

of Medical Genetics (April 1996): 300-307.
Jennifer A. Roggenbuck, MS, CGC
I
Homocystinuria
Definition
The term homocystinuria is actually a description of
a biochemical abnormality, as opposed to the name of a
particular disease, although many refer to homocystin-
uria as a disease. Homocystinuria refers to elevated lev-
els of homocysteine in the urine. This can be caused by
different biochemical abnormalities and in fact there are
Homocysteine is involved with the catabolism of
methionine. Methionine is an essential amino acid.
Amino acids are the building blocks of proteins. Over 100
amino acids are found in nature, but only 22 are found in
humans. Of these 22 amino acids, eight are essential for
human life, including methionine. Methionine comes
from dietary protein. Generally, the amount of methion-
ine that is consumed is more than the body needs. Excess
methionine is converted to homocysteine, which is then
metabolized into cystathionine; cystathionine is then con-
verted to cysteine. The cysteine is excreted in the urine.
Each step along this pathway is carried out by a specific
enzyme and that enzyme may even require help from
vitamin co-factors to be able to complete the job. For
example, the conversion of homocysteine to cystathion-
ine by cystathionine b-synthase requires vitamin B
6
(pyri-
doxine). If cystathionine b-synthase is missing, then

homocysteine cannot be broken down into cystathionine
and cysteine, and instead, homocysteine accumulates and
the elevated levels of homocysteine and methionine can
be found in the blood. Also, decreased levels of cysteine
can be found in the blood. Elevated levels of homocys-
teine lead to a disease state that, if untreated, affects mul-
tiple systems, including the central nervous system, the
eyes, the skeleton, and the vascular system.
Genetic profile
Classical homocystinuria or cystathionine b-syn-
thase (CBS) deficiency is an autosomal recessive condi-
tion. This means that in order to have the condition, an
individual must inherit one copy of the gene for CBS
deficiency from each parent. An individual who has only
one copy of the gene is called a carrier for the condition.
In most cases of autosomal recessive inheritance a car-
rier for a condition does not have any signs, symptoms,
or effects of the condition. This is not necessarily the case
with CBS deficiency. Individuals who are carriers for
CBS deficiency may have levels of homocysteine that are
elevated enough to increase the risk for thromboembolic
events. So, although carriers may not exhibit obvious
physical signs or symptoms of the condition, they may
have clinical effects of elevated levels of homocysteine,
such as vascular or cardiovascular disease. A carrier for
CBS deficiency can have vascular complications, espe-
cially if they are also carriers for other clotting disorders
such as factor V Leiden thrombophilia.
When two parents are carriers for CBS deficiency,
there is a one in four or 25% chance, with each preg-

nancy, for having a child with CBS deficiency. They have
a one in two or 50% chance for having a child who is a
carrier for the condition and a one in four or 25% chance
for having a child who is neither affected nor a carrier for
CBS deficiency.
562
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
Homocystinuria
KEY TERMS
Anabolism—The energy-using process of building
up complex chemical compounds from simpler
ones in the body.
Catabolism—The energy-releasing process of
breaking down complex chemical compounds
into simpler ones in the body.
Marfan syndrome—A syndrome characterized by
skeletal changes (arachnodactyly, long limbs, lax
joints), ectopia lentis, and vascular defects.
Thrombophilia—A disorder in which there is a
greater tendency for thrombosis (clot in blood
vessel).
at least eight different gene changes that are known to
cause excretion of too much homocysteine in the urine.
The best known and most common cause of homocystin-
uria is the lack of cystathionine b-synthase. For the pur-
pose of this entry we will be referring to “classical
homocystinuria” that is caused by cystathionine b-syn-
thase deficiency (CBS deficiency).
Description
In Northern Ireland in the early 1960s, homocystin-

uria was described in individuals who were mentally
retarded. Soon after that, it was shown that the cause of
the homocystinuria was a deficiency of the enzyme cys-
tathionine b-synthase. This condition is an inborn error of
metabolism, meaning that the cause for this condition is
present from birth and it affects metabolism.
Metabolism is the sum of all of the chemical
processes that take place in the body. Metabolism
includes both construction (anabolism) and break down
(catabolism) of important components. For example,
amino acids are the building blocks for proteins and are
converted to proteins through many steps in the process
of anabolism. In contrast, proteins can also be broken
down into amino acids through many steps in the process
of catabolism. These processes require multiple steps that
involve different substances called enzymes. These
enzymes are proteins that temporarily combine with
reactants and in the process, allow these chemical
processes to occur quickly. Since practically all of the
reactions in the body use enzymes, they are essential for
life. At any point along the way, if an enzyme is missing,
the particular process that requires that enzyme would
not be able to be completed as usual. Such a situation can
lead to disease.
The gene for CBS has been mapped to the long arm
of chromosome 21, specifically at 21q22.3. Approxi-
mately 100 different disease-associated gene changes or
alterations of the CBS gene have been identified. The two
most frequently encountered gene changes are 1278T
and G307S. G307S is the most common cause of CBS

deficiency in Irish patients and the 1278T gene is the
most common cause of CBS deficiency in Italian
patients.
Demographics
The worldwide frequency of individuals with CBS
deficiency who are identified through newborn screening
and clinical detection is approximately one in 350,000;
however, newborn screening may be missing half of
affected patients and thus the worldwide incidence may
be as high as one in 180,000. One study showed that by
lowering the cutoff level of methionine from 2 mg per
deciliter to 1 mg per deciliter in newborn screening, detec-
tion of the deficiency increased from 1 in 275,000 to 1 in
157,000. The incidence of CBS deficiency in the United
States population is 1 in 58,000; in the Irish population it
is estimated to be 1 in 65,000; in the Italian population it
is 1 in 55,000 and in the Japanese population it is 1 in
889,000. CBS deficiency has been seen in persons of
many different ethnic origins living in the United States.
Signs and symptoms
Individuals who have CBS deficiency tend to be tall
and thin with thinning and lengthening of the bones.
They tend to have a long, narrow face and high arched
palate (roof of the mouth). The thinning and lengthening
of the long bones causes individuals to be tall and thin by
the time they reach late childhood. Their fingers tend to
be long and thin as well (referred to as arachnodactyly).
They can have curvature of the spine, called scoliosis.
Their chest can be sunken in (pectus excavatum) or it
may protrude out (pectus carinatum). Osteoporosis may

occur. Also, they tend to have stiff joints. CBS deficiency
affects the eyes, causing dislocated lenses and nearsight-
edness (myopia). Untreated individuals or those individ-
uals who do not respond to treatment develop mental
retardation or learning disabilities. Affected individuals
may also develop psychiatric problems. These psychi-
atric problems may include depression, chronic behav-
ior problems, chronic obsessive-compulsive disorder, and
personality disorders. The most frequent cause of death
associated with CBS deficiency is blood clots that form
in veins and arteries. These are known as thromboem-
bolisms, and include deep vein thrombosis (blood clots
that form in the deep veins of the legs, etc.), pulmonary
embolus (blood clots that form in the lungs), and strokes.
Thromboembolism can occur even in childhood. When
thromboembolism does occur in childhood, CBS defi-
ciency should always be considered as a cause for the
thromboembolic events. These thromboembolic events
can occur in any part of the body. Lastly, another com-
plication of CBS deficiency is severe premature arte-
riosclerosis (hardening of the arteries).
Diagnosis
Approximately 50% of individuals who have CBS
deficiency are diagnosed by newborn screening because
they have an elevated level of methionine in their blood.
The reason for performing newborn screening is so that
infants affected with genetic disorders can be identified
early enough to be treated. The screening is done by col-
lecting blood from a pin-prick on the baby’s heel prior to
leaving the hospital, but at least 24 hours after birth. For

CBS deficiency, the screening test checks for elevated
levels of methionine. If the levels are elevated then fol-
low-up testing to verify the diagnosis is performed. There
are other disorders of methionine metabolism, and fol-
low-up testing determines the underlying cause of the
positive newborn screen.
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
563
Homocystinuria
Homocystinuria
(Gale Group)
If not identified at newborn screening, diagnosis is
made by identifying low levels of cysteine in blood and
urine. Measurements of the amount of methionine and
homocysteine produced by cultured blood cells (lym-
phoblasts) or cultured skin cells (fibroblasts) also can
confirm the diagnosis of CBS deficiency.
DNA testing is available for families in which a gene
alteration is identified. Potentially, this makes prenatal
diagnosis by chorionic villus sampling (CVS) and
amniocentesis available for families who have had a
previously affected child and in which two identifiable
gene alterations for CBS deficiency have been detected.
Prenatal diagnosis is also possible by measuring the
amount of enzyme activity in cultured cells grown from
amniotic fluid.
CBS deficiency has several features in common with
Marfan syndrome, including the tall, thin build with
long limbs and long, thin fingers (arachnodactyly), a
sunken-in chest (pectus excavatum), and dislocated

lenses. The dislocated lens in Marfan syndrome tends to
be dislocated upward; the tendency for the lens disloca-
tion is to be downward in CBS deficiency. Also, individ-
uals who have Marfan syndrome tend to have lens
dislocation from birth (congenital) whereas individuals
who have CBS deficiency have not been identified to
have lens dislocation before 2 years of age.
Treatment and management
The first choice of therapy for patients with CBS
deficiency is administration of pyridoxine (vitamin B
6
).
Vitamin B
6
is the cofactor for the cystathionine b-syn-
thase reaction. Potentially, some individuals who have
CBS deficiency are not missing the enzyme, but rather
have an enzyme that is unable to perform its job. The
addition of pyridoxine can help to push the reaction along
and thus help to reduce the levels of homocysteine and
methionine in the blood. Information suggests that
approximately 50% of patients with CBS deficiency
respond to high doses of pyridoxine (pyridoxine respon-
sive) and show a significant reduction in levels of homo-
cysteine in the blood. Patients who do not respond to
pyridoxine treatment (pyridoxine non-responsive) tend to
be more severely affected than the patients who do
respond. Those non-responding patients are treated with
combinations of folic acid, hydroxycobalamin, and
betaine, which stimulate the conversion of homocysteine

back to methionine. The reason that the addition of folic
acid can help is because within the methylene H4-folate
564
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
Homocystinuria
Pyridoxine (vitamin B
6
)
(co-factor)
+
Cystathionine
b-synthase
dietary intake of
Methionine
(found in dietary protein)
Homocysteine Cystathionine Cysteine
(excreted in urine)
Betaine
acts here
Methionine
synthase
Methyl-B
12
H
4
-folate Methyl-H
4
-folate
Dietary cobalamin
Methylene H

4
-folate
Methylene H
4
-folate reductase
dietary folic acid or folate
acts
here
acts
here
acts
here
acts
here
Flow chart for the chemical processes involved in the breakdown of methionine, an essential amino acid found in dietary
protien. Homocystinuria results when the enzyme cystathionine b-synthase is missing and does not break down
homocystine, a converted form of excess methionine. The elevated levels of methionine and homocystein that result from
the failure of homocysteine to break down into cystathionine and cysteine causes a disease state that affects multiple body
systems.
(Gale Group)
(MTHFR) molecule, there is a molecule known as flavin
adenine dinucleotide, or FAD. The FAD molecule binds
to the MTHFR molecule and helps with the conversion of
homocysteine to methionine. Increased levels of folates
help bind FAD more tightly to MTHFR, protect the
enzyme against heat inactivation, and allow the homo-
cysteine to methionine conversion pathway to proceed.
Betaine and cobalamin also help in the conversion of
homocysteine to methionine by acting as cofactors. The
rationale behind this method of treatment is that although

the methionine levels are raised, the net drop in homo-
cysteine is beneficial as it appears that the elevated levels
of homocysteine are what cause ectopia lentis, osteo-
porosis, mental deficiency, and thromboembolic events.
It appears that the addition of dietary betaine in
B
6
-responsive patients is also beneficial. Homocysteine
that is not metabolized to cysteine is converted back to
methionine in a reaction that uses betaine, so the addition
of betaine may help to make this reaction occur and thus
reduce the levels of homocysteine.
Other treatments include protein restriction, specifi-
cally a low methionine diet with the addition of extra cys-
teine. Dietary treatment includes avoidance of all high
protein foods throughout life, with the use of a nutritional
supplement. Special formulas for infants are available.
The reasoning behind this is to reduce the methionine and
homocysteine levels that accumulate and supplement the
low levels of cysteine.
The occurrence of clinically apparent thromboem-
bolism depends upon the age of the affected individual
and whether or not he/she responds to pyridoxine treat-
ment. In one study, untreated pyridoxine-responsive
patients were at little risk for a thromboembolic event
until age 12. After age 12, the risk for thromboembolism
increased. By age 20, patients who would have been
responsive to pyridoxine had a 25% cumulative risk for a
thromboembolic event. In comparison, individuals with
CBS deficiency who were untreated and not responsive

to pyridoxine treatment had a similar cumulative risk for
a thromboembolic event by age 15.
In reference to the two common CBS gene alter-
ations, CBS deficiency caused by the 1278T gene change
is pyridoxine responsive. CBS deficiency caused by the
G307S gene tends to be pyridoxine non-responsive; how-
ever this is not always the case as some individuals with
the G307S gene change are pyridoxine responsive.
Very little is known about the risks to an unborn
child of a mother with pyridoxine non-responsive CBS
deficiency. There have been numerous reports of healthy
children born to women and men who have pyridoxine
responsive CBS deficiency, however only two reports of
children born to pyridoxine non-responsive women have
been reported and one had multiple birth defects that may
have been related to the mother’s condition. Potentially,
the mother’s elevated levels of homocysteine can cause
problems for a developing baby. This could be similar to
the process by which infants of mothers who have
phenylketonuria are affected by the elevated levels of
phenylalanine if their mothers are not being treated with
dietary restriction during pregnancy.
Prognosis
Untreated CBS deficiency leads to mental retarda-
tion, lens dislocation, and a decreased life expectancy
because of complications associated with blood clots. If
untreated from early infancy, approximately 20% of
affected patients will have seizures. If treated from birth,
prevention or long term delay of the complications of
CBS deficiency can be expected.

Resources
BOOKS
Scriver, C.R., A.L. Beaudet, W.S. Sly, and D. Valle, eds. The
Metabolic Basis of Inherited Disease. 6th ed. New York:
McGraw-Hill Medical Publishing Division, 1989.
ORGANIZATIONS
National Organization for Rare Disorders (NORD). PO Box
8923, New Fairfield, CT 06812-8923. (203) 746-6518 or
(800) 999-6673. Fax: (203) 746-6481. Ͻhttp://www
.rarediseases.orgϾ.
WEBSITES
Climb: Children Living with Inherited Metabolic Diseases
Support Group. ϽϾ.
Reneé A. Laux, MS
Homogentisic acid oxidose deficiency see
Alkaptonuria
I
Human Genome Project
The Human Genome Project (HGP) is the interna-
tional project to sequence the DNA of the human genome.
The sequencing work is conducted in many laboratories
around the world, but the majority of the work is being
done by five institutions: the Whitehead Institute for
Medical Research in Massachusetts (WIMR), the Baylor
College of Medicine in Texas, the University of
Washington, the Joint Genome Institute in California, and
the Sanger Centre near Cambridge in the United Kingdom.
Most of the funding for these centers is provided by the
United States National Institute of Health and Department
GALE ENCYCLOPEDIA OF GENETIC DISORDERS

565
Human Genome Project
of Energy, and the Wellcome Trust, a charitable foundation
in the UK.
Completely sequencing the human genome was first
suggested at a conference in Alta, Utah in 1984. The con-
ference was convened by the U.S. Department of Energy,
which was concerned with measuring the mutation rate
of human DNA when exposed to low-level radiation,
similar to conditions after an attack by nuclear weapons.
The technology to make such measurements did not exist
at the time, and the sequence of the genome was one step
required for this aim to become possible. The genome
was estimated to be 3000Mb long, however, and
sequencing it seemed an arduous task, especially using
the sequencing technology of the time. If most of the
DNA was “junk” (not coding for genes), then scientists
assumed that they could speed the process along by tar-
geting specific genes for sequencing. This could be done
by sequencing complementary DNAs (cDNA) which are
derived from mRNAs used to code for proteins in the
cell. Despite several advocates for this method, it was
decided that the whole genome would be sequenced, with
a target completion date of 2005. The Human Genome
Project quickly became the world’s premier science proj-
ect for biology, involving large factory-like laboratories
rather than small laboratories of independent geneticists.
The strategy employed by the HGP involved three
stages, and is termed hierarchical shotgun sequencing.
The first stage involved generating physical and genetic

maps of the human genome. The second stage was plac-
ing clones from a genomic library on to these maps. The
third stage was fragmenting these genomic clones into
smaller overlapping clones (shotgun cloning), which
were a more suitable size for sequencing. Then, the com-
plete sequence of each chromosome could be recon-
structed by assembling the fragments of sequence that
overlapped with each other to generate the sequence of
the genomic clone. The sequence of each genomic clone
could then be fitted together using the assembly (contig)
of genomic clones on the genetic and physical map.
Although the ultimate aim was high-quality
sequence of the human genome, it was recognized that
the genetic and physical maps generated by the first stage
of the HGP would be by themselves very useful for
genetic research. The first generation physical map was
constructed by screening a yeast artificial chromosome
(YAC) genomic library to isolate YACs, and overlaps
were identified by restriction enzyme digest “finger-
prints” and STS content mapping. These STSs were
sequenced around the highly polymorphic CA-repeat
markers (microsatellites) that were used to generate the
genetic map. Genetic maps were also constructed. These
use recombination between markers in families to deduce
the distance separating and order of these markers. The
first human genetic map used restriction fragment length
polymorphisms (RFLPs) as markers, which only have
two alleles per marker, but common microsatellites were
used to create a high resolution genetic map.
The second stage of human genome sequencing was

made simpler by the development of bacterial artificial
chromosomes (BACs), cloning vectors that could carry up
to 150kb of DNA. Before then, it was assumed that a con-
tig of YACs and cosmids, carrying up to 2Mb and 40kb of
DNA respectively, would be assembled. These two types of
genomic clone were found to be liable to rearrangement;
the DNA in the vector could be in chunks that were not
necessarily in the same order as in the genome. The BAC
vector did not rearrange DNA, and could carry more DNA
than many other types of genomic clone.
The third stage was made easier by development of
high-throughput DNA sequencing and affordable com-
puting power to enable reassembly of the sequence frag-
ments. It was these developments that led to the idea of
whole genome shotgun sequencing of the human
genome. In contrast to the HGP plan involving the use of
genetic contigs and physical maps as a framework for
genomic clones and sequence, scientists suggested that
the whole genome could be fragmented into small
chunks for sequencing, and then reassembled using over-
lap between fragment sequences (whole genome shotgun
sequencing). This required large amounts of computing
power to generate the correct assembly, but was consid-
erably faster than the HGP approach. Many scientists did
not believe that this method would assemble the genome
properly, and suggested that overlap between small frag-
ments could not be the only guide to assembly, because
the genome contained many repeated DNA sequences.
However, American biochemist J. Craig Venter believed
the method could work, and formed Celera, a private

company that would sequence the human genome before
the HGP. Celera demonstrated that the whole genome
shotgun method would work by sequencing the genome
of a model organism, the fruit fly Drosophila
melanogaster. Despite the successful sequencing of the
fly, many people were still skeptical that the method
would be successful for the bigger human genome. The
publicly funded HGP, in light of Celera’s competition,
decided to concentrate, like Celera, on a draft of the
human genome sequence (3x coverage—that is each
nucleotide has been sequenced an average of three
times), before generating a more accurate map of 8x cov-
erage. Celera had an advantage, because the HGP had
agreed to release all its data as it was generated on to a
freely accessible database, as part of the Bermuda rules
(named after the location of a series of meetings during
the early stages of the HGP). This allowed Celera to use
566
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
Human Genome Project
HGP data to link its sequence fragments with the BAC
contigs and genetic/physical maps.
The human genome draft sequence of both groups
were published in February 2001 by Celera and the HGP
consortium in the journals Science and Nature, respec-
tively. Celera had imposed restrictions on access to its
genomic data, and this was a source of disagreement
between the private company and the HGP. Celera scien-
tists argue that their methods are cheaper and quicker
than the HGP framework method, but HGP scientists, in

turn, argue that Celera’s assembly would not have been
possible without the HGP data.
For human geneticists in general, and medical
researchers in particular, the genome sequence is abun-
dantly useful. Even in its draft form (the complete version
is due in 2003) the ability to identify genes, single
nucleotide polymorphisms, from a database search speeds
up research. Previously, mapping and finding (positional
cloning) a gene would take several years of research, a
task which now takes several minutes. The investment in
the sequencing centers will continue to be of use, with a
mouse sequencing project underway, and many genomes
of pathogenic bacteria sequenced. This study of genomes
and parts of genomes has been called genomics. The med-
ical benefits of genomics were emphasized throughout the
project partly to ensure continuing government support.
These benefits are not likely to be immediate nor direct,
but the genome sequence will have the greatest effect on
pharmocogenetics, which studies how genetic variants can
affect how well a drug can treat a disease. The impact on
non-scientists has been substantial, with the HGP sug-
gested to be the ultimate in self knowledge. Although the
mapping of the human genome by the HGP is an impor-
tant scientific achievement, WIMR director Eric Lander
offered a humbling perspective regarding the amount of
information yet to be discovered by future generations of
scientists. In a speech at the White House, Lander said,
“We’ve called the human genome the blueprint, the Holy
Grail, all sorts of things. It’s a parts list. If I gave you the
parts list for the Boeing 777, and it has 100,000 parts, I

don’t think you could screw it together, and you certainly
wouldn’t understand why it flew.”
Edward J. Hollox, PhD
I
Hunter syndrome
Definition
Hunter syndrome is a defect in the ability to metab-
olize a type of molecule known as a mucopolysaccharide.
Only males are affected. Short stature, changes in the
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
567
Hunter syndrome
KEY TERMS
Kyphosis—An abnormal outward curvature of the
spine, with a hump at the upper back.
Mucopolysaccharide—A complex molecule made
of smaller sugar molecules strung together to form
a chain. Found in mucous secretions and intercel-
lular spaces.
normal curvature of the spine (kyphosis), a distinctive
facial appearance characterized by coarse features, an
oversized head, thickened lips, and a broad, flat nose
characterize the syndrome.
Description
Hunter syndrome is a one of a group of diseases
called mucopolysaccharidoses. It is caused by the defi-
ciency of an enzyme that is required to metabolize or
break down mucopolysaccharides (also called gly-
cosaminoglycans). It is also called mucopolysaccharido-
sis Type II (MPS II) because there are several related but

similar diseases. The Hunter syndrome involves a defect
in the extracellular matrix of connective tissue. One of the
components of the extracellular matrix is a molecule
called a proteoglycan. Like most molecules in the body, it
is regularly replaced. When this occurs, one of the prod-
ucts is a class of molecules known as mucopolysaccha-
rides (glycosoaminoglycans). Two of these are important
in Hunter syndrome: dermatan sulfate and heparan sul-
fate. These are found in the skin, blood vessels, heart and
heart valves (dermatan sulfate) and lungs, arteries and
cellular surfaces (heparan sulfate). The partially broken-
down molecules are collected by lysosomes and stored in
various locations in the body. Over time, these accumula-
tions of partially metabolized mucopolysaccharides
impair the heart, nervous system, connective tissue, and
bones.
Both of these molecules require the enzyme
iduronate-2-sulfatase (I2S) to be broken down. In people
with Hunter syndrome, this enzyme is partially or com-
pletely inactive. As a result, unchanged molecules accu-
mulate in cells. These mucopolysaccharides are stored
and interfere with normal cellular functions. The rate of
accumulation is not the same for all persons with Hunter
syndrome. Variability in the age of onset is thought to be
due to lingering amounts of activity by this enzyme.
The cells in which mucopolysaccharides are stored
determine the symptoms that develop. When mucopoly-
saccharides are stored in skin, the proportions of the face
change (coarser features than normal and an enlarged
head). When they are stored in heart valves and walls,

cardiac function progressively declines. If intact
mucopolysaccharides are stored in airways of the lung,
difficulty in breathing develops due to obstruction of the
upper airway. Storage of the molecules in joints
decreases mobility and dexterity. Storage in bones results
in decreased growth and short stature. As mucopolysac-
charides are stored in the brain, levels of mental func-
tioning decline.
There are two variants of Hunter syndrome: a severe
form (MPSIIA) and a mild form (MPSIIB). These can be
diagnosed early in life and are distinguished on the basis
of mental and behavioral differences. External manifesta-
tions of the severe form occur between two and four
years of age and the mild form later, up to age 10.
Genetic profile
In both variants, the missing enzyme is L-
Sulfoiduronate. Hunter syndrome is X-linked meaning
that the I2S gene is located on the X chromosome. The
Y chromosome of a male is never affected in Hunter syn-
drome. Males only have one copy of the I2S gene while
females have two. A male who inherits an abnormal I2S
gene will develop Hunter syndrome. This can occur in
two ways: from a mother who already has the gene (she
is a carrier) or from a fresh mutation. Fresh mutations are
unusual.
There are four possible genetic configurations. (1) A
male can have a normal I2S gene and will be unaffected.
(2) A male can have an abnormal I2S gene and will have
Hunter syndrome. Should this male reproduce, his sons
will not have Hunter syndrome and his daughters will all

be carriers. (3) A female can have two normal I2S genes
and be unaffected. (4) A female can have one abnormal
I2S gene and be a carrier. Should this female reproduce,
half of her sons will, on average, have Hunter syndrome.
Half of her daughters, on average, will be carriers. It is
possible that no sons will have Hunter syndrome or no
daughters will be carriers.
Demographics
Several estimates of the incidence of Hunter syn-
drome have been published. They vary from one in
72,000 male births (Northern Ireland) to one in 150,000
(United States). Because it is carried on the X chromo-
some, only males can be affected.
Signs and symptoms
Individuals with Hunter syndrome experience a
slowing of growth between one and four years of age.
They attain an average height of 4-5 feet (122-152 cm).
The facial features of persons with Hunter syndrome are
coarser than normal. Their heads tend to be large in pro-
portion to their bodies. Over time, their hands tend to
become stiff and assume a claw-like appearance. Their
teeth are delayed in erupting. Progressive hearing loss
eventually leads to deafness. Internal organs such as the
liver and spleen are larger than normal. They are quite
prone to hernias.
Diagnosis
Hunter syndrome can be identified early in life and
is often initially diagnosed by the presence of an enlarged
liver and spleen (hepatosplenomegaly), hernias, or joint
stiffness. Skeletal changes can be seen with radiographs.

Elevated mucopolysaccharide levels in urine focuses the
diagnosis to a group of disorders. The concentration of
dermatan sulfate and heparan sulfate is 5-25 times higher
than in normal urine. Both are present in approximately
the same amounts. The diagnosis of Hunter syndrome is
confirmed by measuring iduronate-2-sulfatase activity in
white blood cells, serum, or skin fibroblasts. Prenatal
diagnosis is widely available by measuring the activity of
I2S enzyme in amniotic fluid.
Hunter syndrome has many diagnostic characteris-
tics in common with Hurler syndrome. However, there
are some distinct differences between the two syn-
dromes. Individuals with Hunter syndrome have clear
corneas and tend to have deposits of mucopolysaccha-
rides in the skin. These are characteristically on the back
of the hands and elbows (the extensor surfaces) and on
the upper surfaces of the shoulders. All are males. These
differences are important in diagnosis.
Treatment and management
General support and treatment of specific symptoms
are the only treatment options presently available.
Iduronate-2-sulfatase can be made using cells that have
been genetically engineered. However, as of 2001, the
safety and clinical effectiveness of injecting I2S into
humans has not been established.
Intrauterine testing of amniotic fluid is reliable. Tests
to detect a carrier state are imperfect. There is no cure for
Hunter syndrome. The heparan sulfate and dermatan sul-
fate in urine has no pathological significance.
Prognosis

In the severe form, death usually occurs by age 10-
15. Persons with the mild form usually live near-normal
lives and have normal intelligence.
568
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
Hunter syndrome
Resources
BOOKS
Jones, K. L. “Hunter Syndrome.” In Smith’s Recognizable
Patterns of Human Malformation. Edited by Kenneth L.
Jones and Judy Fletcher. 5th ed. Philadelphia: Saunders,
1997, pp. 462-463.
McGovern, Margaret M., and Robert J. Desnick. “Lysosomal
storage diseases.” In Cecil Textbook of Medicine. Edited by
Lee Goldman, et al. 21st ed. Philadelphia: Saunders, 1999,
pp. 1104-1108.
Muenzer, Joseph L. “Mucopolysaccharidoses.” In Nelson
Textbook of Pediatrics. Richard E. Behrman et al., 16th ed.
Philadelphia: Saunders, 2000, pp. 420-423.
PERIODICALS
Hunter, C. “A rare disease in two brothers.” Proceedings of the
Royal Society of Medicine. 1917: 10:104.
ORGANIZATIONS
Alliance of Genetic Support Groups. 4301 Connecticut Ave.
NW, Suite 404, Washington, DC 20008. (202) 966-5557.
Fax: (202) 966-8553. ϽϾ.
Canadian Society for Mucopolysaccharide and Related
Diseases. PO Box 64714, Unionville, ONT L3R-OM9
Canada. (905) 479-8701 or (800) 667-1846. Ͻhttp://www
.mpssociety.caϾ.

Children Living with Inherited Metabolic Diseases. The
Quadrangle, Crewe Hall, Weston Rd., Crewe, Cheshire,
CW1-6UR UK. 127 025 0221. Fax: 0870-7700-327.
ϽϾ.
National MPS Society. 102 Aspen Dr., Downingtown, PA
19335. (601) 942-0100. Fax: (610) 942-7188. info
@mpssociety.org. ϽϾ.
National Organization for Rare Disorders (NORD). PO Box
8923, New Fairfield, CT 06812-8923. (203) 746-6518 or
(800) 999-6673. Fax: (203) 746-6481. Ͻhttp://www
.rarediseases.orgϾ.
Society for Mucopolysaccharide Diseases. 46 Woodside Rd.,
Amersham, Buckinghamshire, HP6 6AJ UK. ϩ44 (01494)
434156. ϽϾ.
WEBSITES
“Hunter syndrome.” Transkaryotic Therapies, Inc. Ͻhttp://
www.tktx.com/c_patient_hunter.htmϾ.
“Hunter syndrome.” University of Maryland Medicine.
Ͻ />.htmϾ.
National MPS Society. Ͻ />.htmϾ.
L. Fleming Fallon, Jr., MD, DrPH
Huntington chorea see Huntington disease
I
Huntington disease
Definition
Huntington disease is a progressive, neurodegenera-
tive disease causing uncontrolled physical movements
and mental deterioration. The disease was discovered by
George Huntington of Pomeroy, Ohio, who first
described a hereditary movement disorder.

Description
Huntington disease is also called Huntington chorea,
from the Greek word for “dance,” referring to the invol-
untary movements that develop as the disease progresses.
It is occasionally referred to as “Woody Guthrie disease”
for the American folk singer who died from it.
Huntington disease (HD) causes progressive loss of cells
in areas of the brain responsible for some aspects of
movement control and mental abilities. A person with HD
gradually develops abnormal movements and changes in
cognition (thinking), behavior, and personality.
Demographics
The onset of symptoms of HD is usually between the
ages of 30 and 50, although in 10% of cases, onset is in
late childhood or early adolescence. Approximately
30,000 people in the United States are affected by HD,
with another 150,000 at risk for developing this disorder.
The frequency of HD is four to seven per 100,000 persons.
Genetic profile
Huntington disease is caused by a change in the
gene (an inherited unit which contains a code for a pro-
tein) of unknown function called huntingtin. The
nucleotide codes (building blocks of genes arranged in a
specific code that chemically form proteins), contain
CAG repeats (40 or more of these repeat sequences). The
extra building blocks in the huntingtin gene cause the
protein that is made from it to contain an extra section as
well. It is currently thought that this extra protein section,
or portion, interacts with other proteins in brain cells
where it occurs, and that this interaction ultimately leads

to cell death.
The HD gene is a dominant gene, meaning that only
one copy of it is needed to develop the disease. HD
affects both males and females. The gene may be inher-
ited from either parent, who will also be affected by the
disease. A parent with the HD gene has a 50% chance of
passing it on to each offspring. The chances of passing on
the HD gene are not affected by the results of previous
pregnancies.
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
569
Huntington disease
Cognitive changes include loss of ability to plan and
execute routine tasks, slowed thought, and impaired or
inappropriate judgment. Short-term memory loss usually
occurs, although long-term memory is usually not affected.
The person with late-stage HD usually retains knowledge
of his environment and recognizes family members or
other loved ones, despite severe cognitive decline.
Diagnosis
Diagnosis of HD begins with a detailed medical his-
tory, and a thorough physical and neurological exam.
Family medical history is very important. Magnetic reso-
nance imaging (MRI) or computed tomography scan (CT
scan) imaging may be performed to look for degeneration
in the basal ganglia and cortex, the brain regions most
affected in HD.
A genetic test is available for confirmation of the
clinical diagnosis. In this test, a small blood sample is
taken, and DNA from it is analyzed to determine the

CAG repeat number. A person with a repeat number of 30
or below will not develop HD. A person with a repeat
number between 35 and 40 may not develop the disease
within their normal lifespan. A person with a very high
number of repeats (70 or above) is likely to develop the
juvenile-onset form. An important part of genetic test-
ing is extensive genetic counseling.
Prenatal testing is available. A person at risk for HD
(a child of an affected person) may obtain fetal testing
without determining whether she herself carries the gene.
This test, also called a linkage test, examines the pattern
of DNA near the gene in both parent and fetus, but does
not analyze for the triple nucleotide repeat (CAG). If the
DNA patterns do not match, the fetus can be assumed not
to have inherited the HD gene, even if present in the par-
ent. A pattern match indicates the fetus probably has the
same genetic makeup of the at-risk parent.
Treatment and management
There is no cure for HD, nor any treatment that can
slow the rate of progression. Treatment is aimed at reduc-
ing the disability caused by the motor impairments, and
treating behavioral and emotional symptoms.
Physical therapy is used to maintain strength and
compensate for lost strength and balance. Stretching and
range of motion exercises help minimize contracture, or
muscle shortening, a result of weakness and disuse. The
physical therapist also advises on the use of mobility aids
such as walkers or wheelchairs.
Motor symptoms may be treated with drugs,
although some studies suggest that anti-chorea treatment

rarely improves function. Chorea (movements caused by
abnormal muscle contractions) can be suppressed with
570
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
Huntington disease
KEY TERMS
Cognition—The mental activities associated with
thinking, learning, and memory.
Computed tomography (CT) scan—An imaging
procedure that produces a three-dimensional pic-
ture of organs or structures inside the body, such as
the brain.
Deoxyribonucleic acid (DNA)—The genetic
material in cells that holds the inherited instruc-
tions for growth, development, and cellular func-
tioning.
Heimlich maneuver—An action designed to expel
an obstructing piece of food from the throat. It is
performed by placing the fist on the abdomen,
underneath the breastbone, grasping the fist with
the other hand (from behind), and thrusting it
inward and upward.
Neurodegenerative—Relating to degeneration of
nerve tissues.
Signs and symptoms
The symptoms of HD fall into three categories:
motor or movement symptoms, personality and behav-
ioral changes, and cognitive decline. The severity and
rate of progression of each type of symptom can vary
from person to person.

Early motor symptoms include restlessness, twitch-
ing and a desire to move about. Handwriting may become
less controlled, and coordination may decline. Later
symptoms include:
• Dystonia, or sustained abnormal postures, including
facial grimaces, a twisted neck, or an arched back.
• Chorea, in which involuntary jerking, twisting, or
writhing motions become pronounced.
• Slowness of voluntary movements, inability to regulate
the speed or force of movements, inability to initiate
movement, and slowed reactions.
• Difficulty speaking and swallowing due to involvement
of the throat muscles.
• Localized or generalized weakness and impaired bal-
ance ability.
• Rigidity, especially in late-stage disease.
Personality and behavioral changes include depres-
sion, irritability, anxiety and apathy. The person with HD
may become impulsive, aggressive, or socially with-
drawn.
drugs that deplete dopamine, an important brain chemi-
cal regulating movement. As HD progresses, natural
dopamine levels fall, leading to loss of chorea and an
increase in rigidity and movement slowness. Treatment
with L-dopa (which resupplies dopamine) may be of
some value. Frequent reassessment of the effectiveness
and appropriateness of any drug therapy is necessary.
Occupational therapy is used to design compensa-
tory strategies for lost abilities in the activities of daily
living, such as eating, dressing, and grooming. The occu-

pational therapist advises on modifications to the home
that improve safety, accessibility, and comfort.
Difficulty swallowing may be lessened by prepara-
tion of softer foods, blending food in an electric blender,
and taking care to eat slowly and carefully. Use of a straw
for all liquids can help. The potential for choking on food
is a concern, especially late in the disease progression.
Caregivers should learn the use of the Heimlich maneu-
ver. In addition, passage of food into the airways increases
the risk for pneumonia. A gastric feeding tube may be
needed, if swallowing becomes too difficult or dangerous.
Speech difficulties may be partially compensated by
using picture boards or other augmentative communica-
tion devices. Loss of cognitive ability affects both speech
production and understanding. A speech-language
pathologist can work with the family to develop simpli-
fied and more directed communication strategies, includ-
ing speaking slowly, using simple words, and repeating
sentences exactly.
Early behavioral changes, including depression and
anxiety, may respond to drug therapy. Maintaining a
calm, familiar, and secure environment is useful as the
disease progresses. Support groups for both patients and
caregivers form an important part of treatment.
Experimental transplant of fetal brain tissue has been
attempted in a few HD patients. Early results show some
promise, but further trials are needed to establish the
effectiveness of this treatment.
Prognosis
The person with Huntington disease may be able to

maintain a job for several years after diagnosis, despite
the increase in disability. Loss of cognitive functions and
increase in motor and behavioral symptoms eventually
prevent the person with HD from continuing employ-
ment. Ultimately, severe motor symptoms prevent mobil-
ity. Death usually occurs 15–20 years after disease onset.
Progressive weakness of respiratory and swallowing
muscles leads to increased risk of respiratory infection
and choking, the most common causes of death. Future
research in this area is currently focusing on nerve cell
transplantation.
Resources
BOOK
Watts, R. L., and W. C. Koller, eds. Movement Disorders. New
York: McGraw-Hill, 1997.
ORGANIZATION
Huntington Disease Society of America. 140 W. 22nd St. New
York, NY 10011. (800) 345-HDSA.
Laith F. Gulli, MD
GALE ENCYCLOPEDIA OF GENETIC DISORDERS
571
Huntington disease
Huntington Disease
= Affected Symptomatic individual
= Affected Presymptomatic individual
d.74y
dx.68y
d.59y
dx.50y
d.50y

dx.42y
d.48y
dx.46y
d.30y
dx.29y
d.58y
dx.48y
d.30y
dx.28y
44y40y
46y
26y27y32y28y31y
53y54y60y62y
(Gale Group)