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

High density hypoprotein deficiency seeTangier disease Definition Hirschsprung’s disease, also known as congenital megacolon or aganglionic megacolon, is an abnormality in which certain

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 comuncom-plicated 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

In autosomal dominant HSP, an affected individualhas one copy of a genetic alteration that causes HSP Theindividual has a 50% chance to pass the alteration on toeach of his or her children, regardless of that child’s gen-der There are often other affected family members inprior generations, and often a parent is affected

As of 2000, seven genes have been attributed toautosomal dominant uncomplicated HSP The uncompli-cated form comprises about 80% of families with autoso-mal dominant HSP They are: SPG3 (found on the longarm of chromosome 14 at 14q11–q21), SPG4 or spastin(short arm of chromosome 2 at 2p22), SPG6 (long arm ofchromosome 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 at2q24–q34) Of this group, about 45% of families haveSPG4 or spastin alterations

Autosomal dominant complicated HSP has beenattributed to alterations in the SPG9 gene (on the longarm of chromosome 10 at 10q23.3–q24.2)

In X-linked recessive HSP, only males are affectedwith the condition, because the genetic alterations arefound 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 theirsingle X-chromosome, and they develop symptoms of thecondition Females are carriers, and typically do not havesymptoms However, when carrier females have sons,they have a 50% chance of having an affected son Infamilies with X-linked HSP, males are affected and it ispassed through women in the family

X-linked forms of HSP are complicated HSP TheSPG1 gene on the long arm of chromosome X at Xq28(also known as the L1 cell adhesion molecule) and SPG2gene 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 thaneighty unrelated families had been studied throughout theworld Hereditary spastic paraplegia appears to affectindividuals and various age groups around the world.With the exception of X-linked recessive HSP, it affectsmen and women equally

Signs and symptoms

The symptoms of uncomplicated HSP may appear atany 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 cessive generations had increasingly severe symptoms ofpure HSP, a phenomenon known as “genetic anticipa-tion.” People with pure HSP may experience difficultywalking and often eventually require canes, walkers, orwheelchairs As a later symptom, people may experience

suc-an urgency to urinate, or may have problems with urinarycontrol Generally, the lower extremities experienceincreased reflexes, and may become stiff

Individuals with complicated HSP still have spasticparaplegia of the lower extremities as a common finding,but may also experience other associated health prob-lems These may include seizures, mental delays, visionloss, 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 dromes have been identified Silver syndrome is an auto-somal dominant condition involving progressive spasticparaplegia and loss of muscle mass, particularly in thehands Pelizaeus-Merzbacher disease is an X-linkedrecessive form of complicated HSP It usually develops ininfancy or early childhood with abnormal eye move-ments, severe muscle weakness, feeding problems, anddevelopmental delays These findings can progress toinclude severe muscle spasticity and ataxia

syn-Diagnosis

HSP has classically been diagnosed by a carefulphysical examination, as well as obtaining a detailed per-sonal and family medical history Other similar disordersoften need to be ruled out before considering HSP.Uncomplicated HSP is diagnosed by four clinical criteria:

• Clinical symptoms: Progressive spastic muscle ness of both lower extremities, often with urinaryurgency or lower extremity paresthesia

weak-• Neurologic examination: Increased muscle tone/reflexes at the hamstrings, quadriceps, and ankles; mus-cle weakness at hamstrings and lower limbs; decreasedability to sense vibrations in the lower limbs; abnormalgait with an uneven drop of the foot (Mental delays ordementia are not expected in pure HSP.)

• Family history: Similar to an autosomal dominant tern (several affected family members in different gen-erations), autosomal recessive pattern (siblings may beaffected 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 otherthrough their mothers)

pat-• Exclusion of other conditions

K E Y T E R M SAmniocentesis—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 carrimoth-ers

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 ened lifespan, because involvement of other health prob-lems can worsen an individual’s prognosis For example,

short-in Pelizaeus-Merzbacher disease, lifespan is shortenedbecause 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.

inher-neous albinism that also includes a bleeding tendency

and have typical skin pigmentation However, each timethey have a child, the chance for the child to have HPS is25%, 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 exactlocation in 1996 The protein produced by the HPS genehelps organelles (specialized parts) of the cell’s cyto-plasm (portion of the cell between the membrane andnucleus) to develop and function normally

In 1999, another group of researchers identified amutation, or gene change, in the AP3B1 gene located onchromosome 5 as another cause of HPS This gene makesAP3, a molecule that helps to sort proteins within thebody’s cells

Demographics

In northwest Puerto Rico, HPS is a common ited disorder More than 300 persons are affected Thecarrier rate is about one in 21 Intermarriage accounts forthe high frequency Researchers have traced the origin ofHPS to southern Spain Cases have also been reported inthe Dutch, Swiss, and Japanese Both sexes are equallyaffected However, females will have more lung symp-toms than males

inher-Signs and symptoms

People with HPS have a broad range of skin colorfrom tan to white, reflecting the partial absence of pig-mentation Hair color ranges from brown to white, alsoreflecting how much pigmentation is present

Poor vision and eye abnormalities are common inpeople 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 animproper muscle balance called strabismus Sensitivity tobright 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, sowill eye color Red, brown, hazel, and violet eyes havebeen reported

A bleeding tendency distinguishes HPS from othertypes of albinism People with HPS will bruise easily andbleed for an extended time after dental extractions andsurgical 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 thatcause them to clump together during the clotting process.The third finding of HPS is the accumulation ofceroid in certain cells of the body such as bone marrow

K E Y T E R M SBioptics—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-far-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 Bywearing 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 theaffected 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 tohave lung disease The first sign is difficulty in breathing,followed by a cough that does not bring up sputum, amixture 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 Beforeany surgery, treatment with desmopressin, a drug thatstimulates clotting activity, can be effective Also, indi-viduals with HPS should avoid aspirin, because it makesblood less likely to clot

Prognosis

Many people with HPS may have concerns abouttheir physical appearance and decreased vision.Education about the disorder is important to prevent iso-lation and stigmatization Once the visual difficulties areaddressed, people with albinism can participate in mostactivities

Although many preventive efforts can improve thequality of life for a person with HPS, the progressive lungdisease cannot be halted The inability to breathe gener-ally becomes fatal when the affected person is 40–50years old

Resources BOOKS

Kanski, Jack J Clinical Ophthalmology: A Systematic

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.

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

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

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 pseudoherher-maphroditism 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 havehypospadias Pseudohermaphroditism refers to gonadaldysgenesis

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 formale pseudohermaphrodites is 46XY Female pseudoher-maphroditism is more complicated The condition iscaused by deficiencies in the activity of enzymes Thegenetic basis for three enzyme deficiencies have beenidentified Deficiency of 3B hydroxysteroid dehydroge-nase—Type 2 is due to an abnormality on chromosome1p13.1 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 onchromosome 8q21

Demographics

True hermaphrodites are extremely rare.Approximately 500 individuals have been identified inthe world to date Because of the ambiguity of genitaliaand difficulties in making an accurate diagnosis, the inci-dence of pseudohermaphroditism is not well established.The incidence of male pseudohermaphroditism has beenestimated at between 3 and 15 per 100,000 people Theincidence of female pseudohermaphroditism has beenestimated at between 1 and 8 per 100,000 people

K E Y T E R M SCorpora 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 onic development

embry-Follicle—A pouch-like depression.

Mosaicism—A genetic condition resulting from a

mutation, crossing over, or nondisjunction of mosomes during cell division, causing a variation

chro-in the number of chromosomes chro-in the cells

Semineferous tubules—Long, threadlike tubes that

are packed in areolar tissue in the lobes of thetestes

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 exterinter-nal 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,

1761-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, ton, DC 20008-2304 (800) 336-GENE (Helpline) or (202) 966-5557 Fax: (888) 394-3937 info@geneticalliance.

Washing-⬍http://www.geneticalliance.org⬎.

Hermaphrodite Education and Listening Post PO Box 26292,

High density hypoprotein deficiency see

Tangier 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 quent, occurring in 50% of familial cases (cases whichrun 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 arerequired to develop the disease, and these other factorsare not understood

fre-For persons with a ganglion growth beyond the moid segment of the colon, the inheritance pattern is

sig-autosomal dominant with reduced penetrance (risk closer

to 50%) For persons with smaller segments involved, theinheritance pattern is multifactorial (caused by an inter-action of more than one gene and environmental factors,risk lower than 50%) or autosomal recessive (one diseasegene inherited from each parent, risk closer to 25%) withlow penetrance

Demographics

Hirschsprung’s disease occurs once in every 5,000live births, and it is about four times more common inmales than females Between 4% and 50% of siblings arealso afflicted The wide range for recurrence is due to thefact that the recurrence risk depends on the gender of theaffected individual in the family (i.e., if a female isaffected, the recurrence risk is higher) and the length ofthe aganglionic segment of the colon (i.e., the longer thesegment that is affected, the higher the recurrence risk)

Signs and symptoms

The initial symptom is usually severe, continuousconstipation A newborn may fail to pass meconium (thefirst stool) within 24 hours of birth, may repeatedly vomityellow or green colored bile and may have a distended(swollen, uncomfortable) abdomen Occasionally, infantsmay have only mild or intermittent constipation, oftenwith diarrhea

While two-thirds of cases are diagnosed in the firstthree months of life, Hirschsprung’s disease may also bediagnosed later in infancy or childhood Occasionally,even adults are diagnosed with a variation of the disease

In older infants, symptoms and signs may includeanorexia (lack of appetite or inability to eat), lack of theurge to move the bowels or empty the rectum on physicalexamination, distended abdomen, and a mass in the colonthat can be felt by the physician during examination Itshould be suspected in older children with abnormalbowel habits, especially a history of constipation datingback to infancy and ribbon-like stools

Occasionally, the presenting symptom may be asevere intestinal infection called enterocolitis, which islife threatening The symptoms are usually explosive,

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 creaobstruc-tion 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

K E Y T E R M SAnus—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 chalkysubstance that enhances the visualization of thegastrointestinal tract on x-ray

Colostomy—The creation of an artificial opening

into the colon through the skin for the purpose ofremoving bodily waste Colostomies are usuallyrequired because key portions of the intestinehave 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, ally greenish in color and consisting of mucus, bileand so forth

usu-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 ease or to an affected individual considering pregnancy todiscuss recurrence risks and treatment options Prenataldiagnosis is not available

dis-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)

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 predictsthe brain.” This phrase is generally but not always accu-rate Children may have severe craniofacial abnormalitieswith mild (lobar) holoprosencephaly, or children mayhave severe (alobar) holoprosencephaly with mild facialchanges Since the development of the face, skull, and thefront of the brain are interconnected, the changes in theface often, but do not always, correspond with changes inthe brain Finally, the designation of these disorders fromleast 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 anindication of the severity of the disease, so knowledge ofthese categories and what they represent is useful

Other brain abnormalities in holoprosencephaly

All patients with holoprosencephaly lack a sense ofsmell through the first cranial nerve (the olfactory nerve).Interestingly enough, one has a partial sense of smellthrough 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 itmay be useful to think of persons with holoprosen-cephaly as lacking a portion of what is in common usagereferred to as smell This deficiency in smell can bedetected 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 lefthemispheres with each other, is absent or deficient in per-sons with holoprosencephaly

Synonyms for holoprosencephaly

Arrhinencephaly and familial alobar cephaly are synonyms for this disorder

holoprosen-Genetic profile

Genetic causes of holoprosencephaly

Holoprosencephaly is a feature frequently found inmany 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, andSteinfeld 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

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 prepre-chordal 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

K E Y T E R M SCorpus callosum—A thick bundle of nerve fibers

deep in the center of the forebrain that providescommunications 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 sinkingthe ball means making a normal brain) Thus, each stepdepends on the last step and the next step If one doesn’thave the stick or the cue ball one cannot sink the ball inthe pocket Thus, a number of mutations in genes in theShh signaling pathway, and not just Shh, could causeholoprosencephaly Not just that, but other genesinvolved in cholesterol biosynthesis can have effects ongenes in the Shh signaling pathway Cholesterol appears

to affect the function of the gene Patched In the poolexample, a lack of cholesterol would not mean the cueball 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 onbone morphogenetic proteins (BMPs) in chickens Upuntil now, the problem of holoprosencephaly has beenaddressed as if it occurs when neural tissue is formed.However, the presence of too much BMP in a chickembryo after the time neural tissue is formed can causeholoprosencephaly It appears there are two stages thatcan be interfered with: one that occurs at the time of neu-ral tissue formation involving Shh, and another thatoccurs later involving BMPs Increased levels of BMPsmay cause important neural cells to die It has been spec-ulated that holoprosencephaly is either a failure to growneural cells due to failure in Shh pathway, or an excess ofneural cells dying possibly due to increased levels ofBMPs 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 thesecond 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 setclose together and the nose is abnormal In premaxillaryagenesis the patient has a midline cleft lip and cleft palateand close-set eyes If the face is very abnormal, the patient

is likely to have alobar holoprosencephaly, the most severetype In addition to abnormalities of the face, children withalobar holoprosencephaly also have small brains (less than100g) These children also have small heads unless theyhave excess cerebrospinal fluid Excess cerebrospinalfluid can cause the head to be abnormally large

Persons with holoprosencephaly experience manyproblems due to brain malformations including in utero

or neonatal death Survivors may experience seizures,problems with muscle control and muscle tone, a delay ingrowth, 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 rateabnormalities These problems are usually least severe inlobar holoprosencephaly and most severe in alobar.Children with holoprosencephaly also experience severedeficiencies in their ability to speak and in their motorskills An ominous sign that children with holoprosen-cephaly may exhibit is a sustained (lasting many hours ordays) period of irregular breathing and heart rate Thismay precede death However, episodes lasting only min-utes are usually followed by a full recovery

Diagnosis

Prenatal ultrasound and computerized tomographycan 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 adiagnosis of holoprosencephaly Once a diagnosis ofholoprosencephaly has been made, syndromes of whichholoprosencephaly is a part must be considered Forty-one percent of holoprosencephaly cases are thought tohave 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 ease, symptomatic treatment can reduce the amount offluid surrounding the brain and assist in feeding Medicalintervention can reduce or eliminate seizures and hor-monal deficiencies However, few treatments exist for themost serious aspects of the disease—breathing and heartarrhythmias (irregular heart rate)—or for the problemsassociated with developmental delay and poor musclecontrol One important aspect of treatment is to help par-ents understand the effects of the disease and what may

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

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 conductionpattern of the heart to severe structural defects requiringsurgical intervention for survival The abnormalities ofthe upper limbs are usually bilateral (occurring on bothsides) and asymmetric (not identical from side to side).The severity of the upper limb changes may range fromminor signs, such as clinodactyly (inward curvature ofthe fingers) to disabling defects, such as small or missingbones resulting in very short arms

Some individuals with HOS are so mildly affected,they do not require any special care or treatment Otherindividuals are severely affected and may have signifi-cant disability resulting from abnormalities of the arms,

or may have limited lifespans due to serious heart malities The signs of HOS are usually limited to theheart and skeleton HOS does not cause mentalretardation

abnor-Some references may use the alternative name ofhand-heart syndrome However, Holt-Oram syndrome isone of many hereditary hand-heart syndromes, so the twonames are not truly interchangeable

Genetic profile

HOS is inherited as an autosomal dominant tion, with variable expressivity (meaning that differentindividuals with HOS may have very different signs ofthe condition) and complete penetrance (meaning thatevery individual that has the genetic change causing thecondition has some physical symptoms) An autosomaldominant condition only requires the presence of oneabnormal gene on a non-sex-linked chromosome for the

condi-disorder to occur Some researchers have observed lies with incomplete penetrance (meaning that not everyindividual with the gene abnormality shows symptoms)

fami-as well

In some individuals and families, HOS is caused bymutations in the TBX5 gene located on the long arm ofchromosome 12 The TBX5 gene encodes a transcriptionfactor 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 causeHOS HOS families that have TBX5 mutations do notappear to differ significantly from those which do not.Some patients with HOS have inherited it from anaffected parent, whereas others have it as the result of anew change in a gene The proportion of patients withHOS resulting from new mutations ranges from 8% to85% Regardless of where the gene came from, anaffected individual has a 50% chance of passing on thegene and the condition to each child It is difficult to pre-determine the severity of symptoms a child may have

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 bonehypoplasia

Defects and dysfunction of the heart

The vast majority (95%) of individuals with HOSwho have inherited it from an affected parent have heartinvolvement Most have a defect in the structure of theheart In some patients, there is no structural defect in theheart, but abnormalities are present in the pattern of elec-trical conduction in the heart

The most common heart abnormalities in peoplewith HOS are septal defects, or holes in the heart A holemay occur in the wall separating the atria of the heart(atrioseptal defect or ASD), or the wall separating theventricles of the heart (ventriculoseptal defect or VSD)

In rare cases, more severe and complex heart defects mayoccur, such as hypoplastic left heart (in which the cham-bers of the left side of the heart are too small to functionnormally) or tetralogy of fallot (a specific combination offour heart defects) In the case of severe defects, surgicalcorrection 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 ofelectrical impulses for coordinated contraction of themuscle 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

Diagnosis

The diagnosis of HOS is made on the basis of theclinical judgment by a specialist physician, usually ageneticist, following physical examination and review ofpertinent tests or studies Diagnostic criteria may beemployed to guide this decision One commonly used set

of criteria for the diagnosis of HOS require that there be1) defect(s) of the radial side of the hand/arm, as well as2) 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

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

K E Y T E R M SAtria—The two chambers at the top of the heart,

where blood from the lungs or body pools beforeentering 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 Theheart is divided into the right and left ventricles

Several unusual findings have been described withrespect to the severity of HOS in families Affectedwomen have been reported to have a higher chance ofhaving a severely affected child than do affected men Theseverity of defects associated with HOS has also beenreported 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

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

Definition

The term homocystinuria is actually a description of

a biochemical abnormality, as opposed to the name of aparticular 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 bydifferent biochemical abnormalities and in fact there are

Homocysteine is involved with the catabolism ofmethionine Methionine is an essential amino acid.Amino acids are the building blocks of proteins Over 100amino acids are found in nature, but only 22 are found inhumans Of these 22 amino acids, eight are essential forhuman life, including methionine Methionine comesfrom dietary protein Generally, the amount of methion-ine that is consumed is more than the body needs Excessmethionine is converted to homocysteine, which is thenmetabolized 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 specificenzyme and that enzyme may even require help fromvitamin co-factors to be able to complete the job Forexample, the conversion of homocysteine to cystathion-ine by cystathionine b-synthase requires vitamin B6(pyri-doxine) If cystathionine b-synthase is missing, thenhomocysteine cannot be broken down into cystathionineand cysteine, and instead, homocysteine accumulates andthe elevated levels of homocysteine and methionine can

be found in the blood Also, decreased levels of cysteinecan 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, theeyes, the skeleton, and the vascular system

Genetic profile

Classical homocystinuria or cystathionine thase (CBS) deficiency is an autosomal recessive condi-tion This means that in order to have the condition, anindividual must inherit one copy of the gene for CBSdeficiency from each parent An individual who has onlyone copy of the gene is called a carrier for the condition

b-syn-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 casewith CBS deficiency Individuals who are carriers forCBS deficiency may have levels of homocysteine that areelevated enough to increase the risk for thromboembolicevents So, although carriers may not exhibit obviousphysical signs or symptoms of the condition, they mayhave clinical effects of elevated levels of homocysteine,such as vascular or cardiovascular disease A carrier forCBS deficiency can have vascular complications, espe-cially if they are also carriers for other clotting disorderssuch 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 acarrier for the condition and a one in four or 25% chancefor having a child who is neither affected nor a carrier forCBS deficiency

K E Y T E R M SAnabolism—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 mayoccur Also, they tend to have stiff joints CBS deficiencyaffects the eyes, causing dislocated lenses and nearsight-edness (myopia) Untreated individuals or those individ-

uals who do not respond to treatment develop mentalretardation or learning disabilities Affected individualsmay also develop psychiatric problems These psychi-atric problems may include depression, chronic behav-

ior problems, chronic obsessive-compulsive disorder, andpersonality disorders The most frequent cause of deathassociated with CBS deficiency is blood clots that form

in veins and arteries These are known as bolisms, and include deep vein thrombosis (blood clotsthat form in the deep veins of the legs, etc.), pulmonaryembolus (blood clots that form in the lungs), and strokes.Thromboembolism can occur even in childhood Whenthromboembolism does occur in childhood, CBS defi-ciency should always be considered as a cause for thethromboembolic events These thromboembolic eventscan occur in any part of the body Lastly, another com-plication of CBS deficiency is severe premature arte-riosclerosis (hardening of the arteries)

thromboem-Diagnosis

Approximately 50% of individuals who have CBSdeficiency are diagnosed by newborn screening becausethey have an elevated level of methionine in their blood.The reason for performing newborn screening is so thatinfants affected with genetic disorders can be identified

early enough to be treated The screening is done by lecting blood from a pin-prick on the baby’s heel prior toleaving the hospital, but at least 24 hours after birth ForCBS deficiency, the screening test checks for elevatedlevels of methionine If the levels are elevated then fol-low-up testing to verify the diagnosis is performed Thereare other disorders of methionine metabolism, and fol-low-up testing determines the underlying cause of thepositive newborn screen

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 tohave lens dislocation before 2 years of age

Treatment and management

The first choice of therapy for patients with CBSdeficiency is administration of pyridoxine (vitamin B6).Vitamin B6 is the cofactor for the cystathionine b-syn-thase reaction Potentially, some individuals who haveCBS deficiency are not missing the enzyme, but ratherhave an enzyme that is unable to perform its job Theaddition of pyridoxine can help to push the reaction alongand thus help to reduce the levels of homocysteine andmethionine in the blood Information suggests thatapproximately 50% of patients with CBS deficiencyrespond 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 topyridoxine treatment (pyridoxine non-responsive) tend to

be more severely affected than the patients who dorespond Those non-responding patients are treated withcombinations of folic acid, hydroxycobalamin, andbetaine, which stimulate the conversion of homocysteineback to methionine The reason that the addition of folicacid can help is because within the methylene H4-folate

Pyridoxine (vitamin B6) (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-B12

H4-folate Methyl-H4-folate

Dietary cobalamin

Methylene H4-folate

Methylene H4-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

B6-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 causeproblems for a developing baby This could be similar tothe process by which infants of mothers who havephenylketonuria are affected by the elevated levels ofphenylalanine if their mothers are not being treated withdietary restriction during pregnancy

Prognosis

Untreated CBS deficiency leads to mental tion, lens dislocation, and a decreased life expectancybecause of complications associated with blood clots Ifuntreated from early infancy, approximately 20% ofaffected patients will have seizures If treated from birth,prevention or long term delay of the complications ofCBS deficiency can be expected

retarda-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.

Climb: Children Living with Inherited Metabolic Diseases

Reneé A Laux, MS

Homogentisic acid oxidose deficiency see

Alkaptonuria

The Human Genome Project (HGP) is the tional project to sequence the DNA of the human genome.

interna-The sequencing work is conducted in many laboratoriesaround the world, but the majority of the work is beingdone by five institutions: the Whitehead Institute forMedical Research in Massachusetts (WIMR), the BaylorCollege of Medicine in Texas, the University ofWashington, the Joint Genome Institute in California, andthe Sanger Centre near Cambridge in the United Kingdom.Most of the funding for these centers is provided by theUnited States National Institute of Health and Department

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 Thefirst human genetic map used restriction fragment lengthpolymorphisms (RFLPs) as markers, which only havetwo alleles per marker, but common microsatellites wereused to create a high resolution genetic map

The second stage of human genome sequencing wasmade 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 tig of YACs and cosmids, carrying up to 2Mb and 40kb ofDNA respectively, would be assembled These two types ofgenomic clone were found to be liable to rearrangement;the DNA in the vector could be in chunks that were notnecessarily in the same order as in the genome The BACvector did not rearrange DNA, and could carry more DNAthan many other types of genomic clone

con-The third stage was made easier by development ofhigh-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 ofwhole genome shotgun sequencing of the humangenome In contrast to the HGP plan involving the use ofgenetic contigs and physical maps as a framework forgenomic clones and sequence, scientists suggested thatthe whole genome could be fragmented into smallchunks for sequencing, and then reassembled using over-lap between fragment sequences (whole genome shotgunsequencing) This required large amounts of computingpower to generate the correct assembly, but was consid-erably faster than the HGP approach Many scientists didnot believe that this method would assemble the genomeproperly, and suggested that overlap between small frag-ments could not be the only guide to assembly, becausethe genome contained many repeated DNA sequences.However, American biochemist J Craig Venter believedthe method could work, and formed Celera, a privatecompany that would sequence the human genome beforethe HGP Celera demonstrated that the whole genomeshotgun 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 methodwould be successful for the bigger human genome Thepublicly funded HGP, in light of Celera’s competition,decided to concentrate, like Celera, on a draft of thehuman genome sequence (3x coverage—that is eachnucleotide has been sequenced an average of threetimes), before generating a more accurate map of 8x cov-erage Celera had an advantage, because the HGP hadagreed to release all its data as it was generated on to afreely accessible database, as part of the Bermuda rules(named after the location of a series of meetings duringthe early stages of the HGP) This allowed Celera to use

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

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

K E Y T E R M SKyphosis—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 lular spaces

intercel-normal curvature of the spine (kyphosis), a distinctivefacial appearance characterized by coarse features, anoversized head, thickened lips, and a broad, flat nosecharacterize the syndrome

Description

Hunter syndrome is a one of a group of diseasescalled mucopolysaccharidoses It is caused by the defi-ciency of an enzyme that is required to metabolize orbreak down mucopolysaccharides (also called gly-cosaminoglycans) It is also called mucopolysaccharido-sis Type II (MPS II) because there are several related butsimilar diseases The Hunter syndrome involves a defect

in the extracellular matrix of connective tissue One of thecomponents of the extracellular matrix is a moleculecalled a proteoglycan Like most molecules in the body, it

is regularly replaced When this occurs, one of the ucts is a class of molecules known as mucopolysaccha-rides (glycosoaminoglycans) Two of these are important

prod-in Hunter syndrome: dermatan sulfate and heparan fate These are found in the skin, blood vessels, heart andheart valves (dermatan sulfate) and lungs, arteries andcellular surfaces (heparan sulfate) The partially broken-down molecules are collected by lysosomes and stored invarious locations in the body Over time, these accumula-tions of partially metabolized mucopolysaccharidesimpair the heart, nervous system, connective tissue, andbones

sul-Both of these molecules require the enzymeiduronate-2-sulfatase (I2S) to be broken down In peoplewith Hunter syndrome, this enzyme is partially or com-pletely inactive As a result, unchanged molecules accu-mulate in cells These mucopolysaccharides are storedand interfere with normal cellular functions The rate ofaccumulation is not the same for all persons with Huntersyndrome Variability in the age of onset is thought to bedue to lingering amounts of activity by this enzyme

The cells in which mucopolysaccharides are storeddetermine the symptoms that develop When mucopoly-saccharides are stored in skin, the proportions of the facechange (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 arecoarser than normal Their heads tend to be large in pro-portion to their bodies Over time, their hands tend tobecome stiff and assume a claw-like appearance Theirteeth are delayed in erupting Progressive hearing losseventually leads to deafness Internal organs such as theliver and spleen are larger than normal They are quiteprone to hernias

Diagnosis

Hunter syndrome can be identified early in life and

is often initially diagnosed by the presence of an enlargedliver and spleen (hepatosplenomegaly), hernias, or jointstiffness Skeletal changes can be seen with radiographs.Elevated mucopolysaccharide levels in urine focuses thediagnosis to a group of disorders The concentration ofdermatan sulfate and heparan sulfate is 5-25 times higherthan in normal urine Both are present in approximatelythe same amounts The diagnosis of Hunter syndrome isconfirmed by measuring iduronate-2-sulfatase activity inwhite blood cells, serum, or skin fibroblasts Prenataldiagnosis is widely available by measuring the activity ofI2S enzyme in amniotic fluid

Hunter syndrome has many diagnostic tics in common with Hurler syndrome However, there

characteris-are some distinct differences between the two dromes Individuals with Hunter syndrome have clearcorneas and tend to have deposits of mucopolysaccha-rides in the skin These are characteristically on the back

syn-of the hands and elbows (the extensor surfaces) and onthe upper surfaces of the shoulders All are males Thesedifferences are important in diagnosis

Treatment and management

General support and treatment of specific symptomsare the only treatment options presently available.Iduronate-2-sulfatase can be made using cells that havebeen genetically engineered However, as of 2001, thesafety and clinical effectiveness of injecting I2S intohumans has not been established

Intrauterine testing of amniotic fluid is reliable Tests

to detect a carrier state are imperfect There is no cure forHunter 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-normallives and have normal intelligence

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.

Canadian Society for Mucopolysaccharide and Related

Diseases PO Box 64714, Unionville, ONT L3R-OM9

Children Living with Inherited Metabolic Diseases The

Quadrangle, Crewe Hall, Weston Rd., Crewe, Cheshire,

CW1-6UR UK 127 025 0221 Fax: 0870-7700-327.

Society for Mucopolysaccharide Diseases 46 Woodside Rd.,

neurodegenera-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 ofmovement control and mental abilities A person with HDgradually develops abnormal movements and changes incognition (thinking), behavior, and personality

Demographics

The onset of symptoms of HD is usually between theages of 30 and 50, although in 10% of cases, onset is inlate childhood or early adolescence Approximately30,000 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 Thenucleotide codes (building blocks of genes arranged in aspecific code that chemically form proteins), containCAG repeats (40 or more of these repeat sequences) Theextra building blocks in the huntingtin gene cause theprotein that is made from it to contain an extra section aswell It is currently thought that this extra protein section,

or portion, interacts with other proteins in brain cellswhere it occurs, and that this interaction ultimately leads

to cell death

The HD gene is a dominant gene, meaning that onlyone copy of it is needed to develop the disease HDaffects both males and females The gene may be inher-ited from either parent, who will also be affected by thedisease A parent with the HD gene has a 50% chance ofpassing it on to each offspring The chances of passing onthe HD gene are not affected by the results of previouspregnancies

Cognitive changes include loss of ability to plan andexecute routine tasks, slowed thought, and impaired orinappropriate judgment Short-term memory loss usuallyoccurs, although long-term memory is usually not affected.The person with late-stage HD usually retains knowledge

of his environment and recognizes family members orother loved ones, despite severe cognitive decline

Diagnosis

Diagnosis of HD begins with a detailed medical tory, and a thorough physical and neurological exam.Family medical history is very important Magnetic reso-nance imaging (MRI) or computed tomography scan (CTscan) imaging may be performed to look for degeneration

his-in the basal ganglia and cortex, the brahis-in regions mostaffected in HD

A genetic test is available for confirmation of theclinical diagnosis In this test, a small blood sample istaken, 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 repeatnumber between 35 and 40 may not develop the diseasewithin their normal lifespan A person with a very highnumber of repeats (70 or above) is likely to develop thejuvenile-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 testingwithout 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 doesnot analyze for the triple nucleotide repeat (CAG) If theDNA patterns do not match, the fetus can be assumed not

to have inherited the HD gene, even if present in the ent A pattern match indicates the fetus probably has thesame genetic makeup of the at-risk parent

par-Treatment and management

There is no cure for HD, nor any treatment that canslow the rate of progression Treatment is aimed at reduc-ing the disability caused by the motor impairments, andtreating behavioral and emotional symptoms

Physical therapy is used to maintain strength andcompensate for lost strength and balance Stretching andrange of motion exercises help minimize contracture, ormuscle shortening, a result of weakness and disuse Thephysical therapist also advises on the use of mobility aidssuch as walkers or wheelchairs

Motor symptoms may be treated with drugs,although some studies suggest that anti-chorea treatmentrarely improves function Chorea (movements caused byabnormal muscle contractions) can be suppressed with

K E Y T E R M SCognition—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 strucpic-tures 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 Handwrittwitch-ing 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 speakinclud-ing slowly, usinclud-ing simple words, and repeatinclud-ing

sentences exactly

Early behavioral changes, including depression and

anxiety, may respond to drug therapy Maintaining a

calm, familiar, and secure environment is useful as thedisease progresses Support groups for both patients andcaregivers form an important part of treatment

Experimental transplant of fetal brain tissue has beenattempted in a few HD patients Early results show somepromise, but further trials are needed to establish theeffectiveness of this treatment

Prognosis

The person with Huntington disease may be able tomaintain a job for several years after diagnosis, despitethe increase in disability Loss of cognitive functions andincrease in motor and behavioral symptoms eventuallyprevent 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 swallowingmuscles leads to increased risk of respiratory infectionand choking, the most common causes of death Futureresearch in this area is currently focusing on nerve celltransplantation

Resources BOOK

Watts, R L., and W C Koller, eds Movement Disorders New

= Affected Symptomatic individual

= Affected Presymptomatic individual

46y

26y 27y 32y

28y 31y

53y 54y 60y

62y

(Gale Group)

I Hurler syndrome

Definition

Hurler syndrome is a disorder that results when cells

cannot break down two by-products of normal

metabo-lism These byproducts, dermatan sulfate and heparan

sulfate, build up and disrupt normal cell function, leading

to severe disease The disease affects most body systems,

causing progressive deterioration of tissues and organs

Description

Though present from conception, Hurler syndrome

may be undetectable at birth The newborn often looks

healthy and seems to develop normally for the first few

months However, symptoms begin to appear around the

age of six months, when dermatan sulfate and heparan

sulfate reach dangerous levels

Individuals with Hurler syndrome lack sufficient

amounts of the enzyme needed to break down dermatan

sulfate and heparan sulfate This enzyme,

alpha-L-iduronidase, is part of a biochemical pathway which

splits complex molecules into smaller, recyclable units

Without alpha-L-iduronidase, the complex molecules

cannot be eliminated and deposit themselves in cells,

tis-sues, and organs Deposits in the soft tissues of the face

lead to a typical appearance, causing children with Hurler

syndrome to resemble each other more than they

resem-ble their own healthy siblings The spleen and liver

become enlarged early in the course of the disease

Deposits stored in the growth plates of bones lead to

dwarfism, scoliosis, joint stiffness, and other skeletal

abnormalities Corneal clouding caused by the deposits

results in vision damage Hearing loss usually occurs as

well Deposits in the brain cause loss of skills gained

early in life, and severe mental retardation occurs

The accumulation of dermatan sulfate and heparan

sulfate in the airways leads to frequent respiratory tract

and ear infections Deposits also cause coronary artery

obstruction and damage to the heart In fact, respiratory

complications and heart failure are the most frequent

causes of death in Hurler syndrome patients Many

chil-dren with Hurler syndrome die by the age of 12

Dermatan sulfate and heparan sulfate belong to a

class of complex molecules known as

mucopolysaccha-rides, chains formed by smaller sugar molecules strung

together For this reason, Hurler syndrome is also known

as a mucopolysaccharidosis, a name meaning, “too many

mucopolysaccharides.” To be precise, Hurler syndrome is

called Mucopolysaccharidosis I H (MPS I H) There are

several other mucopolysaccharidoses, each resulting

from absence or deficiency of a different enzyme

Sometimes Hurler syndrome is called a lysosomalstorage disease Lysosomes are cell parts which normallycontain enzymes needed to break down complex mole-cules When the enzymes are absent or deficient, thelysosomes store the complex molecules, expand, andeventually destroy the cells from within

Hurler syndrome takes its most commonly usedname from Gertrud Hurler, the German pediatrician whofirst described the condition in her patients

Genetic profile

Researchers have identified the gene responsible for

Hurler syndrome and have mapped it to the 4p16.3 site

on chromosome 4 The gene is named IDUA, for theiduronidase enzyme which it produces when workingproperly As of 2001, researchers have connected 52 dif-ferent IDUA mutations to cases of Hurler syndrome.Hurler syndrome is an autosomal recessive disorder.This means that it occurs only when a person inherits twodefective copies of the IDUA gene If one copy is normaland the other has a mutation, the person does not haveHurler syndrome However, the person carries themutated gene and can pass it on to the next generation.Carriers of IDUA mutations have only one workinggene As a result, these carriers produce less alpha-L-iduronidase enzyme than do people with two normalIDUA genes Nevertheless, they produce enough enzyme

to break down dermatan sulfate and heparan sulfate, sodisease does not occur

Demographics

Hurler syndrome affects males and females of allraces and ethnic groups It is a rare disorder, occurring inabout one out of 100,000 people

Different IDUA gene mutations appear more quently in certain populations For instance, two specificmutations account for most Hurler syndrome casesamong Northern Europeans, while two other mutationsappear most often in Japanese patients

fre-Signs and symptoms

A child with Hurler syndrome may be born with ahernia In fact, hernia is often the first sign of this disor-der However, since it can also occur in other conditions

or as an isolated event, it does not immediately point toHurler syndrome

Other symptoms appear within six to twelve months

of birth Tissue damage in airways leads to breathing ficulties and frequent respiratory and ear infections Thechild’s face begins to take on the coarse, typical features

of Hurler syndrome The skull appears large and

unusu-ally shaped, scalp veins are prominent, and the bridge of

the nose is flat The lips are large and the mouth is

fre-quently open due to an enlarged, protruding tongue

Teeth may be late to emerge and are usually small, short,

widely spaced, and somewhat malformed The earlobes

are thick, and the eyelids are full

Skeletal abnormalities begin to appear The hands

are broad, with short, stubby fingers Joints are often stiff

and may limit the child’s movement The neck is very

short; the spine is crooked and bends outward, resulting

in a hunchback appearance

Children under the age of one may already show

signs of heart disease This is usually due to tissue

dam-age in the arteries or valves of the heart, caused by

accu-mulation of dermatan sulfate and heparan sulfate

Accumulation also causes the liver and spleen to become

severely enlarged, but these organs continue to function

normally

Hurler syndrome has a devastating effect on mental

development By the age of one or two, developmental

delay occurs The child may make slow progress for a

few more years, but then actually begins to lose skills

gained earlier The mental capacity of a person with

Hurler syndrome is similar to that of a normal

three-year-old Deterioration of the senses makes this situation

worse Corneal clouding damages vision Hearing loss,

narrowed airways, and enlarged tongue contribute to

poor language skills

Many infants with Hurler syndrome grow quickly

during their first few months However, skeletal

abnor-malities and progressive tissue damage cause growth to

slow down and then to stop before it should As a result,

most people with Hurler syndrome do not grow beyond

four feet tall

Diagnosis

Hurler syndrome shares many symptoms with other

mucopolysaccharidoses and with different lysosomal

storage diseases For this reason, laboratory tests are used

to confirm Hurler syndrome diagnosis based on a

physi-cal exam

The simplest test available is urine screening People

with Hurler syndrome excrete increased amounts of

dermatan sulfate and heparan sulfate in their urine In

addition, a blood test reveals deficiency of

alpha-L-iduronidase enzyme White blood cells and skin cells can

be microscopically examined for damage caused by

deposits of dermatan sulfate and heparan sulfate

If Hurler syndrome is present in a family, healthy

family members could carry a mutated IDUA gene

K E Y T E R M SAlpha-L-iduronidase—An enzyme that breaks

down dermatan sulfate and heparan sulfate.People with Hurler syndrome do not make enough

of this enzyme

Hernia—A rupture in the wall of a body cavity,

through which an organ may protrude

Lysosome—Membrane-enclosed compartment in

cells, containing many hydrolytic enzymes; wherelarge molecules and cellular components are bro-ken down

Mucopolysaccharide—A complex molecule made

of smaller sugar molecules strung together to form

a chain Found in mucous secretions and lular spaces

intercel-Mucopolysaccharidosis I H (MPS I H)—Another

name for Hurler syndrome

Tracheostomy—An opening surgically created in

the trachea (windpipe) through the neck toimprove breathing

Several clinical laboratories offer carrier screening tothese individuals A blood sample is all that is required.Most labs screen for carrier status by measuring the level

of the alpha-L-iduronidase enzyme Levels are lower incarriers than they are in people who have two normalIDUA genes It is also possible to examine the actualgenes to see if a Hurler syndrome mutation appears

Since Hurler syndrome is a rare disorder, most ers have children with non-carrier partners Thus there isgenerally no risk of the disease occurring in the children.However, if two carriers have children together, eachchild has a 25% chance of having Hurler syndrome.Carrier screening provides an opportunity to assess therisk and consider reproductive options before pregnancyoccurs

carri-Each child born to two carriers has a 50% risk ofinheriting one mutated gene and one normal gene Thischild, like the parents, is a carrier

Because a rare autosomal recessive gene can bepassed for generations before two carriers have a childtogether, sometimes an affected child is born into a fam-ily with no previous history of Hurler syndrome This isgenerally an indication that both parents carry a mutatedIDUA gene These parents worry not only about thehealth of the affected child, but also about the risk tofuture children

Prenatal testing is available to find out if a fetus has

Hurler syndrome This can be done by amniocentesis or

chorionic villus sampling Amniocentesis involves

removal of a small amount of amniotic fluid from the

uterus Chorionic villus sampling involves removal of a

small sample of placental tissue In either case, the cells

present in the sample are checked for enzyme deficiency

or gene mutations

Treatment and management

Treatment of individual Hurler syndrome symptoms

does not cure the disease, but it does offer some relief

Surgical repair is available to correct a hernia Hearing

aids sometimes improve hearing and language skills, and

eyeglasses may enhance eyesight Some children with

Hurler syndrome improve communication skills by

learn-ing sign language

Skeletal abnormalities require attention, especially if

they affect the upper part of the spine and compress the

spinal cord Spinal cord compression and storage of

der-matan sulfate and heparan sulfate in the surrounding

membranes cause fluid to accumulate in the brain Brain

damage often occurs unless this condition is corrected A

surgeon can implant a shunt in the brain to remove excess

fluid Once present, the mental retardation caused by

Hurler syndrome is generally not reversible

It is important to protect the upper back and neck of

a patient with Hurler syndrome This area should not be

manipulated during chiropractic or physical therapy If

the patient undergoes anesthesia for any reason, care

should be taken to support the neck and upper back at all

times

Orthopedic treatment can help reduce joint stiffness

and its effects on movement

Several options are available to correct breathing

dif-ficulties Some patients respond well to oxygen

treat-ments Others require tonsillectomy, adenoidectomy or

tracheostomy to remove upper airway obstruction

Medications are available to treat common respiratory

infections

If heart disease is limited to valve damage, valve

replacement may be an option for some patients with

Hurler syndrome

Children with Hurler syndrome are generally

easy-going and affectionate They benefit greatly from safe

and caring environments Community support and social

services can improve the quality of life for the entire

fam-ily unit The famfam-ily of a child with Hurler syndrome

experiences grief and loss throughout the lifetime and

upon the death of the child Genetic counseling is

avail-able to offer support, educate families about the disease,

and assess the risk to other family members TheNational MPS Society provides additional support andinformation

As of 2001, bone marrow transplant (BMT) is theonly treatment that appears to improve the long-term out-come of children with Hurler syndrome BMT replacesthe child’s entire blood system with the blood system of

a healthy person The healthy bone marrow contains stemcells, cells from which other cells and tissues arise Thesecells produce enough alpha-L-iduronidase to break downdermatan sulfate and heparan sulfate

Bone marrow transplant is a complicated dure If the donated bone marrow is not compatible withthe child’s own body tissues, the child’s immune systemwill destroy it BMT is most successful if the donor is aclose relative of the patient, since this increases thechance of compatibility between donor and patient bonemarrow To reduce the risk of donor bone marrow rejec-tion, the patient receives drugs and radiation to suppressthe immune system, leaving the patient vulnerable toinfection

proce-Research indicates that children with Hurler drome do better if BMT takes place before the age oftwo Beyond that point, prevention or correction of braindamage is unlikely, and other body tissues may be soseverely affected that the child would not survive BMT

syn-Prognosis

As of 2001, bone marrow transplant is the only ment that can prevent or reduce the effects of Hurler syn-drome However, bone marrow transplant is not an optionfor every patient Some patients with severe disease aretoo weak to survive the transplant procedure or recoveryperiod For some, a donor match is not available Othersdon’t have access to the technological or medical expert-ise needed for the procedure In addition, some patientswho have bone marrow transplants reject the donor cells.Research into long-term therapies is underway Twowhich appear promising are enzyme replacement therapyand gene therapy.

treat-Enzyme replacement involves giving the patient asubstitute for the deficient enzyme The patient wouldreceive regular enzyme injections, similar to insulininjections used by people with diabetes Enzyme replace-ment is complicated in a disorder which affects many dif-ferent tissues, as Hurler syndrome does Each tissueinteracts differently with the enzyme For this reason, it

is difficult to design a substitute which works with ous tissues Furthermore, the brain has a natural barrieragainst outside substances This is called the blood-brainbarrier, and it stops the enzyme substitute from reaching

brain cells Therefore, an enzyme substitute injected into

the blood would not prevent or reduce the brain damage

caused by Hurler syndrome The substitute might,

how-ever, reduce damage to other tissues of the body

Gene therapy attempts to introduce a normal gene

into the patient’s cells In theory, the cells would then

incorporate the gene, copy it, and produce enough

enzyme to break down complex molecules

Until these or other therapies become available,

patients who cannot undergo BMT can receive treatment

for individual Hurler syndrome symptoms While

treat-ment provides temporary relief, it cannot prevent the

progressive damage caused by accumulation of

der-matan sulfate and heparan sulfate Death due to

respira-tory complications or heart failure usually occurs by age

12

Resources

BOOKS

Beighton, Peter, ed McKusick’s Heritable Disorders of

Connective Tissue Fifth Edition St Louis: Mosby, 1993.

Jones, Kenneth L “Hurler Syndrome.” In Smith’s Recognizable

Philadelphia: W.B Saunders Company, 1997, pp 456-457.

Jorde, Lynn, et al Medical Genetics Second Edition St Louis:

Mosby, 2000, pp 147-149.

Scriver, Charles, et al., eds The Metabolic and Molecular

Bases of Inherited Disease Seventh Edition New York:

McGraw-Hill, 1995.

PERIODICALS

Peters, Charles, et al “Hurler Syndrome: II Outcome of

HLA-Genotypically Identical Sibling and HLA-Haploidentical

Related Donor Bone Marrow Transplantation in

Fifty-Four Children.” Blood 91, no 7 (April 1998): 2601-2608.

ORGANIZATIONS

Genetic Alliance 4301 Connecticut Ave NW, #404,

Washington, DC 20008-2304 (800) 336-GENE (Helpline)

from two Greek words: hydros means water and cephalus

means head

There are two main varieties of hydrocephalus: genital and acquired An obstruction of the cerebralaqueduct (aqueductal stenosis) is the most frequent cause

con-of congenital hydrocephalus Acquired hydrocephalusmay result from spina bifida, intraventricular hemor-

rhage, meningitis, head trauma, tumors, and cysts

Description

Hydrocephalus is the result of an imbalance betweenthe formation and drainage of cerebrospinal fluid (CSF).Approximately 500 milliliters (about a pint) of CSF isformed within the brain each day, by epidermal cells instructures collectively called the choroid plexus Thesecells line chambers called ventricles that are locatedwithin the brain There are four ventricles in a humanbrain Once formed, CSF usually circulates among all theventricles before it is absorbed and returned to the circu-latory system The normal adult volume of circulatingCSF is 150 ml The CSF turnover rate is more than threetimes per day Because production is independent ofabsorption, reduced absorption causes CSF to accumu-late within the ventricles

There are three different types of hydrocephalus Inthe most common variety, reduced absorption occurswhen one or more passages connecting the ventriclesbecome blocked This prevents the movement of CSF toits drainage sites in the subarachnoid space just insidethe skull This type of hydrocephalus is called “non-communicating.” In a second type, a reduction in theabsorption rate is caused by damage to the absorptivetissue This variety is called “communicating hydro-cephalus.”

Both of these types lead to an elevation of the CSFpressure within the brain This increased pressure pushesaside the soft tissues of the brain This squeezes and dis-torts them This process also results in damage to thesetissues In infants whose skull bones have not yet fused,the intracranial pressure is partly relieved by expansion

of the skull, so that symptoms may not be as dramatic.Both types of elevated-pressure hydrocephalus mayoccur from infancy to adulthood

A third type of hydrocephalus, called “normal sure hydrocephalus,” is marked by ventricle enlargement

onset hydrocephalus is not known There is no knownway to prevent hydrocephalus.

Signs and symptoms

Signs and symptoms of elevated-pressure cephalus include:

• subtle difficulties in learning and memory

• delay in children achieving developmental milestonesIrritability is the most common sign of hydrocephalus

in infants If this is not treated, it may lead to lethargy.Bulging of the fontanelles, or the soft spots between theskull bones, may also be an early sign When hydro-cephalus occurs in infants, fusion of the skull bones is pre-vented This leads to abnormal expansion of the skull.Symptoms of normal pressure hydrocephalusinclude dementia, gait abnormalities, and incontinence

(involuntary urination or bowel movements)

Diagnosis

Imaging studies—x ray, computed tomography scan(CT scan), ultrasound, and especially magnetic reso-nance imaging (MRI)—are used to assess the presenceand location of obstructions, as well as changes in braintissue that have occurred as a result of the hydrocephalus.Lumbar puncture (spinal tap) may be performed to aid indetermining the cause when infection is suspected

Treatment and management

The primary method of treatment for both elevatedand normal pressure hydrocephalus is surgical installa-tion of a shunt A shunt is a tube connecting the ventri-cles of the brain to an alternative drainage site, usuallythe abdominal cavity A shunt contains a one-way valve

to prevent reverse flow of fluid In some cases of communicating hydrocephalus, a direct connection can

non-be made non-between one of the ventricles and the noid space, allowing drainage without a shunt

subarach-Installation of a shunt requires lifelong monitoring

by the recipient or family members for signs of recurringhydrocephalus due to obstruction or failure of the shunt.Other than monitoring, no other management activity isusually required

Some drugs may postpone the need for surgery byinhibiting the production of CSF These include acetazo-

K E Y T E R M SCerebral ventricles—Spaces in the brain that are

located between portions of the brain and filled

with cerebrospinal fluid

Cerebrospinal fluid—Fluid that circulates

through-out the cerebral ventricles and around the spinal

cord within the spinal canal

Choroid plexus—Specialized cells located in the

ventricles of the brain that produce cerebrospinal

fluid

Fontanelle—One of several “soft spots” on the

skull where the developing bones of the skull have

yet to fuse

Shunt—A small tube placed in a ventricle of the

brain to direct cerebrospinal fluid away from the

blockage into another part of the body

Stenosis—The constricting or narrowing of an

opening or passageway

Subarachnoid space—The space between two

membranes surrounding the brain, the arachnoid

and pia mater

without an apparent increase in CSF pressure This type

affects mainly the elderly

Hydrocephalus has a variety of causes including:

• congenital brain defects

• hemorrhage, either into the ventricles or the

subarach-noid space

• infection of the central nervous system (syphilis,

her-pes, meningitis, encephalitis, or mumps)

• tumor

Genetic profile

Hydrocephalus that is congenital (present at birth) is

thought to be caused by a complex interaction of genetic

and environmental factors Aqueductal stenosis, an

obstruction of the cerebral aqueduct, is the most frequent

cause of congenital hydrocephalus As of 2001, the

genetic factors are not well understood According to the

British Association for Spina Bifida and Hydrocephalus,

in very rare circumstances, hydrocephalus is due to

hereditary factors, which might affect future generations

Demographics

Hydrocephalus is believed to occur in approximately

1–2 of every 1,000 live births The incidence of adult

lamide and furosemide Other drugs that are used to

delay surgery include glycerol, digoxin, and isosorbide

Some cases of elevated pressure hydrocephalus may

be avoided by preventing or treating the infectious

dis-eases which precede them Prenatal diagnosis of

congen-ital brain malformation is often possible

Prognosis

The prognosis for elevated-pressure hydrocephalus

depends on a wide variety of factors, including the cause,

age of onset, and the timing of surgery Studies indicate

that about half of all children who receive appropriate

treatment and follow-up will develop IQs greater than 85

Those with hydrocephalus at birth do better than those

with later onset due to meningitis For individuals with

normal pressure hydrocephalus, approximately half will

benefit by the installation of a shunt

Resources

BOOKS

Drake, James M., and Christian Sainte-Rose Shunt Book.

Boston: Blackwell Science Inc., 1995.

Toporek, Chuck, and Kellie Robinson Hydrocephalus: A Guide for Patients, Families & Friends Cambridge, Mass.:

O’Reilly & Associates, 1999.

PERIODICALS

Grant, Beth “Hydrocephalus: diagnosis and treatment.”

Radiologic Technology 69, no 2 (Nov–Dec 1997): 173–5.

“Hydrocephalus.” Review of Optometry 137, no 8 (August 15,

Shining a bright light behind an infant with hydrocephalus, one can observe the excessive fluid accumulation in the skull.

(Corbis Corporation, Bellevue)

“Hydrocephalus.” American Association of Neurological

www.neurosurgery.org/pubpages/patres/hydrobroch

“Hydrocephalus.” Beth Israel Medical Center, New York, NY.

Hydrolethalus syndrome is a rare disorder that

results in severe birth defects and often, stillbirth

Description

Hydrolethalus syndrome is a condition that causes

improper fetal development Multiple malformations

along the body’s midline, such as heart and brain defects,

a cleft lip or palate, an abnormally shaped nose or jaw,

and incomplete lung development result from this

syn-drome The birth defects are typically extreme enough to

cause stillbirth or death within a few days of birth A less

common name for hydrolethalus syndrome is

Salonen-Herva-Norio syndrome, after the Finnish researchers

who first described it in 1981

Genetic profile

Hydrolethalus syndrome is passed on through an

autosomal recessive pattern of inheritance Autosomal

means that the syndrome is not carried on a sex

chromo-some, while recessive means that both parents must carry

the gene mutation in order for their child to have the

disorder Some cases of hydrolethalus syndrome have

been observed in cases where the parents are related by

blood (consanguineous) Parents with one child affected

by hydrolethalus syndrome have a 25% chance that their

next child will also be affected with the disease

Each parent passes 23 chromosomes, or units of

genetic information, to the infant Structurally, each

chro-mosome has a short segment or “arm,” called the p arm,

and a long arm, called the q arm, extending from a

cen-tral region called the centromere Along each arm the

chromosome is further divided by numbering the bands

down the arm according to their appearance under a

microscope Each band corresponds to specific genes.Based on studies of genetic material from affected andnon-affected families, studies in 1999 assigned the genelocation for hydrolethalus syndrome to 11q23-25, orsomewhere between the 23rd and 25th band of the q arm

of chromosome 11

Demographics

The majority of cases of hydrolethalus syndromehave been reported in people of Finnish ancestry InFinland the incidence of hydrolethalus syndrome is esti-mated at one in every 20,000 Less than twenty caseshave been reported outside of Finland

Hydrolethalus syndrome affects fetal development inthe womb and is a syndrome of infants only, due to theextremely serious birth defects caused by the disorder

No cases of survival into childhood or adulthood havebeen reported The syndrome appears to affect bothmales and females with equal probability

Signs and symptoms

Prenatal symptoms include an excess of amnioticfluid in the womb (hydramnios) Babies with hydro-lethalus syndrome are often delivered pre-term and may

• defects in the structure of the heart

• incomplete development of the lungs

• the presence of extra fingers and toes (polydactyly),especially an extra big toe or little finger

• clubfoot

• a cleft lip or palate

• a small lower jaw (micrognathia)

• abnormal eye and nose formation

• a keyhole-shaped defect at the back of the head

• abnormal genitalia

Diagnosis

Hydrolethalus syndrome can be diagnosed tally by ultrasound scanning in as early as the eleventhweek of gestation After birth, the presence of multiplemalformations, especially the extreme swelling of theskull and other brain and spinal cord defects, can confirmthe diagnosis A family history and genetic testing may

prena-be useful in making the diagnosis certain

Jeanty, Philippe, and Sandra Silva “Hydrolethalus syndrome.”

genetic disorders, infections, anemias, structural birth

defects such as congenital heart disease, and many otherconditions Currently in the United States nonimmune

HF consists of about 90% and immune HF consists ofabout 10% of cases

Description

HF occurs when a baby has a condition or birthdefect that causes accumulation of excess fluid, known asedema, in the skin and other body cavities Immune HFoccurs when a mother’s blood group is Rh negative (thismeans that she does not have the Rh protein on the sur-face of her blood cells) and her baby’s blood group is Rhpositive (the baby has the Rh protein on its blood cells).During the pregnancy a small amount of the baby’s bloodcrosses into the mother’s circulatory system When thishappens, the mother’s immune system recognizes the Rhprotein on the baby’s blood cells as foreign and makesantibodies to the Rh protein The antibodies can thencross back over to the baby and attack its blood cells,destroying them and causing anemia The anemia causesheart failure, subsequent edema, and, ultimately, HF Themother’s immune response becomes greater with eachsubsequent pregnancy in which the baby has Rh-positiveblood and thus the HF becomes worse Administration ofanti-Rh antibodies during all of an Rh-negative mother’s

K E Y T E R M SHydramnios—A condition in which there is too

much amniotic fluid in the womb during

preg-nancy

Hydrocephalus—The excess accumulation of

cerebrospinal fluid around the brain, often causing

enlargement of the head

Micrognathy—Having a very small and receding

jaw

Polydactyly—The presence of extra fingers or toes.

Treatment and management

There is no treatment for hydrolethalus syndrome

other than management of the specific medical

condi-tions of the infant Genetic counseling is particularly

important in the prenatal treatment and management of

hydrolethalus syndrome This is because the severity of

symptoms almost always causes death of the infant

within a few days of birth, even if the fetus survives to

full term

Prognosis

The prognosis for infants with hydrolethalus

syn-drome is extremely poor Most affected infants are

still-born or die within the first day of life Only a handful of

cases of survival past the neonatal period have been

reported and the longest survival period was 44 days

Resources

PERIODICALS

Visapaa, Ilona, et al “Assignment of the locus for hydrolethalus

syndrome to a highly restricted region on 11q23-25.”

American Journal of Human Genetics (September 1999):

1086-95.

ORGANIZATIONS

March of Dimes Birth Defects Foundation 1275

Mamaro-neck Ave., White Plains, NY 10605 (888) 663-4637.

“Entry 236680: Hydrolethalus syndrome.” OMIM—Online

2001).

syndrome), and anemia (alpha-thalassemia,

fetomater-nal transfusion, and twin-twin transfusion) Other causesinclude infections, metabolic disorders, and tumors In allthere are over 100 separate causes of nonimmune HF.All disorders that cause HF do so by three commonmechanisms that include heart failure, hypoproteinemia(low levels of protein in the blood stream), and vascular

or lymphatic obstruction Some disorders combine two ormore of these mechanisms to cause HF Most disorderscause some degree of heart failure Anemia causes heartfailure by increasing the work of the heart so much that itfails (this is termed high output heart failure) Isolatedcongenital heart disease or conditions that have congeni-tal heart disease as a feature often will develop heart fail-ure due to a poorly functioning heart (this is termed lowoutput heart failure) Conditions that block the flow ofblood or lymph can cause edema and HF Examplesinclude tumors and congenital malformations of theblood and lymphatic vessels Conditions that lower thatamount of protein in the blood can cause edema and HF

by allowing fluid to easily leak out of the vessels and lect in the soft tissues and body cavities Examplesinclude metabolic conditions that damage the liver andprevent it from producing enough protein such as

col-Gaucher disease and Sly disease.

Genetic profile

Many causes of hydrops fetalis do not have a geneticetiology Because the recurrence risk can range from0–100% depending on the underlying cause, an accuratediagnosis is important Infectious causes are not geneticand should not recur in subsequent pregnancies Othercauses of HF have a specific genetic profile Immunecauses are due to a difference in the antigens on themother and baby’s blood cells This can recur in subse-quent pregnancies if anti-Rh antibodies are not given tothe mother Recurrence can either be 50% or 100%depending on the father’s Rh-antigen status

If hydrops fetalis is caused by a chromosome ration, the risk of recurrence is about 1%, as most ofthese conditions occur sporadically and are not inherited.Malformations causing HF, such as congenital heart dis-ease, are most commonly inherited as multifactorialtraits This type of inheritance pattern is caused by mul-

aber-tiple genes and environmental factors working in nation The recurrence risk for a multifactorial trait isabout 3–5% with each subsequent pregnancy

combi-Higher risk for recurrence occurs when a single

gene condition is the cause of HF Autosomal recessive

conditions such as alpha-thalassemia, Gaucher disease,and Sly disease have a recurrence risk of 25% with eachsubsequent pregnancy The X-linked recessive disorder

K E Y T E R M SAlpha-thalassemia—Autosomal recessive disorder

where no functional hemoglobin is produced

Leads to severe untreatable anemia

Arrhythmia—Abnormal heart rhythm, examples

are a slow, fast, or irregular heart rate

Congenital heart disease—Structural abnormality

of the heart at birth Examples include a

ventricu-lar septal defect and atrial septal defect

Down syndrome—A genetic condition

character-ized by moderate to severe mental retardation, a

characteristic facial appearance, and, in some

individuals, abnormalities of some internal organs

Down syndrome is always caused by an extra

copy of chromosome 21, or three rather than the

normal two For this reason, Down syndrome is

also known as trisomy 21.

Gaucher disease—Autosomal recessive metabolic

disorder caused by dysfunction of the lysosomal

enzyme beta-glucosidase

Lymphedema distichiasis—Autosomal dominant

condition with abnormal or absent lymph vessels

Common signs include a double row of eyelashes

(distichiasis) and edema of the limbs beginning

around puberty

Myotonic dystrophy—A form of muscular

dystro-phy, also known as Steinert’s condition,

character-ized by delay in the ability to relax muscles after

forceful contraction, wasting of muscles, as well as

other abnormalities

Pericardial cavity—Space occupied by the heart.

Pleural cavity—Area of the chest occupied by the

lungs

Sly disease—Autosomal recessive metabolic

disor-der caused by dysfunction of the lysosomal

enzyme beta-glucuronidase

Turner syndrome—Chromosome abnormality

characterized by short stature and ovarian failure,

caused by an absent X chromosome Occurs only

in females

pregnancies will prevent her from ever developing an

immune response to Rh-positive blood and thus will

pre-vent HF

The most common causes of nonimmune HF include

heart disease (congenital malformations and arrhythmia),

chromosome aberrations (Turner syndrome and Down