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Gale Encyclopedia of Genetic Disorder / Gale Encyclopedia of Genetic Disorders, Two Volume Set - Volume 2 - M-Z - I

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XX male syndrome

Prognosis

The prognosis for patients with L1CAM mutations is highly variable. The most severe cases of L1CAM mutations involve fetal demise, presumably because of the pressure exerted on the developing brain by the hydrocephaly. However, in less severe cases, the lifespan is determined primarily by general health and care factors. A number of patients with less severe L1CAM spectrum disorders have lived at least into their 50s.

Resources

PERIODICALS

Fransen, E., et al. “L1-associated Diseases: Clinical Geneticists Divide, Molecular Geneticists Unite.” Human Molecular Genetics 6 (1997): 1625–1632.

Kenwrick, S., M. Jouet, and D. Donnai. “X Linked Hydrocephalus and MASA Syndrome.” Journal of Medical Genetics 33 (1996): 59–65.

Kenwrick, S., A. Watkins, and E. De Angelis. “Neural Cell Recognition Moleculae L1: Relating Biological Complexity to Human Disease Mutations.” Human Molecular Genetics 9 (2000): 879–886.

ORGANIZATIONS

Guardians of Hydrocephalus Research Foundation. 2618 Avenue Z, Brooklyn, NY 11235-2023. (718) 743-4473 or (800) 458-865. Fax: (718) 743-1171. guardians1 @juno.com.

Hydrocephalus Association. 870 Market St. Suite 705, San Francisco, CA 94102. (415) 732-7040 or (888) 598-3789. Fax: (415) 732-7044. hydroassoc@aol.com.http://neurosurgery.mgh.harvard.edu/ha .

Hydrocephalus Support Group, Inc. PO Box 4236, Chesterfield, MO 63006-4236. (314) 532-8228. hydrobuff @postnet.com.

National Hydrocephalus Foundation. 12413 Centralia, Lakewood, CA 90715-1623. (562) 402-3523 or (888) 2601789. hydrobrat@earthlink.net. http://www.nhfonline

.org .

National Institute of Neurological Disorders and Stroke. 31 Center Drive, MSC 2540, Bldg. 31, Room 8806, Bethesda, MD 20814. (301) 496-5751 or (800) 352-9424.http://www.ninds.nih.gov .

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. http://www

.rarediseases.org .

WEBSITES

L1 Mutation Web Page.

http://dnalab-www.uia.ac.be/dnalab/l1/ .

Ron C. Michaelis, PhD, FACMG

XO syndrome see Turner syndrome

I XX male syndrome

Definition

XX male syndrome occurs when the affected individual appears as a normal male, but has female chromosomes. Two types of XX male syndrome can occur: those with detectable SRY gene and those without detectable SRY (Sex determining region Y). SRY is the main genetic switch for determining that a developing embryo will become male.

Description

XX male syndrome is a condition in which the sex chromosomes of an individual do not agree with the physical sex of the affected person. Normally there are 46 chromosomes, or 23 pairs of chromosomes, in each cell. The first 22 pairs are the same in men and women. The last pair, the sex chromosomes, is two X chromosomes in females (XX) and an X and a Y chromosome in males (XY).

In XX male syndrome, the person has female chromosomes but male physical features. The majority of persons with XX male syndrome have the Y chromosome gene SRY attached to one of their X chromosomes. The rest of the individuals with XX male syndrome do not have SRY detectable in their cells. Hence, other genes on other chromosomes in the pathway for determining sex must be responsible for their male physical features.

Genetic profile

In XX male syndrome caused by the gene SRY, a translocation between the X chromosome and Y chromosome causes the condition. A translocation occurs when part of one chromosome breaks off and switches places with part of another chromosome. In XX male syndrome, the tip of the Y chromosome that includes SRY is translocated to the X chromosome. As a result, an embryo with XX chromosomes with a translocated SRY gene will develop the physical characteristics of a male. Typically, a piece of the Y chromosome in the pseudoautosomal region exchanges with the tip of the X chromosome. In XX male syndrome, this crossover includes the SRY portion of the Y.

In individuals with XX male syndrome who do not have an SRY gene detectable in their cells, the cause of the condition is not known. Scientists believe that one or more genes that are involved in the development of the sex of an embryo are mutated or altered and cause physical male characteristics in a chromosomally female per-

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son. These genes could be located on the X chromosome or on one of the 22 pairs of autosomes that males and females have in common. As of 2001, no genes have been found to explain the female to male sex reversal in people affected with XX male syndrome who are SRY negative. Approximately 20% of XX males do not have a known cause and are SRY negative. It is thought that SRY is a switch point, and the protein that is made by SRY regulates the activity of one or more genes (likely on an autosomal chromosome) that contribute to sex development. Also there have been some studies that demonstrate autosomal recessive and autosomal dominant inheritance for the XX male.

Demographics

XX male syndrome occurs in approximately one in 20,000 to one in 25,000 individuals. The vast majority, about 90%, has SRY detectable in their cells. The remaining 10% are SRY negative, although some research indicates that up to 20% can be SRY negative. XX male syndrome can occur in any ethnic background and usually occurs as a sporadic event, not inherited from the person’s mother of father. However, some exceptions of more than one affected family member have been reported.

Signs and symptoms

SRY positive XX male syndrome

Males with SRY positive XX male syndrome look like and identify as males. They have normal male physical features including normal male body, genitals, and testicles. All males with XX male syndrome are infertile (cannot have biological children) because they lack the other genes on the Y chromosome involved in making sperm. Men with XX male syndrome are usually shorter than an average male, again because they do not have certain genes on the Y chromosome involved in height. A similar syndrome that effects males with two X chromosomes is Klinefelter syndrome. Those individuals with 46XX present with a condition similar to Klinefelter, such as small testes and abnormally long legs.

SRY negative XX male syndrome

People with SRY negative XX male syndrome are more likely to be born with physical features that suggest a condition. Many have hypospadias, where the opening of the penis is not at the tip, but further down on the shaft. They may also have undescended testicles, where the testicles remain in the body and do not drop into the scrotal sac. Occasionally, an SRY negative affected male has

KEY TERMS

Autosomes—Chromosome not involved in specifying sex.

Chromosome—A microscopic thread-like structure found within each cell of the body and consists of a complex of proteins and DNA. Humans have 46 chromosomes arranged into 23 pairs. Changes in either the total number of chromosomes or their shape and size (structure) may lead to physical or mental abnormalities.

Embryo—The earliest stage of development of a human infant, usually used to refer to the first eight weeks of pregnancy. The term fetus is used from roughly the third month of pregnancy until delivery.

Gene—A building block of inheritance, which contains the instructions for the production of a particular protein, and is made up of a molecular sequence found on a section of DNA. Each gene is found on a precise location on a chromosome.

some female structures such as the uterus and fallopian tubes. Men with SRY negative XX male syndrome can also have gynecomastia, or breast development during puberty, and puberty can be delayed. As with SRY positive XX male syndrome, these men are infertile and shorter than average because they lack other Y specific genes. The physical features can vary within a family, but most affected people are raised as males.

A small portion of people with SRY negative XX male syndrome are true hermaphrodites. This means they have both testicular and ovarian tissue in their gonads. They are usually born with ambiguous genitalia, where the genitals of the baby have both male and female characteristics. Individuals with XX male syndrome and true hermaphrodites can occur in the same family, suggesting there is a common genetic cause to both. Research indicates that 15% of 46XX true hermaphrodites have the SRY gene.

Diagnosis

For people with XX male syndrome who have ambiguous genitalia, hypospadias, and/or undescended testicles, the diagnosis is suspected at birth. For males with XX male syndrome and normal male features, the diagnosis can be suspected during puberty when breast development occurs. Many men do not know they have

syndrome male XX

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XX male syndrome

TABLE 1

Disorders associated with multiple X or Y chromosome inheritance

Disorder

Chromosome affected

Karotype

Incidence

Symptoms

Turner syndrome

X

45,X (monosomy)

1 in 2,000

Growth retardation

 

 

 

 

Infertility

 

 

 

 

Cardiovascular malformations

 

 

 

 

Learning disabilities

Klinefelter syndrome

X

47,XXY (trisomy)

1 in 500–800

Taller than average

 

 

 

 

Poor upper body strength;

 

 

 

 

clumsiness

 

 

 

 

Mild intentional tremor (20–50%)

 

 

 

 

Breast enlargement (33%)

 

 

 

 

Decreased testosterone production

 

 

 

 

Infertility

 

 

 

 

Dyslexia (50%)

Triple X

X

47,XXX (trisomy)

1 in 1,000

Mild delays in motor, linguistic and

 

 

 

 

emotional development

 

 

 

 

Learning disabilities

 

 

 

 

Slightly taller than average

XYY syndrome

Y

47,XYY

1 in 1,000

Taller than average

 

 

 

 

Lack of coordination

 

 

 

 

Acne

 

 

 

 

Some infertility

 

 

 

 

Learning disabilities (50%)

 

 

 

 

Behavior problems, especially

 

 

 

 

impulse control

XX male syndrome

Y

46,X,t(X,Y) (translocation

1 in 20,000–25,000

Usually normal male physical

 

 

of the SRY gene [90%]

 

features but may have ambiguous

 

 

or other gene

 

genitalia, hypospadias or

 

 

responsible for male

 

undescended testes

 

 

sex determination)

 

Infertility

 

 

 

 

Shorter than average

XX male syndrome until they try to have their own children, are unable to do so, and therefore are evaluated for infertility.

When the condition is suspected in a male, chromosome studies can be done on a small sample of tissue such as blood or skin. The results show normal sex chromosomes, or XX chromosomes. Further genetic testing is available and needed to determine if the SRY gene is present.

Some affected individuals have had SRY found in testicular tissue, but not in their blood cells. This is called mosaicism. Most males have only their blood cells tested for SRY and not their testicular tissue. Hence, some men who think they have SRY negative XX male syndrome may actually be mosaic and have SRY in their gonads.

XX male syndrome can be detected before a baby is born. This occurs when a mother-to-be has prenatal testing done that shows female chromosomes but on ultrasound male genitals are found. Often the mother has had prenatal testing for a reason other than XX male syndrome, such as for an increased risk of having a baby with Down syndrome due to her age. Genetic testing

for the presence of the SRY gene can be done by an amniocentesis. An amniocentesis is a procedure in which a needle is inserted through the mother’s abdomen into the sac of fluid surrounding the baby. Some of the fluid is removed and used to test for the presence of the SRY gene. Amniocentesis slightly increases the risk of miscarriage.

Treatment and management

For those with XX male syndrome with normal male genitals and testicles, no treatment is necessary. Affected males with hypospadias or undescended testicles may require one or more surgeries to correct the condition. If gynecomastia is severe enough, breast reduction surgery is possible. The rare person with true hermaphrodism usually requires surgery to remove the gonads, as they can become cancerous.

Parents who learn their child has been diagnosed with XX male syndrome are encouraged to gain both emotional and educational support. Issues such as explaining the condition to their child when they are grown is a topic that can be worked through with the help

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of both medical professionals, and those whose own children live with the condition.

Prognosis

The prognosis for males with XX male syndrome is excellent. Surgery can usually correct any physical problems. Men with XX male syndrome have normal intelligence and a normal life span. However, all affected men will be infertile.

Resources

BOOKS

Wilson, J.D., and J.E. Griffin. “Disorders of Sexual Differentiation.” In Harrison’s Online. Edited by Eugene Braunwald, et al. New York: McGraw-Hill, 2001.

PERIODICALS

Abramsky, L., et al. “What Parents Are Told After Prenatal Diagnosis of a Sex Chromosome Abnormality: Interview and Questionnaire Study.” British Medical Journal 322 (2001): 463–466.

Biesecker, B. “Prenatal Diagnoses of Sex Chromosome Conditions: Parents Need More Than Just Accurate Information.” British Medical Journal 322 (2001): 441–2.

Zenteno, Juan, et al. “Two SRY-negative XX Male Brothers Without Genital Ambiguity.” Human Genetics 100 (1997): 606–610.

ORGANIZATIONS

Intersex Society of North America. PO Box 301, Petaluma, CA 94953-0301. http://www.isna.org .

RESOLVE, The National Infertility Association. 1310 Broadway, Somerville, MA 02144-1779. (617) 623-0744. resolveinc@aol.com.

Carin Lea Beltz, MS, CGC

I XYY syndrome

Definition

XYY syndrome is a chromosome disorder that affects males. Males with this disorder have an extra Y chromosome.

Description

The XYY syndrome was previously considered the super-male syndrome, in which men with this condition were thought to be overly aggressive and more likely to become criminals. These original stereotypes came about because several researchers in the 1960s found a high number of men with XYY syndrome in prisons and men-

tal institutes. Based on these observations, men with XYY syndrome were labeled as overly aggressive and likely to be criminals.

These original observations did not consider that the majority of males with XYY syndrome were not in prisons or mental institutes. Since then, broader, less biased studies have been done on males with XYY syndrome. Though males with XYY syndrome may be taller than average and have an increased risk for learning difficulties, especially in reading and speech, they are not overly aggressive. Unfortunately, some text books and many people still believe the inaccurate stereotype of the supermale syndrome.

Genetic profile

Chromosomes are structures in the cells that contain genes. Genes are responsible for instructing our bodies how to grow and develop. Usually, an individual has 46 chromosomes in his or her cells, or 23 pairs. The first 22 pairs are the same in males and females and the last pair, the sex chromosomes, consist of two X chromosomes in a female, and an X chromosome and an Y chromosome in a male.

XYY syndrome occurs when an extra Y chromosome is present in the cells of an affected individual. People with XYY syndrome are always male. The error that causes the extra Y chromosome can occur in the fertilizing sperm or in the developing embryo.

XYY is not considered an inherited condition. An inherited condition usually is one in which the mother and/or father has an alteration in a gene or chromosome that can be passed onto their children. Typically, in an inherited condition, there is an increased chance that the condition will reoccur. The risk of the condition reoccurring in another pregnancy is not increased above the general population incidence.

Demographics

XYY syndrome has an incidence of one in 1,000 newborn males. However, since many males with XYY syndrome look like other males without XYY syndrome, many males are never identified.

Signs and symptoms

There are no physical abnormalities in most males with XYY syndrome. However, some males can have one or more of the follwing characteristics. Males who have XYY syndrome are usually normal in length at birth, but have rapid growth in childhood, typically averaging in the 75th percentile (taller than 75% of males their same

syndrome XYY

GALE ENCYCLOPEDIA OF GENETIC DISORDERS

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XYY syndrome

KEY TERMS

Amniocentesis—A procedure performed at 16–18 weeks of pregnancy in which a needle is inserted through a woman’s abdomen into her uterus to draw out a small sample of the amniotic fluid from around the baby. Either the fluid itself or cells from the fluid can be used for a variety of tests to obtain information about genetic disorders and other medical conditions in the fetus.

Cell—The smallest living units of the body which group together to form tissues and help the body perform specific functions.

Chorionic villus sampling (CVS)—A procedure used for prenatal diagnosis at 10–12 weeks gestation. 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.

Chromosome—A microscopic thread-like structure found within each cell of the body and consists of a complex of proteins and DNA. Humans have 46 chromosomes arranged into 23 pairs. Changes in either the total number of chromosomes or their shape and size (structure) may lead to physical or mental abnormalities.

Embryo—The earliest stage of development of a human infant, usually used to refer to the first eight weeks of pregnancy. The term fetus is used from roughly the third month of pregnancy until delivery.

Hormone—A chemical messenger produced by the body that is involved in regulating specific bodily functions such as growth, development, and reproduction.

age). Many males with XYY syndrome are not overly muscular, particularly in the chest and shoulders. Individuals with XYY syndrome often have difficulties with their coordination. As a result, they can appear to be awkward or clumsy. During their teenage years, males with XYY syndrome may develop severe acne that may need to be treated by a dermatologist.

Men with XYY syndrome have normal, heterosexual function and most are fertile. However, numerous case reports of men with XYY syndrome presenting with infertility have been reported. Most males with XYY

syndrome have normal hormones involved in their sperm production. However, a minority of males with XYY syndrome may have increased amounts of some hormones involved in sperm production. This may result in infertility due to inadequate sperm production. As of 2001, the true incidence of infertility in males with XYY syndrome is unknown.

When XYY men make sperm, the extra Y chromosome is thought to be lost resulting in a normal number of sex chromosomes. As a result, men with XYY syndrome are not at an increased risk for fathering children with chromosome abnormalities. However, some men with XYY syndrome have been found to have more sperm with extra chromosomes than what is found in men without XYY syndrome. Whether these men have an increased risk of fathering a child with a chromosome abnormality is unknown as of 2001.

Men with XYY syndrome usually have normal intelligence, but it can be slightly lower than their brothers and sisters. Approximately 50% of males with XYY syndrome have learning difficulties, usually in language and reading. Speech delay can be noticed in early school years. Males with XYY syndrome may not process information as quickly as their peers and may need additional time for learning.

Males with XYY syndrome have an increased risk of behavior problems. Hyperactivity and temper tantrums can occur more frequently than expected, especially during childhood. As males with XYY syndrome become older, they may have problems with impulse control and appear emotionally immature.

From a psychosocial standpoint, males with XYY syndrome may have low self-esteem due to mild learning disabilities and/or lack of athletic skills due to lack of coordination. Males with XYY syndrome are at risk in stressful environments and have a low ability to deal with frustration.

As of 2001, men with XYY syndrome are not thought to be excessively aggressive or psychotic. However, because some men with XYY syndrome can have mild learning difficulties and/or have difficulty controlling behavior problems such as lack of impulse control, their actions may lead to criminal behavior if placed in the right environment. It is important to emphasize that this occurs only in a small percentage of men with XYY syndrome. Most men with XYY syndrome are productive members of society with no criminal behavior.

Diagnosis

Most individuals with 47,XYY go through their entire lives without being diagnosed with this condition.

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Chromosome studies can be done after birth on a skin or blood sample to confirm the condition. This syndrome can also be diagnosed coincidentally when a pregnant mother undergoes prenatal testing for other reasons, such as being age 35 or older at the time of delivery. Prenatal tests that can determine whether or not an unborn baby will be affected with 47,XXY are the chorionic villi sampling (CVS) and amniocentesis procedures. Both procedures are associated with potential risks of pregnancy loss and therefore are only offered to women who have an increased risk of having a baby born with a chromosome problem or some type of genetic condition.

Treatment and management

Treatment and management for most men with XYY syndrome is not indicated. However, early identification and intervention of learning disabilities and/or behavior difficulties is necessary. Speech therapy, physical therapy, and occupational therapy may be helpful for males with XYY syndrome. Also, because males with XYY syndrome are at risk in stressful environments, a supportive and stimulating home life is important.

Prognosis

Most males who have learning disabilities and/or behavior problems due to XYY syndrome have an excellent prognosis. Learning disabilities are mild and most affected males learn how to control their impulsiveness and other behavior problems. XYY syndrome does not shorten lifespan.

Resources

PERIODICALS

Gotz, M.J., et al. “Criminality and Antisocial Behaviour in Unselected Men with Sex Chromosome Abnormalities.”

Psychological Medicine 29 (1999): 953–962.

Linden M.G., et al. “Intrauterine Diagnosis of Sex Chromosome Aneuploidy.” Obstetrics and Gynecology 87 (1996): 469–75.

ORGANIZATIONS

Chromosome Deletion Outreach, Inc. PO Box 724, Boca Raton, FL 33429-0724. (561) 391-5098 or (888) 2366880. Fax: (561) 395-4252. cdo@worldnet.att.net.http://members.aol.com/cdousa/cdo.htm .

Carin Lea Beltz, MS, CGC

syndrome XYY

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1223

Z

I Zellweger syndrome

Definition

Zellweger syndrome refers to an inherited condition that is present at birth and usually causes death during the first six to twelve months of age. This syndrome is caused by a lack or reduction of peroxisomes, which are specialized organelles that help the body get rid of toxic substances. Zellweger syndrome is a disorder of metabolism. It is one of a group of genetic disorders called the leukodystrophies, diseases that involve abnormal growth of the fatty covering of nerve fibers (myelin sheath).

Description

In 1964, reserchers described a similar pattern of multiple birth defects in two unrelated pairs of siblings in Iowa and Maryland. Hans Zellweger identified the cases in Iowa. Passarge and McAdams reported several similar cases and introduced the name cerebro-hepato-renal-syn- drome. Opitz reviewed the Bowen report and decided that only the Iowa cases represented the same condition reported by others. To recognize Hans Zellweger’s role in identifying the Iowa cases, Opitz proposed the name Zellweger cerebro-hepato-renal syndrome. Most refer to the syndrome as Zellweger syndrome.

Initially, Zellweger syndrome was considered a multiple congenital anomaly disorder. In 1973, researchers reported that individuals who have Zellweger syndrome do not have peroxisomes in their liver and kidneys. Important metabolic processes take place in peroxisomes. Thus, the first evidence that Zellweger syndrome should be reassigned to the metabolic disease category was provided.

Metabolism includes numerous chemical processes involved in both construction (anabolism) and break down (catabolism) of important components. These processes are catalyzed (or helped along) by enzymes. If

KEY TERMS

Amniocentesis—A procedure performed at 16–18 weeks of pregnancy in which a needle is inserted through a woman’s abdomen into her uterus to draw out a small sample of the amniotic fluid from around the baby. Either the fluid itself or cells from the fluid can be used for a variety of tests to obtain information about genetic disorders and other medical conditions in the fetus.

Chorionic villus sampling (CVS)—A procedure used for prenatal diagnosis at 10–12 weeks gestation. 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.

any enzymes are missing in the process, a build-up of an initial substance, or a missing end-product, can result. Either of these situations can lead to disease.

Peroxisomes are small organelles found in cells, particularly of the liver, kidneys, and brain. Substances that are broken down in peroxisomes include very long chain fatty acids, polyunsaturated fatty acids, dicarboxylic fatty acids, prostaglandins, and the side chain of cholesterol. When peroxisomes are absent or deficient, very long chain fatty acids, and other substances that peroxisomes normally help to catalyze, begin to build up in the body.

Peroxisomes also play a part in the initial reactions in the creation of plasmalogens. Plasmalogens are important components in the structure of myelin, a fatty layer that covers the nerve fibers in the body. This covering helps the nerve signals to move correctly from place to place. Since plasmalogens require peroxisomes for their formation, a lack of functioning peroxisomes causes a

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Zellweger syndrome

deficiency in plasmalogens. Since the plasmalogens are required for the formation of myelin, the myelin is defective.

Bile acid formation also requires peroxisomes. Bile is secreted by the liver and stored in the gallbladder. It is released when fat enters the intestines. Bile then helps to break down these fats to prepare them for further digestion. Bile acid is produced during the breakdown of cholesterol.

Babies with Zellweger syndrome have severe developmental retardation and impairment of their central nervous system. They lack muscle tone (hypotonia), and are often blind or deaf. They have a distinctive facial appearance, an enlarged liver, and may have cysts in their kidneys. They will frequently have jaundice in the newborn period that is more serious and lasts longer than usual. Jaundice is a yellow discoloration of the skin and eyes caused by too much bilirubin in the blood. It may be a symptom of many disorders including liver disease. Healthy newborns frequently have jaundice that resolves after a few days.

Genetic profile

Zellweger syndrome is an autosomal recessive condition. This means that in order to have the condition, an individual needs to inherit one copy of the gene for Zellweger syndrome from each parent. An individual who has only one copy of the gene is called a carrier for the condition and does not have any signs or symptoms of the condition. When two parents are carriers for Zellweger syndrome, they have a 25% chance, with each pregnancy, for having an affected child. They have a 50% chance for having a child who is a carrier for the condition and a 25% chance for having a child who is neither affected nor a carrier for Zellweger syndrome.

Changes or mutations in any of several different genes involved in the creation of peroxisomes (peroxisome biogenesis) can cause Zellweger syndrome. There are many gene mutations that have been identified that are involved with the creation of functioning peroxisomes. The gene located on the long arm of chromosome 7, at 7q21-q22, is in part responsible for the creation of peroxisomes. The gene product is called peroxisome biogenesis factor 1 or Peroxin 1 (PEX 1). When a gene change or mutation occurs in this area that does not allow for normal creation of the peroxisomes, then the peroxisomes are not created, leading to Zellweger syndrome. There are several other genes identified on different chromosomes that will not allow for normal peroxisome development if a gene mutation occurs. These include, but are not limited to, peroxisome biogenesis factor 13

(short arm of chromosome 2 at 2p15), peroxisome biogenesis factor 6 (short arm of chromosome 6 at 6p21), peroxisome assembly factor-1 (long arm of chromosome 8 at 8q21), peroxisomal targeting signal 1 receptor (short arm of chromosome 12 at 12p13), and peroxisome biogenesis factor 10 (chromosome 1).

The cause of Zellweger syndrome is a failure of the peroxisomes to be able to bring newly created peroxisomal proteins into the peroxisomes. Instead, the proteins stay outside of the peroxisomes and are broken down. The peroxisome membranes may be present, but are empty, like the wood frame of an empty house. These empty peroxisomes have been called peroxisome “ghosts.”

Demographics

The frequency of this condition is estimated to be 1 in 50,000. There is no reported difference in the incidence in any particular sex or ethnic background.

Signs and symptoms

The characteristic facial features of Zellweger syndrome include:

high forehead

widely spaced eyes (hypertelorism)

low, broad, or flat nasal bridge

“full” cheeks

small chin (micrognathia)

forward tilting (anteverted) nostrils

vertical fold of skin over the inner corner of the eye (epicanthal fold)

upslanting eyes

shallow orbital ridges

minor ear abnormalities

Other characteristics include, but are not limited to:

breech presentation at birth (feet first)

extremely weak muscles (hypotonia)

weak sucking and swallowing reflexes

high arched palate

absent deep tendon reflexes

seizures

deafness

enlarged liver (hepatomegaly)

enlarged spleen

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GALE ENCYCLOPEDIA OF GENETIC DISORDERS

gastrointestinal bleeding

slow growth after birth

severe mental retardation

abnormal brain findings

involuntary, rhythmic movements of the eyes (nystagmus)

large space between the bones of the skull (fontanel)

flat back part of the head (occiput)

tiny white or yellow spots on the colored part of the eyes (brushfield spots)

redundant skin on neck

congenital cloudy lenses of the eye (cataracts)

possible heart defects

a single crease across the palm of the hands (simian creases)

fixed, immovable joints (contractures)

misaligned bones in the front part of the foot/club foot (talipes equinovarus)

undescended testicles (cryptorchidism)

underdeveloped thymus (thymus hypoplasia)

hearing impairment

failure to thrive

psychomotor retardation

high levels of iron or copper in the blood

Diagnosis

Diagnosis is based on clinical characteristics combined with a series of tests to determine the peroxisomal function and structure. Biochemical abnormalities include elevated levels of very long chain fatty acids, a decrease in the levels of a peroxisomal enzyme dihydroxyacetone phosphate acyltransferase (DHAPAT), the presence of abnormal intermediates in bile acid formation, and a lack of plasmalogens in a blood sample. Absence of peroxisomes in liver biopsy specimen is considered essential for the diagnosis of Zellweger syndrome.

Prenatal diagnosis for Zellweger syndrome is possible through chorionic villus sampling (CVS) and amniocentesis. Diagnosis may be made by measuring the synthesis of plasmalogens in cultured CVS or amniotic fluid cells or by measuring the amount of very long chain fatty acids. Other tests may be useful, including measuring the amount of the peroxisomal enzyme DHAPAT in the amniotic fluid.

There are other leukodystrophies, including neonatal adrenoleukodystrophy, infantile Refsum disease, and hyperpipecolic acidemia. The milder diseases may be due to having partial peroxisome function.

Treatment and management

In general there is no cure and no treatment for Zellweger syndrome.

Prognosis

The prognosis for individuals who have Zellweger syndrome is poor. Those with the disease usually only live for a few months after birth. Rarely do individuals with Zellweger syndrome live longer than one year.

Resources

BOOKS

Jones, Kenneth Lyons, ed. Smith’s Recognizable Patterns of Human Malformation. 5th ed. Philadelphia: W.B. Saunders Company, 1997.

ORGANIZATIONS

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. http://www

.rarediseases.org .

United Leukodystrophy Foundation. 2304 Highland Dr., Sycamore, IL 60178. (815) 895-3211 or (800) 728-5483. Fax: (815) 895-2432. http://www. ulf.org .

WEBSITES

“NINDS Zellweger Syndrome Information Page.” National Institute of Neurological Disorders and Stroke.http://www.ninds.nih.gov/health_and_medical/disorders/zellwege_doc.htm .

Renée A. Laux, MS

I Zygote

Definition

The zygote is the single cell that is formed when the sperm cell fertilizes the egg cell. The zygote divides multiple times, producing identical copies of itself. The cells produced by the division of the zygote form the developing embryo, fetus, and baby. The zygote is the first step in the formation of a new person.

Description

When the sperm fuses with the egg, a cascade of events begins. Additional sperm are prevented from fer-

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Zygote

KEY TERMS

Chromosome—A microscopic thread-like structure found within each cell of the body and consists of a complex of proteins and DNA. Humans have 46 chromosomes arranged into 23 pairs. Changes in either the total number of chromosomes or their shape and size (structure) may lead to physical or mental abnormalities.

Gene—A building block of inheritance, which contains the instructions for the production of a particular protein, and is made up of a molecular sequence found on a section of DNA. Each gene is found at a precise location on a chromosome.

Teratogen—Any drug, chemical, maternal disease, or exposure that can cause physical or functional defects in an exposed embryo or fetus.

tilizing the egg. The membranes of the egg and sperm combine, producing one single cell. The egg and sperm prepare to fuse their genetic material (DNA/chromosomes). Finally, the genetic material combines to produce the zygote with one complete set of chromosomes.

Most cells in the human body have two pairs of 23 chromosomes, i.e. 46 chromosomes total. One set of 23 chromosomes is inherited from the mother, and the complementary set is inherited from the father. When the egg and sperm are formed, the two sets of chromosomes divide evenly, from 46 to 23 chromsomes to produce eggs and sperm with 23 chromosomes each. This ensures that when the egg and sperm fuse during conception, the original number of chromosomes (46) is restored.

The reduction of each parent cell from 46 to 23 chromosomes ensures that each parent contributes half of his or her genetic material to form the zygote and the offspring shares 50% of his or her genes with each parent. Duplication of the single zygote occurs through a complete division of the single ball of cells. This begins the process of forming the fetus and eventually the baby. The first division produces two identical cells, the second produces four cells, the third produces eight cells, etc. After many cell divisions, the cells begin to specialize and differentiate (form particular tissues and organs).

Fertilization usually occurs in the fallopian tube, and the first few cell divisions occur as the developing embryo moves to the uterus. The first division occurs about 30 hours after fertilization. As the zygote divides, some of the cells formed will develop into the placenta.

Approximately six days after fertilization, the ball of cells attaches to the uterine wall.

Sex determination

Men and women each have 22 pairs of non-sex chromosomes and two sex chromosomes. Men’s sex chromosomes are X and Y. A mature sperm cell that has undergone the chromosome division process from 46 to 23 chromosomes produces a cell that is either X or Y. Women’s sex chromosomes are X and X. The eggs that women produce have only X chromosomes. Therefore, the sperm determines whether the zygote is XY or XX, which is the initial step on the biological path to becoming a male or female.

Developmental periods

The term embryo refers to the developing baby between the second week after conception and the eighth week after conception. Doctors use the term fetus from the ninth week after conception to birth. A pregnancy is broken down into three trimesters. The first trimester begins with the first day of the woman’s last menstrual period and each trimester is three calendar months.

Twins

Twins may arise in two ways. Identical twins are called “monozygotic” because both individuals are formed from the same zygote. As the zygote divides to form the baby, two separate individuals form instead of one. Fraternal twins are called “dizygotic” because each individual develops from a different zygote. Two eggs are ovulated, and a separate sperm fertilizes each egg. Therefore, identical twins have exactly the same DNA in each cell and fraternal twins share the same amount of DNA as brothers and sisters. Sometimes it is impossible to tell monozygotic twins from dizygotic twins based on the placenta and the fetal membranes. If a person wants to determine whether twins are monozygotic or dizygotic, DNA studies of blood cells will provide a definitive answer.

Abnormalities

The zygote normally contains two complete sets of 23 chromosomes, and two copies of every gene. If the egg or sperm that fuse to form the zygote is abnormal, the zygote will also be abnormal. For example, Down syndrome is caused by an extra chromosome number 21 from the egg or sperm cell. Since the cells formed by division of the zygote are identical to the zygote, any abnormality in the zygote will be in every cell of the baby.

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