The Gale Genetic Disorders of encyclopedia vol 2 - part 9 ppt

Prognosis The prognosis for patients with L1CAM mutations is highly variable. The most severe cases of L1CAM muta- tions involve fetal demise, presumably because of the pressure exerted on the developing brain by the hydro- cephaly. 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. Ͻhttp://neurosurgery.mgh.harvard.edu/haϾ. 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) 260- 1789. hydrobrat@earthlink.net. Ͻhttp://www.nhfonline .orgϾ. 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. Ͻhttp://www.ninds.nih.govϾ. National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. Ͻhttp://www .rarediseases.orgϾ. WEBSITES L1 Mutation Web Page. Ͻhttp://dnalab-www.uia.ac.be/dnalab/l1/Ͼ. Ron C. Michaelis, PhD, FACMG XO syndrome see Turner syndrome I XX male syndrome Definition XX male syndrome occurs when the affected indi- vidual appears as a normal male, but has female chro- mosomes. 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 chromo- somes in females (XX) and an X and a Y chromosome in males (XY). In XX male syndrome, the person has female chro- mosomes but male physical features. The majority of persons with XX male syndrome have the Y chromo- some 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 deter- mining 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 chromo- some 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 translo- cated 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 por- tion 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 phys- ical male characteristics in a chromosomally female per- 1218 GALE ENCYCLOPEDIA OF GENETIC DISORDERS XX male syndrome 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 peo- ple affected with XX male syndrome who are SRY neg- ative. 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 domi- nant 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 phys- ical 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 cer- tain genes on the Y chromosome involved in height. A similar syndrome that effects males with two X chromo- somes 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 tes- ticles remain in the body and do not drop into the scrotal sac. Occasionally, an SRY negative affected male has 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 posi- tive 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 char- acteristics. Individuals with XX male syndrome and true hermaphrodites can occur in the same family, suggesting there is a common genetic cause to both. Research indi- cates 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 GALE ENCYCLOPEDIA OF GENETIC DISORDERS 1219 XX male syndrome KEY TERMS Autosomes—Chromosome not involved in speci- fying sex. Chromosome—A microscopic thread-like struc- ture found within each cell of the body and con- sists of a complex of proteins and DNA. Humans have 46 chromosomes arranged into 23 pairs. Changes in either the total number of chromo- somes 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 deliv- ery. 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. XX male syndrome until they try to have their own chil- dren, are unable to do so, and therefore are evaluated for infertility. When the condition is suspected in a male, chromo- some studies can be done on a small sample of tissue such as blood or skin. The results show normal sex chro- mosomes, 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 test- ing done that shows female chromosomes but on ultra- sound male genitals are found. Often the mother has had prenatal testing for a reason other than XX male syn- drome, 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 1220 GALE ENCYCLOPEDIA OF GENETIC DISORDERS XX male syndrome 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 features but may have ambiguous genitalia, hypospadias or undescended testes Infertility Shorter than average TABLE 1 of the SRY gene [90%] or other gene responsible for male sex determination) GALE ENCYCLOPEDIA OF GENETIC DISORDERS 1221 of both medical professionals, and those whose own chil- dren live with the condition. Prognosis The prognosis for males with XX male syndrome is excellent. Surgery can usually correct any physical prob- lems. Men with XX male syndrome have normal intelli- gence 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. Ͻhttp://www.isna.orgϾ. 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 pris- ons 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 difficul- ties, especially in reading and speech, they are not overly aggressive. Unfortunately, some text books and many people still believe the inaccurate stereotype of the super- male syndrome. Genetic profile Chromosomes are structures in the cells that con- tain genes. Genes are responsible for instructing our bod- ies 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 chromo- somes in a female, and an X chromosome and an Y chro- mosome in a male. XYY syndrome occurs when an extra Y chromo- some 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 fer- tilizing 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 reoccur- ring in another pregnancy is not increased above the gen- eral 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 XYY syndrome 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 hor- mones 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 chromo- some is thought to be lost resulting in a normal number of sex chromosomes. As a result, men with XYY syn- drome 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 intel- ligence, but it can be slightly lower than their brothers and sisters. Approximately 50% of males with XYY syn- drome have learning difficulties, usually in language and reading. Speech delay can be noticed in early school years. Males with XYY syndrome may not process infor- mation 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 dur- ing 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 con- trolling behavior problems such as lack of impulse con- trol, 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 produc- tive members of society with no criminal behavior. Diagnosis Most individuals with 47,XYY go through their entire lives without being diagnosed with this condition. 1222 GALE ENCYCLOPEDIA OF GENETIC DISORDERS 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 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. Chromosome—A microscopic thread-like struc- ture found within each cell of the body and con- sists of a complex of proteins and DNA. Humans have 46 chromosomes arranged into 23 pairs. Changes in either the total number of chromo- somes 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 deliv- ery. Hormone—A chemical messenger produced by the body that is involved in regulating specific bodily functions such as growth, development, and reproduction. Prognosis Most males who have learning disabilities and/or behavior problems due to XYY syndrome have an excel- lent 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) 236- 6880. Fax: (561) 395-4252. cdo@worldnet.att.net. Ͻhttp://members.aol.com/cdousa/cdo.htmϾ. Carin Lea Beltz, MS, CGC GALE ENCYCLOPEDIA OF GENETIC DISORDERS 1223 XYY syndrome 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 sam- pling (CVS) and amniocentesis procedures. Both proce- dures 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 chromo- some 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 ther- apy, and occupational therapy may be helpful for males with XYY syndrome. Also, because males with XYY syndrome are at risk in stressful environments, a support- ive and stimulating home life is important. 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 metab- olism. 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 mul- tiple 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 peroxi- somes. 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 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, par- ticularly 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 impor- tant 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 GALE ENCYCLOPEDIA OF GENETIC DISORDERS 1225 Z 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 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. deficiency in plasmalogens. Since the plasmalogens are required for the formation of myelin, the myelin is defec- tive. 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 diges- tion. Bile acid is produced during the breakdown of cho- lesterol. Babies with Zellweger syndrome have severe devel- opmental 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 new- born 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 con- dition. 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 condi- tion 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 (peroxi- some biogenesis) can cause Zellweger syndrome. There are many gene mutations that have been identified that are involved with the creation of functioning peroxi- somes. 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 bio- genesis 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 peroxi- somes 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 bio- genesis 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 bio- genesis factor 10 (chromosome 1). The cause of Zellweger syndrome is a failure of the peroxisomes to be able to bring newly created peroxiso- mal 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 inci- dence in any particular sex or ethnic background. Signs and symptoms The characteristic facial features of Zellweger syn- drome 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 1226 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Zellweger syndrome • 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 com- bined 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 dihy- droxyacetone phosphate acyltransferase (DHAPAT), the presence of abnormal intermediates in bile acid forma- tion, and a lack of plasmalogens in a blood sample. Absence of peroxisomes in liver biopsy specimen is con- sidered essential for the diagnosis of Zellweger syn- drome. Prenatal diagnosis for Zellweger syndrome is possi- ble through chorionic villus sampling (CVS) and amnio- centesis. 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 measur- ing 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. Ͻhttp://www .rarediseases.orgϾ. United Leukodystrophy Foundation. 2304 Highland Dr., Sycamore, IL 60178. (815) 895-3211 or (800) 728-5483. Fax: (815) 895-2432. Ͻhttp://www. ulf.orgϾ. WEBSITES “NINDS Zellweger Syndrome Information Page.” National Institute of Neurological Disorders and Stroke. Ͻhttp://www.ninds.nih.gov/health_and_medical/disor- ders/zellwege_doc.htmϾ. 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 mul- tiple times, producing identical copies of itself. The cells produced by the division of the zygote form the develop- ing 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- GALE ENCYCLOPEDIA OF GENETIC DISORDERS 1227 Zygote 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/chromo- somes). Finally, the genetic material combines to pro- duce 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 chromo- somes divide evenly, from 46 to 23 chromsomes to pro- duce eggs and sperm with 23 chromosomes each. This ensures that when the egg and sperm fuse during con- ception, the original number of chromosomes (46) is restored. The reduction of each parent cell from 46 to 23 chro- mosomes ensures that each parent contributes half of his or her genetic material to form the zygote and the off- spring shares 50% of his or her genes with each parent. Duplication of the single zygote occurs through a com- plete 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 chro- mosomes and two sex chromosomes. Men’s sex chromo- somes 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 becom- ing 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 dizy- gotic, DNA studies of blood cells will provide a defini- tive 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 syn- drome is caused by an extra chromosome number 21 from the egg or sperm cell. Since the cells formed by divi- sion of the zygote are identical to the zygote, any abnor- mality in the zygote will be in every cell of the baby. 1228 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Zygote KEY TERMS Chromosome—A microscopic thread-like struc- ture found within each cell of the body and con- sists of a complex of proteins and DNA. Humans have 46 chromosomes arranged into 23 pairs. Changes in either the total number of chromo- somes 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. [...]... IL 6061 0- 720 4 Phone: (800) 826 -3 6 32 or (3 12) 6 427 243 Website: http://www.ndmda.org National Down Syndrome Congress 7000 Peachtree-Dunwoody Road, Bldg 5, Suite 100 Atlanta, GA 30 328 -1 6 62 Phone: (770) 60 4 -9 500 or (800) 23 263 72 GALE ENCYCLOPEDIA OF GENETIC DISORDERS National Down Syndrome Society 666 Broadway New York, NY 100 1 2- 2317 Phone: (21 2) 46 0 -9 330 or (800) 22 146 02 Fax: (21 2) 97 9 -2 8 73 E-mail: info@ndss.org... Street # 29 Philadelphia, PA 191 0 2- 4415 Phone: (21 5) 545 -2 3 22 or (800) 47 323 10 Website: http://www.albinism.org National Organization for Rare Disorders (NORD) PO Box 8 92 3 New Fairfield, CT 068 1 2- 8 92 3 Phone: (20 3) 74 6-6 518 or (800) 99 96673 Fax: (20 3) 74 6-6 481 Website: http://www.rarediseases.org National Organization of Mothers of Twins Clubs PO Box 438 Thompson Station, TN 371 79 Phone: (615) 59 5-0 93 6 Website:... 32 33 35 34 Pancreatic cancer 36 Chromosome 10 Chromosome 9 15 2 24 23 22 21 1 p q 14 PAHX: Refsum disease 13 CDKN2: Malignant melanoma 1 12 13 12 11 11 p q 11 1 11 FRDA: Friedreich’s ataxia 12 1 21 13 22 21 2 2 23 22 Familial dysautonomia 3 31 32 33 24 25 OWR1: Olser-Weber-Rendu syndrome 26 Apert syndrome OAT: Gyrate atrophy Crouzon syndrome 34 Distal arthrogryposis syndrome (9) GALE ENCYCLOPEDIA OF. .. PO Box 70 024 8 San Antonio, TX 7 827 0- 024 8 Phone: (21 0) 49 4-6 144 or (21 0) 490 7161 Fax: (21 0) 49 0-7 161 or (21 0) 49 7-3 810 Website: http://www.amda-pompe.org Agenesis of the Corpus Callosum (ACC) Network University of Maine Merrill Hall, Room 18, 57 49 Orono, ME 0446 9- 5 7 49 Phone: (20 7) 58 1-3 1 19 E-mail: um-acc@maine.edu Aicardi Syndrome Awareness and Support Group 29 Delavan Ave Toronto, ON M5P 1T2 Canada... 404 Washington, DC 20 008 Phone: (20 2) 96 6-5 557 Fax: (20 2) 96 6-8 553 Website: http://www.geneticalliance org Alpha 1 National Association 8 120 Penn Ave South, Suite 5 49 Minneapolis, MN 55431 Phone: (6 12) 70 3 -9 97 9 or (800) 521 3 025 E-mail: julie@alpha1 Website: http://www.alpha1.org Alpha One Foundation 29 37 SW 27 th Ave., Suite 3 02, Miami, FL 33133 Phone: (305) 56 7 -9 888 or (877) 22 87 321 E-mail: mserven@alphaone... syndrome 24 25 Chromosome 13 Chromosome 14 13 1 12 13 1 12 11 12 1 13 11 p q 11 p q 11 BRCA2: Breast cancer RB1: Retinoblastoma 1 14 ATP7B: Wilson disease 12 13 21 21 2 22 2 22 23 24 31 3 32 33 31 3 PS1(AD3): Alzheimer disease Krabbe disease 32 34 123 8 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Chromosome 16 FMF: Familial Mediterranean fever 13 1 12 13 11 1 12 p q 11 12 13 1 14 15 Prader-Willi syndrome (15q) 23 ... SCLC1: Lung cancer 22 21 HD: Huntington disease MPS: Mucopolysaccharidoses Achondroplasia 24 25 RIEG: Rieger syndrome 26 13 27 GM1: gangliosidosis LQT4: Long QT syndrome 4 28 21 22 23 31 24 2 3 32 25 FBS: Faconi-Bickel syndrome 33 26 34 27 35 28 29 GALE ENCYCLOPEDIA OF GENETIC DISORDERS 123 5 Chromosome Map Chromosome 3 Chromosome Map Chromosome 6 Chromosome 5 15 25 SRD51A: Steroid 4-alpha reductase 1... National Tay-Sachs and Allied Diseases Association 20 01 Beacon Street, Suite 20 4 Brighton, MA 021 35 Phone: (800) 90 6-8 723 Fax: (617) 27 7-0 134 E-mail: ntasd-Boston@worldnet.att.net Website: http://www.ntsad.org National Tourette Syndrome Association, Inc 4 2- 40 Bell Boulevard Bayside, NY 11361 -2 8 20 Phone: (718) 22 4 -2 9 99 Fax: (718) 27 9- 9 596 E-mail: tourette@ix.netcom.com National Urea Cycle Disorders Foundation... Hill, NC 27 514 Phone: (91 9) 99 3 -9 044 Fax: (91 9) 93 3 -9 604 Website: http://www.cleftline.org American College of Obstetricians and Gynecologists PO Box 96 92 0 , 4 09 12th Street SW Washington, DC 20 09 0-6 92 0 Website: http://www.acog.org American College of Rheumatology 60 Executive Park South, Suite 150 Atlanta, GA 30 3 29 Phone: (404) 63 3-3 777 Website: http://www.rheumatology.org American Council of the Blind... Foundation 350 Parnassus Ave., Suite 90 0 San Francisco, CA 94 117 Phone: (415) 56 6-5 4 02 GALE ENCYCLOPEDIA OF GENETIC DISORDERS Children’s Brittle Bone Foundation 7701 95 th Street Pleasant Prairie, WI 53158 Phone: (847) 43 3-4 98 Website: http://www.cbbf.org Children’s Craniofacial Association PO Box 28 0 29 7 Dallas, TX 7 524 3-4 522 Phone: (9 72) 99 4 -9 9 02 or (800) 5353643 E-mail: contactcca@ccakids.com Website: . Gaucher disease p q 41 32 42 43 44 24 25 31 23 22 21 2 3 4 CHS1: Chediak-Higashi syndrome Chromosome 1 25 23 24 22 21 16 15 14 13 12 11 12 11 13 1 1 2 ETM2: Essential tremor MSH2: Colon cancer CSNU:. 5 CSA: Cockayne syndrome SRD51A: Steroid 4-alpha reductase 1 Cri du chat syndrome 22 23 24 25 21 12 11 11 12 13 14 15 16 1 2 p q 23 24 25 26 27 22 21 1 2 EPM2A: Epilepsy Major histocompatibility. DISORDERS Chromosome Map GALE ENCYCLOPEDIA OF GENETIC DISORDERS 123 5 Chromosome Map 25 26 23 24 22 21 14 13 12 11 12 11 13 1 1 2 VHL: von Hippei-Lindau MLH1: Colon cancer BTD: Biotindase hMLH1: Muir-Torre syndrome HGD: