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

mated to affect less than one in one million people. Onset of dramatic symptoms usually occurs in infancy, but may hold off until adulthood.

•Porphyria cutanea tarda (step 5). Porphyria cutanea tarda (PCT) is also called symptomatic porphyria, porphyria cutanea symptomatica, and idiosyncratic porphyria. PCT may be acquired, typically as a result of disease (especially hepatitis C), drug or alcohol use, or exposure to certain poisons. PCT may also be inherited as an autosomal dominant disorder, however most people remain latent—that is, symptoms never develop. PCT is the most common of the porphyrias, but the incidence of PCT is not well defined.

•Hepatoerythopoietic porphyria (step 5). HEP affects heme biosynthesis in both the liver and the bone marrow. HEP results from a defect in uroporphyrinogen decarboxylase activity (step 5), and is caused by changes in the same gene as PCT. Disease symptoms, however, strongly resemble congenital erythropoietic porphyria. HEP seems to be inherited in an autosomal recessive manner.

•Erythropoietic protoporphyria (step 8). Also known as protoporphyria and erythrohepatic protoporphyria, erythropoietic protoporphyria (EPP) is more common than CEP; more than 300 cases have been reported. In these cases, onset of symptoms typically occurred in childhood.

Causes and symptoms

General characteristics

The underlying cause of all porphyrias is an abnormal enzyme important to the heme biosynthesis pathway. Porphyrias are inheritable conditions. In virtually all cases of porphyria, an inherited factor causes the enzyme’s defect. An environmental trigger—such as diet, drugs, or sun exposure—may be necessary before any symptoms develop. In many cases, symptoms never develop. These asymptomatic individuals may be completely unaware that they have a gene for porphyria.

All of the hepatic porphyrias—except porphyria cutanea tarda—follow a pattern of acute attacks separated by periods in which no symptoms are present. For this reason, this group is often referred to as the acute porphyrias. The erythropoietic porphyrias and porphyria cutanea tarda do not follow this pattern and are considered to be chronic conditions.

The specific symptoms of each porphyria vary based on which enzyme is affected and whether that enzyme occurs in the liver or in the bone marrow. The severity of symptoms can vary widely, even within the same type of porphyria. If the porphyria becomes symptomatic, the

common factor between all types is an abnormal accumulation of protoporphyrins or porphyrin.

ALA dehydratase porphyria (ADP)

ADP is characterized by a deficiency of ALA dehydratase. ADP is caused by mutations in the deltaaminolevulinate dehydratase gene (ALAD) at 9q34. Of the few cases on record, the prominent symptoms were vomiting, pain in the abdomen, arms, and legs, and neuropathy. (Neuropathy refers to nerve damage that can cause pain, numbness, or paralysis.) The nerve damage associated with ADP could cause breathing impairment or lead to weakness or paralysis of the arms and legs.

Acute intermittent porphyria (AIP)

AIP is caused by a deficiency of porphobilogen deaminase, which occurs due to mutations in the hydroxymethylbilane synthase gene (HMBS) located at 11q23.3. Symptoms of AIP usually do not occur unless a person with the deficiency encounters a trigger substance. Trigger substances can include hormones (for example oral contraceptives, menstruation, pregnancy), drugs, and dietary factors. Most people with this deficiency never develop symptoms.

Attacks occur after puberty and commonly feature severe abdominal pain, nausea, vomiting, and constipation. Muscle weakness and pain in the back, arms, and legs are also typical symptoms. During an attack, the urine is a deep reddish color. The central nervous system may also be involved. Possible psychological symptoms include hallucinations, confusion, seizures, and mood changes.

Congenital erythropoietic porphyria (CEP)

CEP is caused by a deficiency of uroporphyrinogen III cosynthase due to mutations in the uroporphyrinogen III cosynthase gene (UROS) located at 10q25.2-q26.3. Symptoms are often apparent in infancy and include reddish urine and possibly an enlarged spleen. The skin is unusually sensitive to light and blisters easily if exposed to sunlight. (Sunlight induces protoporphyrin changes in the plasma and skin. These altered protoporphyrin molecules can cause skin damage.) Increased hair growth is common. Damage from recurrent blistering and associated skin infections can be severe. In some cases facial features and fingers may be lost to recurrent damage and infection. Deposits of protoporphyrins can sometimes lead to red staining of the teeth and bones.

Porphyria cutanea tarda (PCT)

PCT is caused by deficient uroporphyrinogen decarboxylase. PCT is caused by mutations in the uropor-

Porphyrias

Porphyrias

phyrinogen decarboxylase gene (UROD) located on chromosome 1 at 1p34. PCT may occur as an acquired or an inherited condition. The acquired form usually does not appear until adulthood. The inherited form may appear in childhood, but often demonstrates no symptoms. Early symptoms include blistering on the hands, face, and arms following minor injuries or exposure to sunlight. Lightening or darkening of the skin may occur along with increased hair growth or loss of hair. Liver function is abnormal but the signs are mild.

Hepatoerythopoietic porphyria (HEP)

HEP is linked to a deficiency of uroporphyrinogen decarboxylase in both the liver and the bone marrow. HEP is an autosomal recessive disease caused by mutations in the gene responsible for PCT, the uroporphyrinogen decarboxylase gene (UROD), located at 1p34. The gene is the shared, but the mutations, inheritance, and specific symptoms of these two diseases are different. The symptoms of HEP resemble those of CEP.

Hereditary coproporphyria (HCP)

HCP is similar to AIP, but the symptoms are typically milder. HCP is caused by a deficiency of coproporphyrinogen oxidase due to mutations in a gene by the same name at 3q12. The greatest difference between HCP and AIP is that people with HCP may have some skin sensitivity to sunlight. However, extensive damage to the skin is rarely seen.

Variegate porphyria (VP)

VP is caused by a deficiency of protoporphyrinogen oxidase. There is scientific evidence that VP is caused by a mutation in the gene for protoporphyrinogen oxidase located at 1q22. Like AIP, symptoms of VP occur only during attacks. Major symptoms of this type of porphyria include neurological problems and sensitivity to light. Areas of the skin that are exposed to sunlight are susceptible to burning, blistering, and scarring.

Erythropoietic protoporphyria (EPP)

Owing to deficient ferrochelatase, the last step in the heme biosynthesis pathway—the insertion of an iron atom into a porphyrin molecule—cannot be completed. This enzyme deficiency is caused by mutations in the ferrochelatase gene (FECH) located at 18q21.3. The major symptoms of this disorder are related to sensitivity to light—including both artificial and natural light sources. Following exposure to light, a person with EPP experiences burning, itching, swelling, and reddening of the skin. Blistering and scarring may occur but are neither common nor severe. EPP is associated with increased

risks for gallstones and liver complications. Symptoms can appear in childhood and tend to be more severe during the summer when exposure to sunlight is more likely.

Diagnosis

Depending on the array of symptoms an individual may exhibit, the possibility of porphyria may not immediately come to a physician’s mind. In the absence of a family history of porphyria, non-specific symptoms, such as abdominal pain and vomiting, may be attributed to other disorders. Neurological symptoms, including confusion and hallucinations, can lead to an initial suspicion of psychiatric disease. Diagnosis is more easily accomplished in cases in which non-specific symptoms appear in combination with symptoms more specific to porphyria, like neuropathy, sensitivity to sunlight, or certain other manifestations. Certain symptoms, such as urine the color of port wine, are hallmark signs very specific to porphyria. DNA analysis is not yet of routine diagnostic value.

A common initial test measures protoporphyrins in the urine. However, if skin sensitivity to light is a symptom, a blood plasma test is indicated. If these tests reveal abnormal levels of protoporphyrins, further tests are done to measure heme precursor levels in red blood cells and the stool. The presence and estimated quantity of porphyrin and protoporphyrins in biological samples are easily detected using spectrofluorometric testing. Spectrofluorometric testing uses a spectrofluorometer that directs light of a specific strength at a fluid sample. The porphyrins and protoporphyrins in the sample absorb the light energy and fluoresce, or glow. The spectrofluorometer detects and measures fluorescence, which indicates the amount of porphyrins and protoporphyrins in the sample.

Whether heme precursors occur in the blood, urine, or stool gives some indication of the type of porphyria, but more detailed biochemical testing is required to determine their exact identity. Making this determination yields a strong indicator of which enzyme in the heme biosynthesis pathway is defective; which, in turn, allows a diagnosis of the particular type of porphyria.

Biochemical tests rely on the color, chemical properties, and other unique features of each heme precursor. For example, a screening test for acute intermittent porphyria (AIP) is the Watson-Schwartz test. In this test, a special dye is added to a urine sample. If one of two heme precursors—porphobilinogen or urobilinogen—is present, the sample turns pink or red. Further testing is necessary to determine whether the precursor present is porphobilinogen or urobilinogen—only porphobilinogen is indicative of AIP.

Other biochemical tests rely on the fact that heme precursors become less soluble in water (able to be dissolved in water) as they progress further through the heme biosynthesis pathway. For example, to determine whether the Watson-Schwartz urine test is positive for porphobilinogen or urobilinogen, chloroform is added to the test tube. Chloroform is a water-insoluble substance. Even after vigorous mixing, the water and chloroform separate into two distinct layers. Urobilinogen is slightly insoluble in water, while porphobilinogen tends to be water-soluble. The porphobilinogen mixes more readily in water than chloroform, so if the water layer is pink (from the dye added to the urine sample), that indicates the presence of porphobilinogen, and a diagnosis of AIP is probable.

As a final test, measuring specific enzymes and their activities may be done for some types of porphyrias; however, such tests are not done as a screening method. Certain enzymes, such as porphobilinogen deaminase (the abnormal enzyme in AIP), can be easily extracted from red blood cells; other enzymes, however, are less readily collected or tested. Basically, an enzyme test involves adding a certain amount of the enzyme to a test tube that contains the precursor it is supposed to modify. Both the production of modified precursor and the rate at

which it appears can be measured using laboratory equipment. If a modified precursor is produced, the test indicates that the enzyme is doing its job. The rate at which the modified precursor is produced can be compared to a standard to measure the efficiency of the enzyme.

Treatment and management

Treatment for porphyria revolves around avoiding acute attacks, limiting potential effects, and treating symptoms. Treatment options vary depending on the specific type of porphyria diagnosed. Gene therapy has been successful for both CEP and EPP. In the future, scientists expect development of gene therapy for the remaining porphyrias. Given the rarity of ALA dehydratase porphyria, definitive treatment guidelines for this rare type have not been developed.

Acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria

Treatment for acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria follows the same basic regime. A person who has been diagnosed with one of these porphyrias can prevent most attacks by

Porphyrias

avoiding precipitating factors, such as certain drugs that have been identified as triggers for acute porphyria attacks. Individuals must maintain adequate nutrition, particularly in respect to carbohydrates. In some cases, an attack can be stopped by increasing carbohydrate consumption or by receiving carbohydrates intravenously.

When attacks occur, prompt medical attention is necessary. Pain is usually severe, and narcotic analgesics are the best option for relief. Phenothiazines can be used to counter nausea, vomiting, and anxiety, and chloral hydrate or diazepam is useful for sedation or to induce sleep. Hematin, a drug administered intravenously, may be used to halt an attack. Hematin seems to work by signaling the pathway of heme biosynthesis to slow production of precursors. Women, who tend to develop symptoms more frequently than men owing to hormonal fluctuations, may find ovulation-inhibiting hormone therapy to be helpful.

Gene therapy is a possible future treatment for these porphyrias. An experimental animal model of AIP has been developed and research is in progress.

Congenital erythropoietic porphyria

The key points of congenital erythropoietic porphyria treatment are avoiding exposure to sunlight and prevention of skin trauma or skin infection. Liberal use of sunscreens and consumption of beta-carotene supplements can provide some protection from sun-induced damage. Medical treatments such as removing the spleen or administering transfusions of red blood cells can create short-term benefits, but these treatments do not offer a cure. Remission can sometimes be achieved after treatment with oral doses of activated charcoal. Severely affected patients may be offered bone marrow transplantation, which appears to confer long-term benefits.

Porphyria cutanea tarda

As with other porphyrias, the first line of defense is avoidance of factors, especially alcohol, that could bring about symptoms. Regular blood withdrawal is a proven therapy for pushing symptoms into remission. If an individual is anemic or cannot have blood drawn for other reasons, chloroquine therapy may be used.

Erythropoietic protoporphyria

Avoiding sunlight, using sunscreens, and taking beta-carotene supplements are typical treatment options for erythropoietic protoporphyria. The drug, cholestyramine, may reduce the skin’s sensitivity to sunlight as well as the accumulated heme precursors in the liver. Liver transplantation has been used in cases of liver failure, but it has not effected a long-term cure of the porphyria.

Alternative treatment

Acute porphyria attacks can be life-threatening events, so attempts at self-treatment can be dangerous. Alternative treatments can be useful adjuncts to conventional therapy. For example, some people may find relief for the pain associated with acute intermittent porphyria, hereditary coproporphyria, or variegate porphyria through acupuncture or hypnosis. Relaxation techniques, such as yoga or meditation, may also prove helpful in pain management.

Prognosis

Even when porphyria is inherited, symptom development depends on a variety of factors. In the majority of cases, a person remains asymptomatic throughout life. About one percent of acute attacks can be fatal. Other symptoms may be associated with temporarily debilitating or permanently disfiguring consequences. Measures to avoid these consequences are not always successful, regardless of how diligently they are pursued. Although pregnancy has been known to trigger porphyria attacks, dangers associated with pregnancy as not as great as was once thought.

Prevention

For the most part, the porphyrias are attributed to inherited genes; such inheritance cannot be prevented. However, symptoms can be limited or prevented by avoiding factors that trigger symptom development.

People with a family history of an acute porphyria should be screened for the disease. Even if symptoms are absent, it is useful to know about the presence of the gene to assess the risks of developing the associated porphyria. This knowledge also reveals whether a person’s offspring may be at risk. Prenatal testing for certain porphyrias is possible. Prenatal diagnosis of congenital erythropoietic porphyria has been successfully accomplished. Any prenatal tests, however, would not indicate whether a child would develop porphyria symptoms; only that they might have the potential to do so.

Resources

BOOKS

Deats-O’Reilly, Diana. Porphyria: The Unknown Disease.

Grand Forks, ND: Porphyrin Publications Press/

Educational Services, 1999.

PERIODICALS

Gordon, Neal. “The Acute Porphyrias.” Brain & Development 21 (September 1999): 373–77.

Thadani, Helen et al. “Diagnosis and Management of Porphyria.” British Medical Journal 320 (June 2000): 1647–51.

ORGANIZATIONS

American Porphyria Foundation. PO Box 22712, Houston, TX 77227. (713) 266-9617. http://www.enterprise.net/apf/ .

WEBSITES

Gene Clinics. http://www.geneclinics.org .

National Institute of Diabetes & Digestive & Kidney Diseases.

http://www.niddk.nih.gov .

Online Mendelian Inheritance in Man (OMIM).

http://www3.ncbi.nlm.nih.gov/Omim .

Julia Barrett

Judy Hawkins, MS

Portosystemic venous shunt-congenital see

Patent ductus arteriosus

Potter sequence see Oligohydramnios sequence

I Prader-Willi syndrome

Definition

Prader-Willi syndrome (PWS) is a genetic condition caused by the absence of chromosomal material from chromosome 15. The genetic basis of PWS is complex. Characteristics of the syndrome include developmental delay, poor muscle tone, short stature, small hands and feet, incomplete sexual development, and unique facial features. Insatiable appetite is a classic feature of PWS. This uncontrollable appetite can lead to health problems and behavior disturbances.

Description

The first patients with features of PWS were described by Drs. Prader, Willi, and Lambert in 1956. Since that time, the complex genetic basis of PWS has begun to be understood. Initially, scientists found that individuals with PWS have a portion of genetic material deleted (erased) from chromosome 15. In order to have PWS, the genetic material must be deleted from the chromosome 15 received from one’s father. If the deletion is on the chromosome 15 inherited from one’s mother, a different syndrome develops. This was an important discovery. It demonstrated for the first time that the genes inherited from one’s mother can be expressed differently than the genes inherited from one’s father.

Over time, scientists realized that some individuals with PWS do not have a deletion of genetic material from

chromosome 15. Further studies found that these patients inherit both copies of chromosome 15 from their mother. This is not typical. Normally, an individual should receive one chromosome 15 from one’s father and one chromosome 15 from one’s mother. When a person receives both chromosomes from the same parent it is called “uniparental disomy.” When a person receives both chromosomes from one’s mother it is called “maternal uniparental disomy.”

Scientists are still discovering other causes of PWS. A small number of patients with PWS have a change (mutation) in the genetic material on the chromosome 15 inherited from their father. This mutation prevents certain genes on chromosome 15 from working properly. PWS develops when these genes do not work normally.

Newborns with PWS generally have poor muscle tone (hypotonia) and do not feed well. This can lead to poor weight gain and failure to thrive. Genitalia can be smaller than normal. Hands and feet are also typically smaller than normal. Some patients with PWS have unique facial characteristics. These unique facial features are typically subtle and only detectable by physicians.

As children with PWS age, development is typically slower than normal. Developmental milestones, such as crawling, walking, and talking occur later than usual. Developmental delay continues into adulthood for approximately 50% of individuals with PWS. At about one to two years of age, children with PWS develop an uncontrollable, insatiable appetite. Left to their own devices, individuals with PWS will eat until they have life-threatening obesity. The desire to eat can lead to significant behavior problems.

The symptoms and features of PWS require life-long support and care. If food intake is strictly monitored and various therapies provided, individuals with PWS have a normal life expectancy.

Genetic profile

In order to comprehend the various causes of PWS, the nature of chromosomes and genes must be wellunderstood. Human beings have 46 chromosomes in the cells of their body. Chromosomes contain genes. Genes regulate the function and development of the body. An individual’s chromosomes are inherited from their parents. A child should receive 23 chromosomes from the mother and 23 chromosomes from the father.

The 46 chromosomes in the human body are divided into pairs. Each pair is assigned a number or a letter. Chromosomes are divided into pairs based on their physical characteristics. Chromosomes can only be seen when viewed under a microscope. Chromosomes within the

syndrome Willi-Prader

Prader-Willi syndrome

same pair appear identical because they contain the same genes.

Most chromosomes have a constriction near the center called the centromere. The centromere separates the chromosome into long and short arms. The short arm of a chromosome is called the “p arm.” The long arm of a chromosome is called the “q arm.”

Chromosomes in the same pair contain the same genes. However, some genes work differently depending on if they were inherited from the egg or the sperm. Sometimes, genes are silenced when inherited from the mother. Other times, genes are silenced when inherited from the father. When genes in a certain region on a chromosome are silenced, they are said to be “imprinted.” Imprinting is a normal process. Imprinting does not typically cause disease. If normal imprinting is disrupted a genetic disease can develop.

Individuals should have two complete copies of chromosome 15. One chromosome 15 should be inherited from the mother, or be “maternal” in origin. The other chromosome 15 should be inherited from the father, or be “paternal” in origin.

Several genes found on the q arm of chromosome 15 are imprinted. A gene called “SNPRN” is an example of one of these genes. It is normally imprinted, or silenced, if inherited from the mother. The imprinting of this group of maternal genes does not typically cause disease. The genes in this region should not be imprinted if paternal in origin. Normal development depends on these paternal genes being present and active. If these genes are deleted, not inherited, or incorrectly imprinted, PWS develops.

Seventy percent of the cases of PWS are caused when a piece of material is deleted, or erased, from the paternal chromosome 15. This deletion happens in a specific region on the q arm of chromosome 15. The piece of chromosomal material that is deleted contains genes that must be present for normal development. These paternal genes must be working normally, because the same genes on the chromosome 15 inherited from the mother are imprinted. When these paternal genes are missing, the brain and other parts of the body do not develop as expected. This is what causes the symptoms associated with PWS.

In 99% of the cases of PWS the deletion is sporadic. This means that it happens randomly and there is not an apparent cause. It does not run in the family. If a child has PWS due to a sporadic deletion in the paternal chromosome 15, the chance the parents could have another child with PWS is less than 1%. In less than 1% of the cases of PWS there is a chromosomal rearrangement in the family which causes the deletion. This chromosomal

rearrangement is called a “translocation.” If a parent has a translocation the risk of having a child with PWS is higher than 1%.

PWS can also develop if a child receives both chromosome 15s from his or her mother. This is seen in approximately 25% of the cases of PWS. Maternal uniparental disomy for chromosome 15 leads to PWS because the genes on the chromosome 15 that should have been inherited from the father are missing. These paternal genes must be present, since the same genes on both the chromosome 15s inherited from the mother are imprinted.

PWS caused by maternal uniparental disomy is sporadic. This means that it happens randomly and there is no apparent cause. If a child has PWS due to maternal uniparental disomy the chance the parents could have another child with PWS is less than 1%.

Approximately 3–4% of patients with PWS have a change (mutation) in a gene located on the q arm of chromosome 15. This mutation leads to incorrect imprinting and causes genes inherited from the father to be imprinted or silenced. These genes should not normally be imprinted. If a child has PWS due to a mutation that changes imprinting, the chance the parents could have another child with PWS is approximately 5%.

It should be noted that if an individual has a deletion of the same material from the q arm of the maternal chromosome 15 a different syndrome develops. This syndrome is called Angelman syndrome. Angelman syndrome can also happen if an individual receives both chromosome 15s from the father.

Demographics

PWS affects approximately one in 10,000 to 25,000 live births. It is the most common genetic cause of lifethreatening obesity. It affects both males and females. PWS can be seen in all races and ethnic groups.

Signs and symptoms

Infants with PWS have weak muscle tone (hypotonia). This hypotonia causes problems with sucking and eating. Infants with PWS may have problems gaining weight. Some infants with PWS are diagnosed with “failure to thrive” due to slow growth and development. During infancy, babies with PWS may also sleep more than normal and have problems controlling their temperature.

Some of the unique physical features associated with PWS can be seen during infancy. Genitalia that is smaller

syndrome Willi-Prader

Prader-Willi syndrome

Diagnosis

During infancy the diagnosis of PWS may be suspected if poor muscle tone, feeding problems, small genitalia, or the unique facial features are present. If an infant has these features, testing for PWS should be performed. This testing should also be offered to children and adults who display features commonly seen in PWS (developmental delay, uncontrollable appetite, small genitalia, etc.). There are several different genetic tests that can detect PWS. All of these tests can be performed from a blood sample.

Methylation testing detects 99% of the cases of PWS. Methylation testing can detect the absence of the paternal genes that should be normally active on chromosome 15. Although methylation testing can accurately diagnose PWS, it can not determine if the PWS is caused by a deletion, maternal uniparental disomy, or a mutation that disrupts imprinting. This information is important for genetic counseling. Therefore, additional testing should be performed.

Chromosome analysis can determine if the PWS is the result of a deletion in the q arm of chromosome 15. Chromosome analysis, also called karyotyping, involves staining the chromosomes and examining them under a microscope. In some cases the deletion of material from chromosome 15 can be easily seen. In other cases, further testing must be performed. FISH (fluorescence in-situ hybridization) is a special technique that detects small deletions that cause PWS.

More specialized DNA testing is required to detect maternal uniparental disomy or a mutation that disrupts imprinting. This DNA testing identifies unique DNA patterns in the mother and father. The unique DNA patterns are then compared with the DNA from the child with PWS.

PWS can be detected before birth if the mother undergoes amniocentesis testing or chorionic villus sampling (CVS). This testing would only be recommended if the mother or father is known to have a chromosome rearrangement or if they already have a child with PWS syndrome.

Treatment and management

There is currently no cure for PWS. Treatment during infancy includes therapies to improve muscle tone. Some infants with PWS also require special nipples and feeding techniques to improve weight gain.

Treatment and management during childhood, adolescence, and adulthood is typically focused on weight control. Strict control of food intake is vital to prevent severe obesity. In many cases, food must be made inaccessible. This may involve unconventional measures such

as locking the refrigerator or kitchen cabinets. A lifelong restricted-calorie diet and regular exercise program are also suggested. Unfortunately, diet medications have not been shown to significantly prevent obesity in PWS. However, growth hormone therapy has been shown to improve the poor muscle tone and reduced height typically associated with PWS.

Special education may be helpful in treating developmental delays and behavior problems. Individuals with PWS typically excel in highly structured environments.

Prognosis

Life expectancy is normal and the prognosis good if weight gain is well controlled.

Resources

BOOKS

Couch, Cheryl. My Rag Doll. Couch Publishing, 2000.

Jones, Kenneth Lyons. “Prader-Willi Syndrome.” In Smith’s Recognizable Patterns of Human Malformation. 5th ed. Philadelphia: W.B. Saunders, 1997.

PERIODICALS

Butler, Merlin G., and Travis Thompson. “Prader-Willi Syndrome: Clinical and Genetic Findings.” The Endocrinologist 10 (2000): 3S–16S.

State, Matthew W., and Elisabeth Dykens. “Genetics of Childhood Disorders: XV. Prader-Willi Syndrome: Genes, Brain and Behavior.” Journal of the American Academy of

Child and Adolescent Psychiatry 39, no. 6 (June 2000): 797–800.

ORGANIZATIONS

Alliance of Genetic Support Groups. 4301 Connecticut Ave. NW, Suite 404, Washington, DC 20008. (202) 966-5557. Fax: (202) 966-8553. http://www.geneticalliance.org .

International Prader-Willi Syndrome Organization. Bizio 1, 36023 Costozza, Vicenza, Italy 39 0444 555557. Fax:39 0444 555557. http://www.ipwso.org .

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 .

Prader-Willi Foundation. 223 Main St., Port Washington, NY 11050. (800) 253-7993. http://www.prader-willi.org .

Prader-Willi Syndrome Association. 5700 Midnight Pass Rd., Suite 6, Sarasota, FL 34242-3000. (941) 312-0400 or (800) 926-4797. Fax: (941) 312-0142. http://www

.pwsausa.org PWSAUSA@aol.com .

WEBSITES

GeneClinics.

http://www.geneclinics.org/profiles/pws/details.html .

OMIM—Online Mendelian Inheritance in Man. http://www

.ncbi.nlm.nih.gov/htbin-port/Omim/dispmim?176270 .

Holly Ann Ishmael, MS, CGC

I Prion diseases

Definition

Prion diseases are a class of degenerative central nervous system disorders. They are unique in that while a genetic component of the syndrome exists, prion diseases may also be transmitted, and the infectious agent of the disease is a protein. Dr. Stanley Prusiner coined the term “prion,” meaning “proteinaceous infectious particle,” in 1982. Dr. Prusiner’s controversial, but finally accepted, research in the area of prion diseases led to his winning the Nobel Prize in Medicine in 1997.

Description

As of early 2001, there are five forms of prion disease known to occur in humans: kuru, Creutzfeldt-Jakob disease (CJD), Gertsmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI), and new variant Creutzfeld-Jakob disease, popularly known as “mad cow disease.” The prion diseases are also called transmissible spongiform encephalopathies because they can be transmitted between unrelated individuals and they sometimes cause a sponge-like encephalopathy, or degeneration of the brain tissue, in which holes and other abnormal structures are formed in the brain. Prion diseases have also been identified in animals and include scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cows, feline spongiform encephalopathy in cats, and chronic wasting disease in mule, deer, and elk.

Prion diseases have all been associated with the function of a specific cellular protein named the prion protein (PrP). Like all cellular proteins, PrP is a longchain molecule consisting of linked amino acids. A protein can assume many shapes: twisted into a spiral helix as in DNA, extended into linear strands, or folded into sheets of aligned strands. Different shapes of the same molecular sequence are called isomers. It is theorized that the normal form of cellular PrP is a compact shape consisting mainly of four helix regions, whereas in the abnormal isomer (the prion), the protein is refolded into a sheet-helix combination. Furthermore, this prion, through an unknown mechanism, triggers the conversion of normal PrP to the abnormal shape. The abnormal isomer acts as a template to change more and more normal PrP to the abnormal structure. Therefore, once the protein exists in the abnormal form, it is an infectious agent that can be transmitted from one person to another.

Normal proteins are processed by proteases, which are enzymes present in the body that act to break down excess proteins. However, the abnormal isomer of the prion protein is protease resistant and cannot be broken

down by the body’s protease enzymes. Therefore, the abnormal prion protein continues to be produced without being processed. This leads to an accumulation of the abnormal protein in the body. In several forms of prion disease, the abnormal prion protein aggregates in deposits, or plaques, in the brain tissue. It is believed that once the abnormal prion protein accumulates to a certain level in the body, the physical symptoms of impaired mental and physical functioning begin to show themselves. However, the exact mechanisms by which the abnormal isomer causes disease are not known. The onset of symptoms often does not occur until the patient is elderly, suggesting that either the rate of accumulation of the abnormal protein is initially slow, or that some triggering event late in life causes the initial formation of the abnormal isomer, after which the disease can spread.

The normal function of the prion protein is not completely understood, but it is known to be involved with the functions of the synapses (nerve connections) in the brain. PrP is found in the highest concentrations in the brain. PrP is also found in the eyes, lungs, heart, kidney, pancreas, testes, blood, and in the neuromuscular junction. The conversion of normal PrP to the infectious, abnormal isomer form may disrupt the normal functions of the prion protein, and this may be another cause of the degenerative symptoms of the disease.

Body tissues containing the abnormal isomer are a source of transmission of the disease between people and even across species. Prion diseases are also found in animals, and in animal studies it has been shown that the disease can be spread through the ingestion of infected brain tissue. The transmission can also cross the species barrier; it has been found that cows became affected by prion disease after eating feed contaminated with infected sheep brain tissue. It is widely speculated that the outbreak of mad cow disease, the most publicized prion disease, was caused by infection from affected cows in the United Kingdom, although the mode of transmission has still not been determined. Transmission through oral ingestion was also shown to be the cause of kuru in the Fore tribe of New Guinea. After the Fore abandoned their practice of ritual cannibalism in which they consumed the brain tissue of ancestors, the incidence of kuru all but disappeared. Other cases of human infection have been shown to be iatrogenic; in other words, transmitted inadvertently during medical treatment. Most of these iatrogenic cases involve direct contact with brain and nervous system tissue. For example, CJD has been reported to result from the use of contaminated surgical instruments, corneal implants, implantation of dura matter or electrodes in the brain, and from the injection of human

diseases Prion

Prion diseases

growth hormones derived from cadaverous pituitary glands.

Other modes of transmission have been shown to be less efficient in animal studies. The recent outbreak of new variant CJD caused increased concern about possible transmission through blood transfusions and plasmaderived products, but no case of new variant CJD has been proven to result from blood transfusion as of 2001. Laboratory and epidemiological evidence supporting a strong risk of the spread of prion disease through blood transfusion is not present, even though this area has been intensively studied.

Genetic profile

The gene that encodes the prion protein has been mapped to chromosome 20p12. This gene has been named the PRNP gene. Mutations in the PRNP gene can cause alterations in the chemical sequence of amino acids in the prion protein, and this change is believed to make the protein more susceptible to assuming the abnormal conformation. Over 20 different mutations of the gene have been identified, encompassing point mutations (one base pair substituted for another in the gene sequence), insertions (additions to the gene sequence), and deletions (missing parts of the gene sequence). Depending on the specific mutation, different types of prion disease can appear in the patient.

It is estimated that 10-15% of prion disease cases are caused by inherited mutations of the PRNP gene. Because of the delayed onset of the disease and the wide variation in symptoms, more exact statistics are difficult to determine. The inheritance pattern is autosomal dominant, meaning that if either parent passes the mutated gene to their offspring, the child will be affected by the disease. A parent with prion disease has a 50% probability of passing on the mutated gene to his or her child.

Another genetic factor important in prion disease is the genetic sequence of the PRNP gene. Like all genes, the PRNP gene is made up of two strands of DNA. Each DNA strand consists of a sequence of chemical structures called bases, and the two strands together form a sequence of base pairs. Three base pairs together form a unit called a codon, and each codon codes for a specific amino acid. At codon 129 of the PRNP gene, either the amino acid methionine (Met) or valine (Val) can be encoded. Since one gene is inherited from each parent, an individual may either be homozygous, having two of the same amino acids (Met-Met or Val-Val) at this position; or, heterozygous, having different amino acids (Met-Val). Individuals who are homozygous appear to be more susceptible to infection of prion diseases, because it has been shown that a greater percentage of those infected

are homozygous than in the general population. Also, the clinical symptoms, or phenotype, of the prion disease can differ based on whether the individual is Met-Met or ValVal homozygous, and whether the individual has Met or Val on the same gene as another mutation. For example, a specific point mutation at codon 178 has been found to cause familial CJD if the individual has Val at codon 129 on the mutated gene, while the same mutation causes FFI when the individual has Met at codon 129.

Demographics

Prion diseases occur worldwide with a rate of one to two cases per one million. CJD is the most common of the prion diseases, while GSS and FFI are extremely rare, and kuru is now virtually nonexistant due to the abandonment of the practice of cannibalism. There is no gender link to the disease. Several forms of prion disease usually do not cause identifiable symptoms until the individual is more than 60 years old, although other forms have an earlier onset and are seen in teenagers and young adults.

Since prion disease can be either inherited or transmitted through infection, the demographics of the disease have both familial and environmental patterns. Inherited CJD is found with high frequency in Libyan Jews and also in other descendants of Sephardic Jews in Greece, Tunisia, Israel, Italy, Spain, and perhaps South America. Other genetic clusters have been identified in Slovakia, Poland, France, and Germany. Fatal familial insomnia has been linked to family pedigrees in Italy, Australia, and the United States, among others. Families with GSS syndrome have been found in several countries in North America and Europe.

The environmental clusters of the disease include the Fore, a remote tribe of New Guinea in which kuru was transmitted through the practice of ritual cannibalism; a group of over 80 cases in Japan resulting from dura mater (brain membrane) grafts from a single surgical supply company; over 100 cases resulting from cadaveric human growth hormone injections in Europe and the United States; and, most famously, the 40-plus cases of new variant CJD or mad cow disease in the United Kingdom.

Signs and symptoms

Prion disease primarily affects the brain and central nervous system, so the symptoms associated with the disease are all related to neurological function. These may include loss of muscular coordination and uncontrollable body movements (ataxia), visual problems, hallucinations, behavioral changes, difficulty in thinking clearly or remembering, sleep disturbances, speech impairment, and insanity. General complaints such as headache,