Tag Archives: Genetic disorder

Alagille Syndrome

Description:
Alagille syndrome is a genetic disorder that affects the liver, heart, kidney, and other systems of the body. Problems associated with the disorder generally become evident in infancy or early childhood. The disorder is inherited in an autosomal dominant pattern, and the estimated prevalence of Alagille syndrome is 1 in every 100,000 live births.It is named after Daniel Alagille.

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A person with Alagille syndrome has fewer than the normal number of small bile ducts inside the liver. The liver is the organ in the abdomen—the area between the chest and hips—that makes blood proteins and bile, stores energy and nutrients, fights infection, and removes harmful chemicals from the blood.

Bile ducts are tubes that carry bile from the liver cells to the gallbladder for storage and to the small intestine for use in digestion. Bile is fluid made by the liver that carries toxins and waste products out of the body and helps the body digest fats and the fat-soluble vitamins A, D, E, and K. In people with Alagille syndrome, the decreased number of bile ducts causes bile to build up in the liver, a condition also called cholestasis, leading to liver damage and liver disease.

The digestive system:
The digestive system is made up of the gastrointestinal (GI) tract—also called the digestive tract—and the liver, pancreas, and gallbladder. The GI tract is a series of hollow organs joined in a long, twisting tube from the mouth to the anus. The hollow organs that make up the GI tract are the mouth, esophagus, stomach, small intestine, large intestine—which includes the colon and rectum—and anus. Food enters the mouth and passes to the anus through the hollow organs of the digestive system. The liver, pancreas, and gallbladder are the solid organs of the digestive system. The digestive system helps the body digest food.
Symptoms:
The symptoms of Alagille syndrome and their severity vary, even among people in the same family sharing the same gene mutation.

Liver:  In some people, problems in the liver may be the first signs and symptoms of the disorder. These symptoms can occur in children and adults and in infants as early as the first 3 months of life.
Jaundice. Jaundice—when the skin and whites of the eyes turn yellow—is a result of the liver not removing bilirubin from the blood. Bilirubin is a reddish-yellow substance formed when hemoglobin breaks down. Hemoglobin is an iron-rich protein that gives blood its red color. Bilirubin is absorbed by the liver, processed, and released into bile. Blockage of the bile ducts forces bilirubin and other elements of bile to build up in the blood.
Jaundice may be difficult for parents and even health care providers to detect. Many healthy newborns have mild jaundice during the first 1 to 2 weeks of life due to an immature liver. This normal type of jaundice disappears by the second or third week of life, whereas the jaundice of Alagille syndrome deepens. Newborns with jaundice after 2 weeks of life should be seen by a health care provider to check for a possible liver problem.
Dark urine and gray or white stools. High levels of bilirubin in the blood that pass into the urine can make the urine darker, while stool lightens from a lack of bilirubin reaching the intestines. Gray or white bowel movements after 2 weeks of age are very reliable signs of a liver problem.
Pruritus. The buildup of bilirubin in the blood may cause itching, also called pruritus. Pruritus usually starts after 3 months of age and can be severe.
Xanthomas. Xanthomas are fatty deposits that appear as yellow bumps on the skin. They are caused by abnormally high cholesterol levels in the blood, common in people with liver disease. Xanthomas may appear anywhere on the body. However, xanthomas are usually found on the elbows, joints, tendons, knees, hands, feet, or buttocks.
Other Symptoms of Alagille Syndrome are:
Certain signs of Alagille syndrome are unique to the disorder, including those that affect the vertebrae and facial features.

Face.  Many children with Alagille syndrome have deep-set eyes, a straight nose, a small and pointed chin, large ears, and a prominent, wide forehead. These features are not usually recognized until after infancy. By adulthood, the chin is more prominent.

Eyes. Posterior embryotoxon is a condition in which an opaque ring is present in the cornea, the transparent covering of the eyeball. The abnormality is common in people with Alagille syndrome, though it usually does not affect vision.

Skeleton. The most common skeletal defect in a person with Alagille syndrome is when the shape of the vertebrae—bones of the spine—gives the appearance of flying butterflies. This defect, known as “butterfly” vertebrae, rarely causes medical problems or requires treatment.

Heart and blood vessels. People with Alagille syndrome may have the following signs and symptoms having to do with the heart and blood vessels:

heart murmur—an extra or unusual sound heard during a heartbeat. A heart murmur is the most common sign of Alagille syndrome other than the general symptoms of liver disease.1 Most people with Alagille syndrome have a narrowing of the blood vessels that carry blood from the heart to the lungs.1 This narrowing causes a murmur that can be heard with a stethoscope. Heart murmurs usually do not cause problems.

heart walls and valve problems. A small number of people with Alagille syndrome have serious problems with the walls or valves of the heart. These conditions may need treatment with medications or corrective surgery.

blood vessel problems. People with Alagille syndrome may have abnormalities of the blood vessels in the head and neck. This serious complication can lead to internal bleeding or stroke. Alagille syndrome can also cause narrowing or bulging of other blood vessels in the body.
Kidney disease. A wide range of kidney diseases can occur in Alagille syndrome. The kidneys are two bean-shaped organs, each about the size of a fist, that filter wastes and extra fluid from the blood. Some people have small kidneys or have cysts—fluid-filled sacs—in the kidneys. Kidney function can also decrease.
Causes:
Alagille syndrome is caused by a gene mutation, or defect. Genes provide instructions for making proteins in the body. A gene mutation is a permanent change in the DNA sequence that makes up a gene. DNA, or deoxyribonucleic acid, is the material inside cells that carries genetic information and passes genes from parent to child. Approximately 30 to 50 percent of people with Alagille syndrome have an inherited gene mutation, meaning it has been passed on by a parent. In the remaining cases, the gene mutation develops spontaneously.1 In spontaneous cases, neither parent carries a copy of the mutated gene.

Most cases of Alagille syndrome are caused by a mutation in the JAGGED1 (JAG1) gene. In less than 1 percent of cases, a mutation in the NOTCH2 gene is the cause.2

1Spinner NB, Leonard LD, Krantz ID. Alagille syndrome. GeneReviews website. www.ncbi.nlm.nih.gov/books/NBK1273/External NIH Link. Updated February 28, 2013. Accessed July 16, 2014.

2Kamath BM, Bauer RC, Loomes KM, et al. NOTCH2 mutations in Alagille syndrome. Journal of Medical Genetics. 2012;49(2):138–144.
Genetic Disorders: 
Each cell contains thousands of genes that provide the instructions for making proteins for growth and repair of the body. If a gene has a mutation, the protein made by that gene may not function properly, which sometimes creates a genetic disorder. Not all gene mutations cause a disorder.

People have two copies of most genes; one copy is inherited from each parent. A genetic disorder occurs when one or both parents pass a mutated gene to a child at conception. A genetic disorder can also occur through a spontaneous gene mutation, meaning neither parent carries a copy of the mutated gene. Once a spontaneous gene mutation has occurred in a person, it can be passed to the person’s children.
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Complications:
The complications of Alagille syndrome include liver failure, portal hypertension, and growth problems. People with Alagille syndrome usually have a combination of complications, and may not have every complication listed below.:-

Liver failure. Over time, the decreased number of bile ducts may lead to chronic liver failure, also called end-stage liver disease. This condition progresses over months, years, or even decades. The liver can no longer perform important functions or effectively replace damaged cells. A person may need a liver transplant. A liver transplant is surgery to remove a diseased or an injured liver and replace it with a healthy whole liver or a segment of a liver from another person, called a donor.

Portal hypertension. The spleen is the organ that cleans blood and makes white blood cells. White blood cells attack bacteria and other foreign cells. Blood flow from the spleen drains directly into the liver. When a person with Alagille syndrome has advanced liver disease, the blood flow backs up into the spleen and other blood vessels. This condition is called portal hypertension. The spleen may become larger in the later stages of liver disease. A person with an enlarged spleen should avoid contact sports to protect the organ from injury. Advanced portal hypertension can lead to serious bleeding problems.

Growth problems. Alagille syndrome can lead to poor growth in infants and children, as well as delayed puberty in older children. Liver disease can cause malabsorption, which can result in growth problems. Malabsorption is the inability of the small intestine to absorb nutrients from foods, which results in protein, calorie, and vitamin deficiencies. Serious heart problems, if present in Alagille syndrome, can also affect growth.

Malabsorption. People with Alagille syndrome may have diarrhea—loose, watery stools—due to malabsorption. The condition occurs because bile is necessary for the digestion of food. Malabsorption can lead to bone fractures, eye problems, blood-clotting problems, and learning delays.

Long-term Outlook:
The long-term outlook for people with Alagille syndrome depends on several factors, including the severity of liver damage and heart problems. Predicting who will experience improved bile flow and who will progress to chronic liver failure is difficult. Ten to 30 percent of people with Alagille syndrome will eventually need a liver transplant.

Many adults with Alagille syndrome whose symptoms improve with treatment lead normal, productive lives. Deaths in people with Alagille syndrome are most often caused by chronic liver failure, heart problems, and blood vessel problems.

Diagnosis:
The Doctor diagnoses Alagille syndrome by performing a thorough physical examination of the patient and ordering one or more of the following tests and exams:

Blood test. A blood test involves drawing blood at a health care provider’s office or a commercial facility and sending the sample to a lab for analysis. The blood test can show nutritional status and the presence of liver disease and kidney function.

Urinalysis. Urinalysis is the testing of a urine sample. The urine sample is collected in a special container in a health care provider’s office or a commercial facility and can be tested in the same location or sent to a lab for analysis. Urinalysis can show many problems of the urinary tract and other body systems. The sample may be observed for color, cloudiness, or concentration; signs of drug use; chemical composition, including glucose; the presence of protein, blood cells, or bacteria; or other signs of disease.

X ray. An x ray is a picture created by using radiation and recorded on film or on a computer. The amount of radiation used is small. An x-ray technician performs the x ray at a hospital or an outpatient center, and a radiologist—a doctor who specializes in medical imaging—interprets the images. Anesthesia is not needed. The patient will lie on a table or stand during the x ray. The technician positions the x-ray machine over the spine area to look for “butterfly” vertebrae. The patient will hold his or her breath as the picture is taken so that the picture will not be blurry. The patient may be asked to change position for additional pictures.

Abdominal ultrasound. Ultrasound uses a device, called a transducer, that bounces safe, painless sound waves off organs to create an image of their structure. The transducer can be moved to different angles to make it possible to examine different organs. In abdominal ultrasound, the health care provider applies a gel to the patient’s abdomen and moves a handheld transducer over the skin. The gel allows the transducer to glide easily, and it improves the transmission of the signals. A specially trained technician performs the procedure in a health care provider’s office, an outpatient center, or a hospital, and a radiologist interprets the images; anesthesia is not needed. The images can show an enlarged liver or rule out other conditions.

Cardiology exam. A cardiologist—a doctor who treats people who have heart problems—performs a cardiology exam in a health care provider’s office, an outpatient center, or a hospital. During a full exam, a cardiologist may inspect the patient’s physical appearance, measure pulse rate and blood pressure, observe the jugular vein, check for rapid or skipped heartbeats, listen for variations in heart sounds, and listen to the lungs.

Slit-lamp exam. An ophthalmologist—a doctor who diagnoses and treats all eye diseases and eye disorders—performs a slit-lamp exam to diagnose posterior embryotoxon. The ophthalmologist examines the eye with a slit lamp, a microscope combined with a high-intensity light that shines a thin beam on the eye. While sitting in a chair, the patient will rest his or her head on the slit lamp. A yellow dye may be used to examine the cornea and tear layer. The dye is applied as a drop, or the specialist may touch a strip of paper stained with the dye to the white of the patient’s eye. The specialist will also use drops in the patient’s eye to dilate the pupil.

Liver biopsy. A liver biopsy is a procedure that involves taking a piece of liver tissue for examination with a microscope for signs of damage or disease. The health care provider may ask the patient to stop taking certain medications temporarily before the liver biopsy. The patient may be asked to fast for 8 hours before the procedure.

During the procedure, the patient lies on a table, right hand resting above the head. A local anesthetic is applied to the area where the biopsy needle will be inserted. If needed, sedatives and pain medication are also given. The health care provider uses a needle to take a small piece of liver tissue. The health care provider may use ultrasound, computerized tomography scans, or other imaging techniques to guide the needle. After the biopsy, the patient should lie on the right side for up to 2 hours and is monitored an additional 2 to 4 hours before being sent home.

Genetic testing. The health care provider may refer a person suspected of having Alagille syndrome to a geneticist—a doctor who specializes in genetic disorders. For a genetic test, the geneticist takes a blood or saliva sample and analyzes the DNA for the JAG1 gene mutation. The geneticist tests for the JAG1 gene mutation first, since it is more common in Alagille syndrome than NOTCH2. Genetic testing is often done only by specialized labs. The results may not be available for several months because of the complexity of the testing.

The usefulness of genetic testing for Alagille syndrome is limited by two factors:

*Detection of a mutated gene cannot predict the onset of symptoms or how serious the disorder will be.

*Even if a mutated gene is found, no specific cure for the disorder exists.

When to Consider Genetic Counseling:
People who are considering genetic testing may want to consult a genetics counselor. Genetic counseling can help family members understand how test results may affect them individually and as a family. Genetic counseling is provided by genetics professionals—health care professionals with specialized degrees and experience in medical genetics and counseling. Genetics professionals include geneticists, genetics counselors, and genetics nurses.

Genetics professionals work as members of health care teams, providing information and support to individuals or families who have genetic disorders or a higher chance of having an inherited condition. Genetics professionals

*assess the likelihood of a genetic disorder by researching a family’s history, evaluating medical records, and conducting a physical exam of the patient and
*other family members

*weigh the medical, social, and ethical decisions surrounding genetic testing

*provide support and information to help a person make a decision about testing

*interpret the results of genetic tests and medical data

*provide counseling or refer individuals and families to support services

*serve as patient advocates

*explain possible treatments or preventive measures

*discuss reproductive options

Genetic counseling may be useful when a family member is deciding whether to have genetic testing and again later when test results are available.

Treatment:
Treatment for Alagille syndrome includes medications and therapies that increase the flow of bile from the liver, promote growth and development in infants’ and children’s bodies, correct nutritional deficiencies, and reduce the person’s discomfort. Ursodiol (Actigall, Urso) is a medication that increases bile flow. Other treatments address specific symptoms of the disorder.

Liver failure. People with Alagille syndrome who develop end-stage liver failure need a liver transplant with a whole liver from a deceased donor or a segment of a liver from a living donor. People with Alagille syndrome who also have heart problems may not be candidates for a transplant because they could be more likely to have complications during and after the procedure. A liver transplant surgical team performs the transplant in a hospital.

Pruritus. Itching may decrease when the flow of bile from the liver is increased. Medications such as cholestyramine (Prevalite), rifampin (Rifadin, Rimactane), naltrexone (Vivitrol), or antihistamines may be prescribed to relieve pruritus. People should hydrate their skin with moisturizers and keep their fingernails trimmed to prevent skin damage from scratching. People with Alagille syndrome should avoid baths and take short showers to prevent the skin from drying out.

If severe pruritus does not improve with medication, a procedure called partial external biliary diversion may provide relief from itching. The procedure involves surgery to connect one end of the small intestine to the gallbladder and the other end to an opening in the abdomen—called a stoma—through which bile leaves the body and is collected in a pouch. A surgeon performs partial external biliary diversion in a hospital. The patient will need general anesthesia.

Malabsorption and growth problems. Infants with Alagille syndrome are given a special formula that helps the small intestine absorb much-needed fat. Infants, children, and adults can benefit from a high-calorie diet, calcium, and vitamins A, D, E, and K. They may also need additional zinc. If someone with Alagille syndrome does not tolerate oral doses of vitamins, a health care provider may give the person injections for a period of time. A child may receive additional calories through a tiny tube that is passed through the nose into the stomach. If extra calories are needed for a long time, a health care provider may place a tube, called a gastrostomy tube, directly into the stomach through a small opening made in the abdomen. A child’s growth may improve with increased nutrition and flow of bile from the liver.

Xanthomas. For someone who has Alagille syndrome, these fatty deposits typically worsen over the first few years of life and then improve over time. They may eventually disappear in response to partial external biliary diversion or the medications used to increase bile fl

Prevention:
Scientists have not yet found a way to prevent Alagille syndrome. However, complications of the disorder can be managed with the help of Doctors. Routine visits with Doctor are needed to prevent complications from becoming worse.

Hope through Research:The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and other Institutes of the National Institutes of Health (NIH) conduct and support research in digestive disorders, including Alagille syndrome. For example, the NIDDK is sponsoring a study called Evaluating the Genetic Causes and Progression of Cholestatic Liver Diseases (LOGIC). Funded under NIH clinical trial number NCT00571272, LOGIC will investigate the progression of cholestatic liver diseases, which can sometimes be caused by Alagille syndrome. The study will work to provide a better understanding of the causes and effects of these liver diseases, which will promote the development of prevention tactics and treatment strategies.

Clinical trials are research studies involving people. Clinical trials look at safe and effective new ways to prevent, detect, or treat disease. Researchers also use clinical trials to look at other aspects of care, such as improving the quality of life for people with chronic illnesses. To learn more about clinical trials, why they matter, and how to participate, visit the NIH Clinical Research Trials and You website at www.nih.gov/health/clinicaltrialsExternal NIH Link. For information about current studies,…click & see

Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose.
Resources:
http://en.wikipedia.org/wiki/Alagille_syndrome
http://www.niddk.nih.gov/health-information/health-topics/liver-disease/Alagille-Syndrome/Pages/facts.aspx

 

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Phenylketonuria (PKU)

Definition;
Phenylketonuria (PKU) is an autosomal recessive metabolic genetic disorder characterized by a mutation in the gene for the hepatic enzyme phenylalanine hydroxylase (PAH), rendering it nonfunctional.:541 This enzyme is necessary to metabolize the amino acid phenylalanine (Phe) to the amino acid tyrosine. When PAH enzymatic activity is reduced, phenylalanine accumulates and is converted into phenylpyruvate (also known as phenylketone), which is detected in the urine.

Amino acids are the building blocks for body proteins. ‘Essential’ amino acids can only be obtained from the food we eat as our body does not normally produce them. In ‘classic PKU’, the enzyme that breaks down phenylalanine phenylalanine hydroxylase, is completely or nearly completely deficient. This enzyme normally converts phenylalanine to another amino acid, tyrosine. Without this enzyme, phenylalanine and its’ breakdown chemicals from other enzyme routes, accumulate in the blood and body tissues. Although the term ‘hyperphenylalaninemia’ strictly means elevated blood phenylalanine, it is usually used to describe a group of disorders other than classic PKU. These other disorders may be caused by a partial deficiency of the phenylalanine breakdown enzyme or the lack of another enzyme important to the processing of this amino acid. A normal blood phenylalanine level is about 1 mg/dl. In classic PKU, levels may range from 6 to 80mg/dl, but are usually greater than 30mg/dl. Levels are somewhat less in the other disorders of hyperphenylalaninemia. Chronically high levels of phenylalanine and some of its breakdown products can cause significant brain problems. Classic PKU is the most common cause of high levels of phenylalanine in the blood and will be the primary focus of this topic sheet.

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The mean incidence of PKU varies widely in different human populations. In Turkey, 1 in 2600 births (the highest rate in the world) show PKU; in Ireland, 1 in 4,500, 1 in 13,000 in Norway, and fewer than one in 100,000 in Finland. In the United States, about 1 in 15,000 births shows classical PKU. The incidence is relatively high in Italy, China, and Yemen

Classic PKU and the other causes of hyperphenylalaninemia affect about one of every 10,000 to 20,000 Caucasian or Oriental births. The incidence in African Americans is far less. These disorders are equally frequent in males and females.

Since its discovery, there have been many advances in its treatment. It can now be successfully managed by the patient under ongoing medical supervision to avoid the more serious side effects. If, however, the condition is left untreated, it can cause problems with brain development, leading to progressive mental retardation, brain damage, and seizures. In the past, PKU was treated with a low-phenylalanine diet. Latter-day research now has shown diet alone may not be enough to prevent the negative effects of phenylalanine levels. Optimal treatment involves lowering blood Phe levels to a safe range and monitoring diet and cognitive development. Lowering of Phe levels to a safe range may be achieved by combining a low-Phe diet with protein supplements. There is currently no cure for this disease; however, some treatments are available with varying success rates. In general, PKU is detected through newborn screening and diagnosed by a geneticist. PKU clinics around the world provide care for PKU patients to optimize Phe levels, dietary intake, and cognitive outcomes.

Symptoms:
Newborns with phenylketonuria initially don’t have any symptoms. Without treatment, though, babies usually develop signs of PKU within a few months. Phenylketonuria symptoms can be mild or severe and may include:

*Mental retardation
*Behavioral or social problems
*Seizures, tremors or jerking movements in the arms and legs)
*Hyperactivity
*Stunted growth
*Skin rashes (eczema)
*Small head size (microcephaly)
*A musty odor in the child’s breath, skin or urine, caused by too much phenylalanine in the body

*Fair skin and blue eyes, because phenylalanine cannot transform into melanin — the pigment responsible for hair and skin tone

Varying severity
The most severe form of the disorder is known as classic PKU. Children with untreated classic PKU usually develop obvious, permanent mental retardation.

Less severe forms of PKU — sometimes called mild or moderate PKU — have a smaller risk of significant brain damage, but most children with these forms of the disorder still require a special diet to prevent mental retardation and other complications.

Pregnancy and PKU
A woman who has PKU and becomes pregnant is at risk of another form of the condition called maternal PKU. Many people with PKU used to stop following a low-phenylalanine diet during their teen years, as was directed by doctors at the time. But, doctors now know that if a woman doesn’t follow the diet during pregnancy, blood phenylalanine levels can become very high and harm the developing fetus. Because of this, and other reasons, doctors recommend that anyone with PKU follow the low-phenylalanine diet for life.

Although babies born to mothers with high phenylalanine levels may have complications at birth, most don’t actually inherit PKU and won’t need to follow a PKU diet after birth. However, these babies are at risk of being born with:

*Mental retardation
*Abnormally small head (microcephaly)
*Heart defects
*Low birth weights
*Behavioral problems

 

Causes:
A genetic mutation causes PKU. The defective gene contains the instructions for making an enzyme needed to process the amino acid called phenylalanine. Amino acids are the building blocks for protein. In a person with PKU, this gene is defective, causing a complete or near-complete deficiency of the enzyme. Without the enzyme necessary to process phenylalanine, a dangerous buildup of this amino acid can develop when a person with PKU eats foods that are high in protein, such as milk, cheese, nuts or meats. This can eventually lead to serious health problems.
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For a child to inherit PKU, both the mother and father must have and pass on the defective gene. This pattern of inheritance is called autosomal recessive. It’s possible for a parent to have the defective gene, but not have the disease. This is called being a carrier. Most often, PKU is passed down the family tree by parents who are carriers of the disorder, but don’t know it.

.For women affected with PKU, it is essential for the health of their children to maintain low Phe levels before and during pregnancy.  Though the developing fetus may only be a carrier of the PKU gene, the intrauterine environment can have very high levels of phenylalanine, which can cross the placenta. The child may develop congenital heart disease, growth retardation, microcephaly and mental retardation as a result.  PKU-affected women themselves are not at risk from additional complications during pregnancy.
In most countries, women with PKU who wish to have children are advised to lower their blood Phe levels (typically to between 2 and 6 micromol/deciliter) before they become pregnant, and carefully control their levels throughout the pregnancy. This is achieved by performing regular blood tests and adhering very strictly to a diet, in general monitored on a day-to-day basis by a specialist metabolic dietitian. In many cases, as the fetus’ liver begins to develop and produce PAH normally, the mother’s blood Phe levels will drop, requiring an increased intake to remain within the safe range of 2-6 micromol/dL. The mother’s daily Phe intake may double or even triple by the end of the pregnancy, as a result. When maternal blood Phe levels fall below 2 micromol/dL, anecdotal reports indicate the mothers may suffer adverse effects, including headaches, nausea, hair loss, and general malaise. When low phenylalanine levels are maintained for the duration of pregnancy, there are no elevated levels of risk of birth defects compared with a baby born to a non-PKU mother.   Babies with PKU may drink breast milk, while also taking their special metabolic formula. Some research has indicated an exclusive diet of breast milk for PKU babies may alter the effects of the deficiency, though during breastfeeding the mother must maintain a strict diet to keep her Phe levels low. More research is needed. US scientist announced in June 2010 that they would be conducting a thorough investigation on the mutation of genes in the human genome. Their top priority is PKU, as it has become increasingly common, and sufferers often bear children who will be carriers of the recessive gene, and may themselves live past the age of sixty.
Risk factors:
Both parents must pass along a copy of the mutated PKU gene for their child to develop the condition. If only one parent has the PKU gene, there’s no risk of passing PKU to a child. The gene defect occurs mainly in people of Northern European and Native American ancestry. It’s much less common in blacks, Asians and Hispanics.

Children of mothers who have PKU but who didn’t follow the PKU diet during pregnancy also may be affected. Although these children don’t often have PKU, they do have consequences of the high level of phenylalanine in the mother’s blood.

Diagnosis:
PKU can be easily detected with a simple blood test. Most states require a PKU screening test for all newborns. The test is generally done with a heelstick shortly after birth.

If the initial screening test is positive, further blood and urine tests are required to confirm the diagnosis.

•The objective in diagnosing or treating the disorder is to prevent mental retardation.

•Serum phenylalanine levels greater than 4 mg/dl is abnormal, the normal values is 2 mg/dl. Significant brain damage usually occurs when levels are greater than 10 – 15 mg/dl

 

Treatment:
If PKU is diagnosed early enough, an affected newborn can grow up with normal brain development, but only by managing and controlling Phe levels through diet, or a combination of diet and medication. Optimal health ranges (or “target ranges”) are between 120 and 360 µmol/L, and aimed to be achieved during at least the first 10 years. When Phe cannot be metabolized by the body, abnormally high levels accumulate in the blood and are toxic to the brain. When left untreated, complications of PKU include severe mental retardation, brain function abnormalities, microcephaly, mood disorders, irregular motor functioning, and behavioral problems such as ADHD.

All PKU patients must adhere to a special diet low in Phe for optimal brain development. “Diet for life” has become the standard recommended by most experts. The diet requires severely restricting or eliminating foods high in Phe, such as meat, chicken, fish, eggs, nuts, cheese, legumes, milk and other dairy products. Starchy foods, such as potatoes, bread, pasta, and corn, must be monitored. Infants may still be breastfed to provide all of the benefits of breastmilk, but the quantity must also be monitored and supplementation for missing nutrients will be required. The sweetener aspartame, present in many diet foods and soft drinks, must also be avoided, as aspartame consists of two amino acids: phenylalanine and aspartic acid.

Supplementary infant formulas are used in these patients to provide the amino acids and other necessary nutrients that would otherwise be lacking in a low-phenylalanine diet. As the child grows up these can be replaced with pills, formulas, and specially formulated foods. (Since Phe is necessary for the synthesis of many proteins, it is required for appropriate growth, but levels must be strictly controlled in PKU patients.) In addition tyrosine, which is normally derived from phenylalanine, must be supplemented.

The oral administration of tetrahydrobiopterin (or BH4) (a cofactor for the oxidation of phenylalanine) can reduce blood levels of this amino acid in certain patients. The company BioMarin Pharmaceutical has produced a tablet preparation of the compound sapropterin dihydrochloride (Kuvan), which is a form of tetrahydrobiopterin. Kuvan is the first drug that can help BH4-responsive PKU patients (defined among clinicians as about 1/2 of the PKU population) lower Phe levels to recommended ranges.[17] Working closely with a dietitian, some PKU patients who respond to Kuvan may also be able to increase the amount of natural protein they can eat. After extensive clinical trials, Kuvan has been approved by the FDA for use in PKU therapy. Some researchers and clinicians working with PKU are finding Kuvan a safe and effective addition to dietary treatment and beneficial to patients with PKU.

Several other therapies are currently under investigation, including gene therapy, large neutral amino acids, and enzyme substitution therapy with phenylalanine ammonia lyase (PAL). In the past, PKU-affected people were allowed to go off diet after approximately eight, then 18 years of age. Today, most physicians recommend PKU patients must manage their Phe levels throughout life.
Prognosis:
The outlook depends on how early an infant with PKU is diagnosed and begins the special diet, as well as how strictly and consistently the diet is followed throughout life. Infants with PKU who are identified within the first few days after birth and are put on a strict diet before 3 weeks of age have the best prognosis and usually do not experience severe developmental delay or mental retardation.

Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose

Resources:
http://www.nursing-lectures.com/2011/04/phenylketonuria-pku-nursing-care-plan.html
http://www.newbornscreening.info/Parents/aminoaciddisorders/PKU.html
http://health.nytimes.com/health/guides/disease/phenylketonuria/overview.html
http://www.mayoclinic.com/health/phenylketonuria/DS00514
http://www.medhelp.org/lib/pku.htm
http://www.onlymyhealth.com/what-prognosis-phenylketonuria-pku-12977608306
http://en.wikipedia.org/wiki/Phenylketonuria#cite_note-17

Neurofibromatosis

Definition:
Neurofibromatosis (commonly abbreviated NF; neurofibromatosis type 1 is also known as von Recklinghausen disease) is a genetically-inherited disorder in which the nerve tissue grows tumors (i.e., neurofibromas) that may be benign or may cause serious damage by compressing nerves and other tissues. The disorder affects all neural crest cells (Schwann cells, melanocytes and endoneurial fibroblasts). Cellular elements from these cell types proliferate excessively throughout the body, forming tumors; melanocytes also function abnormally in this disease, resulting in disordered skin pigmentation and “cafe-au-lait” spots. The tumors may cause bumps under the skin, colored spots, skeletal problems, pressure on spinal nerve roots, and other neurological problems.
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Neurofibromatosis is an autosomal dominant disorder, which means only one copy of the affected gene is needed for the disorder to develop. Therefore, if only one parent has neurofibromatosis, his or her children have a 50% chance of developing the condition as well. The severity in affected individuals can vary, this may be due to variable expressivity. Approximately half of cases are due to de novo mutations and no other affected family members are seen. It affects males and females equally.

Symptoms:
Three distinct types of neurofibromatosis exist, each with different signs and symptoms.
Neurofibromatosis type 1 (also known as “von Recklinghausen disease”) is the most common form of NF, accounting for up to 90% of the cases. NF 1 has a disorder frequency of 1 in 4,000, making it more common than neurofibromatosis type 2, with a frequency of 1 in 45,000 people. It occurs following the mutation of neurofibromin on chromosome 17q11.2. 100,000 Americans have neurofibromatosis. Neurofibromin is a tumor suppressor gene whose function is to inhibit the p21 ras oncoprotein. In absence of this tumor suppressor’s inhibitory control on the ras oncoprotein, cellular proliferation is erratic and uncontrolled, resulting in unbalanced cellular proliferation and tumor development. The diagnosis of NF1 is made if any two of the following seven criteria are met:

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Plexiform neurofibroma on the neck of a patient; plexiform neurofibromas are a cause of morbidity in the affected individuals.

 

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Patient with multiple small cutaneous neurofibromas and a ‘café au lait spot’ (bottom of photo, to the right of centre). A biopsy has been taken of one of the lesions.

*Two or more neurofibromas on or under the skin, or one plexiform neurofibroma (a large cluster of tumors involving multiple nerves); neurofibromas are the subcutaneous bumps characteristic of the disease, and increase in number with age.

*Freckling of the groin or the axilla (arm pit).

 

*Café au lait spots (pigmented, light brown macules located on nerves, with smooth edged, “coast of California” birthmarks).
*Six or more measuring 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals.

*Skeletal abnormalities, such as sphenoid dysplasia or thinning of the cortex of the long bones of the body (i.e. bones of the leg, potentially resulting in bowing of the legs)

*Lisch nodules (hamartomas of iris), freckling in the iris

*Tumors on the optic nerve, also known as an optic glioma

*Macrocephaly in 30-50% of the pediatric population without any hydrocephalus

*Epilepsy (seizures)

*Juvenile posterior lenticular opacity

NF 1 also increases the risk of tumor development, particularly, meningiomas, gliomas and pheochromocytomas.

Neurofibromatosis type 2 (NF 2):……..CLICK & SEE
Neurofibromatosis type 2 (also called “central neurofibromatosis” is the result of mutation of the merlin (also known as “schwannomin”[1]) in chromosome 22q12. It accounts for only 10% of all cases of NF, and its frequency is lower than NF1. It is also caused by a mutation in a tumor suppressor gene NF2 (whose gene product is schwannomin or merlin). The normal function of merlin is not well understood.  The disorder manifests in the following fashion:

 

*bilateral acoustic neuromas (tumors of the vestibulocochlear nerve or cranial nerve 8 (CN VIII) also known as schwannoma), often leading to hearing loss. In fact, the hallmark of NF 2 is hearing loss due to acoustic neuromas around the age of twenty.

*The tumors may cause:
…#headaches
…#balance problems, and peripheral vertigo often due to schwannoma and involvement of the inner ear
…#facial weakness/paralysis due to involvement or compression of the facial nerve (cranial nerve 7 or CN VII)
…#patients with NF2 may also develop other brain tumors, as well as spinal tumors.
…#deafness and tinnitus

NF 2 increases the risk of meningiomas and ependymomas

Schwannomatosis:
1.Multiple schwannomas occur.
2.The schwannomas develop on cranial, spinal and peripheral nerves.
3.Chronic pain, and sometimes numbness, tingling and weakness
4.About 1/3 of patients have segmental schwannomatosis, which means the schwannomas are limited to a single part of the body, such as an arm, a leg or the spine.
5.Unlike the other forms of NF, the schwannomas do not develop on vestibular nerves, and as a result, no loss of hearing is associated with schwannomatosis.
6.Patients with schwannomatosis do not have learning disabilities related to the disorder.

One must keep in mind, however, that neurofibromatosis can occur in or affect any of the organ systems, whether that entails simply compressing them (from tumor growth) or in fact altering the organs in some fundamental way. This disparity in the disorder is one of many factors that makes it difficult to diagnose, and eventually find a prognosis for.

Patients with neurofibromatosis can be affected in many different ways. Morbidity is often a result of plexiform neuromas, optic gliomas, or acoustic neuromas, but mortality can also be associated with malignant transformation of the neuromas, such as neurofibrosarcomas (often there is a malignant transformation in less than 3% of the cases of NF1). There is a high incidence of learning disabilities or cognitive deficit  in patients with NF, particularly NF-1, however severe retardation is not part of the syndrome. Because of the tumor generating nature of the disorder and its involvement of the nervous system and also because of early onset macrocephaly in the pediatric population, there is often an increased chance of development of epilepsy in those affected. Neurofibromatosis also increases the risk of leukemia particularly in children; Children with NF-1 have 200 to 500 times the normal risk of developing leukemia compared to the general population. Since the tumors grow where there are nerves, they can also grow in areas that are visible, causing considerable social suffering for those affected. The tumors can also grow in places that can cause other medical issues that may require them to be removed for the patient’s safety. Affected individuals may need multiple surgeries (such as reduction surgery, or Gamma knife surgery), depending on where the tumors are located. For instance, those affected with NF 2 might benefit from a surgical decompression of the vestibular tumors to prevent deafness

Causes:
What causes neurofibromatosis has yet to be fully explained, but it appears to be mostly due to genetic defects (mutations) that either are passed on by a parent or occur spontaneously at conception. Each form of neurofibromatosis is caused by mutations in different genes.

Neurofibromatosis 1 (NF1)
The NF1 gene is located on chromosome 17. Normally, this gene produces a protein called neurofibromin, which is abundant in nervous system tissue and helps regulate cell growth. A mutation of the NF1 gene causes a loss of neurofibromin, which allows cells to grow uncontrolled. This results in the tumors characteristic of NF1.

Neurofibromatosis 2 (NF2)
A similar problem occurs with NF2. The NF2 gene is located on chromosome 22, which produces a protein called merlin. A mutation of the NF2 gene causes loss of merlin, which also leads to uncontrolled cell growth.

Schwannomatosis
Because schwannomatosis has only recently been identified as a separate type of neurofibromatosis, its exact cause is still under scrutiny. In a small number of familial cases, it’s been associated with a mutation of the SMARCB1/INI1 gene, but in most cases the cause is unknown. The occurrence of schwannomatosis is more spontaneous (sporadic) than inherited.

Risk Factors:
The biggest risk factor for neurofibromatosis is a family history of the disorder. About half of NF1 and NF2 cases are inherited. The remaining cases result from spontaneous mutations that occur at conception.

NF1 and NF2 are both autosomal dominant disorders, which means that any child of a parent with the disorder has a 50 percent chance of inheriting the genetic mutation.

The inheritance pattern for schwannomatosis is less clear. Researchers currently estimate that the risk of inheriting schwannomatosis from an affected parent is around 15 percent.
Complications:
Complications of neurofibromatosis vary, even within the same family. Generally, complications result from tumor growth distorting nerve tissue or pressing on internal organs.

It’s not possible to predict how the disease will progress in any one individual but most people with neurofibromatosis experience a mild or moderate form of the disorder, regardless of type. Usually, serious complications develop prior to adolescence.

Neurofibromatosis 1 (NF1)
Common complications of NF1 include:

*Neurological problems. Learning difficulties occur in up to 60 percent of NF1 cases and are the most common neurological problem associated with NF1. Uncommon neurological complications associated with NF1 include epilepsy, stroke and buildup of excess fluid in the brain (hydrocephalus).

*Concerns with appearance. Visible signs of neurofibromatosis — such as extensive cafe au lait spots, nerve tumors (neurofibromas) in the facial area or large neurofibromas — can cause anxiety and emotional distress, even if not medically serious.

*Skeletal problems. Some children have abnormally formed bones, which can result in curvature of the spine (scoliosis) and bowed legs. NF1 is also associated with decreased bone mineral density, which increases your risk of weak bones (osteoporosis).

*Visual difficulties. Occasionally in children, a tumor growing on the nerve leading from the eye to the brain (optic nerve) can cause visual problems.

* Increase in neurofibromas. Hormonal changes associated with puberty, pregnancy or menopause may cause an increase in neurofibromas. Most women with NF1 have healthy pregnancies but will likely need to be monitored by an obstetrician familiar with NF1, in addition to her NF1 specialist.

*Cardiovascular problems. People with NF1 have an increased risk of high blood pressure and, rarely, blood vessel abnormalities.

*Cancer. Less than 10 percent of people with NF1 develop cancerous (malignant) tumors. These usually arise from neurofibromas under the skin or plexiform neurofibromas involving multiple nerves. Monitor neurofibromas vigilantly for any change in appearance, size or number. Changes may indicate cancerous growth. The earlier a malignancy is detected, the better the chances for effective treatment. People with NF1 also have a higher risk of other forms of cancer, such as breast cancer, leukemia, brain tumors and some types of soft tissue cancer.

Neurofibromatosis 2 (NF2)
Expanding tumors in people with NF2 may cause:

*Partial or total deafness

*Facial nerve damage

*Visual difficulties

*Weakness or numbness in the extremities

*Multiple benign brain tumors (meningiomas) requiring frequent surgeries

Schwannomatosis complications
The pain caused by schwannomatosis can be debilitating and may require surgical treatment or management by a pain specialist.
Diagnosis:
Prenatal testing

Embryo:
For embryos produced via in vitro fertilisation, it is possible via preimplantation genetic diagnosis (PGD) to screen for NF-1.

“PGD has about 95-98% accuracy but requires that the partner with NF2 have a recognizeable genetic mutation, which is only the case for about 60% of people with a clinical diagnosis of NF2. Having the initial genetic testing to determine if the mutation is recognizeable takes approximately 6 months, and then preparing the probes for the PDG testing takes approximately another 6 months.”

PGD can not be used to detect Schwannomatosis?, because the gene for it has not yet been identified.

Foetus:
Chorionic villus sampling or amniocentesis can be used:

*To detect Neurofibromatosis type I?.

*To detect Neurofibromatosis type II? with 95% accuracy.

*Can not be used to detect Schwannomatosis?, because the gene for it has not yet been identified.

Related disorders:
Neurofibromatosis is considered a member of the neurocutaneous syndromes (phakomatoses). In addition to the types of neurofibromatosis, the phakomatoses also include tuberous sclerosis, Sturge-Weber syndrome and von Hippel-Lindau disease. This grouping is an artifact of an earlier time in medicine, before the distinct genetic basis of each of these diseases was understood.

Genetics:
Neurofibromatosis type 1 is caused by mutation on chromosome 17q11.2 , the gene product being neurofibromin (a regulator of the GTPase activating enzyme (GAP)). Neurofibromatosis type 2 is due to mutation on chromosome 22q, the gene product is merlin, a cytoskeletal protein.

Both NF-1 and NF-2 are autosomal dominant disorders, meaning only one copy of the mutated gene need be inherited to pass the disorder. A child of a parent with NF-1 or NF-2 and an unaffected parent will have a 50%-100% chance of inheriting the disorder, depending on whether the affected parent is heterozygous (Aa) or homozygous (AA) for the trait (“A” depicts the affected dominant allele, while “a” depics the recessive allele).

NF-1 and NF-2 may be inherited in an autosomal dominant fashion, as well as through random mutation.

 

Complicating the question of heritability is the distinction between genotype and phenotype, that is, between the genetics and the actual manifestation of the disorder. In the case of NF1, no clear links between genotype and phenotype have been found, and the severity and the specific nature of the symptoms may vary widely among family members with the disorder. This is a good example of the phenomenon of variable expressivity: the differing severities of disease in different individuals with the same genotype.  In the case of NF-2, however, manifestations are similar among family members; a strong genotype-phenotype correlation is believed to exist. Both NF-1 and NF-2 can also appear to be spontaneous de novo mutations, with no family history. These cases account for about one half of neurofibromatosis cases.

Similar to polydactyly, NF is also a autosomally dominant mutation, that is not prevalent in the society. Neurofibromatosis-1 is found in approximately 1 in 2,500-3,000 live births (carrier incidence 0.0004, gene frequency 0.0002) and is more common than NF-2.

 

Treatment:
There is at present  no cure for NF but the Neurofibromatosis Association is optimistic that there will be an effective treatment within the next five to ten years. For families with NF, genetic screening and counselling is available.

Most people don’t need any treatment but surgery may be necessary to remove some tumours (such as acoustic neuromas or brain tumours) and this can cause complications such as facial paralysis.

Treatment for complications such as epilepsy is given as appropriate. Vision and hearing are regularly tested. Special education is provided for those children with learning difficulties.

Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose
Resources:
http://en.wikipedia.org/wiki/Neurofibromatosis
http://www.mayoclinic.com/health/neurofibromatosis/DS01185
http://www.bbc.co.uk/health/physical_health/conditions/neurofibroma1.shtml

http://www.jyi.org/news/nb.php?id=895

https://runkle-science.wikispaces.com/NEUROFIBROMATOSIS

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Wilson’s Disease

Definition :
Wilson’s disease is an inherited disorder that causes too much copper to accumulate in your liver, brain and other vital organs. Another term for Wilson’s disease is hepatolenticular degeneration.

Copper plays a key role in the development of healthy nerves, bones, collagen and the skin pigment melanin. Normally, copper is absorbed from your food, and any excess is excreted through bile — a substance produced in your liver.

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Normal absorption and distribution of copper. Cu = copper, CP = ceruloplasmin, green = ATP7B carrying copper.

But in people with Wilson’s disease, copper isn’t eliminated properly and instead accumulates, possibly to a life-threatening level. Left untreated, Wilson’s disease is fatal. When diagnosed early, Wilson’s disease is treatable, and many people with the disorder live normal lives.

The excess copper can build up in the liver and/or brain causing liver damage and/or neurological problems. It can also collect in other parts of the body including the eyes and the kidneys.
Copper begins to accumulate immediately after birth but the symptoms usually appear in the 2nd to 3rd decade. The first signs are hepatic (liver) in about 40% of cases, neurological (brain) in about 35% of cases and psychiatric, renal (kidney), haematological (blood), or endocrine (glands) in the remainder.

The condition is due to mutations in the Wilson disease protein (ATP7B) gene. A single abnormal copy of the gene is present in 1 in 100 people, who do not develop any symptoms (they are carriers). If a child inherits the gene from both parents, they may develop Wilson’s disease. Symptoms usually appear between the ages of 6 and 20 years, but cases in much older people have been described. Wilson’s disease occurs in 1 to 4 per 100,000 people.  Wilson’s disease is named after Samuel Alexander Kinnier Wilson (1878–1937), the British neurologist who first described the condition in 1912


Symptoms:
The most pathognomonic sign of Wilson’s disease results from a buildup of copper in the eyes. These rings are
called Kayser – Fleischer rings. Rings are brownish, visible aroound the corneo – scleral junction (limbus).
95% of Wilson’ s disease patients presenting with neurological signs will have Kayser – Fleischer rings and 65% of Wilson’s disease patients presenting with hepatic signs will present a ring.

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Wilson’s disease causes a wide variety of signs and symptoms that are often mistaken for other diseases and conditions. Signs and symptoms vary depending on what parts of your body are affected by Wilson’s disease.
Signs and symptoms of Wilson’s disease include:

*Clumsiness
*Depression
*Difficulty speaking
*Difficulty swallowing
*Difficulty walking
*Drooling
*Easy bruising
*Fatigue
*Involuntary shaking
*Joint pain
*Loss of appetite
*Nausea
*Skin rash
*Swelling of arms and legs
*Yellowing of the skin and eyes (jaundice)

The main sites of copper accumulation are the liver and the brain, and consequently liver disease and neuropsychiatric symptoms are the main features that lead to diagnosis.  People with liver problems tend to come to medical attention earlier, generally as children or teenagers, than those with neurological and psychiatric symptoms, who tend to be in their twenties or older. Some are identified only because relatives have been diagnosed with Wilson’s disease; many of these, when tested, turn out to have been experiencing symptoms of the condition but haven’t received a diagnosis.:

Causes:
Wilson’s disease occurs when a genetic mutation leads to an accumulation of copper in  one’s body.

How the genetic mutation occurs
The genetic mutation that causes Wilson’s disease is most commonly passed from one generation to the next. Wilson’s disease is inherited as an autosomal recessive trait, which means that to develop the disease you must inherit two copies of the defective gene, one from each parent. If you receive only one abnormal gene, you won’t become ill yourself, but you’re considered a carrier and can pass the gene to your children.

How the genetic mutation causes Wilson’s disease
The mutation that causes Wilson’s disease occurs in a gene called ATP7B. When a mutation occurs on this gene, it leads to problems with a protein that’s responsible for moving excess copper out of your liver.

Your body collects copper from the food you eat during the digestive process. The copper is transported to your liver where liver cells use it for everyday tasks. Most people eat more copper than they need. In these cases, the liver takes what it needs and excretes the rest in bile, a digestive juice made by the liver.

But in people with Wilson’s disease, the extra copper doesn’t leave your body. Instead, copper builds up in the liver, where it can cause serious and sometimes irreversible damage. In time, excess copper leaves the liver and begins accumulating in and harming other organs, especially the brain, eyes and kidneys.

 

Complications:
Wilson’s disease can cause serious complications such as:

*Scarring of the liver (cirrhosis). As liver cells try to make repairs to damage done by excess copper, scar tissue forms in the liver. The scar tissue makes it more difficult for the liver to function.

*Liver failure. Liver failure can occur suddenly (acute liver failure), or it can develop slowly over many years. If liver function progresses, a liver transplant may be a treatment option.

*Liver cancer. Damage to the liver caused by Wilson’s disease may increase the risk of liver cancer.

*Persistent neurological problems. Neurological problems usually improve with treatment for Wilson’s disease. However, some people may experience persistent neurological difficulty, despite treatment.
*Kidney problems. Wilson’s disease can damage the kidneys, leading to kidney problems, such as kidney stones and an abnormal number of amino acids excreted in the urine (aminoaciduria).

Diagnosis:
Wilson’s disease may be suspected on the basis of any of the symptoms mentioned above, or when a close relative has been found to have Wilson’s. Most have slightly abnormal liver function tests such as a raised aspartate transaminase, alanine transaminase and bilirubin level. If the liver damage is significant, albumin may be decreased due to an inability of damaged liver cells to produce this protein; likewise, the prothrombin time (a test of coagulation) may be prolonged as the liver is unable to produce proteins known as clotting factors. Alkaline phosphatase levels are relatively low in those with Wilson’s-related acute liver failure. If there are neurological symptoms, magnetic resonance imaging (MRI) of the brain is usually performed; this shows hyperintensities in the part of the brain called the basal ganglia in the T2 setting.  MRI may also demonstrate the characteristic “face of the giant panda” pattern.

There is no totally reliable test for Wilson’s disease, but levels of ceruloplasmin and copper in the blood, as well of the amount of copper excreted in urine during a 24-hour period, are together used to form an impression of the amount of copper in the body. The gold standard or most ideal test is a liver biopsy

Ceruloplasmin
Levels of ceruloplasmin are abnormally low (<0.2 g/L) in 80–95% of cases. It can, however, be present at normal levels in people with ongoing inflammation as it is an acute phase protein. Low ceruloplasmin is also found in Menkes disease and aceruloplasminemia, which are related to, but much rarer than Wilson’s disease.

The combination of neurological symptoms, Kayser–Fleisher rings and a low ceruloplasmin level is considered sufficient for the diagnosis of Wilson’s disease. In many cases, however, further tests are needed.
Serum and urine copper
Serum copper is paradoxically low but urine copper is elevated in Wilson’s disease. Urine is collected for 24 hours in a bottle with a copper-free liner. Levels above 100 ?g/24h (1.6 ?mol/24h) confirm Wilson’s disease, and levels above 40 ?g/24h (0.6 ?mol/24h) are strongly indicative.[1] High urine copper levels are not unique to Wilson’s disease; they are sometimes observed in autoimmune hepatitis and in cholestasis (any disease obstructing the flow of bile from the liver to the small bowel).

In children, the penicillamine test may be used. A 500 mg oral dose of penicillamine is administered, and urine collected for 24 hours. If this contains more than 1600 ?g (25 ?mol), it is a reliable indicator of Wilson’s disease. This test has not been validated in adults.

Liver biopsy
Once other investigations have indicated Wilson’s disease, the ideal test is the removal of a small amount of liver tissue through a liver biopsy. This is assessed microscopically for the degree of steatosis and cirrhosis, and histochemistry and quantification of copper are used to measure the severity of the copper accumulation. A level of 250 ?g of copper per gram of dried liver tissue confirms Wilson’s disease. Occasionally, lower levels of copper are found; in that case, the combination of the biopsy findings with all other tests could still lead to a formal diagnosis of Wilson’s.

In the earlier stages of the disease, the biopsy typically shows steatosis (deposition of fatty material), increased glycogen in the nucleus, and areas of necrosis (cell death). In more advanced disease, the changes observed are quite similar to those seen in autoimmune hepatitis, such as infiltration by inflammatory cells, piecemeal necrosis and fibrosis (scar tissue). In advanced disease, finally, cirrhosis is the main finding. In acute liver failure, degeneration of the liver cells and collapse of the liver tissue architecture is seen, typically on a background of cirrhotic changes. Histochemical methods for detecting copper are inconsistent and unreliable, and taken alone are regarded as insufficient to establish a diagnosis.

Genetic testing
Mutation analysis of the ATP7B gene, as well as other genes linked to copper accumulation in the liver, may be performed. Once a mutation is confirmed, it is possible to screen family members for the disease as part of clinical genetics family counselling

Treatment:
DietaryIn general, a diet low in copper-containing foods is recommended, with the avoidance of mushrooms, nuts, chocolate, dried fruit, liver, and shellfish.

Medication
Various treatments are available for Wilson’s disease. Some increase the removal of copper from the body, while others prevent the absorption of copper from the diet.

Generally, penicillamine is the first treatment used. This binds copper (chelation) and leads to excretion of copper in the urine. Hence, monitoring of the amount of copper in the urine can be done to ensure a sufficiently high dose is taken. Penicillamine is not without problems: about 20% experience a side effect or complication of penicillamine treatment, such as drug-induced lupus (causing joint pains and a skin rash) or myasthenia (a nerve condition leading to muscle weakness). In those who presented with neurological symptoms, almost half experience a paradoxical worsening in their symptoms. While this phenomenon is also observed in other treatments for Wilson’s, it is usually taken as an indication for discontinuing penicillamine and commencing second-line treatment.  Intolerant to penicillamine may instead be commenced on trientine hydrochloride, which also has chelating properties. Some recommend trientine as first-line treatment, but experience with penicillamine is more extensive.  A further agent with known activity in Wilson’s disease is tetrathiomolybdate. This is still regarded as experimental,  although some studies have shown a beneficial effect.

Once all results have returned to normal, zinc (usually in the form of a zinc acetate prescription called Galzin) may be used instead of chelators to maintain stable copper levels in the body. Zinc stimulates metallothionein, a protein in gut cells that binds copper and prevents their absorption and transport to the liver. Zinc therapy is continued unless symptoms recur, or if the urinary excretion of copper increases.

In rare cases where none of the oral treatments are effective, especially in severe neurological disease, dimercaprol (British anti-Lewisite) is still occasionally necessary. This treatment is injected intramuscularly (into a muscle) every few weeks, and has a number of unpleasant side effects such as pain.

People who are asymptomatic (for instance those diagnosed through family screening or only as a result of abnormal test results) are generally treated, as the copper accumulation may cause long-term damage in the future. It is unclear whether these people are best treated with penicillamine or zinc acetate.

Physical therapy
Physiotherapy is beneficial for those patients with the neurologic form of the disease. The copper chelating treatment may take up to six months to start working, and physical therapy can assist in coping with ataxia, dystonia, and tremors, as well as preventing the development of contractures that can result from dystonia.

Transplantation
Liver transplantation is an effective cure for Wilson’s disease, but is used only in particular scenarios because of the numerous risks and complications associated with the procedure. It is used mainly in people with fulminant liver failure who fail to respond to medical treatment, or in those with advanced chronic liver disease. Liver transplantation is avoided in severe neuropsychiatric illness, in which its benefit has not been demonstrated
Lifestyle and home remedies:

Doctors sometimes recommend limiting the amount of copper you consume in your diet during the first year of your treatment for Wilson’s disease. As your signs and symptoms recede and the copper levels in your body drop, you may be able to include copper-containing foods in your diet.

Copper-containing foods
Foods that contain high levels of copper include:

*Copper-containing vitamin and mineral supplements
*Liver
*Shellfish
*Mushrooms
*Nuts
*Chocolate
*Dried fruit
*Dried peas, beans and lentils
*Avocados
*Bran products

Copper in tap water
Have your tap water’s copper levels tested if you have copper pipes in your home or if your water comes from a well. Most municipal water systems don’t contain high levels of copper.

If you have copper pipes, run the tap for several seconds before collecting water for drinking or cooking. Water that sits in the copper pipes can pick up copper particles. Running the water flushes that contaminated water out of the pipes.

Copper pots and pans
Don’t use copper pots, pans or storage containers for your food or drinks.

Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose

Resources:
http://en.wikipedia.org/wiki/Wilson’s_disease
http://www.eurowilson.org/en/living/guide/what/index.phtml
http://www.mayoclinic.com/health/wilsons-disease/DS00411

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Parkinson’s Disease

 

Alternative Names : Parkinson disease, Parkinson’s, idiopathic parkinsonism, primary parkinsonism, PD, or paralysis agitans

Definition:
Parkinson’s disease is the second most common neurodegenerative disorder and the most common movement disorder. It is characterized by progressive loss of muscle control, which leads to trembling of the limbs and head while at rest, stiffness, slowness, and impaired balance. As symptoms worsen, it may become difficult to walk, talk, and complete simple tasks.
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Parkinson’s disease is a progressive disorder of the nervous system that affects movement. It develops gradually, often starting with a barely noticeable tremor in just one hand. But while tremor may be the most well-known sign of Parkinson’s disease, the disorder also commonly causes a slowing or freezing of movement. Many people with Parkinson’s disease live long productive lives, whereas others become disabled much more quickly. Premature death is usually due to complications such as falling-related injuries or pneumonia.

Friends and family may notice that your face shows little or no expression and your arms don’t swing when you walk. Speech often becomes soft and mumbling. Parkinson’s symptoms tend to worsen as the disease progresses.

While there is no cure for Parkinson’s disease, many different types of medicines can treat its symptoms. In some cases,  doctor may suggest surgery.

In the United States, about 1 million people are affected by Parkinson’s disease and worldwide about 5 million. Most individuals who develop Parkinson’s disease are 60 years of age or older. Parkinson’s disease occurs in approximately 1% of individuals aged 60 years and in about 4% of those aged 80 years. Since overall life expectancy is rising, the number of individuals with Parkinson’s disease will increase in the future. Adult-onset Parkinson’s disease is most common, but early-onset Parkinson’s disease (onset between 21-40 years), and juvenile-onset Parkinson’s disease (onset before age 21) also exist.

Descriptions of Parkinson’s disease date back as far as 5000 BC. Around that time, an ancient Indian civilization called the disorder Kampavata and treated it with the seeds of a plant containing therapeutic levels of what is today known as levodopa. Parkinson’s disease was named after the British doctor James Parkinson, who in 1817 first described the disorder in great detail as “shaking palsy.”

Symptoms:
The symptoms of Parkinson’s disease can vary from person to person. Early signs may be subtle and can go unnoticed. Symptoms typically begin on one side of the body and usually remain worse on that side even after symptoms begin to affect both sides.

Parkinson’s signs and symptoms may include:

*Tremor. The characteristic shaking associated with Parkinson’s disease often begins in a hand. A back-and-forth rubbing of your thumb and forefinger, known as pill-rolling, is common, and may occur when your hand is at rest. However, not everyone experiences tremors.

*Slowed motion (bradykinesia). Over time, Parkinson’s disease may reduce your ability to initiate voluntary movement. This may make even the simplest tasks difficult and time-consuming. When you walk, your steps may become short and shuffling. Or your feet may freeze to the floor, making it hard to take the first step.

*Rigid muscles. Muscle stiffness can occur in any part of your body. Sometimes the stiffness can be so severe that it limits the range of your movements and causes pain. People may first notice this sign when you no longer swing your arms when you’re walking.

*Impaired posture and balance. Your posture may become stooped as a result of Parkinson’s disease. Balance problems also may occur, although this is usually in the later stages of the disease.

*Loss of automatic movements. Blinking, smiling and swinging your arms when you walk are all unconscious acts that are a normal part of being human. In Parkinson’s disease, these acts tend to be diminished and even lost. Some people may develop a fixed staring expression and unblinking eyes. Others may no longer gesture or seem animated when they speak.

*Speech changes. Many people with Parkinson’s disease have problems with speech. You may speak more softly, rapidly or in a monotone, sometimes slurring or repeating words, or hesitating before speaking.

*Dementia. In the later stages of Parkinson’s disease, some people develop problems with memory and mental clarity. Alzheimer’s drugs appear to alleviate some of these symptoms to a mild degree.

Causes:
The exact cause of Parkinson’s disease is unknown, but several factors appear to play a role, including:

*Genes. Researchers have found specific genetic mutations that likely play a role in Parkinson’s disease. In addition, scientists suspect that many more changes in genes — whether inherited or caused by an environmental exposure — may be responsible for Parkinson’s disease.

*Environmental triggers. Exposure to toxins or certain viruses may trigger Parkinson’s signs and symptoms.In addition, numerous changes are found in the brains of people with Parkinson’s disease. The role of these factors in the development of the disease, if any, isn’t clear, however. These changes include:

*A lack of dopamine. A substance called dopamine acts as a messenger between two brain areas – the substantia nigra and the corpus striatum – to produce smooth, controlled movements. Most of the movement-related symptoms of Parkinson’s disease are caused by a lack of dopamine due to the loss of dopamine-producing cells in the substantia nigra. When the amount of dopamine is too low, communication between the substantia nigra and corpus striatum becomes ineffective, and movement becomes impaired; the greater the loss of dopamine, the worse the movement-related symptoms. Other cells in the brain also degenerate to some degree and may contribute to non-movement related symptoms of Parkinson’s disease.

Although it is well known that lack of dopamine causes the motor symptoms of Parkinson’s disease, it is not clear why the dopamine-producing brain cells deteriorate. Genetic and pathological studies have revealed that various dysfunctional cellular processes, inflammation, and stress can all contribute to cell damage. In addition, abnormal clumps called Lewy bodies, which contain the protein alpha-synuclein, are found in many brain cells of individuals with Parkinson’s disease. The function of these clumps in regards to Parkinson’s disease is not understood. In general, scientists suspect that dopamine loss is due to a combination of genetic and environmental factors.

*Low norepinephrine levels. People with Parkinson’s disease also have damage to the nerve endings that make another important chemical messenger called norepinephrine. Norepinephrine plays a role in regulating the autonomic nervous system, which controls automatic functions, such as blood pressure regulation.

*The presence of Lewy bodies. Unusual protein clumps called Lewy bodies are found in the brains of many people with Parkinson’s disease. How they got there and what type of damage, if any, Lewy bodies might cause is still unknown.

Risk Factors:
Risk factors for Parkinson’s disease are:

*Age : Age is the largest risk factor for the development and progression of Parkinson’s disease. Most people who develop Parkinson’s disease are older than 60 years years of age.Young adults rarely experience Parkinson’s disease. It ordinarily begins in middle or late life, and the risk continues to increase with age.

*Heredity : Having a close relative with Parkinson’s increases the chances that you’ll also develop the disease, A small number of individuals are at increased risk because of a family history of the disorder. Although your risk is still no more than about 4 to 6 percent.

*Sex: Men are more likely to develop Parkinson’s disease than women are.Men are affected about 1.5 to 2 times more often than women.

*Exposure to toxins: Ongoing exposure to herbicides and pesticides puts you at slightly increased risk of Parkinson’s.Head trauma, illness, or exposure to environmental toxins such as pesticides and herbicides may be a risk factor.
Complications:
Parkinson’s disease is often accompanied by these additional problems:

*Depression:  Depression is common in people with Parkinson’s disease. Receiving treatment for depression can make it easier to handle the other challenges of Parkinson’s disease.

*Sleep problems:  People with Parkinson’s disease often have trouble falling asleep and may wake up frequently throughout the night. They may also experience sudden sleep onset, called sleep attacks, during the day.

*Difficulty chewing and swallowing:  The muscles you use to swallow may be affected in the later stages of the disease, making eating more difficult.

*Urinary problems:  Parkinson’s disease may cause either urinary incontinence or urine retention. Certain medications used to treat Parkinson’s also can make it difficult to urinate.

*Constipation: Many people with Parkinson’s disease develop constipation because the digestive tract works more slowly. Constipation may also be a side effect of medications used to treat the disease.

*Sexual dysfunction:  Some people with Parkinson’s disease may notice a decrease in sexual desire. This may stem from a combination of psychological and physical factors, or it may be the result of physical factors alone.Medications for Parkinson’s disease also may cause a number of complications, including involuntary twitching or jerking movements of the arms or legs, hallucinations, sleepiness, and a drop in blood pressure when standing up.

Diagnosis:
A physician will diagnose Parkinson’s disease from the medical history and a neurological examination.  There is no lab test that will clearly identify the disease, but brain scans are sometimes used to rule out disorders that could give rise to similar symptoms. Patients may be given levodopa and resulting relief of motor impairment tends to confirm diagnosis. The finding of Lewy bodies in the midbrain on autopsy is usually considered proof that the patient suffered from Parkinson’s disease. The progress of the illness over time may reveal it is not Parkinson’s disease, and some authorities recommend that the diagnosis be periodically reviewed.

Other causes that can secondarily produce a parkinsonian syndrome are Alzheimer’s disease, multiple cerebral infarction and drug-induced parkinsonism.  Parkinson plus syndromes such as progressive supranuclear palsy and multiple system atrophy must be ruled out.  Anti-Parkinson’s medications are typically less effective at controlling symptoms in Parkinson plus syndromes. Faster progression rates, early cognitive dysfunction or postural instability, minimal tremor or symmetry at onset may indicate a Parkinson plus disease rather than PD itself.  Genetic forms are usually classified as PD, although the terms familial Parkinson’s disease and familial parkinsonism are used for disease entities with an autosomal dominant or recessive pattern of inheritance.

Medical organizations have created diagnostic criteria to ease and standardize the diagnostic process, especially in the early stages of the disease. The most widely known criteria come from the UK Parkinson’s Disease Society Brain Bank and the US National Institute of Neurological Disorders and Stroke. The PD Society Brain Bank criteria require slowness of movement (bradykinesia) plus either rigidity, resting tremor, or postural instability. Other possible causes for these symptoms need to be ruled out. Finally, three or more of the following features are required during onset or evolution: unilateral onset, tremor at rest, progression in time, asymmetry of motor symptoms, response to levodopa for at least five years, clinical course of at least ten years and appearance of dyskinesias induced by the intake of excessive levodopa. Accuracy of diagnostic criteria evaluated at autopsy is 75–90%, with specialists such as neurologists having the highest rates.

Computed tomography (CT) and magnetic resonance imaging (MRI) brain scans of people with PD usually appear normal.  These techniques are nevertheless useful to rule out other diseases that can be secondary causes of parkinsonism, such as basal ganglia tumors, vascular pathology and hydrocephalus.  A specific technique of MRI, diffusion MRI, has been reported to be useful at discriminating between typical and atypical parkinsonism, although its exact diagnostic value is still under investigation. Dopaminergic function in the basal ganglia can be measured with different PET and SPECT radiotracers. Examples are ioflupane (123I) (trade name DaTSCAN) and iometopane (Dopascan) for SPECT or fludeoxyglucose (18F) for PET. A pattern of reduced dopaminergic activity in the basal ganglia can aid in diagnosing PD

 

Treatment :
There’s no cure for Parkinson’s disease although new research is just starting to suggest that some drugs already used for the condition do have some effect in holding back progression of the disease.

A lot can be done to relieve symptoms, especially in the early stages, by replacing the missing dopamine in the brain. This can be done very effectively with a drug called levodopa – a synthetic chemical that’s converted into dopamine in the brain. However, there can be severe side-effects with prolonged usage.

Because of these problems, doctors usually try to delay using levodopa, especially in younger people. Instead, they use other drugs that boost dopamine activity or mimic its effects, known as dopamine agonists. These drugs also have side-effects and doses have to be carefully tailored to each patient’s needs.

Another option for people with more advanced Parkinson’s is injections of a drug called apomorphine which can ‘rescue’ people from sudden ‘off’ periods (episodes of greatly reduced mobility).

This drug can also be given as a continuous infusion for those with severe movement fluctuations and reduces the dose of levodopa that a person requires.

Occupational therapists and physiotherapists help people manage their condition by assisting with movement and providing advice on how to maintain independence in everyday life. Speech and language therapists help with communication or swallowing difficulties.

Deep brain stimulation is a form of surgery that can be used to treat some of the symptoms of Parkinson’s. A wire with four electrodes at its tip is implanted in one of four target sites in the brain. Then a small unit, which generates electrical signals for the stimulation, is implanted into the person’s chest. When the stimulation is switched on, electrical signals are sent to the brain to stop or reduce the symptoms of Parkinson’s. It’s not suitable for everyone with Parkinson’s, but can provide significant improvement in symptoms and quality of life.

In the future, gene therapy and stem cell therapy may hold some possibility of more effective treatment of Parkinson’s disease.

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Lifestyle and home remedies:
If you’ve received a diagnosis of Parkinson’s disease, you’ll need to work closely with your doctor to find a treatment plan that offers you the greatest relief from symptoms with the fewest side effects. Certain lifestyle changes also may help make living with Parkinson’s disease easier.

Healthy eating
Eat a nutritionally balanced diet that contains plenty of fruits, vegetables and whole grains. These foods are high in fiber, which is important for helping prevent the constipation that is common in Parkinson’s disease. A balanced diet also provides nutrients, such as omega-3 fatty acids, that may be beneficial for people with Parkinson’s disease.

If you take a fiber supplement, such as psyllium powder, Metamucil or Citrucel, be sure to introduce it gradually and drink plenty of fluids daily. Otherwise, your constipation may become worse. If you find that fiber helps your symptoms, use it on a regular basis for the best results.

Walking with care
Parkinson’s disease can disturb your sense of balance, making it difficult to walk with a normal gait.

These suggestions may help:

*Try not to move too quickly.
*Aim for your heel to strike the floor first when you’re walking.
*If you notice yourself shuffling, stop and check your posture. It’s best to stand up straight.

Avoiding falls
In the later stages of the disease, you may fall more easily. In fact, you may be thrown off balance by just a small push or bump.

The following suggestions may help:

*Don’t pivot your body over your feet while turning. Instead, make a U-turn.
*Don’t lean or reach. Keep your center of gravity over your feet.
*Don’t carry things while walking.
*Avoid walking backward.

Dressing
Dressing can be the most frustrating of all activities for someone with Parkinson’s disease. The loss of fine motor control makes it hard to button and zip clothes, and even to step into a pair of pants. An occupational therapist can point out techniques that make daily activities easier.

These suggestions also may help:

*Allow plenty of time so that you don’t feel rushed.
*Lay clothes nearby.
*Choose clothes that you can slip on easily, such as sweat pants, simple dresses or pants with elastic waistbands.
*Use fabric fasteners, such as Velcro, instead of buttons.

Alternative Medications:
Forms of alternative medicine that may help people with Parkinson’s include:

*Coenzyme Q10. People with Parkinson’s disease tend to have low levels of coenzyme Q10, and some research has suggested it may be beneficial. However, subsequent research hasn’t confirmed this benefit. You can buy coenzyme Q10 without a prescription in drugstores and natural food stores. Talk with your doctor before taking this supplement to ensure that it won’t interfere with any medication you may be taking.

*Massage. Massage therapy can reduce muscle tension and promote relaxation, which may be especially helpful to people experiencing muscle rigidity associated with Parkinson’s disease. These services, however, are rarely covered by health insurance.

*Tai chi. An ancient form of Chinese exercise, tai chi employs slow, flowing motions that help improve flexibility and balance. Several forms of tai chi are tailored for people of any age or physical condition.

*Yoga. Yoga is another type of exercise that increases flexibility and balance. Most poses can be modified, depending on your physical abilities.

Prognosis:
PD invariably progresses with time. Motor symptoms, if not treated, advance aggressively in the early stages of the disease and more slowly later. Untreated, individuals are expected to lose independent ambulation after an average of eight years and be bedridden after ten years.  However, it is uncommon to find untreated people nowadays. Medication has improved the prognosis of motor symptoms, while at the same time it is a new source of disability because of the undesired effects of levodopa after years of use.   In people taking levodopa, the progression time of symptoms to a stage of high dependency from caregivers may be over 15 years.  However, it is hard to predict what course the disease will take for a given individual. Age is the best predictor of disease progression. The rate of motor decline is greater in those with less impairment at the time of diagnosis, while cognitive impairment is more frequent in those who are over 70 years of age at symptom onset.

Since current therapies improve motor symptoms, disability at present is mainly related to non-motor features of the disease.Nevertheless, the relationship between disease progression and disability is not linear. Disability is initially related to motor symptoms. As the disease advances, disability is more related to motor symptoms that do not respond adequately to medication, such as swallowing/speech difficulties, and gait/balance problems; and also to motor complications, which appear in up to 50% of individuals after 5 years of levodopa usage. Finally, after ten years most people with the disease have autonomic disturbances, sleep problems, mood alterations and cognitive decline. All of these symptoms, especially cognitive decline, greatly increase disability.

The life expectancy of people with PD is reduced. Mortality ratios are around twice those of unaffected people. Cognitive decline and dementia, old age at onset, a more advanced disease state and presence of swallowing problems are all mortality risk factors. On the other hand a disease pattern mainly characterized by tremor as opposed to rigidity predicts an improved survival. Death from aspiration pneumonia is twice as common in individuals with PD as in the healthy population

Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose

Resources:
http://www.bbc.co.uk/health/physical_health/conditions/parkinsons1.shtml
http://en.wikipedia.org/wiki/Parkinson’s_disease
http://www.medicinenet.com/parkinsons_disease/article.htm
http://en.wikipedia.org/wiki/Parkinson’s_disease
http://www.mayoclinic.com/health/parkinsons-disease/DS00295