text:
Handbook of Genetic Counseling/Alpha 1 Antitrypsin Deficiency

Alpha 1 Antitrypsin Deficiency

Introduction

 * Acknowledge any prior contact
 * Assess concerns and questions they have
 * Explain that their concerns will be addressed

Elicit Medical History

 * Include information about environmental/occupational hazards and smoking

What is Alpha 1 Antitrypsin Deficiency (AAT deficiency)?

 * Alpha-1 antitrypsin deficiency is an inherited disorder that causes low levels of, or no alpha-1 antitrypsin in the blood.
 * Alpha-1 antitrypsin is a protein that is made in the liver. The liver releases this protein into the bloodstream.
 * The deficiency of this protein may predispose an individual to several illnesses
 * The most common illness in adults with alpha 1 antitrypsin deficiency is lung disease during the third and fourth decades of life (and beyond). This is (often) earlier than in those without the deficiency
 * Most commonly it is associated with chronic obstructive pulmonary disease (COPD).
 * COPD is characterized by coughing, shortness of breath, sputum production, rapid breathing, wheezing, and weight loss due to the energy required for labored breathing.
 * COPD includes chronic bronchitis and emphysema
 * chronic bronchitis - inflammation of the lining of the bronchial tubes
 * emphysema - permanent destruction of the alveoli
 * AAT Deficiency is the most common genetic cause of emphysema. It is also the most frequent cause of disability and early death among affected people.
 * AAT deficiency may cause progressive liver damage (cirrhosis) or liver cancer, primarily in those that have a ZZ phenotype.
 * 40-60% of ZZ patients experience liver disease in their lifetime. In infants, it is one of the most common causes for neonatal cholestasis. In a prospective study by Sveger et al in which 200,000 newborns were screened in the 1970's, 127 ZZ newborns were identified that are still followed today.  Their data showed that life-threatening liver disease (over all risk 5%) can occur in the first few months or years of life but that 80% of those individuals are healthy and free of chronic disease by 18 years.
 * Some patients with cirrhosis lead relatively normal lives for relatively long periods of time
 * Some patients have serious liver damage that requires a liver transplant.
 * Less than 3% may develop cancer of the liver.
 * Alpha-1 antitrypsin deficiency is the most common genetic cause of liver disease in children and is the most common genetic disease for which liver transplantation is undertaken in children.
 * Some children show signs of liver failure at birth including jaundice, swelling of the abdomen, and poor feeding
 * In some children, the signs of alpha-1 antitrypsin deficiency do not become apparent until early childhood or adolescence when they may develop hepatitis, enlarged spleen, ascites, pruritus and other signs of liver injury.
 * Only 10-15% of children with alpha-1 antitrypsin deficiency develop liver disease. In some families one child may not show any signs of liver disease whereas a brother or sister may be seriously affected.
 * There is currently no treatment for alpha-1 related liver disease.
 * It is possible to have AAT deficiency without having developed symptoms yet or that has been misdiagnosed. It is possible to have the deficiency and never develop symptoms.  Those with environmental exposures (to lung and/or liver) are more likely to develop symptoms and there is a correlation between environmental exposures and other genetic factors with age of onset and severity.
 * The reasons for the wide variability, from normal life span and normal activity through life, to severe liver or lung disease are largely unknown. There are currently studies underway to understand this.  If you are interested in participating in research, I would encourage you to contact the alpha-1 research registry at 1-877-886-2383.

Who is at risk?

 * An estimated 1 in 1500 to 1 in 7000 people has alpha 1 antitrypsin deficiency world wide and it is found in nearly all populations. In the US about 1 in 4455 has alpha-1(Stoller and Aboussouan, 2012.)
 * It is very rare among people of Asian and African descent.
 * It is most prevalent among people of Northern European (Scandinavian and British) and Iberian (Spanish and Portuguese) descent.
 * 70,000-100,000 people are estimated to be affected in the U.S., and a similar number in Europe are thought to be affected
 * Of the estimated 100,000 in the U.S. less than 10% have been diagnosed
 * It is thought that AAT deficiency is widely underdiagnosed or misdiagnosed as asthma or cigarette smoking induced COPD.
 * Estimated carrier frequencies in the above mentioned at risk populations have been quoted as high as 1:25
 * Research suggests that some carriers may be at increased risk for lung disease at a later age of onset, particularly if they smoke.
 * Other more current research suggests that being a carrier is not a very important determining factor compared to other risks such as smoking.

How does a deficiency lead to lung disease?

 * Alpha-1 antitrypsin protects the lungs against another protein that can harm lung tissue. (It is called neutrophil elastase-- an enzyme released by white blood cells to help fight infections)
 * When the lungs do not have enough alpha-1 antitrypsin, these proteins are free to destroy lung tissue.
 * As a result, the lungs lose some of their ability to expand and contract (elasticity)
 * This leads to difficulty breathing.
 * Destruction of the alveoli can also occur and lead to emphysema
 * The speed at which lung tissue is destroyed varies with each person.
 * It is known that tobacco smoking worsens the lung damage.

How does a deficiency lead to liver disease?

 * Individuals with ZZ type AAT deficiency often do not secrete AAT after it is made by the liver.
 * Some of the AAT is broken down but the portion that is not accumulates in the liver cells.
 * This accumulation is believed to cause damage the liver and lead to cirrhosis.

How is it inherited?

 * Alpha 1 antitrypsin deficiency is an autosomal recessive genetic condition
 * Explain genes and chromosomes
 * Alpha 1 antitrypsin is encoded by a gene (serpina1) located on the distal long arm of chromosome 14.
 * There are at least 120 different variations, or alleles, of the gene that make alpha 1 antitrypsin.
 * We get one copy of this gene from each of our parents
 * The M allele is the most common form (actually there are a group of M alleles along with other very rare normal variants)
 * If a person inherits an M gene from both their parents they will have normal levels of alpha 1 antitrypsin (MM genotype)
 * The Z allele contains a mutation. As a result there is not as much alpha 1 antitrypsin into the blood (~15% of normal amount).
 * The protein formed from the Z allele has a glu changed to a lys
 * This causes misfolding of the polypeptide and polymerization of alpha-1 antitrypsin Z molecules
 * Polymerization of the Z alpha-1 antitrypsin molecules leads to accumulation of abnormal protein in hepatocytes, some of which is subsequently degraded. How and how much gets degraded are largely controlled by epigenetic mechanisms not yet identified but currently being researched
 * When a person inherits the Z gene from both parents they will have very low alpha-1 antitrypsin levels that can lead to tissue damage of the lungs and/or liver disease (ZZ genotype)
 * If a person inherits one M gene and one Z gene they are called a carrier. Although they usually have less alpha 1 antitrypsin in their blood then those with two M genes, they do not usually develop any symptoms because they still have sufficient amounts to protect their lungs. However, it has been shown that smokers that are carriers are at a higher risk for lung disease than the general population, it is therefore recommended that MZ's avoid smoking and working environments that constantly expose the lungs to dust or chemicals.
 * MZ phenotype was associated with an increased prevalence of byssinosis compared with the MM phenotype: 3/8 (38%) and 25/187 (13%). An association between the MZ phenotype and familial allergy was also found, although the association was somewhat weaker.
 * 5% of Scandinavians, 4% of Britons, 1 to 2% of southern Europeans, and 2-3% of the heterogeneous white population in the United States are MZ (carrier) heterozygotes.
 * If both parents are carriers for the Z allele then each pregnancy results in a 25% chance of having a child that will be ZZ and therfore at risk for lung and liver disease
 * The S variant of this gene makes functional alpha 1 antitrypsin, but it is recycled faster and results in about 60% normal amounts secreted into the blood stream.
 * If a person inherits two copies of the S variant then their alpha 1 antitrypsin levels are reduced (slightly higher than the MZ carrier) and they typically don't show any symptoms
 * If a person inherits one S and one Z variant they have a mildly increased risk for lung disease.
 * There is a relatively high frequency of the S allele (0.04-0.08 in U.S. Caucasians). Therefore MS heterozygotes are relatively frequent.
 * 1 in 10 persons of European origin will be heterozygous for either the S or Z variant (MZ or MS genotype)
 * About 5 % of people with alpha 1 antitrypsin deficiency will have other rare allele variants (ex)F, Mmalton, Mheerlen(null), I).
 * In some rare cases, a person's body may not produce any alpha-1 antitrypsin. This condition results from inheriting two genes that produce any functional protein . It is called "null-null type."
 * The null-null phenotype is accompanied by emphysema as are the ZZ and SZ phenotypes but an important difference is that cirrhosis and liver cancer do not occur with the null-null phenotype because there is no abnormal antitrypsin product accumulation.

Who should be tested?

 * The World Health Organization (WHO) recommends that all individuals with COPD as well as adults and adolescents with asthma be tested.
 * Clinical features that suggest the possibility of AAT deficiency and the need for serum testing include emphysema at an early age, emphysema in a nonsmoker (or light smoker), a family history of emphysema, emphysema of the lower lungs (as determined by chest radiograph), adult-onset asthma, and recurrent bronchitis.
 * It is also suggested that testing be done on most patients with chronic or recurrent respiratory symptoms (dyspnea, cough, wheezing) at least once.
 * It has been suggested that carrier screening should be performed on people in high- risk populations.

What is the test?
Lastly, a genotype test typically screens for the S and Z allele (more depending on the lab). Ideally, to have the most accurate diagnosis, the Alpha-1 Antitrypsin Profile will do all 3 (level, phenotype and genotype)
 * It is a simple blood test that can be done on a finger stick or venous blood sample
 * It will determine the amount of AAT in your blood (blood enzyme levels)
 * Serum testing is a screening procedure. Most hospital laboratories report serum AAT levels in mg/dl or g/L, with a normal range from approximately 100-300 mg/dl. Levels less than 58 mg/dL or 11μM suggest severe deficiency. Those that are slightly below normal suggest carrier status, however, often a carrier can have a normal level, so it is important to order a phenotype and/or genotype test in addition to the serum level.
 * Reference laboratories usually report the serum levels in micromolar concentration, with a normal range of 20-60 μM and a threshold level for emphysema at 11 micromol/L.
 * The same blood sample can also be used to determine which type of protein or Pi type (the phenotype) you have by separating the alpha-1 antitrypsin proteins on a gel
 * Therefore the phenotype test can tell you if you are a carrier for one of the genes that causes alpha 1 deficiency
 * The phenotype is usually determined if alpha 1 antitrypsin levels are below 30 micromoles/ liter or if there is a known family history
 * Therefore, to detect all heterozygous carriers it is important to make sure the lab performs phenotype testing.
 * Phenotyping is required to confirm the presence of AAT deficiency. A phenotype should be confirmed with genotype.
 * The phenotype, PiZZ, is responsible for nearly all cases of AAT emphysema and liver disease. PiZZ phenotype serum levels range from 3.4-7 micromol/L, about 10-20% of the normal levels.

Where is testing available?

 * Free (confidential) test kits are available through the Alpha-1 Foundation's Alpha-1 Coded Testing Trial conducted through the Medical University of South Carolina and they take 2-4 weeks for the order to be processed. They test for both levels of protein and genotype. To participate visit their site at www.alphaoneregistry.org or call their Genetic Counselor at 1-877-785-3177 to discuss testing and any questions that you may have.
 * Free genetic screening kits are also available through the drug companies that produce the only treatment specific to alpha-1 antitrypsin deficiency. They are Grifols, CSL Behring and Baxter.  Information may be found online.  Each test is a little different and must be taken to a doctor's office to be completed.
 * Many commercial companies such as LabCorp and Mayo Medical Laboratories also offer alpha-1 testing. I recommend at least a level + genotype or phenotype.  Ideally, the Alpha-1 antitrypsin profile will do the level + phenotype and reflex to a genotype.

Reasons for being tested

 * There are ways to help prevent further tissue damage in the lung such as:
 * receive immunizations for flu and pneumonia
 * receive early treatment for lung infections by seeing your doctor at the first sign of a cold or other lung problem
 * avoid tobacco smoke, noxious fumes, dust, and pollution
 * stay fit by doing regular exercise
 * increase your alpha-1 antitrypsin by protein replacement therapy: intravenous infusion of the purified human alpha-1 antitrypsin protein (augmentation therapy) used to treat patients that are severely deficient.
 * You can also reduce symptoms of shortness of breath by doing the following:
 * using medications (for example, bronchodilators, or inhaled steroids) prescribed by your doctor to help open your airways
 * using oxygen if your doctor prescribes it
 * doing pulmonary rehabilitation (including breathing techniques)

Family planning (knowing risks to future children)

 * As of 1987 prenatal testing is available for fetuses known to be at risk
 * Preimplantation Genetic Diagnosis with IVF is available
 * Gene therapy in the future? Research has been done in mice using gene therapy for AAT deficiency

Possible reasons for not being tested

 * 1)Genetic discrimination- fear of being fired or losing insurance benefits due to a positive genetic test.
 * GINA (genetic information non-discrimination act) went into law in 2008 and protects asymptomatic individuals from discrimination by health insurers and employers. Health insurance is further protected by ACA (Affordable Care Act, 2011).  This does not protect against discrimination for life, long-term care or disability insurance.  I recommend that healthy, asymptomatic individuals consider purchasing before pursuing genetic testing.  For symptomatic individuals it is some what of a moot point as insurance carriers will likely use health information to deny/raise premiums.  Additionally, it does not protect those in the military or work for federal government, although the law is largely observed to this point.
 * There is a reported case where a person lost their job after receiving a bill for treatment procedures in a woman with a positive test for alpha 1 antitrypsin deficiency
 * She was supported by the AlphaNet, the Alpha 1 Association, the Genetic Alliance, the National Partnership for Women and Families and the Coalition for Genetic Fairness
 * She won the right in Nov 2000 to pursue a wrongful discharge law suit.
 * Concerns about this may be avoided by confidential testing
 * 2)Fear of knowing health risks

Other psychosocial issues to consider

 * Anxiety associated with waiting for test results
 * Anxiety and difficult decisions associated with knowing you and/or your partner are carriers and may pass alpha 1 antitrypsin deficiency on to offspring
 * Anxiety that may come if testing positive for AAT deficiency in the absence of present symptoms due to the uncertainty about if, when and how severely one might be affected.
 * May encourage individuals to make healthier life choices


text:
Blender 3D: Noob to Pro/Advanced Tutorials/Advanced Animation/Guided tour/Mesh/env

What is Envelope
Envelope is a new visual tool to help you rig your characters faster and easier. It can often save you a lot of time. Each bone has a special area around it, allowing you to tell Blender what part of the geometry will follow each bone. This zone is customizable so you can move, scale and blend them together.

Edit Envelope
You can edit this white zone in Editmode or posemode by going in Envelope display mode (Buttons Window → Armature  → Display Options  → Envelope), selecting bones and using SKEY or CTRL-ALT-SKEY.

In Editmode: you can select the Tip, the Body or the Root and scale using SKEY. This area in the middle will assign a weight of 1 to all vertices contained in here. All vertices with a weight of 1 will completely follow this bone. The white transparent area around the center is a zone of influence which loses power as you go away from the center. This area is scaled when selecting the body of a bone and doing CTRL-ALT-SKEY. In Posemode: You can only scale the zone of influence with ALT-SKEY when in Envelope display mode. It's real time, and lets you tweak the influence while you animate. So if you notice there is a vertex not following in the new pose you just did: Just select the bone it should follow, and scale the zone a bit until the vertex goes back with his friends. Example:

Envelope Options
It's possible to enable/disable the use of Envelope in the Modifier stack using the "Envelope" toggle.

There are also two important buttons in the Armature Bones panel: Deform and Mult.

Enabling the Deform button will tell Blender to deform geometry with this bone. It's useful because in a more complex rig not all the bones are there to deform, some bones are just there to move other bones.

The Mult option will tell Blender to multiply the weight it gets from envelope (let's say 0.7) with the weight you painted in weight paint (let's say 0.5). The result will be 0.5*0.7=0.35 so in fact you just tweaked the envelope influence to 0.3 when it was at 0.7. If you don't want vertices to be part of the zone, you can always paint it with 0, as 0*(something) will always give 0. This way you can give custom shape to your envelope. More on weight paint on next page.

In this example of a formerly flat surface you can see that all the selected vertices are not following the bone when it is moved upwards. This is because I painted a weight of 0 on them. In weight paint you'll see nothing. But just the fact that they are part of the group with a weight of 0 will make that possible. If Mult is off and you have both a vertex group and envelope, Blender will add value.

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/


text:
Handbook of Genetic Counseling/Alpha Thalassemia

Alpha Thalassemia

 * Hemoglobin is the protein in blood that carries oxygen and gives blood its red color
 * A hemoglobin molecule contains four globin chains
 * There are different types of globin chains
 * One of the chains is designated alpha and the others can be grouped together and called non-alpha
 * The combination of two alpha chains and two non-alpha chains produces a complete hemoglobin molecule
 * The combination of two alpha chains and two gamma chains form "fetal" hemoglobin, termed "hemoglobin F"
 * Fetal hemoglobin is the primary hemoglobin in the developing fetus (With the exception of the first 10 to 12 weeks after conception.
 * The combination of two alpha chains and two beta chains form "adult" hemoglobin, also called "hemoglobin A". Although hemoglobin A is called "adult", it becomes the predominate hemoglobin within about 18 to 24 weeks of birth.
 * Must have the right amount of each type of globin being made if there is an imbalance this will result in thalassemia
 * There are different types of thalassemia
 * The severity and type of thalassemia depends on which genes are affected

Alpha Globin

 * The genes that tell the cell how to make alpha globin are found on chromosome 16
 * Each chromosome 16 has two alpha globin genes that are next to each other on the chromosome
 * Since each cell has two copies of chromosomes 16, a total of four alpha globin genes are usually present in each cell
 * There are several different possible outcomes depending on how many of these copies are not functioning (usually due to being deleted)

Silent Carrier

 * If one of the four copies of the alpha globin gene is not present in an individual they will not have any symptoms because they still make enough alpha globin.
 * This individual is often referred to as a silent carrier

Alpha Thalassemia Trait

 * If two of the genes are not present than the person is said to have the alpha thalassemia trait.
 * Does not cause health problems or symptoms
 * The red blood cells are often small and this is referred to as microcytosis
 * 2 ways of having alpha thalassemia trait which can become important when you want to determine risks to potential children
 * 2 genes on same chromosome not functioning (cis) figure 3
 * 1 gene on each chromosome (trans) figure 4

Hemoglobin H Disease

 * If there are three missing copies of the gene then there is even less alpha globin. This causes Hemoglobin H disease.
 * This causes more serious anemia which often requires transfusions
 * Other symptoms include: jaundice, enlarged spleen, and increased risk of infection
 * Called hemoglobin H disease because of an abnormal hemoglobin that forms from excess beta globin(excess beta globin is present and 4 of these come together instead of having 2 alpha globin chains)
 * Hemoglobin H does not carry oxygen and damages the membrane that surrounds the red cell, accelerating cell destruction.
 * The combination of the very low production of alpha chains and destruction of red cells in hemoglobin H disease produces a severe, life-threatening anemia

HB Bart's Hydrops Fetalis

 * If there are no genes present than the effects are even more serious
 * Often the fetus is stillborn or dies shortly after birth
 * Rarely, problem is detected in utero, if the disorder occurred in an earlier child. In utero blood transfusions have saved some of these children. These patients require life-long transfusions and other medical support.

How does the screening test determine which category a baby fits?

 * Newborn screening test preformed in every US state measures the percentage of different types of hemoglobins. However, not every state newborn screening program tests and reports for alpha thalassemia.
 * Barts hemoglobin consists of 4 gamma globin chains (results from not enough alpha globin to pair up with to form the fetal hemoglobin consisting of 2 alpha and 2 gamma) (gamma globin is no longer made about 18-24 weeks after birth)
 * Depending on how much Barts hemoglobin an infant has will help categorize them
 * Less than 5% -- most likely missing one gene and may be silent carrier
 * 5-10% usually indicates loss of 2 genes and may have alpha thalassemia trait
 * >10% (usually 15-20%) may have Hemoglobin H disease

Testing

 * Testing can be performed to determine the parents' risks for future pregnancies. A primary care physician can order the following blood tests.
 * complete blood count (CBC) - a measurement of size, number, and maturity of different blood cells in a specific volume of blood.
 * hemoglobin electrophoresis with A2 and F quantitation - differentiation of the types of hemoglobin present
 * FEP (free-erythrocyte protoporphyrin) and ferritin - to exclude iron deficiency anemia.
 * The above testing is fairly inexpensive and covered by most types of insurance
 * Gene testing also available, but more expensive and usually not needed. Testing of the alpha globin genes is the only way to determine silent alpha thalassemia trait.
 * FISH can be performed to determine if there is a large deletion on chromosome 16 in the presence of severe developmental delay

Types of mutations

 * Most are deletions of the gene(s)
 * About 5% of alpha thalassemia is due to point mutations
 * Often cause more severe thalassemia than single gene deletions
 * Hemoglobin Constant Spring -- most common point mutation
 * Stop codon mutated results in large alpha globin protein (RNA unstable and little protein is made)
 * Mutations have also been found in regions of DNA that regulate expression of alpha globin gene

Hydrops Fetalis

 * Can be due to a number of different reasons (immune response to blood that is incompatible such as Rh incompatibility or nonimmune hydrops)
 * Nonimmune hydrops includes a number of explanations like cardiovascular, chromosome abnormality, pulmonary infection and homozygous alpha thalassemia (4 copies of alpha globin gene missing has even been seen in some with 3 missing copies)
 * Sometimes the reason can not be determined
 * Treatment for hydrops caused by some is starting to become available
 * Prognosis still is poor

How common is Alpha thalassemia

 * Occurs in people of all ethnic backgrounds
 * More common in Mediterranean, African, and South-east Asian populations
 * Individuals of African descent are more likely to be silent carriers or have alpha thalassemia trait
 * Individuals in Southeast Asia are more likely to have all four possibilities (estimates of carrier frequency are 1/30)
 * Carrier frequency in other populations is not certain

Rare cases of learning difficulties have been associated with alpha thalassemia.

 * Some due to large deletions of chromosome 16 (other genes presumably deleted too that cause learning difficulties)
 * Can also be due to mutation of the ATRX gene(DNA helicase/repair enzyme). This gene is found on chromosome X and is inherited in an X-linked recessive fashion. Individuals with a mutation in ATRX have a condition called Alpha-Thalassemia X-linked Intellectual Disability Syndrome. Symptoms can include: Developmental delay, distinctive facial features, genital anomalies, and anemia secondary to Hemoglobin H disease.

Types of mutations

 * Most are deletions
 * About 5% of alpha thalassemia is due to point mutations
 * Often cause more severe thalassemia than single gene deletions
 * Hemoglobin Constant Spring -- most common point mutation
 * Stop codon mutated results in large alpha globin protein (RNA unstable and little protein is made)
 * Mutations have also been found in regions of DNA that regulate expression of alpha globin gene

Are you planning more children?
A simple blood test can be performed that will detect most types of thalassemia trait
 * May want to consider testing for you and husband in the future so that it can be determined if there are risks for future pregnancies
 * We will have this information in letter so when and if you want to have the testing your physician can order it
 * May be potential risks to _____ offspring
 * Keep this in mind because she may decide with her partner to have him tested

Psychosocial concerns

 * may be nervous and think there is something serious
 * may be a lot of information to understand at once so talk about letter
 * guilt about passing on something
 * concern that other pregnancy with hydrops is related to this
 * help understand that other reasons for hydrops are more likely due to their ethnic background

Websites

 *
 *
 *
 *
 * -- basic information about hemoglobin
 * -- great patient literature


text:
Talk:Statistics/Methods of Data Collection

design a questionnaire

Contents of the page
This page seems unclear to me. I don't know where this classification comes from and I don't understand how Graphical Method can be classified as a method for data collection. It is a way of displaying data but not collect them. PAC2 (talk)

sections
This chapters has three sections : "Experiments", "Sample Surveys" and "observational studies". In my opinion, there is no opposition between those three items. A researcher can design an experiment and collect the information using a sample survey. I think there is an opposition between "experiments" and "observational studies" and another opposition between "sample surveys" and administrative datasets.

PAC2 (talk) 15:27, 23 May 2010 (UTC)

Please keep updating me with any statistical informations in my daily basis on my website as follows: kakwenye@gmail.com.I apreciate your page as it contains usefull informations to as a stundent doing basic statistics.


text:
Handbook of Genetic Counseling/Alport Syndrome

Alport Syndrome

Genetic Etiology

 * Three genes have been associated with Alport syndrome:
 * COL4A3
 * COL4A4
 * COL4A5
 * About 80% of Alport syndrome is caused by mutations in COL4A5 and is X-linked inheritance
 * About 15% of Alport syndrome is caused by mutations in COL4A3 and COL4A4 is autosomal recessive inheritance
 * About 5% of Alport syndrome is caused by mutations in COL4A3 and COL4A4 is inherited in an autosomal dominant manner.

Incidence and carrier frequency

 * Approximately 1 in 50,000 Americans carry the Alport syndrome gene, not all of them get Alport syndrome
 * Twice as many females carry the gene, but a higher percentage of males with the gene have symptoms of the syndrome.
 * There are no racial or geographic concentrations of Alport syndrome
 * Health issues for carriers:
 * About 50% of carriers will have persistent or intermittent microhematuria (small amount of blood in the urine

Risk to various family members

 * Parents of a male proband:
 * The father will not have the disease or be a carrier
 * In a family with more than one affected male, the mother is an obligate carrier
 * In a family with one affected male, the probability the mother is a carrier is 85-90%, chance for a de novo mutation is 10-15%
 * The mother of a male with X-linked Alport syndrome should have a urinanalysis. The presence of microhematuria (blood in the urine too small to be seen by the naked eye) means she is likely a carrier.
 * Siblings of a proband: at conception:
 * If mother is affected:
 * 50% risk of inheriting the mutation
 * males will be affected if they inherit the mutations
 * females will be carriers, may or may not be affected
 * Offspring of a male proband:
 * Will transmit the mutation to all of their daughters and none of their sons

Clinical features
The 3 main findings are renal, cochlear, and ocular involvement.
 * Renal involvement:
 * There is progressive deterioration of the glomerular basement membranes (GBMs), which are microscopic parts of the kidney. This deterioration may lead to chronic renal failure causing excess waste products in the blood (uremia).
 * This kidney malfunction causes the loss of red blood cells and blood plasma proteins in the urine (hematuria, proteinuria).
 * Bleeding into the glomerulus, a bunch of capillaries in the kidney, causes material (including various elements of the blood) to be excreted into the urine.
 * Renal bone disease may occur as a result of renal failure. This can cause:
 * abnormalities of bone
 * abnormalities of calcium, phosphorus, and vitamin D metabolism
 * abnormalities of parathyroid hormone secretion which regulates calcium and phosphate levels in the blood.
 * Uremia (the presence of urea in the blood) can happen when the kidneys fail to remove waste products from the blood. Symptoms include:
 * upset stomach, which may vary from loss of appetite to severe pain
 * nausea
 * vomiting of food and blood
 * weakness
 * fatigue
 * excessive need for sleep
 * dry often itchy skin
 * peculiar-smelling breath similar to urine
 * pale skin
 * shortness of breath
 * hypertension
 * fluid retention
 * swelling (edema)
 * End-stage renal disease (ESRD) is the final stage in chronic renal failure when there is virtually no more functioning nephrons present. Patients with ESRD must depend upon hemodialysis machines to cleanse their blood of waste products.
 * All males with X-linked Alport syndrome develop proteinuria and eventually progressive renal insufficiency, which leads to end-stage renal disease (ESRD).
 * About 60% reach ESRD by age 30 years
 * 90% by age 40 years

Cochlear involvement

 * Diminished hearing is usually detectable by late childhood or early adolescence in boys with XLAS.
 * The hearing loss is progressive and about 80-90% of males with X-linked Alport syndrome have sensorineural deafness by age 40 years

Ocular involvement

 * Abnormalities of the eye may include:
 * The surface of the eye's lens may be cone-shaped (lenticonus) or spherical (spherophakia)
 * The lens of the eye may be opaque or cloudy (cataracts).
 * White dots may appear on the retina (retinal macular flecks or fundus albipunctatis).
 * Children with Alport syndrome may be nearsighted (myopic)

Testing

 * The diagnosis of Alport syndrome is made with the following criteria:
 * history and physical examination, which may include audiologic and ophthalmic evaluation
 * detailed family history and possibly urinalyses on first- and second-degree relatives
 * immunohistochemical analysis of basement membrane type IV collagen expression, using skin and/or renal biopsy specimens
 * examination of renal biopsy specimens by electron microscopy.
 * With these guidelines a suspected diagnosis of Alport syndrome can be confirmed in the great majority of cases, and in most cases the genetic type of Alport syndrome can also be determined.
 * Molecular genetic testing of the type IV collagen gene (COL4A5) implicated in X-linked Alport syndrome and the type IV collagen gene (COL4A3 and COL4A4) implicated in autosomal recessive Alport syndrome is available on a clinical basis
 * detection of mutation >60%
 * Prenatal testing is available for X-linked Alport syndrome

Surveillance, management, and treatment options

 * Chronic renal failure is aggressively treated:
 * Renal function and certain components in the blood are regularly monitored.
 * Fluid intake and diet, particularly salt and protein, may be restricted and regular medications prescribed.
 * Control of blood pressure, prompt and aggressive treatment of urinary tract and ear infections is important.
 * Hemodialysis may be used to treat chronic renal failure and ESRD.
 * Dialysis involves removing blood from the patient's artery, cleansing it of unwanted substances that would normally be excreted in the urine, and returning the cleansed blood to a vein.
 * Kidney transplantation is an alternative treatment. Because of the slight or inapparent disease in some female family members, great care must be taken in selecting living related kidney donors.
 * Hearing loss may stabilize after successful kidney transplantation.
 * Transplantation of the eye's cornea or removal of the eye's lens may be helpful in patients with visual problems.

Differential diagnoses

 * Benign familial hematuria/thin basement membrane disease
 * Fechtner/Epstein syndrome

Psychosocial issues

 * For child: feelings of "being different"
 * Concern and worry over the medical problems and frequent doctor visits
 * Financial considerations, what will treatment cost?
 * Who is their support network?
 * Effects on relationships (parent/child)
 * Concern about telling other family members
 * Future reproductive decisions
 * Possible disruption of marital relationships or family dynamics

Support groups

 * Hereditary Nephritis Foundation
 * 1390 W 6690 S, #202 H
 * Murray UT 84123
 * Phone #: 8012625901
 * e-mail: N/A
 * Home page:

 * National Kidney Foundation
 * 30 East 33rd Street
 * Suite 1100
 * New York, NY 10016
 * Phone: 800-622-9010; 212-889-2210
 * Fax: 212-689-9261
 * Email: info@kidney.org
 *


text:
Handbook of Genetic Counseling/Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS)

What is ALS?

 * a degenerative disease of the nervous system, affecting the brain cells (motor neurons) that carry impulses from the brain and spinal cord to the muscles
 * results in muscular weakness and the progressive wasting of muscles that have lost their nerve supply
 * the most common form of motor neuron disease
 * patients have difficulty speaking, swallowing, and breathing
 * death usually follows within 3 to 5 years
 * onset commonly occurs between the ages of 35 and 65
 * slightly more common in men than in women
 * 5-10% of ALS cases are familial
 * The gene is inherited as an autosomal dominant genetic trait and is located on the long arm of chromosome 21
 * 90% of ALS cases are sporadic, with no obvious genetic cause
 * manifests differently amongst patients, likely due to environmental agents interacting with genetic susceptibility
 * ALS strikes 2 to 7 out of every 100,000 people in the USA
 * no specific treatment yet exists, and patients can be aided only by supportive therapy
 * ALS is also called Lou Gehrig's disease after the baseball star who died of it

Symptoms

 * early symptoms include slight muscle weakness, clumsy hand movements, and/or difficulty performing tasks that require delicate movements of the fingers and/or hands
 * muscular weakness in the legs may cause tripping and falling
 * difficulty swallowing (dysphagia)
 * speech may be slowed
 * progressive weakness of the lips and impairment and/or loss of function of the tongue, mouth, and/or voice box (bulbar symptoms)
 * leg cramps may occur during the night, most frequently in the calf and/or thigh muscles
 * uncontrolled twitching of muscles (fasciculations)
 * exaggerated deep muscle reflexes.
 * severe weight loss occurs in approximately 5% of cases
 * increased risk for respiratory failure and abnormally low levels of oxygen in the blood
 * increased risk for acute inflammation of the lungs, caused by the inhalation of food or stomach contents (aspiration pneumonia).
 * an overall decrease in the ability to move may also result in inadequate nutrition

Resources and Support Groups

 * The ALS Association
 * the only national not-for-profit health agency dedicated to the fight against ALS
 * the mission of The ALS Association (ALSA) is to find a cure for and improve living with amyotrophic lateral sclerosis
 * toll-free information and referral service available to patients, caregivers and family members, staffed by ALSA Patient Service Co-ordinators.
 * 1-800-782-4747 (Monday through Friday 7:30am to 4:00pm PST)
 * to reach ALSA's Patient Services department by e-mail, contact alsinfo@alsa-national.org.
 * Suite 150
 * 27001 Agoura Road
 * Calabasas Hills, CA 91301
 * (818) 880-9007
 *

 * NIH/National Institute of Neurological Disorders & Stroke (NINDS)
 * 9000 Rockville Pike
 * Bethesda MD 20892
 * (301) 496-5751
 * (800) 352-9424

 * ALS Canada:
 * ALS Society of British Columbia:


text:
Handbook of Genetic Counseling/Androgen Insensitivity Syndrome

Androgen Insensitivity Syndrome

Contracting

 * Greet and welcome clients
 * Acknowledge prior contact
 * Thank them for taking time to do the phone intake
 * Acknowledge their previously stated concerns
 * I know you have a lot of questions and concerns and we are going to try and give you as much information as we have regarding this condition/diagnosis
 * Overview of the agenda
 * Since we already have a very detailed medical history, we will talk about family history a little bit
 * Discuss AIS
 * Symptoms
 * Development
 * Inheritance/Recurrence risk
 * Answer any questions
 * Review Intake

Family History

 * I know you main concern is AIS, but while we are taking the family history I am going to be asking a lot of questions about other conditions
 * It is not b/c these things are associated with AIS, this is just to see if there is anything running in your family that we might be concerned about while you are here in genetics
 * Any history of:
 * AIS?
 * Miscarriages, stillbirths, infant deaths?
 * Chromosome abnormalities (like Down syndrome)
 * MR, learning disabilities?
 * Cancer?
 * Heart problems?
 * Hearing or vision problems?
 * Birth defects (ex. CL/P, NTDs)?
 * Metabolic disorders?
 * Unusual facial features?
 * Extra fingers or toes?
 * Consanguinity?
 * Ethnic backgrounds?

Psychosocial Assessment

 * What information have you found out regarding AIS?
 * Where are your main sources of info?
 * Internet, books, media
 * How have you two been dealing with the diagnosis?
 * Who have you been talking to about this besides doctors and other medical professionals?
 * Family
 * Friends
 * Have these people been supportive?
 * What are you planning to tell S about the diagnosis?
 * When will you tell her?
 * Have you sought support from other families with AIS?
 * Are you interested in hearing about support group information?
 * Are your doctors providing you with the information/care that you need?
 * Do you have any concerns about finances?
 * Being able to pay for hormone replacement/surgeries/medical care

Genes & Chromosomes

 * Basics of genes and chromosomes
 * Cells à Chromosomes à Genes
 * 23 pairs of chromosomes, one-copy
 * Karyotype pictures
 * Genetics of AIS
 * "De novo" mutations
 * X-linked Recessive Inheritenace
 * Chromosomes show 46, XY
 * Gene change is on the X chromosome
 * 25% chance with each pregnancy
 * 50% chance with boys

Androgen Insensitivity Syndrome

 * Mode of Inheritance: X-linked recessive
 * Chromosome Location: Xq11-q12
 * Gene: AR gene
 * Gene Product: Androgen receptor
 * Molecular Genetics
 * Sequence analysis available for all three subtypes of AIS
 * >95% detection rate in patients with complete AIS
 * There are normal allelic variants
 * There are pathologic variants
 * At least 150 point mutations in the AR gene cause AIS
 * Majority are missense mutations
 * Impair DNA or androgen binding that cause CAIS or PAIS
 * Point mutations in exon one are relatively infrequent
 * Also small deletions or insertions that cause frameshifts can cause CAIS
 * Prevalence
 * 2-5/100,000 for CAIS
 * PAIS about as common as CAIS
 * Clinical Features
 * Subdivisions of 3 phenotypes
 * Complete AIS (CAIS)
 * Partial AIS (PAIS)
 * Mild Androgen Insensitivity (MAIS)
 * Diagnosis
 * CAIS diagnosed clinically and with lab findings
 * PAIS and MAIS may require a family history/X-linked inheritance
 * General Clinical Features
 * Absence of extragenital abnormalities
 * Two nondysplastic testes
 * Absent or rudimentary mǘllerian structures (i.e. no fallopian tubes, uterus, or cervix) and presence of a short vagina
 * Undermasculinization of the external genitalia at birth
 * Impaired spermatogenesis and/or somatic virilization at puberty
 * CAIS
 * Absent OR rudimentary wolfian duct derivatives
 * Inguinal OR labial testes, short, blind-ending vagina
 * Scant OR absent pubic AND/OR axillary hair
 * PAIS (3 categories)
 * Predominantly Female (incomplete AIS)
 * Inguinal OR labial testes
 * Clitomegaly and labial fusion
 * Distinct urethral and vaginal openings OR a urogenital sinus
 * Ambiguous
 * Microphallus with clitoris-like underdeveloped glans; labia majora-like bifid scrotum
 * Descended OR undescended testes
 * Perineoscrotal hypospadias OR urogenital sinus
 * Gynecomastia
 * Predominantly male
 * Simple (glandular or penile) OR severe isolated hypospadias with a normal-size penis and descended testes OR severe hypospadias with micropenis, bifid scrotum, and either descended OR undescended testes
 * Gynecomastia in puberty
 * MAIS
 * Male (undervirilized male syndrome)
 * Impaired spermatogenesis AND/OR impaired pubertal virilization
 * Gynecomastia in puberty

Testing
 * Laboratory findings needed for diagnosis
 * 46,XY karyotype
 * Evidence of normal or increased synthesis of testosterone (T) by the testes
 * Evidence of normal conversion of testosterone to dihydrotestosterone (DHT)
 * Evidence of normal or increased luteinizing hormone (LH) production by the pituitary gland
 * Evidence of deficient or defective androgen-binding activity of genital skin fibroblasts
 * Family History
 * Diagnosis of PAIS and MAIS may require a family history of the condition with X-linked recessive inheritance
 * Carriers may have asymmetric distribution and sparse or delayed growth of pubic and/or axillary hair
 * Carriers may also have a history of late (15 yrs) or delayed (16 yrs) menarche
 * Molecular genetic testing
 * Greater than 90% of patients with CAIS have an identifiable disease-causing mutations in the AR gene
 * Fewer than 50% of patients with PAIS have identifiable disease-causing mutations in the AR gene
 * Sequence analysis is currently available clinically in USA and Canada
 * Sequencing if eight exons is performed
 * >95% detection rate in patients with CAIS
 * Linage analysis
 * Not clinically available
 * Testing Laboratories
 * All Children's Hospital
 * Molecular Genetics Laboratory
 * St. Petersburg, FL
 * email: muellert@allkids.org
 * phone: (727) 892-8985
 * fax: (727) 892-8367

 * Test performed
 * Diagnostic direct mutation analysis
 * Sequence analysis is performed for the entire coding region of the androgen receptor (AR) gene associated with complete, partial and mild androgen insensitivity syndromes.
 * Specimen requirements
 * In most cases, a single tube of 4 cc whole blood collected in EDTA [lavender top] tubes is sufficient. Minimum specimen on infants is 0.5 cc EDTA whole blood.
 * Turn around time
 * Most testing is completed within a target turn-around time of 21 days following specimen receipt. Test results are phoned in or faxed, as requested, in addition to the written report
 * GeneDx, Inc
 * Gaithersburg, MD
 * email: cheryl@genedx.com
 * phone:(301) 519-2100 ext103
 * fax: (301) 519-2892

Test performed

 * Direct mutation analysis
 * Mutations in the X-linked AR gene are identified by complete sequence analysis of each of 8 AR exons and intron/exon boundaries. The analysis is done on genomic DNA obtained from buccal swabs. Prenatal diagnosis is available once the mutation in a family has been defined.

Specimen requirements

 * Prefer buccal swabs

Turn around time

 * ~6 weeks
 * For prenatal diagnosis where mutation is known: ~2 weeks
 * Costs
 * Mutation detection requires an affected individual and costs $1500
 * DNA testing of relatives for a known mutation is $350
 * Prenatal diagnosis $700 plus any additional cost for ruling out maternal contamination of fetal sample
 * Management
 * Modalities
 * Surgery
 * Psychological Support
 * Hormone replacement or supplementation
 * CAIS
 * Removal of testes
 * Estrogen replacement therapy to initiate puberty, maintain feminization, and avoid osteoporosis
 * PAIS and predominantly female genitalia
 * Prepubertal gonadectomy
 * Psychological support
 * HRT
 * PAIS and ambiguous genitalia
 * Sex assignment in infancy
 * Reconstructive surgeries
 * After puberty, surgery to correct gynecomastia if necessary
 * Androgen replacement therapy to maintain libido
 * MAIS
 * Reduction mammoplasty for gynecomastia
 * Trial of androgen pharmacotherapy to improve virilization
 * Differential Diagnosis
 * Hypospadias not resulting from AR gene mutations
 * MAIS sue to point mutations of the androgen receptor gene
 * Undermasculinization of the external genitalia and pubertal undervirilization are components of many syndromes unrelated to AIS

Prenatal Options

 * Prenatal Diagnosis
 * Can look for complete AIS with direct DNA squencing for mutations
 * To prepare for birth of another baby with AIS or to consider termination
 * Can be done with CVS or with Amniocentesis
 * Preimplantation genetic diagnosis
 * Analyzes eggs prior to implantation to find out sex
 * Daughters are not affected with AIS

Conclusions

 * Review what was discussed in the session
 * Answer any final questions
 * Give resource information and phone number


text:
Handbook of Genetic Counseling/Anencephaly

Anencephaly

Introduction

 * Introduce myself
 * Ask how she is, what she knows, what questions she has. Ask if there is anyone she wants to be with her as she hears information about the baby.

Contracting

 * Go over a few of the things we talked about on the phone: pregnancy and family history
 * Talk about what the ultrasound findings mean
 * Talk about the amniocentesis
 * Talk about other options
 * Along the way, I want to make sure we answer all the questions you may have.

Basic info. on Anencephaly

 * write it down
 * Introduce it through the words of the doctor: absence of the cranial vault.
 * Definition: without brain. There's been a problem in the development of the brain structures. There is an absence of the bones that form the cranial vault (the part that covers our brain)and in the formation of the actual parts of the brain themselves. So what you feel when you put your hand on top of your head is not there. The skin is not there nor is the bony part. Only exposed brain or nothing at all.
 * Incidence: gets lumped in with the Neural tube defects: spina bifida too = 1/1000
 * Recurrence risks: for having another child once a sibling has it = 2.2% (Hall and Solehdin 1998). Most people quote a 3-5% risk.
 * Females are affected 4 times more often than males
 * Related abnormalities associated with anencephaly (PROBABLY NOT USED IN COUNSELING UNLESS THE FINDINGS ARE MADE) - just mention the starred ones.
 * broad nose
 * folded ears
 * short neck
 * large thymus
 * small adrenal glands
 * often polyhydramnios
 * lungs are hypoplastic *
 * can have Cleft lip and palate
 * cyclopia
 * syndactyly
 * absent radius and thumbs
 * clubfoot
 * imperforate anus
 * hernia
 * renal and cardiac anomalies*

Etiology of Anencephaly

 * During the 3rd week after conception the neural folds start to form into what is going to become the spinal cord and the brain. It starts in a central area and then follows particular steps until the entire length of the cord is closed by the 4th week. (the is the 1st and 2nd week after your last menstrual period.) Once it is closed, the brain starts to form all of its distinct parts.
 * Anencephaly is the result of the failure of the anterior neuropore (upper area of the first portion of the spinal column) to close properly. Failure to close = degeneration of the already forming forebrain.

Causes of Anencephaly

 * Multifactorial - 70-80% (combination of genetic factors and the environment) WE DON'T REALLY KNOW exact causes.
 * Single gene changes ex = Meckle Gruber syndrome (will have additional ultrasound anomalies)
 * Chromosomal changes = ex. Trisomy 18, 5p+, ring 13, Trisomy 20p - detectable by amniocentesis
 * Teratogens
 * hyperthermia
 * insulin dependent diabetes
 * seizure disorder medications = Tegretol, valproic Acid (usually associated with SB)
 * Exposures to lead
 * Lack of folic acid

Diagnosis

 * High AFP from triple screen leads to an ultrasound
 * Ultrasound finding is typically the absence of the cranial vault can be done early in 2nd trimester. (>99%) You can still see an outline of the brain but by 17 weeks, it has deteriorated because of exposure to amniotic fluid.
 * You can see it as early as 11 weeks. the brain has a weird outline, abnormally shaped.
 * Amniocentesis with AchE if desired. (>99%)

Prognosis

 * Poor prognosis
 * ~26% have polyhydramnios during the pregnancy.
 * ~7% die in utero.
 * ~34% are born prematurely.
 * ~50% make it to term.
 * ~20% of deliveries end in stillbirth.
 * ~72% are liveborn.
 * Out of the liveborn babies, ~67% die within 24hrs and most of them do not survive past 28 days.

Options

 * Termination by D&E (Dilatation and Evacuation)
 * Can be done up to 24 weeks legally. (Up to 21 weeks here at Univ.)
 * Cost - in hospital = $2500, clinic = less money
 * Have to give pamphlet - WARN HER IF THIS IS SOMETHING SHE WANTS. Remind her that these are pictures of a healthy baby, not what her baby looks like.
 * First step is going in and talking to the doctor
 * Next step is getting lamineria (seaweed dried that will dialate the cervix) = cramping
 * Go Home
 * Come back into office get general anesthesia
 * Take out laminaria
 * Use tubes to finish dilating
 * Suction out amniotic fluid
 * Use forceps to cut umbilical cord
 * Pull out fetal parts
 * Scrape out remainder.
 * Benefits: quick!! Takes only 30sec-5min., outpatient basis, no impact on future fertility.
 * Disadvantages: can't hold or see baby as a baby, no autopsy possible
 * Complications possible: death, hemorrhage, tear in uterus, infection leading to septic shock
 * Ideas: get ultrasound pictures, name baby, keep a journal, write a letter to the baby, make a memorial/service to the baby
 * Termination by induction
 * Between 13-24th week
 * First meet with doctor and see book
 * Lamaria will be placed, go home
 * Enter hospital and start IV
 * Given prostaglandin either suppositories every 3-4 hours, injection into amniotic fluid, or intramuscularly to start uterine contractions. (causes flu like symptoms)
 * Takes 10-20 hours or up to 72 (you are going into labor)
 * You are on the floor with other families delivering healthy babies (nurses attitudes may be different.)
 * You have to deliver placenta right after = may need curettage suction. = you may not get to hold the baby right away.
 * Benefits: you get to see and hold your baby in one piece.
 * Disadvantages: not easy to get done, takes a long time, baby may be alive when you deliver it.
 * Ideas: pictures, baptism, autopsy, footprints, memorial service, other family members can see the baby.
 * Resource: Hand out: We've Been There, Support for Prenatal decision
 * Things to consider after termination
 * Breast milk may come = wear a tight bra and apply cold compresses.
 * Bleeding for 1-2 weeks after delivery and mild cramping. You should rest for a week.
 * A Time to Decide, A Time to Heal - for parents making difficult decisions about babies they love by Molly Minnick, Kathleen Delp, Mary Ciotti
 * Maintain pregnancy
 * Keep a watch on pregnancy...polyhydramnios may be present
 * Prepare for intermittent periods of stable cardiorespiratory function. (a lot of up and down)
 * Prepare family members
 * Contact Starshine Hospice?
 * Contact Fernside for son?
 * Prepare funeral arrangements (in hospital/out of hospital)
 * Good resource is: 1-888-206-7526 - Anencephaly support group
 * Good resource: Your baby has a problem by Janet Ulm and Vickie Hannig
 * Good resource is:
 * Maria La Fond: President, Abiding Hearts, found at P.O. Box 904 Libby, MT 59923 PH: 406-293-4416 FAX:406-587-7197 E-mail: hearts@lclink.

 * Resources to help make the decision
 * Two parents, who had to make the decision, Ms. Fredis chose to terminate, Ms. Crabbis chose to maintain. Here are their phone numbers if you would like to talk with them.
 * Family members, husband, church, etc.
 * Counseling issues
 * How are you feeling right now?
 * Support systems
 * Things you will want to think about:
 * After the death, funeral issues
 * Can you get time off work?
 * Monetary expenses
 * Go home and discuss with your husband. Think about it and give me a call back. If I haven't heard from you in a week, I will call you to check back in.
 * How will you tell your family?
 * How will you tell your friends/people who knew you were pregnant?
 * Grief issues: feelings of guilt, anger, suicide, sadness, etc. Refer to counseling if necessary.


text:
Handbook of Genetic Counseling/Angelman Syndrome-1

Angelman Syndrome              MIM#105830

Etiology

 * Neurobehavioural disorder caused by deficient expression or function of E6AP ubiquitin protein ligase 3A (UBE3A gene product)
 * Due to loss of maternal imprinting in 15q11-q13 region (AS/PWS region) by one of several mechanisms (patients are divided into classes I-V based on these mechanisms):
 * I. Interstitial deletion of the region on copy of chromosome 15 inherited maternally (~4 Mb) (65-75%)
 * II. Paternal uniparental disomy (UPD) - father contributes both copies (3-7%)
 * III. Imprinting defects (2-6%)
 * IV. Mutation in the UBE3A gene (5-11%)
 * V. Unknown mechanisms (11-20%)
 * Patients with deletions usually more severely affected
 * Affects 1 in 12,000 - 40,000 in population
 * The sister syndrome, known as Prader-Willi syndrome, is caused by the loss of the paternally-imprinted copy of the same region. The symptoms are quite different.
 * There are recent data showing that artificial reproductive technology (mainly intraspermal sperm injection) interferes with establishment of imprint and presispose to imprinting disorders (e.g.: AS/PWS, Beckwith-Wiedemanm syndrome(BWS))

Clinical features

 * Key findings (~100%)
 * Severe developmental delay by 6-12 months without loss of skills
 * Speech impairment (no or minimal use of words)
 * Movement or balance disorder (gait ataxia, tremulous movement of limbs, hypermotoric behaviour)
 * Happy demeanor ("happy puppet"), excitability + hand flapping + inappropriate laughter, short attention span
 * Common findings (80%)
 * Delayed or disproportionately slow growth in head circumference
 * Seizures (usually before age 3)
 * Abnormal EEG (large amplitude slow spike and triphasic waves)
 * Associated findings (20-80%)
 * Flat back of head
 * Strabismus
 * Hypopigmentation of skin and eyes
 * Tongue thrusting, sucking/swallowing disorders, excessive chewing and mouthing behaviors
 * Feeding problems during infancy
 * Wide mouth, wide-spaced teeth, prominent mandible (prognathia)
 * Hyperactive tendon reflexes
 * Sleep disorders
 * Uplifted flexed arms while walking
 * Increased sensitivity to heat
 * Sleep disturbance
 * Fascination with water

Diagnostic testing

 * DNA methylation analysis
 * Most sensitive test (identifies 80% of cases)
 * Detects deletions, uniparental disomy, and imprinting defects - such patients will have only unmethylated SNRPN (small nuclear ribonuclear protein-associated polypeptide N) alleles (normally would be one maternal methylated and one paternal unmethylated)
 * FISH
 * Performed if DNA methylation analysis is positive to look for deletion in 15q11-q13
 * May do FISH testing first for children over 5 years of age with classical symptoms and hypopigmentation
 * DNA polymorphism analysis
 * Can distinguish between uniparental disomy and imprinting defects
 * Used if FISH analysis is normal but DNA methylation is positive
 * UBE3A sequence analysis
 * Performed if DNA methylation analysis is normal
 * Identifies UBE3A mutations not detected by other methods
 * High resolution chromosome analysis
 * Can detect rare chromosomal rearrangement that will alter recurrence risk
 * Should be performed for all patients
 * EEG (electroencephalography)
 * 2-3 Hz large-amplitude slow waves
 * normal EEG does not exclude diagnosis

Diagnosis

 * Combination of clinical features, molecular genetic testing, and cytogenetic analysis
 * Unique clinical features not apparent until about 1 year old
 * Developmental delay first noted at 6 months
 * Can take several years until diagnosis is apparent

Differential diagnosis

 * Prader-Willi syndrome
 * Also has deletion in 15q11-q13
 * Distinguished by parent-specific methylation studies
 * Inborn error of metabolism or oxidative phosphorylation ruled out by testing
 * Rett syndrome (in females)
 * Rett syndrome patients do not have characteristic happy personality
 * Angelman syndrome does not cause neurological regression
 * Mowat-Wilson syndrome
 * typical dysmorphic face pattern
 * 22q13 deletion
 * X-linked alpha-thalassaemia/mental retardation syndrome (ATR-X) (in males)
 * small triangular nose + tenting of the upper lip

Risk for family members

 * Risks to siblings depends on genetic cause of syndrome
 * 3-5 MB deletion
 * Sibling risk <1%
 * Mothers should have chromosomal analysis to look for balanced translocation
 * Unbalanced chromosomal translocation or inherited small interstitial deletion
 * Sibling risk as high as 50%
 * Depends on whether rearrangement is inherited or de novo
 * Paternal uniparental disomy
 * Sibling risk <1% if no translocation
 * Risk 100% if father has 15;15 Robertsonian translocation
 * Fathers should have chromosomal analysis
 * Imprinting defect
 * Sibling risk 50% for defect in imprinting center if mother also has defect in imprinting center
 * Risk about <1% if imprinting defect does not involve deletion of imprinting center
 * UBE3A mutation
 * Sibling risk as high as 50% if mother also has a mutation
 * Can also be de novo mutation
 * "Other" mutations
 * Most cases are not familial
 * Risk may be as high as 50%
 * Prenatal testing
 * High risk
 * Includes:
 * Parents with one child with AS caused by deletion or uniparental disomy for reassurance
 * Parents with one child with AS caused by a UBE3A mutation even if mother has tested negative for the mutation as she may be mosaic
 * Testing for an inherited translocation involving chromosome 15 by FISH, DNA methylation, or polymorphism analysis (parent-of-origin studies)
 * Should only be done once genetic cause of syndrome has been established
 * Amniocentesis or CVS
 * Genetic alterations in 15q11-q13 detected by FISH/chromosomal analysis and/or DNA testing
 * Low risk
 * No family history of Angelman syndrome
 * Should be considered in several cases
 * If cytogenetic studies from CVS or amniocentesis indicate 15q11-q13 deletion, FISH or parent-of-origin studies can be done
 * If trisomy 15 or mosaic trisomy 15 is detected on CVS but amniocentesis reveals 46 chromosomes, parent-of-origin studies can be done
 * If de novo translocation of chromosome 15 or dicentric chromosome 15 marker is detected, FISH and parent-of-origin studies can be considered

Management

 * Multidisciplinary child development team care
 * Seizures treated with anticonvulsant medications
 * Developmental delay requires educational training and therapy
 * Physical therapy
 * Occupational therapy
 * Speech therapy focusing on non-verbal methods of communication
 * Picture cards or communication boards
 * Sign language
 * Individualized education program
 * Hyperactivity
 * Behavioral modification effective to prevent disruptive or dangerous behaviors
 * Some may benefit from use of stimulant medications (Ritalin)
 * Sleep disorders may require sedative or administration of melatonin before bed
 * Feeding problems may require special strategies to deal with weak sucking or gastroesophageal reflux
 * Strabismus needs surgical repair
 * Orthotic bracing or surgery for orthopedic problems
 * Scoliosis may require bracing or surgical rod stabilization
 * Dietary monitoring if excessive appetite

Psychosocial/genetic counseling issues

 * Family reaction: guilt, sadness, anger, fear, denial, shock, relief
 * Financial pressures
 * Lifelong management
 * Concerns about future pregnancies

Support information

 * Angelman Syndrome Foundation,
 * Angelman Syndrome Support Education and Research Trust

Resources

 * GeneClinics. "Angelman Syndrome" Web:
 * ORPHANET
 * European Directory of DNA Diagnostic Laboratories
 * NCBI Genes and Disease Webpage
 * GeneImprint


text:
Handbook of Genetic Counseling/Angelman Syndrome-2

Angelman Syndrome

Introduction

 * Introduce myself
 * What are the major concerns that you would like to have addressed today?
 * Who referred you to genetics?
 * Outline session
 * obtain medical history and family history
 * Dr. Saal will come in and do physical exam
 * discuss condition and testing options
 * address specific concerns

Medical History

 * complete intake
 * seizures?
 * medications?
 * sleeping patterns?
 * communications skills?
 * hyperactivity?
 * developmental assessment?
 * services received?
 * unusual behaviors? laughter? generally happy?
 * problems with balance? walking?
 * MRI?
 * complete pedigree

Incidence

 * 1/12,000-1/20,000

Clinical Features

 * Feature present in about 100% of patients
 * normal prenatal and birth history
 * normal birth weight and head circumference
 * no major birth defects
 * normal metabolic and hematologic profile
 * structurally normal brain on MRI
 * mild cortical atrophy or dysmyelination possible
 * delayed motor development
 * apparent by 6-12months
 * usually severe
 * speech impairment
 * usually < 1 or 2 words
 * receptive language better than expressive language
 * movement and balance disorder
 * abnormal gait
 * tremulous movements of limbs
 * Unusual behaviors
 * Frequent laughter and smiling/happy demeanor
 * Excitability
 * Hyperactivity
 * Short attention span
 * Features Present in more than 80% of patients
 * Microcephaly
 * caused by delayed head growth
 * present by age 2
 * Seizures
 * Beginning by age 3
 * Abnormal EEG
 * Characteristic large amplitude slow-spike waves
 * Features found in 20-80% of patients
 * Strabismus
 * Hypopigmentation of skin and eyes
 * Feeding problems in infancy
 * Wide mouth, wide spaced teeth
 * Increased sensitivity to heat
 * Sleep disturbances

Management

 * Behavioral modification for undesirable/socially unacceptable behaviors
 * Medication for seizures
 * Generally do not receive medication for hyperactivity
 * Occupation therapy for fine motor control
 * Speech therapy focusing on nonverbal means of communication
 * Safe, confining bedroom for nighttime sleeplessness
 * Monitoring for onset of scoliosis

Genetics

 * Caused by loss of maternal contribution of region 15q11-q13
 * 65-75% of patients have 3-5Mb interstitial deletion
 * 3-7% of patients have paternal uniparental disomy
 * 2-6% of patients have imprinting defect
 * 5-11% of patients have mutations in the UBE3A gene within this region
 * 11-20% of patients have another unknown cause

Molecular Testing

 * DNA methylation analysis
 * 78% of patients with a deletion, uniparental disomy, or an imprinting defect are detected this way
 * further testing is required to distinguish between these types
 * FISH analysis can detect deletions (70% of patients)
 * DNA polymorphism testing can detect uniparental disomy
 * Patients with imprinting defects have 15q11-q13 polymorphisms from both parents
 * imprinting center defect characterization available on research basis only
 * UBE3A mutation analysis
 * 11% of patients with Angelman syndrome have identifiable mutations

Recurrence Risks

 * Families Genetic Mechanism Risk to Siblings
 * 65-75% 3-5Mb deletion <1%
 * <1% unbalanced translocation as high as 50%
 * small interstitial deletion
 * 3-7% paternal uniparental disomy <1%
 * <1% uniparental disomy with approaching 100% Robertsonian translocation
 * 1-3% imprinting defect as high as 50% (if deletion in imprinting center mother has deletion)
 * 1-3% imprinting defect likely <1% without deletion
 * 11% UBE3A mutation as high as 50% if mother has deletion
 * 10-15% other unidentifiable cause most cases not familial (but could be as high as 50%)

Psychosocial Issues

 * Who is involved in care of patient?
 * What is the living situation?
 * How will having a diagnosis change care and management?
 * How will having a diagnosis affect you?
 * Are there concerns about recurrence risks?


text:
Handbook of Genetic Counseling/AR Sensorineural Hearing Loss (DFNB1/Connexin 26)

AR Sensorineural Hearing Loss (DFNB1/Connexin 26)

Introduction

 * Acknowledge prior phone contact
 * What information have you been given already?
 * Have you done any research on your own? What have you found out?
 * What concerns or questions would you like to have answered today?
 * Outline session

Prevalence

 * DFNB1 accounts for 50% of AR sensorineural hearing loss
 * Prevalence is ~14/100,000
 * 1/2000 congenital hearing impairment
 * 70% of these are nonsyndromic
 * 80% of nonsyndromic hearing loss is AR
 * 50% of these are due to GJB2 mutation
 * 1/30 people in general population are carriers

Genetics

 * Gene: GJB2
 * Chromosome location: 13q11-12
 * Protein: Connexin 26
 * Gap junction protein
 * Involved in conducing signal to the brain
 * Autosomal recessive inheritance
 * 25% risk of hearing loss for future children
 * 50% risk of being a carrier for the mutation
 * 25% risk of being an unaffected noncarrier

Molecular Testing

 * Detects 95% of disease-causing mutations
 * ~66% of mutations - 35delG
 * ~30% of mutations - other GJB2 mutations
 * ~4% mutations - unknown
 * carrier testing is available and can be offered to at-risk family members
 * prenatal testing is available but rarely pursued

Clinical Features

 * nonprogressive sensorineural hearing impairment
 * severe to severe-profound hearing loss
 * diagnosed by Auditory Brainstem Response or pure tone audiometry and presence of no related anomalies
 * no other associated health problems
 * no balance problems

Management

 * When diagnosis is known or suspected
 * Assessment of auditory acuity by ABR or pure tone audiometry
 * Fitting with hearing aids
 * Early intervention
 * Follow-up care
 * semiannual examination by physician familiar with hereditary hearing impairment
 * repeat pure tone audiometry to confirm stability of loss
 * consideration for cochlear implants

Psychosocial Issues

 * Deaf child born to hearing parents
 * How did you feel when you first found out?
 * How have your feelings changed?
 * How have other family members reacted?
 * Have you been in contact with any other families?
 * Have you been in contact with any support groups?

Resources

 * American Society for Deaf Children
 * PO Box 3355
 * Gettysburg, PA 17325
 * Phone: 717-334-7922
 * Fax: 717-334-8808
 * Email: ASDC1@aol.com
 *

 * National Association of the Deaf
 * 814 Thayer
 * Silver Spring, MD 20910
 * Phone: 301-587-1788
 * Fax: 305-587-1791
 * Email: NADinfo@nad.org
 *


text:
Handbook of Genetic Counseling/Arthrogryposis

Arthrogryposis

Contracting

 * Acknowledge prior phone contact
 * What questions or concerns would you like to address today?
 * Overview of agenda for the session

Intake and Family History

 * Pregnancy and medical history
 * Maternal fever or viruses during pregnancy?
 * Oligohydramnios or unusually shaped uterus? (Crumply ears, thin or hyperextensible skin?)
 * Was the baby active throughout the pregnancy?
 * Any problems with hands, wrists, elbows, shoulders, knees, jaw, or back?
 * Any muscle weakness or hypotonia?
 * Has she had any muscle biopsies or other blood tests to rule out possible disorders?
 * Family history
 * Anyone else with club foot, joint dislocations, scoliosis?
 * Individuals who are short in stature?
 * Anyone with any muscular dystrophy, muscle disease, muscle weakness?
 * Anyone with cleft lip and/or palate, hearing loss, mental retardation?

Etiology

 * Condition describing the presence of multiple joint contractures at birth
 * Joint contractures are limitations in the range of motion of joints
 * May affect few or all joints to varying degrees
 * Includes hands, wrists, elbows, shoulders, hips, feet, and knees
 * Severe cases may include the jaw and back
 * Can be caused by anything that prevents normal joint movement before birth
 * When joint is not moved, extra connective tissue may grow around it and fix it in position
 * Tendons connecting to joint not stretched to normal length, making joint movement difficult
 * Four possible reasons for limitation of joint movement prenatally
 * Muscles do not develop properly (atrophy)
 * Muscle diseases, including congenital muscular dystrophies
 * Maternal fever during pregnancy
 * Viruses that damage cells transmitting nerve impulses to muscle
 * There is not sufficient room in the uterus for normal movement
 * Oligohydramnios
 * Abnormally shaped uterus that causes crowding
 * Central nervous system or spinal cord malformations
 * Tendons, bones, joints, or joint linings don't develop properly
 * May be environmental or genetic depending on cause of contractures
 * Genetic cause identified in about 30% of cases
 * Incidence is about 1 in 3000 live births

Causes of Arthrogryposis

 * Diagnosis usually made by ruling out other causes or syndromes
 * Cartilaginous abnormalities
 * Beal Syndrome
 * Linked to fibrillin locus on chromosome 5q23-31
 * Autosomal dominant
 * Crumpled ears, long slim limbs and fingers, frontal bossing, short neck
 * Antley-Bixer Syndrome
 * No confirmatory testing
 * Probably autosomal recessive
 * Crouzon syndrome-like appearance and midface hypoplasia
 * Distal Arthrogryposis Syndrome
 * Autosomal dominant with variable expression
 * Facial features usually normal
 * Arthrogryposis of hands and lesser extent feet
 * Physical constraint to movement
 * Oligohydramnios Sequence
 * Diagnosis made by clinical findings
 * Arthrogryposis usually involves knees and feet
 * Wrinkled skin, squashed nose, low-set ears, short neck
 * Often secondary to bilateral renal agenesis
 * Escobar Syndrome
 * Autosomal recessive condition
 * Thick skin folds keep joints in fixed position
 * Restrict joint motility in neck, axilla, antecubital, popliteal, and digital areas
 * Neurological Abnormalities
 * Trisomy 18 and Trisomy 13
 * Cause distal arthrogryposis
 * Causes severe mental retardation and facial dysmorphism
 * Smith-Lemli-Opitz
 * Autosomal recessive condition
 * Due to defect in cholesterol biosynthesis leading to severe MR and early death
 * Microcephaly, cryptorchidism, hypospadias, and arthrogryposis of hands
 * Zellweger Syndrome
 * Caused by genetic mutations at 7q11.23 and 1p22-21
 * Autosomal recessive inheritance
 * Severe hypotonia, brachycephaly, open fontanels, cryptorchidism, hypospadias, and distal arthrogryposis
 * Infantile Spinal Muscular Atrophy
 * Autosomal recessive and X-linked inheritance
 * Arthrogryposis occurs in 10-20% of neonates with SMA
 * Moebius Syndrome
 * Sporadic or autosomal dominant in some cases
 * Causes bilateral facial weakness and arthrogryposis in about 30% patients
 * Congenital Myotonic Dystrophy
 * Due to trinucleotide repeat expansion at 19q13
 * Autosomal dominant disorder
 * Marked body and facial hypotonia with arthrogryposis in lower extremities
 * Congenital Muscular Dystrophy
 * Inheritance pattern varies depending on type of muscular dystrophy
 * Hypotonia, muscle weakness, and distal arthrogryposis
 * Serum creatine kinase may be normal or elevated

Clinical Manifestations and Natural History

 * Wide variation in degree to which muscles and joints are affected
 * May be accompanied by other conditions tat complicate the picture
 * Outlook is generally very positive
 * Not a progressive condition
 * Substantial improvements seen with treatment
 * Most individuals are of normal intelligence and lead independent lives as adults
 * Possible features
 * Head and neck
 * Facial asymmetry
 * Micrognathia, notched chin, or malar hypoplasia
 * Immobile facies
 * Low-set posteriorly located ears or overfolded helices
 * High nasal bridge
 * Highly arched palate, cleft lip, or cleft palate
 * Eyes
 * Keratoconus
 * Downslanting palpebral fissures
 * Blepharoptosis, hypertelorism, or ophthalmoplegia
 * Retinopathy
 * Short neck, fused cervical vertebrae, and pterygia
 * Chest deformities
 * Inguinal hernia
 * Hand and foot
 * Overlapping fingers, tapered fingers, camptodactyly, or syndactyly
 * Clenched fists
 * Positional foot deformities or clubfoot
 * Single or bridged palmar creases
 * Absent or hypoplastic distal flexion creases
 * Extremities
 * Radial head dislocation, contractures, and limitation of motion
 * Affects shoulder, elbow, wrist, knee, ankle, and hip joints
 * Scoliosis and kyphosis
 * Microphallus and cryptorchidism
 * Elevated serum creatine phosphokinase
 * Occasional growth and mental retardation

Treatment/Management

 * First important to determine the cause
 * Influences prognosis, recurrence risk, and treatment
 * Definite diagnosis may not be possible in neonatal period
 * Important to separate neurological from non-neurological causes
 * MRI study for infants with neurological findings suggesting brain or spinal cord involvement
 * Chromosome analysis or genetic testing for those who appear to have genetic syndrome
 * Physical therapy
 * Helps improve muscle strength and range of motion
 * Includes stretching, strengthening, mobility training, and training in ADL skills
 * Casting or splinting
 * Splints can augment stretching to increase range of motion
 * Casting can improve foot position
 * Removable splint such as bi-valve cast or wearing splint at night often still allows motion and stretching
 * Surgeries
 * Usually considered supportive measure to other forms of treatment
 * Performed on ankles to put feet in weight-bearing position
 * Tendon transfers can sometimes improve muscle function

Psychosocial Issues

 * Parental concern over underlying cause of condition
 * Reaction to infant requiring braces, casts, or surgeries
 * Difficulty bonding with a child who looks different or requires special care
 * Guilt, depression, anger over new diagnosis
 * Concern for child's future

Support Resources

 * National Support Group for Arthrogryposis
 * AVENUES
 * Web:
 * Email: info@avenuesforamc.com

 * NORD (National Organization of Rare Disorders)
 * Web:

Arthrogryposis Multiplex Congenita Support Inc.
 * Web:


text:
Guide to Unix/Explanations/Fake Networking Interfaces

Loopback
The system uses the loopback interface "lo0" to talk to itself. Most systems automatically configure it at boot. Talking-to-oneself is useful for testing servers, and also for any situation where the server and client are on the same computer. (For example, some computer games have a one-player mode where server and client are on the same computer. These games use the "network", but because there is only one computer, they use the loopback interface.)

Use the ifconfig command to check the status of the interface. It probably looks something like: $ ifconfig lo lo0: flags=8049 mtu 33224 groups: lo        inet 127.0.0.1 netmask 0xff000000 inet6 ::1 prefixlen 127 inet6 fe80::1%lo0 prefixlen 64 scopeid 0x5

The IPv4 address of your computer is "127.0.0.1". This is in addition to any address that it has on an actual network. In fact, every computer calls itself "127.0.0.1", so it is impossible to use this address to communicate between computers. (Some jokes involve a person who is given "127.0.0.1" as an attack target and proceeds to destroy their own computer.)

If your system is running an IPv6 stack, then your IPv6 loopback address is "::1". The computer should be able to use IPv6 to communicate with itself, even if it has no connection to an actual IPv6 network.

You probably have no problem pinging the interface with ping or ping6. We use "ping -c3" and "ping6 -c3" to ping 3 times; otherwise it would ping every second until you interrupted with ^C (CTRL+C). $ ping -c3 127.0.0.1 PING 127.0.0.1 (127.0.0.1): 56 data bytes 64 bytes from 127.0.0.1: icmp_seq=0 ttl=255 time=0.206 ms 64 bytes from 127.0.0.1: icmp_seq=1 ttl=255 time=0.094 ms 64 bytes from 127.0.0.1: icmp_seq=2 ttl=255 time=0.096 ms --- 127.0.0.1 ping statistics --- 3 packets transmitted, 3 packets received, 0.0% packet loss round-trip min/avg/max/std-dev = 0.094/0.132/0.206/0.052 ms $ ping6 -c3 ::1 PING6(56=40+8+8 bytes) ::1 --> ::1 16 bytes from ::1, icmp_seq=0 hlim=64 time=0.284 ms 16 bytes from ::1, icmp_seq=1 hlim=64 time=0.118 ms 16 bytes from ::1, icmp_seq=2 hlim=64 time=0.116 ms --- ::1 ping6 statistics --- 3 packets transmitted, 3 packets received, 0.0% packet loss round-trip min/avg/max/std-dev = 0.116/0.173/0.284/0.079 ms

Create interfaces
If you want to use a fake network interface, you often must create it with "ifconfig create".

Some interfaces that you might be able to create: bridge, carp, gif, gre, lo, ppp, pppoe, sl, trunk, tun, vlan.