Amyloidosis, hereditary, transthyretin-related

Hereditary transthyretin amyloidosis is caused by gene changes in the TTR gene. Our genes contain instructions for how our bodies grow and develop in what is called DNA. Genes are inherited from our parents and passed on to our children. Genes make specific proteins that the body needs to grow and work properly. When there is an unexpected change in a gene, the protein that the gene produces may be absent or not work properly.

Changes (or mutations) in the TTR gene cause hereditary transthyretin amyloidosis, and can be associated with very different symptoms of the condition. Gene mutations are passed from parent to child in an autosomal dominant pattern. This means that someone with a TTR gene mutation has a 50/50 chance to pass it to their sons or daughters (and a 50/50 chance not to), with each child. No parent has control over which genes they pass/don’t pass to their children.

To learn more about how hereditary transthyretin amyloidosis runs in families, speak to your doctor or look into a referral to see a genetic counselor. In the U.S., you can find a genetic counselor near you by searching the Find a Genetic Counselor website (from the National Society of Genetic Counselors) at http://www.nsgc.org/findageneticcounselor.

In a family with hereditary transthyretin amyloidosis, tests can be done to see whether other family members are at risk or have the condition. Some people may not show any symptoms of the disorder. However, because the age when symptoms develop can vary, they may be tested to see whether they have an TTR gene change (or mutation), which causes the condition. This is called predictive genetic testing or presymptomatic genetic testing. The specific gene mutation in that family need to be known to perform such a test. If known, all siblings and other at-risk relatives can be offered testing. Molecular genetic testing, which are tests that look for changes to genes, can be performed.

Predictive or presymptomatic genetic testing in at-risk adults is available but the genetic testing process should include genetic counseling for both pre- and post-test guidance. Clinical evaluation of at risk family members can also provide information about any symptoms or signs of hereditary transthyretin amyloidosis. Genetic testing of adolescents under the age of 18 for hereditary transthyretin amyloidosis, a serious adult-onset disorder without a specific treatment, is not typically recommend by most medical professionals.

A genetic counselor or a physician with experience in hereditary transthyretin amyloidosis can provide advice about how a confirmed diagnosis can affect other family members. In the U.S., medical geneticists can be found through the American College of Medical Geneticists.

In the U.S., you can find a genetic counselor near you by searching on the Find a Genetic Counselor website (from the National Society of Genetic Counselors) at http://www.nsgc.org/findageneticcounselor.

Alnylam Pharmaceuticals is sponsoring a third-party genetic testing and counseling program for individuals who may carry a gene mutation known to be associated with hATTR amyloidosis at no charge. These services are only available in the United States. Alnylam does not receive patient-identifiable information. as part of this program. Your doctor will need to sign up for the "Alnylam Act" program at this website: [link url="www.alnylam.com/patients/alnylam-act. ” target=”_blank”>www.alnylam.com/patients/alnylam-act.

Support groups can put you in contact with other people or families with hATTR amyloidosis. Support groups include the Amyloidosis Foundation and the Amyloidosis Support Groups. The Amyloidosis Research Consortium is a nonprofit organization dedicated to address critical needs in clinical trials and related research for systemic amyloid diseases.

There are also online communities for rare disorders such as RareConnect, RareShare, or Inspire, which allow individuals and parents to share experiences and advice about dealing with rare disorders.

The medical cost of hATTR amyloidosis can be significant for some families, and some families may lack the resources necessary to provide for a chronically ill child. There are several organizations that provide financial assistance.

In the U.S.:

Taking care of someone with a long-term or chronic condition can be tiring and challenging and this is no different caregivers of people with hATTR amyloidosis. If you are a caregiver in need of support, try to take time for yourself, set aside time for personal counseling, or look for other resources at the Caregiver Action Network. This organization works to improve the quality of life for people who care for loved ones with chronic conditions, disabilities, disease, or the frailties of old age. Support groups can also help provide support and advice for caregivers.

Support groups for hereditary transthyretin amyloidosis include the Amyloidosis Foundation and the Amyloidosis Support Groups.

General tips for caregivers from a psychologist with experience in the field can be found in a ThinkGenetic article here: https://news.thinkgenetic.com/2017/09/27/resilience-the-art-of-caregiving-preparing-for-curves-bumps-and-wrong-turns-by-adding-a-dose-of-resilience/.

A doctor may suspect someone has hereditary transthyretin amyloidosis because of their symptoms. Problems with the nerves outside of the central nervous system (peripheral neuropathy), pain that results from damage or injury to the nerves (neuropathic pain) and heart disease are common symptoms. Carpal tunnel syndrome, clouding of the gel-like substance of the eye (vitreous), and gastrointestinal issues like diarrhea or constipation are also possible signs. The specific tests can be different. If a person only has heart problems, then the tests a doctor orders will be those that assess the function of the heart.

Hereditary transthyretin amyloidosis is caused by the buildup of a protein called transthyretin in various tissues of the body. Transthyretin is abnormal in people with hereditary transthyretin amyloidosis and forms clumps, called amyloid deposits, in various tissues of the body. Doctors will take a tissue sample, called a biopsy, and study it to see whether there are these amyloid deposits. They may stain the tissue sample with a dye called Congo red, which allows them to see these deposits under a special microscope.

The protein, transthyretin, can be found in the liquid portion of blood (serum). If an antibody against transthyretin is added to the serum sample, it can determine the levels of transthyretin. Antibodies are specialized proteins that react to specific substances.

To confirm a diagnosis, a doctor may offer genetic testing. These tests involve studying TTR gene for changes (mutations). This can include sequence analysis, where a part or sequence of DNA within a gene is examined; targeted mutation analysis, where specific changes (mutations) are looked for; or gene-targeted deletion/duplication analysis, where missing or extra regions of DNA are looked for within a specific gene. Molecular genetic testing must be done at specialized genetic testing laboratories.

Additional tests may be done before or after a diagnosis is made. These tests can include tests to see how well the heart is functioning or whether there is damage to the nerves.

To learn more about genetic testing, discuss it with your doctor or seek a referral to a genetic counselor. In the U.S., you can find a genetic counselor near you by searching on the Find a Genetic Counselor website (from the National Society of Genetic Counselors)
at http://www.nsgc.org/findageneticcounselor.

Alnylam Pharmaceuticals is sponsoring a third-party genetic testing and counseling program for individuals who may carry a gene mutation known to be associated with hATTR amyloidosis at no charge. These services are only available in the United States. Alnylam does not receive patient-identifiable information. as part of this program. Your doctor will need to sign up for the "Alnylam Act" program at this website: [link url="www.alnylam.com/patients/alnylam-act. ” target=”_blank”>www.alnylam.com/patients/alnylam-act.

Hereditary transthyretin amyloidosis can cause heart disease. The disorder is caused by changes (mutations) in a gene called TTR. This gene produces the protein transthyretin. Because of the mutation in this gene, the transthyretin it produces does not work properly and is known as amyloid. Amyloid begins to clump together and build up in tissues of the body.

Sometimes, amyloid builds up in the heart. Some people will only have heart involvement, while other people may have other organs affected. If other organs are involved, a diagnosis of hereditary transthyretin amyloidosis may be made and the heart will be evaluated to see whether amyloid is building up there.

In people with only heart involvement, a family history of the disorder will lead to earlier diagnosis. If there is no family history, a diagnosis may be delayed. A diagnosis of the heart form of hereditary transthyretin amyloidosis is based on identifying the clinical symptoms and then specialized testing including looking for certain markers in the blood (biomarkers) and noninvasive imaging studies.

Biomarkers are substances that can be tested for that suggest a person has a specific disorder or that there is damage to an organ. There are specific biomarkers that suggest people have heart disease caused by amyloidosis. These biomarkers do not distinguish among the different types of amyloidosis.

Noninvasive imaging can include an electrocardiogram (ECG), transthoracic echocardiogram (TTE), or a cardiac MRI (magnetic resonance imaging). An electrocardiogram records the heart’s electrical impulses and may reveal abnormal electrical patterns that suggest heart disease due to amyloid deposits. A transthoracic echocardiogram creates images of the heart using high frequency sound waves. This test can show distinctive changes in the heart in people with cardiac amyloidosis like abnormal thickness of the lower left chamber of the heart. An MRI uses a magnetic field and radio waves to produce images of particular organs. When an MRI is used to create a picture of the heart (cMRI), it can reveal changes or abnormalities in the heart (including deposits of amyloid).

A newer test called scintigraphy can be used to detect amyloid deposits in the heart, distinguish between different types of amyloidosis, monitor the progression of the disease, and assess the response to treatment. Scintigraphy is a form of nuclear medicine. An individual will swallow a radioactive material that will accumulate in a specific area (e.g. the heart). A special camera will be used to detect the levels of radiation producing an image of the heart.

As of September 2017, various therapies are being explored as potential treatments for hereditary transthyretin amyloidosis. This includes several medications.

Doxycycline is a common antibiotic that disrupts the formation the abnormal transthyretin. Doxycycline is used in combination with tauroursodeoxycholic acid, a drug that can reduce the buildup of abnormal transthyretin.

Diflunisal is a nonsteroidal anti-inflammatory or NSAID. NSAIDs are most commonly used as pain relievers. However, diflunisal has shown some ability to stabilize abnormal transthyretin and prevent the buildup of these abnormal proteins in the tissues and cells of the body.

Tafamidis (brand name Vyndaquel) is made by Pfizer, Inc. and has been approved by the European Commission for the treatment of adults with mild to moderate nerve involvement in hereditary transthyretin amyloidosis with polyneuropathy. The effectiveness of this medication for heart disease is being studied.

Alnylam Pharmaceuticals is developing two drugs that are RNAi therapies. These drugs silence or "turn off" the abnormal TTR gene to prevent the creation of abnormally-shaped transthyretin and its accumulation in the cells and tissues of the body. One drug is called Revusiran and is being studied for heart involvement in hATTR amyloidosis. The other drug, called Patisiran, is being studied for nerve involvement in this disorder. Other drugs being studied are doxycycline, diflunisal, and tafamidis.

Ionis Pharmaceuticals and SOM Biotech SL are also working on medications for the treatment of hereditary transthyretin amyloidosis. In 2018, the drug Tegsedi (Inotersen) was approved by the FDA for treatment of hereditary transthyretin amyloidosis.

Support groups may have information about specialists with expertise in treating people for hereditary transthyretin amyloidosis. These include the Amyloidosis Foundation (http://www.amyloidosis.org/resources/#treatment-centers) and Amyloidosis Support Groups (http://amyloidosissupport.org/index.html).

"Wild type" transthyretin amyloidosis is similar to the hereditary form. However, people with wild type transthyretin amyloidosis do not have a gene mutation (change) and the disorder is not inherited. Like hATTR amyloidosis, this disorder is caused by misfolding of the transthyretin protein. When proteins are formed, they are "folded" into a specific shape. Transthyretin is "misfolded" and is abnormally shaped. The misfolded proteins are called amyloid. The altered transthyretin, or amyloid, cannot perform its normal function. In addition, the misfolded proteins start to build up in tissues and organs of the body. The misfolded proteins will begin to merge together to form small or slender fibers called fibrils. When enough of the misfolded proteins (called amyloid) build up, they will damage the surrounding tissues and organs. The heart is most commonly affected in wild type transthyretin amyloidosis.

In hereditary transthyretin amyloidosis, this misfolding is cause by a genetic mutation (a change in a gene). In wild type transthyretin amyloidosis, the misfolding is not caused by a genetic mutation. Wild type transthyretin amyloidosis generally affects older men.

Hereditary transthyretin amyloidosis (or hATTR amyloidosis) can be very different from person to person. As such, it is difficult to make predictions about how the disease will progress for an individual. hATTR amyloidosis can potentially cause life-threatening complications and can lower life expectancy. However, improved surveillance techniques, which lead to prompt treatment of symptoms, has improved the outlook of this disorder in the last several years. There are several potential treatments being studied in clinical trials. Talk to your doctor and entire medical team about you or your family member’s diagnosis and individual prognosis.

Hereditary transthyretin (hATTR) amyloidosis is a rare genetic disorder. Amyloidosis is an "umbrella" term that describes a group of disorders in which certain proteins (called amyloid) build up in the body and clump together. These abnormal clumps are called amyloid deposits and can damage the surrounding tissues or organs. hATTR amyloidosis is caused by a change (mutation) in a gene called TTR, which produces a protein called transthyretin. The change in this gene leads to an altered (misshapen) form of transthyretin, which builds up in tissues of the body. People with the condition may have problems with peripheral nerves (those outside of the central nervous system), and the autonomic nervous system, which controls involuntary actions of the body like sweating, blood pressure, and heart rate. hATTR amyloidosis can also affect the heart, eyes, kidneys, and central nervous system (brain and spinal cord).

How the disease affects one person can be very different from how it affects another person, depending on the specific change in the TTR gene, the age of onset of symptoms, and other factors. For example, some people will have heart disease, but no problems with their nerves (or only very mild problems with their nerves). People with central nervous system problems usually do not have problems with the heart or the peripheral or autonomic nerves. People with peripheral and autonomic nerve involvement may or may not have problems with their hearts. The age when symptoms develop can vary dramatically, anywhere from 20-70 years of age. Symptoms and age of onset tend to be consistent in families. hATTR amyloidosis is inherited in an autosomal dominant manner; this means that a person with the condition has a 50/50 chance to have sons or daughters with it.

In groups where hATTR amyloidosis is more likely to occur something called genetic "anticipation’" may occur. Genetic anticipation is when a disorder becomes more severe and the onset of symptoms occur at an earlier age with each generation of a family.

A medical professional such as a genetic counselor or medical geneticist discuss details about genetic anticipation in hATTR amyloidosis. In the U.S., a listing of medical geneticists can be found at the American College of Medical Geneticists website. In the U.S., you can find a genetic counselor near you by searching on the Find a Genetic Counselor website (from the National Society of Genetic Counselors) at http://www.nsgc.org/findageneticcounselor.

Hereditary transthyretin amyloidosis is caused by changes (such as mutations) in the TTR gene. Several mutations have been described in this gene. Most of these cause some form of hereditary transthyretin amyloidosis. In rare instances, other changes in this gene do not necessarily cause disease, or it is not yet known if they do. These are called variants or variants of unknown significance (VUS) in a gene. If a variant is known to cause a disorder, it is known as a pathogenic or disease-causing variant. However, sometimes scientists are unsure what a variant means yet, because it has not been found before or has only been found in a few people. If you have a variant or VUS in the TTR gene, talk to your doctor about further genetic testing that may help you learn more. A genetic counselor may also be able to help you review your test results. In the U.S., you can find a genetic counselor near you by searching on the Find a Genetic Counselor website (from the National Society of Genetic Counselors) at http://www.nsgc.org/findageneticcounselor.

Rare diseases that affect multiple organ systems like hATTR amyloidosis can benefit from a multidisciplinary approach. This approach involves different healthcare professionals with specialized skills and expertise. They work together to make treatment recommendations and to provide quality care of individuals and families. Depending upon the specific symptoms in an individual multidisciplinary team may require:

People with the polyneuropathy of hereditary transthyretin amyloidosis have problems with the peripheral nervous system and the autonomic nervous system. Polyneuropathy means disease affecting many nerves. The peripheral nervous system are the nerves that are outside the central nervous system. Peripheral nerves control sensation, movement and motor coordination. Individuals may have strange sensations like tingling, burning or a "pins and needles’ feeling in their legs. Sometimes there may be numbness or pain. These nerve problems get progressively worse and people start having trouble walking. As the disease progresses, the thigh, trunk, arms, and fingers will become affected.

Some people have carpal tunnel syndrome, a condition there is tingling, burning and a "pins and needles" sensation in the hands because of a problem with a nerve in the wrist. This is often an early sign of the disorder and can occur before other symptoms are noted.

The autonomic nervous system refers to all the jobs the body performs without a person thinking about them. This includes regulating the heart, sweating, and breathing. Autonomic nervous system problems can cause constipation, diarrhea, a lack of sweating, a drop in blood pressure upon standing (orthostatic hypotension), and, in men, impotence.

Sometimes people with this form of hereditary transthyretin amyloidosis only have problems with the nerves. Other times, the heart or the eyes may be affected. Heart disease is called cardiomyopathy, in which the heart muscle becomes stiff, thickened, or enlarged. This can lead to heart failure.

If the eyes are affected, people may have dry eyes, glaucoma, or cloudiness of the vitreous. The vitreous is the gel-like substance that fills up most of the inside of the eye. These problems can cause a decrease in the sharpness of a person’s vision.

Leptomeningeal amyloidosis is a specific form of hereditary transthyretin amyloidosis. Leptomeningeal refers to the membranes (meninges) covering the brain and spinal cord. Individuals can have seizures, stiffening of the muscles, poor coordination, bleeding on the brain, psychosis or dementia. This is an extremely rare form. Sometimes, people also have problems with their eyes including clouding of the gel-like substance that fills up most of the eye (vitreous opacity). This is sometimes called familial oculoleptomeningeal amyloidosis.

How hereditary or familial transthyretin amyloidosis affects a person can be very different from person to person. Within families, the symptoms tend to be very similar. The most common form of hereditary transthyretin amyloidosis affects the nerves of the peripheral and autonomic nervous systems. The peripheral nerves are those outside of the central nervous system (the brain and spinal cord). Symptoms of peripheral nerve involvement include strange sensations like tingling, burning or a "pins and needles’ feeling in their legs. Sometimes there may be numbness or pain. These nerve problems get progressively worse and people start having trouble walking. As the disease progresses, the thigh, trunk, arms, and fingers will become affected.

Some people have carpal tunnel syndrome, a condition where there is tingling, burning and a "pins and needles" sensation in the hands because of a problem with a nerve in the wrist. This is often an early sign of the disorder and can occur before other symptoms are noted.

The autonomic nervous system refers to all the jobs the body performs without a person thinking about them. This includes regulating the heart, sweating, and breathing. Autonomic nervous system problems can cause constipation, diarrhea, a lack of sweating, a drop in blood pressure upon standing (orthostatic hypotension), and, in men, impotence.

The heart can be affected. Sometimes, the heart is affected by itself and sometimes along with the peripheral and autonomic nervous systems. Symptoms of heart involvement can be very mild or severe and life-threatening. Dizziness, heart palpitations, unintended weight loss, fatigue, problems sleeping, shortness of breath and fluid buildup in the legs causing swelling (edema). Other symptoms include irregular heartbeats (arrhythmias), fainting or passing out, and conduction defects. Conduction defects means that the transfer of electrical impulses, called conduction, that regulate the normal pumping action of the heart is abnormal. Conduction defects may not cause symptoms, but if they are severe, they can lead to sudden death.

Some people may develop restrictive cardiomyopathy. In this condition, the upper chamber of the heart does fill with blood as it normally does. This occurs because the heart muscle is stiff (due to the buildup of amyloid). Restrictive cardiomyopathy can cause difficult, labored breathing (dyspnea) and eventually lead to heart failure.

Less often, the eyes or the brain can be affected. If the eyes are affected, there can be dry eyes, glaucoma or cloudiness of the vitreous. The vitreous is the gel-like substance that fills up most of the inside of the eye. These problems can cause a decrease in the sharpness of a person’s vision. If the brain is affected, there can be seizures, stiffening of the muscles, poor coordination, bleeding on the brain, psychosis or dementia.

Hereditary transthyretin amyloidosis can affect the heart. Sometimes only the heart is involved; other times, the heart is one of several organs affected. Heart problems in hereditary transthyretin amyloidosis are caused because of the buildup of abnormal proteins called amyloid in heart tissues. Symptoms of heart involvement can be very mild or severe and life-threatening. Dizziness, heart palpitations, unintended weight loss, fatigue, problems sleeping, shortness of breath and fluid buildup in the legs causing swelling (edema). Other symptoms include irregular heartbeats (arrhythmias), fainting or passing out, and conduction defects. Conduction defects means that the transfer of electrical impulses, called conduction, that regulate the normal pumping action of the heart is abnormal. Conduction defects may not cause symptoms, but if they are severe, they can lead to sudden death.

Some people may develop restrictive cardiomyopathy. In this condition, the upper chamber of the heart does fill with blood as it normally does. This occurs because the heart muscle is stiff (due to the buildup of amyloid). Restrictive cardiomyopathy can cause difficult, labored breathing (dyspnea) and eventually lead to heart failure.

After a diagnosis of hereditary transthyretin amyloidosis is made, families should seek a medical specialist such as a metabolic genetics specialist with experience in the disorder. Support groups may have information about specialists with expertise in treating people for hereditary transthyretin amyloidosis. These include the Amyloidosis Foundation (http://www.amyloidosis.org/resources/#treatment-centers) and Amyloidosis Support Groups (http://amyloidosissupport.org/index.html).

People diagnosed with hATTR amyloidosis will usually go through a series of tests to see how far along the disease has progressed. Doctors will examine the heart, kidneys, eyes and conduct neurological tests. These can tell a physician what parts of the body are affected and to what extent. Other initial steps will depend on how the disorder is affecting a person.

Families should see a genetic counselor to help understand the genetic aspects of this disorder. In the U.S., you can find a genetic counselor near you by searching on the Find a Genetic Counselor website (from the National Society of Genetic Counselors) at http://www.nsgc.org/findageneticcounselor.

Hereditary transthyretin (hATTR) amyloidosis can be known by lots of different names. This can be very confusing for individuals and families after they receive a diagnosis of this disorder. Some of the other names for hATTR amyloidosis include:

Diuretics (sometimes called "water pills") are commonly used to treat heart disease. Diuretics are medications that help to remove fluid from the body. These medications can help to relieve swelling that is caused by heart disease. However, the use of diuretics in hATTR amyloidosis is complicated. Although they can benefit a person by helping to management fluid levels, they can cause complications, particularly in people who also have kidney disease.

Talk to your doctor and entire medical team (including a heart specialist, a cardiologist) about your specific treatment plan.

Because children who have a parent with hATTR amyloidosis have a 50% chance of inheriting the gene change (mutation) that causes it, some wonder about whether their at-risk children should have genetic testing. However, many doctors caution that genetic testing should not be performed unless the child has developed symptoms (which is extremely rare, since symptoms usually happen in adults). Testing a child who does not show symptoms, sometimes called presymptomatic genetic testing, has drawbacks. There are also drawbacks in presymptomatic genetic testing in adult at risk for hATTR amyloidosis who does not show symptoms. There are many factors to consider before pursuing this option.

Genetic counselors can help a family learn about the option of genetic testing, including pros/cons and limitations. Discussion with a genetic counselor should happen before presymptomatic genetic testing should occur. In the U.S., you can find a genetic counselor near you by searching on the Find a Genetic Counselor website (from the National Society of Genetic Counselors) at http://www.nsgc.org/findageneticcounselor.

Hereditary transthyretin amyloidosis is a complex disorder and the treatment options for one person may be very different from the treatment options for another. Families should seek a medical consultation with a physician such as a metabolic genetic specialist with experience with the disorder.

Hereditary transthyretin amyloidosis is caused because a change (or mutation) in a gene leads to an altered (misshapen) of the protein transthyretin. This misshapen protein buildups in the tissues and cells of the body, damaging the affected area.

Most of this protein is created in the liver, and doctors have tried liver transplants to treat this disorder. The donated liver will not have the underlying gene mutation and should produce normal versions of the transthyretin protein. A liver transplant has been effective in treating certain people with this disorder, particularly people who have had disease symptoms for less than 5 years, are younger than 60 years old, have nerve disease limited to the lower legs or only have autonomic nerve involvement, and no significant problems with their hearts or kidneys. Liver transplants have not improved heart problems associated with hereditary transthyretin amyloidosis and sometimes the nerve disease also does not improve. These transplants are not effective in people with leptomeningeal amyloidosis or hereditary oculoleptomeningeal amyloidosis. A liver transplant for hereditary transthyretin amyloidosis can be an effective treatment for certain people with this disorder.

Any type of transplant comes with both risks and benefits. Anyone considering this option should talk with the primary care physician and entire medical team to understand all aspects of the procedure. There are organizations that provide information on transplants. This includes the National Foundation for Transplants. The American Liver Foundation also provides information on liver transplants.

A pacemaker or defibrillator may be needed for some people with hereditary transthyretin amyloidosis affecting the heart. Some people may need a heart transplant. The American Heart Association can provide information on pacemakers, defibrillators, and heart transplants.

Kidney disease may require hemodialysis. Hemodialysis is a procedure in which a machine is used to perform some of the functions of the kidney – filtering waste products from the bloodstream, helping to control blood pressure, and helping to maintain proper levels of essential chemicals. Sometimes, a kidney transplant may be necessary. The National Kidney Foundation can provide information on hemodialysis and kidney transplants.

Some people may need more than one transplant. For example, they may need a liver transplant and a heart transplant.

Medications can be used treat irregular heartbeats, nerve pain, and various symptoms of autonomic dysfunction like diarrhea, low blood pressure upon standing (orthostatic hypotension), urinary incontinence, and erectile dysfunction.

Surgery can be used to treat carpal tunnel syndrome and clouding of the gel-like substance that fills up most of the eye (vitreous clouding).

Because hereditary transthyretin amyloidosis is a complex disorder that can cause very different symptoms in people, individuals and families should discuss treatment options with their entire medical team, preferably one located at a specialized medical center. Support groups may have the latest information about specialists with expertise in treating people for hereditary transthyretin amyloidosis. These include the Amyloidosis Foundation (http://www.amyloidosis.org/resources/#treatment-centers) and Amyloidosis Support Groups (http://amyloidosissupport.org/index.html).

ClinicalTrials.gov lists all available clinical trials associated with hATTR amyloidosis. As there are many types of amyloidosis, makes sure you are looking specifically for trials on hATTR amyloidosis. The ClinicalTrials.gov website provides regularly updated information about federally and privately supported clinical trials is a universal source for clinical trials. As of June 2019, there are several studies regarding hATTR. Check the clinicaltrials.gov website for the most up-to-date studies.

There is a patient registry for hATTR amyloidosis. This is a database set up by researchers that contains information about patients with a particular disorder or group of disorders. This information helps researchers learn about a disorder, plan or study treatments, how a disorder progresses or affects people and other information. Patient registries require that patients either directly or through their doctor submit personal information. Talk to a genetic counselor about the pros or cons of participating in a patient registry.

As of September 2017, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is a study open to all physicians treating, and all individuals diagnosed with, or carrying a mutation that puts them at risk of transthyretin (TTR) amyloidosis.

The autonomic nervous system can be affected in people living with hereditary transthyretin amyloidosis. The autonomic nervous system controls actions of the body that occur without thinking about them. This means that these actions occur without a person’s conscious thought about performing these actions. This includes regulating the heartbeat, sweating, the production of various fluids including tears and saliva, parts of the digestive process, and regulating body temperature.

Symptoms of autonomic nervous system dysfunction in hereditary transthyretin amyloidosis can include alternating bouts of diarrhea and constipation, a lack of sweating, a drop in blood pressure upon standing (orthostatic hypotension), and, in men, impotence.

Some people with hATTR amyloidosis will ultimately need palliative or hospice care. Palliative care ensures that a dying person is as pain free as possible and that all their physical, social, emotional, and spiritual needs are met. Hospice care is a special institution that provides palliative care in an in-patient setting. Palliative and hospice care requires a close cooperation among family members, immediate relatives, and physicians, and other medical personnel. A primary care physician or local hospital may be able to offer advice and local resources for palliative care. Hospice care may also be recommended. A hospice is an institution that provides care for the chronically sick, particularly people who are terminally ill.

The National Hospice and Palliative Care Organization has specific information and support for families considering palliative or hospice care for a family member.

Hereditary transthyretin amyloidosis is caused by a change (mutation) in the TTR gene. This gene makes a protein called transthyretin. Because of the gene change, the transthyretin protein that is made is abnormally shaped. When proteins are formed, they are "folded" into a specific shape. Transthyretin is "misfolded" and is abnormally shaped. The misfolded proteins are called amyloid. The altered transthyretin, or amyloid, cannot perform its normal function. In addition, the misfolded proteins start to build up in tissues and organs of the body. The misfolded proteins will begin to merge together to form small or slender fibers called fibrils. When enough of the misfolded proteins (called amyloid) build up, they will damage the surrounding tissues and organs. The nerves, heart, kidneys, and gastrointestinal tract are commonly affected.

Following a healthy diet and getting proper nutrition is important for everyone, including people with hATTR amyloidosis. People should make an effort to eat right and have a balanced, healthy diet. Individuals with hATTR amyloidosis should talk to their medical team about eating right and proper nutrition. Sometimes, doctors may encourage people to modify their diet. For example, a low-salt diet may be recommended to lower fluid retention, which can help people with hATTR amyloidosis who have heart or kidney involvement.

The symptoms of hATTR amyloidosis can begin anywhere from the 20s to the 80s. hATTR amyloidosis is a genetic disorder. People have an altered gene called TTR that leads to an abnormal (misfolded) transthyretin protein. This misfolded and abnormally-shaped protein is called amyloid. These abnormal transthyretin proteins or amyloid are present in a person from birth, but they may not clump together to form amyloid deposits until later in life. This may be due, in part, to how people’s chemical makeups in their bodies change as they age. The specific alteration (mutation) in the TTR gene can also influence when symptoms are most likely to start.

To find a medical professional nearby who can discuss information about gene changes in the TTR gene and the likely age of onset of symptom of hATTR amyloidosis a U.S. listing of medical geneticists can be found at the American College of Medical Geneticists website. In the U.S., you can find a genetic counselor near you by searching on the Find a Genetic Counselor website (from the National Society of Genetic Counselors) at http://www.nsgc.org/findageneticcounselor.

Hereditary transthyretin amyloidosis is caused by changes (mutations) to the TTR gene. These changes affect the protein (transthyretin) made by the gene. When proteins are formed, they are "folded" into a specific shape. Because of the change in the TTR gene, transthyretin is "misfolded" and is abnormally shaped. The misfolded proteins are called amyloid. Amyloid builds up in the body and damages surrounding tissues and organs. Some people are carriers of this disorder. This means that they have a change in the TTR gene, but do not have any symptoms. Some people never develop symptoms, while others may not develop symptoms until very late in life.

A genetic counselor can tell you much more about being a carrier of the condition, and symptoms that can happen. In the U.S., you can find a genetic counselor near you by searching on the Find a Genetic Counselor website (from the National Society of Genetic Counselors) at http://www.nsgc.org/findageneticcounselor.

We each get two copies of most of our genes from our parents. One copy comes from our mother and the other copy comes from our father. A person who has hereditary transthyretin amyloidsosis passes the gene change (or mutation) on to sons or daughters in an autosomal dominant manner. This means a son or daughter only needs one TTR gene mutation to have the condition. So, someone with hereditary transthyretin amyloidosis has a 50/50 chance passing on the gene mutation to a child, and a 50/50 chance to not pass it on. Most people with hereditary transthyretin amyloidosis inherit it from a parent. No parent has control over which genes they pass/don’t pass to their children.

Other times, people who have hereditary transthyretin amyloidosis are the first person in the family with the disorder. This occurs because of a de novo mutation, which means that the TTR gene mutation happened randomly, most likely at the time of conception. In families with a child with a de novo mutation, the likelihood of having another child with hereditary transthyretin amyloidosis is extremely low. A de novo mutation in the TTR gene is an extremely rare occurrence, but can happen.

If you have a family member with hATTR amyloidosis or you would like to learn more about the genetics of the disorder, talk to your doctor or seek a referral to speak to a genetic counselor. In the U.S., you can find a genetic counselor near you by searching on the Find a Genetic Counselor website (from the National Society of Genetic Counselors) at http://www.nsgc.org/findageneticcounselor.

Hereditary transthyretin amyloidosis is inherited in an autosomal dominant manner. This is one way a disorder or trait can be passed down through a family. The first word, "autosomal," means on a chromosome that both males and females carry. Therefore, hereditary transthyretin amyloidosis can affect either males or females. The second word, "dominant," means a change in one copy of a person’s TTR gene is enough for them to develop the disorder. We have two copies of every gene – one from our mother and one from our father – for a dominant condition, only one of them needs to have the problem. This means that if a parent carries TTR gene change (or mutation), they have a 50% chance to pass the gene mutation to each of their offspring, regardless of gender. This also means that there is a 50% chance that an affected parent would not pass the gene mutation on to their children. No parent has control over which genes they pass/don’t pass to their children.

Genetic testing is available to determine if someone has inherited a TTR gene mutation. If you have a family member with hereditary transthyretin amyloidosis and you would like to know if you are a carrier, talk to your doctor or seek a referral to speak to a genetic counselor to discuss genetic testing in more detail. In the U.S., you can find a genetic counselor near you by searching on the Find a Genetic Counselor website (from the National Society of Genetic Counselors) at http://www.nsgc.org/findageneticcounselor.

Hereditary transthyretin amyloidosis is caused by changes (mutations) in the TTR gene. The TTR gene usually makes a protein. This protein moves other substances through the body, specifically vitamin A and thyroxine (a thyroid hormone). When proteins are made, they are "folded" into a specific shape. A mutation in the TTR gene causes transthyretin to be "misfolded" and abnormally shaped. The misfolded transthyretin proteins will clump together and form amyloid deposits. The abnormal transthyretin cannot perform its transporter job. In addition, the misfolded proteins start to build up in tissues and organs of the body. The misfolded proteins begin to merge together to form small or slender fibers called fibrils. When enough of the misfolded proteins (called amyloid) build up, they will damage the surrounding tissues and organs. The nerves, heart, kidneys, and gastrointestinal tract are commonly affected in people.

Hereditary transthyretin amyloidosis is caused by a change (mutation) in a gene called TTR. The protein made by this gene, called transthyretin, is unstable and becomes abnormally shaped. When proteins are formed, they are "folded" into a specific shape. Because of the change in the TTR gene, transthyretin is "misfolded." The misfolded proteins are called amyloid. In addition, the misfolded proteins start to build up in tissues and organs of the body. The misfolded proteins will begin to merge together to form small or slender fibers called fibrils. When enough of the misfolded proteins (called amyloid) build up, they will damage the surrounding tissues and organs. The nerves, heart, kidneys, and gastrointestinal tract are commonly affected.

Most transthyretin is made in the liver. The liver itself is not affected by the disease. Some people with hATTR amyloidosis may be candidates for a liver transplant because doctors believe the donor liver will make normal transthyretin. A liver transplant has been effective in treating certain people with this disorder, particularly people who have had disease symptoms for less than 5 years, are younger than 60 years old, have nerve disease limited to the lower legs or only have autonomic nerve involvement, and no significant problems with their hearts or kidneys. Liver transplants have not improved heart problems associated with hATTR amyloidosis and sometimes the nerve disease also does not improve. These transplants are not effective in people with leptomeningeal amyloidosis or familial oculoleptomeningeal amyloidosis. A liver transplant for hATTR amyloidosis is an effective treatment for certain people with this disorder.

Any type of transplant comes with both risks and benefits. Anyone considering this option should talk with the primary care physician and entire medical team to understand all aspects of the procedure. There are organizations that provide information on transplants. This includes the National Foundation for Transplants. The American Liver Foundation also provides information on liver transplants.

Testing for hereditary transthyretin amyloidosis can happen through an examination with a doctor that would check for certain symptoms. Problems with the nerves outside of the central nervous system (peripheral neuropathy), pain that results from damage or injury to the nerves (neuropathic pain) and heart disease are common symptoms. Carpal tunnel syndrome, clouding of the gel-like substance of the eye (vitreous), and gastrointestinal issues like diarrhea or constipation are also possible signs. If a person has several of these symptoms, a doctor may order tests to check for hereditary transthyretin amyloidosis. If some of symptoms run in a family, a doctor is more likely to offer tests.

Tests that may be run include testing a tissue (biopsy) sample for the buildup of amyloid. The tissue sample is stained with a dye called Congo red, which allows doctors to see amyloid deposits under a special microscope. Doctors may also test a tissue sample for antibodies against transthyretin. To confirm a diagnosis, genetic testing may also be offered. These tests involve studying the TTR gene for changes (mutations).

If you believe that you or someone in your family has hATTR amyloidosis, you can request or seek out a referral to a genetics clinic that may be more familiar with these disorders. The Genetics and Rare Diseases Information Center provides information on how to find healthcare professionals with experience in specific conditions, specialty treatment centers, genetics clinics, and researchers who are studying a specific condition.

If you think that someone in your family has hATTR amyloidosis, you should also talk to a genetic counselor to learn more. In the U.S., you can find a genetic counselor near you by searching on the Find a Genetic Counselor website (from the National Society of Genetic Counselors) at http://www.nsgc.org/findageneticcounselor.” target=”_blank”>http://www.nsgc.org/findageneticcounselor” target=”_blank”>http://www.nsgc.org/findageneticcounselor.

Alnylam Pharmaceuticals is sponsoring a third-party genetic testing and counseling program for individuals who may carry a gene mutation known to be associated with hATTR amyloidosis at no charge. These services are only available in the United States. Alnylam does not receive patient-identifiable information. as part of this program. Your doctor will need to sign up for the "Alnylam Act" program at this website: [link url="www.alnylam.com/patients/alnylam-act. ” target=”_blank”>www.alnylam.com/patients/alnylam-act.

To learn about ongoing clinical research into hATTR amyloidosis, you can ask a medical specialist in the disorder. This can include genetic counselors and medical geneticists. In the U.S., you can find a genetic counselor near you by searching on the Find a Genetic Counselor website (from the National Society of Genetic Counselors) at http://www.nsgc.org/findageneticcounselor. In the U.S., you can find a medical geneticist near you at medical geneticists. These specialists are excellent sources of information about ongoing clinical trials and can offer information about the pros and cons about participating in such a trial.

Ongoing studies for hATTR amyloidosis can also be found on clinicaltrials.gov, a service of the U.S. National Institutes of Health. In Europe, the EU Clinical Trial Register performs a similar service.

Support groups also have information about ongoing clinical trials as well as information and advice about participating in clinical trials. Support groups for transthyretin amyloidosis include the Amyloidosis Foundation and the Amyloidosis Support Groups. The Amyloidosis Research Consortium is a nonprofit organization dedicated to address critical needs in clinical trials and related research for systemic amyloid diseases.

The best way to obtain the most accurate, current, clear, and comprehensive information on hATTR amyloidosis is to be seen at an Amyloidosis Treatment Centers. These are genetic centers that specialize in the treatment of patients with amyloidosis. At most centers, you will see a medical geneticist, genetic counselor, nurse and other specialists who work as a team to answer your questions, discuss testing, identify your at-risk family members, and develop a comprehensive evaluation and treatment plan for you. A Center will work with your current doctors to organize the treatment, tests, and specialists you need.

Support groups may have information about specialists with expertise in treating people for hereditary transthyretin amyloidosis. These include the Amyloidosis Foundation (http://www.amyloidosis.org/resources/#treatment-centers) and Amyloidosis Support Groups (http://amyloidosissupport.org/index.html).

Hereditary transthyretin amyloidosis is the most common type of inherited amyloidosis. As of 2017, the overall worldwide prevalence of hereditary transthyretin amyloidosis is not known. However, it is a little more common in people from northern Portugal (estimated to be in 1 in 538 people of this background), Sweden, and Japan. Americans of European ancestry may have it less commonly, perhaps at a rate of 1 in 100,000 people. The form of hereditary transthyretin amyloidosis that significantly affects the heart (the cardiac form) is more common in people of African background, particularly from West Africa, and in Denmark.

Gene changes (mutations) in the TTR that causes hereditary transthyretin amyloidosis have decreased penetrance. Penetrance is the chance that someone with a mutation in a gene will actually develop symptoms of the disease. If a genetic disease has a 100% penetrance, that means that everyone who inherits a mutation in that gene will develop the disease. However, in hereditary transthyretin amyloidosis, there is decreased penetrance. This means that not everyone who has the gene change will develop symptoms of the disease. Some research suggests that the penetrance is affected by the region of the world. If you do not have symptoms but know you have a gene mutation in the TTR gene, a genetic counselor or medical geneticist can help you understand your risks. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website.

Amyloidosis may occur for reasons beyond genetics and gene changes (or mutations). Hereditary transthyretin amyloidosis is caused by mutations in the TTR gene. Several mutations have been found in the TTR gene. A specific mutation may be more likely to cause certain symptoms. Researchers have also learned that many genetic disorders are influenced by environmental factors and changes in other genes (called modifier genes). Scientists are trying to figure out how different changes in the TTR gene can lead to different forms of hereditary transthyretin amyloidosis and to determine whether anything else can influence how the disorder develops in a person.

Parents who have a family history of hereditary transthyretin amyloidosis (or if one parent has the TTR gene change or mutation that causes the disorder) may choose to have their child tested for the disorder before the child is born. This is known as prenatal diagnosis. If the gene change(s) that causes TTR are known in a family, genetic testing (to detect these mutations) can be used for prenatal diagnosis. Prenatal testing for genetic conditions that commonly present in adulthood is uncommon and need careful consideration and genetic counseling is recommended.

Preimplantation genetic diagnosis (PGD) in which embryos can be genetically tested is also available. During this process, embryos are created through in vitro fertilization (IVF) by taking eggs from the mother and sperm from the father. The two are then combined in the laboratory. A few cells are removed from the embryo and are then tested to determine whether or not that specific embryo inherited the altered TTR gene. Then, the family can choose to only have the embryos without hereditary transthyretin amyloidosis transferred to create the pregnancy.

To learn more about the option of genetic testing and what is involved, please seek out a referral to see a genetic counselor.
In the U.S., you can find a genetic counselor near you by searching on the Find a Genetic Counselor website (from the National Society of Genetic Counselors) at http://www.nsgc.org/findageneticcounselor.

Hereditary transthyretin amyloidosis can be diagnosed anywhere from the 20s to the 80s. A diagnosis is often delayed several years after the onset of symptoms because the disorder is not well known and the initial symptoms are not specific for hATTR amyloidosis and can occur in more common disorders. Because hATTR amyloidosis does not follow a consistent pattern or path, and because symptoms can vary greatly, the age and time it takes to get a diagnosis can vary greatly among people with the disorder.

Several organizations for hereditary ATTR amyloidosis provide support, information, advice, referrals to physicians and medical centers, and up-to-date information on research and treatments. Support groups include: the Amyloidosis Foundation and the Amyloidosis Support Groups. The Amyloidosis Research Consortium is a nonprofit organization dedicated to address critical needs in clinical trials and related research for systemic amyloid diseases.

Some organizations can provide information about specific symptoms associated with hereditary transthyretin amyloidosis, including the Foundation for Peripheral Neuropathy or the American Heart Association. The American Liver Foundation can provide information about a liver transplant, which is a treatment option for people with hereditary transthyretin amyloidosis. This is because the abnormal transthyretin protein that causes the disorder is made in the liver.

There are different forms of hereditary transthyretin amyloidosis. This disorder is caused by changes (mutations) in the TTR gene. Different mutations can be associated with different symptoms or different forms.

hATTR amyloidosis with polyneuropathy is the most common form. People with this disorder may have problems with peripheral nerves (those outside of the central nervous system), and the autonomic nervous system, which controls involuntary actions of the body like sweating, blood pressure, and heart rate. Sometimes other symptoms can develop that affect the gastrointestinal system, the eyes, the heart and the kidneys.

hATTR amyloidosis with cardiomyopathy predominantly affects the heart. This can cause enlargement of the heart, irregular heart rhythms (arrhythmias), chest pain, congestive heart failure and potentially sudden death. Neurological involvement is either absent or very mild.

Leptomeningeal transthyretin amyloidosis affects the central nervous system and the brain. This form is extremely rare. People may have seizures, poor coordination (ataxia), stiffening of the muscles (spasticity), bleeding in the brain, psychosis, and dementia. Sometimes the eyes may be affected and this may be called oculoleptomeningeal transthyretin amyloidosis or familial oculoleptomeningeal transthyretin amyloidosis.

The kidneys can be affected in hereditary transthyretin amyloidosis, but often no symptoms will develop. In rare instances, kidney damage can occur because of the buildup of transthyretin protein, called amyloid, that defines the disorder. The need for dialysis or a kidney transplant is possible in rare instances.