familial amyloidosis

Familial amyloidosis

Familial amyloidosis also known as hereditary amyloidosis, refers to a group of inherited conditions in which abnormal protein deposits called amyloid in almost every tissue in your body. Hereditary amyloidosis is one type of the systemic amyloidosis diseases that are caused by inheriting a gene mutation. That genetic mutation then produces an amyloid protein that forms into an abnormal shape. These abnormal “misfolded” amyloid proteins can be deposited and cluster in the body’s nerves and other organs and once they build up, this may affect and harm tissue and/or organ function. In familial amyloidosis, amyloid deposits most often occur in tissues of the heart, kidneys, and nervous system 1). These protein deposits damage the tissues and interfere with how organs work. While symptoms of familial amyloidosis may appear in childhood, most individuals do not experience symptoms until adulthood 2). Even though you are born with a gene mutation, normally the harmful amyloid deposits don’t occur until adulthood. Although all the types of the familial amyloidosis can cause serious complications, there are some carriers of this genetic mutation that may not show symptoms of the disease at all. Others may have a few, more minor, health issues.

There are 2 main classifications of hereditary amyloidosis diseases:

  1. ATTR. ATTR amyloidosis means A for amyloid and the TTR is short for the protein “transthyretin”. In the past, because ATTR often involves nerve or cardiac involvement, some terms were used when the chemical variations were less defined. Examples of these outdated terms include FAP (Familial Amyloid Polyneuropathy) and FAC (Familial Amyloid Cardiomyopathy). Today, the different forms of ATTR are termed according to the “chemically based” name of the transthyretin protein variation. An example of this would be ATTRV30M (for ATTR Val30Met), which is the most common ATTR variation.
  2. Non-TTR = Non-transthyretin amyloidosis. These diseases are considered even more rare than the transthyretin amyloidosis (ATTR) variations. Examples of non-transthyretin amyloidosis (Non-TTR) include, but are not limited to, apolipoprotein AI amyloidosis (A ApoAI), gelsolin amyloidosis (A Gel), lysozyme amyloidosis (A Lys), cystatin C amyloidosis (A Cys), fibrinogen Aα-chain amyloidosis (A Fib), and apolipoprotein AII amyloidosis (A ApoAII) 3).

Moreover, it is further complicated by the fact that there are approximately 136 different genetic variations in ATTR, and at least 60 genetic variations in Non-TTR hereditary amyloidosis diseases. It is possible that more may be discovered as research continues. Each family with a certain hereditary form of amyloidosis has its own pattern of organ involvement, approximate age of onset and associated symptoms.

Most types of familial amyloidosis or hereditary amyloidosis are inherited in an autosomal dominant manner 4).

Typically, families know when they have a hereditary form of amyloidosis because of similar symptoms and causes of illness among blood relatives, so family history is a key indicator.

Familial amyloidosis treatment is focused on addressing symptoms of organ damage and slowing down the production of amyloid when possible through methods such as liver transplants.

How does someone get ATTR or Non-TTR familial amyloidosis?

ATTR and Non-TTR familial amyloidosis are not contagious. They are considered to be an inherited, autosomal dominant disease. This means that to get this disease, a person needs one copy of the mutant gene – in other words, it can be inherited from one parent. Each off spring of an affected parent has a 50/50 chance of inheriting the gene. If an offspring is not born with the gene mutation, then they can’t pass it onto their own offspring.

Is there a special diet that I can follow?

Eating a well-balanced, heart-healthy and nutritious diet is always recommended. Although amyloid is an abnormal protein, the amount of protein in the diet does not affect the onset of the disease. A diet low in protein and/or sodium may be necessary when the kidneys are involved. Consult with your physician on any dietary changes, and report any vitamins or other supplements that you take. You are a part of the team of people who must keep in communication with each other about your health.

Should physical activities be restricted?

If fatigue or shortness of breath occurs, it is important to rest. Patients should not push themselves or attempt strenuous activities beyond what is recommended by the doctor. Normal daily activities may be carried out as usual. Usually patients can continue working and are encouraged to do so.

ATTR (transthyretin) amyloidosis

ATTR amyloidosis means A for Amyloid and the TTR is short for the protein “transthyretin”. Transthyretin is a protein mainly manufactured in the liver that helps carry thyroid hormone and vitamin A in the blood. Normally, TTR is made up of four identical parts. ATTR is one term that represents different kinds of mutations in a TTR gene that is inherited. That gene mutation makes the transthyretin unstable, so amyloid protein misfolding occurs. In ATTR amyloidosis, the protein becomes unstable, breaks apart, and deposits in the heart and/or the nerves. The amyloid fibrils then go out into the body and can damage nerves and/or organs, depending on the type of TTR mutation that the patient has inherited.

There are two types of ATTR amyloidosis:

  1. Hereditary (familial) ATTR amyloidosis. In this form, there is a change (mutation) in the DNA that is inherited and can be passed from one generation to the next. This makes the TTR protein more unstable and more likely to form amyloid fibrils. Different mutations lead to different symptoms — some may affect the nerves; some may affect the heart; and some may affect both. In the past, because ATTR often involves nerve or cardiac involvement, some terms were used when the chemical variations were less defined. Examples of these outdated terms include FAP (Familial Amyloid Polyneuropathy) and FAC (Familial Amyloid Cardiomyopathy). Today, the different forms of ATTR are termed according to the “chemically based” name of the transthyretin protein variation. An example of this would be ATTRV30M (for ATTR Val30Met), which is the most common ATTR variation.
  2. Wild-type ATTR amyloidosis (historically known as senile/age related amyloidosis). Unlike hereditary ATTR amyloidosis, wild-type does not involve abnormal DNA and cannot be passed on to family members. Instead, as you get older, the normal TTR protein becomes unstable, misfolds and forms amyloid fibrils.

The majority of hereditary amyloidosis types are TTR-related, and there are many different variations within ATTR. Most ATTR diseases have a hereditary pattern of organ involvement, approximate age of onset and associated symptoms. It is common that symptoms do not appear until a person is an adult and the degree and severity of illness depends on the individual.

If a patient has a clear family history along with clinical signs of amyloidosis, then ATTR is highly possible. However, there are times when someone is the first case to be identified in his or her family. Since many amyloidosis and other diseases can cause similar symptoms, it is vital that the patient is diagnosed properly with the type of amyloid protein clearly identified.

Symptoms of ATTR vary, depending on the TTR genetic variant that is involved and the organ (or multiple organs) that are affected by the amyloid deposits. It also depends on the degree that the organ function is impaired. The most common sites of amyloid deposits are associated with cardiac and/or nerve involvement (called cardiomyopathy and neuropathy) and the gastrointestinal tract. The kidneys, eyes, and carpal ligament (also known as carpal tunnel syndrome) are among other possibilities that can be affected.

ATTR amyloidosis symptoms indicating the arms are affected include:

  • Carpal tunnel syndrome.
  • Numbness, burning and/or tingling (peripheral neuropathy).
  • Biceps tendon rupture.

Symptoms indicating the back is affected include:

  • Lumbar spinal stenosis.

Symptoms indicating the legs are affected include:

  • Swelling of the feet or legs.
  • Numbness, burning and/or tingling (peripheral neuropathy).
  • Leg weakness.

Symptoms indicating the head and neck are affected include:

  • Eye floaters (vitreous opacities).
  • Lightheadedness upon standing.

Symptoms indicating the heart and lungs are affected include:

  • Shortness of breath.
  • Palpitations.
  • Chest pain.
  • Fatigue.

Symptoms indicating the stomach or intestines are affected include:

  • Poor appetite.
  • Bloating or excessive gas.
  • Diarrhea or constipation.

ATTR (transthyretin) amyloidosis causes

Mutations in the TTR gene cause transthyretin amyloidosis. The TTR gene provides instructions for producing a protein called transthyretin. Transthyretin transports vitamin A (retinol) and a hormone called thyroxine throughout the body. To transport retinol and thyroxine, four transthyretin proteins must be attached (bound) to each other to form a four-protein unit (tetramer). Transthyretin is produced primarily in the liver. A small amount of this protein is produced in an area of the brain called the choroid plexus and in the light-sensitive tissue that lines the back of the eye (the retina).

TTR gene mutations are thought to alter the structure of transthyretin, impairing its ability to bind to other transthyretin proteins and altering its normal function.

There are more than 125 different TTR mutations that have been identified in ATTR. That means that within the one ATTR type, there exist many different variations, which are then identified by the amino acid protein involvement.

The most common TTR variants in the United States are:

  • Val30Met (also the most found worldwide). What was once termed FAP (Familial amyloid polyneuropathy) is most commonly caused by Val30Met.
  • Thr60Ala
  • Leu58His
  • Ser77Tyr
  • Val122Ile — predominantly seen in the African-American population; associated with cardiomyopathy (heart conditions). What was once termed FAC (Familial amyloid cardiomyopathy) is commonly caused by Val122lle.

ATTR (transthyretin) amyloidosis signs and symptoms

The presenting signs and symptoms in patients with ATTR are fairly nonspecific and are often attributed to more common diseases affecting both the heart and the peripheral nervous system (PNS) and autonomic nervous system. There are three main types of ATTR, identified by the organ system involved: cardiac, neuropathic, and leptomeningeal.

Cardiac ATTR

Patients with cardiac amyloid deposition typically present with the following typical symptoms of chronic heart failure:

  • Symptoms suggestive of right-sided heart failure (ie, dyspnea on exertion, peripheral edema, hepatomegaly, ascites, elevated jugular venous pressure), diastolic dysfunction, and/or arrhythmias (ie, palpitations, lightheadedness, syncope, ECG changes)
  • Heart failure with preserved ejection fraction (HFpEF) predominates in ATTR
  • Patients may also present with atrial arrhythmias or conduction system disease due to amyloid fibril deposition within areas responsible for electrical impulse conduction.
  • Cardiomegaly may be noted on chest imaging/echocardiogram 5).

Congestive heart failure and atrial fibrillation are the most common symptoms. The term “arrhythmia” refers to changes in the normal electrical impulses that cause the heart to beat. The result is a heart that can beat too fast, too slow or erratically. Atrial fibrillation (or a-fib for short) is one of the many forms of arrhythmia. During a-fib, the heart’s two small upper chambers cause an abnormal heart rhythm, usually rapid and irregular beating. This may result in increased heart damage, stroke or heart failure.

Neuropathic ATTR

The term neuropathy means nerve damage. Neuropathic involvement in patients affected by ATTR–familial amyloid polyneuropathy (FAP) is classically a symmetric, ascending length−dependent, sensorimotor, axonal polyneuropathy subtype and may include the following:

  • Peripheral neuropathy or peripheral nervous system sensimotor impairment affecting all functional classes of nerve fibers: motor, sensory and autonomic fibers (diarrhea or contipation, urinary incontinence, orthostatic hypotension, sexual impotence, glaucoma). Peripheral neuropathy can be caused by inflammation of, or damage to, the nerves. It can result in tingling, numbness and burning pain in any part of the body, but commonly is felt in the hands, feet and lower legs. Some patients may experience an increased sensitivity to pain. A loss of sensitivity to temperature may also occur. Sensorimotor impairment means the loss of a combination of sensory and motor activities. This can decrease a patient’s ability to move and feel (sensation) because of nerve damage. Restless leg syndrome (RLS) is also considered a sensorimotor disorder.
  • Autonomic neuropathy is a condition that results from damage to nerves that assist in organ and organ system functioning. Autonomic nerves control the functions of our internal organs such as the heart, stomach and intestines, as well as the glands. Nerves affected by ATTR amyloid deposits may cause the inability to control the muscles that expand or contract blood vessels, which affects the heart rate (irregular heart beats) and blood pressure. If a patient has a sudden drop in blood pressure (such as when moving from a seated to a standing position), then dizziness, fainting, or lightheadedness may occur. Other body functions may also be affected, including perspiration patterns, poor digestion, bowel motility and erectile function.
  • Lower-limb neuropathy (eg, in patients with the TTR V30M mutation)
  • Upper-limb neuropathy (eg, TTR I84S, TTR L58H) 6)
  • ATTR V30M variant: Lower extremity weakness, pain, and/or impaired sensation; autonomic dysfunction, often manifesting as sexual or urinary dysfunction 7)
  • Weakness and paresthesias of one or both hands, due to carpal ligament deposits (eg, in variant TTR L58H, normal-sequence TTR); symptoms of localized carpal ligament deposition sometimes precede other clinical manifestations by as long as 20 years.

Digestive system

The digestive system is also called the gastrointestinal tract (or GI tract). Amyloid deposits in the digestive system can affect the nerves that control intestinal muscle contractions causing nausea, diarrhea or constipation, and bladder control problems. Other symptoms may include weight loss, loss of appetite, or a feeling of fullness in the stomach after eating small amounts.

Kidneys

Amyloid deposits in the kidneys can affect how they filter toxins and proteins in the blood. This may result in a condition called nephrotic syndrome, where there is excess protein in the urine and the lower legs can become swollen (also called “edema”). Swelling can affect the belly, arms, and lungs as well. In some cases, the amyloid deposits will cause the kidneys to lose the ability to purify the blood, which can lead to kidney failure; also known as “renal” failure. These patients may need dialysis to replace the function of the kidneys.

Leptomeningeal involvement

Patients with rare TTR variants that cause CNS disease may present with the following features:

  • Nystagmus and pyramidal signs, with spastic paraparesis 8)
  • Seizures, subarachnoid hemorrhages, cerebrovascular attacks (ischemic strokes), dementia, in patients with leptomeningeal/cerebrovascular deposits 9)
  • Hearing loss, cerebellar ataxia, in patients with isolated leptomeningeal disease (rare) 10)

Other symptoms

Swelling may develop and cause other symptoms as a result of the amyloid deposits. For example, patients may have carpal tunnel syndrome. This is when amyloid deposits in the wrist area squeeze and irritate the nerve, causing tingling and numbness in the fingers and thumb.

ATTR (transthyretin) amyloidosis diagnosis

First, a patient is tested to determine if they have amyloid proteins in their body. If amyloidosis is confirmed but the type is not clearly found in these tests, it will be important to do more tests to find the exact type and also to determine the variation of ATTR.

The main diagnostic testing for any amyloidosis disease includes blood tests, urine tests and biopsies. Some tests are only done once to confirm a diagnosis, while others may be repeated to monitor the disease and response to therapy.

Blood and urine tests will be done to help your doctor determine the diagnosis of amyloidosis. These tests can also help to show which organs are involved and how much damage they may have.

In addition, a tissue biopsy will be performed. This involves the removal of a small sample of tissue for lab examination. A tissue sample is essential to confirm the diagnosis and type of amyloidosis. A “Congo red stain” is put on the biopsy tissue and if the lab examiner then sees the light wave change to an apple green color (called “birefringence”) then amyloidosis is diagnosed.

With ATTR, after amyloidosis is confirmed and it is determined that there is transthyretin amyloid protein (via biopsy and Congo red staining in the lab), the protein needs to be identified by protein sequence analysis and DNA sequencing must be performed.

When scientists examine your blood for certain genetic markers it is called genome sequencing. A simple blood sample is sent to a lab and experts examine the DNA chains. If a certain condition is in question, then sections of the DNA chain will be checked for genetic markers of the condition or defect.

Since the hereditary amyloidosis variations affect individuals differently, it is important to establish which variation you have in order to identify a treatment plan that is tailored for your type of amyloidosis. The DNA sequence analysis of TTR identifies more than 99% of disease-causing mutations.

A person should never ignore any health problem. Early detection can be important with any disease and the more tests that are done, the more accurate the diagnosis.

ATTR (transthyretin) amyloidosis treatment

Today’s treatment plans are two-fold:

  1. Supportive treatment – treating your symptoms and organ damage
  2. Source treatment – slowing down, or stopping, the overproduction of amyloid at the source of the disease.

Supportive treatment

Supportive treatment is helpful for various symptoms, including peripheral neuropathy, autonomic neuropathy, and cardiac and kidney problems, and can change the quality of life for many people. There are several medications that can be prescribed to treat peripheral neuropathy, which can cause tingling or burning in some parts of the body. These medications can help with pain relief and nerve damage. If a patient has autonomic neuropathy, symptoms can vary, with common problems affecting blood pressure, heart rate, digestion, and perspiration, depending on the location of the damage to the nerves. Other gastrointestinal dysfunctions may require treatment for symptoms that include poor nutritional health, diarrhea or constipation, and nausea or vomiting. Doctors can prescribe medications to help with these symptoms to lessen the pain and the symptom itself.

Management of heart problems, heart failure, and kidney dialysis (when needed) make a significant improvement on a patient’s quality of life. Reversing any damage to the organs and other parts of the body is difficult to achieve. If treatment begins during the early onset of clinical symptoms, the overall success rate is higher, so early detection is essential.

Source treatment

For most ATTR variations, the liver is the main source of amyloid production. However, the liver itself is not affected by the disease in most cases and the amyloid burden causes damage in other parts of the body. A liver transplant is very helpful in reducing (or stopping) the amyloid deposits. It can stabilize or improve neurological symptoms as well as gastrointestinal problems (which can correct poor nutrition and overall health). However, the statistics vary as to who can benefit from these transplants, with the more common ATTR Val30Met having the highest success rate. The outcome of liver transplantation is largely dependent on the mutation that exists in the patient. In some cases, amyloid deposition does completely stop after transplantation, so research is ongoing in this area. For those patients with cardiac symptoms, studies have shown that heart problems may continue after a liver transplant. In some situations, a combined heart and liver transplant will help a patient with an ATTR variant that produces advanced cardiac problems.

Several medications have been approved by the Food and Drug Administration (FDA) for treating patients with ATTR amyloidosis. Other medications continue to be investigated. In 2018, two drugs were approved by the FDA for ATTR polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. The first was Patisiran (Onpattro) lipid complex injection, a first of its kind RNA interference therapeutic. This drug aims to silencing the gene expression. The second drug approved in 2018 is Inotersen (Tegsedi) which reduces the production of TTR protein through a once a week subcutaneous injection. In 2019, Tafamidis (Vyndamax and Vyndaqel) were approved by the FDA for ATTR cardiomyopathy. These drugs are for oral administration taken once daily. In clinical trials, new therapies include aiming to treat the root cause of the disease, destabilized and folded TTR, using monoclonal antibodies to specifically target and clear misfolded (toxic) form a the TTR amyloid protein, and using a drug designed to reduce the production of transthyretin (TTR protein) in all types of TTR amyloidosis. Another RNA interference therapeutic is also currently in clinical trial. Advances in other treatments are likely, with new studies and clinical trials currently in view. It is possible that ATTR can cause serious health complications, so it should not be taken lightly. However, do not assume that disability or severe health issues are stamped on your future. There are treatments available and research continues.

ATTR silencers

These medications act on the liver to decrease the production of TTR. Two ATTR silencers approved by the FDA to treat patients with the hereditary type of ATTR who also have neuropathy.

  • Patisiran (Onpattro®) is an infusion that is given every three weeks.
  • Inotersen (Tegsedi®) is an injection given once a week and requires weekly lab work.

ATTR stabilizers

These medications stabilize the TTR protein, which in turn prevents it from breaking apart and forming amyloid fibrils.

  • Tafamidis (Vyndamax®, Vyndaqel®) is approved by the FDA for patients with hereditary or wild-type ATTR that has affected their heart.
  • AG10 is a medication currently being tested in a clinical trial.
  • Diflunsial (Dolobid®) is a nonsteroidal anti-inflammatory drug (NSAID) that has been shown to also stabilize the TTR protein. However, this medication has not been fully studied in patients with ATTR that has affected the heart and also may not be tolerated due to side effects.

Fibril disruptors

These medications may help break up and clear ATTR amyloid fibrils. Doxycycline (antibiotic) and green tea extract (over-the-counter supplement)have only been tested in small studies and there is limited evidence that these medications would be helpful in treating amyloidosis.

An antibody that removes TTR amylod fibrils, called PRX-004, is being tested in clinical trials.

Familial amyloidosis causes

Familial transthyretin amyloidosis is caused by changes (mutations) in the TTR gene. The TTR gene is responsible for making a protein called transthyretin (TTR) which transports vitamin A (retinol) and a hormone called thyroxine to many parts of the body. To transport thyroxine, four transthyretin proteins must be attached (bound) to each other to form a four-protein unit (tetramer). To transport retinol, transthyretin must form a tetramer and also bind to retinol binding protein. Transthyretin is produced primarily in the liver. A small amount of this protein is produced in an area of the brain called the choroid plexus and in the light-sensitive tissue that lines the back of the eye (the retina). Mutations in TTR lead to a transthyretin protein that is not made correctly. The faulty protein then folds up to form amyloid. Amyloid builds up in various parts of the body causing nerve and tissue damage 11). Currently, >150 mutations of the TTR gene are known; most of them are amyloidogenic, producing a broad range of phenotypes associated with familial amyloid polyneuropathy 12). The original mutation described Val30Met (alternatively named pVal50Met) is the most common worldwide and is primarily associated with neuropathy 13).

Most people who have familial amyloid polyneuropathy have inherited the TTR mutation from a family member. However, a few people with familial amyloid polyneuropathy will have no family history of the disease and have a new (de novo) mutation in the TTR gene 14). Not all people who have a TTR gene mutation will develop transthyretin amyloidosis.

Familial amyloidosis inheritance pattern

Familial amyloidosis is inherited in an autosomal dominant manner. This means that one altered copy of the disease-causing gene (called a mutation) in each cell is sufficient to cause the disease. The disease-causing mutation can be inherited from a parent or it can occur for the first time in an individual. Each child of an individual affected with familial amyloidosis has a 50% (1 in 2) risk to inherit the disease-causing mutation and a 50% chance of not inheriting the mutation. However, not all individuals with a mutation in a gene that causes familial amyloidosis will develop signs and symptoms of the disease.

Often autosomal dominant conditions can be seen in multiple generations within the family. If one looks back through their family history they notice their mother, grandfather, aunt/uncle, etc., all had the same condition. In cases where the autosomal dominant condition does run in the family, the chance for an affected person to have a child with the same condition is 50% regardless of whether it is a boy or a girl. These possible outcomes occur randomly. The chance remains the same in every pregnancy and is the same for boys and girls.

  • When one parent has the abnormal gene, they will pass on either their normal gene or their abnormal gene to their child. Each of their children therefore has a 50% (1 in 2) chance of inheriting the changed gene and being affected by the condition.
  • There is also a 50% (1 in 2) chance that a child will inherit the normal copy of the gene. If this happens the child will not be affected by the disorder and cannot pass it on to any of his or her children.

There are cases of autosomal dominant gene changes, or mutations, where no one in the family has it before and it appears to be a new thing in the family. This is called a de novo mutation. For the individual with the condition, the chance of their children inheriting it will be 50%. However, other family members are generally not likely to be at increased risk.

Figure 1 illustrates autosomal dominant inheritance. The example below shows what happens when dad has the condition, but the chances of having a child with the condition would be the same if mom had the condition.

Figure 1. Familial amyloidosis autosomal dominant inheritance pattern

Familial amyloidosis autosomal dominant inheritance pattern

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

Familial amyloidosis symptoms

ATTR symptoms

Symptoms of ATTR vary, depending on the TTR genetic variant that is involved and the organ (or multiple organs) that demonstrate signs of amyloid deposition. The most common sites of amyloid deposits are associated with cardiac and/or nerve involvement (called cardiomyopathy and neuropathy) and the gastrointestinal tract. The kidneys, eyes, and carpal ligament (also known as carpal tunnel syndrome) are among other possibilities that can be affected.

For each patient, the symptoms will depend on which organs are affected by the amyloid deposits. It also depends on the degree that the organ function is impaired.

Heart symptoms

When amyloid deposits cause cardiomyopathy, it can result in a stiffening of the heart. Some patients may experience:

  • Nausea
  • Weight loss
  • Inability to sleep
  • Increasing fatigue
  • Dizziness
  • Shortness of breath
  • Leg swelling (edema)
  • Palpitations and abnormal heart rhythms (atrial fibrillation)
  • Chest pain.

Congestive heart failure and atrial fibrillation are the most common symptoms. The term “arrhythmia” refers to changes in the normal electrical impulses that cause the heart to beat. The result is a heart that can beat too fast, too slow or erratically. Atrial fibrillation (or a-fib for short) is one of the many forms of arrhythmia. During a-fib, the heart’s two small upper chambers cause an abnormal heart rhythm, usually rapid and irregular beating. This may result in increased heart damage, stroke or heart failure.

Nervous system symptoms

The term neuropathy means nerve damage.

  • Peripheral neuropathy: The following ATTR symptoms are caused by a condition known as peripheral neuropathy. Peripheral neuropathy (PN) can be caused by inflammation of, or damage to, the nerves. It can result in tingling, numbness and burning pain in any part of the body, but commonly is felt in the hands, feet and lower legs. Some patients may experience an increased sensitivity to pain. A loss of sensitivity to temperature may also occur. Sensorimotor impairment means the loss of a combination of sensory and motor activities. This can decrease a patient’s ability to move and feel (sensation) because of nerve damage. Restless leg syndrome (RLS) is also considered a sensorimotor disorder.
  • Autonomic neuropathy: Autonomic neuropathy is a condition that results from damage to nerves that assist in organ and organ system functioning. Autonomic nerves control the functions of our internal organs such as the heart, stomach and intestines, as well as the glands. Nerves affected by ATTR amyloid deposits may cause the inability to control the muscles that expand or contract blood vessels, which affects the heart rate (irregular heart beats) and blood pressure. If a patient has a sudden drop in blood pressure (such as when moving from a seated to a standing position), then dizziness, fainting, or lightheadedness may occur. Other body functions may also be affected, including perspiration patterns, poor digestion, bowel motility and erectile function.

Digestive system symptoms

The digestive system is also called the gastrointestinal tract (or GI tract). Amyloid deposits in the digestive system can affect the nerves that control intestinal muscle contractions causing nausea, diarrhea or constipation, and bladder control problems. Other symptoms may include weight loss, loss of appetite, or a feeling of fullness in the stomach after eating small amounts.

Kidney symptoms

Amyloid deposits in the kidneys can affect how they filter toxins and proteins in the blood. This may result in a condition called nephrotic syndrome, where there is excess protein in the urine and the lower legs can become swollen (also called “edema”). Swelling can affect the belly, arms, and lungs as well. In some cases, the amyloid deposits will cause the kidneys to lose the ability to purify the blood, which can lead to kidney failure; also known as “renal” failure. These patients may need dialysis to replace the function of the kidneys.

Other symptoms

Swelling may develop and cause other symptoms as a result of the amyloid deposits. For example, patients may have carpal tunnel syndrome. This is when amyloid deposits in the wrist area squeeze and irritate the nerve, causing tingling and numbness in the fingers and thumb.

Non-TTR symptoms

Non-TTR symptoms can vary with each mutation, including problems with the kidneys, liver, heart or peripheral neuropathy. Some mutations have symptoms that involve the brain or the eye.

Each individual can present with different clinical symptoms. The symptoms, as well as the prognosis, depend on the tissue and organ(s) affected by the amyloid deposits. Although all the hereditary amyloidoses may cause serious complications for some individuals, there are some carriers of genetic mutations that may not show symptoms of the disease at all. Others may have a few, more minor, health issues.

Like ATTR, there are numerous variations within the protein identification.

  • Apolipoprotein AI – 22 known variations with differing symptoms, including amyloid deposit involvement in the kidneys, liver, heart, peripheral neuropathy, cutaneous (skin) areas, and laryngeal (larynx).
  • Fibrinogen Aa – 14 variations with symptoms that only involve the kidneys, with 1 also involving neuropathy.
  • Lysozyme – 7 variations that involve kidney and/or liver symptoms, with 1 also involving the GI tract.
  • Apolipoprotein AII – 5 variations that involve kidney symptoms only.
  • Gelsolin – 4 variations with peripheral neuropathy symptoms, 1 also involving the eye.
  • Cystatin C – 1 variation with cerebral hemorrhage complications.

Familial amyloidosis diagnosis

In the case of familial amyloidosis, the existence of a family history or similar illness is of great assistance in diagnosing the condition. However, not everyone with a mutation in a gene associated with hereditary amyloidosis will develop symptoms. Additionally, symptoms of the disease typically do not appear until older age and the condition may have been misdiagnosed in other affected family members. For these reasons, the absence of a family history may be misleading 15).

The diagnosis of amyloidosis is usually made by performing a tissue biopsy (the removal of a small piece of tissue) and staining the tissue with Congo red stain to detect the presence or absence of amyloid deposits. The biopsy may be from any affected organ, but biopsying the rectal mucosa generally results in better detection of the following familial amyloidosis: transthyretin amyloidosis, apolipoprotein AI amyloidosis, fibrinogen Aα-chain amyloidosis (A Fib), and apolipoprotein AII amyloidosis (A ApoAII) 16).

A bone scan called a technetium pyrophosphate (TcPYP) scan can detect ATTR in the heart. A positive TcPYP scan, along with blood and urine tests to rule out other forms of amyloidosis, can confirm the diagnosis without the need for a heart biopsy. When ATTR amyloidosis is confirmed, a blood test is used to find out if the ATTR is hereditary or wild-type.

Several other tests may be used to check organ function:

  • Blood samples to check the kidneys, heart, and liver.
  • An electrocardiogram (EKG) and echocardiogram (ultrasound of the heart) to check the heart.
  • An MRI of the heart may also be done.

Additionally, when a familial amyloidosis is suspected, genetic testing may be able to confirm a diagnosis. It is important to note that genetic testing may not be available for all types of familial amyloidosis. For those individuals interested in pursuing genetic testing, it is recommended that you schedule a genetics consultation to determine whether genetic testing would be appropriate and available.

Familial amyloidosis treatment

ATTR (transthyretin) amyloidosis treatment

Today’s treatment plans are two-fold:

  1. Supportive treatment – treating your symptoms and organ damage
  2. Source treatment – slowing down, or stopping, the overproduction of amyloid at the source of the disease.

Supportive treatment

Supportive treatment is helpful for various symptoms, including peripheral neuropathy, autonomic neuropathy, and cardiac and kidney problems, and can change the quality of life for many people. There are several medications that can be prescribed to treat peripheral neuropathy, which can cause tingling or burning in some parts of the body. These medications can help with pain relief and nerve damage. If a patient has autonomic neuropathy, symptoms can vary, with common problems affecting blood pressure, heart rate, digestion, and perspiration, depending on the location of the damage to the nerves. Other gastrointestinal dysfunctions may require treatment for symptoms that include poor nutritional health, diarrhea or constipation, and nausea or vomiting. Doctors can prescribe medications to help with these symptoms to lessen the pain and the symptom itself.

Management of heart problems, heart failure, and kidney dialysis (when needed) make a significant improvement on a patient’s quality of life. Reversing any damage to the organs and other parts of the body is difficult to achieve. If treatment begins during the early onset of clinical symptoms, the overall success rate is higher, so early detection is essential.

Source treatment

For most ATTR variations, the liver is the main source of amyloid production. However, the liver itself is not affected by the disease in most cases and the amyloid burden causes damage in other parts of the body. A liver transplant is very helpful in reducing (or stopping) the amyloid deposits. It can stabilize or improve neurological symptoms as well as gastrointestinal problems (which can correct poor nutrition and overall health). However, the statistics vary as to who can benefit from these transplants, with the more common ATTR Val30Met having the highest success rate. The outcome of liver transplantation is largely dependent on the mutation that exists in the patient. In some cases, amyloid deposition does completely stop after transplantation, so research is ongoing in this area. For those patients with cardiac symptoms, studies have shown that heart problems may continue after a liver transplant. In some situations, a combined heart and liver transplant will help a patient with an ATTR variant that produces advanced cardiac problems.

Several medications have been approved by the Food and Drug Administration (FDA) for treating patients with ATTR amyloidosis. Other medications continue to be investigated. In 2018, two drugs were approved by the FDA for ATTR polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. The first was Patisiran (Onpattro) lipid complex injection, a first of its kind RNA interference therapeutic. This drug aims to silencing the gene expression. The second drug approved in 2018 is Inotersen (Tegsedi) which reduces the production of TTR protein through a once a week subcutaneous injection. In 2019, Tafamidis (Vyndamax and Vyndaqel) were approved by the FDA for ATTR cardiomyopathy. These drugs are for oral administration taken once daily. In clinical trials, new therapies include aiming to treat the root cause of the disease, destabilized and folded TTR, using monoclonal antibodies to specifically target and clear misfolded (toxic) form a the TTR amyloid protein, and using a drug designed to reduce the production of transthyretin (TTR protein) in all types of TTR amyloidosis. Another RNA interference therapeutic is also currently in clinical trial. Advances in other treatments are likely, with new studies and clinical trials currently in view. It is possible that ATTR can cause serious health complications, so it should not be taken lightly. However, do not assume that disability or severe health issues are stamped on your future. There are treatments available and research continues.

ATTR silencers

These medications act on the liver to decrease the production of TTR. Two ATTR silencers approved by the FDA to treat patients with the hereditary type of ATTR who also have neuropathy.

  • Patisiran (Onpattro®) is an infusion that is given every three weeks.
  • Inotersen (Tegsedi®) is an injection given once a week and requires weekly lab work.

ATTR stabilizers

These medications stabilize the TTR protein, which in turn prevents it from breaking apart and forming amyloid fibrils.

  • Tafamidis (Vyndamax®, Vyndaqel®) is approved by the FDA for patients with hereditary or wild-type ATTR that has affected their heart.
  • AG10 is a medication currently being tested in a clinical trial.
  • Diflunsial (Dolobid®) is a nonsteroidal anti-inflammatory drug (NSAID) that has been shown to also stabilize the TTR protein. However, this medication has not been fully studied in patients with ATTR that has affected the heart and also may not be tolerated due to side effects.

Fibril disruptors

These medications may help break up and clear ATTR amyloid fibrils. Doxycycline (antibiotic) and green tea extract (over-the-counter supplement)have only been tested in small studies and there is limited evidence that these medications would be helpful in treating amyloidosis.

An antibody that removes TTR amylod fibrils, called PRX-004, is being tested in clinical trials.

Non-ATTR amyloidosis treatment

Non-ATTR amyloidosis treatment include:

  1. Supportive treatment – treating your symptoms and organ damage; and,
  2. Source treatment – slowing down, or stopping, the overproduction of amyloid at the source of the disease.

Supportive treatment

Supportive treatment can vary with each mutation of the non-TTR diseases, however, many of them present with kidney or heart damage, so organ transplantation has been used in these cases with success. Although not a cure, and even if production of the variant amyloid protein continues, an organ transplant can slow the progression of the disease, improve quality of life and prolong survival significantly.

Source treatment

Liver transplants are less of a source treatment option for most of the Non-TTR amyloidosis diseases. However, Fibrinogen is one variation that has amyloid production occurring solely in the liver, so a liver transplant can slow, or stop, amyloid production at the source. Often, a kidney transplant is also performed because kidney damage is the main target of this disease. So, transplants of both these organs can provide a successful supportive (kidney), and source (liver), treatment in this Fibrinogen variation.

Lysozyme, Apo lipoprotein A-I and AII, along with the other Non-TTR variations, are so varied that you should consult with a specialist at an amyloid center to recommend a treatment for your individual needs. Source treatments for the hereditary Non-TTR amyloidosis variants are not as advanced as they are for ATTR. These types are more rare and seem to progress slowly.

Current organ transplants and other treatments include:

  • Apolipoprotein A1
    • Supportive Treatment Possibilities (affected organ) – kidney and/or heart transplant, depending on organ damage
    • Source Treatment (to reduce amyloid production) – liver transplant
  • Fibrinogen Aa
    • Supportive Treatment Possibilities (affected organ) – kidney transplant
    • Source Treatment (to reduce amyloid production) – liver transplant
  • Lysozyme
    • Supportive Treatment Possibilities (affected organ) – kidney and/or liver transplant, depending on organ damage
    • Source Treatment (to reduce amyloid production) – none at this time
  • Apolipoprotein A2
    • Supportive Treatment Possibilities (affected organ) – kidney transplant
    • Source Treatment (to reduce amyloid production) – none at this time
  • Gelsolin
    • Supportive Treatment Possibilities (affected organ) – cornea transplant
    • Source Treatment (to reduce amyloid production) – none at this time
  • Cystatin C
    • Supportive Treatment Possibilities – avoid fever
    • Source Treatment (to reduce amyloid production) – none at this time

Familial amyloidosis prognosis

The prognosis and life expectancy for each person with familial transthyretin amyloidosis (hereditary transthyretin amyloidosis) varies and depends on the TTR gene mutation present, organ(s) involved, and how early a person is diagnosed and treated. Some people whose symptoms begin at a younger age may live for only a few years after diagnosis, while older patients with slowly progressive disease can live for many years 17). Life expectancy on average of people with familial amyloid polyneuropathy typically live for 7-12 years after they are first diagnosed 18). Death is most often due to cardiac dysfunction, infection, or cachexia 19).

The long-term outlook after liver transplant is also influenced by many factors, including the type of amyloid present, nutritional status, age, and how much the brain and heart are involved 20). Newer medications are now available that help slow the build-up of amyloid and delay symptoms and it is not yet clear how these medications will affect the long-term outlook for people with familial amyloid polyneuropathy. People with questions about their personal outlook should speak with their healthcare providers.

Familial amyloid polyneuropathy prognosis

The natural course of familial amyloid polyneuropathy can be classified into the following three stages 21):

  • Stage 1 – Sensory polyneuropathy
  • Stage 2 – Progressive walking disability
  • Stage 3 – Wheelchair bound or bedridden

The prognosis depends on the presence and identity of a TTR variant and the organ(s) involved. Patients with early-onset of variant-sequence TTR may die within a few years of diagnosis. Older patients with slowly progressive disease can live for decades after the onset of symptoms and may never develop life-threatening disease 22).

Penetrance of the individual TTR mutations vary. The penetrance of the same mutation in different geographic areas can also vary, for example, the Portuguese population showing much higher penetrance of the Val30Met mutation during middle age (80% at 50 years) compared with the French population (18% at 50 years) 23).

In contrast to light chain amyloidosis (AL), symptomatic cardiac involvement in familial amyloid polyneuropathy does not necessarily portend a poor prognosis. Median survival in cardiac light chain amyloidosis is about 6 months, but is several years in older patients with cardiac familial amyloid polyneuropathy, even in those with a TTR variant. Familial amyloid polyneuropathy usually proves fatal within 7–12 years from the onset of symptoms, most often due to cardiac dysfunction, infection, or cachexia 24).

Within most of the regions in which it is endemic, clinical onset of familial amyloid polyneuropathy often occurs before age 40 years with progressive sensory-motor and autonomic neuropathy, leading to cachexia and eventually death. Length-dependent small-fiber sensory and motor polyneuropathy with life-threatening autonomic dysfunction is a distinguishing feature of familial amyloid polyneuropathy in these areas. In addition, cardiac, renal, and ocular involvement are also common 25).

In nonendemic areas, and in endemic regions of Sweden, the onset of disease-related symptoms tends to be later in life, from age 50 years onward and with a male predominance for the late-onset familial amyloid polyneuropathy. Neuropathy tends to affect all fibers and may closely resemble chronic inflammatory demyelinating polyneuropathy (CIDP). Typically, sensory and motor neuropathy symptoms of upper and lower extremities occur, associated with mild autonomic symptoms 26).

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