In patients with familial amyloid polyneuropathy (FAP), TTR amyloid deposits cause nerve disease (peripheral and autonomic neuropathy). FAP was first identified as a distinct condition in 1952, when it was described in several families in Portugal. The most common type of FAP, caused by the Val30Met variant of TTR, affects about 1 in 500 people in some regions of Northern Portugal. But FAP is rare in most parts of the world, affecting only 1 in 100,000 people throughout most of the US and Europe. It has been estimated that worldwide about 10,000 people have FAP. FAP is also relatively more common in some parts of Sweden, Japan, Brazil, Majorca and Ireland. People living elsewhere who are diagnosed with FAP often have ancestors from these regions.
Both FAP and FAC are caused by inherited alterations in the TTR gene. The genes in the nucleus of each cell of our bodies act like a blueprint or a recipe for building the proteins which make up the entire human body. Gene alterations lead to alterations in the construction of body proteins, just like alterations in the blueprint for building a house will lead the builders to alter the structure of the house.
The inherited TTR gene alterations that cause FAP and FAC are called mutations. People born with these inherited mutations produce abnormal, variant TTR protein all of their lives. Over 100 different mutations in the TTR gene have been observed, most of which cause production of variant TTR with a tendency to misfold into amyloid fibrils, which then form TTR amyloid deposits in the tissues, mainly in the nerves and heart, sometimes in the eyes and rarely in the kidneys, thyroid, adrenals and blood vessels.
Amyloid deposits tend to build up slowly, over the course of many years, so organ damage accumulates slowly, leading to the symptoms of FAP or FAC which can appear at any time from early adult life to old age.
Symptoms of FAP tend to present earlier than symptoms of FAC, but there is still much variability. For example, in Portugal, FAP commonly presents up to 25 years earlier than it does in Sweden although the mutation Val30Met is the same. Very rarely, young adults may develop FAC, but FAC is far more common in elderly people. The most common FAC mutation (Val122Ile) is most frequent in men of African ethnic origin over the age of 60 years. Because this mutation is so common, it is known as a polymorphism (meaning a normal gene variant) rather than a mutation. This genetic variant has been found in about 1 in 20 African Americans (1.3 million people), including about 13,000 people who carry two copies of the gene variant.
The clinical symptoms of FAC are very similar to those of senile systemic amyloidosis (SSA), which is caused by amyloid deposits made of normal wild type TTR in people without mutations in the TTR gene.
FAC, FAP and SSA are compared in more detail in this Table.
FAP and FAC are inherited in a manner known as ‘autosomal dominant’. This means that the condition may be passed down to children either from the mother or from the father. Only one copy of the mutated gene is necessary to cause the disease.
As shown in the Figure here, an affected parent has a 50% chance of passing on the mutated gene to each child. Girls and boys have an equal chance of inheriting the mutated gene. Any children who receive the mutated gene then also have a 50% chance of passing it on to each of their children. Children of an affected parent who did NOT inherit a mutated gene cannot pass the condition on to their own children. Brothers and sisters of a patient with FAP or FAC have a 50% chance of having the mutated gene.
The situation is further complicated by an additional factor known as ‘incomplete penetrance’. This means that inheritance of a TTR gene mutation does not always lead to symptoms of FAP or FAC. Some people inherit a TTR gene mutation but do not develop any TTR amyloid deposits, while others develop small TTR deposits but no symptoms. FAP is equally common in men and women. FAC that is caused by the Val122Ile mutation is more common in men than in women although girls and boys have an equal chance of inheriting the Val122Ile mutation. Many people carry a TTR mutation all their lives but do not develop TTR amyloidosis. The reason for this is unclear.
Sometimes a patient diagnosed with FAP or FAC may be unaware of any other affected family members. This may be because other family members did not develop disease despite carrying the mutation. Alternatively, the mutation may have arisen for the first time in that patient, or other affected family members may have not been correctly diagnosed, or may have died of other causes before reaching the age when they would have developed symptoms.
Healthy family members of patients with FAP or FAC may be concerned about their own risk of developing the disease. Risk assessment can be complicated, and a doctor with expertise in amyloidosis should be consulted. In order to give personalized genetic counselling regarding the likelihood that someone with the TTR mutation will actually develop FAP or FAC, doctors will require information on family health history in addition to genetic testing for TTR mutations. Genetic testing of healthy people can identify the mutations in the TTR gene but cannot predict whether or not the person will develop FAP or FAC (or both).
The symptoms of FAP and FAC are described in the table below.
In FAP, symptoms are usually first detected after age 30, but sometimes can occur as early as age 20 or as late as age 80.
Symptoms of FAC usually appear after age 50. If there are small TTR amyloid deposits in the heart, they may cause no symptoms at all. When the deposits are large, they can cause symptoms of heart disease like those described in the table below. Carpal tunnel syndrome (pain and tingling in the wrists and hands) often appears several years before heart disease. It may be caused by TTR amyloid deposits in the wrists.
|Organ affected by TTR amyloid deposits||Symptoms|
Nerve disease (neuropathy) affecting:
Heart disease (restrictive cardiomyopathy):
Amyloid deposits in the heart cause stiffening and thickening of the heart muscle, so the heart cannot pump the blood around the body as efficiently as usual.
Local symptoms related to the organ affected:
blurred vision, blindness, protein loss in the urine, kidney failure, goiter (thyroid swelling), etc.
More than 100 different TTR gene mutations have been reported in the medical literature. The disease spectrum is wide and different mutations have been associated with different disease courses resulting in considerable variability in the type and severity of symptoms. The same mutation can cause different clinical features in different families, and even within the same family. For example, some mutations cause mostly neuropathy, while others cause mostly heart disease, and others cause equal amounts of both. Some mutations seem to cause severe, early onset disease in all affected family members, while others cause quite mild, late onset disease.
In patients from Portugal and Japan with the Val30Met mutation (the most common FAP-causing mutation), symptoms of neuropathy usually appear after age 30, while patients from Sweden with the Val30Met mutation often develop neuropathy after age 50. Heart disease is less common with the Val30Met mutation than with other mutations. In contrast, patients with the Val122lle mutation typically present only with FAC and have little involvement of the peripheral nerves.
The Thr60Ala mutation is most common in people with Irish ancestry, and they usually develop both neuropathy and heart disease.
The presence of a TTR gene mutation known to cause TTR amyloidosis does not necessarily mean that symptoms will develop. There have been case reports of people over 60 years of age with two copies of the TTR gene mutation which produces the amyloidogenic Val30Met TTR protein but no symptoms of FAP.
FAP is one of many different diseases that can cause neuropathy, most of which are far more common than FAP. Doctors may suspect neuropathy on the basis of the patient’s complaints and on findings from physical examinations. Peripheral neuropathy may be confirmed with nerve function tests such as:
The following tests may sometimes be of use for investigation of suspected autonomic neuropathy, depending on the symptoms:
If these tests confirm neuropathy, doctors may suspect FAP if there is known family history of the condition. If there is no family history, features suspicious of FAP include: peripheral and autonomic neuropathy appearing together, carpal tunnel syndrome and neuropathy together with heart disease.
Tissue biopsy to detect TTR amyloid deposits is necessary to confirm or rule out FAP, with a sample taken from a nerve, or from abdominal fat, or the heart if there is heart disease.
Biopsy is the ‘gold standard’ test for diagnosing amyloidosis. This means that it is the best available test, and all other tests should be compared to it. To perform a biopsy, a needle is used to remove a small tissue sample from the body. The sample is then processed in the laboratory using special techniques for identifying amyloid fibrils and examined under a microscope.
Patients with all types of TTR amyloidosis may have amyloid deposits in the fat under the skin in the stomach area. Sampling of this fat is called an abdominal fat biopsy. The procedure is simple, quick, safe and relatively painless and may be easily performed in an outpatient clinic.
For performance of an abdominal fat biopsy, a doctor numbs a small area of the skin in the abdomen with local anesthetic then inserts a needle into the numb area to take out some fat tissue from underneath the skin.
The fat tissue is then preserved and sent to the laboratory for analysis.
Nerve biopsy may be helpful for diagnosing FAP in patients with symptoms of neuropathy. It is a minor procedure involving removal of a small nerve sample, for examination under the microscope to detect amyloid deposits. Nerve biopsy is usually taken from one of the following three nerves:
Any resulting loss of sensation from one of these nerves is minor with no risk of movement being affected.
Local anesthetic is used to numb the skin region where the biopsy is planned and the nerve is then exposed through a small cut to the skin. After taking a small sample the doctor stitches the wound closed.
The procedure is generally safe and painless. The patient can usually go home later the same day if the biopsy was taken from a nerve in the arm, but an overnight stay in hospital may be recommended if the sample was taken from the leg.
The gold standard laboratory test for identification of amyloid in tissue biopsies is staining with the dye called ‘Congo red’, followed by examination of the stained tissue under intense, cross polarized light. When all these techniques are performed correctly, amyloid has a characteristic ‘apple green’ appearance which changes to red as the plane of polarized light is rotated.
If any step in the process is not performed correctly, amyloid may be missed. For this reason, it is important for biopsies to be performed or checked in medical centers experienced in the diagnosis of amyloidosis. False positive and false negative biopsies are quite common when biopsies are performed in insufficiently experienced facilities. Amyloidosis specialist centers may request preserved biopsy slides for review in their own laboratories when seeing patients who were diagnosed elsewhere.
After positive Congo red staining has identified amyloid deposits, further tests are used to identify the type of amyloid present. A technique called immunohistochemistry uses specific antibody molecules that recognize and distinguish between different types of amyloid. If antibodies to TTR stick to the amyloid deposits, this shows that the fibrils are formed from TTR. Another technique that can be useful is called proteomics. This involves use of a laser to cut out amyloid deposits from a section of tissue. The amyloid deposit is then digested with enzymes to break down all the proteins into smaller fragments which can then be precisely identified in a machine called a mass spectrometer. The precise type of TTR amyloidosis can be identified by detection of specific TTR variants in FAP and FAC, and wild type TTR in SSA.
Genetic testing involving examination of the DNA from the patient’s blood cells can help doctors to reach an accurate diagnosis. Ordinary blood samples drawn from the patient’s vein are used.
Genetic techniques can identify mutations in the TTR gene. The precise mutation identified may provide information about the likely clinical course. For example, the most common TTR gene mutation worldwide, the Val30Met mutation, often causes FAP with amyloid deposits mostly in the nerves. In contrast, the Val122lle mutation usually leads to FAC with amyloid deposits mostly in the heart, not in the nerves. If amyloid fibril analysis detects wild type TTR protein and genetic testing does not detect any TTR gene mutations, then the diagnosis is SSA.
The principles of currently available treatment for TTR amyloidosis are listed below. Unfortunately, no treatments are currently approved for FAC or SSA except supportive care.
At present the only available treatment that reduces the supply of precursor proteins in TTR amyloidosis is liver transplantation for some types of FAP. Liver transplantation is not used to treat TTR cardiac disease, like FAC or SSA. Some new drugs that are currently under evaluation in clinical trials may also reduce TTR amyloid precursor protein supply, such as Ionis’ clinical development program.
All of the TTR in the bloodstream is made in the liver. TTR from the liver forms the amyloid deposits everywhere in the body except in the eye and the blood vessels around the brain. Liver transplantation is therefore a treatment option for some patients with FAP. Surgery is performed to remove the patient’s own liver which forms the abnormal, variant TTR. It is replaced by a donor liver making normal, wild type TTR. The aim is to prevent the formation of further amyloid deposits by reducing the supply of the amyloid forming precursor variant TTR.
Since the procedure was introduced in 1991 in a collaboration between Swedish physicians and surgeons and the team from the UK National Amyloidosis Centre, and shown by them to be effective in 1993, hundreds of liver transplantations for FAP have been performed throughout the world. In many patients this has led to stabilization of disease. Most successful outcomes have occurred in patients with the TTR Val30Met mutation, especially if transplantation was performed at a young age and early in the disease course before the heart or nerves sustained too much damage. See The Familial Amyloidotic Polyneuropathy World Transplant Register (FAPWTR) and the Domino Transplant Register: http://www.fapwtr.org/
Unfortunately, amyloid deposits sometimes continue progressing and may even accelerate after transplantation. The existing TTR amyloid deposits apparently act as a template encouraging normal wild type TTR from the donor liver to also form TTR amyloid fibrils and TTR amyloid may therefore continue to accumulate. This problem arises most often in older patients with mutations other than TTR Val30Met.
Liver transplantation is not a treatment for FAC or senile systemic amyloidosis (SSA), because the cardiomyopathy continues to progress due to continued deposition of wild type TTR in the heart.
Tafamidis was first developed as a specific drug for FAP. It works by binding and stabilizing TTR in the blood to make it less amyloidogenic. In a trial of tafamidis in 128 patients, early FAP neuropathy progressed at a slower rate in patients who received the drug than in those who did not (Neurology 2012;79:785–792). Tafamidis was approved in Europe to treat Stage 1 FAP in 2012 and in Japan for all stages in 2013. Tafamidis has not been approved in the U.S. Tafamidis is now being tested in cardiac TTR amyloidosis but has not received approval for this indication. Information on the safety profile of tafamidis can be found in the product label.
Diflunisal is a “non-steroidal anti-inflammatory” (NSAID). This type of drug is often prescribed as a pain killer, for conditions such as arthritis. Diflunisal works by binding and stabilizing TTR in the blood to make it less amyloidogenic. Diflunisal has not been approved for use for TTR amyloidsis by any regulatory body, but a placebo controlled Phase 3 study to look at the efficacy of diflunisal in FAP patients was published in January 2014 (JAMA 2013;310(24):2658-2667). In this study neuropathy progressed at a slower rate in 64 patients with FAP who received diflunisal for 2 years relative to 66 patients who received placebo (dummy pills). Information on the safety profile of diflunisal can be found in the product label.
In TTR amyloidosis, supportive treatment is necessary for heart disease and/ or neuropathy, depending on the symptoms.
TTR amyloid deposits in the heart cause it to stiffen so it cannot pump the blood around the body efficiently, and symptoms of heart failure appear. Standard medications used for heart failure are not helpful for patients with cardiac amyloidosis but simple measures with a focus on careful fluid balance can be helpful.
Fluid build- up due to heart stiffness causes leg swelling (edema) and breathlessness due to fluid in the lungs. This problem may be exacerbated if the patient drinks too much fluid. So doctors may recommend that patients with TTR cardiac amyloidosis should limit their fluid intake.
Medical recommendations may include paying attention to the 3 Ds:
Support stockings may be recommended for patients with leg edema (swelling).
If there is light-headedness, fatigue on minor exertion or fainting due to blood pressure drops, doctors may advise careful position changing from lying to sitting, sitting to standing and standing to walking.
Doctors may recommend that the following drug classes should be used with caution by patients with TTR amyloid in the heart:
In some cases anticoagulation (warfarin) may be recommended.
A pacemaker or an implantable cardioverter-defibrillator (ICD) may be recommended if there is a slow or irregular heart rate, or episodes of very fast heart rate, tachycardia.
Combined heart and liver transplant has been performed in a few dozen patients with FAP worldwide. This is major surgery with significant associated risks, so it is only a possible option for a small minority of patients, usually those who are diagnosed at a relatively young age.
Heart transplantation is a major operation with a high risk of complications, especially in elderly people, so it is not usually a viable option for patients with FAC and SSA. Very rarely these conditions may be diagnosed at a younger age than 60, and heart transplantation may occasionally be considered if such patients are otherwise healthy.
Doctors may prescribe various drugs to combat neuropathic pain. Appropriate foot care and footwear can be crucial and medical advice should be sought in order to prevent painless pressure point ulcers and protect areas of the foot that lack sensation.
Patients with orthostatic hypotension (drops in blood pressure and faintness on standing up from sitting or lying positions) may benefit from wearing elastic stockings and sometimes from certain drugs. If there is vomiting and diarrhea, careful administration of intravenous fluids and anti‑nausea drugs may be necessary. It is, however, important to avoid fluid overload if there is heart disease, so fluid balance should be supervised by experienced medical professionals. There are also drugs available for diarrhea, constipation and erectile dysfunction.
A number of new drugs for TTR amyloidosis are in various stages of development, around the world, offering hope for the near future to patients with TTR amyloidosis. These include IONIS-TTRRx (described below), patisiran, ALN-TTRsc, CPHPC+anti-SAP antibodies, doxycycline and TUCA.
IONIS-TTRRx is a new, first in class drug developed by Ionis Pharmaceuticals with the aim of reducing the supply of TTR precursor proteins in patients with TTR amyloidosis. IONIS-TTRRx is currently in clinical trials in patients with FAP. Studies to evaluate IONIS-TTRRx in patients with FAC or SSA may initiate in the near future. It is not yet licensed and is only available at present to patients with FAP who are participating in these trials.
IONIS-TTRRx directly targets and reduces TTR production at the level of the genetic machinery inside the liver cells. When TTR production is shut down in this manner, the supply of TTR protein is reduced, which should reduce or prevent the formation of new TTR amyloid deposits in the tissues. Existing deposits may then become smaller, as the body clears them away, and organ function may stop deteriorating. Because IONIS-TTRRx reduces production of both variant and wild type TTR, this drug has the potential to be beneficial for patients with all three types of TTR amyloidosis (FAP, FAC, and SSA). A short-term clinical trial in healthy volunteers demonstrated that IONIS-TTRRx was well-tolerated and dramatically reduced TTR concentrations in the blood. Evidence regarding efficacy in controlling TTR amyloidosis is not yet available.