Transthyretin amyloidosis (ATTR) is a disease caused by the abnormal accumulation of protein molecules in body tissues. These protein accumulations or “amyloid deposits” are made from a blood protein, transthyretin (TTR), which normally transports thyroid hormone and vitamin A to the body tissues. When an inherited defect in the TTR protein occurs, this abnormal form of TTR has the tendency to accumulate in tissues such as the heart, kidneys, nerves, and intestine. The presence of these deposits interferes with the normal functions of the organs, and as the deposits enlarge more tissue damage occurs and the disease (TTR amyloidosis) worsens. TTR amyloidosis can also occur in older individuals (mostly men) and is not associated with a mutation in the TTR gene. Clinical disease is mainly cardiomyopathy (heart failure or arrythmias) with symptoms starting after age 70, although a few have been younger.
What is transthyretin?
TTR is a normal blood protein. Its function is to carry thyroid hormone and vitamin A to tissues where they are needed for normal metabolism. Like all proteins TTR is made from the 20 different amino acids which are linked end to end to make large molecules. Each protein is identified by the arrangement of the amino acids in the protein chain and this arrangement is determined (coded) by a specific gene.
In the case of TTR a single gene located on chromosome 18 codes for the amino acid alignment (sequence) which is characteristic of this protein and distinguishes it from all other proteins.
What causes transthyretin amyloidosis?
The hereditary form of TTR amyloidosis is caused by mutations in the TTR protein. A mutation occurs when the position of one amino acid in the protein chain is replaced by a different amino acid. This causes a structural change in the protein molecule, and the protein then has a tendency to deposit in the tissues. The protein that actually deposits in the tissues has changed its structure so that aggregation of many protein molecules makes fibrils (B-fibrils) which are very resistant to being dissolved or degraded by normal body functions. More than than 100 TTR mutations have been discovered. In older individuals with ATTR who do not have a mutation in the TTR protein there must be some (as yet unknown) abnormality in the individuals metabolism that allows normal TTR protein to follow the path to amyloid fibril formation.
Who gets transthyretin amyloidosis?
The hereditary form of TTR amyloidosis is a genetically transmitted disease. A mutation in the gene for TTR protein is passed from one generation to another. It is an autosomal dominant disease which means that both men and women get the disease and that only one copy of the mutated gene is required to cause the disease. An individual with a mutant form of TTR may have obtained the genetic trait from either their mother or father and they in turn are capable of passing the mutant gene on to their children. Each child has an equal chance (50/50) of inheriting the mutant gene instead of the normal gene. TTR amyloidosis almost always occurs after age 20 and in most individuals the disease begins after age 50. By that time most individuals with mutated TTR genes have had the opportunity to raise families and, therefore, have passed the gene on to their children before they themselves develop the clinical disease.
What happens in transthyretin amyloidosis?
While TTR amyloid deposits may occur in any organ, the hereditary type of ATTR most commonly affects the peripheral nerves, heart, intestine, and the kidney. For any one individual it is difficult to predict which organ will be involved to the greatest extent and, therefore, cause disease symptoms that will be recognized by the patient and their physician. Amyloid involvement of the peripheral nerves most commonly causes numbness or tingling in the feet or hands at the beginning and then may progress to cause difficulties in walking or performing fine hand movements. Involvement of the heart often causes congestive heart failure with tiredness, weakness, and swelling of the feet from water retention. Involvement of the intestine may cause constipation, or diarrhea, or alternating constipation and diarrhea. In some patients with specific forms of TTR arnyloidosis, deposits of the protein occur in the eye and obstruct vision. A few individuals developed deposits of amyloid in the linings around the brain and this may cause headache and stroke-like symptoms. In individuals with the older age onset (wild-type) the heart is the major site of involvement with heart failure the most common presenting feature.
The diagnosis of TTR amyloidosis can only be firmly established by tissue biopsy. Biopsy of an affected organ such as peripheral nerve, intestine, heart, or kidney allows the demonstration of amyloid deposits with special stains on microscopic sections of the tissue. First, however, it is necessary for the physician to suspect the diagnosis of amyloidosis so that a biopsy will be done. For many individuals a family history will suggest that TTR amyloidosis diagnosis should be considered. If an affected individual reports that their mother or father had a similar illness or was found to have amyloidosis when they died this will raise the likely diagnosis of amyloidosis. The same is true if an affected person has a brother or sister who has the disease. Now we have the ability to test the DNA of individuals suspected of having TTR amyloidosis and determine if they have one of the mutant genes which causes this disease. By isolating DNA from a sample of blood, tests can be done to detect the genetic mutation associated with TTR amyloidosis. In addition, DNA tests can be done for any person who wants to know if they have a TTR gene mutation that can cause the disease before they develop any signs. This will allow that person to seek medical advice and counseling without being subjected to extensive medical tests for other diseases which might be suspected if the results of DNA analysis were not known. If tissue biopsy shows TTR amyloid but DNA analysis does not show a TTR mutation the diagnosis is “wild-type” ATTR.
TTR amyloidosis is a progressive disease which usually causes increasing organ dysfunction over a time of several years. The rate of progression varies considerably depending on which TTR mutation causes the disease. Major causes of disability include bowel dysfunction with severe diarrhea and weight loss, congestive heart failure with generalized weakness, and difficulties breathing from fluid retention. A smaller number of individuals develop kidney failure and require dialysis. It is not unusual for affected individuals to live 5, 10, 15, or sometimes even 20 years after the first signs of disease.
TTR (both normal and mutant) is made in the liver so liver transplantation will stop production of mutant TTR and leave only normal TTR in the blood. Many ATTR individuals have benefited from liver transplantation but subsequently can continue to have progression of their disease due to amyloid deposits from the normal (not mutated) form of TTR. There are new drugs which inhibit the liver production of mutant and normal TTR that have been shown to decrease or stop the progression of ATTR. There are two drugs available to inhibit TTR production by the liver, TegsediTM (inotersen) provided by Akcea Therapeutics and Ionis Pharmaceuticals and OnpattroTM (patisiran) provided by Alnylam Pharmaceuticals. In addition a drug to “stabilize” TTR in the blood, VyndaqelTM/VynadmaxTM (tafamidis) manufactured by Pfizer Pharmaceuticals has been approved for ATTR affecting the heart. It is also approved for early stage ATTR neuropathy in Europe but not the US.
Immunoglobulin Light Chain Amyloidosis
AL or immunoglobulin light chain amyloidosis is a plasma cell disorder where parts of the antibody molecules known as free light chains deposit in organs and tissues. AL amyloidosis most commonly affects the kidneys and the heart, but most organ systems are affected to some degree. Symptoms may include bruising around the eyes, a large tongue, numbness and tingling in the hands and feet, low blood pressure, heart failure, and kidney dysfunction.
Treatments focus on reducing the production of free light chains and may include chemotherapy and stem cell transplantation.
AA amyloidosis is caused by inflammatory disorders that lead to the overproduction of SAA protein by the liver. At this time there are no approved specific therapies, but therapies that target inflammation in the underlying disorder may be useful.
Leukocyte chemotactic factor 2 (LECT 2) amyloidosis is caused by over production of LECT 2 by the liver. ALECT2 amyloidosis most commonly affects the kidney and liver. This type of amyloidosis is more common in individuals of Mexican and Native American descent.
At this time no specific treatment is available.
Despite the advent of specific treatments for ATTR there is need for continued research:
- TedgsediTM and OnpattroTM are approved for ATTR neuropathy. Ongoing studies are testing these drugs for cardiac involvement.
- More “stabilizer”drugs are being tested for ATTR.
- There may be more types of familial amyloidosis waiting to be discovered and benefit from novel treatments.