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transthyretin amyloidosis

What is transthyretin

Transthyretin is a plasma transport protein primarily synthesized in the liver for the thyroid hormone, thyroxine, and retinol (vitamin A)-binding protein 1. Transthyretin is the tertiary carrier of thyroxine (T4) in plasma, carrying less thyroxine (T4) than thyroxine-binding globulin (TBG) and albumin. Transthyretin has been widely studied for its role in amyloid diseases associated with protein misfolding and aggregation, resulting in deposits of toxic, fibrillar aggregates in specific organs 2. Dysregulated or reduced transthyretin has also been implicated in Alzheimer disease and overexpression of a wild-type human transthyretin transgene has been shown to ameliorate the disease in the transgenic murine model of human Alzheimer disease 3. Transthyretin is a 127 amino acid protein and in its native form assumes a homotetrameric quaternary configuration (i.e. four single chain transthyretin monomers form a tetrameric complex). Post-translational modifications of the transthyretin monomer result in detection of several isoforms 4. Circulating transthyretin is also a validated marker of malnutrition and has a putative role in oocyte maturation and inflammation 5.

Transthyretin amyloidosis

Transthyretin amyloidosis also called familial amyloid polyneuropathy, Portuguese polyneuritic amyloidosis or Swiss type amyloid polyneuropathy, is a slowly progressive condition characterized by the buildup of abnormal deposits of a protein called amyloid (amyloidosis) in the body’s organs and tissues. These protein deposits most frequently occur in the peripheral nervous system, which is made up of nerves connecting the brain and spinal cord to muscles and sensory cells that detect sensations such as touch, pain, heat, and sound. Protein deposits in these nerves result in a loss of sensation in the extremities (peripheral neuropathy). The autonomic nervous system, which controls involuntary body functions such as blood pressure, heart rate, and digestion, may also be affected by amyloidosis. In some cases, the brain and spinal cord (central nervous system) are affected. Other areas of amyloidosis include the heart, kidneys, eyes, and gastrointestinal tract. The age at which symptoms begin to develop varies widely among individuals with this condition, and is typically between ages 20 and 70.

Familial amyloid polyneuropathy is a rare disorder with the exact incidence of transthyretin amyloidosis is unknown. In northern Portugal, the incidence of familial amyloid polyneuropathy is thought to be one in 538 people. Transthyretin amyloidosis is less common among Americans of European descent, where it is estimated to affect one in 100,000 people. The cardiac form of transthyretin amyloidosis is more common among people with African ancestry. It is estimated that this form affects between 3 percent and 3.9 percent of African Americans and approximately 5 percent of people in some areas of West Africa.

There are three major forms of transthyretin amyloidosis, which are distinguished by their symptoms and the body systems they affect.

  1. The neuropathic form of transthyretin amyloidosis primarily affects the peripheral and autonomic nervous systems, resulting in peripheral neuropathy and difficulty controlling bodily functions. Impairments in bodily functions can include sexual impotence, diarrhea, constipation, problems with urination, and a sharp drop in blood pressure upon standing (orthostatic hypotension). Some people experience heart and kidney problems as well. Various eye problems may occur, such as cloudiness of the clear gel that fills the eyeball (vitreous opacity), dry eyes, increased pressure in the eyes (glaucoma), or pupils with an irregular or “scalloped” appearance. Some people with this form of transthyretin amyloidosis develop carpal tunnel syndrome, which is characterized by numbness, tingling, and weakness in the hands and fingers.
  2. The leptomeningeal form of transthyretin amyloidosis primarily affects the central nervous system. In people with this form, amyloidosis occurs in the leptomeninges, which are two thin layers of tissue that cover the brain and spinal cord. A buildup of protein in this tissue can cause stroke and bleeding in the brain, an accumulation of fluid in the brain (hydrocephalus), difficulty coordinating movements (ataxia), muscle stiffness and weakness (spastic paralysis), seizures, and loss of intellectual function (dementia). Eye problems similar to those in the neuropathic form may also occur. When people with leptomeningeal transthyretin amyloidosis have associated eye problems, they are said to have the oculoleptomeningeal form.
  3. The cardiac form of transthyretin amyloidosis affects the heart. People with cardiac amyloidosis may have an abnormal heartbeat (arrhythmia), an enlarged heart (cardiomegaly), or orthostatic hypertension. These abnormalities can lead to progressive heart failure and death. Occasionally, people with the cardiac form of transthyretin amyloidosis have mild peripheral neuropathy.

Familial amyloid polyneuropathy key points

Familial amyloid polyneuropathy also called hereditary amyloidogenic transthyretin amyloidosis is an autosomal dominant, adult-onset systemic disease that usually presents as a progressive peripheral neuropathy and is caused by point mutations in the gene that encodes transthyretin (TTR).

  • Familial amyloid polyneuropathy (hereditary amyloidogenic transthyretin amyloidosis) was initially considered to be endemic to certain regions but is now known to occur worldwide; there are many variants of the TTR gene, which creates large genetic and phenotypic heterogeneity.
  • Dissociation of mutant TTR homotetramers, disruption of the blood–nerve barrier and misfolding and aggregation of TTR that causes endoneurial toxicity are major events in the pathogenesis of ATTRv amyloidosis.
  • Clinical presentation is diverse, including length-dependent small-fibre polyneuropathy, all-fiber polyneuropathy, pseudo-chronic inflammatory demyelinating polyneuropathy, upper-limb-onset neuropathy and motor neuropathy; half of patients also have cardiac amyloidosis.
  • Diagnosis is based on TTR gene sequencing to detect causal mutations and biopsy to detect amyloid deposits or scintigraphy to assess cardiac uptake of bone tracers when biopsy samples are negative.
  • Disease-modifying therapy includes liver transplantation, TTR stabilizers and TTR gene-silencing therapies; trials of RNA interference therapy have produced improvements in neuropathy and quality of life, suggesting reversal of the disease.

Transthyretin amyloidosis causes

Mutations in the transthyretin (TTR) gene cause transthyretin amyloidosis. The transthyretin (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.

Transthyretin amyloidosis inheritance pattern

Transthyretin amyloidosis is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In most cases, an affected person inherits the mutation from one affected parent. Not all people who have a TTR gene mutation will develop transthyretin amyloidosis.

Rarely, transthyretin amyloidosis cases result from new mutations in the gene and occur in people with no history of the disorder in their family. This is called a de novo mutation.

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.

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. Transthyretin amyloidosis autosomal dominant inheritance pattern

Transthyretin 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:

Transthyretin amyloidosis symptoms

Familial amyloid polyneuropathy or familial transthyretin amyloidosis is a slowly progressing, adult-onset condition. Symptoms depend on which body parts are most affected. The age symptoms begin may also vary by country. In Portugal and Japan, people with familial transthyretin amyloidosis usually start developing symptoms in their late 20s to 40s. In other parts of the world, people with familial transthyretin amyloidosis may not have symptoms until after age 50.

The most common form of familial transthyretin amyloidosis affects the peripheral nervous system. The peripheral nerves send messages from the brain and spinal cord to the rest of the body. Other forms of familial transthyretin amyloidosis can affect the brain, spinal cord, heart, and eyes.

Symptoms of familial amyloid polyneuropathy include 6:

  • Weakness, numbness or pain in the lower legs and feet
  • Carpal tunnel syndrome in both wrists
  • Sexual impotence
  • Urinary problems, protein in the urine
  • Diarrhea or constipation
  • Unexplained weight loss
  • Dry eyes, increased pressure in the eyes (glaucoma), seeing ‘floaters’
  • Abnormal heart beat, enlarged heart
  • Getting dizzy when moving from sitting to standing (orthostatic hypotension)
  • Dry eyes and mouth

Later symptoms may include muscle weakness and stiffness, difficulty with coordination, stroke, seizures, dementia, and congestive heart failure 7.

Less common symptoms include skin changes, hearing loss, shortness of breath, and anemia 7.

Polyneuropathy

The main neuropathic feature of familial amyloid polyneuropathy is a progressive sensori-motor and autonomic neuropathy. Val30Met (valine in position 30 is replaced by methionine) is the most common TTR mutation in patients presenting with neuropathy. The disease onset is usu-ally in the third or fourth decade, but can occur later. The dis-ease initially affects small unmyelinated nerve fibers which medi-ate pain and temperature sensations, and autonomic nerve functions. Typically, sensory neuropathy with paresthesia (numbness and tingling) and hypesthesia starts in the feet and progresses proximally. By the time the sensory neuropathy has progressed to the knee level, the hands have usually become involved. With progression of the neuropathy, larger myelinated fibers become involved, impacting position and vibratory sensations, and re-flexes. Carpal tunnel syndrome with median nerve compression is common and may be the first presenting symptom.

Motor neuropathy usually follows within a few years. Foot drop, wrist drop and disability of the hands and feet are frequent symptoms of motor neuropathy leading to difficulties in walking and performing fine hand movements.

Subjects with the Val30Met mutation also have evidence of cardiac involvement with conduction disease manifestation early in the course of the disease. As the disease progresses, features of a restrictive cardiomyopathy develop with resulting heart failure and atrial arrhythmias.

Autonomic neuropathy

Autonomic neuropathy often accompanies the sensory and mo-tor deficits and may represent the initial disease presentation. Symptoms include orthostatic hypotension, constipation alter-nating with diarrhea, nausea, vomiting, delayed gastric emptying, erectile dysfunction, anhydrosis, urinary retention and in-continence. The gastrointestinal involvement results in weight loss and ultimately in cachexia.

Symptoms from the central nervous system (CNS) are rarely found in familial amyloid polyneuropathy except in very rare forms of familial leptomeningeal amyloidosis, in which there may be cerebral hemorrhage with stroke like symptoms.

Transthyretin amyloid cardiomyopathy

Cardiomyopathy may be the predominant feature of familial amyloid polyneuropathy for some patients ormay develop after the onset of neuropathy in patients with familial amyloid polyneuropathy. Transthyretin amyloid cardiomyopathy occurs when transthyretin amyloid fibrils infiltrate the myocardium, causing myocardial stiffness, reduction in chamber capacitance and restrictive filling patterns seen on Doppler echocardiography. This initially results in diastolic dysfunction, and without treatment will progress to symptomatic heart failure typical of restrictive cardiomyopathy.

The phenotype is characterized by progressive heart failure, of-ten with severe right-sided symptoms. When a low cardiac out-put supervenes, renal impairment may occur, although autopsy studies have not shown renal involvement by amyloid deposits.

The onset of transthyretin amyloid cardiomyopathy may occur at any age from the third decade onward, with the typical age of onset > 55 in patients with the Val122Ile mutation. Cardiac involvement can present with conduction system disease (sinus node or atrioventricular node dysfunction) or congestive heart failure including shortness of breath, peripheral edema, syncope, exertional dyspnea, generalized fatigue or with heart block. The echocardiographic findings often show thicker ventricular walls than in amyloid fibrils derived from monoclonal immunoglobulin light-chains and include thickened ventricular walls (concentric hypertrophy, both right and left) with a normal to small left ventricular cavity, increased myocardial echogenicity, normal or mildly reduced ejection fraction, often with evidence of diastolic dysfunction and severe impairment of contraction along the longitudinal axis, and bi-atrial dilation with impaired atrial contraction. Subjects with transthyretin amyloid usually have more severe left ventricular thickening than those with amyloid fibrils derived from monoclonal immunoglobulin light-chains amyloidosis.

Similar to amyloid fibrils derived from monoclonal immunoglobulin light-chains amyloidosis, the voltage on the ECG may be nor-mal, although low voltage may be seen despite the increased wall thickness on echocardiography. Low voltage is a marker of advanced disease and lacks sensitivity in isolation for identification of the phenotype. As many as 15% of subjects with familial amyloid polyneuropathy can have electrocardiographic evidence of left ventricular hypertrophy. Clinicians are encouraged to measure the volt-age to mass ratio as this is a more sensitive marker than the EKG voltage alone. Also, poor precordial R wave progression and pseudoinfarcts (q waves in the absence of previous myocardial infarctions) are quite common in subjects with familial amyloid polyneuropathy and provides clues to the diagnosis. Marked axis deviation, bundle branch block and AV block is common, as is atrial fibrillation.

Ocular manifestations

The TTR gene is also expressed in the retinal pigment epithelium of the eye, and approximately 20% of amyloidogenic TTR mutations are associated with vitreous opacities derived from amyloid, and may lead to visual impairment. Transthyretin amyloid can be visualized in the vitreous body with typical cotton wool inclusions. Demonstration of such deposits is helpful for the diagnosis of familial amyloid polyneuropathy.

Transthyretin amyloidosis diagnosis

The diagnosis of familial amyloid polyneuropathy (familial transthyretin amyloidosis) can be difficult because the signs and symptoms of familial transthyretin amyloidosis often look like other, more common conditions. Doctors and nurses use a combination of signs and symptoms and laboratory and genetic tests to determine if someone has familial transthyretin amyloidosis. Laboratory tests include examination of a biopsy of an affected area, along with genetic testing to look for a mutation in TTR gene 7.

Transthyretin amyloidosis treatment

There is no treatment available for familial transthyretin amyloidosis (familial transthyretin amyloidosis) that reverses damage caused by amyloid deposits, but there are treatments that may prevent or delay progression 8. Treatment depends on which tissues are affected and how far the disease has progressed 9.

Liver transplantation is the “gold standard” for treatment for familial transthyretin amyloidosis, because it replaces the main source of amyloid. It may slow or halt progression of peripheral neuropathy, but the disease often still progresses in the eyes and brain. Transplantation ideally should be done as early as possible before there are severe neurological problems 8.

Several medications have been developed that slow the build-up of amyloid along nerves and in other parts of the body. These include tafamidis, diflunsial, and more recently inotersen and patisiran. There are other drugs that are currently under investigation for this condition 10.

Additional treatments may include heart and/or kidney transplantation, replacement of the liquid part of the eye (vitrectomy) for eye involvement, and carpal tunnel surgery 9.

Diuretics, medications that remove excess water and salt from the body, are often used to manage congestive heart failure associated with the disease. Other symptoms of familial transthyretin amyloidosis are treated as they arise 9.

FDA-approved treatments

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition. Learn more orphan products.

  • Patisiran (Brand name: Onpattro) – Manufactured by Alnylam Pharmaceuticals, Inc. FDA-approved indication: August 2018, patisiran (Onpattro) was approved for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.
  • Inotersen (Brand name: Tegsedi) – Manufactured by Ionis Pharmaceuticals, Inc. FDA-approved indication: October 2018, inotersen (Tegsedi) was approved for the treatment of the polyneuropathy of hereditary transthyretinmediated amyloidosis in adults.

Transthyretin amyloidosis life expectancy

The outlook and life expectancy for each person with familial 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 8. On average, people with familial transthyretin amyloidosis typically live for 7-12 years after they are first diagnosed 9.

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 11. 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 transthyretin amyloidosis. People with questions about their personal outlook should speak with their healthcare providers.

References
  1. Raz A., Goodman D.S. The interaction of thyroxine with human plasma prealbumin and with the prealbumin-retinol-binding protein complex. J Biol Chem. 1969;244:3230–3237.
  2. Hammarström P., Wiseman R.L., Powers E.T., Kelly J.W. Prevention of transthyretin amyloid disease by changing protein misfolding energetics. Science. 2003;299:713–716.
  3. Buxbaum J.N., Ye Z., Reixach N., Friske L., Levy C., Das P., Golde T., Masliah E., Roberts A.R., Bartfai T. Transthyretin protects Alzheimer’s mice from the behavioral and biochemical effects of Abeta toxicity. Proc Natl Acad Sci U S A. 2008;105:2681–2686.
  4. Altland K., Winter P., Saraiva M.J., Suhr O. Sulfite and base for the treatment of familial amyloidotic polyneuropathy: two additive approaches to stabilize the conformation of human amyloidogenic transthyretin. Neurogenetics. 2004;5:61–67.
  5. Henze A., Rohn S., Gericke B., Raila J., Schweigert F.J. Structural modifications of serum transthyretin in rats during protein-energy malnutrition. Rapid Commun Mass Spectrom. 2008;22:3270–3274.
  6. Pinto MV, Barreria AA, Bulle AS, Gomes de Freitas MR, et al. Brazilian consensus for diagnosis, management and treatment for transthyretin familial amyloid polyneuropathy. Arg Neuropsiquiatr. Sep 2018; 76(9):609-621. https://www.ncbi.nlm.nih.gov/pubmed/30365625
  7. Sekijima Y. Hereditary Transthyretin Amyloidosis. 2001 Nov 5 [Updated 2018 Dec 20]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1194
  8. Transthyretin-Related Amyloidosis. https://emedicine.medscape.com/article/335301-overview
  9. Ando Y, Coelho T, Berk JL. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet Journal of Rare Diseases. 2013; 8(31):https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-8-31
  10. Obici L, Kuks JB, Buades J, et al. Recommendations for presymptomatic genetic testing and management of individuals at risk for hereditary transthyretin amyloidosis. Curr Opin Neurol. February, 2016; Suppl 1:S27-35. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4739313
  11. Plante-Bordeneuve V. Transthyretin familial amyloid polyneuropathy: an update. Jl of Neuro. 2018; 265:976-983. https://www.ncbi.nih.gov/pubmed/29249054
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