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Disease Profile

Familial transthyretin amyloidosis

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

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ICD-10

#N/A

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Amyloidosis, hereditary, transthyretin-related; Transthyretin amyloidosis; Familial amyloid polyneuropathy;

Categories

Nervous System Diseases

Summary

Familial transthyretin amyloidosis (FTA) is a rare inherited condition characterized by abnormal build-up of a protein called amyloid in the body's organs and tissues.[1][2] Symptoms start in adulthood and get worse over time. Signs and symptoms depend on where the amyloid protein is building up.[1] Amyloid build-up in the nerves of the peripheral nervous system causes a loss of sensation in the lower limbs, feet, and hands (peripheral neuropathy). Amyloid build-up can also affect the involuntary body functions, such as blood pressure, heart rate, and digestion.[1][2] Other areas of the body that may be affected are the heart, kidneys, eyes, and gastrointestinal tract.[1]

FTA is caused by changes (mutations) in the TTR gene. Inheritance is autosomal dominant, but not all people with a TTR gene mutation will develop FTA.[2][3] Diagnosis of FTA is suspected by signs and symptoms and confirmed by tissue biopsy and genetic testing.[1]

Primary treatment is a liver transplantation. This procedure removes the main source of amyloid from the body, but amyloid may still build-up in the heart, brain, and eyes. New medications have become available that block the formation of amyloid and may provide an alternative to liver transplant. Other treatments include heart and/or kidney transplantation, putting in a pacemaker, replacing the fluid in the eye (vitrectomy), and various medications.[3] FTA is typically a fatal condition, but life expectancy depends on many factors.[1][3]

Symptoms

Familial transthyretin amyloidosis (FTA) is a slowly progressing, adult-onset condition.[1][13890] Symptoms depend on which body parts are most affected. The age symptoms begin may also vary by country. In Portugal and Japan, people with FTA usually start developing symptoms in their late 20s to 40s. In other parts of the world, people with FTA may not have symptoms until after age 50.[2]

The most common form of FTA 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 FTA can affect the brain, spinal cord, heart, and eyes.[1][2][4]

Symptoms of FTA include[5] 

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.[3][4]

Less common symptoms include skin changes, hearing loss, shortness of breath, and anemia.[3]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
Percent of people who have these symptoms is not available through HPO
Adult onset
Symptoms begin in adulthood
0003581
Amyloid deposition in the vitreous humor
0007841
Amyloidosis
0011034
Ataxia
0001251
Autosomal dominant inheritance
0000006
Cardiomegaly
Enlarged heart
Increased heart size

[ more ]

0001640
Cardiomyopathy
Disease of the heart muscle
0001638
Constipation
0002019
Constrictive median neuropathy
0012185
Dementia
Dementia, progressive
Progressive dementia

[ more ]

0000726
Diarrhea
Watery stool
0002014
Dysarthria
Difficulty articulating speech
0001260
Headache
Headaches
0002315
Hearing impairment
Deafness
Hearing defect

[ more ]

0000365
Hemiparesis
Weakness of one side of body
0001269
Hyporeflexia
Decreased reflex response
Decreased reflexes

[ more ]

0001265
Impotence
Difficulty getting a full erection
Difficulty getting an erection

[ more ]

0000802
Increased CSF protein
0002922
Leptomeningeal enhancement
0032070
Muscle weakness
Muscular weakness
0001324
Nystagmus
Involuntary, rapid, rhythmic eye movements
0000639
Orthostatic hypotension due to autonomic dysfunction
0004926
Paraplegia
Leg paralysis
0010550
Peripheral axonal neuropathy
0003477
Polyneuropathy
Peripheral nerve disease
0001271
Progressive
Worsens with time
0003676
Seizure
0001250
Spasticity
Involuntary muscle stiffness, contraction, or spasm
0001257
Stroke-like episode
0002401
Tremor
0001337
Urinary incontinence
Loss of bladder control
0000020
Visual impairment
Impaired vision
Loss of eyesight
Poor vision

[ more ]

0000505

Cause

Familial transthyretin amyloidosis (FTA) is caused by changes (mutations) in the TTR gene. This gene is responsible for making a protein called transthyretin which transports vitamin A and a hormone called thyroxin to many parts of the body. 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.[4]

Most people who have FTA have inherited the TTR mutation from a family member. However, a few people with FTA will have no family history of the disease and have a new (de novo) mutation in the TTR gene.[1][4]

Diagnosis

The diagnosis of familial transthyretin amyloidosis (FTA) can be difficult because the signs and symptoms of FTA 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 FTA. Laboratory tests include examination of a biopsy of an affected area, along with genetic testing to look for a mutation in TTR gene.[3][4]

Treatment

There is no treatment available for familial transthyretin amyloidosis (FTA) that reverses damage caused by amyloid deposits, but there are treatments that may prevent or delay progression.[1][3] Treatment depends on which tissues are affected and how far the disease has progressed.[3] 

Liver transplantation is the "gold standard" for treatment for FTA, 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.[1] 

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.[3][6]

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.[3]

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 FTA are treated as they arise.[3]

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.
    National Library of Medicine Drug Information Portal
  • 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.
    National Library of Medicine Drug Information Portal

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

    Social Networking Websites

    • RareConnect has an online community for patients and families with this condition so they can connect with others and share their experiences living with a rare disease. The project is a joint collaboration between EURORDIS (European Rare Disease Organisation) and NORD (National Organization for Rare Disorders).

      Learn more

      These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

      Where to Start

      • Amyloidosis Awareness is an illustrated booklet for patients and physicians developed by Amyloidosis Support Groups Inc. Versions of the booklet are also available in Spanish and Portuguese.
      • Genetics Home Reference (GHR) contains information on Familial transthyretin amyloidosis. This website is maintained by the National Library of Medicine.

        In-Depth Information

        • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
        • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
        • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
        • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
        • PubMed is a searchable database of medical literature and lists journal articles that discuss Familial transthyretin amyloidosis. Click on the link to view a sample search on this topic.

          References

          1. Roberts JR. Transthyretin-Related Amyloidosis. Medscape Reference. Updated 10/10/2018; https://emedicine.medscape.com/article/335301-overview.
          2. Transthyretin amyloidosis. Genetics Home Reference. Updated 10/30/2018; https://ghr.nlm.nih.gov/condition/transthyretin-amyloidosis.
          3. 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.
          4. Sekijima Y, Yoshida K, Tokuda T, Ikeda S-I. Familial transthyretin amyloidosis. GeneReviews. Updated January 26, 2012; https://www.ncbi.nlm.nih.gov/books/NBK1194/. Accessed 11/15/2018.
          5. 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.
          6. 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/.
          7. 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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