What are the other Names for this Condition? (Also known as/Synonyms)

• Amyloidosis, Hereditary, Transthyretin-Related
• Familial Amyloid Polyneuropathy
• Hereditary ATTR Amyloidosis

What is Familial Transthyretin Amyloidosis? (Definition/Background Information)

• Familial Transthyretin Amyloidosis 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
• Amyloid deposits in the nerves of the peripheral nervous system 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) as well as the central nervous system (brain and spinal cord) may also be affected. Other areas of the body affected include the heart, kidneys, eyes, and gastrointestinal tract
• The age at which symptoms develop varies widely among affected individuals, and may be between ages 20 and 70 years
• Mutations in the TTR gene cause the condition. Although it is inherited in an autosomal dominant pattern, not all people who have a TTR gene mutation will develop Familial Transthyretin Amyloidosis
• There are three major forms of Familial Transthyretin Amyloidosis, which are distinguished by their symptoms and the body systems they affect:
  • The neuropathic form of transthyretin amyloidosis primarily affects the peripheral and autonomic nervous systems, resulting in peripheral neuropathy and difficulty controlling bodily functions
  • The leptomeningeal form of transthyretin amyloidosis primarily affects the central nervous system
  • The cardiac form of transthyretin amyloidosis affects the heart

(Source: Familial Transthyretin Amyloidosis; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Who gets Familial Transthyretin Amyloidosis? (Age and Sex Distribution)

• Familial Transthyretin Amyloidosis is a rare disorder. The presentation of symptoms commonly occur in the 20-70 years’ age group
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Familial Transthyretin Amyloidosis? (Predisposing Factors)

• A positive family history is an important risk factor, since Familial Transthyretin Amyloidosis may be inherited

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Familial Transthyretin Amyloidosis? (Etiology)

• Familial Transthyretin Amyloidosis is a genetic disorder that is known to be caused by mutations in the TTR gene that is inherited in an autosomal dominant manner
• However, research scientists have established that not all individuals with TTR gene mutations develop the disorder

What are the Signs and Symptoms of Familial Transthyretin Amyloidosis?

The signs and symptoms of Familial Transthyretin Amyloidosis include:

• Amyloid deposition in the vitreous humor
• Amyloidosis
• Ataxia
• Cardiomegaly
• Cardiomyopathy
• Constipation
• Dementia
• Diarrhea
• Dysarthria
• Dysautonomia
• Headache
• Hearing impairment
• Hemiparesis
• Hyporeflexia
• Impotence
• Increased CSF protein
• Nystagmus
• Orthostatic hypotension due to autonomic dysfunction
• Paraplegia
• Peripheral axonal neuropathy
• Polyneuropathy
• The condition is known to be progressive
• Seizures
• Spasticity
• Stroke-like episode
• Tremor
• Urinary incontinence
• Visual impairment

(Source: Familial Transthyretin Amyloidosis; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Familial Transthyretin Amyloidosis Diagnosed?

There have been several recommendations proposed for evaluating and treating individuals with Familial Transthyretin Amyloidosis. To establish the extent of the disease in a newly diagnosed individual, evaluation may include:

• Complete neurologic assessment including baseline nerve conduction studies (which measure the speed at which nerves conduct impulses)
• Evaluation of the heart for cardiomyopathy and to evaluate amyloid deposition in the heart
• Gadolinium-enhanced MRI of the brain and spinal cord to evaluate central nervous system (CNS) amyloidosis
• Ophthalmologic (eye) evaluation
• Evaluation of renal function

(Source: Familial Transthyretin Amyloidosis; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the Possible Complications of Familial Transthyretin Amyloidosis?

The complications of Familial Transthyretin Amyloidosis may include:

• Involvement of the central nervous system leading to severe neurological symptoms
• Heart abnormalities

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Familial Transthyretin Amyloidosis Treated?

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. Treatment depends on which tissues are affected and how far the disease has progressed.

• 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
• 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
• 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
• 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

(Source: Familial Transthyretin Amyloidosis; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Newer medications to alter the effects of abnormal proteins using RNA interference (RNAi) and other molecular technologies are in various stages of development and commercialization. The medical provider may help with information on advancements in new treatment methods.

How can Familial Transthyretin Amyloidosis be Prevented?

Currently, Familial Transthyretin Amyloidosis may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Familial Transthyretin Amyloidosis? (Outcomes/Resolutions)

• The prognosis for individuals with Familial Transthyretin Amyloidosis depends on the presence and type of transthyretin protein being deposited, as well as the organ(s) affected by the disease
• Patients with early-onset disease and certain types of transthyretin protein may die within a few years of diagnosis, while older patients with slowly progressive disease can live for decades after the onset of symptoms and may never develop life-threatening disease
• Unlike in other types of amyloidosis, symptomatic cardiac involvement does not necessarily mean a poor prognosis

(Source: Familial Transthyretin Amyloidosis; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Additional and Relevant Useful Information for Familial Transthyretin Amyloidosis:

Familial Transthyretin Amyloidosis is also known by the following names:

• Amyloidosis, Transthyretin-Related
• Transthyretin Amyloid Neuropathy
• Transthyretin Amyloid Polyneuropathy
• Transthyretin Amyloidosis
• TTR Amyloid Neuropathy

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/