Familial transthyretin amyloidosis

Other Names: Amyloidosis, hereditary, transthyretin-related; Transthyretin amyloidosis; Familial amyloid polyneuropathy; Amyloidosis Transthyretin related; Transthyretin amyloid neuropathy; TTR amyloid neuropathy; Transthyretin amyloid polyneuropathy; Hereditary ATTR amyloidosis

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.

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. Other areas of the body that may be affected are the heart, kidneys, eyes, and gastrointestinal tract.

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.

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.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

Familial transthyretin amyloidosis (FTA) is inherited in families in an autosomal dominant pattern. This means only one copy of a mutated TTR gene is needed for a person to have the condition. The mutation can be inherited from a parent or can happen by chance for the first time (de novo) in an individual. Each child of a person with FTA has a 50% chance of inheriting the mutation. Most children who inherit a TTR mutation will develop FTA, although they could be more or less severely affected than their parent. For reasons that are unclear, some people have mutations in the TTR gene and never develop FTA.

Signs and symptoms

Symptoms start in adulthood and get worse over time. Signs and symptoms depend on where the amyloid protein is building up Familial transthyretin amyloidosis (FTA) 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 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

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. Symptoms of FTA include •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. Less common symptoms include skin changes, hearing loss, shortness of breath, and anemia.

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. Laboratory tests include examination of a biopsy of an affected area, along with genetic testing to look for a mutation in TTR gene.

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. 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.

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

• Patisiran (Brand name: Onpattro)patisiran (Onpattro) was approved for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.
• Inotersen (Brand name: Tegsedi)inotersen (Tegsedi) was approved for the treatment of the polyneuropathy of hereditary transthyretinmediated amyloidosis in adults.

Prognosis

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