hATTR amyloidosis is an inherited, rapidly progressive, life-threatening disease.1-3 hATTR amyloidosis is caused by a mutation in the transthyretin (TTR) gene that results in misfolded TTR proteins accumulating as amyloid fibrils in multiple tissues in the body, including the nerves, heart, and gastrointestinal tract.2,4,5
hATTR amyloidosis is an autosomal dominant disease; meaning a person only needs to inherit one copy of the affected gene from one parent in order to develop the condition. When one parent carries an autosomal dominant mutation, any child will have a 50% chance of inheriting that mutation.2,6
hATTR amyloidosis affects an estimated 50,000 people worldwide.5 In the disease continuum of hATTR amyloidosis some individuals present primarily with nerve-related symptoms, historically known as familial amyloidotic polyneuropathy (FAP).5,6 Others present primarily with heart-related symptoms, historically known as familial amyloidotic cardiomyopathy (FAC).5,6 More than half of people with hATTR amyloidosis present with a mix of both types of symptoms.7,8
The symptom presentation of hATTR amyloidosis is highly varied among individuals, even within the same mutation or the same family. In addition to the varied symptom presentation, the age of onset is wide-ranging – the median age is 39 years, with some people presenting as early as their 20s.6,9
The disease affects multiple organs, resulting in a variety of symptoms.3,10,11
Possible signs and symptoms of hATTR amyloidosis10
Central Nervous System (CNS) manifestations:
- Stroke-like episodes
- Progressive dementia
- Loss of movement control
- Abnormalities of the pupil or blood vessels on the white of the eye
- Blurred or spotty vision
- Detached retina
- Kidney dysfunction/failure
- Increasing fatigue
- Shortness of breath
- Leg swelling (edema)
- Palpitations and abnormal heart rhythms (atrial fibrillation)
- Chest pain
- Nausea & vomiting
- Severe constipation
- Alternating episodes of diarrhea & constipation
- Unintentional weight loss
Carpal Tunnel Syndrome
- Dizziness upon standing
- Recurrent urinary tract infections
- Sexual dysfunction
- Excessive sweating
Peripheral sensory-motor neuropathy
- Numbness and tingling, usually in the hands and feet
- Burning pain
- Loss of sensitivity to temperature
- Impaired balance
- Difficulty walking
hATTR amyloidosis is caused by a mutation in the transthyretin (TTR) gene that results in misfolded TTR proteins accumulating as amyloid fibrils in multiple tissues in the body, including the nerves, heart, and gastrointestinal tract.2,4,5
Because the symptoms of hATTR amyloidosis may overlap with those of other diseases, detailed medical history may help to identify people with hATTR amyloidosis.6,10,12,13
Obtaining a family history is an important step in the diagnostic process.10 Though individuals may be unaware of hATTR amyloidosis in their family, inquiring about relatives who have experienced any of the symptoms, the presentation of which could be different even within the same family, can help identify a family history. Additionally, noting relatives who have died prematurely can be useful in the diagnostic process.
In the presence of clinical symptoms or family history, genetic testing and genetic counseling may be recommended. A genetic test will tell a person if he or she carries a mutation in the TTR gene associated with hATTR amyloidosis. Once a gene mutation is identified, family members of an affected individual can use this information to help determine their own risk.
Genetic counseling can help individuals understand their chances of developing the condition as well as make them familiar with the testing process and implications of a potential diagnosis. Genetic counselors can also help individuals understand the issues related to genetic testing—from personal risk to possible insurance impact, and can help determine if a genetic test may be the right choice.
Current Treatment Options
- Liver transplant removes approximately 95% of the production of TTR. It can improve long-term survival but does not permanently halt disease progression and requires lifelong use of drugs called immunosuppressants that help prevent the body from rejecting the new liver6,15
- Transplant may be less effective for patients who present primarily with heart-related symptoms
- The limited availability of organs, as well as the exclusion of older patients and patients with advanced disease or with other serious medical conditions, warrants the development of other treatment options
Transthyretin (TTR) tetramer stabilizers bind to the TTR protein and prevent the formation of amyloid fibrils that cause the symptoms of the disease 6,15,16
Investigational Therapies in Development
Investigational therapies are therapies that are in clinical studies to determine if they are safe and effective in the treatment of hATTR amyloidosis:
- RNA interference (RNAi) therapeutics are double stranded small interfering RNAi that binds to TTR messenger RNA (mRNA) and prevent production of TTR 6,15,17
- Antisense Oligonucleotides (ASOs) are short chemically modified oligonucleotides that bind to TTR mRNA and prevent production of TTR protein 6,15,17
Investigational therapies that may help to reduce fibril accumulation:
- Monoclonal antibodies may suppress ATTR amyloid deposition by binding to amyloid fibrils and targeting them for immune system destruction15,17,18
- Fibril disruptors bind to amyloid fibrils and disrupt their association15,17
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