Hereditary ATTR (ATTRv)
Amyloidosis is the name given to a group of rare disorders in which amyloid deposits, consisting of misfolded proteins which are relatively insoluble, deposit and accumulate in tissues and organs of the body. As these deposits progressively build up they interfere with the working of the organs. Without treatment this will eventually leads to organ failure.
ATTR amyloidosis comprises two groups of multisystem diseases:
- Non-hereditary wild type (ATTRwt)
- Hereditary diseases (ATTRv)
This section concentrates on hereditary ATTR (ATTRv).
- ATTRv is a progressive inherited disease, primarily characterized by sensory, motor, and autonomic neuropathy and/or cardiomyopathy.
- Because the heart and the nervous system are usually the main organs involved, ATTRv is sometimes referred to as familial amyloidotic polyneuropathy (FAP) or familial amyloidotic cardiomyopathy (FAC).
- ATTRv can be found in families from most ethnic background.
What do the letters ATTR stand for?
- The A in ATTR stands for Amyloidosis. TTR stands for Transthyretin, the precursor protein and “v” stands for variant. Sometimes it is written as ATTRm or ATTRh with the “m” standing for mutation and “h” for hereditary.
What is TTR?
- TTR is an abbreviation for the name of the protein called transthyretin (Trans-thy-retin). which is primarily made in the liver and secreted into the blood in healthy people,
- TTR transports the thyroid hormone thyroxin and vitamin A (retinol) in the blood
- In hereditary ATTR, a mutation or mistake in the TTR gene results in the production of a variant TTR protein.
- This variant TTR is much more prone to misfolding and forming amyloid than the normal TTR protein.
ATTRv is an autosomal dominant disease. What does that mean?
- An individual only needs to inherit one copy of the mutated gene from one parent to develop the disease. If one parent has ATTRv there is a 50% chance their child will inherit the mutation.
- In many hereditary diseases all people with the mutation will develop the disease. THIS IS NOT SO in hereditary systemic amyloidosis where there is an additional genetic principle known as incomplete penetrance, meaning:
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- Some people who carry the gene WILL NOT develop any amyloid at all.
- Some people who carry the gene will only develop a small amount of amyloidosis which will not produce any clinical symptoms.
- Some people will never inherit the gene and therefore they cannot pass on hereditary amyloidosis to their children.
See section on “Hereditary Amyloidosis” and “Autosomal Dominance“
- ATTRv is further complicated by the fact that over 100 genetic variations have been observed. Many are very rare.
The most common mutations are:
- V30M. Found mostly in Portugal, Spain, France, Sweden, Japan and descendants of these region. It can occur as an early onset form in younger adults or as a late onset form in older ages.
- T60A. This is the commonest form of ATTRv amyloidosis seen in the UK. It is sometimes referred to as Thr60Ala amyloidosis. It occurs most frequently in those with Irish ancestry. Symptoms can appear between ages 45 and 80 but most often after age 60. It is slightly more common in men than in women.
- V122I. Predominantly seen in the African-American population. It is associated with cardiomyopathy (heart condition) appearing in older individuals.
How common is ATTRv?
This is not known because the disease clusters in certain areas of the world. In Australia and the US, it’s quite sporadic. It is also misdiagnosed making true numbers difficult to calculate. In Australia ATTRv is not a reportable disease.
Symptoms
- Symptoms often mimic those seen in other diseases.
- Symptoms can appear between the ages of mid 20’s to 80’s but many do not appear until middle age.
- Symptoms will vary according to the mutation and degree of organ involvement.
- Most commonly symptoms are due to nerve and heart involvement.
- Each family will have its own pattern of organ involvement but there may be variations within families.
Symptoms caused by heart involvement.
Amyloid protein deposition into the heart can result in a type of heart failure causing the following symptoms:
- Shortness of breath, sometimes just after mild exertion, sometimes when lying flat.
- Palpitations due to abnormal heart rhythms, most frequently atrial fibrillation or atrial flutter.
- Ankle swelling (oedema).
- Fatigue, nausea, weight loss.
- Dizziness and fainting, may occur after exertion, or after eating.
- Disrupted sleep.
- Angina (chest pain)
Symptoms caused by Peripheral and Autonomic nerve involvement
Amyloid deposition in the peripheral and autonomic nerves causing the symptoms below:
- Numbness, tingling, pins and needles in the feet and hands
- Weakness and pain in the arms and legs
- Loss of sensation and feeling making it difficult to distinguish heat and cold.
- Impotence
- Dizziness or fainting on standing
- Diarrhoea or constipation, or sometimes both
The eye many be involved resulting in blurred vision and vision loss.
Other organ involvement below is rare:
- Kidneys
- Thyroid gland
- Adrenal gland
- Blood Vessels
Diagnosis
A diagnosis of amyloidosis can only definitively be made through a tissue or organ biopsy:
- A tissue biopsy involves taking a small piece of tissue from the body, often the fat pad on the tummy the gastrointestinal tract, the lip or the bone marrow. Sometimes a more invasive biopsy may be taken from the symptomatic organs, the heart or nerves.
- The biopsy is stained with the dye Congo red in the laboratory.
- If amyloid is present, the biopsy will appear red under normal light and green (apple-green birefringence) under special polarized light.
- Occasionally the diagnosis can be made without a tissue biopsy because a DPD or PYP scan shows amyloid in the heart or because genetic testing confirms the diagnosis
2nd procedure in the laboratory
- Further testing of the biopsy may be done to identify the type of amyloidosis by identifying the protein composition of the amyloid fibrils.
- It is important to identify the “type” as treatment is different for each type of amyloid.
The existence of a family history of hereditary ATTR may greatly assist in diagnosing the type of the disease. However, a number of people diagnosed with ATTRv will have no known family history.
Tests
Tests listed below may be performed to help with the diagnosis, typing and assessment of organ involvement and damage and to form a treatment plan. Some of these tests will be repeated over time to monitor the result of any treatment and disease progress.
- Genetic testing to analyze the TTR gene associated with this type of hereditary amyloidosis
- ECG
- Echocardiogram
- MRI of the heart (troponin and BNP or NT-ProBNP)
- Nerve conduction tests
- DPD or PYP scan.
(Traditionally used for imaging bones, these scans involve special molecules which are injected into the body and become trapped in the heart when it is full of transthyretin amyloidosis thus helping with the diagnosis and identification of this type of amyloid. - Urine analysis
- Eye tests
Treatment
Suggested reading:
Evan Bittner: “My Journey” – A personal reflection from a patient
Understanding the Genetics of hATTR/ATTRm Amyloidosis
Managing hATTR Amyloidosis