TTR amyloidosis
hATTR amyloidosis
Hereditary ATTR amyloidosis, also called variant ATTR amyloidosis (ATTRv or hATTR), is caused by a disease-causing variant in the TTR gene, inherited from a parent. It is the same protein as in wild-type ATTR, but destabilised from the outset rather than by age alone. It can strike the nerves, the heart, or both — and because it runs in families, the diagnosis is never about one person only.
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What is hATTR?
Key idea
The mutation comes from one parent. Symptoms can appear at any point from early adulthood onwards — and the same variant behaves differently from one family to the next.
A mutated protein
hATTR is caused by a mutation in the TTR gene, inherited from a parent. Transmission is autosomal dominant. The mutation makes transthyretin fold abnormally; the misfolded protein aggregates into amyloid fibrils, which accumulate over the years.
More than 130 variants of the gene are known. Some are tied to particular regions and particular communities — in the United Kingdom, V122I and T60A are among the most frequently seen.
When it begins
Symptoms can declare themselves at any time from the start of adult life. The age at which they do depends on the variant, and on family origin.
In the polyneuropathic form, the disease begins around the age of 30 in patients of Portuguese descent, and around 60 on average in others. Two people carrying the same mutation may fall ill decades apart.
130+
known variants of the TTR gene, with important differences in geographic distribution and clinical presentation.
Diagnostic delay varies widely between people, clinical presentations and healthcare systems; early recognition remains a major challenge worldwide.
ATTRv occurs worldwide, but prevalence varies greatly by country, ancestry and TTR variant, with recognised endemic areas in several regions.
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Two forms, one disease
The variant carried decides, in large part, where the amyloid settles. Doctors describe two clinical pictures — though a great many patients have something of both.
hATTR-PN
Hereditary amyloid polyneuropathy
Also known as familial amyloid polyneuropathy. The nerves bear the brunt of it: sensation fades in the feet, the autonomic nerves falter, and walking becomes uncertain. The heart is frequently involved as well.
Left untreated, it is potentially very serious and disabling.
hATTR-CM
Familial amyloid cardiomyopathy
A hereditary systemic amyloidosis in which the cardiac manifestations dominate. Deposits stiffen and thicken the ventricle walls, shrinking the chambers and weakening the flow of blood.
Carpal tunnel syndrome often precedes it by five to ten years.
In clinical practice these two pictures are rarely as separate as their names suggest. For a great many patients the manifestations overlap substantially — mixed neurological and cardiac forms.
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Symptoms
The disease usually announces itself in the feet, quietly, and is put down to something else. On average, three to six years pass before it is named.
Nerves and sensation
Where it starts
Feeling for temperature and pain fades in the feet. Burning sensations and pins and needles arrive unbidden. Injuries go unnoticed because they cannot be felt. Weakness spreads from the feet towards the hands, and walking and balance suffer.
The autonomic system
The nerves you never think about
Nausea, sluggish digestion, loss of appetite, vomiting. Constipation alternating with diarrhoea. Erectile dysfunction. Dizziness or fainting on standing up. Bladder trouble. Unintended weight loss of more than five kilos over six months.
The heart
One in three needs a pacemaker
Conduction slows, sometimes to an extreme bradycardia, with a risk of cardiac arrest: roughly one patient in three requires a pacemaker. Amyloid infiltrates the muscle itself, and heart failure brings breathlessness on exertion.
The eyes
Deposits in the vitreous, seen in 20 to 30% of patients, appear as floaters drifting across the vision. Glaucoma affects around 20%. Dry, gritty eyes are common.
Carpal tunnel syndrome
In the cardiomyopathic form it precedes the heart symptoms by five to ten years, in one hand or in both. It is often the earliest thing the disease says.
When to seek advice
These signs matter especially if amyloidosis is already known in your family. Say so to your doctor: it changes what they look for.
- Numbness or burning in the feet
- Injuries to the feet that go unnoticed
- Unsteady walking, loss of balance
- Nausea, vomiting, feeling full too soon
- Constipation alternating with diarrhoea
- Dizziness or fainting on standing
- Erectile dysfunction
- Bladder trouble
- Weight loss over five kilos in six months
- Floaters drifting across the vision
hATTR runs in families. A diagnosis in one person is a question posed to everyone related to them.
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How hATTR is diagnosed
One test settles the question, and it is a blood test. The difficulty lies upstream of it: in a neuropathy that looks like a hundred others, and that is attributed to them for three to six years.
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See a specialist
A neurologist for the polyneuropathic form, a cardiologist for the cardiac one. Symptoms are readily attributed to more common causes of neuropathy, and the delay before diagnosis averages three to six years.
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A genetic blood test
It confirms the mutation in the TTR gene. This is the test that names the disease — and the one that tells wild-type ATTR apart from the hereditary form.
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Show the amyloid
A biopsy demonstrates the deposits. Where the heart is concerned, echocardiography or cardiac MRI reveals the thickened walls, and bone scintigraphy supports the diagnosis without a biopsy. AL amyloidosis must be ruled out.
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Screen the family
Once a mutation has been identified, relatives can be offered a test. In the cardiomyopathic form this leads to a systematic assessment of the family, to find the disease before it has spoken.
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Treatment
Several drugs now slow this disease down. None of them undoes what it has already done.
Start before the damage is done
Once a nerve has been lost, it does not come back. The damage this disease causes is generally irreversible, and no treatment reverses it. What treatment does is stop the disease going further.
That single fact explains everything else on this page: why the diagnostic delay matters, why carriers are monitored every year, and why families are tested.
TTR stabilisers
A stabiliser, taken by mouth each day. Two doses exist: a lower one for the polyneuropathy, a higher one where the heart is the problem. It slows the disease down.
Gene silencers (infusion)
Given as a drip every three weeks. Transient abdominal pain and swelling of the limbs are possible. No routine blood monitoring is needed.
Antisense therapy
An injection under the skin once a week. It calls for closer watching: platelet counts every fortnight, and regular checks of kidney function.
Gene silencers (injection)
Injected under the skin once every three months, in hospital or at home. No premedication, no routine blood tests.
Liver transplant
For a long time the only way to stop the production of the mutated protein. Now that drugs have taken its place, it is only exceptionally indicated.
Living with the symptoms
Specific painkillers and medicated patches for neuropathic pain. Careful foot care, since a wound that cannot be felt will not be tended. A pacemaker for conduction problems. Vitrectomy for vitreous deposits that threaten sight, with good recovery of vision. Drops, laser or surgery for glaucoma, and artificial tears for dryness.
If the heart is involved
Cutting down on salt, together with diuretics, eases breathlessness and swelling. Where the rhythm is irregular, anticoagulation prevents clots forming inside the heart.
As in wild-type ATTR, some drugs given as a matter of course in ordinary heart failure — beta-blockers and vasodilators among them — can make matters worse, and are avoided. That is a decision for your cardiologist. Never stop a treatment on your own.
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Genetics and family
This is what sets hATTR apart from every other form of amyloidosis: it does not concern one person at a time.
A diagnosis that concerns more than one person
hATTR is passed on in an autosomal dominant way: the variant comes from one parent, and each child of a carrier has a one-in-two chance of inheriting it in turn.
Carrying the variant does not mean the disease will declare itself at any particular age — two people with the same mutation may fall ill decades apart, and some never do. What it does mean is being followed.
Presymptomatic testing
Once a mutation has been identified in a family, relatives can be offered a genetic test. Those who carry the variant but have no symptoms are monitored once a year, so that the first signs are caught as they appear rather than years later.
The reason is blunt: the damage, once done, is generally irreversible. Whether or not to be tested remains a personal decision, and one that nobody should have to weigh alone — your centre is there to help you think it through.
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Follow-up and outlook
A regular rhythm
A neurology consultation every six to twelve months. A cardiac review each year: examination, ECG, echocardiography, BNP and troponin, with Holter monitoring where it is needed. If a pacemaker has been fitted, it is checked every six months. Gastroenterology and urology are called on as required.
More than doctors
Care is organised around a multidisciplinary centre. Psychologists, social workers, occupational therapists and physiotherapists are part of it — because a disease that reaches the nerves, the gut, the eyes and the heart reaches a life as well.
Left untreated, the disease moves inexorably towards greater disability. Treated early, its course changes. That is the whole argument for testing — and for testing families.
FAQ
Common questions
Will my children inherit it?
hATTR is transmitted in an autosomal dominant way, which means each child of a carrier has a one-in-two chance of inheriting the variant. A genetic test can answer the question directly. Whether and when to take it is a decision your centre can help you think through.
If I carry the variant, will I become ill?
Not necessarily, and not at a predictable age. Symptoms can appear at any point from early adulthood onwards, and the age of onset varies with the variant and with family origin — two people carrying the same mutation may fall ill decades apart. Carriers without symptoms are monitored once a year, so that the disease is caught at its very beginning.
Is hATTR the same disease as wtATTR?
The same protein misfolds in both, but for different reasons. In wild-type ATTR the gene is normal and age alone destabilises the protein. In hATTR an inherited mutation does it. They can look alike in the heart, which is exactly why a genetic test is part of the diagnosis — and why the answer matters to your relatives and not only to you.
Can the nerve damage be reversed?
Generally not. The manifestations of the disease are usually irreversible, and today’s treatments slow it rather than undo it. This is the reason so much weight is placed on early diagnosis, on annual monitoring of carriers, and on testing families.
What is the difference between hATTR-PN and hATTR-CM?
Which organ the amyloid chiefly settles in. In hATTR-PN it is the nerves, in hATTR-CM the heart. But the distinction is cleaner in the names than in the clinic: a great many patients have a significant overlap of both, and the heart is often involved in the polyneuropathic form too.
This page is intended as general information for patients, families and healthcare professionals. It does not replace medical advice. The availability of the treatments named here varies from country to country. Always discuss your situation with your own specialist team.