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Amyloidosis hereditaria transthyretinica
A treatable inherited disease disguised as an ordinary polyneuropathy — here above all the speed of recognition decides.
Also known as: Transthyretin amyloidosis · ATTRv · familial amyloid polyneuropathy · FAP · TTR gene variant
Open in the tool — with search and all the links →This compilation is for information and replaces neither medical diagnosis nor treatment. If you have symptoms, see a doctor.
A rare inherited disease in which a transport protein from the liver — transthyretin — becomes unstable, misfolds and is deposited as amyloid in nerves, heart and other organs. It typically starts as a polyneuropathy in the feet, but progresses markedly faster than the usual forms: sensory disturbance, burning pain and weakness move upward within months to a few years. Onset can be anywhere between the ages of 20 and 80. Because it is so rare it is often missed or treated as another nerve disease — classically as CIDP, where the absence of improvement under immune therapy is itself a warning sign. A number of red flags together point the suspicion: a family clustering of neurological disease, early disturbance of the autonomic nervous system such as circulatory problems on standing, unintended weight loss, alternating constipation and diarrhoea, cardiac involvement, bilateral carpal tunnel syndrome and clouding of the vitreous body in the eye. The combination of polyneuropathy and heart muscle disease should especially raise attention. Inheritance is autosomal dominant. The diagnosis is reliably secured by genetic testing of the transthyretin gene; a tissue biopsy is unreliable because the amyloid is deposited patchily. Why the diagnosis matters so much: untreated, the disease is fatal over about seven to twelve years — but effective drugs now exist that slow progression, including stabilisers of the protein and agents that suppress its production in the liver. They work better the earlier they are started. That is exactly why it is worth actively thinking of it with a rapidly progressive polyneuropathy plus one of the red flags.
Individually each sign is unspecific — together they form a pattern: rapidly progressive polyneuropathy, family clustering, weight loss, circulatory problems on standing, alternating bowel habit, cardiac involvement, bilateral carpal tunnel, vitreous clouding.
Carpal tunnel syndrome on both sides, especially years before other symptoms, counts as an early clue and is often dismissed as wear and tear.
If a polyneuropathy treated as CIDP does not improve under immune therapy, rethinking the diagnosis is worthwhile — this point has already saved many people years.
Testing the transthyretin gene secures the diagnosis reliably. A biopsy can look normal despite the disease, because the amyloid is deposited patchily.
Because nerves and heart can be affected together, a cardiological assessment belongs to the work-up — it changes treatment and follow-up.
There are drugs today that slow progression. Their benefit is greater the fewer nerve fibres have already been lost — time is the decisive factor here.
The trait is passed on dominantly. Relatives can seek counselling and testing if they wish — which matters especially here, because early treatment is possible.
Dizziness on standing, digestive or bladder problems, reduced sweating are often not mentioned because they are not linked to the feet — yet they belong to the picture.
The new drugs act at three points: they stabilise the misfolded protein, they slow its production in the liver through RNA-based agents, or they switch the gene off. What they do is halt or clearly slow the progression — they clear the deposits in nerves and heart only partly. So early diagnosis is the real lever; from the first signs to the right classification, years often pass.
More than a hundred and thirty different changes are known; which one is present determines the course and whether nerves or heart are more affected. Onset lies, depending on the variant, between the third and seventh decade. Untreated, the nerve damage advances over five to fifteen years. The time to the right classification averages three to four years and several wrong diagnoses — most often polyneuropathy of unclear cause.
Numbness, burning and weakness that travel from the toes to above the knees within months. The usual forms take years for that — this speed is the most important warning sign.
If a thickened heart wall, rhythm disturbances or unexplained heart failure come with a nerve disorder, that does not fit an ordinary polyneuropathy.
Dizziness on standing up, diarrhoea alternating with constipation, bladder trouble, erection problems, no more sweating. This involvement of the involuntary nervous system is a strong pointer.
An operation on both wrists years before everything else is a known forerunner. A rupture of the long biceps tendon and a narrow spinal canal also belong to this prelude.
An important pointer to cardiac involvement — polyneuropathy plus heart is a central red flag.
Can stay mildly elevated with amyloid deposits in the heart muscle — have it interpreted by cardiology.
Not proof of ATTR — used to exclude the common, treatable causes of polyneuropathy.
Without B12 the insulating layer of the nerves is not maintained. A lack causes tingling, numbness and unsteadiness in the dark — and it is one of the few reasons for nerve trouble that can be fully undone if found early.
The nerves cover their energy needs through thiamine. It runs short with alcohol, after stomach operations, with long-lasting vomiting and under water tablets.
Here both count: a lack harms the nerves, and too high an intake over months harms them as well. Supplements therefore belong taken in a dose that has a reason.
Works together with B12. Given alone, folate can improve the blood count while the B12 deficiency goes on damaging the nerves — which is why both are looked at together.
A point that holds this way only in this condition: transthyretin is at the same time the carrier protein for vitamin A. Under the medicines that switch it off the vitamin A level falls, and replacement then belongs — but guided and in limited amounts, because too much vitamin A does damage of its own.
With an already damaged nerve fibre high-dose B6 is the most avoidable additional harm. Normal amounts are unproblematic; 100 mg and more over months are not.
Clearly worthwhile and well supported when deficient — vegan, older adults, certain drugs. No energy boost without a deficiency.
In pregnancy clearly established against neural-tube defects, otherwise mainly with deficiency. Can mask a B12 deficiency — watch both.
The protein that deposits here is called transthyretin — and it is called that because it does exactly that: it transports thyroxine, that is T4, in the blood. The condition therefore sits literally on a thyroid transporter, without the thyroid itself being ill.
Because several proteins carry T4 in the blood, the thyroid values mostly stay normal in this condition — transthyretin drops out as a carrier and the others make up for it. Abnormal values therefore belong explained differently.
The deposits also affect the nerves that regulate blood pressure, bladder and bowel. Blacking out on standing, alternating diarrhoea and constipation and bladder problems therefore belong to the picture — they are often treated separately, without anyone reading them together.
Alternating diarrhoea and constipation, early fullness and weight loss belong to the picture. Small energy-dense meals and regular weighing is the usual approach.
Maintenance training and aids accompany the course. Treatment of the underlying disease has changed greatly in recent years — it belongs with a specialised centre.