Familial Amyloid Polyneuropathy (hATTR Amyloidosis)

What causes it

Transthyretin is a transport protein made mainly by the liver. It normally circulates as a stable four-part structure. Over 130 TTR gene variants can destabilize it. The protein then breaks apart, misfolds and builds up as amyloid fibrils in tissues, damaging them.

Common variants include Val30Met (V30M), found in clusters in Portugal, Sweden, Japan and Brazil, and Val122Ile (V122I), carried by about 3% to 4% of African Americans and mainly linked to heart disease. Not everyone with a variant develops disease, and age at onset varies widely.

It differs from wild-type ATTR amyloidosis, which affects older adults without a gene variant and mainly causes heart disease, and from AL amyloidosis, caused by a blood cell disorder. See amyloidosis.

Symptoms

Peripheral nerves

• burning pain, numbness and tingling starting in the feet and rising up the legs, later affecting the hands
• loss of pain and temperature sensation, leading to unnoticed injuries and foot ulcers
• muscle weakness and difficulty walking
• carpal tunnel syndrome, often in both hands, sometimes years before other symptoms

Autonomic nerves

Autonomic neuropathy causes:

• dizziness or fainting on standing (orthostatic hypotension)
• alternating diarrhea and constipation, nausea, early fullness
• unintentional weight loss
• erectile dysfunction
• bladder problems
• reduced sweating

Heart

• thickened, stiff heart muscle (amyloid cardiomyopathy)
• heart failure symptoms: breathlessness, leg swelling, fatigue
• heart rhythm problems and conduction block

Other organs

• eyes: vitreous opacities, glaucoma, dry eyes
• kidneys: protein in the urine
• brain and spinal coverings in rare variants

Diagnosis

The disease is often misdiagnosed for years as diabetic neuropathy, CIDP or another neuropathy. Clues include rapidly progressive neuropathy, early autonomic symptoms, unexplained weight loss, bilateral carpal tunnel syndrome, heart thickening and family history.

• Genetic testing for TTR variants, the key confirmatory test
• Nerve conduction studies and EMG
• Tissue biopsy (fat pad, nerve, salivary gland or other organ) stained with Congo red, with typing to confirm transthyretin amyloid
• Heart evaluation: ECG, echocardiogram, cardiac MRI and technetium pyrophosphate (PYP) or DPD scan
• Blood and urine tests to exclude AL amyloidosis
• Autonomic testing and eye examination

Treatment

TTR silencers

These reduce production of transthyretin in the liver:

• patisiran (IV every 3 weeks) and vutrisiran (injection every 3 months): RNA interference medicines
• inotersen and eplontersen: antisense oligonucleotides

They can stabilize or improve neuropathy and quality of life.

TTR stabilizers

• tafamidis: binds and stabilizes the TTR tetramer. Approved for cardiomyopathy in the US and for polyneuropathy in other countries
• diflunisal: an NSAID that stabilizes TTR, used off-label with monitoring of kidneys and bleeding risk
• acoramidis: a newer stabilizer approved for cardiomyopathy

Liver transplant

Historically the main treatment for early V30M disease, since the liver makes most TTR. It is now used less often because of effective medicines.

Supportive care

• nerve pain medicines
• compression stockings, fluids, salt and medicines for orthostatic hypotension
• diet changes and medicines for gut symptoms
• heart failure treatment and pacemakers for conduction disease
• foot care to prevent ulcers
• physical and occupational therapy

Genetic counseling and family testing

Relatives of a person with hATTR amyloidosis can have predictive genetic testing with counseling. Carriers can be monitored, so treatment can start at the earliest signs.

Outlook

Untreated, hATTR polyneuropathy is progressive and historically fatal within about 7 to 12 years of symptom onset. Disease-modifying medicines have transformed the outlook, especially when started early, often halting or slowing progression.

Frequently asked questions

What is familial amyloid polyneuropathy?

It is an inherited disease in which a faulty transthyretin protein forms amyloid deposits in nerves and organs, causing progressive nerve damage, autonomic problems and often heart disease. It is now called hereditary transthyretin (hATTR) amyloidosis.

What are the first symptoms of hATTR amyloidosis?

Early symptoms often include burning, tingling or numbness in the feet, carpal tunnel syndrome in both hands, dizziness on standing, diarrhea or constipation, and unexplained weight loss. Heart symptoms may appear early in some variants.

How is familial amyloid polyneuropathy inherited?

It is autosomal dominant. A parent with a TTR variant has a 50% chance of passing it to each child. Not everyone with the variant develops symptoms, and age at onset varies by variant and family.

Is there a treatment for hATTR amyloidosis?

Yes. TTR silencers such as patisiran, vutrisiran, inotersen and eplontersen reduce production of the faulty protein, and stabilizers such as tafamidis slow its breakdown. Supportive treatments manage pain, autonomic and heart symptoms.

Can hATTR amyloidosis be cured?

There is no cure yet, but modern medicines can slow, halt or partly reverse nerve damage in many patients, especially when started early. Gene-editing approaches are in clinical trials.