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Hereditary transthyretin amyloidosis (hATTR)

February 20, 2024 — published by Pyramidale Communication

Amylose Héréditaire à Transthyrétine (hATTR)

Key numbers for hereditary transthyretin amyloidosis (hATTR) – familial amyloid neuropathy

One in one million adults worldwide has transthyretin amyloidosis (ATTR). In endemic areas, such as northern Portugal, Sweden, and certain villages in Japan, prevalence is higher, at approximately 1 in 1,000. In France, around 500 cases of hATTR have been reported.¹

What is hereditary transthyretin amyloidosis (hATTR)?

Hereditary transthyretin amyloidosis (hATTR), also known as familial amyloid neuropathy (ATTR-PN), is a rare, systemic, and autosomal dominant genetic disease causing debilitating neuropathy, that can be fatal if left untreated.^1,4,5

The disease is characterized by the extracellular deposition of an amyloid fibrils composed of misfolded transthyretin (TTR) in target tissues, such as the peripheral nervous system or the heart. Transthyretin is primarily produced by the liver in a tetrameric form and is responsible for transporting thyroxine and vitamin A.^1,3

Mutations in the TTR gene, located on chromosome 18q12.1, lead to structural changes in the protein. The monomers dissociate, and the resulting insoluble misfolded proteins aggregate into insoluble amyloid fibrils. These fibrils cause a chronic disease primarily affecting the nerves and/or the heart, gastrointestinal tract, kidneys, eyes, and synovial tissues (tendons and ligaments).^1,4,6

“From a neurological perspective, it is a peripheral neuropathy, initially manifesting as sensory impairment, which can sometimes be painful.”

Interview with Prof. L. Magy, neurologist

To learn more about hereditary transthyretin amyloidosis, listen to Prof. Magy’s explanations on RARE à l’écoute, the podcast dedicated to rare diseases. Click here to listen.

Diagnostic criteria and medical care

Hereditary transthyretin amyloidosis (hATTR) is a progressive neuropathy. This rare disease primarily presents with sensory and motor impairments that first affect the lower limbs and later the upper limbs. Patients experience increasing difficulty walking and loss of balance. Within 5 years, patients often require walking aids, followed by wheelchairs.
Damage to the autonomic nervous system caused by amyloid fibril deposits leads to orthostatic hypotension, weight loss, and alternating diarrhea and constipation. Without treatment, death typically occurs around 10 years after symptom onset.^6,7

The diagnosis of hereditary transthyretin amyloidosis (hATTR) is based on clinical examination, including patient history to identify potential familial origin, genetic testing to confirm the presence of a transthyretin (TTR) gene mutation, and tissue biopsy to demonstrate amyloid deposits.^1,5

The therapeutic strategy for managing hATTR has two main objectives. The first is to slow disease progression by limiting the formation of new amyloid deposits. Anti-amyloid drug therapies either reduce transthyretin (TTR) gene expression through RNA interference or stabilize the TTR tetramer to prevent aggregation and amyloid fibril formation. Liver transplantation may be proposed for patients under the age of 70 and, when performed early, is effective in approximately 70% of cases.^1,8,9
The second therapeutic objective is to relieve neuropathic pain, improve quality of life, and compensate for organ dysfunction. This includes symptomatic treatments, analgesics, lifestyle and dietary measures. Rehabilitation is often prescribed to address motor impairment.^1,5

“Therapeutic management relies on anti-amyloid treatments to slow or halt disease progression, and on symptomatic measures aimed at improving patient-reported symptoms, quality of life, and compensating for certain organ dysfunctions.”

Interview with Dr. C. Cauquil, neurologist

For more information on hereditary transthyretin amyloidosis (hATTR), listen to Dr. Cauquil’s explanations on RARE à l’écoute, the podcast dedicated to rare diseases, by clicking here.

Management is multidisciplinary and involves specialists according to the type of organ involvement. Therapeutic education is also essential and is available in dedicated centers.^1,4,5

Would you like to learn more about hereditary transthyretin amyloidosis (hATTR)?

Click here to listen to the season dedicated to hATTR on our RARE medical Podcast – RARE à l’écoute.

Listen to interviews with experts such as Prof. L. Magy, Dr. E. Delmont, G. Solé, and C. Cauquil, as well as a testimonial from Mr. Fidalgo, a patient and active member of the French Association Against Amyloidosis (AFCA).

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References:

PNDS neuropathies amyloïdes familiales : https://www.has-sante.fr/upload/docs/application/pdf/2017-05/dir2/pnds_-_neuropathies_amyloides_familiales.pdf
Adams D, et al. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. Journal of Neurology. 2021;268:2109-2122.
Benson MD, Kincaid JC. The molecular biology and clinical features of amyloid neuropathy. Muscle Nerve. 2007 Oct;36(4):411-23.
Orphanet – Amylose ATTR familiale : https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=11720
Association française contre l’amylose – Amylose héréditaire : https://amylose.asso.fr/amyloses/amylose-ttr/lamylose-hereditaire-a-transthyretine/
Vionnet J, et al. Amyloïdose héréditaire à transthyrétine. Rev Med Suisse. 2016 Aug 31;12(528):1434-40.
Planté-Bordeneuve V, Said G. Familial amyloid polyneuropathy. Lancet Neurol. 2011 Dec;10(12):1086-97.
Ioannou A, et al. RNA Targeting and Gene Editing Strategies for Transthyretin Amyloidosis. BioDrugs. 2023;37:127-142.
Carroll A, et al. Novel approaches to diagnosis and management of hereditary transthyretin amyloidosis. J Neurol Neurosurg Psychiatry. 2022;0:1-11.