Understanding What is hATTR PN and Its Treatment

October 7, 2025 •

5 min read

Hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) is a rare and progressive genetic disorder, estimated to affect between 10,000 and 40,000 people globally. This condition is caused by a gene mutation that results in abnormal protein deposits that damage the nervous system and other vital organs.

Quick Summary

hATTR-PN is a rare, hereditary disease resulting from a mutated TTR protein forming amyloid deposits in nerves and organs. This causes progressive nerve damage, affecting sensory, motor, and involuntary bodily functions.

Key Points

Genetic Cause: hATTR PN is a hereditary disease caused by a mutation in the TTR gene, passed down in an autosomal dominant pattern.
Protein Misfolding: The genetic mutation leads to misfolded transthyretin (TTR) proteins that aggregate into amyloid fibrils, which damage nerves and organs.
Multi-System Symptoms: Key symptoms include sensory and motor neuropathy (pain, numbness, weakness) and autonomic neuropathy (GI issues, low blood pressure), often alongside cardiac and renal complications.
Challenging Diagnosis: Diagnosis is often delayed due to varied symptoms and can involve tissue biopsy, cardiac imaging, and definitive genetic testing.
Effective Treatments: Modern therapies, including TTR stabilizers and gene silencers, target the underlying cause by reducing the production or preventing the misfolding of the TTR protein.
Improved Prognosis: Early diagnosis and treatment are critical for slowing disease progression, managing symptoms, and significantly improving the patient's long-term quality of life.

What is hATTR PN? The Genetic Basis of Disease

hATTR PN, also known as hereditary transthyretin amyloidosis with polyneuropathy, is a progressive and life-threatening condition caused by a genetic mutation. It is part of a larger group of diseases called amyloidosis, which are characterized by the abnormal buildup of proteins called amyloid fibrils in various organs and tissues. In hATTR PN, the mutation is in the transthyretin (TTR) gene, leading to the production of an unstable TTR protein.

The Role of the Transthyretin (TTR) Protein

Normally, the TTR protein is a stable molecule that transports thyroxine (thyroid hormone) and vitamin A throughout the body. It is primarily produced in the liver, with smaller amounts made in the choroid plexus in the brain and the retina of the eye. In individuals with hATTR PN, the genetic mutation causes the TTR protein to misfold and break apart into unstable fragments. These fragments then clump together to form amyloid fibrils, which are deposited in and around the nerves. The buildup of these deposits can damage and interfere with the normal function of the nerves and organs over time, leading to the symptoms and complications of the disease.

Diverse Symptoms of hATTR PN

Because amyloid deposits can affect multiple systems throughout the body, hATTR PN presents with a wide range of symptoms. These symptoms often vary greatly depending on the specific TTR mutation and the age of disease onset.

Neuropathy Symptoms

Peripheral and autonomic neuropathy are key features of hATTR PN.

Peripheral Neuropathy: Affects the sensory and motor nerves, often starting in the feet and lower limbs and progressing upwards.
- Numbness, tingling, or burning sensations.
- Loss of sensation to pain and temperature.
- Muscle weakness and atrophy, leading to difficulty walking, tripping, and foot drop.
- Carpal tunnel syndrome, especially if bilateral and aggressive, can be an early sign.
Autonomic Neuropathy: Affects the nerves that control involuntary bodily functions.
- Orthostatic hypotension, causing dizziness or fainting when standing up.
- Gastrointestinal issues, such as alternating diarrhea and constipation, nausea, and early satiety.
- Bladder control problems, including incontinence or urinary retention.
- Erectile dysfunction.
- Abnormal sweating or heat intolerance.

Non-Neurological Symptoms

Amyloid deposits can also affect other parts of the body, leading to systemic complications.

Cardiac Involvement: Can lead to cardiomyopathy, where the heart muscle thickens and stiffens.
- Heart failure, arrhythmias, and conduction defects.
Renal Involvement: Amyloid buildup in the kidneys can impair their filtering function.
- Proteinuria (protein in urine) and eventual kidney failure.
Ocular Involvement: Amyloid can deposit in the eyes.
- Vitreous floaters and glaucoma.
Other Manifestations: Significant weight loss and fatigue are also common symptoms.

Diagnosing hATTR PN

Diagnosis can be challenging and is often delayed due to the nonspecific nature of the symptoms, which can mimic other, more common conditions like diabetic neuropathy. Early and accurate diagnosis is critical for managing the disease and improving outcomes.

Diagnostic Tools and the Challenge of Misdiagnosis

Clinicians rely on a combination of tests to confirm a diagnosis of hATTR PN:

Medical and Family History: A detailed history is taken, focusing on neurological, cardiac, and digestive symptoms, as well as any family history of neuropathy or cardiomyopathy.
Physical and Neurological Examination: Assessments for sensory and motor nerve function, reflexes, and balance.
Tissue Biopsy: A biopsy, often of the abdominal fat pad or skin, can reveal amyloid deposits. In some cases, a biopsy from a more affected organ may be necessary.
Genetic Testing: A blood, saliva, or cheek swab sample can be tested to identify a TTR gene mutation, which is the only way to confirm a hereditary diagnosis.
Cardiac Imaging: A technetium-labeled cardiac scintigraphy can identify TTR-specific amyloid deposits in the heart, helping to differentiate from other types of amyloidosis.

Treatment Options for hATTR PN

Treatment focuses on slowing or stopping the production of the misfolded TTR protein and managing symptoms. Advances in medical science have introduced several disease-modifying therapies that have significantly improved the prognosis for patients.


Comparison of hATTR PN Treatments	Treatment Class	Mechanism of Action	Examples	Administration	Notes
Gene Silencers	Reduces the amount of TTR protein produced by the liver by targeting the messenger RNA.	Patisiran (Onpattro), Vutrisiran (Amvuttra), Eplontersen (Wainua), Inotersen (Tegsedi)	Intravenous (infusion) or Subcutaneous (injection)	Have shown to slow progression and improve quality of life.
TTR Stabilizers	Stabilizes the TTR protein to prevent it from breaking apart and forming amyloid fibrils.	Tafamidis (Vyndaqel/Vyndamax), Diflunisal (off-label)	Oral (tablet)	Slows disease progression in some cases, with Tafamidis also approved for related cardiomyopathy.
Liver Transplant	Replaces the primary source of the mutated TTR protein.	N/A	Major surgery	Historically used, but newer pharmacotherapies are now often preferred, especially for early-stage disease.

Supportive Therapies

In addition to disease-modifying treatments, supportive care is crucial for managing symptoms and maintaining quality of life. This can include working with a multidisciplinary care team comprising cardiologists, neurologists, nephrologists, and physical therapists.

Navigating Life with hATTR PN and Outlook

Living with hATTR PN can present significant challenges, impacting daily activities and work. The progressive nature of the disease can lead to increased dependence on others over time. However, the outlook has improved significantly due to early diagnosis and the availability of effective treatments.

The Importance of Early Intervention

Early diagnosis is key to starting treatment before irreversible organ damage occurs. For example, early-onset hATTR-PN (before age 50) was associated with about a 12-year average survival, while late-onset was around seven years, though newer therapies are altering this prognosis positively. Access to a specialized amyloidosis center can also optimize care. Individuals with a family history or suspected symptoms should seek early genetic counseling and testing.

Conclusion

What is hATTR PN is a question with a complex answer involving genetics, protein misfolding, and progressive, multi-system damage. It is a rare, inherited condition caused by mutations in the TTR gene, leading to debilitating polyneuropathy and potential organ failure. While historically life-threatening, modern treatment options, particularly gene-silencing therapies and TTR stabilizers, have transformed the prognosis. Prompt diagnosis, enabled by advanced genetic testing and improved clinical awareness, is more crucial than ever. With early intervention, patients can hope to slow disease progression, manage symptoms effectively, and significantly improve their quality of life. For more detailed information, the Amyloidosis Research Consortium is a valuable resource.

Frequently Asked Questions

hATTR PN is inherited in an autosomal dominant pattern, meaning that a child only needs to inherit one copy of the mutated TTR gene from one parent to be at risk for the disease. Individuals who have a parent with hATTR PN have a 50% chance of inheriting the mutation.

Initial symptoms often involve the peripheral nerves and can include numbness, tingling, or burning sensations in the feet. Early signs may also include carpal tunnel syndrome, dizziness upon standing, and gastrointestinal issues like diarrhea or constipation.

While there is no cure, recent advances in treatment, particularly gene-silencing and TTR-stabilizer therapies, can significantly slow disease progression and improve quality of life. These treatments aim to stop the production or prevent the misfolding of the mutated protein.

hATTR is a hereditary condition caused by a genetic mutation in the TTR gene. Wild-type ATTR (wtATTR), on the other hand, is an age-related condition where the normal (wild-type) TTR protein destabilizes and forms amyloid deposits, typically affecting older Caucasian men.

Historically, liver transplantation was the primary treatment for hATTR PN, as it replaces the main source of the mutated TTR protein. However, with the development of effective new pharmacotherapies, liver transplantation is no longer the standard first-line treatment and is reserved for specific cases.

Due to the multi-system nature of the disease, a multidisciplinary care team is essential. This often includes a neurologist, cardiologist, nephrologist, ophthalmologist, and genetic counselor.

Diagnosis is confirmed through genetic testing, which identifies the specific TTR mutation. A tissue biopsy is also often used to confirm the presence of amyloid deposits. Clinicians consider hATTR PN when patients present with progressive neuropathy alongside systemic symptoms, particularly if there is a family history.