What’s the connection between numbness, fatigue, and diarrhea? In rare cases, these seemingly unrelated symptoms may be caused by a condition called transthyretin amyloid polyneuropathy (ATTR-PN).

ATTR-PN is a type of hereditary ATTR (hATTR) amyloidosis, also known as familial amyloidosis. This condition occurs when mutations (changes) in the transthyretin (TTR) gene cause abnormal proteins to misfold and build up in the body. People living with ATTR-PN may experience neurologic (nerve-related), gastrointestinal (digestive), and cardiovascular (heart-related) symptoms that can significantly affect daily life.

Although ATTR-PN is rare, health experts estimate that it affects 10,000 to 40,000 people worldwide. Symptoms usually begin around age 30 or after 50, depending on the specific genetic variant.

ATTR-PN falls under the umbrella of a condition called amyloidosis. In amyloidosis, certain proteins in the body fold incorrectly and form sticky clumps called amyloid fibrils. These fibrils build up in tissues and organs, interfering with how those parts of the body work.

Living with a rare disease like ATTR-PN can be overwhelming. You might not have heard of it before, and you may not know what to expect. Here are six important facts to help you better understand ATTR-PN — including its causes, symptoms, diagnosis, and available treatment options.

1. A Gene Mutation Causes ATTR-PN

ATTR-PN is a hereditary condition caused by a mutation in the transthyretin gene. This change causes TTR proteins to fold incorrectly. These misshapen proteins stick together to form amyloid fibrils (fibers), which build up in organs and tissues and may lead to damage over time. When amyloid fibrils collect around the peripheral nerves, the condition is called transthyretin amyloid polyneuropathy.

2. ATTR-PN Symptoms Vary and May Be Mistaken for Another Condition

ATTR-PN tends to affect sensory, motor, and autonomic nervous systems — including functions you don’t consciously control, like digestion, blood pressure, and body temperature. Because of this, people who have the disease often experience a range of symptoms, such as:

• Burning sensations
• Cold skin
• Constipation
• Depression
• Diarrhea
• Digestive system blockages
• Dizziness or fainting
• Fatigue
• Frequent vomiting
• Increased sensitivity to touch
• Insomnia
• Loss of appetite
• Mood changes
• Muscle weakness and pain
• Numbness or lack of sensitivity
• Sexual dysfunction
• Sudden drops in blood pressure
• Upset stomach
• Urinary incontinence
• Vision and hearing problems

Symptoms related to ATTR-PN are usually vague, meaning they could be signs of something other than the disease. This can contribute to delays in diagnosis, as can a lack of awareness of the condition itself.

3. Diagnosing ATTR-PN Can Be Complex

Diagnosing ATTR-PN typically involves two main steps:

• Taking a thorough medical history
• Performing a neurological exam to check factors like gait (walking pattern), balance, and motor function

If ATTR-PN is still suspected after the history and exam, a doctor — usually a neurologist — may order further tests to confirm the diagnosis. These tests may include:

• A biopsy (sometimes taking tissue from more than one area of the body) to check for amyloid fibril deposits
• A test to identify the specific type of amyloid if the biopsy shows deposits
• Genetic testing to look for a TTR gene mutation

Diagnosing ATTR-PN often requires collaboration between specialists — typically neurologists, cardiologists, and geneticists. Because ATTR-PN can affect multiple systems in the body, it’s also important to monitor whether it has spread to organs like the heart, kidneys, or eyes.

ATTR-PN is extremely rare — only about 10,000 to 40,000 people worldwide live with this condition.

Detecting and treating ATTR-PN early is critical to helping prevent organ damage, which can be serious and sometimes permanent.

4. Treatments for ATTR-PN Help Slow Progression

The liver produces most of the TTR protein involved in ATTR-PN, so liver transplantation was the first widely used treatment for this condition. Although a liver transplant is still an option for some people living with ATTR-PN, doctors now better understand its limitations. For example, transplantation tends to be more effective in people with certain genetic mutations.

Researchers have also developed drugs to treat the disease that don’t require a major surgical procedure. These new medications focus on preventing or slowing disease progression. That means they stop amyloid fibrils from forming or collecting around the peripheral nerves.

Some medications have been approved by the U.S. Food and Drug Administration (FDA) to treat ATTR-PN. Others are used off-label — they’re approved for a different condition but have been shown to be effective for ATTR-PN.

FDA-approved drugs for ATTR-PN include:

• Eplontersen (Wainua)
• Patisiran (Onpattro)
• Vutrisiran (Amvuttra)

These drugs are known as gene silencers. They recognize and block the instructions for making TTR proteins.

Examples of off-label treatments include:

• Diflunisal, a nonsteroidal anti-inflammatory drug that keeps TTR proteins from folding improperly
• Tafamidis (Vyndamax, Vyndaqel), which is FDA-approved for ATTR cardiomyopathy (ATTR-CM, a type of amyloidosis affecting the heart)

Supportive Therapies for ATTR-PN

Because ATTR-PN affects motor function, doctors may recommend supportive therapies to help reduce symptoms and improve quality of life.

For example, occupational therapy can help improve quality of life by making activities of daily living — like eating, bathing, and dressing — easier. Physical therapy can help improve strength and reduce pain in the bones and joints.

5. New Therapies Are Improving ATTR-PN Outlook

Life expectancy for hereditary transthyretin amyloidosis depends on several factors, including:

• The specific gene mutation a person has
• The person’s age at diagnosis
• The presence of cardiomyopathy (a condition in which amyloid buildup stiffens the heart muscle and affects how well it works)

ATTR-PN usually progresses in three stages:

• Stage 1 — Loss of sensory function in the feet that moves up the legs and, eventually, to the hands
• Stage 2 — Increasing loss of mobility, with many people needing walking aids within three to five years of symptom onset
• Stage 3 — Significant mobility loss, with most people requiring a wheelchair 10 years after the disease onset

For some people with early-onset ATTR-PN (appearing around age 30) and a Val30Met mutation, the expected survival rate is about 12 years after the disease begins. For those with late-onset ATTR-PN (appearing at or after age 50), the median survival is seven years.

Symptoms related to ATTR-PN are usually vague, meaning they could be signs of something other than the disease. This can contribute to delays in diagnosis.

Therapies like liver transplantation and medications can help slow disease progression and improve survival in early stages.

6. Support Can Make Life With ATTR-PN More Manageable

Despite improvements in diagnosis and treatment, people living with ATTR-PN may still face challenges. MyAmyloidosisTeam members have shared difficulties with managing symptoms, getting appointments with neurologists, and affording their treatments:

• “My neuropathy pain and weakness is making life difficult.”
• “Make your appointments right away. I had to wait three months.”
• “Finally received approval of my treatment through Healthwell Foundation. How long does it take to improve polyneuropathy?”

Support groups — like MyAmyloidosisTeam — provide an important resource for both people living with the disease and their family members as they navigate this rare disease. “I’m glad to finally have people to talk to who understand and can relate to my symptoms,” one member shared.

Join the Conversation

On MyAmyloidosisTeam, people share their experiences with amyloidosis, get advice, and find support from others who understand.

Are you living with ATTR-PN? Let others know in the comments below.