Understanding hATTR Amyloidosis With Polyneuropathy

Hereditary transthyretin amyloidosis with polyneuropathy (damage to your peripheral nerves), (hATTR-PN), is a rare disease that attacks your nervous system. It occurs when a defect in the transthyretin (TTR) protein is passed to you from a parent.

The damaged gene changes the shape and function of TTR. When normal, TTR transports thyroid hormone and vitamin A through your body.

Damaged TTR will likely cluster and form toxic amyloid deposits in your nerves, heart, and other tissue. This form of the disease mainly affects your sensory functions that involve touch, pressure, and pain.

Having hATTR-PN can make it hard to move and perform daily tasks. When found early, some cases may slow or improve from novel treatments that target how much damaged TTR your body makes.

This article explains the symptoms, risks, and complications of this disease. It also includes treatments, disease outcomes, and ways to cope.

hATTR Amyloidosis and Polyneuropathy Symptoms

The condition hATTR amyloidosis with polyneuropathy, also known as familial amyloidosis with polyneuropathy, is considered the most serious hereditary polyneuropathy of adult-onset disease. The disease onset and presentation are typically progressive, devastating, and life-threatening.

Symptoms of this rare disease can be highly varied based on the specific mutation that develops. There are more than 120 mutations in the TTR gene. The predominant clinical feature will give hATTR its name as either polyneuropathy (hATTR-PN) or cardiomyopathy (hATTR-CM). One of the most common variations is hATTR amyloidosis with polyneuropathy. Most people have a combination of both heart and nerve involvement.

While symptoms can be unpredictable and vary by the mutant involved, initial symptoms or early-stage (onset younger than age 50) of hATTR-PN include the following:

• Pain, paresthesia (tingling), and numbness in the feet
• Loss of sensitivity to temperature
• Dysfunctions of the autonomic nervous system, a part of the peripheral nervous system that regulates involuntary physiologic processes, leading to problems with blood pressure, respiration, digestion, and sexual arousal
• Fatigue
• Weight loss
• Plantar ulcers (a type of foot ulcer)
• Cardiac arrhythmias (irregular heart rhythm)

Advancing or late-stage (onset at age 50 or older) hATTR-PN tends to proceed with the following symptoms related to the peripheral nervous system:

• Progression of sensory loss to the lower limbs, hands, and arms, often causing symptoms similar to carpal tunnel syndrome in the arms
• Loss of reflexes
• Reduced motor skills
• Muscle weakness
• Cardiac dysfunction

Risks and Complications

Risks associated with having hATTR-PN are passed from parent to child in an autosomal dominant manner. You have a 50% chance of inheriting the TTR mutation if one of your parents is affected or known to have the variant. While the majority of people who have hereditary amyloidosis develop symptoms, some of those affected never get the disease.

The variability of disease onset and presentation differs based on factors including your country of origin and the parent's gender from whom you inherited the mutation. The Val30Met mutation is the most common TTR mutation worldwide, accounting for about half of TTR variants globally. It is typically associated with polyneuropathy.

While hATTR-PN predominantly affects your nervous system, it is a systemic disease, meaning it affects other organs and tissue as well. When amyloid deposits interfere with normal function in other areas, the following complications can occur:

• Cardiac problems: Many people with hATTR-PN also develop symptoms of cardiac amyloidosis. You have a 50% risk of having cardiomyopathy (cardiac disease that makes your heart larger, thicker, or stiffer than normal) if you have any type of hATTR amyloidosis. Amyloid deposits in your heart can lead to cardiac arrhythmias, conduction defects, and heart failure.
• Damage to the peripheral nerves: As hATTR-PN progresses, it can lead to muscle weakness and eventually leave an affected person unable to walk and needing assistive devices such as a wheelchair.
• Damage to the autonomic nervous system: The weakening of nerves that control your body functions, such as heartbeat and digestion, can lead to problems such as incontinence, severe diarrhea and/or constipation, sexual dysfunction, and malabsorption.
• Dysfunction of your kidney's filtering system: Amyloid deposits can damage your kidneys' filtering system, and lead to proteinuria (the presence of protein in your urine). The result can lead to kidney failure, swelling, and the need for dialysis.
• Vision and eye damage: About 20% of TTR mutations can impact your eyes. Symptoms can include floaters, dry eyes, glaucoma, and impaired vision.
  

Treatment to Manage hATTR Amyloidosis With Polyneuropathy

As recently as 1990, the only treatments available for hATTR-PN were therapies to manage symptoms because the condition was regarded as incurable. However, novel therapies have improved disease outcomes since then.

Drug Treatments

While the specific therapy you receive depends on many factors, early diagnosis is critical to achieve the best results. Newer treatments are most effective during the early stages of the disease. They have successfully lowered TTR levels, reduced neuropathic symptoms, and improved quality of life. Some treatments may also help slow disease progression.

Treatment to manage hATTR-PN includes the following pharmacotherapies:

TTR gene silencers that interfere with the production of the TTR protein in your liver:

• Wainua (eplontersen), injection
• Tegesedi (inotersen), injection
• Onpattro (patisiran), intravenous (IV) infusion
• Amvuttra (vutrisiran), injection

TTR stabilizers that prevent the TTR proteins from misfolding and forming amyloid deposits:

• Vyndaquel/Vyndamax (tafamidis), oral
• Dolobid (diflunisal) (off-label), oral
• Green tea extract, oral
• Acoramidis

Amyloid fibrils degraders that degrade or destroy existing amyloid deposits:

• Doxycycline (off-label antibiotic), oral
• Doxycycline plus the bile acid TUDCA, oral
  

Liver Transplant

TTR is primarily produced in your liver, where mutant genes trigger the production of defective TTR. While the liver itself is not typically damaged by the disease, liver transplantation focuses on removing the source that produces the mutant protein and replacing it with a healthy one.

Until the recent approval of pharmacotherapies for hATTR amyloidosis, liver transplantation was the only available treatment. It is most effective for people with early-onset hATTR amyloidosis with polyneuropathy.

However, liver transplantation is costly and of high risk. With the introduction of pharmacotherapies for hATTR amyloidosis with polyneuropathy, liver transplantation is rarely a first-level treatment.

Other Organ Transplants

Since the amyloid deposits that accumulate with hATTR-PN have the potential to damage other tissue and organs, transplantation of affected organs, such as a heart or kidneys, may be advised.

Prognosis and Easier Ways to Cope

Research indicates that people with hATTR-PN typically require assistance with walking after five to six years and have a life expectancy of seven to 10 years from the onset of neuropathy. However, recently approved treatments are changing the natural history of this progressive disorder. Early diagnosis can lead to earlier treatment with therapies that show improved outcomes.

Generally, a prognosis for hATTR-PN is also impacted by factors that include the following:

• Type of TTR mutation: Some TTR mutations are more likely to cause neuropathy symptoms, while others are more likely to cause cardiomyopathy symptoms. People with cardiomyopathy symptoms generally have a poorer prognosis.
• Age of onset: Typically, people with late-onset hATTR-PN have more severe neurologic and cardiac findings than those who have late onset of this disease.
• Origin of the inherited mutation: Male offspring who inherit hATTR amyloidosis from their mothers tend to have disease symptoms earlier and more severely than female offspring who inherit the disease from their fathers.

Living with hATTR-PN can be challenging. The pain and numbness accompanying nerve damage can make it harder to continue your everyday activities as nerve damage worsens.

Talk to your healthcare provider about ways that can make it easier to cope with this disease and whether the following strategies can work for you:

• Oral prescriptions to manage nerve pain and other neuropathy symptoms, like Neurontin (gabapentin), Elavil (amitriptyline), Lyrica (pregabalin), Cymbalta (duloxetine), Oxycontin (oxycodone), or other opioids
• Topical over-the-counter creams applied directly to the skin of targeted areas, like lidocaine ointment/lidocaine patch, capsaicin (active ingredient in chili peppers), cannabidiol (CBD)/delta-9-tetrahydrocannabinol (THC) products, complementary/alternative therapies, supplements, meditation, acupuncture, massage, physical therapy, and electrotherapy
• Therapies to address specific symptoms such as gastrointestinal issues or incontinence
• Home safety equipment and assistive devices such as grab bars that can help you maintain your functional capabilities
• Home modifications such as stair lifts and ramps to help you maintain independence at home

Summary

Hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) is a rare disease that is passed from parent to child. It occurs when a damaged gene changes the space and function of the protein transthyretin. The change causes the gene to misfold and form clusters of amyloid deposits that damage your nerves.

The impact of hATTR-PN can be severe as symptoms of pain and numbness prevent you from doing daily tasks. Without treatment, nerve damage can progress to the degree that you need a wheelchair.

However, early diagnosis is key to getting better outcomes for this disease. Novel treatments can reduce symptoms, improve quality of life, and slow disease progression for many people.

Know your risk factors for hATTR-PN so you can get an early diagnosis. This can help you and your family improve your outcomes with this severe disease.