Hereditary Neuropathic Amyloidosis

Hereditary neuropathic amyloidosis is a rare inherited disease where abnormal proteins build up in the body’s nerves and organs, slowly causing damage that can affect sensation, movement, and many bodily functions.

ATTRv Amyloidosis, Familial Amyloid Polyneuropathy, Familial Transthyretin Amyloidosis, hATTR, Hereditary Amyloidogenic Transthyretin Amyloidosis, Hereditary ATTR Amyloidosis, Hereditary Transthyretin-Mediated Amyloidosis

Table of contents

• What Is Hereditary Neuropathic Amyloidosis?
• Causes and Inheritance
• Signs and Symptoms
• How Common Is It?
• Diagnosis and Testing
• Treatment and Management
• Living With the Condition

What Is Hereditary Neuropathic Amyloidosis?

Hereditary neuropathic amyloidosis, also known as hereditary transthyretin amyloidosis (hATTR or ATTRv), is a rare inherited disease that causes abnormal protein deposits to build up in the body’s tissues and organs^[1]. This condition is caused by changes in a gene that makes a protein called transthyretin, which normally carries vitamin A and thyroid hormones through the bloodstream^[2].

In people with this condition, the transthyretin protein becomes unstable and breaks apart, folding incorrectly into clumps called amyloid fibrils^[3]. These clumps travel through the blood and deposit in various parts of the body, particularly in the nerves, heart, digestive system, eyes, and kidneys^[1]. The buildup of these protein deposits damages the structure and function of the organs where they collect^[3].

The disease is progressive, meaning it gets worse over time. It typically begins in adulthood, with symptoms usually appearing between the ages of 20 and 70^[2]. In areas like Portugal and Japan where the condition is more common, symptoms often start in the third to fifth decade of life, while in other regions, the onset tends to be later^[1].

• Peripheral nervous system
• Heart
• Digestive system
• Eyes
• Kidneys
• Autonomic nervous system
• Brain and spinal cord (central nervous system)

Causes and Inheritance

Hereditary neuropathic amyloidosis is caused by changes (mutations) in the TTR gene^[2]. This gene provides instructions for making the transthyretin protein, which is primarily produced in the liver^[3]. When the TTR gene has a mutation, it causes the transthyretin protein to become unstable^[7].

The condition is inherited in an autosomal dominant pattern^[8]. This means that if one parent has the genetic mutation, there is a 50% chance that their child will inherit it^[3]. However, not everyone who inherits the mutation will develop symptoms of the disease^[3].

More than 120 to 150 different mutations in the TTR gene have been identified worldwide^[7][9]. Each mutation can cause different patterns of disease onset, symptoms, and progression. Some mutations are found more commonly in specific geographic regions and populations^[3]. For example, the V30M variant is most common in Portugal, Spain, France, Sweden, and Japan, while the V122I variant is seen in 3 to 4 percent of African Americans^[9].

Signs and Symptoms

The symptoms of hereditary neuropathic amyloidosis vary widely depending on which organs are affected by the amyloid deposits and how much damage has occurred^[7]. The disease most commonly affects the nervous system, but can also involve the heart, digestive system, eyes, and kidneys^[3].

Nerve-Related Symptoms

The peripheral nervous system, which includes nerves that connect the brain and spinal cord to the rest of the body, is often the first area affected^[1]. Typically, sensory problems begin in the feet with tingling and numbness, a condition called peripheral neuropathy^[1]. Within a few years, these symptoms can progress to affect motor nerves, causing muscle weakness and difficulty walking^[4].

The autonomic nervous system, which controls involuntary body functions, is also commonly affected^[1]. This can lead to a wide range of symptoms including^[1][7]:

• Dizziness and low blood pressure when standing up (orthostatic hypotension)
• Digestive problems like constipation, diarrhea, nausea, and vomiting
• Delayed stomach emptying
• Sexual dysfunction in men
• Loss of ability to sweat (anhidrosis)
• Problems with bladder control

Many people with this condition also develop carpal tunnel syndrome, which causes numbness, tingling, and weakness in the hands and fingers^[3][17]. This may appear as an early symptom, sometimes years before other signs of the disease^[17].

Heart-Related Symptoms

When amyloid deposits affect the heart, they cause the heart muscle to thicken and stiffen, a condition called restrictive cardiomyopathy^[1]. This makes it harder for the heart to pump blood effectively. Heart-related symptoms may include^[7]:

• Shortness of breath, especially with activity
• Swelling in the legs and ankles
• Abnormal heart rhythms (arrhythmias)
• Palpitations
• Chest pain
• Extreme fatigue

Digestive System Symptoms

The digestive system can be affected by amyloid deposits in the nerves that control digestion^[3]. Common symptoms include^[7]:

• Unintended weight loss
• Loss of appetite
• Nausea
• Diarrhea or constipation
• Stomach pain

Eye Problems

Eye involvement in hereditary neuropathic amyloidosis can cause several problems^[1][7]:

• Cloudy vision or spots in vision
• Dry eyes
• Increased eye pressure (glaucoma)
• Cloudiness of the gel inside the eye (vitreous opacity)
• Unusual pupil appearance

Other Symptoms

Other parts of the body that may be affected include^[1][12]:

• Kidneys, causing protein in the urine and kidney disease
• Brain and spinal cord, potentially causing confusion, headaches, seizures, or difficulty with coordination
• Spinal canal, causing pain and weakness in the legs

It’s important to note that symptoms can seem unrelated because amyloid deposits can accumulate in various organs, making the condition difficult to diagnose^[3].

How Common Is It?

The exact number of people affected by hereditary neuropathic amyloidosis is not known^[2]. The condition is considered rare, but experts believe it may be more common than currently recognized because it is often underdiagnosed^[6].

The frequency varies significantly by geographic region and ethnic background. In northern Portugal, the condition is estimated to affect about 1 in 538 people, making it much more common there than in other parts of the world^[2]. Among Americans of European descent, the condition is less common, affecting approximately 1 in 100,000 people^[2].

Certain genetic mutations are more prevalent in specific populations. For example, an estimated 1 in 25 Black people have a changed TTR gene, though not everyone with this genetic change develops the disease^[6]. The condition affects between 3 and 3.9 percent of African Americans and approximately 5 percent of people in some areas of West Africa^[2].

Because family members of people with hereditary neuropathic amyloidosis often carry the genetic mutation, they are at risk of developing the disease and are important to monitor^[12].

Diagnosis and Testing

Diagnosing hereditary neuropathic amyloidosis can be challenging because symptoms are varied and can resemble other, more common conditions^[3]. Many people experience a long journey to diagnosis, sometimes taking several years^[4][17].

Clinical Evaluation

The diagnostic process typically begins with a thorough medical history and physical examination^[17]. Doctors will ask about symptoms affecting the nerves, heart, digestive system, and other organs. A family history of similar symptoms is an important clue, as hereditary neuropathic amyloidosis runs in families^[7].

Tissue Biopsy

To confirm the presence of amyloid deposits, doctors perform a tissue biopsy^[9]. This involves removing a small sample of tissue to examine under a microscope. Common biopsy sites include^[9]:

• Abdominal fat pad (a simple procedure using a needle)
• Gastrointestinal tract
• Heart
• Skin
• Kidney
• Nerve

Once amyloid deposits are found, additional tests are used to determine what type of protein is forming the amyloid. These tests include immunohistochemistry (using antibodies to identify proteins) and mass spectrometry (a technique that identifies proteins based on their molecular weight)^[9].

Genetic Testing

Definitive diagnosis of hereditary neuropathic amyloidosis requires genetic testing^[1]. A blood test can identify mutations in the TTR gene^[9]. The test will show which specific variant is present, which can help predict the pattern of disease and guide treatment decisions.

When someone is diagnosed with hereditary neuropathic amyloidosis, other family members may be advised to consider genetic testing, even if they don’t have symptoms^[9].

Organ Function Tests

To determine which organs are affected and how severely, doctors order various tests^[9][12]:

• Heart tests: electrocardiogram (ECG), echocardiogram, and cardiac MRI to assess heart function
• Nerve tests: nerve conduction studies and electromyography to evaluate nerve damage
• Blood and urine tests: to check kidney function and look for protein in the urine
• Eye examination: to detect vision problems and eye involvement
• Autonomic function tests: to assess the nervous system’s control of automatic body functions
• Digestive system evaluation: to identify gastrointestinal problems

Some specialized imaging tests can help identify the type of amyloidosis affecting the heart and distinguish it from other conditions^[9].

Treatment and Management

While there is no cure for hereditary neuropathic amyloidosis, several treatments are now available that can slow disease progression and improve quality of life^[1][9].

Disease-Modifying Therapies

Pharmacologic treatments are now considered first-line therapy for people with hereditary neuropathic amyloidosis^[1]. These medications work in different ways to reduce the production or stabilize the abnormal transthyretin protein^[10]:

Gene-silencing therapies reduce the liver’s production of transthyretin protein. Two medications in this category, patisiran and inotersen, are approved for treating the nerve-related symptoms of hereditary neuropathic amyloidosis^[10]. A newer gene-silencing medication called eplontersen is also available^[3]. Another gene-silencing drug, vutrisiran, is approved for both nerve and heart involvement^[10].

Transthyretin stabilizers work by preventing the transthyretin protein from breaking apart and forming amyloid deposits. Tafamidis is approved for treating heart involvement in this condition^[10]. A newer stabilizer called acoramidis has also been approved^[10].

Liver Transplantation

Since the 1990s, liver transplantation has been used to treat hereditary neuropathic amyloidosis because the liver produces most of the body’s transthyretin protein^[10]. However, with the introduction of effective medications, the use of liver transplantation has declined significantly^[10]. It is now considered only for selected patients, particularly those in the early stage of disease^[1][9].

Symptom Management

In addition to disease-modifying treatments, managing specific symptoms is an important part of care^[1][14]:

For nerve pain: Medications specifically for neuropathic pain can help reduce discomfort^[1].

For carpal tunnel syndrome: Surgical release may be recommended if symptoms are severe^[1].

For muscle weakness: Physical therapy and ankle-foot braces can help with walking and mobility^[1].

For low blood pressure: Increasing salt and fluid intake, wearing compression stockings, and specific medications can help manage dizziness when standing^[14][16].

For digestive problems: Dietary changes, medications for nausea and motility, and smaller, more frequent meals can help^[14].

For heart problems: Standard heart failure treatments may be used, and some people may need a pacemaker if the heart’s electrical system is affected^[1].

For eye problems: Surgery may be needed for vitreous opacity or glaucoma, and artificial tears can help with dry eyes^[1].

For kidney problems: People with severe kidney disease may eventually need dialysis^[1].

Monitoring and Follow-Up

Regular monitoring is essential for people with hereditary neuropathic amyloidosis^[12]. This typically includes periodic assessments every 6 to 12 months of^[12]:

• Nutritional status and weight
• Heart function
• Nerve function
• Kidney function
• Eye health
• Autonomic nervous system function
• Overall quality of life

For family members who carry the genetic mutation but don’t yet have symptoms, regular screening is recommended to detect disease onset early^[12]. Annual routine assessments are often suggested, with more frequent monitoring as needed^[1].

Living With the Condition

Living with hereditary neuropathic amyloidosis requires adapting to a chronic condition that affects multiple aspects of daily life. However, with proper treatment and self-care strategies, many people can maintain a good quality of life^[17].

Daily Management Strategies

Several practical approaches can help manage symptoms and improve day-to-day functioning^[16][17]:

Monitoring fluid and salt intake: For people with heart involvement or low blood pressure, carefully managing how much fluid and salt you consume can help reduce swelling and prevent dizziness. Your doctor can provide personalized recommendations^[16].

Weighing yourself regularly: Daily weight monitoring can help detect fluid buildup early, which is important for people with heart involvement^[16].

Creating a routine: Planning activities around your energy levels and symptoms can help you accomplish more while avoiding exhaustion. Many people find that energy levels fluctuate throughout the day^[17].

Using assistive devices: Mobility aids like canes, walkers, or ankle braces can improve safety and independence for people experiencing weakness or difficulty walking^[17].

Managing temperature carefully: Because the disease can affect the body’s ability to regulate temperature and sweating, avoiding extreme heat and staying well-hydrated is important^[14].

Emotional and Social Support

The chronic nature of hereditary neuropathic amyloidosis can take an emotional toll on both patients and caregivers^[19]. Connecting with others who understand the challenges of living with this condition can provide valuable support, encouragement, and practical advice^[19].

Patient support organizations offer various resources^[19]:

• Educational materials about the disease
• Peer mentorship programs that connect patients with others who have experience with the condition
• Online and local support groups
• Information about treatment centers and clinical trials
• Financial assistance resources

Working With Your Healthcare Team

Because hereditary neuropathic amyloidosis affects multiple organ systems, care typically involves a team of specialists including neurologists, cardiologists, genetic counselors, and others^[17]. Open communication with all members of your healthcare team is essential^[17].

It’s helpful to keep detailed records of your symptoms, medications, and how you’re responding to treatment. This information can help your doctors make the best decisions about your care^[17].

Family Considerations

Because this condition is inherited, family members may benefit from genetic counseling and testing^[9]. Early detection in family members who carry the genetic mutation allows for prompt treatment if symptoms develop, which can significantly improve outcomes^[12].