A man looks down tired at his desk, symbolizing the physical and emotional toll of living with hereditary amyloidosis.

Disclaimer: This article is for informational purposes only and is not intended to diagnose any conditions. LifeDNA does not provide diagnostic services for any conditions mentioned in this or any other article.

Hereditary amyloidosis is a genetic disorder and one of the subtypes of amyloidosis. It is characterized by abnormal accumulation of amyloids, or protein aggregates in various tissues and organs due to mutations that happen in certain genes. This accumulation disrupts normal organ function which can- lead to serious health complications. While hereditary amyloidosis may not be widely known like other genetic conditions, it is crucial to understand its causes, symptoms, types, and treatment options. Early diagnosis can significantly affect patient outcomes and quality of life. In this comprehensive article, we will explore the key aspects of hereditary amyloidosis to provide a clear understanding for those who are not familiar with this rare condition.

What is Hereditary Amyloidosis?

Hereditary amyloidosis, often referred to as familial amyloidosis occurs due to genetic mutations that lead to the misfolding of specific proteins. These misfolded proteins aggregate into amyloid fibrils, which then deposit in various organ tissues and can later lead to disruption of their normal function. The most common type of hereditary amyloidosis is transthyretin amyloidosis (ATTRv), caused by mutations in the transthyretin (TTR) gene. Understanding hereditary amyloidosis is vital, especially for individuals with a family history of the condition or those experiencing unexplained symptoms that could indicate amyloid deposition.

Types of Hereditary Amyloidosis

Hereditary amyloidosis is a group of genetic disorders where abnormal protein aggregates called amyloids build up in organs and tissues, causing them to function poorly. This happens because certain gene mutations cause proteins to fold incorrectly, allowing them to form clumps that the body cannot break down. These different types are named after the specific protein involved, each affecting the body in unique ways.

1. Transthyretin Amyloidosis (ATTRv)

ATTRv is the most common type of hereditary amyloidosis caused by mutations in the TTR gene, which  causesperipheral sensorimotor and/or autonomic neuropathy.  The TTR gene is responsible for creating transthyretin, a protein made in the liver that helps transport thyroid hormones, particularly thyroxine (T4), as well as retinol (vitamin A) in the blood. Mutated transthyretin – causes amyloid deposits  in various organ tissues and later affects their vital functions.

2. Apolipoprotein A-I Amyloidosis

Apolipoprotein AI amyloidosis is linked to mutations in the APOA1 gene, a gene that aids in the production of  a high-density lipoprotein (HDL)  component called apolipoprotein A-I , a protein responsible for cholesterol and phospholipids transport through the bloodstream. When mutation is present, this protein misfold causing  amyloid deposits, primarily affecting the heart and kidneys.

3. Gelsolin Amyloidosis

This type of amyloidosis is caused by mutations in the GSN gene, which helps maintain the structure of cells. When the GSN gene is mutated, amyloid deposits can form in the skin and nervous system affecting skin structure, motor, and sensory function.

4. Lysozyme Amyloidosis

Lysozyme amyloidosis stems from mutations in the LYZ gene, a gene that encodes the lysozyme enzyme. This enzyme is synthesized through hepatocytes and macrophages and helps the body fight harmful bacteria. When mutation is present, it causes the lysozyme to build up as amyloid, particularly affecting renal, cardiac, and gastrointestinal health.

5. Fibrinogen Aα-chain Amyloidosis

Mutations in the FGA gene lead to fibrinogen Aα-chain amyloidosis. The protein produced by this gene is involved in blood clotting (coagulation) to prevent excessive bleeding. But when mutated, the protein  can accumulate as amyloid deposits in the kidneys and liver.

6. Cystatin C Amyloidosis

This type results from mutations in the CST3 gene, responsible for producing cystatin C, a protein involved in regulating other proteins in the body. When it misfolds due to genetic mutation, cystatin amyloids can build up in the nervous system and kidneys.

Risk Factors for Hereditary Amyloidosis

Hereditary amyloidosis is primarily determined by genetic factors, with several considerations influencing its development:

  • Family History: Having a family member with hereditary amyloidosis significantly increases the risk. The condition follows an autosomal dominant inheritance pattern, meaning a mutation in just one copy of the gene can lead to disease manifestation.
  • Age: Symptoms typically begin in adulthood, with the age of onset varying based on the specific type of amyloidosis.
  • Genetic Mutations: Specific mutations in the TTR gene and other related genes are directly linked to different forms of hereditary amyloidosis. Genetic testing can identify individuals at risk.
  • Ethnicity: Certain populations, particularly those of Scandinavian and African descent, are more likely to carry mutations associated with hereditary amyloidosis, especially ATTRv.

Complications of Hereditary Amyloidosis

The complications arising from hereditary amyloidosis can vary based on the type of amyloidosis and the organs affected. Here are some common complications:

  1. Cardiac Complications
    Amyloid deposits in the heart can lead to serious complications. Heart failure may develop as the amyloid buildup weakens the heart’s ability to pump blood efficiently, resulting in fatigue and fluid retention. Additionally, arrhythmias, or irregular heart rhythms, can arise from disruptions in the heart’s electrical pathways. These abnormal rhythms can pose severe risks, potentially leading to dangerous cardiac events that require careful monitoring and medical intervention.
  2. Kidney Damage
    The kidneys are particularly vulnerable to amyloid deposits, which can impair their function over time. One of the first signs of kidney involvement is proteinuria, or increased protein levels in the urine, which suggests that the kidneys are struggling to filter waste properly. As amyloid accumulation progresses, it can lead to kidney failure, making dialysis or even a kidney transplant necessary to sustain kidney function and overall health.
  3. Neurological Issues
    Amyloidosis can also damage the nervous system, leading to various neurological symptoms. Peripheral neuropathy, characterized by tingling, numbness, and pain in the hands and feet, can make daily tasks challenging. In some cases, autonomic neuropathy occurs, affecting the involuntary functions of the body, like blood pressure control and digestion, which can lead to dizziness, changes in sweating, and digestive difficulties.
  4. Gastrointestinal Complications
    Amyloid deposits may affect the gastrointestinal system, disrupting normal digestion and causing symptoms like nausea and vomiting, often due to nerve damage affecting gut motility. Some individuals may experience diarrhea or constipation as well, which can result from autonomic nerve involvement that disrupts the regular rhythm of the digestive tract, making it difficult for the body to process food comfortably and consistently which could lead to poor nutrient absorption and low energy.

Symptoms of Hereditary Amyloidosis

  1. Heart Issues
    Hereditary amyloidosis can cause a variety of heart-related problems as amyloid protein aggregates accumulate in heart tissue. This buildup can weaken the heart muscle, leading to heart failure, a condition where the heart cannot pump blood effectively. This often results in fatigue, shortness of breath, and swelling in the legs and feet due to fluid retention. Additionally, amyloid deposits may interfere with the heart’s electrical signals, causing arrhythmias, or irregular heartbeats, which can sometimes be life-threatening if not addressed early and managed properly.
  2. Kidney Problems
    The kidneys are commonly affected by amyloid deposits, which can damage their ability to filter waste from the blood. This often leads to proteinuria, where excess protein appears in the urine, signaling that the kidneys are under strain. Over time, kidney function may progressively decline, leading to kidney failure in severe cases. This can necessitate treatments such as dialysis or, in some cases, a kidney transplant, to help maintain essential kidney function.
  3. Neuropathy
    Amyloid deposits can impact the nervous system, particularly the peripheral nerves, which are responsible for sensation and movement in the limbs. Peripheral neuropathy often develops, leading to symptoms like tingling, numbness, and pain in the hands and feet. This can make everyday activities difficult and uncomfortable. In addition, amyloid deposits may affect the autonomic nerves, which control involuntary bodily functions, causing autonomic neuropathy. This can lead to dizziness, digestive issues, and other disruptions in bodily functions like blood pressure regulation.
  4. Gastrointestinal Symptoms
    Amyloidosis can affect the gastrointestinal tract, resulting in digestive issues that disrupt normal eating and digestion patterns. Many people experience symptoms such as nausea and vomiting, often due to nerve damage that slows food movement through the digestive tract. This condition, called gastroparesis, can make it difficult to eat comfortably. Additionally, people may experience diarrhea or constipation, both of which can result from nerve involvement in the digestive system and lead to unpredictable bowel habits.
  5. Eye Problems
    In certain types of hereditary amyloidosis, amyloid deposits can affect eye structures, potentially causing vision issues. This may lead to clouding of the cornea, difficulty focusing, or even retinal damage in severe cases. The presence of amyloid in the eyes may cause discomfort or blurred vision and could potentially require specialized ophthalmologic care to manage these symptoms and protect vision.
  6. Skin Changes
    In some individuals, amyloidosis may cause noticeable changes to the skin. This can include thickening or waxy areas on the skin, particularly around the eyes. The skin might also bruise more easily than usual due to the impact of amyloid on blood vessel integrity. These skin changes, while not life-threatening, can be distressing and may require management by a dermatologist.
  7. Carpal Tunnel Syndrome
    A common symptom in hereditary amyloidosis is carpal tunnel syndrome, which occurs when amyloid deposits accumulate around the median nerve in the wrist. This can lead to numbness, tingling, and pain in the hands, often making it difficult to grip objects or perform fine motor tasks. Carpal tunnel syndrome can be an early symptom, sometimes appearing years before other signs of amyloidosis, and may require intervention such as wrist splints or surgery to relieve symptoms.

Diagnosis of Hereditary Amyloidosis

Diagnosing hereditary amyloidosis involves a multi-faceted approach, often requiring several tests and evaluations:

  1. Medical History and Physical Examination: A healthcare provider will review the patient’s medical and family history, alongside a physical examination to identify any symptoms or signs of organ involvement.
  2. Blood Tests: These can help assess kidney and liver function and detect abnormal protein levels, such as that of the  Transthyretin (TTR).
  3. Urine Tests: A 24-hour urine collection may be conducted to check for protein levels, particularly light chains indicative of amyloid involvement.
  4. Imaging Studies: Techniques such as echocardiograms, MRI, or CT scans can help assess the extent of organ involvement.
  5. Biopsy: A definitive diagnosis often requires a biopsy of affected tissue to confirm the presence of amyloid deposits. Common biopsy sites include fat tissue, bone marrow, or organs suspected to be involved.
  6. Genetic Testing: Genetic testing is crucial for confirming hereditary amyloidosis and identifying specific mutations. This information is valuable for family members regarding their risk of developing the condition.

Treatment Options for Hereditary Amyloidosis

Although there is no cure for hereditary amyloidosis, treatment options have been researched with an aim to manage symptoms by addressing the root cause of amyloid buildup. The approach can vary depending on the specific amyloidosis type and affected organs. Here are some common treatment options to help manage this condition:

Targeting the Underlying Genetic Cause
For transthyretin amyloidosis (ATTRv), the goal is to target the genetic root of the disorder.

  • Medications: New treatments aim to stabilize or reduce amyloid deposits by targeting the TTR protein. For example, patisiran (an RNA interference therapy) and inotersen (an antisense oligonucleotide) can lower the production of abnormal TTR proteins, potentially slowing disease progression.
  • Diflunisal: This is a nonsteroidal anti-inflammatory drug that can also stabilize the TTR protein, helping to delay the progression of the condition.
  • Liver Transplantation: Since the liver produces the abnormal TTR protein in ATTRv, a liver transplant may be considered in severe cases to replace the source of amyloid production, reducing amyloid deposits and improving symptoms.

Supportive Care
Overall supportive care is vital for improving quality of life in hereditary amyloidosis.

  • Nutritional Support: Ensuring that patients have adequate nutrition can help manage weight loss and general weakness often associated with the disease.
  • Counseling and Emotional Support: Living with hereditary amyloidosis can be challenging, so counseling and psychological support can help patients and their families navigate the emotional aspects of the condition, improve coping skills, and enhance overall well-being.

Living with Hereditary Amyloidosis

Managing life with hereditary amyloidosis involves multiple aspects to ensure physical, emotional, and overall well-being. Here are some key areas of focus:

  1. Medical Management
    Routine medical care is essential for monitoring the progression of amyloidosis and managing symptoms. Regular check-ups, blood tests, and imaging studies can help track the impact on organs like the heart, kidneys, and nervous system. Staying in close contact with a healthcare provider allows for adjustments in treatment and medication as needed, ensuring patients receive timely care and interventions.
  2. Diet and Nutrition
    Nutrition plays an important role in managing hereditary amyloidosis, especially when vital organs such as the kidneys are affected. A well-balanced diet tailored to individual needs can support overall health, and a low-salt or low-protein diet may help reduce strain on the heart and kidneys. Consulting with a dietitian will help in choosing nutrient-rich foods that align with the dietary restrictions, helping to manage symptoms and maintain energy levels.
  3. Physical Activity and Mobility
    Staying active can help maintain muscle strength, improve circulation, and support heart health, even as symptoms progress. For individuals with neuropathy or cardiac symptoms, engaging in gentle, regular physical activities like walking or stretching may help preserve mobility and reduce discomfort. A physical therapist can recommend exercises tailored to each person’s needs, ensuring safe and effective movement practices.
  4. Emotional and Psychological Support
    Living with a chronic illness can take an emotional toll, so psychological support is vital. Connecting with support groups or mental health counselors provides patients and families with an understanding of community and professional guidance. Talking about the challenges and emotions associated with amyloidosis can help reduce feelings of isolation and provide strategies for coping.
  5. Adaptations for Daily Living
    Over time, hereditary amyloidosis can impact physical abilities, making daily tasks more challenging. Home adaptations, such as handrails, shower chairs, and ramps, can create a safer environment, while assistive devices like button hooks and grip aids help with daily tasks. Occupational therapists can provide recommendations for home modifications that increase independence and comfort.
  6. Building a Support Network
    Having a strong support system of family, friends, and caregivers is invaluable for individuals with hereditary amyloidosis. A support network provides practical help, such as assistance with medical appointments, daily needs, and emotional encouragement. For both patients and their families, this network is key to navigating the journey and finding comfort during challenging times.
  7. Planning for the Future
    As hereditary amyloidosis is a progressive condition, it’s important to plan for future healthcare needs. This may include discussing long-term care options, such as home health services or care facilities, with family and healthcare providers. Planning ahead can help reduce stress and ensure that support is available when needed, enabling patients and families to feel more prepared and in control of their care journey.

Each of these strategies can help individuals with hereditary amyloidosis manage the complexities of the condition and live as fully and independently as possible.

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