# Hereditary ATTR Amyloidosis
What is it
Hereditary ATTR amyloidosis (hereditary transthyretin amyloidosis) is a rare genetic disease in which the body produces abnormal proteins that accumulate in tissues and organs. The protein is called transthyretin (TTR) and is made by the liver. In people with this hereditary form, the TTR protein contains a small change (mutation) in the genetic blueprint. This defective protein folds incorrectly and forms fine threads, called amyloid. These accumulations slowly damage the nerves, heart, and sometimes other organs.
The disease is hereditary: if a parent has the faulty TTR gene, each child has a 50% chance of inheriting the gene. Not everyone with the gene develops symptoms, and the age at which it happens varies greatly between families and even within families.
Causes
The cause is a mutation in the *TTR* gene on chromosome 4. This gene provides the instructions for making the transthyretin protein. The protein is produced by the liver and normally transports certain substances through the blood, such as retinol (vitamin A).
In hereditary ATTR, something goes wrong with how the protein folds. The misshapen protein cannot work properly and begins to clump together in fibers (amyloid). These accumulations grow over time and damage the surrounding tissues.
More than 100 different mutations are known. Some mutations more often cause nerve problems (neuropathy), others mainly heart complaints. Geographic origin also plays a role: certain mutations are more common in certain population groups.
How the disease progresses
Hereditary ATTR is a slowly progressive disease. Some people carry the mutation but feel nothing their entire lives. Others develop symptoms, usually sometime between their 30s and 60s, although both earlier and later are possible.
Once symptoms have begun, they typically worsen gradually over years to decades. The speed varies greatly between individuals. The course depends on the type of mutation, the age at which symptoms begin, which organs are involved, and whether treatment has been started.
There are roughly two forms:
- **Peripheral neuropathy**: usually begins with tingling and numbness in feet and legs, and spreads outward
- **Cardiac form**: the heart is affected and loses its pumping power; can develop rapidly, especially with certain mutations
Many patients have a mixed form with both nerve and heart problems. Sometimes other organs are involved: gastrointestinal system, eyes, kidneys, or even the nervous system in the brain and spinal cord (central nervous system).
Symptoms by phase
**Early phase (no or minimal symptoms)**
- Many carriers notice nothing and are diagnosed by chance through family screening
- Sometimes mild, subtle tingling in feet
**Development phase (first years of symptoms)**
*With nerve involvement:*
- Tingling, numbness, or burning sensation in feet and legs
- Fatigue and exhaustion
- Muscle weakness that slowly climbs upward
- Balance and coordination difficulties
- Sensitivity to temperature changes
- Diarrhea or constipation
- Erectile dysfunction (in men)
- Swelling of hands and feet
*With heart involvement:*
- Shortness of breath, first with exertion, later also at rest
- Fatigue
- Irregular heartbeat
- Swelling of legs and feet
- Chest stiffness
**Later stage**
- Severe weakness of legs, arms, and torso
- Dependence on aids (walking stick, walker, wheelchair)
- Difficulty speaking or swallowing
- Severe heart failure (can be life-threatening)
- Visual problems
- Potential cognitive symptoms (in central forms)
- Severe loss of sensation, so that injuries are no longer felt
The speed of worsening and severity vary enormously from person to person. Some remain in the same phase for years, others deteriorate more quickly.
What it means for daily life
ATTR amyloidosis can be far-reaching, depending on which phase you are in and which parts of the body are affected.
**In the beginning:**
- You can usually still do everything, but you feel symptoms emerging
- Working is usually still possible, though fatigue may increase
- Family and friends may sometimes notice nothing
**In the progressive phase:**
- Household work becomes more difficult
- You may no longer be allowed to drive (especially if balance or vision declines)
- Adjusting or stopping work is often necessary
- Earning an income can become difficult
- You become more dependent on others
- Medical appointments increase
**Later:**
- Care at home or in a facility becomes necessary
- Falls and injuries are a real risk
- Personal care requires assistance
- Communication may become more difficult
- Intimate life changes
**Practical:**
- You must be careful with temperature (some feel cold/heat poorly)
- Adjusting nutrition may be necessary (with swallowing difficulties or stomach problems)
- Regular check-ups with cardiologist, neurologist and other specialists
- Taking medication (planning, side effects)
- For some, special therapists: physiotherapy, speech therapy, dietetics
**Emotional and social:**
- Uncertainty about your future
- Grief over loss of independence
- Fear of inheritance in your own children
- Financial concerns (medical costs, benefits, mortgage)
- Isolation if you go out less
Outlook
The outlook for hereditary ATTR has changed in recent years due to the availability of disease-modifying medications. These medications inhibit or stop the production of the defective TTR protein by the liver.
**Without treatment:**
For persons with peripheral neuropathy, the average progression is severe: without therapy, patients can become substantially disabled within 5-10 years from symptom onset. For some it is faster, for others slower. With cardiac involvement, deterioration can sometimes progress faster.
**With treatment:**
Modern therapies (including stabilizers that stabilize the protein, and genetic approaches that inhibit production) have shown that they can slow or sometimes even halt progression, especially when started early. The earlier treatment begins, the better it seems to work. However: these are group figures. No one can say in advance how your disease will behave.
**Important nuance:**
- Survival rates and prognosis vary widely depending on mutation type, age of onset, which organs are involved, and individual genetic and medical factors
- Treatment can stop or slow progression, but usually cannot repair damaged nerves or heart tissue
- Some patients have achieved stabilization and live well with the disease for years
- For others the disease continues to progress nonetheless, though possibly more slowly
It is essential to discuss regularly with your healthcare provider what your personal situation means.
Frequently asked questions
**I have been tested and have the mutation, but feel nothing. Will I definitely get symptoms?**
No, not necessarily. About 10-25% of carriers with certain mutations never develop symptoms, or only at very advanced age. This depends on the type of mutation. Regular medical check-ups (especially heart ultrasound and nerve examinations) can help detect changes early, so you can start treatment before you feel symptoms.
**Can I pass this on to my children?**
Yes, if you are a carrier (with or without symptoms), each child of yours has a 50% chance of inheriting the gene. It is important to talk openly with your family about this and encourage them to be tested. Genetic counselors can help facilitate this conversation.
**Does diet or lifestyle help against the disease?**
There is no proven diet that cures or stops ATTR. However, healthy living (not smoking, eating well, moderate exercise as able) is important for your overall health and heart. Some people with stomach complaints must adjust their diet. It is best to discuss this with your healthcare team.
**Working has become difficult. What are my options?**
This depends on your situation. Many employers can make adjustments (flexible hours, working from home, lighter work). The UWV can offer benefits or reintegration programmes. An occupational physician can look at what is possible together with your employer. Social workers and patient organisations can provide information about financial support.
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_This information never replaces a doctor's judgment. Always discuss your situation with your own healthcare provider._