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If you’re living with hereditary transthyretin (hATTR) amyloidosis, you may be curious about what it means for your family. The condition is an autosomal dominant disease, meaning there’s a 50 percent chance your children will inherit the gene — and likely develop the condition. Like many parents, you’re left waiting to see if and when your children start showing signs of hATTR amyloidosis.
The age of onset refers to the age when a person first starts showing symptoms of a disease. If you’ve done genetic testing and know you or your child is at risk of developing hATTR amyloidosis, you’re likely wondering when symptoms may begin.
In this article, we’ll cover what you should know about when people with hATTR amyloidosis start showing symptoms and what factors play a role. While there’s nothing that can be done to change your or your child’s genetics, there are several treatment options available to help control the disease.
Mutations (changes) in the transthyretin (TTR) gene cause hATTR amyloidosis. These changes interfere with how well the TTR protein can fold into the correct shape. A normal TTR protein is made of four strands woven together — known as a tetramer.
In people with hATTR amyloidosis, the TTR protein can’t properly form a tetramer and instead stays as separate monomers (strands). These protein strands form abnormal clumps called amyloid fibrils that become stuck in organs throughout the body. Known as amyloid deposits, the clumps begin interfering with how well your organs work and eventually lead to symptoms.
The genetic mutations responsible for causing hATTR amyloidosis are passed down from parents to their children. They’re known as autosomal dominant mutations. This means that you only need one mutated copy of the TTR gene to develop the disease (you have two copies of every gene, one from each parent).
As mentioned, there’s a 50 percent chance that a parent with hATTR amyloidosis passes the disease to their children. It’s also worth noting that if your child has a mutation in their TTR gene, it doesn’t automatically mean that they’ll develop hATTR amyloidosis. Even still, many parents wonder if and when their child may develop symptoms.
Researchers use the scientific term “penetrance” to refer to the number of people with a gene mutation who develop symptoms. Some mutations and populations have a higher penetrance than others.
Symptoms of hATTR amyloidosis can begin appearing in people as young as 20 years old and as old as 80. Studies show that in the U.S., the median age of onset for hATTR amyloidosis is 68.1 years. This means that half of people develop symptoms before the age of 68, while the other half develop them after.
In the U.S., the median age of onset for hATTR amyloidosis symptoms is 68.1 years.
The age of onset varies depending on family history, the type of mutation, and the types of symptoms.
Doctors and researchers have discovered more than 120 mutations related to hATTR amyloidosis. Some of the most common gene mutations seem to be associated with certain ages of onset. Also, specific mutations are found in some countries more than others.
In the U.S., doctors usually see the following mutations:
V122M mutations are found in around 3.2 percent of African Americans in the U.S., according to the Amyloidosis Research Consortium. Symptoms of hATTR amyloidosis for people with V122M mutations tend to develop in people over the age of 60.
The V30M mutation is common in people from Japan, Sweden, and Portugal. According to the Amyloidosis Research Consortium, 80 percent of people from Portugal with the V30M mutation develop hATTR amyloidosis symptoms by age 50, and 91 percent have symptoms by age 70.
By comparison, people from Sweden are much less likely to develop symptoms at an early age. Only 11 percent of people with the V30M mutation show signs of hATTR amyloidosis by age 50 and 52 percent by their 80th birthday.
The T60A mutation tends to affect people of Irish descent. This mutation is associated with a later onset of symptoms — between the ages of 45 and 78 — and most commonly after age 60.
Males and females have an equal chance of inheriting mutated TTR genes from their parents. This is because the TTR gene is located on chromosome 18, which isn’t a sex chromosome (X or Y). Doctors and researchers aren’t quite sure why, but males tend to develop hATTR amyloidosis more often and at a younger age than females.
The age of onset for hATTR amyloidosis can vary based on your family history of the disease. For example, if you started developing symptoms at age 60, your child is likely to start experiencing them around the same age. People with a family history of hATTR amyloidosis are also more likely to develop early-onset disease (under the age of 50).
If you started developing symptoms at age 60, your child is likely to start experiencing them around the same age.
Did you know that the type of mutation and age of onset can affect which hATTR amyloidosis symptoms you experience?
You may have come across the terms “familial amyloid polyneuropathy” and “amyloid cardiomyopathy” as you’ve learned about this disease. Today, we understand that there are more types of amyloidosis and they can be broken down by age of onset.
Some studies have looked into the differences between early-onset and late-onset hATTR amyloidosis. People with early-onset disease develop symptoms before the age of 50, while late-onset develops after age 50.
In a study from the journal Neurology and Therapy, reseachers examined nearly 1,400 people with V30M mutations to find out the differences between early-onset and late-onset disease. They found that people with late-onset disease typically had more motor neuropathy symptoms. This means they were more likely to experience weakness in their arms and legs, making movement more difficult.
Symptoms can differ depending on whether you developed hATTR amyloidosis before age 50 (early onset) or after (late onset).
On the other hand, those with early-onset hATTR amyloidosis tended to have more autonomic neuropathy. Your autonomic nervous system is responsible for regulating your body’s normal functions. hATTR amyloidosis can damage these nerves, leading to problems with:
Late-onset disease is also associated with peripheral neuropathy symptoms like numbness and tingling in the hands and feet. This group tends to develop carpal tunnel syndrome more often as well, leading to wrist problems.
Cardiovascular problems were also more common in people with late-onset hATTR amyloidosis. People with heart problems from this disease can experience shortness of breath, arrhythmias (abnormal heart rhythms), and dizziness.
Eventually, the buildup of amyloid fibrils in the heart — known as cardiac amyloidosis — can lead to heart failure.
It can be scary to think about the potential of developing hATTR amyloidosis. Fortunately, there are several treatment options available to slow disease progression and help you or a family member live a longer, healthier life.
The U.S. Food and Drug Administration (FDA) has approved two TTR stabilizers for hATTR amyloidosis — tafamadis (Vyndamax) and tafamadis meglumine (Vyndaqel). These treatments work by stopping TTR proteins from misfolding and making fibrils. Diflunisal (Dolobid) isn’t FDA-approved for hATTR amyloidosis, but it is sometimes prescribed off-label. This means that the doctor is prescribing a drug for something other than what the FDA officially approved.
Gene-silencing therapies interfere with the genetic instructions used to make TTR proteins. When these instructions can’t be used, your liver stops making abnormal TTR proteins and stops amyloid fibril formation. There are three FDA-approved gene-silencing therapies:
If you’re interested in learning more about the available hATTR amyloidosis treatments and when you or a family member should start treatment, talk to your doctor. Your health care team is here to help you by offering personalized information, discussing potential benefits and risks, and guiding you in making informed decisions about managing your condition. They are dedicated to supporting you on your journey, ensuring the best possible care that is tailored to your needs.
MyAmyloidosisTeam is the social media network for people with amyloidosis and their loved ones. Members come together to ask questions, give advice, and share their experiences with others who understand life with amyloidosis.
Do you still have questions about the age of onset with hereditary transthyretin amyloidosis? Leave a comment below, or start a conversation by posting on your Activities page.
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Richard LoCicero, M.D.
has a private practice specializing in hematology and medical oncology at the Longstreet Clinic Cancer Center, in Gainesville, Georgia. Review provided by VeriMed Healthcare Network.
Learn more about him here.
Emily Wagner, M.S.
holds a Master of Science in biomedical sciences with a focus in pharmacology. She is passionate about immunology, cancer biology, and molecular biology.
Learn more about her here.
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