Your DNA is composed of over 20,000 “coding genes,” which determine pretty much everything to do with your body and mind — from the color of your hair follicles to your cells’ ability to repair and regenerate. (1)
A genetic variant is a change that occurs in the DNA sequence. Genetic variants can lie inside one of these coding genes and can form sporadically, meaning they just pop up by chance. They can form in response to some form of environmental exposure, such as air pollution or tobacco smoke. They can also be inherited from one or both parents. (2) While most variants are harmless, some can cause or contribute to the formation of disease. (2)
Most types of amyloidosis (a disorder characterized by the abnormal buildup of amyloid protein) are not caused by an inherited genetic variant and may occur in association with other disorders. There are two types of hereditary amyloidosis that are caused by an inherited genetic variant. These two subtypes of hereditary amyloidosis are known as familial transthyretin-associated amyloidosis (ATTR amyloidosis) and non-TTR amyloidosis (2).
ATTR Amyloidosis Originates in the Liver, Where Transthyretin Proteins Are Made
The “A” in ATTR stands for amyloid. (3) The “TTR” refers to transthyretin, which is both the name of the gene and the protein that it encodes. The transthyretin protein is a protein that mostly gets produced in the liver and ends up in the blood where it helps to transport certain vitamins and hormones to different parts of your body.
As with all forms of amyloidosis, ATTR amyloidosis is a result of the erroneous folding of protein molecules. These misfolded proteins aggregate and are called amyloids, and amyloids can accumulate in different parts of the body and cause problems. (3)
ATTR amyloidosis tends to show up in adults ages 20 to 70, and its symptoms can range from mild to severe. (4) If ATTR amyloidosis symptoms are very mild, someone could live a normal, healthy life with the disorder never knowing they have it (and without it ever causing problems). (3) Other cases cause much more serious problems.
While ATTR amyloidosis tends to be considered a rare disease — and one that develops in just 1 out of 100,000 people in the United States — there’s one variation of ATTR that seems to be common in people of African-American descent. There’s some evidence that 4 percent of African-Americans carry this gene variant, which puts them at greater risk for heart trouble. (3)
It’s also important to note that there are many different varieties of ATTR amyloidosis that can affect multiple organ systems of the body — all involve the misfolded proteins that build up to form amyloid protein. ATTR amyloidosis can be grouped into three main categories, based on their symptoms and the parts of the body they strike: (4)
- ATTR Amyloid Neuropathy This form of amyloidosis affects the nervous system and tends to cause symptoms like nerve damage and pain, tingling or numbness in the hands and feet, gastrointestinal (GI) issues like diarrhea and constipation, vision problems, and issues controlling bodily functions. (4)
- ATTR Leptomeningeal/CNS Amyloidosis This form occurs in the leptomeninges, which are layers of tissue that surround the brain and spinal cord. Stroke and bleeding of the brain are two possible complications, and symptoms include problems with coordination and balance, muscle stiffness and weakness, seizures, and dementia. (4)
- ATTR Cardiac Amyloidosis This form attacks the heart and causes symptoms and side effects like an abnormal heartbeat, hypertension, and — in advanced stages — heart disease and heart failure. (4)
Most of the Time Non-TTR Amyloidosis Affects Genes Involved in Kidney Function
The second subtype of hereditary amyloidosis is called non-TTR because it is caused by variants that do not affect the TTR gene. This subtype of amyloidosis is thought to be even rarer than ATTR, and it can affect a range of genes and cause a number of diverse side effects and symptoms. (4)
That said, most cases of non-TTR amyloidosis tend to involve genes that play a role in kidney function, which sometimes leads to kidney damage and disease. Other symptoms include liver or heart trouble, nerve and muscle pain, and GI issues like constipation and diarrhea. (3)
Hereditary Types of Amyloidosis Are Usually Diagnosed With Urine, Blood, Tissue Biopsy, and Genetic Tests
As with other forms of amyloidosis, ATTR and non-TTR are diagnosed using a combination of urine or blood analysis, as well as tissue biopsies. In some cases, genetic testing may also be helpful in identifying these types of amyloidosis and in determining whether other members of a patient’s family may be at risk. (5)
RELATED: Everything You Need to Know About Amyloidosis Diagnosis
Treatment for these types of amyloidoses depends on a patient’s condition. Along with drugs to manage heart damage, nerve pain, or other symptoms, there are also some treatments that can stop the production of amyloid in some patients, potentially slowing or stopping the progression of the disease. (6) Such treatments may include liver transplant, as well as the drug patisiran (Onpattro) — the first approved by the U.S. Food and Drug Administration (FDA) to treat hereditary amyloidosis. Some other drugs are also currently being investigated in clinical trials.
Symptoms of Hereditary Amyloidosis Are Similar to Symptoms of Many Other Conditions, Making It Difficult to Recognize
As with other forms of amyloidosis, the symptoms of hereditary amyloidosis are “nonspecific,” meaning they could be caused by a lot of different health conditions — including many that aren’t serious. It’s highly unlikely that someone experiencing the symptoms or side effects listed above will turn out to have a form of hereditary amyloidosis.
Also, if a person has inherited one of the gene variants that cause hereditary amyloidosis, there’s a good chance they will have a family history of heart disease, liver or kidney problems, or some of the other health concerns mentioned above. (7)
But that’s not always the case. The genetic variants that cause ATTR and non-TTR amyloidosis can also be “de novo,” meaning they occur by chance instead of being inherited from a parent. But even though these genetic variants are not inherited, they can still be subsequently passed down to a patient’s biological children.
Can hereditary amyloidosis be deadly? Yes, it can be. All types of amyloidosis can lead to organ disease and failure, which can be fatal. But again, all types of the disease are rare.
That said, if the symptoms and complications mentioned here sound familiar — and especially if they seem to run in your family — tell your doctor. (3)