How genetic testing can guide hATTR-PN diagnosis and treatment
Fact-checked by Genetic testing is one of the key steps used to confirm a diagnosis of hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN), a rare inherited disease that causes progressive damage to the nerves outside the brain and spinal cord (peripheral nerves).
Mutations in the TTR gene cause hATTR-PN by making the structure of the protein transthyretin less stable. When transthyretin becomes unstable, it can form clumps called amyloid deposits. These deposits can accumulate in the body’s tissues, particularly the peripheral nerves, and cause damage.
Identifying the problematic TTR mutation is not only important for confirming an hATTR-PN diagnosis, but also for helping doctors in making treatment decisions, predicting a person’s prognosis, and making recommendations for family member testing.
Importance of early diagnosis for hATTR-PN
In hATTR-PN, amyloid buildup and subsequent nerve damage progressively worsen over time. Most hATTR-PN treatments focus on slowing disease progression by preventing new amyloid deposits from forming. However, they don’t clear existing deposits or repair nerves that have already been damaged.
This is why it is critical that hATTR-PN be diagnosed and treated as early as possible, before extensive and irreversible damage accumulates.
By putting the brakes on disease progression quickly, severe disability, organ failure, and other life-threatening complications may be avoided. With a lower symptom burden, people with the disease can also have a better overall quality of life.
An early diagnosis of hATTR-PN for one person can also facilitate the early testing of family members for potential disease risk.
The role of genetics in hATTR-PN
Over 150 TTR mutations have been identified to date, many of which can lead to hATTR-PN.
Each individual inherits two copies of the TTR gene — one from each parent. hATTR-PN has an autosomal dominant inheritance pattern, meaning that only one of these gene copies has to be mutated for hATTR-PN to develop. The biological child of a person with a TTR mutation has a 50% chance of inheriting it.
Some people with a TTR mutation, called asymptomatic carriers, don’t develop hATTR-PN symptoms, but can still pass the mutation to their children. This asymptomatic transmission is why there might not always be an obvious family history of the disease.
Rarely, TTR mutations are not inherited and instead occur spontaneously, or de novo.
When to consider genetic testing for hATTR-PN
There are two main reasons a doctor might recommend genetic testing for hATTR-PN, including:
- if there is a pattern of red flag signs and symptoms
- if an asymptomatic person has a family history
For symptomatic people, genetic testing may be considered if a person is experiencing unexplained, progressive sensory-motor neuropathy, a type of nerve damage that leads to abnormal sensations (e.g., numbness, tingling, or pain) and movement problems.
This type of damage can occur in several conditions, but hATTR-PN may be particularly suspected if the neuropathy is rapidly progressing and/or occurs alongside:
- a family history of hATTR-PN
- other early hATTR-PN symptoms, such as carpal tunnel syndrome affecting both wrists or gastrointestinal issues
- signs of disease involvement in other organs, especially heart problems
For people who do not have hATTR-PN symptoms, genetic testing may be recommended if they are closely related to a person who has received an hATTR-PN diagnosis. This may involve a process called cascade testing, in which relatives are sequentially screened based on their relationship to people with confirmed mutations, starting with first-degree relatives.
Families in this situation will likely be referred for genetic counseling. During genetic counseling, an expert will provide information about the inheritance of the disease, the genetic testing process, and who should get tested.
They’ll also help families understand the test results and what they mean for future decisions related to a person’s own health and family planning.
Types of genetic tests for hATTR-PN
The general premise of genetic testing for hATTR-PN is to look for TTR gene mutations associated with the disease. A healthcare provider will collect a small sample of blood, saliva, or cells from a cheek swab and send it to the lab for a DNA analysis.
DNA, including the TTR gene, is made up of a sequence of building blocks called nucleotides. The most common type of genetic testing for hATTR-PN involves scanning the TTR sequence to look for unexpected changes in nucleotides that may affect transthyretin production.
TTR sequencing can identify mutations commonly associated with hATTR-PN and new mutations that haven’t been seen before. Commercially available genetic testing kits are not comprehensive and will typically only look for a few common mutations.
People with TTR mutations may also opt for prenatal testing to guide their family planning decisions. For people conceiving through in vitro fertilization, or IVF, this involves harvesting eggs and sperm, creating embryos in the lab, and then screening the embryos for TTR mutations. Potential parents can choose a non-mutated embryo to implant.
How genetic testing informs treatment decisions
Each TTR gene mutation is associated with certain symptom profiles and disease courses. Knowing the specific mutation helps doctors develop the most appropriate treatment and monitoring plan for each individual case.
For example, some TTR mutations often cause heart disease in addition to nerve damage. For people with such mutations, regular heart health tests are important.
If a person who is asymptomatic tests positive for a TTR mutation, treatment might not be started right away. But knowing the risk enables careful and regular monitoring, allowing any new signs or symptoms to be addressed as soon as they appear.
People who test positive for TTR mutations — whether symptomatic or not — may wish to consult with a specialized amyloidosis center. These centers have the clinical expertise to develop an effective treatment and/or monitoring plan.
Potential barriers to genetic testing
While genetic testing is vital for an accurate hATTR-PN diagnosis, accessing it may be difficult for some people. Barriers to genetic testing for hATTR-PN include:
- the lack of standardized diagnostic pathways for genetic testing
- gaps in communication between physicians and patients
- concerns about the security of genetic data after testing
- high costs and variable insurance coverage for the procedure
- limited clinical awareness of hATTR-PN
- low access to specialist medical providers and genetic counselors
Racial and socioeconomic inequities in healthcare access may lead to greater testing barriers for some groups. People in rural or underserved areas, in particular, may lack access to facilities most equipped to facilitate genetic testing.
Amyloidosis News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
