Causes of hATTR-PN

Hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN), also known as familial amyloid polyneuropathy (FAP), is a form of familial amyloidosis caused by mutations in the TTR gene, which contains instructions for cells to produce a protein called transthyretin (TTR). These mutations cause TTR protein misfolding, ultimately leading to the accumulation of toxic protein deposits in multiple organs and tissues that progressively damage them over time.

Identifying specific TTR gene mutations is a crucial part of diagnosis and can help predict disease severity, progression, and other features. These factors may guide treatment decisions.

Genetic causes of hATTR-PN

Everyone inherits one copy of the TTR gene from each parent. hATTR-PN is an autosomal dominant disorder, meaning it can arise if one of the two gene copies is mutated. However, because the disease has incomplete penetrance, it’s possible for people to carry a mutated TTR gene copy without developing disease symptoms.

Because of hATTR-PN’s inheritance pattern, the biological child of someone with a TTR gene mutation has a 50% chance of inheriting the disease-causing mutation and being at risk of developing the condition. If a family member receives an hATTR-PN diagnosis, relatives may want to seek genetic testing for hATTR-PN. Genetic counseling can help people with hATTR-PN or those at risk of developing the disease to make informed decisions about their health.

How the mutation affects the body

TTR is mainly produced in the liver and serves as a carrier for certain hormones and vitamins in the body. Under normal conditions, TTR has a stable tetramer structure made up of four protein subunits. hATTR-PN-causing mutations can destabilize the protein’s tetramer structure, leading to its dissociation into single subunits (monomers), which are prone to misfold and clump together. These, in turn, can form amyloid fibrils that deposit in different tissues and organs.

hATTR-PN causes progressive nervous system damage because amyloid deposits tend to accumulate in the peripheral nerves found outside the brain and spinal cord. These toxic protein deposits can also accumulate in other parts of the body, such as the heart, kidneys, eyes, and gastrointestinal system, resulting in a wide range of possible symptoms.

Can hATTR-PN occur without a family history?

Rarely, a new, noninherited TTR mutation can appear. People with these de novo mutations don’t have a family history of hATTR-PN, but can still develop the disease and pass it on to their biological children.

hATTR-PN can also seem to develop without an apparent family history if affected people in previous generations had mild symptoms that weren’t recognized as being associated with hATTR-PN, died before symptoms manifested, or only started experiencing symptoms later in life. 

Are there different genetic variants?

More than 150 TTR mutations have been identified to date, many of which are disease-causing. Some are mostly associated with nerve damage, while others primarily result in heart-related symptoms; most lead to a mix of both.

The most common genetic mutation in hATTR-PN is Val30Met, which is predominantly associated with peripheral nerve involvement. This mutation is particularly common among people living in certain areas of Portugal, Spain, Japan, Brazil, and Sweden.

Other notable TTR mutations, many of which are associated with specific geographical regions, include:

• Ser50Arg in Mexico
• Thr60Ala in Ireland and the U.K.
• Glu89Gln in Italy and Bulgaria
• Phe64Leu in Sicily
• Ser77Tyr and Ser77Phe in France
• Ala97Ser in Taiwan

hATTR-PN variants can present with distinct disease features, including age of onset, severity, and progression. For example, Val30Met mutations have been associated with both early- and late-onset disease. Early-onset disease, where symptoms arise before the age of 50, generally has a more favorable course. Mutations associated with late-onset disease or heart involvement typically lead to a more aggressive disease course and a shorter life expectancy.

Environmental and nongenetic factors

Although environmental and lifestyle factors alone don’t cause hATTR-PN, nongenetic factors can influence hATTR-PN progression, severity, or presentation. Among such factors are:

• Sex: Men usually have an earlier disease onset and more commonly have heart involvement, while women are more likely to remain asymptomatic.
• Sex of parent: When disease-causing mutations are inherited from a person’s biological mother, the disease tends to manifest earlier and with higher penetrance.
• Epigenetic modifications: Changes to gene regulation and activity that don’t alter the DNA sequence can affect clinical presentation.
• Environment: Exposure to certain chemicals may be linked to disease presentation, although research remains limited.