Familial amyloid polyneuropathy (FAP) is an inherited condition in which a misshapen protein gradually builds up in nerves and organs, causing progressive nerve damage throughout the body. The protein involved is called transthyretin (TTR), which normally carries thyroid hormone and vitamin A in the blood. A mutation in the TTR gene causes the protein to become unstable, misfold, and clump into insoluble fibers called amyloid. These fibers deposit in peripheral nerves, the heart, the gut, and other tissues, disrupting their function over time.
How the Disease Works
Your body produces transthyretin mainly in the liver. In FAP, a single change in the gene’s DNA blueprint causes the protein to take on an abnormal shape. Instead of circulating harmlessly, these misfolded proteins aggregate into amyloid fibrils that accumulate outside cells in nerve tissue. The buildup damages the small nerve fibers first (the ones responsible for pain, temperature, and autonomic functions like blood pressure regulation), then progresses to larger nerve fibers that control movement and coordination.
Over 100 different mutations in the TTR gene can cause the disease, but the most common one is called Val30Met, in which a single amino acid is swapped at position 30 of the protein. The condition follows an autosomal dominant pattern, meaning you only need one copy of the mutated gene from one parent to be at risk. Not everyone who carries the mutation develops symptoms, though, and the age of onset and severity vary widely even within families.
Where FAP Is Most Common
FAP clusters in specific regions of the world. The three largest known concentrations are in northern Portugal, northern Sweden (particularly the municipality of Skellefteå), and Japan. Portuguese ancestry accounts for nearly all cases identified in Brazil, and cases in Mallorca may also trace back to Portuguese origins. Outside these endemic areas, FAP occurs sporadically in families of virtually any ethnic background, which makes it easy to miss in regions where doctors rarely encounter it.
Symptoms and How They Progress
FAP typically begins in adulthood, often between the ages of 30 and 50 in endemic regions, though some mutations cause later onset. The disease is staged using a system developed by Coutinho that tracks how much the neuropathy limits mobility:
- Stage 0: You carry the mutation but have no symptoms. People at this stage are identified through predictive genetic testing, usually because a family member has been diagnosed.
- Stage 1: Painful tingling, numbness, and reduced ability to feel temperature or pain in the feet. Walking is still independent and unaided. This is when most people first seek medical attention.
- Stage 2: Nerve damage has progressed enough to cause difficulty walking. Unsteadiness from sensory loss, foot drop, and drops in blood pressure upon standing may require one or two walking aids.
- Stage 3: The person is wheelchair-bound or bedridden. At this stage, currently approved treatments are no longer indicated.
The earliest nerve symptoms tend to affect the feet and legs, then gradually move upward. About half of patients in one study first noticed limb tingling, while others initially experienced alternating diarrhea and constipation, sexual dysfunction, or blurred vision from amyloid deposits in the eyes.
Autonomic Nerve Damage
One of FAP’s most disabling features is damage to the autonomic nervous system, the network that controls involuntary functions. Early autonomic symptoms include orthostatic hypotension (a sudden blood pressure drop when you stand, causing dizziness or fainting), gastrointestinal problems like nausea, bloating, diarrhea, or constipation, and loss of normal sweating. These symptoms often appear alongside or even before the sensory neuropathy, which is one reason FAP is frequently misdiagnosed as diabetic neuropathy or other more common conditions.
Heart Involvement
Amyloid deposits don’t stop at the nerves. The heart is commonly affected, with amyloid stiffening the heart walls and creating restrictive physiology that limits its ability to fill properly. Some TTR mutations are more strongly associated with heart disease than with neuropathy, but many patients develop both. In one study of FAP patients, two-thirds had asymptomatic thickening of the heart muscle. When heart failure does develop and goes untreated, life expectancy drops to roughly 2.5 to 3.5 years.
How FAP Is Diagnosed
Diagnosis rests on two pillars: detecting amyloid deposits in tissue and confirming a TTR gene mutation. Genetic sequencing of the TTR gene is now considered the gold standard, and it should be performed in anyone with a strong clinical suspicion. A single blood draw is all that’s needed for the test.
Tissue biopsy provides supporting evidence. Amyloid can be found in skin, nerve, heart, kidney, abdominal fat, salivary glands, or the lining of the gastrointestinal tract. Nerve biopsy has a sensitivity of about 80%, while fat or muscle biopsies are less reliable, with sensitivity ranging from 14% to 83%. In some European countries, a biopsy of the salivary glands inside the lip is a common first-line test when a progressive, unexplained neuropathy raises suspicion.
Misdiagnosis is a significant problem. FAP can look very similar to chronic inflammatory demyelinating polyneuropathy (CIDP), a treatable autoimmune nerve condition. A key difference is that FAP primarily damages the nerve fibers themselves (axonal damage), while CIDP damages the insulating coating around nerves (demyelination). Ultrasound imaging of the median nerve can help distinguish the two: CIDP causes patchy, irregular nerve swelling, while FAP produces more uniform, milder enlargement. Another telling clue is that CIDP responds to immune-suppressing therapy, while FAP does not.
Treatment Options
Treatment for FAP has changed dramatically in the past decade. The goal of all current therapies is to reduce the amount of misfolded TTR circulating in the blood, either by stabilizing the protein so it doesn’t misfold or by preventing the liver from making it in the first place.
TTR Stabilizers
Tafamidis works by binding to the transthyretin protein and holding it in its normal shape, preventing the misfolding that leads to amyloid deposits. In a randomized trial of early-stage FAP patients, those taking tafamidis showed 52% less neurological deterioration over 18 months compared to placebo. The placebo group experienced five times greater decline in small-fiber nerve function. Among patients who completed the full course, 60% on tafamidis maintained stable nerve function, compared to 38% on placebo. Treatment with TTR stabilizers has also been associated with significantly improved survival in patients with cardiac involvement, reducing the risk of death by roughly 70 to 80% in adjusted analyses.
Gene-Silencing Therapies
A newer class of drugs uses RNA interference to stop the liver from producing transthyretin altogether. Vutrisiran, given as a subcutaneous injection once every three months, significantly improved neuropathy scores, quality of life, walking speed, and overall disability compared to an external placebo group over 18 months. An earlier drug in this class, patisiran, requires intravenous infusion every three weeks. Both work by intercepting the genetic instructions for TTR before the protein is made.
Liver Transplantation
Before drug therapies were available, liver transplantation was the primary treatment, since the liver produces most of the body’s transthyretin. Replacing the liver eliminates the source of mutant protein. However, transplant carries surgical risks, requires lifelong immunosuppression, and doesn’t reverse amyloid already deposited in tissues. It is now generally reserved for cases where drug therapy is insufficient or unavailable.
Outlook and Timing
The single most important factor in FAP outcomes is how early treatment begins. All currently approved therapies work best in stage 1, when nerve damage is still limited. By stage 3, the available treatments are no longer approved for use because the disease has progressed beyond what they can meaningfully slow. For patients diagnosed before heart failure develops, five-year survival is approximately 82%, and treatment with stabilizers substantially improves those numbers. Untreated, the disease typically progresses over 7 to 12 years from symptom onset to severe disability, though this varies considerably by mutation type and geographic population.
If you have a family history of unexplained neuropathy, especially combined with heart problems or gastrointestinal symptoms, genetic testing can identify the mutation years or even decades before symptoms appear. Predictive testing allows carriers to begin monitoring and start treatment at the earliest sign of disease activity, which offers the best chance of preserving nerve function long-term.