Japanese Experts Develop Guidelines for the Country’s Unique TTR-FAP Variations

Japanese experts have developed guidelines for treating people in their country with transthyretin familial amyloid polyneuropathy that are different from other countries’ guidelines.

That’s because TTR-FAP manifests itself differently in Japanese than in people elsewhere. It has a broader range of symptoms in Japanese patients, for example.

The guidelines are aimed at improving Japanese doctors’ diagnosis of the disease and helping them make better treatment decisions.

An article about the guidelines, titled “Diagnosis and management of transthyretin familial amyloid polyneuropathy in Japan: red-flag symptom clusters and treatment algorithm,” was published in the Orphanet Journal of Rare Diseases.

There are lots of amyloidosis diseases, and their hallmark is proteins clumping together in tissues and organs. The clumps themselves are called amyloids.

Mutations of the TTR gene cause TTR-FAP, the most common form of genetic amyloidosis. The mutations produce misfolded TTR proteins with sticky surfaces. The proteins clump together into amyloid deposits, altering the function of nerves and tissue.

Until recently, the only treatment for TTR-FAP was a liver transplant — because it replaces the main source of the abnormal protein. Nowadays, 40 countries, including those in the European Union and Japan, have an alternative to a transplant. It’s Pfizer’s Vyndaqel (tafamidis), which prevents the formation of toxic amyloid deposits. The United States has yet to approve a treatment for TTR-FAP.

The variety of symptoms that TTR-FAP patients can display frequently leads to doctors either misdiagnosing the disease or diagnosing it late. Because it’s a condition that worsens, a timely diagnosis is crucial to starting treatment that can achieve the best patient outcomes.

Experts’ identification of groups of symptoms that suggest TTR-FAP — called red-flag symptom clusters — has helped doctors worldwide do a better job of diagnosing it. But in Japan, the disease has characteristics that are different from those in other countries. One is that the age of the disease’s onset is wider. In addition, patients have a broader range of symptoms.

To help doctors diagnose and treat Japanese with TTR-FAP earlier, a team of doctors developed Japan-specific red-flag symptom clusters and treatment guidelines.

The team said one or more of the red flags, combined with nerve degeneration in several parts of a person’s body, were a sign the person could have TTR-FAP.

Four of the red flags are relatives with the disease, internal organ dysfunction, gastrointestinal disorders, or cardiac disease. Another is carpal tunnel syndrome, which is characterized by pain, numbness, and tingling in the hand and arm. Still another is failure to respond to an immunomodulatory treatment, or one that regulates the immune system.

The Japanese experts said a liver transplant should continue to be the first-line treatment for TTR-FAP. In Japan, the procedure involves living donors because they lead to higher survival rates and patients living longer. If a patient does not meet the criteria for a liver transplant, the experts recommended Vyndaqel.

“The Japan-specific red-flag symptom clusters proposed herein may simplify diagnosis for physicians and prevent misdiagnosis or delayed diagnosis of ATTR-FAP,” the team wrote.

The guidelines for treatment decisions, which were “also based on treatment outcomes observed in Japan, may guide clinicians [doctors] regarding apt and judicious use of available treatment modalities,” they wrote.