New FAP treatment guidelines can help US doctors: Expert panel
Nerve damage may be disease sign, should be considered in diagnosing patients
Clinicians should consider familial amyloid polyneuropathy (FAP) when they see people with unexplained progressive nerve damage, or neuropathy, especially if it’s associated with bodywide symptoms or a family history of the disease, a panel of experts said in new FAP diagnosis and treatment guidelines aimed at helping U.S. doctors better recognize the rare disease.
The recommendations were made in article titled “Diagnosis and treatment of hereditary transthyretin amyloidosis with polyneuropathy in the United States: Recommendations from a panel of experts” and published in the journal Muscle & Nerve.
Treatment should be started as soon as possible after diagnosis, the panel said. The experts recommended, as a first-line option, medications that reduce production of the abnormal transthyretin (TTR) protein that forms toxic clumps in FAP.
FAP is part of a group of inherited conditions called hereditary transthyretin (hATTR) amyloidosis, caused by mutations in the TTR gene. The mutations lead to the accumulation of an abnormal version of the TTR protein that misfolds and forms protein clumps, or amyloid fibrils, that deposit in organs and tissues.
In patients, amyloid fibrils accumulate mostly in peripheral nerves, or those outside the brain and spinal cord, causing damage that typically leads to symptoms such as numbness, tingling, or burning in the legs and feet. Amyloid deposits also can build up in the heart muscle and cause damage.
Providing U.S.-specific guidance on FAP
In the U.S., “there is a lack of specific guidance for recognizing symptoms” of FAP, and no guidelines for monitoring or treatment, the panel of seven U.S.-based neurologists wrote.
That can lead to delays in diagnosis and treatment, wrote the neurologists, all of whom have FAP expertise. FAP is more prevalent in countries including Portugal, Brazil, and Japan, but in the U.S. there are many disease-causing mutations and no characteristic disease presentation.
The experts said they wanted to provide “U.S.-specific insights into disease awareness, diagnosis, monitoring, and guidance on the most appropriate treatments” for FAP.
Rapid, unexplained progressive neuropathy was one of a few red flags the authors cited as possible symptoms of FAP. Others were carpal tunnel syndrome —a condition that affects nerves in the wrist — and problems with the autonomic nervous system that controls involuntary bodily processes, such as blood pressure and gastrointestinal function.
Accompanying symptoms may include motor weakness and problems with the heart, muscles, eyes, and kidneys. A family history of hATTR amyloidosis or of unexplained symptoms, such as progressive neuropathy or heart problems, also may be signs of FAP, the neurologists wrote.
Genetic screening is a “key tool” to confirm a FAP diagnosis and to exclude other causes of neuropathy, the experts wrote. They recommended genetic counseling be provided before genetic testing, and if TTR mutations are detected, testing be extended to at-risk family members who may carry the mutations.
A tissue biopsy, which can look for the presence of amyloid fibrils, can help confirm a diagnosis. Tissue samples can be obtained directly from the affected organ (nerves or heart) or preferably from more accessible tissues such as skin, abdominal fat, salivary glands, or the rectum.
Without a definitive biopsy result, clinicians may also consider a radioactive scanning method called cardiac technetium-based scintigraphy to detect amyloid fibrils in the heart.
Monitoring important for those without symptoms
Not all people with TTR mutations will develop the disease, while others may remain asymptomatic (without symptoms). The panel recommended monitoring asymptomatic patients for five to 10 years before the predicted age of onset for the disease, based on the specific mutation, region, and family history.
The panel recommended TTR gene silencer therapeutics as a first-line FAP treatment. These therapies, which include Onpattro (patisiran), Amvuttra (vutrisiran), Tegsedi (inotersen), and Wainua (eplontersen), work by reducing TTR protein production.
Treatments including physiotherapy to improve walking skills and balance, leg- and ankle-supporting devices, and medications can be used to relieve symptoms, the panel said.
Patients undergoing treatment should be assessed at least every six months, the panel said. Assessment should include an examination of neurologic symptoms and checking for other complications and evidence of disease progression, the neurologists wrote.
While there’s a lack of evidence to support “the definition of disease progression and how to treat patients who do not respond to/worsen on current treatments,” all aspects of the disease, including its expected natural course and impact on symptoms and quality of life, “should be evaluated before determining the clinical effectiveness of a specific treatment or whether a treatment should be stopped completely,” the panel wrote.
“Ongoing or planned clinical trials in patients with [FAP] remain fundamental to provide robust evidence to support future recommendations in this rapidly evolving field,” they wrote.
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