Individuals diagnosed with hereditary ATTR amyloidosis see a build-up of amyloid fibrils around nerves (above), the heart and other organs, gradually reducing their function. Credit: SCIEPRO/Science Photo Library/Getty Images
Hereditary ATTR amyloidosis is a progressive and fatal disease caused by misfolding of transthyretin (TTR) protein. Primarily produced in the liver, TTR is involved in the transport of thyroxine and retinol in the blood and cerebrospinal fluid. More than 130 genetic mutations have been associated with hereditary ATTR amyloidosis1. The resulting amyloid builds up around and/or within nerves, the heart and other organs, reducing function and causing irreversible damage2. The disease is estimated to affect around 50,000 people worldwide3, but some studies suggest that it is under recognized and often misdiagnosed4.
Hereditary ATTR amyloidosis can be challenging to diagnose because it manifests in many different ways, and disease progression and neurologic symptoms can be variable and unpredictable among patients5. Symptoms which include gastrointestinal tract disturbances and heart problems5,6,7, can strike at any time from the mid-20s to the 90s, and are caused by sensorimotor neuropathy and autonomic neuropathy. Hereditary ATTR amyloidosis with polyneuropathy can be misdiagnosed as many other conditions, such as chronic inflammatory demyelinating polyneuropathy (CIDP)6.
Worldwide, the most common mutation associated with hereditary ATTR amyloidosis is p.V50M, formally known as V30M, predominantly found in families from Portugal, Spain, France, Japan, and Sweden8. In these patients, hereditary ATTR amyloidosis usually presents as a peripheral sensory, motor and autonomic neuropathy starting in a person’s 20s or 30s. In the United States, the most common genetic mutation is p.V142I (V122I), although this may vary regionally, and is frequently found in African Americans. Some mutations are more associated with cardiomyopathy; others with neuropathy. However, both manifestations can be present in variable proportions5.
“No two patients present the same way,” says Louis O’Dea, Chief Medical Officer at Akcea Therapeutics, a biopharmaceutical company focused on serious and rare diseases. “Since many of the symptoms are found in much more common diseases, clinicians may not be thinking about rarer diseases such as hereditary ATTR amyloidosis. There’s an adage in medicine that says if you hear hoof-beats, think of horses not zebras. Hereditary ATTR amyloidosis is a zebra.”
On the lookout for the tell-tale signs
Because hereditary ATTR is an inherited and multi-symptom disease, obtaining a detailed medical history can help to separate the zebras from the horses, as can identifying ‘red-flag’ symptom clusters.
The presence of progressive peripheral sensorimotor neuropathy and at least one of the following is suggestive of hereditary ATTR amyloidosis: autonomic dysfunction; bilateral carpal tunnel syndrome; gastrointestinal complaints; unexplained weight loss; and cardiac hypertrophy6. Neuropathy that begins at the toes and moves up is a common feature of hereditary ATTR amyloidosis. Rapid disease progression and lack of response to prior therapies for misdiagnosed disease can also be tell-tale signs6.
“Genetic testing is the only way to confirm whether patients who are suspected to have hereditary ATTR amyloidosis with polyneuropathy or have a family history of the disease carry a genetic mutation,” says Sami Khella, chief of the Department of Neurology at Penn Presbyterian Medical Center at the University of Pennsylvania, Philadelphia. “The accuracy of these tests can remove the need for traditional nerve biopsy, an invasive procedure that can be painful, and serves as a diagnostic tool for at-risk patients who present with unexplained neuropathies.”
Easy, confidential genetic testing is available through Akcea Therapeutics’ hATTR Compass program, in the United States, Canada and Puerto Rico at no cost to patients and their families.
A delayed diagnosis can be potentially devastating for patients as the disease can progress rapidly, leading to worsening symptoms, significant disability, and a deteriorating quality of life. Typically, patients require assistance walking within 6 years and become wheelchair bound within 11 years from symptom onset9.
“Because of the irreversible progression of the polyneuropathy of hereditary ATTR amyloidosis, disease awareness and early diagnosis are critical to optimal disease management,” says O’Dea. Thanks to an increase in disease awareness among neurologists and the availability of genetic tests to confirm diagnosis, patients will be able to benefit from the latest research and most appropriate management recommended by their physicians.