Genetic screening can help diagnose FAP when polyneuropathy evident 

Mutations spotted in 10% of group with various red flags for the disease

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Running a genetic screening may help to diagnose familial amyloid polyneuropathy (FAP) among people with sensory-motor polyneuropathy — damage to many nerves involved in sensations and motor skills — and at least two symptoms suggestive of FAP.

That’s according to a study in Italy that identified FAP in 10% of the nearly 150 people meeting these criteria and more than one-third of their relatives.

Notably, those positive for the rare disease were more likely to have unexplained weight loss, gastrointestinal problems, and a family history of cardiomyopathy, or heart muscle disease.

Study findings highlight that “a focused approach for the screening of [FAP] could lead to an earlier diagnosis and identification of asymptomatic carriers, who will be promptly treated after a strict follow-up at the clinical onset,” the researchers wrote. Asymptomatic carriers are those carrying FAP-causing mutations but not yet showing overt symptoms.

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1 in 4 with ATTR amyloidosis have neurological and heart symptoms

An early FAP diagnosis is challenging, as symptoms often start in adulthood

The study, “Genetic screening for hereditary transthyretin amyloidosis with polyneuropathy in western Sicily: Two years of experience in a neurological clinic,” was published in the European Journal of Neurology.

Also called hereditary transthyretin amyloidosis with polyneuropathy or ATTRv-PN, FAP is caused by mutations in the TTR gene. These mutations lead to the formation of abnormal clumps of the transthyretin protein, mostly in peripheral nerves, those that lie outside the brain and spinal cord.

This buildup results in disease symptoms that include a loss of sensation, weakness in the extremities, and autonomic dysfunction, or difficulty controlling bodily functions such as blood pressure, heart rate, and digestion.

Symptoms may not manifest until late in adulthood, so when there is no known family history of the disease, diagnosing FAP early can be challenging. However, some red flags may raise suspicions.

A team of researchers in Sicily ran a genetic screening for FAP-causing mutations in the TTR gene in adults with sensory-motor polyneuropathy and two or more other red flags usually linked to FAP. All were seen at a neurological clinic in western Sicily.

Red flags included carpal tunnel syndrome in both hands, gastrointestinal problems of unknown cause, unexplained weight loss, autonomic dysfunction, cardiomyopathy (heart muscle disease), kidney impairment, and/or a family history of polyneuropathy, cardiomyopathy, or FAP.

Carpal tunnel syndrome is a common symptom of FAP that affects nerves in the wrist, causing tingling and pain in the fingers.

Unexplained weight loss plus polyneuropathy should raise suspicions

Of the 145 people tested, 14 (10%) were diagnosed with FAP. Five different mutations — Phe64Leu, Val122Ile, His90Asn, Val20Ala, and Ser77Phe — were identified. The most common was Phe64Leu, which is known to run in Sicilian families. His90Asn, Val20Ala, and Ser77Phe were reported for the first time in Sicily, the researchers noted.

FAP patients were a mean of 7.1 years older than people without the disease (71.6 vs. 64.5 years) and were significantly more likely to have unexplained weight loss (64% vs. 27%).

As such, “unexplained weight loss associated with … polyneuropathy had the highest predictive value in the guidance of clinical suspicion,” the researchers wrote.

People with FAP also were more likely to have gastrointestinal symptoms (64% vs. 38%) and a family history of cardiomyopathy (57% vs. 31%), but these differences reached only near-statistical significance.

Carpal tunnel syndrome in both hands (10 patients, 71%), “associated with unexplained weight loss, gastrointestinal disturbances, and autonomic dysfunction (nine patients, 64%), were the most recurring “red flags” among TTR-mutated patients,” the team wrote.

Anorexia, an eating disorder that leads to low body weight, was the most common misdiagnosis among people with FAP (29%), followed by amyotrophic lateral sclerosis, a disease that results in progressive loss of the nerve cells that control movement (21%).

Genetic screening in 84 first-degree relatives identified FAP-causing mutations in an additional 33 people (39.3%). Seven had evidence of sensory-motor polyneuropathy and were started on treatment, while 26 had no symptoms and began regular follow-up.

“Diagnosis of ATTRv-PN is difficult, with a relevant diagnostic delay, misdiagnosis, and high costs for the community, but a systematic screening for ATTRv-PN in the neurological setting might contribute to significantly reducing the diagnostic delay,” the researchers wrote.