FAP More Diverse Than Previously Believed, Review Study Contends

Patricia Inacio PhD avatar

by Patricia Inacio PhD |

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A review of 542 cases of hereditary transthyretin amyloid polyneuropathy (ATTR-PN) from more than 100 countries suggests that the clinical symptoms and geographical occurrence of the disease is more variable than described previously.

The review study,“Epidemiological and clinical characteristics of symptomatic hereditary transthyretin amyloid polyneuropathy: a global case series,” was published in the Orphanet Journal of Rare Diseases.

ATTR-PN, also known as familial amyloid polyneuropathy (FAP), is a rare genetic disease; estimates point to a global prevalence of 5,000 to 10,000 people. However, a recent analysis reported that the disease may affect 38,000 persons worldwide, a much higher incidence.

The disease is caused by mutations in the transthyretin (TTR) gene. Currently more than 100 ATTR mutations have been identified across approximately 40 countries.

The first mutation identified, and also the most common, was Val30Met and, in countries where this mutation predominates, the onset symptoms typically affects both sensory and motor function.

However, other patients show damage to the nerves. Moreover, the age of onset of symptoms is also variable, as some patients have symptom onset in their 30s and 40s, while others develop symptoms later.

To get a more comprehensive view of the clinical presentation of ATTR-PN, a group of researchers performed a systematic review of ATTR-PN studies published from 2005 to 2016.

In total, they analyzed data from 542 cases reported in 108 studies across 32 countries. About 18 percent of cases were from countries known as ATTR-PN endemic, namely Portugal, Japan and Sweden, but East Asia contributed with 37 percent of patients.

About 70 percent of the studied population had one of the four most common genetic mutations in the TTR gene: 47.6 percent had the Val30Met mutation, 10 percent had Ser77Tyr, 6.5 percent had Ala97Ser, and 4.4 percent had Phe64Leu mutation.

Because the Val30Met mutation is the most prevalent genetic error found in endemic countries, it was no surprise it had this high frequency. Patients with other not-so-frequent mutations showed clinical symptoms at an earlier age — a mean age of 49.2 years and diagnosis at age 53. For those with the Phe64Leu mutation, the mean age of onset of symptoms was 67.5 and diagnosis at around age 71.

Researchers noted that the average age for first symptoms across all the ATTR-PN cases included in the analysis was 61.5 years, whereas previous studies reported disease onset by age 50. This indicates that a study done on a more heterogeneous population could indeed provide more information about rarer cases of ATTR-PN.

They also observed that 87 percent of all the cases reported damage to sensory nerves at time of diagnosis.

Interestingly, researchers saw that the type of mutation also influenced the type of first symptoms. In Ala97Ser cases there was an increase of impotence (67 percent compared with 21 percent for all cases) and for Ser77Tyr a high rate (93 percent) for non-motor visual symptoms like visual opacities and glaucoma, compared to all other cases (only 16 percent).

Overall, “knowledge of ATTR-PN appears largely derived from endemic areas and persons with early-onset Val30Met disease because the disease is exceedingly rare otherwise,” researchers wrote.

“It is hoped that comprehensive case series such as this will help broaden the understanding of ATTR-PN — providing insight into non-endemic areas and less common genotypes — so that afflicted persons can receive prompt, accurate diagnosis and begin treatment when it will be most effective,” the study concluded.