FAP Shows Wide Genetic and Clinical Variety in Chinese Patients, Study Finds

Chinese patients with hereditary transthyretin (ATTR) amyloidosis, also known as familial amyloid polyneuropathy (FAP), have highly variable genetic and clinical profiles, a retrospective study has found.

Yet, according to study findings, Val30Met remains the most common genetic mutation associated with the disease in China.

The study “Hereditary transthyretin amyloidosis in mainland China: a unicentric retrospective study,” was published in the journal Annals of Clinical and Translational Neurology.

FAP is caused by mutations in the TTR gene, which provides instructions for making a protein called transthyretin. These mutations result in the production of a faulty protein that aggregates and forms toxic deposits in different tissues and organs, particularly in the heart, nerves, and kidneys.

For this reason, patients can have a wide spectrum of symptoms affecting multiple organs and systems, which also differ areas of the world.

A team of researchers with Peking University First Hospital evaluated the clinical and genetic profiles of 54 FAP patients — 42 men and 12 women, with a mean age of 47.8 at disease onset — from 39 unrelated families across China, whose cases were reported between January 2000 and September 2020.

Researchers performed genetic testing and analyzed TTR gene variants. They also performed biopsies in the sural nerve (a nerve in the leg) of 40 patients. Clinical and laboratory findings were collected and analyzed.

A total of 29 patients (53.7%) had a late-onset form of FAP, whereas 25 (46.3%) had an early onset form, or disease before age 50. About half of the patients (56.4%) had a family history of FAP. Initial symptoms included tingling, burning, and numbness in the limbs or paresthesia (61.1%), autonomic dysfunction (e.g., gastrointestinal and sexual issues; 27,8%), and blurred vision (11.1%).

A total of 22 different mutations in the TTR gene were identified, including the Val30Met (25.6%) in 10 families, Ala97Ser in four families (10.3%), Glu42Gly in three families (7.7%), and Phe33Val, Glu61Lys and Ala36Pro in two families each (5.1%).

Interestingly, all families with the Val30Met TTR mutation came from North China, while those with the Ala97Ser mutation came from South China.

All remaining TTR gene mutations were identified in one family each. Of note, the Val30Met mutation is the most common TTR gene variant associated with FAP, and has been documented in patients from countries that include Japan, Portugal, Brazil, and Sweden.

Electrophysiological studies to assess nerve function were performed in 44 patients. Most motor and sensory nerves showed signs of nerve fiber (axonal) impairment in 33 (75%) patients. Mixed neuropathies (nerve damage), including both axonal and demyelinating (myelin loss) impairments, were observed in nine cases and isolated carpal tunnel syndrome in two cases.

In nearly half of the patients (40%), sural nerve biopsies were positive for congo red staining, which shows the presence of harmful protein deposits (amyloid deposits).

In total, 46 patients were followed up. Three received a liver transplant, five were treated with tafamidis (sold as Vyndaqel), and 16 with diflunisal (sold as Dolobid). Ten patients died either suddenly, or from respiratory failure after becoming bedridden. The median interval between disease onset and death was 10 years (ranging from four to 25 years).

Researchers noted some limitations to their findings, including the retrospective nature of the study, the fact that more cases came from North China, and the difficulty in including patients who did not show signs of peripheral neuropathy.

Nonetheless, this study “revealed the heterogeneity [variability] of ATTR phenotypes and genotypes [clinical and genetic characteristics] in Chinese populations,” they concluded.

“Val30Met is the most common mutation type in mainland China, but it might be greatly underestimated because of the high proportion of sporadic and late-onset patients. There are genotypic differences between North and South China,” they added.