Origin of sporadic late-onset hereditary ATTR Val30Met amyloidosis in Japan.

Hereditary transthyretin (ATTRm) amyloidosis, formerly known as familial amyloid polyneuropathy, is a major type of hereditary systemic amyloidosis, in which the disease is caused by mutant transthyretin (TTR). Although more than 140 different point mutations have been identified in the TTR gene, ATTRm amyloidosis patients with the TTR Val30Met mutation are most frequently found worldwide. Interestingly, the onset age of the ATTR Val30Met amyloidosis is highly varied among countries and regions. The reason for these differences in onset age and penetrance remains to be elucidated. We recently performed an epidemiological study to analyze the clinical and genetic characteristics of ATTRm amyloidosis patients in Japan. Our results led us to the following questions: Why did most of the non-endemic patients with the same TTR Val30Met mutation not have a family history of the disease, a typical autosomal dominant hereditary disorder? Why does ATTR Val30Met amyloidosis alone demonstrate foci of occurrence? Why is only this type of ATTRm amyloidosis nationally and globally distributed? In this mini-review, we discuss these unanswered questions based on recent genetic epidemiological studies on ATTR Val30Met amyloidosis.