This retrospective, single-center study revealed that patients with V30M mutations in non-endemic areas and non-V30M mutations were more common than previously reported. Clinical characteristics differed between V30M patients in endemic and non-endemic areas as well as in non-V30M patients. Endemic V30M cases were diagnosed earlier because of the higher prevalence of family history and periodic monitoring. In contrast, non-endemic V30M and non-V30M patients, often lacking a family history, were frequently misdiagnosed. Additionally, patients with carpal tunnel syndrome (CTS) or polyneuropathy at onset experienced longer diagnostic delays. Understanding these differences is crucial for early diagnosis and timely intervention, particularly, given the availability of disease-modifying therapies.

ATTRv amyloidosis, previously thought to be confined to endemic regions, is now known to affect both endemic and non-endemic areas worldwide [2,3,4,5,6,7]. In this study, 46 TTR mutations were detected in 235 symptomatic patients, compared to 25 mutations identified in 104 patients over a 5-year period in our earlier study. These findings highlight the increasing potential of diagnosing additional cases in Japan [6].

Clinical characteristics varied among patients with V30M mutations in endemic and non-endemic areas and those with non-V30M mutations. Endemic V30M cases exhibited early-onset, high penetrance, and female predominance, whereas non-endemic V30M cases showed late-onset, low penetrance, and male predominance. Non-V30M cases presented with diverse symptoms, late-onset, low penetrance, and male predominance. The causes of these differences remain unclear but are likely influenced by multiple factors. First, the geographic origin of the TTR V30M mutation may affect disease onset and penetrance, with early onset and high penetrance observed in Portugal and Japanese endemic regions, and late onset and low penetrance seen in Sweden and non-endemic areas of Japan [6, 8, 20, 21]. Second, mutations in non-coding regions of the TTR gene may regulate gene expression and influence both the age at onset and the clinical phenotype spectrum. Third, sex differences may contribute to phenotypic variation, as cardiac involvement is more frequently observed in male patients with non-endemic V30M or non-V30M mutations. Additionally, maternal inheritance may be associated with an earlier age at onset and higher disease penetrance [22].

Possible explanations include differences in pathology: early-onset cases exhibit small-fiber and neuronal cell loss with amyloid deposition in the sympathetic ganglia, whereas late-onset cases show preserved unmyelinated fibers and amyloid deposition in the dorsal root ganglia [20]. Phenotypic differences may also be related to TTR fragmentation; late-onset cases contain C-terminal TTR fragments in amyloid deposits, whereas early-onset cases have only full-length TTR [23]. Additionally, the stability of variant TTR and ERAD mechanisms play a role, as destabilized variants such as A25T can bypass ERAD with T4 chaperoning, leading to CNS-selective amyloidosis [24].

Patients with ATTR V30M amyloidosis in endemic areas were diagnosed earlier than those in non-endemic areas and patients with non-V30M amyloidosis, consistent with findings from a global survey [25]. Early diagnosis in endemic areas is attributed to the high prevalence of family history and regular monitoring of at-risk family members, which facilitate timely detection [26]. In contrast, patients with non-endemic V30M and non-V30M rarely have a family history, complicating early diagnosis. These cases are frequently misdiagnosed as CIDP, diabetic neuropathy, or lumbar canal stenosis, highlighting the need for increased clinical awareness to improve diagnostic accuracy [27, 28].

This study has few limitations. It relied on retrospective data from a single referral center with a limited number of patients. Moreover, the cohort included more cases of V30M in non-endemic areas and non-V30M mutations than V30M mutations in endemic areas, reflecting higher referral rates from specialists in non-endemic regions.

In conclusion, this study highlights the genetic and clinical diversity of patients with ATTRv amyloidosis. Patients with V30M in non-endemic areas and non-V30M mutations were more prevalent than expected, with observed variations in clinical features and diagnostic timelines based on the mutation type and initial symptoms.