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Peer-reviewedCC BY 4.0Frontiers in Neurology

Hereditary transthyretin amyloidosis in peripheral neuropathy: prevalence, clinical features, and neurology-based screening in non-endemic Japan

  • Yurika Okuma1
  • Kenji Isahaya1
  • Sachiko Ohori2
  • Satomi Mitsuhashi1
  • Tomoo Sato1,3
  • Yoshihisa Yamano1,3
  1. 1Department of Neurology, St. Marianna University School of Medicine
  2. 2Department of Laboratory Medicine, St. Marianna University School of Medicine
  3. 3Department of Rare Diseases Research, Institute of Medical Science, St. Marianna University School of Medicine
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Abstract

Introduction: Hereditary transthyretin amyloidosis (ATTRv) is a progressive, potentially fatal disease caused by pathogenic TTR variants. Although increasingly recognized as a cardiac disorder, ATTRv may initially present with peripheral neuropathy. Prospective data on the prevalence and clinical features of ATTRv among patients attending neurology clinics in non-endemic regions of Japan remain limited.

Methods: We prospectively enrolled 130 consecutive patients evaluated for suspected peripheral neuropathy at a neurology clinic in a non-endemic region of Japan between 2020 and 2025. The entire TTR coding region was analyzed by bidirectional Sanger sequencing of genomic DNA obtained from peripheral blood. Clinical, neurological, and cardiac findings were evaluated.

Results: Pathogenic TTR variants were identified in three patients (3/130, 2.31%; exact 95% CI, 0.5–6.6%): ATTRV122I [p.(Val142Ile)], ATTRI127V [p.(Ile147Val)], and ATTRV30M [p.(Val50Met)]. Two of the three variants were non-V30M variants unrelated to the Japanese endemic foci. All three patients had late-onset disease without a family history, with neurological manifestations ranging from established axonal or mixed polyneuropathy to early, mild involvement. Cardiac amyloid involvement was demonstrated in all three patients, including one with a structurally normal echocardiogram. A low-voltage electrocardiogram (ECG) was observed in all three ATTRv patients (3/3, 100%) compared with 5 of 95 (5.3%) variant-negative patients with available ECG data.

Discussion: ATTRv was identified in 2.31% of patients evaluated for suspected peripheral neuropathy in a non-endemic Japanese neurology clinic, a frequency comparable to that reported in European cohorts. These findings highlight the importance of considering ATTRv in patients with unexplained progressive neuropathy, even without a family history or residence in an endemic region, and support early TTR genetic testing when clinical red flags are present. The observation of low-voltage ECGs in all three ATTRv patients suggests that ECG may provide a complementary clue to occult cardiac involvement. However, this finding is preliminary and hypothesis-generating and requires validation in larger, independent prospective cohorts.

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Cite

BibTeXRIS
BibTeX
@article{okuma2026hereditary,
  title = {{Hereditary transthyretin amyloidosis in peripheral neuropathy: prevalence, clinical features, and neurology-based screening in non-endemic Japan}},
  author = {Yurika Okuma and Kenji Isahaya and Sachiko Ohori and Satomi Mitsuhashi and Tomoo Sato and Yoshihisa Yamano},
  journal = {Frontiers in Neurology},
  year = {2026},
  month = oct,
  doi = {10.3389/fneur.2026.1955913},
  url = {https://www.frontiersin.org/articles/10.3389/fneur.2026.1955913/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Hereditary transthyretin amyloidosis in peripheral neuropathy: prevalence, clinical features, and neurology-based screening in non-endemic Japan
AU  - Yurika Okuma
AU  - Kenji Isahaya
AU  - Sachiko Ohori
AU  - Satomi Mitsuhashi
AU  - Tomoo Sato
AU  - Yoshihisa Yamano
PY  - 2026
DA  - 2026/10/22
JO  - Frontiers in Neurology
DO  - 10.3389/fneur.2026.1955913
UR  - https://www.frontiersin.org/articles/10.3389/fneur.2026.1955913/full
AB  - Introduction: Hereditary transthyretin amyloidosis (ATTRv) is a progressive, potentially fatal disease caused by pathogenic TTR variants. Although increasingly recognized as a cardiac disorder, ATTRv may initially present with peripheral neuropathy. Prospective data on the prevalence and clinical features of ATTRv among patients attending neurology clinics in non-endemic regions of Japan remain limited.  Methods: We prospectively enrolled 130 consecutive patients evaluated for suspected peripheral neuropathy at a neurology clinic in a non-endemic region of Japan between 2020 and 2025. The entire TTR coding region was analyzed by bidirectional Sanger sequencing of genomic DNA obtained from peripheral blood. Clinical, neurological, and cardiac findings were evaluated.  Results: Pathogenic TTR variants were identified in three patients (3/130, 2.31%; exact 95% CI, 0.5–6.6%): ATTRV122I [p.(Val142Ile)], ATTRI127V [p.(Ile147Val)], and ATTRV30M [p.(Val50Met)]. Two of the three variants were non-V30M variants unrelated to the Japanese endemic foci. All three patients had late-onset disease without a family history, with neurological manifestations ranging from established axonal or mixed polyneuropathy to early, mild involvement. Cardiac amyloid involvement was demonstrated in all three patients, including one with a structurally normal echocardiogram. A low-voltage electrocardiogram (ECG) was observed in all three ATTRv patients (3/3, 100%) compared with 5 of 95 (5.3%) variant-negative patients with available ECG data.  Discussion: ATTRv was identified in 2.31% of patients evaluated for suspected peripheral neuropathy in a non-endemic Japanese neurology clinic, a frequency comparable to that reported in European cohorts. These findings highlight the importance of considering ATTRv in patients with unexplained progressive neuropathy, even without a family history or residence in an endemic region, and support early TTR genetic testing when clinical red flags are present. The observation of low-voltage ECGs in all three ATTRv patients suggests that ECG may provide a complementary clue to occult cardiac involvement. However, this finding is preliminary and hypothesis-generating and requires validation in larger, independent prospective cohorts.
SN  - 1664-2295
ER  -