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Elderly patients with suspected Charcot-Marie-Tooth disease should be tested for the TTR gene for effective treatments

Journal of Human Genetics volume 67, pages 353–362 (2022)Cite this article

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Abstract

Background and aims

Some hereditary transthyretin (ATTRv) amyloidosis patients are misdiagnosed as Charcot−Marie−Tooth disease (CMT) at onset. We assess the findings to identify ATTRv amyloidosis among patients with suspected CMT to screen transthyretin gene variants for treatments.

Methods

We assessed clinical, cerebrospinal fluid, and electrophysiological findings by comparing ATTRv amyloidosis patients with suspected CMT (n = 10) and CMT patients (n = 489).

Results

The median (interquartile range) age at onset of neurological symptoms was 69 (64.2–70) years in the ATTRv amyloidosis vs 12 (5–37.2) years in CMT group (Mann−Whitney U, p < 0.01).

The proportion of patients with initial sensory symptoms was 70% in the ATTRv amyloidosis group vs 7.1% in CMT group (Fisher’s exact, p < 0.01). The proportion of patients with histories of suspected chronic inflammatory demyelinating polyneuropathy (CIDP) were 50% in the ATTRv amyloidosis group vs 8.7% in CMT group (Fisher’s exact, p < .01). Other measures and outcomes were not different between the two groups. Five of the six patients with ATTRv amyloidosis received treatment and survived.

Interpretation

For effective treatments, the transthyretin gene should be screened in patients with suspected CMT with old age at onset of neurological symptoms, initial sensory symptoms, and histories of suspected CIDP.

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Fig. 1: Schematic diagram of the present study and family trees of ATTRv amyloidosis patients.
Fig. 2: Age of onset, proportion of patients with initial neurological symptoms and that of initial sensory symptoms in ATTRv amyloidosis and CMT group.
Fig. 3: Clinical, laboratory, cerebrospinal fluid and electrophysiological findings in ATTRv amyloidosis and CMT group.

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References

  1. Andrade C. A peculiar form of peripheral neuropathy; familial atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain. 1952;75:408–27.

    Article  CAS  PubMed  Google Scholar 

  2. Yamamoto H, Hashimoto T, Kawamura S, Kawamura S, Hiroe M, Yamashita T, et al. Hereditary cardiac amyloidosis associated with Pro24Ser transthyretin mutation: a case report. J Med Case Rep. 2018;12:370.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ando Y, Coelho T, Berk JL, Cruz MW, Ericzon B, Ikeda S, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013;8:31.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Lahuerta Pueyo C, Aibar Arregui MÁ, Gracia Gutierrez A, Bueno Juana E, Menao Guillén S. Estimating the prevalence of allelic variants in the transthyretin gene by analysing large-scale sequencing data. Eur J Hum Genet. 2019;27:783–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sekijima Y, Ueda M, Koike H, Misawa S, Ishii T, Ando Y. Diagnosis and management of transthyretin familial amyloid polyneuropathy in Japan: red-flag symptom clusters and treatment algorithm. Orphanet J Rare Dis. 2018;13:6.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kato-Motozaki Y, Ono K, Shima K, Morinaga A, Machiya T, Nozaki I, et al. Epidemiology of familial amyloid polyneuropathy in Japan: identification of a novel endemic focus. J Neurol Sci. 2008;270:133–40.

    Article  PubMed  Google Scholar 

  7. Ando Y, Nakamura M, Araki S. Transthyretin-related familial amyloidotic polyneuropathy. Arch Neurol. 2005;62:1057–62.

    Article  PubMed  Google Scholar 

  8. Araki S, Mawatari S, Ohta M, Nakajima A, Kuroiwa Y. Polyneuritic amyloidosis in a Japanese family. Arch Neurol. 1968;18:593–602.

    Article  CAS  PubMed  Google Scholar 

  9. Ikeda S, Nakazato M, Ando Y, Sobue G. Familial transthyretin-type amyloid polyneuropathy in Japan: clinical and genetic heterogeneity. Neurology. 2002;58:1001–7.

    Article  CAS  PubMed  Google Scholar 

  10. Kito S, Itoga E, Kamiya K, Kishida T, Yammamura Y. Studies on familial amyloid polyneuropathy in Ogawa Village, Japan. Eur Neurol. 1980;19:141–51.

    Article  CAS  PubMed  Google Scholar 

  11. Sobue G, Hoike H, Misu K, Hattori N, Yamamoto M, Ikeda S, et al. Clinicopathologic and genetic features of early- and late-onset FAP type I (ATTR Val30Met) in Japan. Amyloid. 2003;10 Suppl 1:32–9.

    Article  CAS  PubMed  Google Scholar 

  12. Adams D, Suhr OB, Hund E, Obici L, Tournev I, Campistol JM, et al. First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy. Curr Opin Neurol. 2016;29:S14–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mathis S, Magy L, Diallo L, Boukhris S, Vallat JM. Amyloid neuropathy mimicking chronic inflammatory demyelinating polyneuropathy. Muscle Nerve. 2012;45:26–31.

    Article  PubMed  Google Scholar 

  14. Grandis M, Geroldi A, Gulli R, Manganelli F, Gotta F, Lamp M, et al. Autosomal-dominant transthyretin (TTR)-related amyloidosis is not a frequent CMT2 neuropathy “in disguise”. Orphanet J Rare Dis. 2018;13:177.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Cappellari M, Cavallaro T, Ferrarini M, Cabrini I, Taioli F, Ferrari S, et al. Variable presentations of TTR-related familial amyloid polyneuropathy in seventeen patients. J Peripher Nerv Sys. 2011;16:119–29.

    Article  Google Scholar 

  16. Yoshimura A, Yuan JH, Hashiguchi A, Ando M, Higuchi Y, Nakamura T, et al. Genetic profile and onset features of 1005 patients with Charcot-Marie-Tooth disease in Japan. J Neurol Neurosurg Psychiatry. 2019;90:195–202.

    Article  PubMed  Google Scholar 

  17. Keohane D, Schwarts J, Gundapaneni B, Stewart M, Amass L. Tafamidis delays disease progression in patients with early stage transthyretin familial amyloid polyneuropathy: additional supportive analyses from the pivotal trial. Amyloid. 2017;24:30–6.

    Article  CAS  PubMed  Google Scholar 

  18. Benson MD, Dasgupta NR, Rissing SM, Smith J, Feigenbaum H. Safety and efficacy of a TTR specific antisense oligonucleotide in patients with transthyretin amyloid cardiomyopathy. Amyloid. 2017;24:219–25.

    PubMed  Google Scholar 

  19. Adams D, Gonzalez-Duarte A, O’Riordan WD, Yang CC, Ueda M, Kristen AV, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. 2018;379:11–21.

    Article  CAS  PubMed  Google Scholar 

  20. Hashiguchi A, Higuchi Y, Nomura M, Nakamura T, Arata H, Yuan J, et al. Neurofilament light mutation causes hereditary motor and sensory neuropathy with pyramidal sings. J Peripher Nerv Syst. 2014;19:311–6.

    Article  CAS  PubMed  Google Scholar 

  21. Maeda K, Idehara R, Hashiguchi A, Takashima H. A family with distal hereditary motor neuropathy and a K141Q mutation of small heat shock protein HSPB1. Intern Med. 2014;53:1655–8.

    Article  PubMed  Google Scholar 

  22. Higuchi Y, Hashiguchi A, Yuan J, Yoshimura A, Mitsui J, Ishiura H, et al. Mutations in MME cause an autosomal-recessive Charcot-Marie-Tooth disease type 2. Ann Neurol. 2016;79:659–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ando M, Hashiguchi A, Okamoto Y, Yoshimura A, Hiramatsu Y, Yuan J, et al. Clinical and genetic diversities of Charcot-Marie-Tooth disease with MFN2 mutations in a large case study. J Peripher Nerv Syst. 2017;22:191–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Derouault P, Chauzeix J, RizzoD, Miressi F, magdelaine C, Bourthoumieu S, et al. CovCopCan: an efficient tool to detect copy number variation from amplicon sequencing data in inherited disease and cancer. PLoS Comput Biol. 2020;16:e1007503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guideline for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Harding AE, Thomas PK. The clinical feature of hereditary motor and sensory neuropathy types I and II. Brain 1980;103:259–80.

    Article  CAS  PubMed  Google Scholar 

  27. Uzunkulaoğlu A, Afsar SI, Tepeli B. Terminal latency index, residual latency, and Median-Ulnar F-wave latency difference in Carpal tunnel syndrome. Ann Indian Acad Neurol. 2019;22:175–9.

    PubMed  PubMed Central  Google Scholar 

  28. Van den Bergh PYK, van Doorn PA, Hadden RDM, Avau B, Vankrunkelsven P, Allen JA, et al. European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision. Eur J Neurol. 2021;28:3556–83.

    Article  PubMed  Google Scholar 

  29. Koike H, Tanaka F, Hashimoto R, Tomita M, Kawagashira Y, Iijima M, et al. Natural history of transthyretin Val30Met familial amyloid polyneuropathy: analysis of late-onset cases from non-endemic areas. J Neurol Neurosurg Psychiatry. 2012;83:152–8.

    Article  PubMed  Google Scholar 

  30. Koike H, Misu K, Ikeda S, Ando Y, Nakazato M, Ando E, et al. Type I (Transthyretin Met30) familial amyloid polyneuropathy in Japan. Arch Neurol. 2002;59:1771–6.

    Article  PubMed  Google Scholar 

  31. Kotani N, Hattori T, Yamagata S, Tokuda T, Shirasawa A, Yamaguchi S, et al. Transthyretin Thr60Ala Appalachian-type mutation in a Japanese family with familial amyloidotic polyneuropathy. Amyloid. 2002;9:31–4.

    Article  CAS  PubMed  Google Scholar 

  32. Jang MA, Lee GY, Kim K, Kim JS, Lee SY, Kim HJ, et al. Asp58Ala is the predominant mutation of the TTR gene in Korean patients with hereditary transthyretin-related amyloidosis. Ann Hum Genet. 2015;79:99–107.

    Article  CAS  PubMed  Google Scholar 

  33. Yazak M, Take Y, Katoh M, Ikeda S. Postmortem findings in two familial amyloidosis patients with transthyretin variant Asp38Ala. Amyloid. 2000;7:270–7.

    Article  CAS  PubMed  Google Scholar 

  34. Hattori T, Takei Y, Koyama J, Nakazato M, Ikeda S. Clinical and pathological studies of cardiac amyloidosis in transthyretin type familial amyloid polyneuropathy. Amyloid. 2003;10:229–39.

    Article  CAS  PubMed  Google Scholar 

  35. Choi K, Seok JM, Kim BJ, Choi YC, Shin HY, Sunwoo IN, et al. Characteristics of South Korean patients with hereditary transthyretin amyloidosis. J Clin Neurol. 2018;14:537–41.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Koike H, Okumura T, Murohara T, Katsuno M. Multidisciplinary approaches for transthyretin amyloidosis. Cardiol Ther. 2021;10:289–311.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Koike H, Hashimoto R, Tomita M, Kawagashira Y, Iijima M, Tanaka F, et al. Diagnosis of sporadic transthyretin Val30Met familial amyloid polyneuropathy: a practical analysis. Amyloid. 2011;18:56–62.

    Article  CAS  Google Scholar 

  38. Ando Y, Obayashi Y, Tanaka T, Tsuji T, Uchino M, Takahashi M, et al. Radiolabelled meta-iodobenzylguanidine in assessment of autonomic dysfunction. Lancet. 1994;343:984–5.

    Article  CAS  PubMed  Google Scholar 

  39. Hattori N, Yamamoto M, Yoshihara T, Koike H, Nakagawa M, Yoshikawa H, et al. Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin- related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients. Brain. 2003;126:134–51.

    Article  PubMed  Google Scholar 

  40. Taniguchi T, Ando M, Okamoto Y, Yoshimra A, Higuchi Y, Hashiguchi A, et al. Genetic spectrum of Charcot–Marie–Tooth disease associated with myelin protein zero gene variants in Japan. Clin Genet. 2021;99:359–75.

    Article  CAS  PubMed  Google Scholar 

  41. Simovic D, Weinberg DH. The median nerve terminal latency index in carpal tunnel syndrome: a clinical case selection study. Muscle Nerve. 1999;22:573–7.

    Article  CAS  PubMed  Google Scholar 

  42. Bae JS, Kim BJ. Subclinical diabetic neuropathy with normal conventional electrophysiological study. J Neurol. 2007;254:53–9.

    Article  PubMed  Google Scholar 

  43. Vahdatpour B, Khosrawi S, Chatraei M. The role of median nerve terminal latency index in the diagnosis of carpal tunnel syndrome in comparison with other electrodiagnostic parameters. Adv Biomed Res. 2016;5:110.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Panosyan FB, Kirk CA, Marking D, Reilly MM, Scherer SS, Shy ME, et al. Carpal tunnel syndrome in inherited neuropathies: a retrospective survey. Muscle Nerve. 2018;57:388–394.

    Article  PubMed  Google Scholar 

  45. Adams D, Ando Y, Beirao JM, Coelho T, Gertz MA, Gillmore JD, et al. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. J Neurol. 2021;268:2109–22.

    Article  PubMed  Google Scholar 

  46. Vogt B, Chahin N, Wiszniewski W, Ragole T, Karam C. Screening for genetic mutations in patients with neuropathy without definite etiology is useful. J Neurol. 2020;267:2648–54.

    Article  CAS  PubMed  Google Scholar 

  47. Schmidt HH, Waddington-Cruz M, Botteman MF, Carter JA, Chopra AS, Hopps M, et al. Estimating the global prevalence of transthyretin familial amyloid polyneuropathy. Muscle Nerve. 2018;57:829–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors appreciate Tomoko Ohnishi for her great technical assistance. The authors are supported by Enago (www.enago.jp) for reviewing the English in this report. We appreciate the Joint Research Laboratory, at the Kagoshima University Graduate School of Medicine and Dental Sciences, for the use of their facilities.

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Authors and Affiliations

  1. Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

    Takaki Taniguchi, Masahiro Ando, Yuji Okamoto, Akiko Yoshimura, Yujiro Higuchi, Akihiro Hashiguchi & Hiroshi Takashima

  2. Department of Neurology, Imakiire General Hospital, Kagoshima, Japan

    Takaki Taniguchi

  3. Department of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, Kagoshima, Japan

    Yuji Okamoto

  4. Department of Neurology, Fukushima Medical University, Fukushima, Japan

    Nozomu Matsuda

  5. Department of Neurology, University of Toyama, Toyama, Japan

    Mamoru Yamamoto

  6. Department of Neurology, Hiroshima Prefectural Hospital, Hiroshima, Japan

    Eisuke Dohi

  7. Department of Neuroscience of Disease, Brain Research Institute, Niigata University, Niigata, Japan

    Eisuke Dohi

  8. Department of Neurology, Kanto Central Hospital, Tokyo, Japan

    Makoto Takahashi

  9. Department of Neurology, Obihiro Kosei Hospital, Hokkaido, Japan

    Masanao Yoshino

  10. Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan

    Masanao Yoshino, Taichi Nomura, Masaaki Matsushima & Ichiro Yabe

  11. Department of Neurology, Akita University Graduate School of Medicine, Akita, Japan

    Yui Sanpei

  12. Department of Neurology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan

    Hiroyuki Ishiura

  13. Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Jun Mitsui & Shoji Tsuji

  14. North Medical Center, Kyoto prefectural University of Medicine, Kyoto, Japan

    Masanori Nakagawa

  15. Institute of Medical Genomics, International University of Health and Welfare, Chiba, Japan

    Shoji Tsuji

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  1. Takaki Taniguchi
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Contributions

All authors contributed to acquisition of patients’ data, analysis or interpretation of data, drafting or revising of the manuscript. MA, YH, YO and HT contributed to study conception and supervision.

Corresponding author

Correspondence to Hiroshi Takashima.

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Competing interests

HT has been funded by Grants-in-Aid from the Research Committee of Ataxia, Health Labour Sciences Research Grant, the Ministry of Health, Labour and Welfare, Japan (201610002B), Japan Agency for Medical Research and Development (AMED) and Japan Society for the Promotion of Science (JSPS). YH and MA have been funded by Japan Society for the Promotion of Science (JSPS). Grant numbers of AMED are 201442014A, 201442071A, 17929553, and those of JSPS are JP18H02742, JP20K16604, JP21K15702, JP21H02842.

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Taniguchi, T., Ando, M., Okamoto, Y. et al. Elderly patients with suspected Charcot-Marie-Tooth disease should be tested for the TTR gene for effective treatments. J Hum Genet 67, 353–362 (2022). https://doi.org/10.1038/s10038-021-01005-w

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