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Skin biopsy and quantitative sensory assessment in an Italian cohort of ATTRv patients with polyneuropathy and asymptomatic carriers: possible evidence of early non-length dependent denervation

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Abstract

Aim

Study of intraepidermal nerve fiber density (IENFD) by skin biopsy represents a promising tool in the evaluation of patients with ATTRv polyneuropathy (ATTRv-PN). Herein, we retrospectively analyze intraepidermal innervation and quantitative sensory test (QST) data from an Italian cohort of Italian ATTRv-PN patients and asymptomatic carriers aimed to provide insights into early nerve pathological and functional changes in this disease.

Methods

IENFD and QST data of 14 ATTRv-PN patients and 14 asymptomatic carriers were retrospectively analyzed together with clinical and paraclinical data such as disease stage and severity, neuropathic pain scales, and sural SNAP amplitude.

Results

Given an estimated time to the predicted age of onset of symptomatic disease of 20.27 + / − 7.9 years, small nerve fiber loss seems to be unexpectedly early in carriers. Moreover, carriers showed skin denervation at the proximal (thigh) site, suggesting a non-length-dependent neuropathic process. IENFD at ankle correlated with disease severity and other paraclinical variables such as sural nerve potential amplitude and QST parameters. Patients at earlier stages of the disease did not show significant differences in ankle IENFD compared with asymptomatic carriers, but significant differences in terms of QST parameters, small fiber neuropathy symptoms, and neuropathic pain.

Conclusions

Skin biopsy can disclose an early non-length-dependent small fiber loss in ATTRv-PN and, together with QST, could provide a useful insight disease onset and progression.

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References

  1. Benson MD, Buxbaum JN, Eisenberg DS, Merlini G, Saraiva MJM, Sekijima Y, Sipe JD, Westermark P (2018) Amyloid nomenclature 2018: recommendations by the International Society of Amyloidosis (ISA) nomenclature committee. Amyloid 25:215–219

    Article  CAS  Google Scholar 

  2. Adams D, Coelho T, Obici L et al (2015) Rapid progression of familial amyloidotic polyneuropathy: a multinational natural history study. Neurology 85:675–682

    Article  CAS  Google Scholar 

  3. Coutinho P, Martins da Silva A, Lopes Lima J, Resende Barbosa A (1980) Forty years of experience with type I amyloid neuropathy (review of 483 cases). In: Glenner GG, Pinho e Costa P, Falcão de Freitas (eds) Amyloid and amyloidosis. Excerpta Medica, Amsterdam

  4. Yang NC, Lee MJ, Chao CC et al (2010) Clinical presentations and skin denervation in amyloid neuropathy due to transthyretin Ala97Ser. Neurology 75:532–538

    Article  CAS  Google Scholar 

  5. Masuda T, Ueda M, Suenaga G (2017) Early skin denervation in hereditary and iatrogenic transthyretin amyloid neuropathy. Neurology 88(23):2192–2197

    Article  CAS  Google Scholar 

  6. Ebenezer GJ et al (2017) Cutaneous nerve biomarkers in transthyretin familial amyloid polyneuropathy. Ann Neurol 82:44–56

    Article  CAS  Google Scholar 

  7. Chao CC, Hsueh HW, Kan HW et al (2019) Skin nerve pathology: biomarkers of premanifest and manifest amyloid neuropathy. Ann Neurol 85(4):560–573

    Article  CAS  Google Scholar 

  8. Lauria G, Hsieh ST, Johansson O, Kennedy WR et al (2010) European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol 17(7):903–12 (e44-9)

    Article  CAS  Google Scholar 

  9. Provitera V, Gibbons CH, Wendelschafer-Crabb G et al (2016) A multi-center, multinational age- and gender-adjusted normative dataset for immunofluorescent intraepidermal nerve fiber density at the distal leg. Eur J Neurol 23(2):333–338

    Article  CAS  Google Scholar 

  10. Provitera V, Gibbons CH, Wendelschafer-Crabb G, Donadio V, Vitale DF, Loavenbruck A, Stancanelli A, Caporaso G, Liguori R, Wang N, Santoro L, Kennedy WR, Nolano M (2018) The role of skin biopsy in differentiating small-fiber neuropathy from ganglionopathy. Eur J Neurol 25(6):848–853

    Article  CAS  Google Scholar 

  11. Vollert J, Attal N, Baron R, Freynhagen R, Haanpää M, Hansson P, Jensen TS, Rice AS, Segerdahl M, Serra J, Sindrup SH, Tölle TR, Treede RD, Maier C (2016) Quantitative sensory testing using DFNS protocol in Europe: an evaluation of heterogeneity across multiple centers in patients with peripheral neuropathic pain and healthy subjects. Pain 157(3):750–758

    Article  Google Scholar 

  12. Berk JL, Suhr OB, Obici L et al (2013) Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA 310:2658–2667

    Article  CAS  Google Scholar 

  13. Dyck PJ, Sherman WR, Hallcher LM, Service FJ, O’Brien PC, Grina LA, Palumbo PJ, Swanson CJ (1980) Human diabetic endoneurial sorbitol, fructose, and myo-inositol related to sural nerve morphometry. Ann Neurol 8(6):590–596

    Article  CAS  Google Scholar 

  14. Spallone V, Morganti R, D’Amato C, Greco C, Cacciotti L, Marfia GA (2012) Validation of DN4 as a screening tool for neuropathic pain in painful diabetic polyneuropathy. Diabet Med 29(5):578–585

    Article  CAS  Google Scholar 

  15. Bakkers M, Merkies IS, Lauria G, Devigili G, Penza P, Lombardi R, Hermans MC, van Nes SI, De Baets M, Faber CG (2009) Intraepidermal nerve fiber density and its application in sarcoidosis. Neurology 73(14):1142–1148

    Article  CAS  Google Scholar 

  16. England JD, Gronseth GS, Franklin G, Carter GT, Kinsella LJ, Cohen JA, Asbury AK, Szigeti K, Lupski JR, Latov N, Lewis RA, Low PA, Fisher MA, Herrmann DN, Howard JF Jr, Lauria G, Miller RG, Polydefkis M, Sumner AJ (2009) American Academy of Neurology. Practice Parameter: evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology 72(2):185–92

    Article  CAS  Google Scholar 

  17. Conceição I, Damy T, Romero M, Galán L, Attarian S, Luigetti M, Sadeh M, Sarafov S, Tournev I, Ueda M (2019) Early diagnosis of ATTR amyloidosis through targeted follow-up of identified carriers of TTR gene mutations. Amyloid 26(1):3–9

    Article  CAS  Google Scholar 

  18. Adams D, Koike H, Slama M, Coelho T (2019) Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. Nat Rev Neurol 15(7):387–404

    Article  CAS  Google Scholar 

  19. Kapoor M, Foiani M, Heslegrave A, Zetterberg H, Lunn MP, Malaspina A, Gillmore JD, Rossor AM, Reilly MM (2019) Plasma neurofilament light chain concentration is increased and correlates with the severity of neuropathy in hereditary transthyretin amyloidosis. J Peripher Nerv Syst 24(4):314–319

    Article  CAS  Google Scholar 

  20. Hanyu N, Ikeda S, Nakadai A, Yanagisawa N, Powell HC (1989) Peripheral nerve pathological findings in familial amyloid polyneuropathy: a correlative study of proximal sciatic nerve and sural nerve lesions. Ann Neurol 25(4):340–350

    Article  CAS  Google Scholar 

  21. Fujitake J, Mizuta H, Fujii H, Ishikawa Y, Katsuyama E, Takasu K, Saida K, Tatsuoka Y (2003) Late-onset familial amyloid polyneuropathy: an autopsy study of two Japanese brothers. Amyloid 10(3):198–205

    Article  Google Scholar 

  22. Granata G, Luigetti M, Coraci D et al (2014) Ultrasound evaluation in transthyretin-related amyloid neuropathy. Muscle Nerve 50(3):372–376

    Article  Google Scholar 

  23. Kollmer J, Hund E, Hornung B, Hegenbart U, Schonland SO, Kimmich C et al (2015) In vivo detection of nerve injury in familial amyloid polyneuropathy by magnetic resonance neurography. Brain 138:549–562

    Article  Google Scholar 

  24. Podnar S, Sarafov S, Tournev I, Omejec G, Zidar J (2017) Peripheral nerve ultrasonography in patients with transthyretin amyloidosis. Clin Neurophysiol 128:505–511

    Article  Google Scholar 

  25. Salvalaggio A, Coraci D, Cacciavillani M, Obici L, Mazzeo A, Luigetti M, Pastorelli F, Grandis M, Cavallaro T, Bisogni G, Lozza A, Gemelli C, Gentile L, Ermani M, Fabrizi GM, Plasmati R, Campagnolo M, Castellani F, Gasparotti R, Martinoli C, Padua L, Briani C (2020) Nerve ultrasound in hereditary transthyretin amyloidosis: red flags and possible progression biomarkers. J Neurol 268(1):189–198

    Article  CAS  Google Scholar 

  26. Russo M, Obici L, Bartolomei I, Cappelli F, Luigetti M, Fenu S, Cavallaro T, Chiappini MG, Gemelli C, Pradotto LG, Manganelli F, Leonardi L, My F, Sampaolo S, Briani C, Gentile L, Stancanelli C, Di Buduo E, Pacciolla P, Salvi F, Casagrande S, Bisogni G, Calabrese D, Vanoli F, Di Iorio G, Antonini G, Santoro L, Mauro A, Grandis M, Di Girolamo M, Fabrizi GM, Pareyson D, Sabatelli M, Perfetto F, Rapezzi C, Merlini G, Mazzeo A, Vita G (2020) ATTRv amyloidosis Italian Registry: clinical and epidemiological data. Amyloid 27(4):259–265

    Article  CAS  Google Scholar 

  27. Luigetti M, Romozzi M, Bisogni G, Cardellini D, Cavallaro T, Di Paolantonio A, Fabrizi GM, Fenu S, Gentile L, Grandis M, Marucci G, Massucco S, Mazzeo A, Pareyson D, Romano A, Russo M, Schenone A, Tagliapietra M, Tozza S, Vita G, Sabatelli M (2020) hATTR Pathology: Nerve Biopsy Results from Italian Referral Centers. Brain Sci 10(11):E780

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), Sant’Andrea Hospital, Sapienza University of Rome, 1035-39 Grottarossa St., Rome, Italy

    Luca Leonardi, Fiammetta Vanoli, Laura Fionda, Matteo Garibaldi, Girolamo Alfieri, Antonio Lauletta, Stefania Morino, Marco Salvetti & Giovanni Antonini

  2. Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy

    Eleonora Galosi, Alessandra Fasolino, Giuseppe Di Pietro & Andrea Truini

  3. Fondazione Policlinico Universitario A. Gemelli IRCCS, UOC Neurologia, Rome, Italy

    Marco Luigetti

  4. Università Cattolica del Sacro Cuore, Rome, Italy

    Marco Luigetti & Mario Sabatelli

  5. Centro Clinico NEMO, Rome, Italy

    Mario Sabatelli

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  1. Luca Leonardi
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  2. Eleonora Galosi
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  3. Fiammetta Vanoli
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Correspondence to Luca Leonardi.

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Leonardi, L., Galosi, E., Vanoli, F. et al. Skin biopsy and quantitative sensory assessment in an Italian cohort of ATTRv patients with polyneuropathy and asymptomatic carriers: possible evidence of early non-length dependent denervation. Neurol Sci 43, 1359–1364 (2022). https://doi.org/10.1007/s10072-021-05434-5

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