Phenotypic Differences of Glu89Gln Genotype in ATTR Amyloidosis From Endemic Loci: Update From THAOS

Luca Gentile, Ivailo Tournev, Leslie Amass, Doug Chapman, Anna Mazzeo, THAOS investigators, Fabio Barroso, Johan van Cleemput, Hartmut Schmidt, Burkhard Gess, Pablo Garcia Pavia, José Luis Muñoz Blanco, Claudio Rapezzi, Giuseppe Vita, Giampaolo Merlini, Marco Luigetti, Yesim Parman, Mathew Maurer, Samantha LoRusso, Luca Gentile, Ivailo Tournev, Leslie Amass, Doug Chapman, Anna Mazzeo, THAOS investigators, Fabio Barroso, Johan van Cleemput, Hartmut Schmidt, Burkhard Gess, Pablo Garcia Pavia, José Luis Muñoz Blanco, Claudio Rapezzi, Giuseppe Vita, Giampaolo Merlini, Marco Luigetti, Yesim Parman, Mathew Maurer, Samantha LoRusso

Abstract

Introduction: Transthyretin amyloidosis (ATTR amyloidosis) is a progressive, clinically heterogeneous disease with spontaneous (wild-type) and hereditary (ATTRv) forms. The Glu89Gln variant is primarily associated with cardiomyopathy and prevalent in Italy and Bulgaria. The objective of this analysis was to better understand the profile of patients with ATTRv Glu89Gln amyloidosis in the Transthyretin Amyloidosis Outcomes Survey (THAOS).

Methods: THAOS is an ongoing, global, longitudinal, observational survey of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic carriers with mutations in the transthyretin gene. Demographic and clinical characteristics of all symptomatic patients with the ATTRv Glu89Gln variant enrolled in THAOS are described (data cutoff, January 6, 2020).

Results: There were 91 patients with ATTRv Glu89Gln amyloidosis with the majority from Bulgaria (n = 53) or Italy (n = 29). All patients were Caucasian and 50.5% were male. Patients from Bulgaria had a mean (standard deviation) age at enrollment of 57.1 (8.2) years, and duration of symptoms of 8.6 (9.6) years, compared with 54.8 (8.6) and 5.0 (4.1) years in Italy. In Bulgaria, 39.6% of patients were of a predominantly cardiac phenotype, 18.9% predominantly neurologic, and 41.5% mixed. In Italy, 3.4% of patients were predominantly cardiac, 62.1% predominantly neurologic, and 34.5% mixed.

Conclusions: The majority of patients with ATTRv Glu89Gln amyloidosis in THAOS are from Bulgaria or Italy. There were notable phenotypic differences, with the cardiac phenotype more common in Bulgaria and the neurologic phenotype more common in Italy. Over one-third of patients had a mixed phenotype, suggesting a potential role of multiple genetic and/or environmental factors and the need for comprehensive assessment of all patients.

Trial registration: ClinicalTrials.gov: NCT00628745.

Keywords: ATTR; Bulgaria; Glu89Gln; Italy; Transthyretin amyloidosis.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Phenotypic categories of patients from Bulgaria and Italy with symptomatic ATTRv Glu89Gln amyloidosis at enrollment in THAOS (data cutoff, January 6, 2020). ATTRv Glu89Gln amyloidosis ATTRv amyloidosis associated with the Glu89Gln variant; THAOS Transthyretin Amyloidosis Outcomes Survey

References

    1. Planté-Bordeneuve V, Said G. Familial amyloid polyneuropathy. Lancet Neurol. 2011;10(12):1086–1097. doi: 10.1016/S1474-4422(11)70246-0.
    1. Adams D, Cauquil C, Labeyrie C. Familial amyloid polyneuropathy. Curr Opin Neurol. 2017;30(5):481–489. doi: 10.1097/WCO.0000000000000476.
    1. Russo M, Gentile L, Toscano A, Aguennouz M, Vita G, Mazzeo A. Advances in treatment of ATTRv amyloidosis: state of the art and future prospects. Brain Sci. 2020;10(12):952. doi: 10.3390/brainsci10120952.
    1. Ruberg FL, Maurer MS, Judge DP, Zeldenrust S, Skinner M, Kim AY, et al. Prospective evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy: the Transthyretin Amyloidosis Cardiac Study (TRACS) Am Heart J. 2012;164(2):222–228. doi: 10.1016/j.ahj.2012.04.015.
    1. Nehashi T, Oikawa M, Amami K, Kanno Y, Yokokawa T, Misaka T, et al. Sporadic cardiac amyloidosis by amyloidogenic transthyretin V122I variant. Int Heart J. 2019;60(6):1441–1443. doi: 10.1536/ihj.19-134.
    1. Rowczenio D, Wechalekar A. Mutations in hereditary amyloidosis (2015). . Accessed Dec, 18 2020.
    1. Mazzeo A, Russo M, Di Bella G, Minutoli F, Stancanelli C, Gentile L, et al. Transthyretin-related familial amyloid polyneuropathy (TTR-FAP): a single-center experience in Sicily, an Italian endemic area. J Neuromuscul Dis. 2015;2(s2):S39–S48. doi: 10.3233/JND-150091.
    1. Kirov A, Sarafov S, Pavlova Z, Todorov T, Chamova T, Gospodinova M, et al. Founder effect of the Glu89Gln TTR mutation in the Bulgarian population. Amyloid. 2019;26(4):181–185. doi: 10.1080/13506129.2019.1634539.
    1. Damy T, Kristen AV, Suhr OB, Maurer MS, Planté-Bordeneuve V, Yu CR, et al. Transthyretin cardiac amyloidosis in continental Western Europe: an insight through the Transthyretin Amyloidosis Outcomes Survey (THAOS) Eur Heart J. 2019 doi: 10.1093/eurheartj/ehz173.
    1. Finsterer J, Iglseder S, Wanschitz J, Topakian R, Löscher WN, Grisold W. Hereditary transthyretin-related amyloidosis. Acta Neurol Scand. 2019;139(2):92–105. doi: 10.1111/ane.13035.
    1. Russo M, Obici L, Bartolomei I, Cappelli F, Luigetti M, Fenu S, et al. ATTRv amyloidosis Italian registry: clinical and epidemiological data. Amyloid. 2020;27(4):259–265. doi: 10.1080/13506129.2020.1794807.
    1. Coelho T, Maurer MS, Suhr OB. THAOS—the Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis. Curr Med Res Opin. 2013;29(1):63–76. doi: 10.1185/03007995.2012.754348.
    1. Planté-Bordeneuve V, Suhr OB, Maurer MS, White B, Grogan DR, Coelho T. The Transthyretin Amyloidosis Outcomes Survey (THAOS) registry: design and methodology. Curr Med Res Opin. 2013;29(1):77–84. doi: 10.1185/03007995.2012.754349.
    1. González-Duarte A, Barroso F, Mundayat R, Shapiro B. Blood pressure and orthostatic hypotension as measures of autonomic dysfunction in patients from the Transthyretin Amyloidosis Outcomes Survey (THAOS) Auton Neurosci. 2019;222:102590. doi: 10.1016/j.autneu.2019.102590.
    1. Maurer MS, Hanna M, Grogan M, Dispenzieri A, Witteles R, Drachman B, et al. Genotype and phenotype of transthyretin cardiac amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey) J Am Coll Cardiol. 2016;68(2):161–172. doi: 10.1016/j.jacc.2016.03.596.
    1. Kristen AV, Maurer MS, Rapezzi C, Mundayat R, Suhr OB, Damy T. Impact of genotype and phenotype on cardiac biomarkers in patients with transthyretin amyloidosis - report from the Transthyretin Amyloidosis Outcome Survey (THAOS) PLoS ONE. 2017;12(4):e0173086. doi: 10.1371/journal.pone.0173086.
    1. Coelho T, Vinik A, Vinik EJ, Tripp T, Packman J, Grogan DR. Clinical measures in transthyretin familial amyloid polyneuropathy. Muscle Nerve. 2017;55(3):323–332. doi: 10.1002/mus.25257.
    1. Griffin JM, Maurer MS. Transthyretin cardiac amyloidosis: a treatable form of heart failure with a preserved ejection fraction. Trends Cardiovasc Med. 2019;31(1):59–66. doi: 10.1016/j.tcm.2019.12.003.
    1. Gentile L, Di Bella G, Minutoli F, Cucinotta F, Obici L, Mussinelli R, et al. Description of a large cohort of Caucasian patients with V122I ATTRv amyloidosis: neurological and cardiological features. J Peripher Nerv Syst. 2020;25(3):273–278. doi: 10.1111/jns.12385.
    1. Stancanelli C, Gentile L, Di Bella G, Minutoli F, Russo M, Vita G, et al. Phenotypic variability of TTR Val122Ile mutation: a Caucasian patient with axonal neuropathy and normal heart. Neurol Sci. 2017;38(3):525–526. doi: 10.1007/s10072-016-2767-7.
    1. Adams D, Slama M. Hereditary transthyretin amyloidosis: current treatment. Curr Opin Neurol. 2020;33(5):553–561. doi: 10.1097/WCO.0000000000000852.
    1. Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379(11):1007–1016. doi: 10.1056/NEJMoa1805689.
    1. Vita G, Vita GL, Stancanelli C, Gentile L, Russo M, Mazzeo A. Genetic neuromuscular disorders: living the era of a therapeutic revolution. Part 1: peripheral neuropathies. Neurol Sci. 2019;40(4):661–669. doi: 10.1007/s10072-019-03778-7.

Source: PubMed

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