M Waddington Cruz, A Berensztejn, MV Pinto, R Mundayat Late-Onset Transthyretin Familial Amyloid Polyneuropathy: Characterization of Brazilian Subjects from the THAOS Registry M Waddington Cruz, A Berensztejn, MV Pinto, R Mundayat

Introduction A late-onset form of TTR-FAP, in which symptoms manifest in patients’ fifth decade, has been reported in several countries.1–4 Late-onset TTR-FAP is distinct from the more typical, early-onset, form of disease as it involves both small and large sensory fibres, has fewer autonomic symptoms, and more severe motor and cardiac involvement. Despite growing numbers of patients diagnosed with late-onset FAP, the condition remains poorly characterised, and little is known of this population in Brazil 1. Jacobson DR, et al., 1997. N Engl J Med. 1997;336:466-473. 2. Misu K, et al., Brain. 1999;122:1951-1962. 3. Koike H, et al., Arch Neurol. 2002;59:1771-1776. 4. Conceicão I and de Carvalho M. Muscle Nerve. 2007;35:116-118.

Objective To improve characterization of late-onset TTR-FAP by comparing demographic and clinical characteristics of patients with late-onset and early-onset TTR-FAP in Brazil.

Methods All symptomatic Val30Met TTR-FAP subjects in Brazil* were included in the analysis and divided into two groups: Late-onset, subjects with symptom onset at age ≥50 years Early-onset, subjects with symptom onset at age <50 years Descriptive analyses of patients’ demographic information, medical history and clinical assessments at enrollment were performed. Assessments included: Neuropathy Impairment Score in the Lower Limbs (NIS-LL), Neurologic composite score and subscale reflex, motor and sensory scores, Modified Polyneuropathy Disability Score (mPND), electrocardiogram (ECG) and echocardiogram (ECHO). *Data cut-off: January 30, 2017

Results: Demographics and Clinical Characteristics at Enrollment From a total of 162 Brazilian subjects enrolled in THAOS, 148 (91.4%) had the Val30Met mutation, of which 96 were symptomatic and were included in this analysis: 25 (26.0%) were late-onset; 71 (74.0%) were early-onset. Late-onset (N = 25) Early-onset (N = 71) Male, n (%) 15 (60.0) 45 (63.4) Age at symptom onset, years, mean (SD) 62.1 (5.5) 30.5 (8.5) Time from symptom onset to diagnosis, years, mean (SD) 5.1 (4.1) 2.8 (4.4) Misdiagnosis, n (%) 17 (68.0) 19 (26.8) Family history, n (%) 10 (40.0) 68 (95.8) Autonomic neuropathy, n (%) 20 (80.0) 67 (94.4) Motor neuropathy, n (%) 23 (92.0) Sensory neuropathy, n (%) 25 (100.0) 70 (98.6) Cardiac disorder, n (%) 30 (42.3) GI, n (%) 21 (84.0) 66 (93.0) Data Source: Text: THAOS Abstract for WCN Brazil Late Onset Final tables v0.2.0 MARKED, Table 2, p3; Table 3, p4; Table 5, p8 (Calculation: 25/96*100%= 26.04%), Table 4, p6 (Calculation: 71/96*100%=73.96%) Table: THAOS Abstract for WCN Brazil Late Onset Final tables v0.2.0 MARKED: Table 4, p6 and Table 5, p8 (Calculations: 15/25*100=60.0%; 45/71*100=63.4%); Table 5, p8 and Table 4, p6; Table 5, p9 and Table 4, p7; Table 11, p15 and Table 10, p14; Table 9, p13 and Table 8, p12; Table 12, p16; Table 12, p18; Table 12, p20; Table 12, p17; Table 12, p17

Results: Neurological Impairment at Enrollment in Late- and Early-Onset Subjects 43.8 101.0 40.4 70.0 NOTES: Neuropathy Impairment Score in the Lower Limbs (NIS-LL) ranging from 0 (normal) to 88 (total impairment). Neurologic composite score (NCS; range = 0 - 294) and subscale reflex (range = 0 - 10), motor (range = 0 - 160) and sensory (range 0 - 124) scores. Data Source: THAOS Abstract for WCN Brazil Late Onset Final tables v0.2.0 MARKED: Table 13, p21; Table 13, p21 and p22 7.7 58.4 35.1 4.8 42.3 24.6

Results: mPND Status at Enrollment in Early- and Late-Onset Subjects *mPND ≤ 2 – preserved walking capacity (mPND score 0, I, or II)1 **mPND > 2 – altered walking capacity (mPND score IIIa, IIIb, or IV)1 53.3% 46.7% 64.7% 35.3% NOTES: Modified Polyneuropathy Disability Score (mPND): 0: normal walking; I: sensory disturbance in lower limbs but preserved walking capacity; II: difficulties in walking but no need of a walking stick; IIIa: one stick or one crutch required for walking; IIIb: two sticks or two crutches required for walking; IV: patient confined to a wheelchair or bed. Data Source: THAOS Abstract for WCN Brazil Late Onset Final tables v0.2.0 MARKED: Data source: Table 14, p23 Calculations: Table: Late-onset: 8/15*100%=53.3%; 4/15*100%=26.7%; 3/15*100%=20%   Early-onset: 1/17*100%=5.9%; 10/17*100%=58.8%; 6/17*100%= 35.3% Graphs: Late onset 8/18*100%=53.3%; (4+3)/15*100%=46.7% Early onset: (1+10)/17*100%=64.7%; 6/17*100%=35.3% mPND status Late-onset (n = 15) Early-onset (n = 17) 0 (0.0) 1 (5.9) I or II 8 (53.3) 10 (58.8) IIIa or IIIb 4 (26.7) 6 (35.3) IV 3 (20.0) mPND ≤ 2* mPND > 2** Data shown as n (%) 1. Planté-Bordeneuve V, et al. J Neurol. 2016;264:268-276.

Results: Cardiac Impairment at Enrollment in Early- and Late-Onset Subjects Early-onset N Mean (SD) Ventricular rate (bpm) 18 65.8 (14.9) 64 76.6 (13.74) QRS axis 28.1 (55.9) 59 54.2 (40.3) PR (msec) 17 168.4 (53.5) 63 160.1 (73.0) QRS (msec) 103.3 (22.5) 109.6 (30.2) QT (msec) 425.8 (51.2) 62 392.3 (54.3) 88.9% 59.4% Late-onset Early-onset % n/N Rhythm abnormalities 20.0 3/15 15.8 6/38 Conduction abnormalities 86.7 13/15 77.8 28/36 First degree AV block 23.1 3/13 42.3 11/26 Abnormalities in morphology 6.7 1/15 16.7 6/36 Low voltage 13.3 2/15 2.3 1/43 ST Segment – T wave abnormalities 40.0 6/15 Data Source: THAOS Abstract for WCN Brazil Late Onset Final tables v0.2.0 MARKED: Graphs: Table 15, p24; Table 16, p37 Tables: Table 15, p24; Table 15, p27; Table 15, p28; Table 15, p24; Table 15, p29; Table 15, p29; Table 15, p32; Table 15, p34; Table 15, p36 0.0%

Results: EQ-5D Index Score at Enrollment Scores from EuroQol five-dimension questionnaire (EQ-5D), obtained for both late- and early-onset subjects, were broadly similar in both groups EQ-5D Score Late-onset Early-onset Data Source: THAOS Abstract for WCN Brazil Late Onset Final tables v0.2.0 MARKED: Table 17, p38

Conclusions The late-onset form of TTR-FAP is common in the Brazilian population and while it presents with a more severe phenotype than early-onset TTR-FAP, it is more frequently misdiagnosed, and delays in diagnosis are more common. Late-onset TTR-FAP subjects tend to be more likely to suffer from more severe neurological and cardiac impairments, but less likely to experience autonomic symptoms. Further characterization and recognition of late-onset TTR-FAP could enable earlier recognition and improve patient treatment and outcomes.

Acknowledgments We thank all THAOS patients and investigators for their important contributions to this study.