Supplementary Material s95

SUPPLEMENTARY MATERIAL

Supplementary methods

Assessment tools:

1)  Neuropathy Impairment Score (NIS) (0-244 points, 0 is normal) and its subscale NIS–Lower Limbs (NIS-LL) (0-88 points): the scale captures clinically meaningful changes in neurological function (muscle weakness, reflexes, sensation) and has been previously employed in studies on inherited transthyretin amyloidosis (ATTR) [1,2].

2)  Kumamoto scale: a 14-item composite score, ranging from 0 (normal) to 96 points, which entails sensory disturbances, motor weakness, autonomic dysfunction and visceral organ impairment [3]

3)  CMTNS (0-36, 0 is normal) and its clinical component CMT Examination Score (CMTES) (0-28), version 2 [4]: the 9-item CMTNS is a composite impairment and disability scale, which comprises symptoms and signs (CMTES), as well as neurophysiology (CMTNS). CMTNS has been validated in CMT, the most common hereditary neuropathy. Nerve conduction study (NCS) was performed as part of the CMTNS at baseline and every 12 months thereafter. Amplitudes of sensory radial nerve and motor ulnar nerves (non-dominant side) were considered.

4)  FAP Stage: stage 1, predominantly sensory neuropathy affecting lower limbs, walk without any help; stage 2, walking difficulties, needing help for walking; stage 3, patient confined to a wheelchair [5]. In ambulant patients (stage 1), neurological impairment is further graded according to PND: Polyneuropathy Disability Score as follows: PND1, sensory disturbances in the extremities with preserved walking capacity; PND2, difficulty with walking but without the need for a stick [6].

5)  Modified Body Mass Index (mBMI), calculated by multiplying BMI by serum albumin concentration (Kg/m2*gr/L) to correct for weight gain due to swelling and edema[7].

6)  Blood routine testing including N-terminal pro-hormone brain natriuretic peptide (NT-proBNP), a biomarker of cardiac dysfunction, which may have prognostic value for patients with ATTR [8]. Values of NT-proBNP >1000 pg/mL were defined highly elevated, and levels between 1000 and age-and gender-adjusted upper limit of normality moderately elevated.

7)  Echocardiography, performed at baseline and every 6 months, including measure of left inter-ventricular septal thickness (IVS). IVS >12 mm was considered diagnostic of amyloid heart involvement and an increase of IVS ≥ 2 mm defined the presence of cardiac disease progression, as indexed by International Society of Amyloidosis criteria [9]. Conventional 12-lead electrocardiogram was also recorded.

8)  Adverse Events (AEs) were monitored throughout the study. Serious AEs were those that resulted in death, life-threatening, requiring hospitalization or leading to significant disability.

SUPPLEMENTARY REFERENCES

1. Coelho T, Maia LF, Martins da Silva A, Waddington Cruz M, Planté-Bordeneuve V, Lozeron P, et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology. 2012;79(8):785–92.

2. Dyck PJ, Davies JL, Litchy WJ, O’Brien PC. Longitudinal assessment of diabetic polyneuropathy using a composite score in the Rochester Diabetic Neuropathy Study cohort. Neurology. 1997;49(1):229–39.

3. Tashima K, Ando Y, Ando E et al. Heterogenous Clinical Symptoms of Patients with Familial Amyloidotic Polyneuropathy FAP-TTR Met30. Amyloid. 1997;4:108–11.

4. Murphy SM, Herrmann DN, McDermott MP, Scherer SS, Shy ME, Reilly MM, et al. Reliability of the CMT neuropathy score (second version) in Charcot-Marie-Tooth disease. J Peripher Nerv Syst. settembre 2011;16(3):191–8.

5. Coutinho P, Martins da Silva A, Lopes Lima J, Resende Barbosa A. Forty years of experience with type I amyloid neuropathy. Review of 483 cases.In: Glenner GG, Pinho e Costa P, Falcao de Freitas A, editors. Amyloid and amyloidosis. Amsterdam: Excerpta Medica; 1980. p. 88–98.

6. Berk JL, Suhr OB, Obici L, Sekijima Y, Zeldenrust SR, Yamashita T, et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA. 2013;310(24):2658–67.

7. Suhr O, Danielsson A, Holmgren G, Steen L. Malnutrition and gastrointestinal dysfunction as prognostic factors for survival in familial amyloidotic polyneuropathy. J Intern Med. 1994;235(5):479–85.

8. Lehrke S, Steen H, Kristen AV, Merten C, Lossnitzer D, Dengler TJ, et al. Serum levels of NT-proBNP as surrogate for cardiac amyloid burden: new evidence from gadolinium-enhanced cardiac magnetic resonance imaging in patients with amyloidosis. Amyloid. 2009;16(4):187–95.

9. Gertz MA, Comenzo R, Falk RH, Fermand JP, Hazenberg BP, Hawkins PN, et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004. Am J Hematol. 2005;79(4):319–28.