Short communication| Volume 345, ISSUE 1-2, P231-235, October 15, 2014

Efficacy of diflunisal on autonomic dysfunction of late-onset familial amyloid polyneuropathy (TTR Val30Met) in a Japanese endemic area


      • We performed diflunisal therapy for late-onset FAP in a Japanese endemic area.
      • The treatment resulted in improvement of autonomic symptoms, and maintenance of mBMI.
      • Delayed H/M ratios on 123I-MIBG imaging increased significantly.
      • Motor and sensory symptoms gradually deteriorated.
      • There was no adverse event of diflunisal except reversible hematuria in a patient.



      To evaluate the long-term efficacy and safety of diflunisal in late-onset familial amyloid polyneuropathy (FAP) in a Japanese endemic area.


      Consecutive six FAP patients (mean age: 65.8 ± 7.3 years) with a transthyretin (TTR) Val30Met mutation from an endemic area of late-onset FAP were prospectively recruited to an open label study with oral diflunisal (250 mg twice a day). We evaluated clinical symptoms, Kumamoto FAP score, modified body mass index (mBMI), Medical Research Council sum score, nerve conduction studies (NCS), electrocardiogram (ECG), ECG Holter monitor test, echocardiography, and 123iodine-metaiodobenzylguanidine (123I-MIBG) myocardial scintigraphy.


      One patient ceased to take diflunisal because of hematuria which was reversible. The other five patients were treated with diflunisal for 3–5 (4.4 ± 0.9 years) years. Autonomic symptoms (orthostatic hypotension and gastrointestinal symptoms) disappeared after treatment in two of the four patients with the symptoms. Delayed heart to mediastinum ratio on 123I-MIBG imaging, a marker of cardiac postganglionic sympathetic nerve function, increased during the three-year treatment. mBMI was maintained through observation period. While, motor and sensory symptoms, Kumamoto FAP scores, and data on NCS gradually deteriorated.


      Diflunisal might be effective especially for autonomic dysfunction in late-onset FAP with a TTR Val30Met mutation.


      ATTR (transthyretin-related amyloid), AV (atrioventricular), DcT (deceleration time), E/A ratio (ratio of mitral peak velocity of early filling to mitral peak velocity of late filling), E/e′ ratio (ratio of mitral peak velocity of early filling (E) to early diastolic mitral annular velocity (e′)), EF (ejection fraction), FAP (familial amyloid polyneuropathy), H/M (heart to mediastinum), 123I-MIBG (123iodine-metaiodobenzylguanidine), IVST (interventricular septal thickness), LAD (left atrial dimension), LT (liver transplantation), LV (left ventricular), mBMI (modified body mass index), MRC (Medical Research Council), NCS (nerve conduction studies), OH (orthostatic hypotension), PWT (posterior wall thickness), TTR (transthyretin), TTR (transthyretin gene)


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Zeldenrust S.R.
        • Benson M.D.
        Familial and senile amyloidosis caused by transthyretin.
        in: Ramirez-Alvarado M. Kelly J.W. Dobson C.M. Protein misfolding diseases: current and emerging principles and therapies. John Wiley & Sons, New York2010: 795-815
        • Hund E.
        • Linke R.P.
        • Willig F.
        • Grau A.
        Transthyretin-associated neuropathic amyloidosis. Pathogenesis and treatment.
        Neurology. 2001; 56: 431-435
        • Plante-Bordeneuve V.
        • Lalu T.
        • Misrahi M.
        • Reilly M.M.
        • Adams D.
        • Lacroix C.
        • et al.
        Genotypic-phenotypic variations in a series of 65 patients with familial amyloid polyneuropathy.
        Neurology. 1998; 51: 708-714
        • 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 C.G. Pinho e Costa P. Falcao de Freitas A. Amyloid and amyloidosis. Excerpta Medica, Amsterdam1980: 88-98
        • Hammarstrom P.
        • Jiang X.
        • Hurshman A.R.
        • Powers E.T.
        • Kelly J.W.
        Sequence-dependent denaturation energetics: a major determinant in amyloid disease diversity.
        Proc Natl Acad Sci U S A. 2002; 99: 16427-16432
        • Okamoto S.
        • Wixner J.
        • Obayashi K.
        • Ando Y.
        • Ericzon B.G.
        • Friman S.
        • et al.
        Liver transplantation for familial amyloidotic polyneuropathy: impact on Swedish patients' survival.
        Liver Transpl. 2009; 15: 1229-1235
        • Bulawa C.E.
        • Connelly S.
        • Devit M.
        • Wang L.
        • Weigel C.
        • Fleming J.A.
        • et al.
        Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade.
        Proc Natl Acad Sci U S A. 2012; 109: 9629-9634
        • Berk J.L.
        • Suhr O.B.
        • Obici L.
        • Sekijima Y.
        • Zeldenrust S.R.
        • Yamashita T.
        • et al.
        Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial.
        JAMA. 2013; 310: 2658-2667
        • Coelho T.
        • Maia L.F.
        • Martins da Silva A.
        • Waddington Cruz M.
        • Plante-Bordeneuve V.
        • Lozeron P.
        • et al.
        Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial.
        Neurology. 2012; 79: 785-792
        • Lozeron P.
        • Theaudin M.
        • Mincheva Z.
        • Ducot B.
        • Lacroix C.
        • Adams D.
        Effect on disability and safety of Tafamidis in late onset of Met30 transthyretin familial amyloid polyneuropathy.
        Eur J Neurol. 2013; 20: 1539-1545
        • Coelho T.
        • Maia L.F.
        • da Silva A.M.
        • Cruz M.W.
        • Plante-Bordeneuve V.
        • Suhr O.B.
        • et al.
        Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy.
        J Neurol. 2013; 260: 2802-2814
        • Sousa A.
        • Coelho T.
        • Barros J.
        • Sequeiros J.
        Genetic epidemiology of familial amyloidotic polyneuropathy (FAP)-type I in Povoa do Varzim and Vila do Conde (north of Portugal).
        Am J Med Genet. 1995; 60: 512-521
        • Holmgren G.
        • Holmberg E.
        • Lindstrom A.
        • Lindstrom E.
        • Nordenson I.
        • Sandgren O.
        • et al.
        Diagnosis of familial amyloidotic polyneuropathy in Sweden by RFLP analysis.
        Clin Genet. 1988; 33: 176-180
        • Ando Y.
        • Nakamura M.
        • Araki S.
        Transthyretin-related familial amyloidotic polyneuropathy.
        Arch Neurol. 2005; 62: 1057-1062
        • Ikeda S.
        • Nakazato M.
        • Ando Y.
        • Sobue G.
        Familial transthyretin-type amyloid polyneuropathy in Japan: clinical and genetic heterogeneity.
        Neurology. 2002; 58: 1001-1007
        • Andersson R.
        Familial amyloidosis with polyneuropathy. A clinical study based on patients living in northern Sweden.
        Acta Med Scand Suppl. 1976; 590: 1-64
        • Munar-Ques M.
        • Saraiva M.J.
        • Viader-Farre C.
        • Zabay-Becerril J.M.
        • Mulet-Ferrer J.
        Genetic epidemiology of familial amyloid polyneuropathy in the Balearic Islands (Spain).
        Amyloid. 2005; 12: 54-61
        • 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: 133-140
        • Misu K.
        • Hattori N.
        • Nagamatsu M.
        • Ikeda S.
        • Ando Y.
        • Nakazato M.
        • et al.
        Late-onset familial amyloid polyneuropathy type I (transthyretin Met30-associated familial amyloid polyneuropathy) unrelated to endemic focus in Japan. Clinicopathological and genetic features.
        Brain. 1999; 122: 1951-1962
        • Tashima K.
        • Ando Y.
        • Terazaki H.
        • Yoshimatsu S.
        • Suhr O.B.
        • Obayashi K.
        • et al.
        Outcome of liver transplantation for transthyretin amyloidosis: follow-up of Japanese familial amyloidotic polyneuropathy patients.
        J Neurol Sci. 1999; 171: 19-23
        • Kleyweg R.P.
        • van der Meche F.G.
        • Schmitz P.I.
        Interobserver agreement in the assessment of muscle strength and functional abilities in Guillain–Barre syndrome.
        Muscle Nerve. 1991; 14: 1103-1109
        • 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: 479-485
        • Yoshita M.
        Differentiation of idiopathic Parkinson's disease from striatonigral degeneration and progressive supranuclear palsy using iodine-123 meta-iodobenzylguanidine myocardial scintigraphy.
        J Neurol Sci. 1998; 155: 60-67
        • Okuda K.
        • Nakajima K.
        • Hosoya T.
        • Ishikawa T.
        • Konishi T.
        • Matsubara K.
        • et al.
        Semi-automated algorithm for calculating heart-to-mediastinum ratio in cardiac Iodine-123 MIBG imaging.
        J Nucl Cardiol. 2011; 18: 82-89
        • Obayashi K.
        • Ando Y.
        Focus on autonomic dysfunction in familial amyloidotic polyneuropathy (FAP).
        Amyloid. 2012; 19: 28-29
        • Fong V.H.
        • Vieira A.
        Transthyretin aggregates induce production of reactive nitrogen species.
        Neurodegener Dis. 2013; 11: 42-48
        • Hou X.
        • Richardson S.J.
        • Aguilar M.I.
        • Small D.H.
        Binding of amyloidogenic transthyretin to the plasma membrane alters membrane fluidity and induces neurotoxicity.
        Biochemistry. 2005; 44: 11618-11627
        • Coutinho M.C.
        • Cortez-Dias N.
        • Cantinho G.
        • Conceicao I.
        • Oliveira A.
        • Bordalo e Sa A.
        • et al.
        Reduced myocardial 123-iodine metaiodobenzylguanidine uptake: a prognostic marker in familial amyloid polyneuropathy.
        Circ Cardiovasc Imaging. 2013; 6: 627-636
        • Nakajima K.
        • Okuda K.
        • Matsuo S.
        • Yoshita M.
        • Taki J.
        • Yamada M.
        • et al.
        Standardization of metaiodobenzylguanidine heart to mediastinum ratio using a calibration phantom: effects of correction on normal databases and a multicentre study.
        Eur J Nucl Med Mol Imaging. 2012; 39: 113-119