[12] FFI 2 2 DNA (TIANGEN ) 10 PCR dntp Taq DNA ( DNA PCR ) TSAP(Promega ) Exon (New England BioLabs ) BigDye(ABI ) Hi-Di TM (ABI ) 9700 (A

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1 , ( ) (FFI) PRNP FFI PCR DNA PRNP FFI PRNP 2 c.532g>a(p.d178n) c. 385AA(p.129MM) FFI Meta FFI PRNP D178N-129MM FFI FFI PRNP Clinical Features and Mutation Analysis of PRNP Gene in Chinese Patients with Fatal Familial Insomnia LIU Zhi-Jun 1,2, ZHAO Gui-Xian 1, WU Jian-Jun 1, WANG Jian 1, WU Zhi-Ying 1 1 Department of Neurology, Huashan Hospital, Fudan University, Shanghai ; 2 Department of Neurology, the First Hospital Affiliated to Fujian Medical University, Fuzhou , China KRY WORDS fatal familial insomnia; clinical features; PRNP gene; gene mutation ABSTRACT Aim: To investigate the clinical features and characteristics of PRNP gene mutation in Chinese patients with fatal familial insomnia (FFI). Methods: The mutation analysis of PRNP was performed via DNA direct sequencing in one Chinese patient with FFI and the clinical data were retrospectively analyzed. Results: The heterozygous mutation c.532g>a (p.d178n) and the single nucleotide polymorphism (SNP) of c.385aa genotype (p.129mm) were found in the proband who therefore could be identified as FFI. The clinical features of Chinese FFI patients were typical and the haplotype was D178N-129MM. Conclusion: Although the FFI manifestations are typical, genetic screening of PRNP mutations is still need for diagnosing FFI patients. (fatal familial insomnia FFI) [5~11] 10 ( ) (prion protein PrP) PRNP FFI [1] PRNP 1986 Lugaresi [2] FFI [3] [4] (2012) R749.1 A, ( 1987-),,,, zhiyingwu@fudan.edu.cn

2 [12] FFI 2 2 DNA (TIANGEN ) 10 PCR dntp Taq DNA ( DNA PCR ) TSAP(Promega ) Exon (New England BioLabs ) BigDye(ABI ) Hi-Di TM (ABI ) 9700 (ABI µmol L -1 Taq DNA 0.5 U 9700 ) PRISM TM 3730DNA (ABI 94 5 min ) 1993 Gambetti [12] 60 s min FFI 6 3. DNA PCR 6~32 TSAP Exon 5 µl ( ) 20~30 ng 3.2 pmol L -1 (EEG) BigDye 1 µl s 56 5 s 18 F-PET 60 4 min 25 75% PRNP 129Met-178Asn 1~5 2 2 FFI PRISM TM 3730 DNA DNA 6 1~5 1 FFI ml DNA DNA 1. PRNP [13] ( 1) PRNP 2 2. (polymerase chain reaction PCR) 25 µl 50 ng DNA 10 PCR 2.5 µl 25 µmol L µl dntp s 45 s( 1) 72 Hi-Di TM 7 µl PRNP DNA (NCBI Sequence Viewer 2 NC_ ) kg g / / 150/88 mmhg(1 mmhg=0.13 3kPa)

3 655 6~38 12 PRNP 3 mm D178N-129MM PET-CT 5 (+++) (+) (+) (+) ( ) (+) 87U L -1 ( 0~50 U L U L -1 ( 11~50 U L -1 ) 47 U L -1 ( <30 U L -1 ) 217 U L -1 ( 106~211 U L -1 ) 8.1 mmol L -1 ( 3.9~5.8 mmol L -1 ) PRG<0.64 nmol L -1 ( 0.86~2.9 nmol L -1 ) B pmol L -1 ( 139~543 pmol L -1 ) (FT 3 FT 4 TSH TgAb TmAb) HIV ( ) 611 mg L -1 ( 150~450 mg L -1 ) B MRI 7 PRNP 2 c.532g>a(p.d178n) ( 2) 2 (single nucleotide polymorphism SNP)c.385A>G (p.m129v) c.385aa (p.129mm) 3 10 Notes The normal male family member, The normal female family member, The affected male family member, The dead male member of affected The proband, FFI ( 2) FFI 21~ p. D N Notes Above, normal control Below, the p.d178n heterozygous mutation of the proband

4 656 * Note Not described *Not described in detail FFI (Gerstmann-Straussler- Scheinker syndrome 3 10% [14] GSS) FFI (family Cruetzfeldt- Jacob disease FCJD) Gerstmann-Straussler-Scheinker

5 657 PRNP p.129mm (20p13) 2 FFI PRNP FFI FCJD PRNP / ( org/) FFI PRNP 2 PRNP c.532g>a(p.d178n) c.385a>g(p.m129v) A p.d178n FCJD FFI FCJD p.m129v p.129mm p.129mv [1] FFI p.129vv FCJD FFI 2 D178N-129MM D178N-129MV FFI 20~72 [15] ~44 11 K [10] FFI PRNP D178N-129MM FFI F F I (dementia with Lewy body DLB) [12] DLB DLB [14] PET FFI - p.129mm p.129mv [16] p.129mm [17] 7 FFI 129 p.129mm p.129mv [18] FFI [2] [3] [4] [5] [6] [7] [8] [9] [11] [13] [15] [16] [17] [18] Montagna P, Gambetti P, Cortelli P, et al. Familial and sporadic fatal insomnia[j]. Lancet Neurol,2003,2: Lugaresi E, Medori R, Montagna P, et al. Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei [J]. N Engl J Med,1986,315: Imran M, Mahmood S. An overview of human prion diseases[j]. Virol J,2011,8: Spacey SD, Pastore M, McGillivray B, et al. Fatal familial insomnia: the first account in a family of Chinese descent[j]. Arch Neurol, 2004,61: ,,,. ( 1 )[J].,2007,14: Yu S, Zhang Y, Li S, et al. Early onset fatal familial insomnia with rapid progression in a Chinese family line[j]. J Neurol,2007,254: ,,,. [J].,2010,11: Zhang B, Hao YL, Jia FJ, et al. Fatal familial insomnia: a middleage-onset Chinese family kindred[j]. Sleep Med,2010,11: Shi XH, Han J, Zhang J, et al. Clinical, histopathological and genetic studies in a family with fatal familial insomnia[j]. Infect Genet Evol,2010,10: ,,,. 2 [ J ]., 2011,37: ,,,2012,7:71-72,. 1 [ J ]. Gambetti P, Petersen R, Monari L, et al. Fatal familial insomnia and the widening spectrum of prion diseases[j]. Br Med Bull,1993,49: ,, b p Creutzfeldt-Jakob [J].,2006,14: DeArmond SJ, Prusiner SB. Etiology and pathogenesis of prion diseases[j]. Am J Pathol,1995,146: Harder A, Gregor A, Wirth T, et al. Early age of onset in fatal familial insomnia. Two novel cases and review of the literature[j]. J Neurol,2004,251: Gambetti P, Parchi P, Petersen RB, et al. Fatal familial insomnia and familial Creutzfeldt-Jakob disease: clinical, pathological and molecular features[j]. Brain Pathol,1995,5:43-51 Harder A, Jendroska K, Kreuz F, et al. Novel twelve-generation kindred of fatal familial insomnia from germany representing the entire spectrum of disease expression[j]. Am J Med Genet,1999,87: Capellari S, Strammiello R, Saverioni D, et al. Genetic Creutzfeldt-Jakob disease and fatal familial insomnia: insights into phenotypic variability and disease pathogenesis[j]. Acta Neuropathol,2011,121:21-37 ( )

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