Molecular characterisation of SGCE-associated myoclonus-dystonia ...

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Discussion 81 that the mitochondrial network was fragmented in PINK1 mutant patient fibroblasts (2007). Here, no fragmentation of the mitochondrial network was observed in any of the available fibroblast cultures when treated under basal conditions. Thus, the findings from this thesis further support the reports by Poole et al. (2008) and Yang et al. (2006).
Discussion 82 4.4 Conclusions Project A: Deletions in the SGCE gene are an underestimated cause of M-D. According to the literature deletions in SGCE are a rare cause of M-D (cp. Fig 11, p. 55). In the current study, however, 9% of the included cases showed a deletion in SGCE (cp. Table 5, p. 48). Therewith, gene dosage alterations accounted for a third of the mutations detected here, emphasizing the importance of quantitative screening methods. Deletions were only recently discovered as a type of mutation in M-D. Though, recent developments of reliable and easily applicable qPCR techniques, such as MLPA, allow standard screenings for gene dosage alterations nowadays. The result of this thesis suggests a much higher identification quote of deletions in SGCE in future screens. There is a link between genotype and phenotype in M-D patients. The investigated M-D patients were classified according to their phenotype into definite, probable and possibly affected (see Table 3, p. 19). This preselection led to a mutational detection rate of 36% in SGCE for the first two groups. When compared with previous studies from the literature on SGCE screening in M-D cases mutations were detected in only 23%. Concentrating on patients with a diagnosis of definite M-D, the mutation rate in the screen, processed here, further increased to 60% (cp. 4.1.1, p. 70). Apparently, the risk for M-D patients to harbour a mutation in SGCE increases with certain clinical characteristics. However, no explicit correlation between the type or location of the mutations and the phenotype could be observed for cases with small sequence alterations in SGCE (cp. 3.1.1., p. 46 and 4.1.1, p. 70). Only in two M-D cases who presented with additional non-motor signs a specific genetic link was identified. In those patients, the particular features could be explained by large deletions involving several genes surrounding SGCE on chromosome 7q. Consequently, a comprehensive clinical examination, including a careful accounting for nonmotor signs, should precede molecular investigations.
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Aus der Klinik für Neurologie (Pro
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This thesis is dedicated to my fami
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List of content II 2.2.6 Equipment
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List of content IV 4 DISCUSSION ...
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List of tables VI LIST OF TABLES Ta
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Introduction 2 The EPS has been imp
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Introduction 4 7, 9, 10, 13, and 15
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Introduction 6 chromosome contained
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Introduction 8 PD is the most commo
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Introduction 10 results in a p.W437
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Introduction 12 showed good respons
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Introduction 14 sequentially from o
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Introduction 16 favourable (Boyer,
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Introduction 18 1.5 Hypotheses The
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Patients, material and methods 20 T
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III:1 F2129 II:1 IP2123 III:2 F2130
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Patients, material and methods 24 E
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Patients, material and methods 26 H
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Patients, material and methods 28 S
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Page 55 and 56: Results 46 3 RESULTS This thesis is
Page 57 and 58: Table 5 Demographic, clinical and g
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Page 61 and 62: Results 52 Fig 9 (previous page) Sc
Page 63 and 64: Results 54 3.1.4 Qualitative mutati
Page 65 and 66: Results 56 3.2 Parkinson’s diseas
Page 67 and 68: Results 58 3.2.2 Haplotype analysis
Page 69 and 70: Results 60 sequence alterations wer
Page 71 and 72: Results 62 3.3 Parkinson’s diseas
Page 73 and 74: Results 64 activity in the nonsense
Page 75 and 76: Results 66 4.00 3.50 Basal conditio
Page 77 and 78: Results 68 3.3.7 Mitochondrial netw
Page 79 and 80: Discussion 70 4 DISCUSSION The outc
Page 81 and 82: Discussion 72 reports about genotyp
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Page 85 and 86: Discussion 76 4.2.4 Genotype-phenot
Page 87 and 88: Discussion 78 cellular ATP levels (
Page 89: Discussion 80 However, the protein
Page 93 and 94: Discussion 84 overall increase of t
Page 95 and 96: Perspectives 86 In addition, mutant
Page 97 and 98: Summary 88 1.0 in mutation-negative
Page 99 and 100: Zusammenfassung 90 mutationspositiv
Page 101 and 102: References 92 8 REFERENCES Abou-Sle
Page 103 and 104: References 94 Butler AG, Duffey PO,
Page 105 and 106: References 96 Exner N, Treske B, Pa
Page 107 and 108: References 98 Hedrich K, Hagenah J,
Page 109 and 110: References 100 Klein C, Lohmann-Hed
Page 111 and 112: References 102 Martin MA, Molina JA
Page 113 and 114: References 104 Piccoli C, Sardanell
Page 115 and 116: References 106 Schüle B, Kock N, S
Page 117 and 118: References 108 Wharton DC, Tzagolof
Page 119 and 120: Appendix 110 FL - Fluorescence emis
Page 121 and 122: Appendix 112 9.2 Supplementary mate
Page 123 and 124: Appendix 114 Table S4 Primer for th
Page 125 and 126: Appendix 116 04 - 06/2006 Erasmus M
Page 127 and 128: Appendix 118 ABSTRACTS 1. Grünewal
Page 129 and 130: Appendix 120 I would like to thank
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