The copyright of this thesis vests in the author. No quotation from it or information derived from it is to be published without full acknowledgementTown of the source. The thesis is to be used for private study or non- commercial research purposes only. Cape Published by the University ofof Cape Town (UCT) in terms of the non-exclusive license granted to UCT by the author. University Peripheral Neuropathies of Childhood Jo M Wilmshurst Thesis presented for the Degree of Doctor of Medicine PERIPHERAL NEUROPATHIES OF CHILDHOOD: Jo M Wilmshurst MB BS (London), MRCP (London), FCP (SA) Thesis presented for the Degree of DOCTOR OF MEDICINE Town Department of Paediatric Neurology School of Child and AdolescentCape Health Faculty of Healthof Sciences UNIVERSITY OF CAPE TOWN University 1 Peripheral Neuropathies of Childhood Jo M Wilmshurst Thesis presented for the Degree of Doctor of Medicine CONTENTS PAGE Title 1 Contents 2-7 Acknowledgements 8 Funding 9 Previous publications 9 Permissions / ethics 9 Declaration 10 Synopsis 11-13 Chapter 1: 14-39 Introduction, literature review and diagnostic tables Table 1.1: Summary of previous large studies of peripheralTown neuropathies in childhood 18 Table 1.2: Hereditary peripheral neuropathies 19-29 Figure 1.1: Transverse sectionCape of HNPP 30 Figure 1.2 Transverse sectionof of CMT3 30 Figure 1.3 Electron micrograph of CMTX 31 Table 1.3: Neurodegenerative disorders with peripheral neuropathy 32-33 Table 1.4: Specific protein deficiency or mutation 34-39 Chapter 2: 40-67 The role of nerveUniversity biopsy a. Introduction 41-42 b. Principles and technique 42-54 Figure 2.1: Transverse section of a patient with CMTIA 45 Figure 2.2: Transverse section of a patient with CMT 45 Figure 2.3: Teased fibre appearance of demyelination 46 Figure 2.4: Teased fibre appearance of axonal degeneration 47 Figure 2.5: Electron micrograph of neuroaxonal dystrophy. 48 Figure 2.6: Electron micrograph of a patient with Po mutation 49 2 Peripheral Neuropathies of Childhood Jo M Wilmshurst Thesis presented for the Degree of Doctor of Medicine Figure 2.7: Electron micrograph active axonal degeneration. 50 Figure 2.8: Normal MF diameter changes with age.4 54 c. Biopsy findings in relevant diseases 54-64 Table 2.1: Inflammatory and infectious disorders 56 Table 2.2: Neurodegenerative and Metabolic disorders 57-59 Figure 2.9: Transverse section from a patient with Friedreich’s ataxia 59 Figure 2.10: Electron micrograph from a patient with giant axonal neuropathy. 60 Figure 2.11: Electron micrograph of a patient with metachromatic leukodystrophy 61 Figure 2.12: Transverse section from a patient with Cockayne syndrome Town 61 Table 2.3: Toxic, nutritional deficiencies and miscellaneous 62-63 Figure 2.13: Transverse section from a patient with neurofibromatosis. Cape 64 d. Conclusion of 64 e. Case examples 65-67 Chapter 3: 68-125 Chronic Peripheral Neuropathies Presenting In Childhood – 37 Years of Data from an Australian Population a. SummaryUniversity 68-69 b. Introduction 70 c. Methodology 70-71 d. Results 72-115 Figure 3.1: Summary of total group with peripheral neuropathies 73 Table 3.1: Summary of the motor sensory neuropathies with genetic correlation 73-74 Figure 3.2: Flow chart of patient breakdown leading to definitive genetic confirmation in the CMT group 75 3 Peripheral Neuropathies of Childhood Jo M Wilmshurst Thesis presented for the Degree of Doctor of Medicine 1. Hereditary neuropathies 76-108 Figure 3.3: Charcot Marie Tooth diseases broad categories 76 i. Demyelinating forms of CMT 77-85 Figure 3.4: Demyelinating group n=73 77 Figure 3.4a: Teased fibre analysis of patient with CMT1A. 78 Figure 3.4b: Light microscopy study of a patient with CMT3 due to PMP22 mutation. 81 Figure 3.4c: Teased fibre analysis of a patient with CMT3 due to myelin protein zero mutation 81 Figure 3.4d: Transverse section of a CMT4B patient 84 Figure 3.4e: Transverse section of a patient with CMT4B due to fabrin mutation. Town 85 ii. Axonal forms of CMT 86-96 Figure 3.5: Axonal neuropathies n=81 86 Figure 3.5a: TransverseCape section of a patient with EOHMSN due to ofmitofusin mutation. 90 Figure 3.5b: EM section of a patient with MFN2 mutation with reduced myelinated fibre density and an onion bulb formation 91 Figures 3.5c i and ii EM from a patient with Universityconfirmed MFN2 mutation 91-92 Figure 3.6: Hereditary sensory and autonomic neuropathies n=6 96 iii. Mixed forms of CMT 97-98 Figure 3.7: Mixed axonal / demyelinating neuropathies n=7 97 iv. Summary of genetic data from patients with CMT spectrum 99-101 4 Peripheral Neuropathies of Childhood Jo M Wilmshurst Thesis presented for the Degree of Doctor of Medicine Figure 3.8: Summary of patients who underwent genetic screens 99 Figure 3.9: Summary of the genetic mutations 101 Peripheral neuropathies associated with inherited disorders 102-108 v. Neurodegenerative and metabolic disorders 102-107 Figure 3.10: Neurodegenerative progressive and metabolic disorders with peripheral neuropathy 102 vi. Inherited structural disorders 107-108 2. Acquired neuropathies 109-115 Figure 3.11: Acquired disorders and pathology types n=48 109 Figure 3.11a: Teased fibre analysis of a patient with CIDP 111 Figure 3.11b: Transverse section of a patientTown with a vasculitic neuropathy. 113 Figure 3.11c: Transverse section 3 month old infant, vasculitis demonstrating recanalised vessel.Cape 114 Figure 3.11d: Transverseof section perineuroma 114 d. Discussion 116-125 Chapter 4: 126-141 Peripheral Neuropathies presenting in Infancy from an Australian Population a. Summary 126 b. IntroductionUniversity 127 c. Method 127 d. Results 128-136 Table 4.1: Summary of the diagnostic categories of infantile-onset peripheral neuropathy 128 Figure 4.1: Sural nerve section electron micrography plate from a patient with myelin protein zero mutation CMT3. 130 Figure 4.2: Transverse section from the sural nerve of a patient with CMT with myelin-outfolding 131 5 Peripheral Neuropathies of Childhood Jo M Wilmshurst Thesis presented for the Degree of Doctor of Medicine e. Discussion 137-140 Algorithm 4.1: An approach through nerve conduction studies to Hereditary Motor and Sensory Neuropathies 141 Chapter 5: 142-183 Children presenting with Chronic Peripheral neuropathy in a South African population a. Summary 142 b. Introduction 143-145 c. Methods 145-146 d. Results 146-178 Figure 5.1: Summary of hereditary peripheral neuropathies 146 Figure 5.2: Patient with confirmed CMT1A. 148 Figure 5.3: Nerve biopsy of a patient with CMT1ATown 149 Figure 5.4: Affected CMT3 patient 150 Figure 5.5. Nerve biopsy of a patient with clinical phenotype of CMT3 Cape 151 Figure 5.6. Electron microscopyof onion bulb formation 151 Figure 5.7: Hands from father and son with CMT2. 153 Figure 5.8: Electron microscopy of patient with axonal neurophysiology but genetic diagnosis of CMT1A. 154 Figure 5.9: Clinical phenotype of patient with EOHMSN 155 UniversityFigure 5.10: (a & b). Clinical phenotype of patient with EOHMSN with extreme distal wasting. 156 Figures 5.11 Light microscopy from patient in Figure 5.9. 156 Figure 5.12 (a & b): Light microscopy patient with EOHMSN (Figure 5.10) 157 Figure 5.13: EM from the patient in Figure 5.10 158 Figure 5.14 (a & b). Girl with miscellaneous axonal disease 160 Figure 5.15: Patient with SIANR 162 Figure 5.16: Patient with the juvenile form of SIANR 162 6 Peripheral Neuropathies of Childhood Jo M Wilmshurst Thesis presented for the Degree of Doctor of Medicine Figure 5.17: Chest X-ray patient with juvenile SIANR 163 Figure 5.18. Muscle biopsy patient with Vitamin E deficiency 167. Figure 5.19: Summary of acquired conditions 170 Figure 5.20a. Image of the hands from the eleven year old girl with HIV-1 infection 172 Figure 5.20b. The lower limbs of the patient in Figure 5.20a. 173 Table 5.1: Summary of the patients who underwent peripheral nerve biopsy 174-178 e. Discussion 179-183 Chapter 6: 184-193 Conclusion and recommendations - guideline approach to investigations and diagnosis of Peripheral Neuropathies in childhood in resource-limited setting Table 6.1: Summary of conditions commonlyTown associated with specific clinical features. 192 Figure 6.1: Approach to the child with suspected peripheral neuropathy in a resourceCape-limited setting 193 Figure 6.2: Approach toof the HIV infected child with distal weakness / sensory disturbances. 194 References 195-220 University 7 Peripheral Neuropathies of Childhood Jo M Wilmshurst Thesis presented for the Degree of Doctor of Medicine Acknowledgements My husband Mark, and daughters Tabitha and Jasmine for their understanding and support. My parents and friends for their support both with child care and patient interest in a topic they had never heard of. My father especially, for proof reading the text. The neurology team at Red Cross Children’s Hospital who covered my clinical duties for 3 months. Dr Komala Pillay and her team for their assistance with the South African histopathology analysis and providing images of the biopsy samples. My Supervisors, Professor Robert Ouvrier, Head of the Institute for Neuromuscular Research at The Children’s Hospital at Westmead in Sydney, Australia, for his great support and patience during the creation of this magnum opus. Prof Colin Sinclair-Smith, Head of Histopathology, at Red Cross Children’sTown Hospital, University of Cape Town, who sadly died in October 2008, for his enthusiasm and interest in such a specialized area. Professor Heather Zar, who stepped in at short noticeCape to cover Colin’s place. Dr Min Wang from the Institute of Nerve Research,of University of Sydney for assisting me with access to the pathology and images from many of the patients.