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Peripheral Nerve AXONAL NEUROPATHIES Hereditary
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Peripheral Nerve AXONAL NEUROPATHIES Hereditary

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  • 1. Peripheral Nerve
  • 2. AXONAL NEUROPATHIES Hereditary Vasculitis Paraproteinaemic Systemic diseases – diabetes, sarcoidosis, vitamin deficiencies, connective tissue disease, alcohol, organ failure, malignancies Infectious Toxic Idiopathic
  • 3. DEMYELINATING NEUROPATHIES Hereditary Acquired inflammatory neuropathies Paraproteinaemic neuropathies
  • 4. CLASSIFICATION OF THE INHERITED NEUROPATHIES 1. Neuropathies in which the neuropathy is the sole or primary party of the disease 2. Neuropathoes in which the neuropathy is part of a more widespread neurological or multisystem disorder
  • 5. 1. HEREDITARY NEUROPATHIES (SOLE) Charcot-Marie-tooth disease (CMT) Hereditary neuropathy with liability to pressure palsies (HNPP) Hereditary sensory and autonomic neuropathies (HSAN / HSN) Familial amyloid polyneuropathy (FAP) Hereditary motor neuronopathies (HMN / SMA) X-linked bulbospinal neuronopathy
  • 6. 2. HEREDITARY NEUROPATHIES (MULTISYSTEM) Disorders of lipid metabolism Porphyrias Defective DNA repair Mitochondrial disorders Hereditary ataxias Miscellaneous
  • 7. IS THE NEUROPATHY HEREDITARY? Family history Long history / slowly progressive Foot deformity (eg. Pes cavus) Positive sensory symptoms usually not prominent Neurophysiology Lack of other cause / ? hereditary (esp. axonal)
  • 8. CLASSIFICATION Charcot-Marie-Tooth disease (CMT) Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) Distal Hereditary Motor Neuronopathy (dHMN / dSMA) Hereditary Sensory and Autonomic Neuropathy (HSAN / HSN)
  • 9. HMSN (CMT) CLINICAL CLASSIFICATION I Demyelinating II Axonal III Severe demyelinating / hypomyelinating IV Refsum’s Disease V + Pyramidal VI + Optic atrophy VII + Deafness VIII + Pigmentory retinopathy
  • 10. CLASSIFICATION OF CMT CMT1 Demyelinating (<38 m/s) CMT2 Axonal (>38 m/s) CMT intermediate (30 – 45 m/s)
  • 11. CLASSIFY CMT 1 (DEMYELINATING) Demyelinating CMT 1 (<38 m/s) Dejerine Sottas Disease (<10 m/s) Congenital Hypomyelinating Neuropathy (dysmyelination)
  • 12. CLASSIFICATION CMT Autosomal dominant Autosomal recessive X-linked “Sporadic”
  • 13. CLASSIFICATION CMT CMT1 AD AR X-linked DSD AD AR CHN AD AR HNPP AD CMT2 AD AR X-linked
  • 14. HMSN I (CMT 1) Slowly progressive distal wasting and weakness Onset 1st or 2nd decade Areflexia, distal sensory loss and foot deformity Demyelinating (slow motor nerve conduction velocities) Pathology hypertrophic, demyelinating
  • 15. CMT 1 LEGS
  • 16. PES CAVUS
  • 17. HSAN I TOE
  • 18. HSAN I FEET
  • 19. HSAN I FEET
  • 20. CMT 1 HANDS
  • 21. CMT 1 ONION BULBS
  • 22. CMT 1 TEASED FIBRES
  • 23. CMT1 AD CMT 1A duplication PMP-22 mutations PMP-22 CMT 1B mutations P0 CMT 1C mutations LITAF/SIMPLE CMT 1D mutations EGR2
  • 24. HMSN III (DEJERINE-SOTTAS DISEASE (DSD)) Severe demyelinating / hypomyelinating neuropathy Early onset Extremely slow motor nerve conduction velocities Pathology demyelination / amyelination / basal lamina onion bulbs / classical onion bulbs
  • 25. DEJERINE SOTTAS DISEASE (DSD) DSD A AD/AR mutation PMP-22 DSD B AD/AR mutation Po DSD C AD mutation EGR2 DSD D AD 8q23 – q24
  • 26. CONGENITAL HYPOMYELINATING NEUROPATHY (CHN) CHN A AD mutation PMP-22 CHN B AD mutation Po CHN C AD/AR mutation EGR2
  • 27. HNPP Autosomal dominant Episodic, recurrent demyelinating neuropathy Reduced motor / sensory conduction velocities Pathology sausage like myelin thickenings (tomacula) Linked to chromosome 17
  • 28. HNPP HNPP chromosome 17 deletion PMP-22 point mutations
  • 29. CMT 1 AR (RECESSIVE) CMT1 AR A (CMT4A) GDAP1 CMT1 AR B1 (CMT4B1) MTMR2 CMT1 AR B2 (CMT4B2) SBF2 CMT 1AR C SH3/TPR CMT1 AR D (HMSNL) NDRG1 CMT1 AR E (CCFND) 18q CMT1 AR F (CMT4F) Periaxin CMT1 AR G (HMSNR) 10q22-q23
  • 30. CMT1 X-LINKED Clinically similar to CMT1 No male to male transmission Males more severe than females Males demyelinating / females axonal Patchy neurophysiology Central nervous system involvement
  • 31. CMT X1 Linked to Xq13.1 Gap junction protein connexin 32 in that area Mutations in connexin 32 in X-linked HMSN I families
  • 32. HMSN II (CMT 2) Similar phenotype to HMSN I Later age of onset Axonal neuropathy (normal motor nerve conduction velocities) Patholgy axonal
  • 33. CMT 2 (AXONAL / DOMINANT) CMT 2A KIF1Bβ CMT 2B RAB7 CMT 2C unknown CMT 2D GARS CMT 2E NF-L CMT 2F 7q11-q21 CMT 2 Po CMT 2G (HMSNP) 3q13.1
  • 34. CMT 2 (RECESSIVE) CMT2 AR A LMNA CMT2 AR B 8q21.3 CMT2 AR C 19q13.3 CMT2 AR D GDAP1
  • 35. CMT 2 (X-LINKED) CMT 2X Xq24 - 26
  • 36. INTERMEDIATE CMT CX 32 PO GDAP1 ?NFL DI CMT 10q24.1-q25.1 DI CMT 19p12-p13
  • 37. Peripheral nerve
  • 38. Peripheral Nerve
  • 39. Peripheral Nerve
  • 40. MOLECULAR DIAGNOSIS Chromosome 17 duplication / deletion widely available PMP-22, P0 and CX-32 specialised laboratories EGR2, NF-L, KIFIBß, MTMR2, NDRG1, Periaxin, GDAP1, LMNA research laboratories only
  • 41. CMT DIAGNOSIS FLOW CHART
  • 42. WHY DIAGNOSE CMT ? Definite diagnosis Prognosis Prevents unnecessary tests (eg. Nerve biopsy) Genetic counselling family / diagnostic / predictive / ante-natal Treatment therapy / orthopaedic
  • 43. TREATMENT OF CMT Gene therapy
  • 44. CMT GENE THERAPY Transgenic mouse study CMT 1A Regulation of PMP-22 overexpression possible Overexpression causes demyelination Demyelination corrected when ovexpression turned off

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