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Clinical features of Demyelinating Charcot-Marie-Tooth disease

Clinical features of Demyelinating Charcot-Marie-Tooth disease. Davide Pareyson “C.Besta” National Neurological Institute Milan, Italy. Prague May 25, 2004. CMT network in Italy Clinical studies of demyelinating CMT Role of gender and pregnancy in CMT1A Involvement of CNS in CMTX

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Clinical features of Demyelinating Charcot-Marie-Tooth disease

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  1. Clinical features of Demyelinating Charcot-Marie-Tooth disease Davide Pareyson “C.Besta” National Neurological Institute Milan, Italy Prague May 25, 2004

  2. CMT network in Italy • Clinical studies of demyelinating CMT • Role of gender and pregnancy in CMT1A • Involvement of CNS in CMTX • Examples of mutations in new genes • Current studies • Future therapies?

  3. Demyelinating CMT Autosomal dominant • CMT1A PMP22 duplication (17p11.2) 60-90% PMP22 point mutation 1-3 % • CMT1B MPZ (P0) 4-5% • CMT1C LITAF/SIMPLE rare • CMT1D EGR2 ++ rare X-linked • CMTX GJ1/Cx32 7-10% of all CMT

  4. Demyelinating CMT Autosomal recessive • CMT4A GDAP1 • CMT4B1 MTMR2 • CMT4B2 MTMR13 • CMT4C KIAA1985 • CMT4D (DSD) PERIAXIN (PRX) • HMSN-L NDRG1

  5. CMT1A (PMP22 duplication) • MOST FREQUENT CMT SUBTYPE (40-50%) • CLINICAL PHENOTYPE • relatively mild, although variable • NERVE CONDUCTION:mostly MCV 12-35 m/s • diffuse & uniform slowing, no conduction block • NEUROPATHOLOGY • diffuse onion bulbs, • de-remyelination • MODIFIER FACTORS?

  6. Progesterone and derivates increase PMP22 expression

  7. Animal model of CMT1A: worsening with progesterone, improvement with its antagonist onapristone (Sereda, 2003)

  8. EFFECTS OF PROGESTERONE ON CMT1A? • Progesterone and derivates increases PMP22 expression • Animal model of CMT1A: worsening with progesterone, improvement with its antagonist onapristone (Sereda, 2003) • Reported cases of CMT worsening during pregnancy (dramatic increase in progesterone levels)

  9. Is there an effect of gender and pregnancy on CMT1A severity? • Retrospective evaluation of 84 CMT1A pts. • Clinical and electrophysiologic data: • Rankin score; presence and severity of clinical signs • MCV, DL, CMAPs, F-lat, SCV, SAP ampl. • Comparison between females and males • Subgroup analysis for females in fertile age (15 to 50-yr-old) vs males same age • Retrospective interview about disease course during pregnancy

  10. Results. Clinical data • Females 48, Males 36 • Age at onset was similar • Females = 10.9 ± 10.8; Males = 8.3 ± 11.3 yrs. • Age at evaluation higher in females • Females = 34.6 ± 16.9; Males = 26.5 ± 17.5 yrs. • Overall no difference in disease severity • Upper limb sensory loss F > M (p = 0.05; p < 0.03 for 15 to 50-year-old patients)

  11. CMT1A & PREGNANCY • N. pts. = 20; pregnancy = 44 • 4 patients had CMT worsening (gait disturbances, unsteadiness, weakness, sensory disturbances) • 6 patients had minor complaints (paresthaesias, cramps, pain)

  12. Conclusions • The effect of sex hormones on PMP22 does not result in relevant difference in disease severity between the two genders. • Mild differences in upper limb clinical and electrophysiologic findings might be due to median nerve involvement at the carpal tunnel. • Some female patients reported worsening of symptoms during pregnancy. Disease and normal controls need to be evaluated to establish whether this is truly a CMT1A-related phenomenon.

  13. X-linked Charcot-Marie-Tooth disease (CMTX) • 2nd most common CMT variety (7-10%) • Connexin-32 (GJ1/Cx32) gene mutations, Xq13.1 • Hemizygous males more severely affected • Isolated reports of central nervous system (CNS) involvement: • 9 patients with transient CNS symptoms • few pts. abnormal examination (Babinski sign, etc) • evoked potentials and brain MRI abnormalities

  14. PNS: non-compact myelin gap-junctions in Schwann cells CNS: oligodendrocytes, some neurons. function? Connexin-32

  15. CNS involvement • Evoked potentials (central components): • Brainstem acoustic BAEPs 18 pts. • Visual Pattern-VEPs & Flash-VEPs 16 “ • Somatosensory SEPs 16 “ • Motor MEPs 16 “ • Clinic ex. (27 pts: 13 M, 14 F, from 11 families): 2 M Babinski, 2 (1 M + 1 F) rest tremor • Brain MRI 14 “

  16. Brainstem auditory evoked potential (BAEP)

  17. I III V II ms/D V/D #Avg R1/R2 Left (Cz-A1) 2 0.2u 5022/5213 Control V 2 0.2u 5011/3866 Right (Cz-A2) III II I V Left (Cz-A1) 1 0.5u 2133/2446 I III II CMTX V Right (Cz-A2) 2342/2377 1 0.5u III II I 1 D

  18. BAEPs:clear abnormalities 12/18 pts (8/9 M, 4/9 F)borderline 4 pts, normal 2 pts (2 F) I-V Interpeak time (ms) NORMAL 3.95  0.17 CMTX FEMALES 4.30  0.43 CMTX MALES 5.48  0.9

  19. SEP MEP N20 Somatosensory and motor evoked potential (SEP, MEP) CCT N13 registration stimulus

  20. SEPs: N13-N20 • normal values:  7.1 msec • CMTX: Right 7.6  2.5 msec, range 5.1-13.6 msec Left 7.4  2.0 msec, range 5,3-11.5 msec • MEPs: CCT • normal values:  7.2 msec • CMTX: Right 7,1  1,5 msec, range 5,5-10 msec Left 7,2  1,8 msec, range 5,1-12 msec

  21. Evoked potential abnormalities • E.P. tot M F • BAEP 12/18 8/9 4/9 • SEP (N13-N20) 8/16 5/8 3/8 • MEP (CCT) 7/16 5/9 2/7 • VEP-pattern 1/16 1/8 0/8 • VEP-flash 9/15 4/7 5/8

  22. CMTX NORMAL

  23. CMTX Axial brain MRI, FLAIR sequence: mild hyperintensity in the piramidal tracts

  24. A CMTX B Axial Brain MRI (A) Marked hypointensity in the periferic portion of dentate nuclei on T2 w.i. Coronal MRI (B) Small foci of hyperintensity in the hilum of the dentate nuclei on FLAIR sequence

  25. CMTX Hypointensity on T2 w.i. in the postero-lateral aspect of the putamina Normal

  26. NEURORADIOLOGY Pts. M F BRAIN MRI 14 6 8 subtle abnormalities 9 3 6 = mild atrophy 4 2 2 = mild Corticospinal tract hyperintensity 6 1 5 = hypointensity of dentate n. & putamina 2 0 2

  27. Arg164Gln Arg164Leu * Val181Met Thr185Ile Arg22Stop (2) Leu9Trp Arg220Stop (2)

  28. Conclusions • Subclinical CNS involvement in: 18/19 pts. (9/10 M, 9/9 F) • BAEPs most reliable (overall 67%; males 89%) • SEPs (50%) & MEPs (44%) useful • Flash-VEPs high % abnormalities (73%) • role of MRI ? • pathophysiology? Cx32 in CNS • oligodendrocytes, neuronal populations of brainstem, cortex, basal ganglia, nigra • interaction with other connexins?

  29. CNS involvement in CMT1A?Evoked potential studies (central components) • E.P. N° exams abnormal • BAEP 20 2 borderline • SEP (N13-N20) 12 0 • MEP (CCT) 5 0 • VEP-pattern 5 0 • VEP-flash 5 0

  30. CMT1C • Chr 16p13.3-p12 • LITAF = LIPOPOLYSACCHARIDE-INDUCED TUMOR NECROSIS FACTOR-ALPHA FACTOR • (SIMPLE = SMALL INTEGRAL MEMBRANE PROTEIN OF LYSOSOME/LATE ENDOSOME) • LITAF may play a role in protein degradation pathways • Widely expressed, including cytoplasm of Schwann cells

  31. Severe CMT1 due to LITAF mutation(Thr49Met) Marked motor and sensory impairment, scoliosis NCV < 35 m/s absent distal CMAPs & SAPs

  32. PERIAXIN

  33. PERIAXIN • PRX gene on 19q13.1-13.2 code for L e S-periaxin • Interaction between L-periaxin, cytoskeleton & membrane proteins like dystroglican-sarcoglican complex • Necessary for PNS myelin maintainance • Mutations in families with DSD & CMT4 • PRX k.o. mouse develop a severe demyelinating neuropathy with allodinia e iperalgesia

  34. Recessive CMT4/DSD due to PRX gene mutations (Glu547Stop - Pro807fs) II-8. Early onset, delayed motor milestones, severe sensory-motor impairment, scoliosis. MCV 5-9 m/s II-9. Later onset, less severe involvement. MCV 12-16 m/s 5 3 II-8 II-9

  35. Ongoing studies • Quality of life in CMT (funded by Telethon) Future studies • Therapy? • Steroids – I.V. Immunoglobulin (IVIG) • NT3 • Progesterone antagonists • Ascorbic Acid

  36. Franco Taroni Micaela Milani Matilde Laurà Angelo Sghirlanzoni Vidmer Scaioli Claudia Ciano Michela Morbin Isabella Moroni Alessandra Erbetta Luisa Chiapparini “C.Besta” National Neurological Institute, Milan - Italy

  37. BAEPs:clear abnormalities 12/18 pts (8/9 M, 4/9 F)borderline 4 pts, normal 2 pts (2 F) dx (ms) sin (ms) normal I wave 1,63  0,14 1,67  0,35 1,59 III “ 4,12  0,34 * 4,21  0,49 * 3,70 V “ 6,55  1,05 ** 6,65  1,04 ** 5,54 I-III int. 2,51  0,33 * 2,54  0,37 * 2,10 III-V “ 2,42  0,73 ** 2,44  0,62 ** 1,85 I-V “ 4,92  1,01 ** 4,98  0,92 ** 3,95

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