High Dose VItamin C Treatment for Patients with Charcot-Marie-Tooth Disease 1A: Results of a Randomized Double-Masked Controlled Trial (S07.006)

Lewis, Regina; Herrmann, David N.; McDermott, M.; Höke, Ahmet; Feely, Shawna; Miller, Leslie W.; Siskind, Carly E.; Clawson, Lora; Luebbe, Elizabeth; Smith, P; Group, Muscle Study; Shy, Michael E.

doi:10.1212/wnl.78.1_meetingabstracts.s07.006

Cited by 10 publications

(13 citation statements)

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“…The primary end-point of our RCT, the CMTNS, showed rather poor responsiveness (SRM 0.13). Indeed, the CMTNS decline in our placebo group was lower (0.17 point/year) than that reported in previous studies in CMT1A (0.68/year reported by Shy et al [5], 0.3/year by Verhamme et al [7] and 0.5/year by Micallef et al [2]), although Lewis et al [8] described even an improvement in the placebo group in their high-dose AA RCT (À0.46/year). It is true that data obtained from natural history studies [5,7] are difficult to compare with those obtained in clinical trials [2,4,8] as patients recruited in an RCT tend to behave better because of a 'trial effect' [17].…”

Section: Discussioncontrasting

confidence: 68%

“…*CMAP, compound muscle action potential; **SNAP, sensory nerve action potential. et al found that the CMTNS improved over 2 years in both the AA-treated (0.21 point) and the placebo (0.92 point) groups, compared to a non-contemporaneous reference cohort who worsened, as mentioned above, by 0.68 point/year [6,8], suggesting that participation in an RCT alone could be a positive prognostic factor [8].…”

Section: Introductionmentioning

confidence: 89%

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Responsiveness of clinical outcome measures in Charcot−Marie−Tooth disease

Piscosquito

Reilly

Schenone

et al. 2015

Euro J of Neurology

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Section: Discussioncontrasting

confidence: 68%

Section: Introductionmentioning

confidence: 89%

Responsiveness of clinical outcome measures in Charcot−Marie−Tooth disease

Piscosquito

Reilly

Schenone

et al. 2015

Euro J of Neurology

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“…To date, increased expression of PMP22 represents the most likely molecular mechanism underlying CMT1A. However, CMT1A shows wide phenotypic heterogeneity and PMP22 mRNA as well as protein levels are extremely variable among patients and do not correlate with disease severity and clinical outcome measures [Scherer and Wrabetz, ; Katona et al., ; Schenone et al., ; Lewis et al., ; Nobbio et al., ]. Animal models were developed by integration in their genome of extra copies of the PMP22 gene.…”

Section: Introductionmentioning

confidence: 99%

Alternative Splicing in the HumanPMP22Gene: Implications in CMT1A Neuropathy

et al. 2015

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CMT1A patients commonly share PMP22 genetic overloading but they show phenotypic heterogeneity and variability in PMP22 mRNA and protein expression. Moreover, PMP22 mRNA levels do not correlate with clinical outcome measures in these patients, suggesting their uselessness as a disease biomarker. Thus, in-depth analysis of PMP22 transcription and translation might help to define its pathogenic role in CMT1A. We focused on the alternative splicing of PMP22 gene to verify whether mRNA processing is altered in CMT1A. We identified three new PMP22 transcripts enriched in human sural nerve biopsies. One of them was an untranslated variant, whereas the other two originated from a PMP22 undescribed exon and encoded for a new putative protein localized in the endoplasmic reticulum. As splicing events in the PMP22 gene are differently regulated in tissues and during development, we analyzed the levels of PMP22 transcripts and their splicing pattern in human and experimental CMT1A. We found an altered PMP22 splicing ratio in the CMT1A rat. In addition, we showed a remarkable derangement in rat QKI expression, which is a critical regulator of splicing during myelination. Overall, our data suggest that an alteration of mRNA processing could be a pathogenic mechanism in CMT1A.

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“…10 These techniques are typically limited to the study of distal nerves, which are often severely damaged and, therefore, unavailable for these tests. Due in part to this limitation, recent CMT1A clinical trials 12,13 noted difficulty in detecting disease progression when using CMTNS as an outcome measure. In addition, quality of life assessments have shown little sensitivity to disease progression.…”

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confidence: 99%

Proximal nerve magnetization transfer MRI relates to disability in Charcot-Marie-Tooth diseases

et al. 2014

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Objective: The objectives of this study were (1) to develop a novel magnetization transfer ratio (MTR) MRI assay of the proximal sciatic nerve (SN), which is inaccessible via current tools for assessing peripheral nerves, and (2) to evaluate the resulting MTR values as a potential biomarker of myelin content changes in patients with Charcot-Marie-Tooth (CMT) diseases.Methods: MTR was measured in the SN of patients with CMT type 1A (CMT1A, n 5 10), CMT type 2A (CMT2A, n 5 3), hereditary neuropathy with liability to pressure palsies (n 5 3), and healthy controls (n 5 21). Additional patients without a genetically confirmed subtype (n 5 4), but whose family histories and electrophysiologic tests were consistent with CMT, were also included. The relationship between MTR and clinical neuropathy scores was assessed, and the interscan and inter-rater reliability of MTR was estimated.Results: Mean volumetric MTR values were significantly decreased in the SN of patients with CMT1A (33.8 6 3.3 percent units) and CMT2A (31.5 6 1.9 percent units) relative to controls (37.2 6 2.3 percent units). A significant relationship between MTR and disability scores was also detected (p 5 0.01 for genetically confirmed patients only, p 5 0.04 for all patients). From interscan and inter-rater reliability analyses, proximal nerve MTR values were repeatable at the slicewise and mean volumetric levels. Charcot-Marie-Tooth (CMT) diseases are a group of inherited neuropathies that affect motor and sensory nerves. A majority of CMT phenotypes can be classified as primary demyelination/dysmyelinating (CMT1) or primary axonal (CMT2) neuropathies.1,2 CMT type 1A (CMT1A z 80% of CMT1 cases 3,4 ) arises from duplication of the peripheral myelin protein 22 (PMP22) gene 5,6 and results in dysmyelination and secondary axonal loss. 7 CMT type 2A (CMT2A z 35% of CMT2 cases 8 ) is caused by missense mutations in the gene that encodes for mitofusin 2 9 and leads to primary axonal degeneration. 8 Although the pathologic features of CMT1A/CMT2A are different, length-dependent axonal loss occurs in both and is predictive of outcomes.

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High Dose VItamin C Treatment for Patients with Charcot-Marie-Tooth Disease 1A: Results of a Randomized Double-Masked Controlled Trial (S07.006)

Cited by 10 publications

References 0 publications

Responsiveness of clinical outcome measures in Charcot−Marie−Tooth disease

Responsiveness of clinical outcome measures in Charcot−Marie−Tooth disease

Alternative Splicing in the HumanPMP22Gene: Implications in CMT1A Neuropathy

Proximal nerve magnetization transfer MRI relates to disability in Charcot-Marie-Tooth diseases

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