Development and validation of the Charcot-Marie-Tooth Disease Infant Scale

Mandarakas, Melissa R; Menezes, Manoj P.; Rose, Kristy; Shy, Rosemary; Eichinger, K; Foscan, Maria; Estilow, Timothy; Kennedy, Rachel; Herbert, Karen; Bray, Paula; Refshauge, Kathryn M.; Ryan, Monique M.; Yiu, Eppie M; Farrar, Michelle A.; Sampaio, Hugo; Moroni, Isabella; Pagliano, Emanuela; Pareyson, Davide; Yum, Sabrina W.; Herrmann, David N.; Acsádi, Gyula; Shy, Michael E.; Burns, Joshua; Sanmaneechai, Oranee

doi:10.1093/brain/awy280

Cited by 26 publications

(29 citation statements)

References 21 publications

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“…Rodent models have shown that neuropathy is reversible upon reduction of PMP22 mRNA levels, as was shown in transgenic mice that overexpressed PMP22 through an inducible promoter. 5,6 However, given that neuropathy is slowly progressive, there is a clear need for sensitive biomarkers that measure disease progression and target engagement in patients. 3 Although it remains to be seen whether reversibility can be expected in CMT1A patients, therapeutic approaches are currently being developed to decrease PMP22 expression.…”

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confidence: 99%

“…4 Clinical outcome assessments, such as the Rasch modified CMT Neuropathy or Exam Scores (CMTNS-R/ CMTES-R), measure severity of neuropathy in adults and children with CMT1A. 5,6 However, given that neuropathy is slowly progressive, there is a clear need for sensitive biomarkers that measure disease progression and target engagement in patients. Recent studies have tested for biomarkers of disease impairment and/or progression in CMT1A.…”

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confidence: 99%

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Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies

Svaren

Moran

et al. 2019

Annals of Neurology

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Objective: Charcot-Marie-Tooth (CMT) disease is most commonly caused by duplication of a chromosomal segment surrounding Peripheral Myelin Protein 22, or PMP22 gene, which is classified as CMT1A. Several candidate therapies reduce Pmp22 mRNA levels in CMT1A rodent models, but development of biomarkers for clinical trials in CMT1A is a challenge given its slow progression and difficulty in obtaining nerve samples. Quantitative PCR measurements of PMP22 mRNA in dermal nerves were performed using skin biopsies in human clinical trials for CMT1A, but this approach did not show increased PMP22 mRNA in CMT1A patients compared to controls. One complicating factor is the variable amounts of Schwann cells (SCs) in skin. The objective of the study was to develop a novel method for precise evaluation of PMP22 levels in skin biopsies that can discriminate CMT1A patients from controls. Methods: We have developed methods to normalize PMP22 transcript levels to SC-specific genes that are not altered by CMT1A status. Several CMT1A-associated genes were assembled into a custom Nanostring panel to enable precise transcript measurements that can be normalized to variable SC content. Results: The digital expression data from Nanostring analysis showed reproducible elevation of PMP22 levels in CMT1A versus control skin biopsies, particularly after normalization to SC-specific genes. Interpretation: This platform should be useful in clinical trials for CMT1A as a biomarker of target engagement that can be used to optimize dosing, and the same normalization framework is applicable to other types of CMT.

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confidence: 99%

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confidence: 99%

Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies

Svaren

Moran

et al. 2019

Annals of Neurology

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“…The cross‐sectional design of our study might be inadequate to explore the effect of age on CMTNS2, and the inclusion of pediatric CMT patients or a larger number of those ≥50 years might have yielded different results. We excluded pediatric CMT patients because of the scarcity of information of normative CSA values in patients under the age of 16 years and the limited sensitivity of the CMTNS2 in children; other clinical scales are more appropriate . Previous data on pediatric CMT1A suggested a correlation between CSA and clinical scores, but with potential bias effect of age …”

Section: Discussionmentioning

confidence: 99%

Nerve size correlates with clinical severity in Charcot–Marie–Tooth disease 1A

et al. 2019

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Introduction Nerve cross‐sectional area (CSA) is larger than normal in Charcot–Marie–Tooth disease 1A (CMT1A), although to a variable extent. We explored whether CSA is correlated with CMT clinical severity measured with neuropathy score version 2 (CMTNS2) and its examination subscore (CMTES2) in CMT1A. Methods We assessed 56 patients with CMT1A (42 families). They underwent nerve conduction study (NCS) and nerve high‐resolution ultrasound (HRUS) of the left median, ulnar, and fibular nerves. Results Univariate analysis showed NCS and HRUS variables to be significantly correlated with CMTNS2 and CMTES2 and with each other. Multivariate analysis showed that ulnar motor nerve conduction velocity (β: −0.19) and fibular compound muscle action potential amplitude (−1.50) significantly influenced CMTNS2 and that median forearm CSA significantly influenced CMTNS2 (β: 5.29) and CMTES2 (4.28). Discussion Nerve size is significantly associated with clinical scores in CMT1A, which suggests that it might represent a potential biomarker of CMT damage and progression.

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“…75 Similar advances have also been made in pediatric cohorts with the development and validation of reliable and sensitive scales such as the CMT pediatric and CMT infant scales, crucial for monitoring of early-onset phenotypes. 76,77 In addition, objective biomarkers for monitoring disease progression and disability have also been developed and applied in clinical trials. Serum neurofilament light chain has been identified as a promising biomarker of disease activity, correlating with both disease severity and the validated CMT clinical scores.…”

Section: Outcome Measuresmentioning

confidence: 99%

Inherited Neuropathies

et al. 2019

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The inherited neuropathies are a common and heterogeneous group of slowly progressive disorders affecting motor, sensory, and autonomic nerves. These hereditary conditions can be confined to the peripheral nervous system, termed the primary hereditary neuropathies, or can occur as part of a multisystem disease. Identification of systemic involvement is necessary to distinguish the primary and secondary hereditary neuropathies to prevent the misdiagnosis of potentially treatable entities. Recent genetic and technological advances have dramatically improved our understanding of the underlying pathophysiology of these inherited neuropathies and hence provide the correct milieu for the future development of disease-modifying therapies. This review provides clinical, neurophysiological, genetic, pathophysiological, and treatment insights into the primary inherited neuropathies, and those associated with multisystem diseases, including porphyria and mitochondrial disorders.

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Development and validation of the Charcot-Marie-Tooth Disease Infant Scale

Cited by 26 publications

References 21 publications

Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies

Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies

Nerve size correlates with clinical severity in Charcot–Marie–Tooth disease 1A

Inherited Neuropathies

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