Reliability of the CMT neuropathy score (second version) in Charcot‐Marie‐Tooth disease

Murphy, Sinéad M.; Herrmann, David N.; McDermott, Michael P.; Scherer, Steven S.; Shy, Michael E.; Reilly, Mary M.; Pareyson, Davide

doi:10.1111/j.1529-8027.2011.00350.x

Cited by 288 publications

(281 citation statements)

References 24 publications

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“…A subset of participants was evaluated using the non-NCS portion of the CMT neuropathy score protocol, as previously described. 22 The score is referred to the clinical CMT neuropathy score (CMTNS C ) and is composed of scored evaluations (range 0-4) of sensory and motor symptoms in limbs, pin and vibration sensitivity, and limb muscle strength (CMTNS C range 0-28; higher scores indicate increased impairment). The portion of the CMTNS C taken from the legs (CMTNS L range 0-20) was also extracted for comparison to the MRI measures obtained in the legs.…”

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

et al. 2014

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“…We performed detailed clinical assessments on all patients with pathogenic mutations. Data ascertained when possible included age of symptom onset, clinical history and examination findings, CMT examination and neuropathy scale, as an indicator of neuropathy severity, 11 nerve conduction studies (NCS) and EMG, plasma creatine kinase and lactate, CSF lactate, central motor conduction times, and MRI studies.…”

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Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease

Pitceathly¹,

Murphy²,

Cottenie³

et al. 2012

Neurology

104

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Objective: Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, affecting 1 in 2,500 individuals. Mitochondrial DNA (mtDNA) mutations are not generally considered within the differential diagnosis of patients with uncomplicated inherited neuropathy, despite the essential requirement of ATP for axonal function. We identified the mtDNA mutation m.9185TϾC in MT-ATP6, encoding the ATP6 subunit of the mitochondrial ATP synthase (OXPHOS complex V), at homoplasmic levels in a family with mitochondrial disease in whom a severe motor axonal neuropathy was a striking feature. This led us to hypothesize that mutations in the 2 mtDNA complex V subunit encoding genes, MT-ATP6 and MT-ATP8, might be an unrecognized cause of isolated axonal CMT and distal hereditary motor neuropathy (dHMN). Methods:A total of 442 probands with CMT type 2 (CMT2) (270) and dHMN (172) were screened for MT-ATP6/8 mutations after exclusion of mutations in known CMT2/dHMN genes. Mutation load was quantified using restriction endonuclease analysis. Blue-native gel electrophoresis (BN-PAGE) was performed to analyze the effects of m.9185TϾC on complex V structure and function.Results: Three further probands with CMT2 harbored the m.9185TϾC mutation. Some relatives had been classified as having dHMN. Patients could be separated into 4 groups according to their mutant m.9185TϾC levels. BN-PAGE demonstrated both impaired assembly and reduced activity of the complex V holoenzyme. Conclusions:We have shown that m.9185TϾC in MT-ATP6 causes CMT2 in 1.1% of genetically undefined cases. This has important implications for diagnosis and genetic counseling. Recognition that mutations in MT-ATP6 cause CMT2 enhances current understanding of the pathogenic basis of axonal neuropathy. Neurology ® 2012;79:1145-1154 GLOSSARY BN-PAGE ϭ blue-native polyacrylamide gel electrophoresis; CMT ϭ Charcot-Marie-Tooth; CMT2 ϭ Charcot-Marie-Tooth type 2; dHMN ϭ distal hereditary motor neuropathy; LS ϭ Leigh syndrome; mtDNA ϭ mitochondrial DNA; NARP ϭ neurogenic muscle weakness, ataxia, and retinitis pigmentosa; NCS ϭ nerve conduction studies; OXPHOS ϭ oxidative phosphorylation; UMN ϭ upper motor neuron.Mitochondrial ATP generation by oxidative phosphorylation (OXPHOS) underpins key molecular processes that are essential for normal central and peripheral nervous system axonal function. Axonal peripheral neuropathies are a well-recognized complication of primary mitochondrial DNA (mtDNA) mutations; however, the neuropathy is rarely the presenting or predominant clinical manifestation of the disease. [1][2][3][4][5][6][7][8] In contrast, mutations in the nuclearencoded mitochondrial genes MFN2 9 and GDAP1, 10 which encode outer mitochondrial membrane proteins, usually present with isolated peripheral neuropathy and are now recognized to be important causes of both the axonal and demyelinating forms of Charcot-Marie-Tooth (CMT) disease.One of the major unresolved challenges in neuromuscular diseases, such as CMT type 2 (CMT2) and distal heredit...

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“…Clinical impairment was evaluated using the validated CMT Neuropathy Score version 2 (CMTNSv2). 9 All patients but one underwent skin biopsies that were processed for indirect immunofluorescence (IF), electron microscopy (EM), or Western blot (WB) analysis. A control population of healthy age-matched controls was included for the morphologic and morphometric studies.…”

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Reduced neurofilament expression in cutaneous nerve fibers of patients with CMT2E

et al. 2015

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Objective: To investigate the effects of NEFL Glu396Lys mutation on the expression and assembly of neurofilaments (NFs) in cutaneous nerve fibers of patients with Charcot-Marie-Tooth disease type 2E (CMT2E).Methods: A large family with CMT2E underwent clinical, electrophysiologic, and skin biopsy studies. Biopsies were processed by indirect immunofluorescence (IF), electron microscopy (EM), and Western blot analysis. Results:The clinical features demonstrated intrafamilial phenotypic variability, and the electrophysiologic findings revealed nerve conductions that were either slow or in the intermediate range. All patients had reduced or absent compound muscular action potential amplitudes. Skin biopsies showed axons labeled with the axonal markers protein gene product 9.5 and a-tubulin, but not with NFs. The results of Western blot analysis were consistent with those of IF, showing reduced or absent NFs and normal expression of a-tubulin. EM revealed clusters of regenerated fibers, in absence of myelin sheath abnormalities. Both IF and EM failed to show NF aggregates in dermal axons. The morphometric analysis showed a smaller axonal caliber in patients than in controls. The study of the nodal/paranodal architecture demonstrated that sodium channels and Caspr were correctly localized in patients with CMT2E.Conclusions: Decrease in NF abundance may be a pathologic marker of CMT2E. The lack of NF aggregates, consistent with prior studies, suggests that they occur proximally leading to subsequent alterations in the axonal cytoskeleton. The small axonal caliber, along with the normal molecular architecture of nodes and paranodes, explain the reduced velocities detected in patients with CMT2E. Our results also demonstrate that skin biopsy can provide evidence of pathologic and pathogenic abnormalities in patients with CMT2E. Charcot-Marie-Tooth disease (CMT) is a group of peripheral neuropathies associated with mutations in more than 80 distinct genes. CMT is divided into different forms based on the pattern of inheritance and neurophysiology. Electrophysiologic studies allow for classification of CMT into demyelinating (CMT1) and axonal (CMT2) forms.1 The classification of CMT has been further divided into subtypes, identified by letters, as defined by the mutated gene.2 CMT2E refers to autosomal dominant CMT2 caused by mutations in the neurofilament light chain (NEFL) gene. Some patients with NEFL mutations have slow conduction velocities, in the "demyelinating" range, and are characterized as having CMT1F. Patients with CMT2E and CMT1F are clinically heterogeneous and the age at onset ranges from infancy, typically with severe impairment, to adulthood with milder impairment. Usually those with slowed conductions present early either in infancy with delayed motor milestones or in late childhood/early adolescence.

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Reliability of the CMT neuropathy score (second version) in Charcot‐Marie‐Tooth disease

Cited by 288 publications

References 24 publications

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

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

Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease

Reduced neurofilament expression in cutaneous nerve fibers of patients with CMT2E

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