CMT Neuropathy Score Research Articles

Patient-reported disease burden in the Accelerate Clinical Trials in Charcot-Marie-Tooth Disease Study.

The Charcot-Marie-Tooth Disease Health Index (CMT-HI) is a disease-specific, patient-reported disease burden measure. As part of an international clinical trial readiness study, individuals with CMT1A (ages 18-75 years) underwent clinical outcome assessments (COAs), including the CMT-HI, to capture their longitudinal perspective on the disease burden. Two hundred and fifteen participants underwent serial COAs including the CMT-HI, CMT Functional Outcome Measure (CMT-FOM), CMT Neuropathy Score (CMTNSv2R), and CMT Exam Score (CMTES/CMTES-R). Correlations between the total and subscale scores for the CMT-HI and other COAs were determined. Changes in the CMT-HI scores over 12 months were assessed using paired t-tests. The minimum clinically important difference (MCID) for the CMT-HI and its subscales were calculated by anchoring to a participant global impression of change scale. At baseline, CMT1A participants were 44.5 ± 15 years old (range: 18-75) and 58% were women. The mean CMT-HI was 25.7 ± 18.8 (range: 0-91.9; 100 reflecting maximal disease burden). The CMT-HI correlated with the CMT-FOM (r = .54, p < .0001), CMTNSv2R (r = .48, p < .0001), and CMTES/CMTES-R (r = .52/r = .54, p < .0001). Disease burden was greater in women than in men (CMT-HI 29.1 ± 19.1 vs. 21.2 ± 17.3, p = .001). Over 12 months, there was a nonsignificant mean increase in CMT-HI of 0.40 ± 10.0 (n = 189, p = .89). The MCID for the CMT-HI total score was 3.8 points (95% CI: 1.7-5.9). Patient-reported disease burden in CMT1A as measured by the CMT-HI is associated with measures of neurologic impairment and physical functioning. Women reported a higher disease burden than men. These data will inform the design of clinical trials in CMT1A.

Plasma neurofilament light chain level is not a biomarker of Charcot-Marie-Tooth disease progression: Results of 3-year follow-up study.

Charcot-Marie-Tooth disease (CMT) is a hereditary, slowly progressive neuropathy. Currently, there are no effective pharmacological treatments or sensitive disease activity biomarkers available. The aim of this study was to demonstrate the change in plasma neurofilament light chain (NfL) over time in a CMT cohort and analyse the association between CMT severity and NfL level. Initially, 101 CMT patients and 64 controls were enrolled in the study. Repeated evaluation was performed in 73 patients and 28 controls at a 3-year interval. Disease severity assessment included clinical evaluation with CMT Neuropathy Score version 2 (CMTNSv2). Plasma NfL concentration was measured using the Simoa (single molecule array) NfL assay. Plasma NfL concentration was increased in the CMT group compared with controls (p < 0.001). Overall NfL level increased over the 3-year interval in both CMT (p = 0.012) and control (p = 0.001) groups. However, in 22 of 73 CMT patients and seven of 28 controls, the NfL level decreased from the baseline. Analysing the association between 3-year change in plasma NfL and disease severity (CMTNSv2), there was no correlation in the CMT group (r = 0.228, p = 0.052) or different CMT subgroups. Our study verifies increased plasma NfL concentrations in patients with CMT compared with controls. Longitudinal 3-year data showed a variable change in NfL levels between CMT subtypes. There was no association between change in NfL over time and disease severity. These findings suggests that NfL is not a biomarker for CMT progression.

Neuropathy due to bi-allelic SH3TC2 variants: genotype-phenotype correlation and natural history.

Recessive SH3TC2 variants cause Charcot-Marie-Tooth disease type 4C (CMT4C). CMT4C is typically a sensorimotor demyelinating polyneuropathy, marked by early onset spinal deformities, but its clinical characteristics and severity are quite variable. Clear relationships between pathogenic variants and the spectrum of disease manifestations are to date lacking. Gene replacement therapy has been shown to ameliorate the phenotype in a mouse model of CMT4C, emphasizing the need for natural history studies to inform clinical trial readiness. Data, including both genetic information and clinical characteristics, were compiled from the longitudinal, prospective dataset of the Inherited Neuropathy Consortium, a member of the Rare Diseases Clinical Research Network (INC-RDCRN). The Charcot Marie Tooth Neuropathy Score (CMTNS), Examination Score (CMTES) and the Rasch-weighted CMTES (CMTES-R) were used to describe symptoms, neurological examinations and neurophysiological characteristics. Standardized response means were calculated at yearly intervals and a mixed model for repeated measures was used to estimate the change in CMTES and CMTES-R over time. Fifty-six individuals (59% female), median age 27 years (range 2-67 years) with homozygous or compound heterozygous variants in SH3TC2 were identified, including 34 unique variants, 14 of which have not previously been published. Twenty-eight participants had longitudinal data available. While there was no significant difference in the CMTES in those with protein truncating versus non-protein truncating variants, there were significant differences in the mean ulnar nerve compound muscle action potential amplitude, the mean radial sensory nerve action potential amplitude, and in the prevalence of scoliosis, suggesting the possibility of a milder phenotype in individuals with one or two non-protein-truncating variants. Overall, the mean value of the CMTES was 13, reflecting moderate clinical severity. There was a high rate of scoliosis (81%), scoliosis surgery (36%), and walking difficulty (94%) among study participants. The CMTES and CMTES-R appeared moderately responsive to change over extended follow-up, demonstrating a standardized response mean of 0.81 standard deviation units or 0.71 standard deviation units, respectively, over 3 years. Our analysis represents the largest cross-sectional and only longitudinal study to date, of the clinical phenotype of both adults and children with CMT4C. With the promise of upcoming genetic treatments, these data will further define the natural history of the disease and inform study design in preparation for clinical trials.

Identification and clinical characterization of Charcot-Marie-Tooth disease type 1C patients with LITAF p.G112S mutation.

Charcot-Marie-Tooth disease type 1C (CMT1C) is a rare subtype associated with LITAF gene mutations. Until now, only a few studies have reported the clinical features of CMT1C. This study was performed to find CMT1C patients with mutation of LITAF in a Korean CMT cohort and to characterize their clinical features. In total, 1,143 unrelated Korean families with CMT were enrolled in a cohort. We performed whole exome sequencing to identify LITAF mutations, and examined clinical phenotypes including electrophysiological and MRI features for the identified CMT1C patients. We identified 10 CMT1C patients from three unrelated families with p.G112S mutation in LITAF. The frequency of CMT1C among CMT1 patients was 0.59%, which is similar to reports from Western populations. CMT1C patients showed milder symptoms than CMT1A patients. The mean CMT neuropathy score version 2 was 7.7, and the mean functional disability scale was 1.0. Electrophysiological findings showed a conduction block in 22% of affected individuals. Lower extremity MRIs showed that the superficial posterior and anterolateral compartments of the calf were predominantly affected. We found a conduction block in Korean CMT1C patients with p.G112S mutation and first described the characteristic MRI findings of the lower extremities in patients with LITAF mutation. These findings will be helpful for genotype-phenotype correlation and will widen understanding about the clinical spectrum of CMT1C.

Clinical and Genetic Aspects of Childhood-Onset Demyelinating Charcot-Marie-Tooth's Disease in Brazil.

Charcot-Marie-Tooth's disease (CMT) represents the most common inherited neuropathy. Most patients are diagnosed during late stages of disease course during adulthood. We performed a review of clinical, neurophysiological, and genetic diagnoses of 32 patients with genetically defined childhood-onset demyelinating CMT under clinical follow-up in a Brazilian Center for Neuromuscular Diseases from January 2015 to December 2019. The current mean age was 33.1 ± 18.3 years (ranging from 7 to 71 years) and mean age at defined genetic diagnosis was 36.1 ± 18.3 years. The mean age at onset was 6.1 ± 4.4 years. The most common initial complaint was bilateral pes cavus. The genetic basis included PMP22 duplication (CMT1A) ( n = 18), GJB1 (CMTX1) ( n = 5), MPZ (CMT1B) ( n = 3), FIG4 (CMT4J) ( n = 3), SH3TC2 (CMT4C) ( n = 1), PLEKHG5 (CMTRIC) ( n = 1), and PRX (CMT4F) ( n = 1). Almost all patients ( n = 31) presented with moderate or severe compromise in the CMT neuropathy score 2 with the highest values observed in CMT1B. Medical history disclosed obstructive sleep apnea ( n = 5), aseptic meningitis ( n = 1/ MPZ ), akinetic-rigid parkinsonism ( n = 1/ FIG4 ), and overlapping chronic inflammatory demyelinating polyneuropathy ( n = 1/ MPZ ). Motor conduction block was detected in three individuals ( PMP22 , FIG4 , MPZ ). Acute denervation occurred in seven patients. Nonuniform demyelinating patterns were seen in four individuals (two CMT1A, one CMT1B, and one CMTX1). Abnormal cerebral white matter findings were detected in CMT1A and CMTX1, while hypertrophic roots were seen in CMT1A, CMT1B, and CMTX1. Our study emphasizes a relative oligogenic basis in childhood-onset demyelinating CMT and atypical findings may be observed especially in MPZ , PMP22 , and GJB1 gene variants.

Phenotypic Variability and Diagnostic Characteristics in Inherited Peripheral Neuropathy in Latvia

Abstract Inherited peripheral neuropathies (IPN) are a clinically and genetically heterogeneous group of disorders. The most common IPN is Charcot-Marie-Tooth (CMT) disease. Here we describe IPN clinical variability and diagnostic characteristics in the Latvian population. A total of 101 patients were enrolled in the study. Genetic testing consisted of PMP22 copy number analysis and whole-exome sequencing (WES). Clinical assessment comprised CMT Neuropathy Score version 2 (CMTNSv2), CMT Examination Score, pain, anxiety and memory/cognitive ability testing. The diagnostic yields for PMP22 copy number detection and WES were 45.8% and 77.8%, respectively. Disease severity assessment indicated high clinical heterogeneity, with CMTNSv2 scores ranging between 0 and 33. More than one-third of patients reported pain, and it was found to be significantly more common in patients with at least a mild anxiety level. From the initial development of symptoms, on average, it took more than 13 years for a diagnosis of IPN to be confirmed. This study updates the IPN genetic and clinical profile of the Latvian population and demonstrates the presence of a high level of heterogeneity. The time to diagnosis for IPN patients needs to be improved by employing multiplex ligation-dependent probe amplification initially followed by WES.

Intraepineurial fat quantification and cross-sectional area analysis of the sciatic nerve using MRI in Charcot-Marie-Tooth disease type 1A patients

The objectives of this study were to assess the fat fraction (FF) and cross-sectional area (CSA) of the sciatic nerve in Charcot-Marie-Tooth disease type 1A (CMT1A) patients using Dixon-based proton density fat quantification MRI and to elucidate its potential association with clinical parameters. Thigh MRIs of 18 CMT1A patients and 18 age- and sex-matched volunteers enrolled for a previous study were reviewed. Analyses for FF and CSA of the sciatic nerve were performed at three levels (proximal to distal). CSA and FF were compared between the two groups and among the different levels within each group. The relationship between the MRI parameters and clinical data were assessed in the CMT1A patients. The CMT1A patients showed significantly higher FF at level 3 (p = 0.0217) and significantly larger CSA at all three levels compared with the control participants (p < 0.0001). Comparisons among levels showed significantly higher FF for levels 2 and 3 than for level 1 and significantly larger CSA for level 2 compared with level 1 in CMT1A patients. CSA at level 3 correlated positively with the CMT neuropathy score version 2 (CMTNSv2). In conclusion, the sciatic nerve FF of CMT1A patients was significantly higher on level 3 compared with both the controls and the measurements taken on more proximal levels, suggesting the possibility of increased intraepineurial fat within the sciatic nerves of CMT1A patients, with a possible distal tendency. Sciatic nerve CSA at level 3 correlated significantly and positively with CMTNSv2, suggesting its potential value as an imaging marker for clinical severity.

Charcot-Marie-Tooth neuropathy score and ambulation index are both predictors of orthotic need for patients with CMT

Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy with an estimated prevalence of 1 person affected on 2500. Frequent symptoms include distal weakness and muscle wasting, sensory loss, reduced deep tendon reflexes, and skeletal deformities, such as hammer toes and pes cavus. CMT is a progressive disease and patients’ needs change over their lifetime. In particular, ambulation aids are increasingly needed to maintain ambulation and reduce the risk of falls. We performed a retrospective analysis of medical records from 149 patients with confirmed CMT to evaluate patients ambulation needs related to the severity of their CMT as measured by the CMT Neuropathy Score (CMTNS) and Ambulation Index (AI). Most patients required some form of orthotics (86.6%). The CMTNS and AI scores both differed significantly between patients with no orthotics compared to those who wore insoles/inserts. The CMTNS and AI also differed significantly between patients wearing insoles and those with ankle foot orthotics (AFOs). CMTNS and the AI were valid predictors of the type and choice of the orthotics. Both the CMTNS and AI can be effective tools to aid in the correct choice of orthotics in patients affected by CMT.

Quantitative assessment of muscle echogenicity in Charcot-Marie-Tooth disease type 1A by automatic thresholding methods

ObjectiveTo investigate the utility of automatic thresholding methods for quantitative muscle echogenicity assessment as a marker of disease severity in Charcot-Marie-Tooth disease type 1A (CMT1A). MethodsMuscle ultrasound was performed in 15 CMT1A patients and 7 healthy controls. Muscle echogenicity of six limb muscles in each subject was assessed by 16 automatic thresholding methods and conventional grey-scale analysis. Echogenicity of each method in CMT1A patients was compared with that in controls. A correlation between the echogenicity and CMT neuropathy score (CMTNS) was also analysed in CMT1A patients. ResultsSignificant differences in mean echogenicity of the 6 muscles between CMT1A patients and controls were found both in grey-scale analysis (p < 0.01) and 11 of the 16 automatic thresholding methods (p < 0.05 in each method). In CMT1A patients, mean echogenicity of the 6 muscles was positively correlated with CMTNS in 8 of the 16 automatic thresholding methods, but not in grey-scale analysis. ConclusionAutomatic thresholding methods can be used to detect the difference in muscle echogenicity between CMT1A patients and controls. Echogenicity parameters correlate with the disease severity. SignificanceQuantitative muscle echogenicity assessment by automatic thresholding methods shows potential as a surrogate marker of disease progression in CMT1A.

The impact of symptoms on daily life as perceived by patients with Charcot-Marie-Tooth type 1A disease

IntroductionIn Charcot-Marie-Tooth type 1A (CMT1A) patients, daily life is mainly influenced by mobility and ambulation dysfunctions. The aim of our work was to evaluate the perception of disturbances that mostly impact on daily life in CMT1A patients and its difference on the basis of age, gender, disability, and quality of life.MethodsForty-one CMT1A patients underwent neurological assessment focused on establishing clinical disability through the Charcot-Marie-Tooth Neuropathy Score (CMTNS) and quality of life through the Short Form-36 (SF-36) questionnaire. We identified from CMT disturbances 5 categories [weakness in lower limbs (WLL), weakness in upper limbs (WUL), skeletal deformities (SD), sensory symptoms (SS), balance (B)] and patients classified the categories from the highest to the lowest impact on daily life (1: highest; 5: lowest). Ranking of the 5 categories, in the overall sample and in the different subgroups (dividing by gender, median of age and disease duration, CMTNS, domains of SF-36), was obtained and differences among subgroups were assessed using a bootstrap approach.ResultsRank analysis showed that WLL was the most important disturbance on daily life whereas WUL had the lowest impact. In the older CMT1A group, the most important disturbance on daily life was B that was also the most relevant disturbance in patients with a greater disability. SD influenced daily life in younger patients. SS had less impact on daily life, with the exception of patients with a milder disability.DiscussionOur findings demonstrated that the perception of disturbances that mostly impact on CMT1A patients’ daily life changes over the lifetime and with degree of disability.

Employment status of patients with Charcot-Marie-Tooth type 1A.

Previous studies showed that being unemployed is associated with lower quality of life in patients with Charcot-Marie-Tooth type 1A (CMT1A). The aim of this study was to assess the differences between CMT1A patients capable of working and CMT1A patients incapable of working due to CMT1A. Forty-four patients with genetically confirmed CMT1A were included. Medical Research Council (MRC) Sum Score, Charcot-Marie-Tooth Neuropathy Score (CMTNS), CMT Examination Score (CMTES), Overall Neuropathy Limitations Scale (ONLS), Beck Depression Inventory (BDI), Krupp's Fatigue Severity Scale (FSS), and Falls Efficacy Score (FES) were used. Whole cohort was divided into two groups: 1. CMT1A patients capable of working (employed and unemployed not due to CMT) and 2. CMT1A patients incapable of working due to CMT1A (unemployed due to CMT and retired due to CMT). At time of testing, 38.6% patients were employed, 13.6% were unemployed due to CMT, 6.8% were unemployed but not due to CMT, and 40.9% were retired early due to disability caused by CMT. Patients retired due to CMT1A at the age of 43 ± 10years. ONLS total score and physical work appeared as significant independent predictors of being incapable of working due to CMT1A. Patients incapable of working were almost four times more likely to have fatigue (OR = 3.7, 95% CI 1.0-13.1, p < 0.05) and 11 times more likely to have fear of falling (OR = 11.0, 95% CI 2.0-59.7, p < 0.01). Patients with more severe functional disability and physical type of job were most likely incapable of working due to CMT1A. Incapability of working was associated with fatigue and fear of falling.

The application of scales and characteristics of disability in the common genotypes of Charcot-Marie-Tooth disease

Objective: To analyze the correlations among different common scales for evaluating the severity of the first-visit Charcot-Marie-Tooth disease (CMT), and explore the cross-sectional characteristics of neurological dysfunction in patients with four common genotypes (CMT1A, CMT1X, CMT2A and MPZ-related CMT) at their first visits. Methods: A total of 117 genetically confirmed CMT patients (aged ≥10 years) from the Department of Neurology of the Third Xiangya Hospital from 2009 to 2019 were included in the study, which consisted of 45 CMT1A, 41 CMT1X, 19 CMT2A, and 12 MPZ-related CMT patients. Clinical data of these patients at first visits were collected and neurological deficits were evaluated by Charcot-Marie-Tooth Neuropathy Score (CMTNS), Charcot-Marie-Tooth Examination Score (CMTES), Overall Neuropathy Limitation Scale (ONLS) and Functional Disability Scale (FDS). Spearman's correlation was performed to analyze the relationship between CMTNS, CMTES, ONLS and FDS. The age of onset, duration of disease, scores of CMTNS, CMTES, ONLS and FDS were compared among four genotypes. Results: In the 117 CMT patients, the male to female ratio was 1.79/1, and the age of onset was (19±13) years. The duration of disease was 10(3, 15) years, and the scores of CMTNS, CMTES, ONLS and FDS were 11.4±6.2, 8.8±5.7, 2.7±1.4 and 2.6±1.3, respectively. There was a significant correlation between CMTES, ONLS, FDS and CMTNS in the overall CMT patients and four subtypes respectively (r≥0.40, P<0.05). CMTNS, CMTES and ONLS scores of four subtypes showed positive correlations with duration of disease (P<0.05), but FDS scores of CMT1A, CMT1X and MPZ-related CMT patients exhibited no correlation with duration of disease (P>0.05) at their first visits. The age of onset in CMT2A patients was younger than that of the patients with the other three genotypes (P<0.05), furthermore, the scores of four scales in early-onset CMT2A patients were higher than those of adult-onset type CMT2A patients (CMTNS: P=0.031, CMTES: P=0.048, ONLS: P=0.042, FDS: P=0.047). In CMT1X patients, the males had higher scores than those of females for all four scales (CMTNS: P=0.028, CMTES: P=0.014, ONLS: P=0.023, FDS: P=0.002). Conclusions: CMTNS, CMTES and ONLS could be used in natural history studies and clinical trials according to the different clinical situations. In the four genotypes, CMT2A patients have younger age of onset, and the earlier the age of onset, the severer the dysfunction. Moreover, male CMT1X patients relatively have severer neurological dysfunction than female patients.

Plasma neurofilament light chain as a potential biomarker in Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth (CMT) disease is a chronic, slowly progressing disorder. The lack of specific disease progression biomarkers limits the execution of clinical trials. However, neurofilament light chain (NfL) has been suggested as a potential biomarker for peripheral nervous system disorders. Ninety-six CMT disease patients and 60 healthy controls were enrolled in the study. Disease severity assessment included clinical evaluation with CMT Neuropathy Score version 2 (CMTNSv2). Blood plasma NfL concentrations were measured using the single-molecule array NfL assay. The NfL concentration was significantly higher in the CMT disease patient group than in the controls (p<0.001). Of the CMT disease patients, those with type CMTX1 had a higher NfL level than those in the two other analysed subgroups (CMT1A and other CMT disease types) (p=0.0498). The NfL concentration had a significant but weak correlation with the CMTNSv2 (rs =0.25, p=0.012). In one CMT disease patient with an extremely elevated NfL level, overlap with chronic inflammatory demyelinating polyneuropathy was suspected. Receiver operating characteristic analysis showed that an NfL concentration of 8.9pg/ml could be used to discriminate CMT disease patients from controls, with an area under the curve of 0.881. Our study confirmed that the plasma NfL concentration is significantly higher in CMT disease patients than in controls. Plasma NfL concentration was found to significantly, albeit weakly, reflect the clinical severity of CMT disease. In the future, NfL may be used, either individually or collaboratively, as a biomarker in the clinical context of suspected CMT disease; however, several issues need to be addressed first.

Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study

Mitofusin-2 (MFN2) is one of two ubiquitously expressed homologous proteins in eukaryote cells, playing a critical role in mitochondrial fusion. Mutations in MFN2 (most commonly autosomal dominant) cause Charcot-Marie-Tooth disease type 2A (CMT2A), the commonest axonal form of CMT, with significant allelic heterogeneity. Previous, moderately-sized, cross sectional genotype-phenotype studies of CMT2A have described the phenotypic spectrum of the disease, but longitudinal natural history studies are lacking. In this large multicentre prospective cohort study of 196 patients with dominant and autosomal recessive CMT2A, we present an in-depth genotype-phenotype study of the baseline characteristics of patients with CMT2A and longitudinal data (1-2 years) to describe the natural history. A childhood onset of autosomal dominant CMT2A is the most predictive marker of significant disease severity and is independent of the disease duration. When compared to adult onset autosomal dominant CMT2A, it is associated with significantly higher rates of use of ankle-foot orthoses, full-time use of wheelchair, dexterity difficulties and also has significantly higher CMT Examination Score (CMTESv2) and CMT Neuropathy Score (CMTNSv2) at initial assessment. Analysis of longitudinal data using the CMTESv2 and its Rasch-weighted counterpart, CMTESv2-R, show that over 1 year, the CMTESv2 increases significantly in autosomal dominant CMT2A (mean change 0.84 ± 2.42; two-tailed paired t-test P = 0.039). Furthermore, over 2 years both the CMTESv2 (mean change 0.97 ± 1.77; two-tailed paired t-test P = 0.003) and the CMTESv2-R (mean change 1.21 ± 2.52; two-tailed paired t-test P = 0.009) increase significantly with respective standardized response means of 0.55 and 0.48. In the paediatric CMT2A population (autosomal dominant and autosomal recessive CMT2A grouped together), the CMT Pediatric Scale increases significantly both over 1 year (mean change 2.24 ± 3.09; two-tailed paired t-test P = 0.009) and over 2 years (mean change 4.00 ± 3.79; two-tailed paired t-test P = 0.031) with respective standardized response means of 0.72 and 1.06. This cross-sectional and longitudinal study of the largest CMT2A cohort reported to date provides guidance for variant interpretation, informs prognosis and also provides natural history data that will guide clinical trial design.

Charcot-Marie-Tooth disease type 1A: Longitudinal change in nerve ultrasound parameters.

This study aimed to elucidate the longitudinal changes in nerve ultrasound parameters of adult Charcot-Marie-Tooth disease type 1A (CMT1A) patients. Fifteen adult patients with CMT1A prospectively underwent nerve ultrasound and clinical assessment (CMT neuropathy score [CMTNS]) at baseline and 5 y later. Nerve cross-sectional area (CSA) and echogenicity were measured in the median and sural nerves. Changes in ultrasound parameters and CMTNS and correlation between changes of ultrasound parameters and CMTNS were analyzed. Median and sural nerve CSAs did not change over 5 y, although CMTNS increased (P < .01). Nerve echogenicity in the sural nerve decreased over 5 y (P = .045). No correlations between changes in nerve ultrasound parameters and CMTNS were identified. No longitudinal changes in nerve size was detected in adult CMT1A. Exploring the factors that determine nerve size in childhood CMT1A may lead to the development of treatments.

Microstructural Integrity of Peripheral Nerves in Charcot-Marie-Tooth Disease: An MRI Evaluation Study.

Charcot-Marie-Tooth (CMT) disease is diagnosed through clinical findings and genetic testing. While there are neurophysiological tools and clinical functional scales in CMT, objective disease biomarkers that can facilitate in monitoring disease progression are limited. To investigate the utility of diffusion tensor imaging (DTI) in determining the microstructural integrity of sciatic and peroneal nerves and its correlation with the MRI grading of muscle atrophy severity and clinical function in CMT as determined by the CMT neuropathy score (CMTNS). Prospective case-control. Nine CMT patients and nine age-matched controls. 3 T T1 -weighted in-/out-of phase spoiled gradient recalled echo (SPGR) and DTI sequences. Fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) values for sciatic and peroneal nerves were obtained from DTI. Muscle atrophy was graded according to the Goutallier classification using in-/out-of phase SPGRs. DTI parameters and muscle atrophy grades were compared between CMT and controls, and the relationship between DTI parameters, muscle atrophy grades, and CMTNS were assessed. The Wilcoxon Signed Ranks test was used to compare DTI parameters between CMT and controls. The relationship between DTI parameters, muscle atrophy grades, and CMTNS were analyzed using the Spearman correlation. Receiver operating characteristic (ROC) analyses of DTI parameters that can differentiate CMT from healthy controls were done. There was a significant reduction in FA and increase in RD of both nerves (P < 0.05) in CMT, with significant correlations between FA (negative; P < 0.05) and RD (positive; P < 0.05) with muscle atrophy grade. In the sciatic nerve, there was significant correlation between FA and CMTNS (r = -0.795; P < 0.05). FA and RD could discriminate CMT from controls with high sensitivity (77.8-100%) and specificity (88.9-100%). There were significant differences of DTI parameters between CMT and controls, with significant correlations between DTI parameters, muscle atrophy grade, and CMTNS. Level of Evidence 2 Technical Efficacy Stage 2 J. MAGN. RESON. IMAGING 2021;53:437-444.

Rate of Changes in CMT Neuropathy and Examination Scores in Japanese Adult CMT1A Patients.

Introduction: We aimed to clarify when adult patients with Charcot-Marie-Tooth disease type 1A (CMT1A), especially those diagnosed at middle or advanced ages, first showed symptoms and whether the rate of disease progression is accelerated by aging.Methods: Medical records of CMT1A outpatients between 2012 and 2019 were reviewed. The age at diagnosis, age when symptoms first appeared, and rate of disease progression, assessed based on clinical outcome measures including the CMT Neuropathy Score (CMTNS), Rasch-modified CMTNS (CMTNS-R), CMT Examination Score (CMTES), and Rasch-modified CMTES (CMTES-R) were analyzed.Results: Among 45 adult CMT1A patients, 42% had been diagnosed after 50 years of age, whereas 91% of all patients had exhibited some CMT-related symptoms before 20 years of age. The annual increase of all clinical outcome measures did not differ between patients under and over 50 years. Even when limited to patients whose initial CMTES-R showed mild to moderate severity, the rate of change in CMTES-R did not differ between the two age groups (the annual mean ± standard deviation, under 50 years: 1.1 ± 1.0, and over 50 years: 0.9 ± 1.1, p = 0.68). To determine whether patients with disabilities at a young age have a higher deterioration rate, they were classified into three groups according to their current age and age at diagnosis: patients under 50 years of age, patients over 50 years of age but diagnosed before 50, and patients diagnosed after 50 years of age. The mean annual increase of all clinical outcome measures, however, did not differ among these groups (CMTES-R: 1.03 ± 1.01 vs. 0.94 ± 1.57 vs. 0.81 ± 0.88, respectively, p = 0.87).Discussion: CMT1A patients develop symptoms in childhood and adolescence even if such symptoms are not noticeable until reaching an advanced age. Deterioration rates of clinical outcome measures are constant irrespective of the age in their adulthood, although we cannot rule out the limitation that the difference did not reach significance because of the small number of patients. Being aware of the existence of a considerable number of undiagnosed CMT patients will help promote the avoidance of inadequate medication.

Quality of life in hereditary neuropathy with liability to pressure palsies is as impaired as in Charcot–Marie–Tooth disease type 1A

To date, only one study assessed quality of life (QoL) in patients with hereditary neuropathy with liability to pressure palsies (HNPP). We aimed to fill in this gap by investigating QoL in a cohort of patients with HNPP compared to Charcot-Marie-Tooth type 1A (CMT1A) patients, as well as to analyze sociodemographic and clinical features associated with QoL in HNPP. Eighteen genetically confirmed HNPP patients were age-and gender-matched with 18 CMT1A patients. SF-36 questionnaire was used to assess QoL. Medical Research Council (MRC) Sum Score, CMT Neuropathy Score (CMTNS), Overall Neuropathy Limitation Scale Score (ONLS), Falls Efficacy Score (FES), Visual Analog Pain Scale, Beck Depression Inventory (BDI) and Fatigue Severity Scale (FSS) were also used in our study. Although HNPP patients were less clinically impaired, no difference was observed in these two cohorts regarding SF-36 scores. Worse QoL in HNPP patients was associated with lower education (p < 0.01), physical work (p < 0.05), higher number of clinically affected nerves during the disease course (p < 0.01), worse MRC-SS score (p < 0.01), worse ONLS score (p < 0.01), and with more severe pain (p < 0.01), depression (p < 0.01), and fatigue (p < 0.01). Worse pain at the moment of testing appeared as a significant independent predictor of worse QoL in HNPP patients (β = -0.93, p < 0.001). QoL was similarly impaired in patients with HNPP and patients with CMT1A. We identified different factors associated with QoL in HNPP, and many of these factors are amenable to treatment which is of special interest in these still incurable disease.

Multidimensional evaluation is necessary to assess hand function in patients with Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth (CMT) disease type 1A (CMT1A) is the most common hereditary neuropathy. Several studies have assessed the relation between axonal loss and grip strength; however, the functional impact on dexterity and health-related quality of life (HRQoL) is unknown. We hypothesized that the severity of axonal loss will be correlated with loss of function and HRQoL. The purpose of this study was to evaluate the relation between severity of electroneuromyography impairment and its impact on function and HRQoL in adults with CMT1A. Grip and lateral pinch strength were evaluated with specific dynamometers: the Jamar and the Pinch Gauge. Dexterity was explored with the Sollerman, Jebsen, and Nine-hole Peg tests. The CMT impact on well-being was assessed by the validated Medical Outcomes Study Short Form 36 (SF-36), Beck Depression Inventory, and Fatigue Severity Scale, and disease severity by the CMT neuropathy score and Inflammatory Neuropathy Cause and Treatment sensory sum score. Finally, axonal loss and demyelination process was assessed by electroneuromyography. We included 33 participants with CMT1A (23 females, mean [SD] age 47.0 [4.7] years). We found lack of correlation between severe electroneuromyography impairment (frequency of abnormal results >80%), significant distal amyotrophy (70%) and quality of life (mean [SD] scores for physical and mental SF-36 36.4 [10.0] and 48.4 [11.5]), autonomy for activities of daily living, and hand function that remains relatively preserved. We found a correlation between lateral pinch and dexterity according to the Sollerman test (r=0.52, p<0.05) but a lack of correlation among the other parameters. Electrophysiological follow-up seems to be of little relevance to follow HRQoL in individuals with CMT1A and manual function related to functional objectives for everyday physical medicine and rehabilitation practice. The manual function is complex and requires an overall, quantitative, qualitative and multidisciplinary assessment. Each tool (Pinch Gauge, Jamar, Sollerman, Jebsen, Nine-hole Peg) measures a specific element of manual function and is necessary when performing a grip function analysis.

Length-dependent MRI of hereditary neuropathy with liability to pressure palsies.

ObjectiveHereditary neuropathy with liability to pressure palsies (HNPP) is caused by heterozygous deletion of the peripheral myelin protein 22 (PMP22) gene. Patients with HNPP present multifocal, reversible sensory/motor deficits due to increased susceptibility to mechanical pressure. Additionally, age‐dependent axonal degeneration is reported. We hypothesize that length‐dependent axonal loss can be revealed by MRI, irrespective of the multifocal phenotype in HNPP.MethodsNerve and muscle MRI data were acquired in the proximal and distal leg of patients with HNPP (n = 10) and matched controls (n = 7). More specifically, nerve magnetization transfer ratios (MTR) were evaluated to assay proximal‐to‐distal gradients in nerve degeneration, while intramuscular fat percentages (F per) were evaluated to assay muscle fat replacement following denervation. Neurological disabilities were assessed via the Charcot‐Marie‐Tooth neuropathy score (CMTNS) for correlation with MRI.Results F per values were elevated in HNPP proximal muscle (9.8 ± 2.2%, P = 0.01) compared to controls (6.9 ± 1.0%). We observed this same elevation of HNPP distal muscles (10.5 ± 2.5%, P < 0.01) relative to controls (6.3 ± 1.1%). Additionally, the amplitude of the proximal‐to‐distal gradient in F per was more significant in HNPP patients than controls (P < 0.01), suggesting length‐dependent axonal loss. In contrast, nerve MTR values were similar between HNPP subjects (sciatic/tibial nerves = 39.4 ± 2.0/34.2 ± 2.5%) and controls (sciatic/tibial nerves = 37.6 ± 3.8/35.5 ± 1.2%). Proximal muscle F per values were related to CMTNS (r = 0.69, P = 0.03), while distal muscle F per and sciatic/tibial nerve MTR values were not related to disability.InterpretationDespite the multifocal nature of the HNPP phenotype, muscle F per measurements relate to disability and exhibit a proximal‐to‐distal gradient consistent with length‐dependent axonal loss, suggesting that F per may be a viable biomarker of disease progression in HNPP.