Validation of the Italian version of the Charcot‐Marie‐Tooth disease Pediatric Scale

The Charcot‐Marie‐Tooth disease Pediatric Scale (CMTPedS) is a Rasch‐built clinical outcome measure of disease severity. It is valid, reliable, and responsive to change for children and adolescents aged 3 to 20 years. The aim of this study was to translate and validate an Italian version of the CMTPedS using a validated framework of transcultural adaptation. The CMTPedS (Italian) was translated and culturally adapted from source into Italian by two experts in CMT with good English language proficiency. The two translations were reviewed by a panel of experts in CMT. The agreed provisional version was back translated into English by a professional translator. The definitive Italian version was developed during a consensus teleconference by the same panel. CMT patients were assessed with the final version of the outcome measure and a subset had a second assessment after 2 weeks to evaluate test‐retest reliability. Seventeen patients with CMT aged 5 to 20 years (eight female) were evaluated with the CMTPedS (Italian), and test‐retest was performed in three patients. The CMTPedS (Italian) showed a high test‐retest reliability. No patient had difficulty in completing the scale. The instructions for the different items were clearly understood by clinicians and therefore the administration of the outcome measure was straight forward and easily understood by the children assessed. The CMTPedS (Italian) will be used for clinical follow‐up and in clinical research studies in the Italian population. The data is fully comparable to that obtained from the English language version.     

Functional outcome measures for infantile Charcot‐Marie‐Tooth disease: a systematic review

A functional outcome measure for infants (aged 0–3 years) with Charcot‐Marie‐Tooth (CMT) disease is needed for upcoming disease‐modifying trials. A systematic review of outcome measures for infants with neuromuscular disorders was completed to determine if validated measures were available for the CMT infant population. We assessed 20,375 papers and identified seven functional outcome measures for infants with neuromuscular disorders. Six were developed and validated for spinal muscular atrophy (SMA). There were no CMT‐specific outcome measures identified; however, one (motor function measure) assessed a range of neuromuscular disorders including 13 infants and children with CMT. The included studies exhibited “good” face, discriminant, convergent and concurrent validity, and reported excellent intra‐ and inter‐rater reliability. No outcome measure was subjected to item response theory. Studies reported outcome measures comprising of 51 different items assessing six domains of function: reflexive movement, axial movement, limb movement, positioning, gross motor, and fine‐motor skills. Scoring of items ranged from 2‐ to 7‐point rating scales; and none were scaled to normative reference values to account for changes in growth and development. The SMA focus of most items is likely to produce ceiling effects and lack sensitivity and responsiveness for within and between types of CMT in infants. Nevertheless, several items across scales assessing distal strength, gross‐ and fine‐motor function, could be included in the development of a composite functional outcome measure for infants with CMT to assess disease‐modifying interventions.     

Transitioning outcome measures: relationship between the CMTPedS and CMTNSv2 in children,adolescents, and young adults with Charcot‐Marie‐Tooth disease

Long‐term studies of Charcot‐Marie‐Tooth (CMT) disease across the entire lifespan require stable endpoints that measure the same underlying construct (e.g., disability). The aim of this study was to assess the relationship between the CMT Pediatric Scale (CMTPedS) and the adult CMT Neuropathy Score (CMTNSv2) in 203 children, adolescents, and young adults with CMT. There was a moderate curvilinear correlation between the CMTPedS and the CMTNSv2 (Spearman's rho ρ = 0.716, p < 0.0001), although there appears to be a floor effect of the CMTNSv2 in patients with a milder CMT phenotype. Univariate analyses indicate that the relationship between the CMTPedS and CMTNSv2 scores improves with worsening disease severity and advancing age. Although one universal scale throughout life would be ideal, our data supports the transition from the CMTPedS in childhood to the CMTNSv2 in adulthood as a continuum of measuring lifelong disability in patients with CMT.     

Validation of the Italian version of the Charcot‐Marie‐Tooth Health Index

The Charcot‐Marie‐Tooth Health Index (CMT‐HI) is a disease‐specific patient‐reported outcome measure measuring overall disease burden in Charcot‐Marie‐Tooth (CMT) patients, designed for natural history studies and clinical trials in English‐speaking affected individuals. We developed and validated its Italian Charcot‐Marie‐Tooth Health Index (I‐CMT‐HI) version. The questionnaire was translated and culturally adapted from source into Italian by two neurologists experienced in CMT and neuromuscular disorders (NMDs). The two translations were reviewed by a panel of seven experts in CMT and NMD. The provisional version was back‐translated into English by a professional translator. The definitive Italian version was developed during a consensus teleconference by the panel and a patient representative from ACMT‐Rete. A series of clinically and genetically characterized CMT patients completed the final questionnaire; 11 participated in a test‐retest reliability assessment of the instrument. The I‐CMT‐HI was administered to 30 CMT patients (13 CMT1A, eight CMTX1, two CMT1B, two CMT1E, two CMT2I, one CMT2A, one CMT2N, one distal Hereditary Motor Neuropathy), with test‐rest in 11:14 females and 16 males, aged (mean ± SD) 48.0 ± 16.4 years (range 18‐81), with CMT Examination Score (CMTES) = 10.0 ± 4.4 (range 2‐18). The I‐CMT‐HI mean total score was 29.4 ± 21.2 (range 0.1‐60.3). The I‐CMT‐HI showed a high test‐retest reliability: intraclass correlation coefficient = 0.95 (95% confidence interval, 0.84‐0.99). No patient had difficulty in completing the questionnaire and none reported any problem with the questions' formulation. The total CMT‐HI score was positively correlated with age and CMTES, with higher disease burden with increasing age and disease severity according to the CMTES. The I‐CMT‐HI is now ready for use in clinical studies in the Italian population.     

Systematic review of exercise for Charcot‐Marie‐Tooth disease

Charcot‐Marie‐Tooth disease (CMT) is a slowly progressive hereditary degenerative disease and one of the most common neuromuscular disorders. Exercise may be beneficial to maintain strength and function for people with CMT, however, no comprehensive evaluation of the benefits and risks of exercise have been conducted. A systematic review was completed searching numerous electronic databases from earliest records to February 2015. Studies of any design including participants of any age with confirmed diagnosis of CMT that investigated the effects of exercise were eligible for inclusion. Of 13,301 articles identified following removal of duplicates, 11 articles including 9 unique studies met the criteria. Methodological quality of studies was moderate, sample sizes were small, and interventions and outcome measures used varied widely. Although the majority of the studies identified changes in one or more outcome measurements across exercise modalities, the majority were non‐significant, possibly due to Type II errors. Significant effects described included improvements in strength, functional activities, and physiological adaptations following exercise. Despite many studies showing changes in strength and function following exercise, findings of this review should be met with caution due to the few studies available and moderate quality of evidence. Well‐powered studies, harmonisation of outcome measures, and clearly described interventions across studies would improve the quality and comparability of the evidence base. The optimal exercise modality and intensity for people with CMT as well as the long‐term safety of exercise remain unclear.     

POLG mutations presenting as Charcot‐Marie‐Tooth disease

We report on two patients, with different POLG mutations, in whom axonal neuropathy dominated the clinical picture. One patient presented with late onset sensory axonal neuropathy caused by a homozygous c.2243G>C (p.Trp748Ser) mutation that resulted from uniparental disomy of the long arm of chromosome 15. The other patient had a complex phenotype that included early onset axonal Charcot‐Marie‐Tooth disease (CMT) caused by compound heterozygous c.926G>A (p.Arg309His) and c.2209G>C (p.Gly737Arg) mutations.     

Prospective study of muscle cramps in Charcot‐Marie‐Tooth disease

Introduction: This study aims to assess the frequency, location, severity, duration, and fluctuation over time of muscle cramps in Charcot‐Marie‐Tooth disease (CMT). Methods: Inherited Neuropathies Consortium Contact Registry participants recorded the occurrence and characteristics of muscle cramps using an 11‐question survey administered 3 times over 8 weeks. Results: A total of 110 adult patients with CMT completed the survey. Weekly cramp frequency was 9.3 (SD 12.3), and 23% had daily muscle cramps. Twenty‐two percent reported a significant impact on quality of life. Over 8 weeks, the daily frequency and severity of muscle cramps did not change significantly. Conclusions: Patients with CMT have muscle cramps that vary little over an 8‐week period, and they may interfere with quality of life. These data may be useful in the planning of clinical trials of agents to treat adults with CMT‐associated muscle cramps. Muscle Nerve 51: 485–488, 2015     

Autosomal recessive Charcot‐Marie‐Tooth disease: from genes to phenotypes

The prevalence of Charcot‐Marie‐Tooth (CMT) disease or hereditary motor and sensory neuropathy (HMSN) varies in different populations. While in some countries of Western Europe, the United States and Japan the dominant form of HMSN is the most frequent, in other countries such as those of the Mediterranean Basin, the autosomal recessive form (AR‐CMT) is more common. Autosomal recessive CMT cases are generally characterized by earlier onset, usually before the age of 2 or 3 years, and rapid clinical progression that results in severe polyneuropathy and more marked distal limb deformities such as pes equino‐varus, claw‐like hands, and often major spinal deformities. Recent clinical, morphological and molecular investigations of CMT families with autosomal recessive inheritance allowed the identification of many genes such as GDAP1, MTMR2, SBF2, NDRG1, EGR2, SH3TC2, PRX, FGD4, and FIG4, implicated in demyelinating forms (ARCMT1 or CMT4), and LMNA, MED25, HINT1, GDAP1, LRSAM1, NEFL, HSPB1 and MFN2 in axonal forms (ARCMT2). However, many patients remain without genetic diagnosis to date, prompting investigations into ARCMT families in order to help discover new genes and common pathways. This review summarizes recent advances regarding the genotypes and corresponding phenotypes of AR‐CMT.     

Innovative quantitative testing of hand function in Charcot‐Marie‐Tooth neuropathy

To describe a new test to quantitatively evaluate hand function in patients affected by Charcot‐Marie‐Tooth neuropathy (CMT). The sensor‐engineered glove test (SEGT) was applied to CMT patients (N: 26) and compared with a cohort of healthy controls (HC, N: 26). CMT patients were further divided into subjects with clinically normal (group 1) or impaired hand (group 2) function. The SEGT parameters evaluated were touch duration, inter‐tapping interval, and movement rate parameters of two different sequences: finger tapping (FT) and index‐medium‐ring‐little (IMRL) performed at self‐paced mode (SPM) and maximum velocity (MV). Hand function and strength were assessed by the 9‐hole peg test (9HPT) and dynamometry. Disability of patients was measured by the CMT neuropathy score. CMT patients had significantly worst performances at SEGT than controls regarding the rate of execution of both FT (at MV) and IMRL sequences (at SPM and MV). The rate parameter at MV in IMRL sequence showed a significant trend of decreasing in its average between HC (n: 26, rate = 3.08 ± 0.52 Hz), group 1 (n: 9, rate = 2.64 ± 0.66 Hz) and group 2 (n: 17, rate = 2.19 ± 0.45 Hz) (p for trend <0.001). No correlations were found with either 9HPT, dynamometry, electrophysiology, and the CMT neuropathy score. The SEGT test is sensitive to show hand dysfunction in CMT patients, with and without clinically impaired hands.     

A pilot study of proximal strength training in Charcot‐Marie‐Tooth disease

Gait analysis of people with Charcot‐Marie‐Tooth (CMT) disease revealed proximal adaptive gait strategies to compensate for foot drop. We previously demonstrated that hip flexor muscle fatigue can limit walking endurance. This pilot study used a single‐blinded cross over design to investigate the effect of a 16‐week home‐based programme of resistance training on hip flexor muscle strength. Measures of walking endurance, gait speed, exertion, fatigue, and general activity were also recorded. The exercise protocol was based on American College of Sports Medicine recommendations. A mixed effects model was used for analysis. Twenty‐six people finished the study, with average reported exercise participation of 93%. No negative effects of exercise were observed. Significant increase in hip flexor muscle strength was observed on the left, but not the right. No changes were observed in walking speed and endurance measures. This pilot study of home‐based resistance training showed a modest improvement in hip strength but only on one side. The lack of a more significant improvement and no improvement in walking measures suggests that this training protocol may not be optimal for people with CMT and that patients may need to stratified differently for training studies in CMT.     

Handwriting difficulties of children with Charcot‐Marie‐Tooth disease type 1A

Hand weakness and impaired manual dexterity have been reported in children with Charcot‐Marie‐Tooth disease type 1A (CMT1A). This early onset of upper limb involvement might explain frequent clinical referrals for assessment and treatment of impaired handwriting performance. The aim of this study was to examine the impact of CMT1A on handwriting speed and legibility, and identify demographic, anthropometric, and physical measures that might relate to handwriting performance. Handwriting speed (Handwriting Speed Test), handwriting legibility (Evaluation Tool of Children's Handwriting‐Cursive), and hand strength (hand‐held dynamometry of tip pinch, lateral pinch and grip) were assessed in 30 children with CMT1A (aged 8–17 years) and 30 age‐ and sex‐matched controls. Children with CMT1A exhibited 34% slower handwriting speed (p < 0.0001) with 4% reduced legibility (p = 0.001) and 37–48% lower hand strength (p < 0.0001). All measures of strength, age, height, and weight were positively associated with handwriting speed (r = 0.39–0.79, p < 0.01). None of these factors related to handwriting legibility (p > 0.05). Regression modelling identified a diagnosis of CMT1A, lateral pinch weakness and younger age as significant independent predictors of slower handwriting speed, explaining 78% of the variance. Children with CMT1A have considerable handwriting difficulties, primarily with speed, and substantial associated hand and finger weakness. Understanding the cause–effect relationship between strength and function might provide modifiable targets for upper limb intervention.     

Novel GARS mutation presenting as autosomal dominant intermediate Charcot‐Marie‐Tooth disease

We report the first family with a glycyl‐tRNA synthetase (GARS) mutation with autosomal dominant intermediate Charcot‐Marie‐Tooth disease (DI‐CMT). The proband and the proband's father presented with gait disturbance and hand weakness. Both patients displayed moderately decreased conduction velocities (MNCV) (ranging from 29.2 to 37.8 m/s). A sural nerve biopsy of the father revealed evidence of both axonal loss and demyelination. On exome sequencing, in both the proband and his father, we identified a novel missense mutation (c.643G > C, p.Asp215His) in the GARS gene in a heterozygous state, which is considered to be pathogenic for this DI‐CMT family. The present study broadens current knowledge about intermediate CMT and the phenotypic spectrum of defects associated with GARS.     

Clinical and genetic diversities of Charcot‐Marie‐Tooth disease with MFN2 mutations in a large case study

Charcot‐Marie‐Tooth disease (CMT) constitutes a heterogeneous group affecting motor and sensory neurons in the peripheral nervous system. MFN2 mutations are the most common cause of axonal CMT. We describe the clinical and mutational spectra of CMT patients harboring MFN2 mutations in Japan. We analyzed 1,334 unrelated patients with clinically suspected CMT referred by neurological and neuropediatric departments throughout Japan. We conducted mutation screening using a DNA microarray, targeted resequencing, and whole‐exome sequencing. We identified pathogenic or likely pathogenic MFN2 variants from 79 CMT patients, comprising 44 heterozygous and 1 compound heterozygous variants. A total of 15 novel variants were detected. An autosomal dominant family history was determined in 43 cases, and the remaining 36 cases were reported as sporadic with no family history. The mean onset age of CMT in these patients was 12 ± 14 (range 0–59) years. We observed neuropathic symptoms in all patients. Some had optic atrophy, vocal cord paralysis, or spasticity. We detected a compound heterozygous MFN2 mutation in a patient with a severe phenotype and the co‐occurrence of MFN2 and PMP22 mutations in a patient with an uncommon phenotype. MFN2 is the most frequent causative gene of CMT2 in Japan. We present 15 novel variants and broad clinical and mutational spectra of Japanese MFN2‐related CMT patients. Regardless of the onset age and inheritance pattern, MFN2 gene analysis should be performed. Combinations of causative genes should be considered to explain the phenotypic diversity.     

Long‐term walking ability and patient satisfaction after lower limb functional surgery in patients affected by Charcot‐Marie‐Tooth disease: A retrospective study

Structural foot deformities consequent to Charcot Marie Tooth (CMT) can be treated by functional surgery (FS). This study aims to evaluate both long‐term walking ability and patients' satisfaction in CMT subjects who underwent FS during their lifetime. We conducted a retrospective observational study. Age, sex, CMT type, comprehensive surgical history, current walking ability assessed by the Walking Handicap Scale (WHS) and patients' global impression of change (pGIC) were retrieved from a custom database managed at our institution. WHS and pGIC were assessed between mid‐2018 and mid‐2019. Data from 79 patients were screened and 63 were included, 35W‐28M, mean age 42 (15), with demyelinating (75%), axonal (20%), and other types (5%) of CMT, who underwent FS between 1967 and 2018. FS evolved significantly over the years from bone‐related procedures (e.g., arthrodesis) to both bone and soft tissues‐related procedures. The re‐intervention rate decreased from 70% before 2000 to 32% in the last decade. Complications arose in five cases. FS was mainly performed on adults (73%). WHS was ≥ 5 in three‐quarters of the sample (range 1‐6) and was significantly affected by age groups in patients with demyelinating CMT (n=47, p<0.01, non‐parametric ANOVA). Nearly 80% of patients were satisfied with FS (pGIC ≥ 4). In conclusion, CMT subjects who underwent FS surgery maintained a high gait efficiency in the long‐term period, with middle to high levels of satisfaction in the majority of the cases. This confirms the validity of FS in the management of acquired foot deformities in CMT patients.     

Screening of dominantly inherited Charcot–Marie–Tooth neuropathies

Sixty-three families with dominantly inherited Charcot–Marie–Tooth (CMT) neuropathies including 730 subjects (total) from which 356 affected were studied clinically, electrophysiologically (MNCVs and EMGs), by genetic linkage, and screened for DNA duplication. Thirtyeight families (60.3%) were type 1A (demyelinating CMT mapped on chromosome 17). DNA duplication was present in 36 families (94.8% of CMT1A families). One CMT1A family (2.6%) showed no duplication but suggested genetic linkage with markers of chromosome 17. One CMT1A family (2.6%) revealed nonduplication in some affected members and duplication in other affected members. The disease in that family segregated with the same chromosome 17 markers regardless of duplication status. The other CMT families with dominant inheritance but without duplication included one family with CMT1B (demyelinating CMT mapped on chromosome 1) (1.6%), 14 families with CMT2 axonal neuropathy (22.2%), and 10 families with X-linked dominant CMT (15.9%). © 1993 John Wiley & Sons, Inc.