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.     

Psychometrics evaluation of Charcot‐Marie‐Tooth Neuropathy Score (CMTNSv2) second version,using Rasch analysis

Charcot‐Marie‐Tooth Neuropathy Score second version (CMTNSv2) is a validated clinical outcome measure developed for use in clinical trials to monitor disease impairment and progression in affected CMT patients. Currently, all items of CMTNSv2 have identical contribution to the total score. We used Rasch analysis to further explore psychometric properties of CMTNSv2, and in particular, category response functioning, and their weight on the overall disease progression. Weighted category responses represent a more accurate estimate of actual values measuring disease severity and therefore could potentially be used in improving the current version. Copyright © 2014 John Wiley & Sons, Ltd.     

Phrenic nerve involvement and respiratory muscle weakness in patients with Charcot‐Marie‐Tooth disease 1A

Diaphragm weakness in Charcot‐Marie‐Tooth disease 1A (CMT1A) is usually associated with severe disease manifestation. This study comprehensively investigated phrenic nerve conductivity, inspiratory and expiratory muscle function in ambulatory CMT1A patients. Nineteen adults with CMT1A (13 females, 47 ± 12 years) underwent spiromanometry, diaphragm ultrasound, and magnetic stimulation of the phrenic nerves and the lower thoracic nerve roots, with recording of diaphragm compound muscle action potentials (dCMAP, n = 15), transdiaphragmatic and gastric pressures (twPdi and twPgas, n = 12). Diaphragm motor evoked potentials (dMEP, n = 15) were recorded following cortical magnetic stimulation. Patients had not been selected for respiratory complaints. Disease severity was assessed using the CMT Neuropathy Scale version 2 (CMT‐NSv2). Healthy control subjects were matched for age, sex, and body mass index. The following parameters were significantly lower in CMT1A patients than in controls (all P < .05): forced vital capacity (91 ± 16 vs 110 ± 15% predicted), maximum inspiratory pressure (68 ± 22 vs 88 ± 29 cmH₂O), maximum expiratory pressure (91 ± 23 vs 123 ± 24 cmH₂O), and peak cough flow (377 ± 135 vs 492 ± 130 L/min). In CMT1A patients, dMEP and dCMAP were delayed. Patients vs controls showed lower diaphragm excursion (5 ± 2 vs 8 ± 2 cm), diaphragm thickening ratio (DTR, 1.9 [1.6‐2.2] vs 2.5 [2.1‐3.1]), and twPdi (8 ± 6 vs 19 ± 7 cmH₂O; all P < .05). DTR inversely correlated with the CMT‐NSv2 score (r = ?.59, P = .02). There was no group difference in twPgas following abdominal muscle stimulation. Ambulatory CMT1A patients may show phrenic nerve involvement and reduced respiratory muscle strength. Respiratory muscle weakness can be attributed to diaphragm dysfunction alone. It relates to neurological impairment and likely reflects a disease continuum.     

A novel mutation of LRSAM1 in a Chinese family with Charcot‐Marie‐Tooth disease

Charcot‐Marie‐Tooth (CMT) disease is the most common inherited peripheral neuropathy characterized by progressive distal muscle weakness and atrophy with decreased or absent tendon reflexes. Mutations in LRSAM1 have been identified to cause CMT disease type 2P. We report a novel LRSAM1 mutation c.2021‐2024del (p.E674VfsX11) in a Chinese autosomal dominant CMT disease type 2 family. The phenotype was characterized by late onset and mild sensory impairment. Electrophysiological findings showed normal or mildly to moderately reduced motor and sensory nerve conduction velocities in lower and upper limb nerves.     

Diabetes mellitus exacerbates motor and sensory impairment in CMT1A

Abstract Charcot‐Marie‐Tooth disease type 1A (CMT1A) is caused by a duplication of PMP22 on chromosome 17 and is the most commonly inherited demyelinating neuropathy. Diabetes frequently causes predominantly sensory neuropathy. Whether diabetes exacerbates CMT1A is unknown. We identified 10 patients with CMT1A and diabetes and compared their impairment with 48 age‐matched control patients with CMT1A alone. Comparisons were made with the Charcot‐Marie‐Tooth disease (CMT) neuropathy score (CMTNS) and by electrophysiology. The CMTNS was significantly higher in patients with diabetes (20.25 ± 2.35) compared with controls (15.19 ± 0.69; p = 0.01). Values were particularly higher for motor signs and symptoms. Seven of the 10 diabetic patients had CMTNS >20 (severe CMT), while only 7 of the 48 age‐matched controls had scores >20. There was a trend for CMT1A patients with diabetes to have low compound muscle action potentials and sensory nerve action potentials, although nerve conduction velocities were not slower in diabetic patients compared with controls. Diabetes was associated with more severe motor and sensory impairment in patients with CMT1A.     

A novel NDRG1 mutation in a non‐Romani patient with CMT4D/HMSN‐Lom

Charcot‐Marie‐Tooth disease type 4D (CMT4D), also known as hereditary motor and sensory neuropathy Lom type (HMSNL), is an autosomal recessive, early onset, severe demyelinating neuropathy with hearing loss, caused by N‐Myc downstream‐regulated gene 1 (NDRG1) mutations. CMT4D is rare with only three known mutations, one of which (p.Arg148Ter) is found in patients of Romani ancestry and accounts for the vast majority of cases. We report a 38‐year‐old Italian female with motor development delay, progressive neuropathy, and sensorineural deafness. Magnetic resonance imaging showed slight atrophy of cerebellum, medulla oblongata, and upper cervical spinal cord. She had a novel homozygous NDRG1 frameshift mutation (c.739delC; p.His247ThrfsTer74). The identification of this NDRG1 mutation confirms that CMT4D is not a private Romani disease and should be considered in the differential diagnosis of recessive demyelinating 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.     

Mutational screening of the SH3TC2 gene in Greek patients with suspected demyelinating recessive Charcot‐Marie‐Tooth disease reveals a varied and unusual phenotypic spectrum

Charcot‐Marie‐Tooth disease type 4 C (CMT4C) is an autosomal recessive form of demyelinating peripheral neuropathy caused by mutations in SH3TC2, characterized by early onset, spine deformities, and cranial nerve involvement. We screened SH3TC2 in 50 unrelated Greek patients with suspected demyelinating Charcot‐Marie‐Tooth disease and pedigree compatible with recessive inheritance. All patients had been previously screened for PMP22, GJB1, and MPZ mutations. We found five previously identified pathogenic mutations in SH3TC2 distributed among 13 patients in homozygosity or compound heterozygosity (p. Arg954Stop, Arg1109Stop, Gln892Stop, Ala878Asp, and Arg648Trp). Although most cases had early onset and spine deformities were almost omnipresent, a wide phenotypic spectrum was observed. Particularly notable were two siblings with Roussy‐Lévy syndrome and one patient with young‐onset trigeminal neuralgia. In conclusion, mutations in SH3TC2 are responsible for 26% of Greek patients with suspected CMT4, identifying CMT4C as the most common recessive demyelinating neuropathy in the Greek population, in accordance with other Mediterranean cohorts.     

Reliability of the Charcot‐Marie‐Tooth functional outcome measure

The CMT‐FOM is a 13‐item clinical outcome assessment (COA) that measures physical ability in adults with Charcot‐Marie‐Tooth disease (CMT). Test‐retest reliability, internal consistency and convergent validity have been established for the CMT‐FOM. This current study sought to establish inter‐rater reliability. Following an in‐person training of six international clinical evaluators we recruited 10 participants with genetically diagnosed CMT1A, (aged 18‐74 years, 6 female). Participants were evaluated using the CMT‐FOM over 2 days. Participants were given at least a 3 hour rest between evaluations, and were assessed twice each day. Following the provision of training by master trainers, all 13 items of the CMT‐FOM exhibited excellent inter‐rater reliability for raw scores (ICC_1,1 0.825‐0.989) and z‐scores (ICC_1,1 0.762‐0.969). Reliability of the CMT‐FOM total score was excellent (ICC_1,1 0.983, 95% CI 0.958‐0.995). The CMT‐FOM is a reliable COA used by clinical evaluators internationally. The next steps are to establish further validation through psychometric evaluation of the CMT‐FOM in the Accelerate Clinical Trials in CMT (ACT‐CMT) study.     

A novel INF2 mutation in a Korean family with autosomal dominant intermediate Charcot‐Marie‐Tooth disease and focal segmental glomerulosclerosis

Mutations in the inverted formin‐2 (INF2) gene were recently identified in patients with autosomal dominant intermediate Charcot‐Marie‐Tooth (DI‐CMT) disease and focal segmental glomerulosclerosis (FSGS). Here, we identified a novel p.L132P INF2 mutation in a Korean family with DI‐CMT and FSGS by whole‐exome sequencing. This mutation was cosegregated with affected individuals in the family and was not found in the 300 controls. The two affected members exhibited juvenile onset sensorimotor polyneuropathy and FSGS. Nerve conduction studies showed an intermediate range of motor nerve conduction velocities. We report a novel INF2 mutation in a family with DI‐CMT and FSGS as the first case in Koreans. The INF2 mutation appears to be a major cause of CMT with FSGS.     

Early onset Charcot‐Marie‐Tooth neuropathy type 2A and severe developmental delay: expanding the clinical phenotype of MFN2‐related neuropathy

Charcot‐Marie‐Tooth (CMT) syndromes are a group of clinically heterogeneous disorders of the peripheral nervous system. Mutations of mitofusin 2 (MFN2) have been recognized to be associated with CMT type 2A (CMT2A). CMT2A is primarily an axonal disorder resulting in motor and sensory neuropathy. We report a male child with psychomotor delay, dysmorphic features, and weakness of lower limbs associated with electrophysiological features of severe, sensory‐motor, axonal neuropathy. The patient was diagnosed with early onset CMT2A and severe psychomotor retardation associated with c.310C>T mutation (p.R104W) in MFN2 gene. CMT2A should be considered in patients with both axonal sensory‐motor neuropathy and developmental delay.     

Intermediate Charcot–Marie–Tooth disease: an electrophysiological reappraisal and systematic review

Charcot–Marie–Tooth disease (CMT) is the most frequent form of inherited neuropathy with great variety of phenotypes, inheritance patterns, and causative genes. According to median motor nerve conduction velocity (MNCV), CMT is divided into demyelinating (CMT1) with MNCV below 38 m/s, axonal (CMT2) with MNCV above 38 m/s, and intermediate CMT with MNCV between 25 and 45 m/s. In each category, transmission may be autosomal dominant, autosomal recessive, or X-linked. The nosology of intermediate CMT is controversial because of concerns about electrophysiological delimitation. A systematic computer-based literature search was conducted on PubMed, using the following MeSH: (1) intermediate Charcot–Marie–Tooth; (2) X-linked intermediate Charcot–Marie–Tooth; and (3) X-linked Charcot–Marie–Tooth and electrophysiology. We retrieved 225 articles reporting X-linked CMT or intermediate CMT with electrophysiological information. After eligibility, 156 papers were used for this review. In assessing median MNCV, compound muscle action potential (CMAP) amplitudes were taken into account. In cases with attenuated CMAP and wherever possible, proximal median MNCV was used for accurate definition of conduction slowing in the intermediate range. In the vast majority of males with X-linked CMT associated with GJB1 mutation (CMTX1), median MNCV was intermediate. CMT associated with DRP2 mutation is another well-documented X-linked intermediate disorder. Autosomal dominant intermediate CMT (DI-CMT) encompasses 11 different types; six of them with assigned phenotype MIM number and the remaining five being unnumbered. Based on available electrophysiological information, we wonder if DI-CMTA should be reclassified within CMT2. Autosomal recessive intermediate CMT (RI-CMT) covers four numbered MIM phenotypes though, in accordance with reported electrophysiology, two of them (RI-CMTB and RI-CMTD) should probably be reclassified within AR-CMT2. We conclude that intermediate CMT is a complex inherited syndrome, whose characterization requires a specific electrophysiological protocol comprising evaluation of upper limb proximal nerve trunks when distal CMAP amplitudes are reduced, and that an updated version of MIM phenotype numbering is needed.     

Histopathological features of a patient with Charcot‐Marie‐Tooth disease type 2U/AD‐CMTax‐MARS

Charcot‐Marie‐Tooth (CMT) disease is a complex of peripheral nervous system disorders. CMT type 2U (CMT2U) is an autosomal dominant (AD) disease caused by mutations in the MARS gene encoding methionyl‐tRNA synthetase; this disease has thus been newly called AD‐CMTax‐MARS. A few families with mutations in the MARS gene have been reported, without detailed histopathological findings. We describe a 70‐year‐old woman who had bilateral dysesthesia of the soles since the age of 66 years. Sural nerve biopsy showed a decrease in the density of large myelinated nerve fibers. Increased clusters of regenerating myelinated nerve fibers were noted. Electron microscopic analyses revealed degeneration of unmyelinated nerves. There was no vasculitis or inflammatory cell infiltration. Genetic analysis identified a heterozygous p.P800T mutation, a reported mutation in the MARS gene. We report the detailed histopathological findings in a patient with CMT2U/AD‐CMTax‐MARS. The findings are similar to those found in CMT2D caused by mutations in the GARS gene, encoding glycyl‐tRNA synthetase.     

CMT4D (NDRG1 mutation): genotype–phenotype correlations

Charcot‐Marie‐Tooth (CMT) disease is a heterogeneous condition with a large number of clinical, electrophysiological and pathological phenotypes. More than 40 genes are involved. We report a child of gypsy origin with an autosomal recessive demyelinating phenotype. Clinical data, familial history, and electrophysiological studies were in favor of a CMT4 sub‐type. The characteristic N‐Myc downstream‐regulated gene 1 (NDRG1) mutation responsible for this CMT4D phenotype was confirmed: p.R148X. The exact molecular function of the NDRG1 protein has yet to be elucidated.     

Relationship between physical performance and quality of life in Charcot‐Marie‐Tooth disease: a pilot study

Charcot‐Marie‐Tooth (CMT) is a rare inherited peripheral neuropathy in which quality of life (QoL) is reduced compared with the general population. This paper investigates the relationship between QoL and physical performance in people with CMT with the aim of identifying avenues for future research into rehabilitation strategies. Cross‐sectional data was obtained from 10 participants (5 men, 5 women, age 46 ± 13 years, height 1.7 ± 0.1 m, body mass 77 ± 17 kg) with CMT (CMT1A n = 5; CMT‐X n = 3; unknown genetic origin n = 2). Participants were evaluated for QoL, falls efficacy (FES), balance, mobility, muscle strength, and power. Physical component score (PCS) of the Short Form‐36 (SF‐36) was significantly and directly related to higher leg press power (r = 0.75, p = 0.02). Better FES scores were significantly related to faster habitual gait speed (r = ?0.70, p = 0.02), left hip abduction, and seated row strength (r = ?0.68, p = 0.03; r = ?0.73, p = 0.03, respectively). Future research should aim to substantiate these preliminary findings in a larger cohort and investigate whether interventions targeting muscle strength and power can improve QoL and mobility outcomes in people with CMT.     

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     

Successful Treatment of Charcot‐Marie‐Tooth Chronic Pain with Spinal Cord Stimulation: A Case Study

Objectives: Charcot‐Marie‐Tooth (CMT) disease is one of the most common hereditary neuropathies affecting one in 2500 people in the United States. CMT disease is associated with moderate to severe chronic extremity pain. We present the case of a young man with chronic intractable lower extremity pain associated with CMT disease treated with spinal cord stimulation (SCS). Materials and Methods: This was an Institutional Review Board‐approved case study involving a 37‐year‐old man diagnosed with CMT disease with pain of more than 20 years. He was implanted with an SCS device and patient pain and quality of life was assessed one and six months later using the SF‐McGill Pain Questionnaire, Visual Analog Scale, Oswestry Disability Questionnaire, Pain Disability Index, and SF‐36. Baseline measures were obtained retrospectively. Qualitative data were collected from the medical record. Results: SCS was effective in decreasing pain, improving quality of life and reducing medication consumption at both one and six months post‐implant. In addition, the patient was satisfied with SCS treatment. Conclusion: SCS produced favorable results in a patient with CMT and should be considered a treatment option for pain resulting from this condition.     

Clinical characterization and genetic analysis of Korean patients with X‐linked Charcot‐Marie‐Tooth disease type 1

Mutations in the gap junction protein beta 1 gene (GJB1) cause X‐linked Charcot‐Marie‐Tooth disease type 1 (CMTX1). CMTX1 is representative of the intermediate type of CMT, having both demyelinating and axonal neuropathic features. We analyzed the clinical and genetic characterization of 128 patients with CMTX1 from 63 unrelated families. Genetic analysis revealed a total of 43 mutations including 6 novel mutations. Ten mutations were found from two or more unrelated families. p.V95M was most frequently observed. The frequency of CMTX1 was 9.6% of total Korean CMT family and was 14.8% when calculated within genetically identified cases. Among 67 male and 61 female patients, 22 females were asymptomatic. A high‐arched foot, ataxia, and tremor were observed in 87%, 41%, and 35% of the patients, respectively. In the male patients, functional disability scale, CMT neuropathy score, and compound muscle action potential of the median/ulnar nerves were more severely affected than in the female patients. This study provides a comprehensive summary of the clinical features and spectrum of GJB1 gene mutations in Korean CMTX1 patients.     

Insights into the pathogenesis of ATP1A1‐related CMT disease using patient‐specific iPSCs

The development of patient‐specific induced pluripotent stem cells (iPSCs) offered interesting insights in modeling the pathogenesis of Charcot‐Marie‐Tooth (CMT) disease and thus we decided to explore the phenotypes of iPSCs derived from a single CMT patient carrying a mutant ATP1A1 allele (p.Pro600Ala). iPSCs clones generated from CMT and control fibroblasts, were induced to differentiate into neural precursors and then into post‐mitotic neurons. Control iPSCs differentiated into neuronal precursors and then into post‐mitotic neurons within 6‐8 days. On the contrary, the differentiation of CMT iPSCs was clearly defective. Electrophysiological properties confirmed that post‐mitotic neurons were less mature compared to the normal counterpart. The impairment of in vitro differentiation of CMT iPSCs only concerned with the neuronal pathway, because they were able to differentiate into mesendodermal cells and other ectodermal derivatives. ATP1A1 was undetectable in the few neuronal cells derived from CMT iPSCs. ATP1A1 gene mutation (p.Pro600Ala), responsible for a form of axonal CMT disease, is associated in vitro with a dramatic alteration of the differentiation of patient‐derived iPSCs into post‐mitotic neurons. Thus, the defect in neuronal cell development might lead in vivo to a decreased number of mature neurons in ATP1A1‐CMT disease.     

X‐linked Charcot–Marie–Tooth disease predominates in a cohort of multiethnic Malaysian patients

Introduction: Data regarding Charcot–Marie–Tooth disease is lacking in Southeast Asian populations. We investigated the frequency of the common genetic mutations in a multiethnic Malaysian cohort. Methods: Patients with features of Charcot–Marie–Tooth disease or hereditary liability to pressure palsies were investigated for PMP22 duplication, deletion, and point mutations and GJB1, MPZ, and MFN2 point mutations. Results: Over a period of 3 years, we identified 25 index patients. A genetic diagnosis was reached in 60%. The most common were point mutations in GJB1, accounting for X‐linked Charcot–Marie–Tooth disease (24% of the total patient population), followed by PMP22 duplication causing Charcot–Marie–Tooth disease type 1A (20%). We also discovered 2 novel GJB1 mutations, c.521C>T (Proline174Leucine) and c.220G>A (Valine74Methionine). Conclusions: X‐linked Charcot–Marie–Tooth disease was found to predominate in our patient cohort. We also found a better phenotype/genotype correlation when applying a more recently recommended genetic approach to Charcot–Marie–Tooth disease. Muscle Nerve 49 : 198–201, 2014