Charcot-Marie-Tooth Patients Research Articles

Catheter-based distal sciatic nerve block in patients with Charcot-Marie-Tooth disease

BackgroundThe use of peripheral nerve blocks in patients with Charcot-Marie-Tooth (CMT) disease is scarcely reported; however, when performed it has proven to be effective for postoperative pain control.MethodsA distal catheter-based sciatic nerve block for postoperative pain control was offered to 27 consecutive CMT patients scheduled for elective foot surgery. 18 of the 27 CMT patients consented to the offered sciatic nerve block. Localization of the sciatic nerve was guided by a nerve stimulator. The threshold current required to generate a motor response was assessed and a catheter inserted. Postoperative pain was assessed by recording the dose of analgesics to maintain visual analog score < 3 the next 48 hours. On demand patients received boluses of ropivacaine (2 mg/mL) via the catheter and/or analgesics in case of insufficient pain relief. Total postoperative ropivacaine dosage and analgesic consumption were recorded. About one year after the block patients were contacted to report their actual status by self-assessment.ResultsIn 17 patients a catheter could be placed. In 7 patients placement of the catheter was difficult (several attempts, high electrical impedance). Patients with nerve block had lower analgesics consumption compared to patients without a block. Surprisingly, the 7 patients with “difficult” catheter-placement had the overall lowest ropivacaine and analgesics consumption compared to all other patients with or without peripheral block. No anesthesia related complications were reported by the questionnaire.ConclusionsIn our small series catheter-based distal sciatic block within CMT patients had safely been used for pain relief up to three days. The infusion of local anesthetics via a catheter was not associated with any complication.

Genetics of Charcot-Marie-Tooth (CMT) Disease within the Frame of the Human Genome Project Success

Charcot-Marie-Tooth (CMT) neuropathies comprise a group of monogenic disorders affecting the peripheral nervous system. CMT is characterized by a clinically and genetically heterogeneous group of neuropathies, involving all types of Mendelian inheritance patterns. Over 1,000 different mutations have been discovered in 80 disease-associated genes. Genetic research of CMT has pioneered the discovery of genomic disorders and aided in understanding the effects of copy number variation and the mechanisms of genomic rearrangements. CMT genetic study also unraveled common pathomechanisms for peripheral nerve degeneration, elucidated gene networks, and initiated the development of therapeutic approaches. The reference genome, which became available thanks to the Human Genome Project, and the development of next generation sequencing tools, considerably accelerated gene and mutation discoveries. In fact, the first clinical whole genome sequence was reported in a patient with CMT. Here we review the history of CMT gene discoveries, starting with technologies from the early days in human genetics through the high-throughput application of modern DNA analyses. We highlight the most relevant examples of CMT genes and mutation mechanisms, some of which provide promising treatment strategies. Finally, we propose future initiatives to accelerate diagnosis of CMT patients through new ways of sharing large datasets and genetic variants, and at ever diminishing costs.

Animal models and therapeutic prospects for Charcot–Marie–Tooth disease

Charcot-Marie-Tooth (CMT) neuropathies are inherited neuromuscular disorders caused by a length-dependent neurodegeneration of peripheral nerves. More than 900 mutations in 60 different genes are causative of the neuropathy. Despite significant progress in therapeutic strategies, the disease remains incurable. The increasing number of genes linked to the disease, and their considerable clinical and genetic heterogeneity render the development of these strategies particularly challenging. In this context, cellular and animals models provide powerful tools. Efficient motor and sensory tests have been developed to assess the behavioral phenotype in transgenic animal models (rodent and fly). When these models reproduce a phenotype comparable to CMT, they allow therapeutic approaches and the discovery of modifiers and biomarkers. In this review, we describe the most convincing transgenic rodent and fly models of CMT and how they can lead to clinical trial. We also discuss the challenges that the research, the clinic, and the pharmaceutical industry will face in developing efficient and accessible treatment for CMT patients.

Neuropathic pain in hereditary peripheral neuropathy

Charcot-Marie-Tooth (CMT) disease is the most common inherited motor and sensory neuropathy. Previous studies have shown that neuropathic pain is an occasional symptom of CMT referred by CMT patients. However, neuropathic pain is not considered a significant symptom in CMT patient and no researchers have studied profoundly the pathophysiology of neuropathic pain in CMT. Here, we highlight the relationship between CMT disease and neuropathic pain via previous several studies.

Functional and dynamic response characteristics of a custom composite ankle foot orthosis for Charcot–Marie–Tooth patients

BackgroundCustom carbon-fiber composite ankle foot orthoses (AFOs) have been anecdotally reported to improve gait of Charcot–Marie–Tooth (CMT) patients. The purpose of the study was to characterize the spatio-temporal, joint kinetic and mechanical responses of a custom carbon fiber AFO during locomotion for persons diagnosed with CMT. MethodsEight volunteers were fitted with custom AFOs. Three of the devices were instrumented with eight strain gauges to measure surface deformation of the shell during dynamic function. Following a minimum 10 weeks accommodation period, plantar- and dorsiflexor strength was measured bilaterally. Volunteers then walked unbraced and braced, at their preferred pace over a force platform and instrumented walkway while being tracked with a 12-camera motion capture system. Strength, spatio-temporal and lower extremity joint kinetic parameters were evaluated between conditions (single subject) using the model statistic procedure. Mechanical loads were presented descriptively. ResultsAll participants walked faster (89.4±13.3 vs 115.6±18.0cm/s) in the braced condition with ankle strength negatively correlated to speed increase. As Δvelocity increased, maximum joint moments during loading response shifted from the hip joint to the ankle and knee joints. During propulsion, the hip joint moment dominated. Subjects exhibiting the greatest and least Δvelocity imposed an average load of 54.6% and 16.6% of body weight on the braces, respectively. Energy storage in the brace averaged 9.6±6.6J/kg. ConclusionSubject-specific effects of a custom AFO on gait for CMT patients were documented. The force-deflection properties of carbon-fiber composite braces may be important considerations in their design.

Mutation of SIMPLE in Charcot‐Marie‐Tooth 1C Alters Production of Exosomes

Charcot‐Marie‐Tooth (CMT) disease is an inherited neurological disorder. Mutations in protein SIMPLE accounts for the rare autosomal dominant demyelination in type 1C CMT patients (CMT1C). Understanding the molecular basis of CMT1C pathogenesis is impeded, in part, by the perplexity for the role of SIMPLE, an evolutionarily conserved protein expressed in multiple cell types. Here, we show that SIMPLE plays a role in the production of exosomes, which are nanovesicles secreted extracellularly. We find that SIMPLE resides within the intraluminal vesicles of multivesicular bodies and inside exosomes. Expression of SIMPLE increases the production of exosomes. Conversely, endogenous SIMPLE carrying CMT1C mutation in primary mouse embryonic fibroblasts shows reduced secretion of exosomes, in part, due to improper formation of MVBs. CMT1C patient B cells also show similar defects in exosomes and MVBs. Together, these data indicate that SIMPLE regulates the production of exosomes via modulating the formation of MVBs. Dysregulated endosomal trafficking and changes in the landscape of exosome‐mediated intercellular communications may place an overwhelming burden on the nervous systems and, account for the CMT1C molecular pathogenesis.

Ultrasound-guided Infraclavicular Brachial Plexus Block for Supracondylar Humerus Fracture in a Patient with Central Obstructive Sleep Apnoea due to Charcot-Marie-Tooth Disease

The use of regional anaesthesia techniques in the presence of degenerative neurological disease is a relative contraindication. The subsequent reticence of anaesthesiologists is perhaps reflected in the absence of any published cases of a CharcotMarie-Tooth (CMT) patient that received a peripheral nerve blockade for surgery. We report a CMT patient, who presented with a supracondylar distal humerus fracture that benefited from an ultrasound-guided infraclavicular brachial plexus block.

Establishing a Charcot-Marie-Tooth (CMT) Induced Pluripotent Stem Cell Bank: Towards a Human Disease Model for CMT (S27.001)

Objective: To establish a Charcot-Marie-Tooth Induced pluripotent stem cell (iPS) bank as a human platform for mechanistic and drug screening studies. Background Induced pluripotent stem cells are derived from somatic cells after the forced expression of defined transcription factors. Like embryonic stem cells, they are capable of being differentiated into cell types from the three embryonic germ layers. Previous studies have demonstrated the feasibility of differentiating iPS cells from patients with neurological diseases into functional neurons. This approach could be particularly useful in the pathophysiological study of distinct forms of inherited neuropathies where a basic biological understanding is already available. Design/Methods: We have performed skin biopsies and developed iPS cell lines by retroviral transduction with Klf-3/4, Sox-2, Oct-4, and c-Myc of fibroblasts from 12 CMT patients, including 4 with CMT 1A (PMP22 duplication), two with CMT 1X (GJB1), 2 with CMT4J (FIG4) and one each for the following types: CMT1B (MPZ), CMT2A (MFN2), CMT2E (NEFL) and CMT4A (GDAP1). Results: All iPS CMT lines have a normal karyotype, carry the respective disease causing mutation and express pluripotency factors, as determined by immunostaining and gene expression profiling. These cells can also be spontaneously differentiated into cell types from the three embryonic germ layers. More importantly, these cells can be directed to differentiate into ventral spinal cord motor neurons that express appropriate antigens, including the transcription factors ISLET1 and HB9, the intermediate filaments peripherin and internexin and the enzyme Choline acetyltransferase. They also present ultrastructural features of neurons and demonstrate spontaneous and induced calcium channel transients. Conclusions: Human motor neurons can be consistently derived from patient-specific CMT iPS cells and can be used in multiple assays including gene expression studies, time lapse microscopy and electrophysiological studies, providing an authentic human model for mechanistic and drug screening studies of different types of inherited neuropathies. Supported by: M.S. was funded by a Rare Disease Clinical Research Network Fellowship from the National Institutes of Health. This study was also supported by iPierian Inc. Disclosure: Dr. Saporta has nothing to disclose. Dr. Shy has nothing to disclose. Dr. Dimos has received personal compensation for activities with iPierian Inc. as an employee.Dr. Dimos has received research support from iPierian Inc.

Exercise training improves autonomic profiles in patients with Charcot–Marie–Tooth disease

The effect of an interval exercise training (ITE) program on heart rate variability (HRV) was studied in 8 patients with Charcot-Marie-Tooth (CMT) disease and 8 healthy controls. At baseline, all subjects underwent ambulatory 24-hour Holter electrocardiographic (ECG) monitoring to evaluate HRV. HRV analysis was repeated on CMT patients after they completed a 24-week ITE program on a cycle ergometer. Before exercise, all HRV indices were lower in patients compared with controls, and the difference reached statistical significance for pNN50 (percent of differences between adjacent R-R intervals exceeding 50 ms). After ITE, time- and frequency-domain indices were significantly improved, particularly at night (+8% mean R-R interval, +95% pNN50, 52% reduction in low/high-frequency ratio). We observed significant increases in some of the time and frequency parameters, and values sometimes exceeded those of controls at baseline. Our results suggest that ITE improves HRV modulation in CMT patients by enhancing parasympathetic activity.

Outcome Measures and Rehabilitation Treatment in Patients Affected by Charcot-Marie-Tooth Neuropathy

: We evaluated the sensitivity of various rehabilitation and lung function scales to detect differences between people with Charcot-Marie-Tooth (CMT) disease and healthy controls. We also studied whether these measurements are sensitive to disclose changes in patients with CMT disease after rehabilitative treatment. : Eight patients with different types of CMT participated in the study. Data were gathered at baseline; at the end of the treadmill training, stretching, respiratory, and proprioceptive exercise (TreSPE) treatment period; and after a washout period of 6 mos. The following instruments were used for data collection: Medical Research Council scale for lower limb strength; Tinetti Balance Scale; Physical Performance Battery; ankle angle, oxygen consumption, and lung function tests; peak treadmill velocity and slope; time to walk 6 m; and CMT Neuropathy Score. The participants underwent TreSPE treatment twice every week for 8 wks. : All rehabilitative measures were significantly worse in subjects with CMT disease than in healthy controls. Lung function was always normal except for the maximum expiratory pressure and maximum inspiratory pressure. No dropouts or worsening in any of the different outcome measures were observed after TreSPE. The ankle angle and the time to walk 6 m were the only measures that significantly improved after treatment. : The rehabilitative outcome measures used in this protocol are useful in detecting clinical impairment in people with CMT disease. Lung function tests were confirmed to be minimally abnormal in patients with CMT disease. The TreSPE treatment, besides being safe and well tolerated, induced some training effects in CMT neuropathy, in the absence of lung function amelioration and effort tolerance. Follow-up showed that CMT patients should be treated at least twice every year because a regression of all outcome measures to the baseline state was found after a 6-mo washout period.

Reliability of instrumented movement analysis as outcome measure in Charcot–Marie–Tooth disease: Results from a multitask locomotor protocol

Some neurodegenerative diseases at early stage may not drastically affect basic gait ability, whereas more demanding locomotor tasks are more prone to disease-induced abnormalities. In this study, we evaluated the interday test–retest reliability, 4–6 weeks apart, of instrumented movement analysis on a group of 20 subjects with Charcot–Marie–Tooth (CMT) disease considering a set of kinematic and kinetic curves and related parameters obtained during natural walking (NW) and faster walking, heel and toe-walking, step ascending and descending.Results showed that the reliability was good for NW, with the exception of trunk curves, pelvic tilt and EMG profiles (moderate reliability), and trunk ROM in sagittal/transverse plane (poor reliability). Comparing our results with literature, CMT patients did not present a greater variability during NW than healthy subjects or patients with diseases of CNS. Additional locomotor tasks showed a slight reduction of reliability, although the moderate-to-good level shown in NW was almost never reduced to poor. Most of SEM values (absolute measurement errors) were smaller than 5°, a clinically acceptable threshold. In particular THS, an ankle joint related parameter computed across heel and toe-walking tasks, showed an optimal reliability (ICC=0.95, SEM=2.7°) and correlation with CMT clinical scores. Toe and heel-walking and step ascending tasks maximised the number of parameters with a moderate-to-good correlation with patients’ clinical status. We concluded that, in addition to natural walking, more challenging locomotor tasks are good candidates to provide reliable and sensitive outcome measures for CMT patients.

Inherited Neuropathies

Inherited peripheral neuropathies are among the most common hereditary diseases of the nervous system. Charcot-Marie-Tooth (CMT) disease, also known from previous classifications as hereditary motor and sensory neuropathy (HMSN), is certainly the most common inherited neuropathy. In the past several years, various treatments for CMT have been proposed, although specific therapies are not yet available. In clinical practice, rehabilitative strategies remain the most helpful therapeutic approach to these patients. There is still a lack of consensus on the best way to rehabilitate patients affected by CMT. Based on our personal experience and on a review of the literature, we first recommend the prescription of ankle-foot orthoses (AFO) for patients affected by CMT; the choice of which patient, which AFO, and when to apply it depends on the individual condition of each patient and on the experience of the physician/therapist. Second, adaptive equipment (eg, button hook, long-handled shoehorn, elastic shoe laces) is available to compensate for hand deformities, sensory loss, and weakness. Third, moderate to intense strength training and aerobic exercise are well tolerated by patients affected by CMT; further studies are needed to establish whether these approaches are effective in improving their motor function and strength. There is not enough evidence to recommend muscle stretching exercises or proprioceptive kinesiotherapy, although in our experience both approaches may be helpful in selected CMT patients to prevent tendon retractions, muscle tightening, and loss of strength, and to improve balance. There is growing knowledge of the underlying genetic defects and molecular pathophysiology in CMT. To date, only a few clinical trials in CMT patients have been performed. A neurotrophic factor, neurotrophin 3, was used in a small sample of CMT1A patients with promising results, but it has not been tested in a larger cohort and there is currently no reason to suggest this therapy for CMT1A neuropathy. Based on positive results in an animal model of CMT1A, three trials with ascorbic acid (AA) were completed in a large number of patients with this neuropathy, with results that were negative overall. Therefore, it is not possible to recommend the use of AA in CMT1A patients at this time, but the results of a larger Italian-UK study and an American trial with higher doses of AA are still awaited. It is important to remember that a superimposed inflammatory/disimmune process may complicate the course of the neuropathy; in this case, severe worsening (especially motor) in a matter of weeks or months is a "red flag" that should suggest immunosuppressive or immunomodulatory treatment such as steroids, intravenous immunoglobulin, or plasma exchange. In fact, steroid-sensitive cases of HMSN were described many years ago, well before the genetic diagnosis was available. Symptomatic treatment to reduce neuropathic and nociceptive pain, both of which have been reported in patients affected by CMT, should be prescribed according to recently published guidelines for the therapy of pain. No evidence suggests any specific surgical intervention or change in diet or lifestyle for patients affected by various types of CMT.

Foot Deformity in Charcot Marie Tooth Disease According to Disease Severity

ObjectiveTo investigate the characteristics of foot deformities in patients with Charcot-Marie-Tooth (CMT) disease compared with normal persons according to severity of disease.MethodSixty-two patients with CMT disease were recruited for this study. The normal control group was composed of 28 healthy people without any foot deformity. Patients were classified into a mild group and a moderate group according to the CMT neuropathy score. Ten typical radiological angles representing foot deformities such as pes equinus and pes varus were measured. The CMT group angles were compared with those of the normal control group, and those of the mild group were also compared with those of the moderate group.ResultsThe lateral (Lat.) talo-first metatarsal angle, anteroposterior talo-first metatarsal angle, Lat. calcaneal-first metatarsal angle, Lat. naviocuboid overlap, Lat. calcaneal pitch, Lat. tibiocalcaneal angle, and Lat. talocalcaneal angle in the CMT group showed a significant difference compared to the normal control group (p<0.05). These findings revealed CMT patients have pes cavus, forefoot adduction, midfoot supination and pes varus deformity. Compared to the mild group, the moderate group significantly showed an increased Lat. calcaneal pitch and decreased Lat. calcaneal-first metatarsal angle, Lat. tibiocalcaneal angle, Lat. talocalcaneal angle, and Lat. talo-first metatarsal angle (p<0.05). These findings revealed that the pes cavus deformity of CMT patients tend to be worse with disease severity.ConclusionThe characteristic equinovarus foot deformity patterns in CMT patients were revealed and these deformities tended to be worse with disease severity. Radiographic measures may be useful for the investigation of foot deformities in CMT patients.

Mechanisms of neuropathic pain in patients with Charcot-Marie-Tooth 1 A: A laser-evoked potential study

Charcot-Marie-Tooth (CMT) disease is the most common inherited neuropathy. The CMT1A type can be considered the typical phenotype of this disease. Although pain is not considered a relevant symptom in CMT patients by physicians and no study assessed it comprehensively, this symptom is frequently complained by patients. The objective of the present study was to investigate the nociceptive system in a sample of CMT1A patients suffering from pain by laser-evoked potentials (LEPs). Moreover, we also used a pain specific questionnaire in order to obtain patient-oriented data about their painful symptoms, the Neuropathic Pain Diagnostic Questionnaire (DN4). We evaluated 16 patients affected by CMT1A and 14 controls. All subjects underwent a standard LEP recording session (foot, hand, and face stimulation) and filled in the DN4. While the N2/P2 amplitude to foot stimulation was lower in CMT patients than in controls (p=0.003), no difference in LEP amplitude to both hand and face stimulation was found between patients and healthy subjects (p>0.05). This result is probably due to a length-dependent Aδ-fiber loss which involves mostly the longer fibers coming from the lower limb. In our patients, there was a significant association between a reduced N2/P2 amplitude to foot stimulation and a high DN4 score (p=0.03), meaning that patients with highly probable neuropathic pain had also low N2/P2 amplitude values to painful foot stimulation. This suggests that in our CMT1A patients neuropathic pain is probably related to a reduction of the Aδ afferents.

Laryngeal neuropathy of Charcot‐Marie‐Tooth disease: Further observations and novel mutations associated with vocal fold paresis

To describe and define laryngeal neuropathy in Charcot-Marie-Tooth (CMT) disease. Retrospective record review from a university laryngology practice. Four adult CMT patients presented with laryngeal symptoms. Three patients exhibited bilateral vocal fold palsy, in each case with more severe hypomobility on the left. One case exhibited an isolated left vocal fold palsy. All patients complained of hoarseness and stridor, three had dyspnea, two patients had dysphagia, and one had obstructive sleep apnea (OSA). One patient has required airway surgery to date. Genetic testing revealed known sequence alterations in one case and sequence alterations previously not associated with laryngeal dysfunction in two cases. One case was familial and two were sporadic; information is not available in a fourth. The clinical course of the cases suggests slowly progressive neuropathy that appears to be nerve length dependent. The lack of severe respiratory distress despite dense bilateral paresis is consistent with existing reports and with the reported low rate of tracheostomy in adults with laryngeal manifestations of CMT. Genetic testing does not currently inform expectations or management of laryngeal disease. Dyspnea, dysphagia, and OSA symptoms in patients with CMT require careful laryngologic evaluation.

Screening of the 17p11.2–p12 region in a large cohort of patients with Charcot-Marie-Tooth (CMT) disease or hereditary neuropathy with liability to pressure palsies (HNPP)

Within the last decade, numerous methods have been applied to detect the most common mutation in patients affected with Charcot-Marie-Tooth (CMT) disease, i.e. submicroscopic duplication in the 17p11.2--p12 region. In 1993, another neuropathy - known as hereditary neuropathy with liability to pressure palsies (HNPP) - has been shown to be caused by a 17p11.2--p12 deletion. Historically, Southern blot analysis was the first approach to identify CMT1A duplication or HNPP deletion. This time- and labor-consuming method requires prior selection of DNA samples. In fact, only CMT patients affected with the demyelinating form of CMT1 have been screened for CMT1A duplication. After the 17p11.2--p12 duplication was identified in the CMT1 families, subsequent studies revealed additional axonal features in the patients harboring the 17p11.2--p12 duplication. Thus it seems reasonable to test all patients affected with CMT for the presence of the 17p11.2--p12 duplication. To evaluate the utility of real-time polymerase chain reaction (Q-PCR) and restriction fragment length polymorphism PCR (RFLP-PCR), we screened a large group of 179 families with the diagnosis of CMT/HNPP for the presence of the 17p11.2--p12 duplication/deletion. Due to a high frequency of CMT1A duplication in familial cases of CMT, we propose (in contrast to the previous studies) to perform Q-PCR analysis in all patients diagnosed with CMT.

Mutational analysis of GJB1, MPZ, PMP22, EGR2, and LITAF/SIMPLE in Serbian Charcot‐Marie‐Tooth patients

We report the results of mutational analysis in the following genes: GJB1, MPZ, PMP22, EGR2, and LITAF/SIMPLE in 57 Charcot-Marie-Tooth (CMT) patients of Serbian origin without the PMP22 duplication. We found 10 different mutations in 14 CMT patients: 6 mutations in GJB1, 3 in MPZ, and 1 in PMP22. Five of six GJB1 mutations are reported for the first time, and the most frequent one appears to be a founder mutation in the Serbian population. No mutations were found in EGR2 or LITAF. Thus, GJB1 mutation analysis should be done in patients without the PMP22 duplication and male-to-male transmission of CMT.

Cavus Foot Reconstruction in 3 Patients with Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth (CMT) is a progressive genetic disorder that produces motor and sensory neuropathy that affects the legs, feet, and hands. A dorsally based closing wedge midfoot osteotomy at the apex of the cavus foot deformity combined with soft tissue and other osseous procedures are procedures performed for CMT patients at The Western Pennsylvania Hospital. The focus of this article is to present a prospective evaluation of 3 patients using radiographic assessment, static biomechanical and the malleolar valgus index (MVI), dynamic alignment, and function results using the F-scan. These results demonstrate that patients have improved function with a plantigrade foot and decreased pain. The Short Form McGill Pain Questionnaire (SF-MPQ) showed that there was a decrease in pain. There was a decrease in the MVI and improved function comparing the preoperative and postoperative F-scan in all patients. The midfoot osteotomy addresses the apex of the progressive cavus foot deformity and provides a plantigrade foot in 3 CMT patients. 4.

Charcot-Marie-Tooth and pain: correlations with neurophysiological, clinical, and disability findings

Pain is not considered a relevant symptom in Charcot-Marie-Tooth (CMT) patients and no studies have comprehensively assessed it. We performed a multidimensional assessment in 211 consecutive CMT patients to evaluate the clinical features, quality of life (QoL) and disability. For QoL we used the SF-36, which comprises one domain called "Bodily Pain" (BP), which is a generic measure of intensity of pain. Results showed that pain is a relevant symptom related to gender, CMT subtypes, clinical picture, disability, and mildly to neurophysiological impairment. In our study the importance of pain was an occasional finding. Because of the study design we are not able to ascertain if pain is primarily due to the neuropathy or if it is due to the muscoloskeletal deformities arising as a consequence of the neuropathy. Our study underlined that pain should be considered as a relevant symptom in CMT patients and further studies should be performed.

A 71‐nucleotide deletion in the periaxin gene in a Romani patient with early‐onset slowly progressive demyelinating CMT

Mutations in the periaxin (PRX) gene cause autosomal recessive demyelinating neuropathy Charcot-Marie-Tooth (CMT) type 4F. To date, 10 non-sense or frameshift PRX mutations have been reported in patients with early-onset neuropathy and further disease course consistent with either Dejerine-Sottas neuropathy or slow-progressive demyelinating CMT. We sequenced 59 patients from 55 Czech families including four unrelated patients of Romani (Gypsy) origin with early-onset CMT displaying decreased nerve conduction velocities. We identified a novel homozygous mutation c.3286_3356del71 (K1095fsX18) in one Romani patient showing very slow disease progression. Amongst non-Romani Czech CMT patients, PRX mutations have been proven to be very rare.