• Journal of Genetic Medicine
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• v.18 no.2
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• pp.83-93
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• 2021

Charcot-Marie-Tooth disease (CMT) is the most common hereditary motor and sensory peripheral neuropathy. CMT is usually classified into two categories based on pathology: demyelinating CMT type 1 (CMT1) and axonal CMT type 2 (CMT2) neuropathy. CMT1 can be distinguished by assessing the median motor nerve conduction velocity as greater than 38 m/s. The main clinical features of axonal CMT2 neuropathy are distal muscle weakness and loss of sensory and areflexia. In addition, they showed unusual clinical features, including delayed development, hearing loss, pyramidal signs, vocal cord paralysis, optic atrophy, and abnormal pupillary reactions. Recently, customized treatments for genetic diseases have been developed, and pregnancy diagnosis can enable the birth of a normal child when the causative gene mutation is found in CMT2. Therefore, accurate diagnosis based on genotype/phenotypic correlations is becoming more important. In this review, we describe the latest findings on the phenotypic characteristics of axonal CMT2 neuropathy. We hope that this review will be useful for clinicians in regard to the diagnosis and treatment of CMT.

• Annals of Clinical Neurophysiology
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• v.7 no.2
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• pp.65-74
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• 2005

Charcot-Marie-Tooth (CMT) disease was described by Charcot and Marie in France and, independently, by Tooth in England in 1886. CMT is the most common form of inherited motor and sensory neuropathy, and is a genetically heterogeneous disorder of the peripheral nervous system. Therefore, many genes have been identified as CMT-causative genes. Traditionally, subclassification of CMT have been divided into autosomal dominant inherited demyelinating (CMT1) and axonal (CMT2) neuropathies, X-linked neuropathy (CMTX), and autosomal recessive inherited neuropathy (CMT4). Recently, intermediate type (CMT-Int) with NCVs between CMT1 and CMT2 is considered as a CMT type. There are several related peripheral neuropathies, such as $D{\acute{e}}j{\acute{e}}rine$-Sottas neuropathy (DSN), congenital hypomyelination (CH), hereditary neuropathy with liability to pressure palsies (HNPP) and giant axonal neuropathy (GAN). Great advances have been made in understanding the molecular basis of CMT, and 17 distinct genetic causes of CMT have been identified. The number of newly discovered mutations and identified genetic loci is rapidly increasing, and this expanding list has proved challenging for physicians trying to keep up with the field. Identifying the genetic cause of inherited neuropathies is often important to determine at risk family members as well as diagnose the patient. In addition, the encouraging studies have been published on rational potential therapies for the CMT1A. Now, we develop a model of how the various genes may interact in the pathogenesis of CMT disorder.

• Journal of Electrodiagnosis and Neuromuscular Diseases
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• v.20 no.2
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• pp.148-152
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• 2018

Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystem disorder and one of the most common muscular dystrophies affecting adults. Charcot-Marie-Tooth (CMT) disease, a common hereditary neuropathy, is characterized by atrophy of the distal limbs and peripheral nerve abnormalities. The authors report a rare case involving a 24-year-old female who was diagnosed simultaneously with both DM1 and CMT1A based on the results of a nerve conduction study (NCS). The patient, who had previously been diagnosed with DM1, was admitted for lower extremity pain. Her electrodiagnostic examination continued to reveal severe sensorimotor demyelinating polyneuropathy, and a genetic study was performed to confirm whether she had other hereditary neuropathies, except DM1, that suggested CMT1A, the most common phenotype of CMT. Severe abnormalities in an NCS in a DM1 patient may suggest the incidental coexistence of hereditary neuropathies, and further evaluations, such as genetic studies, should be performed for proper diagnosis.

• Annals of Clinical Neurophysiology
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• v.21 no.1
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• pp.57-60
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• 2019

Axonal Charcot-Marie-Tooth disease (CMT2) has most frequently been associated with mutations in the MFN2 gene. MFN2 encodes mitofusin 2, which is a mitochondrial fusion protein that plays an essential role in mitochondrial function. We report CMT2 in a Korean father and his son that manifested with gait difficulties and progressive atrophy of the lower legs. Molecular analysis revealed a novel heterozygous c.2096T>C (p.Leu699Pro) mutation in the exon 18 of MFN2 in both subjects. We suggest that this novel mutation in MFN2 is probably a pathogenic mutation for CMT2.

• Animal cells and systems
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• v.15 no.4
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• pp.301-309
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• 2011

Charcot-Marie-Tooth disease (CMT) is clinically heterogeneous hereditary motor and sensory neuropathies with genetic heterogeneity, age-dependent penetrance, and variable expressivity. Rare copy number variations by nonrecurrent rearrangements have recently been suggested to be associated with Charcot-Marie-Tooth 1A (CMT1A) neuropathy. In our previous study, we found three Korean CMT1A families with rare copy number variations (CNVs) on 17p12 by nonrecurrent rearrangement. Careful clinical examinations were performed in all the affected individuals with rare CNVs (n=19), which may be the first full study of a subject from a large CMT1A family with nonrecurrent rearrangement. The clinical phenotype showed no significant difference compared with common CMT1A patients, but with variable phenotypes. In particular, a broad intrafamilial phenotypic spectrum was observed within the same family, which may suggest the existence of a genetic modifier. This study may broaden the understanding of the role of CNVs in the pathogenesis of CMT.

• Journal of Korean Neurosurgical Society
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• v.55 no.6
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• pp.370-374
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• 2014

To present a case of cauda equina syndrome (CES) caused by chronic inflammatory demyelinating polyneuropathy (CIDP) which seemed clinically similar to Charcot-Marie-Tooth disease type1 (CMT1). CIDP is an immune-mediated polyneuropathy, either progressive or relapsing-remitting. It is a non-hereditary disorder characterized by symmetrical motor and sensory deficits. Rarely, spinal nerve roots can be involved, leading to CES by hypertrophic cauda equina. A 34-year-old man presented with low back pain, radicular pain, bilateral lower-extremity weakness, urinary incontinence, and constipation. He had had musculoskeletal deformities, such as hammertoes and pes cavus, since age 10. Lumbar spine magnetic resonance imaging showed diffuse thickening of the cauda equina. Electrophysiological testing showed increased distal latency, conduction blocks, temporal dispersion, and severe nerve conduction velocity slowing (3 m/s). We were not able to find genetic mutations at the PMP 22, MPZ, PRX, and EGR2 genes. The pathologic findings of the sural nerve biopsy revealed thinly myelinated nerve fibers with Schwann cells proliferation. We performed a decompressive laminectomy, intravenous IgG (IV-IgG) and oral steroid. At 1 week after surgery, most of his symptoms showed marked improvements except foot deformities. There was no relapse or aggravation of disease for 3 years. We diagnosed the case as an early-onset CIDP with cauda equine syndrome, whose initial clinical findings were similar to those of CMT1, and successfully managed with decompressive laminectomy, IV-IgG and oral steroid.

• Journal of Genetic Medicine
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• v.12 no.1
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• pp.25-30
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• 2015

Purpose: Charcot-Marie-Tooth disease (CMT) is a peripheral neuropathy mainly divided into CMT type 1 (CMT1) and CMT2 according to the phenotype and genotype. Although molecular pathologies for each genetic causative have not been revealed in CMT2, the correlation between cell death and accumulation of misfolded proteins in the endoplasmic reticulum (ER) of Schwann cells is well documented in CMT1. Establishment of in vitro models of ER stress-mediated Schwann cell death might be useful in developing drug-screening systems for the treatment of CMT1. Materials and Methods: To develop high-throughput screening (HTS) systems for CMT1, we generated cell models using transient expression of mutant proteins and chemical induction. Results: Overexpression of wild type and mutant peripheral myelin protein 22 (PMP22) induced ER stress. Similar results were obtained from mutant myelin protein zero (MPZ) proteins. Protein localization revealed that expressed mutant PMP22 and MPZ proteins accumulated in the ER of Schwann cells. Overexpression of wild type and L16P mutant PMP22 also reduced cell viability, implying protein accumulation-mediated ER stress causes cell death. To develop more stable screening systems, we mimicked the ER stress-mediated cell death in Schwann cells using ER stress inducing chemicals. Thapsigargin treatment caused cell death via ER stress in a dose dependent manner, which was measured by expression of ER stress markers. Conclusion: We have developed genetically and chemically induced ER stress models using Schwann cells. Application of these models to HTS systems might facilitate the elucidation of molecular pathology and development of therapeutic options for CMT1.

• Molecules and Cells
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• v.23 no.1
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• pp.39-48
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• 2007

Charcot-Marie-Tooth (CMT) disease and hereditary neuropathy with liability to pressure palsies (HNPP) are frequent forms of genetically heterogeneous peripheral neuropathies. Reciprocal unequal crossover between flanking CMT1A-REPs on chromosome 17p11.2-p12 is a major cause of CMT type 1A (CMT1A) and HNPP. The importance of a sensitive and rapid method for identifying the CMT1A duplication and HNPP deletion is being emphasized. In the present study, we established a molecular diagnostic method for the CMT1A duplication and HNPP deletion based on hexaplex PCR of 6 microsatellite markers (D17S921, D17S9B, D17S9A, D17S918, D17S4A and D17S2230). The method is highly time-, cost- and sample-saving because the six markers are amplified by a single PCR reaction and resolved with a single capillary in 3 h. Several statistical and forensic estimates indicated that most of these markers are likely to be useful for diagnosing the peripheral neuropathies. Reproducibility, as determined by concordance between independent tests, was estimated to be 100%. The likelihood that genotypes of all six markers are homozygous in randomly selected individuals was calculated to be $1.6{\times}10^{-4}$, which indicates that the statistical error rate for this diagnosis of HNPP deletion is only 0.016%.

• Journal of Life Science
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• v.29 no.7
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• pp.800-808
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• 2019

Charcot-Marie-Tooth disease (CMT) is a group of rare peripheral neuropathies characterized by progressive muscle weakness and atrophy and areflexia in the upper and lower extremities. The most common subtype of CMT is CMT1A, which is caused by a tandem duplication of the PMP22 gene in the 17p12 region. Patients with CMT1A show a loose genotype-phenotype correlation, which suggests the existence of secondary genetic or association factors. Recently, polymorphisms of rs71428439 (n.83A>G) and rs2292832 (n.86T>C) in the MIR149 have been reported to be associated with late onset and mild phenotypic CMT1A severity. The aim of this study was to examine the intrafamilial heterogeneities of clinical phenotypes according to the genotypes of these two SNPs in MIR149. For this study, we selected 6 large CMT1A families who showed a wide range of phenotypic variation. This study suggested that both SNPs were related to the onset age and severity in the dominant model. In particular, the AG+GG (n.83A>G) and TC+CC genotypes (n.86T>C) were associated to late onset and mild symptoms. Motor nerve conduction velocity (MNCV) was not related to the MIR149 genotypes. These results were consistent with the previous studies. Therefore, we suggest that the rs71428439 and rs2292832 variants in MIR149 may serve as genetic modifiers of CMT1A intrafamilial phenotypic heterogeneity, as they have a role in the unrelated patients. This is the first study to show an association using large families with variable clinical CMT1A phenotypes. The results will be helpful in the molecular diagnosis and treatment of patients with CMT1A.

• Annals of Clinical Neurophysiology
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• v.4 no.2
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• pp.125-132
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• 2002

Objectives : Although the diagnosis of hereditary neuropathy with liability to pressure palsies (HNPP) is important for correct prognostic evaluation and genetic counseling, the diagnosis is frequently missed or delayed. Our main aim on undertaking this study was to characterize the electrodiagnostic features of HNPP. Material and Methods : Clinical, electrophysiologic and molecular studies were performed on Korean HNPP patients with 17p11.2 deletion. The results of electrophysiologic studies were compared with those of Charcot-Marie-Tooth disease type 1A (CMT1A) patients carrying 17p11.2 duplication. Results : Eight HNPP (50 motor, 39 sensory nerves) and six CMT1A (28 motor, 16 sensory nerves) patients were included. The slowing of sensory conduction in nearly all nerves and the distal accentuation of motor conduction abnormalities are the main features of background polyneuropathy in HNPP. In contrast to CMT1A, where severity of nerve conduction slowing was not different among nerve groups, HNPP sensory nerve conduction was more slowed in the median and ulnar nerves than in the sural nerve (p<0.01), and DML was more prolonged in the median nerve than in the other motor nerves (p<0.01). TLIs were significantly lower in HNPP than in the normal control and CMT1A patients for the median and ulnar nerves (p<0.01), and were also significantly reduced for the peroneal nerve (p<0.05) compared with those of the normal controls. Conclusion : The distribution and severity of the background electrophysiologic abnormalities are closely related to the topography of common entrapment or compression sites, which suggests the possible pathogenetic role of subclinical pressure injury at these sites in the development of the distinct background polyneuropathy in HNPP.