Charcot-Marie-Tooth Disease/physiopathology* ; Humans ; Male ; Sexual Dysfunction, Physiological/physiopathology* ; Ultrasonography ; Young Adult

OBJECTIVETo study the electromyographic and genetic characteristics in children with Charcot-Marie-Tooth disease type 1 (CMT1).

METHODSRoutine electromyography and nerve conduction were performed in 24 children with CMT1. Polymerase chain reaction (PCR) combined with restriction enzyme digestion was used to detect gene duplication on chromosome 17p11.2-12. Ten healthy children served as the control group.

RESULTSThe peripheral nerve conduction velocity slowed or disappeared in all of the 24 patients (100%). The lesions of the sensory nerves were more severe than the motor nerves, and the lesions of the lower limbs were more severe than the upper limbs. Of 72 muscles detected, 40 (56%) showed neurogenic lesions. The older the patients, the more severe the muscle lesions. Specific junction fragments (1760 bp) were identified in 13 (54%) out of 24 patients, but were not identified in the healthy controls.

CONCLUSIONSThe electromyographic changes are characterized by peripheral nerve conduction velocities slowing and neurogenic lesions of muscles in children with CMT1. The PCR combined with restriction enzyme digestion may be a simple and accurate method for gene diagnosis of CMT1.

Adolescent ; Charcot-Marie-Tooth Disease ; genetics ; physiopathology ; Child ; Electromyography ; Female ; Humans ; Male ; Neural Conduction

BACKGROUNDAmong patients with Charcot-Marie-Tooth disease (CMT), the X-linked variant (CMTX) caused by gap junction protein beta 1 (GJB1) gene mutation is the second most frequent type, accounting for approximately 90% of all CMTX. More than 400 mutations have been identified in the GJB1 gene that encodes connexin 32 (CX32). CX32 is thought to form gap junctions that promote the diffusion pathway between cells. GJB1 mutations interfere with the formation of the functional channel and impair the maintenance of peripheral myelin, and novel mutations are continually discovered.

METHODSWe included 79 unrelated patients clinically diagnosed with CMT at the Department of Neurology of the Chinese People's Liberation Army General Hospital from December 20, 2012, to December 31, 2015. Clinical examination, nerve conduction studies, and molecular and bioinformatics analyses were performed to identify patients with CMTX1.

RESULTSNine GJB1 mutations (c.283G>A, c.77C>T, c.643C>T, c.515C>T, c.191G>A, c.610C>T, c.490C>T, c.491G>A, and c.44G>A) were discovered in nine patients. Median motor nerve conduction velocities of all nine patients were < 38 m/s, resembling CMT Type 1. Three novel mutations, c.643C>T, c.191G>A, and c.610C>T, were revealed and bioinformatics analyses indicated high pathogenicity.

CONCLUSIONSThe three novel missense mutations within the GJB1 gene broaden the mutational diversity of CMT1X. Molecular analysis of family members and bioinformatics analyses of the afflicted patients confirmed the pathogenicity of these mutations.

Adolescent ; Adult ; Charcot-Marie-Tooth Disease ; genetics ; physiopathology ; Computational Biology ; Connexins ; genetics ; Female ; Genotype ; Humans ; Male ; Middle Aged ; Mutation, Missense ; Neural Conduction ; Phenotype

Charcot-Marie-Tooth disease (CMT) is the most common inherited motor and sensory neuropathy. Previous studies have found that, according to CMT patients, neuropathic pain is an occasional symptom of CMT. However, neuropathic pain is not considered to be a significant symptom associated with CMT and, as a result, no studies have investigated the pathophysiology underlying neuropathic pain in this disorder. Thus, the first animal model of neuropathic pain was developed by our laboratory using an adenovirus vector system to study neuropathic pain in CMT. To this end, glycyl-tRNA synthetase (GARS) fusion proteins with a FLAG-tag (wild type [WT], L129P and G240R mutants) were expressed in spinal cord and dorsal root ganglion (DRG) neurons using adenovirus vectors. It is known that GARS mutants induce GARS axonopathies, including CMT type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V). Additionally, the morphological phenotypes of neuropathic pain in this animal model of GARS-induced pain were assessed using several possible markers of pain (Iba1, pERK1/2) or a marker of injured neurons (ATF3). These results suggest that this animal model of CMT using an adenovirus may provide information regarding CMT as well as a useful strategy for the treatment of neuropathic pain.
Animals ; Charcot-Marie-Tooth Disease/*diagnosis/*physiopathology ; *Disease Models, Animal ; Glycine-tRNA Ligase/*genetics/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutagenesis, Site-Directed ; Mutation/genetics ; Neuralgia/*diagnosis/*physiopathology

Charcot-Marie-Tooth disease (CMT) is the most common inherited motor and sensory neuropathy. Previous studies have found that, according to CMT patients, neuropathic pain is an occasional symptom of CMT. However, neuropathic pain is not considered to be a significant symptom associated with CMT and, as a result, no studies have investigated the pathophysiology underlying neuropathic pain in this disorder. Thus, the first animal model of neuropathic pain was developed by our laboratory using an adenovirus vector system to study neuropathic pain in CMT. To this end, glycyl-tRNA synthetase (GARS) fusion proteins with a FLAG-tag (wild type [WT], L129P and G240R mutants) were expressed in spinal cord and dorsal root ganglion (DRG) neurons using adenovirus vectors. It is known that GARS mutants induce GARS axonopathies, including CMT type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V). Additionally, the morphological phenotypes of neuropathic pain in this animal model of GARS-induced pain were assessed using several possible markers of pain (Iba1, pERK1/2) or a marker of injured neurons (ATF3). These results suggest that this animal model of CMT using an adenovirus may provide information regarding CMT as well as a useful strategy for the treatment of neuropathic pain.
Animals ; Charcot-Marie-Tooth Disease/*diagnosis/*physiopathology ; *Disease Models, Animal ; Glycine-tRNA Ligase/*genetics/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutagenesis, Site-Directed ; Mutation/genetics ; Neuralgia/*diagnosis/*physiopathology

OBJECTIVETo report a Chinese Charcot-Marie-Tooth disease (CMT) family whose proband had abnormal brainstem auditory evoked potentials (BAEPs) and to study its relationship with connexin 32 (Cx32) gene mutation.

METHODSAll family members were studied through clinical examinations, out of them, the proband was subjected to electromyography and BAEPs examination. Mutation analysis of Cx32 was screened by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) combined with DNA direct sequencing in the proband, 8 family members and 50 unrelated normal individuals.

RESULTSThe proband had highly decreased nerve conduction velocities and delayed BAEPs. Leu131Pro mutation was found in the proband and 3 family members, not found in 50 normal controls.

CONCLUSIONThis mutation has not been reported previously. Central nervous system can be affected in CMT patients.

Asian Continental Ancestry Group ; genetics ; Charcot-Marie-Tooth Disease ; genetics ; physiopathology ; Connexins ; genetics ; Electrophysiology ; Evoked Potentials, Auditory, Brain Stem ; Female ; Humans ; Male ; Mutation ; Pedigree ; Polymerase Chain Reaction ; methods ; Polymorphism, Single-Stranded Conformational ; Sequence Analysis, DNA

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant inherited disorder characterized by recurrent pressure palsies. Most HNPP patients have a 1.5 mb deletion in chromosome 17p11.2-p12. The present study aimed at evaluating the deletion of the 17p11.2-p12 region in Korean subjects with families exhibiting HNPP phenotype, and to determine the clinical, electrophysiological and morphological aspects specifically associated with this deletion in HNPP patients. By genotyping six microsatellite markers (D17S921, D17S955, D17S1358, D17S839, D17S122 and D17S261), HNPP with the deletion was observed in 79% (19 of 24) of HNPP families. Nerve conduction studies were performed in 35 HNPP patients from these 19 families. The observed HNPP deletion frequency in Koreans is consistent with findings in other populations. Disease onset occurred at a significantly earlier age in patients with recurrent pressure palsies than in those with a single attack (P<0.01). Nerve conduction studies demonstrated diffuse mild to moderate slowing of nerve conduction velocities that were worse over the common entrapment sites, regardless of the clinical manifestations. A long duration of compound muscle action potentials without a conduction block or a temporal dispersion is a characteristic of this disease. A sural nerve biopsy with teasing was performed in four patients, and tomacula of the myelin sheath was found in 56.4%. Our findings appear to support the existence of a phenotype/genotype correlation in HNPP patients of Korean ancestry with the deletion, and suggest that HNPP patients with earlier symptom onset face an increased chance of having recurrent attacks.
Adolescent ; Adult ; Age of Onset ; Aged ; Charcot-Marie-Tooth Disease/genetics ; Child ; Child, Preschool ; *Chromosome Deletion ; *Chromosomes, Human, Pair 17 ; DNA Mutational Analysis ; Electrophysiology ; Female ; Genotype ; Hereditary Motor and Sensory Neuropathies/*genetics/pathology/physiopathology ; Humans ; Korea ; Male ; Microsatellite Repeats ; Middle Aged ; Paralysis/*genetics/pathology/physiopathology ; Pedigree ; Phenotype ; Research Support, Non-U.S. Gov't ; Sural Nerve/pathology/physiopathology

Distal hereditary motor neuropathy (dHMN) is a heterogeneous disorder characterized by degeneration of motor nerves in the absence of sensory abnormalities. Recently, mutations in the small heat shock protein 27 (HSP27) gene were found to cause dHMN type II or Charcot-Marie-Tooth disease type 2F (CMT2F). The authors studied 151 Korean axonal CMT or dHMN families, and found a large Korean dHMN type II family with the Ser135Phe mutation in HSP27. This mutation was inherited in an autosomal dominant manner, and was well associated with familial members with the dHMN phenotype. This mutation site is located in the ?-crystallin domain and is highly conserved between different species. The frequency of this HSP27 mutation in Koreans was 0.6%. Magnetic resonance imaging analysis revealed that fatty infiltrations tended to progressively extend distal to proximal muscles in lower extremities. In addition, fatty infiltrations in thigh muscles progressed to affect posterior and anterior compartments but to lesser extents in medial compartment, which differs from CMT1A patients presenting with severe involvements of posterior and medial compartments but less involvement of anterior compartment. The authors describe the clinical and neuroimaging findings of the first Korean dHMN patients with the HSP27 Ser135Phe mutation. To our knowledge, this is the first report of the neuroimaging findings of dHMN type II.
Adolescent ; Adult ; Age of Onset ; Animals ; Asian Continental Ancestry Group ; Charcot-Marie-Tooth Disease/*genetics/physiopathology/radionuclide imaging ; Child ; Child, Preschool ; Female ; *Genetic Predisposition to Disease ; Humans ; Intracellular Signaling Peptides and Proteins/*genetics ; Korea ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Muscular Atrophy/physiopathology/radionuclide imaging ; *Mutation, Missense ; Neural Conduction/genetics ; Pedigree ; Protein-Serine-Threonine Kinases/*genetics ; alpha-Crystallins/genetics