Peripheral Myelin Protein 22 Gene Research Articles

PERP May Affect the Prognosis of Lung Adenocarcinoma by Inhibiting Apoptosis.

PERP, a member of the peripheral myelin protein gene family, is a new therapeutic target in cancer. The relationships between PERP and immune cell infiltration in lung cancer have not been studied. Therefore, the role of PERP in the tumour microenvironment (TME) of lung cancer needs to be further explored. In this study, we explored the association between PERP expression and clinical characteristics by analysing data from the TCGA database. Cox regression and Kaplan‒Meier methods were used to investigate the relationship between the expression of PERP and overall survival in patients with lung adenocarcinoma (LUAD). The relationship between PERP expression and the degree of infiltration of specific immune cell subsets in LUAD was evaluated using the TIMER database and GEPIA. We also performed GO enrichment analysis and KEGG enrichment analysis to reveal genes coexpressed with PERP using the Coexpedia database. Finally, we verified the expression and function of PERP in LUAD tissues and the A549 cell line by RT‒PCR, Western blot, CCK-8, IHC, and wound healing assays. The mouse model was used to study the in vivo effects of PERP. According to our results, PERP expression was significantly higher in LUAD tissues and associated with the clinical characteristics of the disease. Survival was independently associated with PERP in LUAD patients. We further verified that PERP might regulate B-cell infiltration in LUAD to affect the prognosis of LUAD. To identify PERP-related signalling pathways in LUAD, we performed a genome-aggregation analysis (GSEA) between low and high PERP expression datasets. LUAD cells express higher levels of PERP than paracarcinoma cells, and PERP inhibits the proliferation and metastasis of A549 cells through apoptosis. PERP may affect the prognosis of lung adenocarcinoma by inhibiting apoptosis and is associated with immune cell infiltration.

AAV-mediated editing of PMP22 rescues Charcot-Marie-Tooth disease type 1A features in patient-derived iPS Schwann cells

BackgroundCharcot-Marie-Tooth disease type 1A (CMT1A) is one of the most common hereditary peripheral neuropathies caused by duplication of 1.5 Mb genome region including PMP22 gene. We aimed to correct the duplication in human CMT1A patient-derived iPS cells (CMT1A-iPSCs) by genome editing and intended to analyze the effect on Schwann cells differentiated from CMT1A-iPSCs.MethodsWe designed multiple gRNAs targeting a unique sequence present at two sites that sandwich only a single copy of duplicated peripheral myelin protein 22 (PMP22) genes, and selected one of them (gRNA3) from screening their efficiencies by T7E1 mismatch detection assay. AAV2-hSaCas9-gRNAedit was generated by subcloning gRNA3 into pX601-AAV-CMV plasmid, and the genome editing AAV vector was infected to CMT1A-iPSCs or CMT1A-iPSC-derived Schwann cell precursors. The effect of the genome editing AAV vector on myelination was evaluated by co-immunostaining of myelin basic protein (MBP), a marker of mature myelin, and microtubule-associated protein 2(MAP2), a marker of neurites or by electron microscopy.ResultsHere we show that infection of CMT1A-iPS cells (iPSCs) with AAV2-hSaCas9-gRNAedit expressing both hSaCas9 and gRNA targeting the tandem repeat sequence decreased PMP22 gene duplication by 20–40%. Infection of CMT1A-iPSC-derived Schwann cell precursors with AAV2-hSaCas9-gRNAedit normalized PMP22 mRNA and PMP22 protein expression levels, and also ameliorated increased apoptosis and impaired myelination in CMT1A-iPSC-derived Schwann cells.ConclusionsIn vivo transfer of AAV2-hSaCas9-gRNAedit to peripheral nerves could be a potential therapeutic modality for CMT1A patient after careful examinations of toxicity including off-target mutations.

Genetic study of inherited peripheral neuropathy disease (Charcot–Marie Tooth) disease

Background Charcot-Marie-Tooth disease (CMT) is the most common hereditary neuromuscular disorder. Charcot-Marie-Tooth disease can be caused by mutations in many different genes. These genes provide instructions for making proteins involved in the functioning of the peripheral nerves of the feet, legs, and hands. Peripheral myelin protein 22 (PMP22) related neuropathies account for over 50% of inherited peripheral neuropathies. Agene copy variation results in CMT1A (duplication of 17p11.2.p12) and hereditary neuropathy with liability to pressure palsies (HNPP; single deletion). Point mutation comprise both phenotypes. The underlying pathological mechanisms are incompletely understood and biallilic mutations of PMP22 are very rare. Objective To study clinical characteristics of a cohort of Egyptian patients with CMT; frequency of PMP22 gene duplication and deletion by MLPA and molecular diagnosis. Methodology We applied our study on 97 Egyptian patients from 70 unrelated families with suspected CMT disease, patients were referred from different provinces to Ain Shams neuromuscular outpatient clinic. After an informed and written consent, all patients were examined neurologically and systemically. Diagnosis was based on clinical symptoms, electromyography and genetic study. Results Clinical classification of our patients revealed high incidence rate of AR CMT type patients (43.3%) and sporadic cases (39.3%), while AD CMT type represents (17.5%), the cause of the high rate of negative family history of same disease affection may be for many reasons mild subclinical expression in other family members, autosomal recessive inheritance, or a de novo heterozygous pathogenic variant in a gene associated with autosomal dominant inheritance. Neurophysiological classification according to median NCV shows that 53 patients (51.5%) have axonal sensory-motor affection with median NCV <38 m/s, 26 patients (26.8%) have demyelinating CMT type, and 19 patients (19.6%) have intermediate type (mixed axonal and demyelinating affection with median NCV range between 35 m/s to 45 m/s. Thus the commonest form is CMT 2 (axonal AR type) followed by CMT 4 (demyelinating AR type) with lower incidence of CMT 1 (demyelinating AD type). Conclusion from our study we concluded that (AR CMT type) is not uncommon in Egypt because of the high prevalence of consanguinity, and that PMP22 duplication is not a common cause of Egyptian inherited neuropathy disease.

HP39: PMP22 neuropathies: Charcot-Marie-Tooth disease type 1A in a boy and changes in electroneuromyography

Charcot-Marie-Tooth (CMT) disease is the most frequent inherited neuropathy, affecting 1/1500 to 1/10000 (60%-70% of all CMT and is caused by a duplication on chromosome 17p11.2 leading to an overexpression of the Peripheral Myelin Protein 22 (PMP22)). CMT1A characterized by distal muscle weakness and atrophy, sensory loss, and slow nerve conduction velocity. Early diagnosis is necessary for further prognosis and management of the patient. At the boy from 9 years parents noticed gait disturbances: it was difficult to step on a heel. Within a few years, the symptoms progressed and there was a sensitivity disorder. According to the neurological status, the knee reflexes were reduced and there were no Achilles. We performed electroneuromyography and recorded a significant decrease in motor and sensory responses (less than 1 μV). Needle myography showed secondary denervation changes in the muscles. We sent the patient's blood for genetic analysis (Comprehensive Neuropathies Panel). We received a Pathogenic variant, Gain (Entire coding sequence), was identified in PMP22. This variant is a gross duplication of the genomic region encompassing exons 2-5 of the PMP22 gene. Therefore, it is assumed that the entire gene is duplicated. Duplications of the region on chromosome 17p11.2 which contain the PMP22 gene cause Charcot-Marie-Tooth type 1A (CMT1A). The patient was also found to have mutations of uncertain significance: in SCN11A (associated with autosomal dominant hereditary sensory and autonomic neuropathy type 7) and SCN9A. After the diagnosis, we also provided him with recommendations for multidisciplinary management together with rehabilitation specialists and orthopedists.

Coexistence of Charcot-Marie-Tooth 1A and nondystrophic myotonia due to PMP22 duplication and SCN4A pathogenic variants: a case report

BackgroundCharcot-Marie-Tooth disease (CMT) is a genetically heterogeneous hereditary neuropathy, and CMT1A is the most common form; it is caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. Mutations in the transient sodium channel Nav1.4 alpha subunit (SCN4A) gene underlie a diverse group of dominantly inherited nondystrophic myotonias that run the spectrum from subclinical myopathy to severe muscle stiffness, disabling weakness, or frank episodes of paralysis.Case presentationWe describe a Chinese family affected by both CMT1A and myotonia with concomitant alterations in both the PMP22 and SCN4A genes. In this family, the affected proband inherited the disease from his father in an autosomal dominant manner. Genetic analysis confirmed duplication of the PMP22 gene and a missense c.3917G > C (p. Gly1306Ala) mutation in SCN4A in both the proband and his father. The clinical phenotype in the proband showed the combined involvement of skeletal muscle and peripheral nerves. Electromyography showed myopathic changes, including myotonic discharges. MRI revealed the concurrence of neurogenic and myogenic changes in the lower leg muscles. Sural nerve biopsies revealed a chronic demyelinating and remyelinating process with onion bulb formations in the proband. The proband’s father presented with confirmed subclinical myopathy, very mild distal atrophy and proximal hypertrophy of the lower leg muscles, pes cavus, and areflexia.ConclusionThis study reports the coexistence of PMP22 duplication and SCN4A mutation. The presenting features in this family suggested that both neuropathy and myopathy were inherited in an autosomal dominant manner. The proband had a typical phenotype of sodium channel myotonia (SCM) and CMT1A. However, his father with the same mutations presented a much milder clinical phenotype. Our study might expand the genetic and phenotypic spectra of neuromuscular disorders with concomitant mutations.

A novel case of concurrent occurrence of demyelinating-polyneuropathy-causing PMP22 duplication and SOX10 gene mutation producing severe hypertrophic neuropathy

BackgroundHereditary motor and sensory neuropathy, also referred to as Charcot–Marie–Tooth disease (CMT), is most often caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. This duplication causes CMT type 1A (CMT1A). CMT1A rarely occurs in combination with other hereditary neuromuscular disorders. However, such rare genetic coincidences produce a severe phenotype and have been reported in terms of “double trouble” overlapping syndrome. Waardenburg syndrome (WS) is the most common form of a hereditary syndromic deafness. It is primarily characterized by pigmentation anomalies and classified into four major phenotypes. A mutation in the SRY sex determining region Y-box 10 (SOX10) gene causes WS type 2 or 4 and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS, and Hirschsprung disease. We describe a 11-year-old boy with extreme hypertrophic neuropathy because of a combination of CMT1A and WS type 2. This is the first published case on the co-occurrence of CMT1A and WS type 2.Case presentationThe 11-year-old boy presented with motor developmental delay and a deterioration in unstable walking at 6 years of age. In addition, he had congenital hearing loss and heterochromia iridis. The neurological examination revealed weakness in the distal limbs with pes cavus. He was diagnosed with CMT1A by the fluorescence in situ hybridization method. His paternal pedigree had a history of CMT1A. However, no family member had congenital hearing loss. His clinical manifestation was apparently severe than those of his relatives with CMT1A. In addition, a whole-body magnetic resonance neurography revealed an extreme enlargement of his systemic cranial and spinal nerves. Subsequently, a genetic analysis revealed a heterozygous frameshift mutation c.876delT (p.F292Lfs*19) in the SOX10 gene. He was eventually diagnosed with WS type 2.ConclusionsWe described a patient with a genetically confirmed overlapping diagnoses of CMT1A and WS type 2. The double trouble with the genes created a significant impact on the peripheral nerves system. Severe phenotype in the proband can be attributed to the cumulative effect of mutations in both PMP22 and SOX10 genes, responsible for demyelinating neuropathy.

Fatigue in patients with hereditary neuropathy with liability to pressure palsies.

ObjectiveHereditary Neuropathy with Liability to Pressure Palsies (HNPP) is caused by a heterozygous deletion of peripheral myelin protein‐22 (PMP22) gene resulting in focal sensorimotor deficits. Our lab has identified a disruption of myelin junctions in excessively permeable myelin that impairs action potential propagation. This mechanism is expected to cause fatigue in patients with HNPP. Therefore, the objective was to characterize fatigue in patients with HNPP and determine the relationship of fatigue to nerve pathology, disability, and quality of life.MethodsNine females with HNPP participated in a single visit that included genotyping, nerve conduction studies, neurological exam, quantitative magnetic resonance imaging, and a physical therapy exam incorporating upper and lower extremity function and survey measures of fatigue. This visit was followed by 2 weeks of ecological momentary assessment (wrist‐worn device) that captured fatigue ratings five times per day.ResultsParticipants demonstrated mild neurological impairment (CMTNS: 5.7 ± 2.8), yet reported high fatigue levels (average fatigue intensity over 2 weeks: 5.9 out of 10). Higher fatigue levels were associated with poorer quality of life and more pain. Higher fatigue was associated with significantly greater distal nerve proton density changes on peripheral nerve MRI, which is in line with hyper‐permeable myelin in HNPP.InterpretationFatigue is common and severe among patients with HNPP whose disabilities are minimal by conventional outcome measures. Therapeutic interventions targeting fatigue have the potential to improve quality of life and may serve as a robust outcome measure to show longitudinal changes for patients with HNPP.

Downregulation of the human peripheral myelin protein 22 gene by miR-29a in cellular models of Charcot\u2013Marie\u2013Tooth disease

The majority of hereditary neuropathies are caused by duplication of the peripheral myelin protein 22 (PMP22) gene. Therefore, mechanisms to suppress the expression of the PMP22 gene have high therapeutic significance. Here we asked whether the human PMP22 gene is a target for regulation by microRNA 29a (miR-29a). Using bioinformatics, we determined that the human PMP22 gene contains the conserved seed sequence of the miR-29a binding site and this regulatory motif is included in the duplicated region in neuropathic patients. Using luciferase reporter assays in HEK293 cells, we demonstrated that transient transfection of a miR-29a mimic is associated with reduction in PMP22 3′UTR reporter activity. Transfecting normal and humanized transgenic neuropathic mouse Schwann cells with a miR-29a expression plasmid effectively lowered both the endogenous mouse and the transgenic human PMP22 transcripts compared with control vector. In dermal fibroblasts derived from neuropathic patients, ectopic expression of miR-29a led to ~50% reduction in PMP22 mRNA, which corresponded to ~20% decrease in PMP22 protein levels. Significantly, miR-29a-mediated reduction in PMP22 mitigated the reduced mitotic capacity of the neuropathic cells. Together, these results support further testing of miR-29a and/or PMP22-targeting siRNAs as therapeutic agents for correcting the aberrant expression of PMP22 in neuropathic patients.

Hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by recurrent sensory and motor neuropathy in individual nerves starting in adolescence or young adulthood, focal conduction abnormalities at entrapment sites on nerve conduction studies, and sausage-like swellings (tomacula) of the myelin sheaths by nerve biopsy. It is characterized genetically by the deletion of the chromosome 17p11.2-p12 region including the peripheral myelin protein-22 gene in the overwhelming majority of cases. HNPP may be frequently underdiagnosed or misdiagnosed owing to the heterogeneity of clinical and electrophysiological appearance. The main objective of this review is to describe clinical manifestations, paraclinical features such as electrodiagnostic, pathological, radiological and genetics findings, and possible treatments.

Elevated Peripheral Myelin Protein 22, Reduced Mitotic Potential, and Proteasome Impairment in Dermal Fibroblasts from Charcot-Marie-Tooth Disease Type 1A Patients

A common form of hereditary autosomal dominant demyelinating neuropathy known as Charcot-Marie-Tooth disease type 1A (CMT1A) is linked with duplication of the peripheral myelin protein 22 (PMP22) gene. Although studies from animal models have led to better understanding of the pathobiology of these neuropathies, there continues to be a gap in the translation of findings from rodents to humans. Because PMP22 was originally identified in fibroblasts as growth arrest specific gene 3 (gas3) and is expressed broadly in the body, it was tested whether skin cells from neuropathic patients would display the cellular pathology observed in Schwann cells from rodent models. Dermal fibroblasts from two CMT1A pedigrees with confirmed PMP22 gene duplication were studied. Samples from age-matched non-neuropathic individuals were used as controls. CMT1A patient–derived cultures contain approximately 1.5-fold elevated levels of PMP22 mRNA, exhibit reduced mitotic potential, and display intracellular protein aggregates as compared to cells from unaffected individuals. The presence of cytosolic PMP22 coincides with a decrease in proteasome activity and an increase in autophagy-lysosomal proteins, including LC3-II and LAMP1. These results indicate that the abnormalities in the subcellular processing of excess PMP22 elicit a detectable response in human CMT1A fibroblasts, a phenotype that resembles Schwann cells from neuropathic mice. These findings support the use of human CMT1A fibroblasts as a platform for therapy testing.

Charcot-Marie-Tooth Disease Type 1A: Influence of Body Mass Index on Nerve Conduction Studies and on the Charcot-Marie-Tooth Examination Score.

Charcot-Marie-Tooth Disease type 1A (CMT1A) is caused by a duplication of the peripheral myelin protein gene 22 at chromosome 17p11.2-12. There is limited data regarding whether body mass index (BMI) affects electrophysiological or clinical data in those with CMT1A. Electrophysiological data, the Charcot-Marie-Tooth examination score (CMTES) and BMI from 101 patients with known CMT1A were obtained and analyzed. When controlling for age, a higher BMI does not affect ulnar motor nerve conduction studies in those with CMT1A, but rather components of the CMTES (loss of pinprick and motor strength in the lower extremities). BMI and clinical components of the CMTES are correlated, but it is uncertain which came first-whether the loss of lower extremity pinprick sensation and motor strength results in a higher BMI or if higher BMI results in these signs.

A Computational Approach to Identify a Potential Alternative Drug With Its Positive Impact Toward PMP22.

Mutations in the Peripheral Myelin Protein 22 (PMP22) leads to Charcot Marie Tooth type 1A (CMT1A, a subtype of CMT1) disease which is the most common inherited neuropathy of peripheral nervous system. In the present study, we used series of in silico prediction methods to screen and identify the most deleterious non-synonymous SNPs (nsSNPs) in PMP22 gene. Out of 48 nsSNPs, five nsSNPs (L16P, L19P, T23R, W28R, and L147R) associated with PMP22 were predicted to be highly deleterious and destabilizing the protein. To explore the possible structure-function relationship, we employed abinitio modeling strategy using the CABS-fold server to predict the three-dimensional structure models in the absence of crystallized structures in PMP22 protein. We used Cytoscape 3.4.0 plugin Integrated Complex Traits Networks interface (iCTNet) to identify the probable drug-gene interactions in PMP22 gene. A total of 22 chemical compounds yielded from the aforementioned tool was subjected to Molinspiration and OSIRIS program to screen and identify the potent drug molecules for further analysis. Five chemical compounds with excellent bioavailability and drug relevant property were selected for molecular docking simulation study. We modeled five mutant structures at their corresponding positions and performed molecular docking simulation analysis using AutoDock Tools (ADT) version 1.5.6 and ArgusLab 4.0.1 tools to analyze their interaction patterns and binding efficacy. Based on the results obtained from the computational study, we predict that estradiol could be a potential drug of choice for treating patients with CMT1A which needs larger attention from biologists in the near future. J. Cell. Biochem. 118: 3730-3743, 2017. © 2017 Wiley Periodicals, Inc.

The Functional Role of PMP22 Gene in the Proliferation and Invasion of Osteosarcoma.

BackgroundAs the most common primary bone tumor, osteosarcoma has an improved survival rates with advancement of treatment methods. A higher rate of metastasis, however, leads to the aggravation of the disease. Studies have shown that some genes, namely osteosarcoma metastasis-related genes, participate in the process of tumor metastasis. The peripheral myelin protein 22 (PMP22) gene has recently been found to be abundantly expressed in the oncogenesis of osteosarcoma. Its detailed role and function in the tumor metastasis, however, remains unknown.Material/MethodsThe recombinant retroviral plasmid pcDNA3.1-PMP22 was constructed and used to transfect osteosarcoma cells SOSP-M, whose cell proliferation was measured by MTT method. The formation of tumor cell colony, the cell migration and invasion were also measured. The signal transduction pathway MAPK was further analyzed by Western blotting.ResultsThe pcDNA3.1-PMP22 plasmid was confirmed to have a 305bp PMP22 fragment by EcoRI-XhoI dual digestion. Compared to the control group, osteosarcoma cell invasion was significantly facilitated by the transfection of pcDNA3.1-PMP22 plasmid (p<0.05). The recombinant plasmid also significantly potentiated the formation of tumor cell colony and increased the migration and invasion ability of tumor cells (p<0.05 in all cases). Phosphorylated p-ERK and p-P38 were also up-regulated by vector transfection (p<0.05).ConclusionsOsteosarcoma metastasis-related gene PMP22 participates in the proliferation, invasion, migration and colony formation of osteosarcoma cells possibly via the MAPK signal transduction pathway, providing evidences for further investigation of metastatic mechanism of osteosarcoma.

Coexistent Charcot-Marie-Tooth type 1A and type 2 diabetes mellitus neuropathies in a Chinese family.

Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by duplication of the peripheral myelin protein 22 (PMP22) gene on chromosome 17. It is the most common inherited demyelinating neuropathy. Type 2 diabetes mellitus is a common metabolic disorder that frequently causes predominantly sensory neuropathy. In this study, we report the occurrence of CMT1A in a Chinese family affected by type 2 diabetes mellitus. In this family, seven individuals had duplication of the PMP22 gene, although only four had clinical features of polyneuropathy. All CMT1A patients with a clinical phenotype also presented with type 2 diabetes mellitus. The other three individuals had no signs of CMT1A or type 2 diabetes mellitus. We believe that there may be a genetic link between these two diseases.

Co-occurrence of Xp21 microduplication encompassing the DMD locus in conjunction with 17p12/PMP22 microduplication in a female with Charcot–Marie–Tooth disease type 1A

We report on the molecular detection of two microduplications involving chromosomes Xp21.1–Xp21.2 and 17p12 in a 35-year-old female with clinical phenotype of Charcot–Marie–Tooth disease type 1A (CMT1A) documented by chromosomal microarray analysis. The 17p12 microduplication was approximately 1.32Mb in size and contained eleven genes including the peripheral myelin protein 22 (PMP22), while the Xp21.1–Xp21.2 microduplication was estimated to be 626Kb in size and contained part of the dystrophin (DMD) gene. Constitutional interstitial microduplication of 17p12 segment encompassing the PMP22 gene has been reported in individuals with Charcot–Marie–Tooth disease type 1A. Defects in the DMD gene (deletion, duplication, or mutation) are associated with Duchenne and Becker muscular dystrophies (DMD and BMD). Combined microduplications of Xp21/DMD with 17p12/PMP22 are extremely rare with only one published report of a male patient with changes in both the DMD and PMP22 genes.

Abnormal junctions and permeability of myelin in PMP22‐deficient nerves

The peripheral myelin protein-22 (PMP22) gene is associated with the most common types of inherited neuropathies, including hereditary neuropathy with liability to pressure palsies (HNPP) caused by PMP22 deficiency. However, the function of PMP22 has yet to be defined. Our previous study has shown that PMP22 deficiency causes an impaired propagation of nerve action potentials in the absence of demyelination. In the present study, we tested an alternative mechanism relating to myelin permeability. Utilizing Pmp22(+) (/) (-) mice as a model of HNPP, we evaluated myelin junctions and their permeability using morphological, electrophysiological, and biochemical approaches. We show disruption of multiple types of cell junction complexes in peripheral nerve, resulting in increased permeability of myelin and impaired action potential propagation. We further demonstrate that PMP22 interacts with immunoglobulin domain-containing proteins known to regulate tight/adherens junctions and/or transmembrane adhesions, including junctional adhesion molecule-C (JAM-C) and myelin-associated glycoprotein (MAG). Deletion of Jam-c or Mag in mice recapitulates pathology in HNPP. Our study reveals a novel mechanism by which PMP22 deficiency affects nerve conduction not through removal of myelin, but through disruption of myelin junctions.

Hereditary Neuropathy With Liability to Pressure Palsy

Hereditary neuropathy with liability to pressure palsies (HNPP) is an inherited autosomal dominant disorder that causes a polyneuropathy with predisposition for involvement at sites of compression and is often underdiagnosed or misdiagnosed due to its heterogeneity in clinical and electrophysiological presentation. We report 2 cases of HNPP, which were initially diagnosed and treated as either an acquired demyelinating disorder or alternative inherited demyelinating disorder. Thorough evaluation of repeat electrodiagnostic studies and genetic testing confirmed the diagnosis of HNPP in both cases. One case showed the classic peripheral myelin protein 22 (PMP22) deletion and the other case showed a previously reported single base pair deletion at Leu145 causing a frameshift mutation at the PMP22 gene. These cases underscore the difficulty of diagnosing HNPP, because of the variations in clinical and electrophysiological findings and reinforce the importance of a combination high index of clinical suspicion, electrodiagnostic testing, and genetic testing to make the diagnosis.

Electrophysiological Evaluation of Chronic Inflammatory Demyelinating Polyneuropathy and Charcot-Marie-Tooth Type 1: Dispersion and Correlation Analysis

[Purpose] The purpose of this study was to analyze and compare electrophysiological characteristics observed in nerve conduction studies (NCS) of chronic inflammatory demyelinating polyneuropathy (CIDP) and Charcot-Marie-Tooth disease type 1 (CMT 1). [Subjects] A differential diagnosis of acquired and congenital demyelinating neuropathies was based on a study of 35 patients with NCS-confirmed CIDP and 30 patients with CMT 1 genetically proven by peripheral myelin protein-22 (PMP-22) gene analysis, pulsed-field gel electrophoresis (PFGE), and Southern blot analysis. [Methods] We analyzed values collected in motor nerve conduction studies. We conducted dispersion analysis of the amplitudes of the compound muscle action potential (CMAP) of various nerve types and correlation coefficient analysis of the motor nerve conduction velocity (MNCV). [Results] We found that CIDP and CMT 1 were clearly attributable to severe polyneuropathy. In dispersion analysis, CIDP showed greater differences in proximal-to-distal amplitude ratios. Moreover, CMT 1 showed relatively high correlations compared to CIDP based on correlation coefficient analysis of MNCV. [Conclusion] The results of this study suggest that CIDP showed greater asymmetry than CMT 1 in MNCV and CMAP amplitudes.

Central nervous system abnormalities in patients with PMP22 gene mutations: a prospective study

BackgroundMutations of the peripheral myelin protein-22 (PMP22) gene are the most common cause of inherited disease of the peripheral nervous system (PNS), with its deletion resulting in hereditary neuropathy with...

The PMP22 Gene and Its Related Diseases

Peripheral myelin protein-22 (PMP22) is primarily expressed in the compact myelin of the peripheral nervous system. Levels of PMP22 have to be tightly regulated since alterations of PMP22 levels by mutations of the PMP22 gene are responsible for >50 % of all patients with inherited peripheral neuropathies, including Charcot-Marie-Tooth type-1A (CMT1A) with trisomy of PMP22, hereditary neuropathy with liability to pressure palsies (HNPP) with heterozygous deletion of PMP22, and CMT1E with point mutations of PMP22. While overexpression and point-mutations of the PMP22 gene may produce gain-of-function phenotypes, deletion of PMP22 results in a loss-of-function phenotype that reveals the normal physiological functions of the PMP22 protein. In this article, we will review the basic genetics, biochemistry and molecular structure of PMP22, followed by discussion of the current understanding of pathogenic mechanisms involving in the inherited neuropathies with mutations in PMP22 gene.