Last update 19 Sep 2024

Charcot-Marie-Tooth Disease, Type 2I

Last update 19 Sep 2024

Basic Info

Synonyms

Autosomal dominant Charcot-Marie-Tooth disease type 2I, Autosomal dominant Charcot-Marie-Tooth disease type 2I (disorder), CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2I

+ [12]

Introduction

A form of axonal Charcot-Marie-Tooth disease a peripheral sensorimotor neuropathy. A late onset with severe sensory loss associated with distal weakness mainly of the legs and absent or reduced deep tendon reflexes.

Clinical Trials associated with Charcot-Marie-Tooth Disease, Type 2I

NCT05902351 / RecruitingNot Applicable

Global Registry for Inherited Neuropathies Natural History Study for Charcot Marie Tooth Disease

The goal of this Natural History Study for Charcot-Marie-Tooth is to acquire, record, and analyze patient-reported data and associated genetic reports, Electronic Health Records (EHRs) and clinical notes to identify the burden, diagnostic journey, and prevalence of disease that will aid scientists in their work toward finding a cure.
Participants will be asked to complete a Natural History Survey.

Start Date01 Nov 2013

Sponsor / Collaborator

Hereditary Neuropathy Foundation

100 Clinical Results associated with Charcot-Marie-Tooth Disease, Type 2I

100 Translational Medicine associated with Charcot-Marie-Tooth Disease, Type 2I

0 Patents (Medical) associated with Charcot-Marie-Tooth Disease, Type 2I

118

Literatures (Medical) associated with Charcot-Marie-Tooth Disease, Type 2I

05 Aug 2023·Brain : a journal of neurology

Homomeric interactions of the MPZ Ig domain and their relation to Charcot-Marie-Tooth disease.

Article

Author: Christopher P Ptak ; Tabitha A Peterson ; Jesse B Hopkins ; Christopher A Ahern ; Michael E Shy ; Robert C Piper

Mutations in MPZ (Myelin Protein Zero) can cause demyelinating early-onset Charcot-Marie-Tooth Type1B disease or later onset Type2I/J disease characterized by axonal degeneration, reflecting the diverse roles of MPZ in Schwann cells. MPZ holds apposing membranes of the myelin sheath together, with the adhesion role fulfilled by its extracellular Immunoglobulin-like domain (IgMPZ), which oligomerizes. Models for how the IgMPZ might form oligomeric assemblies has been extrapolated from a protein crystal structure in which individual rat IgMPZ subunits are packed together under artificial conditions, forming 3 weak interfaces. One interface organizes the IgMPZ into tetramers, a second 'dimer' interface links tetramers together across the intraperiod line, and a third hydrophobic interface that mediates binding to lipid bilayers or the same hydrophobic surface on another IgMPZ domain. Presently, there are no data confirming whether the proposed IgMPZ interfaces actually mediate oligomerization in solution, whether they are required for the adhesion activity of MPZ, whether they are important for myelination, or whether their loss results in disease. We performed nuclear magnetic resonance spectroscopy and small angle X-ray scattering analysis of wild-type IgMPZ as well as mutant forms with amino-acid substitutions designed to interrupt its presumptive oligomerization interfaces. Here, we confirm the interface that mediates IgMPZ tetramerization, but find that dimerization is mediated by a distinct interface that has yet to be identified. We next correlated different types of Charcot-Marie-Tooth disease symptoms to subregions within IgMPZ tetramers. Variants causing axonal late-onset disease (CMT2I/J) map to surface residues of IgMPZ proximal to the transmembrane domain. Variants causing early-onset demyelinating disease (CMT1B) segregate into two groups: one is described by variants that disrupt the stability of the Ig-fold itself and are largely located within the core of the IgMPZ domain; whereas another describes a region on the surface of IgMPZ tetramers, accessible to protein interactions. Computational docking studies predict that this latter disease-relevant subregion may potentially mediate dimerization of IgMPZ tetramers.

10 Apr 2023·Cognitive processing

Comparing the effect of individual and group cognitive-motor training on reconstructing subjective well-being and quality of life in older males, recovered from the COVID-19.

Article

Author: Amin Amini ; Mohammad Vaezmousavi ; Hossein Shirvani

While the message emanating from physiological and psychological research has extolled the general advantages of exercise in physical and cognitive health, the social distancing and the impossibility of group exercises have revealed more complex conditions. Therefore, we performed an experimental study comparing the effect of individual and group cognitive-motor training on reconstructing subjective well-being (SWB) and quality of life (QOL) in older males who recovered from COVID-19. The study's design is a single-blind, randomized controlled trial (RCT). The participants, 36 older men (65-80 yrs.) recovering from COVID-19, were randomly divided into (1) Group A (cognitive-motor training, G-CMT); (2) Group B (individual cognitive-motor training, I-CMT); and (3) Group C (control). Both training interventions involved performing a training protocol (cognitive-motor training) twice a week for four weeks. The outcomes included an assessment of the SWB and QOL of participants by SWB scale and world health organization QOL scale at baseline and two weeks after interventions. Except for the effect of age and number of children variables on QOL, other demographic variables had no significant effect on the results of SWB or WHOQOL of participants (P > 0.05). The SWB results in G-CMT were better than I-CMT and control groups in emotional and social well-being domains. Also, WHOQOL test results in G-CMT were better than control groups in domains of psychological and social relationships, whereas I-CMT performed better than G-CMT and control groups in domains of cognitive well-being, physical health, and environment. The results revealed that the mean test scores of SWB and WHOQOL in G-CMT and I-CMT were better than the control group (P ≤ 0.001). The positive effects of cognitive-motor training on reconstructing SWB and QOL are associated with the synchronicity of cognitive and motor components in these exercises. We suggest that the emotional, social, and psychological benefits of cognitive-motor training override cognitive, physical, and environmental changes. The future line of the present study will include pathophysiology and further clinical aspect of recovering from COVID-19.

23 Mar 2023·Metabolic brain disease

Complete Loss of Myelin protein zero (MPZ) in a patient with a late onset Charcot-Marie-Tooth (CMT).

Article

Author: Jalal Gharesouran ; Hassan Hosseinzadeh ; Ali Naghiloo ; Soudeh Ghafouri-Fard ; Bashdar Mahmud Hussen ; Mohammad Taheri ; Maryam Rezazadeh ; Mohammad Samadian

Charcot-Marie-Tooth (CMT) comprises a group of hereditary neuropathies with clinical, epidemiological, and molecular heterogeneity in which variants in more than 80 different genes have been reported. One of the important genes which cause 5% of all CMT cases is Myelin protein zero (P0, MPZ). Variants in this gene have been reported in association with different forms of CMT including classical CMT1, severe DSS (CMT3B), DI-CMT, CMT2I and CMT2J with autosomal dominant (AD) inheritance. To our knowledge, MPZ variants have not been described in autosomal recessive (AR) form of CMT in previous studies. Moreover, its complete deletion has not been reported in human. Here, we described clinical characteristics of a patient with CMT symptoms who demonstrated manifestations of the disease late in his life. We performed exome sequencing for identifying CMT subtype and its associated gene, and follow that co-segregation analysis has been done to characterize inheritance pattern of the disorder. Through using exome sequencing, we identified a novel 4074 bp homozygote deletion which encompasses all 6 exons of the MPZ gene in this patient. After identifying the alteration, variant confirmation and co-segregation analysis have been performed by using specific primers. Our result revealed that the patient's parents were heterozygous for the alteration and they did not show any symptoms of CMT. Although most MPZ variants have been described with early onset CMT with AD pattern of inheritance, the reported patient in our study had late onset form and his parents did not show any symptoms. Considering substantial role of MPZ protein in the biogenesis of peripheral nervous system (PNS) myelin, we proposed that there should be another protein in PNS that compensates for lack of MPZ protein. Taken together, our finding is the first report of MPZ association with AR form of CMT with late onset features. Moreover, our results propose the presence of another protein in PNS myelin biogenesis and its assembly. However, functional studies alongside with other molecular studies are needed to confirm our results and identify the proposed protein.

News (Medical) associated with Charcot-Marie-Tooth Disease, Type 2I

23 Jan 2024

·www.biospace.com

Vanda Pharmaceuticals Receives FDA Approval to Proceed with Investigational New Drug VCA-894A, a Novel Antisense Oligonucleotide Candidate for the Treatment of Charcot-Marie-Tooth Disease, Type 2S

WASHINGTON, Jan. 23, 2024 /PRNewswire/ -- Vanda Pharmaceuticals, Inc. (Vanda) (Nasdaq: VNDA) today announced that the U.S. Food and Drug Administration (FDA) has approved the Investigational New Drug (IND) application to evaluate VCA-894A for the treatment of a patient with Charcot-Marie-Tooth disease, axonal, type 2S (CMT2S), caused by cryptic splice site variants within the IGHMBP2 gene. CMT2S is a rare subtype of Charcot-Marie-Tooth disease (CMT), an inherited peripheral neuropathy for which there is no available treatment. CMT2S is characterized by slowly progressive distal muscle weakness and atrophy, affecting the upper and lower limbs in a child's first decade of life, leaving patients with decreased reflexes and sensory impairment1,2 The estimated overall prevalence of CMT is 1 in 2,500 individuals, with varying clinical features dependent on the various genetic variants of CMT.1,2 The prevalence of the CMT2S variant is estimated to be less than 1 in 1,000,000 worldwide.3 "This is an important milestone in the pursuit of personalized medicine, which has the potential to enable the development of treatments tailored to one's genetic variants, in this case specifically for a patient with CMT2S causing genetic mutations," said Mihael H. Polymeropoulos, M.D., Vanda's President, CEO and Chairman of the Board. VCA-894A is a novel antisense oligonucleotide (ASO) with a mechanism of action that specifically targets a cryptic splice site variant within immunoglobulin mu-binding protein 2 (IGHMBP2). Mutations within IGHMBP2 play a pivotal role in the manifestation of CMT2S, likely due to alpha-motor neuron loss, and consequently peripheral nervous system deterioration.4 ASOs have the capacity to modulate gene expression, allowing for the personalized treatment of rare diseases. Delivery of ASOs to the central nervous system has been previously successful in several ASO programs, with a broad applicability in addressing a number of neurodegenerative and neuromuscular disorders.5 References Cottenie, E., et al. (2014). Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2. American journal of human genetics, 95(5), 590–601. Nam, S. H., & Choi, B-O. (2019). Clinical and genetic aspects of Charcot-Marie-Tooth disease subtypes." Precision and Future Medicine, 3(2), 43–68. (2023). Charcot-Marie-Tooth disease type 2S. Orpha.net. Rzepnikowska, W., & Kochański, A. (2021). Models for IGHMBP2-associated diseases: an overview and a roadmap for the future. Neuromuscular disorders: NMD, 31(12), 1266–1278. Crooke, S. T., Liang, X. H., Baker, B. F., & Crooke, R. M. (2021). Antisense technology: A review. The Journal of biological chemistry, 296, 100416. About Vanda Pharmaceuticals Inc. Vanda is a leading global biopharmaceutical company focused on the development and commercialization of innovative therapies to address high unmet medical needs and improve the lives of patients. For more on Vanda Pharmaceuticals Inc., please visit and follow us on Twitter @vandapharma. About VCA-894A VCA-894A is a 2'-O-methoxyethyl (MOE) phosphorothioate oligonucleotide sodium salt. VCA-894A specifically targets a cryptic splice site variant within IGHMBP2, which causes CMT2S. ASOs may have broad applicability in addressing a number of disorders, from nervous system treatments to systemic treatments. CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS Various statements in this press release, including, but not limited to statements regarding the estimated prevalence of CMT and CMT2S and the development of individualized treatments, are "forward-looking statements" under the securities laws. Forward-looking statements are based upon current expectations that involve risks, changes in circumstances, assumptions and uncertainties. Important factors that could cause actual results to differ materially from those reflected in Vanda's forward-looking statements include, among others, the accuracy of the reporting and diagnosis of CMT and CMT2S cases and the ability to successfully complete the clinical development of, and obtain regulatory approval for, VCA-894A in the treatment of CMT2S. Therefore, no assurance can be given that the results or developments anticipated by Vanda will be realized or, even if substantially realized, that they will have the expected consequences to, or effects on, Vanda. Forward-looking statements in this press release should be evaluated together with the various risks and uncertainties that affect Vanda's business and market, particularly those identified in the "Cautionary Note Regarding Forward-Looking Statements", "Risk Factors" and "Management's Discussion and Analysis of Financial Condition and Results of Operations" sections of Vanda's most recent Annual Report on Form 10-K, as updated by Vanda's subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the U.S. Securities and Exchange Commission, which are available at . All written and verbal forward-looking statements attributable to Vanda or any person acting on its behalf are expressly qualified in their entirety by the cautionary statements contained or referred to herein. Vanda cautions investors not to rely too heavily on the forward-looking statements Vanda makes or that are made on its behalf. The information in this press release is provided only as of the date of this press release, and Vanda undertakes no obligation, and specifically declines any obligation, to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law. Corporate Contact: Kevin Moran Senior Vice President, Chief Financial Officer and Treasurer Vanda Pharmaceuticals Inc. 202-734-3400 pr@vandapharma.com Company Codes: NASDAQ-NMS:VNDA

OligonucleotideIND

02 Jun 2023

·www.prnewswire.com

Vanda Pharmaceuticals Announces Orphan Drug Designation Granted for VCA-894A, a Novel Antisense Oligonucleotide Candidate for the Treatment of Charcot-Marie-Tooth Disease, Type 2S

WASHINGTON, June 1, 2023 /PRNewswire/ -- Vanda Pharmaceuticals Inc. (Vanda) (Nasdaq: VNDA) today announced the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation for VCA-894A for the treatment of Charcot-Marie-Tooth disease, axonal, type 2S (CMT2S), caused by cryptic splice site variants within IGHMBP2. CMT2S is a rare subtype of Charcot-Marie-Tooth disease (CMT), an inherited peripheral neuropathy for which there is no available treatment. The estimated prevalence of CMT is 1 in 2,500 individuals, with varying clinical features dependent on the various genetic variants of CMT.1,2 The prevalence of CMT2S is estimated to be less than 1 in 1,000,000 worldwide.3 Onset of CMT2S begins in early childhood.2 CMT2S is characterized by slowly progressive distal muscle weakness and atrophy, affecting the upper and lower limbs in a child's first decade of life, leaving patients with decreased reflexes and sensory impairment.1,2 Because CMT2S is a progressive disease, most patients become wheelchair bound. "This designation is an important milestone, which we believe may enable the development of individualized treatments tailored to one's genetic variants for patients with CMT2S," said Mihael H. Polymeropoulos, M.D., Vanda's President, CEO and Chairman of the Board. VCA-894A is a novel antisense oligonucleotide (ASO) with a mechanism of action that specifically targets a cryptic splice site variant within immunoglobulin mu-binding protein 2 (IGHMBP2). Mutations within IGHMBP2 play a pivotal role in the manifestation of CMT2S, likely due to alpha-motor neuron loss, and consequently peripheral nervous system deterioration.4 ASOs have the capacity to modulate gene expression, allowing for the personalized treatment of rare diseases. Delivery of ASOs to the central nervous system has been previously successful in several ASO programs, with a broad applicability in addressing a number of neurodegenerative and neuromuscular disorders.5 Orphan Drug Designation is granted by the FDA to investigational therapies addressing rare medical conditions and provides benefits to drug developers. References Cottenie, E., et al. (2014). Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2. American journal of human genetics, 95(5), 590–601. Nam, S. H., & Choi, B-O. (2019). Clinical and genetic aspects of Charcot-Marie-Tooth disease subtypes." Precision and Future Medicine, 3(2), 43–68. (2023). Charcot-Marie-Tooth disease type 2S. Orpha.net. Rzepnikowska, W., & Kochański, A. (2021). Models for IGHMBP2-associated diseases: an overview and a roadmap for the future. Neuromuscular disorders: NMD, 31(12), 1266–1278. Crooke, S. T., Liang, X. H., Baker, B. F., & Crooke, R. M. (2021). Antisense technology: A review. The Journal of biological chemistry, 296, 100416. About Vanda Pharmaceuticals Inc. Vanda is a leading global biopharmaceutical company focused on the development and commercialization of innovative therapies to address high unmet medical needs and improve the lives of patients. For more on Vanda Pharmaceuticals Inc., please visit and follow us on Twitter @vandapharma. About VCA-894A VCA-894A is a 2'-O-methoxyethyl (MOE) phosphorothioate oligonucleotide sodium salt. VCA-894A specifically targets a cryptic splice site variant within IGHMBP2, which causes CMT2S. ASOs may have broad applicability in addressing a number of disorders, from nervous system treatments to systemic treatments. CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS Various statements in this press release, including, but not limited to statements regarding the estimated prevalence of CMT and CMT2S and the development of individualized treatments, are "forward-looking statements" under the securities laws. Forward-looking statements are based upon current expectations that involve risks, changes in circumstances, assumptions and uncertainties. Important factors that could cause actual results to differ materially from those reflected in Vanda's forward-looking statements include, among others, the accuracy of the reporting and diagnosis of CMT and CMT2S cases and the ability to successfully complete the clinical development of, and obtain regulatory approval for, VCA-894A in the treatment of CMT2S. Therefore, no assurance can be given that the results or developments anticipated by Vanda will be realized or, even if substantially realized, that they will have the expected consequences to, or effects on, Vanda. Forward-looking statements in this press release should be evaluated together with the various risks and uncertainties that affect Vanda's business and market, particularly those identified in the "Cautionary Note Regarding Forward-Looking Statements", "Risk Factors" and "Management's Discussion and Analysis of Financial Condition and Results of Operations" sections of Vanda's most recent Annual Report on Form 10-K, as updated by Vanda's subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the U.S. Securities and Exchange Commission, which are available at . All written and verbal forward-looking statements attributable to Vanda or any person acting on its behalf are expressly qualified in their entirety by the cautionary statements contained or referred to herein. Vanda cautions investors not to rely too heavily on the forward-looking statements Vanda makes or that are made on its behalf. The information in this press release is provided only as of the date of this press release, and Vanda undertakes no obligation, and specifically declines any obligation, to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law. Corporate Contact: Kevin Moran Senior Vice President, Chief Financial Officer and Treasurer Vanda Pharmaceuticals Inc. 202-734-3400 [email protected] Elizabeth Van Every Head of Corporate Affairs Vanda Pharmaceuticals Inc. 202-734-3400 [email protected] SOURCE Vanda Pharmaceuticals Inc.

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Charcot-Marie-Tooth Disease, Type 2I

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