更新于：2024-11-01

Charcot-Marie-Tooth Disease, Type Ib

腓骨肌萎缩症Ib型

更新于：2024-11-01

基本信息

别名

CHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL DOMINANT, WITH FOCALLY FOLDED MYELIN SHEATHS, TYPE 1B、CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 1B、CHARCOT-MARIE-TOOTH DISEASE, SLOW NERVE CONDUCTION TYPE, LINKED TO DUFFY

+ [25]

简介

Charcot-Marie-Tooth disease caused by mutations in the MPZ gene (mapped to chromosome 1q23.3). It results in sensorineural peripheral neuropathy.

关联

项与腓骨肌萎缩症Ib型相关的药物

Biotin

生物素

靶点

ABCD1

作用机制

ABCD1 inhibitors

在研机构

Harvard Medical School [+5]

原研机构-

在研适应症

糖尿病 [+5]

非在研适应症

肌萎缩侧索硬化 [+9]

最高研发阶段批准上市

首次获批国家/地区-

首次获批日期1800-01-20

项与腓骨肌萎缩症Ib型相关的临床试验

NCT03550300 / Unknown statusN/AIIT

Muscle MRI in Charcot Mary Tooth Disease: a Prospective Cohort Study

This cohort study (participants with CMT and control participants) has two parts (Part 1: CMT1A cohort; Part2: CMT1B, CMT2A and CMTX1 cohort) and is proposed to take place over 3 years across three sites. Participants with CMT aged 5-60 for potential enrolment in the trial will be identified through the existing inherited neuropathy clinics at each site and control participants will be identified among the unaffected relatives and carers of the participants with CMT. If they show interest in participating, they will be given the relevant Patient Information Sheets, Written Consent forms and/or Assent forms. Half of the participants will be recruited at the UK sites (NHNN and GOSH) and the other half at the US collaborating site. Each participant will be invited to two separate research visits (12 months apart) for which travel expenses (return journey) will be reimbursed. Each research visit is expected to last approximately 3 hours and during it, relevant detailed clinical data will be collected (CMTPedS for participants with CMT aged 5-20, CMTESv2-R for participants with CMT over the age of 10, CMT-HI for participants with CMT over the age of 16) and the participant will also undergo an MRI scan (up to 45 minutes) of the lower limbs (feet and calves or calves and thighs). Two separate neuromuscular MRI protocols with specific sequences will be used for the scans of foot and calf muscles and scans of calf and thigh muscles. Blood samples for plasma NEFL levels will be optional at both research visits for the participants at the UK trial sites; plasma NEFL levels will be processed according to our previously published protocol

开始日期2018-09-11

申办/合作机构

University College London

[+1]

NCT02967679 / Completed临床2期

SERENDEM Study: MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study

The single-center, open-label Phase II study has the objective of assess the effect of MD1003 on motor and sensory conduction in patients suffering from demyelinating polyneuropathies in 15 subjects.

开始日期2016-12-05

申办/合作机构

MedDay Pharmaceuticals SAS

NCT05902351 / RecruitingN/A

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.

开始日期2013-11-01

申办/合作机构

Hereditary Neuropathy Foundation, Inc.

100 项与腓骨肌萎缩症Ib型相关的临床结果

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100 项与腓骨肌萎缩症Ib型相关的转化医学

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0 项与腓骨肌萎缩症Ib型相关的专利（医药）

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239

项与腓骨肌萎缩症Ib型相关的文献（医药）

2024-12-01·Cellular and Molecular Life Sciences

Pharmacologically increasing cGMP improves proteostasis and reduces neuropathy in mouse models of CMT1

Article

作者: Feltri, Maria Laura ; Marziali, Leandro N ; Moore, Seth M ; Gawron, Joseph ; VerPlank, Jordan J.S. ; Buys, Emmanuel S ; Stevens, Mckayla ; Milne, G. Todd ; Milne, G Todd ; VerPlank, Jordan J S ; Moore, Seth M. ; Marziali, Leandro N. ; Buys, Emmanuel S.

AbstractIncreasing cyclic GMP activates 26S proteasomes via phosphorylation by Protein Kinase G and stimulates the intracellular degradation of misfolded proteins. Therefore, agents that raise cGMP may be useful therapeutics against neurodegenerative diseases and other diseases in which protein degradation is reduced and misfolded proteins accumulate, including Charcot Marie Tooth 1A and 1B peripheral neuropathies, for which there are no treatments. Here we increased cGMP in the S63del mouse model of CMT1B by treating for three weeks with either the phosphodiesterase 5 inhibitor tadalafil, or the brain-penetrant soluble guanylyl cyclase stimulator CYR119. Both molecules activated proteasomes in the affected peripheral nerves, reduced polyubiquitinated proteins, and improved myelin thickness and nerve conduction. CYR119 increased cGMP more than tadalafil in the peripheral nerves of S63del mice and elicited greater biochemical and functional improvements. To determine whether raising cGMP could be beneficial in other neuropathies, we first showed that polyubiquitinated proteins and the disease-causing protein accumulate in the sciatic nerves of the C3 mouse model of CMT1A. Treatment of these mice with CYR119 reduced the levels of polyubiquitinated proteins and the disease-causing protein, presumably by increasing their degradation, and improved myelination, nerve conduction, and motor coordination. Thus, pharmacological agents that increase cGMP are promising treatments for CMT1 neuropathies and may be useful against other proteotoxic and neurodegenerative diseases.

2024-04-01·Life Science Alliance

Knockout of PA200 improves proteasomal degradation and myelination in a proteotoxic neuropathy

Article

作者: VerPlank, Jordan Js ; Silvestri, Nicholas J ; Feltri, Maria Laura ; Wrabetz, Lawrence ; Gawron, Joseph M

The cellular response to a decrease in protein degradation by 26S proteasomes in chronic diseases is poorly understood. Pharmacological inhibition of proteasomes increases the expression of proteasome subunits and Proteasome Activator 200 (PA200), an alternative proteasome activator. In the S63del mouse model of the peripheral neuropathy Charcot Marie Tooth 1B (CMT1B), proteasomal protein degradation is decreased and proteasome gene expression is increased. Here, we show an increase in PA200 and PA200-bound proteasomes in the peripheral nerves of S63del mice. To test genetically whether the upregulation of PA200 was compensatory, we generated S63del//PA200−/− mice. Unexpectedly, in the sciatic nerves of these mice, there was greater proteasomal protein degradation than in S63del, less polyubiquitinated proteins and markers of the unfolded protein response, and a greater amount of assembled, active 26S proteasomes. These changes were not seen in PA200−/− controls and were therefore specific to the neuropathy. Furthermore, in S63del//PA200−/− mice, myelin thickness and nerve conduction were restored to WT levels. Thus, the upregulation of PA200 is maladaptive in S63del mice and its genetic ablation prevented neuropathy.

2024-03-01·Annals of Clinical and Translational Neurology

Lower limb muscle MRI fat fraction is a responsive outcome measure in CMT X1, 1B and 2A

Article

作者: Milev, Evelin ; Yousry, Tarek A ; Nicolaisen, Emma ; Laura, Matilde ; Pipis, Menelaos ; Zafeiropoulos, Nick ; Thornton, John ; Morrow, Jasper M ; Wastling, Stephen ; Dudzeic, Magdalena ; McDowell, Amy ; Thedens, Daniel ; Skorupinska, Mariola ; Doherty, Carolynne M ; Shah, Sachit ; Howard, Paige ; Feely, Shawna M E ; Nopoulous, Peggy ; Dilek, Nuran ; Grider, Tiffany ; Zuccarino, Riccardo ; Rossor, Alexander M ; Stephens, Katherine J ; Muntoni, Francesco ; Shy, Michael E ; Reilly, Mary M

AbstractObjectiveWith potential therapies for many forms of Charcot‐Marie‐Tooth disease (CMT), responsive outcome measures are urgently needed for clinical trials. Quantitative lower limb MRI demonstrated progressive calf intramuscular fat accumulation in the commonest form, CMT1A with large responsiveness. In this study, we evaluated the responsiveness and validity in the three other common forms, due to variants in GJB1 (CMTX1), MPZ (CMT1B) and MFN2 (CMT2A).Methods22 CMTX1, 21 CMT1B and 21 CMT2A patients and matched controls were assessed at a 1‐year interval. Intramuscular fat fraction (FF) was evaluated using three‐point Dixon MRI at thigh and calf level along with clinical measures including CMT examination score, clinical strength assessment, CMT‐HI and plasma neurofilament light chain.ResultsAll patient groups had elevated muscle fat fraction at thigh and calf levels, with highest thigh FF and atrophy in CMT2A. There was moderate correlation between calf muscle FF and clinical measures (CMTESv2 rho = 0.405; p = 0.001, ankle MRC strength rho = −0.481; p < 0.001). Significant annualised progression in calf muscle FF was seen in all patient groups (CMTX1 2.0 ± 2.0%, p < 0.001, CMT1B 1.6 ± 2.1% p = 0.004 and CMT2A 1.6 ± 2.1% p = 0.002). Greatest increase was seen in patients with 10–70% FF at baseline (calf 2.7 ± 2.3%, p < 0.0001 and thigh 1.7 ± 2.1%, p = 0.01).InterpretationOur results confirm that calf muscle FF is highly responsive over 12 months in three additional common forms of CMT which together with CMT1A account for 90% of genetically confirmed cases. Calf muscle MRI FF should be a valuable outcome measure in upcoming CMT clinical trials.