更新于：2024-09-19

Charcot-Marie-Tooth Disease, X-Linked, 1

X-连锁腓骨肌萎缩症1

更新于：2024-09-19

基本信息

别名

CHARCOT-MARIE-TOOTH DISEASE, X-LINKED DOMINANT, 1、CHARCOT-MARIE-TOOTH NEUROPATHY, X-LINKED, 1、CHARCOT-MARIE-TOOTH PERONEAL MUSCULAR ATROPHY, X-LINKED

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简介

Charcot-Marie-Tooth neuropathy that is inherited in an X-linked manner, and is associated with mutation(s) in the GJB1 gene, encoding gap junction beta-1 protein. The condition is characterized by moderate to severe motor and sensory neuropathy in males, and mild to no symptoms in females.

关联

项与 X-连锁腓骨肌萎缩症1 相关的临床试验

NCT03943290 / Terminated临床2期

An Open-Label Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) Previously Enrolled in Study A083-02 and in Patients With Charcot-Marie Tooth (CMT) Disease Types 1 and X Previously Enrolled in Study A083-03

This is an open-label, multicenter, phase 2 extension study to evaluate the safety, tolerability, PK, PD, and efficacy of ACE-083 in subjects with FSHD previously enrolled in Study A083-02 and subjects with CMT1 and CMTX previously enrolled in Study A083-03. This study will be conducted in two Parts: Part 1, which is a loading phase of 6 months' duration, and Part 2, the maintenance phase, which will last up to 24 months.

开始日期2019-05-10

申办/合作机构

Acceleron Pharma, Inc.

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]

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

100 项与 X-连锁腓骨肌萎缩症1 相关的临床结果

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100 项与 X-连锁腓骨肌萎缩症1 相关的转化医学

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0 项与 X-连锁腓骨肌萎缩症1 相关的专利（医药）

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411

项与 X-连锁腓骨肌萎缩症1 相关的文献（医药）

2024-01-05·BMC pediatrics

A case report of peroneal muscle atrophy type 2A2 with central nervous system involvement as initial presentation.

Article

作者: Xin Xu ; Fen Lu ; Senjie Du ; Li Zhang

BACKGROUND:

Charcot-Marie-Tooth disease (CMT) is a group of single-gene hereditary diseases of peripheral nerve with high clinical variability and genetic heterogeneity. The typical clinical manifestations include progressive muscle weakness and muscle atrophy in the distal extremities, accompanied by disappearance of tendon reflexes and distal sensory disturbances. CMT2A2 (OMIM: 609260) is caused by the mutation of MFN2 (OMIM: 608507), is the most common type of axonal pattern. Although a small number of patients with X-linked CMT1 (CMT1X) present with central nervous system involvement, including reversible white matter lesions, it is rarely in CMT2A2.

CASE PRESENTATION:

A 3-year and 5-month-old girl had experienced motor lag, muscle tension, and abnormal gait for over a year. A reexamination of cranial MRI revealed an anterior enlargement of the abnormal signal range in the lateral ventricles and bilateral frontal lobes. And the whole exon sequencing showed that this girl carried a heterozygous missense mutation c.314C > T of MNF2 gene, inherited from her mother.

CONCLUSIONS:

In this study, we retrospectively analyzed the clinical and molecular genetic findings of a child with Charcot-Marie-Tooth disease A2 with central nervous system involvement as the initial presentation, and explored its pathogenic mechanism.

2024-01-03·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: Carolynne M Doherty ; Jasper M Morrow ; Riccardo Zuccarino ; Paige Howard ; Stephen Wastling ; Menelaos Pipis ; Nick Zafeiropoulos ; Katherine J Stephens ; Tiffany Grider ; Shawna M E Feely ; Peggy Nopoulous ; Mariola Skorupinska ; Evelin Milev ; Emma Nicolaisen ; Magdalena Dudzeic ; Amy McDowell ; Nuran Dilek ; Francesco Muntoni ; Alexander M Rossor ; Sachit Shah ; Matilde Laura ; Tarek A Yousry ; Daniel Thedens ; John Thornton ; Michael E Shy ; Mary M Reilly

OBJECTIVE:

With 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).

METHODS:

22 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.

RESULTS:

All 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).

INTERPRETATION:

Our 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.

2024-01-01·Journal of clinical neurology (Seoul, Korea)

Episodic Neurological Dysfunction in X-Linked Charcot-Marie-Tooth Disease: Expansion of the Phenotypic and Genetic Spectrum.

Article

作者: Feixia Zhan ; Wotu Tian ; Yuwen Cao ; Jingying Wu ; Ruilong Ni ; Taotao Liu ; Yun Yuan ; Xinghua Luan ; Li Cao

BACKGROUND AND PURPOSE:

X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) is characterized by peripheral neuropathy with or without episodic neurological dysfunction. We performed clinical, neuropathological, and genetic investigations of a series of patients with mutations of the gap-junction beta-1 gene (GJB1) to extend the phenotypic and genetic description of CMTX1.

METHODS:

Detailed clinical evaluations, sural nerve biopsy, and genetic analysis were applied to patients with CMTX1.

RESULTS:

We collected 27 patients with CMTX1 with GJB1 mutations from 14 unrelated families. The age at onset (AAO) was 20.9±12.2 years (mean±standard deviation; range, 2-45 years). Walking difficulties, weakness in the legs, and pes cavus were common initial symptoms. Compared with female patients, males tended to have a younger AAO (males vs. females=15.4±9.6 vs. 32.0±8.8 years, p=0.002), a longer disease course (16.8±16.1 vs. 5.5±3.8 years, p=0.034), and more-severe electrophysiological results. Besides peripheral neuropathy, six of the patients had special episodic central nervous system (CNS) evidence from symptoms, signs, and/or reversible white-matter lesions. Neuropathology revealed the loss of large myelinated fibers, increased number of regenerated axon clusters with abnormally thin myelin sheaths, and excessively folded myelin. Genetic analysis identified 14 GJB1 variants, 6 of which were novel.

CONCLUSIONS:

These findings expand the phenotypic and genetic spectrum of CMTX1. Although CMTX1 was found to have high phenotypic and CNS involvement variabilities, detailed neurological examinations and nerve conduction studies will provide critical clues for accurate diagnoses. Further exploration of the underlying mechanisms of connexin 32 involvement in neuropathy or CNS dysfunction is warranted to develop promising therapies.

项与 X-连锁腓骨肌萎缩症1 相关的新闻（医药）

2023-02-22

·BioSpace

CMT Research Foundation and Nanite Inc. Announce Partnership to Enhance Therapeutic Efficacy of Antisense Oligonucleotides in CMT1A

ATLANTA--(BUSINESS WIRE)-- The CMT Research Foundation (CMTRF), a non-profit focused solely on delivering treatments and cures for Charcot-Marie-Tooth (CMT) disease*, today announced a partnership with Nanite, Inc., a Boston-based biotechnology company developing SAYER™, an AI-driven gene delivery platform focused on polymer nanoparticles (PNPs). As part of the partnership agreement, Nanite will design delivery vehicles for genetic medicines to Schwann cells via PNPs, an emerging technology for drug delivery to hard-to-hit targets. This press release features multimedia. View the full release here: Approximately two-thirds of the world’s more than 3 million CMT cases are caused by mutations in genes that are expressed solely or almost solely within myelinating Schwann cells, including CMT1A, CMT1B, and CMT1X, among others. This makes Schwann cells the primary target of genetic therapies in most cases of CMT. However, myelinating Schwann cells are “locked away” behind the blood-nerve barrier (BNB), making the delivery of genetic medicines to Schwann cells a major challenge. The safe delivery of medicines to the Schwann cells of patients with CMT1A, would mark a dramatic step forward in the potential of gene therapies for CMT disease. “A major step forward in the potential treatment of CMT1A was made in 2017 when researchers developed antisense oligonucleotides (ASOs) capable of decreasing PMP22 expression in rats and mice. However, because very little made it past the BNB, the ASOs had to be given at concentrations so high that they caused toxicity,” said Cleary Simpson, CEO of the CMTRF. “Our partnership with Nanite will use their SAYER platform to design PNPs to improve targeting of ASOs to Schwann cells, thereby lowering the effective dose to a point that toxicity is no longer a concern.” “To ensure optimal delivery of ASOs to Schwann cells, PNPs will initially be designed and tested with Schwann cells in a dish to discover and optimize features that promote Schwann cell entry and genetic payload delivery, confirmed by PMP22 reduction,” said Shashi Murthy, Ph.D., Co-Founder and Chief Technology Officer of Nanite. “In the second phase of this partnership, Nanite will use the resulting data and harness the closed-loop optimization capability of SAYER to achieve ASO delivery to Schwann cells in vivo.” The program is one of several building blocks directed towards validating Nanite’s platform as an important addition to the choices available to gene therapy companies. Nanite Inc. is a next-generation non-viral gene delivery company developing a new class of programmable polymer nanoparticles for a range of modalities and indications. The company’s AI-driven platform, SAYER™, combines cutting-edge high-throughput experimental and computational methods to design fit-for-purpose delivery vehicles delivering a broad range of genetic cargoes with tissue specificity. Nanite is headquartered in Boston, MA. Follow us on Twitter @nanitebio. The CMT Research Foundation (CMTRF) is focused solely on delivering treatments and cures for CMT. Founded by two patients who are driven to expedite drug delivery to people who live with CMT globally, the organization funds research for drug development. The 501(c)(3) federal tax-exempt organization is supported by personal and corporate financial gifts. *Charcot-Marie-Tooth encompasses a group of inherited, chronic peripheral neuropathies that result in nerve degradation. CMT patients suffer from progressive muscle atrophy of legs and arms causing walking, running and balance problems and abnormal hand and foot functioning. CMT affects one in 2,500 people (about the same prevalence as multiple sclerosis), including 150,000 Americans and nearly 3 million people worldwide. At the moment, there is no treatment or cure for CMT.

基因疗法寡核苷酸