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Restoring Neurofilaments to Axons in a Mouse Model of CMT2E

https://www.usaspending.gov/award/ASST_NON_R21NS125468_7529

RESTORING NEUROFILAMENTS TO AXONS IN A MOUSE MODEL OF CMT2E – ABSTRACT THIS IS A NEW R21 EXPLORATORY RESEARCH PROPOSAL TO ESTABLISH PROOF-OF-CONCEPT OF A PRE-CLINICAL THERAPEUTIC STRATEGY FOR CHARCOT-MARIE-TOOTH DISEASE TYPE 2E (CMT2E). CMT2E IS CAUSED BY MUTATIONS IN THE NEFL GENE, WHICH CODES FOR NEUROFILAMENT PROTEIN L (NEFL). NEFL IS A SUBUNIT OF NEUROFILAMENTS (NFS), WHICH ARE CYTOSKELETAL POLYMERS THAT FUNCTION TO EXPAND AXON CALIBER AND THEREBY INCREASE AXONAL CONDUCTION VELOCITY. AN INTERESTING FEATURE OF CMT2E IS THAT IT CAN BE CAUSED BY NULL MUTATIONS (INHERITED RECESSIVELY) OR MISSENSE MUTATIONS (INHERITED DOMINANTLY). PRELIMINARY DATA INDICATE THAT THE CELLULAR MECHANISMS OF RECESSIVE AND DOMINANT CMT2E CONVERGE ON AN ABSENCE OF NFS IN PERIPHERAL MYELINATED AXONS, RESULTING IN REDUCED AXON CALIBER AND NERVE CONDUCTION DEFECTS. OUR LONG-TERM GOAL IS TO DEVELOP A GENE THERAPY STRATEGY FOR RESTORING NFS TO THESE NF-DEFICIENT AXONS. THE CENTRAL PREMISE IS THAT THIS WILL RESCUE AXON CALIBER AND NERVE CONDUCTION AND THEREBY AMELIORATE THE DISEASE. AS A FIRST STEP, WE PROPOSE TO TEST THE FEASIBILITY OF THIS STRATEGY IN THE NEFL- /- MOUSE, WHICH IS A MODEL OF RECESSIVE CMT2E CAUSED BY A COMPLETE ABSENCE OF THE NEFL PROTEIN. PRELIMINARY DATA DEMONSTRATE THAT NEFL-/- MICE EXHIBIT PROFOUND IMPAIRMENT OF PERIPHERAL NERVE CONDUCTION BY 4 WEEKS OF AGE OR EARLIER. THE LOGIC IN THIS MOUSE MODEL IS SIMPLE: THESE MICE LACK NFS AND WE SEEK TO REPLACE THEM. TO ACHIEVE THIS GOAL, WE PROPOSE A MULTI-DISCIPLINARY COLLABORATION BETWEEN FOUR PIS AT OHIO STATE UNIVERSITY AND NATIONWIDE CHILDREN’S HOSPITAL WITH DEEP AND COMPLEMENTARY EXPERTISE ON THE CELL BIOLOGY OF NFS, VIRAL GENE THERAPY, NEURODEGENERATIVE DISEASE AND ELECTROPHYSIOLOGICAL ASSESSMENTS OF NEUROMUSCULAR FUNCTION, INCLUDING PROVEN SUCCESS IN PRECLINICAL AND CLINICAL GENE THERAPY STUDIES. IN AIM 1, WE WILL TEST THE HYPOTHESIS THAT EXPRESSION OF NEFL PROTEIN IN NEURONS OF NEFL-/- MICE WILL RESTORE NFS TO THE NF-DEFICIENT AXONS AND THUS INCREASE AXONAL CALIBER. WE WILL DELIVER NEFL TO NEURONS OF P0 NEFL-/- MICE BY INTRA-CEREBROVENTRICULAR INJECTION OF A RECOMBINANT ADENO-ASSOCIATED VIRUS. IN AIM 2 WE WILL TEST THE HYPOTHESIS THAT THE RESTORATION OF NFS TO AXONS OF NEFL-/- MICE WILL RESCUE PERIPHERAL NERVE CONDUCTION. THE PROPOSED RESEARCH WILL ADDRESS THE FOLLOWING FUNDAMENTAL QUESTIONS: (1) CAN WE EXPRESS NEFL PROTEIN EFFICIENTLY IN MOTOR AND SENSORY NEURONS, (2) DOES THE NEFL PROTEIN ASSEMBLE INTO NF POLYMERS (3) ARE THE NF POLYMERS TRANSPORTED INTO THE AXONS OF PERIPHERAL NERVES AND OVER WHAT TIME COURSE, (4) DOES THIS RESULT IN PARTIAL OR COMPLETE RESTORATION OF MYELINATED AXON CALIBER AND G-RATIO, AND (5) DOES THIS RESTORE AXONAL NERVE CONDUCTION? SUCCESSFUL COMPLETION OF THESE AIMS WILL ESTABLISH A PROOF-OF-CONCEPT THAT NFS CAN BE DELIVERED TO NF-DEFICIENT AXONS TO RESCUE AXON MORPHOLOGY AND PHYSIOLOGICAL FUNCTION. THIS WILL LAY THE GROUNDWORK FOR FUTURE DEVELOPMENT OF A GENERAL STRATEGY BOTH FOR DOMINANT AND RECESSIVE CMT2E, OFFERING HOPE TO PATIENTS WITH THIS INTRACTABLE DISEASE.

Actin-mediated regulation of organelle dynamics in Charcot-Marie-Tooth disease

Actin-mediated regulation of organelle dynamics in Charcot-Marie-Tooth disease

https://reporter.nih.gov/search/k52jUHYbvUay11FXFkQtgw/project-details/10327608

Specifically, neurons derived from CMT patient fibroblasts and neurons from mice injected with AAVs directing expression of CMT- mutant INF2, MFN2, or RAB7A will be analyzed. Completion of these aims will provide mechanistic insight into the role of actin in organelle fission and mobility, how these processes are coupled, and test the novel hypothesis that CMT involves global disruption of mobility of multiple organelles. This will further our understanding of the pathogenic mechanism of CMT and perhaps other neurodegenerative disorders.

Investigating SIPA1L2 as a Modifier Gene and Therapeutic Target for Charcot-Marie-Tooth Type 1A

Investigating SIPA1L2 as a Modifier Gene and Therapeutic Target for Charcot-Marie-Tooth Type 1A

Charcot-Marie-Tooth type 1A (CMT1A) is the most common form of inherited peripheral neuropathy and there is currently no treatment. A recent human genetic study identified SIPA1L2 as a second gene that modifies the severity of CMT1A. We will use mouse models to validate the influence of SIPA1L2 on the severity of CMT1A, which could improve the accuracy of prognosis for patients, and our studies will also test whether modulating SIPA1L2 levels may be a therapeutic strategy for CMT1A, which would be a novel target for this and possibly other related neuropathies.

Determine the Safety and Dose of EN001 in Patients With Charcot-Marie-Tooth Disease Type 1A

Category:
Clinical Trials

Title:
Determine the Safety and Dose of EN001 in Patients With Charcot-Marie-Tooth Disease Type 1A

Content:

Arm Intervention/treatment
Experimental: Dose group A (Low dose)

Participants will receive EN001 intravenously (IV) once on Day 0.
 Drug: EN001

EN001 intravenously (IV) in the treatment of Charcot-Marie-Tooth disease (CMT) type 1A Dosage for each group is as follows.

Dose group A (Low dose): 5.0×100000 cells/kg

Other Name: EN001 (allogeneic umbilical cord-derived mesenchymal stem cells)
Experimental: Dose group B (High dose)

Participants will receive EN001 intravenously (IV) once on Day 0.
 Drug: EN001

EN001 intravenously (IV) in the treatment of Charcot-Marie-Tooth disease (CMT) type 1A Dosage for each group is as follows.

Dose group B (High dose): 2.5×1000000 cells/kg

Other Name: EN001 (allogeneic umbilical cord-derived mesenchymal stem cells)

Primary Outcome Measures :

  1. Number of participants of any Adverse Events (AEs)/Serious Adverse Events (SAEs) related investigational product [ Time Frame: Week 16 after treatment ]
    Number of participants with treatment-related AEs/SAEs as assessed by CTCAE v5.0

  2. Determination of Dose-limiting toxicity (DLT) levels of EN001 [ Time Frame: Up to Week 4 after dosing on Day 0 ]
    Among the adverse events occurring for 4 weeks after administration of the investigational product, Grade 3 or higher adverse events according to CTCAE v5.0

  3. Determination of Maximum tolerated dose (MTD) levels of EN001 [ Time Frame: Up to Week 4 after dosing on Day 0 ]
    Among the adverse events occurring for 4 weeks after administration of the investigational product, Grade 3 or higher adverse events according to CTCAE v5.0 Maximum tolerated dose defines the evaluated maximum dose level in which greater than two participants of six participants experience Dose-limiting toxicity (DLT) under the dose level. The dose level where two participants of six participants experience DLT will be the maximum tolerated dose.

  4. Number of participants with Vital Signs abnormalities [ Time Frame: From screening up to Week 16 ]

    Vital Signs include blood pressure (mmHg), pulse (times/minute), respiratory rate (times/minute), and body temperature (℃) and will be assessed by CTCAE v 5.0 to evaluate safety and tolerability of EN001.

    The number of participants with at least one potentially clinically significant abnormal vital sign finding were reported as treatment emergent adverse events (TEAEs).

  5. Number of participants with clinically significant abnormalities of Physical Examinations [ Time Frame: From screening up to Week 16 ]

    Physical Examinations include general appearance, head, ears/eyes/nose/throat, cardiovascular, respiratory, abdomen, skin, lymph nodes, extremities, musculoskeletal and neurologic and will be assessed by CTCAE v 5.0 to evaluate safety and tolerability of EN001.

    Number of participants with potentially clinically significant abnormalities in physical examinations were reported as TEAEs.

  6. Number of participants with abnormalities of Laboratory Parameters [ Time Frame: From screening up to Week 16 ]

    Laboratory Parameters include hematology, chemistry laboratory tests, urinalysis, coagulation test and plasma viral load test and will be assessed by CTCAE 5.0 to evaluate safety and tolerability of EN001.

    Number of participants with at least one potentially clinically significant abnormal finding were reported as TEAEs.

  7. Number of participants with 12-lead Electrocardiography (ECG) abnormalities [ Time Frame: From screening to baseline on Day 1 (Predose to end of infusion and 90 min after completion of infusion) ]
    Measured by result of the ECG measurements and findings

Secondary Outcome Measures :

  1. Incidence of treatment-emergent adverse events (TEAEs) [ Time Frame: From screening to the end of treatment/withdrawal visit (up to approximately 5 years per subject) ]
    Occurrence of any adverse reactions, development of new blood clots, tumors, immune responses (like autoimmune reactions) and death, and/or serious adverse events related investigational product will be summarized by actual treatment groups respectively.

  2. Number of participants with abnormalities of Vital Signs, Physical Findings, and Laboratory Parameters [ Time Frame: From screening to the end of treatment/withdrawal visit (up to approximately 5 years per subject) ]
    Abnormalities of Vital Signs, Physical Findings, and Laboratory parameters (as described above) will be collected and analyzed, and then assessed by CTCAE 5.0 to evaluate the long-term safety of EN001.

  3. Change from baseline in disease severity CMTNS-v2 score [ Time Frame: Screening and baseline on Day 0 (up to approximately 5 years per subject after Week 4) ]
    Disease severity measured by CMTNS-v2 score will be collected and analyzed to evaluate the exploratory efficacy of EN001.

  4. Change from baseline in gait and balance functions [ Time Frame: Screening and baseline on Day 0 (up to approximately 5 years per subject after Week 4) ]
    Gait and balance functions measured by Ten Meter Walking Test(10MWT), Functional Disability Scale (FDS), and Overall Neuropathy Limitation Score (ONLS) leg scale will be collected and analyzed to evaluate the exploratory efficacy of EN001.

  5. Change from baseline in the degree of muscle damage (%) [ Time Frame: Screening and baseline on Day 0 (up to approximately 5 years per subject after Week 4) ]
    The degree of muscle damage measured by lower extremity magnetic resonance imaging (MRI) scan will be collected and analyzed to evaluate the exploratory efficacy of EN001.

  6. Change from baseline in nerve regeneration potential [ Time Frame: Screening and baseline on Day 0 (up to approximately 5 years per subject after Week 4) ]
    Nerve generation potential measured by MNCV, SNCV, CMAP, and SNAP will be collected and analyzed to evaluate the exploratory efficacy of EN001.

Inclusion Criteria:

  1. Males and females aged 19 to 75 years old
  2. Those diagnosed with CMT type 1A by a genetic test
  3. Those whose CMTNS-v2 score is more than 2 and 20 or fewer points, and the severity of the disease is mild to moderate
  4. Those who have dorsiflexion muscle weaknes
  5. Those who can comply with the requirements for clinical trials
  6. For women of childbearing potential, those who have a negative urine pregnancy test at screening
  7. Those who use a medically acceptable method of contraception until clinical trial visit 7 (short-term follow-up visit, 16 weeks): hormonal contraception, intrauterine device (IUD), intrauterine system (IUS), vasectomy, tubal ligation, or double barrier method using a cervical cap or a diaphragm with a male condom.
  8. Those who voluntarily agree to participate in this study and sign an IRB-approved consent form after being informed about the characteristics of this clinical trial prior to all screening tests

Exclusion Criteria:

  1. Those with other neuromuscular diseases that the investigator judges cannot participate in the clinical trial
  2. Patients diagnosed with type 1 or type 2 diabetes
  3. Those with a history of stroke or cerebral ischemic attack within 12 months of screening
  4. Those with a history of coronary artery diseases such as myocardial infarction or unstable angina within 12 months of screening
  5. Those who have undergone orthopedic surgery on the lower extremities (bone and ligament correction, artificial joint insertion, osteotomy, arthroscopic surgery) within 6 months of screening
  6. Those who have ankle contractures or have surgery that may affect muscle strength assessment
  7. Those who have experience with stem cell therapy or gene therapy before screening
  8. Those who have participated in clinical trials for chemical synthetic drugs before screening (except when 5 times the half-life has passed)
  9. Patients with uncontrolled hypertension (If the systolic blood pressure is 180 mmHg or higher or the diastolic blood pressure is 110 mmHg or higher)
  10. If there is a history of malignant tumors other than basal cell carcinoma or squamous cell carcinoma occurring in the skin within 5 years of screening
  11. Those who diagnosed with active pulmonary tuberculosis
  12. Immunosuppressed patients who are taking immunosuppressants, chemotherapy, radiation therapy, etc.
  13. Mental illness patients
  14. Those who are pregnant or lactating
  15. Those with significant heart, lung, liver, kidney, hematological, immunological, behavioral disease, or other clinically significant diseases including malignant tumors
  16. Those who have a previous or current medical condition that may adversely affect the safety of the subject, make it difficult to complete treatment or affect the evaluation of clinical trial results at the discretion of the investigator
  17. Those who do not have the will or ability to comply with clinical trial procedures at the discretion of the investigator

Additional relevant MeSH terms:
Layout table for MeSH terms
Tooth Diseases
Charcot-Marie-Tooth Disease
Nerve Compression Syndromes
Hereditary Sensory and Motor Neuropathy
Stomatognathic Diseases
Nervous System Malformations
Nervous System Diseases 		Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Polyneuropathies
Peripheral Nervous System Diseases
Neuromuscular Diseases
Congenital Abnormalities
Genetic Diseases, Inborn

Description:
Condition:   Charcot-Marie-Tooth Disease, Type IA
Intervention:   Drug: EN001
Sponsor:   ENCell
Recruiting

Sponsor:
ENCell

URL:
https://clinicaltrials.gov/ct2/show/NCT05333406

Date – Posted:
Tue, 19 Apr 2022 12:00:00 EDT

Date – Found:
04/26/22 02:20PM

Date – Published:
2022-04-19T00:00:00.000Z

Therapeutic Potential of CKD-504, a Novel Selective Histone Deacetylase 6 Inhibitor, in a Zebrafish Model of Neuromuscular Junction Disorders

SUMMARY:
CKD-504, a novel HDAC6 inhibitor, was effective in repairing NMJ defects, suggesting that treatment of neurodegenerative diseases via NMJ targeting is possible.

ALT SUMMARY:
CKD-504, a novel HDAC6 inhibitor, was effective in repairing NMJ defects, suggesting that treatment of neurodegenerative diseases via NMJ targeting is possible.

TITLE:
Therapeutic Potential of CKD-504, a Novel Selective Histone Deacetylase 6 Inhibitor, in a Zebrafish Model of Neuromuscular Junction Disorders

DESCRIPTION:
The neuromuscular junction (NMJ), which is a synapse for signal transmission from motor neurons to muscle cells, has emerged as an important region because of its association with several peripheral neuropathies. In particular, mutations in GARS that affect the formation of NMJ result in Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. These disorders are mainly considered to be caused by neuronal axon abnormalities; however, no treatment is currently available. Therefore, in…

CONTENT:
Mol Cells. 2022 Apr 30;45(4):231-242. doi: 10.14348/molcells.2022.5005.

ABSTRACT

The neuromuscular junction (NMJ), which is a synapse for signal transmission from motor neurons to muscle cells, has emerged as an important region because of its association with several peripheral neuropathies. In particular, mutations in GARS that affect the formation of NMJ result in Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. These disorders are mainly considered to be caused by neuronal axon abnormalities; however, no treatment is currently available. Therefore, in order to determine whether the NMJ could be targeted to treat neurodegenerative disorders, we investigated the NMJ recovery effect of HDAC6 inhibitors, which have been used in the treatment of several peripheral neuropathies. In the present study, we demonstrated that HDAC6 inhibition was sufficient to enhance movement by restoring NMJ impairments observed in a zebrafish disease model. We found that CKD-504, a novel HDAC6 inhibitor, was effective in repairing NMJ defects, suggesting that treatment of neurodegenerative diseases via NMJ targeting is possible.

PMID:35356895 | DOI:10.14348/molcells.2022.5005

SOURCE:
Molecules and cells

CATEGORY:
Research

FILTERED
no

DATE – PUBLISHED:
2022-03-31T10:07:59Z

DATE – DOI: 2022-03-31T10:07:59Z
DATE – PUBMED:
DATE OUTPUT MATCHED:

DATE – ADDED:
Thu, 31 Mar 2022 06:00:00 -0400

DATE – RETRIEVED:
04/15/22 12:14AM
2022-04-15T00:14:37-04:00

IDENTIFIER:
pmid:35356895,doi:10.14348/molcells.2022.5005

PUBMED ID:
pubmed:35356895

DOI:
10.14348/molcells.2022.5005

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35356895/

LINK – DOI:
https://doi.org/10.14348/molcells.2022.5005

LINK – PUBLISHER:
http://molcells.org/journal/view.html?doi=10.14348/molcells.2022.5005

REFERENCES:
CMT Treatment Report, Urgent Research LLC, 2022-04-15T00:14:37-04:00, https://www.cmttreatmentreport.com.

Therapeutic Potential of CKD-504, a Novel Selective Histone Deacetylase 6 Inhibitor

https://www.molcells.org/journal/view.html?doi=10.14348/molcells.2022.5005

Mol. Cells 2022; 45(4): 231-242

Published online April 30, 2022

https://doi.org/10.14348/molcells.2022.5005

© The Korean Society for Molecular and Cellular Biology

Although the NMJ has been shown to have a potential association with disease mechanisms of peripheral neuropathy, including CMT and dHMN5, effective NMJ- or GARS-targeted therapy has not been explored for this disorder.

Therapeutic Potential of CKD-504, a Novel Selective Histone Deacetylase 6 Inhibitor, in a Zebrafish Model of Neuromuscular Junction Disorders

COMMENT: Manually corrected date. Publisher listed April 30, 2022, which is in the future. Only the PDF version of the article revealed the correct date: March 30, 2022.

Clinical genetics of Charcot–Marie–Tooth disease

https://www.nature.com/articles/s10038-022-01031-2

In this article, we review the epidemiology, genetic diagnosis, and clinicogenetic characteristics of CMT in Japan. In addition, we discuss the newly identified novel causative genes for CMT/IPNs in Japan, namely MME and COA7. Identification of the new causes of CMT will facilitate in-depth characterization of the underlying molecular mechanisms of CMT, leading to the establishment of therapeutic approaches such as drug development and gene therapy.

NCAM1 and GDF15 are biomarkers of Charcot-Marie-Tooth disease in patients and mice

https://pubmed.ncbi.nlm.nih.gov/35148379/

https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awac055/6527178?login=false

We also identify serum GDF15 as a highly sensitive diagnostic biomarker, which was elevated in all CMT genotypes as well as in Hspb8K141N, Gjb1-null, GarsC201R and GarsP278KY mouse models. Although we cannot fully explain its origin, it may reflect increased stress response or metabolic disturbances in CMT. Further large and longitudinal patient studies should be performed to establish the value of these proteins as diagnostic and prognostic molecular biomarkers for CMT.

The protective role of mesencephalic astrocyte-derived neurotrophic factor in endoplasmic reticulum stress in RT4-D6P2T schwannoma sells with the S63del MPZ mutation

https://www.imrpress.com/journal/FBL/27/1/10.31083/j.fbl2701001

Endoplasmic reticulum stress (ERS) occurred in S63del mutant CMT1B mice model, and few drugs has been studied. Mesencephalic astrocyte-derived neurotrophic factor (MANF) can inhibit ERS. This study aimed at investigating the effect of MANF on ERS of RT4-D6P2T schwannoma cells with S63del MPZ Mutation.

HDAC6 Inhibition Corrects Electrophysiological and Axonal Transport Deficits in a Human Stem Cell-Based Model of Charcot-Marie-Tooth Disease (Type 2D)

https://pubmed.ncbi.nlm.nih.gov/34958183/?utm_source=Other&utm_medium=rss&utm_campaign=None&utm_content=1854v2hhZntSmhEACE68B0jkf9YsWL5KzHFUrhwvQfh3r3hIOk&fc=None&ff=20211227125914&v=2.17.2

HDAC6 Inhibition Corrects Electrophysiological and Axonal Transport Deficits in a Human Stem Cell-Based Model of Charcot-Marie-Tooth Disease (Type 2D)

Charcot-Marie-Tooth disease type 2D (CMT2D), is a hereditary peripheral neuropathy caused by mutations in the gene encoding glycyl-tRNA synthetase (GARS1). Here, human induced pluripotent stem cell (hiPSC)-based models of CMT2D bearing mutations in GARS1 and their use for the identification of predictive biomarkers amenable to therapeutic efficacy screening is described. Cultures containing spinal cord motor neurons generated from this line exhibit network activity marked by significant…

pubmed:34958183

Inversely proportional myelin growth due to altered Pmp22 gene dosage identifies PI3K/Akt/mTOR signaling as a novel therapeutic target in HNPP [preprint]

https://www.biorxiv.org/content/10.1101/2021.11.08.467756v1.full

In Pmp22tg CMT1A mice, we uncovered that the differentiation defect of Schwann cells is independent from PI3K/Akt/mTOR activity, rendering the pathway insufficient as a therapy target on its own. Thus, while CMT1A pathogenesis is governed by dys-differentiation uncoupled from PI3K/Akt/mTOR signaling, targeting the pathway provides novel proof-of-principle for a therapeutic approach to HNPP.

Challenges in Treating Charcot-Marie-Tooth Disease and Related Neuropathies: Current Management and Future Perspectives

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8615778/

Nowadays, the main challenge for CMT is to find disease-modifying treatments. Although no drug treatment for any CMT type is still available, in the last few years, great advances have been made: the first clinical trials in patients have been conducted, others are ongoing or planned, and several therapeutic approaches are being tested in experimental models. There is a cautious optimism among researchers that it will not take a long time to see the first effective therapies for CMT.

Treatment of charcot-marie-tooth axonal type 2d using nt-3 gene therapy

https://patents.google.com/patent/WO2021211713A1

Treatment of charcot-marie-tooth axonal type 2d using nt-3 gene therapy
Abstract
The present disclosure relates to methods of treating Charcot-Marie-Tooth axonal type 2D (CMT2D) using a rAAV vector for neurotrophin 3 (NT-3) gene therapy.

A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot-Marie-Tooth type 1A

https://pubmed.ncbi.nlm.nih.gov/34656144/?utm_source=Other&utm_medium=rss&utm_campaign=None&utm_content=1854v2hhZntSmhEACE68B0jkf9YsWL5KzHFUrhwvQfh3r3hIOk&fc=None&ff=20211018042340&v=2.15.0

A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot-Marie-Tooth type 1A

CONCLUSION: The high-dose group demonstrated a statistically significant improvement in the primary endpoint and a good safety profile. Overall, high-dose PXT3003 is a promising treatment option for patients with Charcot-Marie-Tooth disease type 1A.

pubmed:34656144

https://ojrd.biomedcentral.com/articles/10.1186/s13023-021-02040-8

Axonal Charcot-Marie-Tooth Disease: from Common Pathogenic Mechanisms to Emerging Treatment Opportunities

https://link.springer.com/article/10.1007%2Fs13311-021-01099-2

https://pubmed.ncbi.nlm.nih.gov/34606075/?utm_source=Other&utm_medium=rss&utm_campaign=None&utm_content=1854v2hhZntSmhEACE68B0jkf9YsWL5KzHFUrhwvQfh3r3hIOk&fc=None&ff=20211004193936&v=2.15.0

Axonal Charcot-Marie-Tooth Disease: from Common Pathogenic Mechanisms to Emerging Treatment Opportunities

Inherited peripheral neuropathies are a genetically and phenotypically diverse group of disorders that lead to degeneration of peripheral neurons with resulting sensory and motor dysfunction. Genetic neuropathies that primarily cause axonal degeneration, as opposed to demyelination, are most often classified as Charcot-Marie-Tooth disease type 2 (CMT2) and are the focus of this review. Gene identification efforts over the past three decades have dramatically expanded the genetic landscape of CMT…

pubmed:34606075

Pharmaceutical composition for preventing or treating Charcot-Marie-Tooth disease comprising insulin secreted from mesenchymal stem cells or mesenchymal stem cells

https://patents.google.com/patent/KR20210117771A/en

Pharmaceutical composition for preventing or treating Charcot-Marie-Tooth disease comprising insulin secreted from mesenchymal stem cells or mesenchymal stem cells
Abstract
The present invention relates to a pharmaceutical composition for preventing or treating Charcot-Marie-Tooth disease, comprising mesenchymal stem cells or insulin secreted from mesenchymal stem cells.

Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study

https://www.ncbi.nlm.nih.gov/pubmed/33415332?dopt=Abstract

https://pubmed.ncbi.nlm.nih.gov/33415332/

Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study.

Related Articles

Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study.

Brain. 2021 Jan 08;:

Authors: Pipis M, Feely SME, Polke JM, Skorupinska M, Perez L, Shy RR, Laura M, Morrow JM, Moroni I, Pisciotta C, Taroni F, Vujovic D, Lloyd TE, Acsadi G, Yum SW, Lewis RA, Finkel RS, Herrmann DN, Day JW, Li J, Saporta M, Sadjadi R, Walk D, Burns J, Muntoni F, Ramchandren S, Horvath R, Johnson NE, Züchner S, Pareyson D, Scherer SS, Rossor AM, Shy ME, Reilly MM, Inherited Neuropathies Consortium – Rare Disease Clinical Research Network (INC-RDCRN)

Abstract

Mitofusin-2 (MFN2) is one of two ubiquitously expressed homologous proteins in eukaryote cells, playing a critical role in mitochondrial fusion. Mutations in MFN2 (most commonly autosomal dominant) cause Charcot-Marie-Tooth disease type 2A (CMT2A), the commonest axonal form of CMT, with significant allelic heterogeneity. Previous, moderately-sized, cross sectional genotype-phenotype studies of CMT2A have described the phenotypic spectrum of the disease, but longitudinal natural history studies are lacking. In this large multicentre prospective cohort study of 196 patients with dominant and autosomal recessive CMT2A, we present an in-depth genotype-phenotype study of the baseline characteristics of patients with CMT2A and longitudinal data (1-2 years) to describe the natural history. A childhood onset of autosomal dominant CMT2A is the most predictive marker of significant disease severity and is independent of the disease duration. When compared to adult onset autosomal dominant CMT2A, it is associated with significantly higher rates of use of ankle-foot orthoses, full-time use of wheelchair, dexterity difficulties and also has significantly higher CMT Examination Score (CMTESv2) and CMT Neuropathy Score (CMTNSv2) at initial assessment. Analysis of longitudinal data using the CMTESv2 and its Rasch-weighted counterpart, CMTESv2-R, show that over 1 year, the CMTESv2 increases significantly in autosomal dominant CMT2A (mean change 0.84 ± 2.42; two-tailed paired t-test P = 0.039). Furthermore, over 2 years both the CMTESv2 (mean change 0.97 ± 1.77; two-tailed paired t-test P = 0.003) and the CMTESv2-R (mean change 1.21 ± 2.52; two-tailed paired t-test P = 0.009) increase significantly with respective standardized response means of 0.55 and 0.48. In the paediatric CMT2A population (autosomal dominant and autosomal recessive CMT2A grouped together), the CMT Pediatric Scale increases significantly both over 1 year (mean change 2.24 ± 3.09; two-tailed paired t-test P = 0.009) and over 2 years (mean change 4.00 ± 3.79; two-tailed paired t-test P = 0.031) with respective standardized response means of 0.72 and 1.06. This cross-sectional and longitudinal study of the largest CMT2A cohort reported to date provides guidance for variant interpretation, informs prognosis and also provides natural history data that will guide clinical trial design.

PMID: 33415332 [PubMed – as supplied by publisher]

PubMed:33415332

Pipis M, Feely SME, Polke JM, Skorupinska M, Perez L, Shy RR, Laura M, Morrow JM, Moroni I, Pisciotta C, Taroni F, Vujovic D, Lloyd TE, Acsadi G, Yum SW, Lewis RA, Finkel RS, Herrmann DN, Day JW, Li J, Saporta M, Sadjadi R, Walk D, Burns J, Muntoni F, Ramchandren S, Horvath R, Johnson NE, Züchner S, Pareyson D, Scherer SS, Rossor AM, Shy ME, Reilly MM, Inherited Neuropathies Consortium – Rare Disease Clinical Research Network (INC-RDCRN)

Epigenetic Regulation of CMT: A Lesson from Drosophila Models

https://www.ncbi.nlm.nih.gov/pubmed/33419039?dopt=Abstract

https://www.mdpi.com/1422-0067/22/2/491/htm

Epigenetic Regulation of ALS and CMT: A Lesson from Drosophila Models.

Related Articles

Epigenetic Regulation of ALS and CMT: A Lesson from Drosophila Models.

Int J Mol Sci. 2021 Jan 06;22(2):

Authors: Yamaguchi M, Omori K, Asada S, Yoshida H

Abstract

Amyotrophic lateral sclerosis (ALS) is the third most common neurodegenerative disorder and is sometimes associated with frontotemporal dementia. Charcot-Marie-Tooth disease (CMT) is one of the most commonly inherited peripheral neuropathies causing the slow progression of sensory and distal muscle defects. Of note, the severity and progression of CMT symptoms markedly vary. The phenotypic heterogeneity of ALS and CMT suggests the existence of modifiers that determine disease characteristics. Epigenetic regulation of biological functions via gene expression without alterations in the DNA sequence may be an important factor. The methylation of DNA, noncoding RNA, and post-translational modification of histones are the major epigenetic mechanisms. Currently, Drosophila is emerging as a useful ALS and CMT model. In this review, we summarize recent studies linking ALS and CMT to epigenetic regulation with a strong emphasis on approaches using Drosophila models.

PMID: 33419039 [PubMed – as supplied by publisher]

PubMed:33419039

Yamaguchi M, Omori K, Asada S, Yoshida H

Clinical features of homozygous FIG4-p.Ile41Thr Charcot-Marie-Tooth 4J patients

https://www.ncbi.nlm.nih.gov/pubmed/33405357?dopt=Abstract

https://onlinelibrary.wiley.com/doi/10.1002/acn3.51175

Clinical features of homozygous FIG4-p.Ile41Thr Charcot-Marie-Tooth 4J patients.

Clinical features of homozygous FIG4-p.Ile41Thr Charcot-Marie-Tooth 4J patients.

Ann Clin Transl Neurol. 2021 Jan 06;:

Authors: Lafontaine M, Lia AS, Bourthoumieu S, Beauvais-Dzugan H, Derouault P, Arné-Bes MC, Sarret C, Laffargue F, Magot A, Sturtz F, Magy L, Magdelaine C

Abstract

We describe the clinical, electrodiagnostic, and genetic findings of three homozygous FIG4-c.122T>C patients suffering from Charcot-Marie-Tooth disease type 4J (AR-CMT-FIG4). This syndrome usually involves compound heterozygosity associating FIG4-c.122T>C, a hypomorphic allele coding an unstable FIG4-p.Ile41Thr protein, and a null allele. While the compound heterozygous patients presenting with early onset usually show rapid progression, the homozygous patients described here show the signs of relative clinical stability. As FIG4 activity is known to be dose dependent, these patients’ observations could suggest that the therapeutic perspective of increasing levels of the protein to improve the phenotype of AR-CMT-FIG4-patients might be efficient.

PMID: 33405357 [PubMed – as supplied by publisher]

PubMed:33405357

Lafontaine M, Lia AS, Bourthoumieu S, Beauvais-Dzugan H, Derouault P, Arné-Bes MC, Sarret C, Laffargue F, Magot A, Sturtz F, Magy L, Magdelaine C

Aberrant Splicing in GJB1 and the Relevance of 5′ UTR in CMTX1 Pathogenesis

https://www.ncbi.nlm.nih.gov/pubmed/33375465?dopt=Abstract

https://www.mdpi.com/2076-3425/11/1/24/htm

Aberrant Splicing in GJB1 and the Relevance of 5′ UTR in CMTX1 Pathogenesis.

Related Articles

Aberrant Splicing in GJB1 and the Relevance of 5′ UTR in CMTX1 Pathogenesis.

Brain Sci. 2020 Dec 27;11(1):

Authors: Boso F, Taioli F, Cabrini I, Cavallaro T, Fabrizi GM

Abstract

The second most common form of Charcot-Marie-Tooth disease (CMT) follows an X-linked dominant inheritance pattern (CMTX1), referring to mutations in the gap junction protein beta 1 gene (GJB1) that affect connexin 32 protein (Cx32) and its ability to form gap junctions in the myelin sheath of peripheral nerves. Despite the advances of next-generation sequencing (NGS), attention has only recently also focused on noncoding regions. We describe two unrelated families with a c.-17+1G>T transversion in the 5′ untranslated region (UTR) of GJB1 that cosegregates with typical features of CMTX1. As suggested by in silico analysis, the mutation affects the regulatory sequence that controls the proper splicing of the intron in the corresponding mRNA. The retention of the intron is also associated with reduced levels of the transcript and the loss of immunofluorescent staining for Cx32 in the nerve biopsy, thus supporting the hypothesis of mRNA instability as a pathogenic mechanism in these families. Therefore, our report corroborates the role of 5′ UTR of GJB1 in the pathogenesis of CMTX1 and emphasizes the need to include this region in routine GJB1 screening, as well as in NGS panels.

PMID: 33375465 [PubMed]

PubMed:33375465

Boso F, Taioli F, Cabrini I, Cavallaro T, Fabrizi GM

Plasma neurofilament light chain as a potential biomarker in Charcot-Marie-Tooth disease

https://www.ncbi.nlm.nih.gov/pubmed/33340200?dopt=Abstract

Plasma neurofilament light chain as a potential biomarker in Charcot-Marie-Tooth disease.

Related Articles

Plasma neurofilament light chain as a potential biomarker in Charcot-Marie-Tooth disease.

Eur J Neurol. 2020 Dec 19;:

Authors: Millere E, Rots D, Simrén J, Ashton NJ, Kupats E, Micule I, Priedite V, Kurjane N, Blennow K, Gailite L, Zetterberg H, Kenina V

Abstract

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is a chronic, slowly progressing disorder. The lack of specific disease progression biomarkers limits the execution of clinical trials. However, neurofilament light chain (NfL) has been suggested as a potential biomarker for peripheral nervous system disorders.

METHODS: Ninety-six CMT patients and 60 healthy controls were enrolled in the study. Disease severity assessment included clinical evaluation with CMT Neuropathy Score version 2 (CMTNSv2). Blood plasma NfL concentrations were measured using the single molecule array (Simoa) NfL assay.

RESULTS: The NfL concentration was significantly higher in the CMT patient group than in the controls (p<0.001). Of the CMT patients, ones with type CMTX1 had a higher NfL level than those in the two other analysed subgroups (CMT1A and other CMT types) (p=0.0498). The NfL concentration had a significant but weak correlation with the CMTNSv2 (rs =0.25, p=0.012). In one CMT patient with an extremely elevated NfL level, overlap with chronic inflammatory demyelinating polyneuropathy was suspected. ROC analysis showed that an NfL concentration of 8.9 pg/mL could be used to discriminate CMT patients from controls, with an area under the curve of 0.881. CONCLUSIONS: Our study confirmed that the plasma NfL concentration is significantly higher in CMT patients than in controls. Plasma NfL concentration was found to significantly, albeit weakly, reflect the clinical severity of CMT. In the future, NfL may be used, either individually or collaboratively, as a biomarker in the clinical context of suspected CMT; however, several issues need to be addressed first. PMID: 33340200 [PubMed - as supplied by publisher] PubMed:33340200 Millere E, Rots D, Simrén J, Ashton NJ, Kupats E, Micule I, Priedite V, Kurjane N, Blennow K, Gailite L, Zetterberg H, Kenina V

Aminoacyl-tRNA synthetases in Charcot-Marie-Tooth disease: a gain or a loss?

https://onlinelibrary.wiley.com/doi/10.1111/jnc.15249

https://www.ncbi.nlm.nih.gov/pubmed/33236345?dopt=Abstract

Aminoacyl-tRNA synthetases in Charcot-Marie-Tooth disease: a gain or a loss?

Related Articles

Aminoacyl-tRNA synthetases in Charcot-Marie-Tooth disease: a gain or a loss?

J Neurochem. 2020 Nov 25;:

Authors: Zhang H, Zhou ZW, Sun L

Abstract

Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurodegenerative disorders with an increasing number of CMT-associated variants identified as causative factors, however there has been no effective therapy for CMT to date. Aminoacyl-tRNA synthetases (aaRS) are essential enzymes in translation by charging amino acids onto their cognate tRNAs during protein synthesis. Dominant monoallelic variants of aaRSs have been largely implicated in CMT. Some aaRSs variants affect enzymatic activity, demonstrating a loss-of-function property. In contrast, loss of aminoacylation activity is neither necessary nor sufficient for some aaRSs variants to cause CMT. Instead, accumulating evidence from CMT patient samples, animal genetic studies or protein conformational analysis has pinpointed toxic gain-of-function of aaRSs variants in CMT, suggesting complicated mechanisms underlying the pathogenesis of CMT. In this review, we summarize the latest advances in studies on CMT-linked aaRSs, with a particular focus on their functions. The current challenges, future direction and the promising candidates for potential treatment of CMT are also discussed.

PMID: 33236345 [PubMed – as supplied by publisher]

PubMed:33236345

Zhang H, Zhou ZW, Sun L

The expanding genetic landscape of hereditary motor neuropathies

https://academic.oup.com/brain/advance-article-abstract/doi/10.1093/brain/awaa311/5989972?redirectedFrom=fulltext

https://www.ncbi.nlm.nih.gov/pubmed/33210134?dopt=Abstract

The expanding genetic landscape of hereditary motor neuropathies.

Related Articles

The expanding genetic landscape of hereditary motor neuropathies.

Brain. 2020 Nov 19;:

Authors: Beijer D, Baets J

Abstract

Hereditary motor neuropathies are clinically and genetically diverse disorders characterized by length-dependent axonal degeneration of lower motor neurons. Although currently as many as 26 causal genes are known, there is considerable missing heritability compared to other inherited neuropathies such as Charcot-Marie-Tooth disease. Intriguingly, this genetic landscape spans a discrete number of key biological processes within the peripheral nerve. Also, in terms of underlying pathophysiology, hereditary motor neuropathies show striking overlap with several other neuromuscular and neurological disorders. In this review, we provide a current overview of the genetic spectrum of hereditary motor neuropathies highlighting recent reports of novel genes and mutations or recent discoveries in the underlying disease mechanisms. In addition, we link hereditary motor neuropathies with various related disorders by addressing the main affected pathways of disease divided into five major processes: axonal transport, tRNA aminoacylation, RNA metabolism and DNA integrity, ion channels and transporters and endoplasmic reticulum.

PMID: 33210134 [PubMed – as supplied by publisher]

PubMed:33210134

Beijer D, Baets J

Phase I/IIa Trial of scAAV1.tMCK.NTF3 for Treatment of Charcot-Marie-Tooth Type 1A (CMT1A)

https://clinicaltrials.gov/ct2/show/NCT03520751?type=Intr&cond=Charcot-Marie-Tooth&lupd_s=11%2F21%2F2018&lupd_d=14

Phase I/IIa Trial of scAAV1.tMCK.NTF3 for Treatment of CMT1A

Condition :   Charcot-Marie-Tooth Neuropathy Type 1A

Intervention :   Drug: scAAV1.tMCK.NTF3

Sponsor :   Nationwide Children’s Hospital

Recruiting

NCT03520751

Thu, 10 May 2018 12:00:00 EDT

Dec 5, 2018 update – start date delayed +3 months from oct 2018 to jan 2019
Feb 20, 2019 update – start date delayed again +6 months from jan 2019 to july 2019
Jun 13, 2019 update – status changed from recruiting to not yet recruiting [is this normal? was it recruiting before? find out] Oct 16, 2019 update – start date delayed again +6 months from jul 2019 to jan 2020
Nov 19, 2020 update – recruiting

Burst mitofusin activation reverses neuromuscular dysfunction in murine CMT2A

https://elifesciences.org/articles/61119

https://www.ncbi.nlm.nih.gov/pubmed/33074106?dopt=Abstract

Burst mitofusin activation reverses neuromuscular dysfunction in murine CMT2A.

Burst mitofusin activation reverses neuromuscular dysfunction in murine CMT2A.

Elife. 2020 Oct 19;9:

Authors: Franco A, Dang X, Walton EK, Ho JN, Zablocka B, Ly C, Miller TM, Baloh RH, Shy ME, Yoo AS, Dorn Ii GW

Abstract

Charcot-Marie-Tooth disease type 2A (CMT2A) is an untreatable childhood peripheral neuropathy caused by mutations of the mitochondrial fusion protein, mitofusin (MFN) 2. Here, pharmacological activation of endogenous normal mitofusins overcame dominant inhibitory effects of CMT2A mutants in reprogrammed human patient motor neurons, reversing hallmark mitochondrial stasis and fragmentation independent of causal MFN2 mutation. In mice expressing human MFN2 T105M, intermittent mitofusin activation with a small molecule, MiM111, normalized CMT2A neuromuscular dysfunction, reversed pre-treatment axon and skeletal myocyte atrophy, and enhanced axon regrowth by increasing mitochondrial transport within peripheral axons and promoting in vivo mitochondrial localization to neuromuscular junctional synapses. MiM111-treated MFN2 T105M mouse neurons exhibited accelerated primary outgrowth and greater post-axotomy regrowth, linked to enhanced mitochondrial motility. MiM111 is the first pre-clinical candidate for CMT2A.

PMID: 33074106 [PubMed – as supplied by publisher]

PubMed:33074106

Franco A, Dang X, Walton EK, Ho JN, Zablocka B, Ly C, Miller TM, Baloh RH, Shy ME, Yoo AS, Dorn Ii GW

Recent Advances in Drosophila Models of Charcot-Marie-Tooth Disease

https://www.mdpi.com/1422-0067/21/19/7419

https://www.ncbi.nlm.nih.gov/pubmed/33049996?dopt=Abstract

Recent Advances in Drosophila Models of Charcot-Marie-Tooth Disease.

Recent Advances in Drosophila Models of Charcot-Marie-Tooth Disease.

Int J Mol Sci. 2020 Oct 08;21(19):

Authors: Kitani-Morii F, Noto YI

Abstract

Charcot-Marie-Tooth disease (CMT) is one of the most common inherited peripheral neuropathies. CMT patients typically show slowly progressive muscle weakness and sensory loss in a distal dominant pattern in childhood. The diagnosis of CMT is based on clinical symptoms, electrophysiological examinations, and genetic testing. Advances in genetic testing technology have revealed the genetic heterogeneity of CMT; more than 100 genes containing the disease causative mutations have been identified. Because a single genetic alteration in CMT leads to progressive neurodegeneration, studies of CMT patients and their respective models revealed the genotype-phenotype relationships of targeted genes. Conventionally, rodents and cell lines have often been used to study the pathogenesis of CMT. Recently, Drosophila has also attracted attention as a CMT model. In this review, we outline the clinical characteristics of CMT, describe the advantages and disadvantages of using Drosophila in CMT studies, and introduce recent advances in CMT research that successfully applied the use of Drosophila, in areas such as molecules associated with mitochondria, endosomes/lysosomes, transfer RNA, axonal transport, and glucose metabolism.

PMID: 33049996 [PubMed – in process]

PubMed:33049996

Kitani-Morii F, Noto YI

Curcumin-cyclodextrin/cellulose Nanocrystals Improve the Phenotype of Charcot-Marie-Tooth-1A Transgenic Rats Through the Reduction of Oxidative Stress

https://www.sciencedirect.com/science/article/pii/S0891584920312636?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/32980538?dopt=Abstract

Curcumin-cyclodextrin/cellulose Nanocrystals Improve the Phenotype of Charcot-Marie-Tooth-1A Transgenic Rats Through the Reduction of Oxidative Stress.

Related Articles

Curcumin-cyclodextrin/cellulose Nanocrystals Improve the Phenotype of Charcot-Marie-Tooth-1A Transgenic Rats Through the Reduction of Oxidative Stress.

Free Radic Biol Med. 2020 Sep 24;:

Authors: Caillaud M, Msheik Z, Ndong-Ntoutoume GM, Vignaud L, Richard L, Favreau F, Faye PA, Sturtz F, Granet R, Vallat JM, Sol V, Desmoulière A, Billet F

Abstract

The most prevalent form of Charcot-Marie-Tooth disease (CMT type 1A) is characterized by duplication of the PMP22 gene, peripheral dysmyelination and decreased nerve conduction velocities leading to muscle weakness. Recently, oxidative stress was reported as a feature in CMT1A patients. Curcumin exhibits antioxidant activities and has shown beneficial properties on peripheral nerves. However, curcumin presents unfavorable pharmacokinetics. We developed curcumin-cyclodextrin/cellulose nanocrystals (Nano-Cur) to bypass this limitation. The present study investigated the therapeutic potential of Nano-Cur in vitro in Schwann cells (SCs) and in vivo in the transgenic CMT1A rat model. In vitro, Nano-Cur treatment (0.01 μM for 8h) reduced reactive oxygen species and improved mitochondrial membrane potential in CMT1A SCs. Moreover, Nano-Cur treatment (0.01 μM for 1 week) increased the expression of myelin basic protein in SCs/neurons co-cultures. Primary in vivo experiments carried out in WT rats showed that intraperitoneal (i.p.) injection of Nano-Cur treatment containing 0.2 mg/kg of curcumin strongly enhanced the bioavailability of curcumin. In 1-month-old male CMT1A rats, Nano-Cur treatment (0.2 mg/kg/day, i.p. for 8 weeks) significantly improved sensori-motor functions (grip strength, balance performance, mechanical and thermal sensitivities). Importantly, sensory and motor nerve conduction velocities were improved. Further histological and biochemical analyses indicated that myelin sheath thickness and myelin protein expression (myelin protein zero and PMP22) were increased. In addition, oxidative stress markers were decreased in sciatic nerve and gastrocnemius muscle. Finally, Nrf2 expression and some major antioxidant enzymes were increased in sciatic nerve. Therefore, Nano-Cur significantly improved cellular, electrophysiological, and functional features of CMT1A rats.

PMID: 32980538 [PubMed – as supplied by publisher]

PubMed:32980538

Caillaud M, Msheik Z, Ndong-Ntoutoume GM, Vignaud L, Richard L, Favreau F, Faye PA, Sturtz F, Granet R, Vallat JM, Sol V, Desmoulière A, Billet F

Phosphorylation of eIF2α promotes Schwann cell differentiation and myelination in CMT1B mice with activated UPR

https://www.jneurosci.org/content/early/2020/09/24/JNEUROSCI.0957-20.2020

https://www.ncbi.nlm.nih.gov/pubmed/32973043?dopt=Abstract

Phosphorylation of eIF2α promotes Schwann cell differentiation and myelination in CMT1B mice with activated UPR.

Related Articles

Phosphorylation of eIF2α promotes Schwann cell differentiation and myelination in CMT1B mice with activated UPR.

J Neurosci. 2020 Sep 24;:

Authors: Scapin C, Ferri C, Pettinato E, Bianchi F, Del Carro U, Feltri ML, Kaufman RJ, Wrabetz L, D’Antonio M

Abstract

Myelin Protein Zero (MPZ/P0) is the most abundant glycoprotein of peripheral nerve myelin. P0 is synthesized by myelinating Schwann cells, processed in the endoplasmic reticulum (ER) and delivered to myelin via the secretory pathway. The mutant P0S63del, that causes Charcot-Marie-Tooth type 1B (CMT1B) neuropathy in humans and a similar demyelinating neuropathy in transgenic mice, is instead retained the ER where it activates an unfolded protein response (UPR). Under stress conditions, the ER-resident kinase PERK phosphorylates eIF2α to attenuate global translation, thus reducing the misfolded protein overload in the ER. Genetic and pharmacological inactivation of Gadd34, a subunit of the PP1 phosphatase complex that promotes the dephosphorylation of eIF2α, prolonged eIF2α phosphorylation and improved motor, neurophysiological and morphological deficits in S63del mice. However, PERK ablation in S63del Schwann cells ameliorated, rather than worsened S63del neuropathy, despite reduced levels of P-eIF2α. These contradictory findings prompted us to genetically explore the role of eIF2α-phosphorylation in P0S63del-CMT1B neuropathy through the generation of mice in which eIF2α cannot be phosphorylated specifically in Schwann cells. Morphological and electrophysiological analysis of male and female S63del mice showed a worsening of the neuropathy in the absence of eIF2α phosphorylation. However, we did not detect significant changes in ER-stress levels but, rather, a dramatic increase of the MEK/ERK/c-Jun pathway accompanied by reduction in myelin genes expression and a delay in Schwann cell differentiation. Our results support the hypothesis that eIF2α-phosphorylation is protective in CMT1B and unveil a possible crosstalk between eIF2α and the MEK/ERK pathway in neuropathic nerves.SIGNIFICANCE STATEMENT:In the P0S63del mouse model of CMT1B, the genetic and pharmacological inhibition of Gadd34 prolonged eIF2α phosphorylation leading to a proteostatic rebalance that significantly ameliorated the neuropathy. Yet, ablation of the kinase PERK also ameliorated the S63del neuropathy, despite reduced levels of P-eIF2α. In this study we provide genetic evidence that eIF2α-phosphorylation has a protective role in CMT1B Schwann cells by limiting ERK/c-Jun hyperactivation. Our data support the targeting of the P-eIF2α/Gadd34 complex as a therapeutic avenue in CMT1B and also suggest that PERK may hamper myelination via mechanisms outside its role in the UPR.

PMID: 32973043 [PubMed – as supplied by publisher]

PubMed:32973043

Scapin C, Ferri C, Pettinato E, Bianchi F, Del Carro U, Feltri ML, Kaufman RJ, Wrabetz L, D’Antonio M

Identification of Candidate Genes Associated with Charcot-Marie-Tooth Disease by Network and Pathway Analysis

https://www.hindawi.com/journals/bmri/2020/1353516/

https://www.ncbi.nlm.nih.gov/pubmed/33029488?dopt=Abstract

Identification of Candidate Genes Associated with Charcot-Marie-Tooth Disease by Network and Pathway Analysis.

Identification of Candidate Genes Associated with Charcot-Marie-Tooth Disease by Network and Pathway Analysis.

Biomed Res Int. 2020;2020:1353516

Authors: Zhong M, Luo Q, Ye T, Zhu X, Chen X, Liu J

Abstract

Charcot-Marie-Tooth Disease (CMT) is the most common clinical genetic disease of the peripheral nervous system. Although many studies have focused on elucidating the pathogenesis of CMT, few focuses on achieving a systematic analysis of biology to decode the underlying pathological molecular mechanisms and the mechanism of its disease remains to be elucidated. So our study may provide further useful insights into the molecular mechanisms of CMT based on a systematic bioinformatics analysis. In the current study, by reviewing the literatures deposited in PUBMED, we identified 100 genes genetically related to CMT. Then, the functional features of the CMT-related genes were examined by R software and KOBAS, and the selected biological process crosstalk was visualized with the software Cytoscape. Moreover, CMT specific molecular network analysis was conducted by the Molecular Complex Detection (MCODE) Algorithm. The biological function enrichment analysis suggested that myelin sheath, axon, peripheral nervous system, mitochondrial function, various metabolic processes, and autophagy played important roles in CMT development. Aminoacyl-tRNA biosynthesis, metabolic pathways, and vasopressin-regulated water reabsorption were significantly enriched in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway network, suggesting that these pathways may play key roles in CMT occurrence and development. According to the crosstalk, the biological processes could be roughly divided into a correlative module and two separate modules. MCODE clusters showed that in top 3 clusters, 13 of CMT-related genes were included in the network and 30 candidate genes were discovered which might be potentially related to CMT. The study may help to update the new understanding of the pathogenesis of CMT and expand the potential genes of CMT for further exploration.

PMID: 33029488 [PubMed – in process]

PubMed:33029488

Zhong M, Luo Q, Ye T, Zhu X, Chen X, Liu J

Helixmith starts local trials of VM202 for treating Charcot-Marie-Tooth disease

http://www.koreabiomed.com/news/articleView.html?idxno=9280

Helixmith starts local trials of VM202 for treating rare disorder
Lee Han-soo Published 2020.09.22 14:54

Helixmith said that it has administered the first dose of VM202 to patients with Charcot-Marie-Tooth (CMT) disease, as part of its local phase 1 and 2a clinical trial.

Helixmith has administered the first dose of VM202 to a patient with Charcot-Marie-Tooth disease. (Helixmith)
During the trial, a research team, led by Professor Choi Byung-ok at Samsung Medical Center, plans to evaluate the safety and tolerability of VM202 in 12 CMT patients.

Dominant mutations in ITPR3 cause Charcot-Marie-Tooth disease

https://onlinelibrary.wiley.com/doi/10.1002/acn3.51190

https://www.ncbi.nlm.nih.gov/pubmed/32949214?dopt=Abstract

Dominant mutations in ITPR3 cause Charcot-Marie-Tooth disease.

Related Articles

Dominant mutations in ITPR3 cause Charcot-Marie-Tooth disease.

Ann Clin Transl Neurol. 2020 Sep 19;:

Authors: Rönkkö J, Molchanova S, Revah-Politi A, Pereira EM, Auranen M, Toppila J, Kvist J, Ludwig A, Neumann J, Bultynck G, Humblet-Baron S, Liston A, Paetau A, Rivera C, Harms MB, Tyynismaa H, Ylikallio E

Abstract

OBJECTIVE: ITPR3, encoding inositol 1,4,5-trisphosphate receptor type 3, was previously reported as a potential candidate disease gene for Charcot-Marie-Tooth neuropathy. Here, we present genetic and functional evidence that ITPR3 is a Charcot-Marie-Tooth disease gene.

METHODS: Whole-exome sequencing of four affected individuals in an autosomal dominant family and one individual who was the only affected individual in his family was used to identify disease-causing variants. Skin fibroblasts from two individuals of the autosomal dominant family were analyzed functionally by western blotting, quantitative reverse transcription PCR, and Ca2+ imaging.

RESULTS: Affected individuals in the autosomal dominant family had onset of symmetrical neuropathy with demyelinating and secondary axonal features at around age 30, showing signs of gradual progression with severe distal leg weakness and hand involvement in the proband at age 64. Exome sequencing identified a heterozygous ITPR3 p.Val615Met variant segregating with the disease. The individual who was the only affected in his family had disease onset at age 4 with demyelinating neuropathy. His condition was progressive, leading to severe muscle atrophy below knees and atrophy of proximal leg and hand muscles by age 16. Trio exome sequencing identified a de novo ITPR3 variant p.Arg2524Cys. Altered Ca2+ -transients in p.Val615Met patient fibroblasts suggested that the variant has a dominant-negative effect on inositol 1,4,5-trisphosphate receptor type 3 function.

INTERPRETATION: Together with two previously identified variants, our report adds further evidence that ITPR3 is a disease-causing gene for CMT and indicates altered Ca2+ homeostasis in disease pathogenesis.

PMID: 32949214 [PubMed – as supplied by publisher]

PubMed:32949214

Rönkkö J, Molchanova S, Revah-Politi A, Pereira EM, Auranen M, Toppila J, Kvist J, Ludwig A, Neumann J, Bultynck G, Humblet-Baron S, Liston A, Paetau A, Rivera C, Harms MB, Tyynismaa H, Ylikallio E

A Novel Pharmacologic Approach [KU-596] to Treat CMT1X

https://projectreporter.nih.gov/project_info_description.cfm?aid=10043231

Project Number: 1R61NS114355-01A1 Contact PI / Project Leader: DOBROWSKY, RICK T
Title: A NOVEL PHARMACOLOGIC APPROACH TO TREAT CMT1X Awardee Organization: UNIVERSITY OF KANSAS LAWRENCE
Abstract Text:
SUMMARY Novologues are small molecule neurotherapeutics whose chemical biology is directed at modulating the activity and expression of molecular chaperones, such as heat shock protein 90 (Hsp90) and Hsp70. Over the last decade we have published rigorous pre-clinical data showing that novologues improve metabolic and clinical indices of diabetic peripheral neuropathy (DPN). Pharmacodynamically, novologues require Hsp70 for efficacy since the drugs cannot improve nerve function in diabetic Hsp70 knockout (KO) mice. KU-596 is our most clinically advanced novologue and extensive PK/PD and pre-clinical GLP toxicology studies have been accepted by the FDA. A Phase 1 trial of KU-596 has been completed and the drug showed acceptable PK/PD profiles, a negligible adverse event profile and is now poised to enter to Phase 2 trials. However, new pre-clinical data supports that the therapeutic benefit of KU-596 may also extend to certain inherited neuropathies. charcot-marie-tooth 1X (CMT1X) is an X-linked inherited neuropathy that can result from a null mutation in the gene for connexin 32 (Cx32). Cx32 deficient (Cx32def) mice are an authentic model of the human disease and our preliminary data supports that oral dosing of KU-596 improves neuromuscular function in Cx32def mice in an Hsp70-dependent manner. However, many CMT1X patients do not have a null mutation but express mutant forms of Cx32 that exhibit altered intracellular trafficking. These individuals develop a clinical neuropathy like patients with null mutations, but it is unclear whether the beneficial drug response phenotype is maintained with expression of mis-localized Cx32 mutants. Thus, the goals of this IGNITE proposal are to validate the therapeutic strengths and limitations of KU-596 in treating peripheral and CNS symptoms arising from mis-localized Cx32 mutations. Our R61 Phase will test the hypothesis that drug efficacy is maintained in T55I-Cx32def mice, which retain Cx32 in the endoplasmic reticulum (ER). We will determine if ER retention affects drug efficacy using measures of nerve conduction as the objective milestone. In the R33 phase aim 1 will identify whether improvements in markers of axonal damage correlate with the electrophysiologic recovery observed in the T55I-Cx32def mice. These data will assess whether prophylactic therapy may improve the predemyelinating axonopathy in young CMT1X patients. Aim 2 will test the hypothesis that novologue therapy decreases peripheral nerve inflammation and fulminant CNS dysfunction in Cx32def and T55I-Cx32def mice. These studies will assess the disease modifying potential of KU-596 toward reducing peripheral and central symptoms in CMT1X. Aim 3 will test the hypothesis that drug efficacy is maintained with golgi retention of Cx32. Since ER and golgi retention of Cx32 are not necessarily equivalent in their response to therapies, these data will further therapeutic advancement by broadening the breadth of CMT1X patients that may respond to KU-596. Importantly, this work has high translational impact given the lack of neurotherapeutic options for this orphan neurologic disorder and the drug’s Phase 2 readiness.
Public Health Relevance Statement:
PROJECT NARRATIVE charcot marie tooth 1X (CMT1X) is an inherited neuropathy for which there is no pharmacologic treatment. This project focuses on investigating the translational potential of a new class of small molecule therapeutics that we have developed and which may ameliorate peripheral nerve degeneration and improve the medical management of CMT1X.

Microstructural Integrity of Peripheral Nerves in Charcot-Marie-Tooth Disease: An MRI Evaluation Study

https://www.ncbi.nlm.nih.gov/pubmed/32918328?dopt=Abstract

https://onlinelibrary.wiley.com/doi/10.1002/jmri.27354

Microstructural Integrity of Peripheral Nerves in Charcot-Marie-Tooth Disease: An MRI Evaluation Study.

Microstructural Integrity of Peripheral Nerves in Charcot-Marie-Tooth Disease: An MRI Evaluation Study.

J Magn Reson Imaging. 2020 Sep 11;:

Authors: Cheah PL, Krisnan T, Wong JHD, Rozalli FI, Fadzli F, Rahmat K, Shahrizaila N, Tan LK, Nawawi O, Ramli N

Abstract

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is diagnosed through clinical findings and genetic testing. While there are neurophysiological tools and clinical functional scales in CMT, objective disease biomarkers that can facilitate in monitoring disease progression are limited.

PURPOSE: To investigate the utility of diffusion tensor imaging (DTI) in determining the microstructural integrity of sciatic and peroneal nerves and its correlation with the MRI grading of muscle atrophy severity and clinical function in CMT as determined by the CMT neuropathy score (CMTNS).

STUDY TYPE: Prospective case-control.

SUBJECTS: Nine CMT patients and nine age-matched controls.

FIELD STRENGTH/SEQUENCE: 3 T T1 -weighted in-/out-of phase spoiled gradient recalled echo (SPGR) and DTI sequences.

ASSESSMENT: Fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) values for sciatic and peroneal nerves were obtained from DTI. Muscle atrophy was graded according to the Goutallier classification using in-/out-of phase SPGRs. DTI parameters and muscle atrophy grades were compared between CMT and controls, and the relationship between DTI parameters, muscle atrophy grades, and CMTNS were assessed.

STATISTICAL TESTS: The Wilcoxon Signed Ranks test was used to compare DTI parameters between CMT and controls. The relationship between DTI parameters, muscle atrophy grades, and CMTNS were analyzed using the Spearman correlation. Receiver operating characteristic (ROC) analyses of DTI parameters that can differentiate CMT from healthy controls were done.

RESULTS: There was a significant reduction in FA and increase in RD of both nerves (P < 0.05) in CMT, with significant correlations between FA (negative; P < 0.05) and RD (positive; P < 0.05) with muscle atrophy grade. In the sciatic nerve, there was significant correlation between FA and CMTNS (r = -0.795; P < 0.05). FA and RD could discriminate CMT from controls with high sensitivity (77.8-100%) and specificity (88.9-100%). DATA CONCLUSION: There were significant differences of DTI parameters between CMT and controls, with significant correlations between DTI parameters, muscle atrophy grade, and CMTNS. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2. PMID: 32918328 [PubMed - as supplied by publisher] PubMed:32918328 Cheah PL, Krisnan T, Wong JHD, Rozalli FI, Fadzli F, Rahmat K, Shahrizaila N, Tan LK, Nawawi O, Ramli N

Deep geno- and phenotyping in two consanguineous families with CMT2 reveals HADHA as an unusual disease-causing gene and an intronic variant in GDAP1 as an unusual mutation

https://link.springer.com/article/10.1007/s00415-020-10171-4

https://www.ncbi.nlm.nih.gov/pubmed/32897397?dopt=Abstract

Deep geno- and phenotyping in two consanguineous families with CMT2 reveals HADHA as an unusual disease-causing gene and an intronic variant in GDAP1 as an unusual mutation.

Related Articles

Deep geno- and phenotyping in two consanguineous families with CMT2 reveals HADHA as an unusual disease-causing gene and an intronic variant in GDAP1 as an unusual mutation.

J Neurol. 2020 Sep 08;:

Authors: Khani M, Taheri H, Shamshiri H, Moazzeni H, Hardy J, Bras JT, InanlooRahatloo K, Alavi A, Nafissi S, Elahi E

Abstract

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is a prevalent and heterogeneous peripheral neuropathy. Most patients affected with the axonal form of CMT (CMT2) do not harbor mutations in the approximately 90 known CMT-associated genes. We aimed to identify causative genes in two CMT2 pedigrees.

METHODS: Neurologic examination, laboratory tests and brain MRIs were performed. Genetic analysis included exome sequencing of four patients from the two pedigrees. The predicted effect of a deep intronic mutation on splicing was tested by regular and real-time PCR and sequencing.

RESULTS: Clinical data were consistent with CMT2 diagnosis. Inheritance patterns were autosomal recessive. Exome data of CMT2-101 did not include mutations in known CMT-associated genes. Sequence data, segregation analysis, bioinformatics analysis, evolutionary conservation, and information in the literature strongly implicated HADHA as the causative gene. An intronic variation positioned 23 nucleotides away from following intron/exon border in GDAP1 was ultimately identified as cause of CMT in CMT2-102. It was shown to affect splicing.

CONCLUSION: The finding of a HADHA mutation as a cause of CMT is of interest because its encoded protein is a subunit of the mitochondrial trifunctional protein (MTP) complex, a mitochondrial enzyme involved in long chain fatty acid oxidation. Long chain fatty acid oxidation is an important source of energy for skeletal muscles. The mutation found in CMT2-102 is only the second intronic mutation reported in GDAP1. The mutation in the CMT2-102 pedigree was outside the canonical splice site sequences, emphasizing the importance of careful examination of available intronic sequences in exome sequence data.

PMID: 32897397 [PubMed – as supplied by publisher]

PubMed:32897397

Khani M, Taheri H, Shamshiri H, Moazzeni H, Hardy J, Bras JT, InanlooRahatloo K, Alavi A, Nafissi S, Elahi E

Animal Models of CMT2A: State-of-art and Therapeutic Implications

https://link.springer.com/article/10.1007%2Fs12035-020-02081-3

https://www.ncbi.nlm.nih.gov/pubmed/32856204?dopt=Abstract

Animal Models of CMT2A: State-of-art and Therapeutic Implications.

Related Articles

Animal Models of CMT2A: State-of-art and Therapeutic Implications.

Mol Neurobiol. 2020 Aug 27;:

Authors: De Gioia R, Citterio G, Abati E, Nizzardo M, Bresolin N, Comi GP, Corti S, Rizzo F

Abstract

Charcot-Marie-Tooth disease type 2A (CMT2A), arising from mitofusin 2 (MFN2) gene mutations, is the most common inherited axonal neuropathy affecting motor and sensory neurons. The cellular and molecular mechanisms by which MFN2 mutations determine neuronal degeneration are largely unclear. No effective treatment exists for CMT2A, which has a high degree of genetic/phenotypic heterogeneity. The identification of mutations in MFN2 has allowed the generation of diverse transgenic animal models, but to date, their ability to recapitulate the CMT2A phenotype is limited, precluding elucidation of its pathogenesis and discovery of therapeutic strategies. This review will critically present recent progress in in vivo CMT2A disease modeling, discoveries, drawbacks and limitations, current challenges, and key reflections to advance the field towards developing effective therapies for these patients.

PMID: 32856204 [PubMed – as supplied by publisher]

PubMed:32856204

De Gioia R, Citterio G, Abati E, Nizzardo M, Bresolin N, Comi GP, Corti S, Rizzo F

Exploiting Sphingo- and Glycerophospholipid Impairment to Select Effective Drugs and Biomarkers for CMT1A

https://www.sciencedirect.com/science/article/pii/S0891584920312636?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/32982928?dopt=Abstract

Exploiting Sphingo- and Glycerophospholipid Impairment to Select Effective Drugs and Biomarkers for CMT1A.

Related Articles

Exploiting Sphingo- and Glycerophospholipid Impairment to Select Effective Drugs and Biomarkers for CMT1A.

Front Neurol. 2020;11:903

Authors: Visigalli D, Capodivento G, Basit A, Fernández R, Hamid Z, Pencová B, Gemelli C, Marubbi D, Pastorino C, Luoma AM, Riekel C, Kirschner DA, Schenone A, Fernández JA, Armirotti A, Nobbio L

Abstract

In Charcot-Marie-Tooth type 1A (CMT1A), Schwann cells exhibit a preponderant transcriptional deficiency of genes involved in lipid biosynthesis. This perturbed lipid metabolism affects the peripheral nerve physiology and the structure of peripheral myelin. Nevertheless, the identification and functional characterization of the lipid species mainly responsible for CMT1A myelin impairment currently lack. This is critical in the pathogenesis of the neuropathy since lipids are many and complex molecules which play essential roles in the cell, including the structural components of cellular membranes, cell signaling, and membrane trafficking. Moreover, lipids themselves are able to modify gene transcription, thereby affecting the genotype-phenotype correlation of well-defined inherited diseases, including CMT1A. Here we report for the first time a comprehensive lipid profiling in experimental and human CMT1A, demonstrating a previously unknown specific alteration of sphingolipid (SP) and glycerophospholipid (GP) metabolism. Notably, SP, and GP changes even emerge in biological fluids of CMT1A rat and human patients, implying a systemic metabolic dysfunction for these specific lipid classes. Actually, SP and GP are not merely reduced; their expression is instead aberrant, contributing to the ultrastructural abnormalities that we detailed by X-ray diffraction in rat and human internode myelin. The modulation of SP and GP pathways in myelinating dorsal root ganglia cultures clearly sustains this issue. In fact, just selected molecules interacting with these pathways are able to modify the altered geometric parameters of CMT1A myelinated fibers. Overall, we propose to exploit the present SP and GP metabolism impairment to select effective drugs and validate a set of reliable biomarkers, which remain a challenge in CMT1A neuropathy.

PMID: 32982928 [PubMed]

PubMed:32982928

Visigalli D, Capodivento G, Basit A, Fernández R, Hamid Z, Pencová B, Gemelli C, Marubbi D, Pastorino C, Luoma AM, Riekel C, Kirschner DA, Schenone A, Fernández JA, Armirotti A, Nobbio L

Conversations with CMT Experts : Demystifying the Drug Development Process [Video]

Conversations with CMT Experts : Demystifying the Drug Development Process

The CMT Research Foundation is asking and answering the most pressing questions patients have about the need for treatments and cures. In episode 1, CMT Research

Foundation CEO Susan Ruediger interviews NIH’s Dr. Chris Austin and Dr. Sindhu Ramchandren to learn more about the drug development process, when patients can expect treatments for CMT, and action YOU can take now to speed progress. Learn more and get involved at cmtrf.org.

An altered lipid metabolism characterizes Charcot-Marie-Tooth type 2B peripheral neuropathy

https://www.sciencedirect.com/science/article/pii/S1388198120301979?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/32829064?dopt=Abstract

An altered lipid metabolism characterizes Charcot-Marie-Tooth type 2B peripheral neuropathy.

An altered lipid metabolism characterizes Charcot-Marie-Tooth type 2B peripheral neuropathy.

Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Aug 20;:158805

Authors: Giudetti AM, Guerra F, Longo S, Beli R, Romano R, Manganelli F, Nolano M, Mangini V, Santoro L, Bucci C

Abstract

Charcot-Marie Tooth type 2B (CMT2B) is a rare inherited peripheral neuropathy caused by five missense mutations in the RAB7A gene, which encodes a small GTPase of the RAB family. Currently, no cure is available for this disease. In this study, we approached the disease by comparing the lipid metabolism of CMT2B-derived fibroblasts to that of healthy controls. We found that CMT2B cells showed increased monounsaturated fatty acid level and increased expression of key enzymes of monounsaturated and polyunsaturated fatty acid synthesis. Moreover, in CMT2B cells a higher expression of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), key enzymes of de novo fatty acid synthesis, with a concomitantly increased [1-14C]acetate incorporation into fatty acids, was observed. The expression of diacylglycerol acyltransferase 2, a rate-limiting enzyme in triacylglycerol synthesis, as well as triacylglycerol levels were increased in CMT2B compared to control cells. In addition, as RAB7A controls lipid droplet breakdown and lipid droplet dynamics have been linked to diseases, we analyzed these organelles and showed that in CMT2B cells there is a strong accumulation of lipid droplets compared to control cells, thus reinforcing our data on abnormal lipid metabolism in CMT2B. Furthermore, we demonstrated that ACC and FAS expression levels changed upon RAB7 silencing or overexpression in HeLa cells, thus suggesting that metabolic modifications observed in CMT2B-derived fibroblasts can be, at least in part, related to RAB7 mutations.

PMID: 32829064 [PubMed – as supplied by publisher]

PubMed:32829064

Giudetti AM, Guerra F, Longo S, Beli R, Romano R, Manganelli F, Nolano M, Mangini V, Santoro L, Bucci C

Expanding the phenotypic spectrum of TRIM2-associated Charcot-Marie-Tooth disease

https://pubmed.ncbi.nlm.nih.gov/32815244/

https://www.ncbi.nlm.nih.gov/pubmed/32815244?dopt=Abstract

Expanding the phenotypic spectrum of TRIM2-associated Charcot-Marie-Tooth disease.

Related Articles

Expanding the phenotypic spectrum of TRIM2-associated Charcot-Marie-Tooth disease.

J Peripher Nerv Syst. 2020 Aug 19;:

Authors: Magri S, Danti FR, Balistreri F, Baratta S, Ciano C, Pagliano E, Taroni F, Moroni I

Abstract

BACKGROUND AND AIMS: Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group of distal symmetric polyneuropathies due to progressive and length-dependent degeneration of peripheral nerves. Cranial nerve involvement has been described in association with various CMT-genes mutations, such as GDAP1, TRPV4, MFN2, MTMR2 and EGR2. Compound heterozygous mutations in the TRIM2 gene, encoding an E3 ubiquitin ligase, were previously identified in two patients with early-onset axonal CMT (CMT2). One of them also had bilateral vocal cord paralysis. The aim of this study is to further delineate the phenotypic and molecular genetic features of TRIM2-related CMT.

METHODS: We studied clinical, genetic and neurophysiological aspects of two unrelated CMT2 patients. Genetic analysis was performed by next generation sequencing of a multigene CMT panel.

RESULTS: Patients presented with congenital hypotonia and bilateral clubfoot, delayed motor milestones, and severely progressive axonal neuropathy. Interestingly, along with vocal cord paralysis, they exhibited clinical features secondary to the involvement of several other cranial nerves, such as facial weakness, dysphagia, dyspnoea and acoustic impairment. Genetic analysis revealed two novel TRIM2 mutations in each patient.

INTERPRETATION: Our results expand the genotypic and phenotypic spectrum of TRIM2 deficiency showing that cranial nerves involvement is a core feature in this CMT2-subtype. Its finding should prompt physicians to suspect TRIM2 neuropathy. Conversely, patients carrying TRIM2 variants should be carefully evaluated for the presence of cranial nerve dysfunction in order to prevent and manage its impact on auditory and respiratory function and nutrition. This article is protected by copyright. All rights reserved.

PMID: 32815244 [PubMed – as supplied by publisher]

PubMed:32815244

Magri S, Danti FR, Balistreri F, Baratta S, Ciano C, Pagliano E, Taroni F, Moroni I

Understanding medication safety and Charcot-Marie-Tooth disease: a patient perspective

https://link.springer.com/article/10.1007%2Fs11096-020-01123-z

https://www.ncbi.nlm.nih.gov/pubmed/32804316?dopt=Abstract

Understanding medication safety and Charcot-Marie-Tooth disease: a patient perspective.

Understanding medication safety and Charcot-Marie-Tooth disease: a patient perspective.

Int J Clin Pharm. 2020 Aug 17;:

Authors: Socha Hernandez AV, Deeks LS, Shield AJ

Abstract

Background Charcot-Marie-Tooth disease is a common inherited neuropathy where patients may be sensitive to adverse effects of certain medicines; however, information about medication safety in this group of people is limited. Objective This study aimed to investigate the experience of Australian individuals with Charcot-Marie-Tooth disease in using medications, including perceived impact of drug-induced adverse effects. Secondarily, it aimed to determine whether individuals with Charcot-Marie-Tooth disease feel adequately supported to make decisions about medication safety. Setting Focus groups and interviews (face-to-face or telephone) of individuals with Charcot-Marie-Tooth disease in Australia. Method A mixed methods qualitative study was conducted between September 2015 and August 2016 using semi-structured interviews. Thematic analysis of interview transcripts was conducted independently by two researchers using inductive coding until concept saturation was achieved. Main outcome measure Perceptions of medicines safety in people with Charcot-Marie-Tooth disease, including barriers to making informed decisions about medication safety. Results Twenty-four adults with Charcot-Marie-Tooth disease participated. Anaesthetics (18%) and pregabalin (15%) were the medications most frequently reported as impacting on Charcot-Marie-Tooth symptoms. Participants sought medication information primarily from general practitioners or neurologists. The main barriers identified by participants were a perceived poor understanding in non-specialist health professionals about Charcot-Marie-Tooth disease and lack of attention to medication safety concerns in people with Charcot-Marie-Tooth disease; this resulted in dissatisfaction about the advice provided. Many individuals who faced uncertainty in obtaining and understanding medicines information turned to internet resources, peer groups, and use of complementary and alternative medicines to self-manage Charcot-Marie-Tooth exacerbations. Conclusion Participants reported drug-related adverse effects and a difficulty in obtaining safety information about medication. This study highlights the need for improved evidence about medication safety in people with Charcot-Marie-Tooth disease. Development of evidence-based resources, increased awareness amongst health professionals about Charcot-Marie-Tooth disease and a team-based care approach could facilitate shared decisions about medication use for people with Charcot-Marie-Tooth disease.

PMID: 32804316 [PubMed – as supplied by publisher]

PubMed:32804316

Socha Hernandez AV, Deeks LS, Shield AJ

A novel missense pathogenic variant in NEFH causing rare Charcot-Marie-Tooth neuropathy type 2CC (CMT2CC)

https://link.springer.com/article/10.1007/s10072-020-04595-z

https://www.ncbi.nlm.nih.gov/pubmed/32780247?dopt=Abstract

A novel missense pathogenic variant in NEFH causing rare Charcot-Marie-Tooth neuropathy type 2CC.

Related Articles

A novel missense pathogenic variant in NEFH causing rare Charcot-Marie-Tooth neuropathy type 2CC.

Neurol Sci. 2020 Aug 11;:

Authors: Yan J, Qiao L, Peng H, Liu A, Wu J, Huang J

Abstract

The purpose of this research is to explore the underlying genes of Charcot-Marie-Tooth (CMT). Technologies such as electrophysiological testing and gene sequencing have been applied. We identified a novel variant NEFH c.2215C>T(p.P739S)(HGNC:7737) in a heterozygous state, which was considered to be pathogenic for CMT2CC(OMIM:616924).The proband and his brothers presented with muscle atrophy of hand and calf and moderately decreased conduction velocities. By whole exome sequencing analysis, we found the novel missense pathogenic variant in the proband, his brother and mother. This report broadened current knowledge about intermediate CMT and the phenotypic spectrum of defects associated with NEFH. In addition, the proband carried other five variants {HSPD1c.695C>A (p.S232X), FLNCc.1073A>G (p.N358S), GUSBc.323C>A (p.P108Q), ACY1 c.1063-1G>A and APTX c.484-2A>T}, which have not been reported until now. The NEFH c.2215C>T (p.P739S) give us a new understanding of CMT, which might provide new therapeutic targets in the future.

PMID: 32780247 [PubMed – as supplied by publisher]

PubMed:32780247

Yan J, Qiao L, Peng H, Liu A, Wu J, Huang J

Altered Sensory Neuron Development in CMT2D Mice Is Site-Specific and Linked to Increased GlyRS Levels

https://www.frontiersin.org/articles/10.3389/fncel.2020.00232/full

https://www.ncbi.nlm.nih.gov/pubmed/32848623?dopt=Abstract

Altered Sensory Neuron Development in CMT2D Mice Is Site-Specific and Linked to Increased GlyRS Levels.

Related Articles

Altered Sensory Neuron Development in CMT2D Mice Is Site-Specific and Linked to Increased GlyRS Levels.

Front Cell Neurosci. 2020;14:232

Authors: Sleigh JN, Mech AM, Aktar T, Zhang Y, Schiavo G

Abstract

Dominant, missense mutations in the widely and constitutively expressed GARS1 gene cause peripheral neuropathy that usually begins in adolescence and principally impacts the upper limbs. Caused by a toxic gain-of-function in the encoded glycyl-tRNA synthetase (GlyRS) enzyme, the neuropathology appears to be independent of the canonical role of GlyRS in aminoacylation. Patients display progressive, life-long weakness and wasting of muscles in hands followed by feet, with frequently associated deficits in sensation. When dysfunction is observed in motor and sensory nerves, there is a diagnosis of Charcot-Marie-Tooth disease type 2D (CMT2D), or distal hereditary motor neuropathy type V if the symptoms are purely motor. The cause of this varied sensory involvement remains unresolved, as are the pathomechanisms underlying the selective neurodegeneration characteristic of the disease. We have previously identified in CMT2D mice that neuropathy-causing Gars mutations perturb sensory neuron fate and permit mutant GlyRS to aberrantly interact with neurotrophin receptors (Trks). Here, we extend this work by interrogating further the anatomy and function of the CMT2D sensory nervous system in mutant Gars mice, obtaining several key results: (1) sensory pathology is restricted to neurons innervating the hindlimbs; (2) perturbation of sensory development is not common to all mouse models of neuromuscular disease; (3) in vitro axonal transport of signaling endosomes is not impaired in afferent neurons of all CMT2D mouse models; and (4) Gars expression is selectively elevated in a subset of sensory neurons and linked to sensory developmental defects. These findings highlight the importance of comparative neurological assessment in mouse models of disease and shed light on key proposed neuropathogenic mechanisms in GARS1-linked neuropathy.

PMID: 32848623 [PubMed]

PubMed:32848623

Sleigh JN, Mech AM, Aktar T, Zhang Y, Schiavo G

Demyelinating Charcot Marie Tooth neuropathy associated with FBLN5 mutations

https://onlinelibrary.wiley.com/doi/abs/10.1111/ene.14463

https://www.ncbi.nlm.nih.gov/pubmed/32757322?dopt=Abstract

Demyelinating Charcot Marie Tooth neuropathy associated with FBLN5 mutations.

Related Articles

Demyelinating Charcot Marie Tooth neuropathy associated with FBLN5 mutations.

Eur J Neurol. 2020 Aug 05;:

Authors: Šafka Brožková D, Stojkovic T, Haberlová J, Mazanec R, Windhager R, Fernandes Rosenegger P, Hacker S, Züchner S, Kochański A, Leonard-Louis S, Francou B, Latour P, Senderek J, Seeman P, Auer-Grumbach M

Abstract

BACKGROUND AND PURPOSE: Charcot-Marie-Tooth disease type 1 (CMT1) is a group of autosomal-dominantly inherited demyelinating sensorimotor neuropathies. Symptoms usually start in the 1st -2nd decade and include distal muscle weakness and wasting, sensory disturbances and foot deformities. The most frequent cause is a duplication of PMP22 while point mutations in PMP22 and other genes are rare causes. Recently, FBLN5 mutations have been reported in CMT1 families.

METHODS: Individuals with FBLN5-associated CMT1 were compiled from clinical and research genetic testing laboratories. Clinical data were extracted from medical records or obtained during patients’ visits at our centres or primary care sites.

RESULTS: We ascertained 19 CMT1 families containing 38 carriers of three different FBLN5 missense variants and confirmed a mutational hot spot at c.1117C>T (p.Arg373Cys). Compared to patients with the common PMP22 duplication, individuals with FBLN5 variants had later age of diagnosis (3rd -5th decade) and less severely reduced motor median nerve conduction velocities (around 31 m/s). The most frequent clinical presentations were prominent sensory disturbances and painful sensations, often as initial symptom and pronounced in the upper limbs, contrasting with rather mild to moderate motor deficits.

CONCLUSIONS: Our study confirms the relevance of FBLN5 mutations in CMT1. We propose to include FBLN5 in the genetic work-up of individuals suspected with CMT1, particularly when diagnosis is established beyond the 1st -2nd decade and comparably moderate motor deficits contrast with early and marked sensory involvement. FBLN5-associated CMT1 has a recognizable clinical phenotype and should be referred to as CMT1H according to the current classification scheme.

PMID: 32757322 [PubMed – as supplied by publisher]

PubMed:32757322

Šafka Brožková D, Stojkovic T, Haberlová J, Mazanec R, Windhager R, Fernandes Rosenegger P, Hacker S, Züchner S, Kochański A, Leonard-Louis S, Francou B, Latour P, Senderek J, Seeman P, Auer-Grumbach M

Investigating SIPA1L2 as a Modifier Gene and Therapeutic Target for Charcot-Marie-Tooth Type 1A

https://projectreporter.nih.gov/project_info_description.cfm?aid=10072528

Project Number: 1R21NS116936-01A1 Contact PI / Project Leader: BURGESS, ROBERT W
Title: INVESTIGATING SIPA1L2 AS A MODIFIER GENE AND THERAPEUTIC TARGET FOR CHARCOT-MARIE-TOOTH TYPE 1A Awardee Organization: JACKSON LABORATORY
Abstract Text:
PROJECT SUMMARY/ABSTRACT The goals of this project are to validate SIPA1L2 as a genetic modifier of the severity of Charcot-Marie-Tooth type 1A (CMT1A), to understand the normal function of SIPA1L2, and to determine whether modulating SIPA1L2 levels may be a therapeutic strategy for CMT1A. CMT1A is the most common form of inherited peripheral neuropathy, comprising around half of all diagnosed CMT cases, and it is caused by a genetic duplication resulting in the overexpression of peripheral myelin protein 22 (PMP22), leading to a demyelinating peripheral neuropathy. Despite the genetic reproducibility of CMT1A, the clinical severity is variable, and a recent case-only GWAS identified an association between multiple SNPs in SIPA1L2 and the severity of foot dorsiflexion in CMT1A patients. Furthermore, SIPA1L2 was found to be in the same SOX10/EGR2 gene co- expression network as other myelin genes, providing a possible mechanism for its modifier effect and suggesting that the down regulation of SIPA1L2 may be a therapeutic strategy that would result in the down regulation of PMP22, providing a novel treatment for CMT1A. However, given the low overall frequency of CMT1A, additional validation in human cohorts is a challenge, and testing the therapeutic potential of SIPA1L2 as a treatment for CMT1A requires an in vivo system modeling the demyelinating neuropathy. For this, we propose to use the established C3-PMP22 transgenic mouse model of CMT1A. In addition, we have deleted the Sipa1l2 gene from the mouse genome using CRISPR/Cas9 technology. Therefore, we are now able to use these mouse models to better understand the normal function of Sipa1l2 and to test whether changing Sipa1l2 levels will change the severity the demyelinating phenotype of the C3-PMP22 mouse model. We propose two aims. In Aim 1, we will study the loss-of-function phenotype of Sipa1l2 heterozygous and homozygous knockout mice to understand its normal function. We will use a combination of behavioral, neurophysiological and histopathological tests, focusing primarily on the neuromuscular system. We will also perform gene expression analysis by RNAseq to help define pathways that are altered by the loss of Sipa1l2, and to determine if changing Sipa1l2 levels in vivo leads to decreased expression of other myelin genes in the sciatic nerve. In Aim 2, we will combine the Sipa1l2 knockout mice with the C3-PMP22 transgenic model to determine if reducing Sipa1l2 levels changes the severity of the demyelinating phenotype. We will again use behavioral, neurophysiological and histopathological outcomes relevant to CMT1A, as well as gene expression analysis to determine the effects of Sipa1l2 in the C3-PMP22/CMT1A background. We anticipate that reducing Sipa1l2 will result in a decrease in the severity of the phenotype through reduced expression of other myelin genes. Our results to date indicate that the loss of Sipa1l2 on its own does not produce a strong phenotype, making down regulation of SIPA1L2 a more attractive strategy for treating CMT1A. The results of Aim 2 will provide an indication of the potential efficacy of such as approach.
Public Health Relevance Statement:
RELEVANCE TO PUBLIC HEALTH Charcot-Marie-Tooth type 1A (CMT1A) is the most common form of inherited peripheral neuropathy and there is currently no treatment. A recent human genetic study identified SIPA1L2 as a second gene that modifies the severity of CMT1A. We will use mouse models to validate the influence of SIPA1L2 on the severity of CMT1A, which could improve the accuracy of prognosis for patients, and our studies will also test whether modulating SIPA1L2 levels may be a therapeutic strategy for CMT1A, which would be a novel target for this and possibly other related neuropathies.

Isoform-specific loss of dystonin causes hereditary motor and sensory neuropathy

https://ng.neurology.org/content/6/5/e496

https://www.ncbi.nlm.nih.gov/pubmed/32802955?dopt=Abstract

Isoform-specific loss of dystonin causes hereditary motor and sensory neuropathy.

Isoform-specific loss of dystonin causes hereditary motor and sensory neuropathy.

Neurol Genet. 2020 Oct;6(5):e496

Authors: Motley WW, Züchner S, Scherer SS

Abstract

Objective: To determine the genetic cause of axonal Charcot-Marie-Tooth disease in a small family with 2 affected siblings, one of whom had cerebellar features on examination.

Methods: Whole-exome sequencing of genomic DNA and analysis for recessively inherited mutations; PCR-based messenger RNA/complementary DNA analysis of transcripts to characterize the effects of variants identified by exome sequencing.

Results: We identified compound heterozygous mutations in dystonin (DST), which is alternatively spliced to create many plakin family linker proteins (named the bullous pemphigoid antigen 1 [BPAG1] proteins) that function to bridge cytoskeletal filament networks. One mutation (c.250C>T) is predicted to cause a nonsense mutation (p.R84X) that only affects isoform 2 variants, which have an N-terminal transmembrane domain; the other (c.8283+1G>A) mutates a consensus splice donor site and results in a 22 amino acid in-frame deletion in the spectrin repeat domain of all BPAG1a and BPAG1b isoforms.

Conclusions: These findings introduce a novel human phenotype, axonal Charcot-Marie-Tooth, of recessive DST mutations, and provide further evidence that BPAG1 plays an essential role in axonal health.

PMID: 32802955 [PubMed – as supplied by publisher]

PubMed:32802955

Motley WW, Züchner S, Scherer SS

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