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Treating PMP22 gene duplication-related Charcot-Marie-Tooth disease: The past, the present and the future

July 18, 2020

https://www.translationalres.com/article/S1931-5244(20)30175-4/pdf

https://www.ncbi.nlm.nih.gov/pubmed/32693030?dopt=Abstract

Treating PMP22 gene duplication-related Charcot-Marie-Tooth disease: The past, the present and the future.

Transl Res. 2020 Jul 18;:

Authors: Boutary S, Echaniz-Laguna A, Adams D, Loisel-Duwattez J, Schumacher M, Massaad C, Massaad-Massade L

Abstract

Charcot-Marie-Tooth (CMT) disease is the most frequent inherited neuropathy, affecting 1/1500 to 1/10000. CMT1A represents 60-70% of all CMT and is caused by a duplication on chromosome 17p11.2 leading to an overexpression of the Peripheral Myelin Protein 22 (PMP22). PMP22 gene is under tight regulation and small changes in its expression influences myelination and affect motor and sensory functions. To date, CMT1A treatment is symptomatic and classic pharmacological options have been disappointing. Here, we review the past, present and future treatment options for CMT1A, with a special emphasis on the highly promising potential of PMP22-targeted small interfering RNA (siRNA) and antisense oligonucleotides (ASO).

PMID: 32693030 [PubMed – as supplied by publisher]

PubMed:32693030

Boutary S, Echaniz-Laguna A, Adams D, Loisel-Duwattez J, Schumacher M, Massaad C, Massaad-Massade L

Egr2-guided histone H2B monoubiquitination is required for peripheral nervous system myelination

July 16, 2020

https://academic.oup.com/nar/article/doi/10.1093/nar/gkaa606/5872470

https://www.ncbi.nlm.nih.gov/pubmed/32672815?dopt=Abstract

Egr2-guided histone H2B monoubiquitination is required for peripheral nervous system myelination.

Nucleic Acids Res. 2020 Jul 16;:

Authors: Wüst HM, Wegener A, Fröb F, Hartwig AC, Wegwitz F, Kari V, Schimmel M, Tamm ER, Johnsen SA, Wegner M, Sock E

Abstract

Schwann cells are the nerve ensheathing cells of the peripheral nervous system. Absence, loss and malfunction of Schwann cells or their myelin sheaths lead to peripheral neuropathies such as Charcot-Marie-Tooth disease in humans. During Schwann cell development and myelination chromatin is dramatically modified. However, impact and functional relevance of these modifications are poorly understood. Here, we analyzed histone H2B monoubiquitination as one such chromatin modification by conditionally deleting the Rnf40 subunit of the responsible E3 ligase in mice. Rnf40-deficient Schwann cells were arrested immediately before myelination or generated abnormally thin, unstable myelin, resulting in a peripheral neuropathy characterized by hypomyelination and progressive axonal degeneration. By combining sequencing techniques with functional studies we show that H2B monoubiquitination does not influence global gene expression patterns, but instead ensures selective high expression of myelin and lipid biosynthesis genes and proper repression of immaturity genes. This requires the specific recruitment of the Rnf40-containing E3 ligase by Egr2, the central transcriptional regulator of peripheral myelination, to its target genes. Our study identifies histone ubiquitination as essential for Schwann cell myelination and unravels new disease-relevant links between chromatin modifications and transcription factors in the underlying regulatory network.

PMID: 32672815 [PubMed – as supplied by publisher]

PubMed:32672815

Wüst HM, Wegener A, Fröb F, Hartwig AC, Wegwitz F, Kari V, Schimmel M, Tamm ER, Johnsen SA, Wegner M, Sock E

Physical Activity in Persons With Charcot-Marie-Tooth: Developing a Measurement Instrument

July 13, 2020

https://clinicaltrials.gov/ct2/show/NCT04461613?type=Intr&cond=Charcot-Marie-Tooth&lupd_s=06%2F24%2F2020&lupd_d=14

Physical Activity in Persons With Charcot-Marie-Tooth: Developing a Measurement Instrument

Conditions : Hereditary Motor and Sensory Neuropathy; Charcot-Marie-Tooth; Polyneuropathies

Interventions : Other: Original IPAQ followed by a revised one.; Other: Revised IPAQ followed by an original one.

Sponsors : Oslo University Hospital; Norwegian National Advisory Unit on Rare Disorders (NKSD); University of Oslo; Foreningen for Muskelsyke

Not yet recruiting

NCT04461613

Wed, 08 Jul 2020 12:00:00 EDT

Direct Relationship Between Increased Expression and Mistrafficking of the Charcot-Marie-Tooth-Associated Protein PMP22

July 9, 2020

https://www.jbc.org/content/early/2020/07/09/jbc.AC120.014940

https://www.ncbi.nlm.nih.gov/pubmed/32647009?dopt=Abstract

Direct Relationship Between Increased Expression and Mistrafficking of the Charcot-Marie-Tooth-Associated Protein PMP22.

J Biol Chem. 2020 Jul 09;:

Authors: Marinko JT, Carter BD, Sanders CR

Abstract

Charcot-Marie-Tooth disease (CMT) is a neuropathy of the peripheral nervous system that afflicts ~1:2500 people. The most common form of this disease (CMT1A, 1:4000) is associated with duplication of chromosome fragment 17p11.2-12, which results in a third wild-type PMP22 allele. In rodent models overexpressing the peripheral myelin protein 22 (PMP22) protein and in dermal fibroblasts from patients with CMT1A, PMP22 aggregates have been observed. This suggests that overexpression of PMP22 under CMT1A conditions overwhelms the endoplasmic reticulum (ER) quality control, leading to formation of cytotoxic aggregates. In this work, we used a single-cell flow-cytometry trafficking assay to quantitatively examine the relationship between PMP22 expression and trafficking efficiency in individual cells. We observed that as expression of wild-type or disease variants of PMP22 is increased, the amount of intracellular PMP22 increases to a greater extent than the amount of surface-trafficked protein. This was true for both transiently transfected cells as well as PMP22 stable expressing cells. Our results support the notion that overexpression of PMP22 in CMT1A leads to a disproportionate increase in misfolding and mis-trafficking of PMP22, which is likely a contributor to disease pathology and progression.

PMID: 32647009 [PubMed – as supplied by publisher]

PubMed:32647009

Marinko JT, Carter BD, Sanders CR

A novel HSPB1 mutation associated with a late onset CMT2 phenotype: Case presentation and systematic review

July 8, 2020

https://onlinelibrary.wiley.com/doi/abs/10.1111/jns.12395

https://www.ncbi.nlm.nih.gov/pubmed/32639100?dopt=Abstract

A novel HSPB1 mutation associated with a late onset CMT2 phenotype: Case presentation and systematic review of the literature.

J Peripher Nerv Syst. 2020 Jul 08;:

Authors: Taga A, Cornblath DR

Abstract

Mutations in the HSPB1 gene are associated with Charcot-Marie-Tooth (CMT) disease type 2F (CMT2F) and distal hereditary motor neuropathy type 2 (dHMN2). More than 18 pathogenic mutations spanning across the whole HSPB1 gene have been reported. Three family members with a novel p.P57S (c.169C>T) HSPB1 mutation resulting in a late onset axonal neuropathy with heterogeneous clinical and electrophysiological features are detailed. We systematically reviewed published case reports and case series on HSPB1 mutations. While a genotype-phenotype correlation was not obvious, we identified a common phenotype, which included adult onset, male predominance, motor more frequently than sensory involvement, distal and symmetric distribution with preferential involvement of plantar flexors, and a motor and axonal electrophysiological picture.

PMID: 32639100 [PubMed – as supplied by publisher]

PubMed:32639100

Taga A, Cornblath DR

DTx Pharma Study Discovers Multiple Therapeutic Candidates for CMT1A

July 1, 2020

DTx Pharma Study Discovers Multiple Therapeutic Candidates for CMT1A

DTx Pharma Study Discovers Multiple Therapeutic Candidates for CMT1A

Transient, Recurrent Central Nervous System Clinical Manifestations of X-Linked Charcot-Marie-Tooth Disease (CMTX1): Is Prolonged Sun Exposure a Provoking Factor?

June 27, 2020

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336214/

https://www.hindawi.com/journals/crinm/2020/9753139/

https://www.ncbi.nlm.nih.gov/pubmed/32685222?dopt=Abstract

Transient, Recurrent Central Nervous System Clinical Manifestations of X-Linked Charcot-Marie-Tooth Disease Presenting with Very Long Latency Periods between Episodes: Is Prolonged Sun Exposure a Provoking Factor?

Case Rep Neurol Med. 2020;2020:9753139

Authors: Tziakouri A, Natsiopoulos K, Kleopa KA, Michaelides C

Abstract

Charcot-Marie-Tooth disease is one of the most common inherited neurological disorders affecting the peripheral nervous system. The common clinical manifestations of the disease are distal muscle weakness and atrophy, often associated with a characteristic steppage gait and foot deformities. Transient acute and recurrent or chronic central nervous system manifestations, predominantly, dysarthria, dysphagia, motor weakness, and ataxia, have been recognized as a feature of the X-linked type 1 of CMT (CMTX1). The CNS symptoms occur typically in young age and often precede the clinical manifestation of the polyneuropathy. Several predisposing factors such as exercise, fever, and returning from areas of high altitude have been described as triggers of the CNS symptoms; however, in many cases, a substantial cause remains undetermined. In this report, we describe a patient with three attacks of transient CNS deficits at the ages of 11, 21, and 38 years, respectively, which were also accompanied by transient white matter abnormalities on MRI. Two of the attacks occurred after prolonged exposure to sunlight. In our knowledge, this is the first documented case with such long latency periods between CNS attacks as well as the only report describing intense sun exposure as a possible provoking factor.

PMID: 32685222 [PubMed]

PubMed:32685222

Tziakouri A, Natsiopoulos K, Kleopa KA, Michaelides C

Optimized Protocol to Generate Spinal Motor Neuron Cells from Induced Pluripotent Stem Cells from Charcot Marie Tooth Patients

June 27, 2020

https://www.mdpi.com/2076-3425/10/7/407

https://www.ncbi.nlm.nih.gov/pubmed/32605002?dopt=Abstract

Optimized Protocol to Generate Spinal Motor Neuron Cells from Induced Pluripotent Stem Cells from Charcot Marie Tooth Patients.

Brain Sci. 2020 Jun 27;10(7):

Authors: Faye PA, Vedrenne N, Miressi F, Rassat M, Romanenko S, Richard L, Bourthoumieu S, Funalot B, Sturtz F, Favreau F, Lia AS

Abstract

Modelling rare neurogenetic diseases to develop new therapeutic strategies is highly challenging. The use of human-induced pluripotent stem cells (hiPSCs) is a powerful approach to obtain specialized cells from patients. For hereditary peripheral neuropathies, such as Charcot-Marie-Tooth disease (CMT) Type II, spinal motor neurons (MNs) are impaired but are very difficult to study. Although several protocols are available to differentiate hiPSCs into neurons, their efficiency is still poor for CMT patients. Thus, our goal was to develop a robust, easy, and reproducible protocol to obtain MNs from CMT patient hiPSCs. The presented protocol generates MNs within 20 days, with a success rate of 80%, using specifically chosen molecules, such as Sonic Hedgehog or retinoic acid. The timing and concentrations of the factors used to induce differentiation are crucial and are given hereby. We then assessed the MNs by optic microscopy, immunocytochemistry (Islet1/2, HB9, Tuj1, and PGP9.5), and electrophysiological recordings. This method of generating MNs from CMT patients in vitro shows promise for the further development of assays to understand the pathological mechanisms of CMT and for drug screening.

PMID: 32605002 [PubMed]

PubMed:32605002

Faye PA, Vedrenne N, Miressi F, Rassat M, Romanenko S, Richard L, Bourthoumieu S, Funalot B, Sturtz F, Favreau F, Lia AS

DTx Pharma Achieves Second Milestone in Study to Advance Treatments for CMT1A

June 26, 2020

DTx Pharma Achieves Second Milestone in Study to Advance Treatments for CMT1A

DTx Pharma Achieves Second Milestone in Study to Advance Treatments for CMT1A

Synergistic PXT3003 therapy uncouples neuromuscular function from dysmyelination in male Charcot-Marie-Tooth disease type 1A (CMT1A) rats

June 26, 2020

https://onlinelibrary.wiley.com/doi/full/10.1002/jnr.24679

https://www.ncbi.nlm.nih.gov/pubmed/32588471?dopt=Abstract

Synergistic PXT3003 therapy uncouples neuromuscular function from dysmyelination in male Charcot-Marie-Tooth disease type 1A (CMT1A) rats.

J Neurosci Res. 2020 Jun 26;:

Authors: Prukop T, Wernick S, Boussicault L, Ewers D, Jäger K, Adam J, Winter L, Quintes S, Linhoff L, Barrantes-Freer A, Bartl M, Czesnik D, Zschüntzsch J, Schmidt J, Primas G, Laffaire J, Rinaudo P, Brureau A, Nabirotchkin S, Schwab MH, Nave KA, Hajj R, Cohen D, Sereda MW

Abstract

Charcot-Marie-Tooth disease 1 A (CMT1A) is caused by an intrachromosomal duplication of the gene encoding for PMP22 leading to peripheral nerve dysmyelination, axonal loss, and progressive muscle weakness. No therapy is available. PXT3003 is a low-dose combination of baclofen, naltrexone, and sorbitol which has been shown to improve disease symptoms in Pmp22 transgenic rats, a bona fide model of CMT1A disease. However, the superiority of PXT3003 over its single components or dual combinations have not been tested. Here, we show that in a dorsal root ganglion (DRG) co-culture system derived from transgenic rats, PXT3003 induced myelination when compared to its single and dual components. Applying a clinically relevant (“translational”) study design in adult male CMT1A rats for 3 months, PXT3003, but not its dual components, resulted in improved performance in behavioral motor and sensory endpoints when compared to placebo. Unexpectedly, we observed only a marginally increased number of myelinated axons in nerves from PXT3003-treated CMT1A rats. However, in electrophysiology, motor latencies correlated with increased grip strength indicating a possible effect of PXT3003 on neuromuscular junctions (NMJs) and muscle fiber pathology. Indeed, PXT3003-treated CMT1A rats displayed an increased perimeter of individual NMJs and a larger number of functional NMJs. Moreover, muscles of PXT3003 CMT1A rats displayed less neurogenic atrophy and a shift toward fast contracting muscle fibers. We suggest that ameliorated motor function in PXT3003-treated CMT1A rats result from restored NMJ function and muscle innervation, independent from myelination.

PMID: 32588471 [PubMed – as supplied by publisher]

PubMed:32588471

Prukop T, Wernick S, Boussicault L, Ewers D, Jäger K, Adam J, Winter L, Quintes S, Linhoff L, Barrantes-Freer A, Bartl M, Czesnik D, Zschüntzsch J, Schmidt J, Primas G, Laffaire J, Rinaudo P, Brureau A, Nabirotchkin S, Schwab MH, Nave KA, Hajj R, Cohen D, Sereda MW

Pharnext Provides Regulatory and Clinical Update on PXT3003 Phase III Study for the Treatment of Charcot-Marie-Tooth Type 1A

June 10, 2020

https://ca.news.yahoo.com/pharnext-provides-regulatory-clinical-pxt3003-051500112.html

https://www.pharnext.com/images/PDF/press_releases/2020.06.10_Clin_Reg_Update_EN.pdf

https://www.reuters.com/article/brief-pharnext-to-begin-last-pxt3003-pha/brief-pharnext-to-begin-last-pxt3003-phase-iii-study-before-end-q1-21-idUSFWN2DM16J

Pharnext Provides Regulatory and Clinical Update on PXT3003 Phase III Study for the Treatment of Charcot-Marie-Tooth Type 1A

Peripheral myelin protein 22 preferentially partitions into ordered phase membrane domains

June 8, 2020

https://www.pnas.org/content/117/25/14168

https://www.ncbi.nlm.nih.gov/pubmed/32513719?dopt=Abstract

Peripheral myelin protein 22 preferentially partitions into ordered phase membrane domains.

Proc Natl Acad Sci U S A. 2020 Jun 08;:

Authors: Marinko JT, Kenworthy AK, Sanders CR

Abstract

The ordered environment of cholesterol-rich membrane nanodomains is thought to exclude many transmembrane (TM) proteins. Nevertheless, some multispan helical transmembrane proteins have been proposed to partition into these environments. Here, giant plasma membrane vesicles (GPMVs) were employed to quantitatively show that the helical tetraspan peripheral myelin protein 22 (PMP22) exhibits a pronounced preference for, promotes the formation of, and stabilizes ordered membrane domains. Neither S-palmitoylation of PMP22 nor its putative cholesterol binding motifs are required for this preference. In contrast, Charcot-Marie-Tooth disease-causing mutations that disrupt the stability of PMP22 tertiary structure reduce or eliminate this preference in favor of the disordered phase. These studies demonstrate that the ordered phase preference of PMP22 derives from global structural features associated with the folded form of this protein, providing a glimpse at the structural factors that promote raft partitioning for multispan helical membrane proteins.

PMID: 32513719 [PubMed – as supplied by publisher]

PubMed:32513719

Marinko JT, Kenworthy AK, Sanders CR

PMP22 is critical in cholesterol metabolism, and this mechanism is likely a contributing factor in PMP22-linked hereditary neuropathies such as Charcot-Marie-Tooth (CMT)

June 8, 2020

https://onlinelibrary.wiley.com/doi/abs/10.1002/glia.23840

https://www.ncbi.nlm.nih.gov/pubmed/32511821?dopt=Abstract

Subcellular diversion of cholesterol by gain- and loss-of-function mutations in PMP22.

Glia. 2020 Jun 08;:

Authors: Zhou Y, Borchelt D, Bauson JC, Fazio S, Miles JR, Tavori H, Notterpek L

Abstract

Abnormalities of the peripheral myelin protein 22 (PMP22) gene, including duplication, deletion and point mutations are a major culprit in Type 1 Charcot-Marie-Tooth (CMT) diseases. The complete absence of PMP22 alters cholesterol metabolism in Schwann cells, which likely contributes to myelination deficits. Here, we examined the subcellular trafficking of cholesterol in distinct models of PMP22-linked neuropathies. In Schwann cells from homozygous Trembler J (TrJ) mice carrying a Leu16Pro mutation, cholesterol was retained with TrJ-PMP22 in the Golgi, alongside a corresponding reduction in its plasma membrane level. PMP22 overexpression, which models CMT1A caused by gene duplication, triggered cholesterol sequestration to lysosomes, and reduced ATP-binding cassette transporter-dependent cholesterol efflux. Conversely, lysosomal targeting of cholesterol by U18666A treatment increased wild type (WT)-PMP22 levels in lysosomes. Mutagenesis of a cholesterol recognition motif, or CRAC domain, in human PMP22 lead to increased levels of PMP22 in the ER and Golgi compartments, along with higher cytosolic, and lower membrane-associated cholesterol. Importantly, cholesterol trafficking defects observed in PMP22-deficient Schwann cells were rescued by WT but not CRAC-mutant-PMP22. We also observed that myelination deficits in dorsal root ganglia explants from heterozygous PMP22-deficient mice were improved by cholesterol supplementation. Collectively, these findings indicate that PMP22 is critical in cholesterol metabolism, and this mechanism is likely a contributing factor in PMP22-linked hereditary neuropathies. Our results provide a basis for understanding how altered expression of PMP22 impacts cholesterol metabolism.

PMID: 32511821 [PubMed – as supplied by publisher]

PubMed:32511821

Zhou Y, Borchelt D, Bauson JC, Fazio S, Miles JR, Tavori H, Notterpek L

6-phenylhexanamide Derivatives as Therapeutic Agents for Charcot-Marie-Tooth Disease type 2A (CMT2A)

June 8, 2020

https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c00366

https://www.ncbi.nlm.nih.gov/pubmed/32506913?dopt=Abstract

Discovery of 6-Phenylhexanamide Derivatives as Potent Stereoselective Mitofusin Activators for the Treatment of Mitochondrial Diseases.

J Med Chem. 2020 Jun 08;:

Authors: Dang X, Zhang L, Franco A, Li J, Rocha AG, Devanathan S, Dolle RE, Bernstein PR, Dorn Ii GW

Abstract

Mutations in the mitochondrial fusion protein mitofusin (MFN) 2 cause the chronic neurodegenerative condition Charcot-Marie-Tooth Disease type 2A (CMT2A), for which there is currently no treatment. Small molecule activators of MFN1 and MFN2 enhance mitochondrial fusion and offer promise as therapy for this condition, but prototype compounds have poor pharmacokinetic properties. Herein, we describe rational design of a series of 6-phenylhexanamide derivatives whose pharma-cokinetic optimization yielded a 4-hydroxy cyclohexyl analog, 13, with the potency, selectivity, and oral bioavailability of a preclinical candidate. Studies of 13 cis- and trans- 4-hydroxy cyclohexyl isostereomers unexpectedly revealed functionality and protein engagement exclusively for the trans- form, 13B. Preclinical ADME and in vivo target engagement studies of 13B support further development of 6-phenylhexanamide derivatives as therapeutic agents for human CMT2A.

PMID: 32506913 [PubMed – as supplied by publisher]

PubMed:32506913

Dang X, Zhang L, Franco A, Li J, Rocha AG, Devanathan S, Dolle RE, Bernstein PR, Dorn Ii GW

RESEARCH: Pharmacological inhibition of mTORC1 signaling may be viable treatment option for Charcot-Marie-Tooth (CMT) neuropathies

June 5, 2020

https://www.nature.com/articles/s41467-020-16696-6

Rab35-regulated lipid turnover by myotubularins represses mTORC1 activity and controls myelin growth

June 5, 2020

https://www.ncbi.nlm.nih.gov/pubmed/32503983?dopt=Abstract

https://www.nature.com/articles/s41467-020-16696-6

Rab35-regulated lipid turnover by myotubularins represses mTORC1 activity and controls myelin growth.

Nat Commun. 2020 Jun 05;11(1):2835

Authors: Sawade L, Grandi F, Mignanelli M, Patiño-López G, Klinkert K, Langa-Vives F, Di Guardo R, Echard A, Bolino A, Haucke V

In conclusion, our findings suggest an intimate relationship between the synthesis and turnover of PI 3-phosphates mediated by Rab35-associated MTMRs and the activity of late endosomal/lysosomal mTORC1 that crucially controls myelin growth, thereby unraveling a common effector pathway for myelination in the peripheral nervous system. Based on this model it appears that interference with the synthesis of PI 3-phosphates, in particular of PI(3,5)P2 and/or pharmacological perturbation of mTORC1 signaling may represent viable options for the treatment of CMT patients suffering from inherited neuropathies with abnormal myelin growth, e.g. by local administration of mTORC1 or PIKFYVE inhibitors.

Abstract

Inherited peripheral neuropathies (IPNs) represent a broad group of disorders including Charcot-Marie-Tooth (CMT) neuropathies characterized by defects primarily arising in myelin, axons, or both. The molecular mechanisms by which mutations in nearly 100 identified IPN/CMT genes lead to neuropathies are poorly understood. Here we show that the Ras-related GTPase Rab35 controls myelin growth via complex formation with the myotubularin-related phosphatidylinositol (PI) 3-phosphatases MTMR13 and MTMR2, encoded by genes responsible for CMT-types 4B2 and B1 in humans, and found that it downregulates lipid-mediated mTORC1 activation, a pathway known to crucially regulate myelin biogenesis. Targeted disruption of Rab35 leads to hyperactivation of mTORC1 signaling caused by elevated levels of PI 3-phosphates and to focal hypermyelination in vivo. Pharmacological inhibition of phosphatidylinositol 3,5-bisphosphate synthesis or mTORC1 signaling ameliorates this phenotype. These findings reveal a crucial role for Rab35-regulated lipid turnover by myotubularins to repress mTORC1 activity and to control myelin growth.

PMID: 32503983 [PubMed – as supplied by publisher]

PubMed:32503983

Sawade L, Grandi F, Mignanelli M, Patiño-López G, Klinkert K, Langa-Vives F, Di Guardo R, Echard A, Bolino A, Haucke V

Patient-derived motor neurons (MNCMTX6): an excellent neuronal system for compound screening approaches to identify drugs for the treatment of X-linked Charcot-Marie-Tooth (CMTX6)

June 5, 2020

https://www.nature.com/articles/s41598-020-66266-5

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275085/

https://www.ncbi.nlm.nih.gov/pubmed/32504000?dopt=Abstract

Energy metabolism and mitochondrial defects in X-linked Charcot-Marie-Tooth (CMTX6) iPSC-derived motor neurons with the p.R158H PDK3 mutation.

Sci Rep. 2020 Jun 05;10(1):9262

Authors: Perez-Siles G, Cutrupi A, Ellis M, Screnci R, Mao D, Uesugi M, Yiu EM, Ryan MM, Choi BO, Nicholson G, Kennerson ML

Abstract

Charcot-Marie-Tooth (CMT) is a group of inherited diseases clinically and genetically heterogenous, characterised by length dependent degeneration of axons of the peripheral nervous system. A missense mutation (p.R158H) in the pyruvate dehydrogenase kinase 3 gene (PDK3) has been identified as the genetic cause for an X-linked form of CMT (CMTX6) in two unrelated families. PDK3 is one of four PDK isoenzymes that regulate the activity of the pyruvate dehydrogenase complex (PDC). The balance between kinases (PDKs) and phosphatases (PDPs) determines the extend of oxidative decarboxylation of pyruvate to generate acetyl CoA, critically linking glycolysis and the energy producing Krebs cycle. We had shown the p.R158H mutation causes hyperactivity of PDK3 and CMTX6 fibroblasts show hyperphosphorylation of PDC, leading to reduced PDC activity and ATP production. In this manuscript we have generated induced pluripotent stem cells (iPSCs) by re-programming CMTX6 fibroblasts (iPSCCMTX6). We also have engineered an isogenic control (iPSCisogenic) and demonstrated that genetic correction of the p.R158H mutation reverses the CMTX6 phenotype. Patient-derived motor neurons (MNCMTX6) show increased phosphorylation of the PDC, energy metabolism defects and mitochondrial abnormalities, including reduced velocity of trafficking mitochondria in the affected axons. Treatment of the MNCMTX6 with a PDK inhibitor reverses PDC hyperphosphorylation and the associated functional deficits founds in the patient motor neurons, demonstrating that the MNCMTX6 and MNisogenic motor neurons provide an excellent neuronal system for compound screening approaches to identify drugs for the treatment of CMTX6.

PMID: 32504000 [PubMed – as supplied by publisher]

PubMed:32504000

Perez-Siles G, Cutrupi A, Ellis M, Screnci R, Mao D, Uesugi M, Yiu EM, Ryan MM, Choi BO, Nicholson G, Kennerson ML

Sarepta Therapeutics and Dyno Therapeutics Announce Agreement to Develop Next-Generation Gene Therapy Vectors for Muscle Diseases including Charcot-Marie-Tooth

May 11, 2020

https://www.globenewswire.com/news-release/2020/05/11/2030949/0/en/Sarepta-Therapeutics-and-Dyno-Therapeutics-Announce-Agreement-to-Develop-Next-Generation-Gene-Therapy-Vectors-for-Muscle-Diseases.html

Sarepta Therapeutics and Dyno Therapeutics Announce Agreement to Develop Next-Generation Gene Therapy Vectors for Muscle Diseases

Pmp22 Super-enhancer Deletion Causes Tomacula Formation and Conduction Block in Peripheral Nerves

April 30, 2020

https://academic.oup.com/hmg/article-abstract/29/10/1689/5827383?redirectedFrom=fulltext

http://ncbi.nlm.nih.gov/pmc/articles/PMC7322568/

https://www.ncbi.nlm.nih.gov/pubmed/32356557?dopt=Abstract

Pmp22 Super-enhancer Deletion Causes Tomacula Formation and Conduction Block in Peripheral Nerves.

Hum Mol Genet. 2020 Apr 30;:

Authors: Pantera H, Hu B, Moiseev D, Dunham C, Rashid J, Moran JJ, Krentz K, Rubinstein CD, Won S, Li J, Svaren J

Abstract

Copy number variation of the peripheral nerve myelin gene Peripheral Myelin Protein 22 (PMP22) causes multiple forms of inherited peripheral neuropathy. Duplication of a 1.4 Mb segment surrounding this gene in chromosome 17p12 (c17p12) causes the most common form of Charcot-Marie-Tooth disease, CMT type 1A (CMT1A), while the reciprocal deletion of this gene causes a separate neuropathy termed Hereditary Neuropathy with Liability to Pressure Palsies (HNPP). PMP22 is robustly induced in Schwann cells in early postnatal development, and several transcription factors and their cognate regulatory elements have been implicated in coordinating the gene’s proper expression. We previously found that a distal super-enhancer domain was important for Pmp22 expression in vitro, with particular impact on a Schwann cell-specific alternative promoter. Here, we investigate the consequences of deleting this super-enhancer in vivo. We find that loss of the super-enhancer in mice reduces Pmp22 expression throughout development and into adulthood, with greater impact on the Schwann cell-specific promoter. Additionally, these mice display tomacula formed by excessive myelin folding, a pathological hallmark of HNPP, as have been previously observed in heterozygous Pmp22 mice as well as sural biopsies from patients with HNPP. Our findings demonstrate a mechanism by which smaller copy number variations, not including the Pmp22 gene, are sufficient to reduce gene expression and phenocopy a peripheral neuropathy caused by the HNPP-associated deletion encompassing PMP22.

PMID: 32356557 [PubMed – as supplied by publisher]

PubMed:32356557

Pantera H, Hu B, Moiseev D, Dunham C, Rashid J, Moran JJ, Krentz K, Rubinstein CD, Won S, Li J, Svaren J

High glucose level as a modifier factor in CMT1A patients: strict blood sugar control may be a useful measure

April 29, 2020

https://onlinelibrary.wiley.com/doi/abs/10.1111/jns.12379

https://www.ncbi.nlm.nih.gov/pubmed/32347995?dopt=Abstract

High glucose level as a modifier factor in CMT1A patients.

J Peripher Nerv Syst. 2020 Apr 29;:

Authors: Secchin JB, Leal R, Lourenço CM, Marques VD, Toscano P, Cleriston A, Tomaselli P, Marques W

Abstract

BACKGROUND AND AIMS: Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common type of hereditary neuropathy worldwide and diabetes mellitus (DM) is the most frequent cause of peripheral neuropathy in the Western world. CMT1A typically manifest as a predominant motor neuropathy, whilst, DM-related neuropathy often manifests as a predominant sensory disorder. There are some evidences that CMT1A patients that also had DM had a more severe neuropathy. Though the real frequency and the underlying mechanisms related to this association has not yet been addressed in the literature. We sought to characterize the phenotypic variability of CMT1A patients with persistent high glucose levels (DM or impaired glucose tolerance [IGT]).

METHODS: Nineteen patients with CMT1A and DM (CMTdiab), seven with CMT1A and IGT (CMTintol) and 27 with CMT1A without comorbidities were analyzed. They were evaluated through clinical assessment, application of the following scales: visual analogue scale, McGill, CMTNS, SF-36 and COMPASS 31 and electrophysiological studies.

RESULTS: Patients CMTdiab had a more severe motor and sensory neuropathy, more intense autonomic symptoms and worse quality of life. Surprisingly, proximal weakness and temporal dispersion on nerve conduction studies are frequently observed in this group. Patients CMTintol also had a more severe neuropathy. Curiously, we observed that the association of CMT1A and glucose metabolism disorders (CMTglic) clustered in some families.

INTERPRETATION: Patients CMTglic develop a more severe neuropathy. As there is yet no cure to CMT1A, a strict blood sugar control may be a useful measure. This article is protected by copyright. All rights reserved.

PMID: 32347995 [PubMed – as supplied by publisher]

PubMed:32347995

Secchin JB, Leal R, Lourenço CM, Marques VD, Toscano P, Cleriston A, Tomaselli P, Marques W

Small heat shock proteins in neurodegenerative diseases: how mutations in HSPB1, HSPB3, and HSPB8 are linked to inherited peripheral neuropathies like Charcot-Marie-Tooth (CMT) disease

April 22, 2020

https://link.springer.com/article/10.1007/s12192-020-01101-4

https://www.ncbi.nlm.nih.gov/pubmed/32323160?dopt=Abstract

Small heat shock proteins in neurodegenerative diseases.

Cell Stress Chaperones. 2020 Apr 22;:

Authors: Vendredy L, Adriaenssens E, Timmerman V

Abstract

Small heat shock proteins are ubiquitously expressed chaperones, yet mutations in some of them cause tissue-specific diseases. Here, we will discuss how small heat shock proteins give rise to neurodegenerative disorders themselves while we will also highlight how these proteins can fulfil protective functions in neurodegenerative disorders caused by protein aggregation. The first half of this paper will be focused on how mutations in HSPB1, HSPB3, and HSPB8 are linked to inherited peripheral neuropathies like Charcot-Marie-Tooth (CMT) disease and distal hereditary motor neuropathy (dHMN). The second part of the paper will discuss how small heat shock proteins are linked to neurodegenerative disorders like Alzheimer’s, Parkinson’s, and Huntington’s disease.

PMID: 32323160 [PubMed – as supplied by publisher]

PubMed:32323160

Vendredy L, Adriaenssens E, Timmerman V

Genetic spectrum of MCM3AP and its relationship with phenotype of Charcot-Marie-Tooth disease

April 21, 2020

https://onlinelibrary.wiley.com/doi/abs/10.1111/jns.12377

https://www.ncbi.nlm.nih.gov/pubmed/32319184?dopt=Abstract

Genetic spectrum of MCM3AP and its relationship with phenotype of Charcot-Marie-Tooth disease.

J Peripher Nerv Syst. 2020 Apr 21;:

Authors: Dong HL, Wei Q, Li JQ, Li HF, Bai G, Ma H, Wu ZY

Abstract

BACKGROUND AND AIMS: Mutations in MCM3AP have recently been reported to cause autosomal recessive Charcot-Marie-Tooth disease (CMT). However, only 9 CMT families with MCM3AP mutations have been reported and genotype-phenotype correlation remains unclear. This study aimed to investigate the genetic spectrum of MCM3AP and its relationship with phenotype of CMT.

METHODS: Whole exome sequencing (WES) was performed in the family and variants were validated by Sanger sequencing. Reverse transcription-PCR (RT-PCR) were performed in splicing analysis.

RESULTS: We reported a novel splicing variant (c.5634-1G > T) and a known missense variant (c.2633G > A, p.Arg878His). Functional studies showed that c.5634-1G > T led to splicing defect and aberrant transcript eliminated by nonsense-mediated mRNA decay. The symptom of the patient was less severe and slowly progressed with axonal peripheral neuropathy compared to the reported CMT patients. Genotype-phenotype correlation analysis indicated that affected individuals with null mutations presented with delayed independent walking. The percentage of intellectual disability and loss of ambulation in the null group tended to be greater, although this failed to reach statistical significance.

INTERPRETATION: Our findings expand the genetic spectrum of MCM3AP and suggest that genotype-phenotype correlation would help genetic counseling of MCM3AP in CMT patients. This article is protected by copyright. All rights reserved.

PMID: 32319184 [PubMed – as supplied by publisher]

PubMed:32319184

Dong HL, Wei Q, Li JQ, Li HF, Bai G, Ma H, Wu ZY

Charcot-Marie-Tooth Type 2B: A New Phenotype Associated with a Novel RAB7A Mutation and Inhibited EGFR Degradation

April 21, 2020

https://www.mdpi.com/2073-4409/9/4/1028

https://www.ncbi.nlm.nih.gov/pubmed/32326241?dopt=Abstract

Charcot-Marie-Tooth Type 2B: A New Phenotype Associated with a Novel RAB7A Mutation and Inhibited EGFR Degradation.

Cells. 2020 Apr 21;9(4):

Authors: Saveri P, De Luca M, Nisi V, Pisciotta C, Romano R, Piscosquito G, Reilly MM, Polke JM, Cavallaro T, Fabrizi GM, Fossa P, Cichero E, Lombardi R, Lauria G, Magri S, Taroni F, Pareyson D, Bucci C

Abstract

The rare autosomal dominant Charcot-Marie-Tooth type 2B (CMT2B) is associated with mutations in the RAB7A gene, involved in the late endocytic pathway. CMT2B is characterized by predominant sensory loss, ulceromutilating features, with lesser-to-absent motor deficits. We characterized clinically and genetically a family harboring a novel pathogenic RAB7A variant and performed structural and functional analysis of the mutant protein. A 39-year-old woman presented with early-onset walking difficulties, progressive distal muscle wasting and weakness in lower limbs and only mild sensory signs. Electrophysiology demonstrated an axonal sensorimotor neuropathy. Nerve biopsy showed a chronic axonal neuropathy with moderate loss of all caliber myelinated fibers. Next-generation sequencing (NGS) technology revealed in the proband and in her similarly affected father the novel c.377A>G (p.K126R) heterozygous variant predicted to be deleterious. The mutation affects the biochemical properties of RAB7 GTPase, causes altered interaction with peripherin, and inhibition of neurite outgrowth, as for previously reported CMT2B mutants. However, it also shows differences, particularly in the epidermal growth factor receptor degradation process. Altogether, our findings indicate that this RAB7A variant is pathogenic and widens the phenotypic spectrum of CMT2B to include predominantly motor CMT2. Alteration of the receptor degradation process might explain the different clinical presentations in this family.

PMID: 32326241 [PubMed – in process]

PubMed:32326241

Saveri P, De Luca M, Nisi V, Pisciotta C, Romano R, Piscosquito G, Reilly MM, Polke JM, Cavallaro T, Fabrizi GM, Fossa P, Cichero E, Lombardi R, Lauria G, Magri S, Taroni F, Pareyson D, Bucci C

Shift Pharmaceuticals partners with CMT Research Foundation to further research CMT1A treatment

April 18, 2020

Shift Pharmaceuticals partners with CMT Research Foundation to further research CMT1A treatment

Shift Pharmaceuticals partners with CMT Research Foundation to further research CMT1A treatment
April 18, 2020
Steve Oconnor

CMT Research Foundation funds Shift to explore novel series of drugs created to control the expression of PMP22 gene

Conduction Block in Charcot-Marie Tooth Neuropathy Type 4J (230)

April 14, 2020

https://n.neurology.org/content/94/15_Supplement/230

Conduction Block in Charcot-Marie Tooth Neuropathy Type 4J (230)
Jacqueline Li, Mark Stefanelli
First published April 14, 2020,

With $30M Investment, Regenacy Plans Phase 2 Trial Testing Ricolinostat for CMT Type 2

April 3, 2020

With $30M Investment, Regenacy Plans Phase 2 Trial Testing Ricolinostat for CMT Type 2

With $30M Investment, Regenacy Plans Phase 2 Trial Testing Ricolinostat for CMT Type 2

Defective nucleotide-dependent assembly and membrane fusion in Mfn2 CMT2A variants improved by Bax

April 3, 2020

https://www.life-science-alliance.org/content/3/5/e201900527

https://www.ncbi.nlm.nih.gov/pubmed/32245838?dopt=Abstract

Defective nucleotide-dependent assembly and membrane fusion in Mfn2 CMT2A variants improved by Bax.

Life Sci Alliance. 2020 May;3(5):

Authors: Samanas NB, Engelhart EA, Hoppins S

Abstract

Mitofusins are members of the dynamin-related protein family of large GTPases that harness the energy from nucleotide hydrolysis to remodel membranes. Mitofusins possess four structural domains, including a GTPase domain, two extended helical bundles (HB1 and HB2), and a transmembrane region. We have characterized four Charcot-Marie-Tooth type 2A-associated variants with amino acid substitutions in Mfn2 that are proximal to the hinge that connects HB1 and HB2. A functional defect was not apparent in cells as the mitochondrial morphology of Mfn2-null cells was restored by expression of any of these variants. However, a significant fusion deficiency was observed in vitro, which was improved by the addition of crude cytosol extract or soluble Bax. All four variants had reduced nucleotide-dependent assembly in cis, but not trans, and this was also improved by the addition of Bax. Together, our data demonstrate an important role for this region in Mfn2 GTP-dependent oligomerization and membrane fusion and is consistent with a model where cytosolic factors such as Bax are masking molecular defects associated with Mfn2 disease variants in cells.

PMID: 32245838 [PubMed – as supplied by publisher]

PubMed:32245838

Samanas NB, Engelhart EA, Hoppins S

Pharnext Announces PXT3003 for the Treatment of Charcot-Marie-Tooth Disease Type 1A has Been Granted Promising Innovative Medicine (PIM) Designation by UK Medicines and Healthcare Products Regulatory Agency

March 18, 2020

https://finance.yahoo.com/news/pharnext-announces-pxt3003-treatment-charcot-123000576.html

https://www.reuters.com/article/brief-pharnext-says-pxt3003-for-treatmen/brief-pharnext-says-pxt3003-for-treatment-of-charcot-marie-tooth-disease-type-1a-granted-pim-designation-idUSFWN2BB0BP

Pharnext Announces PXT3003 for the Treatment of Charcot-Marie-Tooth Disease Type 1A has Been Granted Promising Innovative Medicine (PIM) Designation by UK Medicines and Healthcare Products Regulatory Agency

Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Charcot-Marie Tooth (CMT) Disease Type 1 (CMT1) and Type X (CMTX) [Terminated]

March 13, 2020

https://clinicaltrials.gov/ct2/show/NCT03943290?type=Intr&cond=Charcot-Marie-Tooth&lupd_s=04%2F25%2F2019&lupd_d=14

Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)

Conditions : Facioscapulohumeral Muscular Dystrophy; Charcot-Marie-Tooth Disease

Intervention : Drug: ACE-083

Sponsor : Acceleron Pharma, Inc.

Recruiting

NCT03943290

Thu, 09 May 2019 12:00:00 EDT

Acceleron Abandons Charcot-Marie-Tooth Program (ACE-083) After Phase II Trial Failure

March 10, 2020

https://www.biospace.com/article/acceleron-s-ace-083-flunks-charcot-marie-tooth-disease-trial/

Acceleron Abandons Charcot-Marie-Tooth Program After Trial Failure

Cambridge, Massachusetts-based Acceleron Pharma announced that its Phase II clinical trial of ACE-083 in patients with Charcot-Marie-Tooth disease (CMT) failed to show functional improvement

HDAC6 inhibition [SW-100] promotes α-tubulin acetylation and ameliorates CMT2A peripheral neuropathy in mice

March 5, 2020

https://pubmed.ncbi.nlm.nih.gov/32147437-hdac6-inhibition-promotes-tubulin-acetylation-and-ameliorates-cmt2a-peripheral-neuropathy-in-mice/?dopt=Abstract

https://www.sciencedirect.com/science/article/abs/pii/S0014488620301126?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/32147437?dopt=Abstract

HDAC6 inhibition promotes α-tubulin acetylation and ameliorates CMT2A peripheral neuropathy in mice.

Exp Neurol. 2020 Mar 05;:113281

Authors: Picci C, Wong VSC, Costa CJ, McKinnon MC, Goldberg DC, Swift M, Alam NM, Prusky GT, Shen S, Kozikowski AP, Willis DE, Langley B

Abstract

Charcot-Marie-Tooth type 2A (CMT2A) peripheral neuropathy, the most common axonal form of CMT, is caused by dominantly inherited point mutations in the Mitofusin 2 (Mfn2) gene. It is characterized by progressive length-dependent degeneration of motor and sensory nerves with corresponding clinical features of motor and sensory impairment. There is no cure for CMT, and therapeutic approaches are limited to physical therapy, orthopedic devices, surgery, and analgesics. In this study we focus on histone deacetylase 6 (HDAC6) as a therapeutic target in a mouse model of mutant MFN2 (MFN2R94Q)-induced CMT2A. We report that these mice display progressive motor and sensory dysfunction as well as a significant decrease in α-tubulin acetylation in distal segments of long peripheral nerves. Treatment with a new, highly selective HDAC6 inhibitor, SW-100, was able to restore α-tubulin acetylation and ameliorate motor and sensory dysfunction when given either prior to or after the onset of symptoms. To confirm HDAC6 is the target for ameliorating the CMT2A phenotype, we show that genetic deletion of Hdac6 in CMT2A mice prevents the development of motor and sensory dysfunction. Our findings suggest α-tubulin acetylation defects in distal parts of nerves as a pathogenic mechanism and HDAC6 as a therapeutic target for CMT2A.

PMID: 32147437 [PubMed – as supplied by publisher]

PubMed:32147437

Picci C, Wong VSC, Costa CJ, McKinnon MC, Goldberg DC, Swift M, Alam NM, Prusky GT, Shen S, Kozikowski AP, Willis DE, Langley B

Novel EGR2 variant that associates with Charcot-Marie-Tooth disease when combined with lipopolysaccharide-induced TNF-α factor T49M polymorphism

March 3, 2020

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164973/

https://www.ncbi.nlm.nih.gov/pubmed/32337334?dopt=Abstract

Novel EGR2 variant that associates with Charcot-Marie-Tooth disease when combined with lipopolysaccharide-induced TNF-α factor T49M polymorphism.

Neurol Genet. 2020 Apr;6(2):e407

Authors: Blanco-Cantó ME, Patel N, Velasco-Aviles S, Casillas-Bajo A, Salas-Felipe J, García-Escrivá A, Díaz-Marín C, Cabedo H

Abstract

Objective: To identify novel genetic mechanisms causing Charcot-Marie-Tooth (CMT) disease.

Methods: We performed a next-generation sequencing study of 34 genes associated with CMT in a patient with peripheral neuropathy.

Results: We found a non-previously described mutation in EGR2 (p.P397H). P397H mutation is located within the loop that connects zinc fingers 2 and 3, a pivotal domain for the activity of this transcription factor. Using promoter activity luciferase assays, we found that this mutation promotes decreased transcriptional activity of EGR2. In this patient, we also found a previously described nonpathogenic polymorphism in lipopolysaccharide-induced TNF-α factor (LITAF) (p.T49M). We show that the p.T49M mutation decreases the steady-state levels of the LITAF protein in Schwann cells. Loss of function of LITAF has been shown to produce deregulation in the NRG1-erbB signaling, a pivotal pathway for EGR2 expression by Schwann cells. Surprisingly, our segregation study demonstrates that p.P397H mutation in EGR2 is not sufficient to produce CMT disease. Most notably, only those patients expressing simultaneously the LITAF T49M polymorphism develop peripheral neuropathy.

Conclusions: Our data support that the LITAF loss-of-function interferes with the expression of the transcriptional-deficient EGR2 P397H mutant hampering Schwann cell differentiation and suggest that in vivo both genes act in tandem to allow the proper development of myelin.

PMID: 32337334 [PubMed]

PubMed:32337334

Blanco-Cantó ME, Patel N, Velasco-Aviles S, Casillas-Bajo A, Salas-Felipe J, García-Escrivá A, Díaz-Marín C, Cabedo H

Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients (PLEO-CMT) (PLEO-CMT) [Completed]

February 27, 2020

https://clinicaltrials.gov/ct2/show/NCT02579759

https://clinicaltrials.gov/ct2/show/NCT02579759?recrs=abdef&type=Intr&cond=Charcot-Marie-Tooth&rank=10

>>> completed

Mutations in Notch ligand Jagged1 (JAG1) cause peripheral nerve disease Charcot-Marie-Tooth disease type 2 (CMT2)

February 17, 2020

https://www.jci.org/articles/view/128152

https://www.ncbi.nlm.nih.gov/pubmed/32065591?dopt=Abstract

Autosomal dominant mutations in the canonical Notch ligand Jagged1 (JAG1) are a cause of the peripheral nerve disease Charcot-Marie-Tooth disease type 2 (CMT2)

Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy.

J Clin Invest. 2020 Feb 17;:

Authors: Sullivan JM, Motley WW, Johnson JO, Aisenberg WH, Marshall KL, Barwick KE, Kong L, Huh JS, Saavedra-Rivera PC, McEntagart MM, Marion MH, Hicklin LA, Modarres H, Baple EL, Farah MH, Zuberi AR, Lutz CM, Gaudet R, Traynor BJ, Crosby AH, Sumner CJ

Abstract

Notch signaling is a highly conserved intercellular pathway with tightly regulated and pleiotropic roles in normal tissue development and homeostasis. Dysregulated Notch signaling has also been implicated in human disease, including multiple forms of cancer, and represents an emerging therapeutic target. Successful development of such therapeutics requires a detailed understanding of potential on-target toxicities. Here, we identify autosomal dominant mutations of the canonical Notch ligand Jagged1 (or JAG1) as a cause of peripheral nerve disease in 2 unrelated families with the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2 (CMT2). Affected individuals in both families exhibited severe vocal fold paresis, a rare feature of peripheral nerve disease that can be life-threatening. Our studies of mutant protein posttranslational modification and localization indicated that the mutations (p.Ser577Arg, p.Ser650Pro) impair protein glycosylation and reduce JAG1 cell surface expression. Mice harboring heterozygous CMT2-associated mutations exhibited mild peripheral neuropathy, and homozygous expression resulted in embryonic lethality by midgestation. Together, our findings highlight a critical role for JAG1 in maintaining peripheral nerve integrity, particularly in the recurrent laryngeal nerve, and provide a basis for the evaluation of peripheral neuropathy as part of the clinical development of Notch pathway-modulating therapeutics.

PMID: 32065591 [PubMed – as supplied by publisher]

PubMed:32065591

Sullivan JM, Motley WW, Johnson JO, Aisenberg WH, Marshall KL, Barwick KE, Kong L, Huh JS, Saavedra-Rivera PC, McEntagart MM, Marion MH, Hicklin LA, Modarres H, Baple EL, Farah MH, Zuberi AR, Lutz CM, Gaudet R, Traynor BJ, Crosby AH, Sumner CJ

Intraepidermal nerve fibre density as biomarker in Charcot-Marie-Tooth disease type 1A

February 12, 2020

https://academic.oup.com/braincomms/article/2/1/fcaa012/5734661

https://www.ncbi.nlm.nih.gov/pubmed/32954280?dopt=Abstract

Intraepidermal nerve fibre density as biomarker in Charcot-Marie-Tooth disease type 1A.

Brain Commun. 2020;2(1):fcaa012

Authors: Hartmannsberger B, Doppler K, Stauber J, Schlotter-Weigel B, Young P, Sereda MW, Sommer C

Abstract

Charcot-Marie-Tooth disease type 1A, caused by a duplication of the gene peripheral myelin protein 22 kDa, is the most frequent subtype of hereditary peripheral neuropathy with an estimated prevalence of 1:5000. Patients suffer from sensory deficits, muscle weakness and foot deformities. There is no treatment approved for this disease. Outcome measures in clinical trials were based mainly on clinical features but did not evaluate the actual nerve damage. In our case-control study, we aimed to provide objective and reproducible outcome measures for future clinical trials. We collected skin samples from 48 patients with Charcot-Marie-Tooth type 1A, 7 patients with chronic inflammatory demyelinating polyneuropathy, 16 patients with small fibre neuropathy and 45 healthy controls. To analyse skin innervation, 40-µm cryosections of glabrous skin taken from the lateral index finger were double-labelled by immunofluorescence. The disease severity of patients with Charcot-Marie-Tooth type 1A was assessed by the Charcot-Marie-Tooth neuropathy version 2 score, which ranged from 3 (mild) to 27 (severe) and correlated with age (P < 0.01, R = 0.4). Intraepidermal nerve fibre density was reduced in patients with Charcot-Marie-Tooth type 1A compared with the healthy control group (P < 0.01) and negatively correlated with disease severity (P < 0.05, R = -0.293). Meissner corpuscle (MC) density correlated negatively with age in patients with Charcot-Marie-Tooth type 1A (P < 0.01, R = -0.45) but not in healthy controls (P = 0.07, R = 0.28). The density of Merkel cells was reduced in patients with Charcot-Marie-Tooth type 1A compared with healthy controls (P < 0.05). Furthermore, in patients with Charcot-Marie-Tooth type 1A, the fraction of denervated Merkel cells was highly increased and correlated with age (P < 0.05, R = 0.37). Analysis of nodes of Ranvier revealed shortened paranodes and a reduced fraction of long nodes in patients compared with healthy controls (both P < 0.001). Langerhans cell density was increased in chronic inflammatory demyelinating polyneuropathy, but not different in Charcot-Marie-Tooth type 1A compared with healthy controls. Our data suggest that intraepidermal nerve fibre density might be used as an outcome measure in Charcot-Marie-Tooth type 1A disease, as it correlates with disease severity. The densities of Meissner corpuscles and Merkel cells might be an additional tool for the evaluation of the disease progression. Analysis of follow-up biopsies will clarify the effects of Charcot-Marie-Tooth type 1A disease progression on cutaneous innervation. PMID: 32954280 [PubMed] PubMed:32954280 Hartmannsberger B, Doppler K, Stauber J, Schlotter-Weigel B, Young P, Sereda MW, Sommer C

Whole exome sequencing establishes diagnosis of Charcot-Marie-Tooth 4J, 1C, and X1 subtypes

February 5, 2020

https://onlinelibrary.wiley.com/doi/full/10.1002/mgg3.1141

https://www.ncbi.nlm.nih.gov/pubmed/32022442?dopt=Abstract

Whole exome sequencing establishes diagnosis of Charcot-Marie-Tooth 4J, 1C, and X1 subtypes.

Mol Genet Genomic Med. 2020 Feb 05;:e1141

Authors: Michaelidou K, Tsiverdis I, Erimaki S, Papadimitriou D, Amoiridis G, Papadimitriou A, Mitsias P, Zaganas I

Abstract

BACKGROUND: Charcot-Marie-Tooth (CMT) hereditary polyneuropathies pose a diagnostic challenge. Our aim here is to describe CMT patients diagnosed by whole exome sequencing (WES) following years of fruitless testing.

METHODS/RESULTS: Three patients with polyneuropathy suspected to be genetic in origin, but not harboring PMP22 gene deletion/duplication, were offered WES. The first patient, a 66-year-old man, had been suffering from progressive weakness and atrophies in the lower and upper extremities for 20 years. Due to ambiguous electrophysiological findings, immune therapies were administered to no avail. Twelve years after PMP22 deletion/duplication testing, WES revealed two pathogenic variants in the FIG4 gene (p.Ile41Thr and p.Phe598fs, respectively), as a cause of CMT 4J. The second patient, a 19-year-old man, had been suffering from hearing and gait impairment since at least his infancy, and recently presented with weakness and dystonia of the lower extremities. In this patient, WES identified the p.Leu122Val LITAF gene variant in heterozygous state, suggesting the diagnosis of CMT 1C, several years after initial genetic analyses. The third patient, a 44-year-old man, presented with progressive weakness and atrophies of the lower and upper extremities since the age of 17 years old. In this patient, WES identified the hemizygous p.Arg164Gln pathogenic variant in the GJB1 gene, establishing the diagnosis of CMT X1, 8 years after testing for PMP22 deletion/duplication.

CONCLUSION: Novel diagnostic techniques, such as WES, offer the possibility to decipher the cause of CMT subtypes, ending the diagnostic Odyssey of the patients and sparing them from unnecessary and potentially harmful treatments.

PMID: 32022442 [PubMed – as supplied by publisher]

PubMed:32022442

Michaelidou K, Tsiverdis I, Erimaki S, Papadimitriou D, Amoiridis G, Papadimitriou A, Mitsias P, Zaganas I

CMT Research Foundation Funds Shift Pharmaceuticals to Advance Search for CMT1A Treatment — Shift to Develop and Analyze Novel Series of Drugs Designed to Control Expression of PMP22 Gene

January 30, 2020

https://cmtrf.org/blog/cmt-research-foundation-funds-shift-pharmaceuticals-to-advance-search-for-cmt1a-treatment/

CMT Research Foundation Funds Shift Pharmaceuticals to Advance Search for CMT1A Treatment

Shift to Develop and Analyze Novel Series of Drugs Designed to Control Expression of PMP22 Gene

Long term AAV2/9-mediated silencing of PMP22 prevents CMT1A disease in rats and validates skin biomarkers as treatment outcome measure [Preprint]

January 30, 2020

https://www.biorxiv.org/content/10.1101/2020.01.29.924605v1.full

Long term AAV2/9-mediated silencing of PMP22 prevents CMT1A disease in rats and validates skin biomarkers as treatment outcome measure
Benoit Gautier, Helene Hajjar, Sylvia Soares, Jade Berthelot, Marie Deck, Scarlette Abbou, Graham Campbell, Claire-Maelle Fovet, Vlad Schütza, Antoine Jouvenel, Cyril Rivat, Michel Zerah, Virginie François Le Ravazet, Caroline Le Guiner, Patrick Aubourg, View ORCID ProfileRobert Fledrich, View ORCID ProfileNicolas Tricaud
doi: https://doi.org/10.1101/2020.01.29.924605

HDAC6 inhibitors: translating genetic and molecular insights into a therapy for axonal CMT

January 30, 2020

https://pubmed.ncbi.nlm.nih.gov/32006555-hdac6-inhibitors-translating-genetic-and-molecular-insights-into-a-therapy-for-axonal-cmt/

https://www.ncbi.nlm.nih.gov/pubmed/32006555?dopt=Abstract

HDAC6 inhibitors: translating genetic and molecular insights into a therapy for axonal CMT.

Brain Res. 2020 Jan 29;:146692

Authors: Rossaert E, Van Den Bosch L

Abstract

Histone deacetylase 6 (HDAC6) plays a central role in various processes that are key for neuronal survival. In this review, we summarize the current evidence related to disease pathways in the axonal form of Charcot-Marie-Tooth disease (CMT) and highlight the role of HDAC6 in these pathways. We hypothesize that HDAC6 might in fact actively contribute to the pathogenesis of certain forms of axonal CMT. HDAC6 plays a deacetylase activity-dependent, negative role in axonal transport and axonal regeneration, which are both processes implicated in axonal CMT. On the other hand, HDAC6 coordinates a protective response during elimination of toxic misfolded proteins, but this is mostly mediated independent of its deacetylase activity. The current mechanistic insights on these functions of HDAC6 in axonal CMT, along with the selective druggability against its deacetylase activity, make the targeting of HDAC6 particularly attractive. We elaborate on the preclinical studies that demonstrated beneficial effects of HDAC6 inhibitors in axonal CMT models and outline possible modes of action. Overall, this overview ultimately provides a rationale for the use of small-molecule HDAC6 inhibitors as a therapeutic strategy for this devastating disease.

PMID: 32006555 [PubMed – as supplied by publisher]

PubMed:32006555

Rossaert E, Van Den Bosch L

Gene Therapies for various forms of Charcot-Marie-Tooth disease (CMT): Available Strategies, Successes to Date, and What to Target Next

January 27, 2020

https://www.sciencedirect.com/science/article/abs/pii/S0006899320300391?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/32001243?dopt=Abstract

Gene Therapies for Axonal Neuropathies: Available Strategies, Successes to Date, and What to Target Next.

Brain Res. 2020 Jan 27;:146683

Authors: Morelli KH, Hatton CL, Harper SQ, Burgess RW

Abstract

Nearly one-hundred loci in the human genome have been associated with different forms of Charcot-Marie-Tooth disease (CMT) and related inherited neuropathies. Despite this wealth of gene targets, treatment options are still extremely limited, and clear “druggable” pathways are not obvious for many of these mutations. However, recent advances in gene therapies are beginning to circumvent this challenge. Each type of CMT is a monogenic disorder, and the cellular targets are usually well-defined and typically include peripheral neurons or Schwann cells. In addition, the genetic mechanism is often also clear, with loss-of-function mutations requiring restoration of gene expression, and gain-of-function or dominant-negative mutations requiring silencing of the mutant allele. These factors combine to make CMT a good target for developing genetic therapies. Here we will review the state of relatively established gene therapy approaches, including viral vector-mediated gene replacement and antisense oligonucleotides for exon skipping, altering splicing, and gene knockdown. We will also describe earlier stage approaches for allele-specific knockdown and CRIPSR/Cas9 gene editing. We will next describe how these various approaches have been deployed in clinical and preclinical studies. Finally, we will evaluate various forms of CMT as candidates for gene therapy based on the current understanding of their genetics, cellular/tissue targets, validated animal models, and availability of patient populations and natural history data.

PMID: 32001243 [PubMed – as supplied by publisher]

PubMed:32001243

Morelli KH, Hatton CL, Harper SQ, Burgess RW

PXT3003 Improves Clinical Outcomes and Stabilizes Disease Progression in CMT1A Patients, Extension Study Shows

January 17, 2020

PXT3003 Improves Clinical Outcomes and Stabilizes Disease Progression in CMT1A Patients, Extension Study Shows

PXT3003 Improves Clinical Outcomes and Stabilizes Disease Progression in CMT1A Patients, Extension Study Shows

InFlectis BioScience Announces Successful Completion of Phase 1 Clinical Trial of Oral IFB-088 — Data supports initiation of Phase 2 trial in Charcot-Marie-Tooth disease

January 7, 2020

http://www.inflectisbioscience.com/wp-content/uploads/2020/01/IB-PR-InFlectis-Phase-1-Final.pdf

Good news for CMT 1A and 1B

InFlectis BioScience Announces Successful Completion of Phase 1 Clinical Trial of Oral IFB-088
Data supports initiation of Phase 2 trial in Charcot-Marie-Tooth disease

Targeting Axon Degeneration – a treatment for all types of CMT?

January 7, 2020

https://cmtrf.org/blog/targeting-axon-degeneration-a-treatment-for-all-types-of-cmt/

Targeting Axon Degeneration – a treatment for all types of CMT?

Pharnext Announces Encouraging Data from Open-Label Phase 3 Extension Study of PXT3003 in Charcot-Marie-Tooth Disease Type 1A (CMT1A)

January 6, 2020

https://www.bloomberg.com/press-releases/2020-01-06/pharnext-announces-encouraging-data-from-open-label-phase-3-extension-study-of-pxt3003-in-charcot-marie-tooth-disease-type-1a

http://s.info.actifin.fr/3706/www/2020/PHARNEXT-CP-20200106-EN.pdf

Pharnext Announces Encouraging Data from Open-Label Phase 3 Extension Study of PXT3003 in Charcot-Marie-Tooth Disease Type 1A (CMT1A)

2019 – A Year of Closing the Gaps in CMT Drug Development

December 31, 2019

https://cmtrf.org/blog/2019-a-year-of-closing-the-gaps-in-cmt-drug-development/

2019 – A Year of Closing the Gaps in CMT Drug Development

Summary of outcome measures for clinical trials in Charcot-Marie-Tooth disease

December 30, 2019

https://www.ncbi.nlm.nih.gov/pubmed/31899213?dopt=Abstract

https://www.sciencedirect.com/science/article/abs/pii/S0006899319306791?via%3Dihub

Are we prepared for clinical trials in Charcot-Marie-Tooth disease?

Brain Res. 2019 Dec 30;:146625

Authors: Rossor AM, Shy ME, Reilly MM

Abstract

There has been considerable progress in developing treatments for Charcot-Marie-Tooth disease with a number of therapies either completing or nearing clinical trials. In the case of CMT1A, the commonest subtype of CMT, there have been more than five randomised, double blind placebo-controlled trials. Although these trials were negative for the primary outcome measure, considerable lessons have been learnt leading to the collection of large prospective natural history data sets with which to inform future trial design as well as the development of new and sensitive outcome measures. In this review we summarise the difficulties of conducting clinical trials in a slowly progressive disease such as CMT1A and the requirement for sensitive, reproducible and clinically relevant outcome measures. We summarise the current array of CMT specific outcome measures subdivided into clinical outcome measures, functional outcome measures, patient reported outcome measures, biomarkers of disease burden and treatment specific biomarkers of target engagement. Although there is now an array of CMT specific outcome measures, which collectively incorporate clinically relevant, sensitive and reproducible outputs, a single outcome measure incorporating all three qualities remains elusive.

PMID: 31899213 [PubMed – as supplied by publisher]

PubMed:31899213

Rossor AM, Shy ME, Reilly MM

The Impact of Charcot-Marie-Tooth Disease in the Real World [Observational Study]

December 24, 2019

https://clinicaltrials.gov/ct2/show/NCT03782883

The Impact of Charcot-Marie-Tooth Disease in the Real World

Study Type : Observational [Patient Registry] Estimated Enrollment : 2000 participants
Observational Model: Ecologic or Community
Time Perspective: Prospective
Target Follow-Up Duration: 30 Months
Official Title: The Impact of Charcot-Marie-Tooth Disease in the Real World
Actual Study Start Date : October 9, 2018
Estimated Primary Completion Date : April 9, 2021
Estimated Study Completion Date : April 9, 2021

CMTRF partners with DTx Pharma to optimize antisense oligonucleotides as a gene therapy for CMT1A

December 20, 2019

https://cmtrf.org/blog/partnership-with-dtx-pharma-to-advance-gene-therapy-development-for-cmt1a/

A new partnership to optimize antisense oligonucleotides as a gene therapy for CMT1A

CMTRF partners with DTx Pharma to optimize antisense oligonucleotides as a gene therapy for CMT1A
Dec 20, 2019 | CMT Research News, CMTRF Funded Research, Gene Therapy, Press Releases, Research news, Therapy Types | 0 comments

ATLANTA (December 20, 2019) The CMT Research Foundation (CMTRF), a nonprofit focused solely on delivering treatments and cures for Charcot-Marie-Tooth, today announced it has partnered with DTx Pharma, an RNA medicines company breaking open new therapeutic areas for oligonucleotide (short DNA or RNA molecules) drugs by overcoming the delivery challenge that has limited the utility of this promising new potential gene therapy for CMT1A.

Identification of novel pathogenic copy number variations in Charcot-Marie-Tooth disease

December 18, 2019

https://www.nature.com/articles/s10038-019-0710-5

https://www.ncbi.nlm.nih.gov/pubmed/31852984?dopt=Abstract

Identification of novel pathogenic copy number variations in Charcot-Marie-Tooth disease.

J Hum Genet. 2019 Dec 18;:

Authors: Mortreux J, Bacquet J, Boyer A, Alazard E, Bellance R, Giguet-Valard AG, Cerino M, Krahn M, Audic F, Chabrol B, Laugel V, Desvignes JP, Béroud C, Nguyen K, Verschueren A, Lévy N, Attarian S, Delague V, Missirian C, Bonello-Palot N

Abstract

Charcot-Marie-Tooth disease (CMT) is a hereditary sensory-motor neuropathy characterized by a strong clinical and genetic heterogeneity. Over the past few years, with the occurrence of whole-exome sequencing (WES) or whole-genome sequencing (WGS), the molecular diagnosis rate has been improved by allowing the screening of more than 80 genes at one time. In CMT, except the recurrent PMP22 duplication accounting for about 60% of pathogenic variations, pathogenic copy number variations (CNVs) are rarely reported and only a few studies screening specifically CNVs have been performed. The aim of the present study was to screen for CNVs in the most prevalent genes associated with CMT in a cohort of 200 patients negative for the PMP22 duplication. CNVs were screened using the Exome Depth software on next generation sequencing (NGS) data obtained by targeted capture and sequencing of a panel of 81 CMT associated genes. Deleterious CNVs were identified in four patients (2%), in four genes: GDAP1, LRSAM1, GAN, and FGD4. All CNVs were confirmed by high-resolution oligonucleotide array Comparative Genomic Hybridization (aCGH) and/or quantitative PCR. By identifying four new CNVs in four different genes, we demonstrate that, although they are rare mutational events in CMT, CNVs might contribute significantly to mutational spectrum of Charcot-Marie-Tooth disease and should be searched in routine NGS diagnosis. This strategy increases the molecular diagnosis rate of patients with neuropathy.

PMID: 31852984 [PubMed – as supplied by publisher]

PubMed:31852984

Mortreux J, Bacquet J, Boyer A, Alazard E, Bellance R, Giguet-Valard AG, Cerino M, Krahn M, Audic F, Chabrol B, Laugel V, Desvignes JP, Béroud C, Nguyen K, Verschueren A, Lévy N, Attarian S, Delague V, Missirian C, Bonello-Palot N

Sporadic de novo EGR2 variant identified as cause of severe early-onset Charcot-Marie-Tooth Neuropathy Type 3 (CMT3), Dejerine-Sottas Neuropathy (DSN)

December 18, 2019

https://www.nature.com/articles/s41598-019-55875-4

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920433/

https://www.ncbi.nlm.nih.gov/pubmed/31852952?dopt=Abstract

EGR2 mutation causes severe early-onset Charcot-Marie-Tooth Neuropathy Type 3 (Dejerine-Sottas Neuropathy).

A de novo EGR2 variant, c.1232A > G p.Asp411Gly, causes severe early-onset Charcot-Marie-Tooth Neuropathy Type 3 (Dejerine-Sottas Neuropathy).

Sci Rep. 2019 Dec 18;9(1):19336

Authors: Grosz BR, Golovchenko NB, Ellis M, Kumar K, Nicholson GA, Antonellis A, Kennerson ML

Abstract

EGR2 (early growth response 2) is a crucial transcription factor for the myelination of the peripheral nervous system. Mutations in EGR2 are reported to cause a heterogenous spectrum of peripheral neuropathy with wide variation in both severity and age of onset, including demyelinating and axonal forms of Charcot-Marie Tooth (CMT) neuropathy, Dejerine-Sottas neuropathy (DSN/CMT3), and congenital hypomyelinating neuropathy (CHN/CMT4E). Here we report a sporadic de novo EGR2 variant, c.1232A > G (NM_000399.5), causing a missense p.Asp411Gly substitution and discovered through whole-exome sequencing (WES) of the proband. The resultant phenotype is severe demyelinating DSN with onset at two years of age, confirmed through nerve biopsy and electrophysiological examination. In silico analyses showed that the Asp411 residue is evolutionarily conserved, and the p.Asp411Gly variant was predicted to be deleterious by multiple in silico analyses. A luciferase-based reporter assay confirmed the reduced ability of p.Asp411Gly EGR2 to activate a PMP22 (peripheral myelin protein 22) enhancer element compared to wild-type EGR2. This study adds further support to the heterogeneity of EGR2-related peripheral neuropathies and provides strong functional evidence for the pathogenicity of the p.Asp411Gly EGR2 variant.

PMID: 31852952 [PubMed – in process]

PubMed:31852952

Grosz BR, Golovchenko NB, Ellis M, Kumar K, Nicholson GA, Antonellis A, Kennerson ML

S1P/S1P Receptor Signaling in Neuromuscolar Disorders: potential druggable targets in Charcot-Marie-Tooth disease

December 17, 2019

https://www.mdpi.com/1422-0067/20/24/6364/htm

https://www.ncbi.nlm.nih.gov/pubmed/31861214?dopt=Abstract

S1P/S1P Receptor Signaling in Neuromuscolar Disorders.

Int J Mol Sci. 2019 Dec 17;20(24):

Authors: Meacci E, Garcia-Gil M

Abstract

The bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P), and the signaling pathways triggered by its binding to specific G protein-coupled receptors play a critical regulatory role in many pathophysiological processes, including skeletal muscle and nervous system degeneration. The signaling transduced by S1P binding appears to be much more complex than previously thought, with important implications for clinical applications and for personalized medicine. In particular, the understanding of S1P/S1P receptor signaling functions in specific compartmentalized locations of the cell is worthy of being better investigated, because in various circumstances it might be crucial for the development or/and the progression of neuromuscular diseases, such as Charcot-Marie-Tooth disease, myasthenia gravis, and Duchenne muscular dystrophy.

PMID: 31861214 [PubMed – in process]

PubMed:31861214

Meacci E, Garcia-Gil M

Novel HDAC6 inhibitors increase tubulin acetylation and rescue axonal transport of mitochondria in a model of Charcot-Marie-Tooth Type 2F

December 17, 2019

https://pubs.acs.org/doi/10.1021/acschemneuro.9b00338

https://www.ncbi.nlm.nih.gov/pubmed/31845794?dopt=Abstract

Novel HDAC6 inhibitors increase tubulin acetylation and rescue axonal transport of mitochondria in a model of Charcot-Marie-Tooth Type 2F.

ACS Chem Neurosci. 2019 Dec 17;:

Authors: Adalbert R, Kaieda A, Antoniou C, Loreto A, Yang X, Gilley J, Hoshino T, Uga K, Makhija MT, Coleman MP

Abstract

Disruption of axonal transport causes a number of rare, inherited axonopathies and is heavily implicated in a wide range of more common neurodegenerative disorders, many of them age-related. Acetylation of α-tubulin is one important regulatory mechanism, influencing microtubule stability and motor protein attachment. Of several strategies so far used to enhance axonal transport, increasing microtubule acetylation through inhibition of the deacetylase enzyme HDAC6 has been one of the most effective. Several inhibitors have been developed and tested in animal and cellular models but better drug candidates are still needed. Here we report the development and characterisation of two highly potent HDAC6 inhibitors, which show low toxicity, promising pharmacokinetic properties, and enhance microtubule acetylation in the nanomolar range. We demonstrate their capacity to rescue axonal transport of mitochondria in a primary neuronal culture model of the inherited axonopathy Charcot-Marie-Tooth Type 2F, caused by a dominantly acting mutation in heat shock protein beta 1.

PMID: 31845794 [PubMed – as supplied by publisher]

PubMed:31845794

Adalbert R, Kaieda A, Antoniou C, Loreto A, Yang X, Gilley J, Hoshino T, Uga K, Makhija MT, Coleman MP

Transmembrane protease serine 5 (TMPRSS5): a novel Schwann cell plasma marker for CMT1A and potential treatment-responsive biomarker with good disease specificity for clinical trials

December 12, 2019

https://onlinelibrary.wiley.com/doi/full/10.1002/acn3.50965

https://www.ncbi.nlm.nih.gov/pubmed/31833243?dopt=Abstract

Transmembrane protease serine 5: a novel Schwann cell plasma marker for CMT1A.

Transmembrane protease serine 5 (TMPRSS5): a novel Schwann cell plasma marker for CMT1A and potential treatment-responsive biomarker with good disease specificity for clinical trials

Ann Clin Transl Neurol. 2019 Dec 12;:

Authors: Wang H, Davison M, Wang K, Xia TH, Kramer M, Call K, Luo J, Wu X, Zuccarino R, Bacon C, Bai Y, Moran JJ, Gutmann L, Feely SME, Grider T, Rossor AM, Reilly MM, Svaren J, Shy ME

Abstract

OBJECTIVE: Development of biomarkers for Charcot-Marie-Tooth (CMT) disease is critical for implementing effective clinical trials. The most common form of CMT, type 1A, is caused by a genomic duplication surrounding the PMP22 gene. A recent report (Neurology 2018;90:e518-3524) showed elevation of neurofilament light (NfL) in plasma of CMT1A disease patients, which correlated with disease severity. However, no plasma/serum biomarker has been identified that is specific to Schwann cells, the most directly affected cells in CMT1A.

METHODS: We used the Olink immuno PCR platform to profile CMT1A patient (n = 47, 2 cohorts) and normal control plasma (n = 41, two cohorts) on five different Olink panels to screen 398 unique proteins.

RESULTS: The TMPRSS5 protein (Transmembrane protease serine 5) was elevated 2.07-fold (P = <0.0001) in two independent cohorts of CMT1A samples relative to controls. TMPRSS5 is most highly expressed in Schwann cells of peripheral nerve. Consistent with early myelination deficits in CMT1A, TMPRSS5 was not significantly correlated with disease score (CMTES-R, CMTNS-R), nerve conduction velocities (Ulnar CMAP, Ulnar MNCV), or with age. TMPRSS5 was not significantly elevated in smaller sample sets from patients with CMT2A, CMT2E, CMT1B, or CMT1X. The Olink immuno PCR assays confirmed elevated levels of NfL (average 1.58-fold, P < 0.0001), which correlated with CMT1A patient disease score. INTERPRETATION: These data identify the first Schwann cell-specific protein that is elevated in plasma of CMT1A patients, and may provide a disease marker and a potentially treatment-responsive biomarker with good disease specificity for clinical trials. PMID: 31833243 [PubMed - as supplied by publisher] PubMed:31833243 Wang H, Davison M, Wang K, Xia TH, Kramer M, Call K, Luo J, Wu X, Zuccarino R, Bacon C, Bai Y, Moran JJ, Gutmann L, Feely SME, Grider T, Rossor AM, Reilly MM, Svaren J, Shy ME

Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease

December 11, 2019

https://n.neurology.org/content/94/1/e51

https://www.ncbi.nlm.nih.gov/pubmed/31827005?dopt=Abstract

Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease.

Neurology. 2019 Dec 11;:

Authors: Cortese A, Wilcox JE, Polke JM, Poh R, Skorupinska M, Rossor AM, Laura M, Tomaselli PJ, Houlden H, Shy ME, Reilly MM

Abstract

OBJECTIVE: To investigate the effectiveness of targeted next-generation sequencing (NGS) panels in achieving a molecular diagnosis in Charcot-Marie-Tooth disease (CMT) and related disorders in a clinical setting.

METHODS: We prospectively enrolled 220 patients from 2 tertiary referral centers, one in London, United Kingdom (n = 120), and one in Iowa (n = 100), in whom a targeted CMT NGS panel had been requested as a diagnostic test. PMP22 duplication/deletion was previously excluded in demyelinating cases. We reviewed the genetic and clinical data upon completion of the diagnostic process.

RESULTS: After targeted NGS sequencing, a definite molecular diagnosis, defined as a pathogenic or likely pathogenic variant, was reached in 30% of cases (n = 67). The diagnostic rate was similar in London (32%) and Iowa (29%). Variants of unknown significance were found in an additional 33% of cases. Mutations in GJB1, MFN2, and MPZ accounted for 39% of cases that received genetic confirmation, while the remainder of positive cases had mutations in diverse genes, including SH3TC2, GDAP1, IGHMBP2, LRSAM1, FDG4, and GARS, and another 12 less common genes. Copy number changes in PMP22, MPZ, MFN2, SH3TC2, and FDG4 were also accurately detected. A definite genetic diagnosis was more likely in cases with an early onset, a positive family history of neuropathy or consanguinity, and a demyelinating neuropathy.

CONCLUSIONS: NGS panels are effective tools in the diagnosis of CMT, leading to genetic confirmation in one-third of cases negative for PMP22 duplication/deletion, thus highlighting how rarer and previously undiagnosed subtypes represent a relevant part of the genetic landscape of CMT.

PMID: 31827005 [PubMed – as supplied by publisher]

PubMed:31827005

Cortese A, Wilcox JE, Polke JM, Poh R, Skorupinska M, Rossor AM, Laura M, Tomaselli PJ, Houlden H, Shy ME, Reilly MM

Gene therapy approaches targeting Schwann cells for demyelinating neuropathies

November 29, 2019

https://www.ncbi.nlm.nih.gov/pubmed/31790684?dopt=Abstract

https://www.sciencedirect.com/science/article/abs/pii/S0006899319306262?via%3Dihub

Gene therapy approaches targeting Schwann cells for demyelinating neuropathies.

Brain Res. 2019 Nov 29;:146572

Authors: Sargiannidou I, Kagiava A, Kleopa KA

Abstract

Charcot-Marie-Tooth disease (CMT) encompasses numerous genetically heterogeneous inherited neuropathies, which together are one of the commonest neurogenetic disorders. Axonal CMT types result from mutations in neuronally expressed genes, whereas demyelinating CMT forms mostly result from mutations in genes expressed by myelinating Schwann cells. The demyelinating forms are the most common, and may be caused by dominant mutations and gene dosage effects (as in CMT1), as well as by recessive mutations and loss of function mechanisms (as in CMT4). The discovery of causative genes and increasing insights into molecular mechanisms through the study of experimental disease models has provided the basis for the development of gene therapy approaches. For demyelinating CMT, gene silencing or gene replacement strategies need to be targeted to Schwann cells. Progress in gene replacement for two different CMT forms, including CMT1X caused by GJB1 gene mutations, and CMT4C, caused by SH3TC2 gene mutations, has been made through the use of a myelin-specific promoter to restrict expression in Schwann cells, and by lumbar intrathecal delivery of lentiviral viral vectors to achieve more widespread biodistribution in the peripheral nervous system. This review summarizes the molecular-genetic mechanisms of selected demyelinating CMT neuropathies and the progress made so far, as well as the remaining challenges in the path towards a gene therapy to treat these disorders through the use of optimal gene therapy tools such as using clinically translatable delivery methods and adeno-associated viral (AAV) vectors.

PMID: 31790684 [PubMed – as supplied by publisher]

PubMed:31790684

Sargiannidou I, Kagiava A, Kleopa KA

Schwann cell-axon interactions are impaired in the pathogenesis of demyelinating Charcot-Marie-Tooth Disease

November 24, 2019

https://link.springer.com/chapter/10.1007%2F978-981-32-9636-7_19

https://www.ncbi.nlm.nih.gov/pubmed/31760652?dopt=Abstract

Schwann Cell and the Pathogenesis of Charcot-Marie-Tooth Disease.

Adv Exp Med Biol. 2019;1190:301-321

Authors: Murakami T, Sunada Y

Abstract

Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy and genetically heterogeneous. CMT1 and CMTX are autosomal dominant and X-linked demyelinating neuropathies, respectively. CMT1A, CMT1B, and CMTX1 are the common forms of CMT, which are attributed to the genes encoding the myelin or gap junction proteins expressed in the myelinating Schwann cells. CMT4 is a rare autosomal recessive demyelinating neuropathy that usually shows an early-onset severe phenotype. Twelve genes have been described as CMT4, which encodes many kinds of proteins including mitochondrial proteins, phosphatases in the endosomal pathway, endocytic recycling proteins, and trafficking proteins. The genes responsible for CMT4 are expressed in Schwan cells and necessary for the development and maintenance in the peripheral nervous system. However, CMT1, CMT4, and CMTX1 are primarily demyelinating neuropathies, axonal degeneration is necessary for symptoms to develop. Schwann cell-axon interactions are impaired in the pathogenesis of demyelinating CMT.

PMID: 31760652 [PubMed – in process]

PubMed:31760652

Murakami T, Sunada Y

New research has demonstrated that a class of cytoplasmic enzymes called tRNA synthetases can cause Charcot-Marie-Tooth disease (CMT) by interfering with gene transcription

November 21, 2019

https://www.sciencedaily.com/releases/2019/11/191121121730.htm

New mechanism of neurodegeneration
Date:
November 21, 2019
Source:
VIB (the Flanders Institute for Biotechnology)
Summary:
Charcot-Marie-Tooth disease (CMT) is an inherited neurodegenerative condition that affects 1 in 2500 individuals. Currently, however, it is still lacking effective treatment options. New research has demonstrated that a class of cytoplasmic enzymes called tRNA synthetases can cause CMT by interfering with the gene transcription in the nucleus.

Charcot-Marie-Tooth type 4B2 demyelinating neuropathy: a new canine clinical model that could reveal the biological mechanisms responsible for the disease

November 21, 2019

https://peerj.com/articles/7983/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875392/

https://www.ncbi.nlm.nih.gov/pubmed/31772832?dopt=Abstract

Charcot-Marie-Tooth type 4B2 demyelinating neuropathy in miniature Schnauzer dogs caused by a novel splicing SBF2 (MTMR13) genetic variant: a new spontaneous clinical model.

PeerJ. 2019;7:e7983

Authors: Granger N, Luján Feliu-Pascual A, Spicer C, Ricketts S, Hitti R, Forman O, Hersheson J, Houlden H

Abstract

Background: Charcot-Marie-Tooth (CMT) disease is the most common neuromuscular disorder in humans affecting 40 out of 100,000 individuals. In 2008, we described the clinical, electrophysiological and pathological findings of a demyelinating motor and sensory neuropathy in Miniature Schnauzer dogs, with a suspected autosomal recessive mode of inheritance based on pedigree analysis. The discovery of additional cases has followed this work and led to a genome-wide association mapping approach to search for the underlying genetic cause of the disease.

Methods: For genome wide association screening, genomic DNA samples from affected and unaffected dogs were genotyped using the Illumina CanineHD SNP genotyping array. SBF2 and its variant were sequenced using primers and PCRs. RNA was extracted from muscle of an unaffected and an affected dog and RT-PCR performed. Immunohistochemistry for myelin basic protein was performed on peripheral nerve section specimens.

Results: The genome-wide association study gave an indicative signal on canine chromosome 21. Although the signal was not of genome-wide significance due to the small number of cases, the SBF2 (also known as MTMR13) gene within the region of shared case homozygosity was a strong positional candidate, as 22 genetic variants in the gene have been associated with demyelinating forms of Charcot-Marie-Tooth disease in humans. Sequencing of SBF2 in cases revealed a splice donor site genetic variant, resulting in cryptic splicing and predicted early termination of the protein based on RNA sequencing results.

Conclusions: This study reports the first genetic variant in Miniature Schnauzer dogs responsible for the occurrence of a demyelinating peripheral neuropathy with abnormally folded myelin. This discovery establishes a genotype/phenotype correlation in affected Miniature Schnauzers that can be used for the diagnosis of these dogs. It further supports the dog as a natural model of a human disease; in this instance, Charcot-Marie-Tooth disease. It opens avenues to search the biological mechanisms responsible for the disease and to test new therapies in a non-rodent large animal model. In particular, recent gene editing methods that led to the restoration of dystrophin expression in a canine model of muscular dystrophy could be applied to other canine models such as this before translation to humans.

PMID: 31772832 [PubMed]

PubMed:31772832

Granger N, Luján Feliu-Pascual A, Spicer C, Ricketts S, Hitti R, Forman O, Hersheson J, Houlden H

The role of small heat shock proteins (sHsps) in human neurodegenerative disorders such as Charcot-Marie-Tooth disease (CMT): a review

November 14, 2019

https://link.springer.com/article/10.1134%2FS000629791911004X

https://www.ncbi.nlm.nih.gov/pubmed/31760916?dopt=Abstract

Small Heat Shock Proteins and Human Neurodegenerative Diseases.

Biochemistry (Mosc). 2019 Nov;84(11):1256-1267

Authors: Muranova LK, Ryzhavskaya AS, Sudnitsyna MV, Shatov VM, Gusev NB

Abstract

The review discusses the role of small heat shock proteins (sHsps) in human neurodegenerative disorders, such as Charcot-Marie-Tooth disease (CMT), Parkinson’s and Alzheimer’s diseases, and different forms of tauopathies. The effects of CMT-associated mutations in two small heat shock proteins (HspB1 and HspB8) on the protein stability, oligomeric structure, and chaperone-like activity are described. Mutations in HspB1 shift the equilibrium between different protein oligomeric forms, leading to the alterations in its chaperone-like activity and interaction with protein partners, which can induce damage of the cytoskeleton and neuronal death. Mutations in HspB8 affect its interaction with the adapter protein Bag3, as well as the process of autophagy, also resulting in neuronal death. The impact of sHsps on different forms of amyloidosis is discussed. Experimental studies have shown that sHsps interact with monomers or small oligomers of amyloidogenic proteins, stabilize their structure, prevent their aggregation, and/or promote their specific proteolytic degradation. This effect might be due to the interaction between the β-strands of sHsps and β-strands of target proteins, which prevents aggregation of the latter. In cooperation with the other heat shock proteins, sHsps can promote disassembly of oligomers formed by amyloidogenic proteins. Despite significant achievements, further investigations are required for understanding the role of sHsps in protection against various neurodegenerative diseases.

PMID: 31760916 [PubMed – in process]

PubMed:31760916

Muranova LK, Ryzhavskaya AS, Sudnitsyna MV, Shatov VM, Gusev NB

Potential treatment path shown for subtype of Charcot-Marie-Tooth disease: A new study could pave the way for developing a viable therapy for CMT patients affected by TyrRS mutations

November 12, 2019

Potential treatment path shown for subtype of Charcot-Marie-Tooth disease

Potential treatment path shown for subtype of Charcot-Marie-Tooth disease
A new study could pave the way for developing a viable therapy for Charcot-Marie-Tooth patients affected by TyrRS mutations.

Targeted PMP22 TATA-box editing by CRISPR/Cas9 reduces demyelinating neuropathy of Charcot-Marie-Tooth disease type 1A in mice

November 12, 2019

https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkz1070/5622709

https://www.ncbi.nlm.nih.gov/pubmed/31713617?dopt=Abstract

Targeted PMP22 TATA-box editing by CRISPR/Cas9 reduces demyelinating neuropathy of Charcot-Marie-Tooth disease type 1A in mice.

Nucleic Acids Res. 2019 Nov 12;:

Authors: Lee JS, Lee JY, Song DW, Bae HS, Doo HM, Yu HS, Lee KJ, Kim HK, Hwang H, Kwak G, Kim D, Kim S, Hong YB, Lee JM, Choi BO

Abstract

Charcot-Marie-Tooth 1A (CMT1A) is the most common inherited neuropathy without a known therapy, which is caused by a 1.4 Mb duplication on human chromosome 17, which includes the gene encoding the peripheral myelin protein of 22 kDa (PMP22). Overexpressed PMP22 protein from its gene duplication is thought to cause demyelination and subsequently axonal degeneration in the peripheral nervous system (PNS). Here, we targeted TATA-box of human PMP22 promoter to normalize overexpressed PMP22 level in C22 mice, a mouse model of CMT1A harboring multiple copies of human PMP22. Direct local intraneural delivery of CRISPR/Cas9 designed to target TATA-box of PMP22 before the onset of disease, downregulates gene expression of PMP22 and preserves both myelin and axons. Notably, the same approach was effective in partial rescue of demyelination even after the onset of disease. Collectively, our data present a proof-of-concept that CRISPR/Cas9-mediated targeting of TATA-box can be utilized to treat CMT1A.

PMID: 31713617 [PubMed – as supplied by publisher]

PubMed:31713617

Lee JS, Lee JY, Song DW, Bae HS, Doo HM, Yu HS, Lee KJ, Kim HK, Hwang H, Kwak G, Kim D, Kim S, Hong YB, Lee JM, Choi BO

For the first time, potential treatment path becomes clear for subtype of Charcot-Marie-Tooth disease

November 6, 2019

https://www.scripps.edu/news-and-events/press-room/2019/20191106-yang-MCT.html

https://www.technologynetworks.com/neuroscience/news/unexpected-finding-could-lead-to-charcot-marie-tooth-treatment-327013

For the first time, potential treatment path becomes clear for subtype of Charcot-Marie-Tooth disease

Scripps Research scientists discover a way to stop a problematic enzyme from wreaking havoc on peripheral nervous system cells.

Transcriptional dysregulation by a nucleus-localized aminoacyl-tRNA synthetase associated with Charcot-Marie-Tooth neuropathy

November 6, 2019

https://www.nature.com/articles/s41467-019-12909-9

Transcriptional dysregulation by a nucleus-localized aminoacyl-tRNA synthetase associated with Charcot-Marie-Tooth neuropathy

These data highlight that this translation factor may contribute to transcriptional regulation in neurons, and suggest a therapeutic strategy for CMT

Targeting the Programmed Axon Degeneration Pathway as a Potential Therapeutic for Charcot-Marie-Tooth Disease

November 2, 2019

https://www.sciencedirect.com/science/article/abs/pii/S0006899319305931?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/31689415?dopt=Abstract

Targeting the Programmed Axon Degeneration Pathway as a Potential Therapeutic for Charcot-Marie-Tooth Disease.

Brain Res. 2019 Nov 02;:146539

Authors: Moss KR, Höke A

Abstract

The programmed axon degeneration pathway has emerged as an important process contributing to the pathogenesis of several neurological diseases. The most crucial events in this pathway include activation of the central executioner SARM1 and NAD+ depletion, which leads to an energetic failure and ultimately axon destruction. Given the prevalence of this pathway, it is not surprising that inhibitory therapies are currently being developed in order to treat multiple neurological diseases with the same therapy. Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of neurological diseases that may also benefit from this therapeutic approach. To evaluate the appropriateness of this strategy, the contribution of the programmed axon degeneration pathway to the pathogenesis of different CMT subtypes is being actively investigated. The subtypes CMT1A, CMT1B and CMT2D are the first to have been examined. Based on the results from these studies and advances in developing therapies to block the programmed axon degeneration pathway, promising therapeutics for CMT are now on the horizon.

PMID: 31689415 [PubMed – as supplied by publisher]

PubMed:31689415

Moss KR, Höke A

Overlapping spectrums: the clinicogenetic commonalities between Charcot-Marie-Tooth and other neurodegenerative diseases aids in the search for necessary therapeutic targets

October 31, 2019

https://www.sciencedirect.com/science/article/abs/pii/S0006899319305864?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/31678418?dopt=Abstract

Overlapping spectrums: the clinicogenetic commonalities between Charcot-Marie-Tooth and other neurodegenerative diseases.

Brain Res. 2019 Oct 31;:146532

Authors: Martin PB, Hicks AN, Holbrook SE, Cox GA

Abstract

Charcot-Marie-Tooth (CMT) disease is a progressive and heterogeneous inherited peripheral neuropathy. A myriad of genetic factors have been identified that contribute to the degeneration of motor and sensory axons in a length-dependent manner. Emerging biological themes underlying disease include defects in axonal trafficking, dysfunction in RNA metabolism and protein homeostasis, as well deficits in the cellular stress response. Moreover, genetic contributions to CMT can have overlap with other neuropathies, motor neuron diseases (MNDs) and neurodegenerative disorders. Recent progress in understanding the molecular biology of CMT and overlapping syndromes aids in the search for necessary therapeutic targets.

PMID: 31678418 [PubMed – as supplied by publisher]

PubMed:31678418

Martin PB, Hicks AN, Holbrook SE, Cox GA

Gene therapy to promote regeneration in Charcot-Marie-Tooth disease

October 24, 2019

https://www.sciencedirect.com/science/article/abs/pii/S0006899319305876?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/31669284?dopt=Abstract

Gene therapy to promote regeneration in Charcot-Marie-Tooth disease.

Brain Res. 2019 Oct 24;:146533

Authors: Sahenk Z, Ak BO

Abstract

The molecular pathogenesis underlying Charcot-Marie-Tooth (CMT) neuropathy subtypes is becoming increasingly variable and identification of common approaches for treatment, independently of the disease causing gene defect, is therefore much desirable. Gene therapy approach from the clinical translational view point is particularly challenging for the most common “demyelinating” CMT1 subtypes, caused by primary Schwann cell genetic defects. Studies have shown that impaired regenerative capacity of distal axons is major contributing factor to distal axonal loss in primary Schwann cell genetic defects and neurotrophin 3 (NT-3) improves impaired regeneration in CMT1 mouse models. This review surveys the evidence supporting the rationale for AAV1.NT-3 surrogate gene therapy to improve nerve regeneration in CMT1A. The translational process, from proof of principal studies to the design of the phase I/IIa trial evaluating scAAV1.tMCK.NTF3 gene therapy for treatment of CMT1A is summarized.

PMID: 31669284 [PubMed – as supplied by publisher]

PubMed:31669284

Sahenk Z, Ak BO

Reduction of oxidative stress may constitute a promising therapeutic strategy for Charcot-Marie-Tooth disease type 2K (CMT2K)

October 23, 2019

https://www.sciencedirect.com/science/article/pii/S0014488619302183?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/31655048?dopt=Abstract

the reduction of oxidative stress may constitute a promising therapeutic strategy for CMT2K

Oxidative stress contributes differentially to the pathophysiology of Charcot-Marie-Tooth disease type 2K.

Exp Neurol. 2019 Oct 23;:113069

Authors: Cassereau J, Chevrollier A, Codron P, Goizet C, Gueguen N, Verny C, Reynier P, Bonneau D, Lenaers G, Procaccio V

Abstract

Charcot-Marie-Tooth (CMT) disease is a common inherited peripheral neuropathy. The CMT2K axonal form is associated with GDAP1 dominant mutations, which according to the affected domain cause a gradient of severity. Indeed, the p.C240Y mutation, located within GDAP1 glutathione S-transferase (GST) domain and associated to a mitochondrial complex I defect, is related to a faster disease progression, compared to other mutations, such as the p.R120W located outside the GST domain. Here, we analysed the pathophysiology of six CMT2K fibroblast cell lines, carrying either the p.C240Y or p.R120W mutations. We show that complex I deficiency leads to a redox potential alteration and a significant reduction of sirtuin 1 (SIRT1) expression, a major deacetylase sensitive to the cellular redox state, and NRF1 the downstream target of SIRT1. In addition, we disclosed that the p.C240Y mutation is associated with a greater mitochondrial oxidative stress than the p.R120W mutation. Moreover, complex I activity is further restored in CMT2K mutant cell lines exposed to resveratrol. Together, these results suggest that the reduction of oxidative stress may constitute a promising therapeutic strategy for CMT2K.

PMID: 31655048 [PubMed – as supplied by publisher]

PubMed:31655048

Cassereau J, Chevrollier A, Codron P, Goizet C, Gueguen N, Verny C, Reynier P, Bonneau D, Lenaers G, Procaccio V

Emerging Landscape of Modifier Genes in CMT

October 21, 2019

https://cmtrf.org/blog/emerging-landscape-of-modifier-genes-in-cmt/

Emerging Landscape of Modifier Genes in CMT

VIDEO: How the CMTRF is changing the landscape of the development of treatments for CMT

October 3, 2019

Next-generation sequencing in Charcot-Marie-Tooth disease: opportunities and challenges

October 3, 2019

https://www.nature.com/articles/s41582-019-0254-5

https://www.ncbi.nlm.nih.gov/pubmed/31582811?dopt=Abstract

Next-generation sequencing in Charcot-Marie-Tooth disease: opportunities and challenges.

Nat Rev Neurol. 2019 Oct 03;:

Authors: Pipis M, Rossor AM, Laura M, Reilly MM

Abstract

Charcot-Marie-Tooth disease and the related disorders hereditary motor neuropathy and hereditary sensory neuropathy, collectively termed CMT, are the commonest group of inherited neuromuscular diseases, and they exhibit wide phenotypic and genetic heterogeneity. CMT is usually characterized by distal muscle atrophy, often with foot deformity, weakness and sensory loss. In the past decade, next-generation sequencing (NGS) technologies have revolutionized genomic medicine and, as these technologies are being applied to clinical practice, they are changing our diagnostic approach to CMT. In this Review, we discuss the application of NGS technologies, including disease-specific gene panels, whole-exome sequencing, whole-genome sequencing (WGS), mitochondrial sequencing and high-throughput transcriptome sequencing, to the diagnosis of CMT. We discuss the growing challenge of variant interpretation and consider how the clinical phenotype can be combined with genetic, bioinformatic and functional evidence to assess the pathogenicity of genetic variants in patients with CMT. WGS has several advantages over the other techniques that we discuss, which include unparalleled coverage of coding, non-coding and intergenic areas of both nuclear and mitochondrial genomes, the ability to identify structural variants and the opportunity to perform genome-wide dense homozygosity mapping. We propose an algorithm for incorporating WGS into the CMT diagnostic pathway.

PMID: 31582811 [PubMed – as supplied by publisher]

PubMed:31582811

Pipis M, Rossor AM, Laura M, Reilly MM

Regulating PMP22 Expression as a Dosage Sensitive Neuropathy Gene

October 3, 2019

https://www.sciencedirect.com/science/article/abs/pii/S0006899319305451?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/31586623?dopt=Abstract

Regulating PMP22 Expression as a Dosage Sensitive Neuropathy Gene.

Brain Res. 2019 Oct 03;:146491

Authors: Pantera H, Shy ME, Svaren J

Abstract

Structural variation in the human genome has emerged as a major cause of disease as genomic data have accumulated. One of the most common structural variants associated with human disease causes the heritable neuropathy known as Charcot-Marie-Tooth (CMT) disease type 1A. This 1.4 Mb duplication causes nearly half of the CMT cases that are genetically diagnosed. The PMP22 gene is highly induced in Schwann cells during development, although its precise role in myelin formation and homeostasis is still under active investigation. The PMP22 gene can be considered as a nucleoprotein complex with enzymatic activity to produce the PMP22 transcript, and the complex is allosterically regulated by transcription factors that respond to intracellular signals and epigenomic modifications. The control of PMP22 transcript levels has been one of the major therapeutic targets of therapy development, and this review summarizes those approaches as well as efforts to characterize the regulation of the PMP22 gene.

PMID: 31586623 [PubMed – as supplied by publisher]

PubMed:31586623

Pantera H, Shy ME, Svaren J

‘Relaxed’ enzymes may be at the root of Charcot-Marie-Tooth disease

October 1, 2019

https://www.sciencedaily.com/releases/2019/10/191001083950.htm

‘Relaxed’ enzymes may be at the root of Charcot-Marie-Tooth disease
Date:
October 1, 2019
Source:
Scripps Research Institute
Summary:
Treatments have been hard to pinpoint for a rare neurological disease called Charcot-Marie-Tooth, in part because so many variations of the condition exist. So far, mutations on more than 90 genes have been positively linked to the disorder; a patient needs just one of those mutations for the disease to emerge. Scientists just moved a step closer to finding a possible root cause.

Charcot-Marie-Tooth Disease Type 2E/1F Mutant Neurofilament Proteins Assemble into Neurofilaments

October 1, 2019

https://onlinelibrary.wiley.com/doi/abs/10.1002/cm.21566

https://www.ncbi.nlm.nih.gov/pubmed/31574566?dopt=Abstract

Charcot-Marie-Tooth Disease Type 2E/1F Mutant Neurofilament Proteins Assemble into Neurofilaments.

Cytoskeleton (Hoboken). 2019 Oct 01;:

Authors: Stone EJ, Uchida A, Brown A

Abstract

Charcot-Marie-Tooth disease type 2E/1F (CMT2E/1F) is a peripheral neuropathy caused by mutations in neurofilament protein L (NFL), which is one of five neurofilament subunit proteins that co-assemble to form neurofilaments in vivo. Prior studies on cultured cells have shown that CMT2E/1F mutations disrupt neurofilament assembly and lead to protein aggregation, suggesting a possible disease mechanism. However, electron microscopy of axons in peripheral nerve biopsies from patients has revealed accumulations of neurofilament polymers of normal appearance and no evidence of protein aggregates. To reconcile these observations, we re-examined the assembly of seven CMT2E/1F NFL mutants in cultured cells. None of the mutants assembled into homopolymers in SW13vim- cells, but P8R, P22S, L268/269P, and P440/441L mutant NFL assembled into heteropolymers in the presence of neurofilament protein M (NFM) alone, and N98S, Q332/333P, and E396/397K mutant NFL assembled in the presence of NFM and peripherin. P8R, P22S, N98S, L268/269P, E396/397K and P440/441L mutant NFL co-assembled into neurofilaments with endogenous NFL, NFM, and α-internexin in cultured neurons, though the N98S and E396/397K mutants showed reduced filament incorporation, and the Q332/333P mutant showed limited incorporation. We conclude that all the mutants are capable of assembling into neurofilaments but for some of the mutants this was dependent on the identity of the other neurofilament proteins available for co-assembly, and most likely also their relative expression level. Thus, caution should be exercised when drawing conclusions about the assembly capacity of CMT2E/1F mutants based on transient transfections in cultured cells. This article is protected by copyright. All rights reserved.

PMID: 31574566 [PubMed – as supplied by publisher]

PubMed:31574566

Stone EJ, Uchida A, Brown A

Analysis of Pain and Quality of Life in Patients With Charcot-Marie-Tooth Neuropathy (CMT) [Observational Study]

September 27, 2019

https://clinicaltrials.gov/ct2/show/NCT03966287

Analysis of Pain and Quality of Life in Patients With Charcot-Marie-Tooth Neuropathy (CMT)

Study Type : Observational
Estimated Enrollment : 200 participants
Observational Model: Cohort
Time Perspective: Retrospective
Official Title: Analysis of Pain and Quality of Life in Patients With Charcot-Marie-Tooth Neuropathy (CMT)
Actual Study Start Date : June 3, 2019
Estimated Primary Completion Date : November 30, 2019
Estimated Study Completion Date : December 31, 2019

Allele-specific RNA interference prevents neuropathy in Charcot-Marie-Tooth disease type 2D mouse models

September 26, 2019

https://www.jci.org/articles/view/130600

https://www.ncbi.nlm.nih.gov/pubmed/31557132?dopt=Abstract

Efficacy of allele-specific RNAi as a potential therapeutic for Charcot-Marie-Tooth type 2D (CMT2D)

Allele-specific RNA interference prevents neuropathy in Charcot-Marie-Tooth disease type 2D mouse models.

J Clin Invest. 2019 Sep 26;:

Authors: Morelli KH, Griffin LB, Pyne NK, Wallace LM, Fowler AM, Oprescu SN, Takase R, Wei N, Meyer-Schuman R, Mellacheruvu D, Kitzman JO, Kocen SG, Hines TJ, Spaulding EL, Lupski JR, Nesvizhskii A, Mancias P, Butler IJ, Yang XL, Hou YM, Antonellis A, Harper SQ, Burgess RW

Abstract

Gene therapy approaches are being deployed to treat recessive genetic disorders by restoring the expression of mutated genes. However, the feasibility of these approaches for dominantly-inherited diseases-where treatment may require reduction in the expression of a toxic mutant protein resulting from a gain-of-function (GoF) allele-is unclear. Here we show the efficacy of allele-specific RNAi as a potential therapeutic for Charcot-Marie-Tooth type 2D (CMT2D), caused by dominant mutations in glycyl tRNA-synthetase (GARS). A de novo mutation in GARS was identified in a patient with a severe peripheral neuropathy, and a mouse model precisely recreating the mutation was produced. These mice developed a neuropathy by 3-4 weeks-of-age, validating the pathogenicity of the mutation. RNAi sequences targeting mutant GARS mRNA, but not wild-type, were optimized and then packaged into AAV9 for in vivo delivery. This almost completely prevented the neuropathy in mice treated at birth. Delaying treatment until after disease onset showed modest benefit, though this effect decreased the longer treatment was delayed. These outcomes were reproduced in a second mouse model of CMT2D using a vector specifically targeting that allele. The effects were dose dependent, and persisted for at least one year. Our findings demonstrate the feasibility of AAV9-mediated allele-specific knockdown and provide proof-of-concept for gene therapy approaches for dominant neuromuscular diseases.

PMID: 31557132 [PubMed – as supplied by publisher]

PubMed:31557132

Morelli KH, Griffin LB, Pyne NK, Wallace LM, Fowler AM, Oprescu SN, Takase R, Wei N, Meyer-Schuman R, Mellacheruvu D, Kitzman JO, Kocen SG, Hines TJ, Spaulding EL, Lupski JR, Nesvizhskii A, Mancias P, Butler IJ, Yang XL, Hou YM, Antonellis A, Harper SQ, Burgess RW

A Registered Cohort Study on Charcot-Marie-Tooth Disease in China [Observational Study]

September 23, 2019

https://clinicaltrials.gov/ct2/show/NCT04010188

Study Type : Observational [Patient Registry] Estimated Enrollment : 500 participants
Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 20 Years
Official Title: A Registered Observational Cohort Study of Charcot-Marie-Tooth Disease
Actual Study Start Date : July 1, 2019
Estimated Primary Completion Date : December 31, 2039
Estimated Study Completion Date : December 31, 2049

Assessing Long Term Safety and Tolerability of PXT3003 in Patients With Charcot-Marie-Tooth Disease Type 1A (PLEO-CMT-FU)

September 19, 2019

https://clinicaltrials.gov/ct2/show/NCT03023540

CMTRF/AcuraStem Partnership Yields First Significant Milestone in Search for CMT Cure

September 18, 2019

https://cmtrf.org/blog/cmtrf-acurastem-partnership-yields-first-significant-milestone-in-search-for-cmt-cure/

CMTRF/AcuraStem Partnership Yields First Significant Milestone in Search for CMT Cure

Newly identified genetic modifiers and risk genes may offer alternative targets for pharmacotherapy of Charcot-Marie-Tooth (CMT)

September 13, 2019

https://www.ncbi.nlm.nih.gov/pubmed/31525351?dopt=Abstract

https://www.sciencedirect.com/science/article/abs/pii/S000689931930513X?via%3Dihub

Genetic Modifiers and Non-Mendelian Aspects of CMT.

Brain Res. 2019 Sep 13;:146459

Authors: Bis-Brewer DM, Fazal S, Züchner S

Abstract

Charcot-Marie-Tooth (CMT) neuropathies are amongst the most common inherited diseases in neurology. While great strides have been made to identify the genesis of these diseases, a diagnostic gap of 30-60% remains. Classic models of genetic causation may be limited to fully close this gap and, thus, we review the current state and future role of alternative, non-Mendelian forms of genetics in CMT. Promising synergies exist to further define the full genetic architecture of inherited neuropathies, including affordable whole-genome sequencing, increased data aggregation and clinical collaboration, improved bioinformatics and statistical methodology, and vastly improved computational resources. Given the recent advances in genetic therapies for rare diseases, it becomes a matter of urgency to diagnose CMT patients with great fidelity. Otherwise, they will not be able to benefit from such therapeutic options, or worse, suffer harm when pathogenicity of genetic variation is falsely evaluated. In addition, the newly identified modifier and risk genes may offer alternative targets for pharmacotherapy of inherited and, potentially, even acquired forms of neuropathies.

PMID: 31525351 [PubMed – as supplied by publisher]

PubMed:31525351

Bis-Brewer DM, Fazal S, Züchner S

Roadblocks on the Road to Curing Charcot-Marie-Tooth (CMT)

September 11, 2019

https://cmtrf.org/blog/roadblocks-on-the-road-to-curing-charcot-marie-tooth-cmt/

Roadblocks on the Road to Curing Charcot-Marie-Tooth (CMT)

Passage Bio Licenses Gene Therapy Candidate for CMT2A from Penn, Days after Raising $110M

September 9, 2019

Passage Bio Licenses Gene Therapy Candidate for CMT2A from Penn, Days after Raising $110M

Passage Bio Licenses Gene Therapy Candidate for CMT2A from Penn, Days after Raising $110M

CMT disease severity correlates with mutation-induced open conformation of histidyl-tRNA synthetase, not aminoacylation loss, in patient cells

September 9, 2019

https://www.pnas.org/content/early/2019/09/06/1908288116

https://www.ncbi.nlm.nih.gov/pubmed/31501329?dopt=Abstract

CMT disease severity correlates with mutation-induced open conformation of histidyl-tRNA synthetase, not aminoacylation loss, in patient cells.

Proc Natl Acad Sci U S A. 2019 Sep 09;:

Authors: Blocquel D, Sun L, Matuszek Z, Li S, Weber T, Kuhle B, Kooi G, Wei N, Baets J, Pan T, Schimmel P, Yang XL

Abstract

Aminoacyl-transfer RNA (tRNA) synthetases (aaRSs) are the largest protein family causatively linked to neurodegenerative Charcot-Marie-Tooth (CMT) disease. Dominant mutations cause the disease, and studies of CMT disease-causing mutant glycyl-tRNA synthetase (GlyRS) and tyrosyl-tRNA synthetase (TyrRS) showed their mutations create neomorphic structures consistent with a gain-of-function mechanism. In contrast, based on a haploid yeast model, loss of aminoacylation function was reported for CMT disease mutants in histidyl-tRNA synthetase (HisRS). However, neither that nor prior work of any CMT disease-causing aaRS investigated the aminoacylation status of tRNAs in the cellular milieu of actual patients. Using an assay that interrogated aminoacylation levels in patient cells, we investigated a HisRS-linked CMT disease family with the most severe disease phenotype. Strikingly, no difference in charged tRNA levels between normal and diseased family members was found. In confirmation, recombinant versions of 4 other HisRS CMT disease-causing mutants showed no correlation between activity loss in vitro and severity of phenotype in vivo. Indeed, a mutation having the most detrimental impact on activity was associated with a mild disease phenotype. In further work, using 3 independent biophysical analyses, structural opening (relaxation) of mutant HisRSs at the dimer interface best correlated with disease severity. In fact, the HisRS mutation in the severely afflicted patient family caused the largest degree of structural relaxation. These data suggest that HisRS-linked CMT disease arises from open conformation-induced mechanisms distinct from loss of aminoacylation.

PMID: 31501329 [PubMed – as supplied by publisher]

PubMed:31501329

Blocquel D, Sun L, Matuszek Z, Li S, Weber T, Kuhle B, Kooi G, Wei N, Baets J, Pan T, Schimmel P, Yang XL

Charcot-Marie-Tooth and multiple sclerosis associated with a variant in MCM3AP

September 3, 2019

https://academic.oup.com/braincomms/advance-article/doi/10.1093/braincomms/fcz011/5559499

Charcot-Marie-Tooth and multiple sclerosis associated with a variant in MCM3AP

Recessive Charcot-Marie-Tooth and multiple sclerosis associated with a variant in MCM3AP

September 3, 2019

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425404/

https://www.ncbi.nlm.nih.gov/pubmed/32954258?dopt=Abstract

Recessive Charcot-Marie-Tooth and multiple sclerosis associated with a variant in MCM3AP.

Brain Commun. 2019;1(1):fcz011

Authors: Sedghi M, Moslemi AR, Cabrera-Serrano M, Ansari B, Ghasemi M, Baktashian M, Fattahpour A, Tajsharghi H

Abstract

Variants in MCM3AP, encoding the germinal-centre associated nuclear protein, have been associated with progressive polyneuropathy with or without intellectual disability and ptosis in some cases, and with a complex phenotype with immunodeficiency, skin changes and myelodysplasia. MCM3AP encoded protein functions as an acetyltransferase that acetylates the replication protein, MCM3, and plays a key role in the regulation of DNA replication. In this study, we report a novel variant in MCM3AP (p.Ile954Thr), in a family including three affected individuals with characteristic features of Charcot-Marie-Tooth neuropathy and multiple sclerosis, an inflammatory condition of the central nervous system without known genetic cause. The affected individuals were homozygous for a missense MCM3AP variant, located at the Sac3 domain, which was predicted to affect conserved amino acid likely important for the function of the germinal-centre associated nuclear protein. Our data support further expansion of the clinical spectrum linked to MCM3AP variant and highlight that MCM3AP should be considered in patients with accompaniment of recessive motor axonal Charcot-Marie-Tooth neuropathy and multiple sclerosis.

PMID: 32954258 [PubMed]

PubMed:32954258

Sedghi M, Moslemi AR, Cabrera-Serrano M, Ansari B, Ghasemi M, Baktashian M, Fattahpour A, Tajsharghi H

CMT1A Research Update

September 2, 2019

https://cmtrf.org/blog/cmt1a-research-update/

CMT1A Research Update

Pharnext Provides U.S. Regulatory Update on PLEODRUG(TM) PXT3003 in Charcot-Marie-Tooth Disease Type 1A

August 30, 2019

https://www.accesswire.com/557983/Pharnext-Provides-US-Regulatory-Update-on-PLEODRUGTM-PXT3003-in-C

https://www.bloomberg.com/press-releases/2019-08-30/pharnext-provides-u-s-regulatory-update-on-pleodrug-tm-pxt3003-in-charcot-marie-tooth-disease-type-1a-jzxqnoe7

Pharnext Provides U.S. Regulatory Update on PLEODRUG(TM) PXT3003 in Charcot-Marie-Tooth Disease Type 1A

Nerve size correlates with clinical severity in CMT1A

August 29, 2019

https://onlinelibrary.wiley.com/doi/abs/10.1002/mus.26688

https://www.ncbi.nlm.nih.gov/pubmed/31469427?dopt=Abstract

Nerve size correlates with clinical severity in CMT1A.

Muscle Nerve. 2019 Aug 30;:

Authors: Zanette G, Tamburin S, Taioli F, Lauriola MF, Badari A, Ferrarini M, Cavallaro T, Fabrizi GM

Abstract

INTRODUCTION: Nerve cross sectional area (CSA) is larger than normal in Charcot-Marie-Tooth disease 1A (CMT1A), although to a variable extent. We explored whether CSA is correlated with CMT clinical severity measured with neuropathy score version 2 (CMTNS2) and its examination subscore (CMTES2) in CMT1A.

METHODS: We assessed 56 CMT1A patients (42 families). They underwent nerve conduction study (NCS) and nerve high-resolution ultrasound (HRUS) of the left median, ulnar and fibular nerves.

RESULTS: Univariate analysis showed NCS and HRUS variables to be significantly correlated with CMTNS2 and CMTES2 and with each other. Multivariate analysis showed ulnar motor nerve conduction velocity (β: -0.19) and fibular compound muscle action potential amplitude (-1.50) to significantly influence CMTNS2 and median forearm CSA to significantly influence CMTNS2 (β: 5.29) and CMTES2 (4.28).

DISCUSSION: Nerve size is significantly associated with clinical scores in CMT1A, suggesting it might represent a potential biomarker of CMT damage and progression. This article is protected by copyright. All rights reserved.

PMID: 31469427 [PubMed – as supplied by publisher]

PubMed:31469427

Zanette G, Tamburin S, Taioli F, Lauriola MF, Badari A, Ferrarini M, Cavallaro T, Fabrizi GM

MiR-29a and/or PMP22-targeting siRNAs as potential therapeutic agents in Charcot-Marie-Tooth disease

August 27, 2019

https://www.nature.com/articles/s41434-019-0098-z

https://www.ncbi.nlm.nih.gov/pubmed/31455873?dopt=Abstract

miR-29a and/or PMP22-targeting siRNAs as therapeutic agents for correcting the aberrant expression of PMP22 in Charcot-Marie-Tooth disease patients

Downregulation of the human peripheral myelin protein 22 gene by miR-29a in cellular models of Charcot-Marie-Tooth disease.

Gene Ther. 2019 Aug 27;:

Authors: Serfecz J, Bazick H, Al Salihi MO, Turner P, Fields C, Cruz P, Renne R, Notterpek L

Abstract

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

PMID: 31455873 [PubMed – as supplied by publisher]

PubMed:31455873

Serfecz J, Bazick H, Al Salihi MO, Turner P, Fields C, Cruz P, Renne R, Notterpek L

De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy

August 22, 2019

https://jmg.bmj.com/content/early/2019/08/22/jmedgenet-2019-106273

https://www.ncbi.nlm.nih.gov/pubmed/31439721?dopt=Abstract

De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy.

J Med Genet. 2019 Aug 22;:

Authors: Park J, Flores BR, Scherer K, Kuepper H, Rossi M, Rupprich K, Rautenberg M, Deininger N, Weichselbaum A, Grimm A, Sturm M, Grasshoff U, Delpire E, Haack TB

Abstract

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous disorder of the peripheral nervous system. Biallelic variants in SLC12A6 have been associated with autosomal-recessive hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC). We identified heterozygous de novo variants in SLC12A6 in three unrelated patients with intermediate CMT.

METHODS: We evaluated the clinical reports and electrophysiological data of three patients carrying de novo variants in SLC12A6 identified by diagnostic trio exome sequencing. For functional characterisation of the identified variants, potassium influx of mutated KCC3 cotransporters was measured in Xenopus oocytes.

RESULTS: We identified two different de novo missense changes (p.Arg207His and p.Tyr679Cys) in SLC12A6 in three unrelated individuals with early-onset progressive CMT. All presented with axonal/demyelinating sensorimotor neuropathy accompanied by spasticity in one patient. Cognition and brain MRI were normal. Modelling of the mutant KCC3 cotransporter in Xenopus oocytes showed a significant reduction in potassium influx for both changes.

CONCLUSION: Our findings expand the genotypic and phenotypic spectrum associated with SLC12A6 variants from autosomal-recessive HMSN/ACC to dominant-acting de novo variants causing a milder clinical presentation with early-onset neuropathy.

PMID: 31439721 [PubMed – as supplied by publisher]

PubMed:31439721

Park J, Flores BR, Scherer K, Kuepper H, Rossi M, Rupprich K, Rautenberg M, Deininger N, Weichselbaum A, Grimm A, Sturm M, Grasshoff U, Delpire E, Haack TB

Novel mutation in the periaxin gene causal to Charcot-Marie-Tooth disease type 4F

August 20, 2019

https://www.ncbi.nlm.nih.gov/pubmed/31426691?dopt=Abstract

Novel mutation in the periaxin gene causal to Charcot-Marie-Tooth disease type 4F.

J Int Med Res. 2019 Aug 20;:300060519862064

Authors: Chen YH, Zhang H, Meng LB, Tang XY, Gong T, Yin J

PMID: 31426691 [PubMed – as supplied by publisher]

PubMed:31426691

Chen YH, Zhang H, Meng LB, Tang XY, Gong T, Yin J

Peripheral myelin protein 2 – a novel cluster of mutations causing Charcot-Marie-Tooth neuropathy

August 14, 2019

https://www.ncbi.nlm.nih.gov/pubmed/31412900?dopt=Abstract

Peripheral myelin protein 2 – a novel cluster of mutations causing Charcot-Marie-Tooth neuropathy.

Orphanet J Rare Dis. 2019 Aug 14;14(1):197

Authors: Palaima P, Chamova T, Jander S, Mitev V, Van Broeckhoven C, Tournev I, Peeters K, Jordanova A

Abstract

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder characterized by wide clinical, genetic and pathomechanistic heterogeneity. Recently, the gene encoding peripheral myelin protein 2 (PMP2) was identified as a novel cause for CMT neuropathy with three mutations that structurally cluster together (p.Ile43Asn, p.Thr51Pro, p.Ile52Thr) reported in five families.

RESULTS: Using whole exome sequencing and cohort screening we identified two novel missense substitutions in PMP2 in Bulgarian (p.Met114Thr, c.341C > T) and German (p.Val115Ala, c.344 T > C) families. The mutations affect adjacent and highly conserved amino acid residues outside of the known mutation-rich region in the protein. Crystal structure analysis positions the affected residues within a cluster of highly conserved fatty acid coordinating residues implying their functional significance. The clinical, electrophysiological and imaging features in both families were consistent with a childhood onset polyneuropathy with variable patterns of demyelination, slow to very slow progression, and most severe involvement of the peroneal muscles.

CONCLUSIONS: We expand the genetic and phenotypic spectrum of PMP2-related peripheral neuropathy. Our findings reveal a second mutational cluster in the protein.

PMID: 31412900 [PubMed – in process]

PubMed:31412900

Palaima P, Chamova T, Jander S, Mitev V, Van Broeckhoven C, Tournev I, Peeters K, Jordanova A

Gene replacement therapy after neuropathy onset provides therapeutic benefit in a model of CMT1X

August 14, 2019

https://academic.oup.com/hmg/advance-article-abstract/doi/10.1093/hmg/ddz199/5549642?redirectedFrom=fulltext

https://www.ncbi.nlm.nih.gov/pubmed/31411673?dopt=Abstract

Gene replacement therapy after neuropathy onset provides therapeutic benefit in a model of CMT1X.

Hum Mol Genet. 2019 Aug 14;:

Authors: Kagiava A, Richter J, Tryfonos C, Karaiskos C, Heslegrave AJ, Sargiannidou I, Rossor AM, Zetterberg H, Reilly MM, Christodoulou C, Kleopa KA

Abstract

X-linked Charcot-Marie-Tooth disease (CMT1X), one of the commonest forms of inherited demyelinating neuropathy, results from GJB1 gene mutations causing loss of function of the gap junction protein connexin32 (Cx32). The aim of this study was to examine whether delayed gene replacement therapy after the onset of peripheral neuropathy can provide a therapeutic benefit in the Gjb1-null/Cx32 knockout (KO) model of CMT1X. After delivery of the LV-Mpz.GJB1 lentiviral vector by a single lumbar intrathecal injection into 6-month old Gjb1-null mice we confirmed expression of Cx32 in lumbar roots and sciatic nerves correctly localized at the paranodal myelin areas. Gjb1-null mice treated with LV-Mpz.GJB1 compared to LV-Mpz.Egfp (mock) vector at the age of 6 months showed improved motor performance at 8 and 10 months. Furthermore, treated mice showed increased sciatic nerve conduction velocities, improvement of myelination and reduced inflammation in lumbar roots and peripheral nerves at 10 months of age, along with enhanced quadriceps muscle innervation. Plasma neurofilament light (NEFL) levels, a clinically relevant biomarker, were also ameliorated in fully treated mice. Intrathecal gene delivery after the onset of peripheral neuropathy offers a significant therapeutic benefit in this disease model, providing a proof of principle for treating patients with CMT1X at different ages.

PMID: 31411673 [PubMed – as supplied by publisher]

PubMed:31411673

Kagiava A, Richter J, Tryfonos C, Karaiskos C, Heslegrave AJ, Sargiannidou I, Rossor AM, Zetterberg H, Reilly MM, Christodoulou C, Kleopa KA

ATP1A1 mutations cause intermediate Charcot-Marie-Tooth disease

August 2, 2019

https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.23886

https://www.ncbi.nlm.nih.gov/pubmed/31373411?dopt=Abstract

ATP1A1 mutations cause intermediate Charcot-Marie-Tooth disease.

Hum Mutat. 2019 Aug 02;:

Authors: He J, Guo L, Lin S, Chen W, Xu G, Cai B, Xu L, Hong J, Qiu L, Wang N, Chen W

Abstract

Intermediate Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of inherited neuropathies characterized by progressive muscle weakness and atrophy of the distal extremities, distal sensory loss. There were still a large proportion of causative genes for intermediate CMT failed to be identified. Here, using whole-exome sequencing technique, we identified two novel missense mutations in ATP1A1 gene, c.620C>T (p.S207F) and c.2629G>A (p.G877S), in two Chinese CMT families. Further functional analysis revealed that these mutations led to loss function of the ATP1A1 protein. The two mutations did not affect the levels of mRNA but possessed a damaging effect on ATP1A1 protein expression and they downregulated the protein levels of ATP1A1 by promoting its proteasome degradation. Taken together, we confirmed ATP1A1 as a novel causative gene for intermediate CMT. This article is protected by copyright. All rights reserved.

PMID: 31373411 [PubMed – as supplied by publisher]

PubMed:31373411

He J, Guo L, Lin S, Chen W, Xu G, Cai B, Xu L, Hong J, Qiu L, Wang N, Chen W

CMT Research Foundation: CMT1B project is funded & ready for take off!

August 2, 2019

https://cmtrf.org/blog/cmt1b-is-underway/

CMT1B project is funded & ready for take off!

PMP22 gene: A special association between Charcot-Marie-Tooth type 1A disease and relapsing remitting multiple sclerosis

July 22, 2019

https://www.msard-journal.com/article/S2211-0348(19)30308-6/fulltext

https://www.ncbi.nlm.nih.gov/pubmed/31352181?dopt=Abstract

A special association between Charcot-Marie-Tooth type 1A disease and relapsing remitting multiple sclerosis.

Mult Scler Relat Disord. 2019 Jul 22;35:83-85

Authors: Doğan Y, Gül Ş, Ceylan AC, Kutsal YG

Abstract

BACKGROUND: Central nervous system involvement has been reported in different subtypes of Charcot-Marie-Tooth (CMT) diseases. The increasing number of cases with CMT and MS may provide further information about the common pathway of demyelination and MS pathogenesis.

CASE PRESENTATION: We report the case of a 21-year-old woman with CMT1A and MS. Bilateral rest and intention tremor, steroid associated psychotic episodes, and severe disability at an early age were unexpected aspects of this case.

CONCLUSION: PMP22, the target protein in CMT1A, shares partial homology with other CNS proteins. PMP22 gene might be relevant to a common pathway of the demyelinating process.

PMID: 31352181 [PubMed – as supplied by publisher]

PubMed:31352181

Doğan Y, Gül Ş, Ceylan AC, Kutsal YG

Neurogene Initiates Natural History Study of Charcot-Marie Tooth Disease (CMT4J) – Key data now being collected to support endpoint assessment for future gene therapy clinical trial

July 18, 2019

https://www.businesswire.com/news/home/20190718005061/en/Neurogene-Initiates-Natural-History-Study-Charcot-Marie-Tooth

Neurogene Initiates Natural History Study of Charcot-Marie Tooth Disease (CMT4J)
Key data now being collected to support endpoint assessment for future gene therapy clinical trial

Charcot-Marie-Tooth: From Molecules to Therapy

July 12, 2019

https://www.mdpi.com/1422-0067/20/14/3419

https://www.ncbi.nlm.nih.gov/pubmed/31336816?dopt=Abstract

Charcot-Marie-Tooth: From Molecules to Therapy.

Int J Mol Sci. 2019 Jul 12;20(14):

Authors: Morena J, Gupta A, Hoyle JC

Abstract

Charcot-Marie-Tooth (CMT) is the most prevalent category of inherited neuropathy. The most common inheritance pattern is autosomal dominant, though there also are X-linked and autosomal recessive subtypes. In addition to a variety of inheritance patterns, there are a myriad of genes associated with CMT, reflecting the heterogeneity of this disorder. Next generation sequencing (NGS) has expanded and simplified the diagnostic yield of genes/molecules underlying and/or associated with CMT, which is of paramount importance in providing a substrate for current and future targeted disease-modifying treatment options. Considerable research attention for disease-modifying therapy has been geared towards the most commonly encountered genetic mutations (PMP22, GJB1, MPZ, and MFN2). In this review, we highlight the clinical background, molecular understanding, and therapeutic investigations of these CMT subtypes, while also discussing therapeutic research pertinent to the remaining less common CMT subtypes.

PMID: 31336816 [PubMed – in process]

PubMed:31336816

Morena J, Gupta A, Hoyle JC

Is “Disease-In-A-Dish” in Combination with Animal Models A Faster Track to a Cure for CMT?

July 1, 2019

https://cmtrf.org/blog/is-disease-in-a-dish-in-combination-with-animal-models-a-faster-track-to-a-cure-for-cmt/

Is “Disease-In-A-Dish” in Combination with Animal Models A Faster Track to a Cure for CMT?

Neuroinflammation in the pathogenesis of axonal Charcot-Marie-Tooth disease caused by lack of GDAP1

July 1, 2019

https://www.sciencedirect.com/science/article/pii/S0014488618304291?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/31271761?dopt=Abstract

Neuroinflammation in the pathogenesis of axonal Charcot-Marie-Tooth disease caused by lack of GDAP1.

Exp Neurol. 2019 Jul 01;:113004

Authors: Fernandez-Lizarbe S, Civera-Tregón A, Cantarero L, Herrer I, Juarez P, Hoenicka J, Palau F

Abstract

Mutations in the GDAP1 mitochondrial outer membrane gene cause Charcot-Marie-. Tooth (CMT) neuropathy. Reduction or absence of GDAP1 has been associated with abnormal changes in the mitochondrial morphology and dynamics, oxidative stress and changes in calcium homeostasis. Neuroinflammation has been described in rodent models of genetic demyelinating CMT neuropathies but not in CMT primarily associated with axonopathy. Inflammatory processes have also been related to mitochondrial changes and oxidative stress in central neurodegenerative disorders. Here we investigated the presence of neuroinflammation in the axonal neuropathy of the Gdap1-/- mice. We showed by transcriptome profile of spinal cord and the in vivo detection of activated phagocytes that the absence of GDAP1 is associated with upregulation of inflammatory pathways. We observed reactive gliosis in spinal cord with increase of the astroglia markers GFAP and S100B, and the microglia marker IBA1. Additionally, we found significant increase of inflammatory mediators such as TNF-α and pERK, and C1qa and C1qb proteins of the complement system. Importantly, we observed an increased expression of CD206 and CD86 as M2 and M1 microglia and macrophage response markers, respectively, in Gdap1-/- mice. These inflammatory changes were also associated with abnormal molecular changes in synapses. In summary, we demonstrate that inflammation in spinal cord and sciatic nerve, but not in brain and cerebellum, is part of the pathophysiology of axonal GDAP1-related CMT.

PMID: 31271761 [PubMed – as supplied by publisher]

PubMed:31271761

Fernandez-Lizarbe S, Civera-Tregón A, Cantarero L, Herrer I, Juarez P, Hoenicka J, Palau F

New Grants will Accelerate Clinical Trials in Rare Neurological Disorders such as Charcot-Marie-Tooth

June 26, 2019

https://www.urmc.rochester.edu/news/story/5555/new-grants-will-accelerate-clinical-trials-in-rare-neurological-disorders.aspx

New Grants will Accelerate Clinical Trials in Rare Neurological Disorders