RARE DISEASE
Charcot-Marie-Tooth disease type 2S
Charcot-Marie-Tooth disease type 2S
Charcot-Marie-Tooth disease type 2S
Synonyms: CMT2S
Synonyms: CMT2S
Synonyms: CMT2S
Drug discovery
1
drug
With orphan designation
Overview
Charcot-Marie-Tooth disease type 2S (CMT2S) is a rare autosomal recessive axonal neuropathy caused by biallelic IGHMBP2 mutations. It presents with progressive distal muscle weakness/atrophy (lower > upper limbs), reduced/absent deep tendon reflexes, mild sensory loss, foot deformities (pes cavus), and delayed motor milestones in some cases\ [1][5][20]. Respiratory involvement may occur in severe variants overlapping with spinal muscular atrophy\ [9][14]. Electrophysiology shows axonal damage\ [5][9].
Burden
Progressive disability: 38% develop wheelchair dependence by adulthood\ [9]
Respiratory risks: Diaphragmatic weakness in 14% of cases requiring monitoring\ [5][20]
Diagnostic delays: Median 5-7 years due to phenotypic variability\ [9][12]
Multisystem impact: Scoliosis (20%), autonomic dysfunction, and quality-of-life impairment\ [1][12]
Therapies
Symptomatic management: Physiotherapy, ankle-foot orthoses (AFOs), and occupational therapy to maintain mobility\ [7][16]
Pain control: NSAIDs for musculoskeletal pain; TCAs/anticonvulsants for neuropathic pain\ [7]
Genetic counseling: Critical due to 25% recurrence risk in siblings\ [20]
Experimental: Antisense oligonucleotide (ASO) therapy targeting NEFL mutations shows preclinical promise\ [3][19]
Categories: rare genetic diseases, rare neurological diseases
Research Papers
23 drug discovery papers about Charcot-Marie-Tooth disease type 2S, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
23 drug discovery papers about Charcot-Marie-Tooth disease type 2S, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-05-19 | Neuromuscular junction dysfunction in a subset of Charcot-Marie Tooth and related peripheral neuropathies mouse models.
Charcot-Marie Tooth (CMT) disease is a clinically and genetically heterogeneous inherited peripheral neuropathy for which there is no treatment. CMT patients often present with weakness, fatigue, and muscle atrophy in the distal limbs. Improving function at the neuromuscular junction (NMJ) may improve function in some CMT patients. Using mouse models, we investigated eight CMT subtypes for NMJ phenotypes by morphology and functional deficits assessed by electromyography (EMG). We did not find NMJ abnormalities in mice with mutations in Gjb1Y/Δ2 (CMT1X), or Yars1E196K/E196K (diCMTC). Mice with mutations in Ighmbp2Y918S/Y918S (CMT2S) and Pla2g6M1J/M1J (Infantile Neuroaxonal Dystrophy) have neuromuscular phenotypes that could imply NMJ dysfunction, but we did not find defects in synaptic transmission or anatomy. A transgenic model of PMP22 overexpression (CMT1A) had EMG deficits with high frequency stimulation that are consistent with NMJ involvement. Three models showed indications of altered NMJ morphology and/or function. Gars+/ΔETAQ mice, modeling CMT2D, displayed robust synaptic deficits morphologically and by EMG. Nadk2S330P/S330P mice, modeling an ultrarare neuromuscular disease, had an EMG phenotype coinciding with symptom onset. Nefl+/N98S mice, modeling CMT2E, had normal EMG; but pre-synaptic axon terminals were dysmorphic, with large varicosities, which were more pronounced in proximal muscles. Across multiple models, we found that the extensor digitorum longus was resistant to disease phenotypes based on NMJ innervation status and/or muscle weight and atrophy. Our results indicate that some subtypes of CMT have NMJ deficits, and that assessing neuromuscular disease patients for NMJ dysfunction may reveal a population that could benefit from therapies that enhance transmission.
2016-07-19 | Glutamate signals through mGluR2 to control Schwann cell differentiation and proliferation
Rapid saltatory nerve conduction is facilitated by myelin structure, which is produced by Schwann cells (SC) in the peripheral nervous system (PNS). Proper development and degeneration/regeneration after injury requires regulated phenotypic changes of SC. We have previously shown that glutamate can induce SC proliferation in culture. Here we show that glutamate signals through metabotropic glutamate receptor 2 (mGluR2) to induce Erk phosphorylation in SC. mGluR2-elicited Erk phosphorylation requires ErbB2/3 receptor tyrosine kinase phosphorylation to limit the signaling cascade that promotes phosphorylation of Erk, but not Akt. We found that Gβγ and Src are involved in subcellular signaling downstream of mGluR2. We also found that glutamate can transform myelinating SC to proliferating SC, while inhibition of mGluR2 signaling can inhibit demyelination of injured nerves in vivo. These data suggest pathophysiological significance of mGluR2 signaling in PNS and its possible therapeutic importance to combat demyelinating disorders including Charcot-Marie-Tooth disease.
gene therapies
2026-01-01 | AAV9 gene therapy optimization for SMARD1/CMT2S: safety and long-term efficacy comparison of two vectors in a SMARD1 preclinical model
Abstract Background Mutations in the Immunoglobulin Mu DNA Binding Protein 2 (IGHMBP2) gene cause Spinal Muscular Atrophy with Respiratory Distress type 1 (SMARD1), a rare, infantile, and fatal motor neuron disease, as well as the milder Charcot-Marie-Tooth disease type 2S (CMT2S). Gene therapy has emerged as a promising approach to correcting IGHMBP2 loss in SMARD1 models, but critical challenges remain. Methods In this study, we compared the efficacy of two novel, optimized adeno-associated virus 9 (AAV9)-IGHMBP2 vectors, utilizing either the Chicken β-Actin (CBA) or a truncated form of the methyl-CpG-binding protein 2 (MeCP2) promoter (P546), in the SMARD1 murine model via intracerebroventricular delivery. Treated mice survival, histopathological and molecular profile were analyzed. Results Corroborating previous findings, both constructs effectively rescued the pathological phenotype, significantly improving survival, body weight, and motor function while preserving motor neurons and neuromuscular junctions. Notably, histopathological and RNA sequencing analyses revealed, for the first time, inflammatory marker alterations in the SMARD1 spinal cord, which resolved following treatment. A comparative analysis of the two vectors demonstrated superior long-term efficacy of the P546-promoter construct. Conclusion ICV gene therapy approach can effectively rescue SMARD1 pathological hallmarks, including astrogliosis and microgliosis. Moreover, P546-promoter construct is superior in terms of safety profile and long-term therapeutic efficacy. Graphical abstract
2025-11-24 | The Ighmbp2-R604X mouse presents with the most severe SMARD1 clinical symptoms resulting in failure to thrive, respiratory and feeding deficits, aspiration and severe axon and muscle pathology.
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) and Charcot Marie Tooth type 2S (CMT2S) are due to mutations in immunoglobulin mu binding protein two (IGHMBP2). We generated the Ighmbp2-R604X mouse (R605X-humans) to understand how alterations in IGHMBP2 function impact disease pathology. The IGHMBP2-R605X mutation is associated with patients with SMARD1 or CMT2S. The impact of this mutation is substantial, Ighmbp2R604X/R604X mice have a decreased lifespan (6 days) and weight, and failure to thrive consistent with SMARD1 symptoms. Significant respiratory changes were present along with disease pathology of the phrenic nerve and diaphragm muscle fibers. Ighmbp2R604X/R604X mice also presented with signs of milk aspiration and lung pathology. Interestingly, P0 Ighmbp2R604X/R604X mice had visible milk spots, but demonstrated reduction of the milk spot by P3, indicating deficits in suckling. Alterations in hindlimb electrophysiology were consistent with the pathology of the sciatic nerve, hindlimb neuromuscular junction and muscle. Injection of the ssAAV9-WT-IGHMBP2 vector extended Ighmbp2R604X/R604X survival a few days. Ighmbp2R604X/R604X phenotypes are consistent with the most severe SMARD1 clinical symptoms and for the first time a Ighmbp2 mouse model demonstrates that milk aspiration and loss of the ability to suckle impact survival.
2025-09-05 | The Ighmbp2 -R604X mouse recapitulates the severe SMARD1 clinical symptoms of aspiration, respiratory and feeding deficits.
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) and Charcot Marie Tooth type 2S (CMT2S) are due to mutations in immunoglobulin mu binding protein two (IGHMBP2). We generated the Ighmbp2 -R604X mouse (R605X-humans) to understand how alterations in IGHMBP2 function impact disease pathology. The IGHMBP2-R605X mutation is associated with patients with SMARD1 or CMT2S. The impact of this mutation is substantial, Ighmbp2 R604X/R604X mice have a decreased lifespan (6 days) and weight, and failure to thrive consistent with SMARD1 symptoms. Significant respiratory changes were present along with disease pathology of the phrenic nerve and diaphragm muscle fibers. Ighmbp2 R604X/R604X mice also presented with signs of milk aspiration and lung pathology. Interestingly, Ighmbp2 R604X/R604X mice were born with visible milk spots, but demonstrated reduction of the milk spot by P3, indicating deficits in suckling. Alterations in hindlimb electrophysiology were consistent with the sciatic nerve, hindlimb neuromuscular junction and muscle pathology. Injection of the ssAAV9-WT- IGHMBP2 vector extended Ighmbp2 R604X/R604X survival a few days, due to reduced expression of the vector before death ensued. Ighmbp2 R604X/R604X phenotypes are consistent with the most severe SMARD1 clinical symptoms and for the first time a Ighmbp2 mouse model demonstrates that milk aspiration and loss of the ability to suckle impact survival.
2025-08-30 | Genotypic and Phenotypic Characterization of Axonal Charcot-Marie-Tooth Disease in Childhood: Identification of One Novel and Four Known Mutations.
Background: Charcot-Marie-Tooth disease (CMT) is a genetically and phenotypically heterogeneous hereditary neuropathy. Axonal CMT type 2 (CMT2) subtypes often exhibit overlapping clinical features, which makes molecular genetic analysis essential for accurate diagnosis and subtype differentiation. Methods: This retrospective study included five pediatric patients who presented with gait disturbance, muscle weakness, and foot deformities and were subsequently diagnosed with axonal forms of CMT. Clinical data, electrophysiological studies, neuroimaging, and genetic analyses were evaluated. Whole exome sequencing (WES) was performed in three sporadic cases, while targeted CMT gene panel testing was used for two siblings. Variants were interpreted using ACMG guidelines, supported by public databases (ClinVar, HGMD, and VarSome), and confirmed by Sanger sequencing when available. Results: All had absent deep tendon reflexes and distal muscle weakness; three had intellectual disability. One patient was found to carry a novel homozygous frameshift variant (c.2568_2569del) in the IGHMBP2 gene, consistent with CMT2S. Other variants were identified in the NEFH (CMT2CC), DYNC1H1 (CMT2O), and MPV17 (CMT2EE) genes. Notably, a previously unreported co-occurrence of MPV17 mutation and congenital heart disease was observed in one case. Conclusions: This study expands the clinical and genetic spectrum of pediatric axonal CMT and highlights the role of early physical examination and molecular diagnostics in detecting rare variants. Identification of a novel IGHMBP2 variant and unique phenotypic associations provides new insights for future genotype-phenotype correlation studies.
2025-08-20 | SARM1 Inhibition in Three Mouse Models of Charcot-Marie-Tooth Disease.
Charcot-Marie-Tooth (CMT) disease can be caused by mutations in over 100 different genes, most of which lead to demyelination (type 1) or degeneration (type 2) of peripheral motor and sensory axons. SARM1 is a protein involved in the active process of Wallerian degeneration after axonal injury. Inhibition of SARM1 protects against axon degeneration following injury or in cases such as chemotherapy-induced peripheral neuropathy. However, the effects of SARM1 inhibition on axon degeneration in genetic diseases such as CMT are less clear. Here we tested whether SARM1 inhibition may be of benefit in three different mouse models of axonal CMT: GarsETAQ/CTM2D, NeflN98S/CMT2E, and Ighmbp2Y918C/CMT2S. For these proof-of-concept studies, mice were treated as neonates with an AAV9 to deliver a dominant negative SARM1 construct (dnSARM1) to the nervous system by intracerebroventricular injection. At ages appropriate for each mouse model, animals were then evaluated with a combination of behavioral, neurophysiological, and histological outcomes. We reproduced the protective effects of the dnSARM1 construct in positive control experiments following sciatic nerve crush. However, we did not see a change in the phenotypes of any of the CMT mouse models examined. The neuropathy-related phenotypes neither worsened nor improved. Wild-type littermate controls treated with the AAV9 dnSARM1 had minor reductions in body weight and variable changes in motor performance compared to untreated controls, but no deficits by neurophysiology or histology. Inhibiting SARM1 using a virally delivered dominant negative construct was not efficacious in any of the three mouse models of CMT we tested. These mouse models were chosen for their relevance to the human disease and their prominent axon degeneration, and not for metabolic changes that would suggest SARM1 as a therapeutic target. SARM1 inhibition may remain an option for some forms of CMT, but a method for prescreening CMT subtypes to predict efficacy is needed.
oligonucleotides
2026-07-02 | A class of deep intronic IGHMBP2 variants activate a shared cryptic splice donor, enabling correction of select variants with a single antisense oligonucleotide.
Biallelic disease-causing variants in IGHMBP2 cause spinal muscular atrophy with respiratory distress type I (SMARD1) and Charcot-Marie-Tooth type 2S (CMT2S). We present 12 unrelated patients with clinically suspected IGHMBP2-related-disease, each carrying a variant deep in intron 8 of IGHMBP2 (c.1235+1076G>A (n=6), c.1235+450G>A (n=5), and c.1235+894C>A (n=1)), along with a known deleterious variant in trans. To assess aberrant pathogenic splicing induced by these deep intronic variants in a relevant model, patient-derived induced pluripotent stem cells were differentiated into motor neurons (iMNs). Long-read RNA sequencing revealed introduction of different pseudoexons by each variant: c.1235+450G>A (626bp), c.1235+1076G>A (112bp and 77bp) and c.1235+894C>A (182bp). Although each variant utilizes a unique splice acceptor site, they all activate the same cryptic donor site, enabling a therapeutic approach to redirect aberrant splicing for all the variants using a single shared antisense oligonucleotide (ASO). Treatment of iMNs with this single ASO restored full-length IGHMBP2 protein in c.1235+894G>A and c.1235+1076G>A by decreasing the use of the novel acceptor site. In contrast, ASO treatment did not correct the splicing in c.1235+450G>A, suggesting that additional splice correction will be needed for this specific variant. A CRISPR interference screen of IGHMBP2 loss-of-function in iMNs identified ribonucleoprotein complex biogenesis (RNP), and rRNA and tRNA processing as top pathways implicated in motor neuron vulnerability. Proteomics and transcriptomics analysis of successfully treated patient iMNs revealed correction of RNP biogenesis and rRNA processing defects. This study highlights the importance of characterizing deep intronic variants in disease-relevant cells to assist the diagnostic process and inform therapeutics development.
2025-04-07 | Translating IGHMBP2 Variants with a CMT2S Patient-specific Organ-on-a-chip Model: Personalized Medicine ASO-based Therapeutic Rescue (P12-11.017)
To rescue neuromuscular defects caused by immunoglobulin mu-binding protein 2 (IGHMBP2) variants by targeting a Charcot-Marie-Tooth disease Type 2S (CMT2S) patient-specific splice site variant with a novel antisense oligonucleotide (ASO).
2025-03-10 | Potential ASO-based personalized treatment for Charcot-Marie-Tooth disease type 2S.
Immunoglobulin mu-binding protein 2 (IGHMBP2) pathogenic variants lead to a spectrum of disorders characterized by alpha-motor neuron degeneration. We describe a compound heterozygous patient diagnosed with Charcot-Marie-Tooth disease type 2S with variants in IGHMBP2: a pathogenic missense variant acting in trans with a confirmed intronic cryptic splice site variant. This variant was shown to result in the creation of a new splice acceptor site, loss of reading frame and nonsense-mediated decay. We designed a 19-mer antisense oligonucleotide targeting this cryptic intronic variant to restore IGHMBP2 levels. ASO treatment of patient fibroblasts significantly increased the ratio of restored wild-type transcript to cryptic exon-containing transcript and resulted in over a 50% increase in IGHMBP2 protein levels. Neuromuscular junction analyses revealed high fatigue and chaotic tetanus formulation in untreated patient cells. We demonstrate rescue of NMJ function following ASO treatment, captured by a reduction in fatigue and chaotic tetanus responses. Furthermore, toxicity testing revealed that intrathecal administration of the ASO to wild-type Sprague-Dawley rats over 3 months was well tolerated. Our preclinical data support this ASO as a potential CMT2S treatment by rescuing IGHMBP2. N-of-1 ASO-based therapeutics may prove instrumental in the design of treatments for this diverse genetic disorder.
2024-04-09 | Potential ASO-based Personalized Treatment for Charcot-Marie-Tooth Disease Type 2S (S5.009)
To target a Charcot-Marie-Tooth disease Type 2S (CMT2S) patient-specific cryptic splice site variant within immunoglobulin mu-binding protein 2 (IGHMBP2) with a novel antisense oligonucleotide (ASO), rescuing IGHMBP2 protein levels.
cell therapies
2026-04-25 | [Generation of induced pluripotent stem cells from peripheral blood mononuclear cells of a patient with autosomal recessive Charcot-Marie-Tooth disease type 2S caused by IGHMBP2 mutations].
Charcot-Marie-Tooth disease (CMT) is a group of common monogenic peripheral neuropathies listed in the first National Rare Disease Catalog of China and is characterized by marked clinical and genetic heterogeneity. Immunoglobulin μ-binding protein 2 (IGHMBP2) is a ubiquitously expressed nucleic acid helicase, and mutations in the IGHMBP2 gene can cause autosomal recessive CMT type 2S (AR-CMT2S). However, the underlying pathogenic mechanisms remain unclear. This study aims to generate induced pluripotent stem cells (iPSCs) derived from peripheral blood mononuclear cells (PBMCs) of a patient with AR-CMT2S caused by IGHMBP2 mutations (c.884A>G and c.791G>A), thereby providing a novel cellular model for mechanistic studies and stem cell-based therapeutic research. Clinical data of a patient with AR-CMT2S who was diagnosed in September 2022 at the Department of Neurology, Third Xiangya Hospital of Central South University, were collected and analyzed. Pathogenic variants in IGHMBP2 were confirmed by next-generation sequencing. After obtaining written informed consent, 20 mL of peripheral blood was collected, and PBMCs were isolated. PBMCs were reprogrammed into iPSCs using Sendai virus-mediated transduction. The generated iPSCs were characterized for pluripotency marker expression, self-renewal capacity, in vitro differentiation potential, karyotype integrity, and short tandem repeat (STR) profiling. The iPSCs derived from the AR-CMT2S patient were successfully generated. The established iPSC line retained the same IGHMBP2 mutations as those identified in the patient and expressed key pluripotency markers. The cells exhibited robust self-renewal and the ability to differentiate in vitro. Karyotype analysis demonstrated a normal diploid karyotype (46, XX). An iPSC line derived from a patient with AR-CMT2S caused by IGHMBP2 mutations is successfully established. This patient-specific iPSC line provides a valuable cellular model for investigating the pathogenesis of AR-CMT2S and offers a novel tool for the development of effective therapeutic strategies.
small molecules
2026-05-19 | Neuromuscular junction dysfunction in a subset of Charcot-Marie Tooth and related peripheral neuropathies mouse models.
Charcot-Marie Tooth (CMT) disease is a clinically and genetically heterogeneous inherited peripheral neuropathy for which there is no treatment. CMT patients often present with weakness, fatigue, and muscle atrophy in the distal limbs. Improving function at the neuromuscular junction (NMJ) may improve function in some CMT patients. Using mouse models, we investigated eight CMT subtypes for NMJ phenotypes by morphology and functional deficits assessed by electromyography (EMG). We did not find NMJ abnormalities in mice with mutations in Gjb1Y/Δ2 (CMT1X), or Yars1E196K/E196K (diCMTC). Mice with mutations in Ighmbp2Y918S/Y918S (CMT2S) and Pla2g6M1J/M1J (Infantile Neuroaxonal Dystrophy) have neuromuscular phenotypes that could imply NMJ dysfunction, but we did not find defects in synaptic transmission or anatomy. A transgenic model of PMP22 overexpression (CMT1A) had EMG deficits with high frequency stimulation that are consistent with NMJ involvement. Three models showed indications of altered NMJ morphology and/or function. Gars+/ΔETAQ mice, modeling CMT2D, displayed robust synaptic deficits morphologically and by EMG. Nadk2S330P/S330P mice, modeling an ultrarare neuromuscular disease, had an EMG phenotype coinciding with symptom onset. Nefl+/N98S mice, modeling CMT2E, had normal EMG; but pre-synaptic axon terminals were dysmorphic, with large varicosities, which were more pronounced in proximal muscles. Across multiple models, we found that the extensor digitorum longus was resistant to disease phenotypes based on NMJ innervation status and/or muscle weight and atrophy. Our results indicate that some subtypes of CMT have NMJ deficits, and that assessing neuromuscular disease patients for NMJ dysfunction may reveal a population that could benefit from therapies that enhance transmission.
2016-07-19 | Glutamate signals through mGluR2 to control Schwann cell differentiation and proliferation
Rapid saltatory nerve conduction is facilitated by myelin structure, which is produced by Schwann cells (SC) in the peripheral nervous system (PNS). Proper development and degeneration/regeneration after injury requires regulated phenotypic changes of SC. We have previously shown that glutamate can induce SC proliferation in culture. Here we show that glutamate signals through metabotropic glutamate receptor 2 (mGluR2) to induce Erk phosphorylation in SC. mGluR2-elicited Erk phosphorylation requires ErbB2/3 receptor tyrosine kinase phosphorylation to limit the signaling cascade that promotes phosphorylation of Erk, but not Akt. We found that Gβγ and Src are involved in subcellular signaling downstream of mGluR2. We also found that glutamate can transform myelinating SC to proliferating SC, while inhibition of mGluR2 signaling can inhibit demyelination of injured nerves in vivo. These data suggest pathophysiological significance of mGluR2 signaling in PNS and its possible therapeutic importance to combat demyelinating disorders including Charcot-Marie-Tooth disease.
gene therapies
2026-01-01 | AAV9 gene therapy optimization for SMARD1/CMT2S: safety and long-term efficacy comparison of two vectors in a SMARD1 preclinical model
Abstract Background Mutations in the Immunoglobulin Mu DNA Binding Protein 2 (IGHMBP2) gene cause Spinal Muscular Atrophy with Respiratory Distress type 1 (SMARD1), a rare, infantile, and fatal motor neuron disease, as well as the milder Charcot-Marie-Tooth disease type 2S (CMT2S). Gene therapy has emerged as a promising approach to correcting IGHMBP2 loss in SMARD1 models, but critical challenges remain. Methods In this study, we compared the efficacy of two novel, optimized adeno-associated virus 9 (AAV9)-IGHMBP2 vectors, utilizing either the Chicken β-Actin (CBA) or a truncated form of the methyl-CpG-binding protein 2 (MeCP2) promoter (P546), in the SMARD1 murine model via intracerebroventricular delivery. Treated mice survival, histopathological and molecular profile were analyzed. Results Corroborating previous findings, both constructs effectively rescued the pathological phenotype, significantly improving survival, body weight, and motor function while preserving motor neurons and neuromuscular junctions. Notably, histopathological and RNA sequencing analyses revealed, for the first time, inflammatory marker alterations in the SMARD1 spinal cord, which resolved following treatment. A comparative analysis of the two vectors demonstrated superior long-term efficacy of the P546-promoter construct. Conclusion ICV gene therapy approach can effectively rescue SMARD1 pathological hallmarks, including astrogliosis and microgliosis. Moreover, P546-promoter construct is superior in terms of safety profile and long-term therapeutic efficacy. Graphical abstract
2025-11-24 | The Ighmbp2-R604X mouse presents with the most severe SMARD1 clinical symptoms resulting in failure to thrive, respiratory and feeding deficits, aspiration and severe axon and muscle pathology.
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) and Charcot Marie Tooth type 2S (CMT2S) are due to mutations in immunoglobulin mu binding protein two (IGHMBP2). We generated the Ighmbp2-R604X mouse (R605X-humans) to understand how alterations in IGHMBP2 function impact disease pathology. The IGHMBP2-R605X mutation is associated with patients with SMARD1 or CMT2S. The impact of this mutation is substantial, Ighmbp2R604X/R604X mice have a decreased lifespan (6 days) and weight, and failure to thrive consistent with SMARD1 symptoms. Significant respiratory changes were present along with disease pathology of the phrenic nerve and diaphragm muscle fibers. Ighmbp2R604X/R604X mice also presented with signs of milk aspiration and lung pathology. Interestingly, P0 Ighmbp2R604X/R604X mice had visible milk spots, but demonstrated reduction of the milk spot by P3, indicating deficits in suckling. Alterations in hindlimb electrophysiology were consistent with the pathology of the sciatic nerve, hindlimb neuromuscular junction and muscle. Injection of the ssAAV9-WT-IGHMBP2 vector extended Ighmbp2R604X/R604X survival a few days. Ighmbp2R604X/R604X phenotypes are consistent with the most severe SMARD1 clinical symptoms and for the first time a Ighmbp2 mouse model demonstrates that milk aspiration and loss of the ability to suckle impact survival.
2025-09-05 | The Ighmbp2 -R604X mouse recapitulates the severe SMARD1 clinical symptoms of aspiration, respiratory and feeding deficits.
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) and Charcot Marie Tooth type 2S (CMT2S) are due to mutations in immunoglobulin mu binding protein two (IGHMBP2). We generated the Ighmbp2 -R604X mouse (R605X-humans) to understand how alterations in IGHMBP2 function impact disease pathology. The IGHMBP2-R605X mutation is associated with patients with SMARD1 or CMT2S. The impact of this mutation is substantial, Ighmbp2 R604X/R604X mice have a decreased lifespan (6 days) and weight, and failure to thrive consistent with SMARD1 symptoms. Significant respiratory changes were present along with disease pathology of the phrenic nerve and diaphragm muscle fibers. Ighmbp2 R604X/R604X mice also presented with signs of milk aspiration and lung pathology. Interestingly, Ighmbp2 R604X/R604X mice were born with visible milk spots, but demonstrated reduction of the milk spot by P3, indicating deficits in suckling. Alterations in hindlimb electrophysiology were consistent with the sciatic nerve, hindlimb neuromuscular junction and muscle pathology. Injection of the ssAAV9-WT- IGHMBP2 vector extended Ighmbp2 R604X/R604X survival a few days, due to reduced expression of the vector before death ensued. Ighmbp2 R604X/R604X phenotypes are consistent with the most severe SMARD1 clinical symptoms and for the first time a Ighmbp2 mouse model demonstrates that milk aspiration and loss of the ability to suckle impact survival.
2025-08-30 | Genotypic and Phenotypic Characterization of Axonal Charcot-Marie-Tooth Disease in Childhood: Identification of One Novel and Four Known Mutations.
Background: Charcot-Marie-Tooth disease (CMT) is a genetically and phenotypically heterogeneous hereditary neuropathy. Axonal CMT type 2 (CMT2) subtypes often exhibit overlapping clinical features, which makes molecular genetic analysis essential for accurate diagnosis and subtype differentiation. Methods: This retrospective study included five pediatric patients who presented with gait disturbance, muscle weakness, and foot deformities and were subsequently diagnosed with axonal forms of CMT. Clinical data, electrophysiological studies, neuroimaging, and genetic analyses were evaluated. Whole exome sequencing (WES) was performed in three sporadic cases, while targeted CMT gene panel testing was used for two siblings. Variants were interpreted using ACMG guidelines, supported by public databases (ClinVar, HGMD, and VarSome), and confirmed by Sanger sequencing when available. Results: All had absent deep tendon reflexes and distal muscle weakness; three had intellectual disability. One patient was found to carry a novel homozygous frameshift variant (c.2568_2569del) in the IGHMBP2 gene, consistent with CMT2S. Other variants were identified in the NEFH (CMT2CC), DYNC1H1 (CMT2O), and MPV17 (CMT2EE) genes. Notably, a previously unreported co-occurrence of MPV17 mutation and congenital heart disease was observed in one case. Conclusions: This study expands the clinical and genetic spectrum of pediatric axonal CMT and highlights the role of early physical examination and molecular diagnostics in detecting rare variants. Identification of a novel IGHMBP2 variant and unique phenotypic associations provides new insights for future genotype-phenotype correlation studies.
2025-08-20 | SARM1 Inhibition in Three Mouse Models of Charcot-Marie-Tooth Disease.
Charcot-Marie-Tooth (CMT) disease can be caused by mutations in over 100 different genes, most of which lead to demyelination (type 1) or degeneration (type 2) of peripheral motor and sensory axons. SARM1 is a protein involved in the active process of Wallerian degeneration after axonal injury. Inhibition of SARM1 protects against axon degeneration following injury or in cases such as chemotherapy-induced peripheral neuropathy. However, the effects of SARM1 inhibition on axon degeneration in genetic diseases such as CMT are less clear. Here we tested whether SARM1 inhibition may be of benefit in three different mouse models of axonal CMT: GarsETAQ/CTM2D, NeflN98S/CMT2E, and Ighmbp2Y918C/CMT2S. For these proof-of-concept studies, mice were treated as neonates with an AAV9 to deliver a dominant negative SARM1 construct (dnSARM1) to the nervous system by intracerebroventricular injection. At ages appropriate for each mouse model, animals were then evaluated with a combination of behavioral, neurophysiological, and histological outcomes. We reproduced the protective effects of the dnSARM1 construct in positive control experiments following sciatic nerve crush. However, we did not see a change in the phenotypes of any of the CMT mouse models examined. The neuropathy-related phenotypes neither worsened nor improved. Wild-type littermate controls treated with the AAV9 dnSARM1 had minor reductions in body weight and variable changes in motor performance compared to untreated controls, but no deficits by neurophysiology or histology. Inhibiting SARM1 using a virally delivered dominant negative construct was not efficacious in any of the three mouse models of CMT we tested. These mouse models were chosen for their relevance to the human disease and their prominent axon degeneration, and not for metabolic changes that would suggest SARM1 as a therapeutic target. SARM1 inhibition may remain an option for some forms of CMT, but a method for prescreening CMT subtypes to predict efficacy is needed.
oligonucleotides
2026-07-02 | A class of deep intronic IGHMBP2 variants activate a shared cryptic splice donor, enabling correction of select variants with a single antisense oligonucleotide.
Biallelic disease-causing variants in IGHMBP2 cause spinal muscular atrophy with respiratory distress type I (SMARD1) and Charcot-Marie-Tooth type 2S (CMT2S). We present 12 unrelated patients with clinically suspected IGHMBP2-related-disease, each carrying a variant deep in intron 8 of IGHMBP2 (c.1235+1076G>A (n=6), c.1235+450G>A (n=5), and c.1235+894C>A (n=1)), along with a known deleterious variant in trans. To assess aberrant pathogenic splicing induced by these deep intronic variants in a relevant model, patient-derived induced pluripotent stem cells were differentiated into motor neurons (iMNs). Long-read RNA sequencing revealed introduction of different pseudoexons by each variant: c.1235+450G>A (626bp), c.1235+1076G>A (112bp and 77bp) and c.1235+894C>A (182bp). Although each variant utilizes a unique splice acceptor site, they all activate the same cryptic donor site, enabling a therapeutic approach to redirect aberrant splicing for all the variants using a single shared antisense oligonucleotide (ASO). Treatment of iMNs with this single ASO restored full-length IGHMBP2 protein in c.1235+894G>A and c.1235+1076G>A by decreasing the use of the novel acceptor site. In contrast, ASO treatment did not correct the splicing in c.1235+450G>A, suggesting that additional splice correction will be needed for this specific variant. A CRISPR interference screen of IGHMBP2 loss-of-function in iMNs identified ribonucleoprotein complex biogenesis (RNP), and rRNA and tRNA processing as top pathways implicated in motor neuron vulnerability. Proteomics and transcriptomics analysis of successfully treated patient iMNs revealed correction of RNP biogenesis and rRNA processing defects. This study highlights the importance of characterizing deep intronic variants in disease-relevant cells to assist the diagnostic process and inform therapeutics development.
2025-04-07 | Translating IGHMBP2 Variants with a CMT2S Patient-specific Organ-on-a-chip Model: Personalized Medicine ASO-based Therapeutic Rescue (P12-11.017)
To rescue neuromuscular defects caused by immunoglobulin mu-binding protein 2 (IGHMBP2) variants by targeting a Charcot-Marie-Tooth disease Type 2S (CMT2S) patient-specific splice site variant with a novel antisense oligonucleotide (ASO).
2025-03-10 | Potential ASO-based personalized treatment for Charcot-Marie-Tooth disease type 2S.
Immunoglobulin mu-binding protein 2 (IGHMBP2) pathogenic variants lead to a spectrum of disorders characterized by alpha-motor neuron degeneration. We describe a compound heterozygous patient diagnosed with Charcot-Marie-Tooth disease type 2S with variants in IGHMBP2: a pathogenic missense variant acting in trans with a confirmed intronic cryptic splice site variant. This variant was shown to result in the creation of a new splice acceptor site, loss of reading frame and nonsense-mediated decay. We designed a 19-mer antisense oligonucleotide targeting this cryptic intronic variant to restore IGHMBP2 levels. ASO treatment of patient fibroblasts significantly increased the ratio of restored wild-type transcript to cryptic exon-containing transcript and resulted in over a 50% increase in IGHMBP2 protein levels. Neuromuscular junction analyses revealed high fatigue and chaotic tetanus formulation in untreated patient cells. We demonstrate rescue of NMJ function following ASO treatment, captured by a reduction in fatigue and chaotic tetanus responses. Furthermore, toxicity testing revealed that intrathecal administration of the ASO to wild-type Sprague-Dawley rats over 3 months was well tolerated. Our preclinical data support this ASO as a potential CMT2S treatment by rescuing IGHMBP2. N-of-1 ASO-based therapeutics may prove instrumental in the design of treatments for this diverse genetic disorder.
2024-04-09 | Potential ASO-based Personalized Treatment for Charcot-Marie-Tooth Disease Type 2S (S5.009)
To target a Charcot-Marie-Tooth disease Type 2S (CMT2S) patient-specific cryptic splice site variant within immunoglobulin mu-binding protein 2 (IGHMBP2) with a novel antisense oligonucleotide (ASO), rescuing IGHMBP2 protein levels.
cell therapies
2026-04-25 | [Generation of induced pluripotent stem cells from peripheral blood mononuclear cells of a patient with autosomal recessive Charcot-Marie-Tooth disease type 2S caused by IGHMBP2 mutations].
Charcot-Marie-Tooth disease (CMT) is a group of common monogenic peripheral neuropathies listed in the first National Rare Disease Catalog of China and is characterized by marked clinical and genetic heterogeneity. Immunoglobulin μ-binding protein 2 (IGHMBP2) is a ubiquitously expressed nucleic acid helicase, and mutations in the IGHMBP2 gene can cause autosomal recessive CMT type 2S (AR-CMT2S). However, the underlying pathogenic mechanisms remain unclear. This study aims to generate induced pluripotent stem cells (iPSCs) derived from peripheral blood mononuclear cells (PBMCs) of a patient with AR-CMT2S caused by IGHMBP2 mutations (c.884A>G and c.791G>A), thereby providing a novel cellular model for mechanistic studies and stem cell-based therapeutic research. Clinical data of a patient with AR-CMT2S who was diagnosed in September 2022 at the Department of Neurology, Third Xiangya Hospital of Central South University, were collected and analyzed. Pathogenic variants in IGHMBP2 were confirmed by next-generation sequencing. After obtaining written informed consent, 20 mL of peripheral blood was collected, and PBMCs were isolated. PBMCs were reprogrammed into iPSCs using Sendai virus-mediated transduction. The generated iPSCs were characterized for pluripotency marker expression, self-renewal capacity, in vitro differentiation potential, karyotype integrity, and short tandem repeat (STR) profiling. The iPSCs derived from the AR-CMT2S patient were successfully generated. The established iPSC line retained the same IGHMBP2 mutations as those identified in the patient and expressed key pluripotency markers. The cells exhibited robust self-renewal and the ability to differentiate in vitro. Karyotype analysis demonstrated a normal diploid karyotype (46, XX). An iPSC line derived from a patient with AR-CMT2S caused by IGHMBP2 mutations is successfully established. This patient-specific iPSC line provides a valuable cellular model for investigating the pathogenesis of AR-CMT2S and offers a novel tool for the development of effective therapeutic strategies.
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Drug Discovery Landscape
1 orphan drug designation for Charcot-Marie-Tooth disease type 2S.
1 orphan drug designation for Charcot-Marie-Tooth disease type 2S.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
synthetic 2'-O-methoxyethyl phosphorothioate oligoribonucleotide sodium salt consisting of 19 nucleotide residues with the sequence 5'-MeCMeUGMeUGGAAGMeUGAGGGMeCMeCAG-3' | oligonucleotides | FDA | 2023-05-31 | — | Vanda Pharmaceuticals Inc. |
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