RARE DISEASE
X-linked Charcot-Marie-Tooth disease type 1
X-linked Charcot-Marie-Tooth disease type 1
X-linked Charcot-Marie-Tooth disease type 1
Synonyms: CMT1X, CMTX1
Synonyms: CMT1X, CMTX1
Synonyms: CMT1X, CMTX1
Drug discovery
0
drugs
With orphan designations
Overview
X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) is the second most common hereditary neuropathy, caused by GJB1 gene mutations impairing connexin 32 gap junction function [1][5][13]. It manifests as progressive distal muscle weakness/atrophy, sensory loss, and areflexia, with males showing earlier/severe symptoms due to X-linked dominant inheritance [5][13][17]. Nerve conduction studies reveal intermediate slowing (25-45 m/s) with axonal degeneration [1][9]. Central nervous system involvement (transient white matter lesions, dysarthria) occurs rarely [9][13].
Burden
Progressive ambulatory decline: 34% of males require assistive devices by adulthood [13][18]
Chronic pain (68% patients) and fatigue directly correlate with disability severity [4][16]
Family planning challenges: 100% transmission risk from affected males to daughters [2][17]
Neurophysiological hallmark: Non-uniform conduction slowing (30-40 m/s in males) with temporal dispersion [5][13]
Therapies
Supportive care: Orthotics, physical therapy, and neuropathic pain management (gabapentin/pregabalin) [7][16]
Emerging therapies: Gene replacement (AAV-mediated GJB1 delivery) and neurotrophin-3 (AAV1.tMCK.NT3) in clinical trials [14][15]
Experimental targets: CSF-1 receptor inhibitors and connexin 32 chaperones in preclinical studies [1][3]
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases, rare otorhinolaryngological diseases
Research Papers
134 drug discovery papers about X-linked Charcot-Marie-Tooth disease type 1, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
134 drug discovery papers about X-linked Charcot-Marie-Tooth disease type 1, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-06-10 | Reversible area postrema syndrome in a patient with GJB1 mutation mimicking neuromyelitis optica spectrum disorder.
Area postrema syndrome (APS) is a core feature of neuromyelitis optica spectrum disorder (NMOSD). Charcot-Marie-Tooth disease type 1X (CMT1X), caused by gap junction protein beta-1 (GJB1) mutations, can rarely involve the central nervous system (CNS). To report a case of CMT1X presenting with APS mimicking NMOSD. Clinical, electrophysiological, radiological, and genetic evaluations were performed. A 43-year-old woman experienced intractable hiccups, nausea, and a dorsal medullary lesion. Genetic testing revealed a pathogenic GJB1 p.Arg22Gln variant. The lesion resolved, and she remained relapse-free without maintenance immunotherapy. GJB1-related disorders should be considered in patients with episodic CNS symptoms, particularly when accompanied by features of hereditary neuropathy, to avoid misdiagnosis.
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.
2026-02-03 | Patient-derived neural organoids reveal developmental impairments associated with a novel GJB1 mutation in X-linked Charcot-Marie-Tooth disease.
Charcot-Marie-Tooth disease (CMT) is one of the most prevalent inherited peripheral neuropathies. CMT type X1 (CMTX1), caused by mutations in the GJB1 gene, represents the most common X-linked subtype with central nervous system (CNS) involvement. Here, we report the identification and functional characterization of a novel GJB1 variant (c.554C > T, p.Thr185Ile) in a CMTX1-affected family and its pathogenic impact using patient-derived induced pluripotent stem cells (iPSCs) and three-dimensional (3D) neural organoid models. The GJB1 gene encodes connexin 32 (Cx32), a gap junction protein. Immunofluorescent analysis revealed aberrant intracellular reduction and aggregation of the mutant Cx32 protein, suggesting impaired gap junction function. iPSC-derived neural organoids carrying the GJB1 mutation exhibited significant delay in neural differentiation and disrupted neural rosette organization. These findings underscore the critical role of Cx32 in neural development and provide a physiologically relevant platform for underlying CMTX1 pathological mechanisms on central nervous system. The established GJB1-variant organoid model holds promise for investigating genotype-phenotype correlations and facilitating the development of targeted therapeutic strategies for CMTX1.
2025-09-29 | [A case of X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) diagnosed based on recurrent brain lesions despite peripheral neuropathy responsive to immunotherapy].
The patient is a 17-year-old male. He had a history of hospitalization for influenza at the age of 11, and Brain MRI at that time showed reversible brain lesions in the splenium of the corpus callosum and cerebral white matter. Fifteen months ago, he visited the pediatrics department due to dysphagia, dysarthria, facial paralysis, and muscle weakness. Brain MRI revealed lesions similar to those observed here, and nerve conduction study revealed demyelinating neuropathy. He was treated with intravenous immunoglobulin (IVIg) and intravenous methylprednisolone, and his symptoms disappeared within a few days and Brain MRI 5 weeks after treatment revealed that the lesions had disappeared. Three months ago, while walking, the patient developed a knee strain, which was thought to be a recurrence of the immune-mediated neuropathy. His subjective symptom disappeared after administration of IVIg. The patient was diagnosed with X-linked Charcot-Marie-Tooth disease (CMTX1) based on genetic testing, which revealed a pathological variant of GJB1, c.124A>T (p.Ser42Cys). Peripheral neuropathy in CMTX1 may present with fluctuating symptoms and can be responsive to IVIg treatment. Recurrent brain lesions should also be considered in the diagnosis of CMTX1.
2025-08-13 | Genetic Deletion of Sarm1 in Mouse Models of Three Neurological Diseases.
Degeneration of peripheral motor and sensory axons is a key aspect of the pathophysiology of Charcot-Marie-Tooth disease and related inherited neurodegenerative conditions. Given that mutations in many (> 100) genes can cause these disorders, it is unclear if a generalized therapeutic strategy can be identified that will apply across these disease subtypes; however, strategies to prevent or slow axon degeneration are attractive candidates. Wallerian axon degeneration is an active process following insults such as nerve injury, and SARM1 is a central mediator of this process. When SARM1 is inhibited, axons distal to the site of injury persist for weeks rather than degenerating. In addition, SARM1 inhibition or genetic deletion has been shown to provide benefit in acquired neuropathies such as diabetic/metabolic neuropathy and chemotherapy-induced neuropathy in animal models. Here we examined the effects of genetically deleting Sarm1 in mouse models of CMT. We bred knockout mice lacking Sarm1 to three different mouse models of CMT or related disorders. These include mice lacking Gjb1, modeling CMT1X, mice with mutations in Kif1a, modeling hereditary sensory neuropathy IIC and spastic paraplegia type 30, and mice lacking Fig4, modeling CMT4J and Yunis-Varon syndrome. Clinically relevant outcomes measures including survival (Kif1a and Fig4), grip strength and motor behavior, peripheral neurophysiology, molecular biomarkers, and nerve histopathology were assessed for each model with and without Sarm1 expression. No improvement in the mutant phenotype was found for any model, although elevated levels of circulating neurofilament light chain levels were delayed in the Fig4 mice. Kif1a mice showed deficits slightly earlier in the absence of Sarm1. While we found no benefit from deleting Sarm1 in these mouse models, they were chosen for their human disease relevance and not for biochemical indicators that SARM1 may be a good target. Thus, SARM1 inhibition may still be effective in other forms of inherited neuropathy, but additional research will be required to identify those candidate subtypes.
2026-06-10 | Reversible area postrema syndrome in a patient with GJB1 mutation mimicking neuromyelitis optica spectrum disorder.
Area postrema syndrome (APS) is a core feature of neuromyelitis optica spectrum disorder (NMOSD). Charcot-Marie-Tooth disease type 1X (CMT1X), caused by gap junction protein beta-1 (GJB1) mutations, can rarely involve the central nervous system (CNS). To report a case of CMT1X presenting with APS mimicking NMOSD. Clinical, electrophysiological, radiological, and genetic evaluations were performed. A 43-year-old woman experienced intractable hiccups, nausea, and a dorsal medullary lesion. Genetic testing revealed a pathogenic GJB1 p.Arg22Gln variant. The lesion resolved, and she remained relapse-free without maintenance immunotherapy. GJB1-related disorders should be considered in patients with episodic CNS symptoms, particularly when accompanied by features of hereditary neuropathy, to avoid misdiagnosis.
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.
2026-02-03 | Patient-derived neural organoids reveal developmental impairments associated with a novel GJB1 mutation in X-linked Charcot-Marie-Tooth disease.
Charcot-Marie-Tooth disease (CMT) is one of the most prevalent inherited peripheral neuropathies. CMT type X1 (CMTX1), caused by mutations in the GJB1 gene, represents the most common X-linked subtype with central nervous system (CNS) involvement. Here, we report the identification and functional characterization of a novel GJB1 variant (c.554C > T, p.Thr185Ile) in a CMTX1-affected family and its pathogenic impact using patient-derived induced pluripotent stem cells (iPSCs) and three-dimensional (3D) neural organoid models. The GJB1 gene encodes connexin 32 (Cx32), a gap junction protein. Immunofluorescent analysis revealed aberrant intracellular reduction and aggregation of the mutant Cx32 protein, suggesting impaired gap junction function. iPSC-derived neural organoids carrying the GJB1 mutation exhibited significant delay in neural differentiation and disrupted neural rosette organization. These findings underscore the critical role of Cx32 in neural development and provide a physiologically relevant platform for underlying CMTX1 pathological mechanisms on central nervous system. The established GJB1-variant organoid model holds promise for investigating genotype-phenotype correlations and facilitating the development of targeted therapeutic strategies for CMTX1.
2025-09-29 | [A case of X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) diagnosed based on recurrent brain lesions despite peripheral neuropathy responsive to immunotherapy].
The patient is a 17-year-old male. He had a history of hospitalization for influenza at the age of 11, and Brain MRI at that time showed reversible brain lesions in the splenium of the corpus callosum and cerebral white matter. Fifteen months ago, he visited the pediatrics department due to dysphagia, dysarthria, facial paralysis, and muscle weakness. Brain MRI revealed lesions similar to those observed here, and nerve conduction study revealed demyelinating neuropathy. He was treated with intravenous immunoglobulin (IVIg) and intravenous methylprednisolone, and his symptoms disappeared within a few days and Brain MRI 5 weeks after treatment revealed that the lesions had disappeared. Three months ago, while walking, the patient developed a knee strain, which was thought to be a recurrence of the immune-mediated neuropathy. His subjective symptom disappeared after administration of IVIg. The patient was diagnosed with X-linked Charcot-Marie-Tooth disease (CMTX1) based on genetic testing, which revealed a pathological variant of GJB1, c.124A>T (p.Ser42Cys). Peripheral neuropathy in CMTX1 may present with fluctuating symptoms and can be responsive to IVIg treatment. Recurrent brain lesions should also be considered in the diagnosis of CMTX1.
2025-08-13 | Genetic Deletion of Sarm1 in Mouse Models of Three Neurological Diseases.
Degeneration of peripheral motor and sensory axons is a key aspect of the pathophysiology of Charcot-Marie-Tooth disease and related inherited neurodegenerative conditions. Given that mutations in many (> 100) genes can cause these disorders, it is unclear if a generalized therapeutic strategy can be identified that will apply across these disease subtypes; however, strategies to prevent or slow axon degeneration are attractive candidates. Wallerian axon degeneration is an active process following insults such as nerve injury, and SARM1 is a central mediator of this process. When SARM1 is inhibited, axons distal to the site of injury persist for weeks rather than degenerating. In addition, SARM1 inhibition or genetic deletion has been shown to provide benefit in acquired neuropathies such as diabetic/metabolic neuropathy and chemotherapy-induced neuropathy in animal models. Here we examined the effects of genetically deleting Sarm1 in mouse models of CMT. We bred knockout mice lacking Sarm1 to three different mouse models of CMT or related disorders. These include mice lacking Gjb1, modeling CMT1X, mice with mutations in Kif1a, modeling hereditary sensory neuropathy IIC and spastic paraplegia type 30, and mice lacking Fig4, modeling CMT4J and Yunis-Varon syndrome. Clinically relevant outcomes measures including survival (Kif1a and Fig4), grip strength and motor behavior, peripheral neurophysiology, molecular biomarkers, and nerve histopathology were assessed for each model with and without Sarm1 expression. No improvement in the mutant phenotype was found for any model, although elevated levels of circulating neurofilament light chain levels were delayed in the Fig4 mice. Kif1a mice showed deficits slightly earlier in the absence of Sarm1. While we found no benefit from deleting Sarm1 in these mouse models, they were chosen for their human disease relevance and not for biochemical indicators that SARM1 may be a good target. Thus, SARM1 inhibition may still be effective in other forms of inherited neuropathy, but additional research will be required to identify those candidate subtypes.
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