RARE DISEASE
Autosomal dominant Charcot-Marie-Tooth disease type 2
Autosomal dominant Charcot-Marie-Tooth disease type 2
Autosomal dominant Charcot-Marie-Tooth disease type 2
Synonyms: Autosomal dominant axonal Charcot-Marie-Tooth disease, CMT2, Hereditary motor and sensory neuropathy type 2
Synonyms: Autosomal dominant axonal Charcot-Marie-Tooth disease, CMT2, Hereditary motor and sensory neuropathy type 2
Synonyms: Autosomal dominant axonal Charcot-Marie-Tooth disease, CMT2, Hereditary motor and sensory neuropathy type 2
Drug discovery
1
drug
With orphan designation
Overview
Autosomal dominant Charcot-Marie-Tooth disease type 2 (AD-CMT2) comprises hereditary axonal neuropathies characterized by progressive distal muscle weakness/atrophy, sensory deficits, and reduced deep tendon reflexes. Caused by mutations affecting axonal integrity (e.g., MFN2, GARS, NEFL), it manifests with pes cavus, gait impairment, and variable tremor or ataxia. Onset ranges from childhood to adulthood, with severity influenced by specific genetic variants [1][2][9]. Nerve conduction studies typically show normal velocities with reduced action potential amplitudes [14].
Burden
Therapies
Supportive care: Ankle-foot orthoses, physical therapy, and pain management to preserve mobility [11][12]
Surgical interventions: Tendon transfers or foot reconstruction for progressive deformities [12][18]
Emerging therapies: Antisense oligonucleotides show promise in preclinical CMT2E models targeting NEFL mutations [3], while neurotrophin-3 gene therapy trials demonstrate axonal protection [15]
Categories: rare genetic diseases, rare neurological diseases
Research Papers
153 drug discovery papers about Autosomal dominant Charcot-Marie-Tooth disease type 2, with 1 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
153 drug discovery papers about Autosomal dominant Charcot-Marie-Tooth disease type 2, with 1 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-06 | Pharmacologic eIF2B Activation Rescues Neuropathy in CMT2 Subtypes by Normalizing the Integrated Stress Response
Abstract Among the many subtypes of Charcot–Marie–Tooth (CMT) disease, several result from mutations in genes encoding aminoacyl-tRNA synthetases, enzymes required for tRNA charging during cytoplasmic and mitochondrial translation. We report that activation of the integrated stress response (ISR) pathway is a shared molecular feature of tRNA synthetase-associated and other axonal CMT subtypes. RTX-117, a CNS-penetrant small molecule currently in Phase 1 clinical trials, targets eukaryotic initiation factor 2B (eIF2B), a key modulator of protein synthesis and the ISR pathway. Using cryo-EM studies, we have characterized the binding mode of RTX-117 to the eIF2B decamer. In Gars P278KY/+ mice, which develop early onset motor defects and axonal pathology that recapitulate CMT2D symptoms from tRNA synthetase mutations, RTX-117 treatment started after disease onset reduced chronic ISR activation and produced significant functional and electrophysiological improvement. We further identify ISR targets, including secreted proteins such as GDF15 and FGF21 that may serve as translational biomarkers for treatment response to RTX-117 in CMT disease. Broader surveillance of the ISR pathway across models of neurodegeneration reveals strong activation in several diseases and a correlation with disease progression, particularly in models of Alzheimer’s disease. These findings identify chronic ISR activation as a recurrent, though not universal, pathological mechanism of neurodegenerative disease models. Overall, our study identifies candidate biomarkers for CMT disease subtypes associated with defects in translational homeostasis and supports eIF2ɑ-ATF4 axis modulation as a promising therapeutic strategy for this disease class. One Sentence Summary RTX-117, a clinical stage eIF2B activator, blunts chronic ISR activation and improves nerve and motor function in a mouse model of Charcot-Marie-Tooth Disease Type 2D.
2026-07-24 | Late-Onset Rapidly Progressive Spastic Paraplegia with Extensive White Matter Abnormalities Associated with an MFN2 Variant.
Mitofusin-2 (MFN2) variants are a well-established cause of Charcot-Marie-Tooth disease type 2A, although central nervous system involvement has increasingly been recognized in a subset of affected patients. We report a 51-year-old woman carrying a likely pathogenic MFN2 variant (c.2119C>T, p.Arg707Trp) who developed rapidly progressive spastic paraplegia and became wheelchair-dependent within several months. Neurological examination demonstrated severe pyramidal tract signs with preserved sensory function. Nerve conduction studies were suggestive of distal motor axonal involvement, while transcranial magnetic stimulation and somatosensory evoked potentials indicated corticospinal and central sensory pathway dysfunction in the lower extremities. Brain magnetic resonance imaging revealed extensive bilateral confluent periventricular and deep white matter hyperintensities. Comprehensive investigations excluded inflammatory, vascular, metabolic, infectious, neoplastic, and common genetic causes of hereditary spastic paraplegia. Targeted next-generation sequencing identified a heterozygous likely pathogenic MFN2 p.Arg707Trp variant. Although central nervous system manifestations have previously been described in MFN2-related disease, this phenotype is unusual because of the combination of late-onset rapidly progressive spastic paraplegia, and extensive cerebral white matter abnormalities associated with the p.Arg707Trp variant. This case further expands the recognized phenotypic spectrum of MFN2-related disease and highlights that MFN2 variants should be considered in the differential diagnosis of selected patients with late-onset progressive spastic paraplegia accompanied by cerebral white matter abnormalities and distal motor axonal neuropathy.
2026-06-16 | Restoring the interplay between the endoplasmic reticulum and mitochondria by gene therapy improves Charcot-Marie-Tooth type 2A disease.
Charcot-Marie-Tooth disease type 2A (CMT2A) is the most common axonal CMT and is associated with an early onset and severe motor neuropathy. CMT2A is mainly caused by dominant mutations in the MFN2 gene, encoding mitofusin-2, a GTPase located in the outer membrane of the mitochondria and endoplasmic reticulum (ER). Mutations in MFN2 affect mitochondrial dynamics. We previously demonstrated that mutated MFN2 further disrupts contacts between the ER and the mitochondria, leading to axonal degeneration. There are no treatments for CMT2A, and those currently under development primarily focus on restoring mitochondrial function. Here, we provide proof of concept that neuronal overexpression of wild-type MFN2 (MFN2WT) provides therapeutic benefit in transgenic CMT2A mice as well as in CMT2A-motor neurons derived from induced pluripotent stem cells. Intrathecal delivery of an AAV9 vector expressing MFN2WT effectively targets motor and sensory neurons, restoring ER-mitochondria contacts and mitochondrial morphology, thereby preserving both neuromuscular junction integrity and motor function. Strikingly, therapeutic efficacy is also achieved by administering the vector after the onset of symptoms. Importantly, AAV administration was well tolerated, with no evidence of hepatotoxicity or dorsal root ganglion inflammation. We further show that CMT2A pathology can be corrected in vitro and in vivo using an ER-targeting MFN1 isoform that selectively enhances ER-mitochondria contacts. These results establish that restoring contacts between the ER and mitochondria using gene therapy is a promising therapeutic avenue for CMT2A.
2026-06-06 | Disease-causing MFN2 mutants impair mitochondrial fission dynamics by distinct DRP1 dysregulation.
Mitochondria undergo fusion and fission. While DRP1 regulates fission, fusion is controlled by OPA1, MFN1, and MFN2. The balance between these processes and the crosstalk between machineries remains poorly understood. MFN2 mutations cause Charcot-Marie-Tooth disease type 2 A (CMT2A), affecting mitochondrial fusion and morphology. However, their role in fission is unclear. Using skin fibroblasts from CMT2A patients (L248H and M376V MFN2 mutations) and wild-type mouse embryonic fibroblasts expressing these variants, we studied how MFN2 mutations impact mitochondrial dynamics beyond fusion. We analyzed mitochondrial morphology and dynamics by live-cell confocal microscopy and tested fusion/fission protein levels, oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and oxidative phosphorylation complex subunits. MFN2 mutations impaired mitochondrial fusion and displayed distinct effects on fission and cellular metabolism. L248H-expressing cells showed hyper-elongated mitochondria, impaired fission, and increased OCR, while M376V cells exhibited fragmentation, enhanced fission, and elevated ECAR. These effects correlated with differential Drp1 phosphorylation. Our findings demonstrate that MFN2 mutants differentially influence fission and metabolism, highlighting the need to consider these effects in therapies aimed at modulating mitochondrial dynamics.
2026-04-04 | Arginine ameliorates motor and survival deficits in MFN2-Deficient Drosophila models.
Charcot-Marie-Tooth disease type 2 A (CMT2A) is an inherited axonal neuropathy linked to mutations in MFN2, a key regulator of mitochondrial dynamics. Currently, no effective drug therapies exist. l-arginine has shown promise in treating mitochondrial disorders, though its effect on MFN2-associated neuropathy remains uncertain. To investigate this, we used Drosophila models with the neuron-specific knockdown of Marf, the fly ortholog of MFN2, employing a temporally controlled GAL4/UAS system. Flies were administered different doses of l-arginine to examine its influence on motor ability and lifespan. To evaluate responses under mitochondrial stress, flies were also treated with rotenone, a mitochondrial complex I inhibitor. l-arginine markedly improved climbing performance under baseline conditions and extended lifespan under both baseline and stress conditions. However under rotenone-induced mitochondrial stress, high-dose l-arginine improved survival without a corresponding improvement in locomotor performance. These results support a neuroprotective role for l-arginine in MFN2-deficient Drosophila, possibly through effects on mitochondrial dynamics involving complex I. l-arginine may hold therapeutic promise for CMT2A, meriting further investigation in vertebrate models.
2026-08-06 | Pharmacologic eIF2B Activation Rescues Neuropathy in CMT2 Subtypes by Normalizing the Integrated Stress Response
Abstract Among the many subtypes of Charcot–Marie–Tooth (CMT) disease, several result from mutations in genes encoding aminoacyl-tRNA synthetases, enzymes required for tRNA charging during cytoplasmic and mitochondrial translation. We report that activation of the integrated stress response (ISR) pathway is a shared molecular feature of tRNA synthetase-associated and other axonal CMT subtypes. RTX-117, a CNS-penetrant small molecule currently in Phase 1 clinical trials, targets eukaryotic initiation factor 2B (eIF2B), a key modulator of protein synthesis and the ISR pathway. Using cryo-EM studies, we have characterized the binding mode of RTX-117 to the eIF2B decamer. In Gars P278KY/+ mice, which develop early onset motor defects and axonal pathology that recapitulate CMT2D symptoms from tRNA synthetase mutations, RTX-117 treatment started after disease onset reduced chronic ISR activation and produced significant functional and electrophysiological improvement. We further identify ISR targets, including secreted proteins such as GDF15 and FGF21 that may serve as translational biomarkers for treatment response to RTX-117 in CMT disease. Broader surveillance of the ISR pathway across models of neurodegeneration reveals strong activation in several diseases and a correlation with disease progression, particularly in models of Alzheimer’s disease. These findings identify chronic ISR activation as a recurrent, though not universal, pathological mechanism of neurodegenerative disease models. Overall, our study identifies candidate biomarkers for CMT disease subtypes associated with defects in translational homeostasis and supports eIF2ɑ-ATF4 axis modulation as a promising therapeutic strategy for this disease class. One Sentence Summary RTX-117, a clinical stage eIF2B activator, blunts chronic ISR activation and improves nerve and motor function in a mouse model of Charcot-Marie-Tooth Disease Type 2D.
2026-07-24 | Late-Onset Rapidly Progressive Spastic Paraplegia with Extensive White Matter Abnormalities Associated with an MFN2 Variant.
Mitofusin-2 (MFN2) variants are a well-established cause of Charcot-Marie-Tooth disease type 2A, although central nervous system involvement has increasingly been recognized in a subset of affected patients. We report a 51-year-old woman carrying a likely pathogenic MFN2 variant (c.2119C>T, p.Arg707Trp) who developed rapidly progressive spastic paraplegia and became wheelchair-dependent within several months. Neurological examination demonstrated severe pyramidal tract signs with preserved sensory function. Nerve conduction studies were suggestive of distal motor axonal involvement, while transcranial magnetic stimulation and somatosensory evoked potentials indicated corticospinal and central sensory pathway dysfunction in the lower extremities. Brain magnetic resonance imaging revealed extensive bilateral confluent periventricular and deep white matter hyperintensities. Comprehensive investigations excluded inflammatory, vascular, metabolic, infectious, neoplastic, and common genetic causes of hereditary spastic paraplegia. Targeted next-generation sequencing identified a heterozygous likely pathogenic MFN2 p.Arg707Trp variant. Although central nervous system manifestations have previously been described in MFN2-related disease, this phenotype is unusual because of the combination of late-onset rapidly progressive spastic paraplegia, and extensive cerebral white matter abnormalities associated with the p.Arg707Trp variant. This case further expands the recognized phenotypic spectrum of MFN2-related disease and highlights that MFN2 variants should be considered in the differential diagnosis of selected patients with late-onset progressive spastic paraplegia accompanied by cerebral white matter abnormalities and distal motor axonal neuropathy.
2026-06-16 | Restoring the interplay between the endoplasmic reticulum and mitochondria by gene therapy improves Charcot-Marie-Tooth type 2A disease.
Charcot-Marie-Tooth disease type 2A (CMT2A) is the most common axonal CMT and is associated with an early onset and severe motor neuropathy. CMT2A is mainly caused by dominant mutations in the MFN2 gene, encoding mitofusin-2, a GTPase located in the outer membrane of the mitochondria and endoplasmic reticulum (ER). Mutations in MFN2 affect mitochondrial dynamics. We previously demonstrated that mutated MFN2 further disrupts contacts between the ER and the mitochondria, leading to axonal degeneration. There are no treatments for CMT2A, and those currently under development primarily focus on restoring mitochondrial function. Here, we provide proof of concept that neuronal overexpression of wild-type MFN2 (MFN2WT) provides therapeutic benefit in transgenic CMT2A mice as well as in CMT2A-motor neurons derived from induced pluripotent stem cells. Intrathecal delivery of an AAV9 vector expressing MFN2WT effectively targets motor and sensory neurons, restoring ER-mitochondria contacts and mitochondrial morphology, thereby preserving both neuromuscular junction integrity and motor function. Strikingly, therapeutic efficacy is also achieved by administering the vector after the onset of symptoms. Importantly, AAV administration was well tolerated, with no evidence of hepatotoxicity or dorsal root ganglion inflammation. We further show that CMT2A pathology can be corrected in vitro and in vivo using an ER-targeting MFN1 isoform that selectively enhances ER-mitochondria contacts. These results establish that restoring contacts between the ER and mitochondria using gene therapy is a promising therapeutic avenue for CMT2A.
2026-06-06 | Disease-causing MFN2 mutants impair mitochondrial fission dynamics by distinct DRP1 dysregulation.
Mitochondria undergo fusion and fission. While DRP1 regulates fission, fusion is controlled by OPA1, MFN1, and MFN2. The balance between these processes and the crosstalk between machineries remains poorly understood. MFN2 mutations cause Charcot-Marie-Tooth disease type 2 A (CMT2A), affecting mitochondrial fusion and morphology. However, their role in fission is unclear. Using skin fibroblasts from CMT2A patients (L248H and M376V MFN2 mutations) and wild-type mouse embryonic fibroblasts expressing these variants, we studied how MFN2 mutations impact mitochondrial dynamics beyond fusion. We analyzed mitochondrial morphology and dynamics by live-cell confocal microscopy and tested fusion/fission protein levels, oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and oxidative phosphorylation complex subunits. MFN2 mutations impaired mitochondrial fusion and displayed distinct effects on fission and cellular metabolism. L248H-expressing cells showed hyper-elongated mitochondria, impaired fission, and increased OCR, while M376V cells exhibited fragmentation, enhanced fission, and elevated ECAR. These effects correlated with differential Drp1 phosphorylation. Our findings demonstrate that MFN2 mutants differentially influence fission and metabolism, highlighting the need to consider these effects in therapies aimed at modulating mitochondrial dynamics.
2026-04-04 | Arginine ameliorates motor and survival deficits in MFN2-Deficient Drosophila models.
Charcot-Marie-Tooth disease type 2 A (CMT2A) is an inherited axonal neuropathy linked to mutations in MFN2, a key regulator of mitochondrial dynamics. Currently, no effective drug therapies exist. l-arginine has shown promise in treating mitochondrial disorders, though its effect on MFN2-associated neuropathy remains uncertain. To investigate this, we used Drosophila models with the neuron-specific knockdown of Marf, the fly ortholog of MFN2, employing a temporally controlled GAL4/UAS system. Flies were administered different doses of l-arginine to examine its influence on motor ability and lifespan. To evaluate responses under mitochondrial stress, flies were also treated with rotenone, a mitochondrial complex I inhibitor. l-arginine markedly improved climbing performance under baseline conditions and extended lifespan under both baseline and stress conditions. However under rotenone-induced mitochondrial stress, high-dose l-arginine improved survival without a corresponding improvement in locomotor performance. These results support a neuroprotective role for l-arginine in MFN2-deficient Drosophila, possibly through effects on mitochondrial dynamics involving complex I. l-arginine may hold therapeutic promise for CMT2A, meriting further investigation in vertebrate models.
Access all drug discovery papers and probability of success in trials forecasts:
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Drug Discovery Landscape
1 orphan drug designation for Autosomal dominant Charcot-Marie-Tooth disease type 2.
1 orphan drug designation for Autosomal dominant Charcot-Marie-Tooth disease type 2.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Small molecule mitofusin allosteric activator | small molecules | FDA | 2020-09-04 | — | Mitochondria Emotion Inc. |
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