RARE DISEASE
Charcot-Marie-Tooth disease type 4
Charcot-Marie-Tooth disease type 4
Charcot-Marie-Tooth disease type 4
Synonyms: AR-CMT1, Autosomal recessive demyelinating Charcot-Marie-Tooth, CMT4
Synonyms: AR-CMT1, Autosomal recessive demyelinating Charcot-Marie-Tooth, CMT4
Synonyms: AR-CMT1, Autosomal recessive demyelinating Charcot-Marie-Tooth, CMT4
Drug discovery
0
drugs
With orphan designations
Overview
Charcot-Marie-Tooth disease type 4 (CMT4) is a rare, autosomal recessive subgroup of inherited peripheral neuropathies characterized by progressive demyelinating or axonal sensorimotor polyneuropathy. Symptoms typically manifest in infancy/early childhood, featuring severe distal muscle weakness/atrophy, skeletal deformities (pes cavus, scoliosis), gait abnormalities, and reduced/absent reflexes. CMT4 includes 15+ subtypes (e.g., CMT4A-J) with variable systemic features like deafness, cataracts, or respiratory involvement [1][2][6][11][17].
Burden
Severe disability: Early ambulatory decline (wheelchair dependence by age 30 in CMT4A), scoliosis (70% of CMT4C) [2][6][16]
Multisystem complications: Vocal cord paresis, respiratory insufficiency, and sensory deficits impacting daily function [1][6][11]
Lifespan impact: Generally normal life expectancy but reduced quality of life due to progressive disability [6][17]
Therapies
Supportive care: Orthotics, physiotherapy, and surgery for skeletal deformities [3][15][18]
Experimental therapies: Gene therapy trials (e.g., AAV9-SH3TC2 for CMT4C), RNAi/ASOs, and sorbitol-reduction agents (govorestat for SORD-CMT) [3][5][12][16]
Pain/weakness management: Neuropathic pain medications, adaptive mobility devices [3][18]
Categories: rare genetic diseases, rare neurological diseases
Research Papers
57 drug discovery papers about Charcot-Marie-Tooth disease type 4, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
57 drug discovery papers about Charcot-Marie-Tooth disease type 4, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-04-10 | Clinical and molecular characterization of a novel pathogenic AIFM1 E336K mutation connecting mitochondrial dysfunction and neurodegeneration.
Mutations in the AIFM1 gene, encoding the apoptosis-inducing factor (AIF), have been associated with a spectrum of neurometabolic disorders. However, the mechanistic basis underlying their pathogenicity remains poorly understood. In this work, we identified and comprehensively characterized a novel hemizygous AIFM1 mutation c.1006G > A (E336K) in a male patient presenting with a progressive hereditary axonal sensorimotor polyneuropathy with childhood onset, inherited in an X-linked recessive pattern, associated with sensorineural hearing loss and without cognitive impairment. The clinical phenotype was consistent with Charcot-Marie-Tooth disease type 4 (CMTX4). Patient-derived fibroblasts exhibited reduced AIF protein stability despite preserved mRNA expression, impaired growth in OXPHOS-dependent conditions, decreased basal respiration, and altered assembly of mitochondrial respiratory supercomplexes. These defects were accompanied by reduced CHCHD4 protein levels and mitochondrial content. The purified E336K protein exhibited compromised FAD retention, decreased thermal stability, impaired NADH affinity, destabilization of the charge-transfer complex crucial for sustaining the AIF: CHCHD4 interaction, and a shift in coenzyme preference toward NADPH. Structurally, the substitution of Glu336 with Lys remodels the electrostatic environment of the NADH-binding cleft, thereby compromising redox function and weakening CHCHD4 binding. Despite these defects, the protein with the E336K mutation retained DNA binding, nuclease activity, and binding to nuclear partners, although parthanatos induction was attenuated in patient fibroblasts. Collectively, these molecular alterations converge on defective mitochondrial bioenergetics and dynamics, providing a direct mechanistic link to the patient’s clinical evolution.These findings provide a framework for understanding AIFM1-related disorders and pave the way for the development of future personalized molecular therapies.
2025-09-15 | Effectiveness of Sitagliptin and Empagliflozin Combination Therapy in a Patient With Charcot-Marie-Tooth Disease and Comorbid Diabetes Mellitus: A Case Report.
This case report describes a 61-year-old male with Charcot-Marie-Tooth disease type 1A (CMT1A) who developed poorly controlled type 2 diabetes mellitus. The patient, with a history of CMT1A, was admitted for preoperative glycemic management prior to lumbar spinal stenosis surgery, exhibiting an HbA1c of 8.1%. Treatment with metformin had been insufficient. Considering potential insulin resistance due to decreased skeletal muscle mass from CMT and reduced mobility, a combination therapy of the DPP-4 inhibitor sitagliptin and the SGLT2 inhibitor empagliflozin was initiated post-surgery, alongside diet and exercise. Notably, this combination effectively improved glycemic control without reducing skeletal muscle mass. This suggests that the combination of a DPP-4 inhibitor and an SGLT2 inhibitor may be a viable therapeutic option for managing diabetes mellitus in patients with CMT, warranting further investigation in larger studies due to the rarity of this comorbidity. Long-term glycemic control is crucial for maintaining activities of daily living (ADLs) and quality of life (QOL) in these patients.
2025-08-01 | Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy.
Autosomal recessive mutations in the SH3TC2 gene cause Charcot-Marie-Tooth type 4C (CMT4C) demyelinating peripheral neuropathy. In this nationwide observational retrospective study involving 27 French University Hospitals, we analyzed the clinical, electrophysiological, and genetic features of 103 patients from 89 families with homozygous and compound heterozygous SH3TC2 gene mutations identified between 2003 and 2023. Mean age was 42 years (2-80), and 49% of patients were female. Mean age at disease onset was 14 years (0-52), 60% of patients started the disease before age 10 years, and 24% after age 20 years. Patients presented with distal motor weakness (93% of cases), sensory loss (86%), foot deformities (83%), scoliosis (73%), proximal limb weakness (40%), cranial nerve involvement (48%), hearing loss (37%), scoliosis-related respiratory insufficiency (14%), and genitourinary disorders (6%). Half the patients (48%) walked independently before age 50 years, in contrast with only 13% after age 50 years. After age 50 years, 23% of patients were wheelchair-bound. Nerve conduction studies showed sensorimotor abnormalities within the demyelinating range in all cases. We identified 56 different pathogenic variants in the SH3TC2 gene, including 22 previously undescribed. Patients with two SH3TC2 gene truncating variants had more severe symptoms than patients with one or zero truncating variants. This study shows CMT4C is a severe childhood- and adult-onset demyelinating peripheral neuropathy often associated with scoliosis, hearing loss, and ambulation loss in a significant proportion of patients after age 50 years. Genotype-phenotype correlations suggest two truncating SH3TC2 gene variants cause a more severe phenotype.
2025-07-07 | Increased BNIP3-mediated mitophagy attenuates GDAP1 loss of function - implications for Charcot-Marie-Tooth disease 4A.
Charcot-Marie-Tooth disease type 4 A ((CMT4A), an autosomal recessive neuropathy, is caused by mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1). GDAP1 resides in the outer mitochondrial membrane facing the cytosol and is involved in mitochondrial dynamics and function. Its perturbation affects mitochondrial shape, contact sites, redox homeostasis and cellular metabolism. In response to GDAP1 knockdown in a human neuronal cell line, we found increased mitochondrial turnover, biogenesis and mitophagy. This was associated with more lysosomal proteins in mitochondrial fractions including BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and its homolog BNIP3-like (BNIP3L) - proteins involved in the recruitment of autophagy machinery via direct interaction. Flies with neural Gdap1 knockdown also exhibited upregulated levels of the sole BNIP3 ortholog. Neural expression of human BNIP3 reduced the detrimental effects of Gdap1 knockdown on eclosion and climbing ability in adult flies, while simultaneous knockdown of both genes was detrimental. These findings suggest that increased BNIP3-driven mitophagy may act as a protective mechanism, partially counteracting the cellular dysfunction caused by GDAP1 loss of function, and highlight the potential of targeting mitophagy pathways as a therapeutic strategy for CMT4A.
2025-06-11 | Engineered AAV capsids mediate transduction of murine neurofibroma and sciatic nerve.
Genetic diseases such as Neurofibromatosis type 1 (NF1) and Charcot-Marie Tooth disease involve Schwann cells (SCs) associated with peripheral nerves. Gene therapy using adeno-associated virus (AAV) vector mediated gene delivery is a promising strategy to treat these diseases. However, AAV-mediated transduction of SCs in vivo after intravascular delivery is relatively inefficient, with a lack of extensive characterization of different capsids to date. Here, we performed an in vivo selection with an AAV9 capsid peptide display library in a mouse model of NF1. We chose one capsid variant, AAV-SC3, which was present in NF1 nerves for comparison to two benchmark capsids after systemic injection. AAV-SC3 significantly outperformed one of the two benchmark capsids at levels of transgene mRNA in the neurofibroma. Immunofluorescence microscopy revealed transgene expressing Sox10-positive SCs throughout the neurofibroma with AAV-SC3 injection. Next, we performed a pooled screen with four of the top capsids from our initial selection and AAV9 and identified one capsid, AAV-SC4, with enhanced biodistribution to and transduction of normal sciatic nerve in mice. This capsid displayed a peptide with a known laminin-binding motif, which may provide a conduit for future laminin-targeting strategies. Our results provide a baseline for future AAV-based gene therapies developed for NF1 or other diseases that affect SCs.
2026-04-10 | Clinical and molecular characterization of a novel pathogenic AIFM1 E336K mutation connecting mitochondrial dysfunction and neurodegeneration.
Mutations in the AIFM1 gene, encoding the apoptosis-inducing factor (AIF), have been associated with a spectrum of neurometabolic disorders. However, the mechanistic basis underlying their pathogenicity remains poorly understood. In this work, we identified and comprehensively characterized a novel hemizygous AIFM1 mutation c.1006G > A (E336K) in a male patient presenting with a progressive hereditary axonal sensorimotor polyneuropathy with childhood onset, inherited in an X-linked recessive pattern, associated with sensorineural hearing loss and without cognitive impairment. The clinical phenotype was consistent with Charcot-Marie-Tooth disease type 4 (CMTX4). Patient-derived fibroblasts exhibited reduced AIF protein stability despite preserved mRNA expression, impaired growth in OXPHOS-dependent conditions, decreased basal respiration, and altered assembly of mitochondrial respiratory supercomplexes. These defects were accompanied by reduced CHCHD4 protein levels and mitochondrial content. The purified E336K protein exhibited compromised FAD retention, decreased thermal stability, impaired NADH affinity, destabilization of the charge-transfer complex crucial for sustaining the AIF: CHCHD4 interaction, and a shift in coenzyme preference toward NADPH. Structurally, the substitution of Glu336 with Lys remodels the electrostatic environment of the NADH-binding cleft, thereby compromising redox function and weakening CHCHD4 binding. Despite these defects, the protein with the E336K mutation retained DNA binding, nuclease activity, and binding to nuclear partners, although parthanatos induction was attenuated in patient fibroblasts. Collectively, these molecular alterations converge on defective mitochondrial bioenergetics and dynamics, providing a direct mechanistic link to the patient’s clinical evolution.These findings provide a framework for understanding AIFM1-related disorders and pave the way for the development of future personalized molecular therapies.
2025-09-15 | Effectiveness of Sitagliptin and Empagliflozin Combination Therapy in a Patient With Charcot-Marie-Tooth Disease and Comorbid Diabetes Mellitus: A Case Report.
This case report describes a 61-year-old male with Charcot-Marie-Tooth disease type 1A (CMT1A) who developed poorly controlled type 2 diabetes mellitus. The patient, with a history of CMT1A, was admitted for preoperative glycemic management prior to lumbar spinal stenosis surgery, exhibiting an HbA1c of 8.1%. Treatment with metformin had been insufficient. Considering potential insulin resistance due to decreased skeletal muscle mass from CMT and reduced mobility, a combination therapy of the DPP-4 inhibitor sitagliptin and the SGLT2 inhibitor empagliflozin was initiated post-surgery, alongside diet and exercise. Notably, this combination effectively improved glycemic control without reducing skeletal muscle mass. This suggests that the combination of a DPP-4 inhibitor and an SGLT2 inhibitor may be a viable therapeutic option for managing diabetes mellitus in patients with CMT, warranting further investigation in larger studies due to the rarity of this comorbidity. Long-term glycemic control is crucial for maintaining activities of daily living (ADLs) and quality of life (QOL) in these patients.
2025-08-01 | Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy.
Autosomal recessive mutations in the SH3TC2 gene cause Charcot-Marie-Tooth type 4C (CMT4C) demyelinating peripheral neuropathy. In this nationwide observational retrospective study involving 27 French University Hospitals, we analyzed the clinical, electrophysiological, and genetic features of 103 patients from 89 families with homozygous and compound heterozygous SH3TC2 gene mutations identified between 2003 and 2023. Mean age was 42 years (2-80), and 49% of patients were female. Mean age at disease onset was 14 years (0-52), 60% of patients started the disease before age 10 years, and 24% after age 20 years. Patients presented with distal motor weakness (93% of cases), sensory loss (86%), foot deformities (83%), scoliosis (73%), proximal limb weakness (40%), cranial nerve involvement (48%), hearing loss (37%), scoliosis-related respiratory insufficiency (14%), and genitourinary disorders (6%). Half the patients (48%) walked independently before age 50 years, in contrast with only 13% after age 50 years. After age 50 years, 23% of patients were wheelchair-bound. Nerve conduction studies showed sensorimotor abnormalities within the demyelinating range in all cases. We identified 56 different pathogenic variants in the SH3TC2 gene, including 22 previously undescribed. Patients with two SH3TC2 gene truncating variants had more severe symptoms than patients with one or zero truncating variants. This study shows CMT4C is a severe childhood- and adult-onset demyelinating peripheral neuropathy often associated with scoliosis, hearing loss, and ambulation loss in a significant proportion of patients after age 50 years. Genotype-phenotype correlations suggest two truncating SH3TC2 gene variants cause a more severe phenotype.
2025-07-07 | Increased BNIP3-mediated mitophagy attenuates GDAP1 loss of function - implications for Charcot-Marie-Tooth disease 4A.
Charcot-Marie-Tooth disease type 4 A ((CMT4A), an autosomal recessive neuropathy, is caused by mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1). GDAP1 resides in the outer mitochondrial membrane facing the cytosol and is involved in mitochondrial dynamics and function. Its perturbation affects mitochondrial shape, contact sites, redox homeostasis and cellular metabolism. In response to GDAP1 knockdown in a human neuronal cell line, we found increased mitochondrial turnover, biogenesis and mitophagy. This was associated with more lysosomal proteins in mitochondrial fractions including BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and its homolog BNIP3-like (BNIP3L) - proteins involved in the recruitment of autophagy machinery via direct interaction. Flies with neural Gdap1 knockdown also exhibited upregulated levels of the sole BNIP3 ortholog. Neural expression of human BNIP3 reduced the detrimental effects of Gdap1 knockdown on eclosion and climbing ability in adult flies, while simultaneous knockdown of both genes was detrimental. These findings suggest that increased BNIP3-driven mitophagy may act as a protective mechanism, partially counteracting the cellular dysfunction caused by GDAP1 loss of function, and highlight the potential of targeting mitophagy pathways as a therapeutic strategy for CMT4A.
2025-06-11 | Engineered AAV capsids mediate transduction of murine neurofibroma and sciatic nerve.
Genetic diseases such as Neurofibromatosis type 1 (NF1) and Charcot-Marie Tooth disease involve Schwann cells (SCs) associated with peripheral nerves. Gene therapy using adeno-associated virus (AAV) vector mediated gene delivery is a promising strategy to treat these diseases. However, AAV-mediated transduction of SCs in vivo after intravascular delivery is relatively inefficient, with a lack of extensive characterization of different capsids to date. Here, we performed an in vivo selection with an AAV9 capsid peptide display library in a mouse model of NF1. We chose one capsid variant, AAV-SC3, which was present in NF1 nerves for comparison to two benchmark capsids after systemic injection. AAV-SC3 significantly outperformed one of the two benchmark capsids at levels of transgene mRNA in the neurofibroma. Immunofluorescence microscopy revealed transgene expressing Sox10-positive SCs throughout the neurofibroma with AAV-SC3 injection. Next, we performed a pooled screen with four of the top capsids from our initial selection and AAV9 and identified one capsid, AAV-SC4, with enhanced biodistribution to and transduction of normal sciatic nerve in mice. This capsid displayed a peptide with a known laminin-binding motif, which may provide a conduit for future laminin-targeting strategies. Our results provide a baseline for future AAV-based gene therapies developed for NF1 or other diseases that affect SCs.
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