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
57
papers
On emerging therapies
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:
categories:
Small molecules
proteins
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.
2025-01-01 | The role of Rab proteins in phosphatidylinositol 3,5-bisphosphate- mediated cellular traffic and signalling
Patients suffering from the peripheral neuropathy Charcot-Marie-Tooth type 4B (CMT4B) present mutations in three proteins which belong to the same enzymatic complex acting to dephosphorylate the phosphoinositide lipids phosphatidylinositol 3-phosphate (PI3P) and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2). Either of the catalytically inactive myotubularin-related proteins (MTMR) 5 and 13 forms a complex with the catalytically active MTMR2 to enhance its phosphatase activity toward PI3P and PI(3,5)P2; additionally, MTMR5 and 13 act as activators of small GTPases (involved in protein recruitment to intracellular membranes) through their N-terminal DENN domain. Previous studies isolated the small GTPase Rab35 as a strong interactor with Sbf, the Drosophila melanogaster homologue for MTMR13, but did not pursue this interaction. As it indicates a potential role for the mammalian Rab35 in MTMR13-mediated processes, and thus in CMT4B, I aimed to investigate the interaction of MTMR13 with Rab35 in mammalian cells in the context of CMT4B. We first looked at a CMT4 disease mutant of MTMR13 lacking the last 80 amino acids of the DENN domain (MTMR13Δ) and found that while Rab35 interacts with MTMR13, it does not with MTMR13Δ. We continued to study the interaction by truncating MTMR13; pull-downs with Rab35 show that the DENN domain or the linker between the DENN domain and the subsequent GRAM domain independently do not bind Rab35, indicating that they are necessary but not sufficient for the interaction. However, when we truncated the protein after the first 869 amino acids, thus isolating the DENN domain and the DENN-GRAM linker (a construct we refer to as 869*), this construct strongly interacts with Rab35. Pull-downs with constitutively active or dominant negative Rab35 show that 869* binds both forms, possibly indicating that 869* traps Rab35 in an intermediate stage. 869* localises to dynamic intracellular structures resembling circles, dots, and tubules, and recruits Rab35 to these specific locations. 869* frequently encircles (i.e. appears to coat) markers of lysosomes and occasionally colocalises with them (i.e. appears to be on the same membrane). Under starvation it colocalises or is contiguous with LC3-II-positive structures, and we observed it triggers a delay in the formation of LC3-II punctae in cell expressing 869*. In order to distinguish between endosomal and lysosomal compartments, we treated cells expressing 869* with dextran. After washout dextran-positive vesicles are coated in 869*. Dextran does not exit these compartments and there is a decrease in dextran intensity, indicating it is degraded. Therefore 869* possibly coats terminal stations. LAMP1-positive structures that are either coated by a circular 869* structure or co-localise with 869*-positive rods appear enlarged and are dynamic: a tube coming off an 869* structure surrounding LAMP1 or co-localising with LAMP1 appears to transport LAMP1. We also observe no homotypic fusion of LAMP1 structures when one of them colocalises with, or encircles, 869*, and less dynamic LAMP1-positive structures when coated with 869* than when colocalising with 869* tubules. Lastly, LAMP2 is redistributed to the cell periphery. We further studied the structure of 869*-positive organelles using correlative light and electron microscopy. We found that 869* structures are coated in a filamentous array resembling a helical polymer, similar to complexes containing BAR-domain proteins, such as the retromer. Taken together our data indicate that 869* is likely involved in autophagosome maturation and fusion with lysosomes, and thus may be an intermediate in the formation of autolysosomes.
2024-05-01 | Deciphering the complexity of IGHMBP2 mutations : respiratory deficits as prognostic indicators of lifespan
According to the National Institutes of Health (NIH), over 10,000 rare diseases have been identified, impacting approximately 1 in 10 individuals, totaling around 30 million people in the United States. Nearly 90 percent of neuromuscular diseases (NMDs) fall under the category of rare diseases. Despite their low prevalence, NMDs are collectively common conditions. NMDs encompass a diverse range of neurological disorders, constituting a significant contributor to mortality and lifelong disability in both children and adults. NMDs include 5q-spinal muscular atrophy (SMA), spinal muscular atrophy with respiratory distress type 1 (SMARD1), and Charcot Marie Tooth Type 2S (CMT2S). SMA is a motor neuron disease caused by autosomal recessive mutations in the survival motor neuron gene 1 (SMN1) [1]. SMA is one of the most common genetic causes of infant mortality, with an incidence of 1:10,000 [2]. Progressive muscle weakness begins proximally and develops distally with the initial sparing of the diaphragm. As the disease progresses, intercostal muscles become weak, leading to thoracoabdominal asynchrony, a bell-shaped chest, and, eventually, respiratory failure [3]. In contrast, mutations in the immunoglobulin µ-DNA binding protein 2 human gene (IGHMBP2) gene on Chromosome 11q13 give rise to two different autosomal recessive diseases, SMARD1 and CMT2S. The first cases of SMARD1 were described in 1974 [4]. However, these putative SMARD1 cases were thought to be unusual presentations of an unknown etiology causing the most acute type of SMA, Werdnig Hoffman disease (SMA type 1). SMARD1 is a devastating disease: patients present with respiratory distress 1-2 months after birth due to bilateral diaphragmatic weakness and eventration, while xiv progressive distal to proximal muscle defects were not apparent until 3-4 months of age [4]. Conversely, the milder axonal neuropathy, CMT2S, was not described until 2014, after exome sequencing of two English female patients diagnosed previously with CMT2 but with no identified mutation [5]. In this work, we characterize a novel model for CMT2S, Ighmbp2H922Y/H922Y, and the first compound heterozygous model of SMARD1, Ighmbp2D564N/H922Y. Our studies delve into the intricate role of IGHMBP2 in the pathogenesis of SMARD1 and CMT2S, revealing significant differences between mouse models with homozygous recessive and compound heterozygous mutations. The H922Y homozygous mice exhibited a normal lifespan and did not display respiratory deficiencies. Mild motor function defects emerged later in life, consistent with CMT2S disease progression. Notably, lifespan cohorts in D564N/H922Y mice exhibited three distinct groups, contrasting with H922Y homozygous mice, which showed no reduction in lifespan. A groundbreaking aspect of the research is the identification of early respiratory pathology as a critical predictor of lifespan within the D564N/H922Y survival cohorts, independent of limb pathology. Moreover, this study uniquely separates IGHMBP2 function in respiration from limb motor function, underscoring the significant improvement in lifespan and fitness by reducing respiratory deficits. The findings establish a direct correlation between IGHMBP2 biochemical activity and disease pathogenesis associated with patient mutations in humans and mice, advancing our understanding of IGHMBP2 function and its impact on disease progression.
2019-07-11 | An In Vitro Model of Charcot-Marie-Tooth Disease Type 4B2 Provides Insight Into the Roles of MTMR13 and MTMR2 in Schwann Cell Myelination.
Charcot-Marie-Tooth Disorder Type 4B (CMT4B) is a demyelinating peripheral neuropathy caused by mutations in myotubularin-related (MTMR) proteins 2, 13, or 5 (CMT4B1/2/3), which regulate phosphoinositide turnover and endosomal trafficking. Although mouse models of CMT4B2 exist, an in vitro model would make possible pharmacological and reverse genetic experiments needed to clarify the role of MTMR13 in myelination. We have generated such a model using Schwann cell-dorsal root ganglion (SC-DRG) explants from Mtmr13-/- mice. Myelin sheaths in mutant cultures contain outfoldings highly reminiscent of those observed in the nerves of Mtmr13-/- mice and CMT4B2 patients. Mtmr13-/- SC-DRG explants also contain reduced Mtmr2, further supporting a role of Mtmr13 in stabilizing Mtmr2. Elevated PI(3,5)P2 has been implicated as a cause of myelin outfoldings in Mtmr2-/- models. In contrast, the role of elevated PI3P or PI(3,5)P2 in promoting outfoldings in Mtmr13-/- models is unclear. We found that over-expression of MTMR2 in Mtmr13-/- SC-DRGs moderately reduced the prevalence of myelin outfoldings. Thus, a manipulation predicted to lower PI3P and PI(3,5)P2 partially suppressed the phenotype caused by Mtmr13 deficiency. We also explored the relationship between CMT4B2-like myelin outfoldings and kinases that produce PI3P and PI(3,5)P2 by analyzing nerve pathology in mice lacking both Mtmr13 and one of two specific PI 3-kinases. Intriguingly, the loss of vacuolar protein sorting 34 or PI3K-C2β in Mtmr13-/- mice had no impact on the prevalence of myelin outfoldings. In aggregate, our findings suggest that the MTMR13 scaffold protein likely has critical functions other than stabilizing MTMR2 to achieve an adequate level of PI 3-phosphatase activity.
2009-08-03 | Dlg1, Sec8, and Mtmr2 regulate membrane homeostasis in Schwann cell myelination.
How membrane biosynthesis and homeostasis is achieved in myelinating glia is mostly unknown. We previously reported that loss of myotubularin-related protein 2 (MTMR2) provokes autosomal recessive demyelinating Charcot-Marie-Tooth type 4B1 neuropathy, characterized by excessive redundant myelin, also known as myelin outfoldings. We generated a Mtmr2-null mouse that models the human neuropathy. We also found that, in Schwann cells, Mtmr2 interacts with Discs large 1 (Dlg1), a scaffold involved in polarized trafficking and membrane addition, whose localization in Mtmr2-null nerves is altered. We here report that, in Schwann cells, Dlg1 also interacts with kinesin 13B (kif13B) and Sec8, which are involved in vesicle transport and membrane tethering in polarized cells, respectively. Taking advantage of the Mtmr2-null mouse as a model of impaired membrane formation, we provide here the first evidence for a machinery that titrates membrane formation during myelination. We established Schwann cell/DRG neuron cocultures from Mtmr2-null mice, in which myelin outfoldings were reproduced and almost completely rescued by Mtmr2 replacement. By exploiting this in vitro model, we propose a mechanism whereby kif13B kinesin transports Dlg1 to sites of membrane remodeling where it coordinates a homeostatic control of myelination. The interaction of Dlg1 with the Sec8 exocyst component promotes membrane addition, whereas with Mtmr2, negatively regulates membrane formation. Myelin outfoldings thus arise as a consequence of the loss of negative control on the amount of membrane, which is produced during myelination.
small molecules
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.
2025-01-18 | Phosphodiesterase 4D inhibition improves the functional and molecular outcome in a mouse and human model of Charcot Marie Tooth disease 1 A.
Charcot-Marie-Tooth disease type 1A (CMT1A) is an inherited peripheral neuropathy caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. It is primarily marked by Schwann cell dedifferentiation and demyelination, leading to motor and sensory deficits. Cyclic adenosine monophosphate (cAMP) is crucial for Schwann cell differentiation and maturation. Therefore, increasing cAMP by inhibiting its degraders, phosphodiesterases (PDE), is a potential therapeutic strategy for CMT1A. This study investigated the therapeutic potential of the specific PDE4D inhibitor Gebr32a using the C3-PMP22 mouse model for CMT1A and patient-induced Pluripotent Stem Cell (iPSC)-derived Schwann cells. C3-PMP22 mice, injected subcutaneously with Gebr32a twice a day for 10 weeks, showed significantly increased nerve conduction in sciatic nerves compared to vehicle-injected controls, indicating improved myelination. Additionally, Gebr32a-treated C3-PMP22 mice exhibited improved sensorimotor functions. Grip strength analysis revealed significantly increased strength in all limbs of Gebr32a-treated C3-PMP22 mice. Post-mortem histological and ultrastructural analysis confirmed enhanced myelination in the sciatic nerve of treated mice compared to controls. In primary mouse CMT1A Schwann cells, Gebr32a dose-dependently increased the expression of pro-myelinating genes such as oct6, Krox20, Mbp, Mpz, and Plp, while downregulating the dedifferentiation marker c-Jun and human PMP22. Similar effects on gene expression were observed in iPSC-derived Schwann cells from a CMT1A patient, highlighting the clinical relevance of our findings. In conclusion, inhibition of PDE4D with Gebr32a improves the functional and molecular outcomes in mouse and human models of CMT1A, highlighting its potential as a new therapeutic strategy for CMT1A disease management.
2024-01-09 | A Novel Mutation in Frabin (FGD4) Causing a Mild Phenotype of CMT4H in an Indian Patient.
Charcot-Marie-Tooth disease 4H(CMT4H) is an autosomal recessive demyelinating form of CMT caused by FGD4/FRABIN mutations. CMT4H is characterized by early onset and slowly progressing motor and sensory deficits in the distal extremities, along with foot deformities. We describe a patient with CMT4H who presented with rapidly progressing flaccid quadriparesis during the postpartum period, which improved significantly with steroid therapy. Magnetic resonance imaging and ultrasonography demonstrated considerable nerve thickening with increased cross-sectional area in the peripheral nerves. A nerve biopsy revealed significant demyelination and myelin outfolding. This is the first report of an Indian patient with a novel homozygous nonsense c.1672C>T (p.Arg558Ter) mutation in the FGD4 gene, expanding the mutational and phenotypic spectrum of this disease.
2024-01-01 | P668: PMP22 single exon deletion in a proband with hematologic malignancy and family history of Charcot-Marie-Tooth disease
Charcot-Marie Tooth disease (CMT) is a group of hereditary sensory polyneuropathies that characteristically result in distal muscle weakness and atrophy alongside impaired deep tendon reflexes and pes cavus formation. Symptoms typically occur in the first to third decade and are slowly progressive but can be exacerbated by neurotoxic chemotherapeutic agents. Duplications or gain-of-function variants in the PMP22 gene cause autosomal dominant CMT types 1A and 1E, while loss-of-function changes underlie the allelic condition Hereditary Neuropathy with Liability to Pressure Palsies (HNPP). A four-year-old female presented with acute lymphoblastic leukemia (ALL) and a family history of CMT. The proband's father had experienced delayed walking, toe walking, and frequent falls since childhood and was formally diagnosed at age 23 with CMT1A by PMP22-specific testing which identified an atypical deletion of exon 4. His similarly affected twin brother has not undergone genetic testing and has two sons aged 9 and 11 who are share these symptoms. The proband, who did not show signs of neuropathy, required a timely assessment of the known familial PMP22 variant to guide her chemotherapy treatment. A custom, high-resolution chromosomal microarray (CMA) with >400k probes and exon-targeted coverage detected the familial single exon deletion of less than 1 kb in size. No additional copy number variants related to her ALL diagnosis were identified. Although this variant results in the loss of PMP22 material, previously reported functional studies in unrelated patients with CMT type 1E suggest that this in-frame PMP22 exon 4 deletion invokes a toxic gain-of-function effect. The mutant protein frequently forms aggregates, which are retained in the endoplasmic reticulum and fail to reach the plasma membrane. The detection of the familial PMP22 exon 4 deletion resulted in the selection of a chemotherapeutic agent with a reduced risk of neurotoxicity to not hasten the onset of CMT symptoms in the proband. The patient's CMA results had higher resolution than father's previous testing – in turn, providing him with an updated and more accurate diagnosis. This case provides an example of an atypical gain-of-function change caused by an intragenic PMP22 loss that results in a CMT type 1E phenotype. High-resolution exon-level CMA coverage is critical for the detection of such single exon variants. Moreover, this case highlights the importance of testing for familial CMT variants before chemotherapy treatment to avoid irreversible symptom exacerbation, especially in cases of pediatric malignancy occurring before the natural onset of any CMT symptoms.
2023-05-05 | Imbalance of NRG1-ERBB2/3 signalling underlies altered myelination in Charcot-Marie-Tooth disease 4H.
Charcot-Marie-Tooth (CMT) disease is one of the most common inherited neurological disorders, affecting either axons from the motor and/or sensory neurons or Schwann cells of the peripheral nervous system (PNS) and caused by more than 100 genes. We previously identified mutations in FGD4 as responsible for CMT4H, an autosomal recessive demyelinating form of CMT disease. FGD4 encodes FRABIN, a GDP/GTP nucleotide exchange factor, particularly for the small GTPase Cdc42. Remarkably, nerves from patients with CMT4H display excessive redundant myelin figures called outfoldings that arise from focal hypermyelination, suggesting that FRABIN could play a role in the control of PNS myelination. To gain insights into the role of FGD4/FRABIN in Schwann cell myelination, we generated a knockout mouse model (Fgd4SC-/-), with conditional ablation of Fgd4 in Schwann cells. We show that the specific deletion of FRABIN in Schwann cells leads to aberrant myelination in vitro, in dorsal root ganglia neuron/Schwann cell co-cultures, as well as in vivo, in distal sciatic nerves from Fgd4SC-/- mice. We observed that those myelination defects are related to an upregulation of some interactors of the NRG1 type III/ERBB2/3 signalling pathway, which is known to ensure a proper level of myelination in the PNS. Based on a yeast two-hybrid screen, we identified SNX3 as a new partner of FRABIN, which is involved in the regulation of endocytic trafficking. Interestingly, we showed that the loss of FRABIN impairs endocytic trafficking, which may contribute to the defective NRG1 type III/ERBB2/3 signalling and myelination. Using RNA-Seq, in vitro, we identified new potential effectors of the deregulated pathways, such as ERBIN, RAB11FIP2 and MAF, thereby providing cues to understand how FRABIN contributes to proper ERBB2 trafficking or even myelin membrane addition through cholesterol synthesis. Finally, we showed that the re-establishment of proper levels of the NRG1 type III/ERBB2/3 pathway using niacin treatment reduces myelin outfoldings in nerves of CMT4H mice. Overall, our work reveals a new role of FRABIN in the regulation of NRG1 type III/ERBB2/3 NRG1signalling and myelination and opens future therapeutic strategies based on the modulation of the NRG1 type III/ERBB2/3 pathway to reduce CMT4H pathology and more generally other demyelinating types of CMT disease.
gene therapies
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.
2025-08-01 | 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.
2025-06-11 | 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.
2025-04-23 | A Novel Mutation in CNTNAP1 Gene Causes Disorganization of Axonal Domains, Hypomyelination and Severe Neurological Deficits.
CNTNAP1 encodes the contactin-associated protein 1 (Cntnap1) which localizes to the paranodal region in all myelinated axons and is essential for axonal domain organization and the propagation of action potentials. To date, close to 45 reported human CNTNAP1 variants have been identified that are associated with dysregulation and disorganization of the axonal domains, resulting in various forms of congenital hypomyelinating neuropathies in children. Currently, no treatments are available for neuropathies caused by CNTNAP1 variants, highlighting the importance of fully characterizing these mutations and their impact on Cntnap1 functions. To understand the importance of a novel human CNTNAP1 likely pathogenic variant that changes glycine at position 349 to valine in a child who also carries a CNTNAP1 truncation and displayed severe neurological deficits, we used CRISPR/Cas9 methodology and introduced a single nucleotide substitution in the mouse Cntnap1 gene, resulting in glycine at 350 to valine (Cntnap1G350V). Trans-allelic combination of Cntnap1G350V with a Cntnap1 null allele (Cntnap1G350V/-) mimics human pathologies, recapitulating hypomyelination neuropathies associated with CNTNAP1 mutations as well as loss of paranodal junctions and disorganization of axonal domains in myelinated axons. Expression of the wild type Cntnap1 transgene in Cntnap1G350V/- mice rescued the mutant phenotypes and restored all neurological deficits. Our studies demonstrate that GGT (glycine) to GTT (valine) change in human CNTNAP1 creates a recessive loss of function allele and lays the foundation for potential gene therapy studies aimed at treating CNTNAP1-associated hypomyelinating neuropathies in children.
2025-01-08 | Delineating the genetic landscape of Charcot-Marie-tooth disease in Türkiye: Distinct distribution, rare phenotypes, and novel variants.
Charcot-Marie-Tooth (CMT) disease is the most common inherited neuropathy. In this study, we aimed to analyze the genetic spectrum and describe phenotypic features in a large cohort from Türkiye. Demographic and clinical findings were recorded. Patients were initially screened for PMP22 duplication. Targeted sequencing or whole-exome sequencing was performed in duplication-negative patients. Overall, 311 patients from 265 families were included. Demyelinating CMT (67.4%) was more common than axonal (20.5%) and intermediate subtypes (11.7%). PMP22 duplication was the most frequent mutation, followed by pathogenic variants in GJB1, MFN2, SH3TC2, and GDAP1 genes. MPZ-neuropathy was rare in our cohort (3.0%). Interestingly, CMT4 is the second most common type after CMT1. Lower extremity weakness and foot deformities were the most frequent presenting complaints. Striking clinical features included a high frequency of scoliosis in SH3TC2, peripheral hyperexcitability in HINT1, and central nervous system findings in GJB1. Autosomal recessive CMT subtypes had higher CMTESv2 scores when compared to autosomal dominant ones (12.39 ± 4.81 vs. 8.36 ± 4.15, p: 0.023). Twenty-one patients used wheelchairs during their last examination. Among them, 16 had an autosomal recessive subtype. Causative variants were identified in 31 genes, including 28 novel pathogenic or likely pathogenic changes. Our findings provided robust data regarding the genetic distribution of CMT in Türkiye, which may pave the path for building population-specific diagnostic gene panels. Rare autosomal recessive subtypes were relatively frequent in our cohort. By analyzing genotype-phenotype correlations, our data may provide clinical clues for clinicians.
proteins
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.
2025-01-01 | The role of Rab proteins in phosphatidylinositol 3,5-bisphosphate- mediated cellular traffic and signalling
Patients suffering from the peripheral neuropathy Charcot-Marie-Tooth type 4B (CMT4B) present mutations in three proteins which belong to the same enzymatic complex acting to dephosphorylate the phosphoinositide lipids phosphatidylinositol 3-phosphate (PI3P) and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2). Either of the catalytically inactive myotubularin-related proteins (MTMR) 5 and 13 forms a complex with the catalytically active MTMR2 to enhance its phosphatase activity toward PI3P and PI(3,5)P2; additionally, MTMR5 and 13 act as activators of small GTPases (involved in protein recruitment to intracellular membranes) through their N-terminal DENN domain. Previous studies isolated the small GTPase Rab35 as a strong interactor with Sbf, the Drosophila melanogaster homologue for MTMR13, but did not pursue this interaction. As it indicates a potential role for the mammalian Rab35 in MTMR13-mediated processes, and thus in CMT4B, I aimed to investigate the interaction of MTMR13 with Rab35 in mammalian cells in the context of CMT4B. We first looked at a CMT4 disease mutant of MTMR13 lacking the last 80 amino acids of the DENN domain (MTMR13Δ) and found that while Rab35 interacts with MTMR13, it does not with MTMR13Δ. We continued to study the interaction by truncating MTMR13; pull-downs with Rab35 show that the DENN domain or the linker between the DENN domain and the subsequent GRAM domain independently do not bind Rab35, indicating that they are necessary but not sufficient for the interaction. However, when we truncated the protein after the first 869 amino acids, thus isolating the DENN domain and the DENN-GRAM linker (a construct we refer to as 869*), this construct strongly interacts with Rab35. Pull-downs with constitutively active or dominant negative Rab35 show that 869* binds both forms, possibly indicating that 869* traps Rab35 in an intermediate stage. 869* localises to dynamic intracellular structures resembling circles, dots, and tubules, and recruits Rab35 to these specific locations. 869* frequently encircles (i.e. appears to coat) markers of lysosomes and occasionally colocalises with them (i.e. appears to be on the same membrane). Under starvation it colocalises or is contiguous with LC3-II-positive structures, and we observed it triggers a delay in the formation of LC3-II punctae in cell expressing 869*. In order to distinguish between endosomal and lysosomal compartments, we treated cells expressing 869* with dextran. After washout dextran-positive vesicles are coated in 869*. Dextran does not exit these compartments and there is a decrease in dextran intensity, indicating it is degraded. Therefore 869* possibly coats terminal stations. LAMP1-positive structures that are either coated by a circular 869* structure or co-localise with 869*-positive rods appear enlarged and are dynamic: a tube coming off an 869* structure surrounding LAMP1 or co-localising with LAMP1 appears to transport LAMP1. We also observe no homotypic fusion of LAMP1 structures when one of them colocalises with, or encircles, 869*, and less dynamic LAMP1-positive structures when coated with 869* than when colocalising with 869* tubules. Lastly, LAMP2 is redistributed to the cell periphery. We further studied the structure of 869*-positive organelles using correlative light and electron microscopy. We found that 869* structures are coated in a filamentous array resembling a helical polymer, similar to complexes containing BAR-domain proteins, such as the retromer. Taken together our data indicate that 869* is likely involved in autophagosome maturation and fusion with lysosomes, and thus may be an intermediate in the formation of autolysosomes.
2024-05-01 | Deciphering the complexity of IGHMBP2 mutations : respiratory deficits as prognostic indicators of lifespan
According to the National Institutes of Health (NIH), over 10,000 rare diseases have been identified, impacting approximately 1 in 10 individuals, totaling around 30 million people in the United States. Nearly 90 percent of neuromuscular diseases (NMDs) fall under the category of rare diseases. Despite their low prevalence, NMDs are collectively common conditions. NMDs encompass a diverse range of neurological disorders, constituting a significant contributor to mortality and lifelong disability in both children and adults. NMDs include 5q-spinal muscular atrophy (SMA), spinal muscular atrophy with respiratory distress type 1 (SMARD1), and Charcot Marie Tooth Type 2S (CMT2S). SMA is a motor neuron disease caused by autosomal recessive mutations in the survival motor neuron gene 1 (SMN1) [1]. SMA is one of the most common genetic causes of infant mortality, with an incidence of 1:10,000 [2]. Progressive muscle weakness begins proximally and develops distally with the initial sparing of the diaphragm. As the disease progresses, intercostal muscles become weak, leading to thoracoabdominal asynchrony, a bell-shaped chest, and, eventually, respiratory failure [3]. In contrast, mutations in the immunoglobulin µ-DNA binding protein 2 human gene (IGHMBP2) gene on Chromosome 11q13 give rise to two different autosomal recessive diseases, SMARD1 and CMT2S. The first cases of SMARD1 were described in 1974 [4]. However, these putative SMARD1 cases were thought to be unusual presentations of an unknown etiology causing the most acute type of SMA, Werdnig Hoffman disease (SMA type 1). SMARD1 is a devastating disease: patients present with respiratory distress 1-2 months after birth due to bilateral diaphragmatic weakness and eventration, while xiv progressive distal to proximal muscle defects were not apparent until 3-4 months of age [4]. Conversely, the milder axonal neuropathy, CMT2S, was not described until 2014, after exome sequencing of two English female patients diagnosed previously with CMT2 but with no identified mutation [5]. In this work, we characterize a novel model for CMT2S, Ighmbp2H922Y/H922Y, and the first compound heterozygous model of SMARD1, Ighmbp2D564N/H922Y. Our studies delve into the intricate role of IGHMBP2 in the pathogenesis of SMARD1 and CMT2S, revealing significant differences between mouse models with homozygous recessive and compound heterozygous mutations. The H922Y homozygous mice exhibited a normal lifespan and did not display respiratory deficiencies. Mild motor function defects emerged later in life, consistent with CMT2S disease progression. Notably, lifespan cohorts in D564N/H922Y mice exhibited three distinct groups, contrasting with H922Y homozygous mice, which showed no reduction in lifespan. A groundbreaking aspect of the research is the identification of early respiratory pathology as a critical predictor of lifespan within the D564N/H922Y survival cohorts, independent of limb pathology. Moreover, this study uniquely separates IGHMBP2 function in respiration from limb motor function, underscoring the significant improvement in lifespan and fitness by reducing respiratory deficits. The findings establish a direct correlation between IGHMBP2 biochemical activity and disease pathogenesis associated with patient mutations in humans and mice, advancing our understanding of IGHMBP2 function and its impact on disease progression.
2019-07-11 | An In Vitro Model of Charcot-Marie-Tooth Disease Type 4B2 Provides Insight Into the Roles of MTMR13 and MTMR2 in Schwann Cell Myelination.
Charcot-Marie-Tooth Disorder Type 4B (CMT4B) is a demyelinating peripheral neuropathy caused by mutations in myotubularin-related (MTMR) proteins 2, 13, or 5 (CMT4B1/2/3), which regulate phosphoinositide turnover and endosomal trafficking. Although mouse models of CMT4B2 exist, an in vitro model would make possible pharmacological and reverse genetic experiments needed to clarify the role of MTMR13 in myelination. We have generated such a model using Schwann cell-dorsal root ganglion (SC-DRG) explants from Mtmr13-/- mice. Myelin sheaths in mutant cultures contain outfoldings highly reminiscent of those observed in the nerves of Mtmr13-/- mice and CMT4B2 patients. Mtmr13-/- SC-DRG explants also contain reduced Mtmr2, further supporting a role of Mtmr13 in stabilizing Mtmr2. Elevated PI(3,5)P2 has been implicated as a cause of myelin outfoldings in Mtmr2-/- models. In contrast, the role of elevated PI3P or PI(3,5)P2 in promoting outfoldings in Mtmr13-/- models is unclear. We found that over-expression of MTMR2 in Mtmr13-/- SC-DRGs moderately reduced the prevalence of myelin outfoldings. Thus, a manipulation predicted to lower PI3P and PI(3,5)P2 partially suppressed the phenotype caused by Mtmr13 deficiency. We also explored the relationship between CMT4B2-like myelin outfoldings and kinases that produce PI3P and PI(3,5)P2 by analyzing nerve pathology in mice lacking both Mtmr13 and one of two specific PI 3-kinases. Intriguingly, the loss of vacuolar protein sorting 34 or PI3K-C2β in Mtmr13-/- mice had no impact on the prevalence of myelin outfoldings. In aggregate, our findings suggest that the MTMR13 scaffold protein likely has critical functions other than stabilizing MTMR2 to achieve an adequate level of PI 3-phosphatase activity.
2009-08-03 | Dlg1, Sec8, and Mtmr2 regulate membrane homeostasis in Schwann cell myelination.
How membrane biosynthesis and homeostasis is achieved in myelinating glia is mostly unknown. We previously reported that loss of myotubularin-related protein 2 (MTMR2) provokes autosomal recessive demyelinating Charcot-Marie-Tooth type 4B1 neuropathy, characterized by excessive redundant myelin, also known as myelin outfoldings. We generated a Mtmr2-null mouse that models the human neuropathy. We also found that, in Schwann cells, Mtmr2 interacts with Discs large 1 (Dlg1), a scaffold involved in polarized trafficking and membrane addition, whose localization in Mtmr2-null nerves is altered. We here report that, in Schwann cells, Dlg1 also interacts with kinesin 13B (kif13B) and Sec8, which are involved in vesicle transport and membrane tethering in polarized cells, respectively. Taking advantage of the Mtmr2-null mouse as a model of impaired membrane formation, we provide here the first evidence for a machinery that titrates membrane formation during myelination. We established Schwann cell/DRG neuron cocultures from Mtmr2-null mice, in which myelin outfoldings were reproduced and almost completely rescued by Mtmr2 replacement. By exploiting this in vitro model, we propose a mechanism whereby kif13B kinesin transports Dlg1 to sites of membrane remodeling where it coordinates a homeostatic control of myelination. The interaction of Dlg1 with the Sec8 exocyst component promotes membrane addition, whereas with Mtmr2, negatively regulates membrane formation. Myelin outfoldings thus arise as a consequence of the loss of negative control on the amount of membrane, which is produced during myelination.
small molecules
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.
2025-01-18 | Phosphodiesterase 4D inhibition improves the functional and molecular outcome in a mouse and human model of Charcot Marie Tooth disease 1 A.
Charcot-Marie-Tooth disease type 1A (CMT1A) is an inherited peripheral neuropathy caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. It is primarily marked by Schwann cell dedifferentiation and demyelination, leading to motor and sensory deficits. Cyclic adenosine monophosphate (cAMP) is crucial for Schwann cell differentiation and maturation. Therefore, increasing cAMP by inhibiting its degraders, phosphodiesterases (PDE), is a potential therapeutic strategy for CMT1A. This study investigated the therapeutic potential of the specific PDE4D inhibitor Gebr32a using the C3-PMP22 mouse model for CMT1A and patient-induced Pluripotent Stem Cell (iPSC)-derived Schwann cells. C3-PMP22 mice, injected subcutaneously with Gebr32a twice a day for 10 weeks, showed significantly increased nerve conduction in sciatic nerves compared to vehicle-injected controls, indicating improved myelination. Additionally, Gebr32a-treated C3-PMP22 mice exhibited improved sensorimotor functions. Grip strength analysis revealed significantly increased strength in all limbs of Gebr32a-treated C3-PMP22 mice. Post-mortem histological and ultrastructural analysis confirmed enhanced myelination in the sciatic nerve of treated mice compared to controls. In primary mouse CMT1A Schwann cells, Gebr32a dose-dependently increased the expression of pro-myelinating genes such as oct6, Krox20, Mbp, Mpz, and Plp, while downregulating the dedifferentiation marker c-Jun and human PMP22. Similar effects on gene expression were observed in iPSC-derived Schwann cells from a CMT1A patient, highlighting the clinical relevance of our findings. In conclusion, inhibition of PDE4D with Gebr32a improves the functional and molecular outcomes in mouse and human models of CMT1A, highlighting its potential as a new therapeutic strategy for CMT1A disease management.
2024-01-09 | A Novel Mutation in Frabin (FGD4) Causing a Mild Phenotype of CMT4H in an Indian Patient.
Charcot-Marie-Tooth disease 4H(CMT4H) is an autosomal recessive demyelinating form of CMT caused by FGD4/FRABIN mutations. CMT4H is characterized by early onset and slowly progressing motor and sensory deficits in the distal extremities, along with foot deformities. We describe a patient with CMT4H who presented with rapidly progressing flaccid quadriparesis during the postpartum period, which improved significantly with steroid therapy. Magnetic resonance imaging and ultrasonography demonstrated considerable nerve thickening with increased cross-sectional area in the peripheral nerves. A nerve biopsy revealed significant demyelination and myelin outfolding. This is the first report of an Indian patient with a novel homozygous nonsense c.1672C>T (p.Arg558Ter) mutation in the FGD4 gene, expanding the mutational and phenotypic spectrum of this disease.
2024-01-01 | P668: PMP22 single exon deletion in a proband with hematologic malignancy and family history of Charcot-Marie-Tooth disease
Charcot-Marie Tooth disease (CMT) is a group of hereditary sensory polyneuropathies that characteristically result in distal muscle weakness and atrophy alongside impaired deep tendon reflexes and pes cavus formation. Symptoms typically occur in the first to third decade and are slowly progressive but can be exacerbated by neurotoxic chemotherapeutic agents. Duplications or gain-of-function variants in the PMP22 gene cause autosomal dominant CMT types 1A and 1E, while loss-of-function changes underlie the allelic condition Hereditary Neuropathy with Liability to Pressure Palsies (HNPP). A four-year-old female presented with acute lymphoblastic leukemia (ALL) and a family history of CMT. The proband's father had experienced delayed walking, toe walking, and frequent falls since childhood and was formally diagnosed at age 23 with CMT1A by PMP22-specific testing which identified an atypical deletion of exon 4. His similarly affected twin brother has not undergone genetic testing and has two sons aged 9 and 11 who are share these symptoms. The proband, who did not show signs of neuropathy, required a timely assessment of the known familial PMP22 variant to guide her chemotherapy treatment. A custom, high-resolution chromosomal microarray (CMA) with >400k probes and exon-targeted coverage detected the familial single exon deletion of less than 1 kb in size. No additional copy number variants related to her ALL diagnosis were identified. Although this variant results in the loss of PMP22 material, previously reported functional studies in unrelated patients with CMT type 1E suggest that this in-frame PMP22 exon 4 deletion invokes a toxic gain-of-function effect. The mutant protein frequently forms aggregates, which are retained in the endoplasmic reticulum and fail to reach the plasma membrane. The detection of the familial PMP22 exon 4 deletion resulted in the selection of a chemotherapeutic agent with a reduced risk of neurotoxicity to not hasten the onset of CMT symptoms in the proband. The patient's CMA results had higher resolution than father's previous testing – in turn, providing him with an updated and more accurate diagnosis. This case provides an example of an atypical gain-of-function change caused by an intragenic PMP22 loss that results in a CMT type 1E phenotype. High-resolution exon-level CMA coverage is critical for the detection of such single exon variants. Moreover, this case highlights the importance of testing for familial CMT variants before chemotherapy treatment to avoid irreversible symptom exacerbation, especially in cases of pediatric malignancy occurring before the natural onset of any CMT symptoms.
2023-05-05 | Imbalance of NRG1-ERBB2/3 signalling underlies altered myelination in Charcot-Marie-Tooth disease 4H.
Charcot-Marie-Tooth (CMT) disease is one of the most common inherited neurological disorders, affecting either axons from the motor and/or sensory neurons or Schwann cells of the peripheral nervous system (PNS) and caused by more than 100 genes. We previously identified mutations in FGD4 as responsible for CMT4H, an autosomal recessive demyelinating form of CMT disease. FGD4 encodes FRABIN, a GDP/GTP nucleotide exchange factor, particularly for the small GTPase Cdc42. Remarkably, nerves from patients with CMT4H display excessive redundant myelin figures called outfoldings that arise from focal hypermyelination, suggesting that FRABIN could play a role in the control of PNS myelination. To gain insights into the role of FGD4/FRABIN in Schwann cell myelination, we generated a knockout mouse model (Fgd4SC-/-), with conditional ablation of Fgd4 in Schwann cells. We show that the specific deletion of FRABIN in Schwann cells leads to aberrant myelination in vitro, in dorsal root ganglia neuron/Schwann cell co-cultures, as well as in vivo, in distal sciatic nerves from Fgd4SC-/- mice. We observed that those myelination defects are related to an upregulation of some interactors of the NRG1 type III/ERBB2/3 signalling pathway, which is known to ensure a proper level of myelination in the PNS. Based on a yeast two-hybrid screen, we identified SNX3 as a new partner of FRABIN, which is involved in the regulation of endocytic trafficking. Interestingly, we showed that the loss of FRABIN impairs endocytic trafficking, which may contribute to the defective NRG1 type III/ERBB2/3 signalling and myelination. Using RNA-Seq, in vitro, we identified new potential effectors of the deregulated pathways, such as ERBIN, RAB11FIP2 and MAF, thereby providing cues to understand how FRABIN contributes to proper ERBB2 trafficking or even myelin membrane addition through cholesterol synthesis. Finally, we showed that the re-establishment of proper levels of the NRG1 type III/ERBB2/3 pathway using niacin treatment reduces myelin outfoldings in nerves of CMT4H mice. Overall, our work reveals a new role of FRABIN in the regulation of NRG1 type III/ERBB2/3 NRG1signalling and myelination and opens future therapeutic strategies based on the modulation of the NRG1 type III/ERBB2/3 pathway to reduce CMT4H pathology and more generally other demyelinating types of CMT disease.
gene therapies
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.
2025-08-01 | 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.
2025-06-11 | 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.
2025-04-23 | A Novel Mutation in CNTNAP1 Gene Causes Disorganization of Axonal Domains, Hypomyelination and Severe Neurological Deficits.
CNTNAP1 encodes the contactin-associated protein 1 (Cntnap1) which localizes to the paranodal region in all myelinated axons and is essential for axonal domain organization and the propagation of action potentials. To date, close to 45 reported human CNTNAP1 variants have been identified that are associated with dysregulation and disorganization of the axonal domains, resulting in various forms of congenital hypomyelinating neuropathies in children. Currently, no treatments are available for neuropathies caused by CNTNAP1 variants, highlighting the importance of fully characterizing these mutations and their impact on Cntnap1 functions. To understand the importance of a novel human CNTNAP1 likely pathogenic variant that changes glycine at position 349 to valine in a child who also carries a CNTNAP1 truncation and displayed severe neurological deficits, we used CRISPR/Cas9 methodology and introduced a single nucleotide substitution in the mouse Cntnap1 gene, resulting in glycine at 350 to valine (Cntnap1G350V). Trans-allelic combination of Cntnap1G350V with a Cntnap1 null allele (Cntnap1G350V/-) mimics human pathologies, recapitulating hypomyelination neuropathies associated with CNTNAP1 mutations as well as loss of paranodal junctions and disorganization of axonal domains in myelinated axons. Expression of the wild type Cntnap1 transgene in Cntnap1G350V/- mice rescued the mutant phenotypes and restored all neurological deficits. Our studies demonstrate that GGT (glycine) to GTT (valine) change in human CNTNAP1 creates a recessive loss of function allele and lays the foundation for potential gene therapy studies aimed at treating CNTNAP1-associated hypomyelinating neuropathies in children.
2025-01-08 | Delineating the genetic landscape of Charcot-Marie-tooth disease in Türkiye: Distinct distribution, rare phenotypes, and novel variants.
Charcot-Marie-Tooth (CMT) disease is the most common inherited neuropathy. In this study, we aimed to analyze the genetic spectrum and describe phenotypic features in a large cohort from Türkiye. Demographic and clinical findings were recorded. Patients were initially screened for PMP22 duplication. Targeted sequencing or whole-exome sequencing was performed in duplication-negative patients. Overall, 311 patients from 265 families were included. Demyelinating CMT (67.4%) was more common than axonal (20.5%) and intermediate subtypes (11.7%). PMP22 duplication was the most frequent mutation, followed by pathogenic variants in GJB1, MFN2, SH3TC2, and GDAP1 genes. MPZ-neuropathy was rare in our cohort (3.0%). Interestingly, CMT4 is the second most common type after CMT1. Lower extremity weakness and foot deformities were the most frequent presenting complaints. Striking clinical features included a high frequency of scoliosis in SH3TC2, peripheral hyperexcitability in HINT1, and central nervous system findings in GJB1. Autosomal recessive CMT subtypes had higher CMTESv2 scores when compared to autosomal dominant ones (12.39 ± 4.81 vs. 8.36 ± 4.15, p: 0.023). Twenty-one patients used wheelchairs during their last examination. Among them, 16 had an autosomal recessive subtype. Causative variants were identified in 31 genes, including 28 novel pathogenic or likely pathogenic changes. Our findings provided robust data regarding the genetic distribution of CMT in Türkiye, which may pave the path for building population-specific diagnostic gene panels. Rare autosomal recessive subtypes were relatively frequent in our cohort. By analyzing genotype-phenotype correlations, our data may provide clinical clues for clinicians.
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