Challenges in Treating Charcot-Marie-Tooth Disease and Related Neuropathies: Current Management and Future Perspectives

There is still no effective drug treatment available for Charcot-Marie-Tooth neuropathies (CMT). Current management relies on rehabilitation therapy, surgery for skeletal deformities, and symptomatic treatment of pain; fatigue and cramps are frequent complaints that are difficult to treat. The challenge is to find disease-modifying therapies. Several approaches, including gene silencing, to counteract the PMP22 gene overexpression in the most frequent CMT1A type are under investigation. PXT3003 is the compound in the most advanced phase for CMT1A, as a second-phase III trial is ongoing. Gene therapy to substitute defective genes or insert novel ones and compounds acting on pathways important for different CMT types are being developed and tested in animal models. Modulation of the Neuregulin pathway determining myelin thickness is promising for both hypo-demyelinating and hypermyelinating neuropathies; intervention on Unfolded Protein Response seems effective for rescuing misfolded myelin proteins such as P0 in CMT1B. HDAC6 inhibitors improved axonal transport and ameliorated phenotypes in different CMT models. Other potential therapeutic strategies include targeting macrophages, lipid metabolism, and Nav1.8 sodium channel in demyelinating CMT and the P2X7 receptor, which regulates calcium influx into Schwann cells, in CMT1A. Further approaches are aimed at correcting metabolic abnormalities, including the accumulation of sorbitol caused by biallelic mutations in the sorbitol dehydrogenase (SORD) gene and of neurotoxic glycosphingolipids in HSN1.

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A de novo variant of POLR3B causes demyelinating Charcot-Marie-Tooth disease in a Chinese patient: a case report

BMC Neurology ◽

10.1186/s12883-021-02399-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yan-Yan Xue ◽

Hao-Ling Cheng ◽

Hai-Lin Dong ◽

Hou-Min Yin ◽

Yun Yuan ◽

...

Keyword(s):

De Novo ◽

Hypogonadotropic Hypogonadism ◽

Chinese Patient ◽

Sensory Loss ◽

Neurological Involvement ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Progressive Muscle Weakness ◽

Demyelinating Peripheral Neuropathy ◽

Biallelic Mutations

Abstract Background Charcot-Marie-Tooth (CMT) disease is a group of inherited peripheral neuropathies, which are subdivided into demyelinating and axonal forms. Biallelic mutations in POLR3B are the well-established cause of hypomyelinating leukodystrophy, which is characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. To date, only one study has reported the demyelinating peripheral neuropathy phenotype caused by heterozygous POLR3B variants. Case presentation A 19-year-old male patient was referred to our hospital for progressive muscle weakness of the lower extremities. Physical examination showed muscle atrophy, sensory loss and deformities of the extremities. Nerve conduction studies and electromyography tests revealed sensorimotor demyelinating polyneuropathy with secondary axonal loss. Trio whole-exome sequencing revealed a de novo variant in POLR3B (c.3137G > A). Conclusions In this study, we report the case of a Chinese patient with a de novo variant in POLR3B (c.3137G > A), who manifested demyelinating CMT phenotype without additional neurological or extra-neurological involvement. This work is the second report on POLR3B-related CMT.

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Charcot-Marie-Tooth Disease and Pregnancy

10.1093/med/9780190667351.003.0025 ◽

2018 ◽

Author(s):

Peter D. Creigh ◽

David N. Herrmann

Keyword(s):

Health Care Providers ◽

Clinical Care ◽

Symptomatic Treatment ◽

Care Providers ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Uncomplicated Pregnancy ◽

Primary Focus ◽

Pharmacologic Treatments ◽

Tooth Disease

Charcot-Marie-Tooth neuropathies (CMT) represent the most common hereditary neuropathies and can affect men and women from infancy to adulthood. There are no effective or FDA approved pharmacologic treatments aimed at disease modification for any form of CMT, so the primary focus of clinical care is on symptomatic treatment, maintaining functionality, and limiting secondary injury. CMT does not in general appear to affect a woman’s ability to carry a pregnancy. However, having CMT does increase the risk of delivery related complications (operative delivery, fetal presentation anomalies and postpartum bleeding) and exacerbation of neurologic symptoms during pregnancy is possible. Therefore, understanding the risks and planning appropriately are crucial for all women with CMT considering pregnancy and their health care providers. Overall, with the appropriate medical care, most women with CMT who choose to become pregnant will have an uncomplicated pregnancy and deliver a healthy infant.

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A Deregulated Stress Response Underlies Distinct INF2-Associated Disease Profiles

Journal of the American Society of Nephrology ◽

10.1681/asn.2019111174 ◽

2020 ◽

Vol 31 (6) ◽

pp. 1296-1313 ◽

Cited By ~ 1

Author(s):

Samet Bayraktar ◽

Julian Nehrig ◽

Ekaterina Menis ◽

Kevser Karli ◽

Annette Janning ◽

...

Keyword(s):

Stress Response ◽

Mammalian Cells ◽

Molecular Mechanisms ◽

Cultured Cells ◽

Calcium Influx ◽

Medical Diagnostics ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Monogenic Diseases ◽

Tooth Disease

BackgroundMonogenic diseases provide favorable opportunities to elucidate the molecular mechanisms of disease progression and improve medical diagnostics. However, the complex interplay between genetic and environmental factors in disease etiologies makes it difficult to discern the mechanistic links between different alleles of a single locus and their associated pathophysiologies. Inverted formin 2 (INF2), an actin regulator, mediates a stress response—calcium mediated actin reset, or CaAR—that reorganizes the actin cytoskeleton of mammalian cells in response to calcium influx. It has been linked to the podocytic kidney disease focal segemental glomerulosclerosis (FSGS), as well as to cases of the neurologic disorder Charcot–Marie–Tooth disease that are accompanied by nephropathy, mostly FSGS.MethodsWe used a combination of quantitative live cell imaging and validation in primary patient cells and Drosophila nephrocytes to systematically characterize a large panel of >50 autosomal dominant INF2 mutants that have been reported to cause either FSGS alone or with Charcot–Marie–Tooth disease.ResultsWe found that INF2 mutations lead to deregulated activation of formin and a constitutive stress response in cultured cells, primary patient cells, and Drosophila nephrocytes. We were able to clearly distinguish between INF2 mutations that were linked exclusively to FSGS from those that caused a combination of FSGS and Charcot–Marie–Tooth disease. Furthermore, we were able to identify distinct subsets of INF2 variants that exhibit varying degrees of activation.ConclusionsOur results suggest that CaAR can be used as a sensitive assay for INF2 function and for robust evaluation of diseased-linked variants of formin. More broadly, these findings indicate that cellular profiling of disease-associated mutations has potential to contribute substantially to sequence-based phenotype predictions.

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