Inherited neuropathies known as Charcot-Marie-Tooth (CMT) disease are genetically heterogeneous disorders affecting the peripheral nerves, causing significant and slowly progressive disability over the lifespan. The discovery of their diverse molecular genetic mechanisms over the past three decades has provided the basis for developing a wide range of therapeutics, leading to an exciting era of finding treatments for this, until now, incurable group of diseases. Many treatment approaches, including gene silencing and gene replacement therapies, as well as small molecule treatments are currently in preclinical testing while several have also reached clinical trial stage. Some of the treatment approaches are disease-specific targeted to the unique disease mechanism of each CMT form, while other therapeutics target common pathways shared by several or all CMT types. As promising treatments reach the stage of clinical translation, optimal outcome measures, novel biomarkers and appropriate trial designs are crucial in order to facilitate successful testing and validation of novel treatments for CMT patients.
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http://dx.doi.org/10.3390/ijms22116048 | DOI Listing |
Mol Cell Probes
January 2025
Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland, Mittlere Strasse 91, CH-4031. Electronic address:
The rapid advancements in the field of genetics have significantly propelled the development of gene therapies, paving the way for innovative treatments of various hereditary disorders. This review focuses on the genetics of ophthalmologic conditions, highlighting the currently approved ophthalmic gene therapy and exploring emerging therapeutic strategies under development. Inherited retinal dystrophies represent a heterogeneous group of genetic disorders that manifest across a broad spectrum from infancy to late middle age.
View Article and Find Full Text PDFPLoS Genet
January 2025
Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland.
Inositol 1,4,5-trisphosphate receptors (IP3R) mediate Ca2+ release from intracellular stores, contributing to complex regulation of numerous physiological responses. The involvement of the three IP3R genes (ITPR1, ITPR2 and ITPR3) in inherited human diseases has started to shed light on the essential roles of each receptor in different human tissues and cell types. Variants in the ITPR3 gene, which encodes IP3R3, have recently been found to cause demyelinating sensorimotor Charcot-Marie-Tooth neuropathy type 1J (CMT1J).
View Article and Find Full Text PDFPathogenic variants of GDAP1 cause Charcot-Marie-Tooth disease (CMT), an inherited neuropathy characterized by axonal degeneration. GDAP1, an atypical glutathione S-transferase, localizes to the outer mitochondrial membrane (OMM), regulating this organelle's dynamics, transport, and membrane contact sites (MCSs). It has been proposed that GDAP1 functions as a cellular redox sensor.
View Article and Find Full Text PDFAm J Hum Genet
January 2025
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Institute of Human Genetics, University of Regensburg, 93053 Regensburg, Germany; Institute of Clinical Human Genetics, University Hospital Regensburg, 93053 Regensburg, Germany. Electronic address:
BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive.
View Article and Find Full Text PDFEur J Neurol
January 2025
Neuromuscular Unit, Neurology Department, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
Background: 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.
Methods: Demographic and clinical findings were recorded.
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