Scientists Discover Common Malfunction in Charcot-Marie-Tooth Disease 1C and 4J

According to a story from Charcot-Marie-Tooth News, a recent cell-based study has revealed that Charcot-Marie-Tooth disease type 1C and type 4J share a common pathway malfunction. This is despite the fact that these two variants of the illness are triggered by distinct mutations. The revelation suggests that in the development of future therapies, a single treatment could have the capability of treating multiple disease subtypes.

About Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease is a hereditary disorder of the peripheral nervous system. It is most characterized by a progressive loss of touch sensation and muscle tissue in several different parts of the body. The cause of this disease is usually linked to a genetic mutation, but the mutation involved varies depending on the variant of Charcot-Marie-Tooth disease. There are multiple types of Charcot-Marie-Tooth disease, with all types aside from type 2 having a demyelination effect. Type 2 causes damage to the neuronal axon instead. Symptoms include foot drop, muscle wasting (typically in the arms, legs, and hands), painful muscle spasms, loss of sensation in the limbs, scoliosis, trouble speaking, chewing, and swallowing, and tremors. Treatment typically includes therapy and surgery in order to maintain function. There is no cure. The disease can occur early in life or as late as the 30s and 40s. To learn more about Charcot-Marie-Tooth disease, click here.

About The Study

In this study, the scientists were able to demonstrate that cells which had different genetic mutations linked to the illness saw reductions in processes related to disease activity when they were exposed to a single small molecule. In the most widespread, demyelinating forms of Charcot-Marie-Tooth disease, a pathway called the endolysosomal pathway is sometimes affected.

Type 1C involves mutations impacting the LITAF gene which codes for a protein involved in this pathway. Meanwhile, the type 4J subtype as the result of mutations in the FIG4 gene, which encodes a certain enzyme that is vital for the function of the endolysosomal pathway. The scientists compared fibroblast cells from type 1C patients and fibroblasts with mutations in the LITAF and FIG4 genes with the goal of finding common effects.

The affected cells displayed abnormalities in several organelles, including the lysosomes, endosomes, and vacuoles. In many cases, enlargement was observed. The cells were then treated with a small molecule called ML-SA1. In comparison to a control group of cells, treatment with this molecule was able to bring down the enlargement of organelles in the fibroblast cells with the mutations. This was also confirmed in the fibroblasts from type 1C patients. 

“Although our experiments were on human fibroblasts, they have implications for our understanding of the molecular pathogenesis and approaches to therapy in two subtypes of demyelinating Charcot–Marie–Tooth disease,” the scientists said.

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