Alexander disease (AxD)
https://onlinelibrary.wiley.com/doi/10.1002/acn3.70209
Alexander Disease (AxD) is a rare, genetic neurological disorder caused by mutations in the GFAP gene. It primarily affects astrocytes and leads to symptoms such as developmental delays, seizures, and a severe problem known as failure to thrive, where affected children struggle to gain weight and maintain muscle and fat. This study explores whether the protein Growth Differentiation Factor 15 (GDF‑15) contributes to this failure-to-thrive symptom. The research found that GDF‑15 is elevated in the central nervous system of both AxD rats and human patients, particularly in the cerebrospinal fluid, but not in the blood. In the rat model, GDF‑15 was produced by astrocytes in the brainstem and activated neurons in the area postrema, a brain region that controls appetite and feeding. High levels of GDF‑15 were linked to reduced food intake, muscle loss, and poor weight gain, suggesting that this protein directly contributes to the failure-to-thrive seen in AxD. Importantly, when the researchers reduced GFAP levels using antisense therapy, GDF‑15 levels normalised, and weight gain improved in the animal model. This indicates that targeting astrocyte dysfunction, and specifically the GDF‑15 pathway, may help address feeding and growth problems in AxD. These findings suggest that GDF‑15 could serve as both a biomarker and a therapeutic target in Alexander Disease. Measuring GDF‑15 in cerebrospinal fluid may help monitor disease severity, while simultaneously future treatments aimed at reducing its activity could improve nutrition, growth, and overall quality of life for patients with AxD.