Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC)
https://bmcresnotes.biomedcentral.com/articles/10.1186/s13104-025-07537-0
Oligodendrocytes are specialised cells in the brain and spinal cord that create myelin, the protective coating that helps nerve signals travel quickly and reliably. In children with hypomyelinating leukodystrophy type 6 (HLD6), myelin does not form properly, leading to motor difficulties, developmental delays, and movement disorders. HLD6 is caused by changes in the TUBB4A gene, which helps build microtubules. This study investigated how six known HLD6-associated TUBB4A mutations affect the ability of oligodendrocyte-like cells to grow and mature. In healthy conditions, these cells spread out into large, sheet-like membranes resembling early myelin. However, the researchers found that cells carrying the mutated TUBB4A proteins failed to form these structures and instead their development stalled at an immature stage. The research team discovered two key reasons for this. First, the mutant TUBB4A proteins could not undergo the normal processing required to assemble into microtubules. Instead of forming the cell’s supportive framework, they accumulated in abnormal locations within the cell. Second, the cells showed reduced activity of Akt, a signalling molecule crucial for proper oligodendrocyte differentiation and myelin production. Together, these findings show that TUBB4A mutations disrupt both the structure and signalling pathways needed for cells to shape themselves into myelin-producing oligodendrocytes. This therefore helps explain why myelin fails to develop in children with HLD6. By identifying how these mutations interfere with cell maturity, this study provides important insights that may guide future research toward targeted treatments for HLD6 and related disorders.