New genetic discovery in megalencephalic leukoencephalopathy with subcortical cysts

White matter disease (WMD) covers a large group of disorders that affect the white matter, or myelin. In children these disorders are commonly genetic and often go undiagnosed. In new research, a team led by Raúl Estévez, a lecturer from the Department of Physiological Sciences II, based at the UB's Bellvitge Health Sciences Campus, working with the researcher Marjo van der Knaap, from the University Medical Centre at VU University Amsterdam, have identified mutant GLIALCAM as responsible for 25% of cases of megalencephalic leukoencephalopathy with subcortical cysts (MLC), a rare genetic disease affecting cerebral  myelin.

Also participating in the study, which has been published and selected as a featured article in The American Journal of Human Genetics, were Tania López-Hernández, co-principal author and a postdoctoral fellow at the UB, and the researchers Albert Martínez, from the Institute of Biomedical Research (IRB Barcelona), and Virginia Nunes, a lecturer at the UB and researcher for the Bellvitge Biomedical Research Institute (IDIBELL).

Myelin is required for the correct propagation of nerve impulses between neurons, enabling the brain to send the signals that make us move. In children, diseases affecting this substance are largely genetic and affect a single gene. In adults, the diseases present as inflammatory conditions such as multiple sclerosis. "In the specific case of infant WMD, every type is rare or extremely rare, but if we consider all cases as a single group the incidence is high - 1 patient for every 1,000 individuals," explains Raúl Estévez, ICREA Acadèmia award winner and a member of the Centre for Biomedical Network Research on Rare Diseases (CIBERER). "In addition," he adds, "in a high percentage of children with myelin disorders the diagnosis is not clear and no real conclusions can be reached."

Thanks to the identification in recent years of abnormal patterns in brain MRIs, researchers have been able to define new diseases. In 1995 experts discovered an autosomal recessive myelin disorder called megalencephalic leukoencephalopathy with subcortical cysts (MLC). In 2001 the gene responsible for 75% of the cases of this disease, MLC1, wa discovered and scientists found that other cases existed that were not caused by mutations of this gene. Of the remaining 25% of patients, two clinical phenotypes were observed: in the first case, the clinical progression, showing progressive degeneration, is the same as observed in the larger group; in the second case, the disease improves or disappears altogether. The common feature in all patients is the presence of macrocephaly, which may be accompanied by learning difficulties and autism.

The study published in The American Journal of Human Genetics takes as its starting point the genetic heterogeneity of the disease and looks for other possible mutations behind its development, combining biochemical and genetic studies. The results show that patients presenting a progressive degeneration of their condition exhibit two mutations in the GLIALCAM gene, whose related protein is GlialCAM, while others exhibit only a single mutation in the same gene, which suggests a pattern of autosomal-dominant inheritance. The study, which also describes the biochemical defects observed in the disease, has revealed that mutant GLIALCAM can also lead to benign familial macrocephaly and macrocephaly with mental retardation, with or without autism.

"Although we have yet to determine the exact function of GLIALCAM, our research has shown that further collaborative multi-disciplinary translational studies will be required to learn more about the causes of these rare diseases and to find new treatments," 

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