Scientists identify cause of a mysterious fatal genetic disorder in children

A team from the Washington University’s School of Medicine, St. Louis might have decoded a decades-long mystery revolving around the exact biochemical pathway that causes a fatal genetic disorder in children, which causes developmental regression, seizures, and death, typically around the age of three. The researchers studied a mouse model with the same human illness, known as Krabbe disease, and identified a possible therapeutic strategy. Usually diagnosed before the age of one, the rare condition occurs in patients with infantile globoid cell leukodystrophy and affects 1 in 100,000 births. The team’s work has been published in the Proceedings of the National Academy of Sciences.

The disease progresses rapidly, and the patient eventually loses the protective covering that insulates axons, the wiring of the nervous system. It has been suspected that nerve insulation is destroyed due to the build-up of a toxic compound known as psychosine. Patients who inherit the disorder lack a protein essential for breaking down psychosine, although the source of psychosine has remained unknown, which has made the disease impossible to fight. Senior author Mark S. Sands, Professor of Medicine, describes Krabbe disease as a heart-breaking neurodegenerative disease first described over a century ago, and still does not have any effective treatments. For nearly five decades, the psychosine hypothesis has been presumed to be correct, but it has never been proven, adds Sands. Sands and his team, led by Yedda Li, a graduate student, were able to confirm the hypothesis by giving the mice another lethal genetic disease.

The scientists demonstrated that mice harboring genetic mutations in Krabbe disease and Farber disease, a lethal condition resulting from the loss of another protein, show no signs of Krabbe disease. The missing protein in Farber disease is known as acid ceramidase, and without it, psychosine does not build up, which stopped the disease from developing, proving the hypothesis. Sands hopes that researchers with expertise in drug development would start working on a safe and effective acid ceramidase inhibitor to cure the disorder.

Purushottam Gaurav

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