Cause of Rare, Fatal Disorder (Krabbe Disease) in Young Children Pinpointed; Proof-of-Concept Drug Therapy Benefits Mouse Model of Disease

Scientists at Washington University School of Medicine in St. Louis appear to have solved a decades-long mystery regarding the precise biochemical pathway leading to a fatal genetic disorder in children that results in seizures, developmental regression and death, usually around age 3. Studying a mouse model with the same human illness -- called Krabbe disease -- the researchers also identified a possible therapeutic strategy. The research was published online on September 16, 2019 in PNAS. The article is titled “Genetic Ablation of Acid Ceramidase In Krabbe Disease Confirms the Psychosine Hypothesis and Identifies a New Therapeutic Target.” Patients with infantile globoid cell leukodystrophy, also known as Krabbe disease, gradually lose the protective covering that insulates axons, the wiring of the nervous system. The rare condition -- affecting approximately 1 in 100,000 births -- is typically diagnosed before age 1 and progresses rapidly. Scientists have long suspected that nerve insulation is destroyed in this disorder because of a buildup of a toxic compound called psychosine. Patients with the inherited disorder are missing an important protein involved in breaking down psychosine. But the source of psychosine in Krabbe disease has been elusive, making the problem impossible to correct. "Krabbe disease in infancy is invariably fatal," said senior author Mark S. Sands, PhD, a Professor of Medicine. "It's a heartbreaking neurodegenerative disease first described more than a century ago, but we still have no effective treatments. For almost 50 years, we have assumed the psychosine hypothesis was correct -- that a toxic buildup of psychosine is the cause of all the problems. But we've never been able to prove it."
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