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Comprehensive Long-Term Evaluation of the Gunn Rat Kernicterus Model
The proposed project is the initial phase of a long-term endeavor to develop therapies that will help patients with dyskinetic cerebral palsy related to mitochondrial dysfunction and a Kernicterus-like phenotype. We have evidence that the combination of a genetic predisposition affecting mitochondrial function will reduce the threshold for perinatal brain injury and can result in a distinct clinical picture in children born prematurely. Several patients have been identified at the Kennedy Krieger Institute with a very similar clinical phenotype. All are infants born extremely premature, who did not suffer from significant hyperbilirubinemia (jaundice) but developed a "Kernicterus-like" picture with sensory-neural hearing loss and globus pallidus lesions leading to severe dystonia. We have identified mitochondrial dysfunction in these patients as assessed by metabolic laboratory studies and/or mtDNA analysis. While a rat model for Kernicterus has been reported, presenting with dystonia, sensory-neural hearing loss and cerebellar hypoplasia, no long-term neurobehavioral or neuroimaging studies have been reported. Furthermore, while it is known that the increased bilirubin is a potent mitochondrial toxin, the degree of mitochondrial dysfunction in this model has not been studied.