MOLECULAR DETERMINANTS OF MOTOR DYSFUNCTION ON ANIMAL MODEL FOR KERNICTERUS SPECTRUM DISORDER

Kernicterus spectrum disorder (KSD) is a wide range of chronic auditory, cognitive, and motor signs and symptoms of varying severity caused by bilirubin neurotoxicity as consequence of neonatal hyperbilirubinemia. Using the spontaneous model of KSD, the Gunn rat, we aimed in identifying the biomolecular factors that could explain the variability of the bilirubin-induced chronic motor impairment. Task 1 was completed and published in 2023 reported 16 transcriptomically imprinted genes in the parietal motor cortex (hCtx, a region with an apparent recovery at histological level) in adult jj animals that exhibited worse motor functions vs physiological controls of the standard Gunn rat colony. Current findings in Task 2 using the actual colony of Gunn rat which spontaneously presents a large variability of motor behavior among the hyperbilirubinemic (jj) animals (SP, severe phenotype: frank abnormalities; LP, low phenotype: deficits detectable only by tests), reveal a number of genes expressed in both the hCtx and the cerebellum (Cll) that correlate with the worsening of the motor phenotype. Notably the worsening of the behavioral, biomolecular and histologic phenotype, which could not be fully explained by high bilirubin in the blood and brain, supporting the concept of a genetic individual susceptibility. On-going sequence analyses in Task 3 may provide a better perspective on how the severity of signs and symptoms progress due to bilirubin sensitivity, which can be validated for clinical use in the future. Irrespective of the molecular and genomic determinants, new therapeutic options are an unmet need. Curcumin has previously been demonstrated to restore motor functions in hyperbilirubinemic animals. Aiming in improving its clinical feasibility by reducing the time of treatment (from 15 to 5 days of administration), we discovered that the cerebellum is not responsible for the motor deficits. This direct us in identifying the real CNS region responsible for worsening of the phenotype, as a key information to improve diagnosis and management of hyperbilirubinemic neonates developing dystonia in KSD.

Kernicterus spectrum disorder (KSD) is a wide range of chronic auditory, cognitive, and motor signs and symptoms of varying severity caused by bilirubin neurotoxicity as consequence of neonatal hyperbilirubinemia. Using the spontaneous model of KSD, the Gunn rat, we aimed in identifying the biomolecular factors that could explain the variability of the bilirubin-induced chronic motor impairment. Task 1 was completed and published in 2023 reported 16 transcriptomically imprinted genes in the parietal motor cortex (hCtx, a region with an apparent recovery at histological level) in adult jj animals that exhibited worse motor functions vs physiological controls of the standard Gunn rat colony. Current findings in Task 2 using the actual colony of Gunn rat which spontaneously presents a large variability of motor behavior among the hyperbilirubinemic (jj) animals (SP, severe phenotype: frank abnormalities; LP, low phenotype: deficits detectable only by tests), reveal a number of genes expressed in both the hCtx and the cerebellum (Cll) that correlate with the worsening of the motor phenotype. Notably the worsening of the behavioral, biomolecular and histologic phenotype, which could not be fully explained by high bilirubin in the blood and brain, supporting the concept of a genetic individual susceptibility. On-going sequence analyses in Task 3 may provide a better perspective on how the severity of signs and symptoms progress due to bilirubin sensitivity, which can be validated for clinical use in the future. Irrespective of the molecular and genomic determinants, new therapeutic options are an unmet need. Curcumin has previously been demonstrated to restore motor functions in hyperbilirubinemic animals. Aiming in improving its clinical feasibility by reducing the time of treatment (from 15 to 5 days of administration), we discovered that the cerebellum is not responsible for the motor deficits. This direct us in identifying the real CNS region responsible for worsening of the phenotype, as a key information to improve diagnosis and management of hyperbilirubinemic neonates developing dystonia in KSD.