Gastrointestinal disorders and miglustat therapy: A case report

CO RR EC TE D P RO OF the juvenile forms by age of onset, rate of disease progression and age of death. There are no approved treatments for gangliosidoses. Biomarkers for evaluating disease phenotype, disease progression, and response to therapies would serve to facilitate the design and development of potential treatment of these diseases, but such biomarkers have not been identified. Increasing evidence from animal models and human cadavers suggests inflammatory mediators in the CNS play a role in disease pathology and progression. Hypothesis: The more rapid disease progression and more severe clinical phenotype of the infantile GM1and GM2-gangliosidosis relative to juvenile forms will coincide with levels of disease specific inflammatory mediators in the CNS. Methods: CSF and serum inflammatory markers were quantified by immunoassay in 8 children with infantile forms of gangliosidoses (including patients with Tay–Sachs disease, Sandhoff disease and GM1 gangliosidosis). Findings were compared to values from 4 patients with more slowly progressing forms of gangliosidoses (i.e., late-infantile, juvenile forms) and to values of 9 children with mucopolysaccharidosis (MPS) diseases. Results: Of 188 analytes assayed, elevated inflammatory markers occurredmore often in the CSF of infantile gangliosidosis patients when compared to the more slowly progressing forms of juvenile gangliosidosis and MPS disease. Five candidate biomarkers were distinguished by persistent elevation in the CSF of patients with the severe infantile phenotype: ENA-78, MCP-1, MIP-1α, MIP-1β, TNFR2. Additional candidates for CNS and serum inflammatory markers for infantile and juvenile phenotypes were found. Conclusion: This study identified candidate biomarkers of CNS inflammatory disease in infantile and juvenile gangliosidoses that are promising as markers for evaluating CNS disease progression, distinguishing infantile and juvenile phenotypes and monitoring response to future therapeutic interventions in the gangliosidoses. (Supported by Lysosomal Disease Network, NIH U54NS065768 and Pharmacotherapy for InheritedMetabolic Diseases Fellowship training program, GenzymeSanofi.)