Characterization of genotype ‐ phenotype correlations in Adenylosuccinate Lyase (ADSL) Deficiency

Abstract

ADSL deficiency is inherited disorder of purine metabolism affecting mainly central nervous system. Three forms differing in severity of symptoms and correlating negatively with ratios of accumulating SAdo/SAICAr in body fluids were established. The mechanisms leading to selective neuronopathy and underlying the clinical and biochemical heterogeneity are unknown.We analysed 22 patients, identified 16 ADSL mutations, expressed and characterized catalytic properties of recombinant wild type and mutant proteins, investigated expression patterns of ADSL in available tissues from 3 patients and correlated these data with patients' clinical and biochemical presentation.We found that phenotype severity corresponds with residual enzyme activity (calculated as a mean of homoallelic activities), but the mutant enzymes displayed proportional decrease in activity to both of its substrates, so no ground for the varied SAdo/SAICAr ratios was found.Western blot and immunohistochemistry analyses showed in patients generally reduced amounts of ADSL in investigated tissues.Our results suggest that selective affection of central nervous system is caused by toxic effects of accumulating SAdo‐SAICAr. Phenotype's heterogeneity may be explained by differential activity of metabolite transport across blood‐brain barrier in individual cases.This work was supported by grants GACR 301070600 and MSM CR 20620806.