Rediscovering ADSLD, Recording 6, Dr. Manoj Pandey

Dr. Pandey discusses how genetic enzyme deficiencies can act as critical drivers of complement activation and inflammation in distinct metabolic disorders. In Gaucher disease, deficiency of the lysosomal enzyme glucocerebrosidase leads to pathological accumulation of glucosylceramide, which triggers complement activation and drives both visceral and neuroinflammatory responses. Similarly, in ADSL deficiency disorder (ADSLDD), loss of adenylosuccinate lyase (ADSL) function results in excessive accumulation of SAICAr in the brain, initiating complement activation and C5a generation.

Despite arising from distinct genetic defects, these disorders converge on a shared pathogenic mechanism: toxic metabolite accumulation that activates the C5a–C5aR axis, fueling chronic inflammation and neurodegeneration. Dr. Pandey emphasizes that further studies using mouse models and patient-derived cell models of ADSLDD are essential to determine whether the C5a/C5aR signaling axis plays a causal role in disease pathogenesis, thereby providing a potential avenue for targeted therapeutic intervention.

Thank you Cincinatti Children's Hospital.