Niemann-Pick C-like Endolysosomal Dysfunction in DHDDS Patient Cells, a Congenital Disorder of Glycosylation, Can Be Treated with Miglustat.

DHDDS (dehydrodolichol diphosphate synthetase) and NgBR (Nogo-B Receptor) collectively form an enzymatic complex important for the synthesis of dolichol, a key component of protein N-glycosylation. Mutations in DHDDS and the gene encoding NgBR (NUS1) are associated with neurodevelopmental disorders that clinically present with epilepsy, motor impairments, and developmental delay.[…] Our findings provide further evidence for overlap between NPC2 and DHDDS disorders, showing that DHDDS patient fibroblasts have increased lysosomal volume, store cholesterol and ganglioside GM1, and have altered lysosomal Ca²⁺ homeostasis. Treatment of DHDDS cells, with the approved NPC small molecule therapy, miglustat, improves these disease-associated phenotypes, identifying a possible therapeutic option for DHDDS patients. These data suggest that treatment options currently approved for NPC disease may be translatable to DHDDS/NUS1 patients.