Patient-derived brain organoids link DHDDS variants to dolichol deficiency and identify NMN rescue in rare pediatric neurodegeneration

Patient fibroblasts were reprogrammed into iPSCs and differentiated into 3D brain organoids that recapitulated the progressive phenotype over four months. Defective dolichol synthesis reduced lipid anchors needed for N-glycosylation, producing misfolded glycoproteins and astrocyte cholesterol overload that impaired oxidative phosphorylation. These changes mirrored the children's clinical course of tremor, ataxia, and seizures beginning in early childhood. Organoid screening of repurposed compounds identified NMN, which restored NAD+ pools, lowered cholesterol esters, and improved mitochondrial membrane potential in patient-derived tissue. Early parental reports noted improved gait stability and energy within weeks of off-label use, consistent with prior NMN effects in mitochondrial myopathy and Parkinson disease models. The approach bypasses the absence of DHDDS animal models and enables rapid functional validation for ultra-rare variants. Limitations include the short culture window relative to lifelong disease and lack of vascular or immune components. Next steps require GMP-grade NMN pharmacokinetics and a controlled open-label study measuring motor scales and seizure frequency at six months.