Integration of multi-omics layers empowers precision diagnosis through unveiling pathogenic mechanisms on maple syrup urine disease.

Maple syrup urine disease (MSUD) is a rare inherited metabolic disorder characterized by deficient activity of the branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex, required to metabolize the amino acids leucine, isoleucine, and valine. Despite its profound metabolic implications, the molecular alterations underlying this metabolic impairment had not yet been completely elucidated. We performed a comprehensive multi-omics integration analysis, including genomic, epigenomic, and transcriptomic data from fibroblasts derived from a cohort of MSUD patients and unaffected controls to genetically characterize an MSUD case and to unravel the MSUD pathophysiology.

HepG2 PMM2-CDG knockout model: A versatile platform for variant and therapeutic evaluation.

Phosphomannomutase 2 deficiency (PMM2-CDG), the most frequent congenital disorder of glycosylation, is an autosomal recessive disease caused by biallelic pathogenic variants in the PMM2 gene. There is no cure for this multisystemic syndrome. Some of the therapeutic approaches that are currently in development include mannose-1-phosphate replacement therapy, drug repurposing, and the use of small chemical molecules to correct folding defects.