Sorbitol Is a Severity Biomarker for PMM2-CDG with Therapeutic Implications

Ann Neurol. 2021 Dec;90(6):887-900. doi: 10.1002/ana.26245. Epub 2021 Oct 26.


Objective: Epalrestat, an aldose reductase inhibitor increases phosphomannomutase (PMM) enzyme activity in a PMM2-congenital disorders of glycosylation (CDG) worm model. Epalrestat also decreases sorbitol level in diabetic neuropathy. We evaluated the genetic, biochemical, and clinical characteristics, including the Nijmegen Progression CDG Rating Scale (NPCRS), urine polyol levels and fibroblast glycoproteomics in patients with PMM2-CDG.

Methods: We performed PMM enzyme measurements, multiplexed proteomics, and glycoproteomics in PMM2-deficient fibroblasts before and after epalrestat treatment. Safety and efficacy of 0.8 mg/kg/day oral epalrestat were studied in a child with PMM2-CDG for 12 months.

Results: PMM enzyme activity increased post-epalrestat treatment. Compared with controls, 24% of glycopeptides had reduced abundance in PMM2-deficient fibroblasts, 46% of which improved upon treatment. Total protein N-glycosylation improved upon epalrestat treatment bringing overall glycosylation toward the control fibroblasts' glycosylation profile. Sorbitol levels were increased in the urine of 74% of patients with PMM2-CDG and correlated with the presence of peripheral neuropathy, and CDG severity rating scale. In the child with PMM2-CDG on epalrestat treatment, ataxia scores improved together with significant growth improvement. Urinary sorbitol levels nearly normalized in 3 months and blood transferrin glycosylation normalized in 6 months.

Interpretation: Epalrestat improved PMM enzyme activity, N-glycosylation, and glycosylation biomarkers in vitro. Leveraging cellular glycoproteome assessment, we provided a systems-level view of treatment efficacy and discovered potential novel biosignatures of therapy response. Epalrestat was well-tolerated and led to significant clinical improvements in the first pediatric patient with PMM2-CDG treated with epalrestat. We also propose urinary sorbitol as a novel biomarker for disease severity and treatment response in future clinical trials in PMM2-CDG. ANN NEUROL 20219999:n/a-n/a.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Biomarkers / urine
  • Child
  • Child, Preschool
  • Congenital Disorders of Glycosylation / diagnosis*
  • Congenital Disorders of Glycosylation / drug therapy
  • Congenital Disorders of Glycosylation / urine
  • Enzyme Inhibitors / therapeutic use*
  • Female
  • Glycosylation
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Patient Acuity
  • Phosphotransferases (Phosphomutases) / deficiency*
  • Phosphotransferases (Phosphomutases) / urine
  • Prognosis
  • Rhodanine / analogs & derivatives*
  • Rhodanine / therapeutic use
  • Sorbitol / urine*
  • Thiazolidines / therapeutic use*
  • Young Adult


  • Biomarkers
  • Enzyme Inhibitors
  • Thiazolidines
  • epalrestat
  • Sorbitol
  • Rhodanine
  • Phosphotransferases (Phosphomutases)

Supplementary concepts

  • Congenital disorder of glycosylation type 1A