Glc4 Is Potential Biomarker of Pompe Disease, Study Suggests

Measuring the urinary levels of a particular sugar molecule called tetraglucose (Glc4) could be useful for diagnosing Pompe disease, a study from France suggests.

The study, “Urine glucose tetrasaccharide: A good biomarker for glycogenoses type II and III? A study of the French cohort,” was published in the journal Molecular Genetics and Metabolism Reports.

Pompe disease is characterized by the abnormal buildup of glycogen, a sugar molecule, in cells. Glc4 is produced during the breakdown of glycogen.

Glc4 is detectable in urine, typically at relatively low levels, though it is known to be elevated in the urine of pregnant women. Some evidence has suggested that Glc4 urine levels are higher in people with Pompe disease and other glycogen storage diseases (GSDs), as well as in people with Duchenne muscular dystrophy, pancreatitis, and some cancers. A recent study in Turkey showed that Glc4 levels are higher in people with Pompe disease compared to healthy individuals.

“Although not specific, Glc4 is thus a candidate biomarker for GSD II [Pompe disease] diagnosis and monitoring,” researchers wrote.

The team used mass spectrometry to measure Glc4 levels in urine samples. A total of 332 samples were collected from Pompe patients who had not yet started enzyme replacement therapy — 43 with infantile-onset (IOPD) and 131 with late-onset Pompe disease (LOPD).

The researchers also measured Glc4 levels in samples from 195 people without Pompe disease or another metabolic disease for reference (controls), and in 57 patients with Forbes-Cori disease, also a GSD.

Results showed substantial person-to-person variation in urine Glc4 levels among the controls. As such, the researchers established a typical range for various age groups. A high cutoff — the 90th percentile of the reference range — was set for determining elevated Glc4 levels “in order to minimize the number of false negative results,” the scientists wrote.

Most untreated Pompe disease patients had urine Glc4 levels above the cutoff.

For individuals with IOPD (both classic and non-classic), who were younger than 1 year old at first Glc4 measurement, median levels of the biomarker were at least four times higher than the respective age cutoff for almost all subgroups.

The exception was children diagnosed before 2 months of age. Among the 13 patients analyzed, five had normal Glc4 levels, and the median value was 1.2 times higher than the cutoff.

“Thus, Glc4 may have limitations as a biomarker for the diagnosis of GSD II at an early stage of the disease,” the researchers wrote. “It seems that urinary Glc₄ increases with age in IOPD, representing the glycogen accumulation in parallel with the spontaneous evolution of the disease.”

Urine Glc4 levels in adults with LOPD were between 2.6 and 5.5 times higher than the cutoffs in the respective age references. Although Glc4 levels were lower in adults, “the relative increase is comparable to that in IOPD,” the scientists added.

For children and adolescents (ages 4–20) with LOPD, Glc4 levels were 23 times higher than the cutoff of the respective reference value.

The researchers also said that urine Glc4 levels were particularly high in people with more severe disease at diagnosis.

“Although not specific to GSD II, and not completely sensitive in all cases, this biomarker supports a diagnosis of GSD II and can be very helpful in difficult cases,” they wrote.

Future studies, the researchers added, should focus on whether Glc4 is a suitable biomarker to follow-up Pompe disease. Parameters such as age, treatment duration, and patients’ genetic profile need to be taken into account.

“Further statistical analyses may help to determine if Glc4 is also a good biomarker for monitoring of specific therapies. This is important for the future, as several new treatments are under investigation,” they wrote.