While this measurement looks promising, investigators stress that more research is needed to confirm its clinical utility. Monitoring gangliosides in patients enrolled in clinical trials may verify if they represent true biomarkers of therapy response.
Sanfilippo syndrome, or mucopolysaccharidosis type III (MPS III), comprises a group of four rare genetic disorders caused by a deficiency in one of the enzymes needed to fully break down a complex sugar molecule called heparan sulfate (HS).
As a result, non-degraded or partially degraded HS accumulates in patient tissues, particularly at the central nervous system, including in the brain. This build-up is believed to be the root cause of the marked neurodevelopmental problems accompanying the disease.
In addition to HS, other molecules are known to build up in a patient’s body, namely sugar-fat molecules termed gangliosides — specifically GM2 and GM3.
“Whether these gangliosides play a role in neurological demise or are merely a consequence of it is yet to be determined but they may indeed serve as biomarkers given that they are not normally present in the adult brain,” the researchers said.
All types of MPS III are associated with some degree of mental impairment. The severity and rate of progression depends on the type, but can vary within the same type, and even between affected siblings.
Predicting outcomes or measuring a treatment’s efficacy is a difficult task, especially given the general lack of validated, clinically informative biomarkers for these patients.
After clinical evaluation, the diagnosis of Sanfilippo typically starts with a urine test for HS, followed by measurement of enzyme activity in the blood or a small skin sample. The diagnosis is finally confirmed by a genetic test.
Although the measurement of heparan sulfate in urine has long been used as a biomarker of this disorder, the researchers say this is “largely non-specific.” Finding better biomarkers that can inform on disease burden, and possibly help measure treatment impact, is of great interest for clinicians.
With that in mind, researchers assessed different biomarkers in the urine, plasma and cerebrospinal fluid (CSF) — the fluid that surrounds the spinal cord and brain — in a total 15 MPS IIIA and 8 MPS IIIB patients referred to the Nationwide Children’s Hospital, in Australia.
They compared these samples with those of control subjects who had other metabolic disorders, and also explored how these biomarkers correlated with age at onset of symptoms — as an indicator of disease severity.
Biomarkers measured included: HS fragments (oligosaccharides) normally used for diagnosis; enzyme activity of N-sulphoglucosamine sulphohydrolase (SGSH; deficient in MPS IIIA patients) and N-acetyl-alpha-glucosaminidase (NAGLU; deficient in MPS IIIB patients); and several gangliosides, including GM2 and GM3.
The diagnostic HS oligosaccharides were elevated in the urine, plasma and CSF of all patients, but there was no correlation between the concentrations in each of these body fluids. That suggested they reflect specific tissues and not overall disease burden.
Likewise, there was no significant relationship between age at first symptoms and oligosaccharide concentrations.
Enzyme activity also was of little use in indicating disease severity. Researchers noted it was undetectable in the CSF, but approached normal levels in the plasma of MPS IIIA patients.
GM2 and GM3 gangliosides were found to be more promising biomarkers. Both were significantly higher in the CSF of all patients, compared to controls, and correlated with the age at which they experienced their first symptoms.
“Given that these gangliosides reflect delayed brain development they may be useful measures of disease burden, within the limitations of the clinical surrogates,” the researchers said.
Measuring these molecules in the CSF “may indeed be instructive of CNS disease but further work is required to define their clinical utility,” the team said. Monitoring gangliosides in patients, for instance, might determine if it can work as a therapy response surrogate in clinical trials.
Regarding heparan sulfate oligosaccharides’ measurements, the scientists noted that “given the limitations of using age of first symptom onset as a clinical parameter of disease burden,” their clinical utility “could not be fully appreciated.”