GPD Fatty Molecules May Be Useful Biomarker in Juvenile Batten: Study
Levels of GPDs may be used as diagnostic test or therapy efficacy measure
Levels of fatty molecules called glycerophosphodiesters, or GPDs, are elevated in the blood and other bodily fluids of people with juvenile Batten disease — and may be a useful biomarker for diagnosing or treating the inherited disorder — a new study revealed.
This finding “raises the potential to use these biomarkers as a blood-based diagnostic test or as an efficacy measure for disease-modifying therapies,” the researchers wrote.
The study, “Glycerophosphoinositol is Elevated in Blood Samples From CLN3 Δex7-8 pigs, Cln3 Δex7-8 Mice, and CLN3-Affected Individuals,” was published in Biomarker Insights. The work was funded by the Forebatten Foundation, a U.S.-based nonprofit that supports research in juvenile Batten disease.
Seeking a biomarker for Batten
Juvenile Batten disease, also called CLN3 disease, is caused by mutations in the CLN3 gene, which provides instructions for making a protein of the same name.
While the function of the CLN3 protein has long been unclear, a recent study demonstrated that it is needed to help cells process GPDs, which are produced when the fats used to make cell membranes are broken down. Without functional CLN3, GPDs accumulate to toxic levels in cellular compartments called lysosomes.
Now, a team of U.S. scientists, including researchers at Amicus Therapeutics, conducted a series of experiments aimed at identifying molecules that could serve as a biomarker of juvenile Batten.
Using a pig model of Batten disease, the team analyzed levels of more than 700 fats and other small molecules in blood samples. Among these hundreds of molecules, the team noted that four GPDs were generally elevated in Batten disease pigs.
Specifically, a GPD called glycerophosphoinositol (GPI) showed a pronounced increase in pigs with Batten disease. More modest increases were noted for three other GPD molecules, namely glycerophosphoserine (GPS), glycerophosphocholine (GPC), and glycerophosphoethanolamine (GPE). The researchers noted that the increase in these levels was “remarkably stable over time” in Batten pigs.
Analyses of the fluid around the pigs’ brains and spinal cords — called the cerebrospinal fluid or CSF — also showed elevated levels of GPI, though not the other three GPDs.
The researchers then measured levels of these GPDs in blood samples taken from a mouse model of Batten. Levels of GPI and GPE, but not the other two molecules, were elevated in mice with Batten disease. The researchers noted that the elevations were more variable over time in the mice as compared with the pigs.
“Collectively, the patterns observed across species and time points suggested that the glycerophosphodiesters species may be closely linked to CLN3 disease [development] and could thus be useful as clinical biomarkers of disease status,” the scientists wrote.
To confirm whether these results translated to humans, the researchers analyzed blood samples that were collected as part of an earlier natural history study. This included samples from 22 people affected by juvenile Batten disease, 15 disease carriers — individuals with one CLN3 mutation who do not have Batten disease themselves, but can pass the mutated gene to their biological children— and six people who did not have Batten and were not carriers.
Results showed that GPI and GPE were significantly elevated in the juvenile Batten disease group, with GPI showing the clearest pattern.
To investigate the utility of these molecules as a biomarker, the researchers calculated the area under the receiver operating characteristic curve, or AUC. This is a statistical test that assesses how well a given parameter — in this case, GPD levels — can distinguish between two groups. Here, those two groups were people with or without juvenile Batten disease.
AUC values can range from 0.5 to 1, with higher values reflecting better ability to differentiate. Results showed that GPI had an AUC value of 0.9848 when comparing individuals with juvenile Batten to non-carrier controls.
“GPE and GPI could have utility as biomarkers of CLN3 disease status. GPI, in particular, shows consistent elevations across a diverse cohort of individuals with CLN3, as well as in multiple animal models of the disease,” the researchers concluded.
“These results raise the potential to use these biomarkers as a blood-based diagnostic test (eg, a newborn screen) or as an efficacy measure for disease-modifying therapies,” they added.
Notably, in carriers, average blood levels of GPI were significantly higher than for non-carriers, but significantly lower than in people who had juvenile Batten disease. Given that carriers don’t have any notable symptoms, but may have slightly altered CLN3 protein function, these results are in agreement with the recent report that this protein helps to process GPI and other GPDs.
“Our observation that heterozygous carriers exhibit intermediate serum GPI elevations suggests a dose-response relationship wherein GPI levels are closely linked to levels of functional CLN3 protein,” the researchers wrote.
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