Researchers have identified eight potential biomarkers of disease severity, progression and treatment response in children with late infantile Batten disease.
Considering the nature of these biomarkers, the team suggested that these patients may have a disease-associated brain energetic deficit that could drive neurodegeneration.
The study, “Untargeted Metabolite Profiling of Cerebrospinal Fluid Uncovers Biomarkers for Severity of Late Infantile Neuronal Ceroid Lipofuscinosis (CLN2, Batten Disease),” was published in the journal Scientific Reports.
Late infantile Batten disease, also called CLN2 or Jansky-Bielschowsky disease, is caused by a deficiency, or loss of function, of the tripeptidyl peptidase 1 (TPP1) enzyme due to mutations in the TPP1 gene.
As a result, waste molecules, including lipofuscin, accumulate inside lysosomes — the cellular compartment responsible for breaking down waste — mainly in brain cells, leading to nerve cell damage and death.
Why TPP1 deficiency causes nerve cell death remains unknown, but lysosomal storage diseases (where CLN2 disease is included) are known to induce changes in the cell metabolism.
Researchers at Weill Cornell Medicine analyzed the cerebrospinal fluid (the fluid inside the spinal cord) of children with CLN2 disease for potential metabolic changes and whether they could serve as biomarkers of disease severity and treatment response.
The cerebrospinal fluid of 22 children with CLN2 disease (15 girls and six boys) and 16 healthy children (nine girls and nine boys) was analyzed and compared.
Disease severity of children with late-infantile Batten disease was assessed through the Weill Cornell LINCL Scale (WCLS) , which is based on the feeding, motor abilities, gait, and language development scores, and by whole brain magnetic resonance imaging disease severity score (MRIDSS), which correlates with the WCLS.
The molecular characterization of the cerebrospinal fluid was conducted using a powerful method called liquid chromatography/mass spectrometry combined with tandem mass spectrometry (LC-MS/MS), which separates and identifies all the molecules in a sample and detects their levels of activity with a high degree of specificity and sensitivity.
The team evaluated whether the levels of specific molecules in CLN2 patients were associated with disease severity.
Of a total of 1,433 molecules analyzed, the results identified 29 molecules that were significantly reduced in children with CLN2 disease, compared to healthy children, and associated with disease severity.
Further analysis reduced the list to eight highly-reproducible metabolic changes in the cerebrospinal fluid of CLN2 disease patients, with the potential to be used as biomarkers to monitor disease progression and response to treatment.
They were N-acetylaspartyglutamic acid, N-acetylneuraminic acid (siliac acid), N-acetylneuraminic acid dimer, N-acetylalanine, N-acetylserine and N-acetylthreonine, glycero-3-phosphoinositol and sulfoacetic acid.
Because all but one of these molecules have an acetyl group in their chemical structure, which is associated with the production of acetate — a major energy fuel for the cell — researchers hypothesized that people with CLN2 disease may have an energetic deficit in nerve cells, which may impair nerve cell function.
“Even though the precise functional roles of the downregulated biomarkers in CLN2 disease subjects’ CSF [cerebrospinal fluid] is yet unclear, their identities have previously been associated with neurological disorders and thus may offer insight into TPP1 deficiency as a metabolic disease,” researchers wrote.
They also noted that these are the first cerebrospinal fluid biomarkers identified for CLN2 disease in children and that they may be a molecular signature of the disease.