Brain proton MR spectroscopy measurements in CLN3 disease

Mol Genet Metab. 2023 May;139(1):107584. doi: 10.1016/j.ymgme.2023.107584. Epub 2023 Apr 15.


Background: CLN3 is an autosomal recessive lysosomal disorder with intracellular accumulation of ceroid-lipofuscins. CLN3 classically has onset around 4-6 years of age involving vision loss, followed by developmental regression and seizures. Symptoms are progressive and result in premature death. Because treatments are under development, here we explore magnetic resonance spectroscopy (MRS) measurements of metabolite levels in the brain as a potential objective outcome measures.

Methods: Individuals with genetically confirmed CLN3 were enrolled from October 2017-November 2021 in a prospective natural history study (NCT033007304). Baseline concentrations of brain metabolites measured by MRS were compared to concurrently collected dimensional assessment measures: Vineland-3 Adaptive Behavior Composite (ABC) score, verbal intelligence quotient (VIQ), and the Physical, Capability with actual vision, and Clinical global impression of change sub-domains of the Unified Batten Disease Rating Scale (UBDRS).

Results: 27 participants with typical CLN3 presentation (15F:12M; ages 6.0-20.7 years) completed MRS, ABC, and UBDRS; 20 (12F:8M; ages 6.5-20.7 years) also completed the VIQ assessment. N-acetyl aspartate [B(95% CI) = -0.61(-0.78;-0.45)] and glutamine/glutamate/GABA [B(95% CI) = -0.82(-1.04;-0.6)] in the parietal gray matter (PGM) decreased across the ages. The strongest correlations between MRS metabolite measurements and the clinical severity assessments were found with N-acetyl aspartate [VIQ (ρ = 0.58), Vineland-3 ABC (ρ = 0.59), UBDRS |ρ| range = (0.57;0.7)] and glutamine/glutamate/GABA [VIQ (ρ = 0.57), Vineland-3 ABC (ρ = 0.60), UBDRS |ρ| range = (0.59;0.77)] measured in the midline PGM. These correlations were accounted for when age was considered.

Conclusions: Based on their correlations to established assessments, NAA and glutamine/glutamate/GABA measured in the midline parietal gray matter may be useful indicators of CLN3 disease state. In a clinical trial, divergence of the MRS measurements and clinical severity markers from age may be useful as surrogate measures for treatment responses.

Keywords: Glx; Juvenile neuronal ceroid lipofuscinosis; NAA; Neurodevelopment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adolescent
  • Adult
  • Brain / metabolism
  • Child
  • Glutamic Acid / metabolism
  • Glutamine / metabolism
  • Humans
  • Magnetic Resonance Spectroscopy
  • Membrane Glycoproteins / metabolism
  • Molecular Chaperones / metabolism
  • Neuronal Ceroid-Lipofuscinoses* / diagnosis
  • Neuronal Ceroid-Lipofuscinoses* / genetics
  • Prospective Studies
  • Protons*
  • Young Adult
  • gamma-Aminobutyric Acid / metabolism


  • Protons
  • Membrane Glycoproteins
  • Glutamine
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • CLN3 protein, human
  • Molecular Chaperones