Translational lipidomics reveals BMP and its precursor LPG as biomarkers for CLN5 Batten disease

CLN5 Batten disease, caused by biallelic mutations in CLN5, is a rare, early-onset neurodegenerative lysosomal storage disorder that has no cure and lacks validated biomarkers, hindering accurate diagnosis and assessment of therapeutic response. We recently identified CLN5 as the synthase of bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid crucial for lysosome function and lipid catabolism. This suggested BMP and its precursor lysophosphatidylglycerol (LPG) as clinically relevant biomarkers. It also prompted in vivo confirmation of CLN5 as the biologically relevant lysosomal BMP synthase. Here we show that murine and ovine disease models lacking CLN5 show significant and universal depletion of BMP and elevation of LPG across tissues and brain regions, consistent with the biochemical function of CLN5. Additionally, lysosomal lysates from murine models of CLN5 Batten disease lack the ability to synthesize BMP from its precursor LPG, establishing CLN5 as the main BMP synthase in vivo. Of importance, CLN5 patient-derived fibroblasts show BMP depletion and LPG elevation. Translating these results towards clinical utility, we demonstrate BMP and LPG to be accessible biomarkers for CLN5 Batten disease in both plasma and dried blood spots, enabling early diagnosis and patient screening.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-03-21
DOI
https://doi.org/10.64898/2026.03.19.712969
Primary Topic
Lysosomal Storage Disorders Research
Type
article
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article

Translational lipidomics reveals BMP and its precursor LPG as biomarkers for CLN5 Batten disease

Eshaan S. Rawat, Nadia L. Mitchell, I. Peña, Lena Marie Westermann et al.
bioRxiv (Cold Spring Harbor Laboratory)
Lysosomal Storage Disorders Research
article

Translational lipidomics reveals BMP and its precursor LPG as biomarkers for CLN5 Batten disease

Eshaan S. Rawat, Nadia L. Mitchell, I. Peña, Lena Marie Westermann, Monther Abu-Remaileh, Daan M. Panneman, Stefano Doccini, Filippo Maria Santorelli, Maria Marchese, Samantha J. Murray, Stefania Della Vecchia, Christian Posern, Hisham N. Alsohybe, Angela Schulz, Wentao Dong, Maryam Idris, Peter M. van Hasselt, Nick Manfred
article en

Abstract

CLN5 Batten disease, caused by biallelic mutations in CLN5, is a rare, early-onset neurodegenerative lysosomal storage disorder that has no cure and lacks validated biomarkers, hindering accurate diagnosis and assessment of therapeutic response. We recently identified CLN5 as the synthase of bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid crucial for lysosome function and lipid catabolism. This suggested BMP and its precursor lysophosphatidylglycerol (LPG) as clinically relevant biomarkers. It also prompted in vivo confirmation of CLN5 as the biologically relevant lysosomal BMP synthase. Here we show that murine and ovine disease models lacking CLN5 show significant and universal depletion of BMP and elevation of LPG across tissues and brain regions, consistent with the biochemical function of CLN5. Additionally, lysosomal lysates from murine models of CLN5 Batten disease lack the ability to synthesize BMP from its precursor LPG, establishing CLN5 as the main BMP synthase in vivo. Of importance, CLN5 patient-derived fibroblasts show BMP depletion and LPG elevation. Translating these results towards clinical utility, we demonstrate BMP and LPG to be accessible biomarkers for CLN5 Batten disease in both plasma and dried blood spots, enabling early diagnosis and patient screening.

bioRxiv (Cold Spring Harbor Laboratory)
Harvard University (US), Universität Hamburg (DE), Lincoln University (NZ), Neurosciences Institute (US), Utrecht University (NL), University Medical Center Utrecht (NL), University Medical Center Hamburg-Eppendorf (DE), Palo Alto Institute (US), Fondazione Stella Maris (IT), German Centre for Cardiovascular Research (DE), Stanford Medicine (US), Wilhelmina Children's Hospital (NL), Arc Research Institute, Stanford University (US)
Good health and well-being
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Lysosomal Storage Disorders Research
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