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Original Article
- High Levels of Mutant Huntingtin Protein in Tear Fluid From Huntington’s Disease Gene Expansion Carriers
- Marlies Gijs, Nynke Jorna, Nicole Datson, Chantal Beekman, Cira Dansokho, Alexander Weiss, David E. J. Linden, Mayke Oosterloo
- J Mov Disord. 2024;17(2):181-188. Published online February 21, 2024
- DOI: https://doi.org/10.14802/jmd.24014
- 13,833 View
- 321 Download
- 17 Web of Science
- 17 Crossref
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Abstract
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Supplementary Material - Objective
Huntington’s disease (HD) is an autosomal dominant, fully penetrant, neurodegenerative disease that most commonly affects middle-aged adults. HD is caused by a CAG repeat expansion in the HTT gene, resulting in the expression of mutant huntingtin (mHTT). Our aim was to detect and quantify mHTT in tear fluid, which, to our knowledge, has never been measured before.
Methods
We recruited 20 manifest and 13 premanifest HD gene expansion carriers, and 20 age-matched controls. All patients underwent detailed assessments, including the Unified Huntington’s Disease Rating Scale (UHDRS) total motor score (TMS) and total functional capacity (TFC) score. Tear fluid was collected using paper Schirmer’s strips. The level of tear mHTT was determined using single-molecule counting SMCxPRO technology.
Results
The average tear mHTT levels in manifest (67,223 ± 80,360 fM) and premanifest patients (55,561 ± 45,931 fM) were significantly higher than those in controls (1,622 ± 2,179 fM). We noted significant correlations between tear mHTT levels and CAG repeat length, “estimated years to diagnosis,” disease burden score and UHDRS TMS and TFC. The receiver operating curve demonstrated an almost perfect score (area under the curve [AUC] = 0.9975) when comparing controls to manifest patients. Similarly, the AUC between controls and premanifest patients was 0.9846. The optimal cutoff value for distinguishing between controls and manifest patients was 4,544 fM, whereas it was 6,596 fM for distinguishing between controls and premanifest patients.
Conclusion
Tear mHTT has potential for early and noninvasive detection of alterations in HD patients and could be integrated into both clinical trials and clinical diagnostics. -
Citations
Citations to this article as recorded by
- Comparing Analyte Concentrations in Paired Tear Fluid and Blood Samples
Yutong Wang, Li Liang, Rudy M. M. A. Nuijts, Marlies Gijs
Current Eye Research.2026; 51(10): 1174. CrossRef - Association of tear fluid glutathione synthetase and glutathione levels with amyloid positivity
Nienke van de Sande, Saleh Ahmed, Ward van Deuse, Willemijn J. Jansen, Anouk den Braber, Pieter Jelle Visser, Frans R. J. Verhey, Michelle Thach, Frank D. Verbraak, Femke H. Bouwman, Rudy M.M.A. Nuijts, Inez H. G. B. Ramakers, Carroll A. B. Webers, Ashok
Scientific Reports.2026;[Epub] CrossRef - The gut–brain axis and trimethylamine N-oxide: an emergent biomarker in neurological diseases
Alessia Arangia, Rosanna Di Paola, Salvatore Cuzzocrea, Rosalba Siracusa, Ramona D’Amico, Daniela Impellizzeri
Neuroscience.2026; 607: 88. CrossRef - Recent Developments in Tear Fluid Biomarkers: An Expert Perspective on Clinical Translation
Marlies Gijs, Amalia Enríquez-de-Salamanca, Suzanne Hagan, Andrzej Grzybowski, Piera Versura
Current Eye Research.2026; 51(10): 1228. CrossRef - Introducing the blood-tear barrier: Structure, function, and disruption in ocular surface homeostasis
Marlies Gijs, Li Liang, Fleur Goezinne, Yutong Wang, Sébastien Foulquier, Rudy M.M.A. Nuijts
Progress in Retinal and Eye Research.2026; 114: 101492. CrossRef - Chitinases in Tear Fluid of Patients With Amyotrophic Lateral Sclerosis
Lara Wenz, Lena‐Sophie Scholl, Nya Reinhardt, Ricarda von Heynitz, Vincent Gmeiner, Petra Rau, Philipp Jie Müller, Andreas W. Wolff, Emily Feneberg, Antonia F. Demleitner, Paul Lingor
European Journal of Neurology.2026;[Epub] CrossRef - Advancing non-invasive diagnosis through biomarker detection in biofluids
Howyn Tang, Gary Sun, Chao Lu, Hossein Pouri, Rakshya Panta, Tai Lai Chen, Jin Zhang
Nanotechnology.2026; 37(38): 382002. CrossRef - Fluid and Imaging Biomarkers in Huntington’s Disease
Elizabeth L. Broom, Joelle Hanson-Baiden, Lauren M. Byrne
Current Neurology and Neuroscience Reports.2026;[Epub] CrossRef - A comprehensive scoping review of methodological approaches and clinical applications of tear fluid biomarkers
Marlies Gijs, Nienke van de Sande, Clémence Bonnet, Jente Schmeetz, Rosa Fernandes, Sònia Travé-Huarte, Marcela Huertas-Bello, Jeremy Chung Bo Chiang, Nikolay Boychev, Shruti Sharma, Françoise Brignole-Baudouin, Karima Kessal, Paul Lingor, Maurice M.T.H.
Progress in Retinal and Eye Research.2025; 106: 101338. CrossRef - Global practices of tear fluid collection, storage, and molecular analysis – A questionnaire by the Tear Research Network
Nikolay Boychev, Swaminathan Sethu, Romy op de Laak, Françoise Brignole-Baudouin, Nienke van de Sande, Katherine S Held, Amalia Enríquez de Salamanca, Suzanne Hagan, Clémence Bonnet, Vincent Yeung, Menglu Yang, Arkasubhra Ghosh, Marlies Gijs
Contact Lens and Anterior Eye.2025; 48(4): 102388. CrossRef - The status of standardization in methodologies for tear fluid biomarkers
Marlies Gijs, Suzanne Hagan, Amalia Enríquez-de-Salamanca
Expert Review of Molecular Diagnostics.2025; 25(7): 305. CrossRef - An Exploratory Analysis of Differential Tear Fluid miRNAs in Patients with Parkinson’s Disease and Atypical Parkinsonian Syndromes
Antonia F. Demleitner, Lucas Caldi Gomes, Lara Wenz, Laura Tzeplaeff, Dominik Pürner, Elena Luib, Lea H. Kunze, Paul Lingor
Molecular Neurobiology.2025; 62(12): 16397. CrossRef - Tear fluid proteomics: a comparative study of DIA and DDA mass spectrometry
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Journal of Mass Spectrometry and Advances in the Clinical Lab.2025; 38: 26. CrossRef - Systematic Review with Meta‐Analysis of Biofluid Markers for Huntington's Disease
Jane S. Paulsen, Natalie A. Bovin, Jordan D. Clemsen, Alexander Weiss, Abigail M. Key, Monica L. Janz, Alex Pinto, Deven K. Burks, Henrik Zetterberg, Kathleen M. Shannon
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Acta Ophthalmologica.2025; 103(S287): 3. CrossRef - Unveiling brain disorders using liquid biopsy and Raman spectroscopy
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Nanoscale.2024; 16(25): 11879. CrossRef - Ocular tear fluid biomarkers collected by contact lenses
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Biochemical and Biophysical Research Communications.2024; 734: 150744. CrossRef
- Comparing Analyte Concentrations in Paired Tear Fluid and Blood Samples
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