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Matthis Synofzik
Born
Germany
NationalityGerman
Alma materUniversity of Tübingen & Munich School of Philosophy
Scientific career
FieldsPrecision Medicine, Neurology, Neurogenetics, Neuroscience, Philosophy & Ethics
InstitutionsUniversity of Tübingen, Germany
Websitehttps://www.hih-tuebingen.de/en/research/independent-research-groups/translational-genomics/

Matthis Synofzik is a German translational neurologist and research neuroscientist. He is Professor (apl. Prof.) for Translational Genomics of Neurodegenerative Disease and leads the research division of Translational Genomics of Neurodegenerative Diseases at the Hertie Institute for Clinical Brain Research (HIH), University of Tübingen, Germany.

Education

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Synofzik studied Philosophy at the Munich School of Philosophy and at the University of Tübingen. Concurrently, he studied Medicine. He earned his clinical medical qualification (2006), as well as was awarded his Philosophy degree (Magister artium) from the University of Tübingen. In 2008, he submitted his thesis[1] in the field of cognitive neuroscience and was awarded his doctorate (Dr. med.) at the University of Tübingen. In 2013, he completed his board certification in clinical neurology at the University of Tübingen. In 2014, he was appointed as a consultant neurologist with a main focus on neurodegenerative diseases, and established his research laboratory, focusing on genetic, molecular and cognitive neuroscience levels of systems neurodegeneration. In 2015, he completed his (Habilitation) (Qualification for full professorship) in Neurology at the University of Tübingen titled Clinics and Genetics of autosomal-recessive ataxias (Klinik und Genetik autosomal-rezessiver Ataxien)[2] under the guidance of Ludger Schöls and Thomas Gasser.

Research interests

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His work, which has been widely published and cited, focuses on understanding the mechanisms of neurodegenerative diseases, particularly in the areas of hereditary ataxias, motor neuron diseases (ALS; hereditary spastic paraplegias), frontotemporal dementia and Alzheimer’s Disease. In his next-generation precision medicine and translational neuroscience approach, he combines next-generation genomics, biomarker development of ultra-sensitive fluid protein biomarkers, digital-motor biomarkers, and disease progression modeling to develop and investigate individualized molecular precision therapies. In his clinical practice, he specializes in diagnosing and treating patients with hereditary neurodegenerative disorders like hereditary ataxias, motor neuron diseases, frontotemporal dementia and Alzheimer’s Disease. He focuses on developing and applying advanced therapies, including RNA therapies and personalized medicine approaches. His clinical interests also extend to other rare and complex neurological disorders, where he combines diagnostic precision with cutting-edge research to develop individualized treatment plans for his patients.

Synofzik is known for his contributions to genetic research on ataxias and spastic paraplegias. He leads large-scale genomic initiatives like the PREPARE GENESIS database, which holds over 3,000 next-gen sequencing datasets for ataxia. This work has resulted in the discovery of over 20 novel genes related to ataxia and spasticity (e.g., DNAJC3[3], KCNA2[4], and PRDX3.[5])

For example, in a recent publication,[6] Synofzik helped to identify a novel genetic cause of late-onset cerebellar ataxia—GAA repeat expansions in the FGF14 gene - a previously unexplored cause of disease; and then set forth to demonstrate that this novel disease might be treatable by an already marketed drug (4-Aminopyridine).[7][8] It highlights the importance of examining deep intronic regions in genetic diagnostics, expanding the scope of mutation types considered in late-onset ataxia cases. The discovery of this repeat expansion underlying a treatable disease (as shown by Synofzik) may improve genetic screening and diagnosis for patients with unexplained ataxia, potentially leading to more targeted therapies. ‬ Similarly, in the field of frontotemporal dementia, Synofzik and colleagues demonstrated the genetic underpinnings of frontotemporal dementia in a 2018 paper.[9]

His group has also pioneered the use of neurofilament light chain and other protein biomarkers to track disease progression in neurodegenerative conditions, particularly in frontotemporal dementia and ataxias.[10][11][12] These biomarkers are vital for understanding disease stages and measuring treatment effects. As part of a larger body of work on these biomarker, a large longitudinal study demonstrated that serum neurofilament light and phosphorylated neurofilament heavy can stratify the presymptomatic phase of genetic frontotemporal dementia. These biomarkers track disease progression well before clinical symptoms appear. The findings provide crucial tools for early detection and for designing preventive or early-stage clinical trials for frontotemporal dementia, which is essential for slowing or halting disease progression before significant neurological damage occurs. Synofzik has shown similar metrics of these biomarkers in ataxias and motor neuron diseases.

He also specializes in digital-motor biomarker development[13], creating techniques to capture movement data using body-worn sensors and smartphones to monitor neurodegenerative conditions also remotely in patients’ real life. He is a leader in developing individualized antisense oligonucleotides (ASOs)[14][15], as part of a specific innovative personalized RNA therapy platfom approach for ultra-rare neurological diseases. This 1Mutation 1 Medicine (1M1M) initiative, co-chaired by Synofzik, focuses on creating tailored therapies for patients with specific genetic mutations, representing a novel approach to precision medicine in neurology. In a 2022 paper, Synofzik and colleagues set the stage for a genetic, regulatory, and ethical path[16] for individualized ASO therapies in Europe.

Synofzik has contributed to the creation of multimodal progression models for diseases like frontotemporal dementia and ataxias, incorporating data from fluid biomarkers, clinical outcomes, and neuroimaging. These models are essential for understanding disease dynamics and preparing for clinical trials.

Synofzik’s work thus bridges basic neuroscience, clinical research, and translational applications, advancing the diagnosis and treatment of complex neurodegenerative diseases. His contributions significantly enhance the understanding of the genetic underpinnings and biomarker-based stratification in neurodegenerative diseases, advancing precision medicine and early intervention strategies.

Career

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Following the completion of his Habilitation, Synofzik added clinical subspecialization in Geriatrics (2016) and Palliative Medicine (2018). In 2018, he was appointed professor (apl. Prof.) at the University of Tuebingen. In 2020, he assumed leadership of the research division of Translational Genomics of Neurodegenerative Diseases at the Hertie Institute for Clinical Brain Research. Prof. Synofzik is actively engaged in the clinical, research and ethics community on a local, national and international level:

Awards

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Synofzik has received several awards and honors throughout his career, including:

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References

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  1. ^ Synofzik, Matthis (2008). "Die Rolle interner Modelle bei der Wahrnehmung von Eigenbewegungen". Thesis (in German).
  2. ^ Synofzik, Matthis Benjamin (2015). "Klinik und Genetik autosomal-rezessiver Ataxien". Habilitation (in German).
  3. ^ Synofzik, Matthis; Haack, Tobias B.; Kopajtich, Robert; Gorza, Matteo; Rapaport, Doron; Greiner, Markus; Schönfeld, Caroline; Freiberg, Clemens; Schorr, Stefan; Holl, Reinhard W.; Gonzalez, Michael A.; Fritsche, Andreas; Fallier-Becker, Petra; Zimmermann, Richard; Strom, Tim M. (2014-12-04). "Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration". American Journal of Human Genetics. 95 (6): 689–697. doi:10.1016/j.ajhg.2014.10.013. ISSN 1537-6605. PMC 4259973. PMID 25466870.
  4. ^ Hedrich, Ulrike B. S.; Lauxmann, Stephan; Wolff, Markus; Synofzik, Matthis; Bast, Thomas; Binelli, Adrian; Serratosa, José M.; Martínez-Ulloa, Pedro; Allen, Nicholas M.; King, Mary D.; Gorman, Kathleen M.; Zeev, Bruria Ben; Tzadok, Michal; Wong-Kisiel, Lily; Marjanovic, Dragan (September 2021). "4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy". Science Translational Medicine. 13 (609): eaaz4957. doi:10.1126/scitranslmed.aaz4957. ISSN 1946-6242. PMID 34516822.
  5. ^ Rebelo, Adriana P.; Bender, Benjamin; Haack, Tobias B.; Zuchner, Stephan; PREPARE consortium; Basak, A. Nazli; Synofzik, Matthis (2022-10-21). "Expanding PRDX3 disease: broad range of onset age and infratentorial MRI signal changes". Brain: A Journal of Neurology. 145 (10): e95–e98. doi:10.1093/brain/awac240. ISSN 1460-2156. PMC 10233235. PMID 35792670.
  6. ^ Pellerin, David; Danzi, Matt C.; Wilke, Carlo; Renaud, Mathilde; Fazal, Sarah; Dicaire, Marie-Josée; Scriba, Carolin K.; Ashton, Catherine; Yanick, Christopher; Beijer, Danique; Rebelo, Adriana; Rocca, Clarissa; Jaunmuktane, Zane; Sonnen, Joshua A.; Larivière, Roxanne (2023-01-12). "Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia". The New England Journal of Medicine. 388 (2): 128–141. doi:10.1056/NEJMoa2207406. ISSN 1533-4406. PMC 10042577. PMID 36516086.
  7. ^ Wilke, Carlo; Pellerin, David; Mengel, David; Traschütz, Andreas; Danzi, Matt C.; Dicaire, Marie-Josée; Neumann, Manuela; Lerche, Holger; Bender, Benjamin; Houlden, Henry; RFC1 study group; Züchner, Stephan; Schöls, Ludger; Brais, Bernard; Synofzik, Matthis (2023-10-03). "GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response". Brain: A Journal of Neurology. 146 (10): 4144–4157. doi:10.1093/brain/awad157. ISSN 1460-2156. PMID 37165652.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  8. ^ Pellerin, David; Heindl, Felix; Wilke, Carlo; Danzi, Matt C.; Traschütz, Andreas; Ashton, Catherine; Dicaire, Marie-Josée; Cuillerier, Alexanne; Del Gobbo, Giulia; Boycott, Kym M.; Claassen, Jens; Rujescu, Dan; Hartmann, Annette M.; Zuchner, Stephan; Brais, Bernard (April 2024). "GAA-FGF14 disease: defining its frequency, molecular basis, and 4-aminopyridine response in a large downbeat nystagmus cohort". EBioMedicine. 102: 105076. doi:10.1016/j.ebiom.2024.105076. ISSN 2352-3964. PMC 10960126. PMID 38507876.
  9. ^ Blauwendraat, Cornelis; Wilke, Carlo; Simón-Sánchez, Javier; Jansen, Iris E.; Reifschneider, Anika; Capell, Anja; Haass, Christian; Castillo-Lizardo, Melissa; Biskup, Saskia; Maetzler, Walter; Rizzu, Patrizia; Heutink, Peter; Synofzik, Matthis (February 2018). "The wide genetic landscape of clinical frontotemporal dementia: systematic combined sequencing of 121 consecutive subjects". Genetics in Medicine: Official Journal of the American College of Medical Genetics. 20 (2): 240–249. doi:10.1038/gim.2017.102. ISSN 1530-0366. PMC 5846812. PMID 28749476.
  10. ^ Wilke, Carlo; Reich, Selina; van Swieten, John C.; Borroni, Barbara; Sanchez-Valle, Raquel; Moreno, Fermin; Laforce, Robert; Graff, Caroline; Galimberti, Daniela; Rowe, James B.; Masellis, Mario; Tartaglia, Maria C.; Finger, Elizabeth; Vandenberghe, Rik; de Mendonça, Alexandre (January 2022). "Stratifying the Presymptomatic Phase of Genetic Frontotemporal Dementia by Serum NfL and pNfH: A Longitudinal Multicentre Study". Annals of Neurology. 91 (1): 33–47. doi:10.1002/ana.26265. ISSN 1531-8249. PMID 34743360.
  11. ^ Wilke, Carlo; Mengel, David; Schöls, Ludger; Hengel, Holger; Rakowicz, Maria; Klockgether, Thomas; Durr, Alexandra; Filla, Alessandro; Melegh, Bela; Schüle, Rebecca; Reetz, Kathrin; Jacobi, Heike; Synofzik, Matthis (2022-05-17). "Levels of Neurofilament Light at the Preataxic and Ataxic Stages of Spinocerebellar Ataxia Type 1". Neurology. 98 (20): e1985–e1996. doi:10.1212/WNL.0000000000200257. ISSN 1526-632X. PMC 9162044. PMID 35264424.
  12. ^ Wilke, Carlo; Haas, Eva; Reetz, Kathrin; Faber, Jennifer; Garcia-Moreno, Hector; Santana, Magda M.; van de Warrenburg, Bart; Hengel, Holger; Lima, Manuela; Filla, Alessandro; Durr, Alexandra; Melegh, Bela; Masciullo, Marcella; Infante, Jon; Giunti, Paola (2020-07-07). "Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice". EMBO molecular medicine. 12 (7): e11803. doi:10.15252/emmm.201911803. ISSN 1757-4684. PMC 7338806. PMID 32510847.
  13. ^ Ilg, Winfried; Seemann, Jens; Giese, Martin; Traschütz, Andreas; Schöls, Ludger; Timmann, Dagmar; Synofzik, Matthis (2020-09-01). "Real-life gait assessment in degenerative cerebellar ataxia: Toward ecologically valid biomarkers". Neurology. 95 (9): e1199–e1210. doi:10.1212/WNL.0000000000010176. ISSN 1526-632X. PMID 32611635.
  14. ^ Bonifert, Tobias; Gonzalez Menendez, Irene; Battke, Florian; Theurer, Yvonne; Synofzik, Matthis; Schöls, Ludger; Wissinger, Bernd (2016-11-22). "Antisense Oligonucleotide Mediated Splice Correction of a Deep Intronic Mutation in OPA1". Molecular Therapy. Nucleic Acids. 5 (11): e390. doi:10.1038/mtna.2016.93. ISSN 2162-2531. PMC 5155325. PMID 27874857.
  15. ^ Bonifert, Tobias; Karle, Kathrin N.; Tonagel, Felix; Batra, Marion; Wilhelm, Christian; Theurer, Yvonne; Schoenfeld, Caroline; Kluba, Torsten; Kamenisch, York; Carelli, Valerio; Wolf, Julia; Gonzalez, Michael A.; Speziani, Fiorella; Schüle, Rebecca; Züchner, Stephan (August 2014). "Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier". Brain: A Journal of Neurology. 137 (Pt 8): 2164–2177. doi:10.1093/brain/awu165. ISSN 1460-2156. PMC 4107747. PMID 24970096.
  16. ^ Synofzik, Matthis; van Roon-Mom, Willeke M. C.; Marckmann, Georg; van Duyvenvoorde, Hermine A.; Graessner, Holm; Schüle, Rebecca; Aartsma-Rus, Annemieke (April 2022). "Preparing n-of-1 Antisense Oligonucleotide Treatments for Rare Neurological Diseases in Europe: Genetic, Regulatory, and Ethical Perspectives". Nucleic Acid Therapeutics. 32 (2): 83–94. doi:10.1089/nat.2021.0039. ISSN 2159-3345. PMC 9058873. PMID 34591693.
  17. ^ Synofzik, Matthis; Lindner, Axel; Thier, Peter (2008-06-03). "The cerebellum updates predictions about the visual consequences of one's behavior". Current biology: CB. 18 (11): 814–818. doi:10.1016/j.cub.2008.04.071. ISSN 0960-9822. PMID 18514520.
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