Neurodegeneration or dysfunction in Phelan-McDermid syndrome? A multimodal approach with CSF and computational MRI

Orphanet Journal of Rare Diseases

Research

Hans-Peter Müller¹  Jan Kassubek²  Sarah Jesse²  Albert C. Ludolph²  Tobias M. Boeckers³  Michael Schön⁴  Stephanie Andres⁵  Hans-Jürgen Huppertz⁶ 

[1] Department of Neurology, University Hospital Ulm, Oberer Eselsberg 45, D-89081, Ulm, Germany;Department of Neurology, University Hospital Ulm, Oberer Eselsberg 45, D-89081, Ulm, Germany;German Centre of Neurodegenerative Diseases (DZNE), Ulm, Germany;German Centre of Neurodegenerative Diseases (DZNE), Ulm, Germany;Institute of Anatomy and Cell Biology, Ulm University, Ulm, Germany;Institute of Anatomy and Cell Biology, Ulm University, Ulm, Germany;Medicover München Ost MVZ, Humangenetik, Munich, Germany;Swiss Epilepsy Clinic, Hospital Lengg, Zürich, Switzerland;

关键词: Phelan-McDermid syndrome;    SHANK;    Cerebrospinal fluid;    Tau-protein;    Amyloid-ß;    Neurodegeneration;    Dysfunction;    Magnetic resonance imaging;    White matter;    DTI;   

DOI  :  10.1186/s13023-023-02863-7

 received in 2023-03-16, accepted in 2023-08-20,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundPhelan-McDermid syndrome (PMS) is a rare multisystem disease with global developmental delay and autistic features. Genetically, the disease is based on a heterozygous deletion of chromosome 22q13.3 with involvement of at least part of the SHANK3 gene or heterozygous pathogenic variants in SHANK3. Pathophysiologically, this syndrome has been regarded as a synaptopathy, but current data suggest an additional concept, since axonal functions of neurons are also impaired, thus, the specific pathophysiological processes in this disease are not yet fully understood. Since symptoms of the autism spectrum, regression, and stagnation in development occur, we investigated whether neuroinflammatory and neurodegenerative processes may also play a role. To this end, we analysed biomarkers in cerebrospinal fluid (CSF) and parameters from magnetic resonance imaging with high-resolution structural T1w volumetry and diffusion tensor imaging analysis in 19 Phelan-McDermid syndrome patients.ResultsCSF showed no inflammation but abnormalities in tau protein and amyloid-ß concentrations, however, with no typical biomarker pattern as in Alzheimer’s disease. It could be demonstrated that these CSF changes were correlated with integrity losses of the fibres in the corticospinal tract as well as in the splenium and dorsal part of the cingulum. High CSF levels of tau protein were associated with loss of integrity of fibres in the corticospinal tract; lower levels of amyloid-ß were associated with decreasing integrity of fibre tracts of the splenium and posterior cingulate gyrus. Volumetric investigations showed global atrophy of the white matter, but not the grey matter, and particularly not in temporal or mesiotemporal regions, as is typical in later stages of Alzheimer’s disease.ConclusionsIn summary, alterations of neurodegenerative CSF markers in PMS individuals could be demonstrated which were correlated with structural connectivity losses of the corticospinal tract, the splenium, and the dorsal part of the cingulum, which can also be associated with typical clinical symptoms in these patients. These findings might represent a state of dysfunctional processes with ongoing degenerative and regenerative processes or a kind of accelerated aging. This study should foster further clinical diagnostics like tau- and amyloid-PET imaging as well as novel scientific approaches especially in basic research for further mechanistic proof.

【 授权许可】

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© Institut National de la Santé et de la Recherche Médicale (INSERM) 2023