Dataset Information

Severe white matter damage in SHANK3 deficiency: a human and translational study.

ABSTRACT:

Objective

Heterozygous SHANK3 mutations or partial deletions of the long arm of chromosome 22, also known as Phelan-McDermid syndrome, result in a syndromic form of the autism spectrum as well as in global developmental delay, intellectual disability, and several neuropsychiatric comorbidities. The exact pathophysiological mechanisms underlying the disease are still far from being deciphered but studies of SHANK3 models have contributed to the understanding of how the loss of the synaptic protein SHANK3 affects neuronal function.

Methods and results

Diffusion tensor imaging-based and automatic volumetric brain mapping were performed in 12 SHANK3-deficient participants (mean age 19 ± 15 years) versus 14 age- and gender-matched controls (mean age 29 ± 5 years). Using whole brain-based spatial statistics, we observed a highly significant pattern of white matter alterations in participants with SHANK3 mutations with focus on the long association fiber tracts, particularly the uncinate tract and the inferior fronto-occipital fasciculus. In contrast, only subtle gray matter volumetric abnormalities were detectable. In a back-translational approach, we observed similar white matter alterations in heterozygous isoform-specific Shank3 knockout (KO) mice. Here, in the baseline data sets, the comparison of Shank3 heterozygous KO vs wildtype showed significant fractional anisotropy reduction of the long fiber tract systems in the KO model. The multiparametric Magnetic Resonance Imaging (MRI) analysis by DTI and volumetry demonstrated a pathology pattern with severe white matter alterations and only subtle gray matter changes in the animal model.

Interpretation

In summary, these translational data provide strong evidence that the SHANK3-deficiency-associated pathomechanism presents predominantly with a white matter disease. Further studies should concentrate on the role of SHANK3 during early axonal pathfinding/wiring and in myelin formation.

SUBMITTER: Jesse S

PROVIDER: S-EPMC6952316 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

Severe white matter damage in SHANK3 deficiency: a human and translational study.

Jesse Sarah S Müller Hans-Peter HP Schoen Michael M Asoglu Harun H Bockmann Juergen J Huppertz Hans-Juergen HJ Rasche Volker V Ludolph Albert C AC Boeckers Tobias M TM Kassubek Jan J

Annals of clinical and translational neurology 20191202 1

<h4>Objective</h4>Heterozygous SHANK3 mutations or partial deletions of the long arm of chromosome 22, also known as Phelan-McDermid syndrome, result in a syndromic form of the autism spectrum as well as in global developmental delay, intellectual disability, and several neuropsychiatric comorbidities. The exact pathophysiological mechanisms underlying the disease are still far from being deciphered but studies of SHANK3 models have contributed to the understanding of how the loss of the synapti ...[more]

PMID: 31788990

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Project description:Background Autism spectrum disorder (ASD) is a neurodevelopmental condition, which is characterized by clinical heterogeneity and high heritability. Core symptoms of ASD include deficits in social communication and interaction, as well as restricted, repetitive patterns of behavior, interests, or activities. Many genes have been identified that are associated with an increased risk for ASD. Proteins encoded by these ASD risk genes are often involved in processes related to fetal brain development, chromatin modification and regulation of gene expression in general, as well as the structural and functional integrity of synapses. Genes of the SH3 and multiple ankyrin repeat domains (SHANK) family encode crucial scaffolding proteins (SHANK1-3) of excitatory synapses and other macromolecular complexes. SHANK gene mutations are highly associated with ASD and more specifically the Phelan-McDermid syndrome (PMDS), which is caused by heterozygous 22q13.3-deletion resulting in SHANK3-haploinsufficiency, or by SHANK3 missense variants. SHANK3 deficiency and potential treatment options have been extensively studied in animal models, especially in mice, but also in rats and non-human primates. However, few of the proposed therapeutic strategies have translated into clinical practice yet. Main text This review summarizes the literature concerning SHANK3-deficient animal models. In particular, the structural, behavioral, and neurological abnormalities are described and compared, providing a broad and comprehensive overview. Additionally, the underlying pathophysiologies and possible treatments that have been investigated in these models are discussed and evaluated with respect to their effect on ASD- or PMDS-associated phenotypes. Conclusions Animal models of SHANK3 deficiency generated by various genetic strategies, which determine the composition of the residual SHANK3-isoforms and affected cell types, show phenotypes resembling ASD and PMDS. The phenotypic heterogeneity across multiple models and studies resembles the variation of clinical severity in human ASD and PMDS patients. Multiple therapeutic strategies have been proposed and tested in animal models, which might lead to translational implications for human patients with ASD and/or PMDS. Future studies should explore the effects of new therapeutic approaches that target genetic haploinsufficiency, like CRISPR-mediated activation of promotors.

Project description:Primary progressive aphasia is a clinical syndrome that encompasses three major phenotypes: non-fluent/agrammatic, semantic and logopenic. These clinical entities have been associated with characteristic patterns of focal grey matter atrophy in left posterior frontoinsular, anterior temporal and left temporoparietal regions, respectively. Recently, network-level dysfunction has been hypothesized but research to date has focused largely on studying grey matter damage. The aim of this study was to assess the integrity of white matter tracts in the different primary progressive aphasia subtypes. We used diffusion tensor imaging in 48 individuals: nine non-fluent, nine semantic, nine logopenic and 21 age-matched controls. Probabilistic tractography was used to identify bilateral inferior longitudinal (anterior, middle, posterior) and uncinate fasciculi (referred to as the ventral pathway); and the superior longitudinal fasciculus segmented into its frontosupramarginal, frontoangular, frontotemporal and temporoparietal components, (referred to as the dorsal pathway). We compared the tracts' mean fractional anisotropy, axial, radial and mean diffusivities for each tract in the different diagnostic categories. The most prominent white matter changes were found in the dorsal pathways in non-fluent patients, in the two ventral pathways and the temporal components of the dorsal pathways in semantic variant, and in the temporoparietal component of the dorsal bundles in logopenic patients. Each of the primary progressive aphasia variants showed different patterns of diffusion tensor metrics alterations: non-fluent patients showed the greatest changes in fractional anisotropy and radial and mean diffusivities; semantic variant patients had severe changes in all metrics; and logopenic patients had the least white matter damage, mainly involving diffusivity, with fractional anisotropy altered only in the temporoparietal component of the dorsal pathway. This study demonstrates that both careful dissection of the main language tracts and consideration of all diffusion tensor metrics are necessary to characterize the white matter changes that occur in the variants of primary progressive aphasia. These results highlight the potential value of diffusion tensor imaging as a new tool in the multimodal diagnostic evaluation of primary progressive aphasia.

Dataset Information

Severe white matter damage in SHANK3 deficiency: a human and translational study.

Objective

Methods and results

Interpretation

Publications

Severe white matter damage in SHANK3 deficiency: a human and translational study.

Similar Datasets

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