Diffusion Tensor Imaging Abnormalities in the Uncinate Fasciculus and Inferior Longitudinal Fasciculus in Phelan-McDermid Syndrome

Bassell, Julia L.; Srivastava, Siddharth; Prohl, Anna K.; Scherrer, Benoît; Kapur, Kush; Filip-Dhima, Rajna; Berry‐Kravis, Elizabeth; Soorya, Latha; Thurm, Audrey; Powell, Craig M.; Bernstein, Jonathan A.; Kolevzon, Alexander; Şahin, Mustafa; Buxbaum, Joseph D.; Kravis, Elizabeth Berry; Warfield, Simon K.; Dies, Kira; Siper, Paige M.; Hanson, Ellen; Phillips, Jennifer M.; White, Steven J.

doi:10.1016/j.pediatrneurol.2020.01.006

Cited by 14 publications

(15 citation statements)

References 61 publications

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“…Thus, SHANK3 deficiency was attributed a white matter disease for the first time. A disturbance of white matter organization and volume has been observed in patients with PMDS, along with alterations in brain connectivity [ 30 , 31 ].…”

Section: Introductionmentioning

confidence: 99%

SHANK3 deficiency leads to myelin defects in the central and peripheral nervous system

Malara

Lutz

Incearap

et al. 2022

Cell. Mol. Life Sci.

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Mutations or deletions of the SHANK3 gene are causative for Phelan–McDermid syndrome (PMDS), a syndromic form of autism spectrum disorders (ASDs). We analyzed Shank3Δ11(−/−) mice and organoids from PMDS individuals to study effects on myelin. SHANK3 was found to be expressed in oligodendrocytes and Schwann cells, and MRI analysis of Shank3Δ11(−/−) mice revealed a reduced volume of the corpus callosum as seen in PMDS patients. Myelin proteins including myelin basic protein showed significant temporal and regional differences with lower levels in the CNS but increased amounts in the PNS of Shank3Δ11(−/−) animals. Node, as well as paranode, lengths were increased and ultrastructural analysis revealed region-specific alterations of the myelin sheaths. In PMDS hiPSC-derived cerebral organoids we observed an altered number and delayed maturation of myelinating cells. These findings provide evidence that, in addition to a synaptic deregulation, impairment of myelin might profoundly contribute to the clinical manifestation of SHANK3 deficiency.

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Section: Introductionmentioning

confidence: 99%

SHANK3 deficiency leads to myelin defects in the central and peripheral nervous system

Malara

Lutz

Incearap

et al. 2022

Cell. Mol. Life Sci.

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“…This gene is in the 22nd chromosome, 22q13.33 region. Deletion of this region as well as mutations lead to 22q13 Deletion Syndrome also known as Phelan–McDermid Syndrome (PMS) [ 3 , 4 , 5 , 6 , 7 , 8 ]. In most PMS cases, the SHANK3 gene is affected that is believed to be the major cause of PMS.…”

Section: Introductionmentioning

confidence: 99%

“…Phelan–McDermid Syndrome (PMS) is a rare neurodevelopmental disorder with about 2000 cases identified so far [ 6 ]. However, many PMS cases can go unnoticed, as the diagnosis of PMS is often difficult due to the subtle appearance of the deletion of chromosome 22 and relatively mild physical and nonspecific clinical manifestation of the syndrome.…”

Section: Introductionmentioning

confidence: 99%

40-Hz Auditory Steady-State Response (ASSR) as a Biomarker of Genetic Defects in the SHANK3 Gene: A Case Report of 15-Year-Old Girl with a Rare Partial SHANK3 Duplication

Neklyudova

Portnova

Rebreikina

et al. 2021

IJMS

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SHANK3 encodes a scaffold protein involved in postsynaptic receptor density in glutamatergic synapses, including those in the parvalbumin (PV)+ inhibitory neurons—the key players in the generation of sensory gamma oscillations, such as 40-Hz auditory steady-state response (ASSR). However, 40-Hz ASSR was not studied in relation to SHANK3 functioning. Here, we present a 15-year-old girl (SH01) with previously unreported duplication of the first seven exons of the SHANK3 gene (22q13.33). SH01’s electroencephalogram (EEG) during 40-Hz click trains of 500 ms duration binaurally presented with inter-trial intervals of 500–800 ms were compared with those from typically developing children (n = 32). SH01 was diagnosed with mild mental retardation and learning disabilities (F70.88), dysgraphia, dyslexia, and smaller vocabulary than typically developing (TD) peers. Her clinical phenotype resembled the phenotype of previously described patients with 22q13.33 microduplications (≈30 reported so far). SH01 had mild autistic symptoms but below the threshold for ASD diagnosis and microcephaly. No seizures or MRI abnormalities were reported. While SH01 had relatively preserved auditory event-related potential (ERP) with slightly attenuated P1, her 40-Hz ASSR was totally absent significantly deviating from TD’s ASSR. The absence of 40-Hz ASSR in patients with microduplication, which affected the SHANK3 gene, indicates deficient temporal resolution of the auditory system, which might underlie language problems and represent a neurophysiological biomarker of SHANK3 abnormalities.

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“…These white matter de cits parallel those seen in humans and a mouse model. Clinical assessment and studies of individuals with Shank3 de ciency, 22q13.3 deletion syndrome, and diagnosed PMS showed thinning or hypoplasia of the corpus callosum (6, 7) and reduced FA and increased MD in long association ber tracts (8,9), including the uncinate fasciculus and the inferior fronto-occipital fasciculus. Similarly, Shank3 heterozygous KO mice have signi cantly reduced FA in long ber tract systems compared to WT controls (8).…”

Section: Discussionmentioning

confidence: 99%

“…Understanding how the pathology that results from a Shank3 de ciency affects brain structure in PMS pathogenesis could offer biomarkers to focus on in patients and rodent models. Neuroimaging studies on small cohorts have shown that individuals with PMS have reduced relative volumes of structures in the basal ganglia and cerebellum (4,5), white matter thinning (6,7), and alterations in ber tracts (8,9). However, these abnormalities have not yet been explored in a rat model.…”

Section: Introductionmentioning

confidence: 99%

Reduced Brain Volume and White Matter Alterations in Shank3-Deficient Rats

Golden

Wang

Harony‐Nicolas

et al. 2020

Preprint

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Background: Mutations and deletions in the SHANK3 synaptic gene cause the major neurodevelopmental features of Phelan-McDermid syndrome (PMS). The SHANK3 gene encodes a key structural component of excitatory synapses that is important for synaptogenesis. PMS is characterized by intellectual disability, autism spectrum disorder, cognitive deficits, physical dysmorphic features, sensory hyporeactivity, and alterations in the size of multiple brain regions. Clinical assessments and limited imaging studies have revealed a reduction in volume of multiple brain regions. They have also found white matter thinning and microstructural alterations to be persistent in patients with PMS. While many of these impairments have been replicated in mouse models of PMS, the brain structure of a rat model has not yet been studied. Methods: We assessed the brain structure of haploinsufficient and homozygous Shank3-deficient rats that model the behavioral deficits of PMS with magnetic resonance and diffusion tensor imaging, and compared their brain structure to wild type littermates.Results: Both gray and white matter structures were smaller in Shank3-deficient rats, leading to an overall reduction in brain size compared to wild type littermates. The largest region to be diminished in size was the neocortex. Some regions involved in sensory processing and white matter regions were also reduced in size. Lastly, the microstructure of two white matter tracts, the external capsule and fornix, was abnormal.Conclusions: Shank3-deficient rats replicate the reduced brain volume and altered white matter phenotypes present in individuals with PMS. Therefore, the brain regions that were altered represent potential cross-species structural biomarkers that warrant further study.

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Diffusion Tensor Imaging Abnormalities in the Uncinate Fasciculus and Inferior Longitudinal Fasciculus in Phelan-McDermid Syndrome

Cited by 14 publications

References 61 publications

SHANK3 deficiency leads to myelin defects in the central and peripheral nervous system

SHANK3 deficiency leads to myelin defects in the central and peripheral nervous system

40-Hz Auditory Steady-State Response (ASSR) as a Biomarker of Genetic Defects in the SHANK3 Gene: A Case Report of 15-Year-Old Girl with a Rare Partial SHANK3 Duplication

Reduced Brain Volume and White Matter Alterations in Shank3-Deficient Rats

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