Blood-CSF barrier integrity in amyotrophic lateral sclerosis.

The integrity of the blood-CSF barrier plays a major role in inflammation, but also in shielding the central nervous system from external and systemic - potentially toxic - factors. Here we report results of measurements of the albumin quotient - which is thought to mirror the integrity of the blood/CSF barrier - in 1059 amyotrophic lateral sclerosis patients. The results were compared with groups of patients suffering from Alzheimer´s disease, facial palsy and tension headache. The albumin quotient, an accepted measure of the blood/CSF barrier integrity, was not significantly different from control populations. In addition, we found that the albumin quotient correlated with survival of the patients; this effect was mainly driven by male patients and influenced by age, BMI and diabetes mellitus. We conclude that the blood/CSF barrier is intact in this large cohort of ALS patients and that the albumin quotient correlates with survival. Whether this is important for the pathogenesis of the disease, requires mechanistic studies.

Quantification of blood glial fibrillary acidic protein using a second-generation microfluidic assay. Validation and comparative analysis with two established assays.

OBJECTIVES: Increased levels of glial fibrillary acidic protein (GFAP) in blood have been identified as a valuable biomarker for some neurological disorders, such as Alzheimer's disease and multiple sclerosis. However, most blood GFAP quantifications so far were performed using the same bead-based assay, and to date a routine clinical application is lacking. METHODS: In this study, we validated a novel second-generation (2nd gen) Ella assay to quantify serum GFAP. Furthermore, we compared its performance with a bead-based single molecule array (Simoa) and a homemade GFAP assay in a clinical cohort of neurological diseases, including 210 patients. RESULTS: Validation experiments resulted in an intra-assay variation of 10 %, an inter-assay of 12 %, a limit of detection of 0.9 pg/mL, a lower limit of quantification of 2.8 pg/mL, and less than 20 % variation in serum samples exposed to up to five freeze-thaw cycles, 120 h at 4 °C and room temperature. Measurement of the clinical cohort using all assays revealed the same pattern of GFAP distribution in the different diagnostic groups. Moreover, we observed a strong correlation between the 2nd gen Ella and Simoa (r=0.91 (95 % CI: 0.88-0.93), p<0.0001) and the homemade immunoassay (r=0.77 (95 % CI: 0.70-0.82), p<0.0001). CONCLUSIONS: Our results demonstrate a high reliability, precision and reproducibility of the 2nd gen Ella assay. Although a higher assay sensitivity for Simoa was observed, the new microfluidic assay might have the potential to be used for GFAP analysis in daily clinical workups due to its robustness and ease of use.

Haemodynamics and cerebral oxygenation of neonatal piglets in the immediate ex utero period supported by mechanical ventilation or ex utero oxygenator.

KEY POINTS: The margin of human viability has extended to the extremes of gestational age (<24 weeks) when the lungs are immature and ventilator-induced lung injury is common. Artificial placenta technology aims to extend gestation ex utero in order to allow the lungs additional time to develop prior to entering an air-breathing environment. We compared the haemodynamics and cerebral oxygenation of piglets in the immediate period post-oxygenator (OXY) transition against both paired in utero measures and uniquely against piglets transitioned onto mechanical ventilation (VENT). Post-transition, OXY piglets became hypotensive with reduced carotid blood flow in comparison with both paired in utero measures and VENT piglets. The addition of a pump to the oxygenator circuit may be required to ensure haemodynamic stability in the immediate post-transition period. ABSTRACT: Gestational age at birth is a major predictor of wellbeing; the lower the gestational age, the greater the risk of mortality and morbidity. At the margins of human viability (<24 weeks gestation) immature lungs combined with the need for early ventilatory support means lung injury and respiratory morbidity is common. The abrupt haemodynamic changes consequent on birth may also contribute to preterm-associated brain injury, including intraventricular haemorrhage. Artificial placenta technology aims to support oxygenation, haemodynamic stability and ongoing fetal development ex utero until mature enough to safely transition to a true ex utero environment. We aimed to characterize the impact of birth transition onto either an oxygenator circuit or positive pressure ventilation on haemodynamic and cerebral oxygenation of the neonatal piglet. At 112 days gestation (term = 115 days), fetal pigs underwent instrumentation surgery and transitioned onto either an oxygenator (OXY, n = 5) or ventilatory support (VENT, n = 8). Blood pressure (BP), carotid blood flow and cerebral oxygenation in VENT piglets rose from in utero levels to be significantly higher than OXY piglets post-transition. OXY piglet BP, carotid blood flow and carotid oxygen delivery (DO2 ) decreased from in utero levels post-transition; however, cerebral regional oxygen saturation (rSO2 ) was maintained at fetal-like levels. OXY piglets became hypoxaemic and retained CO2 . Whether OXY piglets are able to maintain cerebral rSO2 under these conditions for a prolonged period is yet to be determined. Improvements to OXY piglet oxygenation may lie in maintaining piglet BP at in utero levels and enhancing oxygenator circuit flow.

Phelan McDermid Syndrome: Multiple Sclerosis as a Rare but Treatable Cause for Regression-A Case Report.

Phelan McDermid syndrome (PMcD) is a neurogenetic disease associated with haploinsufficiency of the SHANK3 gene due to a spectrum of anomalies in the terminal region of the long arm of chromosome 22. SHANK3 is the abbreviation for SH3 domain and ankyrin repeat-containing protein, a gene that encodes for proteins of the postsynaptic density (PSD) of excitatory synapses. This PSD is relevant for the induction and plasticity of spine and synapse formation as a basis for learning processes and long-term potentiation. Individuals with PMcD present with intellectual disability, muscular hypotonia, and severely delayed or absent speech. Further neuropsychiatric manifestations cover symptoms of the autism spectrum, epilepsy, bipolar disorders, schizophrenia, and regression. Regression is one of the most feared syndromes by relatives of PMcD patients. Current scientific evidence indicates that the onset of regression is variable and affects language, motor skills, activities of daily living and cognition. In the case of regression, patients normally undergo further diagnostics to exclude treatable reasons such as complex-focal seizures or psychiatric comorbidities. Here, we report, for the first time, the case of a young female who developed progressive symptoms of regression and a dystonic-spastic hemiparesis that could be traced back to a comorbid multiple sclerosis and that improved after treatment with methylprednisolone.

Consensus recommendations on altered sensory functioning in Phelan-McDermid syndrome.

Altered sensory functioning is often observed in individuals with SHANK3 related Phelan-McDermid syndrome (PMS). Compared to typically developing individuals and individuals with an autism spectrum disorder, it has been suggested that there are distinctive features of sensory functioning in PMS. More hyporeactivity symptoms and less hyperreactivity and sensory seeking behaviour are seen, particularly in the auditory domain. Hypersensitivity to touch, possible overheating or turning red easily and reduced pain response are often seen. In this paper the current literature on sensory functioning in PMS is reviewed and recommendations for caregivers, based on consensus within the European PMS consortium, are given.

Consensus recommendations on Epilepsy in Phelan-McDermid syndrome.

Phelan-McDermid syndrome (PMS) is a 22q13.3 deletion syndrome that presents with a disturbed development, neurological and psychiatric characteristics, and sometimes other comorbidities like seizures. The epilepsy manifests itself in a variety of seizure semiologies. Further diagnostics using electroencephalogram (EEG) and brain magnetic resonance imaging (MRI) are important in conjunction with the clinical picture of the seizures to decide whether anticonvulsant therapy is necessary. As part of the development of European consensus guidelines we focussed on the prevalence and semiology of epileptic seizures in PMS associated with a pathogenic variant in the SHANK3 gene or the 22q13 deletion involving SHANK3, in order to then be able to make recommendations regarding diagnosis and therapy.

Shank3 related muscular hypotonia is accompanied by increased intracellular calcium concentrations and ion channel dysregulation in striated muscle tissue.

Phelan-McDermid syndrome (PMS) is a syndromic form of Autism Spectrum Disorders (ASD) classified as a rare genetic neurodevelopmental disorder featuring global developmental delay, absent or delayed speech, ASD-like behaviour and neonatal skeletal muscle hypotonia. PMS is caused by a heterozygous deletion of the distal end of chromosome 22q13.3 or SHANK3 mutations. We analyzed striated muscles of newborn Shank3Δ11(-/-) animals and found a significant enlargement of the sarcoplasmic reticulum as previously seen in adult Shank3Δ11(-/-) mice, indicative of a Shank3-dependent and not compensatory mechanism for this structural alteration. We analyzed transcriptional differences by RNA-sequencing of muscle tissue of neonatal Shank3Δ11(-/-) mice and compared those to Shank3(+/+) controls. We found significant differences in gene expression of ion channels crucial for muscle contraction and for molecules involved in calcium ion regulation. In addition, calcium storage- [i.e., Calsequestrin (CSQ)], calcium secretion- and calcium-related signaling-proteins were found to be affected. By immunostainings and Western blot analyses we could confirm these findings both in Shank3Δ11(-/-) mice and PMS patient muscle tissue. Moreover, alterations could be induced in vitro by the selective downregulation of Shank3 in C2C12 myotubes. Our results emphasize that SHANK3 levels directly or indirectly regulate calcium homeostasis in a cell autonomous manner that might contribute to muscular hypotonia especially seen in the newborn.

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

BACKGROUND: Phelan-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. RESULTS: CSF 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. CONCLUSIONS: In 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.

Increased Radiation Sensitivity in Patients with Phelan-McDermid Syndrome.

Phelan-McDermid syndrome is an inherited global developmental disorder commonly associated with autism spectrum disorder. Due to a significantly increased radiosensitivity, measured before the start of radiotherapy of a rhabdoid tumor in a child with Phelan-McDermid syndrome, the question arose whether other patients with this syndrome also have increased radiosensitivity. For this purpose, the radiation sensitivity of blood lymphocytes after irradiation with 2Gray was examined using the G0 three-color fluorescence in situ hybridization assay in a cohort of 20 patients with Phelan-McDermid syndrome from blood samples. The results were compared to healthy volunteers, breast cancer patients and rectal cancer patients. Independent of age and gender, all but two patients with Phelan-McDermid syndrome showed significantly increased radiosensitivity, with an average of 0.653 breaks per metaphase. These results correlated neither with the individual genetic findings nor with the individual clinical course, nor with the respective clinical severity of the disease. In our pilot study, we saw a significantly increased radiosensitivity in lymphocytes from patients with Phelan-McDermid syndrome, so pronounced that a dose reduction would be recommended if radiotherapy had to be performed. Ultimately, the question arises as to the interpretation of these data. There does not appear to be an increased risk of tumors in these patients, since tumors are rare overall. The question, therefore, arose as to whether our results could possibly be the basis for processes, such as aging/preaging, or, in this context, neurodegeneration. There are no data on this so far, but this issue should be pursued in further fundamentally based studies in order to better understand the pathophysiology of the syndrome.

CSF oligoclonal IgG bands are not associated with ALS progression and prognosis.

Introduction: Amyotrophic Lateral Sclerosis (ALS) is characterized by progressive motoneuron degeneration through cell autonomous and non-cell autonomous mechanisms; and the involvement of the innate and adaptive immune system has been hypothesized based on human and murine model data. We have explored if B-cell activation and IgG responses, as detected by IgG Oligoclonal bands (OCB) in serum and cerebrospinal fluid, were associated with ALS or with a subgroup of patients with distinct clinical features. Methods: IgG OCB were determined in patients affected by ALS (n=457), Alzheimer Disease (n=516), Mild Cognitive Impairment (n=91), Tension-type Headache (n=152) and idiopathic Facial Palsy (n=94). For ALS patients, clinico-demographic and survival data were prospectively collected in the Register Schabia. Results: The prevalence of IgG OCB is comparable in ALS and the four neurological cohorts. When the OCB pattern was considered (highlighting either intrathecal or systemic B-cells activation), no effect of OCB pattern on clinic-demographic parameters and overall. ALS patients with intrathecal IgG synthesis (type 2 and 3) were more likely to display infectious, inflammatory or systemic autoimmune conditions. Discussion: These data suggest that OCB are not related to ALS pathophysiology but rather are a finding possibly indicative a coincidental infectious or inflammatory comorbidity that merits further investigation.

Guideline "Motor neuron diseases" of the German Society of Neurology (Deutsche Gesellschaft für Neurologie).

INTRODUCTION: In 2021, the Deutsche Gesellschaft für Neurology published a new guideline on diagnosis and therapy of motor neuron disorders. Motor neuron disorders affect upper motor neurons in the primary motor cortex and/or lower motor neurons in the brain stem and spinal cord. The most frequent motor neuron disease amyotrophic lateral sclerosis (ALS) is a rapidly progressive disease with an average life expectancy of 2-4 years with a yearly incidence of 3.1/100,000 in Central Europe (Rosenbohm et al. in J Neurol 264(4):749-757, 2017. https://doi.org/10.1007/s00415-017-8413-3 ). It is considered a rare disease mainly due to its low prevalence as a consequence of short disease duration. RECOMMENDATIONS: These guidelines comprise recommendations regarding differential diagnosis, neuroprotective therapies and multidisciplinary palliative care including management of respiration and nutrition as well as provision of assistive devices and end-of-life situations. CONCLUSION: Diagnostic and therapeutic guidelines are necessary due the comparatively high number of cases and the aggressive disease course. Given the low prevalence and the severe impairment of patients, it is often impossible to generate evidence-based data so that ALS guidelines are partially dependent on expert opinion.

Definition and clinical variability of SHANK3-related Phelan-McDermid syndrome.

Phelan-McDermid syndrome (PMS) is an infrequently described syndrome that presents with a disturbed development, neurological and psychiatric characteristics, and sometimes other comorbidities. As part of the development of European medical guidelines we studied the definition, phenotype, genotype-phenotype characteristics, and natural history of the syndrome. The number of confirmed diagnoses of PMS in different European countries was also assessed and it could be concluded that PMS is underdiagnosed. The incidence of PMS in European countries is estimated to be at least 1 in 30,000. Next generation sequencing, including analysis of copy number variations, as first tier in diagnostics of individuals with intellectual disability will likely yield a larger number of individuals with PMS than presently known. A definition of PMS by its phenotype is at the present not possible, and therefore PMS-SHANK3 related is defined by the presence of SHANK3 haploinsufficiency, either by a deletion involving region 22q13.2-33 or a pathogenic/likely pathogenic variant in SHANK3. In summarizing the phenotype, we subdivided it into that of individuals with a 22q13 deletion and that of those with a pathogenic/likely pathogenic SHANK3 variant. The phenotype of individuals with PMS is variable, depending in part on the deletion size or whether only a variant of SHANK3 is present. The core phenotype in the domains development, neurology, and senses are similar in those with deletions and SHANK3 variants, but individuals with a SHANK3 variant more often are reported to have behavioural disorders and less often urogenital malformations and lymphedema. The behavioural disorders may, however, be a less outstanding feature in individuals with deletions accompanied by more severe intellectual disability. Data available on the natural history are limited. Results of clinical trials using IGF-1, intranasal insulin, and oxytocin are available, other trials are in progress. The present guidelines for PMS aim at offering tools to caregivers and families to provide optimal care to individuals with PMS.

Signal alterations of the basal ganglia in the differential diagnosis of Parkinson's disease: a retrospective case-controlled MRI data bank analysis.

BACKGROUND: Based upon the acquainted loss of dopaminergic neurons in the substantia nigra in Parkinson's disease (PD), we hypothesised changes in magnetic resonance imaging signal intensities of the basal ganglia to be useful as an additional technical tool in the diagnostic work-up. METHODS: Region-of-interest analyses (substantia nigra and globus pallidus internus) of T2-weighted scans were performed in seventy subjects with PD, 170 age- and gender-matched controls and 38 patients with an atypical form of neurodegenerative Parkinsonian syndrome (N = 11 multisystem atrophy, N = 22 progressive supranuclear palsy, N = 5 corticobasal syndrome). RESULTS: In patients with PD, significant changes in signal intensities within the substantia nigra were observed compared to controls at p < 0.001. For the globus pallidus internus, signal alterations in PD and progressive supranuclear palsy were found to be significant (p < 0.001) if compared to controls. Furthermore, signal changes of substantia nigra correlated with signal intensities of globus pallidus internus in the ipsilateral hemisphere in both groups. Sensitivity was 86% and specificity was 90% for the combined analysis of substantia nigra and globus pallidus internus in the complete patient sample versus controls. CONCLUSIONS: Signal alterations of substantia nigra and globus pallidus internus in routine magnetic resonance imaging were useful to distinguish patients with PD from controls. In addition, signal changes in globus pallidus internus could be used to differentiate progressive supranuclear palsy patients from controls. These analyses have the potential to serve as an additional non-invasive technical tool to support the individual differential diagnosis of PD.

Neuroprotective function of cellular prion protein in a mouse model of amyotrophic lateral sclerosis.

Transgenic mice expressing human mutated superoxide dismutase 1 (SOD1) linked to familial forms of amyotrophic lateral sclerosis are frequently used as a disease model. We used the SOD1G93A mouse in a cross-breeding strategy to study the function of physiological prion protein (Prp). SOD1G93APrp-/- mice exhibited a significantly reduced life span, and an earlier onset and accelerated progression of disease, as compared with SOD1G93APrp+/+ mice. Additionally, during disease progression, SOD1G93APrp-/- mice showed impaired rotarod performance, lower body weight, and reduced muscle strength. Histologically, SOD1G93APrp-/- mice showed reduced numbers of spinal cord motor neurons and extended areas occupied by large vacuoles early in the course of the disease. Analysis of spinal cord homogenates revealed no differences in SOD1 activity. Using an unbiased proteomic approach, a marked reduction of glial fibrillary acidic protein and enhanced levels of collapsing response mediator protein 2 and creatine kinase were detected in SOD1G93APrp-/- versus SOD1G93A mice. In the course of disease, Bcl-2 decreases, nuclear factor-kappaB increases, and Akt is activated, but these changes were largely unaffected by Prp expression. Exclusively in double-transgenic mice, we detected a significant increase in extracellular signal-regulated kinase 2 activation at clinical onset. We propose that Prp has a beneficial role in the SOD1G93A amyotrophic lateral sclerosis mouse model by influencing neuronal and/or glial factors involved in antioxidative defense, rather than anti-apoptotic signaling.

Ubiquitin as potential cerebrospinal fluid marker of Creutzfeldt-Jakob disease.

Until today, a definite diagnosis of Creutzfeldt-Jakob disease (CJD) can only be made neuropathologically. At lifetime the early and differential diagnosis is often a problem. With SELDI we analyzed cerebrospinal fluid (CSF) from 32 CJD patients, 32 patients having other dementive diseases and 31 non-demented control subjects for diagnosis-dependent protein pattern differences. In a screening set of patients, peaks that discriminate best between groups were identified. These peaks were subsequently analyzed using an independent validation set of patients. Diagnostic accuracies were compared with established markers like tau protein and 14-3-3-protein. Potential marker proteins were purified and identified by LC-MS/MS. In the validation set only one peak of 8.6 kDa out of ten in the screening set could be confirmed. This protein was identified to be ubiquitin and increased levels in CSF (but not in serum) of CJD patients were confirmed by Western blot. Ubiquitin allows the correct diagnoses of that CJD cases missed by tau protein or 14-3-3-protein. We conclude that ubiquitin is a promising additional CSF biomarker for diagnosis of CJD, especially in differential diagnostically difficult cases. The selective increase of ubiquitin in CSF of CJD patients might point to an involvement of ubiquitin in pathophysiological process.

Lef-1 isoforms regulate different target genes and reduce cellular adhesion.

The lymphoid enhancer factor 1 (Lef-1) belongs to the nuclear transducers of canonical Wnt-signalling in embryogenesis and cancer. Lef-1 acts, in cooperation with beta-catenin, as a context-dependent transcriptional activator or repressor, thereby influencing multiple cellular functions such as proliferation, differentiation and migration. Here we report that an increased Lef-1 expression in human pancreatic cancer correlates with advanced tumour stages. In pancreatic tumours, two different transcripts of Lef-1 have been detected in various stages, as demonstrated by RT-PCR analysis. One transcript was identified as the full length Lef-1 (Lef-1 FL), whereas the second, shorter transcript lacked exon VI (Lef-1 Deltaexon VI) compared to the published sequence. Comparative analysis of these two Lef-1 variants revealed that they exhibit different cellular effects after transient expression in pancreatic carcinoma cells. Forced expression of Lef-1 Deltaexon VI inhibited E-cadherin expression in a beta-catenin-independent way. Increased amounts of Lef-1 Deltaexon VI resulted in reduced cellular aggregation and increased cell migration. Expression of Lef-1 FL, but not the newly identified Lef-1 Deltaexon VI, induced the expression of the cell cycle regulating proteins c-myc and cyclin D1 in cooperation with beta-catenin and it enhanced cell proliferation. Our findings indicate that expression of alternatively spliced Lef-1 isoforms is involved in the determination of proliferative or migratory characteristics of pancreatic carcinoma cells.

Tick-Borne Encephalitis: A Differential Pattern of Intrathecal Humoral Immune Response and Inflammatory Cell Composition Compared with Other Viral CNS Infections.

To investigate whether and how cerebrospinal fluid (CSF) findings can contribute to distinguish tick-borne encephalitis (TBE) from herpes simplex virus (HSV) and varicella zoster virus (VZV) induced central nervous system (CNS) infections (HSV-I, VZV-I). Chart review and identification of TBE, HSV- I, and VZV-I was carried out, fulfilling the following criteria: (1) clinical signs of encephalitis and/or meningitis, (2) complete CSF analysis and confirmed viral etiology by either PCR or antibody testing in CSF, (3) hospitalized patients, and (4) available brain magnetic resonance imaging (MRI). Fifty-nine patients with 118 CSF/serum pairs were included. These comprised 21 with TBE (35 CSF/serum pairs), 20 (40 CSF/serum pairs) with HSV-I, and 18 (43 CSF/serum pairs) with VZV-I. In contrast to HSV-I and VZV-I, CSF cell differentiation in TBE showed more often an increased (>20%) proportion of granulocytes (p < 0.01) and a more frequent quantitative intrathecal IgM synthesis (p = 0.001 and p < 0.01, respectively), while the second was even more pronounced when follow-up CSF analyses were included (p < 0.001). CSF findings help to distinguish TBE from other viral infections. In cases with CSF pleocytosis and a positive history for a stay in or near an endemic area, TBE antibodies in CSF and serum should be determined, especially if granulocytes in CSF cell differentiation and/or an intrathecal IgM synthesis is present.

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

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.