Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities.

We identified via exome sequencing bi-allelic variants in TM2D3 in four affected individuals from four unrelated families with overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features. TM2D3 encodes a transmembrane protein present in many tissues, with a higher abundance in the central nervous system, but little is known about its function and cell localization. Here, by using chemical and genetically encoded probes in SNB75 cells, we show that TM2D3 is an endoplasmic reticulum (ER) protein.

RICTOR variants are associated with neurodevelopmental disorders.

RICTOR is a key component of the mTORC2 signaling complex which is involved in the regulation of cell growth, proliferation and survival. RICTOR is highly expressed in neurons and is necessary for brain development. Here, we report eight unrelated patients presenting with intellectual disability and/or development delay and carrying variants in the RICTOR gene.

Quantitative cytoarchitectural phenotyping of deparaffinized human brain tissues.

Advanced 3D imaging techniques and image segmentation and classification methods can profoundly transform biomedical research by offering deep insights into the cytoarchitecture of the human brain in relation to pathological conditions. Here, we propose a comprehensive pipeline for performing 3D imaging and automated quantitative cellular phenotyping on Formalin-Fixed Paraffin-Embedded (FFPE) human brain specimens, a valuable yet underutilized resource. We exploited the versatility of our method by applying it to different human specimens from both adult and pediatric, normal and abnormal brain regions.

Switching of biological therapy to dupilumab in comorbid patients with severe asthma and CRSwNP.

Purpose: Nowadays, several efficacious biologic drugs are used for severe asthma with or without chronic rhinosinusitis with nasal polyps (CRSwNP). However, it has been observed that not all comorbid patients (asthma/CRSwNP) receiving biologic treatment for asthma experience satisfactory control of both conditions equally.

Methods: We selected 20 patients who had both severe asthma and comorbid CRSwNP under biological treatment with benralizumab, omalizumab or mepolizumab with adequate control of asthma but inadequate control of nasal symptoms.

Generation of human induced pluripotent stem cell line (AOUMEYi001-A) from a patient affected by Congenital disorders of glycosylation (ALG8-CDG) using self-replicating RNA vector.

Congenital Disorders of Glycosylation (CDG) are rare inherited metabolic diseases caused by genetic defects in the glycosylation of proteins and lipids. In this study, we describe the generation and characterization of one human induced pluripotent stem cell (hiPSC) line from a 15-year-old male patient with CDG. The patient carried three variants, one (c.

Morphometric network-based abnormalities correlate with psychiatric comorbidities and gene expression in PCDH19-related developmental and epileptic encephalopathy.

Protocadherin-19 (PCDH19) developmental and epileptic encephalopathy causes an early-onset epilepsy syndrome with limbic seizures, typically occurring in clusters and variably associated with intellectual disability and a range of psychiatric disorders including hyperactive, obsessive-compulsive and autistic features. Previous quantitative neuroimaging studies revealed abnormal cortical areas in the limbic formation (parahippocampal and fusiform gyri) and underlying white-matter fibers. In this study, we adopted morphometric, network-based and multivariate statistical methods to examine the cortex and substructure of the hippocampus and amygdala in a cohort of 20 PCDH19-mutated patients and evaluated the relation between structural patterns and clinical variables at individual level.

Leat-associated seizures the possible role of EAAT2, pyruvate carboxylase and glutamine synthetase.

Background: Drug-resistant epilepsy is a common condition in patients with brain neoplasms. The pathogenesis of tumor-associated seizures is poorly understood. Among the possible pathogenetic mechanisms, the increase in glutamate concentration has been proposed.

Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration.

By converting physical forces into electrical signals or triggering intracellular cascades, stretch-activated ion channels allow the cell to respond to osmotic and mechanical stress. Knowledge of the pathophysiological mechanisms underlying associations of stretch-activated ion channels with human disease is limited. Here, we describe 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes carrying ten distinct heterozygous variants of TMEM63B, encoding for a highly conserved stretch-activated ion channel.

Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development.

Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing.

Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum.

Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of disorders characterized by early-onset, often severe epileptic seizures and EEG abnormalities on a background of developmental impairment that tends to worsen as a consequence of epilepsy. DEEs may result from both nongenetic and genetic etiologies. Genetic DEEs have been associated with mutations in many genes involved in different functions including cell migration, proliferation, and organization, neuronal excitability, and synapse transmission and plasticity.

Phenotypic and genetic spectrum of ATP6V1A encephalopathy: a disorder of lysosomal homeostasis.

Vacuolar-type H+-ATPase (V-ATPase) is a multimeric complex present in a variety of cellular membranes that acts as an ATP-dependent proton pump and plays a key role in pH homeostasis and intracellular signalling pathways. In humans, 22 autosomal genes encode for a redundant set of subunits allowing the composition of diverse V-ATPase complexes with specific properties and expression. Sixteen subunits have been linked to human disease.

Prospective Evaluation of Ghrelin and Des-Acyl Ghrelin Plasma Levels in Children with Newly Diagnosed Epilepsy: Evidence for Reduced Ghrelin-to-Des-Acyl Ghrelin Ratio in Generalized Epilepsies.

Children with epilepsy and identified as responders to antiseizure medications (ASMs) were found to present markedly higher ghrelin plasma levels when compared to drug-resistant patients. However, it was undetermined if this phenotype could be influenced by the ASMs. Here, we prospectively investigated total ghrelin and des-acyl ghrelin (DAG) plasma levels by enzyme-linked immunosorbent assay before and after ASM administration.

Profiling PI3K-AKT-MTOR variants in focal brain malformations reveals new insights for diagnostic care.

Focal malformations of cortical development including focal cortical dysplasia, hemimegalencephaly and megalencephaly, are a spectrum of neurodevelopmental disorders associated with brain overgrowth, cellular and architectural dysplasia, intractable epilepsy, autism and intellectual disability. Importantly, focal cortical dysplasia is the most common cause of focal intractable paediatric epilepsy. Gain and loss of function variants in the PI3K-AKT-MTOR pathway have been identified in this spectrum, with variable levels of mosaicism and tissue distribution.

Large-scale, cell-resolution volumetric mapping allows layer-specific investigation of human brain cytoarchitecture.

Although neuronal density analysis on human brain slices is available from stereological studies, data on the spatial distribution of neurons in 3D are still missing. Since the neuronal organization is very inhomogeneous in the cerebral cortex, it is critical to map all neurons in a given volume rather than relying on sparse sampling methods. To achieve this goal, we implement a new tissue transformation protocol to clear and label human brain tissues and we exploit the high-resolution optical sectioning of two-photon fluorescence microscopy to perform 3D mesoscopic reconstruction.

Preliminary Functional Outcomes and Quality of Life after Tongue Reconstruction with the Vastus Lateralis Myofascial Free Flap.

The aim of the present study is to report our preliminary experience with the vastus lateralis myofascial free flap (VLMFF) for tongue reconstruction according to tongue and donor site functional outcomes. Twelve consecutive patients (F: 5; median age: 54.0 years, interquartile range or IQR 42.

Circulating tumor cells and palbociclib treatment in patients with ER-positive, HER2-negative advanced breast cancer: results from a translational sub-study of the TREnd trial.

Background: Circulating tumor cells (CTCs) are prognostic in patients with advanced breast cancer (ABC). However, no data exist about their use in patients treated with palbociclib. We analyzed the prognostic role of CTC counts in patients enrolled in the cTREnd study, a pre-planned translational sub-study of TREnd (NCT02549430), that randomized patients with ABC to palbociclib alone or palbociclib plus the endocrine therapy received in the prior line of treatment.

Angiocentric glioma-associated seizures: The possible role of EATT2, pyruvate carboxylase and glutamine synthetase.

Purpose: Our purpose was to better understand the pathogenesis of seizures associated with angiocentric glioma. Angiocentric glioma is an indolent and rare low-grade glioma. Its typical clinical presentation is with epileptic seizures.

Is Focal Cortical Dysplasia/Epilepsy Caused by Somatic Mutations Always a Unilateral Disorder?

Objective: To alert about the wide margin of unpredictability that distribution of somatic mosaicism may have in the brain and the risk for independent epileptogenesis arising from the seemingly healthy contralateral hemisphere after complete removal of epileptogenic focal cortical dysplasia (FCD).

Methods: Clinical, EEG, MRI, histopathology, and molecular genetics in 2 patients (1 and 2) treated with focal resections and subsequent complete hemispherectomy for epileptogenic FCD due to somatic mutations. Autoptic brain study of bilateral asymmetric hemispheric dysplasia and identification of alternative allele fraction (AAF) rates for (patient 3).

Somatic Focal Copy Number Gains of Noncoding Regions of Receptor Tyrosine Kinase Genes in Treatment-Resistant Epilepsy.

Epilepsy is a heterogenous group of disorders defined by recurrent seizure activity due to abnormal synchronized activity of neurons. A growing number of epilepsy cases are believed to be caused by genetic factors and copy number variants (CNV) contribute to up to 5% of epilepsy cases. However, CNVs in epilepsy are usually large deletions or duplications involving multiple neurodevelopmental genes.

Atypical Ocular Coloboma in Tuberous Sclerosis-2: Report of Two Novel Cases.

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystemic disorder caused by mutations in either TSC1 or TSC2 genes and is characterized by hamartomas in multiple organs. The most frequent and best-known ocular manifestation in TSC is the retinal hamartoma. Less frequent ocular manifestations include punched out areas of retinal depigmentation, eyelid angiofibromas, uveal colobomas, papilledema, and sector iris depigmentation.

International consensus recommendations on the diagnostic work-up for malformations of cortical development.

Malformations of cortical development (MCDs) are neurodevelopmental disorders that result from abnormal development of the cerebral cortex in utero. MCDs place a substantial burden on affected individuals, their families and societies worldwide, as these individuals can experience lifelong drug-resistant epilepsy, cerebral palsy, feeding difficulties, intellectual disability and other neurological and behavioural anomalies. The diagnostic pathway for MCDs is complex owing to wide variations in presentation and aetiology, thereby hampering timely and adequate management.

High definition three-dimensional exoscope (VITOM 3D) for microsurgery training: a preliminary experience.

Purpose: To assess the feasibility of a high definition 3D exoscope (VITOM) for microsurgery training in a cohort of naïve medical students.

Methods: Twenty-two consecutive medical students performed a battery of four exercises assessing basic microsurgical skills. The students were randomized in two different groups based on two different VITOM holding systems (VERSACRANE™ and ARTip™ cruise).