Severe presentation and complex brain malformations in an individual carrying a CCND2 variant.

Background: Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) is a developmental brain disorder characterized by megalencephaly and bilateral perisylvian polymicrogyria due to defects in genes of the PI3K-AKT pathway. Only a few patients with CCND2 mutations have been reported to date.

Methods: We describe an individual harboring a de novo variant in CCND2 undergoing neuroradiological evaluation including diffusion tensor imaging (DTI).

Targeted gene sequencing in 6994 individuals with neurodevelopmental disorder with epilepsy.

Purpose: We aimed to gain insight into frequencies of genetic variants in genes implicated in neurodevelopmental disorder with epilepsy (NDD+E) by investigating large cohorts of patients in a diagnostic setting.

Methods: We analyzed variants in NDD+E using epilepsy gene panel sequencing performed between 2013 and 2017 by two large diagnostic companies. We compared variant frequencies in 6994 panels with another 8588 recently published panels as well as exome-wide de novo variants in 1942 individuals with NDD+E and 10,937 controls.

Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3'-end processing.

Mutations in either the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA metabolism, including ELAC2. The ELAC2 gene codes for the mitochondrial RNase Z, responsible for endonucleolytic cleavage of the 3' ends of mitochondrial pre-tRNAs.

SCN1A mutations in focal epilepsy with auditory features: widening the spectrum of GEFS plus.

Epilepsy with auditory features (EAF) is a focal epilepsy syndrome characterized by prominent auditory ictal manifestations. Two main genes, LGI1 and RELN, have been implicated in EAF, but the genetic aetiology remains unknown in half of families and most sporadic cases. We previously described a pathogenic SCN1A missense variant (p.

Hypomorphic Variants in Congenital Lymphatic Dysplasia Cause Shape and Hydration Alterations of Red Blood Cells.

PIEZO1 is a cation channel activated by mechanical force. It plays an important physiological role in several biological processes such as cardiovascular, renal, endothelial and hematopoietic systems. Two different diseases are associated with alteration in the DNA sequence of : (i) dehydrated hereditary stomatocytosis (DHS1, #194380), an autosomal dominant hemolytic anemia caused by gain-of-function mutations; (ii) lymphatic dysplasia with non-immune fetal hydrops (LMPH3, #616843), an autosomal recessive condition caused by biallelic loss-of-function mutations.

Diagnostic implications of genetic copy number variation in epilepsy plus.

Objective: Copy number variations (CNVs) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNVs to epilepsies from sizeable populations are not available.

Cortical malformations and COL4A1 mutation: Three new cases.

Aim: The COL4A1 gene (13q34) encodes the α1 chain of type IV collagen, a crucial component of the basal membrane. COL4A1 mutations have been identified as a cause of a multisystem disease. Brain MRI in COL4A1-mutated patients typically shows vascular abnormalities and white matter lesions.

No evidence for a BRD2 promoter hypermethylation in blood leukocytes of Europeans with juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is a common syndrome of genetic generalized epilepsies (GGEs). Linkage and association studies suggest that the gene encoding the bromodomain-containing protein 2 (BRD2) may increase risk of JME. The present methylation and association study followed up a recent report highlighting that the BRD2 promoter CpG island (CpG76) is differentially hypermethylated in lymphoblastoid cells from Caucasian patients with JME compared to patients with other GGE subtypes and unaffected relatives.

encephalopathy: A distinctive generalized developmental and epileptic encephalopathy.

Objective: To delineate the epileptology, a key part of the phenotypic spectrum, in a large patient cohort.

Methods: Patients were recruited via investigators' practices or social media. We included patients with (likely) pathogenic variants or chromosome 6p21.

Neurologic phenotypes associated with / mutations: Expanding the spectrum of disease.

Objective: To characterize the neurologic phenotypes associated with mutations and to seek genotype-phenotype correlation.

Methods: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with mutations.

Results: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype.

HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals.

The application of artificial intelligence to understand the pathophysiological basis of psychogenic nonepileptic seizures.

Psychogenic nonepileptic seizures (PNES) are episodes of paroxysmal impairment associated with a range of motor, sensory, and mental manifestations, which perfectly mimic epileptic seizures. Several patterns of neural abnormalities have been described without identifying a definite neurobiological substrate. In this multicenter cross-sectional study, we applied a multivariate classification algorithm on morphological brain imaging metrics to extract reliable biomarkers useful to distinguish patients from controls at an individual level.

Left inferior frontal cortex can compensate the inhibitory functions of right inferior frontal cortex and pre-supplementary motor area.

Right-IFG and pre-SMA are associated with inhibitory responses. We used functional Magnetic Resonance Imaging to explore whether the contralateral homotopic regions can functionally replace them. An adolescent, with an extensive traumatic lesion of the right cerebral hemisphere having occurred 5 years earlier, performed a motor response inhibition task (Go/Nogo), which was properly accomplished and associated to activations in the left-IFC, precuneus and occipital cortex.

Familial dominant epilepsy and mild pachygyria associated with a constitutional LIS1 mutation.

We describe a mother and son with focal epilepsy, mild cognitive impairment, and pachygyria, which was parieto-occipital in the mother and with remarkable posterior greater than anterior severity in the son. Overall clinical manifestations, although overlapping in type, were likewise slightly more severe in the son. Using targeted resequencing through a gene panel for malformations of cortical development, we identified the c.

Neuroimaging in mitochondrial disorders.

MRI and H magnetic resonance spectroscopy (HMRS) are the main neuroimaging methods to study mitochondrial diseases. MRI can demonstrate seven 'elementary' central nervous system (CNS) abnormalities in these disorders, including diffuse cerebellar atrophy, cerebral atrophy, symmetric signal changes in subcortical structures (basal ganglia, brainstem, cerebellum), asymmetric signal changes in the cerebral cortex and subcortical white matter, leukoencephalopathy, and symmetric signal changes in the optic nerve and the spinal cord. These elementary MRI abnormalities can be variably combined in the single patient, often beyond what can be expected based on the classically known clinical-pathological patterns.

De novo variants in neurodevelopmental disorders with epilepsy.

Epilepsy is a frequent feature of neurodevelopmental disorders (NDDs), but little is known about genetic differences between NDDs with and without epilepsy. We analyzed de novo variants (DNVs) in 6,753 parent-offspring trios ascertained to have different NDDs. In the subset of 1,942 individuals with NDDs with epilepsy, we identified 33 genes with a significant excess of DNVs, of which SNAP25 and GABRB2 had previously only limited evidence of disease association.

Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly.

Purpose: To estimate diagnostic yield and genotype-phenotype correlations in a cohort of 811 patients with lissencephaly or subcortical band heterotopia.

Methods: We collected DNA from 756 children with lissencephaly over 30 years. Many were tested for deletion 17p13.

Clinical and genetic spectrum of AMPD2-related pontocerebellar hypoplasia type 9.

Pontocerebellar hypoplasia (PCH) represents a group of autosomal-recessive progressive neurodegenerative disorders of prenatal onset. Eleven PCH subtypes are classified according to clinical, neuroimaging and genetic findings. Individuals with PCH type 9 (PCH9) have a unique combination of postnatal microcephaly, hypoplastic cerebellum and pons, and hypoplastic or absent corpus callosum.

ATP1A3 spectrum disorders: A video-documented history of 7 genetically confirmed early onset cases.

Mutations in the ATP1A3 gene, which encodes the alpha-subunit of sodium-potassium ATPase, are related to a spectrum of neurological diseases including Rapid onset Dystonia-Parkinsonism (RDP), Alternating Hemiplegia of Childhood (AHC) and Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy and Sensorineural hearing loss (CAPOS) syndrome. Moreover, an increasing number of patients with intermediate and non classical phenotypes have been reported. Herein we describe 7 patients with 6 different de novo ATP1A3 mutations, and we focus on paroxysmal and chronic movement disorders with the help of video documentation.

Painful procedures can affect post-natal growth and neurodevelopment in preterm infants.

Aim: This Italian study evaluated whether painful procedures during the first four weeks of life were related to subsequent weight gain, head circumference (HC) and neurodevelopmental outcomes in preterm infants, METHODS: We evaluated the number of invasive procedures that infants born at less than 32 weeks of gestational age (GA) underwent in the Neonatal Intensive Care Unit of Careggi Hospital, Florence, from January to December 2015. Weight and HC were recorded at birth, 36 weeks of PMA and six and 12 months of CA. Neurological outcomes were assessed at six and 12 months of CA using the Bayley Scales of Infant and Toddler Development - Third Edition.