The odyssey of complex neurogenetic disorders: From undetermined to positive.

The genetic and phenotypic heterogeneity of neurogenetic diseases forces patients and their families into a "diagnostic odyssey." An increase in the variability of genetic disorders and the corresponding gene-disease associations suggest the need to periodically re-evaluate the significance of variants of undetermined pathogenicity. Here, we report the diagnostic and clinical utility of Targeted Gene Panel Sequencing (TGPS) and Whole Exome Sequencing (WES) in 341 patients with suspected neurogenetic disorders from centers in Buenos Aires and Cincinnati over the last 4 years, focusing on the usefulness of reinterpreting variants previously classified as of uncertain significance. After a mean of ±2years (IC 95:0.73-3.27), approximately 30% of the variants of uncertain significance were reclassified as pathogenic. The use of next generation sequencing methods has facilitated the identification of both germline and mosaic pathogenic variants, expanding the diagnostic yield. These results demonstrate the high clinical impact of periodic reanalysis of undetermined variants in clinical neurology.

Visual and auditory socio-cognitive perception in unilateral temporal lobe epilepsy in children and adolescents: a prospective controlled study.

AIM: A high rate of abnormal social behavioural traits or perceptual deficits is observed in children with unilateral temporal lobe epilepsy. In the present study, perception of auditory and visual social signals, carried by faces and voices, was evaluated in children or adolescents with temporal lobe epilepsy. METHODS: We prospectively investigated a sample of 62 children with focal non-idiopathic epilepsy early in the course of the disorder. The present analysis included 39 children with a confirmed diagnosis of temporal lobe epilepsy. Control participants (72), distributed across 10 age groups, served as a control group. Our socio-perceptual evaluation protocol comprised three socio-visual tasks (face identity, facial emotion and gaze direction recognition), two socio-auditory tasks (voice identity and emotional prosody recognition), and three control tasks (lip reading, geometrical pattern and linguistic intonation recognition). All 39 patients also benefited from a neuropsychological examination. RESULTS: As a group, children with temporal lobe epilepsy performed at a significantly lower level compared to the control group with regards to recognition of facial identity, direction of eye gaze, and emotional facial expressions. We found no relationship between the type of visual deficit and age at first seizure, duration of epilepsy, or the epilepsy-affected cerebral hemisphere. Deficits in socio-perceptual tasks could be found independently of the presence of deficits in visual or auditory episodic memory, visual non-facial pattern processing (control tasks), or speech perception. A normal FSIQ did not exempt some of the patients from an underlying deficit in some of the socio-perceptual tasks. CONCLUSION: Temporal lobe epilepsy not only impairs development of emotion recognition, but can also impair development of perception of other socio-perceptual signals in children with or without intellectual deficiency. Prospective studies need to be designed to evaluate the results of appropriate re-education programs in children presenting with deficits in social cue processing.

Clinical next generation sequencing in developmental and epileptic encephalopathies: Diagnostic relevance of data re-analysis and variants re-interpretation.

Developmental and epileptic encephalopathies (DEE) are complex pediatric epilepsies, in which heterogeneous pathogenic factors play an important role. Next-generation-sequencing based tools have shown excellent effectiveness. The constant increase in the number of new genotype-phenotype associations suggests the periodic need for re-interpretation and re-analysis of genetic studies without positive results. In this study, we report the diagnostic utility of targeted gene panel sequencing and whole exome sequencing in 55 Argentine subjects with DEE, focusing on the utility of re-interpretation and re-analysis of undetermined and negative genetic diagnoses. The new information in biomedical literature and databases was used for the re-interpretation. For re-analysis, sequencing data processing was repeated using updated bioinformatics tools. Initially, pathogenic variants were detected in 21 subjects (38%). After an average time of 29 months, 25% of the subjects without a genetic diagnosis were re-categorized as diagnosed. Finally, the overall diagnostic yield increased to 53% (29 subjects). In consequence of the re-interpretation and re-analysis, we identified novel variants in the genes: CHD2, COL4A1, FOXG1, GABRA1, GRIN2B, HNRNPU, KCNQ2, MECP2, PCDH19, SCN1A, SCN2A, SCN8A, SLC6A1, STXBP1 and WWOX. Our results expand the diagnostic yield of this subgroup of infantile and childhood seizures and demonstrate the importance of re-evaluation of genetic tests in subjects without an identified causative etiology.

Abnormal cortical voice processing in autism.

Impairments in social interaction are a key feature of autism and are associated with atypical social information processing. Here we report functional magnetic resonance imaging (fMRI) results showing that individuals with autism failed to activate superior temporal sulcus (STS) voice-selective regions in response to vocal sounds, whereas they showed a normal activation pattern in response to nonvocal sounds. These findings suggest abnormal cortical processing of socially relevant auditory information in autism.

Esclerosis temporo mesial, evaluación diagnóstica y resultados / Temporus mesial sclerosis, diagnostic evaluation and results

La esclerosis temporo-mesial (ETM), dentro de las epilepsias del lóbulo temporal, es el tipo de epilepsia sintomática focal más frecuente, especialmente en formas parciales resistentes a los medicamentos, siendo la cirugía un tratamiento efectivo para la misma con resolución completa entre un 60 a 90% 1 Su fisiopatogenia es debido a la pérdida neuronal segmental y gliosis en el hipocampo; algunos estudios postmortem indican que estos hallazgos también están presentes en una proporción de pacientes en la amígdala, corteza entorrinal y corteza temporal 2 . Se ha demostrado un aumento de la patología en pacientes que presentaron antecedentes de convulsiones febriles en edad pediátrica, predominando en niños con crisis atípicas, hipoxia perinatal o infecciones en del sistema nervioso central.

The temporo-mesial sclerosis (MTS), within the epilepsies of the temporal lobe, is the type of focal symptomatic epilepsy more frequent, especially in partial forms resistant to the medicines, being the surgery an effective treatment for the same with complete resolution between 60 to 90%. Its pathophysiology is due to segmental neuronal loss and gliosis in the hippocampus; Some postmortem studies indicate that these findings are also present in a proportion of patients in the amygdala, entorhinal cortex and temporal cortex. An increase in the pathology has been demonstrated in patients who had a history of febrile convulsions in the pediatric age, predominantly in children with atypical crises, perinatal hypoxia or infections in the central nervous system.

A new intronic mutation in the DPM1 gene is associated with a milder form of CDG Ie in two French siblings.

Congenital disorders of glycosylation (CDG) type I (CDG I) are rare autosomal recessive diseases caused by deficiencies in the assembly of the dolichol-linked oligosaccharide (DLO) that is required for N-glycoprotein biosynthesis. CDG Ie is due to a defect in the synthesis of dolichyl-phosphoryl-mannose (Dol-P-Man), which is needed for DLO biosynthesis as well as for other glycosylation pathways. Human Dol-P-Man synthase is a heterotrimeric complex composed of DPM1p, DPM2p, and DPM3p, with DPM1p being the catalytic subunit. Here, we report two new CDG Ie patients who present milder symptoms than the five other CDG Ie patients described to date. The clinical pictures of the patients MS and his sister MT are dominated by major ataxia, with no notable hepatic involvement. MS cells accumulate the immature DLO species Dol-PP-GlcNAc2Man5 and possess only residual Dol-P-Man synthase activity. One homozygous intronic mutation, g.IVS4-5T>A, was found in the DPM1 gene, leading to exon skipping and transcription of a shortened transcript. Moreover, DPM1 expression was reduced by more than 90% in MS cells, in a nonsense-mediated mRNA decay (NMD)-independent manner. Full analysis of the DPM2 and DPM3 genes revealed a decrease in DPM2 expression and normal expression of DPM3. This description emphasizes the large spectrum of symptoms characterizing CDG I patients.

Topiramate prevents excitotoxic damage in the newborn rodent brain.

Brain lesions induced in newborn mice by the glutamatergic agonists ibotenate (acting on NMDA and metabotropic receptors) and S-bromowillardiine (acting on AMPA-kainate receptors) mimic some aspects of white matter cysts and transcortical necrosis observed in human perinatal brain damage. Topiramate (TPM), already used in children to manage newly diagnosed and refractory epilepsy, has potential neuroprotective effects that may be useful in human perinatal brain lesions. In the excitotoxic newborn mouse model, TPM provided dose-dependent and long-lasting protection of developing white matter and cortical plate against S-bromowillardiine. TPM had no significant effect on ibotenate-induced brain lesions. TPM-induced neuroprotection potentially involved increased survival of pre-oligodendrocytes, decreased neuronal apoptosis, inhibition of microglial activation and astrogliosis, and decreased seizure activity. Diazepam, phenytoin, and carbamazepine had no neuroprotective effect in this model. The present study provides experimental support for the consideration of TPM as a candidate therapy for excitotoxic perinatal brain lesions.

Patterns of excitotoxin-induced brain lesions in the newborn rabbit: a neuropathological and MRI correlation.

There is pressing need to employ new advances in structural MR brain imaging to better diagnose brain damage in newborn infants. Timely application of such technology will enable improved therapeutic interventions. Diffusion-weighted sequences are a sensitive marker of very early neuronal injury, the spatial pattern of which provides critical information regarding the underlying pathophysiology. We have modified our murine model of excitotoxic neonatal brain injury to the rabbit, an animal whose brain is larger and where the neuroanatomic organization of the subcortical white matter more closely resembles that of the human. Utilizing this rabbit model, we undertook an MRI/histopathologic correlation. We found that as with the mouse, there is a spatiotemporal selectivity to the pattern of brain injury, and that the period from postnatal day (P) 7 to P9 in rabbits corresponds to the time of maximum vulnerability of the brain to excitotoxic white matter damage, which neuropathologically simulates periventricular leukomalacia (PVL). We additionally noted that diffusion-weighted imaging provided the most sensitive means of detecting such lesions and that this method was sensitive to structural maturational changes accompanying the normal cortical ontogeny. Taken together, our findings suggest that this rabbit model of perinatal excitotoxic brain injury will be a valuable addition to experimental approaches to further our understanding of perinatal brain damage, that diffusion-weighted imaging will be an invaluable adjunct to the diagnosis of such injury, and that therapeutic strategies aimed at interrupting the evolution of PVL should include targeting the pathophysiologic cascade induced by excitotoxic neonatal brain injury.

Autism severity and temporal lobe functional abnormalities.

Two independent studies have described bilateral temporal hypoperfusion in autistic children. Temporal regions are implicated in social perception, language, and "theory-of-mind," abilities that are impaired in autism. We investigated a putative relationship between cerebral blood flow (rCBF) measured at rest and clinical profile of 45 autistic children (Autism Diagnostic Interview-Revised [ADI-R] scores). A whole-brain covariance analysis was performed. Significant negative correlation was observed between rCBF and ADI-R score in the left superior temporal gyrus. The more severe the autistic syndrome, the more rCBF is low in this region, suggesting that left superior temporal hypoperfusion is related to autistic behavior severity.