Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype-phenotype correlation study.

PURPOSE: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported. METHODS: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp). RESULTS: Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period. CONCLUSION: We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered.

Evidence of the milder phenotypic spectrum of c.1582G>A PIGT variant: Delineation based on seven novel Polish patients.

PIGT is one of over 29 glycosylphosphatidylinositol biosynthesis defect genes. Mutations cause genetically determined disorders characterized mainly by epilepsy with fever-sensitivity, central hypotonia, psychomotor delay and congenital malformations. The disease is known as multiple congenital anomalies-hypotonia-seizures syndrome 3 (MCAHS3) or glycosylphosphatidylinositol biosynthesis defect-7. Twenty-eight cases have been reported until today. We present seven novel Polish patients, all harboring 1582G>A variant in a homozygous or compound heterozygous state which seems to cause a milder phenotype of the disease.

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. METHODS: We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had "epilepsy plus," defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy. RESULTS: Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV. We identified CNVs covering recently reported (HNRNPU) or emerging (RORB) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNVs, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNVs (odds ratio = 4.09, confidence interval = 2.51-6.68; P = 2.34 × 10-9 ). Meta-analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNVs. SIGNIFICANCE: The use of a specifically adapted workflow enabled identification of pathogenic autosomal CNVs in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNVs. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large-scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes.

Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy.

OBJECTIVE: We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype-phenotype correlations. METHODS: We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed. RESULTS: We describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 3' and 5' exons. Seizures in patients with mutations in exons 4-5 were more pharmacoresponsive than in patients with mutations in exons 8-15. CONCLUSIONS: SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers.

De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome.

Dravet syndrome is a severe epilepsy syndrome characterized by infantile onset of therapy-resistant, fever-sensitive seizures followed by cognitive decline. Mutations in SCN1A explain about 75% of cases with Dravet syndrome; 90% of these mutations arise de novo. We studied a cohort of nine Dravet-syndrome-affected individuals without an SCN1A mutation (these included some atypical cases with onset at up to 2 years of age) by using whole-exome sequencing in proband-parent trios. In two individuals, we identified a de novo loss-of-function mutation in CHD2 (encoding chromodomain helicase DNA binding protein 2). A third CHD2 mutation was identified in an epileptic proband of a second (stage 2) cohort. All three individuals with a CHD2 mutation had intellectual disability and fever-sensitive generalized seizures, as well as prominent myoclonic seizures starting in the second year of life or later. To explore the functional relevance of CHD2 haploinsufficiency in an in vivo model system, we knocked down chd2 in zebrafish by using targeted morpholino antisense oligomers. chd2-knockdown larvae exhibited altered locomotor activity, and the epileptic nature of this seizure-like behavior was confirmed by field-potential recordings that revealed epileptiform discharges similar to seizures in affected persons. Both altered locomotor activity and epileptiform discharges were absent in appropriate control larvae. Our study provides evidence that de novo loss-of-function mutations in CHD2 are a cause of epileptic encephalopathy with generalized seizures.

Age and Gender-Related Changes in Biogenic Amine Metabolites in Cerebrospinal Fluid in Children.

Metabolites of cerebrospinal biogenic amines (dopamine and serotonin)are an important tool in clinical research and diagnosis of children with neurotransmitter disorders. In this article we focused on finding relationships between the concentration of biogenic amine metabolites, age, and gender. We analyzed 148 samples from children with drug resistant seizures of unknown etiology and children with mild stable encephalopathy aged 0-18 years. A normal profile of biogenic amineswas found in 107 children and those children were enrolled to the study group. The CSF samples were analyzed by HPLC with an electrochemical detector. The concentrations of the dopamine and serotonin metabolites homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), respectively, were high at birth, gradually decreasing afterward until the 18 years of age. Nevertheless, the HVA/5-HIAA ratio did not vary with age, except in the children below 1 year of age. In the youngest group we observed a strong relationship between the HVA/5-HIAA ratio and age (r = 0.69, p < 0.001). There were no statistical differences in the level of both dopamine and serotonin metabolites between boys and girls, although a tread toward lower HVA and 5-HIAA in the boys was noticeable. Significant inter-gender differences in the level of HVA and 5-HIAA were noted only in the age-group of 1-4 years, with 5-HIAA being higher in the girls than boys (p = 0.004). In conclusion, the study revealed that the concentration of biogenic amine metabolites is age and sex dependent.

Alexander disease - astrogliopathy considered as leukodystrophy - experience of an institution.

Alexander Disease (ALXDRD) is an autosomal dominant leukodystrophy caused by mutation in one allele of GFAP gene, encoding glial fibrillary acidic protein (GFAP). Most cases occur due to de novo. There are three clinical subtypes of ALXDRD: infantile, juvenile and adult form, but congenital form is also outlined. The disease's spectrum comprises of macrocephaly, progressive pyramidal signs, and seizures in congenital and infantile subtypes. Neuropathologically are enormous number of Rosenthal fibers (RF) mainly around vessels, in subependymal and subpial regions are found. The diagnosis is based on the typical findings on MRI: diffuse white mater lesions with frontal regions preponderance and possibly on the detection of the gene mutation. Here we present six Polish children affected of Alexander disease with congenital (1), infantile (4) and juvenile (1) form. Five of them were previously misdiagnosed as cerebral palsy or unspecific developmental delay; two patients had MRI because of another suspicion, before specific diagnosis was established. Molecular analysis performed in four cases confirmed mutations of GFAP gene; all mutation were de novo. The role of astroglia in brain is shortly reviewed.

From focal epilepsy to Dravet syndrome--Heterogeneity of the phenotype due to SCN1A mutations of the p.Arg1596 amino acid residue in the Nav1.1 subunit.

OBJECTIVE: The aim of this study was to analyze the intra-/interfamilial phenotypic heterogeneity due to variants at the highly evolutionary conservative p.Arg1596 residue in the Nav1.1 subunit. MATERIALS/PARTICIPANTS: Among patients referred for analysis of the SCN1A gene one recurrent, heritable mutation was found in families enrolled into the study. Probands from those families even clinically diagnosed with atypical Dravet syndrome (DS), generalized epilepsy with febrile seizures plus (GEFS+), and focal epilepsy, had heterozygous p.Arg1596 His/Cys missense substitutions, c.4787G>T and c.4786C>T in the SCN1A gene. METHOD: Full clinical evaluation, including cognitive development, neurological examination, EEGs, MRI was performed in probands and affected family members in developmental age. The whole SCN1A gene sequencing was performed for all probands. The exon 25, where the identified missense substitutions are localized, was directly analyzed for the other family members. RESULTS: Mutation of the SCN1A p.1596Arg was identified in three families, in one case substitution p.Arg1596Cys and in two cases p.Arg1596His. Both mutations were previously described as pathogenic and causative for DS, GEFS+ and focal epilepsy. Spectrum of phenotypes among presented families with p.Arg1596 mutations shows heterogeneity ranged from asymptomatic cases, through FS and FS+ to GEFS+/Panayiotopoulos syndrome and epilepsies with and without febrile seizures, and epileptic encephalopathy such as DS. Phenotypes differ among patients displaying both focal and generalized epilepsies. Some patients demonstrated additionally Asperger syndrome and ataxia. CONCLUSION: Clinical picture heterogeneity of the patients carrying mutation of the same residue indicates the involvement of the other factors influencing the SCN1A gene mutations' penetrance.

Glucose transporter type 1 deficiency due to SLC2A1 gene mutations--a rare but treatable cause of metabolic epilepsy and extrapyramidal movement disorder; own experience and literature review.

THE AIM: To present the molecular and clinical characteristics of three children with glucose deficiency syndrome, an inborn rare metabolic disease, caused by mutations in the SLC2A1 gene. MATERIAL AND METHODS: The investigation was carried out in three children: two girls and one boy showing symptoms of GLUT1 deficiency syndrome (GLUT1-DS). They were referred for SLC2A1 gene analysis. RESULTS: The presence of mutations in all of them was confirmed. Only point mutations were identified, two missenses p.Gly132Ser, p.Arg212Cys and amino acid insertion p.Ser_Val227insValProPro. In two cases the mutations arose de novo, one was heritable of paternal origin. CONCLUSIONS: GLUT1-DS shows high clinical variability. It should be suspected in children of any age presenting with single features or a combination of any form of intractable epilepsy with seizures of various types, movement disorders and paroxysmal events, especially triggered by exercise, exertion, or fasting, and any unexplainable neurological deterioration. The basic diagnostic hallmarks of GLUT1-DS are CSF hypoglycorrhachia and lowered CSF/Blood serum glucose ratio. This is why lumbar punction should be considered more frequently than it is in practice being performed nowadays. Antiepileptic drug treatment may be ineffective or even potentially detrimental. Early identification and molecular confirmation of GLUT1-DS is important, because this is a metabolic disorder and patients should as soon as possible primarily be treated with a ketogenic diet.

[Patterns of the EEG records in children with West Syndrome]. / Wzorce zapisu EEG u dzieci z zespolem Westa.

INTRODUCTION: West Syndrome (WS) (infantile myoclonic encephalopathy with hypsarrhythmia--IMEH) belongs to the infantile epileptic encephalopathies and is characterized by infantile spasms, hypsarrythmia in EEG, and abnormal psychomotor development of children. AIM: Evaluation of the EEG patterns of patients with WS, correlation of the EEG patterns with the cause of epilepsy and an assessment of the influence of antiepileptic drugs (AEDs). CASE REPORTS: EEG patterns of four children with symptomatic WS of different etiology (tuberous sclerosis, brain defects, autoimmune) were analyzed before and during treatment with various antiepileptic drugs. SUMMARY: The basic pattern of EEG in children with WS is hypsarrhythmia. Variabilities of the patterns are the results of degree of development of the child's brain, the etiology of disease, as well as the effects of administration of different antiepileptic drugs..

Genetic epilepsies with febrile seizures plus: clinical spectrum of Polish patients with SCN1A mutation - preliminary report.

UNLABELLED: Diseases caused by mutations in SCN1A are currently named Genetic Epilepsies with Febrile Seizures Plus, and this term stands for expanded spectrum of syndrome previously called as GEFS+ (Generalized Epilepsy with Febrile Seizures Plus). SCN1A is the uniquely identified gene directly linked to specific type of epilepsy, and its testing has been included in the screening processes. THE AIM: To diagnose and describe epileptic syndromes caused by SCN1A mutations. MATERIAL AND METHODS: 203 patients were included in the screening process with suspected SCN1A mutation, based on clinical features and family history. Study group was selected based on inclusion and exclusion criteria and then preliminary epilepsy diagnosis was verified using ILAE classification. Molecular testing to screen SCN1A mutations was performed in the study group. RESULTS: Mutations were detected in 57 cases. Majority of patients (50 cases - 87.5%) suffered from Dravet syndrome, 8.8% (5 cases) were diagnosed as GEFS+, 3% as vaccines encephalopathy and Panayotopoulous syndrome. Mutations were not detected in children with isolated febrile seizures, family febrile seizures nor in patients with myoclonic - astatic epilepsy. CONCLUSIONS: Frequency of mutations in SCN1A in Dravet syndrome and GEFS+ in Polish populations are similar to other countries. Diagnostic clinical criteria are currently insufficient to draw precise diagnosis. There is a strong need to establish clinical criteria for molecular testing and this topic will be investigated in the future.

Recurrent distal 7q11.23 deletion including HIP1 and YWHAG identified in patients with intellectual disabilities, epilepsy, and neurobehavioral problems.

We report 26 individuals from ten unrelated families who exhibit variable expression and/or incomplete penetrance of epilepsy, learning difficulties, intellectual disabilities, and/or neurobehavioral abnormalities as a result of a heterozygous microdeletion distally adjacent to the Williams-Beuren syndrome region on chromosome 7q11.23. In six families with a common recurrent ∼1.2 Mb deletion that includes the Huntingtin-interacting protein 1 (HIP1) and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma (YWHAG) genes and that is flanked by large complex low-copy repeats, we identified sites for nonallelic homologous recombination in two patients. There were no cases of this ∼1.2 Mb distal 7q11.23 deletion copy number variant identified in over 20,000 control samples surveyed. Three individuals with smaller, nonrecurrent deletions (∼180-500 kb) that include HIP1 but not YWHAG suggest that deletion of HIP1 is sufficient to cause neurological disease. Mice with targeted mutation in the Hip1 gene (Hip1⁻(/)⁻) develop a neurological phenotype characterized by failure to thrive, tremor, and gait ataxia. Overall, our data characterize a neurodevelopmental and epilepsy syndrome that is likely caused by recurrent and nonrecurrent deletions, including HIP1. These data do not exclude the possibility that YWHAG loss of function is also sufficient to cause neurological phenotypes. Based on the current knowledge of Hip1 protein function and its proposed role in AMPA and NMDA ionotropic glutamate receptor trafficking, we believe that HIP1 haploinsufficiency in humans will be amenable to rational drug design for improved seizure control and cognitive and behavioral function.

[Regression of cystic lesions on brain MRI in a child with hypoxic-ischemic encephalopathy treated with selective head cooling]. / Regresja zmian torbielowatych w obrazie MR mozgu u dziecka z noworodkowa encefalopatia niedotlenieniowo-niedokrwienna, poddanego hipotermii leczniczej.

The authors present the first case of regression of cystic lesions on brain MRI in a newborn after therapeutic hypothermia in Poland. Multicystic encephalopathy is the most severe form of hypoxic-ischemic encephalopathy and its regression is described very rarely in the literature. Magnetic resonance imaging is an accepted, optimal method of evaluation of the brain and establishing prognosis in children with HIE. After normal pregnancy an emergency cesarean section was performed at 37 weeks gestation due to the markers of intrauterine hypoxia on CTG. The condition of the newborn was serious: 3, 5, 7, 8 points according to Apgar score in 1st, 3nd, 5th and 10th minute of life, respectively. The infant required resuscitation. The cooling procedure lasted 72 hours. The first MRI study was performed at the age of 3 weeks and revealed cavities in the frontal and parietal lobed. The Evans index was 0.33. The second MRI investigation was carried out at the age of 5 weeks. The cavitary appearance did not change, the Evans index decreased to 0.32. The child underwent third MRI at the age of 2 years 4 months. No cystic lesions were found. There were signs of gliosis in their place and focal cortical-subcortical atrophy. The Evans index was 0.28 (within the normal limits). The neuropsychological status of the child at the age of 2.5 years is normal and brain MRI reveals strikingly mild lesions as compared to cavitary injury reported at the age of 3 and 5 weeks. The presented case shows that severe hypoxic-ischemic lesions such as cavities in an infant after cooling procedure do not necessarily mean poor prognosis, as with time even such lesions may regress. Therefore, even after the MRI diagnosis of multicystic encephalopathy the prognosis should be made with care.

Clinical improvement of the aggressive neurobehavioral phenotype in a patient with a deletion of PITX3 and the absence of L-DOPA in the cerebrospinal fluid.

The development of midbrain dopamine (DA) neurons is regulated by several transcription factors, including Nurr1, Wnt1, Lmx1a/1b, En1, En2, Foxa1, Foxa2, and Pitx3. PITX3 is an upstream co-activator of the TH (tyrosine hydroxylase) promoter. Pitx3(-/-) mice have a selective loss of dopaminergic neurons in the substantia nigra and ventral tegmental area, leading to the significantly reduced DA levels in the nigrostriatal pathway and in the dorsal striatum and manifest anomalous striatum-dependent cognitive impairment and neurobehavioral activity. Treatment with L-DOPA, dopamine, or dopamine receptor agonists in these mice reversed several of their sensorimotor impairments. Heterozygous missense mutations in PITX3 have been reported in patients with autosomal dominant congenital cataract and anterior segment (ocular) mesenchymal dysgenesis (ASMD) whereas homozygous missense mutations have been found in patients with microphthalmia and neurological impairment. Using a clinical oligonucleotide array comparative genomic hybridization (aCGH), we have identified an ∼317 kb hemizygous deletion in 10q24.32, involving PITX3 in a 17-year-old male with a Smith-Magenis syndrome-like phenotype, including mild intellectual impairment, sleep disturbance, hyperactivity, and aggressive and self-destructive behavior. Interestingly, no eye anomalies were found in our patient. Analysis of neurotransmitters in his cerebrospinal fluid revealed an absence of L-DOPA and significantly decreased levels of catecholamine metabolites. Importantly, L-DOPA treatment of our patient has led to mild mitigation of his aggressive behavior and mild improvement of his attention span, extended time periods of concentration, and better sleep.

Application of array comparative genomic hybridization in 102 patients with epilepsy and additional neurodevelopmental disorders.

Copy-number variants (CNVs) collectively represent an important cause of neurodevelopmental disorders such as developmental delay (DD)/intellectual disability (ID), autism, and epilepsy. In contrast to DD/ID, for which the application of microarray techniques enables detection of pathogenic CNVs in -10-20% of patients, there are only few studies of the role of CNVs in epilepsy and genetic etiology in the vast majority of cases remains unknown. We have applied whole-genome exon-targeted oligonucleotide array comparative genomic hybridization (array CGH) to a cohort of 102 patients with various types of epilepsy with or without additional neurodevelopmental abnormalities. Chromosomal microarray analysis revealed 24 non-polymorphic CNVs in 23 patients, among which 10 CNVs are known to be clinically relevant. Two rare deletions in 2q24.1q24.3, including KCNJ3 and 9q21.13 are novel pathogenic genetic loci and 12 CNVs are of unknown clinical significance. Our results further support the notion that rare CNVs can cause different types of epilepsy, emphasize the efficiency of detecting novel candidate genes by whole-genome array CGH, and suggest that the clinical application of array CGH should be extended to patients with unexplained epilepsies.

Aicardi-Goutières Syndrome due to a SAMHD1 Mutation Presenting with Deep White Matter Cysts.

We report on the first Polish patient diagnosed with the Aicardi-Goutières syndrome 5 (AGS5). AGS is caused by mutations in one of 9 genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, IFIH, LSM11, RNU7-1) which stimulate the type I interferon response. The diagnosis was confirmed by identifying a compound heterozygous mutation p.(Phe165Ser)/p.(Gln235*) in the SAMHD1 gene using whole-exome sequencing. The cystic lesions in the temporal lobes are an uncommon finding in the presented patient carrying a SAMHD1 mutation. Reporting new cases expands the range of phenotypes and plays the crucial role in understanding the AGS pathogenesis and creates new therapy approaches.

The neuropathological findings of developmental and epileptic encephalopathy-43 (DEE43) and delineation of a the molecular spectrum of novel case.

Developmental and epileptic encephalopathies (DEE) constitute an expanding group of severely disabling and, most frequently, drug-resistant disorders starting in the first year of life. Among them, there is DEE43, caused by dominant mutations in the GABRB3 gene. We present first neuropathological findings in a novel, molecularly confirmed case with the fatal course. The neuropathological analysis revealed co-existing developmental anomalies and retardation of myelination resulting from disturbed early brain growth as well as lesions caused by epileptic hypoxic-ischemic episodes. Developmental anomalies included misplaced neurons in the cerebellar white matter, heterotopic neurons in the cortical molecular layer and in the molecular layer of the hippocampal dentate gyrus, dysmorphic cerebellar dentate nuclei and inferior olivary nuclei in the medulla oblongata. The migrational and maturational disorders leading to the neuronal network dysfunction could be the cause of both the lack of development and the ineffectiveness of antiepileptic treatment in children affected by DEE. Giving the presented neuropathological description and based on the literature, we discuss the pathomechanism of the disease, to improve current understanding of both the lack of development and the ineffectiveness of treatment of affected children.

Exome Sequencing Reveals Novel Variants and Expands the Genetic Landscape for Congenital Microcephaly.

Congenital microcephaly causes smaller than average head circumference relative to age, sex and ethnicity and is most usually associated with a variety of neurodevelopmental disorders. The underlying etiology is highly heterogeneous and can be either environmental or genetic. Disruption of any one of multiple biological processes, such as those underlying neurogenesis, cell cycle and division, DNA repair or transcription regulation, can result in microcephaly. This etiological heterogeneity manifests in a clinical variability and presents a major diagnostic and therapeutic challenge, leaving an unacceptably large proportion of over half of microcephaly patients without molecular diagnosis. To elucidate the clinical and genetic landscapes of congenital microcephaly, we sequenced the exomes of 191 clinically diagnosed patients with microcephaly as one of the features. We established a molecular basis for microcephaly in 71 patients (37%), and detected novel variants in five high confidence candidate genes previously unassociated with this condition. We report a large number of patients with mutations in tubulin-related genes in our cohort as well as higher incidence of pathogenic mutations in MCPH genes. Our study expands the phenotypic and genetic landscape of microcephaly, facilitating differential clinical diagnoses for disorders associated with most commonly disrupted genes in our cohort.

Quality of life in childhood epilepsy with lateralized epileptogenic foci.

BACKGROUND: Measuring quality of life (QOL) helps to delineate mechanisms underlying the interaction of disease and psychosocial factors. In adults, epileptic foci in the left temporal lobe led to lower QOL and higher depression and anxiety as compared to the right-sided foci. No study addressed the development of QOL disturbances depending on the lateralization of epileptogenic focus. The objective of our study was to examine QOL in children with lateralized epileptiform discharges. METHODS: Thirty-one parents of children with epilepsy filled the Health-Related Quality of Life in Childhood Epilepsy Questionnaire (QOLCE). Fifteen children had foci in the left hemisphere and sixteen in the right, as verified with Electroencephalography (EEG) examinations. RESULTS: We found a significant correlation between foci lateralization and reduced QOL (Spearman's rho = 0.361, p < 0.046). Children with right hemispheric foci exhibited lower overall QOL, particularly in five areas: anxiety, social-activities, stigma, general-health, and quality-of-life. CONCLUSIONS: We demonstrated for the first time that in children left- and right-hemispheric foci were associated with discordant QOL scores. Unlike in adults, foci in the right hemisphere led to worse emotional and social functioning demonstrating that seizures impact the brain differentially during development.