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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.

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.

Objective/Purpose. Evaluation of efficacy and safety of autologous adipose-derived regenerative cells (ADRCs) treatment in autoimmune refractory epilepsy. Patients. Six patients with proven or probable autoimmune refractory epilepsy (2 with Rasmussen encephalitis, 2 with antineuronal autoantibodies in serum, and 2 with possible FIRES) were included in the project with approval of the Bioethics Committee. Method. Intrathecal injection of autologous ADRC acquired through liposuction followed by enzymatic isolation was performed. The procedure was repeated 3 times every 3 months with each patient. Neurological status, brain MRI, cognitive function, and antiepileptic effect were monitored during 12 months. Results. Immediately after the procedure, all patients were in good condition. In some cases, transient mildly elevated body temperature, pain in regions of liposuction, and slight increasing number of seizures during 24 hours were observed. During the next months, some improvements in school, social functioning, and manual performance were observed in all patients. One patient has been seizure free up to the end of trial. In other patients, frequency of seizures was different: from reduced number to the lack of improvement (3-year follow-up). Conclusion. Autologous ADRC therapy may emerge as a promising option for some patients with autoimmune refractory epilepsy. Based on our trial and other clinical data, the therapy appears to be safe and feasible. Antiepileptic efficacy proved to be various; however, some abilities improved in all children. No signs of psychomotor regression were observed during the first year following the treatment.

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.

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.

In 1999, based on a single family, spondyloepimetaphyseal dysplasia (SEMD) with mental retardation (MR) was described as a novel syndrome with probably X-linked recessive inheritance and unknown molecular defect (MIM 300232). Our purpose was to search for the causative defect in the originally described family and in an independently ascertained second family. All patients had slowly progressive neurodegeneration with central and peripheral involvement and identical skeletal dysplasia. Whole exome sequencing performed in two subjects showed a single plausible candidate - the p.Asp237Gly variant in AIFM1 (chr. Xq26.1). The p.Asp237Gly segregated with disease as indicated by linkage analysis [maximum logarithm of odds score (LOD) score at theta 0 for the two families was 3.359]. This variant had not been previously reported and it was predicted to be pathogenic by Polyphen2, SIFT, MutationTaster and Mutation Assessor. AIFM1 encodes mitochondria associated apoptosis-inducing factor. The AIFM1 gene has been linked with COXPD6 encephalomyopathy (MIM 300816), Cowchock syndrome (MIM 310490) and X-linked deafness with neuropathy (DFNX5, MIM 300614), none of which are similar to SEMD-MR. Our results place SEMD as the third instance of a skeletal phenotype associated with a mitochondrial disease (the others being EVEN-PLUS syndrome caused by mutations of HSPA9 and CODAS syndrome due to LONP1 mutations).

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.

Malformations of cortical development (MCDs) manifest with structural brain anomalies that lead to neurologic sequelae, including epilepsy, cerebral palsy, developmental delay, and intellectual disability. To investigate the underlying genetic architecture of patients with disorders of cerebral cortical development, a cohort of 54 patients demonstrating neuroradiologic signs of MCDs was investigated. Individual genomes were interrogated for single-nucleotide variants (SNV) and copy number variants (CNV) with whole-exome sequencing and chromosomal microarray studies. Variation affecting known MCDs-associated genes was found in 16/54 cases, including 11 patients with SNV, 2 patients with CNV, and 3 patients with both CNV and SNV, at distinct loci. Diagnostic pathogenic SNV and potentially damaging variants of unknown significance (VUS) were identified in two groups of seven individuals each. We demonstrated that de novo variants are important among patients with MCDs as they were identified in 10/16 individuals with a molecular diagnosis. Three patients showed changes in known MCDs genes and a clinical phenotype beyond the usual characteristics observed, i.e., phenotypic expansion, for a particular known disease gene clinical entity. We also discovered 2 likely candidate genes, CDH4, and ASTN1, with human and animal studies supporting their roles in brain development, and 5 potential candidate genes. Our findings emphasize genetic heterogeneity of MCDs disorders and postulate potential novel candidate genes involved in cerebral cortical development.

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. publisher: Elsevier articletitle: De Novo Loss-of-Function Mutations in CHD2 Cause a Fever-Sensitive Myoclonic Epileptic Encephalopathy Sharing Features with Dravet Syndrome journaltitle: The American Journal of Human Genetics articlelink: http://dx.doi.org/10.1016/j.ajhg.2013.09.017 content_type: article copyright: Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. ispartof: American Journal Of Human Genetics vol:93 issue:5 pages:967-975 ispartof: location:United States status: published

Dravet Syndrome (DS) and Genetic Epilepsy with Febrile Seizures plus (GEFS+) are very often caused by mutations in the SCNA1A gene. These mutations also have been identified in families with migraine phenotypes, supporting the link between migraine and epilepsy. The SCN1A substitution p.Trp1174Ser has been reported as a cause of familial migraine and familial mixed phenotypes with seizures / hemiplegic migraine. We present this mutation as a causative factor of familial GEFS+ syndrome, but also as a factor potentially changing the phenotypes of the epileptic encephalopathies caused by mutations in the SCN1A, ARX or PCDH19 genes. Substitution p.Trp1174Ser was identified in five probands clinically diagnosed as spectrum of GEFS+ or DS. As it has not been regarded as significant for the epileptic encephalopathy, they underwent additional testing according to the revised phenotypes. Probands were finally diagnosed with GEFS+ (p.Trp1174Ser SCN1A mutation only) and epileptic encephalopathies: DS (p.Arg712* and p.Arg1245* in SCN1A), Epilepsy and Mental Retardation Limited to Females (p.Asp155Tyr in PCDH19) and atypical West Syndrome (del79nt IVS4/Ex5 in ARX). This study indicates a complex involvement of some SCN1A mutations in epilepsies / epileptic encephalopathies also as a modifying factor with the SCN1A, PCDH19, ARX and possibly mutations in other genes. In cases with atypical or "plus" course or more severe course the possible involvement of other genetic factors should always be considered. Additional modifiers identification may influence on clinical prognosis, patient management and genetic counselling.

BMC neurology 10, 69 (2010). doi:10.1186/1471-2377-10-69, Published by BioMed Central, London

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.

Pelizaeus-Merzbacher disease (PMD) is X-linked hypomyelinating leukodystrophy caused by mutations of the PLP1 gene, which codes the proteolipid protein 1. The result of mutations is abnormal myelination - hypomyelination and dysmyelination of cerebral white matter, and in some form of the disease hypomyelinating peripheral neuropathy. DNA samples from 68 patients suspected of PMD due to the clinical course and hypomyelination at magnetic resonance imaging (MRI) were analyzed. Medical history and detailed clinical course of PMD patients were also analyzed. Different mutations of the PLP1 gene were detected in 14 boys from 11 families (~20%). Amongst the molecularly confirmed patients, 13 presented classical PMD forms but clinical phenotypes varied in the severity even amongst siblings. One patient presented a severe connatal form. One mother, obligate carrier, presented complicated SPG2 (spastic paraparesis). There was no phenotype-genotype correlation in our material. In many cases PMD was suspected with a delay of many years, sometimes only after birth of another affected child in the family. Pelizaeus-Merzbacher disease was most frequently misdiagnosed as cerebral palsy.

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.