Aicardi Syndrome Is a Genetically Heterogeneous Disorder.

Aicardi Syndrome (AIC) is a rare neurodevelopmental disorder recognized by the classical triad of agenesis of the corpus callosum, chorioretinal lacunae and infantile epileptic spasms syndrome. The diagnostic criteria of AIC were revised in 2005 to include additional phenotypes that are frequently observed in this patient group. AIC has been traditionally considered as X-linked and male lethal because it almost exclusively affects females. Despite numerous genetic and genomic investigations on AIC, a unifying X-linked cause has not been identified. Here, we performed exome and genome sequencing of 10 females with AIC or suspected AIC based on current criteria. We identified a unique de novo variant, each in different genes: KMT2B, SLF1, SMARCB1, SZT2 and WNT8B, in five of these females. Notably, genomic analyses of coding and non-coding single nucleotide variants, short tandem repeats and structural variation highlighted a distinct lack of X-linked candidate genes. We assessed the likely pathogenicity of our candidate autosomal variants using the TOPflash assay for WNT8B and morpholino knockdown in zebrafish (Danio rerio) embryos for other candidates. We show expression of Wnt8b and Slf1 are restricted to clinically relevant cortical tissues during mouse development. Our findings suggest that AIC is genetically heterogeneous with implicated genes converging on molecular pathways central to cortical development.

A case of Aicardi syndrome associated with duplication event of Xp22 including SHOX.

BACKGROUND: Aicardi syndrome is a neurodevelopmental disorder characterized by a triad of partial or complete agenesis of the corpus callosum, infantile spasms, and pathognomonic chorioretinal lacunae. METHODS: Examination, multimodal imaging, and genetic testing were used to guide diagnosis. RESULTS: We report a case of a pediatric patient who was initially diagnosed with refractory infantile spasms. The patient was unresponsive to conventional antiepileptic therapy, and genetic testing with whole exome and mitochondrial genome sequencing could not identify the underlying cause, so vigabatrin was initiated. The ophthalmic examination under anesthesia for vigabatrin toxicity screening revealed chorioretinal atrophy in the retinal periphery of both eyes, with two 3-disc diameter chorioretinal lacunae superotemporal and inferonasal to the optic nerve in the left eye. Given the neuroimaging findings of corpus callosum hypoplasia with polymicrogyria and ocular findings, the patient was diagnosed with Aicardi syndrome. Genetic testing revealed a novel duplication event at the Xp22 locus. CONCLUSIONS: Aicardi syndrome, albeit a rare condition, should always be considered in the differential diagnosis when investigating a female child with refractory seizures in early childhood. Genetic testing may help further our understanding of AIS and the search for a genetic etiology.

Síndrome de Aicardi-Goutières: un caso familiar por alteración del gen RNASEH2B / Aicardi-Goutières syndrome: a family case due to alteration of the RNASEH2B gene

Introducción: El síndrome de Aicardi-Goutières es una encefalopatía progresiva de inicio en el primer año de vida que condiciona retraso psicomotor, microcefalia y disfunción piramidal. Tiene una prevalencia de 1-5 de cada 10.000 recién nacidos vivos. La mayoría de los casos tiene transmisión autosómica recesiva, por alteración en siete genes implicados en el metabolismo del interferón, lo cual condiciona un aumento de sus niveles en la sangre y el líquido cefalorraquídeo, y afecta al cerebro (leucodistrofia, atrofia corticosubcortical, calcificaciones en los núcleos basales…), la piel y el sistema inmunitario. Caso clínico: Se trata de dos hermanos que presentan la variante p.Ala177Thr en homocigosis en el gen RNASEH2B; ambos progenitores, consanguíneos, son portadores. El primer hermano comenzó a los 10 meses con hipotonía axial, hipertonía de las extremidades, regresión psicomotriz y movimientos distónicos. El segundo hermano presentó desde el nacimiento tono axial bajo con hipertonía de las extremidades, a los 4 meses se hallaron calcificaciones en los núcleos lenticuloestriados mediante ecografía transfontalar y a los 6 meses inició movimientos distónicos y nistagmo intermitente. Ambos han desarrollado tetraparesia espástica y permanecen estables con 8 y 10 años, pese a las complicaciones propias del síndrome. Conclusiones: El síndrome de Aicardi-Goutières es una entidad rara que debe tenerse presente ante situaciones que cursen con alteración del desarrollo psicomotor y calcificaciones intracraneales; destacamos la importancia del diagnóstico genético tanto para conocer el pronóstico de nuestros pacientes en función de su alteración genética como para ofrecer consejo genético a sus familias.(AU)

Introduction: Aicardi-Goutières syndrome is a progressive encephalopathy with onset in the first year of life that conditions psychomotor retardation, microcephaly and pyramidal dysfunction. It has a prevalence of 1-5 in 10,000 newly live births. Most cases have autosomal recessive transmission, due to alteration in seven genes involved in the metabolism of interferon, which causes an increase in its levels in the blood and cerebrospinal fluid, and affects the brain (leukodystrophy, corticosubcortical atrophy, calcifications in the basal ganglia…), the skin and the immune system. Clinical case: They are two brothers who present the homozygous p.Ala177Thr variant in the RNASEH2B gene; both of them parents, consanguineous, are carriers. The first sibling started at 10 months with axial hypotonia, hypertonia of the extremities, psychomotor regression and dystonic movements. The second brother presented from the birth low axial tone with hypertonia of the extremities, at 4 months calcifications were found in the nuclei lenticulostriated by transfontalar ultrasound and, at 6 months, she started dystonic movements and intermittent nystagmus. Both have developed spastic tetraparesis and remain stable at 8 and 10 years, despite complications typical of the syndrome. Conclusions: The Aicardi-Goutières syndrome is a rare entity that should be taken into account in situations that occur with altered psychomotor development and intracranial calcifications; we highlight the importance of diagnosis both to know the prognosis of our patients based on their genetic alteration and to offer genetic counseling to their families.(AU)

Agenesis of the corpus callosum and hepatoblastoma.

Agenesis of the corpus callosum is a congenital brain malformation that can occur in isolation or as a component of a congenital syndrome. Hepatoblastoma (HB) is a rare tumor that comprises two thirds of primary hepatic neoplasms in children and adolescents. Up to 20% of children with HB have associated congenital anomalies. In addition to defined genetic syndromes such as Familial Adenomatous Polyposis, Beckwith-Wiedemann syndrome, Trisomy 13, and Trisomy 18, HB is significantly associated with kidney/bladder abnormalities. We present two children with multiple congenital anomalies, including agenesis of the corpus callosum, who were subsequently diagnosed with HB. Review of the literature revealed two patients with clinically-diagnosed Aicardi syndrome and HB. Due to the rarity of both agenesis of the corpus callosum and HB, this is likely a true association. Further investigation into the underlying genetic and molecular basis of this probable association is warranted.

Aicardi syndrome, an unsolved mystery: Review of diagnostic features, previous attempts, and future opportunities for genetic examination.

Aicardi syndrome is a rare, severe neurodevelopmental disorder classically characterized by the triad of infantile spasms, central chorioretinal lacunae, and agenesis of the corpus callosum. Aicardi syndrome only affects females, with the exception of a few males with a 47, XXY chromosome constitution. All cases are de novo and the only cases of definitive recurrence in families are in identical twins. It is now recognized that individuals with Aicardi syndrome commonly exhibit a variety of other neuronal migration defects, eye anomalies, and other somatic features, including skin, skeletal, and craniofacial systems. The etiology of Aicardi syndrome remains unknown despite an international effort exploring different genetic mechanisms. Although various technologies examining candidate genes, copy number variation, skewing of X-chromosome inactivation, and whole-exome sequences have been explored, no strong genetic candidates have been identified to date. New technologies that can detect low-level mosaicism and balanced rearrangements, as well as platforms examining changes at the DNA and chromatin level affecting regulatory regions are all potential avenues for future studies that may one day solve the mystery of the etiology of Aicardi syndrome.

Exploring genome-wide DNA methylation patterns in Aicardi syndrome.

AIM: To explore differential DNA methylation (DNAm) in Aicardi syndrome (AIC), a severe neurodevelopmental disorder with largely unknown etiology. PATIENTS & METHODS: We characterized DNAm in AIC female patients and parents using the Illumina 450 K array. Differential DNAm was assessed using the local outlier factor algorithm, and results were validated via qPCR in a larger set of AIC female patients, parents and unrelated young female controls. Functional epigenetic modules analysis was used to detect pathways integrating both genome-wide DNAm and RNA-seq data. RESULTS & CONCLUSION: We detected differential methylation patterns in AIC patients in several neurodevelopmental and/or neuroimmunological networks. These networks may be part of the underlying pathogenic mechanisms involved in the disease.

Autopsy findings in EPG5-related Vici syndrome with antenatal onset.

Vici syndrome is one of the most extensive inherited human multisystem disorders and due to recessive mutations in EPG5 encoding a key autophagy regulator with a crucial role in autophagosome-lysosome fusion. The condition presents usually early in life, with features of severe global developmental delay, profound failure to thrive, (acquired) microcephaly, callosal agenesis, cataracts, cardiomyopathy, hypopigmentation, and combined immunodeficiency. Clinical course is variable but usually progressive and associated with high mortality. Here, we present a fetus, offspring of consanguineous parents, in whom callosal agenesis and other developmental brain abnormalities were detected on fetal ultrasound scan (US) and subsequent MRI scan in the second trimester. Postmortem examination performed after medically indicated termination of pregnancy confirmed CNS abnormalities and provided additional evidence for skin hypopigmentation, nascent cataracts, and hypertrophic cardiomyopathy. Genetic testing prompted by a suggestive combination of features revealed a homozygous EPG5 mutation (c.5870-1G>A) predicted to cause aberrant splicing of the EPG5 transcript. Our findings expand the phenotypical spectrum of EPG5-related Vici syndrome and suggest that this severe condition may already present in utero. While callosal agenesis is not an uncommon finding in fetal medicine, additional presence of hypopigmentation, cataracts and cardiomyopathy is rare and should prompt EPG5 testing.

Variaciones fenotípicas en el síndrome de Aicardi-Goutières causado por mutaciones en el genRNASEH2B: presentación de dos nuevos casos / Phenotypic variations in Aicardi-Goutières syndrome caused by RNASEH2B gene mutations: report of two new cases

Introducción. El síndrome de Aicardi-Goutières es un trastorno inmunitario raro debido a mutaciones en siete genes que codifican proteínas llamadas TREX1, el complejo ribonucleasa H2, SAMHD1, ADAR e IFIH1 (MAD5), las cuales están implicadas en el metabolismo de los ácidos nucleicos. A continuación se presentan dos nuevos casos por mutación en el gen RNASEH2B, uno de los cuales presenta una mutación no descrita hasta la fecha. Casos clínicos. Caso 1: varón que consultó porque desde los 5 meses, coincidiendo con cuadros febriles de repetición, presentaba pérdida de los ítems madurativos adquiridos hasta la fecha. Caso 2: niño de 4 meses que desde los 2 meses mostraba gran irritabilidad con dificultades en la alimentación, asociado a un grave retraso psicomotor. En ambos casos se constató un aumento de las pterinas en el líquido cefalorraquídeo, principalmente de la neopterina, con calcificaciones en los ganglios basales. El diagnóstico se confirmó mediante secuenciación del gen RNASEH2B; el caso 2 presentaba una mutación no descrita en la literatura médica. Conclusiones. Los casos corresponden a la descripción clásica realizada por Aicardi-Goutières. Debe tenerse en cuenta este síndrome ante un paciente con un cuadro de encefalopatía subaguda de comienzo en el primer año de vida, distonía/espasticidad en grado variable e importante afectación/regresión del desarrollo psicomotor, especialmente si asocia aumento de las pterinas (neopterina) en el líquido cefalorraquídeo y calcificaciones en los ganglios basales (AU)

Introduction. Aicardi-Goutières syndrome is a rare immune disorder due to mutations in seven different genes that encode proteins called TREX1, ribonuclease H2 complex, SAMHD1, ADAR and IDIH1 (MDA5), which are involved in acid nucleic metabolism. Two cases are described in detail below caused by RNASEH2B gene mutation, one of which displays a mutation no described to date. Case reports. Case 1: male consulting because from 5-month-old shows loss of maturity items acquired until then, coming with several fever episodes. Case 2: a 4-month-old boy showing since 2-month-old great irritability and oral-feeding trouble with severe psychomotor impairment. In both cases it was found an increase of pterines in the cerebrospinal fluid, mainly neopterine, with calcifications in the basal ganglia. The diagnosis was proved by sequencing RNASEH2B gene, founding in case 2 a new mutation not described previously. Conclusions. The reported cases belong to the description already done by Aicardi-Goutières, it should be noticed this syndrome in a patient with a subacute encephalopathy of debut in the first year of life, dystonia/spasticity in variable degree and important affectation/regression of psychomotor development, particularly in those with increase of pterines (neopterine) in the cerebrospinal fluid and calcifications in the basal ganglia (AU)

Early Infantile Epileptic Encephalopathy with a de novo variant in ZEB2 identified by exome sequencing.

Early Infantile Epileptic Encephalopathy (EIEE) presents shortly after birth with frequent, severe seizures, a burst-suppression EEG pattern, and progressive disturbance of cerebral function. We present a case of EIEE associated with a de novo missense variant in ZEB2. Heterozygous truncating mutations or deletions in ZEB2 are known to cause Mowat-Wilson syndrome (MWS), which is characterized by seizures with onset in the second year of life, distinctive dysmorphic facial features and malformations that were absent in this patient. This unique case expands the range of phenotypes associated with variants in ZEB2 and indicates that this gene should be included in the molecular investigation of EIEE cases.

Cortical interneuron dysfunction in epilepsy associated with autism spectrum disorders.

Autism and epilepsy are two associated disorders that are highly prevalent, share common developmental origins, and demonstrate substantial heritability. In this review, cross-disciplinary data in a rapidly evolving field that bridges neurology and psychiatry are synthesized to identify shared biologic mechanisms. The relationship between these debilitating, lifelong conditions is examined at the clinical, genetic, and neurophysiologic levels in humans and in animal models. Scopus and PubMed searches were used to identify relevant literature. Clinical observations have prompted speculation about the interdependence of autism and epilepsy, but causal relationships have proved difficult to determine. Despite their heritability, the genetic basis of autism spectrum disorder (ASD) and epilepsy has remained largely elusive until the advent of next-generation sequencing. This approach has revealed that mutations that are either causal or confer an increased disease risk are found in numerous different genes, any one of which accounts for only a small percentage of cases. Conversely, even cases with identical clinical phenotypes can be genetically heterogeneous. Candidate gene identification has facilitated the development of mouse genetic models, which in parallel with human studies have implicated shared brain regions and circuits that mediate disease expression. Diverse genetic causes of ASD and epilepsy converge on cortical interneuron circuits as one important mediator of both disorders. Cortical interneurons are among the most diverse cell types in the brain and their unique chemical and electrical coupling exert a powerful inhibitory influence on excitatory neurons via the release of the neurotransmitter, γ-aminobutyric acid (GABA). These multifaceted approaches have validated theories derived from the field of developmental neurobiology, which propose that the neurologic and neuropsychiatric manifestations are caused by an altered ratio of excitation to inhibition in the cortex.

Turkish cases of early infantile epileptic encephalopathy: two novel mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene.

Cyclin-dependent kinase-like 5 gene-related epileptic encephalopathy is gradually becoming better known in child neurology practice. The related gene mutations cause early infantile epileptic encephalopathy characterized by intractable epilepsy, severe mental retardation and, later, the development of Rett syndrome-like features. Herein, we report the first two Turkish cases of cyclin-dependent kinase-like 5 gene-related epileptic encephalopathy with novel mutations in exon 8, which is located in the catalytic domain of the gene.

Severe CNS involvement in WWOX mutations: Description of five new cases.

Recently, mutations in WWOX have been identified in the setting of central nervous system (CNS) disorders, highlighting a previously unrevealed role of this gene in the normal development and function of the CNS. In this report, we add five patients from two seemingly unrelated families presenting with a primarily neurological phenotype. All the children were product of consanguineous marriages. Whole exome sequencing revealed the same homozygous mutation (NM_016373.3:c.606-1G>A) of WWOX in all five patients. All patients and carriers in the family share the same haplotype indicating the families are in fact related to one another. The clinical presentation included progressive microcephaly, early onset of spasticity in the first 3 months of life, intractable epilepsy, severe failure to thrive, and profound developmental delay. Retinopathy was observed in two patients. All five patients died before their third birthday. Neuroimaging showed extensive neurodegeneration characterized by periventricular white matter volume loss and atrophy of the corpus callosum. Additional degeneration selectively affecting the mediodorsal nucleus of the thalamus was observed in one patient. Our findings in five new patients affected by WWOX mutation with early infantile phenotype confirm the features of the disease represented by early infantile epileptic encephalopathy. We suggest that neuroimaging in these patients reveals a characteristic pattern of neurodegeneration in which the cerebellum is spared that could help with early diagnosis in the appropriate clinical setting.

De novo inbred heterozygous Zeb2/Sip1 mutant mice uniquely generated by germ-line conditional knockout exhibit craniofacial, callosal and behavioral defects associated with Mowat-Wilson syndrome.

Mowat-Wilson syndrome (MOWS) is caused by de novo heterozygous mutation at ZEB2 (SIP1, ZFHX1B) gene, and exhibit moderate to severe intellectual disability (ID), a characteristic facial appearance, epilepsy and other congenital anomalies. Establishing a murine MOWS model is important, not only for investigating the pathogenesis of this disease, but also for identifying compounds that may improve the symptoms. However, because the heterozygous Zeb2 knockout mouse could not be maintained as a mouse line with the inbred C57BL/6 background, it was difficult to use those mice for the study of MOWS. Here, we systematically generated de novo Zeb2 Δex7/+ mice by inducing the Zeb2 mutation in the germ cells using conditional recombination system. The de novo Zeb2 Δex7/+ mice with C57BL/6 background developed multiple defects relevant to MOWS, including craniofacial abnormalities, defective corpus callosum formation and the decreased number of parvalbumin interneurons in the cortex. In behavioral analyses, these mice showed reduced motor activity, increased anxiety and impaired sociability. Notably, during the Barnes maze test, immobile Zeb2 mutant mice were observed over repeated trials. In contrast, neither the mouse line nor the de novo Zeb2 Δex7/+ mice with the closed colony ICR background showed cranial abnormalities or reduced motor activities. These results demonstrate the advantages of using de novo Zeb2 Δex7/+ mice with the C57BL/6 background as the MOWS model. To our knowledge, this is the first time an inducible de novo mutation system has been applied to murine germline cells to produce an animal model of a human congenital disease.

Síndrome de Aicardi con malformación tipo Dandy-Walker / Aicardi syndrome with Dandy-Walker type malformation

Introducción. El síndrome de Aicardi (OMIM 304050) fue descrito en 1965. Su tríada clásica está compuesta por espasmos infantiles, agenesia parcial o total del cuerpo calloso y alteraciones oculares, como lagunas coriorretinianas. Se postula un mecanismo de herencia ligado a X dominante. Caso clínico. Niña nacida a término, sin antecedentes familiares patológicos ni consanguinidad parental, con diagnóstico prenatal de malformación tipo Dandy-Walker, quien presentó episodios convulsivos, coloboma del nervio óptico, bloque vertebral torácico con presencia de escoliosis, ecografía transfontanelar con agenesia del cuerpo calloso y cariotipo 46,XX. Se diagnosticó de síndrome de Aicardi y falleció con mes y medio de edad. En la autopsia se evidenció hidrocefalia supratentorial con presencia de papiloma de los plexos coroideos, quiste en la fosa posterior (cuarto ventrículo), hipoplasia del vermis cerebeloso, agenesia del hemisferio del cuerpo calloso y cerebeloso izquierdo, rasgos faciales característicos del síndrome, paladar ojival, pectus excavatum, escoliosis, quiste paraovárico y hepatomegalia. Conclusiones. Pocos casos han descrito la asociación de la patología y la presencia de malformación de Dandy-Walker. Se comunica un nuevo caso con esta asociación, teniendo en cuenta que las alteraciones relacionadas, principalmente agenesia o hipoplasia del cuerpo calloso, sugieren que tiene un componente genético de base. El estudio de búsqueda de la etiología de centrarse en evaluar aquellos genes que tengan relación con el neurodesarrollo y su activación en la etapa de organogenia. El diagnóstico definitivo establece el pronóstico, manejo y asesoría genética a la familia (AU)

Introduction. Aicardi syndrome (OMIM 304050) was first described in 1965. Its classic triad consists of infantile spasms, partial or total agenesis of the corpus callosum and ocular disorders, such as chorioretinal lacunae. It has been posited that it is due to a mechanism involving X-linked dominant inheritance. Case report. We report the case of a full-term female, with no pathological familial history or parental consanguinity, with a prenatal diagnosis of Dandy-Walker type malformation, who presented convulsions, coloboma of the optic nerve, thoracic vertebral block with presence of scoliosis, transfontanellar ultrasound imaging showing agenesis of the corpus callosum and karyotype 46,XX. She was diagnosed with Aicardi syndrome and died at the age of one and a half months. The autopsy revealed supratentorial hydrocephalus with the presence of choroid plexus papilloma, a cyst in the posterior fossa (fourth ventricle), hypoplasia of the cerebellar vermis, agenesis of the left hemisphere of the corpus callosum and cerebellum, characteristic facial features of the syndrome, ogival palate, pectus excavatum, scoliosis, paraovarian cyst and hepatomegaly. Conclusions. Few cases of an association between the pathology and the presence of Dandy-Walker malformation have been described. We report a new case of the association, bearing in mind that the related disorders, mainly agenesis or hypoplasia of the corpus callosum, suggest the existence of an underlying genetic component. A study of the search for the aetiology must be focused on evaluating those genes that are related with neurodevelopment and its activation in the organogenesis stage. The definitive diagnosis establishes the prognosis, management and genetic counselling of the family (AU)

A De Novo Mutation in TEAD1 Causes Non-X-Linked Aicardi Syndrome.

PURPOSE: Aicardi syndrome (AIC) is a congenital neurodevelopmental disorder characterized by infantile spasms, agenesis of the corpus callosum, and chorioretinal lacunae. Variation in phenotype and disease severity is well documented, but chorioretinal lacunae represent the most constant pathological feature. Aicardi syndrome is believed to be an X-linked-dominant disorder occurring almost exclusively in females, although 46, XY males with AIC have been described. The purpose of this study is to identify genetic factors and pathways involved in AIC. METHODS: We performed exome/genome sequencing of 10 children diagnosed with AIC and their parents and performed RNA sequencing on blood samples from nine cases, their parents, and unrelated controls. RESULTS: We identified a de novo mutation in autosomal gene TEAD1, expressed in the retina and brain, in a patient with AIC. Mutations in TEAD1 have previously been associated with Sveinsson's chorioretinal atrophy, characterized by chorioretinal degeneration. This demonstrates that TEAD1 mutations can lead to different chorioretinal complications. In addition, we found that altered expression of genes associated with synaptic plasticity, neuronal development, retinal development, and cell cycle control/apoptosis is an important underlying potential pathogenic mechanism shared among cases. Last, we found a case with skewed X inactivation, supporting the idea that nonrandom X inactivation might be important in AIC. CONCLUSIONS: We expand the phenotype of TEAD1 mutations, demonstrate its importance in chorioretinal complications, and propose the first putative pathogenic mechanisms underlying AIC. Our data suggest that AIC is a genetically heterogeneous disease and is not restricted to the X chromosome, and that TEAD1 mutations may be present in male patients.

Variable clinical expression in patients with mosaicism for KCNQ2 mutations.

Mutations in the KCNQ2 gene, encoding a potassium channel subunit, were reported in patients presenting epileptic phenotypes of varying severity. Patients affected by benign familial neonatal epilepsy (BFNE) are at the milder end of the spectrum, they are affected by early onset epilepsy but their subsequent neurological development is usually normal. Mutations causing BFNE are often inherited from affected parents. Early infantile epileptic encephalopathy type 7 (EIEE7) is at the other end of the severity spectrum and, although EIEE7 patients have early onset epilepsy too, their neurological development is impaired and they will present motor and intellectual deficiency. EIEE7 mutations occur de novo. Electrophysiological experiments suggested a correlation between the type of mutation and the severity of the disease but intra and interfamilial heterogeneity exist. Here, we describe the identification of KCNQ2 mutation carriers who had children affected with a severe epileptic phenotype, and found that these individuals were mosaic for the KCNQ2 mutation. These findings have important consequences for genetic counseling and indicate that neurological development can be normal in the presence of somatic mosaicism for a KCNQ2 mutation.

Somatic mosaicism of a CDKL5 mutation identified by next-generation sequencing.

INTRODUCTION: CDKL5-related encephalopathy is an X-linked dominantly inherited disorder that is characterized by early infantile epileptic encephalopathy or atypical Rett syndrome. We describe a 5-year-old Japanese boy with intractable epilepsy, severe developmental delay, and Rett syndrome-like features. Onset was at 2 months, when his electroencephalogram showed sporadic single poly spikes and diffuse irregular poly spikes. METHODS: We conducted a genetic analysis using an Illumina® TruSight™ One sequencing panel on a next-generation sequencer. RESULTS: We identified two epilepsy-associated single nucleotide variants in our case: CDKL5 p.Ala40Val and KCNQ2 p.Glu515Asp. CDKL5 p.Ala40Val has been previously reported to be responsible for early infantile epileptic encephalopathy. In our case, the CDKL5 heterozygous mutation showed somatic mosaicism because the boy's karyotype was 46,XY. The KCNQ2 variant p.Glu515Asp is known to cause benign familial neonatal seizures-1, and this variant showed paternal inheritance. CONCLUSIONS: Although we believe that the somatic mosaic CDKL5 mutation is mainly responsible for the neurological phenotype in the patient, the KCNQ2 variant might have some neurological effect. Genetic analysis by next-generation sequencing is capable of identifying multiple variants in a patient.

Novel STXBP1 mutations in 2 patients with early infantile epileptic encephalopathy.

The authors describe 2 patients with early infantile epileptic encephalopathy caused by 2 novel mutations involving the STXBP1 gene. The authors suggest that in spite of the rarity of STXBP1 mutations, molecular analysis of STXBP1 gene should be performed in patients with early infantile epileptic encephalopathy, after exclusion of ARX mutations in male patients and CDKL5 mutations in female patients. The potential mechanisms explaining the variable clinical phenotypes caused by STXBP1 mutations are discussed and the designation of early-onset epileptic encephalopathies, including an updated genetic classification, is proposed to encompass the epileptic encephalopathies beginning in the first 6 months of life.

Epilepsy and mental retardation restricted to females: X-linked epileptic infantile encephalopathy of unusual inheritance.

Epilepsy in females with mental retardation (EFMR) is a rare early infantile epileptic encephalopathy (EIEE), phenotypically resembling Dravet syndrome (DS). It is characterised by a variable degree of intellectual deficits and epilepsy. EFMR is caused by heterozygous mutations in the PCDH19 gene (locus Xq22.1) encoding protocadherin-19, a protein that is highly expressed during brain development. The protein is involved in cell adhesion and probably plays an important role in neuronal migration and formation of synaptic connections. EFMR is considered X-linked of variable mutations' penetrance. Mutations in the PCDH19 gene mainly arise de novo, but if inherited, they show a unique pattern of transmission. Females with heterozygous mutations are affected, while hemizygous males are not, regardless of mutation carriage. This singular mode might be explained by cell interference as a pathogenic molecular mechanism leading to neuronal dysfunction. Recently, PCDH19-related EIEE turned out to be more frequent than initially thought, contributing to around 16% of cases (25% in female groups) in the SCN1A-negative DS-like patients. Therefore, the PCDH19 gene is now estimated to be the second, after SCN1A, most clinically relevant gene in epilepsy.