PEHO syndrome caused by compound heterozygote variants in ZNHIT3 gene.

PEHO syndrome is characterized by Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy, which was first described in Finnish patients. A homozygous missense substitution p.Ser31Leu in ZNHIT3 was recently identified as the primary cause of PEHO syndrome in Finland. Variants in ZNHIT3 have not been identified in patients with PEHO or PEHO-like syndrome in other populations. It has therefore been suggested that PEHO syndrome caused by ZNHIT3 variants does not occur outside of the Finnish population. We describe the first patient outside Finland who carries compound heterozygous variants in ZNHIT3 gene causing PEHO syndrome. Trio genome sequencing was carried out and the identified variants were confirmed by Sanger sequencing. The patient filled all diagnostic clinical criteria of PEHO syndrome. We identified biallelic missense variants in ZNHIT3 gene: the c.92C > T p.(Ser31Leu) variant (NM_004773.3), which is described previously as causing PEHO syndrome and the second novel variant c.41G > T p.(Cys14Phe). There are only eight heterozygous carriers of c.41G > T variant in the gnomAD database and it is predicted damaging by multiple in silico algorithms. The ZNHIT3-associated PEHO syndrome exists outside of the Finnish population.

Heterozygous RNF13 Gain-of-Function Variants Are Associated with Congenital Microcephaly, Epileptic Encephalopathy, Blindness, and Failure to Thrive.

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) initiates a stress response mechanism to clear out the unfolded proteins by either facilitating their re-folding or inducing their degradation. When this fails, an apoptotic cascade is initiated so that the affected cell is eliminated. IRE1α is a critical sensor of the unfolded-protein response, essential for initiating the apoptotic signaling. Here, we report an infantile neurodegenerative disorder associated with enhanced activation of IRE1α and increased apoptosis. Three unrelated affected individuals with congenital microcephaly, infantile epileptic encephalopathy, and profound developmental delay were found to carry heterozygous variants (c.932T>C [p.Leu311Ser] or c.935T>C [p.Leu312Pro]) in RNF13, which codes for an IRE1α-interacting protein. Structural modeling predicted that the variants, located on the surface of the protein, would not alter overall protein folding. Accordingly, the abundance of RNF13 and IRE1α was not altered in affected individuals' cells. However, both IRE1α-mediated stress signaling and stress-induced apoptosis were increased in affected individuals' cells. These results indicate that the RNF13 variants confer gain of function to the encoded protein and thereby lead to altered signaling of the ER stress response associated with severe neurodegeneration in infancy.

PRRT2 mutations in familial infantile seizures, paroxysmal dyskinesia, and hemiplegic migraine.

OBJECTIVE: To perform a clinical and genetic study of a family with benign familial infantile seizures (BFIS) and, upon finding a PRRT2 gene mutation, to study a cohort of probands with a similar phenotype. We extended the study to all available family members to find out whether PRRT2 mutations cosegregated with additional symptoms. METHODS: We carried out a clinical and genealogic study of a 3-generation family and of 32 additional probands with BFIS (11 families), infantile convulsions and paroxysmal choreoathetosis (ICCA) (9 families), BFIS/generalized epilepsy with febrile seizures plus (5 families), and sporadic benign neonatal or infantile seizures (7 probands/families). We performed a genetic study consisting of linkage analysis and PRRT2 screening of the 33 probands/families. RESULTS: We obtained a positive linkage in the 16p11.3-q23.1 chromosomal region in the large BFIS family. Mutation analysis of PRRT2 gene revealed a c.649dupC (p.Arg217Profs*8) in all affected individuals. PRRT2 analysis of the 32 additional probands showed mutations in 10, 8 familial and 2 sporadic, probands. Overall we found PRRT2 mutations in 11 probands with a mutation rate of 11 out of 33 (33%). BFIS co-occurred with migraine and febrile seizures in 2 families, with childhood absence epilepsy in one family and with hemiplegic migraine in one family. CONCLUSION: Our results confirm the predominant role of PRRT2 mutations in BFIS and expand the spectrum of PRRT2-associated phenotypes to include febrile seizures, childhood absence seizures, migraine, and hemiplegic migraine.

Benign infantile seizures and paroxysmal dyskinesia: a well-defined familial syndrome.

UNLABELLED: The aim of this study was to analyze the electroclinical features and evolution in patients with benign infantile seizures (BIS) associated with paroxysmal dyskinesia (PD). PATIENTS AND METHODS: Among 198 patients with BIS (78 of whom were familial cases), we evaluated 12 unrelated patients with BIS and PD seen at two pediatric neurology departments from January 1990 to February 2009. RESULTS: The patients were eight boys and four girls, one of whom was not a familial case. The time of follow-up was between 6 and 19 years. Median age at onset of epilepsy was 7 months (R: 5-18 m). Seizures were brief, focal, with or without secondary generalization, and occurred in clusters in 58% of the cases. Seven of 12 patients with BIS and 13 family members had PD. The age at onset of PD was between 5 and 18 years and it was characterized by choreoathetosis in 12 and dystonia in 8. PD was kinesigenic in all cases. As to family history, BIS was found in mothers in two patients, in fathers in five, in a grandfather in one, in grand-uncle in one, in uncles in four, in brothers in three, and in sisters in three other patients. PD was found in fathers in four patients, in the mother in one, in a brother in one, in a cousin in three, in an uncle in one, in an aunt in one, and in grandfathers in two. During follow-up, one patient and a relative with BIS from two different families presented Rolandic epilepsy. The father of the case with BIS and Rolandic epilepsy also had BIS and benign focal seizures of adolescence. CONCLUSIONS: BIS and PD syndrome is a well-defined familial syndrome. BIS had the similar features described in patients with familial and non-familial BIS. The patient with non-familial BIS who developed PD later, suggests that non-familial forms may have a genetic cause and may be caused by de novo mutations.

Electroclinical features of benign infantile seizures with mild gastroenteritis.

The purpose of this study was to analyze the electroclinical features of patients with benign infantile seizures with mild gastroenteritis and demonstrate the benign nature of this entity. From 30 patients who were included in the study, five were excluded (two with developmental delay, one with microcephaly and two lost during follow-up). Twenty-five patients who fulfilled the diagnostic criteria for benign infantile seizures with mild gastroenteritis were assessed and followed at the Pediatric Department, Armed Forces Hospital, Southern Region, Khamis Mushayt, Saudi Arabia, between January 2004 and January 2009. The median age at presentation was 10.4 months. Of the infants, 14 were females and 11 were males. Seizures were focal tonic or clonic in eight (32%) patients, focal with secondary generalisation in three (12%), generalised tonic-clonic in nine (36%) and consisted of staring only with no motor components in five (20%). Interictal electroencephalograms and brain imaging were normal for all patients. No patient required treatment with antiepileptic drugs. All the patients were found to have normal psychomotor development and neurological examination after a follow-up period of between 15 and 56 months. The limitations of this study are the relatively small sample size, relatively short study period and the fact that the study was conducted in a tertiary referral hospital. The prevalence of this entity may be more common at the level of primary health centres. Increasing the awareness of clinicians regarding the existence of this syndrome and its benign nature in children will limit unnecessary investigations. [Published with video sequences].

Aicardi syndrome: the importance of an ophthalmologist in its diagnosis.

Aicardi syndrome is a rare genetic disorder. The salient features of this syndrome include agenesis of corpus callosum, chorioretinal lacunae and infantile spasms. Of these three, chorioretinal lacunae is the most constant feature present. This case highlights the importance of fundus findings by an ophthalmologist in making the diagnosis of this rare syndrome.

Cerebellar migration defects in aicardi syndrome: an extension of the neuropathological spectrum.

The Aicardi syndrome is characterized by infantile spasms, corpus callosum agenesis, and chorioretinal lacunae and almost exclusively affects females (very rarely, 47, XXY males). The crucial genetic mishap likely occurs in the postzygotic stage, but the variable clinical phenotype among the approximately 450 known cases has not been explained. No consistent mutations or deletions exist among patients. We encountered a baby girl with early onset infantile spasms. She had left-sided cleft lip/palate, costovertebral defects, scoliosis, callosal agenesis, and microphthalmia. She expired at the age of 3 months of respiratory infection. On autopsy she had thoracic hemivertebrae with rib defects, bilateral microphthalmia, microcornea, posterior colobomata, abnormalities of the retinal pigment epithelium, absence of normal ganglion cells in the retina, gross asymmetry of the brain with cerebral polymicrogyria, total callosal agenesis, cerebral subcortical and subependymal nodular heterotopias, cerebellar nodular heterotopias, and tegmental/basal unilateral brainstem hypoplasia. Cerebellar and retinal migration defects have not been described before in Aicardi syndrome and may have had a bearing on this patient's eventual outcome.

Aicardi syndrome with favorable outcome: case report and review.

Aicardi syndrome is a congenital disorder characterized by severe psychomotor retardation, corpus callosum agenesis, chorioretinal lacunae, and early-onset infantile spasms. The prognosis is generally poor for children with the classical form. We report a peculiar case of Aicardi syndrome characterized by corpus callosum hypoplasia, brain malformations with subependymal heterotopias, extensive chorioretinal lacunae, seizures, and normal cognitive functions. Therefore, the clinical picture of the syndrome is broader than originally described. Cognitive disorders should not be considered inevitable and the prognosis not ineludibly poor.

Aicardi syndrome.

Aicardi syndrome (AS) is characterized by a triad of callosal agenesis, infantile spasms and chorioretinal 'lacunae'. It occurs only in individuals with two X chromosomes and is not familial. The outcome of AS is severe, with a high early mortality, considerable morbidity and a generally poor developmental outcome. However, the spectrum of AS seems broader than previously defined with a small proportion of the affected girls only moderately or mildly retarded. Several novel and important features should be added to the classic triad. The brain malformation is complex with cortical migration abnormalities, often cystic formations and sometimes choroid plexus papillomas; the eye anomalies, often feature a coloboma in addition to the lacunae, and focal seizures rather than spasms, are common. AS has been reported in 2 boys, both with an XXY complement, supporting the hypothesis of an X-linked gene lethal early in pregnancy for male conceptuses. A locus at Xp22.3 has been suggested but has not been confirmed. Treatment is only symptomatic.

Fetal stroke.

Fetal stroke, or that which occurs between 14 weeks of gestation and the onset of labor resulting in delivery, has been associated with postnatal epilepsy, mental retardation, and cerebral palsy. The entity is caused by antenatal ischemic, thrombotic, or hemorrhagic injury. We present seven new cases of fetal stroke diagnosed in utero and review the 47 cases reported in the literature. Although risk factors could not be assigned to 50% of the fetuses with stroke, the most common maternal conditions associated with fetal stroke were alloimmune thrombocytopenia and trauma. Magnetic resonance imaging was optimal for identifying fetal stroke, and prenatal imaging revealed hemorrhagic lesions in over 90% of studies; porencephalies were identified in just 13%. Seventy-eight percent of cases with reported outcome resulted in either death or adverse neurodevelopmental outcome at ages 3 months to 6 years. Fetal stroke appears to have different risk factors, clinical characteristics, and outcomes than other perinatal or childhood stroke syndromes. A better understanding of those risk factors predisposing a fetus to cerebral infarction may provide a basis for future therapeutic intervention trials. Ozduman K, Pober BR, Barnes P, Copel JA, Ogle EA, Duncan CC, Ment LR. Fetal stroke.

Magnetoencephalographic studies of two cases of diffuse subcortical laminar heterotopia or so-called double cortex.

Two cases (a young male and a girl, suffering intractable epilepsy) of diffuse subcortical laminar heterotopia, or so-called double cortex (DC) have been investigated using magnetoencephalography (MEG). MEG confirmed involvement of both cortices (hetero- and normocortex) in the genesis of interictal spikes, and, according to the heterogeneity of DC syndrome, some differences were observed: spike initiation in the normocortex and latter involvement of the heterotopic cortex in the man, and rather a cancellation in both cortices in the girl. In addition, participation of heterotopic cortex in physiological activities could be demonstrated in the man.

Long-term follow-up study of West syndrome: Differences of outcome among symptomatic etiologies.

OBJECTIVES: To evaluate the outcome of West syndrome and to elucidate the differences in the outcome related to the timing of brain injury. STUDY DESIGN: Medical records of 60 patients who were followed regularly for more than seven years were reviewed. The following clinical features were assessed: onset, seizure evolution, electroencephalography and intelligence. Those variables were compared among five groups: cryptogenic, prenatal, preterm, term, and postnatal groups. RESULTS: The onset ages of the postnatal group were later than those of the others (P<.05). The relapse after adrenocorticotropic hormone therapy of the preterm group was the earliest among the groups (P<.05). Regarding encelphalography, the ratio of patients with focal discharges was higher in the postnatal group than in the prenatal group (P<.05). The ratios of patients in whom focal epilepsy developed were higher in the term and postnatal group than in the cryptogenic and prenatal group (P<.05). The term group showed similar characteristics to those of the postnatal group. Seven of the 60 had normal intelligence, including three girls with tuberous sclerosis. CONCLUSION: The diverse outcomes of West syndrome depending on etiology seemed to be related to the timing of brain injury and brain development.

Agyria-pachygyria: clinical, neuroimaging, and neurophysiologic correlations.

Agyria-pachygyria complex is a disorder of neuronal migration and organization. Patients suffer either motor or intellectual retardation. We report our experiences of 10 patients with agyria-pachygyria complex and evaluate their clinical features, electroencephalography, and evoked potentials. Of nine electroencephalography examinations, five patients demonstrated characteristically high-amplitude fast activity. One of nine patients had an abnormal brainstem auditory-evoked potential. Three of seven patients had abnormal goggled visual-evoked potential. Six patients received somatosensory-evoked potential examinations, and five of these were abnormal, including four with prolonged central conduction times. Of the 10 patients, eight survived with variable intellectual and motor retardation; two died of sepsis. Patients with grades 1-4 agyria-pachygyria had high incidences of somatosensory-evoked potential abnormalities and also suffered worse neurologic outcomes. Normal brainstem auditory-evoked potential but abnormal cortical somatosensory-evoked potential components and prolonged central conduction time in these patients indicate that agyria-pachygyria is a supratentorial disease. We conclude that somatosensory-evoked potential examination is supplemental to neuroimaging in predicting the neurologic prognosis of patients with agyria-pachygyria.

Cortical dysplasia and epilepsy: functional imaging using single photon emission computed tomography and positron emission tomography.

Functional imaging using single photon emission CT and positron emission tomography have made important contributions to the evaluation of patients with medically intractable epilepsy and cortical dysplasia by identifying patients who previously were not considered surgical candidates. This article reviews the role of functional imaging in the presurgical evaluation of this patient population.

Positive epileptiform discharges in children with neuronal migration disorders.

Most epileptiform abnormalities show a negative polarity on EEG. Focal positive spike waves have rarely been identified in seizure disorders and are generally associated with physiological and neurological impairment. Results of EEG, computed tomography, MRI, and pathologic studies of 15 children with focal neuronal migration disorders who underwent surgery for refractory localization-related epilepsy were compared to examine the association between positive discharges and other findings. Subjects were studied both ictally and interictally by scalp EEG with the International 10-20 system and zygomatic or sphenoidal electrodes, and video EEG telemetry. The 5 children with positive discharges were significantly more likely to develop hemiparesis during the preoperative period (P < or = .025). Correlations were observed between positive discharges and lesions apparent on MRI situated around the rolandic fissure (P < or = .025). Children with positive discharges had a significantly less favorable outcome after surgical treatment (P < or = .025). Positive epilepti-form discharges in children with neuronal migration disorders may signal a more dysfunctional cortex leading to a focal neurological deficit or a more extended lesion than is detected on MRI. This would explain the less favorable outcome of seizures after surgery, since the epileptogenic areas and neuronal migration lesions cannot be completely resected.

Role of ocular involvement in the prediction of visual development and clinical prognosis in Aicardi syndrome.

AIMS/BACKGROUND: This study was undertaken to document visual function and acuity in patients with Aicardi syndrome, and to determine whether there is any relation between ocular features of the syndrome exhibited at birth and later visual function. METHODS: Fourteen patients with Aicardi syndrome, all examined and followed by the same ophthalmologist, were reviewed between 1975 and 1992 and their ocular characteristics and visual acuity described. It was hypothesised that larger lacunae may be associated with poorer clinical outcome and therefore the relation between these two variables was investigated. RESULTS: Visual acuity as documented by Snellen, Sheridan-Gardner, preferential looking, or pattern visual evoked potential tests was in the normal to low normal range in six eyes of four patients. Visual function correlated significantly with macular appearance. Good visual function was preserved if the fovea appeared normal on funduscopic examination and was uninvolved by lacunae. The size of the largest chorioretinal lacuna also correlated significantly with clinical outcome: patients with large lacunae were more likely to be immobile and to have no language skills. CONCLUSION: It was concluded that good visual function in patients with Aicardi syndrome may be anticipated if the fovea is normal. Although many patients have severe psychomotor retardation, the presence of predominantly small chorioretinal lacunae may indicate a better prognosis for mobility and language development.

Infantile spasms: an early epileptic manifestation in some patients with the congenital bilateral perisylvian syndrome.

We report four patients with infantile spasms and the congenital bilateral perisylvian syndrome. Onset of spasms occurred during the first 6 months of life. Response to corticotropin treatment was prompt and resulted in resolution of seizures in all patients. Epilepsy developed in the four children after an interval of 2 to 12 years. Developmental outcome was variable; three were severely restricted and one was married and lived independently. Imaging studies revealed bilateral perisylvian lesions characteristic of polymicrogyria. Infantile spasms may be the presenting seizure type in some patients with the congenital bilateral perisylvian syndrome.

Aicardi syndrome: more than meets the eye.

An eight-month-old girl with infantile spasms and apparent blindness had electroencephalographic findings compatible with Aicardi syndrome. In addition to optic nerve hypoplasia, there were multiple congenital retinal malformations in the right eye, including chorioretinal lacunae, anomalous retinal vessels, posterior scleral ectasia, and a peripheral fibrous ridge. Magnetic resonance imaging demonstrated agenesis of the corpus callosum, absence of the septum pellucidum, optic nerve and chiasmal hypoplasia, pachygyria, cortical heterotopias, colpocephaly, and hypoplasia of the cerebellar vermis. This patient illustrates the broad spectrum of cerebroretinal malformations now known to characterize Aicardi syndrome.