Assessment of glymphatic dysfunction in pediatric idiopathic intracranial hypertension: insights from quantitative diffusivity and perivascular spaces analysis-a case-control study.

Background: The impaired drainage of cerebrospinal fluid through the glymphatic system is thought to play a role in the idiopathic intracranial hypertension (IIH) pathophysiology. Limited data exist regarding the glymphatic system's involvement in pediatric patients with IIH. Therefore, the study's objective was to quantitatively evaluate alterations in parenchymal diffusivity and magnetic resonance imaging (MRI)-visible dilated perivascular spaces (PVS) as imaging indicators of glymphatic dysfunction in pediatric patients with IIH. Methods: Patients diagnosed with IIH in 2017-2022 in a single tertiary center (Sheba Medical Center, Israel) were retrospectively reviewed. Twenty-four pediatric patients were enrolled. All patients underwent clinical 3-T brain MRI. The control group included 24 age- and gender-matched healthy subjects with a normal-appearing brain on imaging. We used automatic atlas-based diffusion-weighted imaging analysis to determine regional diffusivity of the thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, and brain stem. PVS were evaluated using a semi-quantitative rating scale on T2-weighted images. Variables were compared using the Mann-Whitney test. Multivariate analysis of covariance was used to test for differences between controls and IIH patients. Results: No significant differences in regional brain diffusivity were observed between individuals with IIH and healthy controls (P=0.14-0.91 for various brain regions). The number of visible PVS was comparable between patients with IIH and the control group across all evaluated sites (P=0.12-0.74 for various brain regions). Conclusions: Pediatric IIH patients exhibited similar patterns of parenchymal diffusivity and PVS compared to age-matched controls. These findings do not support the hypothesis that the glymphatic system may play a role in the pathophysiology of pediatric IIH, although previously postulated. However, employing more sophisticated magnetic resonance (MR) techniques could enhance the sensitivity in uncovering underlying glymphatic dysfunction. Further research is warranted to validate and explore this association in larger cohorts and investigate the underlying mechanisms involved in IIH.

PRDM16 co-operates with LHX2 to shape the human brain.

PRDM16 is a dynamic transcriptional regulator of various stem cell niches, including adipocytic, hematopoietic, cardiac progenitors, and neural stem cells. PRDM16 has been suggested to contribute to 1p36 deletion syndrome, one of the most prevalent subtelomeric microdeletion syndromes. We report a patient with a de novo nonsense mutation in the PRDM16 coding sequence, accompanied by lissencephaly and microcephaly features. Human stem cells were genetically modified to mimic this mutation, generating cortical organoids that exhibited altered cell cycle dynamics. RNA sequencing of cortical organoids at day 32 unveiled changes in cell adhesion and WNT-signaling pathways. ChIP-seq of PRDM16 identified binding sites in postmortem human fetal cortex, indicating the conservation of PRDM16 binding to developmental genes in mice and humans, potentially at enhancer sites. A shared motif between PRDM16 and LHX2 was identified and further examined through comparison with LHX2 ChIP-seq data from mice. These results suggested a collaborative partnership between PRDM16 and LHX2 in regulating a common set of genes and pathways in cortical radial glia cells, possibly via their synergistic involvement in cortical development.

Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders.

PURPOSE: Missense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy with early-onset seizures and severe intellectual disability. METHODS: By international collaboration, we assembled individuals with pathogenic RHOBTB2 variants and a variable spectrum of neurodevelopmental disorders. By western blotting, we investigated the consequences of missense variants in vitro. RESULTS: In accordance with previous observations, de novo heterozygous missense variants in the BTB domain region led to a severe developmental and epileptic encephalopathy in 16 individuals. Now, we also identified de novo missense variants in the GTPase domain in 6 individuals with apparently more variable neurodevelopmental phenotypes with or without epilepsy. In contrast to variants in the BTB domain region, variants in the GTPase domain do not impair proteasomal degradation of RHOBTB2 in vitro, indicating different functional consequences. Furthermore, we observed biallelic splice-site and truncating variants in 9 families with variable neurodevelopmental phenotypes, indicating that complete loss of RHOBTB2 is pathogenic as well. CONCLUSION: By identifying genotype-phenotype correlations regarding location and consequences of de novo missense variants in RHOBTB2 and by identifying biallelic truncating variants, we further delineate and expand the molecular and clinical spectrum of RHOBTB2-related phenotypes, including both autosomal dominant and recessive neurodevelopmental disorders.

Scoliosis in RETT Syndrome: A National Referral Centre Experience.

STUDY DESIGN: This was a retrospective case series. OBJECTIVE: The objective of this study was to discuss the treatment challenges in scoliosis patients with Rett syndrome (RTT) in a national referral centre for RTT. We describe structural characteristics of curves, age of onset, genetic mutation, ambulation status, and treatment through RTT progression. Based on this unique experience, we aimed to suggest guidelines for scoliosis treatment in RTT patients. SUMMARY OF BACKGROUND DATA: RTT is a neurodevelopmental disorder associated with a mutation in the methyl-CpG binding protein 2 (MECP2) gene, primarily in females with significant features of growth failure, gastrointestinal and pulmonary dysfunction, ataxia, seizures, and intellectual disability. Scoliosis is the most common orthopedic manifestation of RTT and is present in 64%-75% of patients. No clear guidelines for scoliosis treatment in RTT are available, and typically patients are treated according to guidelines of another neuromuscular scoliosis. METHODS: Clinical and radiographic data were gathered, including MECP2 mutation type, scoliosis characteristics, preoperative treatment, surgical treatment, functional status, and postoperative follow-up. RESULTS: Our cohort included 102 patients with RTT. They were 36 who presented with scoliosis; 18 were treated surgically. C-curve was found in 17 patients and S-type in 19. Scoliosis treatment onset was 8.76 years in the C-type group and 13.88 years in the S-type group. The average curve at the time of surgery was 52.42 degrees. The average time until surgery was 2.44 years. Seventeen patients underwent posterior spinal fusion, and 1 patient underwent posterior spinal fusion+anterior spinal fusion with an average correction of 40 degrees. The most common mutation was R255X nucleotide (30% of cases). The most severe curves had mutations R168X and R270X nucleotides. CONCLUSIONS: We advise early monitoring for patients with RTT and scoliosis due to early and rapid progression. Common mutations found were R255X, R168X, R270X, and T158M. We recommend surgical treatment in every curve above 45 degrees, independently of age.

The Long-Term Effectiveness and Safety of Cannabidiol-Enriched Oil in Children With Drug-Resistant Epilepsy.

BACKGROUND: Several retrospective studies on pediatric epilepsy reported positive effects of cannabidiol-enriched artisanal cannabis oil and pure cannabidiol oil on seizure reduction. METHODS: This is a retrospective study of children and adolescents with refractory epilepsy caused by various etiologies who were treated with artisanal cannabis oil during January 2014 to June 2019, with at least one year follow-up. RESULTS: Of 114 patients, 84 (73.3%) reported some improvement in seizure frequency at some point during treatment. Fifty-one (59%) of the 86 patients who continued treatment for at least one year showed >50% improvement in seizure frequency. Seizure etiology, seizure type, and patients' age and sex were not found to be associated with the response to cannabidiol-enriched cannabis oil. Side effects were minor, and positive effects beyond seizure reduction were noted. CONCLUSIONS: Artisanal cannabidiol-enriched cannabis may be an effective and safe long-term treatment for refractory epilepsy.

Neurite density of white matter significantly correlates with tuberous sclerosis complex disease severity.

OBJECTIVE: To assess whether white matter (WM) diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) derived measures correlate with tuberous sclerosis complex (TSC) disease severity. COHORT AND METHODS: A multi-shell diffusion protocol was added to the clinical MRI brain scans of thirteen patients including 6 males and 7 females with a mean ± std age of 17.2 ± 5.8 years. Fractional anisotropy (FA) and mean diffusivity (MD) were generated from DTI and neurite density index (NDI), orientation dispersion index (ODI) and free water index (fiso) were generated from NODDI. A clinical score was determined for each patient according to the existence of epilepsy, developmental delay, autism or psychiatric disorders. Whole-brain segmented WM was averaged for each parametric map and 3 group k-means clustering was performed on the NDI and FA maps. MRI quantitative parameters were correlated with the clinical scores. RESULTS: Segmented whole brain WM averages of MD and NDI values showed significant negative (p = 0.0058) and positive (p = 0.0092) correlations with the clinical scores, respectively. Additionally, the contribution of the low and high NDI-based clusters to the whole brain WM significantly correlated with the clinical scores (p = 0.03 and p = 0.00047, respectively). No correlation was found when the clusters were based on the FA maps. CONCLUSION: Advanced diffusion MRI of TSC patients revealed widespread WM alterations. Neurite density showed significant correlations with disease severity and is therefore suggested to reflect an underlying biological process in TSC WM. The quantification of WM alterations by advanced diffusion MRI may be an additional biomarker for TSC and may be advantageous as a complementary MR protocol for the evaluation of TSC patients.

Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome.

Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.

Reduced Immunogenicity of Intraparenchymal Delivery of Adeno-Associated Virus Serotype 2 Vectors: Brief Overview.

Pre existing immunity to adeno-associated virus (AAV) poses a concern in AAV vector- mediated gene therapy. Localized administration of low doses of carefully chosen AAV serotypes can mitigate the risk of an immune response. This article will illustrate the low risk of immune response to AAV serotype 2 vector-mediated gene therapy to the brain with support from clinical trial data in aromatic L-amino acid decarboxylase deficiency and Parkinson disease.

Prediction of tuberous sclerosis-associated neurocognitive disorders and seizures via machine learning of structural magnetic resonance imaging.

PURPOSE: Tuberous sclerosis complex (TSC) is a genetic disorder characterized by multiorgan hamartomas, including cerebral lesions, with seizures as a common presentation. Most TSC patients will also experience neurocognitive comorbidities. Our objective was to use machine learning techniques incorporating clinical and imaging data to predict the occurrence of major neurocognitive disorders and seizures in TSC patients. METHODS: A cohort of TSC patients were enrolled in this retrospective study. Clinical data included genetic, demographic, and seizure characteristics. Imaging parameters included the number, characteristics, and location of cortical tubers and the presence of subependymal nodules, SEGAs, and cerebellar tubers. A random forest machine learning scheme was used to predict seizures and neurodevelopmental delay or intellectual developmental disability. Prediction ability was assessed by the area-under-the-curve of receiver-operating-characteristics (AUC-ROC) of ten-fold cross-validation training set and an independent validation set. RESULTS: The study population included 77 patients, 55% male (17.1 ± 11.7 years old). The model achieved AUC-ROC of 0.72 ± 0.1 and 0.68 in the training and internal validation datasets, respectively, for predicting neurocognitive comorbidity. Performance was limited in predicting seizures (AUC-ROC of 0.54 ± 0.19 and 0.71 in the training and internal validation datasets, respectively). The integration of seizure characteristics into the model improved the prediction of neurocognitive comorbidity with AUC-ROC of 0.84 ± 0.07 and 0.75 in the training and internal validation datasets, respectively. CONCLUSIONS: This proof of concept study shows that it is possible to achieve a reasonable prediction of major neurocognitive morbidity in TSC patients using structural brain imaging and machine learning techniques. These tools can help clinicians identify subgroups of TSC patients with an increased risk of developing neurocognitive comorbidities.

Dietary-Induced Ketogenesis: Adults Are Not Children.

There is increasing interest in the use of a ketogenic diet for various adult disorders; however, the ability of adults to generate ketones is unknown. Our goal was to challenge the hypothesis that there would be no difference between adults and children regarding their ability to enter ketosis. METHODS: Two populations were studied, both treated with identical very low-carbohydrate high-fat diets: a retrospective series of children with epilepsy or/and metabolic disorders (2009-2016) and a prospective clinical trial of adults with glioblastoma. Dietary intake was assessed based upon written food diaries and 24-h dietary recall. Ketogenic ratio was calculated according to [grams of fat consumed]/[grams of carbohydrate and protein consumed]. Ketone levels (ß-hydroxybutyrate) were measured in blood and/or urine. RESULTS: A total of 168 encounters amongst 28 individuals were analyzed. Amongst both children and adults, ketone levels correlated with nutritional ketogenic ratio; however, the absolute ketone levels in adults were approximately one quarter of those seen in children. This difference was highly significant in a multivariate linear regression model, p < 0.0001. CONCLUSIONS: For diets with comparable ketogenic ratios, adults have lower blood ketone levels than children; consequently, high levels of nutritional ketosis are unobtainable in adults.

An Israeli tuberous sclerosis cohort: the efficacy of different anti-epileptic strategies.

AIM: We aimed to describe the experience of a large single-center cohort for the clinical, radiological, and genetic characteristics, as well as to determine the efficacy of different anti-epileptic strategies in children and adults with tuberous sclerosis complex (TSC). METHODS: We carried out a historical cohort study on 91 TSC patients treated in a single center between 2008 and 2018. RESULTS: Our cohort comprised 46 males and 45 females, with a median age of 15.6 years at the last follow-up. Mean follow-up time was 2.5 ± 0.75-5.5 years (range 0-9.5 years). Of those tested, a disease-causing mutation was identified in 90% of patients, 53% in TSC2, and 37% in TSC1. Epilepsy prevalence was similar among TSC1 and TSC2 mutated patients. The most common radiological finding were cortical tubers in 95% of patients, while subependymal giant cell astrocytoma (SEGA) were detected in 36% of patients. Notably, infantile spasms (IS) were diagnosed in 29%, with SEGA representing the only finding significantly different in prevalence between those with and without IS (62% vs. 28%, respectively, p = 0.009). Lastly, we did not find any difference in efficacy between three anti-epileptic treatments: Vagus nerve stimulation (VNS), CBD-based products, and the ketogenic diet, all showing approximately 30%-40% response rates. SIGNIFICANCE: Altogether, we provide a comprehensive description of our experience in treating TSC, which could serve to expand current knowledge of the disease and its treatments.

Molecular characterization of a 1p36 chromosomal duplication and in utero interference define ENO1 as a candidate gene for polymicrogyria.

While chromosome 1p36 deletion syndrome is one of the most common terminal subtelomeric microdeletion syndrome, 1p36 microduplications are rare events. Polymicrogyria (PMG) is a brain malformation phenotype frequently present in patients with 1p36 monosomy. The gene whose haploinsufficiency could cause this phenotype remains to be identified. We used high-resolution arrayCGH in patients with various forms of PMG in order to identify chromosomal variants associated to the malformation and characterized the genes included in these regions in vitro and in vivo. We identified the smallest case of 1p36 duplication reported to date in a patient presenting intellectual disability, microcephaly, epilepsy, and perisylvian polymicrogyria. The duplicated segment is intrachromosomal, duplicated in mirror and contains two genes: enolase 1 (ENO1) and RERE, both disrupted by the rearrangement. Gene expression analysis performed using the patient cells revealed a reduced expression, mimicking haploinsufficiency. We performed in situ hybridization to describe the developmental expression profile of the two genes in mouse development. In addition, we used in utero electroporation of shRNAs to show that Eno1 inactivation in the rat causes a brain development defect. These experiments allowed us to define the ENO1 gene as the most likely candidate to contribute to the brain malformation phenotype of the studied patient and consequently a candidate to contribute to the malformations of the cerebral cortex observed in patients with 1p36 monosomy.

Loss of Protocadherin-12 Leads to Diencephalic-Mesencephalic Junction Dysplasia Syndrome.

OBJECTIVE: To identify causes of the autosomal-recessive malformation, diencephalic-mesencephalic junction dysplasia (DMJD) syndrome. METHODS: Eight families with DMJD were studied by whole-exome or targeted sequencing, with detailed clinical and radiological characterization. Patient-derived induced pluripotent stem cells were derived into neural precursor and endothelial cells to study gene expression. RESULTS: All patients showed biallelic mutations in the nonclustered protocadherin-12 (PCDH12) gene. The characteristic clinical presentation included progressive microcephaly, craniofacial dysmorphism, psychomotor disability, epilepsy, and axial hypotonia with variable appendicular spasticity. Brain imaging showed brainstem malformations and with frequent thinned corpus callosum with punctate brain calcifications, reflecting expression of PCDH12 in neural and endothelial cells. These cells showed lack of PCDH12 expression and impaired neurite outgrowth. INTERPRETATION: DMJD patients have biallelic mutations in PCDH12 and lack of protein expression. These patients present with characteristic microcephaly and abnormalities of white matter tracts. Such pathogenic variants predict a poor outcome as a result of brainstem malformation and evidence of white matter tract defects, and should be added to the phenotypic spectrum associated with PCDH12-related conditions. Ann Neurol 2018;84:646-655.

A novel inborn error of the coenzyme Q10 biosynthesis pathway: cerebellar ataxia and static encephalomyopathy due to COQ5 C-methyltransferase deficiency.

Primary coenzyme Q10 (CoQ10 ; MIM# 607426) deficiencies are an emerging group of inherited mitochondrial disorders with heterogonous clinical phenotypes. Over a dozen genes are involved in the biosynthesis of CoQ10 , and mutations in several of these are associated with human disease. However, mutations in COQ5 (MIM# 616359), catalyzing the only C-methylation in the CoQ10 synthetic pathway, have not been implicated in human disease. Here, we report three female siblings of Iraqi-Jewish descent, who had varying degrees of cerebellar ataxia, encephalopathy, generalized tonic-clonic seizures, and cognitive disability. Whole-exome and subsequent whole-genome sequencing identified biallelic duplications in the COQ5 gene, leading to reduced levels of CoQ10 in peripheral white blood cells of all affected individuals and reduced CoQ10 levels in the only muscle tissue available from one affected proband. CoQ10 supplementation led to clinical improvement and increased the concentrations of CoQ10 in blood. This is the first report of primary CoQ10 deficiency caused by loss of function of COQ5, with delineation of the clinical, laboratory, histological, and molecular features, and insights regarding targeted treatment with CoQ10 supplementation.

Neonatal nonepileptic myoclonus is a prominent clinical feature of KCNQ2 gain-of-function variants R201C and R201H.

OBJECTIVE: To analyze whether KCNQ2 R201C and R201H variants, which show atypical gain-of-function electrophysiologic properties in vitro, have a distinct clinical presentation and outcome. METHODS: Ten children with heterozygous, de novo KCNQ2 R201C or R201H variants were identified worldwide, using an institutional review board (IRB)-approved KCNQ2 patient registry and database. We reviewed medical records and, where possible, interviewed parents and treating physicians using a structured, detailed phenotype inventory focusing on the neonatal presentation and subsequent course. RESULTS: Nine patients had encephalopathy from birth and presented with prominent startle-like myoclonus, which could be triggered by sound or touch. In seven patients, electroencephalography (EEG) was performed in the neonatal period and showed a burst-suppression pattern. However, myoclonus did not have an EEG correlate. In many patients the paroxysmal movements were misdiagnosed as seizures. Seven patients developed epileptic spasms in infancy. In all patients, EEG showed a slow background and multifocal epileptiform discharges later in life. Other prominent features included respiratory dysfunction (perinatal respiratory failure and/or chronic hypoventilation), hypomyelination, reduced brain volume, and profound developmental delay. One patient had a later onset, and sequencing indicated that a low abundance (~20%) R201C variant had arisen by postzygotic mosaicism. SIGNIFICANCE: Heterozygous KCNQ2 R201C and R201H gain-of-function variants present with profound neonatal encephalopathy in the absence of neonatal seizures. Neonates present with nonepileptic myoclonus that is often misdiagnosed and treated as seizures. Prognosis is poor. This clinical presentation is distinct from the phenotype associated with loss-of-function variants, supporting the value of in vitro functional screening. These findings suggest that gain-of-function and loss-of-function variants need different targeted therapeutic approaches.

Liver Disease in Pediatric Patients With Ataxia Telangiectasia: A Novel Report.

OBJECTIVE: Ataxia telangiectasia (A-T) is a rare genetic multiorgan disease. Although gastrointestinal involvement is known, hepatic involvement in A-T has not been investigated. We aimed to study the hepatic involvement in a large cohort of patients with A-T. METHODS: A retrospective review of patients, studied from January 1986 to January 2015 at a National A-T Center. Clinical data including demographic, genetic, laboratory, nutritional, radiographic, and histological data were retrieved. RESULTS: Fifty-three patients, 27 (49%) boys, age 14.6 ±â€Š5.2 years (range 5.9-26.1 years), were included. Twenty-three patients (43.4%), age 9.9 ±â€Š5.1 years, had consistently abnormal liver enzymes. The mean enzyme levels were alanine aminotransferase 76.8 ±â€Š73.8 IU/L, aspartate aminotransferase 70 ±â€Š50 IU/L, alkaline phosphatase 331 ±â€Š134 IU/L, and gamma glutamyl transferase 114.7 ±â€Š8 IU/L. Evaluation of other etiology of liver disease was negative. Ultrasonography revealed fatty liver in 9 of them (39%). Liver biopsy was performed in 2 patients, revealing mild-to-moderate steatosis in both, and fibrosis in 1 patient. Progression to advanced liver disease occurred in 2 of 23 (9%) patients within 2 to 5 years. Dyslipidemia was significantly associated with abnormal liver enzymes: 3 of 30 (10%) patients without abnormal liver enzymes versus 10 of 23 (45.5%) patients with abnormal liver enzymes, respectively (P < 0.05, Fisher exact test). No correlation was found between hepatic involvement and HbA1C, sex, presence of malignancy, or type of mutation. CONCLUSIONS: Abnormal liver enzymes and fatty liver are common in patients with A-T and may progress to advanced liver disease at a young age. These findings are novel and implicate that patients with A-T with abnormal liver enzymes should be evaluated for the presence of liver disease.

Ataxia telangiectasia.

Ataxia telangiectasia (AT) is an autosomal recessive multisystem genetic disorder caused by a mutation in the ATM gene encoding for the ATM protein. AT systemic manifestations include cutaneous telangiectasias, radiosensitivity, immune deficiency with recurrent sinopulmonary infections, and a tendency to develop lymphoid malignancies. These complications are explained by the major role played by ATM in DNA repair. AT is also the second most common childhood onset neurodegenerative disorder of the cerebellum, presenting with progressive ataxia and oculomotor apraxia and often accompanied by extrapyramidal movement disorders. Ataxia typically begins around the time children start to walk at about 1 year of age and leads to wheelchair dependence by the second decade of life. Cerebellar atrophy is evident on imaging after 2 years of life and is progressive. Abnormal DNA repair mechanisms do not entirely explain the pathophysiology in nondividing neurons. The nervous system involvement is better explained by the role ATM plays in antioxidative defense, mitochondrial homeostasis, and DNA chromatin packing. A better understanding of the underlying pathophysiologic mechanisms of this devastating disease may enable disease-modifying treatments in the future. Meanwhile, treatment is mainly supportive and does not change the poor prognosis of the disease although it improves the patient's quality of life.

Phenotypic spectrum and prevalence of INPP5E mutations in Joubert syndrome and related disorders.

Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain-hindbrain malformation known as the 'molar tooth sign'. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS fetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus.

A forgotten alternative: Bromides for refractory status epilepticus.

We present the cases of a 1-month-old infant diagnosed as having malignant migrating partial epilepsy of infancy and a 2-month-old infant with Ohtahara syndrome, who both presented with severe refractory status epilepticus and were treated with potassium bromide when all other antiepileptic drugs failed. Appropriate augmentation of the dosage of potassium bromide led to reduction in the frequency and duration of seizures in both patients. There was a notable reduction in the occurrence of epileptic seizures in both cases, with no apparent side effects. Potassium bromide was of significant benefit for seizure reduction in two infants with intractable seizures. It could be used safely and within a short period. Potassium bromide should be considered as a relatively safe therapeutic option for infants and children with severe intractable seizures when other antiepileptic drugs fail to control the seizures.

The Israeli retrospective multicenter open-label study evaluating vagus nerve stimulation efficacy in children and adults.

BACKGROUND: The management of intractable epilepsy in children and adults is challenging. For patients who do not respond to anti-epileptic drugs and are not suitable candidates for epilepsy surgery, vagal nerve stimulation (VNS) is a viable alternative for reducing seizure frequency. METHODS: In this retrospective multicenter open-label study we examined the efficacy and tolerability of VNS in patients in five adult and pediatric epilepsy centers in Israel. All patients had drug-resistant epilepsy and after VNS implantation in 2006-2007 were followed for a minimum of 18 months. Patients were divided into two age groups: < 21 and > 21 years old. RESULTS: Fifty-six adults and children had a stimulator implanted in 2006-2007. At 18 months post-VNS implantation, none of the patients was seizure-free, 24.3% reported a reduction in seizures of > or = 75%, 19% reported a 50-75% reduction, and 10.8% a 25-50% reduction. The best response rate occurred in patients with complex partial seizures. Among these patients, 7 reported a > or = 75% reduction, 5 patients a 50-75% reduction, 3 patients a 25-50% reduction, and 8 patients a < 25% reduction. A comparison of the two age groups showed that the older group (< 21 years old) had fewer seizures than the younger group. CONCLUSIONS: VNS is a relatively effective and safe palliative method for treating refractory epilepsy in both adults and children. It is an alternative treatment for patients with drug-resistant epilepsy, even after a relatively long disease duration, who are not candidates for localized epilepsy surgery.