Dean Sarco

Deletions of NRXN1 (Neurexin-1) Predispose to a Wide Spectrum of Developmental Disorders

Research has implicated mutations in the gene for neurexin‐1 (NRXN1) in a variety of conditions including autism, schizophrenia, and nicotine dependence. To our knowledge, there have been no published reports describing the breadth of the phenotype associated with mutations in NRXN1. We present a medical record review of subjects with deletions involving exonic sequences of NRXN1. We ascertained cases from 3,540 individuals referred clinically for comparative genomic hybridization testing from March 2007 to January 2009. Twelve subjects were identified with exonic deletions. The phenotype of individuals with NRXN1 deletion is variable and includes autism spectrum disorders, mental retardation, language delays, and hypotonia. There was a statistically significant increase in NRXN1 deletion in our clinical sample compared to control populations described in the literature (P = 8.9 × 10−7). Three additional subjects with NRXN1 deletions and autism were identified through the Homozygosity Mapping Collaborative for Autism, and this deletion segregated with the phenotype. Our study indicates that deletions of NRXN1 predispose to a wide spectrum of developmental disorders.

AHI1 gene mutations cause specific forms of Joubert syndrome–related disorders

Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. It is characterized by hypoplasia of the cerebellar vermis and a particular midbrain‐hindbrain “molar tooth” sign, a finding shared by a group of Joubert syndrome–related disorders (JSRDs), with wide phenotypic variability. The frequency of mutations in the first positionally cloned gene, AHI1, is unknown.

Copy number variation plays an important role in clinical epilepsy

To evaluate the role of copy number abnormalities detectable using chromosomal microarray (CMA) testing in patients with epilepsy at a tertiary care center.

Angelman Syndrome: Mutations Influence Features in Early Childhood

Angelman syndrome (AS) is a neurodevelopmental disorder caused by a lack of expression of the maternal copy of UBE3A. Although the “classic” features of AS are well described, few large‐scale studies have delineated the clinical features in AS. We present baseline data from 92 children with a molecular diagnosis of AS between 5 and 60 months old who are enrolled in the National Institutes of Health Rare Diseases Clinical Research Network Angelman Syndrome Natural History Study from January 2006 to March 2008. Seventy‐four percent of participants had deletions, 14% had either uniparental disomy (UPD) or imprinting defects, and 12% had UBE3A mutations. Participants with UPD/imprinting defects were heavier (P = 0.0002), while those with deletions were lighter, than the general population (P < 0.0001). Twenty out of 92 participants were underweight, all of whom had deletions or UBE3A mutations. Eight out of 92 participants (6/13 (46%) with UPD/imprinting defects and 2/11 (18%) with UBE3A mutations) were obese. Seventy‐four out of 92 participants (80%) had absolute or relative microcephaly. No participant was macrocephalic. The most common behavioral findings were mouthing behavior (95%), short attention span (92%), ataxic or broad‐based gait (88%), history of sleep difficulties (80%), and fascination with water (75%). Frequent, easily provoked laughter was observed in 60%. Clinical seizures were reported in 65% of participants but all electroencephalograms (EEGs) were abnormal. We conclude that the most characteristic feature of AS is the neurobehavioral phenotype, but specific EEG findings are highly sensitive for AS. Obesity is common among those with UPD/imprinting defects.

Analysis of EEG patterns and genotypes in patients with Angelman syndrome

We prospectively analyzed EEGs from participants in the ongoing NIH Rare Diseases Clinical Research Network Angelman Syndrome Natural History Study. Of the one-hundred-sixty enrolled patients (2006-2010), 115 had complete data (58 boys, median age 3.6 years). Distinct EEG findings were intermittent rhythmic delta waves (83.5%), interictal epileptiform discharges (74.2%), intermittent rhythmic theta waves (43.5%), and posterior rhythm slowing (43.5%). Centro-occipital and centro-temporal delta waves decreased with age (p=0.01, p=0.03). There were no specific correlations between EEG patterns and genotypes. A classification tree allowed the prediction of deletions class-1 (5.9 Mb) in patients with intermittent theta waves in <50% of EEG and interictal epileptiform abnormalities; UPD, UBE3A mutation or imprinting defects in patients with intermittent theta in <50% of EEG without interictal epileptiform abnormalities; deletions class-2 (5.0 Mb) in patients with >50% theta and normal posterior rhythm; atypical deletions in patients with >50% theta but abnormal posterior rhythm. EEG patterns are important biomarkers in Angelman syndrome and may suggest the underlying genetic etiology.

A Therapeutic Trial of Pro-methylation Dietary Supplements in Angelman Syndrome

Angelman syndrome (AS) is due to deficient ubiquitin protein ligase 3a, the gene for which (UBE3A) maps to chromosome 15q11–q13 and is imprinted such that only the maternally inherited gene is expressed. The paternally inherited UBE3A gene is silenced, a process mediated by an antisense transcript. We conducted a trial using methylation‐promoting dietary supplements (betaine, metafolin, creatine, and vitamin B12) in an attempt to reduce antisense transcript production, increase UBE3A expression, and ameliorate the symptoms of AS. Neuropsychological evaluations, biochemical testing, and assessment of DNA methylation were performed at the beginning and at the end of 1 year of supplementation. The primary outcome measures were changes in the level of developmental function (cognitive, motor, and language) as measured using standardized instruments. The secondary outcomes measures were changes in biochemical parameters and global DNA methylation. These data were compared to those of a control group from a previous randomized double‐blind trial using folic acid and betaine. There were no statistically significant changes in the developmental performance of children treated with supplements. There were no unexpected changes in biochemical parameters and no change in site‐specific DNA methylation when comparing samples from before and after treatment. There were 10 adverse events that resulted in study withdrawal of 7 participants (worsening of seizures, onset, or worsening of sleep problems, constipation, and anorexia). Supplementation with betaine, metafolin, creatine, and vitamin B12 appears safe but ineffective in decreasing the severity of AS.

Benign rolandic epileptiform discharges are associated with mood and behavior problems.

Children with benign rolandic epilepsy (BRE) experience elevated rates of cognitive, behavioral, and affective problems. Frequent epileptiform spike discharges may impair behavioral functioning. To elucidate this relationship, we evaluated associations between the EEG spike frequency index (SI) and parental ratings of psychosocial adjustment and executive functioning in school-aged children with EEGs typical of BRE. Twenty-one children (6-12 years) participated. Parents completed validated questionnaires at a median of 5 months (range: 1-8) after a routine outpatient EEG. The EEG SI was calculated for wakefulness and sleep. The strength of association between the SI and behavioral variables was evaluated by simple and multivariate correlation. Higher awake and sleep SIs were associated with more symptoms of depression (P<0.001), aggression and conduct problems (P<0.01). Higher sleep SI was associated with executive dysfunction and anxiety (P<0.05). Symptoms of hyperactivity and inattention had no correlation. Increased epileptiform activity in children with BRE may predict higher rates of mood and behavioral problems.

Yield of Emergent Neuroimaging Among Children Presenting With a First Complex Febrile Seizure

Objectives The objective of this study was to assess the risk of intracranial pathology requiring immediate intervention among children presenting with their first complex febrile seizure (CFS). Design/Methods This is a retrospective cohort review of patients 6 to 60 months of age evaluated in a pediatric emergency department between 1995 and 2008 for their first CFS. Cases were identified using computerized text search followed by manual chart review. We excluded patients with a prior history of a nonfebrile seizure disorder or a prior CFS, an immune-compromised state, an underlying illness associated with seizures or altered mental status, or trauma. Data extraction included age, sex, seizure features, prior simple febrile seizures, temperature, family history of seizures, vaccination status, findings on physical examination, laboratory and imaging studies, diagnosis, and disposition. Results We identified a first CFS in 526 patients. Two hundred sixty-eight patients (50.4%) had emergent head imaging: 4 patients had a clinically significant finding: 2 had intracranial hemorrhage, 1 had acute disseminated encephalomyelitis, and 1 patient had focal cerebral edema (1.5%; 95% confidence interval, 0.5%–4.0%). Assigning low risk to patients not imaged and not returning to the emergency department within a week of the original visit, the risk of intracranial pathology in our sample was 4 (0.8%; 95% confidence interval, 0.2%–2.1%) of 526. Three of these 4 patients had other obvious findings (nystagmus, emesis, and altered mental status; persistent hemiparesis; bruises suggestive of inflicted injury). Conclusions Very few patients with CFSs have intracranial pathology in the absence of other signs or symptoms. Patients presenting with more than one seizure in 24 hours in particular are at very low risk.

Electroencephalography in epilepsy surgery planning

ObjectiveTo describe localizing value of surface EEG recording in the presurgical evaluation of medically intractable pediatric epilepsy patients.MethodsWe review the relevant concepts required for understanding the role of surface EEG in the presurgical evaluation and in identifying the epileptogenic zone. The unique features of EEG and its limitations are discussed.ConclusionDespite recent technological advancements, surface EEG continues to play a crucial role in defining the epileptogenic zone, and thus in presurgical planning.

Septo‐Optic Dysplasia Complicated by Infantile Spasms and Bilateral Choroidal Fissure Arachnoid Cysts

Septo‐optic dysplasia (SOD) is the triad of optic nerve hypoplasia, panhypopituitarism, and agenesis of septum pellucidum, and has been described previously to be associated with heterotopias and midline interhemispheric cyst. We describe a case of SOD with arachnoid cysts, persistent primary hyperplastic vitreous, and malformations of cortical development.