Efficacy, safety, and tolerability of soticlestat as adjunctive therapy for the treatment of seizures in patients with Dup15q syndrome or CDKL5 deficiency disorder in an open-label signal-finding phase II study (ARCADE).

OBJECTIVE: Chromosome 15q duplication (Dup15q) syndrome and cyclin­dependent kinase-like 5 deficiency disorder (CDD) are rare neurodevelopmental disorders associated with epileptic encephalopathies, with a lack of specifically approved treatment options. ARCADE assessed the efficacy and safety of adjunctive soticlestat (TAK-935) for the treatment of seizures in patients with Dup15q syndrome or CDD (NCT03694275). METHODS: ARCADE was a phase II, open-label, pilot study of soticlestat (≤300 mg/day twice daily, weight-adjusted) in pediatric and adult patients 2-55 years of age with Dup15q syndrome or CDD who experienced ≥3 motor seizures per month in the 3 months before screening and at baseline. The 20-week treatment period consisted of a dose-optimization period and a 12-week maintenance period. Efficacy endpoints included the change from baseline in motor seizure frequency during the maintenance period and the proportion of treatment responders. Safety endpoints included the incidence of treatment-emergent adverse effects (TEAEs). RESULTS: The modified-intent-to-treat population included 20 participants who received ≥1 dose of soticlestat and had ≥1 efficacy assessment (Dup15q syndrome, n = 8; CDD, n = 12). Soticlestat administration during the maintenance period was associated with a median change from baseline in motor seizure frequency of +11.7% in the Dup15q syndrome group and -23.6% in the CDD group. Reductions in all seizure frequency of -23.4% and -30.5% were also observed during the maintenance period in the Dup15q syndrome group and the CDD group, respectively. Most TEAEs were of mild or moderate severity. Serious TEAEs were reported by three patients (15.0%); none were considered drug related. The most common TEAEs were constipation, rash, and seizure. No deaths were reported. CONCLUSIONS: Adjunctive soticlestat treatment was associated with a decrease in motor seizure frequency from baseline in patients with CDD and a decrease in all seizure frequency in both patient groups. Soticlestat treatment was associated with an increase in motor seizure frequency in patients with Dup15q syndrome.

Angelman syndrome genotypes manifest varying degrees of clinical severity and developmental impairment.

Angelman Syndrome (AS) is a severe neurodevelopmental disorder due to impaired expression of UBE3A in neurons. There are several genetic mechanisms that impair UBE3A expression, but they differ in how neighboring genes on chromosome 15 at 15q11-q13 are affected. There is evidence that different genetic subtypes present with different clinical severity, but a systematic quantitative investigation is lacking. Here we analyze natural history data on a large sample of individuals with AS (n = 250, 848 assessments), including clinical scales that quantify development of motor, cognitive, and language skills (Bayley Scales of Infant Development, Third Edition; Preschool Language Scale, Fourth Edition), adaptive behavior (Vineland Adaptive Behavioral Scales, Second Edition), and AS-specific symptoms (AS Clinical Severity Scale). We found that clinical severity, as captured by these scales, differs between genetic subtypes: individuals with UBE3A pathogenic variants and imprinting defects (IPD) are less affected than individuals with uniparental paternal disomy (UPD); of those with UBE3A pathogenic variants, individuals with truncating mutations are more impaired than those with missense mutations. Individuals with a deletion that encompasses UBE3A and other genes are most impaired, but in contrast to previous work, we found little evidence for an influence of deletion length (class I vs. II) on severity of manifestations. The results of this systematic analysis highlight the relevance of genomic regions beyond UBE3A as contributing factors in the AS phenotype, and provide important information for the development of new therapies for AS. More generally, this work exemplifies how increasing genetic irregularities are reflected in clinical severity.

Clinical report and biochemical analysis of a patient with fumarate hydratase deficiency.

Fumarate hydratase deficiency (FHD) is a rare metabolic disease caused by two defective copies of the FH gene, which encodes the Krebs cycle enzyme fumarase. FHD is associated with brain and developmental abnormalities, seizures, and high childhood mortality. We describe the symptoms and treatment of a patient with FHD. While infantile spasms are common in FHD, the patient presented with epileptic spasms later in childhood. Also unexpectedly, the patient responded excellently to lacosamide for her non-convulsive status epilepticus and epileptic spasms after three first-line medication trials failed. We biochemically analyzed the patient's two fumarase variants (E432Kfs*17 and D65G). While E432Kfs*17 was extremely enzymatically defective, D65G exhibited only a mild defect, possibly playing a role in the patient's longer survival.

Behavioral characterization of dup15q syndrome: Toward meaningful endpoints for clinical trials.

Duplication of 15q11.2-q13.1 (dup15q syndrome) is one of the most common copy number variations associated with autism spectrum disorders (ASD) and intellectual disability (ID). As with many neurogenetic conditions, accurate behavioral assessment is challenging due to the level of impairment and heterogeneity across individuals. Large-scale phenotyping studies are necessary to inform future clinical trials in this and similar ID syndromes. This study assessed developmental and behavioral characteristics in a large cohort of children with dup15q syndrome, and examined differences based on genetic subtype and epilepsy status. Participants included 62 children (2.5-18 years). Across individuals, there was a wide range of abilities. Although adaptive behavior was strongly associated with cognitive ability, adaptive abilities were higher than cognitive scores. Measures of ASD symptoms were associated with cognitive ability, while parent report of challenging behavior was not. Both genetic subtype and epilepsy were related to degree of impairment across cognitive, language, motor, and adaptive domains. Children with isodicentric duplications and epilepsy showed the greatest impairment, while children with interstitial duplications showed the least. On average, participants with epilepsy experienced seizures over 53% of their lives, and half of children with epilepsy had infantile spasms. Parents of children with isodicentric duplications reported more concerns regarding challenging behaviors. Future trials in ID syndromes should employ a flexible set of assessments, allowing each participant to receive assessments that capture their skills. Multiple sources of information should be considered, and the impact of language and cognitive ability should be taken into consideration when interpreting results.

Diagnosis and management in Pitt-Hopkins syndrome: First international consensus statement.

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder characterized by intellectual disability, specific facial features, and marked autonomic nervous system dysfunction, especially with disturbances of regulating respiration and intestinal mobility. It is caused by variants in the transcription factor TCF4. Heterogeneity in the clinical and molecular diagnostic criteria and care practices has prompted a group of international experts to establish guidelines for diagnostics and care. For issues, for which there was limited information available in international literature, we collaborated with national support groups and the participants of a syndrome specific international conference to obtain further information. Here, we discuss the resultant consensus, including the clinical definition of PTHS and a molecular diagnostic pathway. Recommendations for managing particular health problems such as dysregulated respiration are provided. We emphasize the need for integration of care for physical and behavioral issues. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimization of diagnostics and care.

Angelman syndrome in adolescence and adulthood: A retrospective chart review of 53 cases.

Angelman syndrome is a neurogenetic disorder with varying clinical presentations and symptoms as the individual ages. The goal of this study was to characterize changes over time in the natural history of this syndrome in a large population. We reviewed the medical records of the 53 patients who were born prior to 2000 and seen at the Angelman Syndrome Clinic at Massachusetts General Hospital to assess neurological, sleep, behavioral, gastrointestinal, orthopedic, and ophthalmologic functioning. The average age of this cohort was 24 years. Active seizures were present in 35%, nonepileptic myoclonus in 42%, and clinically significant tremors in 55%. Anxiety was present in 57%, increasing to 71% in those ages 26-43 years. In terms of sleep, 56% reported 8 hr of sleep or more, although 43% reported frequent nocturnal awakenings. Gastrointestinal issues remain problematic with 81% having constipation and 53% gastroesophageal reflux. The majority lived in a parent's home and remained independently mobile, though scoliosis was reportedly present in 30%, and 20% had reported low bone density/osteoporosis. The results of this study suggest that the prevalence of active seizures may decrease in adulthood but that the prevalence of movement disorders such as tremor and nonepileptic myoclonus may increase. Anxiety increases significantly as individuals age while defiant behaviors appear to decrease. Sleep dysfunction typically improves as compared to childhood but remains a significant issue for many adults. Other areas that require monitoring into adulthood include gastrointestinal dysfunction, and orthopedic/mobility issues, such as reported scoliosis and bone density, and ophthalmologic disorders.

Diazepam for outpatient treatment of nonconvulsive status epilepticus in pediatric patients with Angelman syndrome.

Nonconvulsive status epilepticus (NCSE) is present in multiple pediatric neurogenetic syndromes with epileptic encephalopathies. While intravenous (IV) medications are used inpatient for treatment of critical illness-related NCSE, there is no consensus on treatment of ambulatory NCSE. Up to 50% of patients with Angelman syndrome (AS) have NCSE with myoclonic or atypical absence status. Here we report our experience in pediatric patients with AS and NCSE treated outpatient with a tapering course of oral diazepam. We conducted a chart review of 104 patients seen in the Angelman Syndrome Clinic at Massachusetts General Hospital from January 2008 to March 2017, who met the criteria. Response to treatment was defined as cessation of NCSE symptoms with electroencephalogram (EEG) confirmation when possible. Twenty-one patients with NCSE were identified, and 13 patients (9 male) with 25 episodes of NCSE were included. Mean age at NCSE episode was 5years 4months (15months-12years). Six patients had one episode of NCSE, and 7 patients had recurrent episodes (mean: 2.7; range: 2-4). Median diazepam treatment was 6days (4-12days), with a mean dose of 0.32mg/kg/day divided over 2-3 administrations, decreased every 2days. Nine episodes required multiple courses; however, oral diazepam alone was ultimately successful in 80% (20/25) of NCSE episodes. Oral diazepam was well-tolerated with no major side effects. A short course of oral diazepam is well-tolerated and effective in patients with AS who have ambulatory NCSE. It may be considered prior to escalating to inpatient care in AS and possibly other epilepsy syndromes.

Myoclonus in Angelman syndrome.

Angelman syndrome (AS) is a neurogenetic imprinting disorder caused by loss of the maternally inherited Ube3a gene and is characterized by generalized epilepsy, limited expressive speech, sleep dysfunction, and movement disorders. Myoclonic seizures are often the first seizure type to appear, and myoclonic status, associated with developmental regression, may occur in the first few years of life. Additionally, there have been rare reports of prolonged episodes of myoclonus without electrographic correlate in adults with AS. The medical records of 200 individuals seen in the Angelman Syndrome Clinic at the Massachusetts General Hospital and the Lurie Center for Autism were retrospectively reviewed to identify and characterize myoclonic seizures and episodes of nonepileptic myoclonus. Myoclonic seizures were reported in 14% of individuals with age of onset occurring before 8years. These are brief events, unless the individual was experiencing myoclonic status, and electroencephalographs show interictal generalized spike and wave activity. Nonepileptic myoclonus occurred in 40% of individuals over 10years of age, and prevalence appears to increase with age. The episodes of nonepileptic myoclonus arise during puberty or later, with age of onset ranging from 10 to 26years. These events were captured on 5 video electroencephalographs and had no electrographic correlate. They can last from seconds to hours, always occurring in the hands and spreading to the face and all extremities in some individuals. Episodes of nonepileptic myoclonus have a discrete beginning and end, lacks a postictal period, and are not associated with significant alteration of consciousness or developmental regression. These episodes can be difficult to treat and are often refractory to medication; however, levetiracetam, clobazam, and clonazepam appear to be effective for some individuals. Myoclonic seizures are common in AS, typically occurring in young children and associated with epileptiform changes on electroencephalographs. Prolonged episodes are associated with developmental regression. In contrast, nonepileptic myoclonus typically begins in adolescence or early adulthood and has no electroencephalogram (EEG) correlate, alteration in consciousness, or regression but can significantly impact quality of life.

Prevalence of gastrointestinal symptoms in Angelman syndrome.

Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability, expressive speech impairment, movement disorder, epilepsy, and a happy demeanor. Children with AS are frequently reported to be poor feeders during infancy and as having gastrointestinal issues such as constipation, reflux, and abnormal food related behaviors throughout their lifetime. To assess the prevalence of gastrointestinal disorders in individuals with AS, we retrospectively analyzed medical records of 120 individuals seen at the Angelman Syndrome Clinic at Massachusetts General Hospital and 43 individuals seen at the University of North Carolina Comprehensive Angelman Clinic. The majority of patients' medical records indicated at least one symptom of gastrointestinal dysfunction, with constipation and gastroesophageal reflux disease (GERD) the most common. Other gastrointestinal issues reported were cyclic vomiting episodes, difficulty swallowing, excessive swallowing, and eosinophilic esophagitis. Upper gastrointestinal symptoms such as GERD, swallowing difficulties, cyclic vomiting, and eosinophilic esophagitis were more common in those with deletions and uniparental disomy, likely related to the involvement of multiple genes and subsequent hypotonia. The frequency of constipation is consistent among all genetic subtypes while early feeding issues appear to mainly affect those with deletions. Caregivers and healthcare providers should be aware of the high prevalence of these issues, as proper treatment may improve not only gastrointestinal dysfunction but also sleep and behavioral issues.

Low glycemic index treatment for seizure control in Angelman syndrome: A case series from the Center for Dietary Therapy of Epilepsy at the Massachusetts General Hospital.

The low glycemic index treatment, a dietary therapy that focuses on glycemic index and reduced carbohydrate intake, has been successful in reducing seizure frequency in the general epilepsy population. Epilepsy is a common feature of Angelman syndrome and seizures are often refractory to multiple medications, especially in those with maternal deletions. Dietary therapy has become a more frequently used option for treating epilepsy, often in combination with other antiepileptic drugs, due to its efficacy and favorable side effect profile. This study aimed to assess the effectiveness of the low glycemic index treatment for seizure control in Angelman syndrome. Through a retrospective medical record review of 23 subjects who utilized the low glycemic index treatment at the Clinic and Center for Dietary Therapy of Epilepsy at the Massachusetts General Hospital, we found that the high level of seizure control and favorable side effect profile make the low glycemic index treatment a viable treatment for seizures in Angelman syndrome. The majority of subjects in our cohort experienced some level of seizure reduction after initiating the diet, 5 (22%) maintained complete seizure freedom, 10 (43%) maintained seizure freedom except in the setting of illness or non-convulsive status epilepticus, 7 (30%) had a decrease in seizure frequency, and only 1 (4%) did not have enough information to determine seizure control post-initiation. The low glycemic index treatment monotherapy was successful for some subjects in our cohort but most subjects used an antiepileptic drug concurrently. Some subjects were able to maintain the same level of seizure control on a liberalized version of the low glycemic index treatment which included a larger amount of low glycemic carbohydrates. No correlation between the level of carbohydrate restriction and level of seizure control was found. Few subjects experienced side effects and those that did found them to be mild and easily treated. The efficacy of the low glycemic index treatment and its favorable side effect profile make it an excellent alternative or supplement to antiepileptic drug therapy for the treatment of seizures in Angelman syndrome.

Seizure treatment in Angelman syndrome: A case series from the Angelman Syndrome Clinic at Massachusetts General Hospital.

Epilepsy is a common feature of Angelman syndrome (~80-90%), with the most common seizure types including myoclonic, atonic, atypical absence, focal, and generalized tonic-clonic. Seizure types are similar among the various genetic subtypes, but epilepsy in those with maternal deletions is more frequent and more refractory to medication. Treatment with older antiepileptic drugs such as valproic acid and clonazepam is effective, but these medications tend to have less favorable side effect profiles in Angelman syndrome compared with those in newer medications. This study aimed to assess the use of newer antiepileptic drug therapies in individuals with Angelman syndrome followed at the Angelman Syndrome Clinic at the Massachusetts General Hospital. Many of the subjects in this study were on valproic acid therapy prior to their initial evaluation and exhibited increased tremor, decreased balance, and/or regression of motor skills, which resolved after tapering off of this medication. Newer antiepileptic drugs such as levetiracetam, lamotrigine, and clobazam, and to a lesser extent topiramate, appeared to be as effective - if not more so - as valproic acid and clonazepam while offering more favorable side effect profiles. The low glycemic index treatment also provided effective seizure control with minimal side effects. The majority of subjects remained on combination therapy with levetiracetam, lamotrigine, and clobazam being the most commonly used medications, indicating a changing trend when compared with prior studies.

Electroencephalographic patterns during sleep in children with chromosome 15q11.2-13.1 duplications (Dup15q).

Our objective was to define the EEG features during sleep of children with neurodevelopmental disorders due to copy number gains of 15q11-q13 (Dup15q). We retrospectively reviewed continuous EEG recordings of 42 children with Dup15q (mean age: eight years, 32 with idic15), and data collected included background activity, interictal epileptiform discharges, sleep organization, and ictal activity. Three patterns were recognized: Pattern 1: Alpha­delta sleep was noted in 14 children (33%), not associated with any clinical changes. Pattern 2: Electrical status epilepticus in sleep was noted in 15 children (35%), all diagnosed with treatmentresistant epilepsy. Thirteen of the 15 children had clinical seizures. Pattern 3: Frequent bursts of high amplitude bifrontal predominant, paroxysmal fast activity (12­15 Hz) during non-REM sleep was noted in 15 children (35%). All 15 children had treatment-resistant epilepsy. This is the first report of electroencephalographic patterns during sleep of children with Dup15q reporting alpha-delta rhythms, CSWS, and high amplitude fast frequencies. Alpha-delta rhythms are described in children with dysautonomia and/or mood disorders and CSWS in children with developmental regression. The significance of these findings in cognitive function and epilepsy for the children in our cohort needs to be determined with follow-up studies.

Medication prescribing and patient-reported outcome measures in people with epilepsy in Bhutan.

OBJECTIVE: The aim of this study was to assess medication prescribing and patient-reported outcomes among people with epilepsy (PWE) in Bhutan and introduce criteria for evaluating unmet epilepsy care needs, particularly in resource-limited settings. METHODS: People with epilepsy in Bhutan (National Referral Hospital, 2014-2015) completed a questionnaire, the Quality of Life in Epilepsy Inventory (QOLIE-31), and an electroencephalogram (EEG). Management gap was the proportion of participants meeting any of six prespecified criteria based on best practices and the National Institute for Health and Care Excellence (NICE) guidelines. RESULTS: Among 253 participants (53% female, median: 24years), 93% (n=235) were treated with antiepileptic drugs (AEDs). Seventy-two percent (n=183) had active epilepsy (≥1 seizure in the prior year). At least one criterion was met by 55% (n=138) of participants, whereas the treatment gap encompassed only 5% (n=13). The criteria were the following: 1. Among 18 participants taking no AED, 72% (n=13) had active epilepsy. 2. Among 26 adults on subtherapeutic monotherapy, 46% (n=12) had active epilepsy. 3. Among 48 participants reporting staring spells, 56% (n=27) were treated with carbamazepine or phenytoin. 4. Among 101 female participants aged 14-40years, 23% (n=23) were treated with sodium valproate. 5. Among 67 participants reporting seizure-related injuries, 87% (n=58) had active epilepsy. 6. Among 111 participants with a QOLIE-31 score below 50/100, 77% (n=86) had active epilepsy. Years since first AED treatment (odds ratio: 1.07, 95% CI: 1.03, 1.12) and epileptiform discharges on EEG (odds ratio: 1.95, 95% CI: 1.15, 3.29) were significantly associated with more criteria met. CONCLUSIONS: By defining the management gap, subpopulations at greatest need for targeted interventions may be prioritized, including those already taking AEDs.

Angelman syndrome in adulthood.

Angelman syndrome (AS) is a neurogenetic disorder. The goal of this study was to investigate the primary health issues affecting adults with AS and to further characterize the natural history and genotype-phenotype correlations. Standardized phone interviews with caregivers for 110 adolescents and adults with AS were conducted. The impact of age, sex, and genotype on specific outcomes in neurology, orthopedics, internal medicine, and psychiatry were investigated. The mean age of individuals with AS was 24 years (range 16-50y). Active seizures were present in 41% of individuals, and 72% had sleep dysfunction. Significant constipation was present in 85%, and 32% were overweight or obese, with obesity disproportionately affecting women. Scoliosis affected 50% with a mean age at diagnosis of 12 years, and 24% of those diagnosed with scoliosis required surgery, an intervention disproportionately affecting men. Sixty-eight percent were able to walk independently, and 13% were able to speak 5 or more words. Self-injurious behavior was exhibited in 52% of individuals. The results of this study indicate that epilepsy severity may assume a bimodal age distribution: seizures are typically most severe in early childhood but may recur in adulthood. While late-adolescent and adult sleep patterns were improved when compared to the degree of sleep dysfunction present during infancy and childhood, the prevalence of poor sleep in adults remained quite high. Primary areas of clinical management identified include the following: seizures, sleep, aspiration risk, GERD, constipation, dental care, vision, obesity, scoliosis, bone density, mobility, communication, behavior, and anxiety.

Early and effective treatment of KCNQ2 encephalopathy.

OBJECTIVES: To describe the antiepileptic drug (AED) treatment of patients with early infantile epileptic encephalopathy due to KCNQ2 mutations during the neonatal phase and the first year of life. METHODS: We identified 15 patients and reviewed the electroclinical, neuroimaging, and AED treatment data. RESULTS: Seizure onset was between 1 and 4 days of age with daily tonic asymmetric, focal and clonic seizures in nine patients and status epilepticus in the remaining six. Electroencephalography (EEG) showed multifocal epileptiform abnormalities in nine patients and a burst-suppression pattern in six. All patients were trialed with adequate daily doses of several AEDs before they reached seizure freedom. Six patients (40%) achieved seizure control within 2 weeks of carbamazepine (CBZ) administration and five (33%) were seizure-free with phenytoin (PHT). The last four patients (27%) were successfully treated with topiramate (TPM) (two patients), levetiracetam (LEV) (one), and a combination of LEV with TPM (one). Most patients reached seizure freedom within the first year of life and remained seizure-free thereafter. Twelve patients had moderate-to-severe developmental delay at follow-up. However, the two patients whose seizures ceased within a few days of onset showed only mild cognitive impairment. SIGNIFICANCE: Our findings suggest that drugs acting on sodium channels including CBZ and PHT should be considered as first-line treatment in patients with KCNQ2 encephalopathy. Voltage-gated sodium and potassium channels co-localize at the neuronal membrane. Therefore, the efficacy of drugs acting as sodium-channel blockers could be linked to their modulating effect on both channels. The type of KCNQ2 mutation might influence AED response as well as developmental outcome. Early recognition of KCNQ2 encephalopathy followed by the most appropriate and effective treatment may be important for reducing the neurodevelopmental impairment associated with this disorder.

If not Angelman, what is it? A review of Angelman-like syndromes.

Angelman syndrome (AS) is caused by a lack of expression of the maternally inherited UBE3A gene in the brain. However, about 10% of individuals with a clinical diagnosis of AS do not have an identifiable molecular defect. It is likely that most of those individuals have an AS-like syndrome that is clinically and molecularly distinct from AS. These AS-like syndromes can be broadly classified into chromosomal microdeletion and microduplication syndromes, and single-gene disorders. The microdeletion/microduplication syndromes are now easily identified by chromosomal microarray analysis and include Phelan­McDermid syndrome (chromosome 22q13.3 deletion), MBD5 haploinsufficiency syndrome (chromosome 2q23.1 deletion), and KANSL1 haploinsufficiency syndrome (chromosome 17q21.31 deletion). The single-gene disorders include Pitt­Hopkins syndrome (TCF4), Christianson syndrome (SLC9A6), Mowat­Wilson syndrome (ZEB2), Kleefstra syndrome (EHMT1), and Rett (MECP2) syndrome. They also include disorders due to mutations in HERC2, adenylosuccinase lyase (ADSL), CDKL5, FOXG1, MECP2 (duplications), MEF2C, and ATRX. Although many of these single-gene disorders can be caused by chromosomal microdeletions resulting in haploinsufficiency of the critical gene, the individual disorders are often caused by intragenic mutations that cannot be detected by chromosomal microarray analysis. We provide an overview of the clinical features of these syndromes, comparing and contrasting them with AS, in the hope that it will help guide clinicians in the diagnostic work-up of individuals with AS-like syndromes.

A survey of seizures and current treatments in 15q duplication syndrome.

OBJECTIVE: Seizures are common in individuals with duplications of chromosome 15q11.2-q13 (Dup15q). The goal of this study was to examine the phenotypes and treatments of seizures in Dup15q in a large population. METHODS: A detailed electronic survey was conducted through the Dup15q Alliance containing comprehensive questions regarding seizures and their treatments in Dup15q. RESULTS: There were 95 responses from Dup15q families. For the 83 with idic(15), 63% were reported to have seizures, of which 81% had multiple seizure types and 42% had infantile spasms. Other common seizure types were tonic-clonic, atonic, myoclonic, and focal. Only 3 of 12 individuals with int dup(15) had seizures. Broad spectrum antiepileptic drugs (AEDs) were the most effective medications, but carbamazepine and oxcarbazepine were also effective, although typical benzodiazepines were relatively ineffective. There was a 24% response rate (>90% seizure reduction) to the first AED tried. For those with infantile spasms, adrenocorticotropic hormone (ACTH) was more effective than vigabatrin. SIGNIFICANCE: This is the largest study assessing seizures in Duplication 15q syndrome, but because this was a questionnaire-based study with a low return rate, it is susceptible to bias. Seizures are common in idic(15) and typically difficult to control, often presenting with infantile spasms and progressing to a Lennox-Gastaut-type syndrome. Seizures in those with int dup(15) are less common, with a frequency similar to the general autism population. In addition to broad spectrum AED, medications such as carbamazepine and oxcarbazepine are also relatively effective in controlling seizures in this population, suggesting a possible multifocal etiology, which may also explain the high rate of infantile spasms. Our small sample suggests a relative lack of efficacy of vigabatrin and other γ-aminobutyric acid (GABA)ergic medications, such as typical benzodiazepines, which may be attributable to abnormal GABAergic transmission resulting from the duplication of a cluster of GABAß3 receptor genes in the 15q11.2-13 region.

Cardiac fat-containing lesions are common in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a highly variable, multisystem, genetic disorder that affects approximately 1:6,000 individuals. It has previously been thought that the cardiac manifestation of TSC is congenital rhabdomyomas, which occur during infancy and typically regress during childhood. Recently, there have been findings of cardiac fat-containing lesions in adult TSC patients that appear distinct from the presence of cardiac rhabdomyomas. We review the chest CT scans of 73 individuals with TSC to check for cardiac fat-containing lesions. Fat-containing lesions were found in the heart of approximately one-third of adolescents and adults with TSC. In this population with cardiac fat-containing lesions, no statistically significant difference was observed between the genders and between the different mutation types. Compared to those without cardiac fat findings, those with cardiac fat were more than twice as likely to have another abdominal manifestation of TSC. The results indicate that it may be appropriate to consider these cardiac fat foci as a clinical criterion for the diagnosis of TSC, given their frequency in our population. Our findings also suggest that a relation exists between the cardiac fat-containing lesions and other abdominal angiomyolipomas. More research regarding these cardiac fat-containing lesions is needed to better characterize their origin and clinical significance.

Understanding relationships between autism, intelligence, and epilepsy: a cross-disorder approach.

AIM: As relationships between autistic traits, epilepsy, and cognitive functioning remain poorly understood, these associations were explored in the biologically related disorders tuberous sclerosis complex (TSC), neurofibromatosis type 1 (NF1), and epilepsy. METHOD: The Social Responsiveness Scale (SRS), a quantitative measure of autistic traits, was distributed to caregivers or companions of patients with TSC, NF1, and childhood-onset epilepsy of unknown cause (EUC), and these results were compared with SRS data from individuals with idiopathic autism spectrum disorders (ASDs) and their unaffected siblings. Scores and trait profiles of autistic features were compared with cognitive outcomes, epilepsy variables, and genotype. RESULTS: A total of 180 SRS questionnaires were completed in the TSC, NF1, and EUC outpatient clinics at the Massachusetts General Hospital (90 females, 90 males; mean age 21 y, range 4-63 y), and SRS data from 210 patients with ASD recruited from an autism research collaboration (167 males, 43 females; mean age 9 y, range 4-22 y) and 130 unaffected siblings were available. Regression models showed a significant association between SRS scores and intelligence outcomes (p<0.001) and various seizure variables (p<0.02), but not with a specific underlying disorder or genotype. The level of autistic features was strongly associated with intelligence outcomes in patients with TSC and epilepsy (p<0.01); in patients with NF1 these relationships were weaker (p=0.25). For all study groups, autistic trait subdomains covaried with neurocognitive comorbidity, with endophenotypes similar to that of idiopathic autism. INTERPRETATION: Our data show that in TSC and childhood-onset epilepsy, the severity and phenotype of autistic features are inextricably linked with intelligence and epilepsy outcomes. Such relationships were weaker for individuals with NF1. Findings suggest that ASDs are not specific in these conditions.