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.

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.

Low glycemic index treatment for seizures in Angelman syndrome.

PURPOSE: The low glycemic index treatment (LGIT) is a high fat, limited carbohydrate diet used in the treatment of epilepsy. The purpose of this study was to assess the efficacy and tolerability of the LGIT for the treatment of refractory seizures in pediatric patients with Angelman syndrome. METHODS: A pediatric Angelman syndrome cohort with refractory epilepsy was treated with the LGIT and followed prospectively over 4 months. Parents recorded a daily seizure log for a minimum of 1 month prior to the start of treatment as well as throughout the LGIT trial. Electroencephalography (EEG) and neuropsychological assessments (Scales of Independent Behavior-Revised and the Vineland Adaptive Behavior Scales-2nd Edition were obtained for each subject at both baseline and 4-month follow-up time points. Clinical evaluations of subjects were completed by a neurologist and dietitian at the time of enrollment, as well as following both the first and fourth months of dietary therapy. At each time point, blood for laboratory chemistries was drawn and anthropometric measures were obtained. KEY FINDINGS: Six children (mean age 3.3 years, range 1.1-4.8) with genetically confirmed Angelman syndrome initiated the LGIT, and completed the trial with no significant adverse events. Cohort averages for indices of seizure severity were as follows: age of 1.6 years at seizure onset, 3 lifetime antiepileptic drugs tried (range 1-6), and baseline seizure frequency of 10.1 events/week (range: 0.4-30.9). All subjects had a decrease in seizure frequency on the LGIT, with five of six exhibiting >80% seizure frequency reduction. All posttrial EEG studies showed improvement and three of four children with epileptiform activity on his or her baseline EEG had no discharges present on follow-up EEG. Developmental gains were noted by parents in all cases, although few of these neurocognitive gains were statistically significant on neuropsychological assessment. SIGNIFICANCE: This is the first prospective study assessing the LGIT for epilepsy. Our results indicate that this dietary therapy is highly effective in treating Angelman syndrome-related seizures. The diet was well tolerated by subjects as evidenced by five of six subjects remaining on the LGIT after completion of the trial. Beyond the prospective trial window, all five subjects who remained on the diet had >90% seizure reduction after 1 year of LGIT therapy. Despite the small sample size in this prospective study, the results indicate a potentially higher degree of efficacy of the LGIT for the Angelman syndrome population than that observed in the general epilepsy population. Although this study is too small to make definitive recommendations, these results suggest that the LGIT is a promising treatment option for Angelman syndrome-related epilepsy.

Impact of pediatric epilepsy on sleep patterns and behaviors in children and parents.

PURPOSE: Disrupted sleep patterns in children with epilepsy and their parents are commonly described clinically. A number of studies have shown increased frequency of sleep disorders among pediatric epilepsy patients; however, few have characterized the association between epilepsy and parental sleep quality and household sleeping arrangements. The purpose of this study was to explore the effect of pediatric epilepsy on child sleep, parental sleep and fatigue, and parent-child sleeping arrangements, including room sharing and cosleeping. METHODS: Parents of children 2 to 10 years of age with and without epilepsy completed written questionnaires assessing seizure history, child and parent sleep, and household sleeping arrangements. Children's Sleep Habits Questionnaire (CSHQ) scores were used to evaluate sleep disturbances for the child. The Pittsburgh Sleep Quality Index (PSQI) and the Iowa Fatigue Scale (IFS) were used to evaluate parental sleep and fatigue, respectively. The Early Childhood Epilepsy Severity Scale (E-Chess) was used to assess epilepsy severity. KEY FINDINGS: One hundred five households with a child with epilepsy and 79 controls participated in this study. Households with a child with epilepsy reported increased rates of both parent-child room sharing (p < 0.001) and cosleeping (p = 0.005) compared to controls. Children with epilepsy were found to have greater sleep disturbance by total CSHQ score (p < 0.001) and the following subscores: parasomnias (p < 0.001), night wakings (p < 0.001), sleep duration (p < 0.001), daytime sleepiness (<0.001), sleep onset delay (p = 0.009), and bedtime resistance (p = 0.023). Parents of children with epilepsy had increased sleep dysfunction (p = 0.005) and were more fatigued (p < 0.001). Severity of epilepsy correlated positively with degree of child sleep dysfunction (0.192, p = 0.049), parental sleep dysfunction (0.273, p = 0.005), and parental fatigue (0.324, p = 0.001). Antiepileptic drug polytherapy was predictive of greater childhood sleep disturbances. Nocturnal seizures were associated with parental sleep problems, whereas room sharing and cosleeping behavior were associated with child sleep problems. Within the epilepsy cohort, 69% of parents felt concerned about night seizures and 44% reported feeling rested rarely or never. Finally, 62% of parents described decreased sleep quality and/or quantity with cosleeping. SIGNIFICANCE: Pediatric epilepsy can significantly affect sleep patterns for both the affected child and his or her parents. Parents frequently room share or cosleep with their child, adaptations which may have detrimental effects for many households. Clinicians must not only be attentive to the sleep issues occurring in pediatric patients with epilepsy, but also for the household as a whole. These data provide evidence of a profound clinical need for improved epilepsy therapeutics and the development of nocturnal seizure monitoring technologies.

Synthesis and evaluation of substrate analogue inhibitors of trypanothione reductase.

Trypanothione reductase (TR) is found in the trypanosomatid parasites, where it catalyses the NADPH-dependent reduction of the glutathione analogue, trypanothione, and is a key player in the parasite's defenses against oxidative stress. TR is a promising target for the development of antitrypanosomal drugs; here, we report our synthesis and evaluation of compounds 3-5 as low micromolar Trypanosoma cruzi TR inhibitors. Although 4 and 5 were designed as potential irreversible inhibitors, these compounds, as well as 3, displayed reversible competitive inhibition. Compound 3 proved to be the most potent inhibitor, with a K(i) = 2 µM.

Neurologic manifestations of Angelman syndrome.

Angelman syndrome is a neurogenetic disorder characterized by the loss or reduction of the ubiquitin-protein ligase E3A enzyme. Angelman syndrome results from a deletion or mutation of the maternally inherited 15q11.2-13.1 region, paternal uniparental disomy of chromosome 15, or an imprinting error. Epilepsy is common and may present with multiple seizure types, including nonconvulsive status epilepticus. Seizures are often intractable and typically require broad-spectrum antiepileptic medications. Dietary therapy has also proved successful in Angelman syndrome. Electroencephalographic patterns include notched δ and rhythmic θ activity and epileptiform discharges. Sleep disorders are also common, often characterized by abnormal sleep-wake cycles. Movement disorders are nearly universal in Angelman syndrome, most frequently presenting with ataxia and tremor. Neurocognitive impairment is always present to varying degrees, and expressive speech is typically severely affected. Individuals with Angelman syndrome often manifest psychiatric comorbidities including hyperactivity, anxiety, and challenging behaviors such as aggression and self-injury. We focus on a comprehensive whole-child approach to the diagnosis and long-term clinical care of individuals with Angelman syndrome.

Low glycemic index treatment for epilepsy in tuberous sclerosis complex.

Retrospective chart review of 15 patients with tuberous sclerosis complex (TSC) who initiated the low glycemic index treatment (LGIT) for epilepsy management at Massachusetts General Hospital over a five-year period. Prior to dietary therapy, this cohort (average age: 8.5 years) had tried an average of 5.8 anti-epileptic drugs with incomplete seizure control. At 6 months on the LGIT, 7/15 (47%) patients experienced >50% reduction in seizure frequency.

The synthesis and inhibitory activity of dethiotrypanothione and analogues against trypanothione reductase.

Trypanothione reductase (TR) catalyzes the NADPH-dependent reduction of trypanothione disulfide (1). TR plays a central role in the trypanosomatid parasite's defense against oxidative stress and has emerged as a promising target for antitrypanosomal drugs. We describe the synthesis and activity of dethiotrypanothione and analogues (2-4) as inhibitors of Trypanosoma cruzi TR. The syntheses of these macrocycles feature ring-closing olefin metathesis (RCM) reactions catalyzed by ruthenium catalyst 17. Derivative 4 is our most potent inhibitor with a Ki=16 microM.