Quantitative EEG Analysis in Angelman Syndrome: Candidate Method for Assessing Therapeutics.

The goal of these studies was to use quantitative (q)EEG techniques on data from children with Angelman syndrome (AS) using spectral power analysis, and to evaluate this as a potential biomarker and quantitative method to evaluate therapeutics. Although characteristic patterns are evident in visual inspection, using qEEG techniques has the potential to provide quantitative evidence of treatment efficacy. We first assessed spectral power from baseline EEG recordings collected from children with AS compared to age-matched neurotypical controls, which corroborated the previously reported finding of increased total power driven by elevated delta power in children with AS. We then retrospectively analyzed data collected during a clinical trial evaluating the safety and tolerability of minocycline (3 mg/kg/d) to compare pretreatment recordings from children with AS (4-12 years of age) to EEG activity at the end of treatment and following washout for EEG spectral power and epileptiform events. At baseline and during minocycline treatment, the AS subjects demonstrated increased delta power; however, following washout from minocycline treatment the AS subjects had significantly reduced EEG spectral power and epileptiform activity. Our findings support the use of qEEG analysis in evaluating AS and suggest that this technique may be useful to evaluate therapeutic efficacy in AS. Normalizing EEG power in AS therefore may become an important metric in screening therapeutics to gauge overall efficacy. As therapeutics transition from preclinical to clinical studies, it is vital to establish outcome measures that can quantitatively evaluate putative treatments for AS and neurological disorders with distinctive EEG patterns.

A Conceptual Model of Angelman Syndrome and Review of Relevant Clinical Outcomes Assessments (COAs).

BACKGROUND: Angelman syndrome (AS) is a rare, neurological genetic disorder for which no clinical outcomes assessments (COAs) or conceptual models (CM) have been developed. OBJECTIVE: This study aimed to identify symptoms and impacts relevant and important in this patient population and develop a conceptual model of AS, and to evaluate the content validity of selected COA instruments with potential for inclusion in clinical studies of AS to capture treatment benefit. METHODS: For both concept elicitation (CE) and cognitive interviews (CI), caregivers of children, adolescents, and adults with AS and clinicians with AS experience were targeted. For CI, clinicians discussed the Modified Performance-Oriented Mobility Assessment (MPOMA-G) and ProtoKinetics Zeno Walkway™ and caregivers reviewed the Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT), the Anxiety, Depression and Mood Scale (ADAMS), the Aberrant Behavior Checklist-Community (ABC-C), and the Morning Diary. RESULTS: Four clinicians and 34 caregivers participated in CE interviews; three clinicians and 36 caregivers participated in CI. A conceptual model, initially informed by literature, was refined based on interview data. Five domains of symptoms, signs, and characteristics of AS were identified: cognitive and executive functioning, social-emotional, emotional-expressive behavior, sensory-compulsive behavior, and physical. Patient impacts were identified in three domains: activities of daily living, school, and social/community. Caregiver impacts were identified in five domains: mental health, physical health, work, home, and social. While all instruments demonstrated the ability to provide relevant data for the AS population, each instrument either contained some items irrelevant to individuals with AS or was missing important concepts based on the interviews. No single instrument covered all relevant domains specific to AS. CONCLUSION: Future work should consider the adaptation of existing COAs and the development of a novel AS-specific instrument for use in clinical research to ensure outcomes important to this patient population are captured.

Identification of spatiotemporal gait parameters and pressure-related characteristics in children with Angelman syndrome: A pilot study.

BACKGROUND: Angelman syndrome (AS) leads to clinical manifestations that include intellectual impairments, developmental delay and poor motor function. Initiatives to develop therapeutics implie an urgent need to identify methods that accurately measure the motor abilities. METHODS: Six children with AS (6 to 9 years old) walked on an instrumented walkway to get spatiotemporal parameters (STPs) and center of pressure (CoP). These outcomes were compared to typically developing children (TD): 44 TD 6 to 9 years old and 20 TD 4 to 5 years old. RESULTS: Analysis revealed differences in all STPs and gait variability index when compared to TD individuals. When AS participants were compared to younger TD individuals, except step length, STPs were different. Analysis of the CoP pathway revealed a less consistent and efficient pathway in AS. CONCLUSIONS: We could delineate the functional difference between children with AS and TD children. The variability of STP and the CoP were the most valuable components in gait to be considered in AS.

Quantitative Measurement of Communication Ability in Children with Angelman Syndrome.

BACKGROUND: Angelman syndrome is a rare disorder in which most individuals do not develop speech. Testing of communication ability using traditional neuropsychological measures reveals a performance level at or near the floor of the instrument resulting in an inability to detect change when experimental therapeutics are applied. METHODS: Nine individuals, with molecularly confirmed AS, ranging in age from 34 to 126 months, and a single healthy control child (age 16 months) were audio and video-recorded while interacting with a licensed speech-language pathologist in an attempt to elicit vocalization and non-verbal communication. Thirty-minute audio recordings were transcribed and categorized per the Stark Assessment of Early Vocal Development-Revised and a phonetic inventory was created. Using video recordings, gestures were classified by function, either behavioral regulation or social interaction and further categorized as deictic or representational (i.e., behavioral regulation) and joint attention or shared engagement (i.e., social interaction). RESULTS: The range of vocalizations produced by the children with AS was characteristic of children between 0-6 months and none of the children with AS used advanced forms of vocalizations. The mean frequency of reflexive vocalizations, control of phonation and expansion far exceeded the number of uses of canonical syllables, consistant with the characteristics of children around 12 months of age. Most vocalizations were either laughter or isolated vowels, only three children with AS produced consonant-vowel combinations. Children with AS tended to use central and low vowels with few producing high vowels, suggesting the presence of childhood apraxia of speech. CONCLUSION: Our results show the utilization of video-recorded behavioral observations provides a feasible and reliable alternative for quantification of communication ability in this patient population and may be employed during future clinical studies of potential therapeutics.

Ketone ester supplementation attenuates seizure activity, and improves behavior and hippocampal synaptic plasticity in an Angelman syndrome mouse model.

Angelman syndrome (AS) is a rare genetic and neurological disorder presenting with seizures, developmental delay, ataxia, and lack of speech. Previous studies have indicated that oxidative stress-dependent metabolic dysfunction may underlie the phenotypic deficits reported in the AS mouse model. While the ketogenic diet (KD) has been used to protect against oxidative stress and has successfully treated refractory epilepsy in AS case studies, issues arise due to its strict adherence requirements, in addition to selective eating habits and weight issues reported in patients with AS. We hypothesized that ketone ester supplementation would mimic the KD as an anticonvulsant and improve the behavioral and synaptic plasticity deficits in vivo. AS mice were supplemented R,S-1,3-butanediol acetoacetate diester (KE) ad libitum for eight weeks. KE administration improved motor coordination, learning and memory, and synaptic plasticity in AS mice. The KE was also anticonvulsant and altered brain amino acid metabolism in AS treated animals. Our findings suggest that KE supplementation produces sustained ketosis and ameliorates many phenotypes in the AS mouse model, and should be investigated further for future clinical use.

Reelin supplementation recovers synaptic plasticity and cognitive deficits in a mouse model for Angelman syndrome.

The Reelin signaling pathway is implicated in processes controlling synaptic plasticity and hippocampus-dependent learning and memory. A single direct in vivo application of Reelin enhances long-term potentiation, increases dendritic spine density and improves associative and spatial learning and memory. Angelman syndrome (AS) is a neurological disorder that presents with an overall defect in synaptic function, including decreased long-term potentiation, reduced dendritic spine density, and deficits in learning and memory, making it an attractive model in which to examine the ability of Reelin to recover synaptic function and cognitive deficits. In this study, we investigated the effects of Reelin administration on synaptic plasticity and cognitive function in a mouse model of AS and demonstrated that bilateral, intraventricular injections of Reelin recover synaptic function and corresponding hippocampus-dependent associative and spatial learning and memory. Additionally, we describe alteration of the Reelin profile in tissue from both the AS mouse and post-mortem human brain.

An open-label pilot trial of minocycline in children as a treatment for Angelman syndrome.

BACKGROUND: Minocycline, a member of the tetracycline family, has a low risk of adverse effects and an ability to improve behavioral performance in humans with cognitive disruption. We performed a single-arm open-label trial in which 25 children diagnosed with Angelman syndrome (AS) were administered minocycline to assess the safety and tolerability of minocycline in this patient population and determine the drug's effect on the cognitive and behavioral manifestations of the disorder. METHODS: Participants, age 4-12 years old, were randomly selected from a pool of previously screened children for participation in this study. Each child received 3 milligrams of minocycline per kilogram of body weight per day for 8 weeks. Participants were assessed during 3 study visits: baseline, after 8-weeks of minocycline treatment and after an 8-week wash out period. The primary outcome measure was the Bayley Scales of Infant and Toddler Development 3rd Edition (BSID-III). Secondary outcome measures included the Clinical Global Impressions Scale (CGI), Vineland Adaptive Behavior Scales 2nd Edition (VABS-II), Preschool Language Scale 4th Edition (PLS-IV) and EEG scores. Observations were considered statistically significant if p < 0.05 using ANOVA and partial eta squared (η(2)) was calculated to show effect size. Multiple comparisons testing between time points were carried out using Dunnett's post hoc testing. RESULTS: Significant improvement in the mean raw scores of the BSID-III subdomains communication and fine motor ability as well as the subdomains auditory comprehension and total language ability of the PLS-IV when baseline scores were compared to scores after the washout period. Further, improvements were observed in the receptive communication subdomain of the VABS-II after treatment with minocycline. Finally, mean scores of the BSID-III self-direction subdomain and CGI scale score were significantly improved both after minocycline treatment and after the wash out period. CONCLUSION: The clinical and neuropsychological measures suggest minocycline was well tolerated and causes improvements in the adaptive behaviors of this sample of children with Angelman syndrome. While the optimal dosage and the effects of long-term use still need to be determined, these findings suggest further investigation into the effect minocycline has on patients with Angelman syndrome is warranted. TRIAL REGISTRATION: NCT01531582 - clinicaltrials.gov.