Age of diagnosis for children with chromosome 15q syndromes.

OBJECTIVE: The objective of this study was to identify the age of diagnosis for children with one of three neurogenetic conditions resulting from changes in chromosome 15 (Angelman syndrome [AS], Prader-Willi syndrome [PWS], and duplication 15q syndrome [Dup15q]). METHODS: Data about the diagnostic process for each condition were contributed by the advocacy organizations. Median and interquartile ranges were calculated for each condition by molecular subtype and year. Comparison tests were run to explore group differences. RESULTS: The median age of diagnosis was 1.8 years for both AS and Dup15q. PWS was diagnosed significantly younger at a median age of 1 month. Deletion subtypes for both PWS and AS were diagnosed earlier than nondeletion subtypes, and children with isodicentric duplications in Dup15q were diagnosed earlier than those with interstitial duplications. CONCLUSION: Understanding variability in the age of diagnosis for chromosome 15 disorders is an important step in reducing the diagnostic odyssey and improving access to interventions for these populations. Results from this study provide a baseline by which to evaluate efforts to reduce the age of diagnosis for individuals with these conditions.

Dental complications in homocystinurias.

Background: Cystathionine beta synthase deficiency (causing classical homocystinuria) has been associated with high-arched palates and crowded teeth, but little has been said about other oral health complications. Other homocystinurias (e.g., the remethylation defects) also have had little reported in terms of oral health. Individuals with the homocystinurias have been described as having bone density issues which can correlate with oral health. Moreover, elevations in homocysteine have a theoretical impact on tooth health and the paucity of clinical reports of oral health issues in homocystinuria may be the consequence of lack of attention by the medical community. Significance: Oral health is essential to overall health. If inadequate attention is paid to the oral health complications which can be seen in homocystinurias, then appropriate referrals and attention in therapeutic guidelines will not reflect the importance of oral health. Specific aims/research question: What oral health complications are reported by individuals with homocystinurias? Do these differ according to diagnosis? Methods: Data were collected from patients with homocystinurias by a series of questionnaires using the RARE-X platform. All subjects were consented prior to the collection of their data. All research was performed in accordance with the Declaration of Helsinki. Demographic data were collected as the initial questionnaire and other data were collected via the oral health questionnaire. Analysis: Questionnaires were opened to the community in mid-2022 and collection of data for this study ended with data submitted up to November 2022. Descriptive statistics were done. Due to the small size of the cohort, additional statistical analyses were not attempted. Results: Patients with homocystinuria, not related to cystathionine beta synthase deficiency, are reporting some tooth structure differences. The cohort taken as a whole does not have increased risk for gingivitis, but there appears to be a risk for long-term gum disease possibly due to the rate of osteoporosis/osteopenia in this population. A large number of individuals have malalignment and malocclusion of the teeth. These data highlight oral health as an important component of care in individuals with the homocystinurias as is true of the general population at large.

Impact of intellectual and developmental disability on quality-of-life priorities in adults with epilepsy.

OBJECTIVE: Adults living with intellectual and developmental disability (IDD) and epilepsy (IDD-E) face challenges in addition to those faced by the general population of adults with epilepsy, which may be associated with distinct priorities for improving health-related quality of life (HR-QOL). This study sought to (1) conduct a survey of HR-QOL priorities identified by adults with IDD-E and caregivers, and (2) perform an exploratory cross-sectional comparison to adults with epilepsy who do not have IDD. METHODS: This cross-sectional study recruited 65 adults with IDD-E and 134 adults with epilepsy without IDD and caregivers. Using a three-step development process, 256 items from existing quality-of-life scales recommended by the American Academy of Neurology (AAN) were rated by patients/caregivers for their importance as HR-QOL priorities. HR-QOL items identified as critical to the majority of the sample of adults with IDD-E were reported. Health-related quality of life priorities were compared between adults with IDD-E and adults with epilepsy without IDD. RESULTS: Health-related quality of life was significantly lower in adults with IDD-E. Health-related quality of life domains identified as critical priorities by adults with IDD-E included seizure burden, anti-seizure medication side effects, seizure unpredictability, and family impact. Priorities for improving HR-QOL differed between adults with and without IDD-E, with concerns about family impact, difficulty finding appropriate living conditions, inadequate assistance, and difficulty transitioning from pediatric-to-adult care valued significantly more among those with IDD-E. SIGNIFICANCE: Intellectual and developmental disability is an important determinant of HR-QOL among adults with epilepsy. We report HR-QOL priorities identified by adults with IDD-E and their caregivers. These results may help epilepsy clinicians and researchers develop tailored strategies to address priorities of the patient with IDD-E/caregiver community.

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.

Adapting the Mullen Scales of Early Learning for a Standardized Measure of Development in Children With Rett Syndrome.

Rett Syndrome (RTT) is characterized by severe impairment in fine motor (FM) and expressive language (EL) function, making accurate evaluations of development difficult with standardized assessm ents. In this study, the administration and scoring of the Mullen Scales of Early Learning (MSEL) were adapted to eliminate the confounding effects of FM and EL impairments in assessing development. Forty-seven girls with RTT were assessed with the Adapted-MSEL (MSEL-A), a subset (n = 30) was also assessed using the Vineland Adaptive Behavior Scales-Second Edition (Vineland-II) and a further subset (n = 17) was assessed using an eye-tracking version of the MSEL (MSEL-ET). Participants performed better on the visual reception (VR) and receptive language (RL) domains compared to the FM and EL domains on the MSEL-A. Individual performance on each domain was independent of other domains. Corresponding MSEL-A and Vineland-II domains were significantly correlated. The MSEL-ET was as accurate as the MSEL-A in assessing VR and RL, yet took a 44% less time. Results suggested that the MSEL-A and the MSEL-ET could be viable measures for accurately assessing developmental domains in children with RTT.

Visual evoked potentials detect cortical processing deficits in Rett syndrome.

OBJECTIVE: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutation of the X-linked MECP2 gene and characterized by developmental regression during the first few years of life. The objective of this study was to investigate if the visual evoked potential (VEP) could be used as an unbiased, quantitative biomarker to monitor brain function in RTT. METHODS: We recorded pattern-reversal VEPs in Mecp2 heterozygous female mice and 34 girls with RTT. The amplitudes and latencies of VEP waveform components were quantified, and were related to disease stage, clinical severity, and MECP2 mutation type in patients. Visual acuity was also assessed in both mice and patients by modulating the spatial frequency of the stimuli. RESULTS: Mecp2 heterozygous female mice and RTT patients exhibited a similar decrease in VEP amplitude that was most striking in the later stages of the disorder. RTT patients also displayed a slower recovery from the principal peak of the VEP response that was impacted by MECP2 mutation type. When the spatial frequency of the stimulus was increased, both patients and mice displayed a deficit in discriminating smaller patterns, indicating lower visual spatial acuity in RTT. INTERPRETATION: VEP is a method that can be used to assess brain function across species and in children with severe disabilities like RTT. Our findings support the introduction of standardized VEP analysis in clinical and research settings to probe the neurobiological mechanism underlying functional impairment and to longitudinally monitor progression of the disorder and response to treatment.

Atypical hemispheric specialization for faces in infants at risk for autism spectrum disorder.

Among the many experimental findings that tend to distinguish those with and without autism spectrum disorder (ASD) are face processing deficits, reduced hemispheric specialization, and atypical neurostructural and functional connectivity. To investigate the earliest manifestations of these features, we examined lateralization of event-related gamma-band coherence to faces during the first year of life in infants at high risk for autism (HRA; defined as having an older sibling with ASD) who were compared with low-risk comparison (LRC) infants, defined as having no family history of ASD. Participants included 49 HRA and 46 LRC infants who contributed a total of 127 data sets at 6 and 12 months. Electroencephalography was recorded while infants viewed images of familiar/unfamiliar faces. Event-related gamma-band (30-50 Hz) phase coherence between anterior-posterior electrode pairs for left and right hemispheres was computed. Developmental trajectories for lateralization of intra-hemispheric coherence were significantly different in HRA and LRC infants: by 12 months, HRA infants showed significantly greater leftward lateralization compared with LRC infants who showed rightward lateralization. Preliminary results indicate that infants who later met criteria for ASD were those that showed the greatest leftward lateralization. HRA infants demonstrate an aberrant pattern of leftward lateralization of intra-hemispheric coherence by the end of the first year of life, suggesting that the network specialized for face processing may develop atypically. Further, infants with the greatest leftward asymmetry at 12 months where those that later met criteria for ASD, providing support to the growing body of evidence that atypical hemispheric specialization may be an early neurobiological marker for ASD.

Alpha asymmetry in infants at risk for autism spectrum disorders.

An emerging focus of research on autism spectrum disorder (ASD) targets the identification of early-developing ASD endophenotypes using infant siblings of affected children. One potential neural endophenotype is resting frontal electroencephalogram (EEG) alpha asymmetry, a metric of hemispheric organization. Here, we examined the development of frontal EEG alpha asymmetry in ASD high-risk and low-risk infant populations. Our findings demonstrate that low and high-risk infants show different patterns of alpha asymmetry at 6 months of age and opposite growth trajectories in asymmetry over the following 12 months. These results support the candidacy of alpha asymmetry as an early neural ASD endophenotype.

Resting and task-modulated high-frequency brain rhythms measured by scalp encephalography in infants with tuberous sclerosis complex.

The electrophysiological correlates of cognitive deficits in tuberous sclerosis complex (TSC) are not well understood, and modulations of neural dynamics by neuroanatomical abnormalities that characterize the disorder remain elusive. Neural oscillations (rhythms) are a fundamental aspect of brain function, and have dominant frequencies in a wide frequency range. The spatio-temporal dynamics of these frequencies in TSC are currently unknown. Using a novel signal decomposition approach this study investigated dominant cortical frequencies in 10 infants with TSC, in the age range 18-30 months, and 12 age-matched healthy controls. Distinct spectral characteristics were estimated in the two groups. High-frequency [in the high-gamma (>50 Hz) and ripple (>80 Hz) ranges], non-random EEG components were identified in both TSC and healthy infants at 18 months. Additional components in the lower gamma (30-50 Hz) ranges were also identified, with higher characteristic frequencies in TSC than in controls. Lower frequencies were statistically identical in both sub-groups. A significant shift in the high-frequency spectral content of the EEG was observed as a function of age, independently of task performance, possibly reflecting an overall maturation of developing neural circuits. This shift occurred earlier in healthy infants than in TSC, i.e., by age 20 months the highest dominant frequencies were in the high gamma range, whereas in TSC dominant frequencies above 100 Hz were still measurable. At age 28-30 months a statistically significant decrease in dominant high frequencies was observed in both TSC and healthy infants, possibly reflecting increased myelination and neuronal connection strengthening with age. Although based on small samples, and thus preliminary, the findings in this study suggest that dominant cortical rhythms, a fundamental aspect of neurodynamics, may be affected in TSC, possibly leading to impaired information processing in the brain.

Early developmental trajectories associated with ASD in infants with tuberous sclerosis complex.

OBJECTIVE: We performed a longitudinal cohort study of infants with tuberous sclerosis complex (TSC), with the overarching goal of defining early clinical, behavioral, and biological markers of autism spectrum disorder (ASD) in this high-risk population. METHODS: Infants with TSC and typically developing controls were recruited as early as 3 months of age and followed longitudinally until 36 months of age. Data gathered at each time point included detailed seizure history, developmental testing using the Mullen Scales of Early Learning, and social-communication assessments using the Autism Observation Scale for Infants. At 18 to 36 months, a diagnostic evaluation for ASD was performed using the Autism Diagnostic Observation Schedule. RESULTS: Infants with TSC demonstrated delays confined to nonverbal abilities, particularly in the visual domain, which then generalized to more global delays by age 9 months. Twenty-two of 40 infants with TSC were diagnosed with ASD. Both 12-month cognitive ability and developmental trajectories over the second and third years of life differentiated the groups. By 12 months of age, the ASD group demonstrated significantly greater cognitive delays and a significant decline in nonverbal IQ from 12 to 36 months. CONCLUSIONS: This prospective study characterizes early developmental markers of ASD in infants with TSC. The early delay in visual reception and fine motor ability in the TSC group as a whole, coupled with the decline in nonverbal ability in infants diagnosed with ASD, suggests a domain-specific pathway to ASD that can inform more targeted interventions for these high-risk infants.

Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome.

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40-120 µg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.

Atypical lateralization of ERP response to native and non-native speech in infants at risk for autism spectrum disorder.

Language impairment is common in autism spectrum disorders (ASD) and is often accompanied by atypical neural lateralization. However, it is unclear when in development language impairment or atypical lateralization first emerges. To address these questions, we recorded event-related-potentials (ERPs) to native and non-native speech contrasts longitudinally in infants at risk for ASD (HRA) over the first year of life to determine whether atypical lateralization is present as an endophenotype early in development and whether these infants show delay in a very basic precursor of language acquisition: phonemic perceptual narrowing. ERP response for the HRA group to a non-native speech contrast revealed a trajectory of perceptual narrowing similar to a group of low-risk controls (LRC), suggesting that phonemic perceptual narrowing does not appear to be delayed in these high-risk infants. In contrast there were significant group differences in the development of lateralized ERP response to speech: between 6 and 12 months the LRC group displayed a lateralized response to the speech sounds, while the HRA group failed to display this pattern. We suggest the possibility that atypical lateralization to speech may be an ASD endophenotype over the first year of life.

Eye-tracking, autonomic, and electrophysiological correlates of emotional face processing in adolescents with autism spectrum disorder.

Individuals with autism spectrum disorder (ASD) often have difficulty with social-emotional cues. This study examined the neural, behavioral, and autonomic correlates of emotional face processing in adolescents with ASD and typical development (TD) using eye-tracking and event-related potentials (ERPs) across two different paradigms. Scanning of faces was similar across groups in the first task, but the second task found that face-sensitive ERPs varied with emotional expressions only in TD. Further, ASD showed enhanced neural responding to non-social stimuli. In TD only, attention to eyes during eye-tracking related to faster face-sensitive ERPs in a separate task; in ASD, a significant positive association was found between autonomic activity and attention to mouths. Overall, ASD showed an atypical pattern of emotional face processing, with reduced neural differentiation between emotions and a reduced relationship between gaze behavior and neural processing of faces.

Impaired language pathways in tuberous sclerosis complex patients with autism spectrum disorders.

The purpose of this study was to examine the relationship between language pathways and autism spectrum disorders (ASDs) in patients with tuberous sclerosis complex (TSC). An advanced diffusion-weighted magnetic resonance imaging (MRI) was performed on 42 patients with TSC and 42 age-matched controls. Using a validated automatic method, white matter language pathways were identified and microstructural characteristics were extracted, including fractional anisotropy (FA) and mean diffusivity (MD). Among 42 patients with TSC, 12 had ASD (29%). After controlling for age, TSC patients without ASD had a lower FA than controls in the arcuate fasciculus (AF); TSC patients with ASD had even a smaller FA, lower than the FA for those without ASD. Similarly, TSC patients without ASD had a greater MD than controls in the AF; TSC patients with ASD had even a higher MD, greater than the MD in those without ASD. It remains unclear why some patients with TSC develop ASD, while others have better language and socio-behavioral outcomes. Our results suggest that language pathway microstructure may serve as a marker of the risk of ASD in TSC patients. Impaired microstructure in language pathways of TSC patients may indicate the development of ASD, although prospective studies of language pathway development and ASD diagnosis in TSC remain essential.

Atypical face processing in children with tuberous sclerosis complex.

There is a high incidence of autism in tuberous sclerosis complex. Given the evidence of impaired face processing in autism, the authors sought to investigate electrophysiological markers of face processing in children with tuberous sclerosis complex. The authors studied 19 children with tuberous sclerosis complex under age 4, and 20 age-matched controls, using a familiar-unfamiliar faces paradigm. Of the children, 6 with tuberous sclerosis complex (32%) had autism. Children with tuberous sclerosis complex showed a longer N290 latency than controls (276 ms vs 259 ms, P = .05) and also failed to show the expected hemispheric differences in face processing. The longest N290 latency was seen in (1) children with autism and tuberous sclerosis complex and (2) children with temporal lobe tubers. This study is the first to quantify atypical face processing in children with tuberous sclerosis complex. This functional impairment may provide insight into a mechanism underlying a pathway to autism in tuberous sclerosis complex.

Developmental trajectories of resting EEG power: an endophenotype of autism spectrum disorder.

Current research suggests that autism spectrum disorder (ASD) is characterized by asynchronous neural oscillations. However, it is unclear whether changes in neural oscillations represent an index of the disorder or are shared more broadly among both affected and unaffected family members. Additionally, it remains unclear how early these differences emerge in development and whether they remain constant or change over time. In this study we examined developmental trajectories in spectral power in infants at high- or low-risk for ASD. Spectral power was extracted from resting EEG recorded over frontal regions of the scalp when infants were 6, 9, 12, 18 and 24 months of age. We used multilevel modeling to assess change over time between risk groups in the delta, theta, low alpha, high alpha, beta, and gamma frequency bands. The results indicated that across all bands, spectral power was lower in high-risk infants as compared to low-risk infants at 6-months of age. Furthermore high-risk infants showed different trajectories of change in spectral power in the subsequent developmental window indicating that not only are the patterns of change different, but that group differences are dynamic within the first two years of life. These findings remained the same after removing data from a subset of participants who displayed ASD related behaviors at 24 or 36 months. These differences in the nature of the trajectories of EEG power represent important endophenotypes of ASD.

Loss of white matter microstructural integrity is associated with adverse neurological outcome in tuberous sclerosis complex.

RATIONALE AND OBJECTIVES: Tuberous sclerosis complex (TSC) is a genetic neurocutaneous syndrome in which cognitive and social-behavioral outcomes for patients vary widely in an unpredictable manner. The cause of adverse neurologic outcome remains unclear. The aim of this study was to investigate the hypothesis that disordered white matter and abnormal neural connectivity are associated with adverse neurologic outcomes. MATERIALS AND METHODS: Structural and diffusion magnetic resonance imaging was carried out in 40 subjects with TSC (age range, 0.5-25 years; mean age, 7.2 years; median age, 5 years), 12 of whom had autism spectrum disorders (ASD), and in 29 age-matched controls. Tractography of the corpus callosum was used to define a three-dimensional volume of interest. Regional averages of four diffusion scalar parameters of the callosal projections were calculated for each subject. These were the average fractional anisotropy (AFA) and the average mean, radial, and axial diffusivity. RESULTS: Subjects with TSC had significantly lower AFA and higher average mean, radial, and axial diffusivity values compared to controls. Subjects with TSC and ASD had significantly lower AFA values compared to those without ASD and compared to controls. Subjects with TSC without ASD had similar AFA values compared to controls. CONCLUSION: Diffusion tensor scalar parameters provided measures of properties of the three-dimensional callosal projections. In TSC, changes in these parameters may reflect microstructural changes in myelination, axonal integrity, or extracellular environment. Alterations in white matter microstructural properties were associated with TSC, and larger changes were associated with TSC and ASD, thus establishing a relationship between altered white matter microstructural integrity and brain function.

Neural correlates of familiar and unfamiliar face processing in infants at risk for autism spectrum disorders.

Examining the neural correlates associated with processing social stimuli offers a viable option to the challenge of studying early social processing in infants at risk for autism spectrum disorders (ASDs). The present investigation included 32 12-month olds at high risk for ASD and 24 low-risk control infants, defined on the basis of family history. Infants were presented with familiar and unfamiliar faces, and three components of interest were explored for amplitude and latency differences. The anticipated developmental effects of emerging hemispheric asymmetry for face-sensitive components (the N290 and P400) were observed, as were familiarity effects for a component related to attention (the Nc). Although there were no striking group differences in the neural response to faces, there was some evidence for a developmental lag in an attentional component for the high-risk group. The infant ASD endophenotype, though elusive, may be better defined through expanding the age of study and addressing change over time in response to varied stimuli.