Analyzing the Quality of Life in Individuals with Fragile X Syndrome in Relation to Sleep and Mental Health.

The purpose of this paper was to examine the physical, emotional, social and school functioning domains of quality of life of individuals with Fragile X Syndrome, in relation to mental health and sleep patterns to gain a better understanding of how these aspects are affected by the disorder. This study included 119 individuals with Fragile X Syndrome who were given different cognitive examinations by a neuropsychologist or by parent-proxy questionnaires. This study focused on the Pediatric Quality of Life Inventory (PedsQoL), the Anxiety, Depression and Mood Scale (ADAMS), the Children's Sleep Habits Questionnaire (CSHQ), but did include other cognitive tests (Vineland Adaptive Behaviour Scales, Nonverbal IQ, Autism Diagnostic Observation Schedule). We identified significant associations between decreases in emotional, social and school domains of PedsQoL and the ADAMS subtests of Generalized Anxiety, Manic/Hyperactivity and Obsessive/Compulsivity, with the subtest of Depressed Mood having associations with lower physical and emotional domains. We also identified a significant impact between CSHQ subtests of Sleep Anxiety, Night Wakings, Daytime Sleepiness, and Parasomnia with the emotional and school domains of PedsQoL. There were associations connecting school functioning with Bedtime Resistance, and additional associations connecting emotional functioning with Sleep Duration and Sleep Onset Delay. Physical functioning was also associated with Sleep Anxiety. Our study shows how mental health and sleep defects impact improper sleep patterns and mental health which leads to decreases in the quality of life for individuals with FXS, and how it is important to screen for these symptoms in order to alleviate issues.

Developing a cluster-based approach for deciphering complexity in individuals with neurodevelopmental differences.

Objective: Individuals with neurodevelopmental disorders such as global developmental delay (GDD) present both genotypic and phenotypic heterogeneity. This diversity has hampered developing of targeted interventions given the relative rarity of each individual genetic etiology. Novel approaches to clinical trials where distinct, but related diseases can be treated by a common drug, known as basket trials, which have shown benefits in oncology but have yet to be used in GDD. Nonetheless, it remains unclear how individuals with GDD could be clustered. Here, we assess two different approaches: agglomerative and divisive clustering. Methods: Using the largest cohort of individuals with GDD, which is the Deciphering Developmental Disorders (DDD), characterized using a systematic approach, we extracted genotypic and phenotypic information from 6,588 individuals with GDD. We then used a k-means clustering (divisive) and hierarchical agglomerative clustering (HAC) to identify subgroups of individuals. Next, we extracted gene network and molecular function information with regard to the clusters identified by each approach. Results: HAC based on phenotypes identified in individuals with GDD revealed 16 clusters, each presenting with one dominant phenotype displayed by most individuals in the cluster, along with other minor phenotypes. Among the most common phenotypes reported were delayed speech, absent speech, and seizure. Interestingly, each phenotypic cluster molecularly included several (3-12) gene sub-networks of more closely related genes with diverse molecular function. k-means clustering also segregated individuals harboring those phenotypes, but the genetic pathways identified were different from the ones identified from HAC. Conclusion: Our study illustrates how divisive (k-means) and agglomerative clustering can be used in order to group individuals with GDD for future basket trials. Moreover, the result of our analysis suggests that phenotypic clusters should be subdivided into molecular sub-networks for an increased likelihood of successful treatment. Finally, a combination of both agglomerative and divisive clustering may be required for developing of a comprehensive treatment.

Adaptive, behavioral, and cognitive outcomes in individuals with fragile X syndrome with varying autism severity.

This study aimed to determine the association between severity of autism spectrum disorder (ASD) and cognitive, behavioral, and molecular measures in individuals with fragile X syndrome (FXS). Study inclusion criteria included individuals with FXS and (1) age 6-40 years, (2) full-scale IQ < 84, and (3) language ≥3-word phrases. ASD symptom severity was determined by Autism Diagnostic Observation Schedule-2 (ADOS-2). Other measures identified non-verbal IQ, adaptive skills, and aberrant behaviors. Molecular measures included blood FMR1 and CYFIP1 mRNA levels, FMRP and MMP9 levels. Analysis of variance (ANOVA) and Spearman's correlations were used to compare ASD severity groups. Data from 54 individuals was included with no/mild (N = 7), moderate (N = 18), and severe (N = 29) ASD. Individuals with high ASD severity had lower adaptive behavior scores (47.48 ± 17.49) than the no/mild group (69.00 ± 20.45, p = 0.0366); they also had more challenging behaviors, lethargy, and stereotypic behaviors. CYFIP1 mRNA expression levels positively correlated with the ADOS-2 comparison score(r2  = 0.33, p = 0.0349), with no significant correlations with other molecular markers. In conclusion, autism symptom severity is associated with more adverse cognitive and adaptive skills and specific behaviors in FXS, whereas CYFIP1 mRNA expression levels may be a potential biomarker for severity of ASD in FXS.

Sex difference contributes to phenotypic diversity in individuals with neurodevelopmental disorders.

Objective: Gain a better understanding of sex-specific differences in individuals with global developmental delay (GDD), with a focus on phenotypes and genotypes. Methods: Using the Deciphering Developmental Disorders (DDD) dataset, we extracted phenotypic information from 6,588 individuals with GDD and then identified statistically significant variations in phenotypes and genotypes based on sex. We compared genes with pathogenic variants between sex and then performed gene network and molecular function enrichment analysis and gene expression profiling between sex. Finally, we contrasted individuals with autism as an associated condition. Results: We identified significantly differentially expressed phenotypes in males vs. females individuals with GDD. Autism and macrocephaly were significantly more common in males whereas microcephaly and stereotypies were more common in females. Importantly, 66% of GDD genes with pathogenic variants overlapped between both sexes. In the cohort, males presented with only slightly increased X-linked genes (9% vs. 8%, respectively). Individuals from both sexes harbored a similar number of pathogenic variants overall (3) but females presented with a significantly higher load for GDD genes with high intolerance to loss of function. Sex difference in gene expression correlated with genes identified in a sex specific manner. While we identified sex-specific GDD gene mutations, their pathways overlapped. Interestingly, individuals with GDD but also co-morbid autism phenotypes, we observed distinct mutation load, pathways and phenotypic presentation. Conclusion: Our study shows for the first time that males and females with GDD present with significantly different phenotypes. Moreover, while most GDD genes overlapped, some genes were found uniquely in each sex. Surprisingly they shared similar molecular functions. Sorting genes by predicted tolerance to loss of function (pLI) led to identifying an increased mutation load in females with GDD, suggesting potentially a tolerance to GDD genes of higher pLI compared to overall GDD genes. Finally, we show that considering associated conditions (for instance autism) may influence the genomic underpinning found in individuals with GDD and highlight the importance of comprehensive phenotyping.

Intercorrelation of Molecular Biomarkers and Clinical Phenotype Measures in Fragile X Syndrome.

This study contributes to a greater understanding of the utility of molecular biomarkers to identify clinical phenotypes of fragile X syndrome (FXS). Correlations of baseline clinical trial data (molecular measures-FMR1 mRNA, CYFIP1 mRNA, MMP9 and FMRP protein expression levels, nonverbal IQ, body mass index and weight, language level, NIH Toolbox, adaptive behavior rating, autism, and other mental health correlates) of 59 participants with FXS ages of 6-32 years are reported. FMR1 mRNA expression levels correlated positively with adaptive functioning levels, expressive language, and specific NIH Toolbox measures. The findings of a positive correlation of MMP-9 levels with obesity, CYFIP1 mRNA with mood and autistic symptoms, and FMR1 mRNA expression level with better cognitive, language, and adaptive functions indicate potential biomarkers for specific FXS phenotypes. These may be potential markers for future clinical trials for targeted treatments of FXS.

Long-term Memory Testing in Children With Typical Development and Neurodevelopmental Disorders: Remote Web-based Image Task Feasibility Study.

BACKGROUND: Neurodevelopmental disorders (NDD) cause individuals to have difficulty in learning facts, procedures, or social skills. NDD has been linked to several genes, and several animal models have been used to identify potential therapeutic candidates based on specific learning paradigms for long-term and associative memory. In individuals with NDD, however, such testing has not been used so far, resulting in a gap in translating preclinical results to clinical practice. OBJECTIVE: We aim to assess if individuals with NDD could be tested for paired association learning and long-term memory deficit, as shown in previous animal models. METHODS: We developed an image-based paired association task, which can be performed at different time points using remote web-based testing, and evaluated its feasibility in children with typical development (TD), as well as NDD. We included 2 tasks: object recognition as a simpler task and paired association. Learning was tested immediately after training and also the next day for long-term memory. RESULTS: We found that children aged 5-14 years with TD (n=128) and with NDD of different types (n=57) could complete testing using the Memory Game. Children with NDD showed deficits in both recognition and paired association tasks on the first day of learning, in both 5-9-year old (P<.001 and P=.01, respectively) and 10-14-year old groups (P=.001 and P<.001, respectively). The reaction times to stimuli showed no significant difference between individuals with TD or NDD. Children with NDD exhibited a faster 24-hour memory decay for the recognition task than those with TD in the 5-9-year old group. This trend is reversed for the paired association task. Interestingly, we found that children with NDD had their retention for recognition improved and matched with typically developing individuals by 10-14 years of age. The NDD group also showed improved retention deficits in the paired association task at 10-14 years of age compared to the TD group. CONCLUSIONS: We showed that web-based learning testing using simple picture association is feasible for children with TD, as well as with NDD. We showed how web-based testing allows us to train children to learn the association between pictures, as shown in immediate test results and those completed 1 day after. This is important as many models for learning deficits in NDD target both short- and long-term memory for therapeutic intervention. We also demonstrated that despite potential confounding factors, such as self-reported diagnosis bias, technical issues, and varied participation, the Memory Game shows significant differences between typically developing children and those with NDD. Future experiments will leverage this potential of web-based testing for larger cohorts and cross-validation with other clinical or preclinical cognitive tasks.

Leveraging Knowledge Graphs and Natural Language Processing for Automated Web Resource Labeling and Knowledge Mobilization in Neurodevelopmental Disorders: Development and Usability Study.

BACKGROUND: Patients and families need to be provided with trusted information more than ever with the abundance of online information. Several organizations aim to build databases that can be searched based on the needs of target groups. One such group is individuals with neurodevelopmental disorders (NDDs) and their families. NDDs affect up to 18% of the population and have major social and economic impacts. The current limitations in communicating information for individuals with NDDs include the absence of shared terminology and the lack of efficient labeling processes for web resources. Because of these limitations, health professionals, support groups, and families are unable to share, combine, and access resources. OBJECTIVE: We aimed to develop a natural language-based pipeline to label resources by leveraging standard and free-text vocabularies obtained through text analysis, and then represent those resources as a weighted knowledge graph. METHODS: Using a combination of experts and service/organization databases, we created a data set of web resources for NDDs. Text from these websites was scraped and collected into a corpus of textual data on NDDs. This corpus was used to construct a knowledge graph suitable for use by both experts and nonexperts. Named entity recognition, topic modeling, document classification, and location detection were used to extract knowledge from the corpus. RESULTS: We developed a resource annotation pipeline using diverse natural language processing algorithms to annotate web resources and stored them in a structured knowledge graph. The graph contained 78,181 annotations obtained from the combination of standard terminologies and a free-text vocabulary obtained using topic modeling. An application of the constructed knowledge graph is a resource search interface using the ordered weighted averaging operator to rank resources based on a user query. CONCLUSIONS: We developed an automated labeling pipeline for web resources on NDDs. This work showcases how artificial intelligence-based methods, such as natural language processing and knowledge graphs for information representation, can enhance knowledge extraction and mobilization, and could be used in other fields of medicine.

Identifying Potential Gamification Elements for A New Chatbot for Families With Neurodevelopmental Disorders: User-Centered Design Approach.

BACKGROUND: Chatbots have been increasingly considered for applications in the health care field. However, it remains unclear how a chatbot can assist users with complex health needs, such as parents of children with neurodevelopmental disorders (NDDs) who need ongoing support. Often, this population must deal with complex and overwhelming health information, which can make parents less likely to use a software that may be very helpful. An approach to enhance user engagement is incorporating game elements in nongame contexts, known as gamification. Gamification needs to be tailored to users; however, there has been no previous assessment of gamification use in chatbots for NDDs. OBJECTIVE: We sought to examine how gamification elements are perceived and whether their implementation in chatbots will be well received among parents of children with NDDs. We have discussed some elements in detail as the initial step of the project. METHODS: We performed a narrative literature review of gamification elements, specifically those used in health and education. Among the elements identified in the literature, our health and social science experts in NDDs prioritized five elements for in-depth discussion: goal setting, customization, rewards, social networking, and unlockable content. We used a qualitative approach, which included focus groups and interviews with parents of children with NDDs (N=21), to assess the acceptability of the potential implementation of these elements in an NDD-focused chatbot. Parents were asked about their opinions on the 5 elements and to rate them. Video and audio recordings were transcribed and summarized for emerging themes, using deductive and inductive thematic approaches. RESULTS: From the responses obtained from 21 participants, we identified three main themes: parents of children with NDDs were familiar with and had positive experiences with gamification; a specific element (goal setting) was important to all parents, whereas others (customization, rewards, and unlockable content) received mixed opinions; and the social networking element received positive feedback, but concerns about information accuracy were raised. CONCLUSIONS: We showed for the first time that parents of children with NDDs support gamification use in a chatbot for NDDs. Our study illustrates the need for a user-centered design in the medical domain and provides a foundation for researchers interested in developing chatbots for populations that are medically vulnerable. Future studies exploring wide range of gamification elements with large number of potential users are needed to understand the impact of gamification elements in enhancing knowledge mobilization.

Deciphering the Diversity of Mental Models in Neurodevelopmental Disorders: Knowledge Graph Representation of Public Data Using Natural Language Processing.

BACKGROUND: Understanding how individuals think about a topic, known as the mental model, can significantly improve communication, especially in the medical domain where emotions and implications are high. Neurodevelopmental disorders (NDDs) represent a group of diagnoses, affecting up to 18% of the global population, involving differences in the development of cognitive or social functions. In this study, we focus on 2 NDDs, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), which involve multiple symptoms and interventions requiring interactions between 2 important stakeholders: parents and health professionals. There is a gap in our understanding of differences between mental models for each stakeholder, making communication between stakeholders more difficult than it could be. OBJECTIVE: We aim to build knowledge graphs (KGs) from web-based information relevant to each stakeholder as proxies of mental models. These KGs will accelerate the identification of shared and divergent concerns between stakeholders. The developed KGs can help improve knowledge mobilization, communication, and care for individuals with ADHD and ASD. METHODS: We created 2 data sets by collecting the posts from web-based forums and PubMed abstracts related to ADHD and ASD. We utilized the Unified Medical Language System (UMLS) to detect biomedical concepts and applied Positive Pointwise Mutual Information followed by truncated Singular Value Decomposition to obtain corpus-based concept embeddings for each data set. Each data set is represented as a KG using a property graph model. Semantic relatedness between concepts is calculated to rank the relation strength of concepts and stored in the KG as relation weights. UMLS disorder-relevant semantic types are used to provide additional categorical information about each concept's domain. RESULTS: The developed KGs contain concepts from both data sets, with node sizes representing the co-occurrence frequency of concepts and edge sizes representing relevance between concepts. ADHD- and ASD-related concepts from different semantic types shows diverse areas of concerns and complex needs of the conditions. KG identifies converging and diverging concepts between health professionals literature (PubMed) and parental concerns (web-based forums), which may correspond to the differences between mental models for each stakeholder. CONCLUSIONS: We show for the first time that generating KGs from web-based data can capture the complex needs of families dealing with ADHD or ASD. Moreover, we showed points of convergence between families and health professionals' KGs. Natural language processing-based KG provides access to a large sample size, which is often a limiting factor for traditional in-person mental model mapping. Our work offers a high throughput access to mental model maps, which could be used for further in-person validation, knowledge mobilization projects, and basis for communication about potential blind spots from stakeholders in interactions about NDDs. Future research will be needed to identify how concepts could interact together differently for each stakeholder.

How Knowledge Mapping Can Bridge the Communication Gap Between Caregivers and Health Professionals Supporting Individuals With Complex Medical Needs: A Study in Fragile X Syndrome.

The challenges of caring for children with complex health needs, such as intellectual disability (ID) and autism spectrum disorder (ASD), are multiple and experienced by both caregivers and health professionals. Fragile X syndrome (FXS) is the most common single gene cause of ID and ASD, and provides a pertinent model to understand these complexities of care, as well as the communication challenges experienced between caregivers and healthcare professionals. In recent years both caregivers and healthcare professionals have recognized the need for enhancing communication both in clinical and research settings. Knowledge mapping has emerged as a tool to support quality communication between team participants. Here we review how differences in mental models, as well as challenges related to health literacy and knowledge transfer can have an impact on communication. Next, we present different knowledge mapping approaches used in complex situations, with a focus on concept maps and care maps. Finally, we highlight the potential benefits and limitations of mapping to improve communication issues related to caring for individuals with FXS and potentially other neurodevelopmental disorders (NDDs).

Phenotypic Trade-Offs: Deciphering the Impact of Neurodiversity on Drug Development in Fragile X Syndrome.

Fragile X syndrome (FXS) is the most common single-gene cause of intellectual disability and autism spectrum disorder. Individuals with FXS present with a wide range of severity in multiple phenotypes including cognitive delay, behavioral challenges, sleep issues, epilepsy, and anxiety. These symptoms are also shared by many individuals with other neurodevelopmental disorders (NDDs). Since the discovery of the FXS gene, FMR1, FXS has been the focus of intense preclinical investigation and is placed at the forefront of clinical trials in the field of NDDs. So far, most studies have aimed to translate the rescue of specific phenotypes in animal models, for example, learning, or improving general cognitive or behavioral functioning in individuals with FXS. Trial design, selection of outcome measures, and interpretation of results of recent trials have shown limitations in this type of approach. We propose a new paradigm in which all phenotypes involved in individuals with FXS would be considered and, more importantly, the possible interactions between these phenotypes. This approach would be implemented both at the baseline, meaning when entering a trial or when studying a patient population, and also after the intervention when the study subjects have been exposed to the investigational product. This approach would allow us to further understand potential trade-offs underlying the varying effects of the treatment on different individuals in clinical trials, and to connect the results to individual genetic differences. To better understand the interplay between different phenotypes, we emphasize the need for preclinical studies to investigate various interrelated biological and behavioral outcomes when assessing a specific treatment. In this paper, we present how such a conceptual shift in preclinical design could shed new light on clinical trial results. Future clinical studies should take into account the rich neurodiversity of individuals with FXS specifically and NDDs in general, and incorporate the idea of trade-offs in their designs.

Prenatal fruit juice exposure enhances memory consolidation in male post-weanling Sprague-Dawley rats.

OBJECTIVES: Nutritional intake during gestation is known to impact health outcomes for progeny. Correlational evidence in humans suggests that increased fruit consumption of pregnant mothers enhances infant cognitive development. Moreover, wild-type Drosophila supplemented with a combination of orange and tomato juice showed robust enhancements in performance on an associative olfactory memory task. The current study aimed to experimentally test the effects of prenatal fruit juice exposure in a non-human, mammalian model of learning and memory. METHODS: Across three separate birth cohorts, pregnant rats were given access to diluted tomato and orange juice (N = 2 per cohort), with control rats (N = 2 per cohort) receiving only water, in addition to standard rodent chow, throughout the duration of gestation, ending at parturition. Following weaning, male offspring were tested for learning and memory in a spatial version of the circular water maze and an auditory-cued fear-conditioning task. RESULTS: All pregnant rats increased fluid and food intake over the gestational period. Fruit juice-fed pregnant rats had increased fluid intake compared to control pregnant rats. When testing progeny, there were no effects of prenatal fruit juice on spatial learning, while it appeared to impair learning in fear conditioning relative to controls. However, we measured significant enhancements in both spatial memory and conditioned fear memory in the prenatal fruit-juice group compared to controls. Measures of vigilance, in response to the conditioned cue, were increased in prenatal fruit rats compared to controls, suggesting less generalized, and more adaptive, anxiety behaviours. DISCUSSION: Our results corroborate the human and Drosophila findings of prenatal fruit effects on behaviour, specifically that prenatal fruit juice exposure may be beneficial for early-life memory consolidation in rats.

Stress Odorant Sensory Response Dysfunction in Drosophila Fragile X Syndrome Mutants.

Sensory processing dysfunction (SPD) is present in most patients with intellectual disability (ID) and autism spectrum disorder (ASD). Silencing expression of the Fragile X mental retardation 1 (FMR1) gene leads to Fragile X syndrome (FXS), the most common single gene cause of ID and ASD. Drosophila have a highly conserved FMR1 ortholog, dfmr1. dfmr1 mutants display cognitive and social defects reminiscent of symptoms seen in individuals with FXS. We utilized a robust behavioral assay for sensory processing of the Drosophila stress odorant (dSO) to gain a better understanding of the molecular basis of SPD in FXS. Here, we show that dfmr1 mutant flies present significant defects in dSO response. We found that dfmr1 expression in mushroom bodies is required for dSO processing. We also show that cyclic adenosine monophosphate (cAMP) signaling via PKA is activated after exposure to dSO and that several drugs regulating both cAMP and cyclic guanosine monophosphate (cGMP) levels significantly improved defects in dSO processing in dfmr1 mutant flies.

Quantitative phenotypic and network analysis of 1q44 microdeletion for microcephaly.

As genome wide techniques become more common, an increasing proportion of patients with intellectual disability (ID) are found to have genetic defects allowing genotype-phenotype correlations. Previously, AKT3 deletion was suggested to be responsible for microcephaly in patients with 1q43-q44 deletion syndrome, but this does not correspond to all cases. We report a case of a de novo 1q44 deletion in an 8-year-old boy with microcephaly in whom AKT3 is not deleted. We used a systematic review of the literature, our patient, and network analysis to gain a better understanding of the genetic basis of microcephaly in 1q deletion patients. Our analysis showed that while AKT3 deletion is associated with more severe (≤3 SD) microcephaly in 1q43-q44 deletion patients, other genes may contribute to microcephaly in AKT3 intact patients with microcephaly and 1q43-44 deletion syndrome. We identified a potential role for HNRNPU, SMYD3, NLRP3, and KIF26B in microcephaly. Overall, our study highlights the need for network analysis and quantitative measures reporting in the phenotypic analysis of a complex genetic syndrome related to copy number variation.

Cognitive Enhancement in Infants Associated with Increased Maternal Fruit Intake During Pregnancy: Results from a Birth Cohort Study with Validation in an Animal Model.

In-utero nutrition is an under-studied aspect of cognitive development. Fruit has been an important dietary constituent for early hominins and humans. Among 808 eligible CHILD-Edmonton sub-cohort subjects, 688 (85%) had 1-year cognitive outcome data. We found that each maternal daily serving of fruit (sum of fruit plus 100% fruit juice) consumed during pregnancy was associated with a 2.38 point increase in 1-year cognitive development (95% CI 0.39, 4.37; p<0.05). Consistent with this, we found 30% higher learning Performance index (PI) scores in Drosophila offspring from parents who consumed 30% fruit juice supplementation prenatally (PI: 85.7; SE 1.8; p<0.05) compared to the offspring of standard diet parents (PI: 65.0 SE 3.4). Using the Drosophila model, we also show that the cyclic adenylate monophosphate (cAMP) pathway may be a major regulator of this effect, as prenatal fruit associated cognitive enhancement was blocked in Drosophila rutabaga mutants with reduced Ca(2+)-Calmodulin-dependent adenylyl cyclase. Moreover, gestation is a critical time for this effect as postnatal fruit intake did not enhance cognitive performance in either humans or Drosophila. Our study supports increased fruit consumption during pregnancy with significant increases in infant cognitive performance. Validation in Drosophila helps control for potential participant bias or unmeasured confounders.

Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models.

Fragile X is the most common monogenic disorder associated with intellectual disability (ID) and autism spectrum disorders (ASD). Additionally, many patients are afflicted with executive dysfunction, ADHD, seizure disorder and sleep disturbances. Fragile X is caused by loss of FMRP expression, which is encoded by the FMR1 gene. Both the fly and mouse models of fragile X are also based on having no functional protein expression of their respective FMR1 homologs. The fly model displays well defined cognitive impairments and structural brain defects and the mouse model, although having subtle behavioral defects, has robust electrophysiological phenotypes and provides a tool to do extensive biochemical analysis of select brain regions. Decreased cAMP signaling has been observed in samples from the fly and mouse models of fragile X as well as in samples derived from human patients. Indeed, we have previously demonstrated that strategies that increase cAMP signaling can rescue short term memory in the fly model and restore DHPG induced mGluR mediated long term depression (LTD) in the hippocampus to proper levels in the mouse model (McBride et al., 2005; Choi et al., 2011, 2015). Here, we demonstrate that the same three strategies used previously with the potential to be used clinically, lithium treatment, PDE-4 inhibitor treatment or mGluR antagonist treatment can rescue long term memory in the fly model and alter the cAMP signaling pathway in the hippocampus of the mouse model.

Recurrent Diplopia in a Pediatric Patient with Bickerstaff Brainstem Encephalitis.

Introduction. Acute complete external ophthalmoplegia is a rare finding in clinical practice that is associated with diseases affecting the neuromuscular junction, the oculomotor nerves, or the brainstem. Ophthalmoplegia has been reported with acute ataxia in Miller Fisher syndrome (MFS) and Bickerstaff brainstem encephalitis (BBE). Up to 95% of these cases are associated with anti-GQ1b antibodies. Only a small number of cases of anti-GQ1b negative MFS have been documented in pediatric patients. This is the first case reporting a recurrence of ocular symptoms in an anti-GQ1b antibody negative patient with BBE. Case Presentation. An 8-year-old Caucasian boy presented with complete external ophthalmoplegia without ptosis, cerebellar ataxia, and a disturbance of consciousness. He had recently recovered from a confirmed Campylobacter jejuni infection. On subsequent laboratory testing he was anti-GQ1b antibody negative. He had a recurrence of diplopia at four-week follow-up. Conclusions. This patient's recurrence of diplopia was treated with a five-week course of oral corticosteroids which did not worsen his condition, and this may be a therapeutic option for similar patients. We will discuss the symptoms and treatment of reported pediatric cases of anti-GQ1b antibody negative cases of MFS and the variation between cases representing a spectrum of illness.

Mutations in CAPN1 Cause Autosomal-Recessive Hereditary Spastic Paraplegia.

Hereditary spastic paraplegia (HSP) is a genetically and clinically heterogeneous disease characterized by spasticity and weakness of the lower limbs with or without additional neurological symptoms. Although more than 70 genes and genetic loci have been implicated in HSP, many families remain genetically undiagnosed, suggesting that other genetic causes of HSP are still to be identified. HSP can be inherited in an autosomal-dominant, autosomal-recessive, or X-linked manner. In the current study, we performed whole-exome sequencing to analyze a total of nine affected individuals in three families with autosomal-recessive HSP. Rare homozygous and compound-heterozygous nonsense, missense, frameshift, and splice-site mutations in CAPN1 were identified in all affected individuals, and sequencing in additional family members confirmed the segregation of these mutations with the disease (spastic paraplegia 76 [SPG76]). CAPN1 encodes calpain 1, a protease that is widely present in the CNS. Calpain 1 is involved in synaptic plasticity, synaptic restructuring, and axon maturation and maintenance. Three models of calpain 1 deficiency were further studied. In Caenorhabditis elegans, loss of calpain 1 function resulted in neuronal and axonal dysfunction and degeneration. Similarly, loss-of-function of the Drosophila melanogaster ortholog calpain B caused locomotor defects and axonal anomalies. Knockdown of calpain 1a, a CAPN1 ortholog in Danio rerio, resulted in abnormal branchiomotor neuron migration and disorganized acetylated-tubulin axonal networks in the brain. The identification of mutations in CAPN1 in HSP expands our understanding of the disease causes and potential mechanisms.

Reversible white matter lesions associated with mutant EHMT1 and Kleefstra syndrome.

Kleefstra syndrome (KS; OMIM #610253), formerly known as the 9q subtelomeric deletion syndrome, is an autosomal dominant cause of intellectual disability (ID) characterized by hypotonia and facial dysmorphisms.(1,2) The cause of KS is attributed to haploinsufficiency of the euchromatin histone methyltransferase 1 (EHMT1) gene (OMIM *607001) located at chromosome 9q34.3 (i.e., distal long arm of chromosome 9), either by microdeletion or point mutation. EHMT1 encodes a histone H3 methyltransferase at position Lys-9 (H3K9).(1-3).