Neurogenetic Conditions Research Articles

Parent Perspectives on Parent-Mediated Intervention for Young Children With Down Syndrome.

Parent-mediated intervention (PMI) is a potentially scalable approach for tailored interventions in neurogenetic conditions like Down syndrome (DS). Because PMIs require ongoing parent engagement, they must be developed in alignment with the needs of intended users. The present study examined caregiver opinions and preferences to inform the development of syndrome-informed interventions for children with DS. Parents of children with DS (n = 34) participated in focus groups discussing PMI. Interviews were transcribed and a thematic analysis was applied to code the data. Three themes were identified: advantages of PMI, disadvantages of PMI and preferred features of PMI. To align with parent preferences, future PMIs for children with DS should require a brief time commitment, blend intervention activities into daily routines and include family members in activities. Findings have implications for developing novel interventions to support early development in children with DS and other neurogenetic conditions.

1.4 Development of Webcam-Collected and Artificial-Intelligence–Derived Social and Cognitive Performance Measures for Neurodevelopmental and Neurogenetic Conditions

1.4 Development of Webcam-Collected and Artificial-Intelligence–Derived Social and Cognitive Performance Measures for Neurodevelopmental and Neurogenetic Conditions

Investigating the genetic basis of hereditary spastic paraplegia and cerebellar Ataxia in Pakistani families

BackgroundHereditary Spastic Paraplegias (HSPs) and Hereditary Cerebellar Ataxias (HCAs) are progressive neurodegenerative disorders encompassing a spectrum of neurogenetic conditions with significant overlaps of clinical features. Spastic ataxias are a group of conditions that have features of both cerebellar ataxia and spasticity, and these conditions are frequently clinically challenging to distinguish. Accurate genetic diagnosis is crucial but challenging, particularly in resource-limited settings. This study aims to investigate the genetic basis of HSPs and HCAs in Pakistani families.MethodsFamilies from Khyber Pakhtunkhwa with at least two members showing HSP or HCA phenotypes, and who had not previously been analyzed genetically, were included. Families were referred for genetic analysis by local neurologists based on the proband’s clinical features and signs of a potential genetic neurodegenerative disorder. Whole Exome Sequencing (WES) and Sanger sequencing were then used to identify and validate genetic variants, and to analyze variant segregation within families to determine inheritance patterns. The mean age of onset and standard deviation were calculated to assess variability among affected individuals, and the success rate was compared with literature reports using differences in proportions and Cohen’s h.ResultsPathogenic variants associated with these conditions were identified in five of eight families, segregating according to autosomal recessive inheritance. These variants included previously reported SACS c.2182 C > T, p.(Arg728*), FA2H c.159_176del, p.(Arg53_Ile58del) and SPG11 c.2146 C > T, p.(Gln716*) variants, and two previously unreported variants in SACS c.2229del, p.(Phe743Leufs*8) and ZFYVE26 c.1926_1941del, p.(Tyr643Metfs*2). Additionally, FA2H and SPG11 variants were found to have recurrent occurrences, suggesting a potential founder effect within the Pakistani population. Onset age among affected individuals ranged from 1 to 14 years (M = 6.23, SD = 3.96). The diagnostic success rate was 62.5%, with moderate effect sizes compared to previous studies.ConclusionsThe findings of this study expand the genotypic and phenotypic spectrum of HSPs and HCAs in Pakistan and emphasize the importance of utilizing exome/genome sequencing for accurate diagnosis or support accurate differential diagnosis. This approach can improve genetic counseling and clinical management, addressing the challenges of diagnosing neurodegenerative disorders in resource-limited settings.

Laboratory-based measures of executive function and daily living skills in young children with Down syndrome: informing future interventions.

Adaptive behaviour refers to the practical skills necessary for independence and is considered a high-priority intervention target for children with neurogenetic conditions associated with intellectual disability, like Down syndrome (DS). Daily living skills (DLS) are a critical aspect of adaptive behaviour, but they have received little intervention attention, possibly because they involve a wide variety of skills across many settings. The present study aimed to advance DLS intervention science by examining the concurrent and longitudinal association between DLS performances and a cognitive skillset hypothesised to support DLS skill acquisition, executive function (EF). Participants were 71 children with DS between the ages of 2.5 and 8.7years (M=5.23years; standard deviation=1.65) who completed a battery of adapted EF tasks and a primary caregiver who completed the Vineland Adaptive Behavior Scales 3rd Edition Parent/Caregiver Comprehensive Report Form. A subset of caregivers also provided 6- and 12-month follow-up adaptive behaviour information. Results demonstrated a positive association between EF task performance and DLS standard scores and v-scores both concurrently and longitudinally. The findings have implications for potential future intervention approaches that aim to strengthen DLS performances by advancing EF skills in this population.

Cerebral Palsy Phenotypes in Genetic Epilepsies

BackgroundAlthough there are established connections between genetic epilepsies and neurodevelopmental disorders like intellectual disability, the presence of cerebral palsy (CP) in genetic epilepsies is undercharacterized. We performed a retrospective chart review evaluating the motor phenotype of patients with genetic epilepsies. MethodsPatients were ascertained through a research exome sequencing study to identify genetic causes of epilepsy. We analyzed data from the first 100 individuals with molecular diagnoses. We determined motor phenotype by reviewing medical records for muscle tone and motor function data. We characterized patients according to CP subtypes: spastic diplegic, spastic quadriplegic, spastic hemiplegic, dyskinetic, hypotonic-ataxic. ResultsOf 100 individuals with genetic epilepsies, 14% had evidence of possible CP, including 5% characterized as hypotonic-ataxic CP, 5% spastic quadriplegic CP, 3% spastic diplegic CP, and 1% hemiplegic CP. Presence of CP did not correlate with seizure onset age (P = 0.63) or seizure control (P = 0.07). CP occurred in 11% (n = 3 of 27) with focal epilepsy, 9% (n = 5 of 54) with generalized epilepsy, and 32% (n = 6 of 19) with combined focal/generalized epilepsy (P = 0.06). ConclusionsIn this retrospective analysis of patients with genetic epilepsies, we identified a substantial portion with CP phenotypes, representing an under-recognized comorbidity. These findings underscore the many neurodevelopmental features associated with neurogenetic conditions, regardless of the feature for which they were ascertained for sequencing. Detailed motor phenotyping is needed to determine the prevalence of CP and its subtypes among genetic epilepsies. These motor phenotypes require clinical management and represent important targeted outcomes in trials for patients with genetic epilepsies.

Specificity of Early Childhood Hyperphagia Profiles in Neurogenetic Conditions.

Hyperphagia is highly penetrant in Prader-Willi syndrome (PWS) and has increasingly been reported in other neurogenetic conditions (NGC). The Hyperphagia Questionnaire (HQ) was completed by caregivers of 4-8-year-olds with PWS (n = 17), Angelman syndrome (AS; n = 22), Williams syndrome (WS; n = 25), or low-risk controls (LRC; n = 35). All NGC groups were significantly elevated in HQ Total and Behavior scores compared to LRC. Only AS and WS were significantly elevated in the Drive domain, and only PWS in the Severity domain. After controlling for externalizing behavior, HQ Total scores were higher for PWS relative to other groups. Hyperphagic symptoms may not differentiate PWS from other NGCs in early childhood. However, hyperphagic phenotypes may be most severe in PWS. Further investigation of these profiles may inform etiology and syndrome-specific treatments.

The Multiple Odysseys in Research and Clinical Care for Neurogenetic Conditions.

Neurogenetic conditions (NGC; e.g., fragile X, Angelman, Prader-Willi syndromes) represent the cause for intellectual or developmental disabilities in up to 60% of cases. With expanded diagnostic options and an increasing focus on the development of gene therapies comes the potential of improved quality of life for individuals with NGCs and their families. However, these emerging initiatives also bring new challenges and considerations for NGC researchers and clinicians, including considerations for supporting caregivers and assuring outcome measures for clinical trials adequately reflect the lived experiences of people with NGCs. This paper summarizes the advances and current and future challenges of research and clinical service provision for people with NGCs and their caregivers.

Hospitalisation and mortality among privately insured individuals with COVID-19 in the United States: The role of intellectual disabilities and Neurogenetic disorders.

Individuals with intellectual disabilities (IDs) and neurogenetic conditions (IDNDs) are at greater risk for comorbidities that may increase adverse outcomes for this population when they have coronavirus disease 2019 (COVID-19). The study aims are to examine the population-level odds of hospitalisation and mortality of privately insured individuals with COVID-19 with and without IDNDs IDs, controlling for sociodemographics and comorbid health conditions. This is a retrospective, cross-sectional study of 1174 individuals with IDs and neurogenetic conditions within a population of 752237 de-identified, privately insured, US patients diagnosed with COVID-19 between February 2020 and September 2020. Odds of hospitalisation and mortality among COVID-19 patients with IDNDs adjusted for demographic characteristics, Health Resources and Services Administration region, states with Affordable Care Act and number of comorbid health conditions were analysed. Patients with IDNDs overall had higher rates of COVID-19 hospitalisation than those without IDNDs (35.01% vs. 12.65%, P<.0001) and had higher rates of COVID-19 mortality than those without IDNDs (4.94% vs. .88%, P<.0001). Adjusting for sociodemographic factors only, the odds of being hospitalised for COVID-19 associated with IDNDs was 4.05 [95% confidence interval (CI) 3.56-4.61]. Adjusting for sociodemographic factors and comorbidity count, the odds of hospitalisation for COVID-19 associated with IDNDs was 1.42 (95% CI 1.25-1.61). The odds of mortality from COVID-19 for individuals with IDNDs adjusted for sociodemographic factors only was 4.65 (95% CI 3.47-6.24). The odds of mortality from COVID-19 for patients with IDNDs adjusted for sociodemographic factors and comorbidity count was 2.70 (95% CI 2.03-3.60). A major finding of the study was that even when considering the different demographic structure and generally higher disease burden of patients with IDNDs, having a IDND was an independent risk factor for increased hospitalisation and mortality compared with patients without IDNDs. Individuals with IDNDs had significantly higher odds of hospitalisation and mortality after adjusting for sociodemographics. Results remained significant with a slight attenuation after adjusting for sociodemographics and comorbidities. Adjustments for comorbidity count demonstrated a dose-response increase in odds of both hospitalisation and mortality, illustrating the cumulative effect of health concerns on COVID-19 outcomes. Together, findings highlight that individuals with IDNDs experience vulnerability for negative COVID-19 health outcomes with implications for access to comprehensive healthcare.

Linking Angelman and dup15q data for expanded research (LADDER) database: a model for advancing research, clinical guidance, and therapeutic development for rare conditions.

Angelman syndrome (AS) and duplication 15q (dup15q) syndrome are rare neurogenetic conditions arising from a common locus on the long arm of chromosome 15. Individuals with both conditions share some clinical features (e.g. intellectual disability, epilepsy) and often require lifelong care. Disease-modifying therapies for both conditions are emerging, resulting in a significant need for a better understanding of the natural history of both AS and dup15q. Patient advocacy groups for both conditions recognized a need for a data repository that would link data on individuals from multiple sources to expand research, increase understanding of natural history, and accelerate the development of treatments, resulting in the Linking Angelman and Dup15q Data for Expanded Research (LADDER) Database. This paper describes the development and functionality of the LADDER Database - including challenges, lessons learned, and preliminary feasibility - and how it can be used as a model for other rare conditions.

Age of diagnosis for children with chromosome 15q syndromes

ObjectiveThe 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]).MethodsData 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.ResultsThe 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.ConclusionUnderstanding 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.

Experiences of parents of children with rare neurogenetic conditions during the COVID-19 pandemic: an interpretative phenomenological analysis

BackgroundThe Coronavirus disease 2019 (COVID-19) pandemic has impacted parental and child mental health and wellbeing in the UK. This study aimed to explore the experiences of parents of children with rare neurological and neurodevelopmental conditions with a known or suspected genetic cause (neurogenetic) across the first year of the pandemic in the UK.MethodsSemi-structured interviews were conducted with 11 parents of children with rare neurogenetic conditions. Parents were recruited via opportunity sampling from the CoIN Study, a longitudinal quantitative study exploring the impact of the pandemic on the mental health and wellbeing of families with rare neurogenetic conditions. Interviews were analysed using Interpretative Phenomenological Analysis.ResultsFour main themes were identified: (1) “A varied impact on child wellbeing: from detrimental to ‘no big drama’”; (2) “Parental mental health and wellbeing: impact, changes, and coping”; (3) “'The world had shut its doors and that was that’: care and social services during the pandemic”; and (4) “Time and luck: abstract concepts central to parents’ perspectives of how they coped during the pandemic”. The majority of parents described experiencing an exacerbation of pre-pandemic challenges due to increased uncertainty and a lack of support, with a minority reporting positive effects of the pandemic on family wellbeing.ConclusionsThese findings offer a unique insight into the experiences parents of children with rare neurogenetic conditions across the first year of the pandemic in the UK. They highlight that the experiences of parents were not pandemic-specific, and will continue to be highly relevant in a non-pandemic context. Future support should to be tailored to the needs of families and implemented across diverse future scenarios to promote coping and positive wellbeing.

Pilot protocol for the Parent and Infant Inter(X)action Intervention (PIXI) feasibility study.

This paper provides the detailed protocol for a pilot study testing the feasibility, acceptability, and initial efficacy of a targeted two-phase, remotely delivered early intervention program for infants with neurogenetic conditions (NGC) and their caregivers. The Parent and Infant Inter(X)action Intervention (PIXI) is designed to support parents and infants with a NGC diagnosed in the first year of life. PIXI is implemented in two phases, with the first phase focusing on psychoeducation, parent support, and how to establish routines for supporting infant development. Phase II helps parents learn targeted skills to support their infant's development as symptoms may begin to emerge. The proposed non-randomized feasibility pilot study will establish the feasibility of a year-long virtually implemented intervention program to support new parents of an infant diagnosed with an NGC.

Diagnosed in the Autoimmune Neurology Clinic: Two patients with different phenotypes of spinocerebellar ataxia type 27 (P10-5.014)

<h3>Objective:</h3> To describe two cases of spinocerebellar ataxia type 27 (SCA27), with a focus on the importance of differentiating episodic manifestations of neurogenetic conditions from inflammatory/autoimmune neurologic conditions. We emphasize the importance of obtaining an objective evaluation of the response to immunomodulatory treatment trials, and the significance of attaining a comprehensive family history. <h3>Background:</h3> SCA27 is an autosomal dominant condition caused by a pathogenic mutation in the fibroblast growth factor 14 (FGF14) gene located on chromosome 13. Phenotypic expression can vary in patients with the same genetic abnormality, often delaying diagnosis, especially in probands without affected relatives and/or with unremarkable or unavailable family history at the time of presentation. <h3>Design/Methods:</h3> We describe two patients referred to the Autoimmune Neurology clinic at the University of Utah for suspicion of an autoimmune/autoinflammatory disease, ultimately diagnosed with SCA27 as part of an expanded clinical evaluation. <h3>Results:</h3> A 68-year-old male patient (Case 1) presented with episodic dysarthria, dizziness, imbalance, and encephalopathy, with suspicion of a possible autoimmune etiology at the time of referral. At his first presentation, the patient reported no significant family history. Four years later, on revisiting the family history, he noted that his 49-year-old niece (Case 2) had also developed neurologic symptoms of unclear etiology. On evaluation, his niece was noted to have a tremor and ataxia. Both patients had evidence of systemic autoimmunity that likely contributed to suspicion of neurologic autoimmunity, and neither had age-advanced cerebellar or brainstem volume loss on imaging. Ultimately, genetic testing of both patients revealed a pathogenic mutation in the FGF14 gene consistent with SCA27. <h3>Conclusions:</h3> These two cases highlight the importance of a detailed interval family history at each visit, especially in undiagnosed adult patients. The presumptive autoinflammatory diagnosis in both patients reinforces the importance of comprehensive follow-up, including an objective analysis of response to any immunomodulatory diagnostic treatment trials. <b>Disclosure:</b> Dr. Hoshina has nothing to disclose. Dr. Wright has nothing to disclose. Dr. Warner has received intellectual property interests from a discovery or technology relating to health care. Dr. Richards has nothing to disclose. Karen Salzman has received publishing royalties from a publication relating to health care. Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as a Consultant for venrock. Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arrowhead. Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Leverna. Dr. Pulst has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for AAN. Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Leninthal LLC. The institution of Dr. Pulst has received research support from NINDS. Dr. Pulst has received intellectual property interests from a discovery or technology relating to health care. Ms. Spoth has stock in Applied Genetic Technologies Corporation. Ms. Spoth has stock in MeiraGTx Holdings. Ms. Spoth has stock in Ocugen. Ms. Spoth has stock in PTC Therapeutics. Dr. Clardy has received personal compensation for serving as an employee of Veterans Health Administration (VHA). Dr. Clardy has received personal compensation for serving as an employee of University of Utah Health. Dr. Clardy has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology/AAN Publications. The institution of Dr. Clardy has received research support from Sumaira Foundation for NMO. The institution of Dr. Clardy has received research support from Western Institute for Veteran Research. The institution of Dr. Clardy has received research support from NIH/NINDS. Dr. Clardy has received personal compensation in the range of $500-$4,999 for serving as a AAN Summer Meeting CoDirector Travel and Lodging with AAN. Dr. Clardy has received personal compensation in the range of $500-$4,999 for serving as a Grand Rounds Travel and Lodging with U of Iowa. Dr. Clardy has received personal compensation in the range of $500-$4,999 for serving as a Speaker Honoraria for Grand Rounds with Barrow Neurological Institute. Dr. Clardy has received personal compensation in the range of $500-$4,999 for serving as a Speaker Honoraria for Grand Rounds with Beaumont Health.

P285: Genetic testing strategies for rare and undiagnosed neurogenetic conditions: Utilization of exome sequencing, metabolic, and panel testing

P285: Genetic testing strategies for rare and undiagnosed neurogenetic conditions: Utilization of exome sequencing, metabolic, and panel testing

Hope in the uncertainties and certainty for parents of children with rare neurological disorders. Part I (of 3): Uncertainty.

This is the first of three articles exploring the aspects of clinical care for children with rare neurological disorders including uncertainties old and new. The disruptive technologies of genomic sequencing and advanced therapeutics such as gene-based therapies offer parents of children with severe but rare neurological conditions for the first-time unprecedented opportunities for 'precision medicine'. At the same time, the realities of limited genomic diagnostic yields and not infrequent detection of variants of uncertain significance, lack of natural history study data and management guidelines for individually rare neurogenetic conditions, means that high pre-genomic test expectations are all too often replaced by an accumulation of new uncertainties. This can add to the chronic traumatic stress experienced by many families but may also have under-recognised impacts for their clinicians, contributing to 'burn-out' and attendant negative psychosocial impacts. This first article aims to address how clinicians might manage the accumulation of uncertainties to be more helpful to patients and their families. Moreover, it seeks to address how clinicians can move forward providing compassionate care to their patients and a little more consideration for themselves.

The genetic counseling in a patient affected by congenital polyneuropathy after a "diagnostic odyssey" recently solved with WES approach.

Counseling after WES/WGS presents challenges for healthcare providers as the availability of consumer-driven is rapidly increasing. The present report uncovers an extremely rare homozygous nonsense mutation c. 1639C>T (p.Gln547Ter) in PRX gene of a patient with heterogeneous manifestation of Charcot-Marie-Tooth. Such studies can help to conduct genetic counseling and subsequently more accurate support to individual cases with neuro-genetic conditions and solved through whole genome/exome-wide screening.

Neurogenetic disorders across the lifespan: from aberrant development to degeneration.

Intellectual disability and autism spectrum disorder (ASD) are common, and genetic testing is increasingly performed in individuals with these diagnoses to inform prognosis, refine management and provide information about recurrence risk in the family. For neurogenetic conditions associated with intellectual disability and ASD, data on natural history in adults are scarce; however, as older adults with these disorders are identified, it is becoming clear that some conditions are associated with both neurodevelopmental problems and neurodegeneration. Moreover, emerging evidence indicates that some neurogenetic conditions associated primarily with neurodegeneration also affect neurodevelopment. In this Perspective, we discuss examples of diseases that have developmental and degenerative overlap. We propose that neurogenetic disorders should be studied continually across the lifespan to understand the roles of the affected genes in brain development and maintenance, and to inform strategies for treatment.

Compulsively Moral: OCD, Ethics, and the Law.

Compulsively Moral: OCD, Ethics, and the Law.

Behavioral Inflexibility Across Two Neurogenetic Conditions: Down Syndrome and Fragile X Syndrome.

Behavioral inflexibility (BI) has been highlighted to occur across genetic and neurodevelopmental disorders. This study characterized BI in two common neurogenetic conditions: Fragile X syndrome (FXS) and Down syndrome (DS). Caregivers of children with FXS (N = 56; with ASD = 28; FXS only = 28) and DS (N = 146) completed the Behavioral Inflexibility Scale (BIS) via an online survey. Total BIS scores were higher in FXS+ASD than both FXS only and DS (p <.001). Most endorsed items were similar across the three groups, but scores were higher in the FXS+ASD group. In all groups, BI associated with other clinical variables (receptive behaviors, anxiety, social communication). The current data suggest that BI is variable across neurogenetic conditions and higher in individuals with comorbid ASD.

Acceptability and Effectiveness of Humor- and Play-Infused Exposure Therapy for Fears in Williams Syndrome

ABSTRACT Children with Williams syndrome often experience anxieties and fears, yet there are no published studies examining the effectiveness of psychological interventions to address these challenges. In the current study, we present a case series of nine young children with Williams syndrome ages 4 through 10 who participated in a play- and humor-infused approach to exposure therapy in several sessions over a 2–3 day period. Functional assessment was conducted to identify intervention targets. Symptom severity was tracked before the intervention. Following the intervention, symptom severity was once again tracked and measures of treatment acceptability were completed. Longer-term follow-up was also conducted 10–22 months after the intervention with parental ratings and narrative feedback. Results support the promise of this approach for reducing fears and anxieties in children with Williams syndrome. The impact of individual differences on treatment response and direction for further enhancements to the intervention to maximize its effectiveness and accessibility are discussed. Further, implications of this approach for intervention development with children with rare neurogenetic conditions are explored.