Publications by authors named "Elizabeth Berry-Kravis"

223 Publications

Cell-type-specific profiling of human cellular models of fragile X syndrome reveal PI3K-dependent defects in translation and neurogenesis.

Cell Rep 2021 Apr;35(2):108991

Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address:

Transcriptional silencing of the FMR1 gene in fragile X syndrome (FXS) leads to the loss of the RNA-binding protein FMRP. In addition to regulating mRNA translation and protein synthesis, emerging evidence suggests that FMRP acts to coordinate proliferation and differentiation during early neural development. However, whether loss of FMRP-mediated translational control is related to impaired cell fate specification in the developing human brain remains unknown. Here, we use human patient induced pluripotent stem cell (iPSC)-derived neural progenitor cells and organoids to model neurogenesis in FXS. We developed a high-throughput, in vitro assay that allows for the simultaneous quantification of protein synthesis and proliferation within defined neural subpopulations. We demonstrate that abnormal protein synthesis in FXS is coupled to altered cellular decisions to favor proliferative over neurogenic cell fates during early development. Furthermore, pharmacologic inhibition of elevated phosphoinositide 3-kinase (PI3K) signaling corrects both excess protein synthesis and cell proliferation in a subset of patient neural cells.
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http://dx.doi.org/10.1016/j.celrep.2021.108991DOI Listing
April 2021

Spoken language outcome measures for treatment studies in Down syndrome: feasibility, practice effects, test-retest reliability, and construct validity of variables generated from expressive language sampling.

J Neurodev Disord 2021 Apr 8;13(1):13. Epub 2021 Apr 8.

MIND Institute, University of California Davis Health, 2825 50th Street, Sacramento, CA, USA.

Background: The purpose of this study was to evaluate expressive language sampling (ELS) as a procedure for generating spoken language outcome measures for treatment research in Down syndrome (DS). We addressed (a) feasibility, (b) practice effects across two short-term administrations, (c) test-retest reliability across two short-term administrations, (d) convergent and discriminant construct validity, and (e) considered comparisons across the conversation and narration contexts.

Method: Participants were 107 individuals with DS between 6 and 23 years of age who presented with intellectual disability (IQ < 70). The utility of ELS procedures designed to collect samples of spoken language in conversation and narration were evaluated separately. Variables of talkativeness, vocabulary, syntax, utterance planning, and articulation quality, derived from transcripts segmented into C-units (i.e., an independent clause and its modifiers), were considered. A 4-week interval was used to assess practice effects and test-retest reliability. Standardized direct assessments and informant report measures were collected to evaluate construct validity of the ELS variables.

Results: Low rates of noncompliance were observed; youth who were under 12 years of age, had phrase-level speech or less, and had a 4-year-old developmental level or less were at particular risk for experiencing difficulty completing the ELS procedures. Minimal practice effects and strong test-retest reliability across the 4-week test-retest interval was observed. The vocabulary, syntax, and speech intelligibility variables demonstrated strong convergent and discriminant validity. Although significant correlations were found between the variables derived from both the conversation and narration contexts, some differences were noted.

Conclusion: The ELS procedures considered were feasible and yielded variables with adequate psychometric properties for most individuals with DS between 6 and 23 years old. That said, studies of outcome measures appropriate for individuals with DS with more limited spoken language skills are needed. Context differences were observed in ELS variables suggest that comprehensive evaluation of expressive language is likely best obtained when utilizing both contexts.
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http://dx.doi.org/10.1186/s11689-021-09361-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028777PMC
April 2021

Diagnostic profile of the AmplideX Fragile X Dx and Carrier Screen Kit for diagnosis and screening of fragile X syndrome and other FMR1-related disorders.

Expert Rev Mol Diagn 2021 Mar 29:1-13. Epub 2021 Mar 29.

Department of Biochemistry and Molecular Medicine, University of California Davis, School of Medicine, Sacramento, CA, USA.

: In 2009, a novel, CGG repeat primed PCR assay was designed with primers flanking the triplet repeat region, as well as a third chimeric primer complementary to the (CGG)n repeat, that was capable of amplifying alleles throughout the repeat range. This assay for the first time allowed consistent detection of large full mutation alleles with PCR, resolution of heterozygosity in females and mapping of AGG interspersions.: The AmplideX Fragile X Dx and Carrier Screen Kit (Asuragen, Inc.) represents a refined assay that underwent validation with sensitivity analyses for FDA approval. Single-site precision, analytical sensitivity and specificity, limit of detection and diagnostic performance were assessed in comparison to reference methods at three independent sites. Single-site precision across all genotype categories showed 100% agreement at 20 ng input across multiple operators, days, instruments and kit lots. Compared to Southern Blot analysis, the overall percent agreement was over 98% for all expanded alleles.: Limitations include no methylation assessment and hard to see full mutation peaks in some mosaic samples, but overall the assay is considered a highly accurate and time-efficient assay for allele size determination.
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http://dx.doi.org/10.1080/14737159.2021.1899812DOI Listing
March 2021

A Unique Visual Attention Profile Associated With the Premutation.

Front Genet 2021 9;12:591211. Epub 2021 Feb 9.

Roxelyn and Richard Pepper Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL, United States.

Atypical visual attention patterns have been observed among carriers of the fragile X mental retardation gene () premutation (PM), with some similarities to visual attention patterns observed in autism spectrum disorder (ASD) and among clinically unaffected relatives of individuals with ASD. Patterns of visual attention could constitute biomarkers that can help to inform the neurocognitive profile of the PM, and that potentially span diagnostic boundaries. This study examined patterns of eye movement across an array of fixation measurements from three distinct eye-tracking tasks in order to investigate potentially overlapping profiles of visual attention among PM carriers, ASD parents, and parent controls. Logistic regression analyses were conducted to examine whether variables constituting a PM-specific looking profile were able to effectively predict group membership. Participants included 65PM female carriers, 188 ASD parents, and 84 parent controls. Analyses of fixations across the eye-tracking tasks, and their corresponding areas of interest, revealed a distinct visual attention pattern in carriers of the PM, characterized by increased fixations on the mouth when viewing faces, more intense focus on bodies in socially complex scenes, and decreased fixations on salient characters and faces while narrating a wordless picture book. This set of variables was able to successfully differentiate individuals with the PM from controls (Sensitivity = 0.76, Specificity = 0.85, Accuracy = 0.77) as well as from ASD parents (Sensitivity = 0.70, Specificity = 0.80, Accuracy = 0.72), but did not show a strong distinction between ASD parents and controls (Accuracy = 0.62), indicating that this set of variables comprises a profile that is unique to PM carriers. Regarding predictive power, fixations toward the mouth when viewing faces was able to differentiate PM carriers from both ASD parents and controls, whereas fixations toward other social stimuli did not differentiate PM carriers from ASD parents, highlighting some overlap in visual attention patterns that could point toward shared neurobiological mechanisms. Results demonstrate a profile of visual attention that appears strongly associated with the PM in women, and may constitute a meaningful biomarker.
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http://dx.doi.org/10.3389/fgene.2021.591211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901883PMC
February 2021

Application of a glycinated bile acid biomarker for diagnosis and assessment of response to treatment in Niemann-pick disease type C1.

Mol Genet Metab 2020 12 18;131(4):405-417. Epub 2020 Nov 18.

Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Niemann-Pick disease type C (NPC) is a neurodegenerative disease in which mutation of NPC1 or NPC2 gene leads to lysosomal accumulation of unesterified cholesterol and sphingolipids. Diagnosis of NPC disease is challenging due to non-specific early symptoms. Biomarker and genetic tests are used as first-line diagnostic tests for NPC. In this study, we developed a plasma test based on N-(3β,5α,6β-trihydroxy-cholan-24-oyl)glycine (TCG) that was markedly increased in the plasma of human NPC1 subjects. The test showed sensitivity of 0.9945 and specificity of 0.9982 to differentiate individuals with NPC1 from NPC1 carriers and controls. Compared to other commonly used biomarkers, cholestane-3β,5α,6β-triol (C-triol) and N-palmitoyl-O-phosphocholine (PPCS, also referred to as lysoSM-509), TCG was equally sensitive for identifying NPC1 but more specific. Unlike C-triol and PPCS, TCG showed excellent stability and no spurious generation of marker in the sample preparation or aging of samples. TCG was also elevated in lysosomal acid lipase deficiency (LALD) and acid sphingomyelinase deficiency (ASMD). Plasma TCG was significantly reduced after intravenous (IV) 2-hydroxypropyl-β-cyclodextrin (HPβCD) treatment. These results demonstrate that plasma TCG was superior to C-triol and PPCS as NPC1 diagnostic biomarker and was able to evaluate the peripheral treatment efficacy of IV HPβCD treatment.
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http://dx.doi.org/10.1016/j.ymgme.2020.11.005DOI Listing
December 2020

Reduced Expression of Cerebral Metabotropic Glutamate Receptor Subtype 5 in Men with Fragile X Syndrome.

Brain Sci 2020 Nov 24;10(12). Epub 2020 Nov 24.

Department of Psychiatry and Behavioral Sciences-Child Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Glutamatergic receptor expression is mostly unknown in adults with fragile X syndrome (FXS). Favorable behavioral effects of negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGluR) in knockout (KO) mouse models have not been confirmed in humans with FXS. Measurement of cerebral mGluR expression in humans with FXS exposed to NAMs might help in that effort. We used positron emission tomography (PET) to measure the mGluR density as a proxy of mGluR expression in cortical and subcortical brain regions to confirm target engagement of NAMs for mGluRs. The density and the distribution of mGluR were measured in two independent samples of men with FXS ( = 9) and typical development (TD) ( = 8). We showed the feasibility of this complex study including MRI and PET, meaning that this challenging protocol can be accomplished in men with FXS with an adequate preparation. Analysis of variance of estimated mGluR expression showed that mGluR expression was significantly reduced in cortical and subcortical regions of men with FXS in contrast to age-matched men with TD.
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http://dx.doi.org/10.3390/brainsci10120899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760509PMC
November 2020

Development of Neural Response to Novel Sounds in Fragile X Syndrome: Potential Biomarkers.

Am J Intellect Dev Disabil 2020 11;125(6):449-464

Andrew Thaliath, Jeremy Kraff, Karan Nijhawan, and Elizabeth Berry-Kravis, Rush University Medical Center, Chicago.

Auditory processing abnormalities in fragile X syndrome (FXS) may contribute to difficulties with language development, pattern identification, and contextual updating. Participants with FXS (N = 41) and controls (N = 27) underwent auditory event-related potentials during presentation of an oddball paradigm. Data was adequate for analysis for 33 participants with FXS and 27 controls (age 4-51 y, 13 females [FXS]; 4-54 y, 11 females [control]). Participants with FXS showed larger N1 and P2 amplitudes, abnormal lack of modulation of P1 and P2 amplitudes and P2 latency in response to oddball stimuli ) relative to controls: Females with FXS were more similar to controls. Participants with FXS showed a marginal speeding of the P2 latency, suggesting potentiation to oddball stimuli rather than habituation. Participants with FXS showed a heightened N1 habituation effect compared to controls. Gamma power was significantly higher for participants with FXS. Groups did not differ on mismatch negativity. Both controls and participants with FXS showed similar developmental trajectories in P1 and N1 amplitude, P2 latency, and gamma power, but not for P2 amplitude. One month retest analyses performed in 14 participants suggest strong test-retest reliability for most measures. Individuals with FXS show previously demonstrated increased response amplitude and high frequency neural activity. Despite an overall normal developmental trajectory for most measures, individuals with FXS show age-independent but gender-dependent decreases in complex processing of novel stimuli. Many markers show strong retest reliability even in children and thus are potential biomarkers for clinical trials in FXS.
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http://dx.doi.org/10.1352/1944-7558-125.6.449DOI Listing
November 2020

Person Ability Scores as an Alternative to Norm-Referenced Scores as Outcome Measures in Studies of Neurodevelopmental Disorders.

Am J Intellect Dev Disabil 2020 11;125(6):475-480

Judith S. Miller, University of Pennsylvania.

Although norm-referenced scores are essential to the identification of disability, they possess several features which affect their sensitivity to change. Norm-referenced scores often decrease over time among people with neurodevelopmental disorders who exhibit slower-than-average increases in ability. Further, the reliability of norm-referenced scores is lower at the tails of the distribution, resulting in floor effects and increased measurement error for people with neurodevelopmental disorders. In contrast, the person ability scores generated during the process of constructing a standardized test with item response theory are designed to assess change. We illustrate these limitations of norm-referenced scores, and relative advantages of ability scores, using data from studies of autism spectrum disorder and creatine transporter deficiency.
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http://dx.doi.org/10.1352/1944-7558-125.6.475DOI Listing
November 2020

The Effects of Dual Task Cognitive Interference and Fast-Paced Walking on Gait, Turns, and Falls in Men and Women with FXTAS.

Cerebellum 2021 Apr 28;20(2):212-221. Epub 2020 Oct 28.

Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, 60612, USA.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a genetic neurodegenerative disorder characterized by cerebellar ataxia, tremor, and cognitive dysfunction. We examined the impact of dual-task (DT) cognitive-motor interference and fast-paced (FP) gait on gait and turning in FXTAS. Thirty participants with FXTAS and 35 age-matched controls underwent gait analysis using an inertial sensor-based 2-min walk test under three conditions: (1) self-selected pace (ST), (2) FP, and (3) DT with a concurrent verbal fluency task. Linear regression analyses were performed to assess the association between FXTAS diagnosis and gait and turn outcomes. Correlations between gait variables and fall frequency were also calculated. FXTAS participants had reduced stride length and velocity, swing time, and peak turn velocity and greater double limb support time and number of steps to turn compared to controls under all three conditions. There was greater dual task cost of the verbal fluency task on peak turn velocity in men with FXTAS compared to controls. Additionally, stride length variability was increased and cadence was reduced in FXTAS participants in the FP condition. Stride velocity variability under FP gait was significantly associated with the number of self-reported falls in the last year. Greater motor control requirements for turning likely made men with FXTAS more susceptible to the negative effects of DT cognitive interference. FP gait exacerbated gait deficits in the domains of rhythm and variability, and increased gait variability with FP was associated with increased falls. These data may inform the design of rehabilitation strategies in FXTAS.
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http://dx.doi.org/10.1007/s12311-020-01199-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005408PMC
April 2021

Soy-Based Infant Formula is Associated with an Increased Prevalence of Comorbidities in Fragile X Syndrome.

Nutrients 2020 Oct 14;12(10). Epub 2020 Oct 14.

Department of Pediatrics, Rush University Medical Center, Chicago, IL 60612, USA.

A large number of adults and children consume soy in various forms, but little information is available regarding potential neurological side effects. Prior work indicates an association between the consumption of soy-based diets and seizure prevalence in mouse models of neurological disease and in children with autism. Herein, we sought to evaluate potential associations between the consumption of soy-based formula during infancy and disease comorbidities in persons with fragile X syndrome (FXS), while controlling for potentially confounding issues, through a retrospective case-control survey study of participants with FXS enrolled in the Fragile X Online Registry with Accessible Research Database (FORWARD). There was a 25% usage rate of soy-based infant formula in the study population. We found significant associations between the consumption of soy-based infant formula and the comorbidity of autism, gastrointestinal problems (GI) and allergies. Specifically, there was a 1.5-fold higher prevalence of autism, 1.9-fold GI problems and 1.7-fold allergies in participants reporting the use of soy-based infant formula. The major reason for starting soy-based infant formula was GI problems. The average age of seizure and allergy onset occurred long after the use of soy-based infant formula. We conclude that early-life feeding with soy-based infant formula is associated with the development of several disease comorbidities in FXS.
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http://dx.doi.org/10.3390/nu12103136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602206PMC
October 2020

Prodromal Markers of Upper Limb Deficits in Premutation Carriers and Quantitative Outcome Measures for Future Clinical Trials in Fragile X-associated Tremor/Ataxia Syndrome.

Mov Disord Clin Pract 2020 Oct 29;7(7):810-819. Epub 2020 Aug 29.

Department of Neurological Sciences Rush University Medical Center Chicago Illinois USA.

Background: Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a rare, late-onset neurodegenerative disorder characterized by tremor and cerebellar gait ataxia, affecting premutation carriers (PMC) of CGG expansions (range, 55-200) in the fragile X mental retardation 1 () gene. Discovery of early predictors for FXTAS and quantitative characterization of motor deficits are critical for identifying disease onset, monitoring disease progression, and determining efficacy of interventions.

Methods: A total of 39 PMC with FXTAS, 20 PMC without FXTAS, and 27 healthy controls performed a series of upper extremity (UE) motor tasks assessing tremor, bradykinesia, and rapid alternating movements that were quantified using an inertial-based sensor system (Kinesia One; Great Lakes NeuroTechnologies, Cleveland, OH, USA). Sub-scores from the clinician-rated FXTAS Rating Scale were correlated with the severity scores generated by the sensor system to determine its validity in FXTAS.

Results: PMC with FXTAS had significantly worse postural and kinetic tremor compared with PMC without FXTAS ( = 0.02, 0.03) and controls ( = 0.001, 0.0001), respectively, and slower finger tap ( = 0.001), hand movement ( = 0.0001), and rapid alternating movement speed ( = 0.003) and amplitude ( = 0.04) than controls. PMC without FXTAS had significantly worse right finger tap ( = 0.004), hand movement ( = 0.01), and rapid alternating movement speed ( = 0.003) and amplitude ( = 0.02) than controls. FXTAS Rating Scale subscores significantly correlated with all tremorography scores except for finger taps and left rapid alternating movement.

Conclusions: These findings support the use of inertial sensor quantification systems as promising measures for preclinical FXTAS symptom detection in PMC, characterization of the natural history of FXTAS, assessment of medication responses, and outcome assessment in clinical trials.
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http://dx.doi.org/10.1002/mdc3.13045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533995PMC
October 2020

A Genotype-Phenotype Study of High-Resolution Nucleic Acid and Protein Analyses in Fragile X Patients with Neurobehavioral Assessments.

Brain Sci 2020 Sep 30;10(10). Epub 2020 Sep 30.

Asuragen, Inc., Austin, TX 78744, USA.

Fragile X syndrome (FXS) is caused by silencing of the gene, which encodes a protein with a critical role in synaptic plasticity. The molecular abnormality underlying silencing, CGG repeat expansion, is well characterized; however, delineation of the pathway from DNA to RNA to protein using biosamples from well characterized patients with FXS is limited. Since FXS is a common and prototypical genetic disorder associated with intellectual disability (ID) and autism spectrum disorder (ASD), a comprehensive assessment of the DNA-RNA-protein pathway and its correlations with the neurobehavioral phenotype is a priority. We applied nine sensitive and quantitative assays evaluating DNA, RNA, and FMRP parameters to a reference set of cell lines representing the range of expansions. We then used the most informative of these assays on blood and buccal specimens from cohorts of patients with different expansions, with emphasis on those with FXS (N = 42 total, N = 31 with FMRP measurements). The group with FMRP data was also evaluated comprehensively in terms of its neurobehavioral profile, which allowed molecular-neurobehavioral correlations. CGG repeat expansions, methylation levels, and FMRP levels, in both cell lines and blood samples, were consistent with findings of previous genomic and protein studies. They also demonstrated a high level of agreement between blood and buccal specimens. These assays further corroborated previous reports of the relatively high prevalence of methylation mosaicism (slightly over 50% of the samples). Molecular-neurobehavioral correlations confirmed the inverse relationship between overall severity of the FXS phenotype and decrease in FMRP levels (N = 26 males, mean 4.2 ± 3.3 pg FMRP/ng genomic DNA). Other intriguing findings included a significant relationship between the diagnosis of FXS with ASD and two-fold lower levels of FMRP (mean 2.8 ± 1.3 pg FMRP/ng genomic DNA, = 0.04), in particular observed in younger age- and IQ-adjusted males (mean age 6.9 ± 0.9 years with mean 3.2 ± 1.2 pg FMRP/ng genomic DNA, 57% with severe ASD), compared to FXS without ASD. Those with severe ID had even lower FMRP levels independent of ASD status in the male-only subset. The results underscore the link between expansion, gene methylation, and FMRP deficit. The association between FMRP deficiency and overall severity of the neurobehavioral phenotype invites follow up studies in larger patient cohorts. They would be valuable to confirm and potentially extend our initial findings of the relationship between ASD and other neurobehavioral features and the magnitude of FMRP deficit. Molecular profiling of individuals with FXS may have important implications in research and clinical practice.
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http://dx.doi.org/10.3390/brainsci10100694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601415PMC
September 2020

Response to Placebo in Fragile X Syndrome Clinical Trials: An Initial Analysis.

Brain Sci 2020 Sep 11;10(9). Epub 2020 Sep 11.

Kennedy Krieger Institute/The Johns Hopkins Medical Institutions, Department of Psychiatry & Behavioral Sciences-Child Psychiatry, the Johns Hopkins University School of Medicine, 1741 Ashland Ave, Rm 241, Baltimore, MD 21205, USA.

Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability and autism spectrum disorder. Individuals with FXS often present with a wide range of cognitive deficits and problem behaviors. Educational, behavioral and pharmacological interventions are used to manage these and other complex issues affecting individuals with FXS. Despite the success of preclinical models and early-phase drug clinical studies in FXS, large-scale randomized-controlled trials have failed to meet primary endpoints. Currently, no targeted or disease-modifying treatments for FXS have received regulatory approval. Here, we examined the placebo response in FXS clinical trials conducted between 2006 and 2018. Specifically, we performed a meta-analysis of placebo-treated groups in eight double-blind, randomized controlled trials. Placebo groups demonstrated significant improvements on caregiver-rated efficacy endpoints, which were greater in adolescents and adults than in children. Among the latter measures, the Visual Analog Scale scores displayed the greatest improvements, whereas the positive effects on the Vineland-II Adaptive Behavior Composite and the Aberrant Behavior Checklist-Community/fragile X version were statistically significant in both children and adolescents/adults. Although the Clinical Global Impression scale Improvement appears to have exhibited a substantial placebo effect in multiple clinical trials in FXS, limited data availability for meta-analysis, prevented us from drawing conclusions. No placebo-related improvements were observed in performance-rated measures. These findings raise substantial concerns about placebo effects in outcome measures commonly used in the randomized-controlled trials in FXS and suggest several potential improvements in the study design and implementation of such trials. Considering the small number of trials available for this study, larger and more detailed follow up meta-analyses are needed. Meanwhile, efforts to improve the measurement properties of endpoints and rater training in drug trials in FXS should be prioritized.
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http://dx.doi.org/10.3390/brainsci10090629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563217PMC
September 2020

Optimization of Protocols for Detection of De Novo Protein Synthesis in Whole Blood Samples via Azide-Alkyne Cycloaddition.

J Proteome Res 2020 09 20;19(9):3856-3866. Epub 2020 Aug 20.

Centre for Brain Development and Repair, Institute for Stem Cell Science and Regenerative Medicine, Bangalore 560065, India.

Aberrant protein synthesis and protein expression are a hallmark of many conditions ranging from cancer to Alzheimer's. Blood-based biomarkers indicative of changes in proteomes have long been held to be potentially useful with respect to disease prognosis and treatment. However, most biomarker efforts have focused on unlabeled plasma proteomics that include nonmyeloid origin proteins with no attempt to dynamically tag acute changes in proteomes. Herein we report a method for evaluating de novo protein synthesis in whole blood liquid biopsies. Using a modification of the "bioorthogonal noncanonical amino acid tagging" (BONCAT) protocol, rodent whole blood samples were incubated with l-azidohomoalanine (AHA) to allow incorporation of this selectively reactive non-natural amino acid within nascent polypeptides. Notably, failure to incubate the blood samples with EDTA prior to implementation of azide-alkyne "click" reactions resulted in the inability to detect probe incorporation. This live-labeling assay was sensitive to inhibition with anisomycin and nascent, tagged polypeptides were localized to a variety of blood cells using FUNCAT. Using labeled rodent blood, these tagged peptides could be consistently identified through standard LC/MS-MS detection of known blood proteins across a variety of experimental conditions. Furthermore, this assay could be expanded to measure de novo protein synthesis in human blood samples. Overall, we present a rapid and convenient de novo protein synthesis assay that can be used with whole blood biopsies that can quantify translational change as well as identify differentially expressed proteins that may be useful for clinical applications.
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http://dx.doi.org/10.1021/acs.jproteome.0c00299DOI Listing
September 2020

Intracerebroventricular Cerliponase Alfa for Neuronal Ceroid Lipofuscinosis Type 2 Disease: Clinical Practice Considerations From US Clinics.

Pediatr Neurol 2020 09 4;110:64-70. Epub 2020 May 4.

Department of Pediatrics, Irvine School of Medicine, University of California, Orange, California; Department of Metabolic Disorders, Children's Hospital of Orange County, CHOC Children's Specialists, Orange, California.

Background: Neuronal ceroid lipofuscinosis type 2 or CLN2 disease is a rare, autosomal recessive, neurodegenerative lysosomal storage disorder caused by tripeptidyl peptidase 1 deficiency. Cerliponase alfa, a recombinant human tripeptidyl peptidase 1 enzyme, is the first and only approved treatment for CLN2 disease and the first approved enzyme replacement therapy administered via intracerebroventricular infusion.

Methods: A meeting of health care professionals from US institutions with experience in cerliponase alfa treatment of children with CLN2 disease was held in November 2018. Key common practices were identified, and later refined during the drafting of this article, that facilitate safe chronic administration of cerliponase alfa.

Results: Key practices include developing a multidisciplinary team of clinicians, pharmacists, and coordinators, and institution-specific processes. Infection risk may be reduced through strict aseptic techniques and minimizing connections and disconnections during infusion. The impact of intracerebroventricular device design on port needle stability during extended intracerebroventricular infusion is a critical consideration in device selection. Monitoring for central nervous system infection is performed at each patient contact, but with flexibility in the degree of monitoring. Although few institutions had experienced positive cerebrospinal fluid test results, the response to a positive cerebrospinal fluid culture should be determined on a case-by-case basis, and the intracerebroventricular device should be removed if cerebrospinal fluid infection is confirmed.

Conclusions: The key common practices and flexible practices used by institutions with cerliponase alfa experience may assist other institutions in process development. Continued sharing of experiences will be essential for developing standards and patient care guidelines.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.04.018DOI Listing
September 2020

A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the Treatment of Fragile X Syndrome.

Pediatr Neurol 2020 09 23;110:30-41. Epub 2020 May 23.

Neuren Pharmaceuticals, Ltd., Melbourne, Victoria, Australia.

Background: We analyze the safety and tolerability of trofinetide and provide a preliminary evaluation of its efficacy in adolescent and adult males with fragile X syndrome.

Methods: This study was an exploratory, phase 2, multicenter, double-blind, placebo-controlled, parallel group study of the safety and tolerability of orally administered trofinetide in 72 adolescent and adult males with fragile X syndrome. Subjects were randomly assigned in a 1:1:1 ratio to 35 or 70 mg/kg twice daily trofinetide or placebo for 28 days. Safety assessments included adverse events, clinical laboratory tests, vital signs, electrocardiograms, physical examinations, and concomitant medications. Efficacy measurements were categorized into four efficacy domains, which related to clinically relevant phenotypic dimensions of impairment associated with fragile X syndrome.

Results: Both 35 and 70 mg/kg dose levels of trofinetide were well tolerated and appeared to be generally safe. Trofinetide at the 70 mg/kg dose level demonstrated efficacy compared with placebo based on prespecified criteria. On the basis of a permutation test, the probability of a false-positive outcome for the achieved prespecified success was 0.045. In the group analysis, improvement from treatment baseline was demonstrated on three fragile X syndrome-specific outcome measures.

Conclusions: Trofinetide was well tolerated in adolescent and adult males with fragile X syndrome. Despite the relatively short duration of the study, a consistent signal of efficacy at the higher dose was observed in both caregiver and clinician assessments, based on a novel analytical model incorporating evaluation of multiple key symptom areas of fragile X syndrome. This finding suggests a potential for trofinetide treatment to provide clinically meaningful improvement in core fragile X syndrome symptoms.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.04.019DOI Listing
September 2020

Normative database of spatiotemporal gait parameters using inertial sensors in typically developing children and young adults.

Gait Posture 2020 07 21;80:206-213. Epub 2020 May 21.

Department of Occupational Therapy, Rush University, Chicago, IL, United States; Department of Cell & Molecular Medicine, Rush University, Chicago, IL, United States; Department of Neurological Sciences, Rush University, Chicago, IL, United States. Electronic address:

Background: Inertial sensors are increasingly useful to clinicians and researchers to detect gait deficits. Reference values are necessary for comparison to children with gait abnormalities.

Objective: To present a normative database of spatiotemporal gait and turning parameters in 164 typically developing children and young adults ages 5-30 utilizing the APDM Mobility Lab® system.

Methods: Participants completed the i-WALK test at both self-selected (SS) and fast as possible (FAP) walking speeds. Spatiotemporal gait and turning parameters included stride length, stride length variability, gait speed, cadence, stance, swing, and double support times, and foot strike, toe-off, and toe-out angles, turn duration, peak turn velocity and number of steps to turn.

Results: Absolute stride length and gait speed increased with age. Normalized gait speed, absolute and normalized cadence, and stride length variability decreased with age. Normalized stride length and all parameters of gait cycle phase and foot position remained unaffected by age except for greater FSA in children 7-8. Foot position parameters in children 5-6 were excluded due to aberrant values and high standard deviations. Turns were faster in children ages 5-13 and 7-13 in the SS and FAP conditions, respectively. There were no differences in number of steps to turn. Similar trends were observed in the FAP condition except: normalized gait speed did not demonstrate a relationship with age and children ages 5-8 demonstrated increased stance and double support times and decreased swing time compared to children 11-13 and young adults (ages 5-6 only). Females ages 5-6 demonstrated increased stride length variability in the SS condition; males ages 7-8 and 14-30 ha d increased absolute stride length in the FAP condition. Similarities and differences were found between our values and previous literature.

Significance: This normative database can be used by clinicians and researchers to compare abnormal gait patterns and responses to interventions.
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http://dx.doi.org/10.1016/j.gaitpost.2020.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388584PMC
July 2020

Fragile X Gray Zone Alleles Are Associated With Signs of Parkinsonism and Earlier Death.

Mov Disord 2020 08 28;35(8):1448-1456. Epub 2020 May 28.

Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.

Background: Premutation size (55-199 CGG repeats) in the fragile X mental retardation 1 (FMR1) gene cause fragile X-associated tremor/ataxia syndrome, but it is unclear whether smaller "gray" zone expansions of 41-54 repeats are also associated with movement disorders. The objectives of this study were to determine the association between the FMR1 gene gray zone expansions, AGG interspersions, and the presence of parkinsonism and motor and cognitive function in an elderly community-based population.

Methods: Automated FMR1 polymerase chain reaction was performed on existing samples from 2 longitudinal aging studies whose subjects agreed to brain donation. A detailed clinical evaluation including a modified Unified Parkinson's Disease Rating Scale score, a composite score of global motor function, 17 cognitive tests summarized as a global measure of cognition, and neuropathological examination were obtained for genotyped participants.

Results: The average age of the population (n = 2362) was 85.9 ± 7.3 years, and average age at death was 88.6 ± 6.4 years (n = 1326), with 72% women. The prevalence of FMR1 gray zone alleles was 5.2% (122 of 2362). There was no difference between participants with gray zone expansions or those lacking AGG interspersions compared with normal participants in global cognition, global motor function, clinical diagnosis, or pathological changes. Gray zone alleles were associated with signs of parkinsonism in men (P = 0.01), and gray zone carrier men were more likely to die (hazard ratio, 2.34; 95% confidence interval, 1.31-4.16).

Conclusions: This is the largest study to investigate gray zone alleles in a community population. The key findings are that in men, the gray zone allele is associated with signs of parkinsonism and higher risk of death, but not with intranuclear neuronal inclusions. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28086DOI Listing
August 2020

Psychometric Study of the Social Responsiveness Scale in Phelan-McDermid Syndrome.

Autism Res 2020 08 14;13(8):1383-1396. Epub 2020 May 14.

Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

The Social Responsiveness Scale-2 (SRS-2) is a quantitative measure used to characterize symptoms of autism spectrum disorder (ASD). However, research suggests that SRS-2 scores are significantly influenced by language ability and intellectual disability (ID). Efforts to refine the SRS-2 by Sturm, Kuhfeld, Kasari, and Mccracken [Journal of Child Psychology and Psychiatry, 58(9), 1053-1061] yielded a shortened form, yet its psychometric properties in populations with severe ID remain unknown. This study aims to examine the psychometric properties of the SRS-2 in Phelan-McDermid syndrome (PMS), a genetic condition associated with ASD and ID, thereby guiding score interpretation in this population and future development of targeted scales. Analyses, including Item Response Theory (IRT), were conducted on a sample of individuals with PMS (n = 91) recruited at six sites nationally. Psychometric properties evaluated include measures of reliability (internal consistency, test-retest reliability) and validity (structural, construct, content). While both SRS-2 forms are reliable, the shortened SRS-2 shows superior validity to the full SRS-2 for measuring ASD symptoms in PMS. On IRT analysis, the shortened SRS-2 shows excellent discrimination and precisely evaluates respondents across a wide range of ASD symptomatology but interpretation is limited by uncertain content validity and small sample size. The shortened SRS-2 shows some promise for use in PMS, but future refinements and additions are needed to develop items that are tailored to identify ASD in children with severe ID and specifically PMS. LAY SUMMARY: This study determined that a shortened form of the Social Responsiveness Scale, Second Edition (SRS-2) shows both promise and limitations for the characterization of autism symptomatology in individuals with Phelan-McDermid syndrome (PMS), a population characterized by intellectual disability (ID). Caution should be used when interpreting SRS-2 scores in individuals with ID and future research should modify existing items and develop new items to improve the SRS-2's ability to accurately characterize autism symptomatology in PMS. Autism Res 2020, 13: 1383-1396. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/aur.2299DOI Listing
August 2020

Anesthetic management of pediatric patients with Niemann-Pick disease type C for intrathecal 2-hydroxypropyl-β-cyclodextrin injection.

Paediatr Anaesth 2020 07 18;30(7):766-772. Epub 2020 May 18.

Department of Neurology, Rush University, Chicago, USA.

Background: Niemann-Pick disease type C is an autosomal-recessive, lysosomal storage disorder with variable age of onset and a heterogeneous clinical presentation that includes neurological, psychiatric, and visceral findings. Serial intrathecal injections of 2-hydroxypropyl-beta-cyclodextrin are being evaluated as a treatment modality for Niemann-Pick disease type C with a subset of patients requiring anesthesia for this procedure.

Aims: The aim of this study was to evaluate the safety of anesthesia provided for patients undergoing intrathecal injection of 2-hydroxypropyl-beta-cyclodextrin.

Methods: A retrospective review of pediatric patients who received serial intrathecal injections of 2-hydroxypropyl-beta-cyclodextrin with anesthesia at two tertiary care centers was conducted from December 2015 through April 2019. Data were extracted for analysis included preoperative comorbidities, demographics, vital signs, intraoperative anesthesia course, airway management technique, venous access, postoperative course, and perioperative complications. In total, 19 patients were identified and a total of 394 anesthetic encounters were included in this study.

Results: All 394 2-hydroxypropyl-beta-cyclodextrin administration procedures were successfully performed, and there were no changes made in the anesthetic plan during the anesthesia encounters. Three hundred forty-nine anesthetics were performed utilizing inhalation induction and mask maintenance, and 45 anesthetics were performed with placement of a supraglottic airway device due to patient body habitus and provider preference. The incidence of a major adverse event (aspirations, arterial desaturation) was 5/394 (1.3%, 95% CI 0.05%-3.1%). Minor adverse events (emesis, delirium, hypotension, seizure, and airway obstruction) were observed in 19/394 encounters (4.8%, 95% CI 3.0%-7.5%).

Conclusions: Our findings suggest that general anesthesia induced via inhalation induction and maintained with volatile anesthetic via mask or supraglottic airway is a safe and effective option for pediatric patients with Niemann-Pick disease type C undergoing serial intrathecal injections of 2-hydroxypropyl-beta-cyclodextrin, supporting this technique as a viable option for anesthetic care in these patients.
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http://dx.doi.org/10.1111/pan.13902DOI Listing
July 2020

Delineating Repetitive Behavior Profiles across the Lifespan in Fragile X Syndrome.

Brain Sci 2020 Apr 17;10(4). Epub 2020 Apr 17.

Division of Child and Adolescent Psychiatry, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

Restricted repetitive behaviors (RRBs) are a core area of impairment in autism spectrum disorder (ASD), but also affect several other neurodevelopmental disorders including fragile X syndrome (FXS). Current literature has begun to describe the RRB profile in FXS up through adolescence; however, little is known about the subtypes of RRBs in adolescents and adults. Further, literature on the RRB profile of females with FXS is limited. The present study examines the RRB profile across subtypes and specific items in both males and females with FXS while assessing for differences based on age, ASD diagnosis and the impact of IQ. Participants included 154 individuals with FXS (ages 2 to 50 years old). Results revealed a peak in RRB severity in FXS between 7-12 years for the majority of RRB subscales with the exception of Sensory-Motor behaviors peaking between 2 and 12 years before declining. Distinct RRB profiles in males and females with FXS emerged in addition to significant overlap among the item and subscale levels of RRBs across gender. Further, an added diagnosis of ASD significantly increased rates of RRBs across all subscale levels, but not necessarily across all items. Lastly, IQ did not solely account for the presence of RRBs in FXS, with Sensory-Motor behaviors being driven by comorbid ASD in males with FXS, and Restricted Interest behaviors being driven by comorbid ASD regardless of gender. These findings build on the current understanding of RRBs in FXS based on gender and comorbid ASD and lay important groundwork for the development of targeted behavioral and pharmacological treatments.
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http://dx.doi.org/10.3390/brainsci10040239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226450PMC
April 2020

Examination of Correlates to Health-Related Quality of Life in Individuals with Fragile X Syndrome.

Brain Sci 2020 Apr 4;10(4). Epub 2020 Apr 4.

Division of Child and Adolescent Psychiatry, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

Health-related quality of life (HRQoL) is a multidimensional concept involving physical, psychological, social, and cognitive aspects of life. Individuals with Fragile X syndrome (FXS) experience a life-long disorder that impacts the HRQoL of the affected individual and their family. Thus, HRQoL may be an important outcome measure following intervention. However, it is yet not known whether HRQoL concerns relate to observed impairments in FXS. In the present study, we examined the nature and degree of association between HRQoL and established measures of functioning in FXS using the Parent Report for Children version of the PedsQL 4.0 Generic Core Scales and Cognitive Functioning Scale. We observed significant relationships between HRQoL a nd measures of adaptive behavior, maladaptive behaviors, and social functioning. The present study has implications for treatment outcomes for clinical trials in FXS.
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http://dx.doi.org/10.3390/brainsci10040213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226021PMC
April 2020

Language across the Lifespan in Fragile X Syndrome: Characteristics and Considerations for Assessment.

Brain Sci 2020 Apr 4;10(4). Epub 2020 Apr 4.

Departments of Pediatrics, Neurological Sciences, Biochemistry, Rush University Medical Center, Chicago, IL 60612, USA.

While it is widely acknowledged that language development is delayed for the majority of individuals with fragile X syndrome (FXS), there has been limited research into how best to assess this area. This study aimed to deepen the understanding of standardized language assessment in FXS by addressing the three following objectives: (1) Examine the feasibility and validity of widely-used, standardized assessments in participants with FXS; (2) describe linguistic and cognitive profiles for a large sample of individuals with FXS; and (3) Compare results obtained from objective testing in clinic to those obtained using caregiver report. Results indicate that previous results indicating strong correlations between cognition and language results hold true across a wide range of ages as well as across multiple assessments, with an exception in very young children. Caregiver report tended to give lower estimates of language ability than what was found using an objectively administered assessment. Appropriate assessments remain difficult to find as a significant percentage of individuals scored at floor when scaled scores were calculated. Further, a sub-group of participants were coded for behavioral response to testing demands, the majority being able to complete a standardized assessment. These results speak to the need for assessments that provide a wider range of items so individuals can both achieve a valid score and demonstrate progress in their attainment of language skills.
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http://dx.doi.org/10.3390/brainsci10040212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226519PMC
April 2020

Correction to: Expressive language sampling as a source of outcome measures for treatment studies in fragile X syndrome: feasibility, practice effects, test-retest reliability, and construct validity.

J Neurodev Disord 2020 04 2;12(1):11. Epub 2020 Apr 2.

UC Davis MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California, 2825 50th St. Davis, Sacramento, CA, 95817, USA.

In the original publication of this article [1], the author name Leonard Abbeduto was misspelled as Leonardkk Abbeduto. The original article has been corrected.
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http://dx.doi.org/10.1186/s11689-020-09314-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7119274PMC
April 2020

TECPR2 mutation-associated respiratory dysregulation: more than central apnea.

J Clin Sleep Med 2020 06;16(6):977-982

Rush University Children's Hospital, Rush University Medical Center, Chicago, Illinois.

None: Children with rare genetic diseases that cause respiratory dysregulation are at particularly high mortality risk due to development of respiratory failure. The tectonin β-propeller-containing protein 2 (TECPR2) mutations are proposed to cause autophagy defect affecting axonal integrity and development of progressive neurodegenerative and neuromuscular disease. Published TECPR2 mutation cases have described a high prevalence of respiratory failure. We review respiratory pathology in previously published cases and a new case of a 5-year-old girl with previously undescribed TECPR2 mutation demonstrating progressive central apnea due to respiratory cycle dysregulation. This is the first TECPR2 mutation case to demonstrate an ataxic (Biot's) breathing pattern with consistently inconsistent inspiratory and expiratory times and with relatively intact chemoreception during sleep. Therefore, we propose that the central apnea index alone may not be the appropriate marker for mortality risk. Rather, the morbidity and mortality associated with TECPR2 mutations are multisystem in nature and this burden complicates the ultimate needs for ventilation support and prognosis.
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http://dx.doi.org/10.5664/jcsm.8434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849658PMC
June 2020

Expressive language sampling as a source of outcome measures for treatment studies in fragile X syndrome: feasibility, practice effects, test-retest reliability, and construct validity.

J Neurodev Disord 2020 03 24;12(1):10. Epub 2020 Mar 24.

UC Davis MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California, 2825 50th St. Davis, Sacramento, CA, 95817, USA.

Background: The evaluation of treatment efficacy for individuals with fragile X syndrome (FXS) or intellectual disability (ID) more generally has been hampered by the lack of adequate outcome measures. We evaluated expressive language sampling (ELS) as a procedure for generating outcome measures for treatment research in FXS. We addressed: (a) feasibility, (b) practice effects over two administrations, (c) test-retest reliability over the repeated administrations, and (d) construct validity. We addressed these issues for the full sample as well as for subgroups defined by age, IQ, and ASD status.

Methods: Participants were 106 individuals with FXS between ages 6 and 23 years who had IQs within the range of intellectual disability (IQ < 70). ELS procedures for collecting samples in conversation and narration were followed and analyzed separately. Five measures were derived from transcripts segmented into C-units (i.e., an independent clause and its modifiers): number of C-units per minute (talkativeness), number of different word roots (vocabulary), C-unit length in morphemes (syntax), percentage of C-units containing dysfluency (utterance planning), and percentage of C-units that were fully or partly unintelligible (articulatory quality). ELS procedures were administered twice at 4-week intervals for each participant. Standardized tests and informant reports were administered and provided measures for evaluating construct validity of ELS measures.

Results: We found low rates of noncompliance, suggesting the task can be completed meaningfully by most individuals with FXS, although noncompliance was higher for younger, lower IQ, and more autistic participants. Minimal practice effects and strong test-retest reliability over the 4-week interval were observed for the full sample and across the range of ages, IQs, and autism symptom severity. Evidence of convergent construct validity was observed for the measures of vocabulary, syntax, and unintelligibility for the full sample and across the range of IQ and autism symptom severity, but not for participants under age 12. Conversation and narration yielded largely similar results in all analyses.

Conclusions: The findings suggest that the ELS procedures are feasible and yield measures with adequate psychometric properties for a majority of 6 to 23 years with FXS who have ID. The procedures work equally well regardless of level of ID or degree of ASD severity. The procedures, however, are more challenging and have somewhat less adequate psychometric properties for individuals with FXS under age 12.
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http://dx.doi.org/10.1186/s11689-020-09313-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092603PMC
March 2020

Diffusion Tensor Imaging Abnormalities in the Uncinate Fasciculus and Inferior Longitudinal Fasciculus in Phelan-McDermid Syndrome.

Pediatr Neurol 2020 05 31;106:24-31. Epub 2020 Jan 31.

Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address:

Background: This cohort study utilized diffusion tensor imaging tractography to compare the uncinate fasciculus and inferior longitudinal fasciculus in children with Phelan-McDermid syndrome with age-matched controls and investigated trends between autism spectrum diagnosis and the integrity of the uncinate fasciculus and inferior longitudinal fasciculus white matter tracts.

Methods: This research was conducted under a longitudinal study that aims to map the genotype, phenotype, and natural history of Phelan-McDermid syndrome and identify biomarkers using neuroimaging (ClinicalTrial NCT02461420). Patients were aged three to 21 years and underwent longitudinal neuropsychologic assessment over 24 months. MRI processing and analyses were completed using previously validated image analysis software distributed as the Computational Radiology Kit (http://crl.med.harvard.edu/). Whole-brain connectivity was generated for each subject using a stochastic streamline tractography algorithm, and automatically defined regions of interest were used to map the uncinate fasciculus and inferior longitudinal fasciculus.

Results: There were 10 participants (50% male; mean age 11.17 years) with Phelan-McDermid syndrome (n = 8 with autism). Age-matched controls, enrolled in a separate longitudinal study (NIH R01 NS079788), underwent the same neuroimaging protocol. There was a statistically significant decrease in the uncinate fasciculus fractional anisotropy measure and a statistically significant increase in uncinate fasciculus mean diffusivity measure, in the patient group versus controls in both right and left tracts (P ≤ 0.024).

Conclusion: Because the uncinate fasciculus plays a critical role in social and emotional interaction, this tract may underlie some deficits seen in the Phelan-McDermid syndrome population. These findings need to be replicated in a larger cohort.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190002PMC
May 2020

Validation of the NIH Toolbox Cognitive Battery in intellectual disability.

Neurology 2020 03 24;94(12):e1229-e1240. Epub 2020 Feb 24.

From the University of California Davis Medical Center (R.H.S.); Human Development Graduate Group (R.H.S.), University of California Davis, Sacramento; Feinberg School of Medicine (A.J.K., R.C.G.), Northwestern University, Chicago, IL; MIND Institute and Department of Psychiatry and Behavioral Sciences (F.J.M., A.D., S.M.S., D.H.), University of California Davis Medical Center, Sacramento; Morgridge College of Education (J.C., K.R.), University of Denver, CO; Departments of Pediatrics (C.M., E.B.-K.) Neurological Sciences (E.B.-K.), and Biochemistry (E.B.-K.), Rush University Medical Center, Chicago, IL; and Graduate School of Education (K.F.W.), University of California, Riverside.

Objective: To advance the science of cognitive outcome measurement for individuals with intellectual disability (ID), we established administration guidelines and evaluated the psychometric properties of the NIH-Toolbox Cognitive Battery (NIHTB-CB) for use in clinical research.

Methods: We assessed feasibility, test-retest reliability, and convergent validity of the NIHTB-CB (measuring executive function, processing speed, memory, and language) by assessing 242 individuals with fragile X syndrome (FXS), Down syndrome (DS), and other ID, ages 6 through 25 years, with retesting completed after 1 month. To facilitate accessibility and measurement accuracy, we developed accommodations and standard assessment guidelines, documented in an e-manual. Finally, we assessed the sensitivity of the battery to expected syndrome-specific cognitive phenotypes.

Results: Above a mental age of 5.0 years, all tests had excellent feasibility. More varied feasibility across tests was seen between mental ages of 3 and 4 years. Reliability and convergent validity ranged from moderate to strong. Each test and the Crystallized and Fluid Composite scores correlated moderately to strongly with IQ, and the Crystallized Composite had modest correlations with adaptive behavior. The NIHTB-CB showed known-groups validity by detecting expected executive function deficits in FXS and a receptive language deficit in DS.

Conclusion: The NIHTB-CB is a reliable and valid test battery for children and young adults with ID with a mental age of ≈5 years and above. Adaptations for very low-functioning or younger children with ID are needed for some subtests to expand the developmental range of the battery. Studies examining sensitivity to developmental and treatment changes are now warranted.
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http://dx.doi.org/10.1212/WNL.0000000000009131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274932PMC
March 2020

Neurodevelopmental Characterization of Young Children Diagnosed with Niemann-Pick Disease, Type C1.

J Dev Behav Pediatr 2020 Jun/Jul;41(5):388-396

Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS, Bethesda, MD.

Objective: Niemann-Pick disease type C1 (NPC1) is a lysosomal storage disease characterized by progressive neurodegeneration, with the age of diagnosis ranging from the prenatal period through adulthood. Although neurological symptoms usually precede genetic diagnosis, they do not necessarily prompt diagnosis in the early years. Few prospective data are available to describe neurological onset, including neurodevelopmental delays, in children with NPC1. This dearth of information hinders the planning and implementation of adequate monitoring and treatment for the neurodevelopmental sequelae of NPC1.

Method: Twenty-nine infants, toddlers, and preschoolers younger than 6 years participated in a natural history study and were administered neurodevelopmental assessments using instruments commonly used for early intervention screening in the community.

Results: Twenty-two of 29 participants met the criteria for a significant delay of at least 1.5 SDs below the mean in at least one domain of development; the youngest children often met these criteria for a significant delay based on motor delays, but cognitive and language delays were also common. However, only 11 of the 22 participants were reported to receive early intervention services before study entry.

Conclusion: Although neurological symptoms may not prompt the genetic diagnosis of NPC1, the current findings support the use of a multimethod approach to repeated assessments for young children with the diagnosis because of the frequency of developmental delays or decline in multiple domains. The diagnosis of NPC1 alone should qualify children for evaluation for early intervention services and consideration of investigational therapeutic interventions.
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http://dx.doi.org/10.1097/DBP.0000000000000785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592416PMC
February 2020