Research on the Pathogenesis of Cognitive and Neurofunctional Impairments in Patients with Noonan Syndrome: The Role of Rat Sarcoma-Mitogen Activated Protein Kinase Signaling Pathway Gene Disturbances.

Noonan syndrome (NS) is one of the most common genetic conditions inherited mostly in an autosomal dominant manner with vast heterogeneity in clinical and genetic features. Patients with NS might have speech disturbances, memory and attention deficits, limitations in daily functioning, and decreased overall intelligence. Here, 34 patients with Noonan syndrome and 23 healthy controls were enrolled in a study involving gray and white matter volume evaluation using voxel-based morphometry (VBM), white matter connectivity measurements using diffusion tensor imaging (DTI), and resting-state functional magnetic resonance imaging (rs-fMRI). Fractional anisotropy (FA) and mean diffusivity (MD) probability distributions were calculated. Cognitive abilities were assessed using the Stanford Binet Intelligence Scales. Reductions in white matter connectivity were detected using DTI in NS patients. The rs-fMRI revealed hyper-connectivity in NS patients between the sensorimotor network and language network and between the sensorimotor network and salience network in comparison to healthy controls. NS patients exhibited decreased verbal and nonverbal IQ compared to healthy controls. The assessment of the microstructural alterations of white matter as well as the resting-state functional connectivity (rsFC) analysis in patients with NS may shed light on the mechanisms responsible for cognitive and neurofunctional impairments.

Benchmarking framework for machine learning classification from fNIRS data.

Background: While efforts to establish best practices with functional near infrared spectroscopy (fNIRS) signal processing have been published, there are still no community standards for applying machine learning to fNIRS data. Moreover, the lack of open source benchmarks and standard expectations for reporting means that published works often claim high generalisation capabilities, but with poor practices or missing details in the paper. These issues make it hard to evaluate the performance of models when it comes to choosing them for brain-computer interfaces. Methods: We present an open-source benchmarking framework, BenchNIRS, to establish a best practice machine learning methodology to evaluate models applied to fNIRS data, using five open access datasets for brain-computer interface (BCI) applications. The BenchNIRS framework, using a robust methodology with nested cross-validation, enables researchers to optimise models and evaluate them without bias. The framework also enables us to produce useful metrics and figures to detail the performance of new models for comparison. To demonstrate the utility of the framework, we present a benchmarking of six baseline models [linear discriminant analysis (LDA), support-vector machine (SVM), k-nearest neighbours (kNN), artificial neural network (ANN), convolutional neural network (CNN), and long short-term memory (LSTM)] on the five datasets and investigate the influence of different factors on the classification performance, including: number of training examples and size of the time window of each fNIRS sample used for classification. We also present results with a sliding window as opposed to simple classification of epochs, and with a personalised approach (within subject data classification) as opposed to a generalised approach (unseen subject data classification). Results and discussion: Results show that the performance is typically lower than the scores often reported in literature, and without great differences between models, highlighting that predicting unseen data remains a difficult task. Our benchmarking framework provides future authors, who are achieving significant high classification scores, with a tool to demonstrate the advances in a comparable way. To complement our framework, we contribute a set of recommendations for methodology decisions and writing papers, when applying machine learning to fNIRS data.

Perceptions of Cognitive Training Games and Assessment Technologies for Dementia: Acceptability Study With Patient and Public Involvement Workshops.

BACKGROUND: Cognitive training and assessment technologies offer the promise of dementia risk reduction and a more timely diagnosis of dementia, respectively. Cognitive training games may help reduce the lifetime risk of dementia by helping to build cognitive reserve, whereas cognitive assessment technologies offer the opportunity for a more convenient approach to early detection or screening. OBJECTIVE: This study aims to elicit perspectives of potential end users on factors related to the acceptability of cognitive training games and assessment technologies, including their opinions on the meaningfulness of measurement of cognition, barriers to and facilitators of adoption, motivations to use games, and interrelationships with existing health care infrastructure. METHODS: Four linked workshops were conducted with the same group, each focusing on a specific topic: meaningful improvement, learning and motivation, trust in digital diagnosis, and barriers to technology adoption. Participants in the workshops included local involvement team members acting as facilitators and those recruited via Join Dementia Research through a purposive selection and volunteer sampling method. Group activities were recorded, and transcripts were analyzed using thematic analysis with a combination of a priori and data-driven themes. Using a mixed methods approach, we investigated the relationships between the categories of the Capability, Opportunity, and Motivation-Behavior change model along with data-driven themes by measuring the φ coefficient between coded excerpts and ensuring the reliability of our coding scheme by using independent reviewers and assessing interrater reliability. Finally, we explored these themes and their relationships to address our research objectives. RESULTS: In addition to discussions around the capability, motivation, and opportunity categories, several important themes emerged during the workshops: family and friends, cognition and mood, work and hobbies, and technology. Group participants mentioned the importance of functional and objective measures of cognitive change, the social aspect of activities as a motivating factor, and the opportunities and potential shortcomings of digital health care provision. Our quantitative results indicated at least moderate agreement on all but one of the coding schemes and good independence of our coding categories. Positive and statistically significant φ coefficients were observed between several coding themes between categories, including a relatively strong positive φ coefficient between capability and cognition (0.468; P<.001). CONCLUSIONS: The implications for researchers and technology developers include assessing how cognitive training and screening pathways would integrate into existing health care systems; however, further work needs to be undertaken to address barriers to adoption and the potential real-world impact of cognitive training and screening technologies. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1007/978-3-030-49065-2_4.

Wide Fontanels, Delayed Speech Development and Hoarse Voice as Useful Signs in the Diagnosis of KBG Syndrome: A Clinical Description of 23 Cases with Pathogenic Variants Involving the ANKRD11 Gene or Submicroscopic Chromosomal Rearrangements of 16q24.3.

KBG syndrome is a neurodevelopmental autosomal dominant disorder characterized by short stature, macrodontia, developmental delay, behavioral problems, speech delay and delayed closing of fontanels. Most patients with KBG syndrome are found to have a mutation in the ANKRD11 gene or a chromosomal rearrangement involving this gene. We hereby present clinical evaluations of 23 patients aged 4 months to 26 years manifesting clinical features of KBG syndrome. Mutation analysis in the patients was performed using panel or exome sequencing and array CGH. Besides possessing dysmorphic features typical of the KBG syndrome, nearly all patients had psychomotor hyperactivity (86%), 81% had delayed speech, 61% had poor weight gain, 56% had delayed closure of fontanel and 56% had a hoarse voice. Macrodontia and a height range of -1 SDs to -2 SDs were noted in about half of the patients; only two patients presented with short stature below -3 SDs. The fact that wide, delayed closing fontanels were observed in more than half of our patients with KBG syndrome confirms the role of the ANKRD11 gene in skull formation and suture fusion. This clinical feature could be key to the diagnosis of KBG syndrome, especially in young children. Hoarse voice is a previously undescribed phenotype of KBG syndrome and could further reinforce clinical diagnosis.

Within- and Between-Session Prefrontal Cortex Response to Virtual Reality Exposure Therapy for Acrophobia.

Exposure Therapy (ET) has demonstrated its efficacy in the treatment of phobias, anxiety and Post-traumatic Stress Disorder (PTSD), however, it suffers a high drop-out rate because of too low or too high patient engagement in treatment. Virtual Reality Exposure Therapy (VRET) is comparably effective regarding symptom reduction and offers an alternative tool to facilitate engagement for avoidant participants. Neuroimaging studies have demonstrated that both ET and VRET normalize brain activity within a fear circuit. However, previous studies have employed brain imaging technology which restricts people's movement and hides their body, surroundings and therapist from view. This is at odds with the way engagement is typically controlled. We used a novel combination of neural imaging and VR technology-Functional Near-Infrared Spectroscopy (fNIRS) and Immersive Projection Technology (IPT), to avoid these limitations. Although there are a few studies that have investigated the effect of VRET on a brain function after the treatment, the present study utilized technologies which promote ecological validity to measure brain changes after VRET treatment. Furthermore, there are no studies that have measured brain activity within VRET session. In this study brain activity within the prefrontal cortex (PFC) was measured during three consecutive exposure sessions. N = 13 acrophobic volunteers were asked to walk on a virtual plank with a 6 m drop below. Changes in oxygenated (HbO) hemoglobin concentrations in the PFC were measured in three blocks using fNIRS. Consistent with previous functional magnetic resonance imaging (fMRI) studies, the analysis showed decreased activity in the DLPFC and MPFC during first exposure. The activity increased toward normal across three sessions. The study demonstrates potential efficacy of a method for measuring within-session neural response to virtual stimuli that could be replicated within clinics and research institutes, with equipment better suited to an ET session and at fraction of the cost, when compared to fMRI. This has application in widening access to, and increasing ecological validity of, immersive neuroimaging across understanding, diagnosis, assessment and treatment of, a range of mental disorders such as phobia, anxiety and PTSD or addictions.

MAP2K2 mutation as a cause of cardio-facio-cutaneous syndrome in an infant with a severe and fatal course of the disease.

Cardio-facio-cutaneous syndrome (CFCS), a rare congenital disorder of RASopathies, displays high phenotypic variability. Complications during pregnancy and in the perinatal period are commonly reported. Polyhydramnios is observed in over half of pregnancies and might occur with fetal macrocephaly, macrosomia, and/or heart defects. Premature birth is not uncommon and any complications like respiratory insufficiency, edema, and feeding difficulties are present and might delay accurate clinical diagnosis. Besides neonatal complications, CFCS newborns and later infants have distinctive dysmorphic features usually accompanied by neurological (hypotonia with motor delay, neurocognitive delay) findings. Also, heart defects usually present at birth. Herein, we present the case of a female baby born prematurely from a pregnancy complicated with polyhydramnios, presenting at birth with craniofacial features typical for RASopathies, heart defects, neurological abnormalities, and hyperkeratosis unusual for a neonatal period. Due to the presence of a heart defect and other complications related to premature birth, the course of the disease was severe with a fatal outcome at the age of 9 months. The RASopathy, particularly CFCS, clinical diagnosis was confirmed and de novo p.Phe57Ile mutation in MAP2K2 was identified.

[Fragile X syndrome and FMR1-dependent diseases - diagnostic scheme based on own experience .]

The presence of dynamic mutation in the FMR1 gene localized on the X chromosome (Xq28) is the major cause of Fragile X syndrome. As this syndrome is quite frequently diagnosed in patients with intellectual disability and autism spectrum disorders, the genetic testing of the FMR1 gene is a routine procedure performed in these patients. Molecular methods based on the PCR technique are used commonly, as they allow to identify normal (up to 54 CGG repeats, including grey zone alleles - 45-54 CGG repeats), premutation (55-200 CGG repeats) and full mutation (>200 CGG repeats) alleles.The article presents the basic methods used in the molecular diagnosis of Fragile X syndrome and other FMR1-related disorders. The following methods are presented: a screening test with GeneScan analysis, TP-PCR based tests and methods used for methylation analysis. Their pros and cons, as well as the resulting interpretation are discussed. Moreover, there is a presentation of the molecular diagnostic scheme following European Molecular Genetics Quality Network guidelines used in the Department of Medical Genetics.

[Fragile X syndrome and FMR1-dependent diseases - clinical presentation, epidemiology and molecular background].

Fragile X syndrome (FXS) is the second most common inherited cause of intellectual disability (ID), after Down syndrome. The severity of ID in FXS patients varies and depends mainly on the patient's sex. Besides intellectual disorders, additional symptoms, such as psychomotor delay, a specific behavioral phenotype, or emotional problems are present in FXS patients. In over 99% of the cases, the disease is caused by the presence of a dynamic mutation in the FMR1 gene localized on the X chromosome. Due to the expansion of CGG nucleotides (over 200 repeats), FMR1 gene expression is decreased and results in the significant reduction of the FMRP protein level. The CGG expansion to premutation range (55-200 CGG repeats) is equivalent to the FXS carrier status and may cause FMR1-dependent disorders - fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS). In contrast to FXS, clinical symptoms of these diseases occur later in adulthood. The aim of the article is to present the knowledge about the molecular background and epidemiology of fragile X syndrome and other FMR1-related disorders.

Towards a Better Molecular Diagnosis of FMR1-Related Disorders-A Multiyear Experience from a Reference Lab.

The article summarizes over 20 years of experience of a reference lab in fragile X mental retardation 1 gene (FMR1) molecular analysis in the molecular diagnosis of fragile X spectrum disorders. This includes fragile X syndrome (FXS), fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS), which are three different clinical conditions with the same molecular background. They are all associated with an expansion of CGG repeats in the 5'UTR of FMR1 gene. Until 2016, the FMR1 gene was tested in 9185 individuals with the pre-screening PCR, supplemented with Southern blot analysis and/or Triplet Repeat Primed PCR based method. This approach allowed us to confirm the diagnosis of FXS, FXPOI FXTAS in 636/9131 (6.96%), 4/43 (9.3%) and 3/11 (27.3%) of the studied cases, respectively. Moreover, the FXS carrier status was established in 389 individuals. The technical aspect of the molecular analysis is very important in diagnosis of FXS-related disorders. The new methods were subsequently implemented in our laboratory. This allowed the significance of the Southern blot technique to be decreased until its complete withdrawal. Our experience points out the necessity of implementation of the GeneScan based methods to simplify the testing procedure as well as to obtain more information for the patient, especially if TP-PCR based methods are used.