Speech and language in DDX3X-neurodevelopmental disorder: A call for early augmentative and alternative communication intervention.

Pathogenic variants in DDX3X are associated with neurodevelopmental disorders. Communication impairments are commonly reported, yet specific speech and language diagnoses have not been delineated, preventing prognostic counseling and targeted therapies. Here, we characterized speech and language in 38 female individuals, aged 1.69-24.34 years, with pathogenic and likely pathogenic DDX3X variants (missense, n = 13; nonsense, n = 12; frameshift, n = 7; splice site, n = 3; synonymous, n = 2; deletion, n = 1). Standardized speech, language, motor, social, and adaptive behavior assessments were administered. All participants had gross motor deficits in infancy (34/34), and fine motor deficits were common throughout childhood (94%; 32/34). Intellectual disability was reported in 86% (24/28) of participants over 4 years of age. Expressive, receptive, and social communication skills were, on average, severely impaired. However, receptive language was significantly stronger than expressive language ability. Over half of the assessed participants were minimally verbal (66%; 22/33; range = 2 years 2 months-24 years 4 months; mean = 8 years; SD = 6 years) and augmented speech with sign language, gestures, or digital devices. A quarter of the cohort had childhood apraxia of speech (25%; 9/36). Despite speech and language impairments, social motivation was a relevant strength. Many participants used augmentative and alternative communication (AAC), underscoring the need for early, tailored, and comprehensive AAC intervention.

Lessons from two series by physicians and caregivers' self-reported data in DDX3X-related disorders.

INTRODUCTION AND METHODS: We report two series of individuals with DDX3X variations, one (48 individuals) from physicians and one (44 individuals) from caregivers. RESULTS: These two series include several symptoms in common, with fairly similar distribution, which suggests that caregivers' data are close to physicians' data. For example, both series identified early childhood symptoms that were not previously described: feeding difficulties, mean walking age, and age at first words. DISCUSSION: Each of the two datasets provides complementary knowledge. We confirmed that symptoms are similar to those in the literature and provides more details on feeding difficulties. Caregivers considered that the symptom attention-deficit/hyperactivity disorder were most worrisome. Both series also reported sleep disturbance. Recently, anxiety has been reported in individuals with DDX3X variants. We strongly suggest that attention-deficit/hyperactivity disorder, anxiety, and sleep disorders need to be treated.

Ocular manifestations in Koolen-de Vries syndrome: an international study.

OBJECTIVES: Koolen-de Vries Syndrome (KdVS) is a rare multisystem neurodevelopmental disorder. Ocular manifestations, including strabismus, ptosis, and hyperopia, have been reported in KdVS patients, but detailed clinical data are limited. This study aims to investigate the already known ocular malformations and their frequency while uncovering novel ocular associations. METHODS: This was an international cross-sectional study. An anonymous questionnaire was sent to 237 KdVS patients registered in the GenIDA database. The questionnaire inquired about demographic data, ocular symptoms, findings reported by ophthalmologists, and ophthalmologic surgical interventions. The main outcome measures included ocular findings and surgical interventions. RESULTS: Sixty-seven respondents worldwide completed the questionnaire, most (n = 53; 79%) under 18 years of age. Ophthalmologic abnormalities, noted in 79% of patients, included refractive errors (n = 35; 52.2%), strabismus (n = 23; 34.3%), amblyopia (n = 13; 19.5%), and eyelid ptosis (n = 9; 13.4%). Lacrimal disorders were present (n = 6; 9.0%), as were retinal findings (n = 7; 10.4%), including retinal hyperpigmentation or hypopigmentation (n = 4; 7.5%), Sjögren's pigment epithelial reticular dystrophy (n = 1; 1.5%), and macular chorioretinal coloboma (n = 1; 1.5%). Other manifestations included ocular surface disorders (n = 5; 7.5%), cataracts (n = 3; 4.5%), Brown syndrome (n = 1; 1.5%), glaucoma (n = 1; 1.5%), cerebral visual impairment (n = 1; 1.5%), and optic atrophy (n = 1; 1.5%). Fourteen patients (20.8%) had undergone surgical interventions. CONCLUSIONS: KdVS is associated with various ophthalmic findings, such as amblyopia, refractive errors, strabismus, and eyelid ptosis. We describe, for the first time, a high rate of nasolacrimal disorders and retinal abnormalities consisting mainly of pigmentary findings, including a rare case of Sjögren's pigment epithelial reticular dystrophy. A comprehensive ophthalmic evaluation is therefore recommended for all KdVS patients at initial diagnosis or at 4-6 months of age for diagnosed newborns.

A burning question from the first international BPAN symposium: is restoration of autophagy a promising therapeutic strategy for BPAN?

Beta-propeller protein-associated neurodegeneration (BPAN) is a rare neurodegenerative disease associated with severe cognitive and motor deficits. BPAN pathophysiology and phenotypic spectrum are still emerging due to the fact that mutations in the WDR45 (WD repeat domain 45) gene, a regulator of macroautophagy/autophagy, were only identified a decade ago. In the first international symposium dedicated to BPAN, which was held in Lyon, France, a panel of international speakers, including several researchers from the autophagy community, presented their work on human patients, cellular and animal models, carrying WDR45 mutations and their homologs. Autophagy researchers found an opportunity to explore the defective function of autophagy mechanisms associated with WDR45 mutations, which underlie neuronal dysfunction and early death. Importantly, BPAN is one of the few human monogenic neurological diseases targeting a regulator of autophagy, which raises the possibility that it is a relevant model to directly assess the roles of autophagy in neurodegeneration and to develop autophagy restorative therapeutic strategies for more common disorders.Abbreviations: ATG: autophagy related; BPAN: beta-propeller protein-associated neurodegeneration; ER: endoplasmic reticulum; KO: knockout; NBIA: neurodegeneration with brain iron accumulation; PtdIns3P: phosphatidylinositol-3-phosphate; ULK1: unc-51 like autophagy activating kinase 1; WDR45: WD repeat domain 45; WIPI: WD repeat domain, phosphoinositide interacting.

Clinical and radiological assessment of scoliosis in Koolen-de Vries syndrome.

The Koolen-de Vries syndrome (KdVS) is a multisystem disorder characterized by developmental delay, intellectual disability, characteristic facial features, epilepsy, cardiovascular and urogenital malformations, and various musculoskeletal disorders. Scoliosis is a common feature. The aim of this study is to fill the gap in the current knowledge about scoliosis in individuals with KdVS and to provide recommendations for management and follow-up. In total, 54 individuals with KdVS were included in the study, with a mean age of 13.6 years (range 1.9-38.8 years). Spine radiographs, MR scans, and corresponding radiology reports were analyzed retrospectively for scoliosis and additional anomalies. The presence of scoliosis-related clinical conditions was assessed in participants' medical records and by use of a parent survey. Scoliosis was present in 56% of the participants (30/54) with a mean age of onset of 10.6 years and curve progression during the growth spurt. Prevalence at age 6, 10, and 18 years was, respectively, 9%, 41%, and 65%. Most participants were diagnosed with a single curve (13/24, 54%), of which five participants had a long C-curve type scoliosis. No significant risk factors for development of scoliosis could be identified. Severity was mostly classified as mild, although 29% (7/24) of the curves were larger than 30° at last follow-up. Bracing therapy was received in 13% (7/54), and surgical spinal fusion was warranted in 6% (3/54). Remarkably, participants with scoliosis received less often physical therapy compared to participants without scoliosis (P = 0.002). Scoliosis in individuals with KdVS should be closely monitored and radiologic screening for scoliosis and vertebrae abnormalities is recommended at diagnosis of KdVS, and the age of 10 and 18 years.

GenIDA: an international participatory database to gain knowledge on health issues related to genetic forms of neurodevelopmental disorders.

Intellectual disability with or without manifestations of autism and/or epilepsy affects 1-2% of the population, and it is estimated that more than 30-50% of these cases have a single genetic cause. More than 1000 genes and recurrent chromosomal abnormalities are involved in these genetic forms of neurodevelopmental disorders, which often remain insufficiently described in terms of clinical spectrum, associated medical problems, etc., due to their rarity and the often-limited number of patients' phenotypes reported. GenIDA is an international online participatory database that aims to better characterise the clinical manifestations and natural histories of these rare diseases. Clinical information is reported by parents of affected individuals using a structured questionnaire exploring physical parameters, cognitive and behavioural aspects, the presence or absence of neurological disorders or problems affecting major physiological functions, as well as autonomy and quality of life. This strengthens the implication in research of the concerned families. GenIDA aims to construct international cohorts of significant size of individuals affected by a given condition. As of July 2022, GenIDA counts some 1545 documented patient records from over 60 nationalities and collaborates with clinicians and researchers around the world who have access to the anonymized data collected to generate new, medically meaningful information to improve patient care. We present the GenIDA database here, together with an overview of the possibilities it offers to affected individuals, their families, and professionals in charge of the management of genetic forms of neurodevelopmental disorders. Finally, case studies of cohorts will illustrate the usefulness of GenIDA.

The impact of lockdown on young people with genetic neurodevelopmental disabilities: a study with the international participatory database GenIDA.

BACKGROUND: Previous publications suggested that lockdown is likely to impact daily living issues of individuals with intellectual disabilities. The authors notably suspected an intensification of behavioural, eating and sleep problems. METHODS: To test these hypotheses, we conducted an international online survey about the impact of COVID-19-associated first lockdown on people with genetic neurodevelopmental disorders. This survey was carried out using GenIDA, an international participatory database collecting medical information on genetic neurodevelopmental disorders. Patients' relatives took part in this online survey from 30/04/2020 to 09/06/2020. This survey adapted from GenIDA standard questionnaire requested information on diagnosis, lifestyle and was based on yes/no answers to questions regarding behaviour, diet, and sleep, in the 6-months period before lockdown and during lockdown. We also asked relatives to evaluate the intensity of these problems by severity level. Finally, relatives could freely comment in open fields on the medical and/or quality of life problems they had encountered during lockdown. RESULTS: In total 199 participants-144 children and 45 adults-with neurodevelopmental disorders (intellectual disability (79.4%) and/or autism spectrum disorder (21.6%)) of various genetic origins, with near-equal male/female (96/103) contribution and originating mainly from Europe and Northern America, were included. The average lockdown duration at time of the survey was 57 days. We did not find differences in the frequency of behavioural, eating and sleep problems before and during lockdown. Moreover, there was no apparent difference in the intensity of eating and sleep disorders between both periods. However, for persons with behavioural problems at both periods, relatives reported an increase in aggressivity, self-aggressivity, depressiveness, stereotypies, and restricted interests during lockdown, all of which might be interpreted as consequences of a lack of stimulation or a reaction to unexpected changes in daily habits. CONCLUSIONS: Our results support previous studies that suggest that the negative impact of lockdown does not depend on the intellectual disability per se but on the associated comorbidities such as behavioural disorders. This study addresses the need for prevention of behavioural disturbance in the vulnerable population with genetic neurodevelopmental disabilities.

Neurocognitive and neurobehavioral characterization of two frequent forms of neurodevelopmental disorders: the DYRK1A and the Wiedemann-Steiner syndromes.

DYRK1A and Wiedemann-Steiner syndromes (WSS) are two genetic conditions associated with neurodevelopmental disorders (NDDs). Although their clinical phenotype has been described, their behavioral phenotype has not systematically been studied using standardized assessment tools. To characterize the latter, we conducted a retrospective study, collecting data on developmental history, autism spectrum disorder (ASD), adaptive functioning, behavioral assessments, and sensory processing of individuals with these syndromes (n = 14;21). In addition, we analyzed information collected from families (n = 20;20) using the GenIDA database, an international patient-driven data collection aiming to better characterize natural history of genetic forms of NDDs. In the retrospective study, individuals with DYRK1A syndrome showed lower adaptive behavior scores compared to those with WSS, whose scores showed greater heterogeneity. An ASD diagnosis was established for 57% (8/14) of individuals with DYRK1A syndrome and 24% (5/21) of those with WSS. Language and communication were severely impaired in individuals with DYRK1A syndrome, which was also evident from GenIDA data, whereas in WSS patients, exploration of behavioral phenotypes revealed the importance of anxiety symptomatology and ADHD signs, also flagged in GenIDA. This study, describing the behavioral and sensorial profiles of individuals with WSS and DYRK1A syndrome, highlighted some specificities important to be considered for patients' management.

Anti-Aging Potential of a Rosa centifolia Stem Extract with Focus on Phytochemical Composition by Bioguided Fractionation.

Agricultural practices generate huge amounts of by-products, often simply discarded as waste that must be processed at some cost. The natural by-products revalorisation as raw material to produce high-added value ingredients for various industrial sectors may pave the way towards more sustainable industrial practices, via an optimised utilisation of natural resources. Integrating the circular economy precepts to production systems is considered to be a more and more promising management solution to significantly reduce the environmental impact of economic activities. This article discusses the valorisation of Rosa centifolia stem to produce a natural extract with cosmetic anti-aging potential. To do so, the cosmetic potential of 30 extracts obtained by maceration of agricultural by-products in a hydroalcoholic solvent was evaluated: their activities, as well as their inhibitory activities of specific enzymes were assessed in vitro to identify those that could be used effectively as anti-ageing actives while meeting the consumer's expectations in terms of sustainability, naturality, transparency and traceability.[1] A hydroalcoholic extract of R. centifolia stem revealed itself particularly promising due to its valuable anti-hyaluronidase and antioxidant activities, and its interesting anti-elastase and anti-inflammatory potential. The bio-guided fractionation of this extract allows the characterisation of three major compounds, e. g., isoquercitrin, quercitrin and euscaphic acid, never identified in R. centifolia previously.

Extraction of Natural Fragrance Ingredients: History Overview and Future Trends.

For centuries, perfumes consisted in a combination of natural ingredients, mainly of plant origin. From the 19th century on, the advent of organic synthesis enabled the deployment of multiple synthetic olfactory notes, enriching significantly the perfumers' portfolio. Chemistry is ever since the foundation of modern perfumery. However, sustainable-minded consumers, massively rejecting synthetics for safety and ecological issues, engaged a global return to nature in numerous sectors, and the fragrance industry is not outdone. Sustainable extraction of natural products, making use of innovative technologies, process intensification and agro-based solvents, constitutes the answer to develop eco-conceived fragrant ingredients covering every olfactory family without endangering biodiversity any further. The objective of this review is to draw a clear picture of where those technological advances are today and to assess the ones that may be effectively transposed at the industrial scale tomorrow.

UHPLC-HRMS/MS Based Profiling of Algerian Lichens and Their Antimicrobial Activities.

Lichens are complex symbiotic organisms able to produce a vast array of compounds. The Algerian lichen diversity has only prompted little interest even given the 1085 species listed. Herein, the chemodiversity of four Algerian lichens including Cladonia rangiformis, Ramalina farinaceae, R. fastigiata, and Roccella phycopsis was investigated. A dereplication strategy, using ultra high performance liquid chromatography-high resolution-electrospray ionization-mass spectrometry (UHPLC-HRMS/MS), was carried out for a comprehensive characterization of their substances including phenolics, depsides, depsidones, depsones, dibenzofurans, and aliphatic acids. Some known compounds were identified for the first time in some species. Additionally, the lichenic extracts were evaluated for their antifungal and antimicrobial activities on human pathogenic strains (Candida albicans, C. glabrata, Aspergillus fumigatus, Staphylococcus aureus, and Escherichia coli). Cyclohexane extracts were found particularly active against human pathogenic fungi with MIC80 values ranging from 8 to 62.5 µg/mL, without cytotoxicity. This study highlights the therapeutic and prophylactic potential of lichenic extracts as antibacterial and antifungal agents.

Vetiver Essential Oil in Cosmetics: What Is New?

Background: Vetiver is a key ingredient for the perfume industry nowadays. However, with the constant and rapid changes of personal tastes, this appeal could vanish and this sector could decline quite quickly. New dissemination paths need to be found to tap this valuable resource. Methods: In this way, its potential use in cosmetics either as an active ingredient per se (with cosmeceutical significance or presenting antimicrobial activity) has hence been explored in vitro. Results: In this contribution, we demonstrated that vetiver essential oil displays no particularly significant and innovative cosmetic potential value in formulations apart from its scent already largely exploited. However, evaluated against twenty bacterial strains and two Candida species using the in vitro microbroth dilution method, vetiver oil demonstrated notably some outstanding activities against Gram-positive strains and against one Candida glabrata strain. Conclusions: Based on these findings, vetiver essential oil appears to be an appropriate aspirant for the development of an antimicrobial agent for medicinal purposes and for the development of a cosmetic ingredient used for its scent and displaying antimicrobial activity as an added value.

Chemical Composition, Antimicrobial and Insecticidal Activities of Flowers Essential Oils of Alpinia zerumbet (Pers.) B.L.Burtt & R.M.Sm. from Martinique Island.

Alpinia species, used as ornamental plants and flavoring agents, are renowned for their therapeutic properties and their subsequent use in traditional medicines throughout the world. Alpinia zerumbet (Pers.) B.L.Burtt & R.M.Sm. is the most common Alpinia species encountered in Martinique. Several essential oils (EOs) obtained by hydrodistillation of A. zerumbet flowers collected in various locations on the island at different seasons were analysed to evaluate the influence of the collection period and area on the EOs' chemical compositions and to assess their bioactivity. A combination of GC-FID and GC/MS techniques was used to examine the volatile constituents, leading to the identification of a total of 71 components accounting for 97.8 - 99.3% of the respective total GC-FID areas: among them, nineteen compounds were characterized for the first time in A. zerumbet EOs. The antimicrobial activity of these EOs was assessed against eight bacterial, yeast and fungal strains and two multi-resistant strains: some significant bacteriostatic and fungistatic activities of A. zerumbet flower oils were evidenced. Finally, an interesting insecticidal activity of the flower EO was highlighted for the first time against Aedes aegypti.

Identification, Geochemical Characterisation and Significance of Bitumen among the Grave Goods of the 7th Century Mound 1 Ship-Burial at Sutton Hoo (Suffolk, UK).

The 7th century ship-burial at Sutton Hoo is famous for the spectacular treasure discovered when it was first excavated in 1939. The finds include gold and garnet jewellery, silverware, coins and ceremonial armour of broad geographical provenance which make a vital contribution to understanding the political landscape of early medieval Northern Europe. Fragments of black organic material found scattered within the burial were originally identified as 'Stockholm Tar' and linked to waterproofing and maintenance of the ship. Here we present new scientific analyses undertaken to re-evaluate the nature and origin of these materials, leading to the identification of a previously unrecognised prestige material among the treasure: bitumen from the Middle East. Whether the bitumen was gifted as diplomatic gesture or acquired through trading links, its presence in the burial attests to the far-reaching network within which the elite of the region operated at this time. If the bitumen was worked into objects, either alone or in composite with other materials, then their significance within the burial would certainly have been strongly linked to their form or purpose. But the novelty of the material itself may have added to the exotic appeal. Archaeological finds of bitumen from this and earlier periods in Britain are extremely rare, despite the abundance of natural sources of bitumen within Great Britain. This find provides the first material evidence indicating that the extensively exploited Middle Eastern bitumen sources were traded northward beyond the Mediterranean to reach northern Europe and the British Isles.

New insights in the chemical composition of benzoin balsams.

Benzoin balsam is an anthropic exudate obtained from the bark of several species of Styrax trees that is mainly used as a perfume fixative as well as a flavouring agent. Benzoe tonkinensis Laos (also commercialized under the denomination Siam benzoin balsam) displaying characteristic vanilla notes and already being largely used to flavour all kinds of edible goods, was intended to be proposed by Agroforex Company to the Codex Committee on Food Additives for evaluation as a food additive. For this purpose, the present paper reports the phytochemical characterisation of both the volatile and non-volatile fractions of benzoin balsams and the quantitation of some of the major components by gas and liquid chromatography techniques. Four coniferyl and two morinol derivatives were characterised for the first time in Benzoe tonkinensis Laos. Finally, two liquid chromatographic methods used to easily discriminate Siam from Sumatra balsam (also known as Benzoe sumatranus Indonesia) were developed.

Archaeological resinous samples from Asian wrecks: Taxonomic characterization by GC-MS.

Plant resins, and particularly dammars from the Dipterocarpaceae family, were widely used in the past, notably as part of caulking material. The organic composition of resins, already complicated, is not always preserved over time and can be considerably affected by ageing. Hence, their occurrence in archaeological items leads to the necessity to identify them taxonomically with precision. Resinous organic materials collected near and/or on wrecks discovered in South China Sea, supposed to contain dammar resins because of their geographical excavation context, were investigated by gas chromatography-mass spectrometry (GC-MS), together with freshly collected dammars, to establish taxonomic and alteration parameters allowing to identify dammar even in very altered samples or in mixtures together with other organic materials. This study specially focuses on three samples collected within or close to the M1J wreck, a Portuguese wreck lost in the Straight of Malacca during the 16th century. Our analyses establish that all three are made of dammar, two of them in association with pitch and bitumen. In addition, biodegradation biomarkers were detected in all these three samples, indicating that they were submitted to microbial degradation processes during their ageing.