HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder.

Heterogeneous nuclear ribonucleoprotein C (HNRNPC) is an essential, ubiquitously abundant protein involved in mRNA processing. Genetic variants in other members of the HNRNP family have been associated with neurodevelopmental disorders. Here, we describe 13 individuals with global developmental delay, intellectual disability, behavioral abnormalities, and subtle facial dysmorphology with heterozygous HNRNPC germline variants. Five of them bear an identical in-frame deletion of nine amino acids in the extreme C terminus. To study the effect of this recurrent variant as well as HNRNPC haploinsufficiency, we used induced pluripotent stem cells (iPSCs) and fibroblasts obtained from affected individuals. While protein localization and oligomerization were unaffected by the recurrent C-terminal deletion variant, total HNRNPC levels were decreased. Previously, reduced HNRNPC levels have been associated with changes in alternative splicing. Therefore, we performed a meta-analysis on published RNA-seq datasets of three different cell lines to identify a ubiquitous HNRNPC-dependent signature of alternative spliced exons. The identified signature was not only confirmed in fibroblasts obtained from an affected individual but also showed a significant enrichment for genes associated with intellectual disability. Hence, we assessed the effect of decreased and increased levels of HNRNPC on neuronal arborization and neuronal migration and found that either condition affects neuronal function. Taken together, our data indicate that HNRNPC haploinsufficiency affects alternative splicing of multiple intellectual disability-associated genes and that the developing brain is sensitive to aberrant levels of HNRNPC. Hence, our data strongly support the inclusion of HNRNPC to the family of HNRNP-related neurodevelopmental disorders.

Classification of missense variants in the N-methyl-d-aspartate receptor GRIN gene family as gain- or loss-of-function.

Advances in sequencing technology have generated a large amount of genetic data from patients with neurological conditions. These data have provided diagnosis of many rare diseases, including a number of pathogenic de novo missense variants in GRIN genes encoding N-methyl-d-aspartate receptors (NMDARs). To understand the ramifications for neurons and brain circuits affected by rare patient variants, functional analysis of the variant receptor is necessary in model systems. For NMDARs, this functional analysis needs to assess multiple properties in order to understand how variants could impact receptor function in neurons. One can then use these data to determine whether the overall actions will increase or decrease NMDAR-mediated charge transfer. Here, we describe an analytical and comprehensive framework by which to categorize GRIN variants as either gain-of-function (GoF) or loss-of-function (LoF) and apply this approach to GRIN2B variants identified in patients and the general population. This framework draws on results from six different assays that assess the impact of the variant on NMDAR sensitivity to agonists and endogenous modulators, trafficking to the plasma membrane, response time course and channel open probability. We propose to integrate data from multiple in vitro assays to arrive at a variant classification, and suggest threshold levels that guide confidence. The data supporting GoF and LoF determination are essential to assessing pathogenicity and patient stratification for clinical trials as personalized pharmacological and genetic agents that can enhance or reduce receptor function are advanced. This approach to functional variant classification can generalize to other disorders associated with missense variants.

Expansion and mechanistic insights into de novo DEAF1 variants in DEAF1-associated neurodevelopmental disorders.

De novo deleterious and heritable biallelic mutations in the DNA binding domain (DBD) of the transcription factor deformed epidermal autoregulatory factor 1 (DEAF1) result in a phenotypic spectrum of disorders termed DEAF1-associated neurodevelopmental disorders (DAND). RNA-sequencing using hippocampal RNA from mice with conditional deletion of Deaf1 in the central nervous system indicate that loss of Deaf1 activity results in the altered expression of genes involved in neuronal function, dendritic spine maintenance, development, and activity, with reduced dendritic spines in hippocampal regions. Since DEAF1 is not a dosage-sensitive gene, we assessed the dominant negative activity of previously identified de novo variants and a heritable recessive DEAF1 variant on selected DEAF1-regulated genes in 2 different cell models. While no altered gene expression was observed in cells over-expressing the recessive heritable variant, the gene expression profiles of cells over-expressing de novo variants resulted in similar gene expression changes as observed in CRISPR-Cas9-mediated DEAF1-deleted cells. Altered expression of DEAF1-regulated genes was rescued by exogenous expression of WT-DEAF1 but not by de novo variants in cells lacking endogenous DEAF1. De novo heterozygous variants within the DBD of DEAF1 were identified in 10 individuals with a phenotypic spectrum including autism spectrum disorder, developmental delays, sleep disturbance, high pain tolerance, and mild dysmorphic features. Functional assays demonstrate these variants alter DEAF1 transcriptional activity. Taken together, this study expands the clinical phenotypic spectrum of individuals with DAND, furthers our understanding of potential roles of DEAF1 on neuronal function, and demonstrates dominant negative activity of identified de novo variants.

Heterogeneity of comprehensive clinical phenotype and longitudinal adaptive function and correlation with computational predictions of severity of missense genotypes in KIF1A-associated neurological disorder.

PURPOSE: Pathogenic variants in kinesin family member 1A (KIF1A) are associated with KIF1A-associated neurological disorder. We report the clinical phenotypes and correlate genotypes of individuals with KIF1A-associated neurological disorder. METHODS: Medical history and adaptive function were assessed longitudinally. In-person evaluations included neurological, motor, ophthalmologic, and cognitive assessments. RESULTS: We collected online data on 177 individuals. Fifty-seven individuals were also assessed in-person. Most individuals had de novo heterozygous missense likely pathogenic/pathogenic KIF1A variants. The most common characteristics were hypotonia, spasticity, ataxia, seizures, optic nerve atrophy, cerebellar atrophy, and cognitive impairment. Mean Vineland adaptive behavior composite score (VABS-ABC) was low (M = 62.9, SD = 19.1). The mean change in VABS-ABC over time was -3.1 (SD = 7.3). The decline in VABS-ABC was associated with the age at first assessment and abnormal electroencephalogram/seizure. There was a positive correlation between evolutionary scale model (ESM) score for the variants and final VABS-ABC (P = .003). Abnormal electroencephalogram/seizure, neuroimaging result, and ESM explain 34% of the variance in final VABS-ABC (P < .001). CONCLUSION: In-person assessment confirmed caregiver report and identified additional visual deficits. Adaptive function declined over time consistent with both the neurodevelopmental and neurodegenerative nature of the condition. Using ESM score assists in predicting phenotype across a wide range of unique variants.

Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.

Pathogenic heterozygous loss of function variants in CTNNB1 are associated with CTNNB1 neurodevelopmental disorder. We report the clinical phenotype of individuals with CTNNB1 neurodevelopmental disorder using both caregiver-reported data (medical history, adaptive function, quality of life, and behavior issues) and in-person clinical assessments (neurological, motor, and cognitive function) in 32 individuals with likely pathogenic or pathogenic CTNNB1 variants. Most individuals had truncal hypotonia, muscle weakness, hypertonia, dystonia, microcephaly, and many had a history of tethered cord. Visual problems included strabismus, hyperopia, and familial exudative vitreoretinopathy. Half of individuals walked without an assistive device. The mean Gross Motor Functional Measure-66 score was 56.6 (SD = 14.8). Average time to complete Nine-Hole Peg Test was slower than norms. Mean general conceptual ability composite scores from Differential Ability Scales Second Edition were very low (M = 58.3, SD = 11.3). Fifty-five percent of individuals had low adaptive functioning based on the Vineland Adaptive Behavioral Scales. Based upon the Child Behavior Checklist total problems score, the majority (65%) of individuals had behavioral challenges. The mean overall Quality of Life Inventory-Disability score was 81.7 (SD = 11.9). These data provide a detailed characterization of clinical features in individuals with CTNNB1 neurodevelopmental disorder.

Assessing the feasibility of using the ketogenic diet in autism spectrum disorder.

BACKGROUND: Evidence demonstrating efficacy of dietary interventions for autism spectrum disorder (ASD) remains inconsistent. Recent research on the ketogenic diet (KD) for the treatment of ASD has suggested a benefit. Children with ASD often demonstrate ritualised food-specific behaviours, taste and texture aversions, and an increased prevalence of food restrictions and allergies. There is a need to investigate how these features contribute to initiation and adherence of the KD. Two surveys were administered to assess the feasibility of utilising the KD for ASD. METHODS: First, paper surveys were given to caregivers of children presenting to outpatient neurology clinics. Next, experienced clinicians were recruited and surveyed online using Qualtrics. Chi-squared analysis was used to compare ASD and non-ASD caregiver responses. Descriptive metrics were used to present clinician responses. Responses to each question were evaluated individually. RESULTS: One hundred and fourteen surveys were collected from caregivers. There were no significant differences in (1) stated feasibility of adopting a new diet, (2) a carbohydrate restricted diet, (3) diet restrictions, (4) documented allergies or (5) personal/cultural restrictions between groups with and without ASD. Seventy clinician responses were collected. The majority (67.4%) indicated that feasibility for a child with ASD to adopt a KD for any reason depends on ASD severity. Some respondents 73% rated adherence to the KD as more difficult compared to age-matched controls, whereas 26% considered it similar. Multiple familial and child characteristics were rated as increasing the difficulty of successful KD. CONCLUSIONS: The results of the present study suggest that it is feasible for children with ASD to adopt a KD, and success is highly individualised to child and family.

Variant-specific effects define the phenotypic spectrum of HNRNPH2-associated neurodevelopmental disorders in males.

Bain type of X-linked syndromic intellectual developmental disorder, caused by pathogenic missense variants in HRNRPH2, was initially described in six female individuals affected by moderate-to-severe neurodevelopmental delay. Although it was initially postulated that the condition would not be compatible with life in males, several affected male individuals harboring pathogenic variants in HNRNPH2 have since been documented. However, functional in-vitro analyses of identified variants have not been performed and, therefore, possible genotype-phenotype correlations remain elusive. Here, we present eight male individuals, including a pair of monozygotic twins, harboring pathogenic or likely pathogenic HNRNPH2 variants. Notably, we present the first individuals harboring nonsense or frameshift variants who, similarly to an individual harboring a de novo p.(Arg29Cys) variant within the first quasi-RNA-recognition motif (qRRM), displayed mild developmental delay, and developed mostly autistic features and/or psychiatric co-morbidities. Additionally, we present two individuals harboring a recurrent de novo p.(Arg114Trp), within the second qRRM, who had a severe neurodevelopmental delay with seizures. Functional characterization of the three most common HNRNPH2 missense variants revealed dysfunctional nucleocytoplasmic shuttling of proteins harboring the p.(Arg206Gln) and p.(Pro209Leu) variants, located within the nuclear localization signal, whereas proteins with p.(Arg114Trp) showed reduced interaction with members of the large assembly of splicing regulators (LASR). Moreover, RNA-sequencing of primary fibroblasts of the individual harboring the p.(Arg114Trp) revealed substantial alterations in the regulation of alternative splicing along with global transcriptome changes. Thus, we further expand the clinical and variant spectrum in HNRNPH2-associated disease in males and provide novel molecular insights suggesting the disorder to be a spliceopathy on the molecular level.

Diagnostic preferences include discussion of etiology for adults with cerebral palsy and their caregivers.

AIM: To determine the views of individuals with cerebral palsy (CP) and their caregivers (CP community members) about carrying a CP diagnosis, an etiological diagnosis, or both diagnoses together. METHOD: We surveyed CP community members across two registries querying their views on carrying a CP diagnosis, one type of etiological diagnosis (specifically, a genetic diagnosis), or both. Open-ended responses were analyzed using a conventional content analysis approach. RESULTS: Of 197 respondents (108 adults with CP and 89 caregivers), most (75%) valued knowing the cause of their CP. Of those with a diagnostic preference, most preferred carrying both CP and etiological diagnoses together (68%). When compared with carrying an etiological diagnosis alone, significantly more respondents felt a CP diagnosis helped anticipate symptom evolution (84% vs 54%), explain symptoms to others (86% vs 48%), access services (86% vs 48%), and join support communities (78% vs 50%) (p <  0.01, χ2 test). INTERPRETATION: Most CP community members surveyed want to know the cause of their CP and would prefer carrying both CP and etiological diagnoses together. Clinical practice should evolve to meet these community needs.

A novel de novo KDM5C variant in a female with global developmental delay and ataxia: a case report.

BACKGROUND: Pathogenic variants in KDM5C are a cause of X-linked intellectual disability in males. Other features in males include short stature, dysmorphic features, seizures and spasticity. In some instances, female relatives were noted to have learning difficulties and mild intellectual disabilities, but full phenotypic descriptions were often incomplete. Recently, detailed phenotypic features of five affected females with de novo variants were described. (Clin Genet 98:43-55, 2020) Four individuals had a protein truncating variant and 1 individual had a missense variant. All five individuals had developmental delay/intellectual disability and three neurological features. CASE PRESENTATION: Here we report a three-year-old female with global developmental delay, hypotonia and ataxia. Through whole exome sequencing, a de novo c.1516A > G (p.Met506Val) variant in KDM5C was identified. This missense variant is in the jumonji-C domain of this multi domain protein where other missense variants have been previously reported in KDM5C related disorder. The KDM5C gene is highly intolerant to functional variation which suggests its pathogenicity. The probands motor delays and language impairment is consistent with other reported female patients with de novo variants in KDM5C. However, other features reported in females (distinctive facial features, skeletal abnormalities, short stature and endocrine features) were absent. To the best of our knowledge, our proband is the first female patient reported with a diagnosis of ataxia. CONCLUSIONS: This case report provides evidence for an emerging and phenotypic variability that adds to the literature of the role of KDM5C in females with neurodevelopmental disorders as well as movement disorders.

Genetic testing in individuals with cerebral palsy.

AIM To determine which patients with cerebral palsy (CP) should undergo genetic testing, we compared the rate of likely causative genetic variants from whole-exome sequencing in individuals with and without environmental risk factors. METHOD Patients were part of a convenience and physician-referred cohort recruited from a single medical center, and research whole-exome sequencing was completed. Participants were evaluated for the following risk factors: extreme preterm birth, brain bleed or stroke, birth asphyxia, brain malformations, and intrauterine infection. RESULTS A total of 151 unrelated individuals with CP (81 females, 70 males; mean age 25y 7mo [SD 17y 5mo], range 3wks-72y) participated. Causative genetic variants were identified in 14 participants (9.3%). There was no significant difference in diagnostic rate between individuals with risk factors (10 out of 123; 8.1%) and those without (4 out of 28; 14.3%) (Fisher's exact p=0.3). INTERPRETATION While the rate of genetic diagnoses among individuals without risk factors was higher than those with risk factors, the difference was not statistically significant at this sample size. The identification of genetic diagnoses in over 8% of cases with risk factors suggests that these might confer susceptibility to environmental factors, and that further research should include individuals with risk factors. What this paper adds There is no significant difference in diagnostic rate between individuals with and without risk factors. Genetic variants may confer susceptibility to environmental risk factors. Six causative variants were identified in genes not previously associated with cerebral palsy. Global developmental delay/intellectual disability is positively associated with a genetic etiology. Extreme preterm birth, stroke/brain hemorrhage, and older age are negatively associated with a genetic etiology.

Inclusion and perception of hand therapy content in occupational therapy programs: A mixed-method study.

STUDY DESIGN: Mixed-methods with cross-sectional survey and interviews. INTRODUCTION: Hand therapy is a specialty area of practice for occupational (OT) and physical therapists (PT), requiring experience and certification beyond entry-level generalist education. Perspectives and inclusion of content related to hand therapy differs among entry-level OT programs and faculty. PURPOSE: Perception and inclusion of hand therapy content in OT programs was examined in this mixed-method study to better understand the trends in academia regarding integration of content related to hand therapy. METHODS: A survey was developed, peer-reviewed, and emailed to all accredited entry-level masters and doctorate OT programs via Survey Monkey (SurveyMonkey, Inc., San Mateo, CA). Respondents were also given the opportunity to participate in an interview (n = 2; 5%). RESULTS: A total of 43 participants responded to the survey, representing a 23% response rate. Quantitative results revealed that 65% of OT programs report including 41+ hours of hand therapy content and 54% report integration of hand therapy content in 2-3 courses. Qualitative trends included the perception of hand content as necessary and beneficial to other areas of practice as well as the perspective that it is too specialized and advanced for generalist curriculum. DISCUSSION: Educators have a largely positive opinion regarding inclusion and generalizability of hand therapy content within OT curricula with varied content inclusion. While hand therapy related content is valued, increased emphasis on occupation during didactic instruction is recommended for more holistic understanding and occupation-based practice. CONCLUSION: While trends of hand therapy content inclusion were revealed in the survey, perceptions of hand therapy within the broad spectrum of OT curricula were diverse, indicating a possible lack of unity within the profession regarding this specialty area of practice.

Variants in HNRNPH2 on the X Chromosome Are Associated with a Neurodevelopmental Disorder in Females.

Via whole-exome sequencing, we identified six females from independent families with a common neurodevelopmental phenotype including developmental delay, intellectual disability, autism, hypotonia, and seizures, all with de novo predicted deleterious variants in the nuclear localization signal of Heterogeneous Nuclear Ribonucleoprotein H2, encoded by HNRNPH2, a gene located on the X chromosome. Many of the females also have seizures, psychiatric co-morbidities, and orthopedic, gastrointestinal, and growth problems as well as common dysmorphic facial features. HNRNPs are a large group of ubiquitous proteins that associate with pre-mRNAs in eukaryotic cells to produce a multitude of alternatively spliced mRNA products during development and play an important role in controlling gene expression. The failure to identify affected males, the severity of the neurodevelopmental phenotype in females, and the essential role of this gene suggests that male conceptuses with these variants may not be viable.

Hirsutism in Women.

Hirsutism is the excessive growth of terminal hair in a typical male pattern in a female. It is often a sign of excessive androgen levels. Although many conditions can lead to hirsutism, polycystic ovary syndrome and idiopathic hyperandrogenism account for more than 85% of cases. Less common causes include idiopathic hirsutism, nonclassic congenital adrenal hyperplasia, androgen-secreting tumors, medications, hyperprolactinemia, thyroid disorders, and Cushing syndrome. Women with an abnormal hirsutism score based on the Ferriman-Gallwey scoring system should be evaluated for elevated androgen levels. Women with rapid onset of hirsutism over a few months or signs of virilization are at high risk of having an androgen-secreting tumor. Hirsutism may be treated with pharmacologic agents and/or hair removal. Recommended pharmacologic therapies include combined oral contraceptives, finasteride, spironolactone, and topical eflornithine. Because of the length of the hair growth cycle, therapies should be tried for at least six months before switching treatments. Hair removal methods such as shaving, waxing, and plucking may be effective, but their effects are temporary. Photoepilation and electrolysis are somewhat effective for long-term hair removal but are expensive.

Prevalence of Seizures in Pediatric Extracorporeal Membrane Oxygenation Patients as Measured by Continuous Electroencephalography.

OBJECTIVES: Standards for neuromonitoring during extracorporeal membrane oxygenation support do not currently exist, and there is wide variability in practice. We present our institutional experience at an academic children's hospital since establishment of a continuous electroencephalography monitoring protocol for extracorporeal membrane oxygenation patients. DESIGN: Retrospective, single-center study. SETTING: Neonatal ICU and PICU in an urban, quaternary care center. PATIENTS: All neonatal and pediatric patients requiring extracorporeal membrane oxygenation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During the study period, 70 patients were cannulated for extracorporeal membrane oxygenation and had continuous electroencephalography monitoring for greater than 24 hours. Electroencephalographic seizures were observed in 16 of 70 patients (23%), including five patients (7%) who were in status epilepticus. Among patients with continuous electroencephalography seizures, nine (56%) had subclinical nonconvulsive status epilepticus and eight (50%) had seizures in the initial 24 hours of extracorporeal membrane oxygenation support. Survival to hospital discharge was significantly greater for extracorporeal membrane oxygenation patients without seizures (74% vs 44%; p = 0.02). CONCLUSIONS: Seizures occur in a significant proportion of pediatric and neonatal extracorporeal membrane oxygenation patients, frequently in the initial 24 hours after extracorporeal membrane oxygenation cannulation. Because seizures are associated with significantly decreased survival, neuromonitoring early in the extracorporeal membrane oxygenation course is important and useful. Further studies are needed to correlate electroencephalography findings with neurologic outcome.

Self-assembled MmsF proteinosomes control magnetite nanoparticle formation in vitro.

Magnetotactic bacteria synthesize highly uniform intracellular magnetite nanoparticles through the action of several key biomineralization proteins. These proteins are present in a unique lipid-bound organelle (the magnetosome) that functions as a nanosized reactor in which the particle is formed. A master regulator protein of nanoparticle formation, magnetosome membrane specific F (MmsF), was recently discovered. This predicted integral membrane protein is essential for controlling the monodispersity of the nanoparticles in Magnetospirillum magneticum strain AMB-1. Two MmsF homologs sharing over 60% sequence identity, but showing no apparent impact on particle formation, were also identified in the same organism. We have cloned, expressed, and used these three purified proteins as additives in synthetic magnetite precipitation reactions. Remarkably, these predominantly α-helical membrane spanning proteins are unusually highly stable and water-soluble because they self-assemble into spherical aggregates with an average diameter of 36 nm. The MmsF assembly appears to be responsible for a profound level of control over particle size and iron oxide (magnetite) homogeneity in chemical precipitation reactions, consistent with its indicated role in vivo. The assemblies of its two homologous proteins produce imprecise various iron oxide materials, which is a striking difference for proteins that are so similar to MmsF both in sequence and hierarchical structure. These findings show MmsF is a significant, previously undiscovered, protein additive for precision magnetite nanoparticle production. Furthermore, the self-assembly of these proteins into discrete, soluble, and functional "proteinosome" structures could lead to advances in fields ranging from membrane protein production to drug delivery applications.

Bioinspired nanoreactors for the biomineralisation of metallic-based nanoparticles for nanomedicine.

This review explores the synthesis of inorganic metallic-based nanoparticles (MBNPs) (metals, alloys, metal oxides) using biological and biologically inspired nanoreactors for precipitation/crystallisation. Such nanoparticles exhibit a range of nanoscale properties such as surface plasmon resonance (nobel metals e.g. Au), fluorescence (semiconductor quantum dots e.g. CdSe) and nanomagnetism (magnetic alloys e.g. CoPt and iron oxides e.g. magnetite), which are currently the subject of intensive research for their applicability in diagnostic and therapeutic nanomedicine. For such applications, MBNPs are required to be biocompatible, of a precise size and shape for a consistent signal or output and be easily modified with biomolecules for applications. Ideally the MBNPs would be obtained via an environmentally-friendly synthetic route. A biological or biologically inspired nanoreactor synthesis of MBNPs is shown to address these issues. Biological nanoreactors for crystallizing MBNPs within cells (magnetosomes), protein cages (ferritin) and virus capsids (cowpea chlorotic mottle, cowpea mosaic and tobacco mosaic viruses), are discussed along with how these have been modified for applications and for the next generation of new materials. Biomimetic liposome, polymersome and even designed self-assembled proteinosome nanoreactors are also reviewed for MBNP crystallisation and further modification for applications. With the advent of synthetic biology, the research and understanding in this field is growing, with the goal of realising nanoreactor synthesis of MBNPs for biomedical applications within our grasp in the near future.

Oral health education and therapy reduces gingivitis during pregnancy.

BACKGROUND: Pregnant women demonstrate increases in gingivitis despite similar plaque levels to non-pregnant counterparts. AIM: To evaluate an intensive protocol aimed at reducing gingivitis in pregnant women and provide pilot data for large-scale randomized controlled trials investigating oral hygiene measures to reduce pregnancy gingivitis and alter maternity outcomes. MATERIALS AND METHODS: One hundred and twenty participants between 16 and 24 weeks gestation with Gingival Index (GI) scores ≥2 at ≥50% of tooth sites were enrolled. Plaque index (PI), gingival inflammation (GI), probing depth (PD), and clinical attachment levels (CAL) were recorded at baseline and 8 weeks. Dental prophylaxis was performed at baseline and oral hygiene instructions at baseline, 4 and 8 weeks. Pregnancy outcomes were recorded at parturition. Mixed-model analysis of variance was used to compare clinical measurements at baseline and 8 weeks. RESULTS: Statistically significant reductions in PI, GI, PD, and CAL occurred over the study period. Mean whole mouth PI and GI scores decreased approximately 50% and the percentage of sites with PI and GI ≥2 decreased from 40% to 17% and 53% to 21.8%, respectively. Mean decreases in whole mouth PD and CAL of 0.45 and 0.24 mm, respectively, were seen. CONCLUSIONS: Intensive oral hygiene regimen decreased gingivitis in pregnant patients.

Evolving capacity and decision-making in practice: adolescents' access to legal abortion services in Mexico City.

The rights of adolescents and young people in international law and agreements have evolved significantly from a focus on protection to a recognition of "evolving capacities" and decision-making ability. Unclear policies and regulations and variations in actual practice may leave providers with little clarity on how to support adolescent decision-making and instead create unintended barriers. This study in Mexico City in 2009 explored whether regulations and clinical attitudes and practice were supporting or hindering the access of adolescent girls aged 12-17 to information regarding abortion and to abortion services. We surveyed abortion clinic directors and staff, and adolescents arranging or just having had an abortion, and sent mystery clients to clinics to ask for information. While providers were generally positive about adolescents' ability to decide on abortion, they had different understandings about the need for adult accompaniment and who that adult should be, and mystery clients seeking information were more likely to receive complete information if accompanied by an adult. Clarification of consent and accompaniment requirements is needed, and providers need to be made aware of them; adolescents should have access to information and counselling without accompaniment; and improvements in privacy and confidentiality in public sector clinics are also needed. These all support complementary concepts of protection and autonomy in adolescent decision-making on abortion.

Rett-like Phenotypes in HNRNPH2-Related Neurodevelopmental Disorder.

Rett Syndrome (RTT) is a neurodevelopmental disorder with a prevalence of 1:10,000 to 15,000 females worldwide. Classic Rett Syndrome presents in early childhood with a period of developmental regression, loss of purposeful hand skills along with hand stereotypies, gait abnormalities, and loss of acquired speech. Atypical RTT is diagnosed when a child shows some but not all the phenotypes of classic RTT, along with additional supporting criteria. Over 95% of classic RTT cases are attributed to pathogenic variants in Methyl-CpG Binding Protein 2 (MECP2), though additional genes have been implicated in other RTT cases, particularly those with the atypical RTT clinical picture. Other genetic etiologies have emerged with similar clinical characteristics to RTT Syndrome. Our team has characterized HNRNPH2-related neurodevelopmental disorder (HNRNPH2-RNDD) in 33 individuals associated with de novo pathogenic missense variants in the X-linked HNRNPH2 gene, characterized by developmental delay, intellectual disability, seizures, autistic-like features, and motor abnormalities. We sought to further characterize RTT clinical features in this group of individuals by using caregiver report. Twenty-six caregivers completed electronic surveys, with only 3 individuals having previously received an atypical RTT diagnosis, and no individuals with a typical RTT diagnosis. Caregivers reported a high number of behaviors and/or phenotypes consistent with RTT, including the major criteria of the syndrome, such as regression of developmental skills and abnormal gait. Based on the survey results, 12 individuals could meet the diagnostic clinical criteria for atypical RTT Syndrome. In summary, individuals with HNRNPH2-RNDD exhibit clinical characteristics that overlap with those of RTT, and therefore, HNRNPH2-RNDD, should be considered on the differential diagnosis list with this clinical picture.