<strong>Background:</strong> Social desirability bias, the tendency to respond in ways that present the respondent favorably, is well documented in human self-report and has recently been observed in large language models (LLMs) completing personality inventories. Whether it also affects LLM responses to validated health screening instruments, where LLMs are increasingly proposed as simulated patients or synthetic respondents, has not been examined. <strong>Objective:</strong> This formative study aimed to determine whether 4 OpenAI models alter their responses to health screening questionnaires when the instrument and its evaluative purpose can be inferred from the prompt and to quantify the size and direction of any shift. <strong>Methods:</strong> GPT-4o, GPT-4o mini, o1-mini, and o1 were prompted through the OpenAI application programming interface in April 2025 to complete the Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), Alcohol Use Disorders Identification Test (AUDIT), and FANTASTIC lifestyle assessment while adopting the persona of a random member of the public. Each instrument was administered under a naive condition, wherein every item was presented alone in a separate call so that the instrument could not be recognized, and an informed condition, in which all items were presented together, with 100 completed trials per model, instrument, and condition. Naive and informed scores were compared within each model using independent-samples 2-tailed <i>t</i> tests with Bonferroni correction for 16 comparisons, with effect sizes expressed as Cohen <i>d</i> and in units of published general-population SDs. Published human norms served only as descriptive reference points. <strong>Results:</strong> In 14 of 16 model-instrument combinations, scores shifted significantly toward the socially desirable pole when the instrument was recognizable (all <i>P</i><.001): fewer anxiety and depressive symptoms, lower reported alcohol use, and healthier lifestyle behaviors. Mean shifts were 3.2 to 8.2 points on the GAD-7, 2.4 to 11.9 on the PHQ-9, 2.8 to 4.5 on the AUDIT for the o1 models, and 8.2 to 13.5 on the FANTASTIC lifestyle assessment (Cohen <i>d</i>=1.0-8.6). GPT-4o’s AUDIT shift (0.36 points; <i>P</i>=.04) did not survive correction, and GPT-4o mini shifted in the opposite direction on the AUDIT (–2.69 points; <i>P</i><.001). The largest shifts on the mental health instruments occurred in GPT-4o mini, whereas the largest AUDIT shifts occurred in the 2 reasoning models. <strong>Conclusions:</strong> When a screening instrument was recognizable, the 4 OpenAI models tested consistently produced more socially desirable responses than when the same items were presented in isolation. The design cannot separate evaluative inference from other consequences of presenting items together, and the findings are confined to one vendor’s models. Therefore, they constitute formative evidence that social desirability bias may extend to health screening contexts—not evidence of a general property of LLMs. Studies using LLMs as simulated patients or synthetic respondents should report prompt framing and audit for framing-dependent shifts before relying on generated data. <strong>Trial Registration:</strong>
Background: Adolescent mental health needs remain largely unmet, particularly among youth in geographically underserved communities. Digital peer support is a promising approach to expanding access to mental health support, yet real-world evidence on engagement patterns and clinical outcomes remains limited. Objective: The purpose of this study was to characterize engagement patterns and real-world outcomes among adolescents and young adults enrolled in a commercially available, text-based peer support platform. Methods: This retrospective observational study analyzed secondary data from 5673 adolescents and young adults enrolled in a commercially available digital peer support platform from January 29, 2023, through June 3, 2026. Engagement was operationalized as communication days per month. Standardized clinical outcome measures (Patient Health Questionnaire-9 [PHQ-9], Generalized Anxiety Disorder-7 [GAD-7], and World Health Organization-Five Well-Being Index [WHO-5]) were administered as part of routine measurement-based care. Ordinary least squares regression was used to examine predictors of engagement, and complete-case pre-post change scores were evaluated across 4 assessment windows among participants with paired assessments. Results: The sample was predominantly female (4600/5673, 81.1%) with a mean age of 16.4 (SD 2.1) years and moderate-to-severe symptom burden at baseline (PHQ-9: mean 12.6, SD 6.1; GAD-7: mean 10.7, SD 5.0; WHO-5: mean 44.8, SD 21.0). Of enrolled adolescents and young adults, 98.1% (5565/5673) had at least one recorded engagement with the platform, with a mean of 4.56 (SD 6.12) communication days per month. Female sex was a significant positive predictor of engagement intensity (β=.64, SE 0.22; =.004). Hispanic and Latino adolescents and young adults engaged significantly more frequently than White or non-Hispanic adolescents and young adults (β=.61, SE 0.26; =.02). Health Professional Shortage Area (HPSA) shortage score was significantly and positively associated with engagement intensity (β=.08, SE 0.02; <.001). Baseline symptom severity was not associated with engagement intensity (β=.094, SE 0.23; =.68). Among participants with complete baseline and follow-up data (1437/5673, 25.3%), an exploratory complete-case analysis found within-measure paired scores improved significantly from baseline to follow-up across the PHQ-9, GAD-7, and WHO-5. At last assessment, 31.9% (237/742), 36.6% (222/606), and 37.8% (168/442) of adolescents and young adults met clinically meaningful improvement thresholds on the PHQ-9, GAD-7, and WHO-5, respectively. Conclusions: Text-based peer support shows preliminary promise as a scalable approach to expanding mental health access for underserved adolescents, though clinical improvement estimates are based on the subpopulation exposed to the digital peer support platform and may not generalize to the full enrolled population. Prospective, controlled studies with more complete outcome ascertainment are needed to establish causal efficacy.
A study by University of Pittsburgh and UPMC researcher-clinicians has uncovered why many pulmonary hypertension (PH) patients report symptoms of cognitive decline.
The team carried out a multimodal investigation involving brain MRI studies, blood-based molecular profiling, and functional studies in mouse models, and linked specific brain abnormalities in pulmonary hypertension to the same inflammatory processes that drive the disease in the lungs and heart. The findings suggest that cognitive decline may be present in other vascular and inflammatory conditions beyond pulmonary hypertension. The results also point to neural targets that may be relevant for future diagnostic, prognostic, and therapeutic approaches.
“Patients often assume memory issues or trouble concentrating are unrelated to their pulmonary hypertension,” said research lead Stephen Chan, MD, PhD, Vitalant Chair in Vascular Medicine and director of the Vascular Medicine Institute and Center for Pulmonary Vascular Biology and Medicine at the Pitt School of Medicine and UPMC. “Our findings suggest those symptoms are a central part of the disease process and deserve attention.”
Millions of people are affected by pulmonary hypertension, which causes high blood pressure in the blood vessels of the lungs. Common symptoms include shortness of breath, chest pain, and feeling lightheaded. More recently scientists have linked pulmonary hypertension with cognitive issues such as impaired executive function and memory problems. “Cognitive impairment is increasingly recognized in pulmonary hypertension (PH), a disease traditionally viewed as limited to the heart and lungs,” the authors wrote. “Given that inflammation is shared by PH and neurodegenerative diseases, we investigated its role in driving brain and cognitive deficits in PH.”
Recent research by Chan identified a genetic variant in a gene called NCOA7, which produces a protein of the same name. In a quarter of pulmonary hypertension patients, this variant drives inflammatory responses and worsens the odds of survival. Chan hypothesized that the same variant might be connected to brain inflammation that leads to cognitive impairment in people with pulmonary hypertension.
To test that theory, Chan and colleagues used brain MRI scans and blood tests to look for brain changes that were unique to pulmonary hypertension. They first compared the brain scans of people with pulmonary hypertension against those without, using data from a large public health database and a smaller group of UPMC patients to test and confirm their hypothesis.
Patients with pulmonary hypertension in both test groups had a consistent and substantial loss of brain tissue and weakened communication between two brain regions involved in memory, attention and planning—the cerebellum, at the base of the brain, and the frontal lobe, just behind the forehead. Notably, the same brain changes were absent in people with other heart, lung, and psychiatric conditions. “Using structural and functional MRI data from UK Biobank (N = 248 PH) and a prospective validation cohort, we identified reduced cerebellar white matter volume, thinner frontal gyri, and weakened cerebellar-frontal connectivity in patients with PH but not in other heart or lung diseases,” the team reported. These changes were accompanied by worsened executive function and processing speed.”
The brain differences could not be explained by low blood oxygen, poor heart function, or the medications used to treat the disease—evidence that the changes are specific to pulmonary hypertension, rather than a side effect of the disease’s effects on the heart and lungs.
By analyzing genetic data from both groups of patients and conducting additional laboratory studies, the team found that the NCOA7 variant already linked to blood vessel inflammation in pulmonary hypertension is also connected to inflammation in the cerebellum of these patients.
Examining cerebellum tissue from patients and mice with pulmonary hypertension, they saw signs that brain immune cells—microglia—had become overactive, and evidence that neurons were changing in response. Mice that both developed the disease and lacked the NCOA7 gene had more severe cerebellar damage than mice with pulmonary hypertension alone, establishing that the gene plays a causal role in regulating brain inflammation in this disease. “Postmortem analysis and PH mouse models showed cerebellar microglial activation and structural deficits worsened by NCOA7 deficiency,” the investigators wrote in summary. “Collectively, these findings support PH-associated cerebellar–frontal brain deficiencies linked to chronic neuroinflammation and NCOA7 dysfunction.”
Chan suspects that this mechanism is active in other diseases beyond pulmonary hypertension. “I believe that NCOA7 deficiency may underlie a spectrum of inflammatory conditions—including those that may contribute to dementia and aging,” Chan said. “If so, these findings could introduce new diagnostic and therapeutic avenues for preserving brain function in a much broader group of people.” The authors added: “From a translational perspective, the association of inflammatory plasma biomarkers with structural and functional brain alterations may inform new diagnostic and prognostic strategies … Our findings also open avenues for testing whether PH-associated neuroinflammatory changes are therapeutically reversible.”
Current guidelines for managing pulmonary hypertension do not include cognitive screening, and no biological marker exists to predict or track how much the disease affects the brain. This study points to a potential marker and identifies inflammation as a potential therapeutic target for preserving brain function and quality of life.
“This changes the way we look at a disease like pulmonary hypertension,” said Chan. “In medicine, we typically treat the symptoms of one organ system; but the reality is that our bodies are very complex, and disease processes may be affecting multiple parts of the body in a variety of ways.”
<strong>Background:</strong> As Taiwan enters a super-aged society, the prevalence of dementia continues to rise, highlighting the need for scalable, noninvasive approaches to identify behavioral alterations associated with cognitive decline. AI-based analysis of spontaneous affective facial responses has emerged as a potential digital phenotyping tool, but its feasibility for assessing cognitive performance remains underexplored. <strong>Objective:</strong> This study aimed to examine the feasibility of using AI-derived spontaneous affective facial response metrics, including affective expression congruency and onset latency, to characterize differences across cognitive performance levels in older adults with healthy cognition (HC), mild cognitive impairment (MCI), or dementia. <strong>Methods:</strong> A total of 60 participants (HC, MCI, and dementia; 20 per group) were presented with positive and negative emotion-eliciting videos and completed Mini-Mental State Examination (MMSE) recall and calculation tasks. Facial expressions were video-recorded and analyzed using a convolutional neural network–based AI system. AI-derived metrics included affective expression congruency, categorized as congruent, neutral, or incongruent according to the detected facial response, and affective expression onset latency, defined as the time from stimulus presentation to the emergence of a nonneutral facial expression detected by the AI model. Group differences were analyzed using 1-way ANOVA, Pearson chi-square or Fisher-Freeman-Halton exact tests, Bonferroni-adjusted pairwise post hoc comparisons, analysis of covariance adjusting for age and education, and exploratory receiver operating characteristic analyses. <strong>Results:</strong> Affectively congruent responses were generally less frequent among participants with lower cognitive performance. During the 14-second positive stimulus, congruent positive expressions were observed in 65% (13/20) of HC participants, 20% (4/20) of MCI participants, and 0% (0/20) of participants with dementia. During the 48-second negative stimulus, congruent negative expressions were observed in 60% (12/20) of HC participants compared with 5% (1/20) of both MCI and dementia participants. Onset latency differed significantly across groups for the 14-second positive stimulus (<i>F</i><sub>2,57</sub>=19.63; <i>P</i><.001; η<sup>2</sup>=0.41), 52-second positive stimulus (<i>F</i><sub>2,57</sub>=4.25; <i>P</i>=.02; η<sup>2</sup>=0.13), 48-second negative stimulus (<i>F</i><sub>2,57</sub>=15.61; <i>P</i><.001; η<sup>2</sup>=0.35), and MMSE-based cognitive-task condition (<i>F</i><sub>2,57</sub>=11.28; <i>P</i><.001; η<sup>2</sup>=0.28). After adjustment for age and education, the group effect remained significant for all latency outcomes (<i>F</i><sub>2,55</sub>=3.89-10.68; all <i>P</i>≤.03; partial η<sup>2</sup>=0.12-0.28). Exploratory receiver operating characteristic analyses showed stronger separation in several HC vs MCI and HC vs dementia comparisons, whereas MCI vs dementia comparisons showed limited separability. <strong>Conclusions:</strong> AI-assisted analysis of spontaneous affective facial responses revealed differences in expression congruency and onset latency across cognitive performance levels. These preliminary findings suggest that AI-derived facial behavioral metrics may serve as noninvasive adjunctive features for observational cognitive assessment. However, the findings should be interpreted cautiously because of the exploratory design, modest sample size, and absence of internal or external validation.
BackgroundSuicidal behavior among adolescents and young adults remains a major public health concern. In sub-Saharan Africa, however, qualitative work that captures both youth and caregiver perspectives is still limited. This study explored the experiences of suicidal behavior, perceived triggers and responses to it among young people and their caregivers attending a tertiary facility in Nairobi, Kenya.MethodsThis qualitative study was conducted at the outpatient youth mental health clinic of a tertiary facility in Kenya, which receives both walk-in clients and referrals. It included 42 young people aged 13–24 years with personal experience of suicidal behavior and 11 caregivers. Participants were recruited purposively, and semi-structured interviews were conducted separately with young people and caregivers. Interviews were audio-recorded, transcribed verbatim, and analyzed thematically using NVivo.FindingsYoung people described suicidal behavior as developing gradually through cumulative and interacting stressors. Perceived triggers included academic and work-related pressure, family conflict, relationship difficulties, harmful social media experiences, socioeconomic hardship, and psychological or health-related challenges, including depression, substance use, trauma, and abuse. Caregivers expressed concern and willingness to help but frequently reported uncertainty about recognizing distress and responding appropriately.ConclusionSuicidal behavior in this setting reflected the interaction of personal and structural disadvantage rather than a single precipitating event. Prevention should combine youth-friendly mental health care, caregiver psychoeducation, family involvement, school-based support, and community-level action on poverty, stigma, and service access.
Encoded Therapeutics’ reports good interim safety and early efficacy findings from its ongoing Phase I/II trials of its gene therapy for treatment of the rare neurological condition Dravet syndrome.
As reported at the European Society of Gene and Cell Therapy conference in Hamburg, results from 21 patients treated in three open label Phase I/II trials showed no serious adverse events or dose-limiting toxicities of the adeno-associated virus (AAV) vector therapy ETX101.
In addition, positive efficacy results were seen including a significant reduction in seizures and improvements in neurodevelopment in the children treated with ETX101 including better communication, cognition, and skills acquisition.
Dravet syndrome is a rare, severe, lifelong genetic epilepsy, impacting around one in 20,000 births in the U.S., that usually begins in the first year of life. It causes prolonged seizures and is difficult to control with medicines. As children get older, development typically slows and learning, language, movement, and behavior are all adversely affected.
Most cases of Dravet syndrome are caused by a disease-causing variant in the SCN1A gene, which encodes a sodium-channel protein involved in nerve-cell signaling.
There are approved treatments available to control Dravet seizures, but to date no genetic therapies are approved to address the root cause of this condition. ETX101 delivers instructions for an engineered protein that increases SCN1A activity selectively in inhibitory neurons. Rather than replacing or editing the faulty gene, it aims to boost production of NaV1.1, the sodium-channel protein deficient in most Dravet cases.
Speaking at the conference, Salvador Rico, MD, PhD, chief medical officer at Encoded Therapeutics, described the interim results from the three studies, which are open-label, without a control. The team treated 21 children aged six months to seven years with a single brain-ventricle injection of ETX101, while continuing standard antiseizure medicines. Four different doses of the therapy were tested.
Seizure reduction was good particularly at the higher two doses. Three children at dose level 3 had a median reduction of approximately 76% through one year. At the highest dose, four children receiving prednisolone without sirolimus had an approximately 84% reduction between enrollment and week 16.
“Seeing this level of effect in a population this refractory, especially in that period of time … is really remarkable and without precedent,” said Rico.
The researchers also reported communication and adaptive-skill gains after treatment. Children treated at or before age two appeared to acquire cognitive skills at a pace approaching typical development.
“Rather than entering the expected pattern of stagnation, these patients are showing an acquisition of skills that is most consistent with typical development,” explained Rico. “This is suggesting that we may be rescuing learning abilities.”
No serious adverse events were reported to date, but six children developed elevated liver enzymes.
Based on these early promising results, Encode is now testing ETX101 in a larger Phase II clinical trial. Another gene-targeted approach being developed by Stoke Therapeutics/Biogen for treatment of Dravet syndrome, zorevunersen, uses repeatedly administered antisense oligonucleotide (ASO) molecules to increase NaV1.1 production. It has also produced encouraging seizure and developmental findings and is currently in Phase III testing.
Communicator Fellow, SNF Global Center for Child and Adolescent Mental Health at the Child Mind Institute Read More
The second annual Global Summit on Youth Mental Health led by the Stavros Niarchos Foundation (SNF) Global Center at the Child Mind Institute was held during the 81st United Nations General Assembly Week in New York. The opening remarks at this event reminded us that systems are often built for young people without them sitting at the table. Looking back, the whole week felt like a shared effort to change that. Young people and experts from around the world engaged in important conversations that combined science research with advocacy and lived experience.
From beginning to end, the summit was co-organized by the Global Youth Advisory Council (GYAC) at the SNF Global Center. Its members hail from Brazil, Greece, and South Africa: Jennifer Matibi,Kayla Coetzer, Spyros Chronis,Faidra Kamperidi, Mariana Chaves and Denny Oliveira Curini. The chosen theme was “Redefining Mental Health Care: Youth Perspectives in a Changing World” and the event featured panels, workshops, breakout sessions, new research, and interactive activations. The issues that affect young people’s mental health are complex, and complexity demands collaboration.
A dedicated youth networking hour preceded the main summit program on September 24, welcoming the participation of professionals from different organizations. Throughout the week, I had the chance to meet young people and experts from more than 30 countries, all working to push the needle forward for youth mental health. The atmosphere was teeming with collaboration and a deep sense of respect.
Many ideas came to life during the panels and sessions. There was a concrete sense of unity, with GYAC members in meaningful conversations with partners from many organizations including UNICEF, the JED Foundation, Grand Challenges, and the McKinsey Health Institute. Guest speakers also included Shudufhadzo Musida, author, advocate, and UNFPA Global Champion for Women and Girls.
The first panel discussion, “Meeting Young People Where They Are: Bringing Mental Health Support in Schools,” explored the role of schools in redefining mental health care. It was creatively introduced with storytelling from Denny (Brazil) and Kayla (South Africa). The session covered school cultures, how what we measure and reward in academic environments can affect young people’s mental health, and how much it matters for students to be surrounded by a strong network of supportive relationships.
Throughout the morning, we also heard profound discussions on social media and political instability, two of the many pressures young people navigate in an increasingly connected and uncertain world. The panel “Where Young People Connect, Create, and Share: Redefining Youth Mental Health in the Digital Context” highlighted that while conversations about young people and technology tend to focus on the risks, digital spaces are also where many young people express themselves and look for help when they’re struggling. Making these spaces safer should start from the way they are designed, and young people themselves should be involved in shaping them. This topic was later re-addressed during the fireside chat between moderators Kayla and Jennifer (South Africa) and guest speaker Shudufhadzo Musida, who discussed self-care and setting boundaries when advocating for mental health. She also talked about the importance of creating a safe space online for people to reflect and learn about mental health.
Later in the day, the spotlight session “From Aspiration to Action: Reimagining Community Wellbeing” looked at youth mental health from a systems perspective — considering the myriads of factors and stakeholders involved in supporting young people and how mental health support can be reimagined and grounded in communities. The session also reflected on the idea that community well-being cannot be strengthened at scale by one organization alone, and that partnerships are essential to make progress.
With the summit taking place during the same week as the UN General Assembly and Climate Week, the whole of New York City was buzzing. Everything felt like one continuous exchange. During the breaks, I had the chance to reconnect with colleagues and meet many new people working in the field of youth mental health. Two of those conversations have stayed with me, because they both pointed to the same idea: the power of intergenerational dialogue.
Emma Beckwith, a young leader who joined the Child Mind Institute’s Youth Mental Health Academy (YMHA) to work closely with the SNF Global Center during the summer, reminded me that if we want to address the disparities in child and adolescent mental health around the world, going to young people, learning from their lived experience, and working alongside adults to turn ideas into change is essential. And Felipe Paullier, MD, Assistant Secretary General for Youth Affairs at the UN Youth Office, pointed out that young people have a critical role in changing how we approach mental health. He stressed that bringing varied generations into the conversation is also fundamental. These experts come from different seats at the same table. So, hearing them both relay essentially the same message made it resonate stronger for me.
There is so much I am taking home from the summit week. It began with a series of workshops co-hosted with United for Global Mental Health (UGMH). And as an SNF Global Center Communicator Fellow, I co-led a workshop on communications and advocacy with Dave Gill and my fellow colleagues Naomi Grewan and Mary Ann Nobele from Radio Workshop. It was inspiring to see so many people using their own stories to positively influence change in youth mental health care. Stories are powerful, and they are one of the best ways to motivate change.
Vinicius Gaby Vieira Rego, MD Communicator Fellow, Brazil, SNF Global Center at the Child Mind Institute
One moment I keep coming back to is seeing João Marcos Almeida dos Santos, a Brazilian youth counselor for Gentilmmente — a project supported by the SNF Global Center’s Child and Adolescent Mental Health Initiative (CAMHI) in Brazil — talk about challenges the digital environment poses to youth mental health. João also won the nationwide Single Session Intervention (SSI) competition, a partnership between CAMHI Brazil and the Felipe Neto Institute that invited young Brazilians ages 16–20 to share their vision for advancing youth mental health through healthier technology habits. Dos Santos highlighted the need for expanded psychosocial support in schools across Brazil:
Schools in Brazil, for example, often don’t have psychologists or counselors to support students. Teachers aren’t always equipped with the necessary resources to support students who are struggling,” said Dos Santos. “Bullying still happens without structured protection in schools. Students are still under pressure from comparison, along with many other sources of distress. We need to implement more psychosocial support in schools, because that’s exactly where young people are and where they need help the most.
His presentation was delivered in Portuguese and translated in real-time. It was inspiring to see him on stage, raising awareness in his own language, and being able to connect with everyone in the room. For me, that is what powerful youth engagement looks like.
As said by Giovanni Abrahão Salum, MD, PhD, senior vice president of Global Programs during opening remarks, “For us, youth engagement is a condition for quality.”
I am deeply grateful to the GYAC and to everyone at the SNF Global Center who made this summit possible. Now that I am back in São Paulo, after connecting with so many people and reflecting on new learnings, one principle is clearer than ever: youth engagement and intergenerational dialogue are critical conditions for meaningful change in child and adolescent mental health care.
Background: Millions of people now use general-purpose large language models (LLMs) for mental health support, yet how these models respond to emotional disclosures and whether their responses functionally resemble established therapeutic practices remain uncharacterized. Objective: This study aimed to characterize how frontier LLMs respond to emotionally charged messages and examine whether their response patterns resemble therapeutic practices associated with self-awareness. Methods: We generated 54 simulated user inputs representing mild-to-moderate everyday emotional difficulties. These simulated user inputs were generated using 3 LLMs (GPT-5.5, Claude Opus 4.7, and Gemini 2.5 Pro). The simulated user inputs systematically varied across 3 lengths and 5 communicative registers, ranging from raw venting to pragmatic requests. Then, each simulated user input was presented as a standalone user turn to the same 3 frontier LLMs, yielding 162 responses. Two independent clinical coders qualitatively coded the resulting responses using an inductive approach. Results: The codes were compared and consolidated through iterative consensus, which yielded 8 higher-order categories. Acknowledging and validating segments appeared in 89.5% (145/162) of responses, emotion-focused suggestions in 84.6% (137/162), and interpretation in 67.3% (109/162). These patterns converged on emotional self-awareness, a construct associated with adaptive emotion regulation, suggesting that LLMs may repeatedly enact a recognizable micro-process of validation, affect labeling, interpretation, reflection, and regulation support. Models differed in stance, with some assigning emotional labels and interpretations directly rather than prompting users’ own reflection. Conclusions: Frontier LLMs respond to emotional disclosures in patterned, largely convergent ways that approximate therapeutic techniques for building emotional awareness, though delivered more didactically than in clinical practice. Whether these responses build genuine self-awareness, reduce symptoms, or provide therapeutic benefit requires controlled and naturalistic investigation.
<img src="https://jmir-production.s3.us-east-2.amazonaws.com/thumbs/d9ebfe7154b990fb860ef9704b6bcd42" />
BackgroundPPP1R3F deficiency syndrome is an extremely rare, recently identified X-linked recessive neurodevelopmental disorder. It is caused by hemizygous variants in the PPP1R3F gene, which encodes a glycogen-targeting subunit of the brain-specific protein phosphatase 1 (PP1). Dysfunction of PPP1R3F disrupts glycogen metabolism in astrocytes, leading to insufficient energy supply to synapses during critical periods of brain development and subsequently causing neurodevelopmental abnormalities. Only a small number of cases of PPP1R3F deficiency syndrome have been reported to date, which significantly limits our comprehensive understanding of the clinical features of the disease and the relationship between genetic variants and clinical manifestations in patients.MethodsWhole-exome sequencing (WES) was performed on a Chinese male presenting with intellectual disability (ID), developmental delay (DD), and autism spectrum disorder (ASD). Sanger sequencing was then used to identify and determine the origins of the variant. We evaluated the pathogenicity of the identified variant following the established ACMG/AMP guidelines. Additionally, we conducted a thorough review of previously reported cases to summarize the variants and clinical features of PPP1R3F deficiency syndrome.ResultsWe identified a novel hemizygous nonsense variant [NM_033215.5: c.907C>T, p.(Gln303*)] in the PPP1R3F gene in the proband, which was inherited from his mother. The patient we described here exhibited clinical phenotypes similar to those associated with PPP1R3F gene variants but lacked other reported multisystem manifestations, such as epilepsy, brain abnormalities, and dysmorphic features. An analysis of the 15 variants and their associated phenotypes in 15 patients from both the current and previous studies demonstrates that PPP1R3F gene variants can lead to a variety of phenotypic deficits, and a clear genotype–phenotype correlation has not yet been established. Despite the high variability in some clinical manifestations, the core phenotypic features of PPP1R3F variants include varying degrees of ID, DD, speech delay, dysmorphic facial features, and ASD.ConclusionOur findings support DD, ID, ASD, and speech impairment as core features of PPP1R3F deficiency syndrome, while also highlighting the extensive clinical variability. This study further expanded the genetic and phenotypic spectrum associated with PPP1R3F deficiency syndrome.
The cerebellum is an ancient brain component, conserved across mammalian species, that has classically played roles in regulating muscle tone, limb coordination, and equilibrium, as well as in non-motor functions, such as language, cognition, and emotion. Recently, we reported Nestin-expressing cells in the cerebellar cortex of ferret neonates that showed a proliferative potency defined by proliferating cell nuclear antigen (PCNA) immunostaining. We called these cells “internal granular progenitor (IGP).” IGPs were found to be abundant in the internal granular layer adjacent to the Purkinje cell layer and extended GFAP-immunopositive radials progressed through the molecular and external granular layers, forming an immature Bergmann glia-like morphology. The tracking of BrdU-labeling revealed that IGPs differentiated into granular neurons, Bergmann glia, and/or astrocytes. As such, we propose that IGPs may be neural progenitors with an immature Bergmann glia-like morphology that appear in the developing cerebellar cortex, and could serve as another source of granular neurons distinct from external granular progenitors. Further research on IGPs is expected to provide new perspectives for the future investigation of cerebellar corticohistogensis, particularly the difference between motor and non-motor cerebellar regions, and how the abnormal development of IGPs relates to neurodevelopmental disorders associated with non-motor cerebellar function, such as autism spectrum disorder.
