Tag: ADHD

Posted on

AI Tool Helps Link BRSK1 Variants to Neurodevelopmental Disorder

For many families affected by rare genetic conditions, genomic testing does not immediately deliver an answer. Now, researchers have combined artificial intelligence, human genetics, and fruit fly experiments to connect variants in BRSK1 with a complex neurodevelopmental disorder. The findings provide a potential diagnosis for several previously unexplained cases while offering clues about how reduced activity of the gene may disrupt nervous system development.

The study, “Monoallelic variants in BRSK1 are associated with a neurodevelopmental disorder with or without epilepsy,” was led by researchers at Baylor College of Medicine, the Duncan Neurological Research Institute at Texas Children’s Hospital, and the Texome Project, together with collaborating institutions. It was published in the American Journal of Human Genetics.

According to Hugo Bellen, PhD, who is co-lead author of the study, the work began with a child enrolled in the Texome Project, which provides genetic testing to medically underserved people with rare, undiagnosed conditions in Texas. Standard analysis of the child’s and parent’s genomes had not identified a cause. AI-MARRVEL, an artificial intelligence–based tool that analyzes genomic and clinical information to prioritize candidate disease variants, highlighted a rare change in BRSK1. Through GeneMatcher, the researchers identified nine additional affected individuals with rare heterozygous variants in the gene, bringing the group to 10 people from seven unrelated families. The team then modeled three patient-derived variants in Drosophila melanogaster to test their effects in a living organism.

The “affected individuals present with developmental delay and variable phenotypes including anxiety, attention-deficit hyperactivity disorder (ADHD), autism, and seizures,” the authors wrote, adding that the severity and symptoms varied. Symptoms differed even among relatives carrying the same variant, suggesting variable expressivity.

“We studied the fly equivalent of BRSK1, called sff (sugar-free frosting), and found that this gene is active primarily in neurons, mirroring the expression pattern seen in humans,” added Mingxi Deng, PhD, who is first author and a postdoctoral fellow in the Bellen lab. “When the fly gene was disabled, the flies developed difficulties moving, showed increased sensitivity to stressors that can trigger seizure-like behavior, became more vulnerable to heat-induced paralysis and lived shorter lives. These findings indicated that the gene is essential for normal nervous system function.”

Introducing normal human BRSK1 largely corrected the behavioral and neurological defects, whereas three variants (BRSK1p.Ile202Val, BRSK1p.Arg237Cys, and BRSK1p.Thr406Ile) found in affected individuals produced only a partial rescue. The patient variants also failed to normalize neuromuscular junction structure or levels of Futsch, a protein involved in organizing neuronal microtubules. Together, the experiments suggest that the variants partially reduce BRSK1 activity rather than eliminating it.

“Microtubule disruption has been linked to several neurodevelopmental and neurological disorders,” Deng said. “Our findings suggest that reduced BRSK1 function interferes with the cellular machinery needed for healthy brain development and communication between neurons.”

BRSK1 encodes a kinase involved in neuronal polarization, synaptic function, and the internal organization of nerve cells. Reduced activity may therefore interfere with the cellular machinery neurons need to develop and communicate. “This work improves our understanding of the genetic causes of neurodevelopmental disorders and highlights the power of combining AI-driven gene discovery with experimental studies in model organisms to uncover new rare diseases and their underlying biology,” Bellen said.

The diagnosis may help participating families understand the source of their condition and could guide recognition of additional cases. Future studies will be needed to determine why the same variant can produce markedly different symptoms and to define more precisely how altered BRSK1 activity affects the developing brain.

The post AI Tool Helps Link <i>BRSK1</i> Variants to Neurodevelopmental Disorder appeared first on GEN – Genetic Engineering and Biotechnology News.

Posted on

STAT+: Pharmalittle: We’re reading about Novo plans to expand its pipeline, early Alkermes ADHD data, and more

Hello there and welcome to a new week. STAT reporter Andrew Joseph here in London filling in for Mr. Pharmalot for the day. Before we get to the headlines, an extra dose of encouragement to check out all the great pieces that STAT has to offer today, from Reed Jobs opining on the NIH budget to our new trust-in-science reporter Nick Florko outlining his own experience grappling with, as he puts it, “how frustrating it is to realize that modern medicine does not have all the answers.” Now to those headlines. … 

Novo Nordisk is seeking to assure investors that it can regain its momentum in the coming years, outlining plans to expand its pipeline and find new products that it could sell more like consumer goods than traditional medicines, building off what’s occurring with its obesity treatments, STAT shares. At the company’s capital markets day in London, CEO Mike Doustdar said Novo would launch at least five multi-blockbusters by 2030 and deliver revenue growth on par with other major pharma firms. He also presented a strategy that involved investing more in disease areas outside diabetes and obesity and said the company “will be more active within business development,” an acknowledgment of investors’ concerns that Novo was too reliant on its landmark GLP-1 drugs and needed to develop other products.

Drugs called orexin agonists have been hailed for their ability to treat rare sleep disorders, but with new data, Alkermes is showing for the first time that the new class of therapies may benefit people with ADHD, STAT writes. In a randomized Phase 1 study, the company’s new drug, called ALKS 7290, was well tolerated and showed a signal of efficacy. Participants in the study started with a median score of 39 on a diagnostic known as the Adult ADHD Investigator Symptom Rating Scale, indicating that they had moderate to severe symptoms. After two weeks, those taking a high dose of 50 milligrams of ALKS 7290 experienced a 19-point reduction on the scale, indicating that their symptoms had become mild.

Continue to STAT+ to read the full story…

Posted on

STAT+: Alkermes’ orexin agonist shows potential to treat ADHD in early-stage trial

Drugs called orexin agonists have been hailed for their ability to treat rare sleep disorders, but with new data, Alkermes is showing for the first time that the new class of therapies may benefit people with ADHD.

In a randomized Phase 1 study, the company’s new drug, called ALKS 7290, was well tolerated and showed a signal of efficacy, Alkermes said Monday.

Participants in the study started with a median score of 39 on a diagnostic known as the Adult ADHD Investigator Symptom Rating Scale, indicating that they had moderate to severe symptoms. After two weeks, those taking a high dose of 50 milligrams of ALKS 7290 experienced a 19-point reduction on the scale, indicating that their symptoms had become mild.

Continue to STAT+ to read the full story…

Posted on

Strategies to enhance engagement in CBT for adult ADHD: an innovation tournament with stakeholders

ObjectiveAdults with ADHD report challenges engaging in cognitive-behavioral therapy (CBT). This study investigates practices that might be applied to improve intervention fit and therapeutic engagement of CBT for adults with ADHD.MethodWe conducted an Innovation Tournament (IT) and member checking with participants (N=102) who were adults with ADHD and mental health practitioners who regularly treat adults with ADHD. Go-Zone plots were utilized to identify strategies with the highest feasibility and importance as well as strategies with low feasibility and/or importance that might be candidates for de-implementation. Barriers to CBT engagement and practitioner implementation of practices were also evaluated qualitatively.ResultsA range of engagement barriers were identified, chief among them practitioner low understanding of ADHD (44.4%) and lack of attention to relevant impairments (33.3%). The highest rated focal areas for CBT were task management, organization, planning, and prioritization, emotion regulation strategies, responding to negative/maladaptive thoughts, anti-procrastination and self-motivation strategies, and long-term goal setting. Top recommendations for engagement strategies include ensuring high therapist knowledge of ADHD and 17 elements consistent with Motivational Interviewing. Some practices commonly found in CBTs for ADHD were rated as unpopular with stakeholders, most notably providing weekly ratings of ADHD symptoms as progress monitoring. Some practices rated as important to adults with ADHD were rated as not feasible to practitioners—most notably reducing shame and nurturing confidence. Implementation barriers identified were primarily related to low practitioner knowledge and skills, but also sometimes systemic constraints on practice.ConclusionsImplementation of recommended practices noted in this study should be tested empirically to understand the extent to which they increase engagement and effectiveness over standard practice.
Posted on

Brain Protein in Mice Offers Insights Into Brain Development and ADHD

Attention-deficit/hyperactivity disorder (ADHD), marked by excessive activity and impulsivity, is linked to changes in the brain’s dopamine system, though the mechanisms remain unclear. Researchers at the University of Fukui have now found that in genetically modified, conditional knockout mice, loss of a protein called N-ethylmaleimide-sensitive factor (NSF)—which is linked to dopamine receptors—in D2 receptor-expressing cells led to lower dopamine levels and ADHD-like behaviors. Their results also pointed to a potential therapeutic strategy.

The team, headed by assistant professor Min-Jue Xie, PhD, at the Division of Development of Mental Functions, Research Centre for Child Mental Development, suggests that the results offer insight into how brain changes may contribute to ADHD and informing future treatments.

“This is basic research and will not immediately lead to a new treatment,” Xie acknowledged. “However, it provides important clues for understanding how dopaminergic dysfunction may contribute to ADHD. In the future, these findings may help develop new therapeutic strategies targeting D2R function and striatal dopamine signaling, especially for treatment-resistant ADHD.”

Xie is first and corresponding author of the researchers’ published paper in Neuropsychopharmacology, titled “Deletion of N-ethylmaleimide-sensitive factor in dopamine D2 receptor-expressing cells impairs striatal development and dopaminergic function and induces ADHD-like behaviors in mice.”

ADHD is a neurodevelopmental disorder that can affect attention, activity levels, and impulse control, with symptoms often beginning in childhood and sometimes continuing into adulthood. Although the exact causes of ADHD are not fully understood, changes in the brain’s dopamine system have long been linked to the condition. Dopamine is a chemical messenger that helps brain cells communicate and plays an important role in movement, motivation, and behavior.

While dopamine-related changes have been associated with ADHD, it remains unclear how the brain cells that respond to dopamine are maintained and how their disruption may contribute to ADHD-related behaviors. This is particularly relevant to dopamine D2 receptor (D2R)-expressing cells, which are found in the striatum, a brain region involved in movement and behavioral control. Understanding what helps these cells develop and function normally could provide new insights into the biological processes involved in ADHD. “Although D2R has been extensively studied, the upstream mechanisms regulating its function and localization remain unclear,” the authors wrote.

Against this backdrop, a research team from Japan, led by Xie, set out to investigate the role of NSF in these dopamine-related brain cells. NSF regulates membrane fusion, helping brain cells release chemical messengers and move proteins within their membranes. “NSF dysfunction is implicated in neuropsychiatric disorders, with reduced expression in autism spectrum disorder (ASD) and schizophrenia and aggregates in Parkinson’s disease,” the investigators noted.

“The motivation for this study came from previous findings suggesting that NSF may be involved in neurodevelopmental and neuropsychiatric disorders,” Xie explained. “NSF was known to interact with D2R; however, the role of this interaction in vivo remained unclear. Because ADHD is thought to involve reduced striatal dopaminergic function and D2R dysfunction, we hypothesized that NSF may be important for maintaining D2R-expressing neurons and dopaminergic function. This led us to initiate the present study.”

For their study the team created knockout mice in which NSF was removed specifically from D2R-expressing neurons. “… we generated D2R-specific Nsf conditional knockout (Nsf f/f;D2R-Cre) mice to examine NSF function in D2R-expressing cells in vivo,” they explained. They then studied the animals’ brain development, dopamine levels, and behavior. The team also tested whether drugs that affect dopamine signaling could reduce the behavioral changes seen in the modified mice.

The loss of NSF affected the developing brain, resulting in fewer dopamine D2R-expressing cells, increased early developmental cell death, and a smaller striatum. The mice also had markedly lower dopamine levels in this brain region. Together, these findings suggest that NSF helps maintain dopamine-related cells and supports normal development and dopamine function.

The brain changes were accompanied by ADHD-like behaviors. “Nsf f/f;D2R-Cre mice exhibited attention-deficit/hyperactivity disorder (ADHD)-like behaviors, including hyperactivity and impulsivity,” the team reported. The knockout mice were more hyperactive than control mice and showed more impulsive-like behavior in a test that measured how quickly they jumped from an elevated platform. By the end of the seven-minute test, 86% of the experimental group mice had jumped, compared with 31% of the control group mice. “These findings indicate that a reduction in D2R-expressing cells coincides with ADHD-like behaviors, suggesting a link between D2R dysfunction and these abnormalities.”

The researchers then explored whether these behaviors could be reduced by changing dopamine signaling. Methylphenidate, a medicine commonly used to treat ADHD, did not significantly reduce hyperactivity when given alone to the modified mice. However, when it was given together with quinpirole, a drug that activates D2R, the mice became less hyperactive and showed less impulsive-like behavior. During the seven-minute test, the proportion of knockout mice that jumped fell from 78% without treatment to 11% after the two drugs were given together. “Combined administration of methylphenidate and a D2R agonist, quinpirole, alleviated both behaviors, suggesting a potential complementary approach for ADHD treatment,” the investigators wrote.

“This study supports the translational relevance of the Nsf f/f;D2R-Cre model for ADHD and indicates that targeting D2R dysfunction, particularly in treatment-resistant ADHD, may be a promising therapeutic strategy.”

The post Brain Protein in Mice Offers Insights Into Brain Development and ADHD appeared first on GEN – Genetic Engineering and Biotechnology News.