bims-curels 2025-08-03 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2025–08–03
fourteen papers selected by
Cure Mito Foundation

The genotype/phenotype conundrum of inherited mitochondrial disorders: Insights from a survey of mtDNA mutations associated with Leigh syndrome in complex I.
Phosphodiesterase type 5 inhibition as a therapeutic strategy in primary mitochondrial disease: Evidence from patient fibroblasts and clinical observations.
Causes of and Solutions to Mitochondrial Disorders: A Literature Review.
Therapies for Mitochondrial Disease: Past, Present, and Future.
Deep Brain Stimulation in Leigh-Like Syndrome Due to DNM1 Pathogenic Variant.
Mitochondrial complex I deficiency induces Alzheimer's disease-like signatures that are reversible by targeted therapy.
Hypoparathyroidism in a Child with MELAS Syndrome: A Case Report of Severe Lactic Acidosis and Symmetrical Bilateral Basal Ganglia Calcification.
Global partnerships in rare disease research.
How to become partners. Ways to enhance the quality of patient and public involvement in healthcare research.
The rare disease burden: a multidimensional challenge.
Quality of life among children and young adults with rare diseases. A parental perspective.
Patient and Practitioner Perspectives on the Definition and Measurement of Therapeutic Empathy: Qualitative Study.
Media as a Medical Tool.
Bridging psychiatry and rare genetic diseases: a scoping review of therapeutic strategies and diagnostic delay paired with healthcare economic burden analysis.

Biochim Biophys Acta Mol Basis Dis. 2025 Jul 25. pii: S0925-4439(25)00344-8. [Epub ahead of print] 167996

The genotype/phenotype conundrum of inherited mitochondrial disorders: Insights from a survey of mtDNA mutations associated with Leigh syndrome in complex I.

Zeinab Alsadat Ahmadi, Ulrich Brandt.

  Mitochondrial disorders encompass a broad spectrum of genetic disorders impairing mitochondrial function. Considerable advancements have been made in the diagnosis and clinical management of these primary mitochondrial diseases. However, diagnosis and treatment have remained largely empirical, because the pathogenic mechanisms are still poorly understood by which any of the numerous known mutations lead to a specific phenotype in patients. To make inroads into this central challenge of mitochondrial medicine, we performed a focused survey of a cohort of published cases of Leigh syndrome caused by point mutations in subunits of respiratory chain complex I encoded by the mitochondrial genome. Leigh syndrome is one of the most severe mitochondrial disorders and is characterized by clinical and genetic manifestations predominantly affecting the central nervous system and the brain. We found that even basic correlations between a specific molecular defect and disease severity and progression are often obscured by the heterogeneity of the available diagnostic data. Still, our analysis showed that in order to understand the specific pathogenic impact it entails, for each mutation one has to carefully differentiate which functional domain of complex I is actually affected. It seems evident that much more comprehensive and differentiated studies of representative mutations as well as far more complete and standardized diagnostic data from patients should be obtained. This will be prerequisite for understanding and discriminating pathogenic mechanisms as a way to develop effective rational therapies for Leigh syndrome and other mitochondrial disorders.

Keywords:  Complex I; Leigh syndrome; Mitochondrial disease; mtDNA

DOI:  https://doi.org/10.1016/j.bbadis.2025.167996
Mol Genet Metab. 2025 Jul 24. pii: S1096-7192(25)00188-X. [Epub ahead of print]146(1-2): 109197

Phosphodiesterase type 5 inhibition as a therapeutic strategy in primary mitochondrial disease: Evidence from patient fibroblasts and clinical observations.

Graeme Preston, Neil Jacob, Ibrahim Elsharkawi, Eva Morava, Tamas Kozicz.

  Primary mitochondrial diseases are a heterogeneous group of disorders caused by impaired mitochondrial respiratory chain function due to pathogenic variants in nuclear or mitochondrial DNA. These variants disrupt enzyme activity, membrane integrity, or mitochondrial genome maintenance. Phosphodiesterase type 5 (PDE5) inhibitors have recently emerged as potential modulators of mitochondrial function. Prompted by self-reported symptom improvement in an individual with mitochondrial disease taking tadalafil, we investigated the effects of PDE5 inhibitors in this context. Using high-resolution respirometry, we analyzed mitochondrial function in fibroblasts from six individuals with primary mitochondrial disease following treatment with sildenafil or tadalafil. We hypothesized that PDE5 inhibition would improve mitochondrial respiratory function and alleviate clinical symptoms. Clinical outcomes were also assessed in three individuals receiving off-label tadalafil therapy. Patient-derived fibroblasts showed elevated basal and non-mitochondrial respiration, along with increased glycolytic flux. Treatment with PDE5 inhibitors reduced proton leak-associated OCR, improved coupling efficiency, and normalized metabolic profiles. Off-label tadalafil use was associated with acute, dose-dependent, and sustained symptom improvements in all three individuals, with no adverse effects reported. In MELAS fibroblasts responses varied with m.3243 A > G heteroplasmy levels. These findings suggest PDE5 inhibitors may offer safe, accessible, and personalized therapeutic options for mitochondrial diseases, particularly those involving mitochondrial DNA pathogenic variants.

Keywords:  Coupling efficiency; Hypermetabolism-like phenotype; Mitochondria; PDE5; Proton leak; Sildenafil; Tadalafil

DOI:  https://doi.org/10.1016/j.ymgme.2025.109197
Int J Mol Sci. 2025 Jul 11. pii: 6645. [Epub ahead of print]26(14):

Causes of and Solutions to Mitochondrial Disorders: A Literature Review.

Vera Belousova, Irina Ignatko, Irina Bogomazova, Elena Sosnova, Svetlana Pesegova, Anastasia Samusevich, Evdokiya Zarova, Madina Kardanova, Oxana Skorobogatova, Anna Maltseva.

  Mitochondria are currently of great interest to scientists. The role of mitochondrial DNA (mtDNA) mutations has been proven in the genesis of more than 200 pathologies, which are called mitochondrial disorders. Therefore, the study of mitochondria and mitochondrial DNA is of great interest not only for understanding cell biology but also for the treatment and prevention of many mitochondria-related pathologies. There are two main trends of mitochondrial therapy: mitochondrial replacement therapy (MRT) and mitochondrial transplantation therapy (MTT). Also, there are two main categories of MRT based on the source of mitochondria. The heterologous approach includes the following methods: pronuclear transfer technique (PNT), maternal spindle transfer (MST), Polar body genome transfer (PBT) and germinal vesicle transfer (GVT). An alternative approach is the autologous method. One promising autologous technique was the autologous germline mitochondrial energy transfer (AUGMENT), which involved isolating oogonial precursor cells from the patient, extracting their mitochondria, and then injecting them during ICSI. Transmission of defective mtDNA to the next generation can also be prevented by using these approaches. The development of a healthy child, free from genetic disorders, and the prevention of the occurrence of lethal mitochondrial disorders are the main tasks of this method. However, a number of moral, social, and cultural objections have restricted its exploration, since humanity first encountered the appearance of a three-parent baby. Therefore, this review summarizes the causes of mitochondrial diseases, the various methods involved in MRT and the results of their application. In addition, a new technology, mitochondrial transplantation therapy (MTT), is currently being actively studied. MTT is an innovative approach that involves the introduction of healthy mitochondria into damaged tissues, leading to the replacement of defective mitochondria and the restoration of their function. This technology is being actively studied in animals, but there are also reports of its use in humans. A bibliographic review in PubMed and Web of Science databases and a search for relevant clinical trials and news articles were performed. A total of 81 publications were selected for analysis. Methods of MRT procedures were reviewed, their risks described, and the results of their use presented. Results of animal studies of the MTT procedure and attempts to apply this therapy in humans were reviewed. MRT is an effective way to minimize the risk of transmission of mtDNA-related diseases, but it does not eliminate it completely. There is a need for global legal regulation of MRT. MTT is a new and promising method of treating damaged tissues by injecting the body's own mitochondria. The considered methods are extremely good in theory, but their clinical application in humans and the success of such therapy remain a question for further study.

Keywords:  mitochondrial DNA; mitochondrial disorders; mitochondrial replacement therapy; mitochondrial transplantation therapy; review; three-parent baby

DOI:  https://doi.org/10.3390/ijms26146645
J Inherit Metab Dis. 2025 Jul;48(4): e70065

Therapies for Mitochondrial Disease: Past, Present, and Future.

Megan Ball, Nicole J van Bergen, Alison G Compton, David R Thorburn, Shamima Rahman, John Christodoulou.

  Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA-encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre-molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA-based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

Keywords:  clinical trials; gene therapy; mitochondrial disease; small molecule therapy; treatment

DOI:  https://doi.org/10.1002/jimd.70065
Tremor Other Hyperkinet Mov (N Y). 2025 ;15 32

Deep Brain Stimulation in Leigh-Like Syndrome Due to DNM1 Pathogenic Variant.

Leonel Villa-Villegas, Luz Gabriela Lira-Jaime, Katia Carmina Farías-Moreno, Biagio David González-Ruffino, Alberto Soto-Escageda, Rodrigo Mercado-Pimentel, Carlos Eduardo Piña-Avilés, Carlos Zúñiga-Ramírez.

   Clinical vignette: Leigh syndrome (LS) and Leigh-like syndromes (LLS), now collectively referred to as Leigh Syndrome Spectrum (LSS), encompass a wide range of clinical manifestations, including epilepsy, neurodevelopmental delay, and movement disorders such as ataxia, chorea, and dystonia. Although rare, LSS can present atypical symptoms in certain cases. The primary etiological cause of LSS is genetic, resulting from mitochondrial alterations.
Clinical dilemma: Hyperkinesias in LSS or other mitochondrial disorders can be disabling, leading to a significant reduction in the patient's quality of life.
Clinical solution: Globus pallidum deep brain stimulation (GPi-DBS) surgery is an effective treatment for hyperkinesias, such as chorea, and dystonia, caused by mitochondrial defects.
Gap in knowledge: Pathogenic DNM1-related mitochondrial disorders with Leigh syndrome phenotype may show long-term improvement of hyperkinetic movements after GPi-DBS.

Keywords:  Deep brain stimulation; Dynamin 1; Hyperkinesias; Leigh Syndrome; Leigh-like syndrome; Mitofusin 2

DOI:  https://doi.org/10.5334/tohm.1017
Alzheimers Dement. 2025 Aug;21(8): e70519

Mitochondrial complex I deficiency induces Alzheimer's disease-like signatures that are reversible by targeted therapy.

Huanyao Gao, Kate Jensen, Jarred Nesbitt, Mark Ostroot, Gregory A Cary, Jesse Wiley, Sergey Trushin, Jens O Watzlawik, Wolfdieter Springer, Alexander Galkin, Priyanka Baloni, Cory Funk, Eugenia Trushina.

   INTRODUCTION: Mitochondrial dysfunction is implicated in Alzheimer's disease (AD), but whether it drives AD-associated changes is unclear. We assessed transcriptomic alterations in the brains of Ndufs4-/- mice, a model of mitochondrial complex I (mtCI) deficiency, and evaluated the therapeutic effects of the neuroprotective mtCI inhibitor CP2.
METHODS: Cortico-hippocampal tissue from Ndufs4-/- and wild-type mice was subjected to transcriptomic analysis, followed by cross-species comparisons to human late-onset AD and familial AD mouse datasets.
RESULTS: Knockout of Ndufs4-mediated mtCI deficiency disrupted mitochondrial homeostasis, energy metabolism, and synaptic gene expression, recapitulating transcriptomic signatures of AD. CP2 treatment partially reversed these changes, with female Ndufs4-/- mice showing greater compensatory adaptations and treatment responses.
DISCUSSION: Loss of mtCI activity alone is sufficient to induce AD-like molecular changes in the brain, independent of amyloid beta or phosphorylated tau. CP2-mediated rescue highlights the potential of targeting mitochondria as a therapeutic strategy for AD. Sex-specific responses suggest important considerations for personalized therapeutics.
HIGHLIGHTS: Activity of mitochondrial complex I (mtCI) affects broad mitochondrial and neuronal transcriptional networks. A reduction of mtCI activity is sufficient to induce transcriptomic changes reminiscent of those observed in late-onset Alsheimer's disease (AD) patients and familial mouse models of AD. Pharmacological targeting of mtCI mediates neuroprotective signaling. Male and female mice have differential responses to the loss of mtCI activity and to the mitochondria-targeted therapeutics. Mitochondria play a key role in AD development and treatment.

Keywords:  Alzheimer's disease; Ndufs4 knockout mice; biological domains; mitochondrial complex I; mitochondria‐targeted therapeutics; mitophagy; sex‐specific differences; sex‐specific response; transcriptomic analysis; ubiquitin; weak complex I inhibitors

DOI:  https://doi.org/10.1002/alz.70519
Int J Endocrinol Metab. 2025 Apr 30. 23(2): e161585

Hypoparathyroidism in a Child with MELAS Syndrome: A Case Report of Severe Lactic Acidosis and Symmetrical Bilateral Basal Ganglia Calcification.

Ling Wang, Tingting Zhou, Xiaosong Bu, Daoxiang Pan, Xiaojing Liu.

   Introduction: MELAS syndrome is a mitochondrial disorder typically characterized by brain dysfunction and endocrinopathies, but it rarely presents with hypoparathyroidism (HP).
Case Presentation: Here, we report the case of a child who initially presented with vomiting and convulsions. Blood gas analysis revealed significant hyperlactatemia and hypocalcemia. The child's urinary calcium level was markedly decreased, measured at 0.15 mmol/24h, well below the normal range. A brain CT scan showed symmetrical calcification in the bilateral basal ganglia. Endocrine testing confirmed low parathyroid hormone (PTH) levels. During hospitalization, the child received treatment for recurrent seizures, including midazolam and levetiracetam. One month post-discharge, the child was readmitted due to elevated lactate levels. Genetic testing confirmed the diagnosis of MELAS syndrome, identifying the m.3243A > G mutation in the MT-TL1 gene. Under symptomatic treatment, the child has not experienced any further convulsions and has been regularly followed up at our hospital.
Conclusions: This case underscores the importance of considering MELAS syndrome in patients presenting with hypoparathyroidism. Effective management of epileptic seizures and maintaining an appropriate calcium-to-phosphorus balance are crucial for minimizing brain damage and improving the patient's prognosis.

Keywords:  Hypoparathyroidism; MELAS Syndrome; MT-TL1 Gene; Mitochondrial Disease

DOI:  https://doi.org/10.5812/ijem-161585
Dis Model Mech. 2025 Jul 01. pii: dmm052401. [Epub ahead of print]18(7):

Global partnerships in rare disease research.

Sanja Rogic, Guillaume Poirier-Morency, Philip Hieter, Paul Pavlidis.

  Rare diseases collectively impact hundreds of millions worldwide, yet the genetic causes of many remain unknown or poorly understood. Model organisms (MOs) - such as yeast, fly, zebrafish and mouse - provide powerful experimental systems for functional validation of candidate genes and variants, elucidation of gene function and disease mechanisms, and identification of potential therapeutic targets and treatments. However, gaps persist between clinical gene discovery and MO-based research. The Canadian Rare Diseases: Models and Mechanisms (RDMM) Network was established in 2014 to address this gap by linking clinicians with MO researchers through a scientist registry and peer-reviewed funding process. Over the past decade, the RDMM Network has funded over 160 collaborative projects, enabled insights into numerous rare conditions, and led to sustained partnerships and external funding. The RDMM Registry software has been adopted internationally, forming a network of interoperable registries that enable cross-border collaborations and expand access to MO expertise worldwide. Going forward, the Canadian RDMM Network remains committed to sharing its tools, processes and experience to help establish new RDMM-like networks worldwide and invites the global research community to join efforts to accelerate rare disease research.

Keywords:  Functional insights; Gene discovery; International collaboration; Model organisms; Rare genetic diseases

DOI:  https://doi.org/10.1242/dmm.052401
Qual Res Med Healthc. 2025 Jul;9(2): 100016

How to become partners. Ways to enhance the quality of patient and public involvement in healthcare research.

Elna Leth Pedersen, Hanne Agerskov, Torkell Ellingsen, Connie Timmermann.

  There is a growing emphasis on involving patients and the public in healthcare research. This is especially true in qualitative healthcare research, where partnerships are encouraged between patients with lived experiences and researchers with academic expertise. The rationale is that collaboration can enhance the study's relevance to healthcare users and improve the research quality. However, establishing partnerships can be complex and challenging, requiring negotiation and alignment of expectations. In a qualitative study exploring communication in clinical encounters at a Danish university hospital, we invited patients and relatives to become involved in research. This commentary discusses the challenges, insights, and adjustments to our research design that emerged from the process. Through continuous dialogues with various patients and relatives, we, as researchers, gained a deeper understanding of how to make our research relevant to patients and relatives and how to approach involving patients and relatives in our research. By emphasizing the significance of these dialogues, we aim to demonstrate how aligning expectations and building partnerships with patients and relatives resulted in valuable learning experiences for the researchers and considerably impacted the study's design. Furthermore, we want to highlight that building partnerships requires time, flexibility, and a mutual learning approach to negotiate and align expectations effectively. In this commentary we first review the practice of involving patients and the public in healthcare research and provide an overview of the study's context. Next, we outline our efforts to negotiate and align expectations with patients and relatives, highlighting how new insights led to adjustments to the research design. Finally, we address challenges and the requirements researchers face when involving patients and the public in research partnerships.

Keywords:  Building partnerships; Healthcare research; Mutual learning; Patient and public involvement (PPI); Research design

DOI:  https://doi.org/10.1016/j.qrmh.2025.100016
Acta Biochim Pol. 2025 ;72 14777

The rare disease burden: a multidimensional challenge.

Zuzanna Cyske, Edyta Radzanowska-Alenowicz, Estera Rintz, Lidia Gaffke, Karolina Pierzynowska.

  Although there no single, widely accepted definition of a "rare disease," this group of disorders includes conditions that affect only a small fraction of the population. A large number of rare diseases is caused by defined molecular defects, predominantly the occurrence of pathogenic variant(s) of genes. Thus, they are classified as "genetic diseases," among which there are many neurodegenerative disorders. Despite a low incidence of each such disease, majority of them are severe and no effective treatment is available. This creates a battery of problems for millions of people suffering from these disease as well as to their relatives and caregivers. However, the set of problems is larger; therefore, in this narrative review we summarize and discuss various kinds of problems caused by rare disease, including severe symptoms of patients, everyday problems of patients and caregivers, loneliness and social exclusion, diagnostic difficulties, unavailability of effective therapies and economic difficulties in introducing orphan drugs, and a complexity of studies on rare diseases due to low availability of biological material and complicated pathomechanisms. The global picture of the complex problems caused by rare diseases is presented.

Keywords:  diagnostics; molecular causes of diseases; multidisciplinary research; multiple challenges; rare diseases; treatment

DOI:  https://doi.org/10.3389/abp.2025.14777
Eur J Pediatr. 2025 Jul 29. 184(8): 510

Quality of life among children and young adults with rare diseases. A parental perspective.

Eva De Clercq, Hannah V Schmieg, Daniel Gregorowius, Jürg C Streuli.

  Globally the number of children and adolescents living with a rare disease is increasing due to improved periconceptional care, advances in diagnostics and treatments. This exploratory study aimed to examine parents' perceptions of the quality of life of children with rare diseases. The results will provide important insights to healthcare professionals who aim to offer child-centered and family-oriented care. Participating parents were recruited via the knowledge network for children with rare diseases (KMSK). Qualitative data from an open-ended survey question on parents' perceptions of children's quality of life was analyzed using content analysis. Data collection took place from January-June 2023. The study included 108 primary caregivers of children with rare diseases. Five categories of parental perceptions of children's quality of life were identified: (1) pain-free living & joy; (2) partaking in everyday life; (3) the quest for integration: desire for normality & appreciation of difference; (4) obtaining developmental milestones and (5) having access to individualized child- and family-centered care.Conclusions: In addition to positive health outcomes, social integration, respect for diverse developmental paths and holistic healthcare services were reported as essential to quality of life. Healthcare professionals should be aware that parents may worry about stigma and address these concerns thoughtfully. It is also important to ensure that parents feel their knowledge and experiences are valued, and to support families in building confidence in their decisions, as part of a personalized, child- and family-centered approach.

Keywords:  Pediatrics; Quality of life; Rare disease

DOI:  https://doi.org/10.1007/s00431-025-06293-4
J Particip Med. 2025 Jul 31. 17 e71610

Patient and Practitioner Perspectives on the Definition and Measurement of Therapeutic Empathy: Qualitative Study.

Amber Bennett-Weston, Jeremy Howick.

   Background: Most definitions of therapeutic empathy are based on practitioners' perspectives, and few account for patients' views. Therefore, we do not understand what therapeutic empathy means to patients. Given that therapeutic empathy involves a relationship between patients and practitioners, the underrepresentation of the patient voice threatens to undermine the validity of therapeutic empathy definitions and subsequently, how the concept is measured, taught, and practiced.
Objective: The aim of the study is to explore the perspectives of patients and practitioners on the definition of therapeutic empathy and how it should therefore be measured.
Methods: A qualitative study, underpinned by a social constructivist stance, was conducted. Patients and practitioners were purposively sampled from a medical school and a school of health care to represent a diversity of lived experiences and health care professions. In-depth, semistructured interviews were undertaken, and the data were analyzed using reflexive thematic analysis. Data collection ceased upon reaching meaning saturation.
Results: In total, 16 participants (8 patients and 8 practitioners) were interviewed in June and July 2024. Reflexive thematic analysis generated three overarching themes that synthesize the views of patients and practitioners on therapeutic empathy and how it should be measured: (1) therapeutic empathy involves the practitioner showing the patient (that they are interested in the patient as a person, that they are actively listening, that they understand, that they are emotionally engaged, and that they are responding to their needs), (2) context matters (eg, the clinical scenario, time, and the patient), and (3) short, simple scales are a pragmatic approach to measurement.
Conclusions: Patients and practitioners have similar views about what empathy is and define therapeutic empathy as involving the practitioner demonstrating specific attitudes and behaviors to their patients. These attitudes and behaviors should be included in interventions to enhance therapeutic empathy and in measures of the concept. However, contextual factors may influence the expression of therapeutic empathy in practice. The findings highlight the need for, and can inform the development of, a short therapeutic empathy scale that allows the comparison of scores between patients, practitioners, students, and observers.

Keywords:  definition; empathy; measurement; patient-practitioner communication; therapeutic empathy

DOI:  https://doi.org/10.2196/71610
J Am Acad Child Adolesc Psychiatry. 2025 Jul 23. pii: S0890-8567(25)00326-0. [Epub ahead of print]

Media as a Medical Tool.

Justin Schreiber, Misty C Richards.

When we see a patient, we can have a profound impact on their life, the life of their family, and maybe they can even share some skills that can affect some of their peers. Throughout the course of our careers, we will have interactions with thousands of patients and families in which this same kind of influence can be felt. Sometimes, even all of this can feel not enough, especially as we battle misinformation that is being spread to millions of people rapidly through various media sources. This is where media can serve as a tool to provide education, correct misinformation, decrease stigma, and much more to a larger audience in a shorter amount of time. Physicians can participate in media by writing books, being active on social media, contributing to shows or movies that are being created, and much more. Media allow for different levels of time commitment to be involved based on the person's interest and availability. Media can also serve as a tool to help with discussions about topics of child psychiatry, such as utilizing Inside Out as a way to talk about feelings with kids. This is a tool that children and adolescents already recognize and have some comfort with, and it makes it seem less like they are doing work or therapy. Finally, media can be a way for us to learn more about what is happening with our patients in a way that we can't do from just talking to them in the office. Often these books, shows, movies, or posts provide insight that is less filtered because it is from the perspective of youth to be seen by youth.

DOI: https://doi.org/10.1016/j.jaac.2025.06.022
Orphanet J Rare Dis. 2025 Aug 01. 20(1): 393

Bridging psychiatry and rare genetic diseases: a scoping review of therapeutic strategies and diagnostic delay paired with healthcare economic burden analysis.

Sheldon R Garrison, Isaac J Siegel, Christopher R Takala, Sarah L Vaithilingam, Gene W Yang, Anthony W Zoghbi, Madeline M Hartig, Sreya Vadapalli, Margaret E Anderson.

  Rare genetic diseases (RDs) with primary neuropsychiatric symptoms pose unique challenges for diagnosis and management. While the majority of these RDs have neuropsychiatric symptoms that are secondary to the RD, a subset presents with primary neuropsychiatric symptoms directly linked to their underlying pathophysiology. This subset has significant unmet medical need with delayed diagnoses leading to prolonged delays in treatment optimization and the trialing of medications that fail to target the underlying pathophysiology. This comprehensive review identifies 108 RDs with central neuropsychiatric symptoms that have a 7.7-year average diagnostic delay. Optimal management strategies for these RDs typically includes non-psychotropic medications, dietary adjustment, avoidance of certain drug classes and other treatments that target the underlying pathophysiology before improvement of the neuropsychiatric symptoms is observed. Surprisingly, despite the limited number of RDs that fit this unique profile, the annual economic burden for these conditions had an annual mental health care-related inpatient charges totaling $4.2 billion USD. Addressing the diagnostic delay and optimizing management for these specific conditions must include increased involvement across multiple specialties, including psychiatry, family medicine, pediatrics, medical genetics, as well as an enhanced strategy for genetic testing to ensure the prompt initiation of condition-specific therapies for affected individuals.

Keywords:  Addiction; Behavioral health; Diagnostic delay; Medication; Mental health; Orphan drug; Psychiatric; Rare disease; Treatment-resistant

DOI:  https://doi.org/10.1186/s13023-025-03941-8