The potassium-chloride cotransporter 2 (KCC2) is a neuron-specific transporter essential for maintaining low intracellular chloride levels. By extruding chloride ions, KCC2 ensures that activation of GABAA receptors produces hyperpolarizing inhibitory responses rather than depolarizing responses. Disruption of KCC2 function can therefore impair GABAergic signaling and neuronal maturation, contributing to a range of neurodevelopmental and neurological disorders. Pathogenic biallelic variants in SLC12A5, the gene encoding KCC2, are a rare cause of severe early-onset developmental and epileptic encephalopathies, including epilepsy of infancy with migrating focal seizures (EIMFS). Here, we describe a novel homozygous SLC12A5 variant identified in a patient with severe, drug-resistant epilepsy, neonatal encephalopathy, and rapid neurological deterioration. Combined Western blot, thallium (Tl+) flux, and gramicidin-perforated patch-clamp assays revealed significantly reduced ion-transport function of the KCC2 construct encoding the variant, with no change in protein expression abundance or profile. Live-cell surface immunolabeling demonstrated markedly reduced plasma membrane expression and decreased internalization of the variant, suggesting that the functional deficit primarily results from defective trafficking or reduced membrane stability. These findings expand the spectrum of KCC2-related disorders and highlight the critical role of KCC2 in early brain development. By linking a specific SLC12A5 variant to impaired chloride homeostasis and neuronal hyperexcitability, this study provides mechanistic insight into disease pathogenesis and lays the groundwork for therapeutic strategies aimed at restoring or stabilizing KCC2 function.

Abstract Purpose Developing a valid and practical method for obtaining brain tissue samples for transcriptomic and proteomic analyses using tissue adhered to stereoelectroencephalography (SEEG) electrodes, to enable investigation of the molecular mechanisms underlying chronic epilepsy. Method Brain tissue samples adhered to SEEG electrodes were collected from six patients with drug-resistant epilepsy and preprocessed in a hospital environment after electrode removal. RNA extraction was initiated immediately, and proteomics samples were snapfrozen until subsequent analysis. The samples were categorized into three groups according to their electrophysiological profile: epileptogenic zone, propagation zone, and least-involved zone. The omic findings between these zones and anatomical brain areas were compared. Results High-quality RNA and protein samples were obtained from tissue adhered to SEEG electrodes. Neuron- and brain-specific gene expression patterns and proteins were identified. Signs of activation of inflammatory mechanisms were most pronounced in the epileptogenic zone. Transcriptomic and proteomic findings demonstrated concordance. Conclusion SEEG electrodes are a useful source for obtaining brain tissue for molecular characterization of chronic epilepsy. This method will enable the identification of shared and distinct molecular mechanisms in patients with varying etiologies of epilepsy.

BACKGROUND:Neurologic and psychiatric comorbidities are a major contributor to the disease burden in patients with epilepsy. The aim of this family history study was to describe patient-reported neurologic and psychiatric symptoms and diseases in families of persons with epilepsy (PWEs). SUBJECTS:We have previously identified an all-cause epilepsy cohort of 508 PWE, who had participated in prior epilepsy studies at the Oulu University Hospital. A structured questionnaire on neurologic and psychiatric symptoms and diseases in their family was sent to each cohort member, and 172 of them agreed to participate. Five age, sex, and home municipality matched peers per each PWE were identified from the Finnish Population Register Centre. These 884 individuals received similar written questionnaires, and 168 participated. RESULTS:PWE were more likely to report a relative with migraine (RR 1.32, CI 1.07-1.63), or psychiatric diseases (RR 1.98, CI 1.25-3.13) than the controls. Women with epilepsy were also more likely to report relatives with epilepsy or with symptoms referring to epilepsy (RR 1.66, CI 1.14-2.42), or movement disorder symptoms (RR 2.30, CI 1.35-3.91) than controls. CONCLUSIONS:Patient-reported rate of neurologic and psychiatric symptoms and diseases was higher in the families of PWE than those of population-based matched control subjects. Knowledge of the possible increased disease burden in the families of PWE promotes recognition of these conditions in everyday clinical settings.

PURPOSE:Biallelic DIAPH1 pathogenic variants cause a neurodevelopmental syndrome occasionally associated with immunodeficiency. This study aims to define the clinical and immunological spectrum of DIAPH1-related neuroimmunological syndrome and explore the gene's developmental role using vertebrate models. METHODS:A total of 53 individuals with biallelic DIAPH1 variants, including 33 previously unreported patients, were studied. Clinical features were analyzed, and functional studies were conducted using knockout models in Danio rerio and Xenopus tropicalis. RESULTS:Clinical features included developmental delay, intellectual disability, progressive microcephaly, cortical visual impairment or blindness, epilepsy, and frequent occipital-predominant brain abnormalities. Almost half suffered from infections, mainly affecting their respiratory tract related to epilepsy and aspiration. Although the majority had normal lymphocyte subsets and serum immunoglobulins, T cell receptor excision circles and naïve T-lymphocyte counts were consistently low. The Xenopus model mirrored growth and eye defects seen in humans, whereas zebrafish exhibited no overt malformations but showed seizure-like behavior in Phenothiazine assays. CONCLUSION:DIAPH1 is critical for neurodevelopment, immune regulation, and DNA repair. The DNA repair defect may influence susceptibility to infection, lymphoma, or treatment-related toxicity. Although absolute T cell numbers are not consistent with SCID, impaired T cell maturation suggests that these patients could be identified by T cell excision circles newborn screening before neurological symptoms develop.

This study evaluated the diagnostic utility of muscle biopsy and the performance of the Nijmegen and modified Walker criteria in a real-life paediatric cohort with neuromuscular symptoms. A retrospective review at Oulu University Hospital included 220 paediatric patients with unexplained neuromuscular symptoms who underwent muscle biopsy between 1990 and 2024. Clinical data were collected, and patients were classified using both criteria. A genetic diagnosis was confirmed in 58 patients (26%): 12 with primary mitochondrial diseases (21%), 17 with secondary mitochondrial dysfunction (29%), and 29 with other neuromuscular disorders (50%). OXPHOS activities were measured in 189 patients (86%); 49 (26%) showed decreased activity, including 13 with genetic confirmation. Electron microscopy (n=175) showed mitochondrial abnormalities in 49 patients (28%); 75% of these had mitochondrial disease. The modified Walker criteria outperformed the Nijmegen (sensitivity 75% vs 50%; specificity 100% vs 98%). Mean Nijmegen scores were significantly higher in primary mitochondrial disease (p<0.05), also compared with patients with secondary dysfunction. In conclusion, muscle biopsy and mitochondrial disease criteria remain valuable tools distinguishing primary mitochondrial diseases. This study highlights the role of secondary mitochondrial dysfunction in non-mitochondrial genetic conditions and metabolic diseases with undefined genetic aetiologies waiting to be identified in the future.

AIM:To examine the clinical and genetic characteristics of intellectual disability. METHOD:We conducted a population-based retrospective analysis on the clinical and genetic data of 959 children with diagnosed intellectual disability during a 5-year period (2017-2021) at Oulu University Hospital, Finland. RESULTS:Pathogenic or likely pathogenic gene variants were detected in 89 of 194 patients (46%) who underwent exome sequencing. Chromosomal abnormalities, including those with low penetrance, were observed in 106 of 530 patients (20%) who underwent chromosomal microarray testing. Chromosomal abnormalities and causative gene variants were more frequently identified in patients with moderate to profound intellectual disability than in those with mild intellectual disability; however, this difference was not significant in the diagnostic yield analysis. Epilepsy, congenital heart disease, hearing loss, ophthalmological abnormalities, and autism spectrum disorder were more common among patients with moderate to profound intellectual disability, whereas attention-deficit/hyperactivity disorder was associated with mild intellectual disability. Chromosomal abnormalities were associated with congenital heart disease and hearing loss, while pathogenic gene variants were associated with epilepsy and ophthalmological abnormalities. INTERPRETATION:Somatic comorbidities were more common in moderate to profound intellectual disability, whereas attention-deficit/hyperactivity disorder was more frequent in mild intellectual disability.

Fibrosis, neurodegeneration and cerebral angiomatosis (FINCA) is a childhood-onset neurodevelopmental disorder with multi-organ manifestations, including recurrent infections. It is caused by variants in NHLRC2, initiating a cascade of unknown pathological events. We investigated the FINCA disease-causing p.Asp148Tyr variant in NHLRC2 by analysing transcriptional changes in mouse embryonic stem cells (mESCs). We conducted behavioural and immunological phenotyping of FINCA mice compound heterozygous for the Nhlrc2 knockout allele and p.Asp148Tyr variant and explored their T cell populations and cytokine production in splenocytes. Additionally, we employed proximity-labelling mass spectrometry to identify changes in protein-protein interactions resulting from the p.Asp148Tyr variant in human embryonic kidney cells. We discovered significant transcriptional changes in mESCs homozygous for the p.Asp148Tyr variant or Nhlrc2 knockout allele compared to wild-type cells, with genes involved in cell metabolism, adhesion, neurodevelopment and immune response. FINCA mice exhibited hyperactivity and decreased exploration of new object in adolescence, and an altered innate immune response, particularly in interferon γ production. By comparing p.Asp148Tyr-induced changes in gene expression in mouse cells and putative interaction partners in human cells, we identified Rho GTPase signalling as a common affected pathway. Our study provides insights into the molecular pathways impacted by the p.Asp148Tyr NHLRC2. The FINCA mouse, which recapitulates several features of the human condition, particularly neurodevelopmental and immune response defects, serves as a tool for investigations on the role of environmental triggers in disease pathogenesis. Our results suggest that targeting immune pathways could offer a strategy for therapeutic intervention in FINCA disease.

Objectives:Variants of unknown significance (VUS) pose an extensive clinical challenge. Our objective was to explore the diagnostic pipeline from symptom onset to molecular diagnosis in autosomal recessive (Spastic ataxia type 2 [SPAX2], Mendelian Inheritance in Man [MIM] number 611302) caused by a new homozygous variant in the KIF1C gene. Methods:Two unrelated individuals with early-onset spastic ataxia were evaluated for genetic etiology by exome sequencing. Case reports were compiled through a medical chart review. Two cellular models were established to assess variant pathogenicity. Results:Whole exome sequencing revealed a homozygous variant in KIF1C (NM_006612.6: c.833T > C, p.[Leu278Pro]) in a highly conserved motor domain of the KIF1C protein in both individuals. Two cellular models overexpressing a green fluorescent protein (GFP)-tagged KIF1C harboring the p.Leu278Pro variant demonstrated disrupted protein localization, suggesting an impaired trafficking capacity of the mutant KIF1C. A diagnosis of SPAX2 was established based on the in vitro data. Novel clinical findings associated with this KIF1C variant included retinal dysfunction detected by electroretinogram, hypotonia, and a thin corpus callosum in brain MRI. Discussion:Classification of pathogenicity requires extensive multidisciplinary effort, which can be burdensome for affected individuals and families. Like other proteins of the kinesin family, variants in KIF1C may underlie retinal dysfunction.

FINCA disease (fibrosis, neurodegeneration, and cerebral angiomatosis) is a recently identified multiorgan disease with pathogenic variants in the NHL repeat containing 2 (NHLRC2) gene. The patients with FINCA disease suffer from recurrent respiratory infections, respiratory failure, and interstitial lung disease. The aim of this study was to evaluate the expression of NHLRC2 and immune cells in the lungs of patients with FINCA disease. Surgical lung biopsies and lung tissue samples from autopsies of three FINCA patients, an age-matched control, and adult controls were analyzed by immunohistochemical staining against NHLRC2 antibody. mRNA expression of NHLRC2 was studied by mRNA in situ hybridization. Lung tissue samples were stained also for CD3, CD4, CD8, CD20, and CD68 that are markers of various immune cells. In FINCA disease, NHLRC2 was mainly expressed in hyperplastic alveolar epithelial cells, bronchial epithelial cells, and alveolar macrophages. In controls, the highest expression was seen in type II alveolar epithelial cells, bronchial epithelial cells, and macrophages. Numbers of CD8 + and CD68 + immune cells were higher in lung biopsies of FINCA patients than those in a control. Based on our findings, FINCA patients expressed NHLRC2 protein and mRNA in their lungs. Furthermore, an increased expression of macrophages and T-cells including both T-helper and cytotoxic T-cells were observed suggesting an association of the immune mechanisms in the pathogenesis of interstitial lung disorder in FINCA disease.

BACKGROUND:Treatment decisions in metachromatic leukodystrophy (MLD), a rare life-threatening neurological disease, are challenging. Hematopoietic stem cell transplantation or autologous stem-cell-based gene therapy can be life-changing but come with uncertainties, risks, and high costs. To address this, the international MLD treatment eligibility panel was established in collaboration with the European Reference Network on Rare Neurological Diseases. The panel reviews and discusses individual MLD cases and provides consensus-based recommendations on whether to treat and which treatment modality. The goal is to streamline international care and treatment counseling by providing uncomplicated access to expert opinion. METHODS:The panel operates according to a published standard operating procedure and was evaluated between September 2021-2024. Case data were recorded in a Castor EDC-based system and, with consent, included in the MLD Initiative (MLDi) patient registry. Physicians' experiences were assessed via EUsurvey, and patients' feedback was collected through an MLDi registry survey. FINDINGS:The panel discussed 43 cases, recommending treatment in 20, abstaining in 19, and reaching no consensus in 4. Open questions regarding cognitive function and lack of outcome data caused challenges in treatment recommendations in late-onset MLD patients. All treatment recommendations were followed. Physicians reported positive experiences with the panel. INTERPRETATION:The MLD treatment eligibility panel demonstrates how international expert advice can be streamlined across Europe for a rare disease like MLD, where disease-specific guidelines are still in development. By balancing complex clinical, social, and ethical parameters, the panel aids in encouraging appropriate use of innovative and costly therapies and guarantees accessibility to expert advice irrespective of country of origin.

BackgroundAbnormal brain activity is the source of epileptic seizures, which can present a variety of symptoms and influence patients’ quality of life. Therefore, it is critical to track epileptic seizures, diagnose them, and provide potential therapies to manage people with epilepsy. Electroencephalography (EEG) is helpful in the diagnosis and classification of the seizure type, epilepsy, or epilepsy syndrome. Ictal EEG is rarely recorded, whereas interictal EEG is more often recorded, and the results can be abnormal or normal even in the case of epilepsy. The current digital care pathway for epilepsy (DCPE) lacks the integration of data-driven seizure detection, which could potentially enhance epilepsy treatment and management. ObjectiveThis study aimed to determine the requirements for integrating data-driven medical software into the DCPE to meet the project’s goals and demonstrate practical feasibility regarding resource availability, time constraints, and technological capabilities. This adjustment emphasized ensuring that the proposed system is realistic and achievable. Perspectives on the feasibility of data-driven medical software that meets the project’s goals and demonstrates practical feasibility regarding resource availability, time constraints, and technological capabilities are presented. MethodsA 4-round Delphi study using focus group discussions was conducted with 7 diverse panels of experts from Oulu University Hospital to address the research questions and evaluate the feasibility of data-driven medical software for monitoring individuals with epilepsy. This collaborative approach fostered a thorough understanding of the topic and considered the perspectives of various stakeholders. In addition, a qualitative study was carried out using semistructured interviews. ResultsDrawing from the findings of the thematic analytics, a detailed set of guidelines was created to facilitate the seamless integration of the proposed data-driven medical software for EEG seizure monitoring into the DCPE. These guidelines encompass system requirements, data collection and analysis, and user training, offering a comprehensive road map for the effective implementation of the software. ConclusionsThe study outcome presents a comprehensive strategy for improving the quality of care, providing personalized solutions, managing health care resources, and using artificial intelligence and sensor technology in clinical settings. The potential of artificial intelligence and sensor technology to revolutionize health care is exciting. The study identified practical strategies, such as real-time EEG seizure monitoring, predictive modeling for seizure occurrence, and data-driven analytics integration to enhance decision-making. These strategies were aimed at reducing diagnostic delays and providing personalized care. We are actively working on integrating these features into clinical workflows. However, further case studies and pilot implementations are planned for future studies. The results of this study will guide system developers in the meticulous design and development of systems that meet user needs in the DCPE.

Rationale. Northern epilepsy belongs to a group of genetically diverse lysosomal storage diseases, the neuronal ceroid lipofuscinoses (NCLs). A characteristic feature of NCL pathology is the accumulation of autofluorescent ceroid lipofuscin in the central nervous system. Northern epilepsy is a late-infantile -onset disease. Patients develop normally until 5–10 years old when they first present with general tonic-clonic seizures, followed by progressive cognitive impairment and a decline in motor skills. Northern epilepsy is caused by a missense variant in CLN8 , causing a p.R24G amino acid substitution. CLN8 deficiency has been studied traditionally using motor neuron degeneration (mnd) mice, which carry a spontaneous frame shift variant in the murine orthologue Cln8 , which is not known to exist in humans. Methods. We have generated the first Cln8 p.R24G mouse model (Cln8R24G) using CRISPR/Cas9. Phenotyping analysis of the mice was conducted using behavioral and histopathological studies focusing on the brain and retina. Results. At birth, Cln8R24G KI mice were viable and asymptomatic. As the mice aged, a progressive accumulation of autofluorescent ceroid lipofuscin containing the mitochondrial ATP synthase subunit C was evident in different brain regions and retinal layers. Health monitoring revealed that mutant mice developed progressive but mild motor symptoms around 7 months of age. Spontaneous epileptic seizures, like those observed in Northern epilepsy patients, were detected and recorded. An increase in FosB staining intensity, reflecting neuronal hyperactivity, was observed in hippocampal CA1-CA3 pyramidal and dentate granule cells and correlated well with the intensity of seizure activity. Neuroinflammation was evident at 4 months and increased dramatically with age, mainly in the thalamic VPN/VPL nuclei and moderately in the cortex. Neurodegeneration was most prominent in the VPN/VPL thalamic nuclei. Conclusions. We have generated the Cln8R24G mouse model that genocopies, for the first time, the pathogenic CLN8 variant present in patients with Northern epilepsy. These mice phenocopy major clinical features of the human disease, including mild motor impairment and, unlike the mnd mice, spontaneous generalized tonic-clonic seizures. We hypothesize that our mouse model will open new possibilities for developing and testing targeted treatment options for Northern epilepsy and, more broadly, for early-onset neurodegenerative disorders associated with epilepsy. ### Competing Interest Statement The authors have declared no competing interest. Jane and Aatos Erkko Foundation, https://ror.org/03vxy9y38 Lastentautien Tutkimussäätiö, https://ror.org/001wmc692 Research Council of Finland, https://ror.org/05k73zm37, 311934, 346295, 331436, 348906 NCL Foundation Emil Aaltosen Säätiö, https://ror.org/005rt3g54 Sigrid Jusélius Foundation, https://ror.org/00ckakm23 FEBS Excellence Award 2024 European Union, https://ror.org/019w4f821, 101131669

BACKGROUND:The genetic landscape of pediatric cerebellar disorders (PCDs) in Finland is undefined. OBJECTIVES:The objective was to define epidemiological, clinical, neuroradiological, and genetic characteristics of PCDs in Northern Finland. METHODS:A longitudinal population-based cohort study of children with a movement disorder or a cerebellar malformation (diagnosis ≤16 years; study period 1970-2022) was performed in the tertiary catchment area of the Oulu University Hospital, Finland. The genotype-to-phenotype associations were compared with 1007 published cases with matching monogenic etiologies. RESULTS:A total of 107 patients were included (cumulative incidence 21.9 per 100,000 live births). A defined genetic or non-genetic etiology was identified for 59 patients. These etiologies were monogenic (66%), chromosomal (12%), or non-genetic (22%). Ataxia was the most common movement disorder. Friedreich's ataxia was uncommon, whereas ataxias belonging to the Finnish Disease Heritage were overrepresented. Forty-eight cases remained undefined. The diagnostic yield (ie, pathogenic or likely pathogenic variants) of next-generation sequencing (NGS) in ataxia was 65%. Common features were ataxia, developmental delay, seizures, hypotonia, and abnormality in brain MRI, whereas hearing loss, sensory neuropathy, and microcephalia were associated with fewer etiologies. CONCLUSIONS:PCDs are a heterogeneous disease group with a high proportion of genetic etiologies. Age of onset and certain clinical findings may help distinguish between different disease entities. The diagnostic yield of NGS has increased over time. Our dataset will support clinicians to recognize PCDs, their co-morbidities, and genetic etiologies. Further data on epidemiology, shared disease mechanisms, and the natural history of PCDs will be critical for the development of treatment approaches. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Loss-of-function mutations in the endoplasmic reticulum membrane protein CLN8 cause Batten disease, a neurodegenerative lysosomal storage disorder 1 . Together with the lysosomal enzyme CLN5, CLN8 mediates the biosynthesis of bis(monoacylglycero)phosphate (BMP), a phospholipid essential for lysosomal function and distinguished by its unique S,S stereochemistry 2,3 . However, the role of CLN8 in BMP synthesis has remained unclear. Here we establish that CLN8 is a glycerophosphoglycerol (GPG) acyltransferase that catalyses the stereospecific acylation of S,S -GPG to produce S,S -lysophosphatidylglycerol (LPG), the CLN5 substrate in BMP synthesis. Using cryo-electron microscopy, we resolve structures of the CLN8 homodimer in apo and substrate-bound states at 2.7 Å resolution, revealing the active site architecture and a ping-pong acyl transfer mechanism. Batten disease-causing missense mutations impair CLN8 enzymatic activity in vitro and reduce BMP levels in a Cln8 R24G knock- in mouse, whereas the Cln8 mnd mouse frameshift mutation causes complete loss of BMP in vivo. Exogenous S,S -LPG, but not the R,S stereoisomer, restored BMP synthesis in CLN8- deficient cells and mice, and improved neurological phenotypes in cln8 mutant zebrafish. Together, these findings define the enzymatic function of CLN8, elucidate the biochemical basis of CLN8 Batten disease, and establish a proof-of-concept for treating it through stereospecific BMP precursor supplementation.

Leigh syndrome is the most common phenotype of mitochondrial disorders in children. This study demonstrates clinical, neuroradiological, and molecular genetic findings in siblings with Leigh syndrome and isolated complex I assembly defect associated with intronic c.16 + 5G > A variant in the NDUFS7 gene. Whole exome sequencing was carried out to identify the causative variant. The gene and protein expression of NDUFS7 were studied using patient-derived fibroblasts. Assembly of mitochondrial respiratory chain enzymes was analyzed using Blue Native PAGE. This study shows that the NDUFS7 c.16 + 5G > A variant (rs375282422) has a causative role in Leigh syndrome. Evolution of neuroimaging findings related to this gene variant are demonstrated.

Liver involvement in POLG disease is common and associated with high morbidity and mortality. Detailed, large-scale, systematic studies of liver involvement are lacking. This study aims to describe the onset, clinical course and prognostic implications of liver involvement in POLG disease. We conducted a multinational, retrospective study including clinical, genetic and biochemical data from patients with confirmed POLG disease. Patients were stratified according to age of disease onset: early-onset (< 12 years), juvenile/adult-onset (12-40 years), and late-onset (> 40 years). Of the 202 patients, 110 (54%) had liver involvement. This could present at any time during the lifespan, but occurred more frequently in patients with early-onset disease (76/98, 78%). Median onset age for liver involvement in females was 7 years (range: 1 month to 50 years), and 21 months in males (birth to 71 years). Infection-triggered disease onset carried a significantly higher risk of liver involvement than spontaneous or other disease triggers. Eighty-five percent of those with liver involvement also had epilepsy. Liver involvement was an indicator of poor prognosis and was significantly associated with worse survival. This study provides a comprehensive description of liver involvement in a large cohort of POLG disease patients. Liver involvement is common in this disease and associated with significantly worse survival. POLG disease should be considered in children presenting with liver involvement, and rapid genetic testing may guide management decisions. Our findings emphasize the need for early vigilance in monitoring liver involvement in all patients with confirmed POLG disease, particularly those with early-onset disease and during intercurrent infection.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with inattention, hyperactivity, and impulsivity as core symptoms. Current diagnostic methods of ADHD consisting of interviews and self-ratings come with a risk of subjective bias and are dependent on the limited availability of healthcare professionals. However, recent technological advances have opened new opportunities to develop objective and scalable methods for precision diagnostics. The present critical review covers the current literature concerning one of the promising technologies, the use of motion sensors or accelometers for detecting ADHD, particularly evaluating the related clinical potential. Several studies in this field, especially recent studies with advanced computational methods, have demonstrated excellent accuracy in detecting individual participants with ADHD. Machine learning methods provide several benefits in the analysis of rich sensor data, but the existing studies still have critical limitations in explaining the underlying cognitive functions and demonstrating the capacity for differential diagnostics is still underway. Clinical utility of sensor-based diagnostic methods could be improved by conducting rigorous cross-validation against other methods in representative samples and employing multi-sensor solutions with sophisticated analysis methods to improve interpretation of the symptom manifestation. We conclude that motion sensors provide cost-effective and easy-to-use solutions with strong potential to increase the precision and availability of ADHD diagnostics. Nevertheless, these methods should be employed with caution, as only a fraction of ADHD symptoms relate to hyperactivity captured by motion sensors. At best, this technique could complement the existing assessment methods or be used along with other digital tools such as virtual reality.

Intellectual disability (ID) is a common disorder, yet there is a wide spectrum of impairment from mild to profoundly affected individuals. Mild ID is seen as the low extreme of the general distribution of intelligence, while severe ID is often seen as a monogenic disorder caused by rare, pathogenic, highly penetrant variants. To investigate the genetic factors influencing mild and severe ID, we evaluated rare and common variation in the Northern Finland Intellectual Disability cohort (n = 1096 ID patients), a cohort with a high percentage of mild ID (n = 550) and from a population bottleneck enriched in rare, damaging variation. Despite this enrichment, we found only a small percentage of ID was due to recessive Finnish-enriched variants (0.5%). A larger proportion was linked to dominant variation, with a significant burden of rare, damaging variation in both mild and severe ID. This rare variant burden was enriched in more severe ID (p = 2.4e-4), patients without a relative with ID (p = 4.76e-4), and in those with features associated with monogenic disorders. We also found a significant burden of common variants associated with decreased cognitive function, with no difference between mild and more severe ID. When we included common and rare variants in a joint model, the rare and common variants had additive effects in both mild and severe ID. A multimodel inference approach also found that common and rare variants together best explained ID status (ΔAIC = 16.8, ΔBIC = 10.2). Overall, we report evidence for the additivity of rare and common variant burden throughout the spectrum of intellectual disability.

Objective Scalp electroencephalograms (EEGs) are critical for neurological evaluations, particularly in epilepsy, yet they demand specialized expertise that is often lacking in many regions. Artificial intelligence (AI) offers potential solutions to this gap. While existing AI models address certain aspects of EEG analysis, a fully automated system for routine EEG interpretation is required for effective epilepsy management and healthcare professionals' decision-making. This study aims to develop an AI-augmented model for automating EEG seizure tracking, thereby supporting a sustainable digital care pathway for epilepsy (DCPE). The goal is to improve patient monitoring, facilitate collaborative decision-making, ensure timely medication adherence, and promote patient compliance. Method The study proposes an AI-augmented framework using machine learning, focusing on quantitative analysis of EEG data to automate DCPE. A focus group discussion was conducted with healthcare professionals to find the problem of the current digital care pathway and assess the feasibility, usability, and sustainability of the AI-augmented system in the digital care pathway. Results The study found that a combination of random forest with principal component analysis and support vector machines with KBest feature selection achieved high accuracy rates of 96.52% and 95.28%, respectively. Additionally, the convolutional neural networks model outperformed other deep learning algorithms with an accuracy of 97.65%. The focus group discussion revealed that automating the diagnostic process in digital care pathway could reduce the time needed to diagnose epilepsy. However, the sustainability of the AI-integrated framework depends on factors such as technological infrastructure, skilled personnel, training programs, patient digital literacy, financial resources, and regulatory compliance. Conclusion The proposed AI-augmented system could enhance epilepsy management by optimizing seizure tracking accuracy, improving monitoring and timely interventions, facilitating collaborative decision-making, and promoting patient-centered care, thereby making the digital care pathway more sustainable.

Salla disease (SD) is a lysosomal storage disease where free sialic acid (SA) accumulates in lysosomes due to the impaired function of a membrane protein, sialin. Synchrotron radiation-based scanning transmission soft X-ray spectromicroscopy (STXM) was used to analyze both SD patients' fibroblasts and normal human dermal fibroblasts (NHDF) from healthy controls. Both cell lines were also cultured with N-acetyl-d-mannosamine monohydrate (ManNAc) to see if it increased SA concentration in the cells. The STXM technique was chosen to simultaneously observe the morphological and chemical changes in cells. It was observed that free SA did not remain in the lysosomes during the sample processing, leaving empty vacuoles to the fibroblasts. The total cytosol and entire cell spectra, however, showed systematic differences between the SD and NHDF samples, indicating changes in the relative macromolecular concentrations of the cells. The NHDF cell lines contained a higher relative protein concentration compared to the SD cell lines, and the addition of ManNAc increased the relative protein concentration in both cell lines. In this study, two sample preparation methods were compared, resin-embedded thin sections and cells grown directly on sample analysis grids. While the samples grown on the grids exhibited clean, well-resolved spectra not masked by embedding resin, the low penetration depth of soft X-rays hindered the analysis to only the thin region of the microfilaments away from the thick nucleus.