Purine nucleoside phosphorylase (PNP) deficiency causes inadequate purine metabolite detoxification, which leads to combined immunodeficiency and variable neurologic symptoms. Hematopoietic stem cell transplantation (HSCT) cures the immunodeficiency, but large studies on the long-term outcomes are lacking. In a retrospective study of the European Society for Blood and Marrow Transplantation, we investigated 46 patients with PNP deficiency from 21 centers. We analyzed the presenting clinical signs and outcomes after HSCT. Cognition (0-3), hearing (0-3), interaction (0-4), movement (0-4), and occupation (0-3) (CHIMO) were scored at the last follow-up (FU) visit (no impairment, 17; mild, 15-16; moderate, 12-14; and severe impairment, <12). The median age at initial presentation was 7.5 (1-48) months. The patients presented with infections (41%), neurological dysfunction (39%), both (15%), or autoimmune disease (5%). At the time of HSCT (median age, 26 [2-192] months), neurological abnormalities were observed in 88% of patients. After a median FU of 7.9 (1.0-22.3) years, 40 patients were alive with a 3-year overall survival (OS)/event-free survival (EFS) probabilities of 86% (confidence interval [CI], 77%-97%)/75% (CI, 64%-89%), respectively. High-level (>50%-100%)/low-level donor chimerism (11%-50%) was observed in 85%/15% of patients, respectively, leading to resolution of T lymphopenia. The median overall CHIMO score was 14 (6-17), while the median scores for each component were 3 (0-3), 3 (1-3), 4 (1-4), 3 (1-4), and 2 (0-3), respectively. Patients who underwent HSCT before 24 months after the initial presentation demonstrated superior OS (P = .049). Neurological symptoms that occurred before 11 months of age were associated with reduced OS (P = .027). While the overall results were satisfactory, earlier diagnosis could further improve outcomes.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a rare autoimmune disease affecting the central nervous system, frequently manifesting with optic neuritis (ON). Despite often favourable functional visual recovery, structural retinal changes may persist. This prospective study assessed the utility of functional and structural visual outcome measures in paediatric MOGAD. Children with serologically confirmed MOGAD were recruited from across Switzerland, alongside age-matched healthy controls. All participants underwent pattern-reversal visual evoked potentials (VEP; 15′ and 60′ check sizes), spectral-domain optical coherence tomography (OCT), high- and low-contrast distance visual acuity (VA), near VA, and colour vision testing. VEP outcomes were P100 peak times, and OCT outcomes were peripapillary retinal nerve fibre layer (pRNFL) thickness (global, temporal, nasal, and papillomacular bundle (PMB)), macular volume, and central retinal thickness. Discriminative performance was assessed using receiver operating characteristic (ROC) analysis. Twelve paediatric MOGAD patients (10.9 ± 3.1 years) and twelve age-matched controls (11.5 ± 2.8 years) were included. VEP P100 peak times were generally comparable between patients and controls. pRNFL thickness appeared lower in patients than controls. ROC analysis showed excellent to outstanding discrimination for global, PMB, temporal, and nasal pRNFL sectors, both overall and in ON+ and ON– subgroups. VEP P100 peak times exhibited fair or poor discrimination overall, however 15′ check sizes showed excellent discrimination between ON+ and control eyes. In our cohort, OCT-derived pRNFL thickness differentiated MOGAD from controls with high accuracy, including in eyes without prior ON. VEPs showed limited utility, supporting OCT as a more sensitive marker of subclinical structural involvement.

Background:Lyme neuroborreliosis (LNB) is a common manifestation of Lyme disease in children. It is caused by the bacterium Borrelia burgdorferi and can affect both the peripheral nervous system (PNS) and the central nervous system (CNS). This study aimed to describe clinical and immunological features of LNB in children. Methods:We performed a large retrospective cohort study of children diagnosed with LNB at the University Children's Hospital Zurich from 1 January 2006 to 31 December 2020. Results:A total of 190 children diagnosed with LNB were included (median age, 7.6 years). Meningitis was the most frequent manifestation of LNB (n = 115, 60.5%), followed by isolated cranial neuropathy (iCN) (n = 55, 28.9%) and meningoradiculitis (n = 15, 7.9%). Five (2.7%) patients presented with rare, severe CNS manifestations, including acute myelitis and cerebral vasculitis. The most frequent specific clinical signs were facial palsy (n = 136, 71.6%) and a history of erythema migrans (n = 33, 17.4%). Borrelia burgdorferi-specific IgM and IgG antibody responses in cerebrospinal fluid (CSF) and blood were primarily directed against the following 3 antigens: VlsE, p41, and OspC, with broader responses in blood. Compared to patients with meningitis or meningoradiculitis, iCN patients had lower CSF inflammation, reduced positivity in B burgdorferi-specific tests (ELISA, immunoblot, and/or intrathecal antibody production), weaker antibody responses to VlsE, p41, and OspC, and shorter post-treatment symptom duration. Conclusions:Lyme neuroborreliosis in children presents with a broad clinical spectrum, with meningitis and iCN being the most common manifestations. We observed distinct clinico-pathogenic subgroups of LNB: iCN reflects a more localized, PNS-restricted disease, whereas meningitis and meningoradiculitis represent a more systemic involvement of both PNS and CNS. These findings may improve diagnostic accuracy and guide the management of children with LNB.

Dystonia is a rare disease trait for which large-scale genomic investigations are still underrepresented. Genetic heterogeneity among patients with unexplained dystonia warrants interrogation of entire genome sequences, but this has not yet been systematically evaluated.To significantly enhance our understanding of the genetic contribution to dystonia, we (re)analysed 2874 whole-exome sequencing (WES), 564 whole-genome sequencing (WGS), as well as 80 fibroblast-derived proteomics datasets, representing the output of high-throughput analyses in 1990 patients and 973 unaffected relatives from 1877 families. Recruitment and precision-phenotyping procedures were driven by long-term collaborations of international experts with access to overlooked populations.By exploring WES data, we found that continuous scaling of sample sizes resulted in steady gains in the number of associated disease genes without plateauing. On average, every second diagnosis involved a gene not previously implicated in our cohort. Second-line WGS focused on a subcohort of undiagnosed individuals with high likelihood of having monogenic forms of dystonia, comprising large proportions of patients with early onset (81.3%), generalized symptom distribution (50.8%) and/or coexisting features (68.9%). We undertook extensive searches for variants in nuclear and mitochondrial genomes to uncover 38 (ultra)rare diagnostic-grade findings in 37 of 305 index patients (12.1%), many of which had remained undetected due to methodological inferiority of WES or pipeline limitations. WGS-identified elusive variations included alterations in exons poorly covered by WES, RNA-gene variants, mitochondrial-DNA mutations, small copy-number variants, complex rearranged genome structure and short tandem repeats. For improved variant interpretation in WGS-inconclusive cases, we employed systematic integration of quantitative proteomics. This aided in verifying diagnoses related to technically challenging variants and in upgrading a variant of uncertain significance (3 of 70 WGS-inconclusive index patients, 4.3%). Further, unsupervised proteomic outlier analysis supplemented with transcriptome sequencing revealed pathological gene underexpression induced by transcript disruptions in three more index patients with underlying (deep) intronic variants (3/70, 4.3%), highlighting the potential for targeted antisense-oligonucleotide therapy development. Finally, trio-WGS prioritized a de novo missense change in the candidate PRMT1, encoding a histone methyltransferase. Data-sharing strategies supported the discovery of three distinct PRMT1 de novo variants in four phenotypically similar patients, associated with loss-of-function effects in in vitro assays.This work underscores the importance of continually expanding sequencing cohorts to characterize the extensive spectrum of gene aberrations in dystonia. We show that a pool of unresolved cases is amenable to WGS and complementary multi-omic studies, directing advanced aetiopathological concepts and future diagnostic-practice workflows for dystonia. Using whole-genome sequencing and proteomics, Zech et al. have shown that many patients with suspected monogenic dystonia carry mutations that are undetectable with exome analysis alone. Complementary approaches, such as RNA sequencing and functional studies, can improve rates of diagnosis.

Background Lyme disease (LD) is caused by Borrelia burgdorferi and is the most common tickborne disease in the northern hemisphere. Although classical characteristics of LD are well-known, the diagnosis and treatment are often delayed. Laboratory diagnosis by serological testing is recommended for most LD manifestations. The objective of this study was to describe clinical characteristics and associated serological profiles in children with LD. Methods This retrospective cohort study included children aged 0-18 years, diagnosed with LD according to current guidelines at University Children's Hospital Zurich between January 1, 2006 and December 31, 2020. Two-tier serological testing with the recomWell enzyme-linked immunosorbent assay and recomLine Western blot (MIKROGEN Diagnostik, MIKROGEN GmbH, Neuried, Germany) was performed at the Institute of Medical Microbiology, University of Zurich. Findings In total, 469 children diagnosed with LD were included (median age, 7.9 years); 190 patients (40.5%) with Lyme neuroborreliosis (LNB), 171 (36.5%) patients with skin manifestations (erythema migrans, n = 121; multiple erythema migrans, n = 11; borrelial lymphocytoma, n = 37; and acrodermatitis chronica atrophicans, n = 2), and 108 (23.0%) patients with Lyme arthritis. We observed seasonal variations for patients with skin manifestations and LNB, with high prevalence in May-October, but not for patients with Lyme arthritis. Significant differences between LD manifestation groups were found for age, inflammatory parameters, and specificity and concentration of B. burgdorferi-specific serum antibody responses. We observed distinct patterns of pronounced serum antibody responses against B. burgdorferi antigens in LNB (IgM against VlsE, p41, and OspC) and Lyme arthritis (IgG against p100, VlsE, p58, p41, p39, and p18). Interpretation Our study is one of the largest and most detailed for children with LD. We present unique fi ndings regarding the differences in clinical characteristics and immune responses between various manifestations of LD in children. Funding No specific funding to disclose for this study.

BACKGROUND:Cerebral creatine deficiency disorders (CCDD) are rare diseases caused by defects in the enzymes L-arginine: glycine amidinotransferase (AGAT) or guanidinoacetate-N-methyltransferase (GAMT), which are involved in synthesis of creatine; or by a defect in the creatine transporter (CRTR), which is essential for uptake of creatine as important energy source into the target cells. Patients with CCDD can present with a variety of unspecific symptoms: global developmental delay, speech-language disorder, behavioral abnormalities and seizures. Early treatment initiation is essential in AGAT and GAMT deficiencies to achieve a favorable outcome. This study describes the CCDD patient cohort in a single center, and an analysis of the referrals to two Swiss laboratories in Lausanne and Zurich between 2015 and 2023 for the two marker metabolites guanidinoacetate and creatine. RESULTS:The patient cohort comprised 6 patients (defects: 2 GAMT, 4 CRTR), who were initially seen by different subspecialties depending on first symptoms. There was a diagnostic and therapeutic delay between 3 and 32 months (mean 13.8). Numbers of biomarker requests showed a constant increase during the study period, with a majority of tests performed in urine, the preferred sample for CCDD detection. Almost all samples (93.3%) were sent in by large hospitals (mainly from neurology, developmental pediatrics and metabolism) and only few (5.2%) by pediatricians in private practice, although those usually see the patients first. CONCLUSIONS:The data from this study demonstrate a relevant delay in identifying patients with these rare conditions, and a predominance of biomarker analysis requested from pediatric subspecialties that are involved in patient management often long after occurrence of symptoms. To reduce the diagnostic delay and the outcome of patients, the current practice of sample referral should be reflected and first-contact healthcare providers should be encouraged to initiate selective screening.

Predicting and quantifying phenotypic consequences of genetic variants in rare disorders is a major challenge, particularly pertinent for ‘actionable’ genes such as thyroid hormone transporter MCT8 (encoded by the X-linked SLC16A2 gene), where loss-of-function (LoF) variants cause a rare neurodevelopmental and (treatable) metabolic disorder in males. The combination of deep phenotyping data with functional and computational tests and with outcomes in population cohorts, enabled us to: (i) identify the genetic aetiology of divergent clinical phenotypes of MCT8 deficiency with genotype-phenotype relationships present across survival and 24 out of 32 disease features; (ii) demonstrate a mild phenocopy in ~400,000 individuals with common genetic variants in MCT8; (iii) assess therapeutic effectiveness, which did not differ among LoF-categories; (iv) advance structural insights in normal and mutated MCT8 by delineating seven critical functional domains; (v) create a pathogenicity-severity MCT8 variant classifier that accurately predicted pathogenicity (AUC:0.91) and severity (AUC:0.86) for 8151 variants. Our information-dense mapping provides a generalizable approach to advance multiple dimensions of rare genetic disorders.

STUDY AIMS: Our objective was to establish a multicentre foetal-to-neonatal magnetic resonance (MR) neuroimaging programme for neonates undergoing surgery for complex congenital heart disease (CHD). We assessed structural and volumetric MRI findings at different timepoints in various types of CHD and evaluated neurodevelopmental outcomes at one year of age. Additionally, we analysed the feasibility, challenges and limitations of implementing this MR neuroimaging programme. METHODS: In this prospective, multicentre observational study, we examined brain development and growth in infants with complex CHD requiring neonatal cardiac surgery. Brain MRI was performed at multiple timepoints: at the 32nd week of gestation, after birth (both before and after stage I surgery), and before stage II surgery in single-ventricle CHD. We analysed and compared cardiac diagnoses, treatment approaches, structural and volumetric brain MRI findings and neurodevelopmental outcomes at one year of age (assessed using the Bayley III scale) with those of healthy controls. RESULTS: Between April 2020 and September 2023, 81 patients and 15 healthy controls underwent at least one MRI. Cardiac diagnoses were biventricular CHD (66.7%), single-ventricle CHD (25.9%) and borderline left ventricle CHD (7.4%). New structural cerebral lesions were found before stage I or after stage I including white matter injury in 3.8% and 8.7%, respectively, ischaemic cerebral lesions in 11.5 and 11.6%, intraventricular haemorrhages in 7.7% and 7.2%, and subdural haemorrhages in 33.6% and 26.1%. Total brain volume at 32.6 (interquartile range [IQR]: 31.3–33.3) gestational weeks was 228.9 ml (213.1–241.2) in biventricular CHD, 194.4 ml (165.3–223.6) in single-ventricle CHD and 196.4 ml (186.4–235.2) in normal healthy controls. After birth, at 6 days (3–16) of life total brain volume was 337.1 ml (310.3–350.2) in biventricular CHD, 331.6 ml (305.9–350.7) in single-ventricle CHD and 406.8 ml (389.9–438.7) in normal healthy controls. After stage I, at 26.5 days (18.3–40.8) total brain volume was 367.7 ml (341.8–385.5) in biventricular CHD, 353.6 ml (338.2–375.7) in single-ventricle CHD and 514.1 ml (482.9–554.6) at 116 days (94.5–118.5) in patients with single-ventricle CHD. At 12.1 months of age, neurodevelopmental performance determined by the Bayley III scale (mean ± SD [standard deviation]) was lower for patients with single-ventricle CHD (cognitive composite score [CCS]: 92.9 ± 13.1; language composite score [LCS]: 88.5 ± 12.0; motor composite score [MCS]: 85.6 ± 14.5) than in patients with biventricular CHD (CCS: 101.2 ± 11.1; LCS: 95.7 ± 13.1; MCS: 87.6 ± 18.0) or in healthy controls (CCS: 113.3 ± 5.6; LCS: 102.3 ± 7.9; MCS: 100.7 ± 8.2). Feasibility for performing cerebral MRI was limited due to maternal/patient safety reasons and further logistical infrastructural reasons. CONCLUSIONS: Structural cerebral lesions were found at various timepoints in both biventricular and single-ventricle CHD during foetal-to-neonatal serial cerebral MRI. Compared to healthy controls, total brain volume was reduced in patients with complex CHD, and neurodevelopmental outcomes at one year of age were mildly to moderately impaired. Several patient-related and infrastructural challenges limit the feasibility of a routine magnetic resonance neuroimaging programme, necessitating further efforts to optimise its implementation into routine clinical practice in the future. Trial registration: ClinicalTrials.gov NCT04233775

Neuromyelitis optica spectrum disorder (NMOSD) is a rare neuroinflammatory disease with an annual incidence of less than 1 case in 1,000,000 in the White population and a median age of onset at 40 years. NMOSD usually presents with optic neuritis and longitudinally extensive transverse myelitis. Various brainstem, cerebellar, diencephalic, and hemispheric symptoms may also occur. Early diagnosis and treatment are crucial for symptom management and prevention of relapses and disability. We report the case of a prepubertal girl, highlighting unique clinical and magnetic resonance imaging features and the risk of early parenchymal damage.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare neuroinflammatory disease with an annual incidence of less than 1 case in 1,000,000 in the White population and a median age of onset at 40 years. NMOSD usually presents with optic neuritis and longitudinally extensive transverse myelitis. Various brainstem, cerebellar, diencephalic, and hemispheric symptoms may also occur. Early diagnosis and treatment are crucial for symptom management and prevention of relapses and disability. We report the case of a prepubertal girl, highlighting unique clinical and magnetic resonance imaging features and the risk of early parenchymal damage.

BACKGROUND: Inflammatory type focal cerebral arteriopathy (FCA-i) in the anterior circulation (AC) is well characterized, and the focal cerebral arteriopathy severity score (FCASS) reflects the severity of the disease. We identified cases of FCA-i in the posterior circulation (PC) and adapted the FCASS to describe these cases. METHODS: In this comparative cohort study, patients from the Swiss NeuroPaediatric Stroke Registry with ischemic stroke due to FCA-i between January 2000 and December 2018 were analyzed. A comparison between PC and AC cases regarding pediatric National Institutes of Health Stroke Scale score and pediatric stroke outcome measure and FCASS was performed. We estimated infarct size by the modified pediatric Alberta Stroke Program Early Computed Tomography Score in children with AC stroke and the adapted Bernese posterior diffusion–weighted imaging score in the PC. RESULTS: Thirty-five children with a median age of 6.3 (interquartile range, 2.7–8.2 [95% CI, 0.9–15.6]; 20 male; 57.1%) years with FCA-i were identified. The total incidence rate was 0.15/100 000/year (95% CI, 0.11–0.21). Six had PC-FCA-i. Time to final FCASS was longer in the PC compared with AC; the evolution of FCASS did not differ. Initial pediatric National Institutes of Health Stroke Scale score was higher in children with FCA-i in the PC with a median of 10.0 (interquartile range, 5.75–21.0) compared with 4.5 (interquartile range, 2.0–8.0) in those with AC-FCA-i. Different from the anterior cases, PC infarct volume did not correlate with higher discharge, maximum, or final FCASS scores (Pearson correlation coefficient [r], 0.25, 0.35, and 0.54). CONCLUSIONS: FCA-i also affects the PC. These cases should be included in future investigations into FCA-i. Although it did not correlate with clinical outcomes in our cohort, the modified FCASS may well serve as a marker for the evolution of the arteriopathy in posterior FCA-i.

Spina bifida affects spinal cord and cerebral development, leading to motor and cognitive delay. We investigated whether there are associations between thalamocortical connectivity topography, neurological function, and developmental outcomes in open spina bifida. Diffusion tensor MRI was used to assess thalamocortical connectivity in 44 newborns with open spina bifida who underwent prenatal surgical repair. We quantified the volume of clusters formed based on the strongest probabilistic connectivity to the frontal, parietal, and temporal cortex. Developmental outcomes were assessed using the Bayley III Scales, while the functional level of the lesion was assessed by neurological examination at 2 years of age. Higher functional level was associated with smaller thalamo-parietal, while lower functional level was associated with smaller thalamo-temporal connectivity clusters (Bonferroni-corrected P < 0.05). Lower functional levels were associated with weaker thalamic temporal connectivity, particularly in the ventrolateral and ventral anterior nuclei. No associations were found between thalamocortical connectivity and developmental outcomes. Our findings suggest that altered thalamocortical circuitry development in open spina bifida may contribute to impaired lower extremity function, impacting motor function and independent ambulation. We hypothesize that the neurologic function might not merely be caused by the spinal cord lesion, but further impacted by the disruption of cerebral neuronal circuitry.

BACKGROUND:Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) comprises various age-dependent clinical phenotypes and may be monophasic, multiphasic, or chronic. Optic neuritis (ON) is a common manifestation and frequently appears in combination with other MOGAD phenotypes, particularly in young children. Despite permanent structural damage to the retinal nerve fiber layer (RNFL), children often experience complete visual recovery.AIMS:To analyze the progression and impact of MOGAD on the visual system of pediatric patients independently of the history of ON.METHODS:This retrospective study included children who met specific criteria: myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G (IgG) seropositivity, acute presentation of MOGAD, and written general consent. Main outcome measures were global peripapillary retinal nerve fiber layer (pRNFL) thickness, and near and distance visual acuity, analyzed using descriptive statistics.RESULTS:We identified 10 patients with median age of 7.7 years at first event: 7 patients manifested with acute disseminated encephalomyelitis (ADEM) (with ON 5/7, ADEM only 1/7, with transverse myelitis (TM) 1/7), 2 with isolated ON, and 1 patient with neuromyelitis optica spectrum disorder (NMOSD)-like phenotype with ON. Among ON patients, 5/8 were affected bilaterally, with 3 initially diagnosed with unilateral ON but experiencing subsequent involvement of the fellow eye. None of the patients without previous ON showed a deterioration of visual acuity and, if evaluated, a reduction of the pRNFL.CONCLUSION:Most pediatric MOGAD-ON patients in our cohort presented with acute vison loss and optic disc edema. All patients achieved complete visual recovery, independent of number of relapses or initial visual loss. The pRNFL thickness decreased for several months and stabilized at reduced levels after 12 months in the absence of further relapses. MOGAD may not have subclinical/'silent' effects on the visual system, as visual acuity and pRNFL were not affected in patients without ON.

Spina bifida affects spinal cord and cerebral development, leading to motor and cognitive delay. We investigated whether there are associations between thalamocortical connectivity topography, neurological function and developmental outcomes in open spina bifida. Diffusion tensor MRI was used to assess thalamocortical connectivity in 44 newborns with open spina bifida who underwent prenatal surgical repair. We quantified the volume of clusters formed based on the strongest probabilistic connectivity to the frontal, parietal, and temporal cortex. Developmental outcomes were assessed using the Bayley III Scales, while the functional level of the lesion was assessed by neurological examination at two years of age. Higher functional level was associated with smaller thalamo-parietal, while lower functional level was associated with smaller thalamo-temporal connectivity clusters (Bonferroni-corrected p<0.05). Lower functional levels were associated with weaker thalamic temporal connectivity, particularly in the ventrolateral and ventral anterior nuclei. No associations were found between thalamocortical connectivity and developmental outcomes. Our findings suggest that altered thalamocortical circuitry development in open spina bifida may contribute to impaired lower extremity function, impacting motor function and independent ambulation. We hypothesize that the neurologic function might not merely be caused by the spinal cord lesion, but further impacted by the disruption of cerebral neuronal circuitry.

MED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27-related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants. Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ± 12.4 years, range 0.1-45). Follow-up and hitherto unreported clinical features were obtained from the published 12 families. Brain MRI scans from 34 cases were reviewed. MED27-related disease manifests as a broad phenotypic continuum ranging from developmental and epileptic-dyskinetic encephalopathy to variable neurodevelopmental disorder with movement abnormalities. It is characterized by mild to profound global developmental delay/intellectual disability (100%), bilateral cataracts (89%), infantile hypotonia (74%), microcephaly (62%), gait ataxia (63%), dystonia (61%), variably combined with epilepsy (50%), limb spasticity (51%), facial dysmorphism (38%) and death before reaching adulthood (16%). Brain MRI revealed cerebellar atrophy (100%), white matter volume loss (76.4%), pontine hypoplasia (47.2%) and basal ganglia atrophy with signal alterations (44.4%). Previously unreported 39 affected individuals had seven homozygous pathogenic missense MED27 variants, five of which were recurrent. An emerging genotype-phenotype correlation was observed. This study provides a comprehensive clinical-radiological description of MED27-related disease, establishes genotype-phenotype and clinical-radiological correlations and suggests a differential diagnosis with syndromes of cerebello-lental neurodegeneration and other subtypes of 'neuro-MEDopathies'.

The brain and its health are essential for our (physical mental, social, and spiritual) wellbeing, for being able to realize our potential as individuals, and also for a fair, well-functioning, and productive society. However, today the world is facing a healthcare crisis related to the very high (and increasing) burden of brain disorders. As a response to this crisis, the "Swiss Brain Health Plan" (SBHP) was conceptualized in the context of other initiatives launched to value, promote, and protect brain health over the entire life course. In the first section of this position paper, the following fundamental considerations of the SBHP are discussed: (1) the high (and increasing) burden of brain disorders in terms of prevalence (>50% of the population suffers from a brain disorder), disability, mortality, and costs; (2) the prevention of brain disorders; (3) the operational definition of brain health; (4) determinants of brain health; (5) international initiatives to promote brain (including mental) health including the World Health Organization (WHO) intersectorial global action plan on epilepsy and other neurological disorders (NDs) (IGAP) and the WHO comprehensive mental health action plan. In the second section of the paper, the five strategic objectives of the SBHP, which has the vision of promoting brain health for all across the entire life course, are presented: (1) to raise awareness; (2) strengthen cross-disciplinary and interprofessional training/educational programs for healthcare professionals; (3) foster research on brain health determinants and individualized prevention of brain disorders; (4) prioritize a holistic (non-disease-specific), integrated, person-centered public health approach to promote brain health and prevent brain disorders through collaborations across scientific, health care, commercial, societal and governmental stakeholders and insurance providers; (5) support, empower, and engage patients, caregivers, and patient organizations, and reduce the stigma and discrimination related to brain disorders. In the third section of the paper, the first (2024) steps in the implementation of the SHBP, which will be officially launched in Zurich on 22 November 2023, are presented: (1) a definition of the overall organization, governance, specific targets, and action areas of the SBHP; (2) the patronage and/or co-organization of events on such specific topics as brain research (Lausanne), dementia (Geneva), stroke (Basel), neurohumanities (Bellinzona), sleep (Lugano), and psychiatry (Zurich); (3) the conduction of a new study on the global burden of brain disorders in Switzerland; (4) the launching of an international Certificate of Advanced Studies (CAS) on Brain Health at the University of Bern. In the fourth section of the paper, there is a concise executive summary of the SBHP.