Congenital Research Articles

Outcomes and outcome measures.

Advances in haemophilia treatment have resulted in a near-normal life expectancy, lower burden of bleeding and treatment, and improved quality of life in high-income countries. Bleeding rate is approaching zero and novel parameters should be evaluated to assess the efficacy of treatment not only from the clinical point of view by using new methodologies (e.g. joint health assessment), but also from the patient's perspective (e.g. pain, quality of life, treatment satisfaction). This approach should be aimed at combining objective clinical methodologies and patient-reported outcomes (PROs). However, some instruments used for assessing PROs are still suboptimal and not properly validated. Recent evidence suggests that these tools can take advantage from a more personalized designed approach and could be effectively improved and serve to facilitate the patient's self-evaluation. For other congenital bleeding disorders (BDs), a set of patient-relevant outcomes has been also defined that overlap substantially those of haemophilia, including bleeding, side effects and complications, and PROs, such as pain, physical functioning, impact on daily life including school and work and mental health. There is a growing focus on addressing women-specific outcomes in BDs, reflecting an increased awareness of the unique challenges faced by women in this context. However, the development of tailored tools is imperative to further advance the progress in managing women with BDs, ensuring more accurate monitoring and personalized care. How incorporating these outcome measures in the process of approval of novel treatments for these disorders by regulatory authorities remains to be established.

Clinical observation of the patient with monolobar form Caroli disease

Objective. To demonstrate a case of a rare congenital liver disease, Caroli disease, characterized by segmental non-obstructive fibrocystic dilatation of the intrahepatic bile ducts. Main points. Caroli disease was first described by the French doctor Jacques Caroli in 1958. There are 2 types of Caroli disease: True type with dilation of the intrahepatic bile ducts, usually affecting one segment and with a tendency to form stones and develop cholangitis. The second type, which is combined with congenital hepatic fibrosis, polycystic kidney disease and is more common than the true type. When the disease is accompanied by CHF, it is called Caroli syndrome or Grumbach disease. It is important to remember about Crowley’s disease and include it in the differential range of diseases of the biliary tract and liver, such as cholangitis, secondary biliary cirrhosis, portal hypertension of unknown etiology, cholangiocarcinoma. Conclusion.The diagnosis of Caroli disease and Caroli syndrome is made using imaging studies. Treatment is largely supportive and should be individualized, with prognosis depending on the severity of the disease and the presence of concomitant renal dysfunction.

Abstract P391: Case Review of Congenital Ectopic Coronary Artery Disease

Coronary artery anomalies (CAAs), rare congenital conditions affecting approximately 1% of adults, are associated with adverse cardiac events, including sudden cardiac death. This article reviews three recent clinical cases involving CAAs, delving into their origins, clinical presentations, diagnostics, treatments, and outcomes. CAAs involve irregularities in coronary artery origin, distribution, and termination. Notably, the left coronary artery arising from the right sinus (0.15%) and the right coronary artery from the left sinus (0.92%) are common variations. Other anomalies include the left circumflex artery (LCX) originating from the right coronary sinus and the left main coronary artery or Left anterior descending artery (LAD) emerging from opposite sinuses, leading to diverse clinical presentations. Case 1 features a 70-year-old female with hypertension presenting with exertional angina. Surgical revascularization was performed after coronary angiography revealed an ectopic LAD. In Case 2, a 72-year-old male with hypertension presented with chest pain and NSTEMI. Coronary angiography showed an ectopic LCX and significant stenosis in LAD and RCA, treated with PCI. Case 3, involving a 49-year-old female with hypertension and syncope, was managed medically as angiography revealed an anomalous RCA origin without significant obstructive disease. Treatment approaches for CAAs are patient-specific due to limited guidelines. Case 1 underwent coronary artery bypass surgery, Case 2 received PCI, and Case 3 was treated medically. Diagnostic methods encompass stress testing, coronary angiography, and coronary CT angiography (CCTA). CCTA is particularly valuable for distinguishing benign and clinically significant ectopic origins. For intramural courses, coronary unroofing is the preferred surgical technique, while absent intramural courses may require coronary translocation or reimplantation.Percutaneous coronary intervention (PCI) primarily addresses downstream atherosclerotic lesions without directly addressing the CAA. Treatment choice depends on patient-specific risk factors and pathology. In summary, CAAs pose challenges in interventional cardiology, warranting early and accurate diagnosis to prevent adverse events. A personalized approach, considering patient characteristics, is crucial due to the lack of robust guidelines. Advanced imaging technologies like CCTA and MRA aid in assessing CAAs' clinical significance and guiding treatment decisions. Further research is required to establish optimal treatment strategies, including investigating CAAs' prevalence in specific regions such as Arkansas.Top of Form Bottom of Form

Vascularization Reconstruction Strategies in Craniofacial Bone Regeneration

Craniofacial bone defects are usually secondary to accident trauma, resection of tumor, sever inflammation, and congenital disease. The defects of craniofacial bones impact esthetic appearance and functionality such as mastication, pronunciation, and facial features. During the craniofacial bone regeneration process, different osteogenic cells are introduced, including primary osteoblasts or pluripotent stem cells. However, the defect area is initially avascular, resulting in the death of the introduced cells and failed regeneration. Thus, it is vital to establish vascularization strategies to build a timely and abundant blood vessel supply network. This review paper therefore focuses on the reconstruction of both osteogenesis and vasculogenesis. The current challenges, various strategies, and latest efforts applied to enhance vascularization in craniofacial bone regeneration are discussed. These involve the application of angiogenic growth factors and cell-based vascularization strategies. In addition, surface morphology, porous characters, and the angiogenic release property of scaffolds also have a fundamental effect on vasculogenesis via cell behavior and are further discussed.

Timing and causes of death to 1 year among children presenting to emergency departments.

A better characterization of deaths in children following emergency care is needed to inform timely interventions. This study aimed to describe the timing, location, and causes of death to 1 year among a cohort of injured and medically ill children. We conducted a retrospective cohort study of children <18 years requiring emergency care in six states from January 1, 2012, through December 31, 2017, with follow-up through December 31, 2018, for patients who were not discharged from the emergency department (ED). In this cohort, 1-year mortality, time to death within 1 year, and causes of death were assessed from ED, inpatient, and vital status records. There were 546,044 children during the 6-year period. The 1-year mortality rate was 2.2% (n = 1356) for injured children and 1.4% (n = 6687) for medically ill children. Matched death certificates were available for 861 (63.5%) of 1356 deaths in the injury cohort and for 4712 (70.5%) of 6687 deaths in the medical cohort. Among deaths in the injury cohort, 1274 (94.0%) occurred in the ED or hospital. The most common causes of death were motor vehicle collisions, firearm injuries, and pedestrian injuries. Among the 6687 deaths in the medical cohort, 5081 (76.0%) children died in the ED or hospital (primarily in the ED) and 1606 (24.0%) occurred after hospital discharge. The most common causes of death were sudden infant death syndrome, suffocation and drowning, and congenital conditions. The 1-year mortality of children presenting to an ED is 2.2% for injured children and 1.4% for medically ill children with most deaths occurring in the ED. Future interventional trials, quality improvement efforts, and health policy focused in the ED could have the potential to improve outcomes of pediatric patients.

Polycystic Kidney Disease with Breast Nodules in a Male: A Case Report

Background: Polycystic kidney disease is a multisystem and progressive congenital kidney disorder characterized by kidney enlargement and the growth of cysts in the kidneys and other organs. Autosomal dominant polycystic kidney disease (ADPKD) is the most common type of inherited kidney disorder and is observed in 1/500 – 1/1000 people. The diagnosis is usually made by a positive family history , and the Ravine ultrasonographic criteria assess the age and number of cysts in both kidneys.&#x0D; Case presentation: A 37-year-old male was reported with complaints of intermittent hematuria and a painless lump in the right breast for the last 6 years. Patients routinely drink herbal medicine when symptoms appear. Abdominal physical examination revealed renal ballottement. The lump in the right breast is palpable as a lump ± 1 cm from the nipple. No abnormalities in kidney or liver function were found on laboratory examination. Ultrasound was performed, and polycystic kidney disease was obtained in both kidneys and liver, as well as a hypervascular solid nodule in the right breast. The patient was given antibiotics and antifibrinolytics. Healthy lifestyle education is also provided to patients. The patient was then referred for a biopsy of the nodule.&#x0D; Conclusion: Autosomal dominant polycystic kidney disease (ADPKD) is a common disease but only a few cases of ADPKD are accompanied by nodules in the breast, so a further approach is needed.

"When I was Younger, My Story Belonged to Everyone Else": Co-production of Resources for Adults Living with Craniosynostosis.

Despite growing recognition that congenital craniofacial conditions have lifelong implications, psychological support for adults is currently lacking. The aim of this project was to produce a series of short films about living with craniosynostosis in adulthood, alongside a psychoeducational booklet. The resources were developed using multiple focus groups and meetings attended by researchers, patient representatives, a leading charitable organisation, an award-winning film production company, clinicians, and other experts in the field. An online mixed-methods survey was developed based on prior work to request feedback on the acceptability and utility of the resources from the craniosynostosis community. While data collection to evaluate the resources is ongoing, preliminary results (n = 36) highlight an acceptability rating of 100%. The resources developed represent a step forward in addressing the unmet information and support needs of adults with craniosynostosis and highlight the benefits of co-production in research.

Early onset epileptic and developmental encephalopathy and MOGS variants: a new diagnosis in the whole exome sequencing (WES) ERA : Report of a new patient and review of the literature.

Mannosyl-oligosaccharide glucosidase - congenital disorder of glycosylation (MOGS-CDG) is determined by biallelic mutations in the mannosyl-oligosaccharide glucosidase (glucosidase I) gene. MOGS-CDG is a rare disorder affecting the processing of N-Glycans (CDG type II) and is characterized by prominent neurological involvement including hypotonia, developmental delay, seizures and movement disorders. To the best of our knowledge, 30 patients with MOGS-CDG have been published so far. We described a child who is compound heterozygous for two novel variants in the MOGS gene. He presented Early Infantile Developmental and Epileptic Encephalopathy (EI-DEE) in the absence of other specific systemic involvement and unrevealing first-line biochemical findings. In addition to the previously described features, the patient presented a Hirschprung disease, never reported before in individuals with MOGS-CDG.

Comprehensive phenotypic characterization of an allelic series of zebrafish models of NEB-related nemaline myopathy.

Nemaline myopathy (NM) is a rare congenital neuromuscular disorder characterized by muscle weakness and hypotonia, slow gross motor development, and decreased respiratory function. Mutations in at least twelve genes, all of each encode proteins that are either components of the muscle thin filament or regulate its length and stability, have been associated with NM. Mutations in Nebulin (NEB), a giant filamentous protein localized in the sarcomere, account for more than 50% of NM cases. At present, there remains a lack of understanding of whether NEB genotype influences nebulin function and NM-patient phenotypes. In addition, there is a lack of therapeutically tractable models that can enable drug discovery and address the current unmet treatment needs of patients. To begin to address these gaps, here we have characterized five new zebrafish models of NEB-related NM. These mutants recapitulate most aspects of NEB-based NM, showing drastically reduced survival, defective muscle structure, reduced contraction force, shorter thin filaments, presence of electron-dense structures in myofibers, and thickening of the Z-disks. This study represents the first extensive investigation of an allelic series of nebulin mutants, and thus provides an initial examination in pre-clinical models of potential genotype-phenotype correlations in human NEB patients. It also represents the first utilization of a set of comprehensive outcome measures in zebrafish, including correlation between molecular analyses, structural and biophysical investigations, and phenotypic outcomes. Therefore, it provides a rich source of data for future studies exploring the NM pathomechanisms, and an ideal springboard for therapy identification and development for NEB-related NM.

Mitochondrial genes modulate the phenotypic expression of congenital scoliosis syndrome caused by mutations in the TBXT gene

BackgroundCongenital scoliosis (CS) is a spinal disorder caused by genetic-congenital vertebral malformations and may be associated with other congenital defects or may occur alone. It is genetically heterogeneous and numerous genes contributing to this disease have been identified. In addition, CS has a wide range of phenotypic and genotypic variability, which has been explained by the intervention of genetic factors like modifiers and environment genes. The aim of the present study was to determine the possible cause of CS in a Tunisian patient and to examine the association between mtDNA mutations and mtDNA content and CS. MethodsHere we performed Whole-Exome Sequencing (WES) in a patient presenting clinical features suggestive of severe congenital scoliosis syndrome. Direct sequencing of the whole mitochondrial DNA (mtDNA) was also performed in addition to copy number quantification in the blood of the indexed case. In silico prediction tools, 3D modeling and molecular docking approaches were used. ResultsThe WES revealed the homozygous missense mutation c.512A > G (p.H171R) in the TBXT gene. Bioinformatic analysis demonstrated that the p.H171R variant was highly deleterious and caused the TBXT structure instability. Molecular docking revealed that the p.H171R mutation disrupted the monomer stability which seemed to be crucial for maintaining the stability of the homodimer and consequently to the destabilization of the homodimer-DNA complex. On the other hand, we hypothesized that mtDNA can be a modifier factor, so, the screening of the whole mtDNA showed a novel heteroplasmic m.10150T > A (p.M31K) variation in the MT-ND3 gene. Further, qPCR analyses of the patient’s blood excluded mtDNA depletion. Bioinformatic investigation revealed that the p.M31K mutation in the ND3 protein was highly deleterious and may cause the ND3 protein structure destabilization and could disturb the interaction between complex I subunits. ConclusionWe described the possible role of mtDNA genetics on the pathogenesis of congenital scoliosis by hypothesizing that the presence of the homozygous variant in TBXT accounts for the CS phenotype in our patient and the MT-ND3 gene may act as a modifier gene.

Scimitar Syndrome with Acquired Cardiac Disease: A Once-in-a-blue-moon Occurrence

Abstract Scimitar syndrome (SS) is a rare congenital anomaly characterized by various abnormalities observed in both children and adults, primarily involving partial anomalous pulmonary venous drainage from the right lung to the inferior vena cava and right lung hypoplasia. It is also known by alternative names such as congenital venolobar syndrome, Halasz syndrome, mirror-image lung syndrome, hypogenetic lung syndrome, and vena cava bronchovascular syndrome. The clinical presentation of this syndrome varies widely, ranging from asymptomatic cases to severe forms. Surgical intervention is typically required for severe cases, and the diagnosis relies predominantly on imaging studies. We present two instances of SS: one involving a patient with underlying rheumatic heart disease scheduled for valve replacement surgery and the other as an incidental finding in an asymptomatic individual, managed through medical means.

Metabolic etiologies in children with infantile epileptic spasm syndrome: Experience at a tertiary pediatric neurology center

ObjectiveInfantile epileptic spasm syndrome (IESS), including West syndrome (WS) and infantile spasm (IS), causes a challenging prognosis, particularly when associated with metabolic etiologies. MethodsThis study, conducted at a tertiary pediatric neurology center, explored the prevalence and clinical features of inborn errors of metabolism in 112 children with IESS over 10 years. ResultsMost patients presented with seizures, primarily flexor spasms, and the median age at onset was 5 months. Comprehensive clinical evaluation and neuroimaging revealed structural-acquired causes as the most common etiology. Notably, inborn errors of metabolism were identified in 5.4 % of cases, with six distinct diagnoses including nonketotic hyperglycinemia, pyridoxine-dependent epilepsy, primary coenzyme Q10 deficiency 7, congenital disorder of glycosylation type IIM, 6-pyruvoyl tetrahydrobiopterin synthase deficiency, and argininosuccinate lyase deficiency. The prevalence of inborn errors of metabolism in this cohort was consistent with global variations reported in the literature. Genetic testing, including karyotype analysis and whole exome sequencing, was performed in a subset of cases with no clear diagnosis, revealing abnormalities in approximately 50 % of cases. Adrenocorticotropic hormone emerged as the most frequently prescribed antiseizure medication. ConclusionThis study provides insight into the diagnostic challenges associated with IESS and highlights the importance of metabolic investigations, especially in cases without a clear etiology. The findings emphasize the need for further genetic and metabolic studies to enhance prognostic accuracy and guide potential treatment options for children with IESS, particularly in populations with high rates of consanguinity.

Novel PIP5K1C variant identified in a Chinese pedigree with lethal congenital contractural syndrome 3

BackgroundBiallelic pathogenic variants in PIP5K1C (MIM #606,102) lead to lethal congenital contractural syndrome 3 (LCCS3, MIM #611,369), a rare autosomal recessive genetic disorder characterized by small gestational age, severe multiple joint contractures and muscle atrophy, early death due to respiratory failure. Currently, 5 individuals with LCCS3 were reported and 5 pathogenic variants in PIP5K1C were identified. Here, we reported the two fetuses in a Chinese pedigree who displayed multiple joint contractures and other congenital anomalies.MethodsTrio-based whole-exome sequencing (WES) was performed for the parents and the recent fetus to detect the genetic cause for fetus phenotype.ResultsA novel variant, NM_012398.3: c.949_952dup, p.S318Ifs*28 and a previously reported variant, c.688_689del, p.G230Qfs*114 (ClinVar database) in PIP5K1C, were detected in the individuals, and these variants were inherited from the mother and father, respectively. We described the features of multiple joint contractures in our fetuses, including bilateral talipes equinovarus, stiffness in the limbs, extended knees, persistently closed hands and overlapping fingers, which have not been delineated detailedly in previously reported LCCS3 individuals. Furthermore, novel phenotype, bilateral dilated lateral ventricles, was revealed in one fetus.ConclusionsThese findings expanded the genetic variant spectrum of PIP5K1C and enriched the clinical features of LCCS3, which will help with the prenatal diagnosis and genetic counseling for this family.

The CPLANE protein Fuzzy regulates ciliogenesis by suppressing actin polymerization at the base of the primary cilium via p190A RhoGAP.

The primary cilium decorates most eukaryotic cells and regulates tissue morphogenesis and maintenance. Structural or functional defects of primary cilium result in ciliopathies, congenital human disorders affecting multiple organs. Pathogenic variants in the ciliogenesis and planar cell polarity effectors (CPLANE) genes FUZZY, INTU and WDPCP disturb ciliogenesis, causing severe ciliopathies in humans and mice. Here, we show that the loss of Fuzzy in mice results in defects of primary cilia, accompanied by increased RhoA activity and excessive actin polymerization at the basal body. We discovered that, mechanistically, Fuzzy interacts with and recruits the negative actin regulator ARHGAP35 (also known as p190A RhoGAP) to the basal body. We identified genetic interactions between the two genes and found that a mutant ArhGAP35 allele increases the severity of phenotypic defects observed in Fuzzy-/- mice. Based on our findings, we propose that Fuzzy regulates ciliogenesis by recruiting ARHGAP35 to the basal body, where the latter likely restricts actin polymerization and modifies the actin network. Our study identifies a mechanism whereby CPLANE proteins control both actin polymerization and primary cilium formation.

The Influence of Neurotrophins on the Brain-Lung Axis: Conception, Pregnancy, and Neonatal Period.

Neurotrophins (NTs) are four small proteins produced by both neuronal and non-neuronal cells; they include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). NTs can exert their action through both genomic and non-genomic mechanisms by interacting with specific receptors. Initial studies on NTs have identified them only as functional molecules of the nervous system. However, recent research have shown that some tissues and organs (such as the lungs, skin, and skeletal and smooth muscle) as well as some structural cells can secrete and respond to NTs. In addition, NTs perform several roles in normal and pathological conditions at different anatomical sites, in both fetal and postnatal life. During pregnancy, NTs are produced by the mother, placenta, and fetus. They play a pivotal role in the pre-implantation process and in placental and embryonic development; they are also involved in the development of the brain and respiratory system. In the postnatal period, it appears that NTs are associated with some diseases, such as sudden infant death syndrome (SIDS), asthma, congenital central hypoventilation syndrome (CCHS), and bronchopulmonary dysplasia (BPD).

Congenital Tooth Agenesis and Risk of Early-Onset Cancer

There is some evidence that tooth agenesis (congenital absence of 1 or more teeth) is associated with cancer risk, especially carcinomas of the colon and ovaries, but results of previous studies are conflicting, and associations have not yet been evaluated in a population-based setting. To examine the association between tooth agenesis and specific cancer types before 40 years of age. This population-based cohort study used linking data from nationwide registries in Denmark to assess all Danish live-born singletons born from January 1, 1977, to December 31, 2018, and followed up for up to 40 years. Data were analyzed from January through June 2023. Tooth agenesis as documented by the Danish Central Registry of Odontology (Danish municipal pediatric dental care) from January 1, 1988, to December 31, 2018, and from hospital encounters in the Danish National Patient Registry within the entire study period. The primary outcome was first cancer diagnosis before 40 years of age obtained from the Danish Cancer Registry. Associations between tooth agenesis and specific cancers were estimated by Cox proportional hazards regression as hazard ratios (HRs) with 95% CIs. Analyses were split into age groups: younger than 1 year, 1 to younger than 3 years, 3 to younger than 10 years, 10 to younger than 20 years, 20 to younger than 30 years, and 30 to younger than 40 years. Associations with nonsyndromic tooth agenesis were evaluated after exclusion of individuals with known syndromes. Among 2 501 715 included individuals (1 284 292 [51.3%] male), 70 288 (2.8%) had a diagnosis of tooth agenesis (mean [SD] age at diagnosis, 13.2 [4.1] years) and 26 308 (1.1%) had a diagnosis of early-onset cancer within the study period; 778 individuals had co-occurrence of tooth agenesis and cancer. Overall, tooth agenesis was positively associated with several cancer types, including neuroblastoma (age 1 to <3 years; HR, 4.20; 95% CI, 2.24-7.88), nephroblastoma (age 1 to <3 years; HR, 4.59; 95% CI, 2.37-8.91), hepatoblastoma (age 1 to <3 years; HR, 7.10; 95% CI, 2.70-18.68), osteosarcoma (age 10 to <20 years; HR, 2.19; 95% CI, 1.11-4.32), colorectal carcinomas (age 30 to <40 years; HR, 2.81; 95% CI, 1.38-5.71), and carcinomas of bladder (age 20 to <30 years; HR, 3.35; 95% CI, 1.35-8.30). This cohort study found associations between congenital tooth agenesis and several cancer types, from childhood to early adulthood. Further evaluation of these associations is needed to assess possible clinical implications.

Синдром Швахмана–Даймонда. Не редкие симптомы у редкого пациента

The article presents modern information about the congenital disease of the pancreas - Shwachman-Diamond syndrome. Own observation and results of the examination of the child with the specified syndrome are given.

11p13 microduplication: a differential diagnosis of Silver–Russell syndrome?

BackgroundSilver–Russel syndrome (SRS) is a congenital disorder which is mainly characterized by intrauterine and postnatal growth retardation, relative macrocephaly, and characteristic (facial) dysmorphisms. The majority of patients shows a hypomethylation of the imprinting center region 1 (IC1) in 11p15 and maternal uniparental disomy of chromosome 7 (upd(7)mat), but in addition a broad spectrum of copy number variations (CNVs) and monogenetic variants (SNVs) has been reported in this cohort. These heterogeneous findings reflect the clinical overlap of SRS with other congenital disorders, but some of the CNVs are recurrent and have therefore been suggested as SRS-associated loci. However, this molecular heterogeneity makes the decision on the diagnostic workup of patients with SRS features challenging. Case presentationA girl with clinical features of SRS but negatively tested for the IC1 hypomethylation and upd(7)mat was analyzed by whole genome sequencing in order to address both CNVs and SNVs in the same run. We identified a 11p13 microduplication affecting a region overlapping with a variant reported in a previously published patient with clinical features of Silver–Russel syndrome.ConclusionsThe identification of a 11p13 microduplication in a patient with SRS features confirms the considerable contribution of CNVs to SRS-related phenotypes, and it strengthens the evidence for a 11p13 microduplication syndrome as a differential diagnosis SRS. Furthermore, we could confirm that WGS is a valuable diagnostic tool in patients with SRS and related disorders, as it allows CNVs and SNV detection in the same run, thereby avoiding a time-consuming diagnostic testing process.

Newborn screening: a comprehensive approach to the diagnosis of hereditary and congenital diseases

Newborn screening: a comprehensive approach to the diagnosis of hereditary and congenital diseases

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Disorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021. We estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined. Globally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378-521), affecting 3·40 billion (3·20-3·62) individuals (43·1%, 40·5-45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7-26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6-38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5-32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7-2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer. As the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed. Bill & Melinda Gates Foundation.