Median Age Of Onset Research Articles

P145 Single-centre experience of managing patients with anti-HMGCR antibody immune-mediated necrotizing myopathy

Abstract Background/Aims Anti-HMGCR antibodies are associated with a rare form of immune mediated necrotizing myopathy. Statin exposure is common, but statin-naïve presentations can occur. Given its rarity, optimal treatment regimes, alternative cholesterol lowering therapy, and implications of monitoring antibody titre have yet to be established. Methods A retrospective single-centre study was carried out at our tertiary neuromuscular clinic. All patients with a positive anti-HMGCR antibody presenting with a myopathy from 2010-2023, seen in the neuromuscular clinic at the Royal London Hospital, were included. Data on demographics, investigations, and treatments were recorded. Results In total, 39 patients were included in the analysis. Within the anti-HMGCR cohort, ethnically the largest proportion were white (27/39), followed by Asian (n = 7), and four patients black/black-African. 61% of patients were female. The commonest comorbidities were type 2 diabetes mellitus (67%), and hypertension (59%). Median age of onset was 66 (IQR 11). Three patients had no known statin exposure prior to disease onset, of which one had a limb-girdle muscular dystrophy distribution of muscle involvement. Median creatinine kinase (CK) at presentation was 8122 units/L (IQR 5338-14000). Alternative cholesterol lowering therapy was successfully commenced with ezetimibe (n = 18), or PCSK9 inhibitors (n = 3), with no progression of disease. Five malignancies were reported: one breast Ca, one tubo-ovarian, two thyroid, and one low grade NHL. None of the patients had cardiac involvement. 79% of patients were treated with prednisolone. Induction triple therapy of a steroid, IVIg and DMARD was used in 36% of patients. Methotrexate and IVIg were the commonest DMARDs used (59% and 54% respectively), often used in combination with prednisolone. Only four patients had a flare in disease requiring treatment re-escalation, nine patients are in remission off immunosuppression (Table 1). 21% were treated with rituximab, and two patients with abatacept. Where antibody titres were available, anti-HMGCR correlated significantly with CK levels (r = 0.689, p < 0.001). Of the patients with more than one HMGCR titre recorded, 8/14 reduced over time, and of those, 5/8 corresponded to a meaningful improvement in CK, while two patients had an improving CK, with a stable HMGCR titre. 4/14 patients are in remission off all immunosuppression, of which two of these had HMGCR titres below the threshold of positivity, and two had falling titres. Conclusion Anti-HMGCR IMNM remains rare. We demonstrate that remission off immunosuppression is achievable, and that anti-HMGCR titres may be of use to support immunosuppression withdrawal. We also show that, in this cohort of patients, alternative cholesterol lowering therapy is safe, and not associated with worsening disease. Disclosure K.E. Clark: None. R. Thomas: None. S. Kelly: None. L. Walker: None. A. Herrey: None. A. Dougan: None. R. Patel: None. S. Fhadil: None. A. Radunovic: None.

The Association of Heterozygous p.R4810K of RNF213 and Long-Term Unfavorable Outcomes after Encephaloduroarteriosynangiosis in Chinese Pediatric Patients with Moyamoya Disease

Background. Previous studies have established that heterozygous mutation for the p.R4810K variant can influence the severity of the clinical phenotype in patients with moyamoya disease (MMD) at disease onset. However, the relationship between the p.R4810K variant and the clinical phenotype of long-term unfavorable outcomes in Chinese pediatric patients remains unclear. Objectives. The primary aim of this study was to examine the association of heterozygous p.R4810K of RNF213 and long-term unfavorable outcomes after encephaloduroarteriosynangiosis (EDAS) in Chinese pediatric patients with MMD. Method. In this retrospective cohort study, we included 259 pediatric patients with MMD who possessed the known p.R4810K genotype. These individuals underwent EDAS along with genotyping analysis for p.R4810K via a TaqMan probe and the QuantStudio 6 Flex Real-Time PCR System. Subsequently, we evaluated their long-term outcomes. The variables we assessed were age at diagnosis, gender, p.R4810K genotypes, initial modified Rankin scale (mRS), clinical manifestations (such as hemorrhage and ischemia), posterior cerebral artery (PCA) involvement combined with angiographic stage, and their history of risk factors like hyperlipidemia and hyperhomocysteinemia. Furthermore, we scrutinized long-term unfavorable outcomes using both univariate analyses and multivariate logistic regression to identify independent predictive factors. Results. This study enrolled 259 Chinese pediatric patients with MMD, which included both newly and previously diagnosed cases, who underwent EDAS. The cohort comprised 130 male participants (50.19%) and 129 female participants (49.81%), with a median onset age of 8 years (median, IQR: 6-12 years). Among these patients, homozygous mutations were exceptionally rare, identified in only 4 individuals (1.54%), while the prevalence of heterozygous mutations was relatively higher, observed in 85 children (32.82%). The multivariate logistic regression showed that several factors were significantly associated with long-term unfavorable outcomes: older age at diagnosis (OR, 0.82 [95% CI, 0.7-0.96], P=0.014), onset with hematoma (OR, 12.76 [95% CI, 1.52-106.89], P=0.019), initial mRS (OR, 24.53 [95% CI, 6.51-92.41], P<0.001), perioperative infarction (OR, 22.16 [95% CI, 1.45-337.96], P=0.026), and infarction during follow-up (OR, 14.5 [95% CI, 2.04-103.12], P=0.008). Furthermore, the cumulative incidence of initial infarction suggested that pediatric patients with homozygous or heterozygous mutations typically present at a younger age and exhibit a higher incidence of initial infarction compared to those carrying wild-type genotypes. Conclusions. The study suggests that the p.R4810K variant is associated with the onset age of MMD in Chinese pediatric patients, potentially impacting long-term outcomes. Surprisingly low recurrent stroke rates were observed across all genotypes, including homozygous individuals for the pathogenic variant, indicating that nongenetic factors may also play a role in the course and outcomes of MMD in this population.

NR1H4 disease: rapidly progressing neonatal intrahepatic cholestasis and early death.

Clinical studies on progressive familial intrahepatic cholestasis (PFIC) type 5 caused by mutations in NR1H4 are limited. New patients with biallelic NR1H4 variants from our center and all patients from literature were retrospectively analyzed. Three new patients were identified to be carrying five new variants. Liver phenotypes of our patients manifests as low-γ-glutamyl transferase cholestasis, liver failure and related complications. One patient underwent liver transplantation (LT) and survived, and two other patients died without LT. Nine other patients were collected through literature review. Twelve out of 13 patients showed neonatal jaundice, with the median age of onset being 7 days after birth. Reported clinical manifestations included cholestasis (13/13, 100%), elevated AFP (11/11, 100%), coagulopathy (11/11, 100%), hypoglycemia (9/13, 69%), failure to thrive (8/13, 62%), splenomegaly (7/13, 54%), hyperammonemia (7/13, 54%), and hepatomegaly (6/13, 46%). Six of 13 patients received LT at a median age of 6.2 months, and only one patient died of acute infection at one year after LT. Other 7 patients had no LT and died with a median age of 5 months (range 1.2-8). There were 8 patients with homozygous genotype and 5 patients with compound heterozygous genotype. In total, 13 different variants were detected, and 5 out of 12 single or multiple nucleotides variants were located in exon 5. We identified three newly-diagnosed patients and five novel mutations. NR1H4-related PFIC typically cause progressive disease and early death. LT may be the only lifesaving therapy leading to cure.

Deciphering age-specific molecular features in cervical cancer and constructing an angio-immune prognostic model.

Cancer incidence is increasingly seen in younger individuals. Molecular distinctions between young and elderly patients at onset are understudied. This study used public databases to explore genomic, transcriptomic, and immune-related features across age groups in cervical cancer. Additionally, it aims to create a prognostic model applicable across diverse age cohorts, enabling precise patient stratification, and personalized therapies. Gene mutations, expression data, and clinicopathological information were obtained from 317 cervical cancer patients. These patients were divided into a young group and an old group based on the median age of onset. The characteristics of differential gene mutation, gene expression, and immune cells analysis were analyzed by R software. Finally, the prognostic model was constructed by univariate Cox, least absolute shrinkage and selection operator, and multivariate Cox regression analyses of angiogenic and immune gene sets. Its validity was further confirmed using an additional 300 cervical squamous cell carcinoma and endocervical adenocarcinoma tissues. Cervical cancer patients at elderly onset age exhibit a significantly higher frequency of NOTCH1 and TP53 driver mutations compared to young patients, along with a notably higher tumor mutational burden. However, there were no significant differences between the 2 groups in terms of genomic instability and age-related mutational signatures. Differential gene expression analysis revealed that the young group significantly upregulated interferon-alpha and gamma responses and exhibited significantly higher activity in multiple metabolic pathways. Immune microenvironment analysis indicated enrichment of dendritic cells and natural killer cells in the young group, while transforming growth factor-β signature was enriched in the elderly group, indicating a higher degree of immune exclusion. A multigene prognostic model based on angiogenesis and T cell immune gene sets showed excellent prognostic performance independent of clinical factors such as age. High-risk groups identified by the model exhibit significant activation of tumor-promoting processes, such as metastasis and angiogenesis. Our study reveals distinct patterns in cancer-driving mechanisms, biological processes, and immune system status between young and elderly patients at onset with cervical cancer. These findings shed light on the age-specific underlying mechanisms of carcinogenesis. Furthermore, an independent molecular prognostic model is constructed to provide valuable references for patient stratification and the development of potential drug targets.

Characterisation of RT-QuIC negative cases from the UK National CJD Research and Surveillance programme

IntroductionIncorporation of the real-time quaking-induced conversion (RT-QuIC) assays for diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) has transformed diagnosis largely related to its extremely high specificity. However, the test has a c.10% false-negative result and we aim to characterize the clinical features, investigation profile, and molecular subtype in this cohort of patients.Methods250 individuals diagnosed with definite sporadic CJD were identified from the UK National CJD Research and Surveillance Unit from 2012 to 2023. We compared the clinical features and investigation profile in those with a negative CSF RT-QuIC to those with a positive RT-QuIC.Results27 individuals (10.8%) were CSF RT-QuIC negative. Median age of onset was younger (62 years vs 68 years, p = 0.002), median disease duration was longer (4.4 months vs 10.5 months, p < 0.001), and these individuals were less likely to present with gait difficulties (73% vs 93%, p = 0.003) or motor symptoms (62% vs 80%, p = 0.04). The sensitivity of electroencephalography and diffusion-weighted MRI were similar in both groups. In those who were RT-QuIC negative, there was an overrepresentation of the VV1 (32% vs 1%) and MM2 molecular subtypes (21% vs 3%). Co-occurring neurodegenerative disease was found in 33% (9/27) of those who were RT-QuIC negative.ConclusionsIndividuals with sporadic CJD and a negative CSF RT-QuIC present with younger age of onset, different clinical features and are over-represented with the VV1 and MM2 subtypes of sporadic CJD. Further work is required to better understand the biochemical properties contributing to RT-QuIC negative results in these cases.

Fréquence relative des causes de polyuro-polydipsie chez le chien et le chat : étude rétrospective de 205 cas (2015–2020)

Polyuro-polydipsia syndrome is common in veterinary medicine. The conditions causing polyuro-polydipsia are well documented, and the diagnostic approach is consensual. Nevertheless, the veterinary literature is deficient on the relative frequency of its causes. To the best of our knowledge, no case series or cohort studies have been carried out on this topic.The aim of this retrospective study of 122 polyuro-polydipsic dogs and 83 polyuro-polydipsic cats was to describe the epidemiological characteristics of these populations and to assess the relative frequency of causes in the two species. The median age of onset of polyuro-polydipsia was eight years (0,2-16) for dogs and 11 years (0,5-23) for cats. In the canine population, 16 groups of conditions were identified, the most frequent being kidney disease (32.8 %), diabetes mellitus (12,3 %) and hypercorticism (11.5 %). In the feline population, seven types of conditions were found, including 59 % kidney disease and 30 % diabetes mellitus.This clinical study is the first to highlight the relative frequency of the causes of polyuro-polydipsia in dogs and cats helping clinicians to prioritize their hypotheses and the investigations to be carried out in the face of polyuro-polydipsia.

Abstract NG02: Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers

Abstract NG02: Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers

Genetic and pathological features encipher the phenotypic heterogeneity of Gerstmann-Sträussler-Scheinker disease

ObjectivesTo elucidate and compare the genetic, clinical, ancillary diagnostic, and pathological characteristics across different Gerstmann-Sträussler-Scheinker disease (GSS) phenotypes and explore the underlying causes of the phenotypic heterogeneities. MethodsThe genetic, clinical, ancillary diagnostic, and pathological profiles of GSS patients reported in the literature were obtained and analyzed. Additionally, 3 patients with genetically confirmed GSS from our unit were included. Based on clinical presentation, patients were classified into typical GSS, Creutzfeldt-Jakob disease (CJD)-like GSS, GSS with dementia, and other categories. ResultsA total of 329 GSS cases were included with a 1.13:1 female-to-male ratio, median onset age 44, and median duration 4 years. Of the 294 categorized patients, 50.7% had typical GSS, 24.8% showed CJD-like GSS, and 16.3% presented with GSS with dementia. Clinical classification varied significantly based on genotype, with P102L more common in typical GSS and A117V prevalent in CJD-like GSS. Polymorphism at codon 129 has no effect on GSS phenotype, but the 129 M allele acts as a protective factor in GSS patients in Asia and North America. Moderate to severe spongiform degeneration and the presence of PK-resistant small fragments migrating at <11 kDa on electrophoretic gels along with PrP27–30 fragments were more prevalent in CJD-like GSS phenotype, while hyperphosphorylated tau protein co-deposition tends to be characteristic of typical GSS and GSS with dementia. ConclusionThis study reveals GSS's intricate nature, showing significant variations in clinical presentations, diagnostic findings, and pathological features. Mutation sites and pathological changes play crucial roles in determining the GSS clinical heterogeneity.

An exploration of the genetics of the mutant Huntingtin (mHtt) gene in a cohort of patients with chorea from different ethnic groups in sub-Saharan Africa.

Africans are underrepresented in Huntington's disease (HD) research. A European ancestor was postulated to have introduced the mutant Huntingtin (mHtt) gene to the continent; however, recent work has shown the existence of a unique Htt haplotype in South-Africa specific to indigenous Africans. We aimed to investigate the CAG trinucleotide repeats expansion in the Htt gene in a geographically diverse cohort of patients with chorea and unaffected controls from sub-Saharan Africa. We evaluated 99 participants: 43 patients with chorea, 21 asymptomatic first-degree relatives of subjects with chorea, and 35 healthy controls for the presence of the mHtt. Participants were recruited from 5 African countries. Additional data were collected from patients positive for the mHtt gene; these included demographics, the presence of psychiatric and (or) cognitive symptoms, family history, spoken languages, and ethnic origin. Additionally, their pedigrees were examined to estimate the number of people at risk of developing HD and to trace back the earliest account of the disease in each region. HD cases were identified in all countries. Overall, 53.4% of patients with chorea were carriers for the mHTT; median tract size was 45 CAG repeats. Of the asymptomatic relatives, 28.6% (6/21) were carriers for the mHTT; median tract size was 40 CAG. No homozygous carries were identified. Median CAG tract size in controls was 17 CAG repeats. Men and women were equally affected by HD. All patients with HD-bar three who were juvenile onset of <21 years-were defined as adult onset (median age of onset was 40 years). HD transmission followed an autosomal dominant pattern in 84.2% (16/19) of HD families. In familial cases, maternal transmission was higher 52.6% (10/19) than paternal transmission 36.8% (7/19). The number of asymptomatic individuals at risk of developing HD was estimated at ten times more than the symptomatic patients. HD could be traced back to the early 1900s in most African sites. HD cases spread over seven ethnic groups belonging to two distinct linguistic lineages separated from each other approximately 54-16kya ago: Nilo-Sahara and Niger-Congo. This is the first study examining HD in multiple sites in sub-Saharan Africa. We demonstrated that HD is found in multiple ethnic groups residing in five sub-Saharan African countries including the first genetically confirmed HD cases from Guinea and Kenya. The prevalence of HD in the African continent, its associated socio-economic impact, and genetic origins need further exploration and reappraisal.

Evaluation of Psychiatric High and Intensive Care (EPHIC-study): monitoring innovative care from a value-based approach

IntroductionSystematic monitoring and evaluation of innovative healthcare programs are essential to develop sustainable solutions to health needs in the population (Porter &amp; Teisberg, 2006). Development of Psychiatric High and Intensive Care Units (HIC’s) in Belgium, following the Dutch Model (van Mierlo et al., 2013), is an innovative model for patients with acute and severe psychiatric illness, resulting in potential danger. HIC aims to provide intensive, need-adapted care with interventions that reduce (perceived) coercion, focusing on participative processes and continuity of care.Objectives(1) What are the clinical characteristics of admitted patients? (2) How does clinical symptomatology evolve during admission? (3) How do patients, relatives and caregivers experience the process of care and recovery? (4) What is the role of HIC’s in the reformed mental health care?MethodsThis is an explorative, hypothesis-generating study, using a mixed-method approach, consisting of qualitative and quantitative methods against a value-based framework. Data collection lasted 18 months in the first 9 HIC’s in Belgium. Results are based on validated questionnaires completed by adult patients and their HIC caregivers at admission and discharge (N=472).ResultsWe provide the first, preliminary results. Suicidality, psychotic and substance-related symptoms are the most important primary symptoms. Almost 70% have 2 or more symptoms, with psychiatric comorbidity of 50%. Substance-related- and psychotic disorders are the two most common diagnoses, followed by personality disorder cluster B and depressive disorder. 83% have been in residential care in the past, of whom 87% twice or more. The median age is 36 years, but the median age of onset of mental disorders is 21 years, which equals to 15 years in mental disorder progress and comorbidity development. Over 50% meet the criteria for Severe Mental Illness and 56% are involuntary admitted. There is a high degree of unmet needs: no outpatient care is provided for one out of five prior to admission and there is a low follow-up by mobile teams prior to and after admission (around 12% each). We found significant improvements after an average stay of 22 days for aggression, suicidality and crisis (respectively decrease of 68%, 25% and 9%); readiness to change and motivation for treatment (respectively increase of 5% and 14%) The Client Satisfaction Questionnaire scores range from 1 to 4, with an average score 3.15 out of 4.ConclusionsBased on these preliminary results we can conclude that aggression, suicidality, crisis, readiness to change and motivation for treatment all improve significantly after a short stay of 3 weeks. Despite a vulnerable, severely distressed population, patients are generally satisfied with received care. There is a high degree of unmet needs: insufficient provided outpatient care and low follow up by mobile teams.Disclosure of InterestNone Declared

Hydroa vacciniforme lymphoproliferative disorder: a retrospective study of 42 paediatric cases.

Hydroa vacciniforme lymphoproliferative disorder (HVLPD) is a rare disease related to Epstein-Barr virus (EBV), mainly in children, and is an EBV-associated cutaneous T and natural killer (NK) cell lymphoproliferative disorder. The disorder in some patients may progress to EBV-associated systemic T or NK-cell lymphoma. To summarize the characteristics of HVLPD in Chinese paediatric patients and to examine the risk factors indicating poor prognosis. We performed a retrospective analysis of patients with HVLPD from the Department of Dermatology, Beijing Children's Hospital. Based on diagnosis, medical history, examination results, and immunophenotype, we analysed HVLPD in 42 paediatric cases in order to examine the clinical features, prognoses, and risk factors. Forty-two paediatric patients were enrolled, with a median onset age of five years. All patients presented with papulovesicular lesions, and 32 systemic HVLPD (sHVLPD) patients had systemic symptoms, including fever, lymphadenopathy, hepatomegaly, splenomegaly, and liver dysfunction. Of the sHVLPD cases, 13 also had severe mosquito bite allergy (SMBA). Twenty-five cases were T-type, and nine were CD56+-dominant type. Follow-up data showed that 12 patients had complete remission, and three patients died. SMBA is a risk factor for disease progression in patients with HVLPD, and the pathological CD56+-dominant phenotype is associated with poor prognosis.

Spontaneous intestinal perforation among very preterm infants in China: a multicenter cohort study.

Spontaneous intestinal perforation (SIP) is one of the most serious surgical bowel conditions affecting preterm infants. There are limited data on the mortality and morbidities of very preterm infants [VPIs, <32 weeks' gestational age (GA)] with SIP in China. The study aimed to describe the prevalence, treatment, and outcomes of SIP among VPIs in China. This retrospective cohort study included all infants born at 24+0-31+6 weeks GA from January 1, 2019, to December 31, 2020, and admitted within seven days after birth to the neonatal intensive care units in the Chinese Neonatal Network. The primary outcome was survival without major morbidities. The association between SIP and neonatal outcomes was evaluated using multivariate logistic regression controlling for possible confounders. Out of the 15,814 enrolled infants, 150 (1.0%) developed SIP with a median onset age of four (IQR 2-6) days. Infants with GA 24+0-25+6 weeks had the highest incidence of SIP (13/532, 2.4%), followed by those with GA 26+0-27+6 weeks (22/2,005, 1.1%), 28+0-29+6 weeks (44/5,269, 0.8%) and 30+0-31+6 weeks (71/8,008, 0.9%). Ten SIP cases were lost to follow-up with unknown survival status and 41 (29.3%) of the remaining 140 infants with SIP died during hospitalization. Only 29.3% of infants with SIP survived without major morbidities, significantly lower than those without SIP (59.2%; P<0.01). Multivariate analysis revealed SIP was associated with a higher risk of overall death (adjusted OR 3.36; 95% CI: 1.85 to 6.08), late-onset sepsis (adjusted OR 2.10; 95% CI: 1.02 to 4.31), and bronchopulmonary dysplasia (adjusted OR 2.49; 95% CI: 1.44 to 4.30). Among all infants with SIP, 28 (18.7%) did not receive any surgical intervention. Laparotomy was provided to 113 (92.6%) of the remaining 122 infants, solely (84/122, 68.9%) or following peritoneal drainage (29/122, 23.8%), while nine (7.4%) infants underwent peritoneal drainage only. Around 1% of VPIs in China developed SIP, associated with increased risk of mortality and morbidities. Over 90% of VPIs with SIP underwent laparotomy as initial or subsequent surgical treatment. Effective and evidence-based strategies are needed for the prevention and management of SIP.

Factors Associated with the Myopia Degree in Students

Purpose: to identify the most significant factors associated with myopic refraction in medical university students, which can be used for early prediction and prevention of myopia.Materials and methods. The survey data of students of 1–6 courses of Kazan State Medical University and the data on refraction of patients’ eyes obtained from the “Medical record of a patient receiving medical care on an outpatient basis” (registration form No. 025/y) were used. The refraction of the eye in each of the participants was calculated as the average value of the spherical equivalent of the right and left eyes.Results. According to the ophthalmologist’s examination, myopia was detected in 219 (69 %) of the surveyed students. 134 (42 %) students had mild myopia, 66 (21 %) had moderate myopia, 19 (6 %) were highly myopic. Among myopes, 73 % of students wear glasses (160/219), contact lenses — 41 % of respondents (90/219). The median age of onset of spectacle wear was 13 years (Q1–Q3 = 10–26). The median refraction of the right eye (D) was -2.50 D (Q1–Q3 = -1.5…-4.0), the left eye -2.75 D (Q1–Q3 = -1.6…-4.0). The early age of onset of spectacle wear is the factor most significantly associated with myopic refraction (+0.23 D/year, p = 1.30×10-11), and an important prognostic sign of the development of high myopia. Factors associated with stronger myopic refraction are high height and low weight, as well as less physical activity.Conclusion. It is necessary to take into account the anthropometric and behavioral features of the patient when developing an individual plan for the prevention and treatment of myopia, in order to avoid the development of complications leading to vision loss.

Familial aggregation and heritability of childhood-onset and adult-onset type 1 diabetes: a Swedish register-based cohort study

Type 1 diabetes in children is known to be highly heritable, but much less is known about the heritability of adult-onset type 1 diabetes. Thus, our objective was to compare the familial aggregation and heritability of type 1 diabetes in adults and children. This Swedish nationwide register-based cohort study included individuals born from Jan 1, 1982, to Dec 31, 2010, identified through the Medical Birth Register who were linked to their parents, full siblings, half siblings, and cousins through the Multi-Generation Register (MGR). We excluded multiple births, deaths within the first month of life, individuals who could not be linked to MGR, or individuals with contradictory information on sex. Information on diagnoses of type 1 diabetes was retrieved by linkages to the National Diabetes Register and National Patient Register (1982-2020). Individuals with inconsistent records of diabetes type were excluded. We estimated the cumulative incidence and hazard ratios (HRs) of type 1 diabetes in adults (aged 19-30 years) and children (aged 0-18 years) by family history of type 1 diabetes and the heritability of adult-onset and childhood-onset type 1 diabetes based on tetrachoric correlations, using sibling pairs. 2 943 832 individuals were born in Sweden during the study period, 2 832 755 individuals were included in the analysis of childhood-onset type 1 diabetes and 1 805 826 individuals were included in the analysis of adult-onset type 1 diabetes. 3240 cases of adult-onset type 1 diabetes (median onset age 23·4 years [IQR 21·1-26·2]; 1936 [59·7%] male and 1304 [40·2%] female) and 17 914 cases of childhood-onset type 1 diabetes (median onset age 9·8 years [6·2-13·3]; 9819 [54·8%] male and 8095 [45·2%] female) developed during follow-up. Having a first-degree relative with type 1 diabetes conferred an HR of 7·21 (95% CI 6·28-8·28) for adult-onset type 1 diabetes and 9·92 (9·38-10·50) for childhood-onset type 1 diabetes. The HR of developing type 1 diabetes before the age 30 years was smaller if a first-degree relative developed type 1 diabetes during adulthood (6·68 [6·04-7·39]) rather than during childhood (10·54 [9·92-11·19]). Similar findings were observed for type 1 diabetes in other relatives. Heritability was lower for adult-onset type 1 diabetes (0·56 [0·45-0·66]) than childhood-onset type 1 diabetes (0·81 [0·77-0·85]). Adult-onset type 1 diabetes seems to have weaker familial aggregation and lower heritability than childhood-onset type 1 diabetes. This finding suggests a larger contribution of environmental factors to the development of type 1 diabetes in adults than in children and highlights the need to identify and intervene on such factors. Swedish Research Council, the Swedish Research Council for Health, Working Life and Welfare, Swedish Diabetes Foundation, and the China Scholarship Council.

Juvenile Myasthenia Gravis in North Texas: Clinical Features, Treatment Response, and Outcomes

BackgroundJuvenile myasthenia gravis (JMG) is a rare autoimmune disease that causes fatigable muscle weakness in children aged <18 years. There is currently no curative treatment or internationally accepted standard of care for JMG. The objective is to investigate relationships between clinical presentation, antibody status, severity of disease onset, electrodiagnostic evaluation, and response to therapy in JMG. MethodsThis study was a retrospective chart review. Congenital myasthenic syndromes were excluded. Data on demographics, treatments, and outcomes were collected. Disease severity was evaluated using Myasthenia Gravis Foundation of America (MGFA) clinical classifications. ResultsWe identified 84 patients with JMG at Children's Medical Center Dallas between January 2014 and February 2022. It was found that 52% of patients presented with ocular JMG (median onset age 4.5 years) and 48% with generalized JMG (median onset age 11.5 years); 81% tested positive for acetylcholine receptor antibodies. Patients were 17% non-Hispanic white, 29% Hispanic, 39% black, and 12% Asian. There was a significant difference in average MGFA scores between ethnicities (P = 0.047) and age groups (P = 0.004), with postpubertal patients having higher average MGFA scores than prepubertal patients. Seventy-one percent of patients who underwent thymectomy experienced a decrease in MGFA scores postprocedure. ConclusionsOur study showed that there were significant differences in disease severity between ethnicities and age groups and that most patients who underwent thymectomy showed clinical improvement. These outcomes highlight the need for additional therapies in the treatment of JMG and the importance of extending clinical trials to the pediatric population.

Clinical feature, GALC variant spectrum, and genotype-phenotype correlation in Korean Krabbe disease patients: Multicenter experience over 13 years.

Krabbe disease (KD) is an autosomal recessive neurodegenerative disorder caused by deficiency of the galactocerebrosidase (GALC) due to variants in the GALC gene. Here, we provide the first and the largest comprehensive analysis of clinical and genetic characteristics, and genotype-phenotype correlations of KD in Korean in comparison with other ethnic groups. From June 2010 to June 2023, 10 patients were diagnosed with KD through sequencing of GALC. Clinical features, and results of GALC sequencing, biochemical test, neuroimaging, and neurophysiologic test were obtained from medical records. An additional nine previously reported Korean KD patients were included for review. In Korean KD patients, the median age of onset was 2 years (3 months-34 years) and the most common phenotype was adult-onset (33%, 6/18) KD, followed by infantile KD (28%, 5/18). The most frequent variants were c.683_694delinsCTC (23%) and c.1901T>C (23%), while the 30-kb deletion was absent. Having two heterozygous pathogenic missense variants was associated with later-onset phenotype. Clinical features were similar to those of other ethnic groups. In Korean KD patients, the most common phenotype was the adult-onset type and the GALC variant spectrum was different from that of the Caucasian population. This study would further our understanding of KD.

Cardiopulmonary exercise testing on adaptive equipment in children and adults with Friedreich ataxia.

Traditional exercise is often difficult for individuals with Friedreich ataxia (FRDA), and evidence is limited regarding how to measure exercise performance in this population. We evaluated the feasibility, reliability, and natural history of adaptive cardiopulmonary exercise test (CPET) performance in children and adults with FRDA. Participants underwent CPET on either an arm cycle ergometer (ACE) or recumbent leg cycle ergometer (RLCE) at up to four visits (baseline, 2 weeks, 4 weeks, and 1 year). Maximum work, oxygen consumption (peak VO2), oxygen (O2) pulse, and anaerobic threshold (AT) were measured in those who reached maximal volition. Test-retest reliability was assessed with intraclass coefficients, and longitudinal change was assessed using regression analysis. In our cohort (N = 23), median age was 18 years (interquartile range [IQR], 14-23), median age of FRDA onset was 8 years (IQR 6-13), median Friedreich Ataxia Rating Scale score was 58 (IQR 54-62), and GAA repeat length on the shorter FXN allele (GAA1) was 766 (IQR, 650-900). Twenty-one (91%) completed a maximal CPET (n = 8, ACE and n = 13, RLCE). Age, sex, and GAA1 repeat length were each associated with peak VO2. Preliminary estimates demonstrated reasonable agreement between visits 2 and 3 for peak work by both ACE and RLCE, and for peak VO2, O2 pulse, and AT by RLCE. We did not detect significant performance changes over 1 year. Adaptive CPET is feasible in FRDA, a relevant clinical trial outcome for interventions that impact exercise performance and will increase access to participation as well as generalizability of findings.

Seizures as Initial Presentation and Enduring Predisposition to Seizures in Autoimmune Encephalitis

Purpose. This retrospective study is aimed at investigating the clinical characteristics of autoimmune encephalitis (AE) and long-term prognosis of patients who initially present with seizures as well as risk factors for enduring predisposition to seizures in AE. Methods. From January 1, 2013, to October 31, 2021, a total of 343 AE patients from a single center diagnosed with autoimmune encephalitis (AE) were enrolled in this study, including 198 antibody-positive AE and 145 antibody-negative but probable AE. According to initial symptoms, AE patients were divided into two groups: onset with seizure group and onset with nonseizure group. The clinical characteristics were retrospectively reviewed. Patients were clinically evaluated at onset and at 6, 12, and 24 months of follow-up. Modified Rankin Scale (MRS) score, Clinical Assessment Scale in Autoimmune Encephalitis (CASE) score, and seizure-related information were assessed. Results. In AE, patients with seizures as the first presentation were younger, with a median-onset age of 28 years old. Compared with other types of antibody-positive AE, anti-GABABR AE more frequently began with seizures, while anti-CASPR2, anti-AMPAR, and anti-DPPX encephalitis usually began with symptoms other than seizures. The most common type of initial seizures in AE was focal to bilateral seizure (67.6%), with a significant prevalence in antibody-positive AE (P=0.001). In addition, compared with nonseizure group, patients with seizures as an initial presentation had higher MRS and CASE scores at 24 months of follow-up. Older age at onset and focal nonmotor seizure type were independent risk factors for an enduring predisposition to seizures in AE patients. Conclusion. The younger and anti-GABABR-positive AE patients are more prone to onset with seizures. AE patients who initially presented with seizures had worse long-term neurological recovery. Onset age and seizure type should be highly appreciated when formulating the strategy for therapy at post-AE status.

Familial occurrence of seizure disorders across MRI defined structural focal epilepsy etiology

BackgroundPrevious studies have established familial occurrence of epilepsy and seizure disorders and early age of epilepsy onset as predictors of genetic epilepsy, but have not evaluated the rate of their occurrence in patients with different epilepsy etiology. Our study determines the distribution of familial occurrence and age of epilepsy onset across structural focal epilepsy (FE) etiology in a large FE cohort. MethodsRecords of 1354 consecutive patients evaluated for epilepsy and seizure disorders in The Neurology Clinic, University Clinical Center of Serbia from 2008 to 2019 were screened for FE. Structural etiology, lobar diagnosis, familial occurrence, and age at epilepsy onset were determined. Patients with a. nonlesional focal epilepsy (NLFE), b. hippocampal sclerosis (HS) and c. congenital or perinatal etiology (CPE) were classified as NAFE, while patients with an identified acquired focal epilepsy (AFE) constituted the control group. ResultsWe identified 965 patients with FE, 329 (34.1 %) with NLFE, 213 (22.1 %) with HS, 174 (18.0 %) with CPE and 249 (25.8 %) with AFE. Familial occurrence was identified in 160 (16.6 %), 19.1 % of patients with NAFE and 9.2 % of AFE (p = 0.003). Patients with NAFE had a younger age of epilepsy onset (13 vs. 18 years, p < 0.001). The highest proportion of familial occurrence was found in patients with NLFE (23.7 %), while the youngest median age of epilepsy onset was identified in patients with HS (12 years) and CPE (11 years). ConclusionPatients with NAFE frequently have familial occurrence of epilepsy and have an earlier age of epilepsy onset than patients with AFE.

Treatment strategies and treatment-related adverse events in MG according to the age of onset.

Early-onset (EOMG) and late-onset (LOMG) are distinct groups of MG patients. It is unclear if treatment strategies and treatment-related adverse events may differ according to the age of MG onset. This single-center retrospective study includes all MG patients followed at a tertiary center since 2007. We reviewed the electronic clinical records. In total, 212 patients were identified, 142 (67.0%) females, with a median disease duration of 10 years. The median age of symptom onset was 42.0 (26.0-64.5) years, with 130 (61.3%) EOMG cases and 82 (38.7%) LOMG. EOMG were more frequently female, had longer disease duration and often more generalized MG (p < 0.001). Comorbidities were significantly more frequent in LOMG (67.1%) compared to EOMG (53.1%) (p = 0.002). Steroid-related adverse effects motivating the switch to steroid-sparing agents (82.0%) were different between groups, with hypertension, hypercholesterolemia, diabetes mellitus and malignancies being more common in LOMG. At the same time, osteoporosis and dyspepsia were more frequent in EOMG (p < 0.001). The most common first-line choice was azathioprine (45.8%), and rituximab was used in 4 patients (1.9%). Our study shows that treatment modalities are similar between EOMG and LOMG, while steroid-related adverse events appear to be distinct.