Age Of Symptom Onset Research Articles

APOE4 homozygozity represents a distinct genetic form of Alzheimer's disease.

This study aimed to evaluate the impact of APOE4 homozygosity on Alzheimer's disease (AD) by examining its clinical, pathological and biomarker changes to see whether APOE4 homozygotes constitute a distinct, genetically determined form of AD. Data from the National Alzheimer's Coordinating Center and five large cohorts with AD biomarkers were analyzed. The analysis included 3,297 individuals for the pathological study and 10,039 for the clinical study. Findings revealed that almost all APOE4 homozygotes exhibited AD pathology and had significantly higher levels of AD biomarkers from age 55 compared to APOE3 homozygotes. By age 65, nearly all had abnormal amyloid levels in cerebrospinal fluid, and 75% had positive amyloid scans, with the prevalence of these markers increasing with age, indicating near-full penetrance of AD biology in APOE4 homozygotes. The age of symptom onset was earlier in APOE4 homozygotes at 65.1, with a narrower 95% prediction interval than APOE3 homozygotes. The predictability of symptom onset and the sequence of biomarker changes in APOE4 homozygotes mirrored those in autosomal dominant AD and Down syndrome. However, in the dementia stage, there were no differences in amyloid or tau positron emission tomography across haplotypes, despite earlier clinical and biomarker changes. The study concludes that APOE4 homozygotes represent a genetic form of AD, suggesting the need for individualized prevention strategies, clinical trials and treatments.

Acid α-glucosidase (GAA) activity and glycogen content in muscle biopsy specimens of patients with Pompe disease: A systematic review

Pompe disease is a rare genetic disorder characterized by a deficiency of acid α-glucosidase (GAA), leading to the accumulation of glycogen in various tissues, especially in skeletal muscles. The disease manifests as a large spectrum of phenotypes from infantile-onset Pompe disease (IOPD) to late-onset Pompe disease (LOPD), depending on the age of symptoms onset. Quantifying GAA activity and glycogen content in skeletal muscle provides important information about the disease severity. However, the distribution of GAA and glycogen levels in skeletal muscles from healthy individuals and those impacted by Pompe disease remains poorly understood, and there is currently no universally accepted standard assay for GAA activity measurement. This systematic literature review aims to provide an overview of the available information on GAA activity and glycogen content levels in skeletal muscle biopsies from patients with Pompe disease.A structured review of PubMed and Google Scholar literature (with the latter used to check that no additional publications were identified) was conducted to identify peer-reviewed publications on glycogen storage disease type II [MeSH term] + GAA, protein human (supplementary concept), Pompe, muscle; and muscle, acid alpha-glucosidase. A limit of English language was applied. Results were grouped by methodologies used to quantify GAA activity and glycogen content in skeletal muscle. The search and selection strategy were devised and carried out in line with Preferred Reporting of Items in Systematic Reviews and Meta-Analysis guidelines and documented using a flowchart. Bibliographies of papers included in the analysis were reviewed and applicable publications not already identified in the search were included.Of the 158 articles retrieved, 24 (comprising >100 muscle biopsies from >100 patients) were included in the analysis, with four different assays. Analysis revealed that patients with IOPD exhibited markedly lower GAA activity in skeletal muscles than those with LOPD, regardless of the measurement method employed. Additionally, patients with IOPD had notably higher glycogen content levels in skeletal muscles than those with LOPD. In general, however, it was difficult to fully characterize GAA activity because of the different methods used. The findings underscore the challenges in the interpretation and comparison of the results across studies because of the substantial methodological variations. There is a need to establish standardized reference ranges of GAA activity and glycogen content in healthy individuals and in Pompe disease patients based on globally standardized methods to improve comparability and reliability in assessing this rare disease.

0010 Using Chronotype and Polygenic Risk Scores to Predict Age of Mood Symptom Onset in People with Bipolar Disorder

0010 Using Chronotype and Polygenic Risk Scores to Predict Age of Mood Symptom Onset in People with Bipolar Disorder

Paraneoplastic Calmodulin Kinase-Like Vesicle-Associated Protein (CAMKV) Autoimmune Encephalitis.

To report an autoimmune paraneoplastic encephalitis characterized by immunoglobulin G (IgG) antibody targeting synaptic protein calmodulin kinase-like vesicle-associated (CAMKV). Serum and cerebrospinal fluid (CSF) samples harboring unclassified antibodies on murine brain-based indirect immunofluorescence assay (IFA) were screened by human protein microarray. In 5 patients with identical cerebral IFA staining, CAMKV was identified as top-ranking candidate antigen. Western blots, confocal microscopy, immune-absorption, and mass spectrometry were performed to substantiate CAMKV specificity. Recombinant CAMKV-specific assays (cell-based [fixed and live] and Western blot) provided additional confirmation. Of 5 CAMKV-IgG positive patients, 3 were women (median symptom-onset age was 59 years; range, 53-74). Encephalitis-onset was subacute (4) or acute (1) and manifested with: altered mental status (all), seizures (4), hyperkinetic movements (4), psychiatric features (3), memory loss (2), and insomnia (2). Paraclinical testing revealed CSF lymphocytic pleocytosis (all 4 tested), electrographic seizures (3 of 4 tested), and striking MRI abnormalities in all (mesial temporal lobe T2 hyperintensities [all patients], caudate head T2 hyperintensities [3], and cortical diffusion weighted hyperintensities [2]). None had post-gadolinium enhancement. Cancers were uterine adenocarcinoma (3 patients: poorly differentiated or neuroendocrine-differentiated in 2, both demonstrated CAMKV immunoreactivity), bladder urothelial carcinoma (1), and non-Hodgkin lymphoma (1). Two patients developed encephalitis following immune checkpoint inhibitor cancer therapy (atezolizumab [1], pembrolizumab [1]). All treated patients (4) demonstrated an initial response to immunotherapy (corticosteroids [4], IVIG [2]), though 3 died from cancer. CAMKV-IgG is a biomarker of immunotherapy-responsive paraneoplastic encephalitis with temporal and extratemporal features and uterine cancer as a prominent oncologic association. ANN NEUROL 2024;96:21-33.

Phenotypic Expression and Outcomes in Patients with the p.Arg301Gln GLA Variant in Anderson-Fabry Disease.

The p.Arg301Gln variant in the α -galactosidase A gene (GLA) has been poorly described in the literature. The few reports show controversial information, with both classical and nonclassical Anderson-Fabry Disease (AFD) presentation patterns. The aim of this study was to analyze the penetrance, clinical phenotype, and biochemical profile of an international cohort of patients carrying the p.Arg301Gln genetic variant in the GLA gene. This was an observational, international, and retrospective cohort case series study of patients carrying the p.Arg301Gln variant in the GLA gene associated with AFD disease. Forty-nine p.Arg301Gln GLA carriers, 41% male, were analyzed. The penetrance was 63% in the entire cohort and 1.5 times higher in men. The mean age of symptoms onset was 41 years; compared to women, men presented symptoms earlier and with a shorter delay to diagnosis. The typical clinical triad-cornea verticillate, neuropathic pain, and angiokeratomas-affected only 20% of the cohort, with no differences between genders. During follow-up, almost 20% of the patients presented some type of nonfatal cardiovascular and renal event (stroke, need for dialysis, heart failure, and arrhythmias requiring intracardiac devices), predominantly affecting men. Residual levels were the most common finding of α-GAL A enzyme activity, only a few women had a normal level; a small proportion of men had undetectable levels. The incidence of combined outcomes including all causes of death was 33%, and the cumulative incidence of all-cause mortality was 9% at the follow-up. Patients carrying the p.Arg301Gln GLA variant have a high penetrance, with predominantly cardiorenal involvement and clinical onset of the disease in middle age. Only a small proportion showed the classic clinical presentation of AFD. As in other X-linked diseases, males were more affected by severe cardiovascular and renal events. This genotype-phenotype correlation could be useful from a practical clinical point of view and for future decision making.

Earlier age of symptom onset in younger generation of familial cases of multiple sclerosis.

The aim of this study was to assess the prevalence of familial MS (fMS) in Belgrade MS population, discern the differences between the persons with fMS and sporadic MS, and to detect the presence of anticipation phenomenon in fMS patients. The data on the demographic and clinical characteristics of MS patients was obtained from the Belgrade MS population Registry. In cases of vertical transmission of MS, the family members were divided into the younger and older generation, in order to assess the potential presence of anticipation phenomenon. To adjust for follow-up time bias, a secondary analysis including only patients who had the onset of symptoms before 39years (75.percentile), and those who were 39 + years, was performed. The prevalence of fMS in Belgrade MS population is 6.4%. FMS cases had earlier age at MS symptom onset (30.4 vs. 32.3years) compared to sporadic MS cohort. When comparing fMS cases across generations, the younger generation had significantly lower age at onset compared with the older one (25.8 vs. 35.7years, p < 0.001). After adjustment for the different length of the follow-up, the difference in age at symptom onset between the groups was reduced, but it still existed and was statistically significant (30.0years in younger vs. 36.4years in older generation, p = 0.040). In our study, the analysis of fMS cases across generations, showed an earlier age of symptom onset in the younger generation, even after adjustment. These results indicate the possibility of existence of anticipation phenomenon.

Self-Reported Findings of the Korean Intermittent Exotropia Multicenter Study Questionnaire.

To determine subjective symptoms and medical history of patients with intermittent exotropia in a large study population. The Korean Intermittent Exotropia Multicenter Study (KIEMS) is a nationwide, observational, cross-sectional, multicenter study conducted by the Korean Association for Pediatric Ophthalmology and Strabismus including 5,385 patients with intermittent exotropia. Subjective symptoms and medical history of patients with intermittent exotropia were extracted by a comprehensive survey based on a self-administered questionnaire according to the study protocol of the KIEMS. The mean age of symptom onset was 5.5 years. The most common symptom reported in patients with intermittent exotropia was photophobia (52.1%), followed by diplopia at near fixation (7.3%) and distance fixation (6.2%). Preterm birth was found in 8.8%, and 4.1% had perinatal complications. A family history of strabismus was present in 14.9%, and 5.5% of patients had a family member who underwent strabismus surgery. The KIEMS is one of the largest clinical studies on intermittent exotropia. Intermittent exotropia frequently caused photophobia and diplopia, and patients with a family history was not uncommon.

116 The Role of Spinal Surgery Among NF2 Patients With Spinal Tumors: Surgery-associated Characteristics and Response to Bevacizumab

INTRODUCTION: Neurofibromatosis type 2 (NF2) patients develop spinal neoplasms. Determining indications for spine surgery remains challenging, as localization of spine related symptoms can be confounded by intracranial or peripheral neuropathology. Additionally, patient selection must be balanced with pre-existing comorbidities NF2 incurs with the goal to maintain or improve quality of life. METHODS: Seventy-nine patients were enrolled retrospectively based upon NF2 diagnosis and radiographic presence of spine tumors from three tertiary academic centers. Demographic data, clinical findings, treatment course, and spine tumor pathology were collected for all patients. RESULTS: Forty-eight percent of patients received spine surgery (38/79, 48.1%). Patients undergoing spine surgery had lower age of symptom onset (15.4 vs. 25.6, p = 0.015), increased cervical (4.2 vs 2.4, p = 0.005) and overall spine tumor burden (10.3 vs 6.2, p &lt; 0.001) and presence of neck (9 vs 1, p = 0.006) and radicular pain (8 vs 1, p = 0.012). Over a quarter of our patients received BEV (25/79, 31.6%), with majority experiencing symptom onset before age 20 (17/19, 89.5%). Schwannoma was the most common BEV-treated pathology. Only one patient experienced worsening of tumor burden at one year while on BEV, and five patients required spine surgery after receiving BEV. CONCLUSIONS: NF2 patients who require spine surgery typically present at younger ages with large cervical spine tumor burden and associated symptomology. It is crucial that surgery-associated demographics and symptomology are identified. BEV was utilized in patients with aggressive, early-onset spine disease. Further, BEV halted spine disease progression in all patients except one, with minimal additional spine surgery required. Its ability to slow aggressive, NF2-associated spine tumors should be considered for clinical trial.

Analysis of risk factors related to the progression rate of hemifacial spasm.

Although there have been many researches on the etiology and risk factors with the onset of hemifacial spasm, researches on the risk factors related to progression rate are limited. This study aims to analyze the risk factors related to the progression rate of hemifacial spasm. The study enrolled 142 patients who underwent microvascular decompression for hemifacial spasm. Based on the duration and severity of symptoms, patients were classified into rapid progression group and slow progression group. To analyze risk factors, univariate and multivariate logistic regression analyses were conducted. Of 142 patients with hemifacial spasm, 90(63.3%) were classified as rapid progression group, 52(36.7%) were classified as slow progression group. In the univariate analysis, there were significant statistical differences between the two groups in terms of age of onset (P = 0.021), facial nerve angle (P < 0.01), hypertension (P = 0.01), presence of APOE ε4 expression (P < 0.01) and different degrees of brainstem compression in the Root Entry Zone (P < 0.01). In the multivariable analyses, there were significant statistical differences between the two groups in terms of age of symptom onset (P < 0.01 OR = 6.591), APOE ε4 (P < 0.01 OR = 5.691), brainstem compression (P = 0.006 OR = 5.620), and facial nerve angle (P < 0.01 OR = 5.758). Furthermore, we found no significant correlation between the severity of facial spasms and the progression rate of the disease (t = 2.47, P = 0.12>0.05). According to our study, patients with facial nerve angle ≤ 96.5°, severer compression of the brainstem by offending vessels, an onset age > 45 years and positive expression of APOE ε4, may experience faster progression of hemifacial spasm.

Clinical presentation and diagnosis of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia: a literature analysis of case studies.

Because adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare, rapidly progressive, debilitating, and ultimately fatal neurodegenerative disease, a rapid and accurate diagnosis is critical. This analysis examined the frequency of initial misdiagnosis of ALSP via comprehensive review of peer-reviewed published cases. Data were extracted from a MEDLINE search via PubMed (January 1, 1980, through March 22, 2022) from eligible published case reports/series for patients with an ALSP diagnosis that had been confirmed by testing for the colony-stimulating factor-1 receptor gene (CSF1R) mutation. Patient demographics, clinical symptoms, brain imaging, and initial diagnosis data were summarized descriptively. Categorical data for patient demographics, symptoms, and brain imaging were stratified by initial diagnosis category to test for differences in initial diagnosis based on each variable. Data were extracted from a cohort of 291 patients with ALSP from 93 published case reports and case series. Mean (standard deviation) age of symptom onset was 43.2 (11.6) years. A family history of ALSP was observed in 59.1% of patients. Cognitive impairment (47.1%) and behavioral and psychiatric abnormalities (26.8%) were the most frequently reported initial symptoms. Of 291 total cases, an accurate initial diagnosis of ALSP was made in 72 cases (24.7%) and the most frequent initial misdiagnosis categories were frontotemporal dementia (28 [9.6%]) and multiple sclerosis (21 [7.2%]). Of the 219 cases (75.3%) that were initially mis- or undiagnosed, 206 cases (94.1%) were later confirmed as ALSP by immunohistology, imaging, and/or genetic testing; for the remaining 13 cases, no final diagnosis was reported. Initial diagnosis category varied based on age, family history, geographic region, mode of inheritance, and presenting symptoms of pyramidal or extrapyramidal motor dysfunction, behavioral and psychiatric abnormalities, cognitive impairment, and speech difficulty. Brain imaging abnormalities were common, and initial diagnosis category was significantly associated with white matter hyperintensities, white matter calcifications, and ventricular enlargement. In this literature analysis, ALSP was frequently misdiagnosed. Improving awareness of this condition and distinguishing it from other conditions with overlapping presenting symptoms is important for timely management of a rapidly progressive disease such as ALSP.

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.

Risk Factors for Severe Seafood Allergy Among Adults in an Urban City in Vietnam.

Increasing seafood consumption is associated with more frequent reports of food allergy. Little is known about seafood allergy (SFA) among adults in Vietnam. We investigated the characteristics of individuals with SFA and the risk factors for severe SFA. A cross-sectional, web-based survey was conducted among individuals aged ≥ 18 years from universities in Ho Chi Minh City (Vietnam) between December 2021 and July 2022. The survey was based on a structured, validated questionnaire related to FA. Strict definitions of "convincing allergy" were used. Multivariate analysis was used to estimate the risk factors for severe SFA after adjusting for covariates. Data were analyzed using JASP (v.0.16.3) and SPSS (v.22.0). Totally, 1038 out of 2137 (48.57%) individuals completed the questionnaire, of whom 285 (27.46%) had reported SFA. Convincing SFA accounted for 20.13% (209/1038) of the cases, with convincing shellfish allergy being more common than fish allergy. Participants with comorbid shellfish and fish allergy had higher prevalence of atopic dermatitis, peanut/nut allergy, other food allergy, and cutaneous and upper airway symptoms compared to participants with shellfish allergy (p < 0.05). The spectrum of reactive seafood was diverse and characterized by local species. The age of symptom onset was most commonly during late childhood and adolescence, with most reactions persisting into adulthood. A history of anaphylaxis, comorbid peanut, and tree nut allergy, and ≥3 allergens were associated with severe SFA. Features of causative, coexisting seafood allergy, and risk factors for severe SFA were demonstrated, which can provide a reference for future studies.

Profile of HLA-B27-positive enthesitis/spondylitis-related arthritis in Senegal, West Africa

BackgroundEnthesitis/spondylitis-related arthritis (ERA) is a type of juvenile idiopathic arthritis (JIA) frequently associated with HLA-B27. In sub-Saharan Africa, HLA-B27-positive ERA hasn’t been the subject of a specific study.ObjectivesWe aimed to describe the clinical features, disease activity, functional disability and treatment of HLA-B27-positive ERA at diagnosis in Senegal and compare the findings to other populations.MethodsWe conducted a retrospective study by reviewing the medical records of patients diagnosed with ERA with an age of symptom onset < 18 years according to the 2019 PRINTO provisional criteria for ERA from January 2012 to December 2022. We collected demographic, clinical, paraclinical and therapeutic data. Disease activity score was assessed by Ankylosing Spondylitis Disease Activity Score (ASDAS) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Functional disability was assessed using Bath Ankylosing Spondylitis Functional Index (BASFI).ResultsA total of 31 patients with HLA-B27-positive ERA were included. Twenty of 31 (64.5%) were males. Twenty-seven (87%) were Fula (ethnicity). The median age at symptom onset and at diagnosis was 12 years and 19 years, respectively. Seven patients had a family history of Spondyloarthritis. Peripheral arthritis and enthesitis were the most common presenting features at disease onset. Peripheral arthritis was present in 29 (93.5%) and located in the lower limbs in 27/29 (93.1%) patients. Heel enthesitis was present in 26 (83.8%) patients. Axial involvement was present in 27 (87%) patients, dominated by low back pain and sacroiliac pain/ buttock pain in 24 (88.8%) and 22 (81.5%) patients, respectively. Seven (22.5%) patients had anterior uveitis. The ESR and CRP were elevated in 65.5% and 57.1% of cases, respectively. On imaging, sacroiliitis was found in 22 patients. The mean BASDAI was 5.5/10 (77.2% of patients had a high active disease; BASDAI ≥ 4/10). The mean ASDAS-ESR/CRP was 3.8. The mean BASFI was 5.4/10 (80% of patients had high functional disability; BASFI ≥ 4/10). Twenty-seven (87%) patients were treated with methotrexate and non-steroidal anti-inflammatory drugs. After 6 months of treatment, mean BASDAI was 3/10 and mean BASFI was 2.5/10.ConclusionIn our study, HLA-B27-positive ERA was found in our Senegalese cohort mainly in adolescents of the Fula ethnic group. 22 (70.9%) patients developed ankylosing spondylitis at adulthood. The disease was very active at the time of diagnosis with significant functional disability. Treatment was mainly based on methotrexate and NAISDs.

Cortical-sparing chronic traumatic encephalopathy (CSCTE): a distinct subtype of CTE.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease caused by repetitive head impacts (RHI) and pathologically defined as neuronal phosphorylated tau aggregates around small blood vessels and concentrated at sulcal depths. Cross-sectional studies suggest that tau inclusions follow a stereotyped pattern that begins in the neocortex in low stage disease, followed by involvement of the medial temporal lobe and subcortical regions with significant neocortical burden in high stage CTE. Here, we define a subset of brain donors with high stage CTE and with a low overall cortical burden of tau inclusions (mean semiquantitative value ≤1) and classify them as cortical-sparing CTE (CSCTE). Of 620 brain donors with pathologically diagnosed CTE, 66 (11%) met criteria for CSCTE. Compared to typical high stage CTE, those with CSCTE had a similar age at death and years of contact sports participation and were less likely to carry apolipoprotein ε4 (p<0.05). CSCTE had less overall tau pathology severity, but a proportional increase of disease burden in medial temporal lobe and brainstem regions compared to the neocortex (p's<0.001). CSCTE also had lower prevalence of comorbid neurodegenerative disease. Clinically, CSCTE participants were less likely to have dementia (p= 0.023) and had less severe cognitive difficulties (as reported by informants using the Functional Activities Questionnaire (FAQ); p<0.001, meta-cognitional index T score; p=0.002 and Cognitive Difficulties Scale (CDS); p<0.001,) but had an earlier onset age of behavioral (p=0.006) and Parkinsonian motor (p=0.013) symptoms when compared to typical high stage CTE. Other comorbid tauopathies likely contributed in part to these differences: when cases with concurrent Alzheimer dementia or frontal temporal lobar degeneration with tau pathology were excluded, differences were largely retained, but only remained significant for FAQ (p=0.042), meta-cognition index T score (p=0.014) and age of Parkinsonian motor symptom onset (p=0.046). Overall, CSCTE appears to be a distinct subtype of high stage CTE with relatively greater involvement of subcortical and brainstem regions and less severe cognitive symptoms.

Neonatal hemophagocytic lymphohistiocytosis: A meta-analysis of 205 cases.

Neonatal hemophagocytic lymphohistiocytosis (nHLH), defined as HLH that presents in the first month of life, is clinically devastating. There have been few large descriptive studies of nHLH. The objective of this study was to perform a meta-analysis of published cases of nHLH. A comprehensive literature database search was performed. Cases of HLH were eligible for inclusion if clinical analysis was performed at age ≤30days. Up to 70 variables were extracted from each case. A total of 544 studies were assessed for eligibility, and 205 cases of nHLH from 142 articles were included. The median age of symptom onset was day of life 3 (interquartile range [IQR]: 0-11, n=141). Median age at diagnosis was day of life 15 (IQR: 6-27, n=87). Causes of HLH included familial HLH (48%, n=99/205), infection (26%, n=53/205), unknown (17%, n=35/205), macrophage activation syndrome/rheumatologic (2.9%, n=4/205), primary immune deficiency (2.0%, n=5/205), inborn errors of metabolism (2.4%, n=5/205), and malignancy (2.0%, n=4/205). Fever was absent in 19% (n=28/147) of all neonates and 39% (n=15/38) of preterm neonates. Bicytopenia was absent in 26% (n=47/183) of patients. Central nervous system (CNS) manifestations were reported in 63% of cases (n=64/102). Liver injury (68%, n=91/134) and/or liver failure (24%, n=32/134) were common. Flow cytometry was performed in 22% (n=45/205) of cases. Many patients (63%, n=121/193) died within the period of reporting. Discernable values for HLH diagnostic criteria were reported between 30% and 83% of the time. Evaluation of nHLH requires rapid testing for a wide range of differential diagnoses. HLH diagnostic criteria such as fever and bicytopenia may not occur as frequently in the neonatal population as in older pediatric populations. Neurologic and hepatic manifestations frequently occur in the neonatal population. Current reports of nHLH suggest a high mortality rate. Future publications containing data on nHLH should improve reporting quality by reporting all clinically relevant data.

Local Ancestry at the Major Histocompatibility Complex Region is Not a Major Contributor to Disease Heterogeneity in a Multiethnic Lupus Cohort.

Systemic lupus erythematosus (SLE) is an autoimmune disease resulting in debilitating clinical manifestations that vary in severity by race and ethnicity with a disproportionate burden in African American, Mestizo, and Asian populations compared with populations of European descent. Differences in global and local genetic ancestry may shed light on the underlying mechanisms contributing to these disparities, including increased prevalence of lupus nephritis, younger age of symptom onset, and presence of autoantibodies. A total of 1,139 European, African American, and Mestizos patients with SLE were genotyped using the Affymetrix LAT1 World array. Global ancestry proportions were estimated using ADMIXTURE, and local ancestry was estimated using RFMIXv2.0. We investigated associations between lupus nephritis, age at onset, and autoantibody status with both global and local ancestry proportions within the Major Histocompatibility Complex region. Our results showed small effect sizes that did not meet the threshold for statistical significance for global or local ancestry proportions in either African American or Mestizo patients with SLE who presented with the clinical manifestations of interest compared with those who did not. These findings suggest that local genetic ancestry within the Major Histocompatibility Complex region is not a major contributor to these SLE manifestations among patients with SLE from admixed populations.

Clinical use of whole exome sequencing in children with developmental delay/intellectual disability

BackgroundIdentifying the underlying etiology of developmental delay/intellectual disability (DD/ID) is challenging but important. The genetic diagnosis of unexplained DD/ID helps in the treatment and prognosis of the disability in patients. In this study, we reported our experience of using whole exome sequencing (WES) of children with unexplained DD/ID. MethodsWe conducted a retrospective analysis of WES results of children under 19 years of age with unexplained DD/ID between January 2020 and December 2021. The demographic data of all patients and variants identified through WES were evaluated. Furthermore, we evaluated the clinical characteristics that influenced the identification of genetic causes. ResultsForty-one patients with DD/ID were included, of whom 21 (51.2 %) were male. The average age at symptom onset was 1.6 ± 1.3 years, and the duration from symptom onset to diagnosis was 3.1 ± 3.7 years. Hypotonia was the most common symptom (17 patients, 41.5 %), and epilepsy was confirmed in 10 patients (24.4 %). Twenty-two pathogenic/likely pathogenic variants were identified in 20 patients, and three variants of uncertain significance were identified in three patients. Family-based trio Sanger sequencing for candidate variants of 12 families was conducted; 10 variants were de novo, one variant paternally inherited, and two variants compound heterozygous. The diagnostic yield of WES for DD/ID was 48.8 % and was significantly high in patients with an early onset of DD/ID and facial dysmorphism. In contrast, patients with autism spectrum disorder (ASD) were more likely to have negative WES results compared with others without ASD. ConclusionThe diagnostic yield of WES was 48.8 %. We conclude that patients’ characteristics, such as dysmorphic features and the age of symptom onset, can predict the likelihood that WES will identify a causal variant of a phenotype.

Neuropsychological performance and disease burden in individuals at risk of developing Huntington disease

IntroductionHuntington disease (HD) is a hereditary neurodegenerative disorder. Thanks to predictive diagnosis, incipient clinical characteristics have been described in the prodromal phase. ObjectiveTo compare performance in cognitive tasks of carriers (HDC) and non-carriers (non-HDC) of the huntingtin gene and to analyse the variability in performance as a function of disease burden and proximity to the manifest stage (age of symptom onset). MethodA sample of 146 participants in a predictive diagnosis of HD programme were divided into the HDC (41.1%) and non-HDC groups (58.9%). Mathematical formulae were used to calculate disease burden and proximity to the manifest stage in the HDC group; these parameters were correlated with neuropsychological performance. ResultsSignificant differences were observed between groups in performance on the Mini–Mental State Examination (MMSE), Stroop-B, Symbol-Digit Modalities Test (SDMT), and phonological fluency. In the HDC group, correlations were observed between disease burden and performance on the MMSE, Stroop-B, and SDMT. The group of patients close to the manifest stage scored lowest on the MMSE, Stroop-B, Stroop-C, SDMT, and semantic verbal fluency. According to the multivariate analysis of covariance, the MMSE effect shows statistically significant differences in disease burden and proximity to onset of symptoms. ConclusionsMembers of the HDC group close to the manifest phase performed more poorly on tests assessing information processing speed and attention. Prefrontal cognitive dysfunction appears early, several years before the motor diagnosis of HD.

Early childhood-onset rumination syndrome is clinically distinct from adolescent-onset rumination syndrome.

Rumination syndrome (RS) beginning in early childhood or infancy is understudied and challenging to treat. Our objective is to compare the characteristics and outcomes of early-onset (EO) and adolescent-onset (AO) patients with RS. We conducted an ambidirectional cohort study of children diagnosed with RS at our institution. Patients were included in two groups: EO (RS symptom onset ≤5 years and diagnosis ≤12 years) and AO (onset >12 years). Patient characteristics, severity, and outcomes were compared between the groups. We included 49 EO and 52 AO RS patients. The median ages of symptom onset and diagnosis in EO were 3.5 and 6 years, respectively; AO, 14.5 and 15 years. EO RS had a slight male predominance while AO was predominantly female (p = 0.016). EO patients were more likely to have developmental delay (24% vs. 8%, p = 0.029) and less likely to have depression (0% vs. 23%, p < 0.001) or anxiety (14% vs. 40%, p = 0.004). At baseline, EO RS was less severe than AO RS: EO RS had greater regurgitation frequency (p < 0.001) but lower vomiting frequency (p = 0.001), resulting in less meal skipping (p < 0.001), reliance on tube feeding or parenteral nutrition (p < 0.001), and weight loss (p = 0.035). EO RS symptoms improved over time: at follow-up, patients had lower regurgitation (p < 0.001) and vomiting frequency (p < 0.001) compared to baseline. EO RS is clinically distinct from AO RS, with differences in sex distribution, comorbid conditions, and severity of initial presentation. The pathogenesis and natural history of EO RS may be distinct from that of AO RS.

A Retrospective Review of 18 Patients With Childhood-Onset Hereditary Spastic Paraplegia, Nine With Novel Variants

BackgroundHereditary spastic paraplegias (HSPs) are a group of genetically heterogeneous neurodegenerative disorders. Our objective was to determine the clinical and molecular characteristics of patients with genetically confirmed childhood-onset HSPs and to expand the genetic spectrum for some rare subtypes of HSP. MethodsWe reviewed the charts of subjects with genetically confirmed childhood-onset HSP. The age at the disease onset was defined as the point at which the delayed motor milestones were observed. Delayed motor milestones were defined as being unable to hold the head up by four months, sitting unassisted by nine months, and walking independently by 17 months. If there were no delayed motor milestones, age at disease onset was determined by leg stiffness, frequent falls, or unsteady gait. Genetic testing was performed based on delayed motor milestones, progressive leg spasticity, and gait difficulty. The variant classification was determined based on the American College of Medical Genetics standard guidelines for variant interpretation. Variants of uncertain significance (VUS) were considered disease-associated when clinical findings were consistent with the previously described disease phenotypes for pathogenic variants. In addition, in the absence of another pathogenic, likely pathogenic, or VUS variant that could explain the phenotype of our cases, we concluded that the disease is associated with VUS in the HSP-causing gene. Segregation analysis was also performed on the parents of some patients to demonstrate the inheritance model. ResultsThere were a total of 18 patients from 17 families. The median age of symptom onset was 18 months (2 to 84 months). The mean delay between symptom onset and genetic diagnosis was 5.8 years (5 months to 17 years). All patients had gait difficulty caused by progressive leg spasticity and weakness. Independent walking was not achieved at 17 months for 67% of patients (n = 12). In our cohort, there were two subjects each with SPG11, SPG46, and SPG 50 followed by single subject each with SPG3A, SPG4, SPG7, SPG8, SPG30, SPG35, SPG43, SPG44, SPG57, SPG62, infantile-onset ascending spastic paralysis (IAHSP), and spastic paraplegia and psychomotor retardation with or without seizures (SPPRS). Eight novel variants in nine patients were described. Two affected siblings had a novel variant in the GBA2 gene (SPG46), and one subject each had a novel variant in WASHC5 (SPG8), SPG11 (SPG11), KIF1A (SPG30), GJC2 (SPG44), ERLIN1 (SPG62), ALS2 (IAHSP), and HACE1 (SPPRS). Among the novel variants, the variant in the SPG11 was pathogenic and the variants in the KIF1A, GJC2, and HACE1 were likely pathogenic. The variants in the GBA2, ALS2, ERLIN1, and WASHC5 were classified as VUS. ConclusionsThere was a significant delay between symptom onset and genetic diagnosis of HSP. An early diagnosis may be possible by examining patients with delayed motor milestones, progressive spasticity, gait difficulties, and neuromuscular weakness in the context of HSP. Eight novel variants in nine patients were described, clinically similar to the previously described disease phenotype associated with pathogenic variants. This study contributes to expanding the genetic spectrum of some rare subtypes of HSP.