Adult-onset Disorder Research Articles

Parental mental disorders and ages of onset of severe mental disorders in offspring: A nationwide family-link study

ObjectiveThe current study used a retrospective study design to investigate the association between age of onset of severe mental disorders in offspring and the likelihood of diagnoses of parental mental disorder. MethodWe enrolled 212,333 people with severe mental disorder, including schizophrenia, bipolar disorder (BD), or major depressive disorder (MDD) and 2,123,329 controls matched for age, sex, and demographics from the National Health Insurance Database of Taiwan. Poisson regression models were used to examine the likelihood of diagnoses of five mental disorders in their parents compared to the parents of the controls (reported as odds ratio (OR) with 95% confidence interval), including schizophrenia, BD, MDD, alcohol use disorder (AUD), and substance use disorder (SUD). The study cohort was classified into child-onset, adolescent-onset, and adult-onset groups according to the onset of severe mental disorders in the offspring. ResultThe parents of people with child-, adolescent-, and adult-onset schizophrenia (OR range: 1.73–9.08, all p < 0.05) or BD (OR range: 1.97–8.17, all p < 0.05) were more likely to be diagnosed with schizophrenia, BD, MDD, AUD, and substance use disorder (SUD) than controls except for AUD in the child-onset group. However, the parents of people with child-, adolescent-, and adult-onset depressive disorder were more likely to be diagnosed with schizophrenia, BD, MDD, AUD, and SUD (OR range: 1.82–4.76, all p < 0.05) than controls. Sub-analyses stratified by sex showed different patterns of associations between parental mental disorders and offspring mental disorders. ConclusionNo matter when the severe mental disorder of the offsprings occurred at different onset stages, their parents had a higher likelihood of being diagnosed with schizophrenia, BD, MDD, AUD, and SUD.

VEXAS syndrome: an adult-onset autoinflammatory disorder with underlying somatic mutation.

VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) was first described in 2020, where in a cohort of adults with unexplained fever or inflammation, systematic genetic testing was performed and 25 men with a median age of 64 years and somatic mutations in the UBA1 gene were identified. In the current review, we aim to discuss the relevant literature from January 2023 until July 2024 to give new insights into the pathophysiology, epidemiology, diagnosis and treatment of VEXAS. VEXAS affects 1 : 4269 in men over the age of 50. Janus-Kinase-inhibitors (JAKi) and IL-6-inhibitors are more effective immunosuppressants against hyperinflammation. Ruxolitinib is more effective than other JAKi. Azacitidine induces remission in many patients, but only few MDS-associated patients were treated. Allogeneic stem cell transplantation is feasible for selected cases. Infections are the major cause of death. Prognosis is still poor with a 5-year mortality rate of 18-40%. In the current review, we discuss the novelties for VEXAS, including pathogenic pathways, epidemiological data, diagnostic criteria and algorithms, treatment options and complications. We hope that this review may improve rheumatologists understanding of VEXAS. We strongly recommend enrolling VEXAS patients in registries and clinical trials, to improve prognosis of VEXAS in the future.

Genetic counseling development and milestone in Oman

Genetic counseling as an emerging profession has seen an expansion around the world. In the Sultanate of Oman, the profession has developed with the establishment of clinical and biochemical genetic services in 2010 and genetic counseling services in 2011. Currently, three main genetic counseling teams serve the country through qualified genetic counselors who completed internationally-recognized MSc program. The genetic counselors are working in governmental clinical genetic units and play vital roles in enhancing the quality of genetic services dealing with pediatric and adult-onset disorders. The impact of the service is reflected in the escalated demand for preventative measures such as alternative reproductive options, premarital genetic counseling and testing as well as predictive counseling and testing. Despite the limited resources and absence of a licensing body, the genetic counseling profession in Oman is progressing. This special report describes the development of genetic counseling in Oman and the milestones reached. It details the areas of service, scope of practice, and the unique social and cultural nuances inherent to genetic counseling in Oman.

Advancements in the Study of Clinical Features and Molecular Functions in Heterogeneous TAF1-associated Clinical Phenotypes

Purpose of review: TATA-binding protein (TBP)-associated factor 1 (TAF1) encodes the largest component of the transcription factor IID (TFIID) complex, which binds to core promoters and serves as a scaffold for assembly of the RNA polymerase II transcription complex. Variants in TAF1 are associated with X-linked dystonia-parkinsonism (XDP) and X-linked syndromic mental retardation-33 (MRXS33). This review provides a concise summary of the genetic and clinicopathological features of TAF1 variants related to phenotype. Recent findings: XDP is an adult-onset X-linked progressive neurodegenerative disorder presenting dystonia and parkinsonism and caused by a SINE-VNTR-Alu (SVA)-type retrotransposon within TAF1. TAF1/MRXS33 intellectual disability syndrome is characterized by global developmental delay, intellectual disability, facial dysmorphia, generalized hypotonia, and neurological abnormalities due to the missense variants in TAF1. Various symptoms of TAF1 missense mutations may be related to mutations in different functional regions of the protein. The clinical manifestations of XDP and MRXS33, both caused by variants of TAF1, present prominent heterogeneity, which could be influenced by whether the TAF1 mutation is located in the coding region, the time when TAF1 expression decreases, and the effect on downstream gene expression. Summary: TAF1 is linked to many different phenotypes because of its variable regulation of coding and noncoding elements, which makes its mechanistic roles in disease challenging to interpret. However, it is important to note that strategies to correct TAF1 splicing could provide therapeutic benefits in different diseases.

The roles of TAF1 in neuroscience and beyond.

The transcriptional machinery is essential for gene expression and regulation; dysregulation of transcription can result in a range of pathologies, including neurodegeneration, cancer, developmental disorders and cardiovascular disease. A key component of RNA polymerase II-mediated transcription is the basal transcription factor IID, which is formed of the TATA box-binding protein (TBP) and 14 TBP-associated factors (TAFs), the largest of which is the TAF1 protein, encoded on the X chromosome (Xq13.1). TAF1 is dysregulated in X-linked dystonia-parkinsonism and congenital mutations in the gene are causative for neurodevelopmental phenotypes; TAF1 dysfunction is also associated with cardiac anomalies and cancer. However, how TAF1 contributes to pathology is unclear. Here, we highlight the key aspects of the TAF1 gene and protein function that may link transcriptional regulation with disorders of development, growth and adult-onset disorders of motor impairment. We highlight the need to experimentally investigate the full range of TAF1 messenger RNA variants and protein isoforms in human and mouse to aid our understanding of TAF1 biology. Furthermore, the X-linked nature of TAF1-related diseases adds complexity to understanding phenotypes. Overall, we shed light on the aspects of TAF1 biology that may contribute to disease and areas that could be addressed for future research and targeted therapeutics.

Imaging Markers of Multiple System Atrophy and Their Association With Disease Severity: A Cross-Sectional Study.

Background Multiple system atrophy (MSA) is a rare, adult-onset neurodegenerative disorder marked by autonomic failure, parkinsonism, and cerebellar ataxia, with subtypes classified as parkinsonian (MSA-P), cerebellar (MSA-C), and autonomic (MSA-A). This study aims to identify MRI biomarkers for MSA and their correlation with disease severity. Methodology A total of 30 patients with probable MSA (20 MSA-C, 10 MSA-P) aged 45-65 years were studied. Motor and non-motor symptoms were assessed using the Unified Multiple System Atrophy Rating Scale (UMSARS), and all patients underwent 3T MRI brain imaging. Data analysis was performed using SPSS version 22 (IBM Corp., Armonk, NY, USA) with Spearman's correlation for clinical-imaging correlations. Results The mean age of the study population was 54.43 years, with a male predominance (56.7%). The most common symptoms included gait ataxia (43.3%) and urinary dysfunction (96.7%), with orthostatic symptoms in 33.3%. Moderate disease severity was observed, with mean UMSARS scores of 15.9 (Part 1) and 16 (Part 2), showing no significant subtype differences. MRI revealed abnormalities in all patients, predominantly cerebellar atrophy (90%). The "hot cross bun" (HCB) sign was seen in 75% of MSA-C patients, but none of MSA-P patients showed the same. The HCB sign was significantly correlated with severity in MSA-C (USMSARS-4). Putaminal signs were less frequent and slightly more prevalent in MSA-P, without significant clinical-imaging correlation. Conclusions This study reinforces the critical role of MRI biomarkers in the diagnosis of MSA patients. Notably, the HCB sign exhibited a significant association with clinical severity in MSA-C patients, while such correlation was absent in MSA-P cases.

Genetic profiles of multiple system atrophy revealed by exome sequencing, long-read sequencing and spinocerebellar ataxia repeat expansion analysis.

Multiple system atrophy (MSA) is a progressive, adult-onset neurodegenerative disorder clinically characterized by combinations of autonomic failure, parkinsonism, cerebellar ataxia and pyramidal signs. Although a few genetic factors have been reported to contribute to the disease, its mutational profiles have not been systemically studied. To address the genetic profiles of clinically diagnosed MSA patients, exome sequencing and triplet repeat detection was conducted in 205 MSA patients, including one familial case. The pathogenicity of variants was determined according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. In the familial patient, a novel heterozygous COQ2 pathogenic variant (p.Ala351Thr) was identified in the MSA pedigree. In the sporadic patients, 29 pathogenic variants were revealed in 21 genes, and the PARK7 p.Ala104Thr variant was significantly associated with MSA (p = 0.0018). Moreover, burden tests demonstrated that the pathogenic variants were enriched in cerebellar ataxia-related genes in patients. Furthermore, repeat expansion analyses revealed that two patients carried the pathogenic CAG repeat expansion in the CACNA1A gene (SCA6), one patient carried the (ACAGG)exp/(ACAGG)exp expansion in RFC1 and one carried the GAA-pure expansion in FGF14 gene. In conclusion, a novel COQ2 pathogenic variant was identified in a familial MSA patient, and repeat expansions in CACNA1A, RFC1 and FGF14 gene were detected in four sporadic patients. Moreover, a PARK7 variant and the burden of pathogenic variants in cerebellar ataxia-related genes were associated with MSA.

Phase Separation of SARS-CoV-2 Nucleocapsid Protein with TDP-43 Is Dependent on C-Terminus Domains.

The SARS-CoV-2 nucleocapsid protein (N protein) is critical in viral replication by undergoing liquid-liquid phase separation to seed the formation of a ribonucleoprotein (RNP) complex to drive viral genomic RNA (gRNA) translation and in suppressing both stress granules and processing bodies, which is postulated to increase uncoated gRNA availability. The N protein can also form biomolecular condensates with a broad range of host endogenous proteins including RNA binding proteins (RBPs). Amongst these RBPs are proteins that are associated with pathological, neuronal, and glial cytoplasmic inclusions across several adult-onset neurodegenerative disorders, including TAR DNA binding protein 43 kDa (TDP-43) which forms pathological inclusions in over 95% of amyotrophic lateral sclerosis cases. In this study, we demonstrate that the N protein can form biomolecular condensates with TDP-43 and that this is dependent on the N protein C-terminus domain (N-CTD) and the intrinsically disordered C-terminus domain of TDP-43. This process is markedly accelerated in the presence of RNA. In silico modeling suggests that the biomolecular condensate that forms in the presence of RNA is composed of an N protein quadriplex in which the intrinsically disordered TDP-43 C terminus domain is incorporated.

Variable clinical phenotypes of alpha-methylacyl-CoA racemase deficiency: Report of four cases and review of the literature.

Alpha-methylacyl-CoA-racemase (AMACR) deficiency (MIM#604489) is a peroxisomal disorder resulting in the accumulation of pristanic acid, dihydroxycholestanoic acid (DHCA), and trihydroxycholestanoic acid (THCA), with variable clinical features and age of onset from infancy to late adulthood. The purpose of this report is to define clinical variations and follow-up data in AMACR deficiency emphasizing treatment with a review of cases reported in the literature. Here, four patients, from two families, diagnosed with AMACR deficiency and showing phenotypic heterogeneity are presented. A 10-month-old-female presented with coagulopathy, hepatic dysfunction, and elevated pristanic acid, DHCA, and THCA levels. Genetic testing confirmed a homozygous variant c.596G>A in the AMACR gene. Her brother who had macrovesicular hepatosteatosis and elevated pristanic acid levels was diagnosed with family screening. The third patient presented with rhabdomyolysis following a strenuous exercise without any other complaint. Homozygous novel c.1006G>A variant was found on the AMACR gene. His asymptomatic sister carrying the same variant also had elevated pristanic acid levels. They had normal neuropsychologic evaluation. Dietary treatment with low phytanic and pristanic acid content was recommended to the patients but all showed poor compliance. The sibling pairs were followed for periods of 11 and 7 years, respectively. AMACR deficiency is usually described as an adult-onset disorder with neuropsychological problems. The characterization of natural history and new clinical phenotypes may support earlier diagnosis and treatment.

Genetic constraint at single amino acid resolution in protein domains improves missense variant prioritisation and gene discovery

BackgroundOne of the major hurdles in clinical genetics is interpreting the clinical consequences associated with germline missense variants in humans. Recent significant advances have leveraged natural variation observed in large-scale human populations to uncover genes or genomic regions that show a depletion of natural variation, indicative of selection pressure. We refer to this as “genetic constraint”. Although existing genetic constraint metrics have been demonstrated to be successful in prioritising genes or genomic regions associated with diseases, their spatial resolution is limited in distinguishing pathogenic variants from benign variants within genes.MethodsWe aim to identify missense variants that are significantly depleted in the general human population. Given the size of currently available human populations with exome or genome sequencing data, it is not possible to directly detect depletion of individual missense variants, since the average expected number of observations of a variant at most positions is less than one. We instead focus on protein domains, grouping homologous variants with similar functional impacts to examine the depletion of natural variations within these comparable sets. To accomplish this, we develop the Homologous Missense Constraint (HMC) score. We utilise the Genome Aggregation Database (gnomAD) 125 K exome sequencing data and evaluate genetic constraint at quasi amino-acid resolution by combining signals across protein homologues.ResultsWe identify one million possible missense variants under strong negative selection within protein domains. Though our approach annotates only protein domains, it nonetheless allows us to assess 22% of the exome confidently. It precisely distinguishes pathogenic variants from benign variants for both early-onset and adult-onset disorders. It outperforms existing constraint metrics and pathogenicity meta-predictors in prioritising de novo mutations from probands with developmental disorders (DD). It is also methodologically independent of these, adding power to predict variant pathogenicity when used in combination. We demonstrate utility for gene discovery by identifying seven genes newly significantly associated with DD that could act through an altered-function mechanism.ConclusionsGrouping variants of comparable functional impacts is effective in evaluating their genetic constraint. HMC is a novel and accurate predictor of missense consequence for improved variant interpretation.

Tracking longitudinal thalamic volume changes during early stages of SCA1 and SCA2

PurposeSpinocerebellar ataxia SCA1 and SCA2 are adult-onset hereditary disorders, due to triplet CAG expansion in their respective causative genes. The pathophysiology of SCA1 and SCA2 suggests alterations of cerebello-thalamo-cortical pathway and its connections to the basal ganglia. In this framework, thalamic integrity is crucial for shaping efficient whole-brain dynamics and functions. The aims of the study are to identify structural changes in thalamic nuclei in presymptomatic and symptomatic SCA1 and SCA2 patients and to assess disease progression within a 1-year interval.Material and methodsA prospective 1-year clinical and MRI assessment was conducted in 27 presymptomatic and 23 clinically manifest mutation carriers for SCA1 and SCA2 expansions. Cross-sectional and longitudinal changes of thalamic nuclei volume were investigated in SCA1 and SCA2 individuals and in healthy participants (n = 20).ResultsBoth SCA1 and SCA2 patients had significant atrophy in the majority of thalamic nuclei, except for the posterior and partly medial nuclei. The 1-year longitudinal evaluation showed a specific pattern of atrophy in ventral and posterior thalamus, detectable even at the presymptomatic stage of the disease.ConclusionFor the first time in vivo, our exploratory study has shown that different thalamic nuclei are involved at different stages of the degenerative process in both SCA1 and SCA2. It is therefore possible that thalamic alterations might significantly contribute to the progression of the disease years before overt clinical manifestations occur.

Pulmonary manifestations of VEXAS syndrome with acute interstitial pneumonia and diffuse alveolar hemorrhage: a case report and literature review

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an emerging adult-onset systemic autoinflammatory disorder affecting multiple organ systems. While lung involvement is common in this syndrome, literature regarding specific patterns is sparse. In this report, we present a case description of a patient with VEXAS syndrome who presented at the emergency department on two separate occasions with acute interstitial pneumonia (AIP) and diffuse alveolar hemorrhage (DAH). A literature review with a comparison of our observed findings to the general findings of VEXAS syndrome, AIP, and DAH is provided. This report underscores the rarity of specific pulmonary manifestations associated with VEXAS syndrome, contributing valuable insight to the limited literature available on this topic.

Shared and unique alterations of large-scale network connectivity in drug-free adolescent-onset and adult-onset major depressive disorder

Differences in clinical manifestations and biological underpinnings between Major Depressive Disorder (MDD) onset during adolescence and adulthood have been posited in previous studies, implying an influential role of age of onset (AOO) in the clinical subtyping and therapeutic approaches to MDD. However, direct comparisons between the two cohorts and their age-matched controls have been lacking in extant investigations. In this investigation, 156 volunteers participated, comprising 46 adolescents with MDD (adolescent-onset group), 35 adults with MDD (adult-onset group), 19 healthy adolescents, and 56 healthy adults. Resting-state functional MRI scans were undergone by all participants. Large-scale network analyses were applied. Subsequently, a 2 × 2 ANOVA was employed to analyze the main effects of diagnosis, age, and their interaction effect on functional connectivity (FC). Furthermore, regression analysis was employed to scrutinize the association between anomalous FC and HAMD sub-scores. Increased FC in visual network (VN), limbic network (LN), VN-dorsal attention network (DAN), VN-LN, and LN-Default Mode (DMN) was found in both adolescent-onset and adult-onset MDD; however, the increased FC in DAN and LN were only found in adult-onset MDD and the decreased FC in DAN was only found in adolescent-onset MDD. Additionally, the relationship between HAMD factor 1 anxiety somatization and altered FC of DAN, VN, and VN-DAN was moderated by AOO. In conclusion, shared and distinctive large-scale network alterations in adolescent-onset and adult-onset MDD patients were suggested by our findings, providing valuable contributions towards refining clinical subtyping and treatment approaches for MDD.

P093 What’s in a name? Misnaming and renaming of Juvenile Idiopathic Arthritis has long-term impacts

Abstract Background/Aims Juvenile Idiopathic Arthritis (JIA) is a heterogenous group of disorders characterised by chronic joint inflammation of unknown aetiology lasting 6+ weeks, with onset before the age of 16. Historically, some patients with JIA have been labelled as having adult-onset disorders such as Rheumatoid Arthritis (RA) in order to facilitate access to medication. Some have also been incorrectly reclassified at age 16 (with their JIA being relabelled as RA) due to lack of understanding by some healthcare professionals in adult clinics that children and young people get arthritis too. Whilst treatments for RA and JIA are broadly similar, important differences in treatment, management, prognosis and extra-articular manifestations remain. This collaborative study between three patient organisations investigated the extent of the issues arising from misnaming and/or renaming of JIA in a UK population. Methods Adults in the UK aged 18+ who had any diagnosis of a musculoskeletal or rheumatic condition (RMD) were invited to complete a voluntary online survey. Surveys were disseminated through webpages, social media and email mailing lists, enabled by the patient organisations Juvenile Arthritis Research, Arthur’s Place and The Wren Project. Respondents provided information about their diagnosis, experiences, and attitudes across a range of themes and topics. Results In total, 532 respondents with any form of arthritis, and/or other rheumatic or musculoskeletal condition completed the survey (64% female; 68% White ethnicity; median age 35.5 years), covering a primary diagnosis of different rheumatic conditions; 185 (35%) had a second or subsequent additional rheumatic disease. Of 169 respondents with a primary diagnosis of JIA and symptom onset prior to age sixteen, 87 (52%) reported that a doctor or healthcare professional has subsequently told them (whilst under adult services) that their condition is now called something other than Juvenile Arthritis once they reached adulthood. In addition, 134 (25%) respondents reported a primary diagnosis of RA; of these 15 (11%) had symptom onset prior to age 16, indicating their diagnosis should have been JIA. Conclusion Given the importance of accurate diagnosis for patients, both for a patient’s sense of identity and for treatment, care and prognosis reasons, the name given to a disease matters. With 11% of patients with a diagnosis of RA having paediatric-onset JIA, and 52% with JIA being incorrectly told their diagnosis has changed post-16, there are important implications for patients and caregivers. Improved awareness and understanding of the importance of correct labelling of RMDs may help reduce confusion and uncertainty and improve access to appropriate care. Disclosure R.P. Beesley: None. R.M. Beesley: None. K. Middleton: None. A. McBride: None. E.M.D. Smith: None. M.W. Beresford: None.

Ultra-high-field 7-Tesla magnetic resonance imaging in fragile X tremor/ataxia syndrome (FXTAS).

Fragile X tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder characterized by premutation expansion of fragile X mental retardation 1 (FMR1) gene. It is a common single-gene cause of tremor, ataxia, and cognitive decline in adults. FXTAS affects the central, peripheral and autonomic nervous systems, leading to a range of neurological symptoms from dementia to dysautonomia. A characteristic imaging feature of FXTAS is symmetric T2 hyperintensity in the deep white matter of the cerebellar hemispheres and middle cerebral peduncle. However, recent studies have reported additional findings on diffusion weighted images (DWI), such as a symmetric high-intensity band-like signal at the cerebral corticomedullary junction. These findings, along with the characteristic cerebellar signal alterations, overlap with imaging findings seen in adult-onset neuronal intranuclear inclusion disease (NIID). Importantly, recent pathology studies have shown that both FXTAS and NIID can manifest intranuclear inclusion bodies, posing a diagnostic challenge and potential for misdiagnosis. We describe a 58-year-old man with FXTAS who received an erroneous diagnosis based on imaging and histopathology results. We emphasize the potential pitfalls in distinguishing NIID from FXTAS and stress the importance of genetic analysis in all cases with suspected NIID and FXTAS for confirmation. Additionally, we present the 7T MRI brain findings of FXTAS.

Stability of Mosaic Divergent Repeat Interruptions in X-Linked Dystonia-Parkinsonism.

X-Linked dystonia-parkinsonism (XDP) is an adult-onset neurodegenerative disorder characterized by rapidly progressive dystonia and parkinsonism. Mosaic Divergent Repeat Interruptions affecting motif Length and Sequence (mDRILS) were recently found within the TAF1 SVA repeat tract and were shown to associate with repeat stability and age at onset in XDP, specifically the AGGG [5'-SINE-VNTR-Alu(AGAGGG)2AGGG(AGAGGG)n] mDRILS. This study aimed to investigate the stability of mDRILS frequencies and stability of (AGAGGG)n repeat length during transmission in parent-offspring pairs. Fifty-six families (n = 130) were investigated for generational transmission of repeat length and mDRILS. The mDRILS stability of 16 individuals was assessed at two sampling points 1 year apart. DNA was sequenced with long-read technologies after long-range polymerase chain reaction amplification of the TAF1 SVA. Repeat number and mDRILS were detected with Noise-Cancelling Repeat Finder (NCRF). When comparing the repeat domain, 51 of 65 children had either contractions or expansions of the repeat length. The AGGG frequency remained stable across generations at 0.074 (IQR: 0.069-0.078) (z = -0.526; P = 0.599). However, the median AGGG frequency in children with an expansion (0.072 [IQR: 0.066-0.076]) was lower compared with children with retention or contraction (0.080 [IQR: 0.073-0.083]) (z = -0.007; P = 0.003). In a logistic regression model, the AGGG frequency predicted the outcome of either expansion or retention/contraction when including repeat number and sex as covariates (β = 80.7; z-score = 2.63; P = 0.0085). The AGGG frequency varied slightly over 1 year (0.070 [IQR: 0.063-0.080] to 0.073 [IQR: 0.069-0.078]). Our results show that a higher AGGG frequency may stabilize repeats across generations. This highlights the importance of further investigating mDRILS as a disease-modifying factor with generational differences. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

VEXAS syndrome: A new mimicker of idiopathic multicentric Castleman disease

IntroductionIdiopathic Multicentric Castleman Disease (iMCD) is a complex and poorly understood pathophysiological entity, which encompasses a variety of conditions and can mimic or be associated with autoimmune/autoinflammatory diseases, making it challenging to diagnose and treat. Vacuoles, Enzyme E1, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome is an adult-onset autoinflammatory disorder associated with hematological abnormalities and caused by acquired somatic mutations in the ubiquitin-like modifier activating enzyme 1 gene (UBA1) which shares several common clinical and biological signs with iMCD. In this article, we report a patient with VEXAS syndrome initially presenting as iMCD, questioning the link between these two entities. Case descriptionWe report here a patient initially presenting as iMCD, proved on lymph node histology, which turns out to have a mutation at the splice acceptor site of exon 3 of UBA1 exhibiting VEXAS syndrome with Castleman-like lymph node. ConclusionThis is only the second case of VEXAS syndrome presenting as iMCD. VEXAS syndrome should therefore be considered in the presence of iMCD suspicion, including in cases of compatible histology.

Oligodendrocytes in amyotrophic lateral sclerosis and frontotemporal dementia: the new players on stage.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal adult-onset neurodegenerative disorders that share clinical, neuropathological and genetic features, which forms part of a multi-system disease spectrum. The pathological process leading to ALS and FTD is the result of the combination of multiple mechanisms that operate within specific populations of neurons and glial cells. The implication of oligodendrocytes has been the subject of a number of studies conducted on patients and related animal models. In this review we summarize our current knowledge on the alterations specific to myelin and the oligodendrocyte lineage occurring in ALS and FTD. We also consider different ways by which specific oligodendroglial alterations influence neurodegeneration and highlight the important role of oligodendrocytes in these two intrinsically associated neurodegenerative diseases.

Abstract 4629: QClampTM Plex VEXAS syndrome UBA1 mutation detection assay: A noval XNA based assay to simultaneously detect eight UBA1 somatic mutations associated with VEXAS syndrome

Abstract VEXAS syndrome (acronym for Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is a monogenic disease discovered in December 2020. It is an adult-onset systemic inflammatory disorder genetically characterized by somatic mutation of the UBA1 gene which encodes the ubiquitin like modifier activating enzyme 1. VEXAS patients have overlapping rheumatologic and hematologic manifestations, including increased risk for myelodysplastic syndrome (MDS). It is critically important to diagnose VEXAS syndrome, but UBA1 mutation test is still not commercially available. The three most frequent mutations of UBA1 gene are p.M41T(122T&amp;gt;C), p.M41V (c.121A&amp;gt;G), and p.M41L (c.121A&amp;gt;C) in codon 41 of exon 3. Other mutations including splice site mutations at exon 3 (c.118-2A&amp;gt;C, c.118-1G&amp;gt;C and c.118- 9_118-2del), p.S56F (c.167C&amp;gt;T) in codon 56 of exon 3, and p.S621C (c.1861A&amp;gt;T) in codon 621 of exon 16 have been reported. Based on XNA technology, we developed a QClampTM Plex platform to detect all the eight mutations in a single reaction with Luminex system. XNA technology enriches mutant target sequence in a PCR reaction by using synthetic DNA analog XNA (xenonucleic acid) to block wild type DNA. With spiking synthetic mutant DNA in GM24385 cell line DNA, we determined that this assay can detect mutations with a detection limit of variant allele frequency (VAF) for M41T at 0.1%, M41V at 0.1%, M41L at 0.25%, c.118-2A&amp;gt;C at 1%, c.118-1G&amp;gt;C at 1%, c.118- 9_118-2del at 1%, S56F at 0.25% and S621C at 1%, respectively, and specificity of 100% for all mutations. We tested saved DNA samples extracted from whole blood previously collected from suspected VEXAS patients and tested at the National Cancer Institute by Sanger sequencing, including 13 positive and 20 negative samples. Our assay detected all corresponding UBA1 mutations in the 13 positive patient samples, and did not detect UBA1 mutation in 18 of the 20 negative patient samples. Two of the 20 negative samples were also tested positive for UBA1 M41T and M41L on our assay, respectively, due to its significantly higher sensitivity than the Sanger sequencing platform, which has a detection limit of 15-20% VAF. Citation Format: Yunqing Ma. QClampTM Plex VEXAS syndrome UBA1 mutation detection assay: A noval XNA based assay to simultaneously detect eight UBA1 somatic mutations associated with VEXAS syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4629.

Multiple system atrophy: an update and emerging directions of biomarkers and clinical trials.

Multiple system atrophy is a rare, debilitating, adult-onset neurodegenerative disorder that manifests clinically as a diverse combination of parkinsonism, cerebellar ataxia, and autonomic dysfunction. It is pathologically characterized by oligodendroglial cytoplasmic inclusions containing abnormally aggregated α-synuclein. According to the updated Movement Disorder Society diagnostic criteria for multiple system atrophy, the diagnosis of clinically established multiple system atrophy requires the manifestation of autonomic dysfunction in combination with poorly levo-dopa responsive parkinsonism and/or cerebellar syndrome. Although symptomatic management of multiple system atrophy can substantially improve quality of life, therapeutic benefits are often limited, ephemeral, and they fail to modify the disease progression and eradicate underlying causes. Consequently, effective breakthrough treatments that target the causes of disease are needed. Numerous preclinical and clinical studies are currently focusing on a set of hallmarks of neurodegenerative diseases to slow or halt the progression of multiple system atrophy: pathological protein aggregation, synaptic dysfunction, aberrant proteostasis, neuronal inflammation, and neuronal cell death. Meanwhile, specific biomarkers and measurements with higher specificity and sensitivity are being developed for the diagnosis of multiple system atrophy, particularly for early detection of the disease. More intriguingly, a growing number of new disease-modifying candidates, which can be used to design multi-targeted, personalized treatment in patients, are being investigated, notwithstanding the failure of most previous attempts.