Distinct Disorders Research Articles

Treatability of the KMT2-Associated Neurodevelopmental Disorders Using Antisense Oligonucleotide-Based Treatments

Neurodevelopmental disorders (NDDs) of genetic origin are a group of early-onset neurological diseases with highly heterogeneous etiology and a symptomatic spectrum that includes intellectual disability, autism spectrum disorder, and learning and language disorders. One group of rare NDDs is associated with dysregulation of the KMT2 protein family. Members of this family share a common methyl transferase function and are involved in the etiology of rare haploinsufficiency disorders. For each of the KMT2 genes, at least one distinct disorder has been reported, yet clinical manifestations often overlap for multiple of these individually very rare disorders. Clinical care is currently focused on the management of symptoms with no targeted treatments available, illustrating a high unmet medical need and the urgency of developing disease-modifying therapeutic strategies. Antisense oligonucleotides (ASOs) are one option to treat some of these rare genetic disorders. ASOs are RNA-based treatments that can be employed to modulate gene expression through various mechanisms. In this work, we discuss the phenotypic features across the KMT2-associated NDDs and which ASO approaches are most suited for the treatment of each associated disorder. We hereby address variant-specific strategies as well as options applicable to larger groups of patients.

Developmental Dyscalculia in Relation to Individual Differences in Mathematical Abilities.

There is still much debate about the exact nature and frequency of developmental dyscalculia, and about how it should be defined. This article examines several key questions in turn: Is developmental dyscalculia a distinct disorder, or should it be seen as the lower end of a continuum-or possibly more than one continuum-of numerical ability? Do individuals with developmental dyscalculia show atypical brain structure or function? Does the study of acquired dyscalculia have anything to teach us about developmental dyscalculia? In studying dyscalculia, should we look less at arithmetical ability as a single entity, and more at separable components of arithmetical ability? How heterogeneous is developmental dyscalculia, and how important is it to study individual profiles? To what extent is developmental dyscalculia influenced by domain-specific versus domain-general abilities? The conclusion is that, though a significant amount has been discovered through existing research, and though this has some important implications for screening and diagnosis of dyscalculia, there is much more research that still needs to be conducted if we are to answer all of these questions fully. In particular, the study of developmental dyscalculia must be more integrated with the study of individual differences in mathematics in the population as a whole.

Association of serum Spp1 levels with disease progression in ALS and SBMA.

In comparison with amyotrophic lateral sclerosis (ALS), the contribution of neuroinflammation in spinobulbar muscular atrophy (SBMA) has been less explored. We investigated the role of neuroinflammation in the pathogenesis of ALS and SBMA by analyzing systemic inflammatory markers and osteopontin (Spp1). This study involved 105 ALS, 77 SBMA, and 55 healthy controls. We measured their systemic inflammatory markers, serum Spp1, and cytokine levels (interferon-γ, interleukin [IL]-1β, IL-6, IL-8, IL-10, tumor necrosis factor-α, and IL-17A), investigated correlations between Spp1 levels and clinical features, and evaluated ALS survival rates according to Spp1 levels. In the ALS group, systemic inflammatory markers were significantly higher than in the control and SBMA groups. Spp1 levels were observed to be higher in ALS patients, but the difference was not statistically significant among the study groups. Cytokine profiles were comparable. In ALS, higher Spp1 levels were correlated with lower ALS Functional Rating Scale-Revised (ALSFRS-R) scores (r = -0.25, p = 0.02) and faster disease progression rate (r = 0.37, p < 0.001). After adjusting for other prognostic indicators, high Spp1 levels were independently associated with shorter survival in ALS patients (hazard ratio 13.65, 95% confidence interval 2.57-72.53, p < 0.01). Neuroinflammation does not appear to be a primary contributor to the pathogenesis of SBMA. Serum Spp1 levels may serve as a reliable biomarker for disease progression and prognosis in ALS. These findings expand our understanding of these two distinct motor neuron disorders and offer a potential biomarker for future studies.

Bipolar disorders and schizophrenia: discrete disorders?

With similarities in heritability, neurobiology and symptomatology, the question has been raised whether schizophrenia and bipolar disorder are truly distinctive disorders or belong to a continuum. This narrative review summarizes common and distinctive findings from genetics, neuroimaging, cognition and clinical course that may help to solve this ethiopathogenetic puzzle. The authors conducted a literature search for papers listed in PubMed and Google Scholar, using the search terms "schizophrenia" and "bipolar disorder" combined with different terms such as "genes", "neuroimaging studies", "phenomenology differences", "cognition", "epidemiology". Articles were considered for inclusion if they were written in English or Spanish, published as full articles, if they compared subjects with schizophrenia and bipolar disorder, or subjects with either disorder with healthy controls, addressing differences between groups. Several findings support the hypothesis that schizophrenia and bipolar disorder are discrete disorders, yet some overlapping of findings exists. The evidence for heritability of both SZ and BD is obvious, as well as the environmental impact on individual manifestations of both disorders. Neuroimaging studies support subtle differences between disorders, it appears to be rather a pattern of irregularities than an unequivocally unique finding distinguishing schizophrenia from bipolar disorder. The cognitive profile displays differences between disorders in certain domains, such as premorbid intellectual functioning and executive functions. Finally, the timing and trajectory of cognitive impairment in both disorders also differs. The question whether SZ and BD belong to a continuum or are separate disorders remains a challenge for further research. Currently, our research tools may be not precise enough to carve out distinctive, unique and undisputable differences between SZ and BD, but current evidence favors separate disorders. Given that differences are subtle, a way to overcome diagnostic uncertainties in the future could be the application of artificial intelligence based on BigData. Despite the detailed search, this article is not a full and complete review of all available studies on the topic. The search and selection of papers was also limited to articles in English and Spanish. Selection of papers and conclusions may be biased by the personal view and clinical experience of the authors.

Comparing changes in eating disorder psychopathology and comorbid symptoms over treatment in anorexia nervosa and atypical anorexia nervosa in a partial hospitalization program.

The objective of this study is to compare treatment trajectories in anorexia nervosa (AN) and atypical AN. Adolescents and adults with AN (n = 319) or atypical AN (n = 67) in a partial hospitalization program (PHP) completed diagnostic interviews and self-report questionnaires measuring eating disorder (ED), depression, and anxiety symptoms throughout treatment. Premorbid weight loss did not differ between diagnoses. Individuals with atypical AN had more comorbid diagnoses, but groups did not differ on specific diagnoses. ED psychopathology and comorbid symptoms of depression/anxiety did not differ at admission between groups nor did rate of change in ED psychopathology and comorbid symptoms of depression/anxiety from admission to 1-month. From admission to discharge, individuals with atypical AN had a faster reduction in ED psychopathology and comorbid symptoms of depression and anxiety (ps < 0.05; rs = 0.01-0.32); however, there were no group differences in ED psychopathology or depression symptoms at discharge (ps>.50; ds = .01-.30). Individuals with atypical AN had lower anxiety at discharge compared to individuals with AN (p = 0.05; d = .4). Length of stay did not differ between groups (p = 0.11; d = .21). Groups had similar ED treatment trajectories, suggesting more similarities than differences. PHP may also be effective for AAN. This study supports previous research that individuals with AN and atypical AN have more similarities than differences. Results from this study indicate that individuals with AN and atypical AN have similar treatment outcomes for both ED psychopathology and depressive symptoms; however, individuals with atypical AN have lower anxiety symptoms at discharge compared to individuals with AN. AN and atypical AN also have more symptom similarity at admission and throughout treatment, which challenges their current designation as distinct disorders.

Mitochondrial dysfunction in Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome: prospect use of antioxidants and mitochondrial nutrients

Fragile X syndrome (FXS) is a genetic disorder characterized by mutation in the FMR1 gene, leading to the absence or reduced levels of fragile X Messenger Ribonucleoprotein 1 (FMRP). This results in neurodevelopmental deficits, including autistic spectrum conditions. On the other hand, Fragile X-associated tremor/ataxia syndrome (FXTAS) is a distinct disorder caused by the premutation in the FMR1 gene. FXTAS is associated with elevated levels of FMR1 mRNA, leading to neurodegenerative manifestations such as tremors and ataxia.Mounting evidence suggests a link between both syndromes and mitochondrial dysfunction (MDF). In this minireview, we critically examine the intricate relationship between FXS, FXTAS, and MDF, focusing on potential therapeutic avenues to counteract or mitigate their adverse effects. Specifically, we explore the role of mitochondrial cofactors and antioxidants, with a particular emphasis on alpha-lipoic acid (ALA), carnitine (CARN) and Coenzyme Q10 (CoQ10). Findings from this review will contribute to a deeper understanding of these disorders and foster novel therapeutic strategies to enhance patient outcomes.

Use of antipsychotic medication, benzodiazepines, and psychiatric hospitalization in cannabis-related versus cannabis-unrelated schizophrenia - a nationwide, register-based cohort study.

Evidence suggests that cannabis may be a causal factor for development of schizophrenia. We aimed to investigate whether use of antipsychotic medication, benzodiazepines, and psychiatric service use differs among patients with schizophrenia depending on whether psychosis was precipitated by a diagnosis of cannabis use disorder (CUD). We utilized the nationwide Danish registries to identify all individuals with an incident diagnosis of schizophrenia from 1995 to 2016. We also collected information on whether first CUD diagnosis preceded schizophrenia and thus defined a group of potentially cannabis-related schizophrenia. We compared the cannabis-related schizophrenia group both with all non-cannabis-related patients with schizophrenia and with non-cannabis-related patients with schizophrenia that were propensity-score matched to cases using a range of potentially confounding variables. We included 35 714 people with incident schizophrenia, including 4116 (11.5%) that were cannabis-related. In the unmatched-comparison analyses, there were no clear differences over time in use of antipsychotics and benzodiazepines related to whether the diagnosis of schizophrenia was cannabis-related. After propensity-score matching, use of antipsychotics and benzodiazepines was significantly lower among cannabis-related cases of schizophrenia. In the unmatched comparison, the cannabis-related group had significantly more days admitted than the non-cannabis-related group. This was markedly attenuated after propensity-score matching. Our findings indicate the importance of considering cannabis-related cases of schizophrenia as a potentially distinct disorder in terms of prognosis. It is unclear, however, if these differences are due to different biological types of schizophrenia being compared or if they rather indicate behavioral differences such as reduced adherence and treatment-seeking.

Divergent risk of SARS-CoV-2 infection, severe COVID-19 and mortality across psychiatric disorders: analysis from electronic health records in Catalonia

IntroductionPeople with psychiatric disorders are particularly vulnerable to SARS-CoV-2 infection and its associated complications. However, current literature show that not all psychiatric disorders are equally vulnerable to COVID-19.ObjectivesThis study aimed to assess whether individuals with distinct psychiatric disorders exhibit different risk of SARS-CoV-2 infection, COVID-19 hospitalization, and mortality.MethodsWe conducted a case-control study using data of electronic health records from Catalonia. Cases included adults with a hospital admission between 2017 and 2019 for non-affective psychosis, bipolar disorder, depressive disorder, stress-related disorders, neurotic/somatoform disorders, and substance misuse. These were matched to patients without a diagnosis by sex, 5-year age band, and living area. Outcomes included SARS-CoV-2 infection, hospitalization, and COVID-19-related death up to December 2021. Logistic regression analysis were employed to test the association between the six groups of psychiatric disorders and COVID-19 outcomes, controlling for age, sex, smoking, being in a nursing home, and physical comorbidities.Results785,378 subjects were included. Preliminary findings showed that patients diagnosed with psychosis and bipolar disorder had lower risk of infection [OR: 0.85 (95% CI: 0.79-0.92), p&lt;0.001; OR: 0.84 (95% CI: 0.76-0.92), p&lt;0.001], whereas individuals with stress-related and neurotic/somatoform disorders had higher risk of infection [OR: 1.08 (95% CI: 1.04-1.14), p&lt;0.001; OR: 1.06 (95% CI: 1.03-1.10), p&lt;0.001]. People with depressive, stress-related, and neurotic/somatoform disorders had lower risk of COVID-19 hospitalization [OR: 0.87 (95% CI: 0.78-0.97), p = 0.01; OR: 0.71 (95% CI: 0.61-0.84), p&lt;0.001; OR: 0.67 (95% CI: 0.60-0.76), p&lt;0.001]. In line with these results, individuals with stress-related disorders also experienced lower mortality [0.49 (95% CI: 0.33-0.70), p&lt;0.001]. Conversely, people with psychosis, bipolar disorder, and substance misuse exhibited higher risk of COVID-19-related death [OR: 2.9 (95% CI: 1.68-3.1), p&lt;0.001; OR: 1.95 (95% CI: 1.30-2.81), p&lt;0.001; OR: 1.82 (95% CI: 1.49-2.20), p&lt;0.001].ConclusionsWe found different risks of SARS-CoV-2 infection, COVID-19 hospitalization, and COVID-19 mortality for psychiatric disorder groups. Differences in vulnerability to COVID-19 among people with psychiatric disorders might be explained by factors such as shared living facilities, physical comorbidities, psychotropic medications, and difficulties in accessing high-intensity medical care. Special attention should be directed towards individuals with psychosis, bipolar disorder, and substance misuse.Disclosure of InterestNone Declared

Coexistence of ankylosing spondylitis and Behçet's disease: Successful treatment with upadacitinib.

Ankylosing spondylitis (AS) and Behçet's disease(BD) are distinct inflammatory disorders, but their coexistence is a rare clinical entity. This case sheds light on managing this complex scenario with Janus kinase (JAK) inhibitors. A 42-year-old woman presented with a decade-long history of lower back pain, nocturnal spinal discomfort, recurrent eye issues, oral and genital ulcers, hearing loss, pus formation in the left eye, and abdominal pain. Multidisciplinary consultations and diagnostic tests confirmed AS (HLA-B27 positivity and sacroiliitis) and BD (HLA-B51). Elevated acute-phase markers were observed. This case fulfills diagnostic criteria for both AS and BD, emphasizing their coexistence. Notably, treatment with upadacitinib exhibited promising efficacy, underscoring its potential as a therapeutic option in patients with contraindications for conventional treatments. Our findings illuminate the intricate management of patients presenting with these two diverse systemic conditions and advocate for further exploration of JAK inhibitors in similar cases.

New knowledge on anti-IgLON5 disease.

Anti-IgLON5 disease is characterized by a distinctive sleep disorder, associated with a heterogeneous spectrum of neurological symptoms. Initial autopsies showed a novel neuronal tauopathy predominantly located in the tegmentum of the brainstem. Recently, new diagnostic red flags, biomarkers predictors of response to immunotherapy, and novel insights into the autoimmune pathogenesis of the disease have been reported. Patients with diagnosis of neurodegenerative dementia, progressive supranuclear palsy (PSP) or with motor-neuron disease (MND)-like syndrome have been reported to have IgLON5 antibodies, which are the hallmark of anti-IgLON5 disease. Second, low levels of neurofilament light chain in serum and cerebrospinal fluid of patients at disease onset could be a predictor of immunotherapy response. Recent neuropathological studies indicate that the neuronal tau deposits occur late in the course of the disease. Moreover, IgLON5 antibodies induce cytoskeletal changes in cultured hippocampal neurons suggesting that the tauopathy could be secondary of the IgLON5 antibody effects. Anti-IgLON5 disease can mimic and should be considered in atypical presentations of MND, neurodegenerative dementia and PSP. Neurofilament light chain levels seem promising biomarker for disease prognosis. Finally, the neuropathological and in vitro experimental studies strengthen the autoimmune hypothesis of the disease.

Pattern glare sensitivity distinguishes subclinical autism and schizotypy

ABSTRACT Introduction Schizophrenia and autism spectrum disorder are distinct neurodevelopmental disorders sharing clinically relevant behaviours. However, early sensory responses show divergent responses. Individuals with schizophrenia typically exhibit cortical hypo-excitability whereas individuals with autism show cortical hyperexcitability. Identifying reliable neurobiological differences between the disorders can diminish misdiagnosis and optimise treatments. Methods The pattern glare test (PGT) is a simple measure of behavioural hyperexcitability. It measures the number of illusions seen in a static horizontal grating. We collected PGT data from non-clinical adults varying in traits of autism and schizophrenia (schizotypy). 576 undergraduate students completed an online survey consisting of the Schizotypal Personality Questionnaire – Brief Revised, the Autism Spectrum Quotient, and the PGT. Results Subclinical autism and schizotypy traits were highly positively correlated. However, only schizotypy scores were significantly predictive of reporting more pattern glare (PG) illusions. When assessing the subcomponents of the schizotypy and autism scores, positive and disorganised schizotypy traits were predictive of reporting more PG illusions. Whereas, subclinical autism factors were not predictive of PG illusions. Conclusions High schizotypy performed the PGT in a manner consistent with behavioural hyperexcitability. The PGT distinguished subclinical autistic traits from schizotypy, suggesting potential clinical application.

Clinical differences between outpatients with and without internet addiction and emotional disorders: a prospective naturalistic outcome study.

as internet use becomes increasingly ingrained in contemporary society, internet addiction (IA) has emerged as a global public health concern. There is ongoing debate regarding whether IA represents a distinct psychological disorder or a secondary manifestation of other existing disorders. This study aimed to examine the pathological relationship between IA and emotional disorders (ED). this study compared pre-treatment characteristics and treatment process of three groups of patients (N=1292) in a naturalistic treatment setting: IA only, ED only, and comorbidity of IA and ED. the IA only group differed from the other groups by reporting the highest levels of life satisfaction, adaptive emotion regulation, as well as risk behavior urges at intake. In addition, the IA only group displayed the lowest level of depressive and anxiety symptoms throughout the treatment. our findings contribute to a better understanding of the discreteness of IA as a potential psychological disorder and inform more effective treatment strategies for IA and its comorbid conditions.

Metabolic profiling of aortic stenosis and hypertrophic cardiomyopathy identifies mechanistic contrasts in substrate utilization.

Aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) are distinct disorders leading to left ventricular hypertrophy (LVH), but whether cardiac metabolism substantially differs between these in humans remains to be elucidated. We undertook an invasive (aortic root, coronary sinus) metabolic profiling in patients with severe AS and HCM in comparison with non-LVH controls to investigate cardiac fuel selection and metabolic remodeling. These patients were assessed under different physiological states (at rest, during stress induced by pacing). The identified changes in the metabolome were further validated by metabolomic and orthogonal transcriptomic analysis, in separately recruited patient cohorts. We identified a highly discriminant metabolomic signature in severe AS in all samples, regardless of sampling site, characterized by striking accumulation of long-chain acylcarnitines, intermediates of fatty acid transport across the inner mitochondrial membrane, and validated this in a separate cohort. Mechanistically, we identify a downregulation in the PPAR-α transcriptional network, including expression of genes regulating fatty acid oxidation (FAO). In silico modeling of β-oxidation demonstrated that flux could be inhibited by both the accumulation of fatty acids as a substrate for mitochondria and the accumulation of medium-chain carnitines which induce competitive inhibition of the acyl-CoA dehydrogenases. We present a comprehensive analysis of changes in the metabolic pathways (transcriptome to metabolome) in severe AS, and its comparison to HCM. Our results demonstrate a progressive impairment of β-oxidation from HCM to AS, particularly for FAO of long-chain fatty acids, and that the PPAR-α signaling network may be a specific metabolic therapeutic target in AS.

Gait Data-Driven Analysis of Parkinson’s Disease Using Machine Learning

INTRODUCTION: Parkinson's disease is a progressive and complex neurological condition that mostly affects coordination and motor control. Parkinson's disease is most commonly associated with its motor symptoms, which include tremors, bradykinesia (slowness of movement), rigidity, and postural instability. OBJECTIVES: Determine any minor alterations in walking patterns that could be early signs of Parkinson's disease. Track the course of Parkinson's disease over time by using gait data. METHODS: In this study, we applied three types of VGRF datasets ("Dual Tasking, RAS, and Treadmill Walking") and developed an ML-based model using six different classifier methods. The datasets were analysed using 16 sensors, of which 8 were applied to each foot and the total pressure of the left and right foot. The aforementioned three distinct gait patterns movement disorders were the sources of the dataset. The gait signals dataset benefited by the participant demographic data. RESULTS: Then, we passed the outcome of applying the model and measuring performance through a cross-validation operator to check the accuracy and decision-making of the five algorithms i) Deep Learning, ii) Neural Networks, iii) Support Vector Machine (SVM), iv) Gradient Boost Tree (GBT), v) Random Forest”. The following findings compare the effectiveness of the various algorithms utilized and the observed PD very well. CONCLUSION: The different ML classifier algorithms demonstrated good detection capability with different accuracy. Our proposed ensemble model is superior to compare with the existing models. Because we can observe the proposed ensemble model result and accuracy better than the other classifier model. The other classifier model’s highest accuracy is 92.08% whereas our ensemble model got 92.31%. So, it has proved that our proposed ensemble model is excellent and robust.

Using Computational Phenotyping to Identify Divergent Strategies for Effort Allocation Across the Psychosis Spectrum.

Disturbances in effort-cost decision-making have been highlighted as a potential transdiagnostic process underpinning negative symptoms in individuals with schizophrenia. However, recent studies using computational phenotyping show that individuals employ a range of strategies to allocate effort, and use of different strategies is associated with unique clinical and cognitive characteristics. Building on prior work in schizophrenia, this study evaluated whether effort allocation strategies differed in individuals with distinct psychotic disorders. We applied computational modeling to effort-cost decision-making data obtained from individuals with psychotic disorders (n = 190) who performed the Effort Expenditure for Rewards Task. The sample included 91 individuals with schizophrenia/schizoaffective disorder, 90 individuals with psychotic bipolar disorder, and 52 controls. Different effort allocation strategies were observed both across and within different disorders. Relative to individuals with psychotic bipolar disorder, a greater proportion of individuals with schizophrenia/schizoaffective disorder did not use reward value or probability information to guide effort allocation. Furthermore, across disorders, different effort allocation strategies were associated with specific clinical and cognitive features. Those who did not use reward value or probability information to guide effort allocation had more severe positive and negative symptoms, and poorer cognitive and community functioning. In contrast, those who only used reward value information showed a trend toward more severe positive symptoms. These findings indicate that similar deficits in effort-cost decision-making may arise from different computational mechanisms across the psychosis spectrum.

Specific photoreceptor cell fate pathways are differentially altered in NR2E3-associated diseases

Mutations in NR2E3, a gene encoding an orphan nuclear transcription factor, cause two retinal dystrophies with a distinct phenotype, but the precise role of NR2E3 in rod and cone transcriptional networks remains unclear. To dissect NR2E3 function, we performed scRNA-seq in the retinas of wildtype and two different Nr2e3 mouse models that show phenotypes similar to patients carrying NR2E3 mutations. Our results reveal that rod and cone populations are not homogeneous and can be separated into different sub-classes. We identify a previously unreported cone pathway that generates hybrid cones co-expressing both cone- and rod-related genes. In mutant retinas, this hybrid cone subpopulation is more abundant and includes a subpopulation of rods transitioning towards a cone cell fate. Hybrid photoreceptors with high misexpression of cone- and rod-related genes are prone to regulated necrosis. Overall, our results shed light on the role of NR2E3 in modulating photoreceptor differentiation towards cone and rod fates and explain how different mutations in NR2E3 lead to distinct visual disorders in humans.

ASXL3-related disorder: Molecular phenotyping and comprehensive review providing insights into disease mechanism.

ASXL3-related disorder, sometimes referred to as Bainbridge-Ropers syndrome, was first identified as a distinct neurodevelopmental disorder by Bainbridge et al. in 2013. Since then, there have been a number of case series and single case reports published worldwide. A comprehensive review of the literature was carried out. Abstracts were screened, relevant literature was analysed, and descriptions of common phenotypic features were quantified. ASXL3 variants were collated and categorised. Common phenotypic features comprised global developmental delay or intellectual disability (97%), feeding problems (76%), hypotonia (88%) and characteristic facial features (93%). The majority of genetic variants were de novo truncating variants in exon 11 or 12 of the ASXL3 gene. Several gaps in our knowledge of this disorder were identified, namely, underlying pathophysiology and disease mechanism, disease contribution of missense variants, relevance of variant location, prevalence and penetrance data. Clinical information is currently limited by patient numbers and lack of longitudinal data, which this review aims to address.

Bulbar-onset amyotrophic lateral sclerosis in a patient with genetically confirmed Huntington’s disease: a case study

BackgroundThe rationale for this paper is a description of a patient from Southeast Europe with genetically confirmed Huntington’s disease (HD), coexisting with sporadic, bulbar-onset amyotrophic lateral sclerosis (ALS). To the best of our knowledge, the total number of reported cases with confirmed coexistence of HD and ALS is less than 20. Thus, it is an extremely rare condition speculated to be in a range from 2 to 6 per billion, and data from this part of the World are completely missing.Case presentationHere we report a 72-year-old female with a family history of HD who had generalized chorea and hyperreflexia. Using the PCR-based test for the detection of the CAG triplet repeat expansion, the presence of HD was confirmed. After several months, our patient had progressively developed dysarthria and dysphagia, followed by spastic quadriparesis, generalized muscle wasting, spontaneous fasciculations and sialorrhea. The diagnosis of definite ALS was established based on the patient’s neurological status, electromyography findings and current El Escorial criteria.ConclusionsOur study emphasizes the need for the recognition of the co-occurrence of clinically distinct and rare genetic disorders, such as HD and ALS. New insights from the studies dealing with these rare topics could significantly contribute to the contest of new gene therapy trials.

Unveiling the Nanocluster Conversion Pathway for Highly Monodisperse InAs Colloidal Quantum Dots.

Colloidal quantum dots (CQDs) have garnered significant attention in nanoscience and technology, with a particular emphasis on achieving high monodispersity in their synthesis. Recent advances in understanding the chemistry of reaction intermediates such as magic-sized nanoclusters (MSC) have paved the way for innovative synthetic strategies. Notably, monodisperse CQDs of various compositions, including indium phosphide, indium arsenide, and cadmium chalcogenide, have been successfully prepared using nanocluster intermediates as single-source precursors. Still, the early stage conversion chemistry of these nanoclusters preceding CQD formation has not been fully unveiled yet. Herein, we report the first-order conversion of amorphous nanoclusters (AMCs) to InAs MSCs prior to the formation of CQDs. We find that MSC, isolated via gel-permeation chromatography, is more stable than purified AMCs, as demonstrated in various chemical and thermolytic reactions. While the surface of InAs AMCs and MSC is similarly bound with carboxylate ligands, detailed structural analyses employing synchrotron X-ray scattering and X-ray absorption spectroscopy unveil subtle distinctions arising from the distinct surface properties and structural disorder characteristics of InAs nanoclusters. We propose that InAs AMCs undergo a surface reduction and structural ordering process, resulting in the formation of an InAs MSC in a thermodynamically local minimum state. Furthermore, we demonstrate that both types of nanoclusters serve as viable precursors, providing a similar monomer supply rate at elevated temperatures of around 300 °C. This study offers invaluable insights into the interplay of structure and chemical stability in binary nanoclusters, enhancing our ability to design these nanoclusters as precursors for highly monodisperse CQDs.

A novel IGHMBP2 variant and clinical diversity in Vietnamese SMARD1 and CMT2S patients.

Pathogenic variants in the IGHMBP2 gene are associated with two distinct autosomal recessive neuromuscular disorders: spinal muscular atrophy with respiratory distress type 1 (SMARD1; OMIM #604320) and Charcot-Marie-Tooth type 2S (CMT2S; OMIM #616155). SMARD1 is a severe and fatal condition characterized by infantile-onset respiratory distress, diaphragmatic palsy, and distal muscular weakness, while CMT2S follows a milder clinical course, with slowly progressive distal muscle weakness and sensory loss, without manifestations of respiratory disorder. Whole-exome sequencing of the IGHMBP2 gene was performed for eight Vietnamese patients with IGHMBP2-related neuromuscular disorders including five patients with SMARD1 and the others with CMT2S. We identified one novel IGHMBP2 variant c.1574T > C (p.Leu525Pro) in a SMARD1 patient. Besides that, two patients shared the same pathogenic variants (c.1235 + 3A > G/c.1334A > C) but presented completely different clinical courses: one with SMARD1 who deceased at 8 months of age, the other with CMT2S was alive at 3 years old without any respiratory distress. This study is the first to report IGHMBP-2-related neuromuscular disorders in Vietnam. A novel IGHMBP2 variant c.1574T > C (p.Leu525Pro) expressing SMARD1 phenotype was detected. The presence of three patients with the same genotype but distinct clinical outcomes suggested the interaction of variants and other factors including relating modified genes in the mechanism of various phenotypes.