Neurology-Genetics最新文献

Background and objectives: Cerebral white matter hyperintensities (WMHs) on MRI are part of the spectrum of age-related brain vascular injury and are associated with increased risk of stroke and dementia. Genome-wide association studies (GWASs) conducted mostly in populations of European ancestry have identified several genetic loci. Although Hispanic/Latino adults have a greater burden of WMHs than their non-Hispanic White counterparts, they are vastly underrepresented in genetic studies. We sought to characterize the genetic architecture of WMHs in a Hispanic/Latino cohort by investigating the transferability of known WMH genetic loci and by leveraging Hispanic/Latino genetic diversity to map novel loci.

Methods: We conducted genome-wide association and admixture mapping analyses of WMH volume in a sample of 2,159 diverse Hispanic/Latino adults (mean age: 62.4 years; 66% female). We investigated associations at 27 previously identified WMH loci. To identify additional loci, we meta-analyzed our genome-wide association results with those of the largest GWASs published to date.

Results: Accounting for population differences in linkage disequilibrium, we found some evidence of transferability of 20 of the 27 known WMH loci. Owing to power limitations, we could not exclude transferability of the remaining loci. Multiancestry meta-analysis combining our Hispanic/Latino genome-wide association results with those from a GWAS of non-Hispanic White (NHW) and African American (AA) populations identified a novel locus on 12q22 (p = 1.8 × 10^-8) near NTN4 and tagged by rs10859915, which was previously associated with blood pressure and is an expression quantitative trait locus of AMDHD1. Admixture mapping identified a novel locus on 14q13.2, where higher counts of European ancestry at that locus were significantly associated with higher WMH volume (p = 4.9 x 10^-7). This locus spans an 800-kilobase region containing RALGAPA1, with known impact on neuronal function and brain development. Aggregated rare coding variants in this gene were associated with WMHs in a previous analysis of 20,719 stroke-free and dementia-free adults.

Discussion: Our study suggests that WMH loci previously identified in NHW and AA individuals are relevant to Hispanic/Latino adults. It demonstrates the power of the diverse Hispanic/Latino population to fine-map known genetic loci and discover novel ones, augmenting our understanding of the genetic architecture of cerebral WMHs.

Background and objectives: Charcot-Marie-Tooth (CMT) disease comprises a group of inherited peripheral neuropathies caused by pathogenic variants in various genes, including ATP1A1. This gene encodes the ubiquitous α1 subunit of the sodium pump that generates the Na⁺ and K⁺ gradients that are essential for neuronal survival and excitability. We present the clinical cases of 2 unrelated patients with the same ATP1A1 variant causing dominant intermediate CMT disease and the functional characterization of the variant in the heterologous expression system.

Methods: The patients were evaluated by clinical EMG and by whole-exome sequencing. The function of sodium pump variants was studied with voltage clamp electrophysiology or using ouabain survival curves after heterologous expression in Xenopus oocytes or HEK293 cells, respectively. Localization of the variants was evaluated by fluorescence microscopy of HEK293 cells expressing fluorescently tagged sodium pumps.

Results: We describe the cases of 2 unrelated patients who presented in their second decade with a length-dependent and slowly progressive intermediate neuropathy with both axonal and demyelinating features. Whole-exome sequencing identified a de novo c.1645G>A heterozygous variant in ATP1A1 (p.Gly549Arg) in both patients. The pathogenic nature of the variant was tested through a detailed evaluation of the functional consequences of the Gly549Arg substitution using 2 heterologous expression systems and functional assays that included survival curves of transfected cells and electrophysiology. Patch clamp and 2-electrode voltage clamp electrophysiology experiments showed that the Gly549Arg variant reduced NKA function (≥50%), mainly due to a lower NKA density at the plasma membrane and, to a lesser extent, due to a reduced apparent affinity for intracellular Na⁺. The reduced plasma membrane density was also observed in HEK293 cells simultaneously expressing wildtype and Gly549Arg variants, marked with fluorescent proteins of different colors, suggesting that the mutant may be partially retained in intracellular membranes. No clear dominant-negative effects were identified in these experimental systems.

Discussion: Our results demonstrate that the pathogenic nature of this variant causes considerable loss of function due to diminished plasma membrane localization and kinetic impairments on the enzyme, without obvious dominant-negative effects. Our findings are similar to those previously reported for other CMT disease-causing ATP1A1 variants.

This report presents key insights from the 2022 annual conference held in Edinburgh, commemorating the 10th anniversary of the discovery of ATP1A3 variants in alternating hemiplegia of childhood (AHC). This milestone event marked a decade of rapid advancements in research and clinical understanding, bringing together international experts and those with lived experience to reflect on progress, identify ongoing challenges, and shape the future of ATP1A3-related disease research. Over the past 10 years, our knowledge of ATP1A3-related diseases has expanded significantly, revealing a broader clinical spectrum, complex genotype-phenotype correlations, and novel pathophysiologic mechanisms. This symposium provided new data on cardiac and respiratory involvement in AHC, the impact of Na⁺, K⁺-ATPase dysfunction on neurodevelopment, and the evolving understanding of progressive disease trajectories. The conference also showcased emerging therapeutic strategies, including gene therapy, antisense oligonucleotides, and small-molecule interventions. This article synthesizes these discussions, offering a comprehensive overview of a decade of progress while highlighting the urgent need for continued collaboration. By integrating research, clinical expertise, and lived experience advocacy, the ATP1A3 community is paving the way for improved diagnosis, enhanced care, and the development of targeted treatments for these ultra-rare conditions.

Background and objectives: Dystrophinopathies are X-linked recessive diseases caused by pathogenic variants in the Duchenne muscular dystrophy (DMD) gene. Some women carrying a single DMD pathogenic variant manifest variable levels of symptomatology. Those who manifest severe and early-onset symptoms are considered to be affected by dystrophinopathy rather than carriers. The aim of this study was to characterize and compare muscle structure between female DMD carriers who were asymptomatic at the time of the study and female control participants using whole-body MRI (WB-MRI) and correlate the findings with clinical and genetic data.

Methods: We conducted a cross-sectional observational study comparing a group of female carriers of DMD pathogenic variants and a group of healthy noncarrier controls. The first group included obligate and genetically confirmed DMD female carriers, not classified as having dystrophinopathy. Women in the healthy group had no family history of DMD or other muscular dystrophies. All individuals underwent WB-MRI, which was evaluated using qualitative grading scales to assess muscle edema, trophism, and fatty infiltration. Neurologic examinations, serum creatine kinase measurement, DMD genetic screening, and X-chromosome inactivation studies were performed on the DMD carriers.

Results: The study included 29 DMD female carriers and 30 healthy noncarrier controls. All DMD carriers showed signs of muscle involvement on MRI, revealing a larger proportion of skeletal muscle involvement in carriers than in controls (85% vs 27% of 48 examined muscles/group of muscles, p < 0.001). Edema, fatty infiltration, and atrophy were more common in DMD carriers (62.5% vs 8%; 81% vs 35%; and 81% vs 25%, respectively, all p < 0.001), particularly in muscles of the calves, thighs, and pelvic region. The most frequently affected muscles were gastrocnemius, gluteus maximus, and soleus. No correlations were found between the MRI results and the clinical and genetic data.

Discussion: Our findings indicate that DMD female carriers who are asymptomatic at the time of our study may be at risk of developing muscle symptoms at a future time. Multidisciplinary surveillance of DMD female carriers will facilitate early detection and management of complications.

Objectives: This report details a patient with a GRIA1 pathogenic variant presenting with intellectual disability (ID) and epilepsy. We describe clinical features, genetic findings, a personalized treatment approach, and a literature review of GRIA1-related disorders.

Methods: We describe clinical presentation, neuropsychological assessment, and genetic analysis. We conducted a literature review of published GRIA1-related disorders using PubMed, Simons Foundation Autism Research Initiative (SFARI) Gene, and ClinVar databases.

Results: An 8-year-old girl with ID, focal-to-bilateral tonic clonic seizure since age 5, and later atypical absences was diagnosed with a novel, de novo GRIA1 c.2530T > G, p.Leu844Val pathogenic variant. After genetic diagnosis, she was titrated to 4 mg of perampanel, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, which led to seizure control and improvements in cognition and school performance. Literature review identified 31 patients carrying 15 different pathogenic variants. The c.1906G > A, p.Ala636Thr variant was recurrent in 17 individuals. Intellectual disability and autism spectrum disorder were common while epilepsy was reported in approximately a quarter of patients. Two patients with gain-of-function missense variants in GRIA1 and GRIA2, successfully treated with perampanel, have also been reported.

Discussion: This case emphasizes the role of targeted interventions in the management of rare genetic disorders and underscores the potential of precision medicine in addressing GRIA1-related symptoms.

Background and objectives: p.Val142Ile (p.V142I) is one of the most common pathogenic transthyretin (TTR) variants typically presents as transthyretin amyloid cardiomyopathy (ATTRv-CM), although frequent concurrent peripheral nerve involvement has been reported (94%). We aimed to characterize the polyneuropathy in p.V142I ATTR amyloidosis (ATTRv-PN) from the UK amyloidosis cohort.

Methods: We performed a retrospective cohort study of all confirmed p.V142I Variant Transthyretin Amyloidosis (ATTRv) individuals in the National Hospital for Neurology and Neurosurgery Inherited Neuropathy Clinic between January 2019 and October 2024. Because presence of ATTRv-PN was required to access disease-modifying therapy for amyloidosis during this time, all individuals with p.V142I ATTRv were evaluated for neuropathy, providing an unselected cohort.

Results: We identified 52 individuals with p.V142I ATTRv among whom the clinical presentation was cardiac in 47 (90%) and neuropathic in 5 (10%). Age at diagnosis was 71.3 ± 12.2 years. Twenty of the 52 individuals (38%) had symptoms suggestive of neuropathy with an average duration of symptoms of 4.9 ± 3.5 years 20/52 (38%) had signs suggestive of neuropathy with average Neuropathy Impairment Score being 9.0 ± 10.5. After investigations, 21/52 (40%) individuals had clinical features, neurophysiology, and/or skin biopsies consistent with ATTRv-PN (8 large-fiber/13 small-fiber). Six of the 52 individuals (12%) had neuropathies because of alternative etiologies (e.g., diabetes).

Discussion: Real-world experience from the UK national cohort of p.V142I ATTRv indicates that peripheral neuropathy is of a mild severity and less frequent than previously reported.

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Objectives: Typical MRI findings of vanishing white matter disease (VWM) include diffuse white matter lesions with cystic degeneration. However, mild cases may lack these typical features, posing diagnostic challenges.

Methods: We describe 2 of 3 individuals carrying the homozygous c.254T >A variant in EIF2B2 identified at our hospital, excluding 1 previously reported case.¹ Genetic analyses were performed using whole-genome sequence or whole-exome sequence analysis, and detected variants were confirmed by direct nucleotide sequence analysis. Brain MRI findings and clinical features were reviewed for the 2 individuals along with other cases in the literature with the same variant.

Results: A 69-year-old woman presented with recurrent transient dizziness and secondary amenorrhea. MRI of the brain revealed small T2-hyperintense lesions confined to the subcortical white matter with hyperintensities on diffusion-weighted images and mildly elevated apparent diffusion coefficient values. A 28-year-old woman presented with transient dizziness and secondary amenorrhea. MRI of the brain showed mild T2-hyperintense lesions in the cerebral white matter with frontal predominance.

Discussion: This report highlights the clinically mild cases of VWM with subtle abnormalities on brain MRI who had the homozygous c.254T >A in EIF2B2, further expanding the clinical spectrum of VWM and underscoring the importance of genetic assessments in the diagnosis of individuals with mild clinical and MRI findings.

Background and objectives: Limb-girdle muscular dystrophy R2 (LGMDR2) is characterized by progressive muscle weakness usually leading to severe disability. The rate of progression and disease severity is variable among patients, although factors influencing this variability are not completely understood. The Dysferlinopathy Clinical Outcome Study is a natural history study that followed patients with LGMDR2 for 3 consecutive years using functional outcome measures and skeletal muscle MRI.The aim of our study was to develop statistical models able to describe fat fraction (FF) progression of the lower limbs in patients with LGMDR2 using clinical and radiologic variables to better understand which factors influence disease progression and improve the design of future clinical trials.

Methods: We used linear-mixed modeling to analyze changes in FF over time according to patients' age. We calculated the average FF trajectory for each muscle of the lower limbs. We built 2 multivariate models for each segment adding other clinical factors and using likelihood ratio test and residuals' analysis to determine whether they better fitted observed FF values.

Results: Muscles that participated in the same joint movement progressed similarly over time. FF was expected to be higher the older patients were and the earlier the age at symptom onset. Women had absolute FF values 8.8% higher than men in the lower leg. No differences in FF trajectory were seen based on ethnic groups (White, Asian, Black, or Hispanic), genetic variants, or residual dysferlin expression. Although multivariate models showed a better global fit to the data, there was no improvement in representing individual patient variability.

Discussion: In conclusion, this study provides a better understanding of skeletal muscle fat replacement progression in the lower limb muscles of patients with LGMDR2, highlighting the influence of age at symptom onset, sex, and baseline motor function, which should be considered in the design and analysis of clinical trials. Although complex models improved the overall data fit, they did not improve the accuracy in identifying changes at a patient level, underlying the need for further research and validation and the fact that other variables we have not measured are probably influencing progression.