A new era of integration of genetics and neurology.

Spinal muscular atrophy: history and current treatment landscape

In recent years, pediatric neurology has witnessed significant advances in the development of disease-modifying therapies, with spinal muscular atrophy (SMA) emerging as one of the most impactful conditions in this field. This article provides a comprehensive overview of the history of SMA, highlighting its evolving classification and the genetic basis underlying its clinical variability. Moreover, it outlines the development and clinical trial data of the three Food and Drug Administration- and European Medicines Agency-approved therapies: nusinersen, onasemnogene abeparvovec, and risdiplam. These treatments have shifted SMA from a fatal diagnosis to a treatable condition, especially when initiated presymptomatically. Finally, the article discusses future directions, including combination therapies, novel pharmacological targets, biomarker development, and the need for ethical and equitable access to treatment worldwide. With ongoing research, SMA continues to serve as a paradigm for progress in neuromuscular medicine and the potential of personalized, gene-targeted therapies.

GENETIC AND MOLECULAR MECHANISMS IN PEDIATRIC NEUROLOGICAL DISORDERS: A SYSTEMATIC REVIEW

The study provides an integrated framework linking genetic variation to molecular dysfunction and clinical outcomes, offering valuable insights for future research and therapeutic development in pediatric neurology.

Therapeutic Advances and Novel Drug Treatment Opportunities in the Neuromuscular Disorders Area

Modern diagnosis and treatment of multiple sclerosis: advances, challenges, and future directions.

The diagnosis and treatment of multiple sclerosis (MS) remain an evolving challenge in modern neurology. Recent advances are reflected in the 2024 revision of the McDonald criteria, which aim to facilitate earlier, more accurate and biologically informed diagnosis of MS. Key updates include expansion of dissemination in space to incorporate the optic nerve, integration of relapsing and progressive onset MS within a unified diagnostic framework, provision for diagnosis in selected asymptomatic individuals, dispensing with the requirement for dissemination of time in certain situations and incorporation of more specific imaging biomarkers. These include specific radiological features such as the central vein sign and paramagnetic rim lesions, visual pathway assessments using optical coherence tomography, magnetic resonance imaging and visual evoked potentials. Furthermore, oligoclonal bands and kappa free light chain index are now acknowledged as alternative cerebrospinal fluid biomarkers of intrathecal immunoglobulin synthesis. These revisions acknowledge the evolving understanding of MS biology alongside the substantial advances in disease modifying therapies. This review uses the 2024 McDonald criteria as an overarching framework to synthesise and contextualise the recent developments in MS diagnosis and treatment, highlighting their clinical implications, current limitations and future directions.

Epilepsy of infancy with migrating focal seizures: A scoping review of clinical features, diagnostic testing including genetics, long-term outcomes, mortality, and current and emerging therapeutic strategies.

BACKGROUND Epilepsy of infancy with migrating focal seizures (EIMFS) is among the most severe developmental and epileptic encephalopathies (DEEs), marked by intractable multifocal seizures migrating across both hemispheres, profound developmental arrest, and high early mortality. Advances in next-generation sequencing have revealed a heterogeneous genetic architecture dominated by KCNT1 gain-of-function variants across more than 30 implicated genes, creating opportunities for precision therapeutics. OBJECTIVE To systematically map published evidence on the clinical, electrophysiological, neuroimaging, genetic, and therapeutic landscape of EIMFS, and to delineate critical knowledge gaps and future research priorities. METHODS A scoping review was conducted following the Arksey and O'Malley framework, searching PubMed, Ovid MEDLINE, Embase, Cochrane Library/CENTRAL, and ClinicalTrials.gov. RESULTS Of 643 articles screened, 89 met inclusion criteria. Beyond confirmation of the canonical electroclinical phenotype, several gaps emerged: neonatal versus post-neonatal onset stratification by genetic etiology remains largely uncharacterized; genotype-specific EEG biomarkers are lacking except for a single small KCNT1 study; and the clinical significance of atypical EEG features-including burst suppression and hypsarrhythmia-is undefined. Neuroimaging literature documents progressive cerebral atrophy and myelination abnormalities without quantitative volumetry, diffusion tractography markers, or attribution to seizure burden, medication effects, or underlying etiology. Genetic diagnostic yield was 70-80%, with KCNT1 accounting for 30-50% of solved cases; however, genotype-outcome stratification is limited. Seizures were broadly refractory; potassium bromide, ketogenic diet, cannabidiol, and quinidine (in KCNT1-confirmed cases) showed partial efficacy. Emerging precision approaches include sodium channel blockers for SCN2A gain-of-function variants, novel small molecules, fluoxetine, antisense oligonucleotides, and divalent siRNA targeting KCNT1. Systemic-to-pulmonary collateral circulation causing severe cardiopulmonary complications was reported across multiple cases, yet no consensus screening protocol exists. CONCLUSIONS EIMFS remains one of the most refractory epilepsy syndromes of infancy. Precision genetic diagnosis is essential to guide targeted therapy. International collaborative registries, standardized outcome measures, genotype-stratified biomarker studies, and rapid point-of-care genomic testing are urgently needed to advance evidence-based care for this highly vulnerable population.

Beyond Targeted Gene Panels: Whole-Exome Sequencing as a Strategic Platform for Precision Therapeutics in Alzheimer’s Disease

Alzheimer’s disease (AD) continues to be one of the greatest challenges in public health due to its multifactorial and heterogeneous nature, involving multiple physiological axes that encompass a large number of genetic, metabolic, vascular, and inflammatory interactions. In current clinical practice, medical specialties, mainly neurology and psychiatry, still rely on targeted gene panels for genetic evaluation. Although these panels remain effective for certain predefined hypotheses, their restricted and predefined nature limits the detection of the broader spectrum of genetic variation that may contribute to the complex biological interactions underlying neurodegeneration. Whole-exome sequencing (WES) is, from our clinic-based perspective, one of the most comprehensive genomic approaches currently available, since it allows the analysis of the ~19,500 protein-coding regions, and depending on the library approximately 5500 additional clinically relevant genomic loci, including splice sites, untranslated regions, long non-coding RNAs (lncRNAs), pseudogenes, regulatory elements and mitochondrial DNA (mtDNA). It enables the identification of pathogenic variants and variants of uncertain significance (VUS) under the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) classification frameworks. It also expands biological interpretation to variants conventionally classified as benign, which, when interpreted collectively, may contribute to pathway-level contextualization within the hypothesis-generating theoretical framework proposed in this review without implying pathogenicity, causal inference, or immediate clinical actionability. Additionally, WES enables the identification of secondary and incidental findings that may provide clinically relevant information beyond the primary phenotype, thereby supporting preventive surveillance and clinical risk management. This review analyzes the use of WES as a strategic platform for personalized decision-making in contemporary practice given the multifactorial and heterogeneous complexity of AD. It also addresses the complexities and limitations of the ACMG/AMP recommendations for filtering and classification of variants, the lack of standardization between reports and platforms, and the need for physician training, which constitute a great challenge for the translation of data to therapeutic decision-making. While the clinical utility of whole-exome sequencing (WES) in genetic diagnosis and precision medicine is well established, this review additionally proposes a hypothesis-generating theoretical framework whereby variants conventionally classified as benign or of uncertain significance may contribute to pathway-level biological contextualization in Alzheimer’s disease.