Developmental epilepsy (DE) and developmental and epileptic encephalopathy (DEE) comprise neurodevelopmental disorders in which epilepsy occurs alongside developmental impairment of varying contributions from the underlying etiology and epileptic activity. Advances in genetic testing, including whole-exome sequencing (WES), whole-genome sequencing (WGS), and chromosomal microarray analysis (CMA), have facilitated the identification of copy number variants (CNVs); however, data on CNV-associated epilepsy and neurodevelopmental disorders remain limited in Southeast Asia, including Indonesia. This retrospective case series describes the clinical and genetic characteristics of four Indonesian children across the DE–DEE spectrum with pathogenic CNVs identified at a tertiary referral hospital in Yogyakarta, Indonesia. Among 48 patients who underwent WES, CNVs were identified in five; four underwent further genetic characterization and were included in this case series, while one patient died before additional testing could be performed. Clinical manifestations included early-onset seizures, developmental delay or intellectual impairment, and abnormal EEG and/or neuroimaging findings. Genetic findings included a 2q24.3 deletion involving SCN1A in a patient with Dravet syndrome and 15q11.2–q13.1 deletions involving UBE3A in three patients with clinical features of Angelman syndrome. Confirmatory testing using WGS or CMA further characterized the identified CNVs. This case series expands the clinical and molecular data on pathogenic CNVs associated with pediatric epilepsy and neurodevelopmental disorders in an underrepresented Southeast Asian population and illustrates the complementary roles of sequencing and chromosomal analysis in genetic diagnosis.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the central nervous system. To investigate miR‑660‑5p expression among patients with AD and explore the molecular mechanism underlying its regulation of AD‑related pathological progression. A total of 86 AD patients and 86 healthy controls were enrolled. Serum miR‑660‑5p was detected by real‑time quantitative PCR (RT-qPCR). Inflammatory factors were measured via enzyme‑linked immunosorbent assay (ELISA). SH‑SY5Y cells were treated with aggregated Aβ₁‑₄₂ preparation to establish an in‑vitro AD‑like injury model. Serum miR‑660‑5p was significantly downregulated in AD patients (P < 0.001), positively correlated with Mini‑Mental State Examination (MMSE, r = 0.684) and Montreal Cognitive Assessment (MoCA, r = 0.640) scores, and negatively correlated with serum interleukin‑6 (IL‑6, r = − 0.658) and tumor necrosis factor‑α (TNF‑α, r = − 0.614). Receiver‑operating characteristic (ROC) curve analysis for AD yielded an area under the curve (AUC) of 0.873. Mechanistically, miR‑660‑5p targets and inhibits APP expression to mitigate Aβ‑induced neuronal injury and neuroinflammation. miR-660-5p is downregulated in patients with AD. It mitigates aggregated Aβ₁–₄₂ preparation‑triggered neuronal damage and neuroinflammation in vitro by targeted inhibition of APP expression.
ATP1A3-related neurological disorders comprise a rapidly expanding spectrum of rare neurogenetic diseases characterized by remarkable clinical heterogeneity and complex genotype-phenotype relationships. Since the publication of previous comprehensive reviews, the identification of novel ATP1A3-associated phenotypes, refinement of genotype-phenotype correlations, and advances in molecular pathogenesis and precision therapeutic strategies have substantially expanded current understanding of these disorders, highlighting the need for an updated synthesis. This narrative review summarizes recent advances in the clinical spectrum of ATP1A3-related disorders and discusses current insights into genotype–phenotype correlations, molecular mechanisms, and disease pathogenesis. Particular emphasis is placed on the molecular consequences of ATP1A3 dysfunction, including impaired Na⁺/K⁺-ATPase activity, disrupted neuronal excitability, altered ion homeostasis, and downstream cellular responses. We further review current symptomatic management and emerging disease-modifying therapeutic strategies, including antisense oligonucleotide therapy, viral vector-mediated gene delivery, genome editing technologies, and other precision medicine approaches. Current challenges and future research priorities are also discussed. By integrating recent clinical and experimental evidence, this review provides an updated perspective on ATP1A3-related disorders and aims to facilitate improved disease recognition, mechanistic understanding, and the development of targeted therapeutic strategies. Pathogenic variants in ATP1A3, which encodes the neuronal Na⁺/K⁺-ATPase α3 subunit, cause a broad and highly heterogeneous spectrum of neurological disorders, including AHC, RDP, CAPOS, RECA, and overlapping phenotypes. Current management remains largely supportive and focused on trigger avoidance, and no disease-modifying therapy is yet available. This review integrates the expanding clinical spectrum, genotype-phenotype correlations, and multilevel pathogenic mechanisms of ATP1A3-related disorders. It also highlights emerging therapeutic directions, including mechanism-based targeting, antisense strategies, and genome editing approaches such as base editing and prime editing.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects the motor system. A minority of cases are associated with a genetic variant. Variants in C9orf72, SOD1, TARDBP, and FUS are the most common. Compared with other forms of ALS, ALS presenting with FUS variants is relatively aggressive. However, phenotypic heterogeneity has been reported. We describe two cases of ALS with rare FUS variants with contrasting clinical courses. These cases highlight the importance of the different factors that influence ALS phenotypic presentation and the challenges of variant interpretation in ALS, as outlined in the ACMG Guidelines. It is essential to recognise specific genotype-phenotype relationships and environmental factors that could alter the clinical course of the disease and affect therapeutic agent selection.
Purpose: Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder driven by a complex interplay of genetic and environmental factors. This study aimed to characterize the mutational spectrum in a cohort of patients with clinically suspected hereditary PD using complementary genetic testing approaches. Materials and methods: A total of 36 patients underwent genetic evaluation. Targeted next-generation sequencing (NGS) of a 10-gene PD panel was performed in 35 patients, Multiplex ligation-dependent probe amplification (MLPA)-based copy-number analysis using an 8-gene panel was conducted in 9 patients, and targeted Sanger sequencing was performed in one patient with a known familial PRKN variant. Results: The most clinically relevant findings involved the PRKN gene. A homozygous pathogenic variant in the PRKN gene was detected in 3 patients, compound heterozygous deletions involving the PRKN and PACRG genes in one patient, and a single heterozygous PRKN variant classified as pathogenic was detected in one patient. Additionally, variants of uncertain significance were identified in 7 patients in the ATP13A2, PRKN, VPS35, PINK1, and PLA2G6 genes. Conclusion: Using complementary molecular genetic techniques, we identified clinically relevant genetic findings in a cohort of 36 patients with suspected hereditary Parkinson’s disease. These findings provide population-specific data on the mutational spectrum of PD in a Turkish clinical cohort and contribute to the characterization of the regional genetic landscape.
