Lăcrămioara Ionela Butnariu

Epilepsy ranks among the most prevalent neurological disorders globally, with a substantial proportion of cases, particularly in pediatric populations, attributed to genetic etiologies. This study provides the first molecular characterization of suspected genetic epilepsy in a pediatric cohort from the Moldova region of Romania. Following the exclusion of 124 patients with secondary acquired or structural causes from an initial cohort of 159, we enrolled 35 individuals with a high suspicion of primary genetic epilepsy, who underwent targeted gene panel testing or whole-exome sequencing (WES). Pathogenic (P) or likely pathogenic (LP) variants were identified in 13 patients (37.1%); variants of uncertain significance (VUSs) were identified in another 13 patients (37.1%), comprising 15 distinct VUSs; and negative results were observed in the remaining 9 patients (25.7%). Genes regulating ion channels and synaptic signaling, notably SCN1A, KCNB1, and GNAO1, were predominantly implicated in early-onset, drug-resistant epileptic encephalopathies, whereas structural copy number variations (CNVs) underpinned syndromic phenotypes. We identified one novel pathogenic variant in SCN1A, thereby expanding the known mutational spectrum. Furthermore, in silico predictions and de novo occurrence patterns supported the pathogenicity of several VUSs, underscoring the critical value of familial segregation analyses. Despite the notable diagnostic yield, the high VUS rate underscores the ongoing need for refined variant interpretation criteria and the integration of functional validation data to improve classification accuracy. Collectively, our findings support the clinical utility of next-generation sequencing (NGS) in informing therapeutic decisions, enabling genetic counseling, and improving prognostic accuracy. These results suggest that NGS should be considered early in the diagnostic workup of unexplained or drug-resistant epilepsy, particularly in patients with clinical features suggestive of a genetic etiology.

Background: The deep-intronic variant 3849+10kbC>T preserves residual CFTR function and is recurrently associated with pancreatic sufficiency, normal or borderline sweat chloride and diagnosis beyond early childhood. A co-occurring poly-T 5T allele adds a second layer of uncertainty: its penetrance depends on the TG repeat carried in cis, and its contribution to the phenotype can be weighed only once its phase relative to the second variant has been established. Case Presentation: A boy with recurrent respiratory infections from the age of three was diagnosed with cystic fibrosis at 12 years, in 2018—four years before newborn screening became national policy in Romania. Two sweat conductivity measurements, 125 and 80 mmol/L NaCl-equivalent, together with targeted CFTR analysis identifying 3849+10kbC>T and a 5T allele, established the diagnosis. Phase was not determined—parental samples were not obtained and no allele-specific or long-range analysis was performed—so the two findings are reported as co-occurring rather than as demonstrably in trans. His elder brother, who had recurrent spontaneous pneumothorax and two negative sweat tests, was never genotyped because the test was not reimbursed. Bilateral bronchiectasis and chronic airway infection followed; inhaled colistimethate eradicated Pseudomonas aeruginosa, whereas Staphylococcus aureus persisted despite successive antibiogram-guided regimens. Access to elexacaftor/tezacaftor/ivacaftor was granted in January 2026 on the basis of the genotype. Conclusions: Molecular characterisation contributed to a diagnosis that rested on the combination of clinical phenotype, abnormal sweat conductivity, and CFTR analysis, and was, eight years later, the sole criterion for access to modulator therapy; phase and TG-repeat length remain undetermined. No follow-up data are available, therapy having been authorised but not yet started at the time of writing.

Background/Objectives: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by pathogenic variants in the NF1 gene, characterized by high phenotypic variability. Methods: We present clinical and molecular data from a Romanian cohort of 54 patients initially diagnosed clinically. Results: Phenotypic evaluation (n = 54) revealed a high prevalence of café-au-lait macules (100%), Lisch nodules (64.8%), axillary/inguinal freckling (61.1%), and cutaneous neurofibromas (42.6%). Due to financial constraints (genetic testing not covered by the national health system), molecular confirmation by next-generation sequencing (NGS) was possible in only 12 patients (mostly sporadic cases and young children). Genetic testing identified a diverse spectrum of variants, including frameshift (41.7%, n = 5), nonsense (33.3%, n = 4), missense (16.7%, n = 2), and one splicing deletion (8.3%, n = 1). A novel complex NF1 frameshift variant, c.7504_7508delinsC (p.Ser2502Argfs*24) in exon 54, was identified in a patient exhibiting an aggressive phenotype characterized by plexiform neurofibromas, a malignant peripheral nerve sheath tumor (MPNST), and severe skeletal abnormalities. Additionally, a recurrent nonsense variant, NF1 c.910C>T (p.Arg304*), was detected in two unrelated individuals. Conclusions: The high proportion of sporadic cases (58.3%) in the molecularly tested subgroup underscores the critical role of early genetic screening. By integrating clinical data from 54 patients with the first molecular characterization of NF1 in Romania, this study expands the mutational spectrum and provides preliminary, descriptive insights into genotype–phenotype correlations. It also proposes a cost-effective diagnostic algorithm adapted for resource limited settings and lays the groundwork for future multicenter initiatives. Given the exploratory nature of the molecular subgroup (n = 12), all genotype–phenotype observations require validation in larger independent cohorts.

Turner syndrome (TS), a disorder caused by the complete or partial absence of an X chromosome, exhibits significant clinical variability that cannot be fully explained by chromosomal anomalies alone. This narrative review highlights the crucial role of epigenetic mechanisms, particularly X-chromosome inactivation (XCI), in shaping the TS phenotype. The haploinsufficiency of genes that normally escape XCI is a primary driver of TS features. The specific epigenetic consequences depend on the chromosomal anomaly. In complete monosomy (45,X), the absence of escape-mediated dosage compensation genes from a second X chromosome amplifies haploinsufficiency across X-linked escape genes. Isochromosome Xq (i(Xq)) variants involve the loss of the short arm (Xp) and duplication of the long arm (Xq), creating a dual dosage imbalance with extreme XCI skewing. Carriers of i(Xq) also have a heightened risk for autoimmune disorders compared to those with 45,X TS. For ring-X chromosomes (r(X)), which are mitotically unstable, the functional status of the XIST gene is critical. If the ring is XIST-negative, it remains transcriptionally active, resulting in functional disomy and a more severe phenotype with pronounced neurodevelopmental and craniofacial features. Ultimately, the clinical heterogeneity in TS arises from a complex interplay of the specific chromosomal structure, tissue-specific mosaicism, XIST function, and variable escape from XCI, defining TS as a disorder of epigenetic and gene-regulatory imbalance. However, future research requires a better understanding of the complex mechanism of X-chromosome inactivation.

Type 1 Diabetes (T1D) is a complex autoimmune disorder characterized by immune-mediated destruction of pancreatic β cells, driven by genetic susceptibility and modulated by environmental factors, notably the gut microbiome. Dysbiosis, manifested as reduced microbial diversity, perturbations in the Firmicutes/Bacteroidetes ratio, and compromised short-chain fatty acid production, contributes to T1D pathogenesis through mechanisms involving immune system dysregulation and heightened intestinal permeability. Emerging evidence indicates a relationship between the gut and oral microbiomes, as well as the potential influence of the virome and mycobiome. This narrative review synthesizes the current literature on the intricate interplay between the gut microbial ecosystem, the host immune response, and the development of T1D, highlighting the potential for targeted microbiome-based interventions to ameliorate disease progression. A more nuanced understanding of these multi-kingdom interactions is essential for developing precise therapeutic strategies to prevent or delay T1D onset and to improve patient outcomes through restoration of immune tolerance and gut homeostasis.

Background and Objectives: The COVID-19 pandemic caused unprecedented mortality shocks worldwide, but its differential impact across European regions and the mediating mechanisms remain inadequately quantified. Materials and Methods: We conducted a longitudinal multilevel analysis using data from 29 European countries (2015–2023; N = 261 country-years). Linear mixed models estimated the impact of the pandemic on life expectancy, controlling for regional differences, vaccination rates, healthcare expenditures, gross domestic product, and excess mortality. The primary outcome was national life expectancy at birth. Results: The pandemic period was associated with an average reduction of 1.12 years in life expectancy (95% CI: 0.95 to 1.49, p < 0.001) after adjusting for pre-existing trends. Eastern Europe experienced 56% greater impact than Western Europe (interaction β = −0.623, p = 0.002). Excess mortality emerged as the primary mediator, explaining 79% of the pandemic effect. Each 1% increase in excess mortality reduced life expectancy by 0.091 years (p < 0.001). Healthcare expenditures showed protective effects (β = 0.000327 per purchasing power standards (PPS), p = 0.049), while vaccination rates, as a direct predictor, were not significantly associated with life expectancy in multivariate models. This critical finding on vaccination rates does not imply biological inefficacy but rather suggests a misspecification of its role. Conclusions: Excess mortality, rather than its direct component, COVID-19-specific mortality, appears to mediate most of the pandemic’s impact on life expectancy. Regional disparities reflect structural differences in healthcare systems and socioeconomic conditions more than differential vaccination uptake. The protective effect of vaccination on life expectancy operates entirely through the reduction in excess mortality. Consequently, health policies should prioritize strengthening resilient health systems as well as disease-specific interventions.

Background: Vascular abnormalities (VAs) are a broad category of disorders that include vascular malformations (inadequate embryologic blood vessel development) and vascular tumors (characterized by vascular cell hyperplasia). This sometimes-complicated pathology is increasingly being treated with mTOR inhibitors, particularly sirolimus (rapamycin). Only a limited number of neonates treated with sirolimus have been reported in the literature to date, and there is no consensus regarding the optimal treatment regimen for vascular anomalies in this population. The objective of our narrative review is to summarize the most recent information from the specialized literature regarding the efficacy and safety of sirolimus in newborns. Methods: A methodological search was performed through the available data concerning the indications and safety when using sirolimus to treat VAs in newborns. We evaluated articles from the Embase and PubMed academic search engines using the following search terms: (vascular anomalies OR vascular tumors OR venous malformations OR lymphatic malformations OR capillary malformations) AND (neonate) AND (sirolimus OR rapamycin). Results: We identified a lack of consensus regarding indications for treatment initiation, optimal dosing regimens, and duration of therapy. In most published studies, neonates were analyzed within broader pediatric cohorts that included patients up to 18 years of age, rather than as a distinct population. Moreover, only a limited number of investigations have specifically focused on neonates treated with sirolimus and evaluated outcomes from a neonatal subgroup perspective. The available evidence largely consists of isolated case series and reports describing sirolimus use in fetuses and neonates, most commonly for lymphatic malformations or kaposiform hemangioendothelioma; in some instances, sirolimus was administered in combination with propranolol, corticosteroids, or other therapeutic modalities. Nevertheless, across studies and case reports involving fetuses or neonates, sirolimus is generally reported to be effective and well tolerated, with adverse effects that are minimal and reversible. Conclusions: For neonates and even fetuses with large, complex VAs, sirolimus appears to be an effective treatment with no serious adverse events reported to date. Decisions regarding off-label sirolimus initiation should be made by a multidisciplinary team, and parents must be thoroughly informed about potential adverse events. Well-designed randomized controlled trials or high-quality observational studies are needed to further evaluate the efficacy and safety of sirolimus in the neonatal population.

Nephrocalcinosis, defined as the deposition of calcium salts within the renal parenchyma, represents a radiologic and pathologic endpoint shared by a broad spectrum of metabolic and monogenic disorders. Advances in genomic medicine have identified more than 30 genes involved in tubular transport, mineral and acid–base homeostasis, oxalate metabolism, mitochondrial function, ciliary signaling, and nephron development, reframing nephrocalcinosis as a heterogeneous manifestation of discrete molecular defects rather than a single disease entity. Despite this diversity, these conditions converge on common physicochemical pathways of tubular supersaturation, crystal nucleation, growth, and intrarenal retention. These processes are amplified by the intrinsic vulnerability of the renal medulla—characterized by hyperosmolality, hypoxia, and slow tubular flow—and by epithelial injury, loss of crystallization inhibitors, and impaired ciliary signaling. Distinct genotype–phenotype signatures, including age at onset, biochemical profiles, and extrarenal manifestations, provide important diagnostic clues and help differentiate major monogenic entities. The increasing availability of targeted gene panels, whole-exome sequencing, and whole-genome sequencing has substantially improved diagnostic yield, particularly in pediatric populations. Molecular diagnosis now directly informs therapeutic decision-making and long-term management, enabling a shift toward precision nephrology. This narrative review integrates genetic, mechanistic, and clinical perspectives to illustrate how molecular diagnosis reshapes the evaluation, prognosis, and treatment of nephrocalcinosis.

Background: Moyamoya disease (MMD) is a rare, progressive cerebrovascular arteriopathy characterized by stenosis and occlusion of the distal internal carotid arteries with the development of compensatory collateral networks. In children, MMD is a major cause of ischemic stroke; however, neurological morbidity frequently extends beyond cerebrovascular events to include epilepsy, headache, cognitive impairment, and psychiatric manifestations. Data regarding the long-term evolution of these complications in Caucasian pediatric patients remains limited. Case Report: We present the longitudinal case of a Caucasian female diagnosed with advanced MMD after an ischemic stroke at the age of 7 years, followed by indirect surgical revascularization (encephalo-duro-arterio-synangiosis) and chronic antiplatelet therapy. Four years later, she developed recurrent focal aware sensory–motor seizures associated with chronic post-ischemic cortical injury. Despite stable vascular imaging and absence of recurrent infarction, the patient experienced persistent neurological sequelae, including residual spastic hemiparesis, episodic tension-type headaches, and evolving neuropsychological complications. Cognitive assessment initially suggested mild neurocognitive impairment, with subsequent improvement during adolescence. In late follow-up, prominent anxiety symptoms emerged, and psychiatric evaluation confirmed panic disorder requiring psychological and pharmacological support. The patient remained neurologically stable into adulthood under continued multidisciplinary care. This case illustrates the broad spectrum of neurological and psychiatric complications that may accompany pediatric MMD, even in the absence of new ischemic events. The accompanying literature review emphasizes that epilepsy, headache, cognitive dysfunction, and psychiatric disorders represent clinically significant components of the long-term disease burden in children with MMD. Conclusions: Pediatric moyamoya disease should be regarded not only as a cause of childhood stroke, but also as a chronic condition with long-term epileptic, cognitive, and psychiatric sequelae that may evolve independently of recurrent ischemic injury. By providing longitudinal follow-up from childhood into adulthood in a Caucasian patient, this report underscores the importance of integrating neuropsychological and psychiatric surveillance into standard care pathways, alongside vascular and surgical management, to better address the full spectrum of morbidity and improve quality of life.

Globally, chronic kidney disease (CKD) affects over 800 million individuals and is characterized by significant genetic complexity. More than 600 genes are associated with hereditary kidney disease, which may manifest as isolated kidney issues or as part of a syndrome that also includes extrarenal manifestations. The aim of this study was to identify genetic variants in a group of ten patients who presented with clinical signs suggestive of genetic syndromes associated with CKD, or who were asymptomatic but had a positive family history of CKD. Extensive genetic testing (targeted gene panels and whole-exome sequencing—WES) identified a mutation in the PKD1 gene in 3 out of 10 cases. In one patient, a known mutation in the PKD2 gene was identified. Another four patients were diagnosed with Alport syndrome: three of these presented with de novo missense mutations in the COL4A5 gene, and one patient had a mutation in the COL4A3 gene. One patient was diagnosed with MODY5, caused by a known mutation in the HNF1B gene, and one patient was diagnosed with Bartter syndrome type 1, resulting from a known mutation in the SLC12A1 gene. We present genotype–phenotype correlations, highlighting the particularities of each patient within their family context. Our findings emphasize the importance of genotype–phenotype correlations in refining diagnosis, personalizing therapeutic management, and providing essential genetic counseling for at-risk relatives.