Background: Abnormal sodium-dependent hexose reabsorption in the proximal tubule, accompanied by a functional decrease in sodium and water reabsorption under conditions of increased volemia, may be attributed to a dysfunction of primary transporters related to a genetic defect in the Na,K-ATPase gamma subunit. Methods: We examined two sisters, aged 6 and 8 years, who presented with hypercalciuria, glucosuria, fructosuria, galactosuria, and atypical proteinuria. Primary diabetes, galactosemia, and fructosemia were excluded, suggesting a defect in cellular hexose transport in the proximal tubule. We conducted tests on the family members to assess the impact of gradually increasing volemia, using a water-loading test, on tubular H⁺ transport and urinary excretion of calcium, citrate, endothelin-1 (ET-1), and atypical proteins. Whole-exome sequencing was performed in the affected patients to identify the genetic basis of this phenotype. Results: Extended investigations revealed a complex defect in tubular H⁺ transport, calcium and citrate handling, and atypical proteinuria, resulting from water load-driven overproduction of endothelin-1 (ET-1). Genetic analysis identified a heterozygous pathogenic variant, c.80G>A, p.(Arg27His), in the FXYD2 gene, which encodes the gamma subunit of sodium/potassium-transporting ATPase. Conclusions: Our findings provide evidence that a defect in FXYD2 (splice form a) leads to functional impairment of proximal tubular hexose reabsorption. This is the first report on the metabolic consequences of a pathogenic FXYD2 variant affecting the gamma subunit of sodium/potassium-transporting ATPase in humans. The genotype–phenotype correlation in two siblings with a sodium-dependent defect in fructose, galactose, and glucose renal reabsorption allowed us to characterize a disease with a distinct clinical course and biochemical profile, not previously reported in the medical literature or genetic databases. Analysis of this condition was crucial for the early introduction of reno-protective treatment aimed at slowing the progression of nephropathy and for risk assessment in family members, which was essential for genetic counseling.

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Introduction: Epilepsy syndromes show marked clinical and genetic heterogeneity, with numerous functionally diverse genes involved in their etiology. Next-generation sequencing (NGS) has facilitated the identification of many monogenic epilepsy syndromes and enables earlier, more accurate diagnosis in pediatric patients. Materials and Methods: This study analyzes the molecular profiles of 87 pediatric patients with various forms of epilepsy in whom pathogenic or likely pathogenic variants were identified. Next-generation sequencing (NGS) using multi-gene epilepsy panels or whole-exome sequencing (WES) was performed. Results: A total of 88 pathogenic or likely pathogenic variants were detected in 48 epilepsy-related genes; 30 variants occurred de novo. SCN1A and KCNQ2 were the most frequent contributors (12.6% and 9.2%, respectively). The highest percentage of positive diagnoses (48%) was observed in patients with developmental and epileptic encephalopathy (DEE), with variants identified in genes including ALG13, ATP1A2, CACNA1A, CDKL5, CHD2, GABRG2, ITPA, KCNQ2, PCDH19, SCN1A, SCN2A, SCN3A, SCN8A, SMC1A, SPTAN1, STXBP1, and UBA5. Pathogenic variants in ANKRD11 were found in four patients with KBG syndrome, while other genes appeared sporadically. Conclusions: Targeted massively parallel sequencing is an effective diagnostic tool for pediatric epilepsy. The presence of numerous single-case findings highlights the high genetic heterogeneity of epilepsy. This approach enabled more precise diagnoses that would not have been achieved through clinical evaluation alone, underscoring the importance of genetic testing for prognosis and treatment planning in pediatric patients with unexplained epilepsy.

Objective: Copy number variants (CNVs) overlapping genes associated with neurodevelopmental disorders in patients with epilepsy are particularly concentrated in epilepsy hotspot loci. The aim of this study was to evaluate epilepsy as a component of the dysmorphic–neurodevelopmental phenotype in patients with recurrent CNVs. Methods: The study included genetic and clinical data from 177 pediatric patients carrying 17 recurrent CNVs showing well-documented enrichment in epilepsy or associated with genetic OMIM syndromes. Results: Epilepsy was diagnosed in 50 of 177 children (28.2%), developmental delay in 147 (83.0%), dysmorphic features in 104 (58.8%), behavioral problems in 62 (35.0%), and congenital anomalies in 55 (31.1%). Among recurrent CNV hotspots, the del16p11.2 BP4–BP5 deletion was the most frequent, occurring in 39 of 177 patients. Ten children (25.6%) with del16p11.2 presented with epilepsy as part of the phenotype. Other frequently represented CNVs included del15q11.2 BP1–BP2 (OMIM #615656; 19/177 patients, 4/19 with epilepsy), del1q21.1 (OMIM #612474; 15/177, 6/15 with epilepsy), del15q13.3 (OMIM #612001; 13/177, 4/13 with epilepsy), and dup16p11.2 (OMIM #614671; 12/177, 1/12 with epilepsy). The highest proportion of epilepsy as a phenotypic component was observed in patients with del1p36 (OMIM #607872; 6/9 patients) and del1q21.1 (OMIM #612474; 6/15 patients). Conclusions: Our data support the clinical utility of CNV testing in patients with epilepsy accompanied by additional neurodevelopmental or dysmorphic features, in line with current diagnostic guidelines. The epilepsy-plus phenotype may help clinicians identify patients who are most likely to benefit from CNV analysis.

Not available Keywords: Birk-Barel syndrome KCNK9 gene imprinting disorders channelopathy