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Abstract: Fabry nephropathy is a life-threatening complication of Fabry disease characterized by complex and incompletely understood pathophysiological processes possibly linked to premature aging. We aimed to investigate leukocyte telomere length (LTL), oxidative stress, and kidney damage biomarkers in relation to kidney function. The study included 35 Fabry patients and 35 age and sex-matched control subjects. Based on the estimated slope of the glomerular filtration rate, the patients were divided into two groups. Relative LTL was quantified by qPCR, urinary biomarkers 8-hydroxy-2′ -deoxyguanosine (8-OHdG) and malondialdehyde (MDA) by UHPLC-MS/MS, and kidney damage biomarkers by flow cytometry. There was no statistically significant difference in LTL between Fabry patients and controls. However, a significant difference was observed in male patients compared to their matched control subjects (p = 0.013). Oxidative stress biomarkers showed no differences between patients and controls, while significant differences were observed in urinary IGFBP7, EGF, and OPN levels between Fabry patients with stable kidney function and those with progressive nephropathy (FDR = 0.021, 0.002, and 0.013, respectively). Significant differences were also observed in plasma levels of cystatin C, TFF3, and uromodulin between patients with progressive nephropathy and controls (all FDR = 0.039). Along with these biomarkers (FDR = 0.007, 0.017, and 0.010, respectively), NGAL also exhibited a significant difference between the two patient groups (FDR = 0.017). This study indicates accelerated telomere attrition, which may be related to disease burden in males. Furthermore, analyses of urinary oxidative stress markers revealed no notable disparities between the different kidney function groups, indicating their limited utility. However, promising differences were found in some biomarkers of kidney damage in urine and plasma.
Keywords: nephropathy, telomere length, oxidative stress, kidney damage, biomarker, aging
Published in DiRROS: 10.04.2026; Views: 167; Downloads: 115
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Abstract: Background: Branched-chain amino acid transaminase 2 (BCAT2) deficiency is an autosomal recessive disorder that impairs branched-chain amino acid (BCAA) catabolism. Its clinical and metabolic features remain poorly understood due to limited reports in the literature. Methods: We report three novel cases of BCAT2 deficiency from Slovenia: one diagnosed following symptom onset, one through cascade screening of parents, and one by newborn screening. Diagnosis was established through metabolic evaluation and confirmation of pathogenic variants in the BCAT2 gene. In addition, we performed a systematic review of all previously reported cases of BCAT2 deficiency. Results: All three patients were homozygous for the NM_001190.4:c.600C > A (p.Tyr200Ter) variant, with valine concentrations at presentation of 2093, 2589, and 794 μmol/L. Only one patient was symptomatic, presenting with headaches, developmental delay, and intellectual disability, while the remaining two were largely asymptomatic. Notably, insulin resistance was observed in one of the three patients and may be associated with elevated BCAA levels. Systematic literature review identified 8 additional cases of BCAT2 deficiency. Genetic variant c.600C > A was also found in two Pakistani individuals, while the remaining variants were each reported in only a single individual. The most common clinical characteristics were intellectual disability (55%), developmental delay and other neurological symptoms (36%). Abnormal white matter findings on MRI were observed in all patients who underwent imaging. BCAA levels decreased in all patients receiving pyridoxine supplementation; however, only 50% showed clinical improvement. Conclusion: BCAT2 deficiency displays marked interindividual heterogeneity, ranging from asymptomatic cases to severe neurological impairment, which renders its pathogenicity uncertain.
Keywords: BCAT2, branched-chain amino acids, antihistamine branched-chain amino acid transaminase, hypervalinemia, hyperleucine-isoleucinemia, insulin resistance, white matter abnormalities
Published in DiRROS: 19.01.2026; Views: 398; Downloads: 233
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Abstract: ewborn screening for Phenylketonuria enables early detection and timely treatment with a phenylalanine-restricted diet to prevent severe neurological impairment. Although effective and in use for 60 years, screening, diagnostic, and treatment practices still vary widely across countries and centers. To evaluate the Phenylketonuria newborn screening practices internationally, we designed a survey with questions focusing on the laboratory aspect of the screening system. We analyzed 24 completed surveys from 23 countries. Most participants used the same sampling age range of 48–72 h; they used tandem mass spectrometry and commercial non-derivatized kits to measure phenylalanine (Phe), and had non-negative cut-off values (COV) set mostly at 120 µmol/L of Phe. Participants mostly used genetic analysis of blood and detailed amino acid analysis from blood plasma as their confirmatory methods and set the COV for the initiation of dietary therapy at 360 µmol/L of Phe. There were striking differences in practice as well. While most participants reported a 48–72 h range for age at sampling, that range was overall quite diverse Screening COV varied as well. Additional screening parameters, e.g., the phenylalanine/tyrosine ratio were used by some participants to determine the screening result. Some participants included testing for tetrahydrobiopterin deficiency, or galactosemia in their diagnostic process. Results together showed that there is room to select a best practice from the many practices applied. Such a best practice of PKU-NBS parameters and post-screening parameters could then serve as a generally applicable guideline.
Keywords: phenylketonuria, newborn, neonatal, screening, international, survey, laboratory, methods, cut-off
Published in DiRROS: 04.12.2025; Views: 2316; Downloads: 291
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Abstract: Background and aims: Early detection of insulin resistance (IR) and obesity-related complications is crucial for preventing type 2 diabetes. This study aimed to identify dynamic metabolic biomarkers for more precise early detection of IR and metabolic abnormalities. Methods: This cross-sectional cohort study evaluated IR and metabolic biomarkers in 403 children with obesity (median age 13.18 years, 51.3 % female, 98.5 % with obesity) using an enhanced oral glucose tolerance test (eOGTT). IR was assessed via four indices, with the Matsuda Insulin Sensitivity Index (ISI-M) used as the primary measure. Participants were stratified into quartiles based on ISI-M. Results: Participants with the highest IR (Q1) were older (p = 0.002), had a higher body mass index, were in a more advanced pubertal stage (p < 0.001), and had significantly elevated glucose and insulin levels (p < 0.001 for both) compared to the most insulin sensitive (Q4), with significant differences observed across all quartiles (p < 0.050 for all). Insulin at 120 min demonstrated excellent diagnostic accuracy for IR (AUC=0.958). Triglyceride levels in Q1 showed minimal decline during the eOGTT, while greater declines were observed with increasing insulin sensitivity (p = 0.002 across quartiles), suggesting that a lack of decline in triglycerides may help identify IR. High-sensitivity C-reactive protein levels increased with IR (p = 0.024). Baseline beta-hydroxybutyrate levels were highest in the Q4 and showed the greatest absolute decrease during the eOGTT, compared to Q1 (p < 0.001 for both). Conclusions: We validated established IR markers in children with obesity, while demonstrating that eOGTT may offer improved characterization and earlier identification of those at risk for metabolic complications.
Keywords: insulin resistance, oral glucose tolerance test, OGTT, metabolic complications, screening, children, adolescents, obesity
Published in DiRROS: 11.11.2025; Views: 551; Downloads: 243
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