Pathogenic Potential of a PCK1 Gene Variant in Cytosolic PEPCK Deficiency: A Compelling Case Study.

BACKGROUND Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) deficiency is an extremely rare autosomal recessive inherited error of metabolism in which gluconeogenesis is impaired, resulting in life-threatening episodes of hypoglycemia and metabolic acidosis. The diagnosis of gluconeogenesis disorders is challenging. In the diagnostic pathway, the molecular test plays a paramount role. CASE REPORT The aim of the paper is to present the case report of a girl with recurrent episodes of severe hypoglycemia, in whom molecular diagnosis enabled the confirmation of PEPCK - C deficiency. The patient experienced 4 episodes of severe hypoglycemia. Most of them were accompanied by hyperlacticaemia, metabolic acidosis, and elevated liver enzymes. All of the metabolic decompensations were triggered by infectious agents. The episodes resolved after continuous infusion of high-dose glucose. Due to the recurrent character of the disease, a genetic condition was suspected. The differential diagnosis included metabolic and endocrinological causes of hypoglycemia. Two variants in the PCK1 gene were detected: c.265G>A p.(Glu89Lys) in exon 3 and c.925G>A p.(Gly309Arg) in exon 6. As c.925G>A p.(Gly309Arg) is a known pathogenic variant, the second variant was first described in June 2023 in the ClinVar database and described as "with unknown clinical significance". CONCLUSIONS According to the clinical symptoms observed in the presented case, the variant c.265G>A p.(Glu89Lys) in PCK1 gene should be considered likely pathogenic. We suggest considering molecular diagnostics in every patient presented with recurrent, severe hypoglycemia with accompanying liver damage as most accurate, feasible, and reliable method.

Professional activity, gender and disease-related emotions: The impact on parents' experiences in caring for children with phenylketonuria.

Introduction: Clinical management of rare diseases often fails to acknowledge the challenges faced by caregivers. Whilst management of phenylketonuria (PKU) may not be considered as dire as other conditions, most studies primarily concentrate on clinical issues, dietary adherence, or the quality of life of the PKU patients, leaving caregivers in the background. The aim of the study was to evaluate the psychosocial effects of PKU on family caregivers. Methods: Between October 30th, 2022 and February 28th, 2023, we collected data from caregivers of children with PKU using an anonymous, self-administered, computer-assisted online questionnaire. The survey was distributed among to patients during their regular visits to five Polish PKU treatment centers. Results: A total of 159 Polish caregivers of children with PKU completed the survey. This research shows that while women caregivers were more likely to be unemployed due to their responsibilities for childcare (50.3% compared to 0% for men), and men caregivers were more likely to be employed full-time (93.8% compared to 40.6% for women), the former reported higher emotional engagement in caregiving (88.1% vs 56.3% respectively). Significantly, unemployed mothers reported higher levels of loneliness, helplessness, and emotional control problems, and lacked psychological/emotional support more often than employed mothers. This research also shows a statistically significant positive correlation between mothers' education level and financial situation (p < 0.05) and education level and professional activity (p < 0.01). Additionally, a significant positive correlation was found between perceived financial situation and feeling of happiness (p < 0.001), and between financial situation and professional activity (p < 0.001). Finally, a significant positive correlation was observed between feeling of happiness and professional activity (p < 0.05). Conclusions: According to our findings, there is a link between subjective happiness, financial situation, and professional activity among female caregivers. The relationship between these factors goes beyond just the income earned from work. The results of our study imply that there could even be a therapeutic advantage for working mothers. It is crucial to recognize the emotional difficulties that employed mothers may experience while taking care of a child with PKU, and to provide them with the necessary assistance and resources to meet their needs. Additionally, our results may provide a foundation for redefining the support system for caregivers in Poland.

Clinical characteristics and long-term outcomes of patients with glycogen storage disease type 1b: a retrospective multi-center experience in Poland.

Glycogen storage disease type 1b (GSD 1b) is an inherited metabolic defect caused by a deficiency of microsomal glucose-6-phosphate (G6P) transport protein across the endoplasmic reticulum membrane. Patients with GSD 1b have hypoglycemia episodes, lactate acidosis, hypertriglyceridemia, hypercholesterolemia, hyperuricemia, neutropenia and in imaging studies hepatomegaly and/or nephromegaly. The primary goals of treatment are to maintain proper blood glucose levels and to increase the number of properly functioning neutrophils. The aim of the study was a retrospective analysis of the clinical picture and treatment results of pediatric patients with type 1b glycogen storage disease from Poland. The study included 13 patients from 3 clinical centers, with a median age at diagnosis as 5 months. In 11/13 patients, the diagnosis was confirmed by molecular test, by the presence of pathogenic variants on both alleles of the SLC37A4 gene. Ten out of 13 patients developed the first symptoms in the form of severe infection (sepsis and/or pneumonia) already in the neonatal-infant period. A hypoglycemia episode was observed before diagnosis in 8/13 patients, of which 4/8 patients presented symptoms in the form of generalized relaxation and/or seizures. Two patients developed hypertension, and 4/13 required long-term treatment of inflammatory bowel disease.

The effect of endurance and endurance-strength training on body composition and cardiometabolic markers in abdominally obese women: a randomised trial.

Studies comparing the effect of endurance and endurance-strength training on cardiometabolic markers provided inconsistent results. Therefore, the study aimed to compare the effect of endurance and endurance-strength training on body composition and cardiometabolic parameters in abdominally obese women. In this randomised trial, 101 subjects were included and divided into endurance (n = 52) and endurance-strength (n = 49) training. During the 12-week intervention, participants performed supervised one-hour training three times a week. Body composition, blood pressure (BP), markers of glucose and lipid homeostasis, and myoglobin levels were measured before and after the intervention. In total, 85 subjects completed the trial. Both interventions decreased fat mass and visceral adipose tissue and increased free fat mass, appendicular lean mass index and lean mass index. Neither endurance training nor endurance-strength training affected glucose and lipid metabolism. However, only endurance training significantly decreased paraoxonase and myoglobin levels. Both training programmes significantly decreased BP, with a more reduction of diastolic BP noted in the endurance group. In conclusion, both training programmes had a favourable effect on body composition but did not improve glucose and lipid homeostasis. Besides, endurance training decreased paraoxonase activity and myoglobin levels and was more effective in reducing BP.The study was registered with the German Clinical Trials Register (DRKS) within the number: DRKS00019832 (retrospective registration), date of registration: 26/02/2020.

Endurance Training Depletes Antioxidant System but Does Not Affect Endothelial Functions in Women with Abdominal Obesity: A Randomized Trial with a Comparison to Endurance-Strength Training.

Limited data suggested that inclusion of a strength component into endurance exercises might intensify the beneficial effect of training. However, the available data is limited. Therefore, we aimed to compare the effect of endurance and endurance-strength training on anthropometric parameters, endothelial function, arterial stiffness, antioxidant status, and inflammatory markers in abdominally obese women without serious comorbidities. A total of 101 women were recruited and randomly divided into endurance (n = 52) and endurance-strength (n = 49) groups. During the three-month intervention, both groups performed supervised sixty-minute training three times a week. All studied parameters were measured pre- and post-intervention period. In total, 85 women completed the study. Both training significantly decreased anthropometric parameters. Besides, endurance training decreased endothelial nitric oxide synthase, central aortic systolic pressure, pulse wave velocity, glutathione (GSH), total antioxidant status (TAS), interleukin (IL) 8, matrix metalloproteinase (MMP) 9, and tumor necrosis factor alpha, while endurance-strength training decreased MMP-2 concentrations, and increased IL-6, monocyte chemoattractant protein-1, and MMP-9 levels. We observed significant differences between groups for GSH, TAS, and MMP-9 levels. In summary, endurance and endurance-strength training did not differ in the impact on endothelial function and arterial stiffness. However, endurance training significantly depleted the antioxidant defense, simultaneously reducing MMP-9 levels. The study was retrospectively registered with the German Clinical Trials Register within the number DRKS00019832.

Vitamin K Status in Adherent and Non-Adherent Patients with Phenylketonuria: A Cross-Sectional Study.

This is the first study to evaluate vitamin K status in relation to dietary intake and phenylalanine dietary compliance in patients with phenylketonuria (PKU). The dietary and PKU formula intake of vitamin K was calculated in 34 PKU patients, with vitamin K status determined by the measurement of prothrombin induced by vitamin K absence (PIVKA-II). Blood phenylalanine concentrations in the preceding 12 months were considered. There were significantly more phenylalanine results exceeding 6 mg/dL in patients with normal PIVKA-II concentrations than in those with abnormal PIVKA-II levels (p = 0.035). Similarly, a higher total intake of vitamin K and dietary vitamin intake expressed as µg/day (p = 0.033 for both) and %RDA (p = 0.0002 and p = 0.003, respectively) was observed in patients with normal PIVKA-II levels. Abnormal PIVKA-II concentrations were associated with a lower OR (0.1607; 95%CI: 0.0273-0.9445, p = 0.043) of having a median phenylalanine concentration higher than 6 mg/dL. In conclusion, vitamin K deficiency is not uncommon in phenylketonuria and may also occur in patients with adequate vitamin K intake. PKU patients with better dietary compliance have a higher risk of vitamin K deficiency. The present findings highlight the need for further studies to re-evaluate dietary recommendations regarding vitamin K intake, both concerning formula-based and dietary consumption of natural products.

Amaranth Oil Increases Total and LDL Cholesterol Levels without Influencing Early Markers of Atherosclerosis in an Overweight and Obese Population: A Randomized Double-Blind Cross-Over Study in Comparison with Rapeseed Oil Supplementation.

BACKGROUND: Atherosclerosis (AT) is a chronic inflammatory process in which oxidative stress is the key event. Amaranth oil (AmO) has potential hypolipidemic and antiatherogenic effects. The aim of the study was to compare the effects of AmO and rapeseed oil (RaO) supplementation on expression of early markers of AT and lipid profile in obese or overweight subjects. METHODS: A randomized, double-blinded cross-over study was conducted, in which participants took 20 mL of AmO in the first arm and 20 mL RaO in the second arm, switching after the washout period. Serum concentrations of adhesion molecules (sP-selectin, sVCAM-1), high-sensitivity C-reactive protein (hsCRP), asymmetric dimethylarginine (ADMA), and lipid profile were assessed before and after nutritional interventions. In addition, anthropometric parameters were measured. RESULTS: The total (TC) and low-density lipoprotein (LDL) cholesterol concentrations increased significantly in the AmO group in comparison with RaO (ΔTC 5.52 ± 35 vs. -8.43 ± 17.65 mg/dL; p = 0.002 and 4.43 ± 34.96 vs. -7.55 ± 16.41 mg/dL; p = 0.002, respectively). There were no significant differences in other parameters analyzed between the groups. CONCLUSION: The use of AmO instead of RaO may increase cardiovascular risk in obese and overweight subjects.

The Central European diet as an alternative to the Mediterranean diet in atherosclerosis prevention in postmenopausal obese women with a high risk of metabolic syndrome - a randomized nutrition-al trial.

BACKGROUND: Metabolic syndrome (MS) is a powerful risk factor for atherosclerosis (AT). The crucial meth- od of minimizing the development of atherosclerosis and its clinical manifestations is lifestyle modifications, including following a healthy diet. The aim of the study was to check if the Central European Diet (CED) could be an alternative to the Mediterranean Diet (MED) in the prevention of AT in patients with a risk of MS. METHODS: The randomized, single-blind nutritional trial involved 144 obese women with a risk of MS. The subjects were randomly assigned to two groups and followed MED (n = 72) or CED (n = 72) for 16 weeks. The concentrations of high-sensitivity C-reactive protein (hs-CRP) and asymmetrical dimethylarginine (ADMA) were measured before and after nutritional intervention. RESULTS: In both studied groups, the concentrations of hs-CRP decreased significantly after the nutritional in- tervention (CED: p = 0.0107; MED: p = 0.0002). The ADMA levels were significantly lower after nutritional intervention in the CED group (p = 0.0187) but not in the MED group (p = 0.8354). However, the observed changes of hs-CRP concentrations (Δhs-CRP) and ADMA levels (ΔADMA) were not different between the groups (p = 0.5307 and p = 0.0905, respectively). CONCLUSIONS: In the Central European post-menopausal obese population, a well-designed, energy-restricted diet with the use of food items traditional for the region (CED) could be a good alternative to MED in terms of AT prevention.

Serum Phospholipid Fatty Acid Composition in Cystic Fibrosis Patients with and without Liver Cirrhosis.

BACKGROUND/AIMS: Cystic fibrosis (CF) liver disease is the third most frequent cause of death in CF patients. Although it alters fatty acid (FA) metabolism, data concerning the profile of FA in CF patients with liver cirrhosis is lacking. This study aimed to assess the FA composition of serum phospholipids in CF patients with and without liver cirrhosis. METHODS: The study comprised 25 CF patients with liver cirrhosis and 25 without it. We assessed Z-scores for body height and weight, lung function, exocrine pancreatic sufficiency and colonization with Pseudomonas aeruginosa. FAs' profile of serum glycerophospholipids was quantified by gas chromatography mass spectrometry. RESULTS: In CF patients with liver cirrhosis, the levels of C16:0 were higher and the amounts of C20:2n-6, C20:3n-6, C20:4n-6, and all the n-3 polyunsaturated FAs (PUFAs) (C18:3n-3, C20:5n-3, C22:5n-3, C22:6n-3) were lower than those in CF subjects without liver cirrhosis. The n-6/n-3, C20:4n-6/C18:2n-6, total n-6/C18:2n-6, C20:5n-3/C18:3n-3 and total n-3/C18:3n-3 ratios did not differ between the 2 groups. CONCLUSIONS: Liver cirrhosis may associate with profound abnormalities in the composition of serum glycerophospholipids FAs in CF patients. None of the analyzed clinical factors could explain the greater prevalence of low levels of PUFAs in this CF subgroup.

Vitamin K status in cystic fibrosis patients with liver cirrhosis.

The available data on the influence of liver cirrhosis on vitamin K status in CF patients is scarce. Therefore, the aims of the present study were to assess the prevalence of vitamin K deficiency in cirrhotic CF subjects and to determine whether it correlates with liver cirrhosis. The study group comprised of 27 CF patients with and 63 without liver cirrhosis. Vitamin K status was assessed using prothrombin induced by vitamin K absence (PIVKA-II) and the percentage of undercarboxylated osteocalcin (u-OC). PIVKA-II concentrations were higher in cirrhotic than in non-cirrhotic CF patients (median [1st-3rd quartile]: 3.2ng/ml [1.0-10.0] vs. 1.3ng/ml [0.2-2.6], p=0.0029). However, the differences in u-OC percentages between the studied groups did not reach the level of significance (49.4% [7.0-73.8] vs. 8.0% [2.6-59.1], p=0.0501). Based on multiple linear regression analysis the dose of vitamin K and F508del mutation were potentially defined as determinants of vitamin K deficiency. Liver cirrhosis was not documented to be an independent risk factor. In CF patients with liver cirrhosis vitamin K deficiency is not only more frequent, but also more severe. However, not liver cirrhosis, but the presence of a F508del CFTR mutation constitutes an independent risk factor for vitamin K deficiency.

Twelve-week-conjugated linoleic acid supplementation has no effects on the selected markers of atherosclerosis in obese and overweight women.

BACKGROUND: The antiatherogenic effect of conjugated linoleic acid (CLA) has been demonstrated in animal models. Although there are plenty of in vitro studies that suggest the profitable properties of CLA, the results in humans remain inconsistent. OBJECTIVE: In this study, we assessed the impact of CLA supplementation on the levels of atherosclerosis markers - high-sensitivity C-reactive protein (hs-CRP) and asymmetrical dimethylarginine (ADMA). DESIGN: Seventy-four adult female subjects with body mass index ≥25 kg/m2 were enrolled in the double-blind, placebo-controlled nutritional intervention. The study participants were randomly assigned to receive 3 g/day CLA or placebo (sunflower oil) for 12 weeks. In all subjects, we measured hs-CRP and ADMA concentrations by using enzyme-linked immunosorbent assay. RESULTS: No significant differences were found in hs-CRP and ADMA levels before and after nutritional intervention between both groups. The changes in hs-CRP and ADMA concentration values (Δhs-CRP; ΔADMA median [interquartile range]) did not differ between subjects from the placebo (-0.1 [-0.8 to 0.3]; -0.02 [-0.12 to 0.14]) and CLA (0.2 [-0.7 to 0.9]; 0.04 [-0.14 to 0.13]) groups. The incidence of reduction of hs-CRP or ADMA concentration was not different in subjects of the CLA group compared to those of the placebo group (41.9% vs. 50%, relative risk [RR]=0.8387, 95% confidence interval [CI]=0.4887-1.4493, p=0.5232 and 61.3% vs. 56.2%, RR=1.0896, 95% CI=0.7200-1.6589, p=0.6847, respectively). CONCLUSION: Twelve weeks of CLA supplementation had no effect on selected markers of atherosclerosis in obese and overweight women.

Phenylketonuria is not a risk factor for changes of inflammation status as assessed by interleukin 6 and interleukin 8 concentrations.

BACKGROUND: High oxidative stress and a reduced potential for free radical scavenging in phenylketonuria (PKU) patients, a phenomenon confirmed in a few studies, may lead to systemic chronic inflammation. The aim of this study was to compare the inflammation status, as assessed by interleukin 6 and interleukin 8 concentrations, in patients with PKU and in healthy controls. METHODS: Twenty patients with classical PKU, aged 18-34 years and under dietary control, were enrolled in the study. The control group comprised of 20 healthy subjects matched for age and sex. Interleukin 6 and 8 levels were measured by enzyme-linked immunosorbent assay (ELISA) kits in all study participants. RESULTS: IL-6 concentrations in the study group ranged from 0.74 pg/ml to 1.34 pg/ml. No significant differences were found between IL-6 concentration between the study group and the control group (p = 0.989). IL-8 concentrations ranged from 17.56 pg/ml to 20.87 pg/ml. The obtained results of IL-8 levels did not differ significantly between the study group and control group (p = 0.192). No significant correlation was observed between Phe blood levels and IL-6 or IL-8 concentrations in the study group (ρ respectively: -0.225, 0.177). In a multivariate analysis, neither IL-6 nor IL-8 concentrations were correlated with sex, age, BMI and Phe levels. CONCLUSIONS: Phenylketonuria is not a risk factor for changes of inflammation status as assessed by IL-6 and IL-8 concentrations.