Publications by authors named "Ayşe Çiğdem Aktuğlu Zeybek"

11 Publications

  • Page 1 of 1

Identifying and elucidating the roles of Y198N and Y204F mutations in the PAH enzyme through molecular dynamic simulations.

J Biomol Struct Dyn 2021 May 10:1-12. Epub 2021 May 10.

Faculty of Arts and Sciences, Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey.

Phenylketonuria is an autosomal recessive disorder caused by mutations in the phenylalanine hydroxylase gene. In phenylketonuria causes various symptoms including severe mental retardation. PAH gene of a classical Phenylketonuria patient was sequenced, and two novel heterozygous mutations, p.Y198N and p.Y204F, were found. This study aimed to reveal the impacts of these variants on the structural stability of the PAH enzyme. analyses using prediction tools and molecular dynamics simulations were performed. Mutations were introduced to the wild type catalytic monomer and full length tetramer crystal structures. Variant pathogenicity analyses predicted p.Y198N to be damaging, and p.Y204F to be benign by some prediction tools and damaging by others. Simulations suggested p.Y198N mutation cause significant fluctuations in the spatial organization of two catalytic residues in the temperature accelerated MD simulations with the monomer and increased root-mean-square deviations in the tetramer structure. p.Y204F causes noticeable changes in the spatial positioning of T278 suggesting a possible segregation from the catalytic site in temperature accelerated MD simulations with the monomer. This mutation also leads to increased root-mean-square fluctuations in the regulatory domain which may lead to conformational change resulting in inhibition of dimerization and enzyme activation. Our study reports two novel mutations in the PAH gene and gives insight to their effects on the PAH activity. MD simulations did not yield conclusive results that explains the phenotype but gave plausible insight to possible effects which should be investigated further with and studies to assess the roles of these mutations in etiology of PKU. Communicated by Ramaswamy H. Sarma.
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May 2021

Long-term N-carbamylglutamate treatment of hyperammonemia in patients with classic organic acidemias.

Mol Genet Metab Rep 2021 Mar 30;26:100715. Epub 2021 Jan 30.

Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Department of Pediatrics, Division of Nutrition and Metabolism, Istanbul, Turkey.

Background: Classic organic acidurias (OAs) usually characterized by recurrent episodes of acidemia, ketonuria, and hyperammonemia leading to coma and even death if left untreated. Acute hyperammonemia episodes can be treated effectively with N-carbamylglutamate (NCG). The effect of the long-term efficacy of N-carbamylglutamate is little known.

Material-methods: This retrospective study was conducted at Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Pediatric Nutrition and Metabolism Clinic between January 2012 to January 2018. Patients with classic OAs were enrolled in the study. Patients' ammonia levels, hospitalization needs, hyperammonemia episodes, and management of hyperammonemia were recorded. NCG usage for more than consecutively 15 days was considered as a long-term treatment.

Results: Twenty-one patients, consisting of eleven patients with methylmalonic acidemia (MMA) and ten patients with propionic acidemia (PA) were eligible for the study. N-carbamylglutamate was used as ammonia scavenger for a total of 484 months with a median period of 23 months (min-max: 3-51 months) in all patients. A significant decrease in plasma ammonia levels was detected during long term NCG treatment (55.31 ± 13.762 μmol/L) in comparison with pre NCG treatment period (69.64 ± 17.828 μmol/L) ( = 0.021). Hospitalization required hyperammonemia episodes decreased with NCG treatment ( = 0.013). In addition, hyperammonemia episodes were also successfully treated with NCG ( = 0.000). Mean initial and final ammonia levels at the time of hyperammonemia episodes were 142 ± 46.495 μmol/L and 42.739 ± 12.120 μmol/L, respectively. The average NCG dosage was 85 mg/kg/day (range 12.5-250 mg/kg/day). No apparent side effects were observed.

Conclusion: N-Carbamylglutamate may be deemed an effective and safe treatment modality in the chronic management of hyperammonemia in patients with PA and MMA.
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March 2021

Challenges of following patients with inherited metabolic diseases during the COVID-19 outbreak. A cross-sectional online survey study.

J Pediatr Endocrinol Metab 2021 Jan 12;34(1):103-107. Epub 2020 Nov 12.

Cerrahpasa Medical Faculty, Division of Nutrition and Metabolism, Department of Pediatrics, Istanbul University-Cerrahpaşa, Istanbul, Turkey.

Objectives: There has been a recent worldwide outbreak of coronavirus disease (COVID-19). Most of the health system capacity has been directed to COVID-19 patients, and routine outpatient clinics have been suspended. Chronic disease patients, such as inherited metabolic disorders (IMD), have had trouble accessing healthcare services.

Methods: An online cross-sectional survey was conducted among patients with IMDs who were present for a follow-up at our clinic to address their problems during pandemic period. Our clinic's Instagram and Facebook accounts were used to invite the participants. Three reminders were given between May 1, 2020, and May 30, 2020. Survey questions were analyzed using descriptive statics.

Results: A total of 213 patients completed our survey. Incomplete surveys were excluded, and 175 questionnaires were evaluated. Most of patients had a special diet, and 51% of them had some difficulty with their diet. The reported rate of using a special treatment was 38%, and most of these patients (91%) had no problem receiving these special therapies during this time. Parents who were wearing masks while caring for their child were very few (17%), but a vast majority of parents (73.7%) had high handwashing rates. None of the patients had a SARS-COV2 infection until this paper was written.

Conclusion: This is the first study that aims to determine the problems faced by patients with IMD during the COVİD-19 period. Considering that the pandemic will not immediately pass, recognizing the problems faced by patients with chronic diseases and developing solutions would help these patients avoid long-term damage.
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January 2021

Screening for Fabry Disease in Patients With Juvenile Systemic Lupus Erythematosus.

Arch Rheumatol 2020 Mar 7;35(1):7-12. Epub 2020 Feb 7.

Department of Pediatrics, Division of Nutrition and Metabolism, Istanbul University Cerrahpasa-Cerrahpasa Medical Faculty, Istanbul, Turkey.

Objectives: This study aims to determine the prevalence of Fabry disease (FD) among patients with juvenile systemic lupus erythematosus (SLE).

Patients And Methods: This cross-sectional study included 76 juvenile SLE patients (12 males; 64 females; mean age 16±3.3 years; range, 8 to 23.5 years) who were diagnosed according to 1997 update of the 1982 American College of Rheumatology revised criteria for classification of SLE. Since the majority of patients were female, alpha-galactosidase A gene was investigated for mutations resulting in FD. Lysosomal accumulation of globotriaosylsphingosine (lyso-Gb3) was further evaluated in mutation positive subjects by using dried blood spot testing.

Results: Alpha-galactosidase A gene screening did not yield any positive mutation in our 74 subjects. However, a heterozygous p.D313Y mutation was found in two females. These subjects were further investigated for lyso-Gb3 levels in dried blood spot samples and the levels of lyso-Gb3 being normal lead to exclusion of FD in these two patients.

Conclusion: We do not suggest routine screening of FD in patients with juvenile SLE; however, prospective studies with larger sample sizes are needed for further analysis.
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March 2020

Capillary electrophoresis with capacitively coupled contactless conductivity detection for the determination of urinary ethylmalonic acid for the diagnosis of ethylmalonic aciduria.

J Sep Sci 2020 Apr 9;43(7):1365-1371. Epub 2020 Feb 9.

Cerrahpaşa Medical Faculty, Division of Nutrition and Metabolism, Department of Pediatrics, Istanbul University-Cerrahpaşa, Istanbul, Turkey.

Ethylmalonic acid is a metabolic organic acid, and its accumulation in urine is diagnostic of ethylmalonic aciduria. In this study, a simple and fast method employing capillary electrophoresis equipped with capacitively coupled contactless conductivity detection was developed for the detection of ethylmalonic acid in urine samples. The optimized electrophoretic separation was performed in 50 mmol/L 2-(N-morpholino)ethanesulfonic acid solution, buffered at a pH of 6.5, and contained 0.13 mmol/L cetyltrimethylammonium bromide as an electroosmotic modifier. Electrophoresis was run at 28 kV in reversed polarity. The linear range of ethylmalonic acid concentration was between 1 and 100 mg/L with a regression coefficient of 0.9998. This method had good intra- and interday precision with <5% relative standard deviations. The detection limit (signal-to-noise ratio = 3) and the quantification limit (signal-to-noise ratio = 10) values were 0.139 and 0.466 mg/L, respectively. Using our optimized conditions, the method was successfully employed for the detection of ethylmalonic acid in urine sample of ethylmalonic aciduria patient.
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April 2020

Evaluation of the effect of chenodeoxycholic acid treatment on skeletal system findings in patients with cerebrotendinous xanthomatosis.

Turk Pediatri Ars 2019 11;54(2):113-118. Epub 2019 Jul 11.

Division of Nutrition and Metabolism, Department of Pediatrics, İstanbul University-Cerrahpaşa Faculty of Medicine, İstanbul, Turkey.

Aim: The primary purpose of the present study is to evaluate the effect of chenodeoxycholic acid treatment on skeletal system findings in patients with cerebrotendinous xanthomatosis.

Material And Methods: This retrospective study was conducted between June 2013 and December 2018 with seven patients with cerebrotendinous xanthomatosis in Cerrahpasa Medical Faculty Pediatric Nutrition and Metabolism Department. The clinical, epidemiologic, and genotypic features of the patients were reviewed in detail and the following items, especially related with skeletal system involvement, were recorded from medical data: history of a bone fracture, plasma calcium, phosphate, alkaline phosphatase and 25-hydroxy-vitamin D concentrations, bone mineral density values of the posteroanterior lumbar spine (L1-L4), and femoral neck before and after chenodeoxycholic acid treatment.

Results: Regarding the bone mineral metabolism, plasma calcium, phosphate, alkaline phosphatase levels were found in normal ranges in all patients. Plasma 25-hydroxy-vitamin D evaluation at the time of diagnosis showed deficiency in three patients and insufficiency in three patients. Following chenodeoxycholic acid therapy, 25-hydroxy-vitamin D deficiency persisted in only one patient, but insufficiency was observed in four patients. According to the bone mineral density assessments, four patients had Z-scores below the expected range for age both at initial examination and after chenodeoxycholic acid therapy. No significant difference was observed between plasma 25-hydroxy-vitamin D levels and bone mineral density Z-scores before or after treatment.

Conclusion: This study elucidates the necessity of additional medical treatment as a part of chenodeoxycholic acid therapy to improve skeletal system findings in cerebrotendinous xanthomatosis.
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July 2019

Multimodal imaging including optical coherence tomography angiography in patients with type B Niemann-Pick disease.

Int Ophthalmol 2019 Nov 11;39(11):2545-2552. Epub 2019 Apr 11.

Department of Pediatrics, Division of Nutrition and Metabolism, Istanbul University Cerrahpasa Medical Faculty, Istanbul, Turkey.

Purpose: To evaluate accumulation patterns of deposits in retinal layers of type B Niemann-Pick patients by multimodal imaging.

Methods: Seven patients with type B Niemann-Pick disease were included in this study. All participants underwent a complete ophthalmologic evaluation, high-resolution digital colour imaging, spectral-domain optical coherence tomography, blue light fundus autofluorescence and optical coherence tomography angiography (OCTA).

Results: We demonstrated different accumulation patterns in the retinal ganglion cell layer, the retinal nerve fibre layer and the subfoveolar region by multimodal imaging. Local retinal capillary nonflow areas in the superficial plexus, increased vascular tortuosity and deformed foveal avascular areas were shown in OCTA scans.

Conclusion: Multimodal imaging including OCTA is a useful technique for the identification of different types of accumulation patterns, diagnosis and follow-up of type B Niemann-Pick patients.
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November 2019

Coagulation Disturbances in Patients with Argininemia.

Acta Haematol 2018 24;140(4):221-225. Epub 2018 Oct 24.

Division of Nutrition and Metabolism, Department of Pediatrics, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.

Background: Argininemia is an autosomal recessive urea cycle disorder (UCD). Unlike other UCD, hyperammonemia is rarely seen. Patients usually present in childhood with neurological symptoms. Uncommon presentations like neonatal cholestasis or cirrhosis have been reported. Although transient elevations of liver transaminases and coagulopathy have been reported during hyperammonemia episodes, a permanent coagulopathy has never been reported.

Methods: In this retrospective study, coagulation disturbances are examined in 6 argininemia patients. All of the patients were routinely followed up for hepatic involvement due to argininemia. Laboratory results, including liver transaminases, albumin, prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), and clotting factor levels, were assessed in all of the patients.

Results: All of the patients had a prolonged PT and an increased INR, while none of the patients had a prolonged aPTT. Five patients had slightly elevated liver transaminases. A liver biopsy was performed in 1 patient but neither cirrhosis nor cholestasis was documented. Five of the 6 patients had low factor VII and factor IX levels, while other clotting factors were normal.

Conclusions: Argininemia patients should be investigated for coagulation disorders even if there is no apparent liver dysfunction or major bleeding symptoms.
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June 2019

Hereditary Tyrosinemia Type 1 in Turkey.

Adv Exp Med Biol 2017 ;959:157-172

Cerrahpasa Medical Faculty, Central Laboratories, Metabolic Diseases Unit, University of Istanbul, 34098, Kocamustafapasa Fatih, Istanbul, Turkey.

Hereditary tyrosinemia type 1 (HT1, OMIM 276700) is a rare autosomal recessively inherited inborn error of metabolism in the tyrosine catabolic pathway due to deficiency of the enzyme fumarylacetoacetate hydrolase. The clinical features of HT1 are widely heterogenous even within the same family members. Clinical features includes acute or chronic liver disease with increased risk of hepatocellular carcinoma, hypophosphatemic rickets due to renal tubular dysfunction, glomerulosclerosis, failure to thrive, neurological porphyria-like crisis, hypertrophic cardiomyopathy and hypoglycemia due to hyperinsulinism. Currently, the treatment in HT1 consists of two principles: inhibition of the formation of toxic metabolites by nitisinone [2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione; NTBC] and reduction of tyrosine levels by dietary treatment. In this chapter besides presenting the data for 42 patients that had been followed up by Pediatric Metabolic Diseases and Nutrition Unit, Cerrahpasa Medical Faculty, Istanbul University, we also evaluated the data abstracted from the previously published case studies in order to better understand the disease course and gain further insight in the current diagnosis and treatment for HT1 in Turkey.
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December 2017

Screening of Free Carnitine and Acylcarnitine Status in Children With Familial Mediterranean Fever.

Arch Rheumatol 2016 Jun 10;31(2):133-138. Epub 2016 Mar 10.

Department of Pediatrics Division of Rheumatology, İstanbul University Cerrahpaşa Medical Faculty, İstanbul, Turkey.

Objectives: This study aims to demonstrate the patterns of free carnitine (FC) and acylcarnitine (AC) esters in familial Mediterranean fever (FMF) patients.

Patients And Methods: A total of 205 patients (106 males, 99 females; mean age 131.3±52.1 months; range 24 to 254 months) with FMF and 50 healthy controls (27 males, 23 females; mean age 125.7±49.6 months; range 32 to 217 months) were enrolled. Fasting dried blood samples were taken for showing FC and AC ester levels with tandem mass spectrometry from both patients and controls.

Results: Screening of AC profile revealed increased FC, 3-hydroxypalmitoylcarnitine (C16-OH), and 3-Hydroxy octadecanoylcarnitine (C18:2-OH) carnitine levels, while decreased acetyl-carnitine (C2), propionyl-carnitine (C3), butyryl-carnitine (C4), tiglyl-carnitine (C5:1), hexanoyl-carnitine (C6), octanoyl-carnitine (C8), decenoylcarnitine (C10:1), decadienoylcarnitine (C10:2), malonylcarnitine (C3DC), methylmalonylcarnitine (C4DC), glutarylcarnitine (C5DC), hexadecenoylcarnitine (C16:1), 3-Hydroxy butyrylcarnitine (C4-OH), and 3-Hydroxy oleylcarnitine (C18:1-OH) carnitine levels in FMF patients compared to controls. Total AC levels (p<0.001) and AC to FC ratio (p<0.001) were also lower in FMF patients than the controls.

Conclusion: In this study, we were able to detect some of the AC profile variations in FMF patients; however, usage of carnitine in all patients with FMF is not recommended since we were not able to demonstrate secondary carnitine deficiency in FMF patients of this study.
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June 2016

Differences in the gut microbiota of healthy children and those with type 1 diabetes.

Pediatr Int 2014 Jun 29;56(3):336-43. Epub 2014 Jan 29.

Department of Pediatric Metabolic Disease, Akdeniz University Medical Faculty, Antalya.

Background: Intestinal barriers, intestinal flora, and mucosal immunity are the main factors responsible for the development of various allergic and autoimmune diseases. The aim of this study was to investigate the relationship between the intestinal flora of children and the presence of type 1 diabetes, and to determine if gut microbiota could partly explain the etiology of the disease.

Methods: Fecal flora analysis was done using quantitative cultures on selective and non-selective media with different thermal and atmospheric conditions for bacterial and fungal growth. The study group consisted of 35 patients (16 female, 19 male; mean age, 10.73 ± 4.16 years), who had been followed by the University of Istanbul, Cerrahpasa Medical Faculty, Department of Pediatrics, and were newly diagnosed with type 1 diabetes. The control group consisted of 35 healthy subjects (15 female, 20 male; mean age, 9.96 ± 4.09 years), who were randomly selected and had similar demographics.

Results: Bifidobacterium colonization was lower in patients with type 1 diabetes compared to the control group, whereas Candida albicans and Enterobacteriaceae other than Echerichia coli colonization was increased.

Conclusion: A decrease in beneficial anaerobic bacteria levels and a concomitant increase in Enterobacteriaceae other than E. coli and C. albicans colonization may lead to a disturbance in the ecological balance of intestinal flora, which could be a triggering factor in type 1 diabetes etiology.
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June 2014