Publications by authors named "Serap Sivri"

32 Publications

Correction to: DNAJC12 deficiency in patients with unexplained hyperphenylalaninemia: two new patients and a novel variant.

Metab Brain Dis 2021 Jun 9. Epub 2021 Jun 9.

Division of Pediatric Metabolism, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

A Correction to this paper has been published: https://doi.org/10.1007/s11011-021-00759-8.
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http://dx.doi.org/10.1007/s11011-021-00759-8DOI Listing
June 2021

DNACJ12 deficiency in patients with unexplained hyperphenylalaninemia: two new patients and a novel variant.

Metab Brain Dis 2021 May 20. Epub 2021 May 20.

Division of Pediatric Metabolism, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

In addition to tetrahydrobiopterin deficiencies and phenylalanine hydroxylase deficiency (phenylketonuria) due to PAH variants, the deficiency of the co-chaperone protein DNAJC12 was identified in 2017 as a novel cause of inherited hyperphenylalaninemia, revealing the genetic etiology in previously unresolved cases. In this study, we aimed to investigate DNAJC12 deficiency in non-tetrahydrobiopterin-deficient persistent hyperphenylalaninemia cases without biallelic PAH variants in a single pediatric metabolic center. It was determined retrospectively that 471 patients with non-tetrahydrobiopterin deficiency-hyperphenylalaninemia had undergone PAH gene sequencing and 451 patients had biallelic variants in PAH. DNAJC12 sequencing was performed in the remaining 20 patients, identifying a previously reported homozygous splice-site variant (c.158-2A > T) in one patient with axial hypotonia and developmental delay, and a novel, homozygous c.404del (p.Arg135Lysfs*21) frameshift variant in an asymptomatic patient. In segregation analysis, the asymptomatic patient's both parents were also found to be homozygous for this variant and hyperphenylalaninemic. The parents may have had academic difficulties but intellectual disability could not be confirmed due to lack of cooperation. The symptomatic patient significantly benefited from treatment with sapropterin dihydrochloride and neurotransmitter precursors. DNAJC12 deficiency might be responsible for approximately 10% or more of cases with unexplained hyperphenylalaninemia. The phenotypic spectrum is broad, ranging from early infantile hypotonia to incidental diagnosis in adulthood. Similar to tetrahydrobiopterin deficiencies, early diagnosis and treatment with sapropterin dihydrochloride and neurotransmitter precursors can be beneficial, supporting the analysis of DNACJ12 gene in patients with unexplained hyperphenylalaninemia.
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http://dx.doi.org/10.1007/s11011-021-00753-0DOI Listing
May 2021

Complicated peripartum course in a patient with very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency.

Neuromuscul Disord 2021 Apr 9. Epub 2021 Apr 9.

Department of Pediatrics, Pediatric Metabolism and Nutrition Unit, Hacettepe University Faculty of Medicine, Ankara 06230, Turkey. Electronic address:

Very long-chain acyl-coenzyme A (CoA) dehydrogenase (VLCAD) deficiency is an autosomal recessive fatty acid oxidation disorder characterized by rhabdomyolysis, hypoglycemia and cardiomyopathy. The general treatment approach in adult patients is based on the prevention of catabolism. High carbohydrate, low fat diet and supplementation of medium-chain triglycerides are essential in the treatment. There is little experience with pregnancy follow-up in this patient group. We present a complicated peripartum course and successful management in a patient with VLCAD deficiency. Although high-dose glucose infusion was initiated, creatine kinase levels significantly increased in the immediate postpartum period, but the patient remained asymptomatic and rhabdomyolysis resolved rapidly after increasing the glucose infusion rate.
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http://dx.doi.org/10.1016/j.nmd.2021.03.015DOI Listing
April 2021

Evaluation of sleep-disordered breathing and its relationship with respiratory parameters in children with mucopolysaccharidosis Type IVA and VI.

Am J Med Genet A 2021 May 7. Epub 2021 May 7.

Department of Pediatric Pulmonology, School of Medicine, Hacettepe University, Ihsan Dogramaci Children's Hospital, Ankara, Turkey.

The aims of the study were to evaluate the prevalence of sleep-disordered breathing (SDB) by using polysomnography (PSG) in children with MPS IVA and MPS VI who underwent enzyme replacement therapy (ERT) and to analyze the effect on SDB of having upper airway surgery, pulmonary functions, and exercise capacity. A retrospective cross-sectional study was conducted on patients with MPS IVA (n:17) and MPS VI (n:11) aged under 19 years who underwent polysomnography. Descriptive and nonparametric analyses were performed for demographic, PSG, pulmonary function and exercise capacity variables. The frequency of sleep apnea in the study sample was 85.7% (24/28). Four patients (14.3%) had no sleep apnea, 15 (53.6%) had mild, and nine (32.1%) had moderate-to-severe sleep apnea. Two patients (7.1%) had central sleep apnea and 22 had obstructive sleep apnea (OSA) (78.6%). Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were negatively correlated to apnea-hypopnea index (AHI) (r = -0.594, p = .009; r = -0.636, p = .005, respectively). Despite ERT and previous upper airway surgery, the prevalence of OSA was high in patients with MPS IVA-MPS IV, emphasizing the importance of PSG screening for sleep disorders. Pulmonary function tests may be useful for predicting sleep apnea in patients with MPS IVA and MPS VI.
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http://dx.doi.org/10.1002/ajmg.a.62229DOI Listing
May 2021

Brain MR patterns in inherited disorders of monoamine neurotransmitters: An analysis of 70 patients.

J Inherit Metab Dis 2021 Jan 14. Epub 2021 Jan 14.

Inborn Errors of Metabolism Unit, Department of Neurology, Institut de Recerca Sant Joan de Déu and CIBERER-ISCIII, Barcelona, Spain.

Inherited monoamine neurotransmitter disorders (iMNDs) are rare disorders with clinical manifestations ranging from mild infantile hypotonia, movement disorders to early infantile severe encephalopathy. Neuroimaging has been reported as non-specific. We systematically analyzed brain MRIs in order to characterize and better understand neuroimaging changes and to re-evaluate the diagnostic role of brain MRI in iMNDs. 81 MRIs of 70 patients (0.1-52.9 years, 39 patients with tetrahydrobiopterin deficiencies, 31 with primary disorders of monoamine metabolism) were retrospectively analyzed and clinical records reviewed. 33/70 patients had MRI changes, most commonly atrophy (n = 24). Eight patients, six with dihydropteridine reductase deficiency (DHPR), had a common pattern of bilateral parieto-occipital and to a lesser extent frontal and/or cerebellar changes in arterial watershed zones. Two patients imaged after acute severe encephalopathy had signs of profound hypoxic-ischemic injury and a combination of deep gray matter and watershed injury (aromatic l-amino acid decarboxylase (AADCD), tyrosine hydroxylase deficiency (THD)). Four patients had myelination delay (AADCD; THD); two had changes characteristic of post-infantile onset neuronal disease (AADCD, monoamine oxidase A deficiency), and nine T2-hyperintensity of central tegmental tracts. iMNDs are associated with MRI patterns consistent with chronic effects of a neuronal disorder and signs of repetitive injury to cerebral and cerebellar watershed areas, in particular in DHPRD. These will be helpful in the (neuroradiological) differential diagnosis of children with unknown disorders and monitoring of iMNDs. We hypothesize that deficiency of catecholamines and/or tetrahydrobiopterin increase the incidence of and the CNS susceptibility to vascular dysfunction.
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http://dx.doi.org/10.1002/jimd.12360DOI Listing
January 2021

Glutaric aciduria type 1: Genetic and phenotypic spectrum in 53 patients.

Eur J Med Genet 2020 Nov 7;63(11):104032. Epub 2020 Aug 7.

Hacettepe University Faculty of Medicine, Division of Pediatric Metabolism, Ankara, Turkey. Electronic address:

Introduction: Glutaric aciduria type 1 (GA1) is a rare and inherited autosomal-recessive metabolic disorder that occurs in the deficiency of glutaryl-co-enzyme A dehydrogenase (GCDH) enzyme encoded by GCDH gene. In this study, we aim to retrospectively investigate the clinical, biochemical, and neuroradiological parameters and examine the spectrum of GCDH gene variants in Turkish patients with glutaric aciduria type 1.

Methods: This is a descriptive cross-sectional study. The study was conducted in fifty-three patients from 39 unrelated Turkish families who were diagnosed with GA1 based on their clinical presentation, neuroimaging, and biochemical measurements, at the department of pediatric metabolism of a university hospital between June 1998 and August 2019. Pathogenic variants screening of GCDH gene was performed by direct DNA sequence analysis in forty-six patients with GA1. Pathogenicity of the novel variants was predicted via computational programs.

Results: A total of 53 patients were diagnosed with GA1. Of those, 32 (60.3%) had encephalopathic crisis and 33 (62.3%) had macrocephaly. Twenty different pathogenic variants were detected, 7 of which are novel (p.Glu57Lys, p.Ser145Profs*79, p.Ser246Glyfs*96 p.Ala293Val, p.His348Gln, p.His417Tyr, p.Asp418Val). The p.Arg402Trp, p.Pro248Leu and p.Leu340Phe variants were the most common in Turkish patients, with a frequency of 21.2%, 18.2% and 12.1% respectively.

Conclusion: This study is the first comprehensive research from Turkey that provides information about disease-causing variants in the GCDH gene. The identification of common variants and hot spot regions of the GCDH gene is important for genetic counselling and the prenatal diagnosis of Turkish patients with GA1.
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http://dx.doi.org/10.1016/j.ejmg.2020.104032DOI Listing
November 2020

Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH) deficiencies.

Orphanet J Rare Dis 2020 05 26;15(1):126. Epub 2020 May 26.

Division of Child Neurology and Metabolic Disorders, University Children's Hospital, Heidelberg, Germany.

Background: Tetrahydrobiopterin (BH) deficiencies comprise a group of six rare neurometabolic disorders characterized by insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin due to a disturbance of BH biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH deficiencies, apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency and sepiapterin reductase deficiency. Early supplementation of neurotransmitter precursors and where appropriate, treatment of HPA results in significant improvement of motor and cognitive function. Management approaches differ across the world and therefore these guidelines have been developed aiming to harmonize and optimize patient care. Representatives of the International Working Group on Neurotransmitter related Disorders (iNTD) developed the guidelines according to the SIGN (Scottish Intercollegiate Guidelines Network) methodology by evaluating all available evidence for the diagnosis and treatment of BH deficiencies.

Conclusion: Although the total body of evidence in the literature was mainly rated as low or very low, these consensus guidelines will help to harmonize clinical practice and to standardize and improve care for BH deficient patients.
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http://dx.doi.org/10.1186/s13023-020-01379-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251883PMC
May 2020

Caring for a Child with Phenylketonuria: Parental Experiences from a Eurasian Country.

J Dev Behav Pediatr 2020 04;41(3):195-202

Departments of Pediatrics, Pediatric Metabolism, Biostatistics, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Objectives: Phenylketonuria (PKU) and mild hyperphenylalaninemia (HPA) are characterized by increased blood phenylalanine concentrations varying from mild to severe. Management of PKU was reported to be time consuming and burdensome for caregivers. This study intended to explore the experiences of families caring for a child with PKU/HPA in a country with a high PKU rate. The aim of this study was to compare parental well-being between parents of children with and without dietary restrictions and to explore the factors associated with parental psychological well-being.

Methods: Participants were interviewed about their experiences, concerns, and challenges related to the disease by using a semistructured questionnaire. After the interview, parents filled out the Beck Depression Inventory and State-Trait Anxiety Inventory-Trait.

Results: This study highlighted the adverse psychological, financial, and social effects of the diagnosis and management of the disease regarding the lives of the families of children with PKU/HPA. Although parental anxiety scores of children with and without dietary restrictions were similar, depressive symptom scores were higher in parents of children with dietary restrictions. However, in multiple regression analysis, lower household income and absence of perceived social support were found to be independent factors associated with higher depressive symptom scores. Having a daughter diagnosed with PKU/HPA and lower household income were found to be factors associated with higher anxiety scores.

Conclusion: This study revealed that income level, perceived social support, and gender of the child were factors associated with psychological well-being of parents caring for children with PKU/HPA. Health care professionals should identify the challenges faced by families and should be aware of risk factors associated with lower parental well-being to achieve better family adjustment and better health outcomes.
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http://dx.doi.org/10.1097/DBP.0000000000000748DOI Listing
April 2020

Imaging liver nodules in tyrosinemia type-1: A retrospective review of 16 cases in a tertiary pediatric hospital.

Eur J Radiol 2019 Jul 23;116:41-46. Epub 2019 Apr 23.

Department of Radiology, Hacettepe University School of Medicine Ankara, Turkey.

Objective: To describe the liver imaging findings of Hereditary tyrosinemia type-1 (HT1) patients.

Materials And Methods: We report 16 patients (8 Female and 8 Male) with HT-1. Their demographic features, imaging findings and alpha feto protein (AFP) levels were recorded. Imaging features on CT and MR were evaluated for the following characteristics: contour of the liver and liver nodules. Liver nodules were categorized as; regenerative, dysplastic, fatty and malignant nodules (HCC).

Results: Thirteen (81%) patients had multiple liver nodules (>20) on imaging studies. Five patients (31%) had regenerative nodules, six (38%) had dysplastic nodules and ten (63%) had fatty nodules. Dysplastic nodules were encountered in two patients with HCC and in four patients without a tumor. Four patients (25%) had HCC nodule on imaging studies. Those four patients had biopsy and all of them had HCC nodule on histopathology. In the follow-up period, in one patient fatty nodules had increased in size, in one patient regenerative nodules had disappeared and in one patient dysplastic nodules had disappeared.

Conclusions: Multiple fatty nodules can be seen in HT1 patients and in some patients, the regenerative and dysplastic nodules can disappear during the follow-up period.
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http://dx.doi.org/10.1016/j.ejrad.2019.04.016DOI Listing
July 2019

A rare cause of cutaneous ulceration: Prolidase deficiency.

Int Wound J 2019 Aug 14;16(4):1057-1058. Epub 2019 May 14.

Department of Dermatology and Venereology, School of Medicine, Hacettepe University, Ankara, Turkey.

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http://dx.doi.org/10.1111/iwj.13138DOI Listing
August 2019

Cognitive and behavioral impairment in mild hyperphenylalaninemia.

Turk J Pediatr 2018 ;60(6):617-624

Departments of Pediatric Metabolism, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Evinç SG, Pektaş E, Foto-Özdemir D, Yıldız Y, Karaboncuk Y, Bilginer-Gürbüz B, Dursun A, Tokatlı A, Coskun T, Öktem F, Sivri HS. Cognitive and behavioral impairment in mild hyperphenylalaninemia. Turk J Pediatr 2018; 60: 617-624. As elevated phenylalanine (Phe) is detrimental to brain functions, determining a safe upper limit of blood Phe is important for initiation of treatment plans and setting Phe targets in hyperphenlalaninemic patients. It is accepted that Phe levels below 360 μmol/L does not impair brain function and hence does not require treatment. Therefore, we aimed to compare cognitive functions and attention-related problems among healthy children and untreated patients with hyperphenylalaninemia (HPA). This study included 41 hyperphenylalaninemic patients (`all HPA group`) aged 6-16 years with untreated blood Phe between 240 and 600 μmol/L and 29 healthy controls. `All HPA group` was further divided into 2 subgroups according to their lifetime median blood Phe levels as `Phe 360-600 μmol/L` and `Phe 240-360 μmol/L` groups. Wechsler Intelligence Scale for Children-IV (WISC-IV), Conners` Continuous Performance Test (CPT), Strength and Difficulties Questionnaire (SDQ) and Schedule for Affective Disorders and Schizophrenia for School-Age Children: Present and Lifetime Version (K-SADS-PL) were performed as a comprehensive neurocognitive, attention and behavioral assessment. The study illustrated that `all HPA` patients had significantly lower scores on all WISC-IV indexes compared to controls, except for Working Memory. Both `Phe 360-600 μmol/L` and `Phe 240-360 μmol/L` subgroups had lower Full Scale intelligence quotient (IQ) and Verbal Comprehension scores compared to controls. `All HPA` patients also had longer reaction times and more peer problems than controls, indicating attention deficits and behavioral problems. Since the results demonstrated that children with untreated Phe levels between 240-360 μmol/L are at higher risk for cognitive and attention-related problems, lowering the `safe` upper Phe level should be considered.
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http://dx.doi.org/10.24953/turkjped.2018.06.001DOI Listing
January 2018

Deoxyguanosine kinase deficiency: a report of four patients.

J Pediatr Endocrinol Metab 2017 May;30(6):697-702

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Background: Hepatic involvement is a common feature in childhood mitochondrial disorders. Deoxyguanosine kinase (DGUOK) deficiency is one of the mitochondrial DNA depletion syndromes associated with hepatocerebral syndrome. Hepatic disease and neurologic dysfunction occurs within weeks after birth. Low birth weight is one of the common features. This study aims to describe the clinical and laboratory features of four infants carrying four different pathogenic variants in the DGUOK gene.

Case Presentation: Common clinical findings were progressive cholestatic liver failure, hypoglycemia, hypotonia and rotatory nystagmus in our DGUOK deficiency patients. Lactic acidosis, elevated serum tyrosine and ferritin levels were the striking laboratory features. Cholestasis, iron deposits, microvesicular steatosis and fibrosis were the histopathological findings seen in liver biopsies of two patients. All patients died with multi-organ failure between the ages of 42 days and 6 months.

Conclusions: While neurologic findings may occur later in the course of the disease, elevated serum tyrosine levels may alert the physicians to a DGUOK deficiency in a baby with hepatopathy in the presence of the mentioned signs. Early diagnosis is important not only for genetic counseling but also for a possible liver transplantation.
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http://dx.doi.org/10.1515/jpem-2016-0268DOI Listing
May 2017

Efficacy, safety and population pharmacokinetics of sapropterin in PKU patients <4 years: results from the SPARK open-label, multicentre, randomized phase IIIb trial.

Orphanet J Rare Dis 2017 03 9;12(1):47. Epub 2017 Mar 9.

EMD Serono, Billerica, MA, USA.

Background: Sapropterin dihydrochloride, a synthetic formulation of BH, the cofactor for phenylalanine hydroxylase (PAH, EC 1.14.16.1), was initially approved in Europe only for patients ≥4 years with BH-responsive phenylketonuria. The aim of the SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) trial was to assess the efficacy (improvement in daily phenylalanine tolerance, neuromotor development and growth parameters), safety and pharmacokinetics of sapropterin dihydrochloride in children <4 years.

Results: In total, 109 male or female children <4 years with confirmed BH-responsive phenylketonuria or mild hyperphenylalaninemia and good adherence to dietary treatment were screened. 56 patients were randomly assigned (1:1) to 10 mg/kg/day oral sapropterin plus a phenylalanine-restricted diet or to only a phenylalanine-restricted diet for 26 weeks (27 to the sapropterin and diet group and 29 to the diet-only group; intention-to-treat population). Of these, 52 patients with ≥1 pharmacokinetic sample were included in the pharmacokinetic analysis, and 54 patients were included in the safety analysis. At week 26 in the sapropterin plus diet group, mean phenylalanine tolerance was 30.5 (95% confidence interval 18.7-42.3) mg/kg/day higher than in the diet-only group (p < 0.001). The safety profile of sapropterin, measured monthly, was acceptable and consistent with that seen in studies of older children. Using non-linear mixed effect modelling, a one-compartment model with flip-flop pharmacokinetic behaviour, in which the effect of weight was substantial, best described the pharmacokinetic profile. Patients in both groups had normal neuromotor development and stable growth parameters.

Conclusions: The addition of sapropterin to a phenylalanine-restricted diet was well tolerated and led to a significant improvement in phenylalanine tolerance in children <4 years with BH-responsive phenylketonuria or mild hyperphenylalaninemia. The pharmacokinetic model favours once per day dosing with adjustment for weight. Based on the SPARK trial results, sapropterin has received EU approval to treat patients <4 years with BH-responsive phenylketonuria.

Trial Registration: ClinicalTrials.gov, NCT01376908 . Registered June 17, 2011.
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http://dx.doi.org/10.1186/s13023-017-0600-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343543PMC
March 2017

A Fanconi-Bickel syndrome patient with a novel mutation and accompanying situs inversus totalis.

Turk J Pediatr 2017 ;59(6):693-695

Division of Pediatric Metabolism, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Taştemel-Öztürk T, Bilginer-Gürbüz B, Tekşam Ö, Sivri S. A Fanconi-Bickel syndrome patient with a novel mutation and accompanying situs inversus totalis. Turk J Pediatr 2017; 59: 693-695. Fanconi-Bickel syndrome is a rare autosomal recessive disorder of carbohydrate metabolism, caused by mutations in the SLC2A2 gene, that codes for the glucose transporter protein 2 (GLUT2). The disease is characterized by proximal renal tubular dysfunction, impaired glucose and galactose utilization, and accumulation of glycogen in the liver and kidney. Signs and symptoms of Fanconi-Bickel syndrome begin in infancy and include failure to thrive, hepatomegaly, hypophosphatemic rickets, and short stature. Here in we report a Turkish Fanconi-Bickel syndrome case who also has situs inversus totalis and a novel mutation that has not been described before.
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http://dx.doi.org/10.24953/turkjped.2017.06.012DOI Listing
January 2017

Partial hydatidiform mole in a phenylketonuria patient treated with sapropterin dihydrochloride.

Gynecol Endocrinol 2017 Jan 29;33(1):19-20. Epub 2016 Nov 29.

a Division of Pediatric Metabolism , Department of Pediatrics, Faculty of Medicine, Hacettepe University , Ankara , Turkey.

Strict control of hyperphenylalaninemia is necessary in pregnant women with phenylketonuria (PKU) in order to prevent phenylalanine embryopathy in the fetus, characterized by intrauterine growth restriction, dysmorphic facies, congenital heart disease, microcephaly and intellectual disability, collectively known as maternal PKU syndrome. Sapropterin dihydrochloride (SD), an alternative or adjunct to dietary therapy in patients with tetrahydrobiopterin (BH)-responsive PKU, has recently been used in several cases to treat PKU during pregnancy with satisfactory results. Here, we report two pregnancies treated with SD and unrestricted diet in a patient with BH-responsive mild PKU. The first pregnancy resulted in a partial hydatidiform mole and was terminated, whereas a healthy infant was born from the second pregnancy. Phenylalanine control was optimal in both pregnancies. To the best of our knowledge, this is the first report on the development of partial hydatidiform mole associated with SD treatment and the second report on molar pregnancy in PKU. While the relation between SD and molar pregnancy is unknown, further studies may be needed to investigate the possible effects of SD on fertilization.
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http://dx.doi.org/10.1080/09513590.2016.1247796DOI Listing
January 2017

Screening for mucopolysaccharidoses in the Turkish population: Analytical and clinical performance of an age-range specific, dye-based, urinary glycosaminoglycan assay.

Clin Chim Acta 2017 Jan 15;464:72-78. Epub 2016 Nov 15.

Department of Medical Biochemistry, Faculty of Medicine, Hacettepe University, Ankara, Turkey; Clinical Pathology Laboratory, Hacettepe University Hospitals, Ankara, Turkey. Electronic address:

Comprehensive analytical and diagnostic performance of urinary quantitative GAG analysis with dimethylmethylene blue (DMB) and the age-specific reference ranges were determined in Turkish population, which has a high incidence of MPSs. Precision, linearity, recovery and accuracy/trueness, limits, stability, and effect of interferents were tested according to CLSI guideline. Clinical performance was evaluated with ROC analyses including 45 MPS patients. Intra-day and inter-day precisions were <5% and <11% (CV), respectively. LoD was 9.12mg/L and LoQ was 23.3mg/L. The highest reference values for urinary GAG excretion were determined in an age-specific manner. In the 2-13years age cohort, a cut-off of 89.86mg/g creatinine resulted in 98.07% sensitivity and 93.33% specificity. Proteinuria and hematuria interfered with analysis in some instances. Neither leukocyturia nor pH changes affected the assay. Stability analysis indicated that freezing urine samples for transfer is unnecessary. Of the 45 MPS patient samples evaluated, only three tested negative including MPS II, IVA and VI. Despite limitations due to low levels of urinary GAG excretion in some cases, urinary GAG analysis with DMB with its technical simplicity, low cost, and precise quantitative results, is a valuable screening method, particularly in populations with a high rate of MPSs.
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http://dx.doi.org/10.1016/j.cca.2016.11.015DOI Listing
January 2017

A probable new syndrome with the storage disease phenotype caused by the VPS33A gene mutation.

Clin Dysmorphol 2017 Jan;26(1):1-12

Departments of aPediatric Metabolism bPediatric Neurology cPediatric Pathology Unit, Hacettepe University Faculty of Medicine dDepartment of Pediatric Metabolism, Institute of Child Health, Hacettepe University, Ankara eTurkish National Research Institute of Electronics and Cryptology (UEKAE) fTUBITAK Marmara Research Center, Genetic Engineering and Biotechnology Institute (GEBI), Gebze/Kocaeli, Turkey.

We present a novel multisystem disease in two siblings with clinical features resembling a lysosomal storage disease. These included coarse face, dysostosis multiplex, respiratory difficulty, proteinuria with glomerular foamy cells, neurological involvement with developmental delays, pyramidal signs, and severe chronic anemia. Detailed enzymatic analysis for lysosomal diseases and whole-exome sequencing studies excluded known lysosomal storage diseases in the proband. Subsequently, genome-wide genotyping and exome sequencing analysis of the family indicated two large homozygous regions on chromosomes 5 and 12, and strongly suggested that a homozygous p. R498W missense mutation in the VPS33A gene might be responsible for this novel disease. Segregation analysis in family members and mutation prediction tools' results also supported the damaging effect of the missense mutation on the function of the Vps33a protein, which plays a role in the vesicular transport system. Electron microscopic studies of the cornea of the proband showed findings supportive of dysfunction in vesicular transport. The clinical phenotype and genetic studies support the suggestion that the siblings most probably have a novel disease very likely caused by a VPS33A gene defect.
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http://dx.doi.org/10.1097/MCD.0000000000000149DOI Listing
January 2017

Two Turkish siblings with MEGDEL syndrome due to novel SERAC1 gene mutation.

Turk J Pediatr 2015 Jul-Aug;57(4):388-393

Division of Pediatric Metabolism, Department of Pediatrics Faculty of Medicine, Hacettepe University, Ankara, Turkey.

Association of 3-methylglutaconic aciduria with impaired oxidative phosphorylation, deafness, encephalopathy, leigh-like lesions on brain imaging, progressive spasticity and dystonia defined as a distinct entity under the name of MEGDEL syndrome. It is an autosomal recessive disorder due to mutation in the serine active site-containing protein 1 (SERAC1). SERAC1 is localized at the interface between the mitochondria and the endoplasmic reticulum in the mitochondria-associated membrane fraction that is essential for phospholipid exchange. It was identified as a key player in the phosphatidylglycerol remodeling that is essential for both mitochondrial function and intracellular cholesterol trafficking. Here we report two new Turkish sibling patients affected with MEGDEL syndrome due to SERAC1 gene mutation. The patients were presented with 3-methylglutaconic acid and 3-methylglutaric aciduria, microcephaly, growth retardation, dysmorphic features, severe sensorineural deafness, progressive spasticity, dystonia, seizures, basal ganglia involvement. Metabolic acidosis, mild hyperammonemia and lactic acidemia were accompanied with clinical findings in newborn period.
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February 2017

Sapropterin dihydrochloride treatment in Turkish hyperphenylalaninemic patients under age four.

Turk J Pediatr 2015 May-Jun;57(3):213-8

Division of Pediatric Metabolism, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

Sapropterin enhances phenylalanine hydroxylase activity, thus lowering blood phenylalanine (Phe) concentration while increasing protein tolerance in sapropterin-responsive patients. Initiation of sapropterin treatment in responsive patients as early as possible, especially during the time when brain development is fastest, allows intake of more natural protein as well as micro- and macronutrients. Initiation of sapropterin treatment in the newborn period can make exclusive breastfeeding possible. Reports on the efficacy and safety of sapropterin in phenylketonuria (PKU) children under age four are limited in the literature. The purpose of this study is to evaluate the efficacy and safety of sapropterin treatment in infants and children with hyperphenylalaninemia (HPA) and to assess whether genotype analyses are of help in the prediction of responsiveness in these children. Clinical features as well as dietary characteristics were examined in 44 patients undergoing sapropterin treatment. Molecular genetic analysis was performed in 28 of these patients. Phe tolerance increased a median of 2.26-fold (0.88-4.23), from a median of 47.5 mg/kg/day to a median of 114 mg/kg/day (p<0.001). Phe levels could not be kept within normal limits in 5 patients, and thus treatment was stopped due to unsatisfactory metabolic control. In 9 patients, sapropterin treatment was started prior to the initiation of a Phe-restricted diet. Sapropterin treatment was found to be safe and efficacious in patients under age four. Although the BH4 loading test and molecular genetic analysis proved to be useful in detecting responsive patients, these analyses did not enable us to make predictions as to long-term responsiveness.
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August 2016

Glutaric aciduria type 2 presenting with acute respiratory failure in an adult.

Respir Med Case Rep 2015 11;15:92-4. Epub 2015 May 11.

Department of Internal Intensive Care Medicine, Hacettepe University Medicine Faculty Hospital, Ankara, Turkey.

Glutaric aciduria (GTA) type II can be seen as late onset form with myopathic phenotype. We present a case of a 19-year old female with progressive muscle weakness was admitted in intensive care unit (ICU) with respiratory failure and acute renal failure. Patient was unconscious. Pupils were anisocoric and light reflex was absent. She had hepatomegaly. The laboratory results showed a glucose level of 70 mg/dl and the liver enzymes were high. The patient also had hyponatremia (117 mEq/L) and lactate level of 3.9 mmol/L. Tandem MS and organic acid analysis were compatible with GTA type II. Carnitine 1gr, riboflavin 100 mg and co-enzymeQ10 100 mg was arranged. After four months from beginning of treatment tandem MS results are improved. Respiratory failure, acute renal failure due to profound proximal myopathy can be due to glutaric aciduria type II that responded rapidly to appropriate therapy.
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http://dx.doi.org/10.1016/j.rmcr.2015.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501457PMC
August 2015

A case of fucosidosis type II: diagnosed with dysmorphological and radiological findings.

Turk J Pediatr 2014 Jul-Aug;56(4):430-3

Division of Medical Genetics, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Fucosidosis is a rare autosomal recessive lysosomal storage disorder in which fucose-containing glycolipids, glycoproteins and oligosaccharides accumulate in tissues, as a result of a deficiency of α-L-fucosidase. In this report we describe clinical, dysmorphological and radiological findings of a boy with this disorder. Developmental delay, skeletal deformities and mild coarsening of the face began at two years of age. Clinical signs typical for fucosidosis evolved over time. Psychomotor deterioration progressed slowly. At age 12, he could not walk without help; he was admitted to the hospital with intellectual disability, short stature and coarse facial features. A skeletal survey showed dysostosis multiplex. Cranial MRI demonstrated high intensities on the periventricular white matter and low intensities on the basal ganglia on T2-weighted images. Despite the absence of angiokeratoma on the skin, type II fucosidosis with clinical, dysmorphological and radiological signs was suspected. The diagnosis was established on the basis of severely decreased activity of α-L-fucosidase in the leukocytes. The natural history and specific dysmorphic and radiological findings should, even in the absence of angiokeratoma, assist in the differential diagnosis of this rare condition when lysosomal storage disorders are suspected, particularly in populations in which consanguineous marriages are common.
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March 2016

Phenotypic and genotypic spectrum of Turkish patients with isovaleric acidemia.

Eur J Med Genet 2014 Oct 8;57(10):596-601. Epub 2014 Sep 8.

Hacettepe University, Faculty of Medicine, Department of Pediatrics, Metabolism Unit, Ankara, Turkey. Electronic address:

We aim to investigate the genetic basis of isovaleryl-CoA dehydrogenase (IVD) gene mutations and genotype-phenotype correlations in Turkish patients. Accordingly, bi-directional sequencing was performed to screen 26 patients with isovaleric acidemia (IVA). Nine novels (c.145delC, c.234 + 3G > C, c.506_507insT, p.Glu85Gln, p.Met147Val, p.Ala268Val, p.Ile287Met, p.Gly346Asp and p.Arg382Trp) and six previously reported (c.456 + 2T > C, p.Arg21His, p.Arg21Pro, p.Arg363Cys, p.Arg363His p.Glu379Lys) pathogenic mutations were identified. Pathogenicity of the novel mutations was supported using computational programs. No clear genotype-phenotype correlation could be determined. One of the cases with the novel c.234 + 3G > C mutation has portoseptal liver fibrosis, the clinical condition that was first reported for IVA. This study is the first comprehensive report from Turkey related to IVA genetics that provides information about the high number of disease-causing novel mutations.
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http://dx.doi.org/10.1016/j.ejmg.2014.08.006DOI Listing
October 2014

Mucopolysaccharidosis: Otolaryngologic findings, obstructive sleep apnea and accumulation of glucosaminoglycans in lymphatic tissue of the upper airway.

Int J Pediatr Otorhinolaryngol 2014 Jun 27;78(6):944-9. Epub 2014 Mar 27.

Department of Pediatrics, Section of Metabolic Disorders, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Objective: The aim of this study is to evaluate otolaryngologic problems (upper airway obstruction, obstructive sleep apnea, restriction of mouth opening, middle ear effusion, hearing and breathing problems) and their treatments on mucopolysaccharidoses (MPS) patients and to investigate accumulation of glucosaminoglycans (GAG) in the upper airway biochemically and pathologically.

Methods: 76 MPS patients were evaluated. Forty-two MPS patients underwent polysomnography (PSG) for obstructive sleep apnea (OSA). Pre- and postoperative PSG results of 18 patients were compared. The success and complications of treatments for OSA in MPS were evaluated. Biochemical and histopathological accumulation of GAG in tonsil and adenoid tissue and middle ear effusion were analyzed and compared with the control group.

Results: Forty patients out of 42 tested with PSG had OSA (95%). Adenoid grade, Mallampati grade, restricted mouth opening, rate of difficult intubation were significantly different among MPS subtypes. MPS types III and IV had significantly lower Mallampati scores; type VI had significantly worse mouth opening; and type III had significantly better mouth opening and higher rate of easy intubation when compared to other MPS types. There was no significant difference between MPS subtypes according to tonsil grade, adenoid grade, rate of otitis media with effusion and OSA severity. Statistically significant difference was found between GAG accumulation in adenoid tissue and middle ear effusion of MPS and control group (p<0.05). However, GAG accumulation in tonsil was not significantly different between MPS and control group. There was a statistically significant improvement in postop Apnea-Hypopnea Index (AHI) compared to preop AHI (p<0.05).

Conclusions: Most MPS patients have airway obstruction and OSA due to adenotonsillar hypertrophy. Most of these children benefit from adenotonsillectomy, after which OSA significantly improves. They experience high recurrence rate after adenoidectomy; though this is not clinically problematic. They also suffer from conductive hearing loss due to OME, which has to be treated with ventilation tube insertion. However, such operations are usually complicated by difficult endotracheal intubation and restricted mouth opening. Sometimes tracheotomy may be necessary. Tracheotomy is also highly complicated in MPS patients. Significant accumulation of GAG in middle ear fluid and adenoid tissue is present; however, GAG appears not to accumulate in tonsillar tissue.
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http://dx.doi.org/10.1016/j.ijporl.2014.03.021DOI Listing
June 2014

Pregnancy and lactation outcomes in a Turkish patient with lysinuric protein intolerance.

JIMD Rep 2014 20;13:33-6. Epub 2013 Oct 20.

Division of Metabolism, Department of Pediatrics, Hacettepe University, İhsan Doğramacı Children's Hospital, Ankara, Turkey,

Maternal lysinuric protein intolerance (LPI) is associated with increased risk of anemia, toxemia, and retarded growth in fetus during pregnancy, and bleeding complications during delivery. There has been limited number of reports about pregnancy and outcomes of lactation in LPI. Here we present pregnancy and lactation outcomes in a Turkish patient with LPI. In the pregnancy and delivery period, her metabolic status was stable with protein-restricted diet and citrulline. Pathological examination of the placenta revealed multifocal placental infarcts. A successful outcome was achieved with well-controlled anemia, thrombocytopenia despite hemophagocytosis in bone marrow, and placental infarcts during pregnancy. The baby was exclusively breastfed for 6 months. His growth and development was normal. Mild proteinuria started at the fourth month of the delivery. Our case report showed the importance of follow-up of these patients in terms of placental pathologies during pregnancy and for other complications during lactation period.
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http://dx.doi.org/10.1007/8904_2013_259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110330PMC
July 2014

Galactosemia in the Turkish population with a high frequency of Q188R mutation and distribution of Duarte-1 and Duarte-2 variations.

J Hum Genet 2013 Oct 8;58(10):675-8. Epub 2013 Aug 8.

1] Metabolism Unit, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey [2] Institute of Child Health, Hacettepe University, Ankara, Turkey.

Classical galactosemia is an inherited recessive disorder of galactose metabolism caused by deficiency of the enzyme galactose-1-phosphate uridyl transferase (GALT), which is caused by mutations in the GALT gene. In this study, 56 Turkish patients diagnosed with galactosemia were screened for GALT gene mutations using Affymetrix resequencing microarrays. Eleven types of mutations were detected in these patients, including two novel mutations (R258G and G310fsX49) and nine recurrent mutations. We detected six patients who were homozygous for the E340* mutation and for N314D, L218L silent substitutions (Duarte-1 variant) in this study. The haplotype E340*, N314D and L218L has been reported only in Turkish patients, which suggests that the E340* mutation is specific for our population and might be spread by a Turk ancestor. In patients, the Duarte-1 allele was found with a frequency of 10.71%, whereas the Duarte-2 allele was not detected. Duarte-1 and Duarte-2 alleles were found to be present at a frequency of 2.3% and 1.4%, respectively, in the screening of 105 healthy individuals. Considering all detected mutations, it is a very important finding that exons 6 and 10 of the GALT gene account for 79% of all mutant alleles in the Turkish population. The most common mutation is Q188R, with a frequency of 55.35%.
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http://dx.doi.org/10.1038/jhg.2013.76DOI Listing
October 2013

Molecular and clinical evaluation of Turkish patients with lysinuric protein intolerance.

Gene 2013 Jun 28;521(2):293-5. Epub 2013 Mar 28.

Metabolism Unit, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

Lysinuric protein intolerance is an autosomal recessive metabolic disorder caused by defective transport of the cationic amino acids lysine, arginine and ornithine in the epithelial cells of the basolateral membrane in the small intestine and renal tubules. Mutations in the solute carrier family 7, member 7, SLC7A7, gene cause this multisystemic disease with a variety of clinical symptoms such as hepatosplenomegaly, osteoporosis, hypotonia, developmental delay, pulmonary insufficiency or end-stage renal disease. In the present study, genomic structure of SLC7A7 in six Turkish patients with lysinuric protein intolerance was examined in order to detect disease causing mutations by denaturing high pressure liquid chromatography and direct sequencing. Four novel mutations were identified in SLC7A7: c.223insGTC, p.Val74_Ile75insVal; c.283insTGG, p.Glu94_Thr95insTrp; c.344_347delTTGC, p.Leu115LeufsX53; and c.1099insT, p.Ile367TyrfsX16. Clinical and biochemical findings were evaluated together with these molecular analyses.
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http://dx.doi.org/10.1016/j.gene.2013.03.033DOI Listing
June 2013

Microarray based mutational analysis of patients with methylmalonic acidemia: identification of 10 novel mutations.

Mol Genet Metab 2012 Aug 1;106(4):419-23. Epub 2012 Jun 1.

Metabolism Unit, Department of Pediatrics, Hacettepe University, Ankara, Turkey.

Methylmalonic acidemia is an autosomal recessive metabolic disorder affecting the propionate oxidation pathway in the catabolism of several amino acids, odd-chain fatty acids, and cholesterol. Methylmalonic acidemia is characterized by elevated levels of methylmalonic acid in the blood and urine. Mutations in the MUT gene, encoding methylmalonyl-CoA mutase carries out isomerization of L-methylmalonyl-CoA to succinyl-CoA, cause methylmalonic acidemia. In this study, 30 Turkish patients diagnosed with mut methylmalonic acidemia were screened for mutations using custom designed sequencing microarrays. The study resulted in detection of 22 different mutations, 10 of which were novel: p.Q132*, p.A137G, c.753+1T, p.T387I, p.Q514E, p.P615L, p.D625V, c.1962_1963delTC, p.L674F, and c.2115_2116insA. The most common, p.P615T, was identified in 28.0% of patients. These results suggest that microarray based sequencing is a useful tool for the detection of mutations in MUT in patients with mut methylmalonic acidemia.
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http://dx.doi.org/10.1016/j.ymgme.2012.05.014DOI Listing
August 2012

When do we need to perform a diagnostic lumbar puncture for neurometabolic diseases? Positive yield and retrospective analysis from a tertiary center.

Turk J Pediatr 2012 Jan-Feb;54(1):52-8

Unit of Pediatric Neurology, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Neurometabolic diseases diagnosed by cerebrospinal fluid (CSF) examination are GLUT1 deficiency, serine-deficiency syndromes, glycine encephalopathy, cerebral folate deficiency, neonatal vitamin-responsive epileptic encephalopathies, disorders of monoamine metabolism, and y-amino butyric acid (GABA) metabolism. We retrospectively analyzed and compared the demographic, clinical, laboratory, and neuroimaging features of 62 patients in whom CSF examination was performed. Of the 62 patients, 16 (25.8%) had a final diagnosis, including succinic semialdehyde dehydrogenase (SSADH) deficiency (n=4), aromatic amino acid decarboxylase (AADC) deficiency (n=4), L-dopa-responsive dystonia (n=3), glycine encephalopathy (n=2), pyridoxal-phosphate-dependent seizures (n=l), cerebral folate deficiency (n=1), and serine biosynthesi defect (n=1). Parental consanguinity was present in all patients except one Positive yield of a diagnostic lumbar puncture (LP) for the diagnosis of inherited neurotransmitter metabolism disorder was 25.8% overall. Oculogyric crisis (50%), diurnal variation (81.8%) and consanguinity (93.8%) were the only statistically significant variables between patients with and without a specific diagnosis. It is challenging to diagnose neurotransmitter defects, since there is no ideal set of clinical symptoms. In our cohort, consanguinity, diurnal variation and abnormal ocular movements were the most significant findings associated with a diagnosis of a specific neurometabolic disorder based on CSF examination. Early diagnosis is of great importance not only for specific treatment, but also for genetic counseling and prenatal diagnosis.
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April 2012

Four novel mutations in the β-galactosidase gene identified in infantile type of GM1 gangliosidosis.

Clin Biochem 2012 May 3;45(7-8):571-4. Epub 2012 Jan 3.

Department of Medical Biochemistry, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Objectives: The aim of this study is to find out mutations of Turkish GM1 gangliosidosis patients and to make genotype-phenotype correlations.

Design And Methods: β-galactosidase activities were measured by using fluorometric substrate. Mutation screening of 16 exons of β-galactosidase gene and mutation detection were done by PCR-SSCP and DNA sequencing, respectively.

Results: Four new mutations, c.188_189insT in exon 2, c.569_570insA in exon 6, p.K142Q in exon 4, p.G190D in exon 6, and one known mutation p.P549L in exon 15, were identified in the β-galactosidase gene in 5 Turkish patients. Mutations in exons 4 and 6 are in the active site and mutation in exon is in the galactose-binding domain of the β-galactosidase gene.

Conclusion: This is the first mutational analysis performed in Turkish GM1 gangliosidosis patients and shows the molecular heterogeneity of the disease in Turkish population. All identified mutations result in severe enzyme deficiency and infantile phenotype.
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http://dx.doi.org/10.1016/j.clinbiochem.2011.12.019DOI Listing
May 2012