Publications by authors named "Turgay Coşkun"

111 Publications

Molecular Etiology of Isolated Congenital Cataract Using Next-Generation Sequencing: Single Center Exome Sequencing Data from Turkey.

Mol Syndromol 2020 Dec 9;11(5-6):302-308. Epub 2020 Sep 9.

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

Congenital cataract, which refers to lenticular opacity diagnosed at birth or more commonly during the first year of life, is one of the leading causes of childhood blindness. Molecular understanding of the disease pathogenesis has evolved thanks to many studies based on modern technologies. In this study, we aimed to identify and discuss the molecular etiology of nonsyndromic or nonmetabolic bilateral congenital cataract by whole-exome sequencing (WES). Patients with bilateral congenital cataract presumed to be isolated after metabolic and genetic evaluation were enrolled in the study. All patients underwent detailed ophthalmological examination and bilateral cataract surgery. DNA samples of the probands, parents, and available affected family members were analyzed by WES. Variants were validated and confirmed by Sanger sequencing in all probands and in available affected family members. A total of 4 patients (3 girls and 1 boy) were recruited. Two patients had nuclear, 1 patient had total, and 1 patient had combined lamellar and sutural cataract. One family had consanguinity. A heterozygous c.215+1G>A mutation in , heterozygous c.432C>G (p.Tyr144Ter) mutation in , heterozygous c.70A>C (p.Pro24Thr) mutation in , and a heterozygous c.466G>A (p.Gly156Arg) mutation in were detected. All these mutations were confirmed by Sanger sequencing in selected affected individuals. The current study identified all causative mutations of congenital cataract in the crystalline genes. The results confirmed that WES is a very useful tool in the investigation of the diseases with heterogeneous genetic background.
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http://dx.doi.org/10.1159/000510481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802443PMC
December 2020

A new UHPLC-MS/MS method for the screening of urinary oligosaccharides expands the detection of storage disorders.

Orphanet J Rare Dis 2021 Jan 9;16(1):24. Epub 2021 Jan 9.

Division of Metabolism and Metabolic Diseases Research Unit, Bambino Gesù Children's Hospital, IRCCS, Viale San Paolo 15, 00146, Rome, Italy.

Background: Oligosaccharidoses are storage disorders due to enzymatic defects involved in the breakdown of the oligosaccharidic component of glycosylated proteins. The defect cause the accumulation of oligosaccharides (OS) and, depending on the lacking enzyme, results in characteristic profiles which are helpful for the diagnosis. We developed a new tandem mass spectrometry method for the screening of urinary OS which was applied to identify a large panel of storage disorders.

Methods: The method was set-up in urine and dried urine spots (DUS). Samples were analysed, without derivatization and using maltoheptaose as internal standard, by UHPLC-MS/MS with MRM acquisition of target OS transitions, including Glc4, the biomarker of Pompe disease. The chromatographic run was < 30 min. Samples from patients with known storage disorders were used for clinical validation.

Results: The method allowed to confirm the diagnosis of oligosaccharidoses (sialidosis, α-/β-mannosidosis, fucosidosis, aspartylglucosaminuria) and of GM1 and GM2 (Sandhoff type) gangliosidosis, by detecting specific OS profiles. In other storage disorders (mucolipidosis II and III, mucopolysaccharidosis type IVB) the analyisis revealed abnormal OS excretion with non-specific profiles. Besides Pompe disease, the tetrasaccharide Glc4 was increased also in disorders of autophagy (Vici syndrome, Yunis-Varon syndrome, and Danon disease) presenting cardiomuscular involvement with glycogen storage. Overall, results showed a clear separation between patients and controls, both in urine and in DUS.

Conclusion: This new UHPLC/MS-MS method, which is suitable for rapid and easy screening of OS in urine and DUS, expands the detection of storage disorders from oligosaccharidoses to other diseases, including the novel category of inherited disorders of autophagy.
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http://dx.doi.org/10.1186/s13023-020-01662-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796585PMC
January 2021

Creatine Transporter Deficiency Presenting as Autism Spectrum Disorder.

Pediatrics 2020 11;146(5)

Pediatric Neurology, Department of Pediatrics and.

Autism spectrum disorder (ASD) is the most common disability-causing neurodevelopmental disorder in childhood. Although inborn errors of metabolism (IEM) are rare causes of ASD, they are significant for several reasons, including implications in genetic counseling and determination of prognosis. In this article, we present a 6-year-old boy who presented to us with ASD and was diagnosed with creatine transporter deficiency. Physical and neurologic examination of this patient had not previously raised suspicion of IEM, but twin pregnancy, prematurity, NICU stay due to necrotizing enterocolitis, transient infantile hypotonia, gross-motor delay, breath-holding spells, and a single febrile seizure complicated the history. MRI revealed mild T2-hyperintensity in posterior periventricular white matter. Further evaluation with magnetic resonance spectroscopy, which showed a decreased creatine peak, led to diagnostic investigations for disorders of creatine metabolism, revealing increased urinary creatine:creatinine ratio and a de novo, novel hemizygous frameshift variant in Clinicians are advised to maintain a high index of suspicion for IEM and to evaluate patients with ASD for syndromic features. Although current guidelines from relevant organizations differ in their recommendations regarding the necessity and the extent of metabolic screening in ASD, there is a growing trend toward screening for treatable IEM. In this case report, we present challenges and pitfalls in the diagnostic journey for creatine transporter deficiency and underline the significance of a thorough history and physical examination in the evaluation of a child with ASD.
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http://dx.doi.org/10.1542/peds.2019-3460DOI Listing
November 2020

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

Two cases of Vici syndrome presenting with corpus callosum agenesis, albinism, and severe developmental delay.

Turk J Pediatr 2020 ;62(3):474-478

Divisions of Pediatric Nutrition and Metabolism, Hacettepe University Faculty of Medicine, Ankara.

Background: Vici syndrome is a rare autosomal recessive disease with phenotypically heterogeneous presentation. Characteristic features of the disease are oculocutaneous albinism, corpus callosum agenesis, cataract, cardiomyopathy, and immunodeficiency.

Case: Here we report two Turkish patients with Vici syndrome. One of these patients had a novel mutation in EPG5 and presented with idiopathic thrombocytopenic purpura (ITP) and maculopapular rashes similar to Stevens-Johnson syndrome, which has been previously reported in only a few cases in the literature.

Conclusion: Vici syndrome presents with a typical phenotype which may facilitate diagnosis for infants with multisystemic disorders. ITP and maculopapular rashes might be added to the spectrum of findings of patients with Vici syndrome.
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http://dx.doi.org/10.24953/turkjped.2020.03.015DOI Listing
January 2020

Expanding the clinical spectrum of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency with Turkish cases harboring novel HMGCS2 gene mutations and literature review.

Am J Med Genet A 2020 07 7;182(7):1608-1614. Epub 2020 Apr 7.

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

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHS) deficiency is a very rare autosomal recessive inborn error of ketone body synthesis and presents with hypoketotic hypoglycemia, metabolic acidosis, lethargy, encephalopathy, and hepatomegaly with fatty liver precipitated by catabolic stress. We report acute presentation of two patients from unrelated two families with novel homozygous c.862C>T and c.725-2A>C mutations, respectively, in HMGCS2 gene. Affected patients had severe hypoketotic hypoglycemia, lethargy, encephalopathy, severe metabolic and lactic acidosis and hepatomegaly after infections. Surprisingly, molecular screening of the second family showed more affected patients without clinical findings. These cases expand the clinic spectrum of this extremely rare disease.
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http://dx.doi.org/10.1002/ajmg.a.61590DOI Listing
July 2020

Oral health status of children with phenylketonuria.

J Pediatr Endocrinol Metab 2020 Mar;33(3):361-365

Department of Pediatric Dentistry, Faculty of Dentistry, Hacettepe University, Ankara, Turkey.

Background Diet plays an integral role in the maintenance of oral health, but dietary modifications due to medical problems such as phenylketonuria (PKU) can have adverse effects on oral health. This descriptive study was performed to evaluate the oral health status of children with PKU. Methods One hundred and ninety-seven patients with PKU aged between 1 and 22 years were evaluated. Clinical evaluations were performed by one experienced dentist regarding dental caries, gingival health and dental erosion. Categorical variables were assessed with descriptive statistics. Differences in feeding frequencies and sociodemographic characteristics were compared regarding dental caries using chi-square (χ2) tests. Results One hundred and thirty-two patients (67%) had dental caries. The mean plaque index (PI) and gingival index (GI) values were 1.37 ± 0.58 and 1.40 ± 0.64, respectively, which shows moderate plaque accumulation and moderate gingival inflammation. Of the patients, 85.3% did not brush their teeth regularly and 90.4% had never visited a dentist before. No statistically significant differences were found in dental caries according to feeding frequencies (p = 0.448). Conclusions Despite the high prevalence of caries in patients with PKU, most had never seen a dentist. Physicians must encourage patients with PKU and their parents to have regular dental visits to maintain an optimal general and oral health.
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http://dx.doi.org/10.1515/jpem-2019-0439DOI Listing
March 2020

Predictors of acute metabolic decompensation in children with maple syrup urine disease at the emergency department.

Eur J Pediatr 2020 Jul 11;179(7):1107-1114. Epub 2020 Feb 11.

Division of Pediatric Metabolism, Department of Pediatrics, Hacettepe University Ihsan Dogramaci Children's Hospital, Ankara, Turkey.

Acute metabolic decompensation (AMD) of maple syrup urine disease (MSUD) must be promptly recognized and treated. In this study, we aimed to identify simple variables associated with AMD in children with MSUD for use in emergency settings. Data were collected retrospectively from 115 emergency visits of 29 children with MSUD over a 4-year period in a major referral hospital. Variables in visits with and without AMD were compared using t test, Mann-Whitney U test, and chi-square test. Logistic regression was used to identify independent variables associated with decompensations. Cut-off values of laboratory variables were determined with receiver operating characteristic curves and correlations with Spearman's rank correlation. Most important variables independently associated with AMD were poor feeding, malaise, anion gap, and especially uric acid, which correlated with leucine levels. Vomiting, dehydration, neurological signs, ketonuria, and ketoaciduria were also associated with AMD. Although sodium, chloride, and glucose were lower in AMD, they had little diagnostic value.Conclusion: In children with MSUD, uric acid and anion gap are key markers for AMD. Poor feeding and malaise are clues before the onset of neurological symptoms. These simple parameters can help determine the presence of AMD in emergency settings.What is Known:• In maple syrup urine disease, acute metabolic decompensations are characterized by gastrointestinal and neurological findings.• Diagnosis requires detection of significantly elevated leucine, which may take a long time or not be available.What is New:• Poor feeding, malaise, hyperuricemia, and high anion gap are parameters that can help diagnose acute decompensations in children with maple syrup urine disease at emergency departments.• Uric acid may be a biomarker for acute decompensations because of its high sensitivity, specificity, and its strong correlation with leucine.
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http://dx.doi.org/10.1007/s00431-020-03602-xDOI Listing
July 2020

Genotypes and estimated prevalence of phosphomannomutase 2 deficiency in Turkey differ significantly from those in Europe.

Am J Med Genet A 2020 04 25;182(4):705-712. Epub 2020 Jan 25.

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

Phosphomannomutase 2 deficiency (PMM2-CDG) is an autosomal recessive congenital disorder of glycosylation, characterized by multisystem phenotypes, mostly including neurological involvement. In Turkey, due to high rates of consanguinity, many patients with autosomal recessive disorders have homozygous variants and these diseases are more common, compared to Europe. However, published reports of PMM2-CDG from Turkey are scarce. Here, we describe clinical and molecular characteristics of PMM2-CDG patients diagnosed in three centers in Turkey, using data obtained retrospectively from hospital records. We also analyzed an in-house exome database of 1,313 individuals for PMM2 variants and estimated allele, carrier and disease frequencies, using the Hardy-Weinberg law. Eleven patients were identified from 10 families, displaying similar characteristics to previous publications, with the exception of the first report of epilepsia partialis continua and increased prevalence of sensorineural hearing loss. p.Val231Met was the most common variant, and was homozygous in four patients. This novel genotype results in a neurological phenotype with subclinical visceral involvement. Exome database analysis showed an estimated prevalence of 1:286,726 for PMM2-CDG, which is much lower than expected (1:20,000 in Europe) because of the lack of predominance of the common European p.Asp141His allele, associated with a severe phenotype (allele frequency of 1:2,622 compared to 1:252 in gnomAD). These data suggest that prevalence, phenotypes and genotypes of PMM2-CDG in Turkey differ significantly from those in Europe: Milder phenotypes may be more common, but the disease itself rarer, requiring a higher clinical suspicion for diagnosis. The association of sensorineural hearing loss with PMM2-CDG warrants further study.
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http://dx.doi.org/10.1002/ajmg.a.61488DOI Listing
April 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

The effectiveness of enzyme replacement therapy on cardiac findings in patients with mucopolysaccharidosis.

J Pediatr Endocrinol Metab 2019 Oct;32(10):1049-1053

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

Background This study aimed to determine cardiac findings in patients with mucopolysaccharidosis (MPS) and to assess the changes in these findings after enzyme replacement therapy (ERT). Methods A retrospective clinical cohort study was conducted on patients who were diagnosed with MPS between 1995 and 2018 in Hacettepe University, Division of Pediatric Metabolism. A total of 96 patients were diagnosed with MPS during the study period. Of these patients, 81 (84.3%) received ERT. Echocardiographic findings of the patients together with the 6-min walking test (6MWT) results before and after ERT were compared. Results Thirty-one participants (38.2%) were female, while 50 (61.8%) were male. The mean age of the participants was 11.97 ± 6.33 years (range: 1.8-30). Five patients (6.2%) had MPS type I, 14 (17.3%) had type II, 28 (34.6%) had type IVa, 33 (40.7%) had type VI and one (1.2%) had type VII. Before ERT, 69.4% of patients had mitral insufficiency (MI; mild: 40.5%, moderate: 16.5%, severe: 12.7%), 35.4% had aortic insufficiency (AI; mild: 22.8%, moderate: 12.7%) and 45.1% had tricuspid insufficiency (TI; mild: 39.2%, moderate: 2.5%). The median duration of the ERT was 3.5 years. The ERT significantly improved left ventricular hypertrophy (LVH), but all other study variables returned non-significant before and after treatment. ERT may improve LVH in MPS. Bearing in mind that MPS is a progressive disease, ERT seems to prevent significant deterioration of this ailment but is not able to reverse the already settled pathologies except for LVH. ERT is not able to reverse the damage, but provides stabilization; so it is best to initiate treatment before cardiac damage.
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http://dx.doi.org/10.1515/jpem-2019-0293DOI Listing
October 2019

Determinants of Riboflavin Responsiveness in Multiple Acyl-CoA Dehydrogenase Deficiency.

Pediatr Neurol 2019 10 28;99:69-75. Epub 2019 Jun 28.

Division of Pediatric Metabolism, Hacettepe University Children's Hospital, Ankara, Turkey.

Background: Multiple acyl-CoA dehydrogenase (MADD) deficiency, which is a rare metabolic disorder involving electron transport flavoproteins, has a wide array of clinical phenotypes. In this article, we describe 25 patients with MADD deficiency and present the clinical and laboratory characteristics and diagnostic challenges associated with riboflavin-responsive MADD deficiency.

Methods: Hospital records of patients with biallelic mutations in ETFA, ETFB, or ETFDH genes diagnosed in a single center were analyzed retrospectively. Demographic, clinical, and laboratory characteristics of patients with riboflavin-responsive and riboflavin-unresponsive MADD deficiency were compared using Mann-Whitney U and Fisher's exact tests.

Results: Respiratory distress and depressed consciousness were significantly more common in patients with riboflavin-unresponsive MADD deficiency (P = 0.015 and P < 0.001), who presented at a younger age (P < 0.001). Patients with riboflavin-responsive MADD deficiency had favorable outcomes but also had life-threatening complications, longer diagnostic delay (median of two years versus 30 days; P < 0.001), and multiple differential diagnoses, resulting in unnecessary investigations and maltreatment. Biopsies showed lipid storage, and complete autopsy was performed in one newborn with riboflavin-unresponsive MADD deficiency, revealing multiple abnormalities. Metabolic profiles were not distinguishable between riboflavin-responsive and riboflavin-unresponsive MADD deficiency (P > 0.05). Four novel variants were detected in ETFDH, one of which (c.1790C>T) may confer riboflavin responsiveness. Siblings with the common myopathic ETFDH c.1130T>C mutation presented with a new phenotype dominated by chronic fatigue without apparent myopathy.

Conclusions: Symptoms and outcomes significantly differed between riboflavin-responsive and unresponsive MADD deficiency, but metabolic profiles did not. Functional studies are needed to better characterize the novel ETFDH variants. As treatment is available for riboflavin-responsive MADD deficiency, physicians should maintain a high index of suspicion for MADD deficiency in all age groups.
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http://dx.doi.org/10.1016/j.pediatrneurol.2019.06.015DOI Listing
October 2019

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

Do not Miss Rare and Treatable Cause of Early-Onset Hemolytic Uremic Syndrome: Cobalamin C Deficiency.

Nephron 2019 28;142(3):258-263. Epub 2019 May 28.

Division of Pediatric Metabolic Diseases, Department of Pediatrics, Hacettepe University, Ankara, Turkey.

The most common disorder of vitamin B12 metabolism is methylmalonic aciduria and homocystinuria type cobalamin C (cblC), which accounts for most of the cases is referred to as cblC deficiency. Cobalamin deficiency is one of the causes of early-onset hemolytic uremic syndrome (HUS). Here, we present the cases of 2 infants with cobalamin deficiency who presented with early-onset HUS. The first patient was a 5-month-old female who was admitted to the hospital with seizure, pallor, and yellow-colored diarrheal stools. Initial laboratory examination showed direct Coombs test-negative hemolytic anemia. Later, she developed acute kidney injury and thrombocytopenia. Bone marrow aspiration showed megaloblastic features, and urinary examination showed elevated levels of methylmalonic acid (MMA), -methyl citrate, and 3-hydroxypropionic acid. Methionine-restricted diet, parenteral hydroxocobalamine, folinic acid, carnitine, and betaine were initiated. Hemolytic activity was -controlled with this treatment. Genetic screening showed homozygous mutation on the MMACHCgene (p.R161*[c.481C>T]). The second patient was a 3-month-old male infant who was admitted to the hospital with malaise and diarrhea. Laboratory examination showed direct Coombs test-negative hemolytic anemia with leukopenia. Later he developed acute kidney injury and thrombocytopenia. Bone marrow aspiration revealed megaloblastic changes. Urine organic acid test showed increased levels of MMA. Parenteral hydroxocobalamine, folinic acid, carnitine, and betaine were initiated. He died due to respiratory failure and cardiac arrest. Direct sequencing of MMACHC identified homozygous mutation, c.271dup A. CblC deficiency is an important cause of early-onset HUS and prompt diagnosis will provide specific treatment modalities.
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http://dx.doi.org/10.1159/000497822DOI Listing
June 2020

Clinical outcomes of two patients with a novel pathogenic variant in : response to asparagine supplementation and review of the literature.

Hum Genome Var 2019 22;6:24. Epub 2019 May 22.

1Faculty of Medicine and University Hospital Cologne, Department of Pediatrics, University of Cologne, 50931 Cologne, Germany.

Asparagine synthetase deficiency (ASNSD, OMIM #615574) is a rare autosomal recessive neurometabolic inborn error that leads to severe cognitive impairment. It manifests with microcephaly, intractable seizures, and progressive cerebral atrophy. Currently, there is no established treatment for this condition. In our pediatric cohort, we discovered, by whole-exome sequencing in two siblings from Turkey, a novel homozygous missense mutation in asparagine synthetase at NM_133436.3 (_v001): c.1108C>T that results in an amino acid exchange p.(Leu370Phe), in the C-terminal domain. After identification of the metabolic defect, treatment with oral asparagine supplementation was attempted in both patients for 24 months. Asparagine supplementation was well tolerated, and no further disease progression was observed during treatment. One of our patients showed mild developmental progress with increased levels of attention and improved nonverbal communication. These results support our hypothesis that asparagine supplementation should be further investigated as a treatment option for ASNSD. We further reviewed all previously reported ASNSD cases with regard for their clinical phenotypes and brain imaging findings to provide an essential knowledge base for rapid diagnosis and future clinical studies.
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http://dx.doi.org/10.1038/s41439-019-0055-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531480PMC
May 2019

International best practice for the evaluation of responsiveness to sapropterin dihydrochloride in patients with phenylketonuria.

Mol Genet Metab 2019 05 26;127(1):1-11. Epub 2019 Apr 26.

Genetic Metabolic Disorders Service, University of Sydney, Children's Hospital Westmead Clinical School, Sydney, NSW, Australia. Electronic address:

Phenylketonuria (PKU) is an inherited metabolic disease caused by phenylalanine hydroxylase (PAH) deficiency. As the resulting high blood phenylalanine (Phe) concentration can have detrimental effects on brain development and function, international guidelines recommend lifelong control of blood Phe concentration with dietary and/or medical therapy. Sapropterin dihydrochloride is a synthetic preparation of tetrahydrobiopterin (6R-BH4), the naturally occurring cofactor of PAH. It acts as a pharmacological chaperone, reducing blood Phe concentration and increasing dietary Phe tolerance in BH4-responsive patients with PAH deficiency. Protocols to establish responsiveness to sapropterin dihydrochloride vary widely. Two meetings were held with an international panel of clinical experts in PKU management to develop recommendations for sapropterin dihydrochloride response testing. At the first meeting, regional differences and similarities in testing practices were discussed based on guidelines, a literature review, outcomes of a global physician survey, and case reports. Statements developed based on the discussions were sent to all participants for consensus (>70% of participants) evaluation using a 7-level rating system, and further discussed during the second meeting. The experts recommend sapropterin dihydrochloride response testing in patients with untreated blood Phe concentrations of 360-2000 μmol/L, except in those with two null mutations. For neonates, a 24-h sapropterin dihydrochloride loading test is recommended; responsiveness is defined as a decrease in blood Phe ≥30%. For older infants, children, adolescents, and adults, a test duration of ≥48 h or a 4-week trial is recommended. The main endpoint for a 48-h to 7-day trial is a decrease in blood Phe, while improved Phe tolerance is the endpoint to be assessed during a longer trial. Longer trials may not be feasible in some locations due to lack of reimbursement for hospitalization, while a 4-week trial may not be possible due to limited access to sapropterin dihydrochloride or public health regulation. A 48-h response test should be considered in pregnant patients who cannot achieve blood Phe ≤360 μmol/L with a Phe-restricted diet. Durability of response and clinical benefits of sapropterin dihydrochloride should be assessed over the long term. Harmonization of protocols is expected to improve identification of responders and comparability of test results worldwide.
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http://dx.doi.org/10.1016/j.ymgme.2019.04.004DOI Listing
May 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

Genotypic-phenotypic features and enzyme replacement therapy outcome in patients with mucopolysaccharidosis VI from Turkey.

Am J Med Genet A 2017 Nov 8;173(11):2954-2967. Epub 2017 Sep 8.

Hacettepe University Children Hospital, Division of Metabolism, Ankara, Turkey.

Mucopolysaccharidosis type VI (MPS VI) is a lysosomal storage disorder (LSD) characterized by a chronic, progressive course with multiorgan involvement. In our study, clinical, biochemical, molecular findings, and response to enzyme replacement therapy (ERT) for at least 6 months were evaluated in 20 patients with MPS VI. Treatment effects on clinical findings such as liver and spleen sizes, cardiac and respiratory parameters, visual and auditory changes, joints' range of motions, endurance tests and changes in urinary glycosaminoglycan excretions, before and after ERT were analyzed. ERT caused increased physical endurance and decreased urinary dermatan sulfate/chondroitin sulfate ratios. Changes in growth parameters, cardiac, respiratory, visual, auditory findings, and joint mobility were not significant. All patients and parents reported out an increased quality of life, which were not correlated with clinical results. The most prevalent mutation was p.L321P, accounting for 58.8% of the mutant alleles and two novel mutations (p.G79E and p.E390 K) were found. ERT was a safe but expensive treatment for MPS VI, with mild benefits in severely affected patients. Early treatment with ERT is mandatory before many organs and systems are involved.
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http://dx.doi.org/10.1002/ajmg.a.38459DOI Listing
November 2017

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

Late-diagnosed phenylketonuria in an eight-year-old boy with dyslexia and attention-deficit hyperactivity disorder.

Turk J Pediatr 2016 ;58(1):94-96

Pediatric Metabolic Diseases Unit, Department of Pediatrics, Hacettepe University Faculy of Medicine, Ankara, Turkey.

Phenylketonuria, previously a common cause of severe intellectual disability, is a metabolic disorder now promptly diagnosed and effectively treated thanks to newborn screening programs. Here, we report a male patient presenting with dyslexia and attention-deficit hyperactivity disorder, who was diagnosed with mild phenylketonuria at eight years of age. Earlier recognition and treatment before the establishment of irreversible brain damage would have resulted in better neurobehavioural outcomes. Classical phenylketonuria and milder phenotypes of phenylalanine hydroxylase deficiency need to be considered in the differential diagnosis of all cognitive and behavioural problems of unknown cause.
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http://dx.doi.org/10.24953/turkjped.2016.01.014DOI Listing
June 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

Evaluation and identification of IDUA gene mutations in Turkishpatients with mucopolysaccharidosis type I.

Turk J Med Sci 2016 Feb 17;46(2):404-8. Epub 2016 Feb 17.

Department of Biology, Faculty of Science and Arts, Aksaray University, Aksaray, Turkey.

Background/aim: This study aimed to identify IDUA gene mutations in Turkish patients morphologically (phenotypic) diagnosed with MPS type I. It also sought to discuss the possible effects of detected mutations on alpha-L-iduronidase enzyme function based on current knowledge.

Materials And Methods: Genetic analysis was carried out in 15 patients using direct DNA sequencing. Moreover, segregation analysis was performed among family members to predict the pathogenic effect of novel mutations, and computational programs were used to predict their functional impact.

Results: Nine different mutations (c.494-1G>A, c.793-6C>G, c.793-5C>A, p.M1L, p.Y64X, p.A327P, p.W402X, p.P533L, and p.R628X) were identified. Computational analysis results supported the pathogenicity of novel mutations, suggesting improper splicing. Seven already-known polymorphisms were detected in the screened cohort as well.

Conclusion: Our results revealed heterogeneity in the mutation spectrum of Turkish patients. Six of the mutations, including the novel ones, have never before been reported in the Turkish population. Moreover, 5 patients who were phenotypically diagnosed with MPS type I could not be confirmed by genetic analysis, indicating the importance of the molecular characterization of MPS subtypes.
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http://dx.doi.org/10.3906/sag-1411-160DOI Listing
February 2016

Riboflavin-Responsive and -Non-responsive Mutations in FAD Synthase Cause Multiple Acyl-CoA Dehydrogenase and Combined Respiratory-Chain Deficiency.

Am J Hum Genet 2016 Jun;98(6):1130-1145

Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.

Multiple acyl-CoA dehydrogenase deficiencies (MADDs) are a heterogeneous group of metabolic disorders with combined respiratory-chain deficiency and a neuromuscular phenotype. Despite recent advances in understanding the genetic basis of MADD, a number of cases remain unexplained. Here, we report clinically relevant variants in FLAD1, which encodes FAD synthase (FADS), as the cause of MADD and respiratory-chain dysfunction in nine individuals recruited from metabolic centers in six countries. In most individuals, we identified biallelic frameshift variants in the molybdopterin binding (MPTb) domain, located upstream of the FADS domain. Inasmuch as FADS is essential for cellular supply of FAD cofactors, the finding of biallelic frameshift variants was unexpected. Using RNA sequencing analysis combined with protein mass spectrometry, we discovered FLAD1 isoforms, which only encode the FADS domain. The existence of these isoforms might explain why affected individuals with biallelic FLAD1 frameshift variants still harbor substantial FADS activity. Another group of individuals with a milder phenotype responsive to riboflavin were shown to have single amino acid changes in the FADS domain. When produced in E. coli, these mutant FADS proteins resulted in impaired but detectable FADS activity; for one of the variant proteins, the addition of FAD significantly improved protein stability, arguing for a chaperone-like action similar to what has been reported in other riboflavin-responsive inborn errors of metabolism. In conclusion, our studies identify FLAD1 variants as a cause of potentially treatable inborn errors of metabolism manifesting with MADD and shed light on the mechanisms by which FADS ensures cellular FAD homeostasis.
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http://dx.doi.org/10.1016/j.ajhg.2016.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908180PMC
June 2016

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

Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency.

J Inherit Metab Dis 2016 05 1;39(3):331-340. Epub 2016 Apr 1.

Clinic for Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria.

Background: Arginase 1 (ARG1) deficiency is a rare urea cycle disorder (UCD). This hypothesis-generating study explored clinical phenotypes, metabolic profiles, molecular genetics, and treatment approaches in a cohort of children and adults with ARG1 deficiency to add to our understanding of the underlying pathophysiology.

Methods: Clinical data were retrieved retrospectively from physicians using a questionnaire survey. Plasma aminoacids, guanidinoacetate (GAA), parameters indicating oxidative stress and nitric oxide (NO) synthesis as well as asymmetric dimethylarginine (ADMA) were measured at a single study site.

Results: Nineteen individuals with ARG1 deficiency and 19 matched controls were included in the study. In patients, paraparesis, cognitive impairment, and seizures were significantly associated suggesting a shared underlying pathophysiology. In patients plasma GAA exceeded normal ranges and plasma ADMA was significantly elevated. Compared to controls, nitrate was significantly higher, and the nitrite:nitrate ratio significantly lower in subjects with ARG1 deficiency suggesting an advantage for NO synthesis by inducible NO synthase (iNOS) over endothelial NOS (eNOS). Logistic regression revealed no significant impact of any of the biochemical parameters (including arginine, nitrates, ADMA, GAA, oxidative stress) or protein restriction on long-term outcome.

Conclusion: Three main hypotheses which must be evaluated in a hypothesis driven confirmatory study are delineated from this study: 1) clinical manifestations in ARG1 deficiency are not correlated with arginine, protein intake, ADMA, nitrates or oxidative stress. 2) GAA is elevated and may be a marker or an active part of the pathophysiology of ARG1 deficiency. 3) Perturbations of NO metabolism merit future attention in ARG1 deficiency.
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http://dx.doi.org/10.1007/s10545-016-9928-yDOI Listing
May 2016

Conventional and advanced MR imaging in infantile Refsum disease.

Turk J Pediatr 2015 May-Jun;57(3):294-9

Divisions of Pediatric Nutrition and Metabolism, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.

We report magnetic resonance (MR) imaging findings including diffusion-weighted imaging and proton MR spectroscopy findings in a patient with infantile Refsum disease. The initial diagnosis was made on the basis of history, clinical findings and biochemical studies. Bilateral and symmetrical involvement of the peritrigonal white matter, centrum semiovale, thalami, corpus callosum and corticospinal tracts as assessed by increased T2 signal was highly suggestive of a peroxisomal disorder. Facilitated diffusion was observed in diseased parenchyma. Long echo-time (TE: 270 ms) MRS showed decreased N-acetyl-aspartate/creatine and elevated choline/creatine and lactate; short echo-time MRS (TE: 30 ms) revealed increased myoinositol at 3.56 ppm and lipid peaks at 0.9 and 1.3 ppm. A major contribution to the differential diagnosis came from MR imaging and proton MRS, as discussed in this report.
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August 2016

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

Brown-Vialetto-Van Laere syndrome: two siblings with a new mutation and dramatic therapeutic effect of high-dose riboflavin.

J Pediatr Endocrinol Metab 2016 Feb;29(2):227-31

Brown-Vialetto-Van Laere syndrome (BVVLS) is a rare and severe neurometabolic disease. We present two siblings with BVVLS with a novel homozygous mutation in SLC52A3 (formerly C20orf54) gene. The first sibling was admitted with respiratory insufficiency and required mechanical ventilation. After administration of a high dose of riboflavin, all his clinical symptoms were resolved, which also strongly suggested the diagnosis of BVVLS. The second sibling was also found to have the same genetic mutation as her brother. Although she was symptom-free, riboflavin was initiated empirically. On follow-up, she developed no neurologic or metabolic problems with entirely normal growth and development. BVVLS should be considered in the differential diagnosis of unexplained neurologic symptoms such as polyneuropathy and respiratory insufficiency, as BVVLS and multiple acyl-CoA dehydrogenation defect have broadly overlapping symptoms. Furthermore, our cases once again suggest that with proper diagnosis and early high-dose riboflavin treatment, complete reversal of neurologic deficits in BVVLS is possible.
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http://dx.doi.org/10.1515/jpem-2015-0198DOI Listing
February 2016