Melis Köse

Children's Hospital of Philadelphia

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Ebru Canda

Ege University

MÇ

Mahmut Çöker

Ege University

Mehtap Kağnıcı

Antalya Eğitim ve Araştırma Hastanesi

Sema Kalkan Uçar

Ege University

AÜ

Aycan Ünalp

Sağlık Bilimleri Üniversitesi

ÜY

Ünsal Yılmaz

Sağlık Bilimleri Üniversitesi

HÖ

Hüseyin Önay

Ege University

FÖ

Ferda Özkınay

Ege University

Engi̇n Köse

Ankara University

Eser Yıldırım Sözmen

Ege University

Cooperative Institutions

Sağlık Bilimleri Üniversitesi

128

European Atherosclerosis Society

Izmir University

Dr. Behçet Uz Çocuk Hastalıkları Hastanesi

Ege University

Izmir Tepecik Eğitim ve Araştırma Hastanesi

Ministry of Health

University of Health Science

Dokuz Eylül University

Pediatrics and Genetics

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Haematological Manifestations of Inborn Errors of Metabolism

Acta Scientific Paediatrics (2020)

Melis Köse Yeşim Oymak

Introduction: Multisystemic involvement of inborn errors of metabolism (IEMs) makes treatment and follow-up of these diseases difficult.Haematological manifestations are significantly important for both treatment and follow-up processes of IEMs.This study evaluated haematological manifestations that may coexist with IEM disorders and affect the diagnosis process to raise awareness of IEMs coexisting with haematological findings. Materials and Methods:In this study, medical records of 132 patients diagnosed with IEM were examined retrospectively, and the data of 43 patients with haematological findings at the time of diagnosis were evaluated.The information assessed included demographic findings, diagnosis, age at diagnosis, follow-up period, haematological manifestation, and coexisting findings.Results: An evaluation of the haematological abnormalities at the time of diagnosis showed that of the 43 patients 15 (33.3%) had neutropenia, 3 (7.1%)had pancytopenia, 15 (34.3%) had iron deficiency anaemia (IDA), 15 (35.7%) had thrombocytopenia, 7 (16.6%)had coagulation abnormalities, 1 (2.3%) had hemolytic anaemia, 1 (2.3%) had hemophagocytic lymphohistiocytosis (HLH), and 7 (16.6%)had coagulation abnormalities.Overall, 15 (35.7%) patients had chronic anaemia. Conclusion:The results show that hematologic abnormalities are very common features of IEM.The findings are valuable for raising awareness of hematologic manifestations in these disorders.

10.31080/aspe.2021.04.0332

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The Second Case of Saposin A Deficiency and Altered Autophagy

JIMD Reports (2018)

Melis Köse Seçil Akyıldız Demir Gülçin Akıncı Cenk Eraslan Ünsal Yılmaz

Krabbe disease is a lysosomal storage disease caused by galactosylceramidase deficiency, resulting in neurodegeneration with a rapid clinical downhill course within the first months of life in the classic infantile form. This process may be triggered by the accumulation of galactosylceramide (GalCer) in nervous tissues. Both the enzyme galactosylceramidase and its in vivo activator molecule, saposin A, are essential during GalCer degradation. A clinical manifestation almost identical to Krabbe disease is observed when, instead of the galactosylceramidase protein, the saposin A molecule is defective. Saposin A results from posttranslational processing of the precursor molecule, prosaposin, encoded by the PSAP gene. Clinical and neuroimaging findings in a 7-month-old child strongly suggested Krabbe disease, but this condition was excluded by enzymatic and genetic testing. However, at whole exome sequencing, the previously undescribed homozygous, obviously pathogenic PSAP gene NM_002778.3:c.209T>G(p.Val70Gly) variant was determined in the saposin A domain of the PSAP gene. Fibroblast studies showed GalCer accumulation and the activation of autophagy for the first time in a case of human saposin A deficiency. Our patient represents the second known case in the literature and provides new information concerning the pathophysiology of saposin A deficiency and its intralysosomal effects.

Lysosomal storage disease

10.1007/8904_2018_114

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Three-Country Snapshot of Ornithine Transcarbamylase Deficiency

Life (2022)

Berna Şeker Yılmaz Julien Baruteau Nur Arslan Halil İbrahim Aydın Magalie Barth

X-linked ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle defect. The disease severity ranges from asymptomatic carrier state to severe neonatal presentation with hyperammonaemic encephalopathy. We audited the diagnosis and management of OTCD, using an online 12-question-survey that was sent to 75 metabolic centres in Turkey, France and the UK. Thirty-nine centres responded and 495 patients were reported in total. A total of 208 French patients were reported, including 71 (34%) males, 86 (41%) symptomatic and 51 (25%) asymptomatic females. Eighty-five Turkish patients included 32 (38%) males, 39 (46%) symptomatic and 14 (16%) asymptomatic females. Out of the 202 UK patients, 66 (33%) were male, 83 (41%) asymptomatic and 53 (26%) symptomatic females. A total of 19%, 12% and 7% of the patients presented with a neonatal-onset phenotype in France, Turkey and the UK, respectively. Vomiting, altered mental status and encephalopathy were the most common initial symptoms in all three countries. While 69% in France and 79% in Turkey were receiving protein restriction, 42% were on a protein-restricted diet in the UK. A total of 76%, 47% and 33% of patients were treated with ammonia scavengers in Turkey, France and the UK, respectively. The findings of our audit emphasize the differences and similarities in manifestations and management practices in three countries.

Ornithine transcarbamylase deficiency

10.3390/life12111721

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Single center experience of biotinidase deficiency: 259 patients and six novel mutations

Journal of Pediatric Endocrinology and Metabolism (2018)

Ebru Canda Havva Yazıcı Esra Er Melis Köse Güneş Başol

Abstract Background Biotinidase deficiency (BD) is an autosomal recessively inherited disorder of biotin recycling. It is classified into two levels based on the biotinidase enzyme activity: partial deficiency (10%–30% enzyme activity) and profound deficiency (0%–10% enzyme activity). The aims of this study were to evaluate our patients with BD, identify the spectrum of biotinidase ( BTD ) gene mutations in Turkish patients and to determine the clinical and laboratory findings of our patients and their follow-up period. Methods A total of 259 patients who were diagnosed with BD were enrolled in the study. One hundred and forty-eight patients were male (57.1%), and 111 patients were female (42.9%). Results The number of patients detected by newborn screening was 221 (85.3%). By family screening, 31 (12%) patients were diagnosed with BD. Seven patients (2.7%) had different initial complaints and were diagnosed with BD. Partial BD was detected in 186 (71.8%) patients, and the profound deficiency was detected in 73 (28.2%) patients. Most of our patients were asymptomatic. The most commonly found variants were p.D444H, p.R157H, c.98_104delinsTCC. The novel mutations which were detected in this study are p.D401N(c.1201G>A), p.A82G (c.245C>G), p.F128S(c.383T>C), c617_619del/TTG (p.Val207del), p.A287T(c.859G>A), p.S491H(c.1471A>G). The most common mutation was p.R157H in profound BD and p.D444H in partial BD. All diagnosed patients were treated with biotin. Conclusions The diagnosis of BD should be based on plasma biotinidase activity and molecular analysis. We determined the clinical and genetic spectra of a large group of patients with BD from Western Turkey. The frequent mutations in our study were similar to the literature. In this study, six novel mutations were described.

Biotinidase deficiency

10.1515/jpem-2018-0148

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Peroxisome Biogenesis Disorder (PBD): Types 1-14, A (Zellweger) and B

Springer eBooks (2023)

Mahmut Çerkez Ergören Aya Badeea Ismail Melis Köse Şehime Gülsün Temel

Zellweger syndrome

Peroxisomal disorder

10.1007/978-3-319-66816-1_1781-1

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Biallelic ZNFX1 variants are associated with a spectrum of immuno‐hematological abnormalities

Clinical Genetics (2021)

Salem Alawbathani Ana Westenberger Natalia Ordonez‐Herrera Mariam Al‐Hilali Homoud Al Hebby

Biallelic changes in the ZNFX1 gene have been recently reported to cause severe familial immunodeficiency. Through a search of our bio/databank with information from genetic testing of >55 000 individuals, we identified nine additional patients from seven families with six novel homozygous ZNFX1 variants. Consistent with the previously described phenotype, our patients suffered from monocytosis, thrombocytopenia, hepatosplenomegaly, recurrent infections, and lymphadenopathy. The two most severely affected probands also had renal involvement and clinical presentations compatible with hemophagocytic lymphohistiocytosis. The disease was less lethal among our patients than previously reported. We identified two missense changes, two variants predicted to result in complete protein loss through nonsense-mediated decay, and two frameshift changes that likely introduce a truncation. Our findings (i) independently confirm the role of ZNFX1 in primary genetic immunodeficiency, (ii) expand the genetic and clinical spectrum of ZNFX1-related disease, and (iii) illustrate the utility of large, well-curated, and continually updated genotype-phenotype databases in resolving molecular diagnoses of patients with initially negative genetic testing findings.

Hepatosplenomegaly

Proband

Primary Immunodeficiency

Nonsense

Monocytosis

10.1111/cge.14081

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Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants

Genetics in Medicine (2023)

Georg F. Vogel Yael Mozer‐Glassberg Yuval E. Landau Lea D. Schlieben Holger Prokisch

10.1016/j.gim.2023.100828

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A surprising cause of proteinuria: Answers

Pediatric Nephrology (2022)

Belde Kasap Demir Ali Kanık Melis Köse Burcu Öztürk Hişmi Maşallah Baran

Nephrology

10.1007/s00467-021-05363-7

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Clinical and genetic features of 13 patients with mucopolysaccarhidosis type IIIB: Description of two novel NAGLU gene mutations

Molecular Genetics and Metabolism Reports (2021)

Ferda Özkınay Durdugül Ayyıldız Emecen Melis Köse Esra Işık Ayşe Ergül Bozacı

Mucopolysaccharidosis type III B (MPS IIIB) is an autosomal recessive lysosomal storage disease caused by mutations in the NAGLU gene which codes the lysosomal enzyme alpha-N-acetylglucosaminidase. The major symptoms of the disease are cognitive and neurological defects. In this study, the molecular spectrums of 13 MPS IIIB patients were evaluated.Thirteen MPS IIIB patients from 11 families were included in this study. All patients were both clinically and molecularly diagnosed. NAGLU gene sequencing was performed using a next generation sequencing platform (Illumina MiSeq). Demographic, clinical and laboratory findings of the patients were obtained via the hospital records.Ten different mutations from the 13 MPS IIIB patients were identified. Eight of the 10 mutations were missense, one was splice site, and one large deletion was also observed. Two mutations c.509G>T (p.Gly170Val) and c.700C>G (p.Arg234Gly) have been defined for the first time in this study.Our study expanded the mutation spectrum of the NAGLU gene thereby contributing to the improved genetic counselling of MPS IIIB patients. Confirming the literature, missense mutations were also found to be the most common NAGLU mutations in our study.

Compound heterozygosity

Lysosomal storage disease

10.1016/j.ymgmr.2021.100732

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Author response for "Biallelic ZNFX1 variants are associated with a spectrum of immuno-hematological abnormalities"

Salem Alawbathani Ana Westenberger Natalia Ordonez‐Herrera Mariam Al‐Hilali Homoud Al Hebby

10.1111/cge.14081/v2/response1

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