Siblings with Ethylmalonic Encephalopathy: Case Report

Deficiency of mitochondrial sulfur dioxygenase (ETHE1) causes a rare inborn error of metabolism, ethylmalonic encephalopathy, which is characterized by early-onset encephalopathy, chronic hemorrhagic diarrhea, recurrent petechiae, orthostatic acrocyanosis, defective cytochrome C oxidase because of hydrogen sulfide accumulation and death in the first years of life. Biochemical hallmarks of the disease are high level of lactate, C4-C5-acylcarnitines in blood and markedly elevated urinary excretion of methylsuccinic and ethylmalonic acids. We report on two siblings who were admitted to a pediatric metabolic unit with acrocyanosis, chronic diarrhea and psychomotor retardation later diagnosed as ethylmalonic encephalopathy. Molecular analyses revealed a homozygous for p.R163Q (c.488 G>A) mutation in ETHE1 gene

Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic

Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic

Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic

Use of continuous glucose monitoring evaluating the accuracy and the effect on metabolic parameters in patients with gsd i followed at GaziUuniversity hospital pediatric metabolic unit

Giriş: GDH tip I; glukoz 6 fosfataz sisteminde fonksiyon bozukluğu sonucu ortaya çıkan metabolik bir hastalıktır. Glikojenoliz ve glukoneogenezin her ikisinin de birlikte bozulduğu, hepatik glikojenozlar arasında en ciddi seyirli olanıdır ve hepatik GDH'larının %80'ini oluşturmaktadır. Glukoz 6 fosfat'ın sitoplazmadan endoplazmik retikulum lümenine taşınmasını sağlayan glukoz 6 fosfat taşıyıcı protein (G6PT) eksikliği GDH Ib'ye neden olmakta iken, endoplazmik retikulum lümeninde G6P'ın glukoz ve fosfata hidrolizini sağlayan G6Paz eksikliği ise GDH Ia'ya neden olmaktadır. Glikojen depo hastalığı tip Ia'da hepatomegali, 3-4 saatlik açlık sonrasında hipoglisemi, hipertrigliseridemi, hiperlaktatemi, hiperürisemi, taş bebek yüzü, gövdesel tipte şişmanlık, kas kitlesinde azalma, böbrek büyüklüğü, puberte gecikmesi ve büyüme geriliği görülebilmektedir. GDH Ib'de ise ek olarak nötropeni, tekrarlayan enfeksiyonlar ve inflamatuar barsak hastalığı gelişebilmektedir. Amacımız; glikojen depo hastalığı tip 1 hastalarında sürekli glukoz monitorizasyonu kullanımının etkinliği, güvenilirliği ve metabolik parametreler üzerine etkisini belirlemektir. Material-metod: Bu çalışmada; klinik, laboratuar, enzimatik veya moleküler analizler ile GDH Ia ve Ib tanısı alan olgulara 72 saat boyunca Guardian-real time CGM uygulandı. Çalışma yaşları 2-18 yaş arasında 9'u erkek, 7'si kız toplam 16 Glikojen Depo Hastalığı tip I tanılı hastada yapıldı. Çalışmaya katılan hastaların 15'i GDH Ia, 1'i ise GDH Ib hastalarından oluşmakta idi. Sürekli glukoz izlemi sırasında sensör okuma değerlerinden olguların ve doktorların bilgisi yoktu. Kapiller açlık kan şekeri ölçümleri ana ve ara öğünlerden önce değerlendirildi. İlk monitorizasyon ölçümlerine göre diyetteki karbonhidrat ve mısır nişastası oranları arttırıldı. Diyet modifikasyonunun etkilerini değerlendirmek amacıyla olgulara 3-6 ay sonra ikinci CGM cihazı takıldı. Verilerin analizi SPSS (Statistical Package for Social Science, SPSS Inc., Chicago, IL, United States) for Windows 11.5 paket programında yapıldı. Sürekli değişkenlerinin dağılımının normale yakın olup olmadığı Shapiro Wilk testiyle araştırıldı. Diyet revizyonu öncesine göre diyet revizyonu sonrasında metabolik parametrelere ait ölçümlerde ve diyet düzeylerinde istatistiksel olarak anlamlı değişimin olup olmadığı Bağımlı-t testi veya Wilcoxon İşaret testiyle değerlendirildi. Kapiller ve CGM cihazının yapmış olduğu glikoz ölçümleri arasındaki korelasyonun önemliliği Pearson'un Korelasyon testiyle araştırıldı. p<0,05 için sonuçlar istatistiksel olarak anlamlı kabul edildi. Sonuç: Çalışma hastalarının yaş ortalaması 7.59± 4.12 (2-18) yaş idi. Olgularımızın diyet içerikleri 57-64 % karbonhidrat, 25-29 % yağ, 10-16 % protein `den oluşmakta idi. Çalışmaya katılan olgularımızda major advers olayla karşılaşılmadı. Diyet revizyonu öncesi ve sonrası glukometre ile ölçülen kapiller ölçümler ile CGM cihaz ölçüm ortalamaları arasında çok yüksek korelasyon tespit edildi (rho: 0.86, r2:0.74 vs rho: 0.77, r2=0.65). Hastaların diyet revizyonu sonrasında KC boyutunda, laktik asit, Trigliserit, AST, ALT düzeylerinde ve hipoglisemi yüzdesinde istatistiksel olarak anlamlı düşüş olduğu görüldü (p<0,05). Tartışma: Sürekli glukoz monitorizasyonu (continuous glucose mo-nitoring, CGM) bir sensör, bir veri depolama aygıtı ve bir monitörden oluşmaktadır. Bu metod ile deri altına sürekli bir glukoz sensörü yerleştirilmekte ve bu sensör ile okunan kan şekeri değerleri bir monitöre gönderilmektedir. Sensör her 1-5 dakikada bir 288 kez glukoz ölçümü yapmakta ve bu okumayı bir veri saklama aygıtına göndermektedir. Cihaz çok düşük ve yüksek kan şekeri değerlerinde alarm ayarlanabilmektedir. Cihazı belli aralıklarla kapiller kan şekeri ölçümlerine göre kalibre etmek gerekmektedir. Bu çalışma sonuçlarına göre CGM kullanımı GDH I olgularında kullanımı oldukça etkin, güvenilir ve metabolik parametreler üzerine olumlu etkilerinin olduğu kanıtlanmıştır.Introduction: Glycogen storage disease type I (GSD I) is characterized by impaired production of glucose from glycogenolysis and gluconeogenesis, results from defects in the glucose 6-phosphate enzyme system. Glucose-6-phosphatase is affected in GSD Ia, whereas GSD I non-a results from a defect of the G6P transporter, G6P translocase. Type Ia involves the liver, kidney and intestine (and Ib also leucocytes), and the clinical manifestations are hepatomegaly, failure to thrive, severe fasting hypoglycemia within 3-4 h after a meal, hyperlactatemia, hyperuricemia and hyperlipidemia. The aim of the present study was to examine the efficacy of a continuous subcutaneous glucose monitoring system, to determine the magnitude and significance of hypoglycemia in patients with GSD I and to evaluate the efficacy of the revised dietary treatment. Material-Method: Medtronic real time continuous glucose monitoring device was used in the current study. Sixteen children (9 boys and 7 girls) with GSD I were studied over a 72-h period. We have investigated 15 patients with GSD Ia, one patient with GSD Ib with continuous glucose monitoring. The patients and doctors were not aware of the sensor recordings during the time of glucose monitoring. Capillary blood glucose was measured several times before meals and snacks during this time by the parents or doctors using a glucometer which reliably detects blood samples. More uncooked cornstarch was added to the diet of patients and glucose intake was increased according to first CGM glucose concentrations, and altered the time interval between meals. CGM was repeated 3 to 6 months after the first monitoring in all patients to examine the effects of revised dietary instructions on glycemic control. Statistical analyses were performed using the SPSS software version 11,5. The variables were investigated using visual (histogramas, probability plots) and analytical methods (Kolmogorov-Smirnov/Shapiro-Wilk's test) to determine whether or not they are normally distributed. While investigating the associations between non-normally distributed and/or ordinal variables, the correlation coefficients and their significance were calculated using the Pearson test. All tests were considered significant for p values <0.05. Results: Mean age of the study population was 7.59± 4.12 years (range 2-18). During the study, the patients followed a normo-caloric diet suggested by the registered dietician with a distribution of nutrients as recommended for patients with GSD I (57-64 % carbohydrates, 25-29 %lipids, 10-16 %proteins). All the patients completed the study without any major adverse events. Significant periods of asymptomatic hypoglycemia (below 4 mmol/L, 70 mg/dl) were noted. There was a close correlation between CGM sensor and capillary blood glucose values measured by glucometer. The correlation coefficient between glucose values obtained with medtronic real time continuous glucose monitoring device and capillary measurements was 0,86 (r2=0,74) before and 0.77 (r2=0.65) after the diet was modified. CGM indicated a considerable reduction in liver size and duration of hypoglycemia which dropped from 7.06±5.04 % to 2.25±2.79% (p=0.002), and improvements in secondary metabolic derangements such as hyperlacticacidemia, hypertriglyceridemia, AST and ALT levels. Discussion: Real time glucose monitoring device provides glucose measurements every 1-5 minutes, producing 288 measurements per day, consists of a disposable transcutaneous glucose sensor connected to a transmitter and a receiver. The receiver has a screen that displays the glucose level together with graphic representations of the glucose patterns. Medtronic real time continuous glucose monitoring device also has adjustable alarms for high and low glucose levels. The system is calibrated using finger stick blood glucose measurements. From our experience CGM, in combination with other appropriate biochemical monitoring and dietary intake records has been shown to be a useful tool in the practical management of GSD

BEBEKLİKTE YAPILAN DEMİR PROFİLAKSİSİNİN DEMİR EKSİKLİĞİ GELİŞİMİNİ ÖNLEME VE PSİKOMOTOR GELİŞİM ÜZERİNE ETKİSİ

Pek çok geli&#290;mekte olan ülkede olduğu gibi Türkiye&#8223;de de demir eksikliği anemisi (DEA) çok sayıda çocuğu etkilemektedir. Türkiye&#8223;den yapılan bazı çalı&#290;malarda anemi sıklığının %48 ve 75 arasında deği&#290;tiği bildirilmi&#290;tir. Bu çalı&#290;manın amacı bebeklerde anemi için risk faktörlerini incelemek, zamanında doğan bebeklerin 12. ayda demir durumunu değerlendirmek, demir desteğinin demir eksikliği (DE) ve DEA&#8223;sinin geli&#290;imini önleme ve geli&#290;imsel test skorları üzerindeki etkisini incelemektir. Çalı&#290;maya Ocak- Aralık 2005 tarihleri arasında zamanında doğmu&#290;, Gazi Üniversitesi Tıp Fakültesi sağlam çocuk polikliniğinde 1 ya&#290;ına kadar düzenli takipleri yapılan, herhangi bir kronik hastalığı olmayan 400 bebek alındı. 400 vakanın cinsiyetlerinin dağılımı 213 erkek (%53,3), 187 kız (%46,7) idi. Bu vakaların hepsine 4. aylarından itibaren 1mg/kg/gün dozunda demir desteği önerilmi&#290;ti. Bu vakaların 1 ya&#290; kontrolünde yapılan DE anketi ile ailelerin sosyoekonomik ve demografik özellikleri, süt çocuğunun beslenme alı&#290;kanlıkları, önerilen demir profilaksisini kullanıp kullanmadığı saptandı. Kontrollerde bebeklerin antropometrik ölçümleri, ayrıntılı fizik muayeneleri ve zamanı geldikçe a&#290;ıları yapıldı. Demir durumunu değerlendirmek için tam kan sayımı, ferritin değerleri ölçüldü. 10,5 gr/dl altında Hb, 70 fentolitre(fl) altında MCV, 15 ng/ml ve altında ferritin, 14.5% üzerinde RDW, %33 altında Htc değerlerinden en az ikisine sahip olanlar DEA; yalnız serum ferritin düzeyi 15 ng/ml&#8223;nin altında olanlar DE alarak değerlendirildi. Verilerin analizi SPSS for 90 Windows 11,5 istatistik paket programında yapıldı. &#288;statistiksel kar&#290;ıla&#290;tırmada sürekli deği&#290;kenler için t testi ve varyans analizi, kesikli deği&#290;kenler için ki-kare testi kullanıldı. Demir düzeyleri hakkında bilgisi olmayan bölüm psikoloğu tarafından Bayley II Bebekler &#288;çin Geli&#290;im Ölçeği (BBGÖ) tüm bebeklere yapıldı. BAYLEY II sonuçları Kolmogrow-Smirnov testi kullanılarak analiz edildi. Çalı&#290;maya dahil edilen bebeklerin ortalama Hb değeri 12.1 ±1.1 (6.1-15), ortalama ferritin değeri 26.3±32.7 (1-480) olarak bulundu. Çalı&#290;ma grubunda anemi prevelansının %7, DE prevelansının %36,8 olduğu görüldü. DE geli&#290;imini etkileyen faktörler arasında annelerin doğum aralıklarının sık olması, inek sütüne 1 ya&#290;tan önce ba&#290;lanması, önerilen demir profilaksisine uyumsuzluk, erkek cinsiyet, ailenin gelir düzeyinin ve bebeğe bakan ki&#290;inin eğitim seviyesinin dü&#290;ük olması gösterildi. Onikinci aydaki demir durumu üzerinde çok belirgin bir olumsuz etkisi olan inek sütünün erken ba&#290;lanması en önemli diyetsel faktör olarak gösterildi. Demir eksikliği olan bebeklerde BBGÖ II ile zihinsel ve motor test puanlarının daha dü&#290;ük olduğu bulundu. Sonuç olarak DEA&#8223;nin ülkemizde bebek ve çocuklarda çok yaygın olması ve bili&#290;sel i&#290;levleri olumsuz yönde etkilemesi nedeni ile, DEA&#8223;nin önlenmesi için uygun beslenme önerileri ile (ilk 6 ay sadece anne sütü verilmesi, ilk 1 ya&#290;ta inek sütü ba&#290;lanmaması, anne sütü verilemiyorsa demirle zenginle&#290;tirilmi&#290; formulalarla beslenmesi) birlikte gerekli demir desteğinin 4. ayda ba&#290;layarak 2 ya&#290;a kadar devam edilmesi ve DE taramasının 9-12 aylar arasında yapılması gerekmektedir.In Turkey, as well as in other developing nations, iron deficiency anemia (IDA) affects a significant number of children. In some studies from Turkey, anemia prevalence was found to range between 48-75%. The aim of the present study was to investigate risk factors for anemia in infants, evaluate the iron status of full term babies at 12 months of age, the effects of iron supplementation on prevention of ID- IDA and infant developmental test performance. Four hundred healthy term infants who were born between June and December 2005 and regularly followed up at Gazi University Hospital well baby clinics until 12 months of age, were considered for enrollment in the study. Of these infants, 213 (53.3 %) were boys and 187 (46.7%) were girls. Iron supplementation in a dose of 1mg/kg/day was given to all of these patients. Participant families were asked to complete a questionnaire with items on socioeconomic and demographic factors, information on feeding practices, and adherence to the use of iron supplementation. Complete physical examination was perfomed, anthropometric measures were obtained and routine immunizations were applied. Iron status of the infants was determined by complete blood count and ferritin. Those infants having 2 or more of the following abnormal measures were considered to have IDA: hemoglobin level 14,5, Htc<%33. Infants only with serum ferritin &#8804;15 ng/ml were considered to be the non-anemic iron deficient group. All data were analysed using the statistical package SPSS for Windows 11,5. Categorical variables were analysed by chi-square (&#967;2 ) test. In the analysis of other continuous variables, student&#8223;s t-test was used. The Bayley Scales of Infant Development (BSID) II was administered by a tester unaware of the child&#8223;s hematological status. The Kolmogrow-Smirnov test was used to analyse outcomes of BSID II. The infants included in the study had a mean Hb value of 12.1 ±1.1 (6.1-15) and a mean ferritin value of 26.3±32.7 (1-480). The prevalence of IDA was 7% and that of ID was 36.8% in the study group. This study indicates that the main determinants of anemia in infants are increased number of deliveries, low adherence to iron supplementation, male gender, low family income and low education status of the care-giver. The most important dietary factor was early introduction of cows&#8223; milk, a factor which had a clear negative influence on iron status at 12 months of age. Iron deficiency in infancy was associated with lower scores on BSID &#8211;II. The prevalence of IDA is high in infants and young children in our country and since it negatively influences the psychomotor development, measures to prevent ID such as exclusive breast-feeding in the first 6 months, avoiding cows&#8223; milk before 1 year of life, starting iron supplementation at 4-6 months of age in breast-fed infants, and using iron -fortified formula when not breastfeeding together with continuing iron supplementation until 24 months of age and screening for iron deficiency at 9 to 12 months of age should be advised

Clinical, biochemical, and molecular insights into Cerebrotendinous Xanthomatosis: A nationwide study of 100 Turkish individuals

Objective: Cerebrotendinous xanthomatosis (CTX) is an inherited metabolic disorder characterized by progressive neurologic and extraneurologic findings. The aim of this retrospective, descriptive study was to explore the time of presentation and diagnosis, and to expand the phenotype and genotype of CTX, based on a nationwide and comprehensive series of patients in Turkey. Methods: The demographic, clinical, biochemical and genotypic characteristics of the CTX patients were reviewed. Data on molecular analysis, age of onset and diagnosis, diagnostic delay, neurologic and extraneurologic symptomatology, results of plasma cholestanol levels, brain magnetic resonance imaging and electromyography at the time of diagnosis were reviewed. Results: 100 confirmed CTX patients from 72 families were included. The mean age at diagnosis was 28.16 ± 14.28 years, and diagnostic delay was 18.39 ± 13.71 years. 36 patients were diagnosed in childhood. Frequency of intention tremor (p = 0.069), peripheral neuropathy (p = 0.234) and psychiatric manifestations (p = 0.396) did not differ between two groups, demonstrating the high rate in pediatric patients. Three adult patients showed a milder phenotype without neurologic involvement. Seven patients had normal plasma cholestanol levels despite neurological impairment. Sequencing of the CYP27A1 gene revealed 25 different variants, with a novel c.671_672del variant not previously described in literature. Conclusion: Based on the observations of this Turkish CTX cohort, it is emphasized that the true prevalence of CTX is probably underestimated and that it has a wide spectrum of clinical phenotypes even without neurological impairment. In children, abnormal cerebellar findings, peripheral neuropathy and psychiatric findings associated with intellectual disability have been suggested as warning signs to avoid diagnostic delay. In cases of clinical suspicion, molecular analysis is recommended despite normal plasma cholestanol levels, as severe neurologic involvement may occur in CTX patients without elevated cholestanol levels

Three-Country Snapshot of Ornithine Transcarbamylase Deficiency

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