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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., Medical Research Council [MR/S019111/1]; National Institute of Health Research Senior Investigator Award [NIHR202370]; Medical Research Council Clinician Scientist Fellowship [MR/T008024/1]; NIHR Great Ormond Street Hospital Biomedical Research Centre, This work was supported by the Medical Research Council grant, reference: MR/S019111/1. PG is supported by a National Institute of Health Research Senior Investigator Award (Reference NIHR202370). J.B. is supported by Medical Research Council Clinician Scientist Fellowship MR/T008024/1 and NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

Background: The patients with early-onset epileptic encephalopathy (EOEE) suffer from neurodevelopmental delay. The aim of this study was to analyze the clinical manifestations and amplitude-integrated encephalogram (aEEG) characteristics of infants with EOEE with onset within the neonatal period, to make early diagnosis to improve the prognosis. Methods: One-hundred and twenty-eight patients with neonatal seizure were enrolled and followed up till 1 year old. Sixty-six neonates evolved into EOEE were as the EOEE group, the other 62 were as the non-EOEE (nEOEE) group. Then we compared the clinical and aEEG characteristics between the two groups to analyze the manifestations in neonates with EOEE. Results: Compared to the nEOEE group, the incidence of daily seizure attacks, more than two types of convulsions, more than two antiepileptic drugs (AEDs) application, severely abnormal aEEG background, absence of cyclicity, and more than two seizures detection were significantly higher in the EOEE group (P < 0.05) (97% vs. 54.8%; 30.3% vs. 14.5%; 97.0% vs. 25.4%; 39.4% vs. 3.2%; 57.6% vs. 9.7%; and 56% vs. 3.2%, respectively). Severely abnormal background pattern (odds ratio [OR] = 0.081, 95% confidence interval [CI]: 0.009–0.729, P = 0.025) and more than two seizures detection by aEEG (OR = 0.158, 95% CI: 0.043–0.576, P = 0.005) were the independent risk factors for the evolvement into EOEE. The upper and lower margins of active sleep (AS) and quiet sleep (QS) were significantly higher in EOEE group than those of the control group (P < 0.05) (34.3 ± 13.6 vs. 21.3 ± 6.4; 9.9 ± 3.7 vs. 6.7 ± 2.2; 41.2 ± 15.1 vs. 30.4 ± 11.4; and 11.9 ± 4.4 vs. 9.4 ± 4.0; unit: μV, respectively). AS upper margin was demonstrated a higher diagnostic specificity and sensitivity for EOEE than another three parameters according to the receiver operating characteristic curves; the area under the curve was 0.827. Conclusions: The clinical characteristics of the neonatal seizure which will evolve into EOEE were more than two AEDs application, high seizure frequency (daily attack), and more than two types of the seizure. Significant high voltage, severely abnormal background, absence of cyclicity, and more than two seizures detected on aEEG were the meaningful indicators to the prediction of EOEE.

Amaç: Doğuştan metabolik hastalıklardan olan üre döngüsü hastalıkları (ÜDH), proteinlerin yıkımı sonucu oluşan amonyağın hücresel atılımında görevli enzim ve taşıyıcı moleküllerinin eksikliği sonucu oluşmaktadır. Bu çalışmanın amacı, çocukluk çağında görülen ÜDH klinik özelliklerini ve uzun dönem izlem sonuçlarını değerlendirmektir. Yöntemler: Klasik ÜDH (Karbamoil fosfat sentetaz I eksikliği (n=4), Arjininosüksinat liyaz eksikliği (n=4), Arjninosüksinat sentetaz eksikliği (n=3), Arjinaz eksikliği eksikliği (n=1), Ornitin transkarbamilaz eksikliği (n=1)) olan 13 hastanın klinik özellikleri belirlenmiştir. Semptomların 28 günden küçük hastalarda ortaya çıkması durumunda yenidoğan-başlangıçlı ÜDH, 28 günden sonra ortaya çıkan ÜDH için geç-başlangıçlı sözü kullanılmıştır.Bulgular: Hastaların büyük bir çoğunluğu (n=9) yenidoğan döneminde akut metabolik kriz ile ortaya çıkmıştır. Yenidoğan-başlangıçlı ÜDH sepsis benzeri bir tablo ile kendilerini ortaya koyarken, geçbaşlangıçlı olanlarda ise mental retardasyon ön planda saptanmıştır. Kusma ve hipotoni yenidoğan başlangıçlı hastalarda bildirilirken, hareket bozukluğun eşlik ettiği veya etmediği epilepsi geç başlangıçlı ÜDH rapor edilmiştir. Yenidoğan-başlangıçlı ÜDH hiperamoniyemi hastalığın ilk tanısında oldukça yüksek olmakla birlikte, izlem süresinde üst sınırlara yakın olma eğilimini korumuştur. Buna karşın semptomlu geç başlangıçlı hastalarda metabolik kriz ve hiperamonyemi daha az bildirilmiştir. ÜDH akut ve kronik tedavisinde protein kısıtlı yüksek enerjili diyet ve azot "toplayıcı" ilaçların birlikte verilmiştir. Gelişen tedavi olanaklarına rağmen, yenidoğan-başlangıçlı ÜDH da hala ölüm oranı oldukça yüksek bulunmuştur (44% (4/9)).Sonuç: Yenidoğan başlangıçlı ÜDH genellikle yenidoğan döneminde hiperamoniyemi ile kendini ortaya koymuştur. Geç-başlangıçlı ÜDH da nörolojik bulgulardan tanıya gitmek daha sık bildirilmiştir. Bu hastalıkların tanınması ve izlem sonuçlarının iyileştirilmesi amacı ile temel tanı ve tedavi prensiplerinin güncellenip yeniden yapılandırılması gerektiği sonucuna varılmıştır, Objective: The urea cycle disorders (UCD) are inherited deficiencies of the enzymes or transport molecules involved in the cellular excretion of excess ammonia produced during protein metabolism. The aim of this study was to evaluate the clinical characteristics and long-term outcome of pediatric patients with UCD seen during childhood. Methods: Clinical characteristics in 13 patients with classical UCD (carbamoyl phosphate synthetase I deficiency (n=4), argininosuccinate lyase deficiency (n=4), argininosuccinate synthetase deficiency (n=3), arginase deficiency (n=1), and ornithine transcarbamylase deficiency (n=1)) were defined. The term "neonatal-onset" UCD was used if symptoms occurred within 28 days of life, and "late-onset" if symptoms started after that period. Results: The majority of patients (n=9) presented with acute metabolic crisis during newborn period. Core clinical phenotype in neonatal-onset UCD included sepsis-like neonatal crisis revealed in patients within 28 days after birth, whereas mental retardation was predominant peculiarity in late-onset UCD emerging more than 28 days after birth. Vomiting and hypotonia were frequently reported in neonatalonset UCD, and epilepsy with/without movement disorder was found in late-onset UCD patients. For patients with neonatal-onset UCD hyperammonemia was more severe at first diagnosis of the disease, and remained near upper limits of normal during the follow-up period. However, hyperammonemia and metabolic crisis have been reported lomber spinal stenoz frequently in symptomatic patients. A cardinal principal of UCD in acute and long-term management of UCD. Despite these evolving treatment opportunities, still higher mortality rates were found in neonatal-onset UCD (44% (4/9)).Conclusion: Neonatal-onset UCD were generally presents itself as acute onset hyperammonemia during the newborn period. However, neurological manifestations were reportedly more diagnostic in the lateonset UCD. It has been concluded that the basic principles of diagnosis and treatment need to be reorganized to improve recognition and outcome in these diseases

The prerequisite for liver transplantation as a therapeutic option for inherited metabolic diseases should be that the enzyme defect, being responsible for the major clinical (hepatic and/or extra-hepatic) abnormalities, is localised in the liver. Furthermore? no adequate dietary or pharmacological treatment should be available or such treatment should have an unacceptable influence on the quality of life. We report an infant, who developed end-stage liver disease with persistent lactic acidaemia in his first months of life. Analysis of the mitochondrial respiratory chain in liver tissue revealed a combined partial complex I and IV deficiency. No extra-hepatic involvement could be demonstrated by careful screening for multiple organ involvement, including analysis of the mitochondrial respiratory chain in muscle tissue and cultured skin fibroblasts. The boy received a reduced size liver graft at the age of 8 months. He recovered successfully. almost 5 years after transplantation he is in good clinical condition. No clinical or biochemical signs of any organ dysfunction have been demonstrated. The considerations on which basis it was decided that there was no contra-indication to perform liver transplantation in this patient are discussed.Conclusion The possibility of a mitochondrial respiratory chain deficiency should be considered in liver disease of unknown origin prior to liver transplantation. Liver transplantation is a therapeutic option in mitochondrial respiratory chain deficiency-based end-stage liver disease provided that extra-hepatic involvement is carefully excluded.

Peroxisomes are ubiquitous organelles containing enzyme sequences for beta oxidation of fatty acids, synthesis of bile acids, and ether phospholipids. In the inherited peroxisomal diseases one or more enzymes are deficient in hepatic, renal, and fibroblast peroxisomes. We have examined peroxisomes by light and electron microscopy in 29 duodenal biopsy specimens (21 with normal mucosa) after staining for catalase activity, a marker enzyme. Peroxisomes were most numerous in the apices of the nucleus and at the villus base. Two types were distinguished: rounded to oval forms with a median lesser diameter of 0.23-0.31 microns, and tubular, vermiform organelles 0.1 microns thick and up to 3 microns long. Both types coexist in most patients. Tilting of sections and examination of semithin sections at 120 kV did not show connections between individual organelles. By morphometry, volume density was at least 0.45-0.62% of cellular volume, compared to 1.05% in human liver. In contrast, in four out of five individuals surface density of the peroxisomal membrane was 1.4-2.3 times higher than in control livers; this is expected to favour the exchange of metabolites. We suggest that intestinal peroxisomes contribute substantially to the breakdown of very long chain fatty acids.

The prerequisite for liver transplantation as a therapeutic option for inherited metabolic diseases should be that the enzyme defect, being responsible for the major clinical (hepatic and/or extra-hepatic) abnormalities, is localised in the liver. Furthermore? no adequate dietary or pharmacological treatment should be available or such treatment should have an unacceptable influence on the quality of life. We report an infant, who developed end-stage liver disease with persistent lactic acidaemia in his first months of life. Analysis of the mitochondrial respiratory chain in liver tissue revealed a combined partial complex I and IV deficiency. No extra-hepatic involvement could be demonstrated by careful screening for multiple organ involvement, including analysis of the mitochondrial respiratory chain in muscle tissue and cultured skin fibroblasts. The boy received a reduced size liver graft at the age of 8 months. He recovered successfully. almost 5 years after transplantation he is in good clinical condition. No clinical or biochemical signs of any organ dysfunction have been demonstrated. The considerations on which basis it was decided that there was no contra-indication to perform liver transplantation in this patient are discussed. Conclusion The possibility of a mitochondrial respiratory chain deficiency should be considered in liver disease of unknown origin prior to liver transplantation. Liver transplantation is a therapeutic option in mitochondrial respiratory chain deficiency-based end-stage liver disease provided that extra-hepatic involvement is carefully excluded.