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Neurological involvement is frequent in inherited metabolic disease of the intoxication type. Hyperammonemic coma related to these diseases may cause severe neurological sequelae. Early optimal treatment is mandatory combining metabolite scavengers (MS) and sometimes continuous veno-venous hemodialysis (CVVHD). We aimed to describe the therapeutic management of hyperammonemia in neonates upon diagnosis of their metabolic disease and to compare neonates managed with MS alone or with both MS and CVVHD. We conducted a retrospective study including all neonates admitted for initial hyperammonemia to the pediatric intensive care unit of a Reference Center of Inherited Metabolic Diseases, between 2001 and 2012. The study included 35 neonates. Before admission, MS were initiated for 11 neonates. At admission, the median ammonia levels were 391 μmol/L and were significantly lower in neonates who received MS before admission. At admission, ammonia levels were 644 μmol/L in dialyzed and 283 μmol/L in non-dialyzed neonates. The median time to reach a 50% decrease of the initial ammonia levels was significantly shorter in dialyzed neonates; however, the normalization of ammonia levels was similar between dialyzed and non-dialyzed neonates. Hemodynamic disorders were more frequent in dialyzed neonates. Conclusion MS represent an effective treatment for hyperammonemia and should be available in all pediatric units to avoid the need for CVVHD. Although CVVHD enhances the kinetics of toxic metabolite decrease, it is associated with adverse hemodynamic effects.

Purpose We aimed to identify prognostic factors for survival and long-term intellectual and developmental outcome in neonatal patients with early-onset urea cycle disorders (UCD) experiencing hyperammonaemic coma. Methods We retrospectively analysed ammonia (NH3) and glutamine levels, electroencephalogram and brain images obtained during neonatal coma of UCD patients born between 1995 and 2011 and managed at a single centre and correlated them to survival and intellectual and developmental outcome. Results We included 38 neonates suffering from deficiencies of argininosuccinate synthetase (ASSD, N = 12), ornithine transcarbamylase (OTCD, N = 10), carbamoylphosphate synthetase 1 (CPSD, N = 7), argininosuccinate lyase (ASLD, N = 7), N-acetylglutamate synthase (NAGS, N = 1) or arginase (ARGD, N = 1). Symptoms occurred earlier in mitochondrial than in cytosolic UCD. Sixty-eight percent of patients survived, with a mean (standard deviation-SD) follow-up of 10.4 (5.3) years. Mortality was mostly observed in OTCD (N = 7/10) and CPSD (N = 4/7) patients. Plasma NH3 level during the neonatal period, expressed as area under the curve, but not glutamine level was associated with mortality (p = .044 and p = .610). 62.1% of the patients had normal intellectual and developmental outcome. Intellectual and developmental outcome tended to correlate with UCD subtype (p = .052). No difference in plasma NH3 or glutamine level during the neonatal period among developmental outcomes was identified. EEG severity was linked to UCD subtypes (p = .004), ammonia levels (p = .037), duration of coma (p = .043), and mortality during the neonatal period (p = .020). Status epilepticus was recorded in 6 patients, 3 of whom died neonatally, 1 developed a severe intellectual disability while the 2 last patients had a normal development. Conclusion UCD subtypes differed by survival rate, intellectual and developmental outcome and EEG features in the neonatal period. Hyperammonaemia expressed as area under the curve was associated with survival but not with intellectual and developmental outcome whereas glutamine was not associated with one of these outcomes. Prognostic value of video-EEG monitoring and the association between status epilepticus and mortality should be assessed in neonatal hyperammonaemic coma in further studies.

Primary liver cancer (PLC; ranked sixth in incidence and third in mortality worldwide) is a cancer grouping composed of hepatocellular (HCC) and intrahepatic bile duct carcinomas. HCC make up the bulk of PLC and are highly malignant, usually diagnosed at late stages and often have very poor prognosis with limited treatment options. Thus, there is a need to identify early diagnostic biomarkers of HCC risk. Also, it is plausible that metabolic imbalances, reflective of obesity, diabetes, and lifestyle habits play a central role in HCC etiology. Thus, a NMR metabonomic study was undertaken in a case-control study nested within EPIC, a large prospective cohort of over 520,000 subjects from 23 centers in 10 Western European countries. Detailed dietary/lifestyle data and biological samples (stored under liquid nitrogen) were collected at enrolment from the majority of participants. After an average of 7.6 years of follow-up, 112 first primary incident HCC cases were identified and matched to control subjects (1:2; by age, sex, study centre). Serum samples from matched cases and controls were analyzed by high-field 1H NMR spectroscopy with the following objectives: (i) to identify early predictive biomarkers of HCC by following a metabonomic approach and (ii) to identify metabolomic profiles representative of distinct dietary or lifestyle patterns. Although the protocols of the EPIC study were not specifically designed with metabolomic analyses in mind, extensive pilot testing has shown that EPIC serum samples are suitable for this type of analysis. High-resolution one-dimensional 1 H NMR (NOESY and CPMG) spectral profiles were recorded at 800MHz. Additional 2D 1H-1H (Jres, TOCSY) and 1H-13C (HSQC) data were recorded for metabolite assignments. We present here the first results of the metabonomic analysis of the EPIC HCC nested case-control study that enabled the identification of a metabolomic profile discriminating cases from controls based on serum collected prior to diagnosis. The potential of this study to identify both pre-diagnostic biomarkers as well as those related to exposures associated with disease risk, may have relevant public health impact and enhance understanding of HCC cancer aetiology, particularly in HCC cases arising in the absence of hepatitis B or C infections.