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Organic acidurias (OAD) and urea-cycle disorders (UCD) are rare inherited disorders affecting amino acid and protein metabolism. As dietary practice varies widely, we assessed their long-term prescribed dietary treatment against published guideline and studied plasma amino acids levels. We analyzed data from the first visit recorded in the European registry and network for intoxication type metabolic diseases (E-IMD, Chafea no. 2010 12 01). In total, 271 methylmalonic aciduria (MMA) and propionic aciduria (PA) and 361 UCD patients were included. Median natural protein prescription was consistent with the recommended daily allowance (RDA), plasma L-valine (57%), and L-isoleucine (55%) levels in MMA and PA lay below reference ranges. Plasma levels were particularly low in patients who received amino acid mixtures (AAMs-OAD) and L-isoleucine:L-leucine:L-valine (BCAA) ratio was 1.0:3.0:3.2. In UCD patients, plasma L-valine, L-isoleucine, and L-leucine levels lay below reference ranges in 18%, 30%, and 31%, respectively. In symptomatic UCD patients who received AAM-UCD, the median natural protein prescription lay below RDA, while their L-valine and L-isoleucine levels and plasma BCAA ratios were comparable to those in patients who did not receive AAM-UCD. Notably, in patients with ornithine transcarbamylase syndrome (OTC-D), carbamylphosphate synthetase 1 syndrome (CPS1-D) and hyperammonemia-hyperornithinemia-homocitrullinemia (HHH) syndrome selective L-citrulline supplementation resulted in higher plasma L-arginine levels than selective L-arginine supplementation. In conclusion, while MMA and PA patients who received AAMs-OAD had very low BCAA levels and disturbed plasma BCAA ratios, AAMs-UCD seemed to help UCD patients obtain normal BCAA levels. In patients with OTC-D, CPS1-D, and HHH syndrome, selective L-citrulline seemed preferable to selective L-arginine supplementation., (© 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Urea cycle disorders (UCD) are a group of rare inherited metabolic conditions of amino acid catabolism caused by an enzyme deficiency within the hepatic ammonia detoxification pathway. The presentation of these disorders ranges from life-threatening intoxication in the neonate to asymptomatic status in adults. Late-onset UCDs can present for the first time in adulthood and may mimic other causes of acute confusion or psychiatric diseases, and are often associated with neurological symptoms. Late-onset UCDs may become apparent during periods of metabolic stress such as rapid weight loss, gastric bypass surgery, chronic starvation or the postpartum period. Early diagnosis is critical for effective treatment and to prevent long-term complications of hyperammonemia. The challenges of management of adults include for example: (a) poor compliance to dietary and medical treatment which can result in recurrent hospital admissions; (b) severe neurological dysfunction; (c) the management of pregnancy and the postpartum period; and (d) access to multidisciplinary care peri-operatively. In this review, we highlight a number of challenges in the diagnosis and management of adult patient with late-onset UCDs and suggest a systematic management approach., (© 2019 SSIEM.)

In 2012, we published guidelines summarizing and evaluating late 2011 evidence for diagnosis and therapy of urea cycle disorders (UCDs). With 1:35 000 estimated incidence, UCDs cause hyperammonemia of neonatal (~50%) or late onset that can lead to intellectual disability or death, even while effective therapies do exist. In the 7 years that have elapsed since the first guideline was published, abundant novel information has accumulated, experience on newborn screening for some UCDs has widened, a novel hyperammonemia-causing genetic disorder has been reported, glycerol phenylbutyrate has been introduced as a treatment, and novel promising therapeutic avenues (including gene therapy) have been opened. Several factors including the impact of the first edition of these guidelines (frequently read and quoted) may have increased awareness among health professionals and patient families. However, under-recognition and delayed diagnosis of UCDs still appear widespread. It was therefore necessary to revise the original guidelines to ensure an up-to-date frame of reference for professionals and patients as well as for awareness campaigns. This was accomplished by keeping the original spirit of providing a trans-European consensus based on robust evidence (scored with GRADE methodology), involving professionals on UCDs from nine countries in preparing this consensus. We believe this revised guideline, which has been reviewed by several societies that are involved in the management of UCDs, will have a positive impact on the outcomes of patients by establishing common standards, and spreading and harmonizing good practices. It may also promote the identification of knowledge voids to be filled by future research., (© 2019 SSIEM.)

Background: The incidence, prevalence, and molecular epidemiology of urea cycle disorders (UCDs) in Argentina remain underexplored. The present study is the first to thoroughly assess the clinical and molecular profiles of UCD patients examined at a single reference center in Argentina., Results: Forty-nine UCD cases were collected. About half (26/49, 53%) manifested neonatally with classical presentation and had a high mortality (25/26, 96%). Ornithine transcarbamylase deficiency (OTCD) was the most common UCD (26 patients). Argininosuccinate synthetase deficiency (ASSD) was detected in 19 cases, while argininosuccinate lyase deficiency (ASLD) was diagnosed in 4 cases. Molecular genetic analysis revealed 8 private OTC mutations and two large deletion/duplication events in the OTC gene. Most mutations in the ASS1 and ASL genes were recurrent missense changes, and four alterations were novel. The clinical outcome of our UCD cohort was poor, with an overall mortality of 57% (28/49 cases), and a 28% (6/21) disability rate among the survivors., Conclusions: Most patients in our case series showed severe neonatal onset, with high morbidity/mortality. We detected in total 19 mutations, most of them recurrent and of high frequency worldwide. Noteworthy, we highlight the presence of a geographic cluster with high prevalence of a point mutation in the ASS1 gene. This study suggests that these disorders may be more frequent than commonly assumed, and stresses the need for increased awareness amongst health professionals and greater availability of diagnostic tools for accurate identification, early diagnosis, and timely treatment.

Objective: To prospectively characterize acute hyperammonemic episodes in patients with urea cycle disorders (UCDs) in terms of precipitating factors, treatments, and use of medical resources., Study Design: This was a prospective, longitudinal observational study of hyperammonemic episodes in patients with UCD enrolled in the National Institutes of Health-sponsored Urea Cycle Disorders Consortium Longitudinal Study. An acute hyperammonemic event was defined as plasma ammonia level >100 μmol/L. Physician-reported data regarding the precipitating event and laboratory and clinical variables were recorded in a central database., Results: In our study population, 128 patients with UCD experienced a total of 413 hyperammonemia events. Most patients experienced between 1 and 3 (65%) or between 4 and 6 (23%) hyperammonemia events since study inception, averaging fewer than 1 event/year. The most common identifiable precipitant was infection (33%), 24% of which were upper/lower respiratory tract infections. Indicators of increased morbidity were seen with infection, including increased hospitalization rates (P = .02), longer hospital stays (+2.0 days; P = .003), and increased use of intravenous ammonia scavengers (+45%-52%; P = .003-.03)., Conclusion: Infection is the most common precipitant of acute hyperammonemia in patients with UCD and is associated with indicators of increased morbidity (ie, hospitalization rate, length of stay, and use of intravenous ammonia scavengers). These findings suggest that the catabolic and immune effects of infection may be a target for clinical intervention in inborn errors of metabolism., (Published by Mosby, Inc.)

Background: Despite the success of childhood immunizations in prevention of infectious diseases, questions remain about the safety of vaccines in medically fragile children with inborn errors of metabolism such as urea cycle disorders (UCDs). Patients with UCDs are subject to hyperammonemic episodes (HAEs) after infection, fever, or other stressors., Objective: We sought to assess the risk of HAEs that required urgent care or hospitalization after routine vaccinations in pediatric patients with underlying UCDs., Methods: This was a retrospective investigation of vaccine safety in children with UCDs within the longitudinal Rare Diseases Clinical Research Consortium for UCD. Postvaccination exposure periods were defined as 7 or 21 days after any immunization. The association of vaccines and HAEs was modeled by using conditional Poisson regression, adjusting for age, and using a self-controlled case series method including all patients with ≥1 HAE and with any vaccine exposure., Results: The study enrolled 169 children younger than 18 years. Of these children, 74 had records of at least 1 HAE and at least 1 vaccination. With adjustment for age, there was no increase in relative incidence of HAEs in either the 7-day (1.31 [95% confidence interval (CI): 0.80-2.13]) or 21-day (1.05 [95% CI: 0.74-1.47]) exposure period after vaccination compared with HAEs outside of the vaccination periods. No vaccine type was associated with significantly more HAEs., Conclusions: We found no statistically significant association between childhood immunizations and HAEs in children with UCDs. The results support the safety of immunization in this medically vulnerable population.

Mutations in the SLC25A15 gene, encoding the human inner mitochondrial membrane ornithine transporter, are thought to be responsible for hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome, a rare autosomal recessive condition. HHH syndrome has been detected in several small, isolated communities in northern Saskatchewan (SK). To determine the incidence of HHH syndrome in these communities, a PCR method was set up to detect F188Δ, the common French-Canadian mutation. Neonatal blood spots collected from all newborns from the high risk area were genotyped for the F188Δ mutation for seven consecutive years. Using DNA analysis, we estimated that the heterozygote frequency for the mutant allele for HHH syndrome to be about 1 in 19 individuals, predicting one affected child with HHH syndrome for approximately every 1,500 individuals (1 in 1,550 live births; 1 child every 12 years) in this isolated population. The frequency for the mutant allele for HHH syndrome in this isolated community is probably the highest in the world for this rare disorder. We determined that ornithine levels, by tandem mass spectrometry, were not abnormal in newborns with F188Δ mutation, carriers and normals. Ornithine rises to abnormally high levels at some time after birth well past the time that the newborn screening blood spot is collected. The timing or the reasons for the delayed rise of ornithine in affected children with HHH syndrome have not been determined. Newborn screening for HHH Syndrome in this high risk population is only possible by detection of the mutant allele using DNA analysis.