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BACKGROUND:To improve our understanding of urea cycle disorders (UCDs) prospectively followed by two North American (NA) and European (EU) patient cohorts. AIMS:Description of the NA and EU patient samples and investigation of the prospects of combined and comparative analyses for individuals with UCDs. METHODS:Retrieval and comparison of the data from 1095 individuals (NA: 620, EU: 475) from two electronic databases. RESULTS:The proportion of females with ornithine transcarbamylase deficiency (fOTC-D), particularly those being asymptomatic (asfOTC-D), was higher in the NA than in the EU sample. Exclusion of asfOTC-D resulted in similar distributions in both samples. The mean age at first symptoms was higher in NA than in EU patients with late onset (LO), but similar for those with early (≤ 28 days) onset (EO) of symptoms. Also, the mean age at diagnosis and diagnostic delay for EO and LO patients were similar in the NA and EU cohorts. In most patients (including fOTC-D), diagnosis was made after the onset of symptoms (59.9%) or by high-risk family screening (24.7%), and less often by newborn screening (8.9%) and prenatal testing (3.7%). Analysis of clinical phenotypes revealed that EO patients presented with more symptoms than LO individuals, but that numbers of symptoms correlated with plasma ammonium concentrations in EO patients only. Liver transplantation was reported for 90 NA and 25 EU patients. CONCLUSIONS:Combined analysis of databases drawn from distinct populations opens the possibility to increase sample sizes for natural history questions, while comparative analysis utilizing differences in approach to treatment can evaluate therapeutic options and enhance long-term outcome studies.

Background: Ornithine transcarbamylase deficiency (OTCD) due to an X‐linked OTC mutation, is responsible for moderate to severe hyperammonemia (HA) with substantial morbidity and mortality. About 80% of females with OTCD remain apparently "asymptomatic" with limited studies of their clinical characteristics and long‐term health vulnerabilities. Multimodal neuroimaging studies and executive function testing have shown that asymptomatic females exhibit limitations when stressed to perform at higher cognitive load and had reduced activation of the prefrontal cortex. This retrospective study aims to improve understanding of factors that might predict development of defined complications and serious illness in apparent asymptomatic females. A proband and her daughter are presented to highlight the utility of multimodal neuroimaging studies and to underscore that asymptomatic females with OTCD are not always asymptomatic. Methods: We review data from 302 heterozygote females with OTCD enrolled in the Urea Cycle Disorders Consortium (UCDC) longitudinal natural history database. We apply multiple neuroimaging modalities in the workup of a proband and her daughter. Results: Among the females in the database, 143 were noted as symptomatic at baseline (Sym). We focused on females who were asymptomatic (Asx, n = 111) and those who were asymptomatic initially upon enrollment in study but who later became symptomatic sometime during follow‐up (Asx/Sym, n = 22). The majority of Asx (86%) and Asx/Sym (75%) subjects did not restrict protein at baseline, and ~38% of Asx and 33% of Asx/Sym subjects suffered from mild to severe neuropsychiatric conditions such as mood disorder and sleep problems. The risk of mild to severe HA sometime later in life for the Asx and Asx/Sym subjects as a combined group was ~4% (5/133), with ammonia ranging from 77 to 470 μM and at least half (2/4) of subjects requiring hospital admission and nitrogen scavenger therapy. For this combined group, the median age of first HA crisis was 50 years, whereas the median age of first symptom which included neuropsychiatric and/or behavioral symptoms was 17 years. The multimodal neuroimaging studies in female heterozygotes with OTCD also underscore that asymptomatic female heterozygotes with OTCD (e.g., proband) are not always asymptomatic. Conclusions: Analysis of Asx and Asx/Sym females with OTCD in this study suggests that future evidence‐based management guidelines and/or a clinical risk score calculator for this cohort could be useful management tools to reduce morbidity and improve long‐term quality of life. [ABSTRACT FROM AUTHOR]

Epinephrine infusion during moderate intensity exercise increases glucose production and uptake. Am J Physiol Endocrinol Metab 278: E949-E957, 2000.--The glucoregulatory response to intense exercise [IE, [is greater than] 80% maximum [0.sub.2] uptake ([Vo.sub.2max])] comprises a marked increment in glucose production ([R.sub.a]) and a lesser increment in glucose uptake ([R.sub.d]), resulting in hyperglycemia. The [R.sub.a] correlates with plasma catecholamines but not with the glucagon-to-insulin (IRG/IRI) ratio. If epinephrine (Epi) infusion during moderate exercise were able to markedly stimulate [R.sub.a], this would support an important role for the catecholamines' response in IE. Seven fit male subjects (26 [+ or -] 2 yr, body mass index 23 [+ or -] 0.5 kg/[m.sup.2], [Vo.sub.2max] 65 [+ or -] 5 ml [multiplied by] [kg.sup.-1] [multiplied by] [min.sup.-1]) underwent 40 min of postabsorptive cycle ergometer exercise (145 [+ or -] 14 W) once without [control (CON)] and once with Epi infusion [EPI (0.1 [micro]g [multiplied by] [kg.sup.-1] [multiplied by] [min.sup.-1])] from 30 to 40 min. Epi levels reached 9.4 [+ or -] 0.8 nM (20x rest, 10x CON). [R.sub.a] increased ~70% to 3.75 [+ or -] 0.53 in CON but to 8.57 [+ or -] 0.58 mg [multiplied by] [kg.sup.-1] [multiplied by] [min.sup.-1] in EPI (P [is less than] 0.001). Increments in [R.sub.a] and Epi correlated ([r.sup.2] = 0.923, P [is less than or equal to] 0.01). In EPI, peak [R.sub.d] (5.55 [+ or -] 0.54 vs. 3.38 [+ or -] 0.46 mg [multiplied by] [kg.sup.-1] [multiplied by] [min.sup.-1], P = 0.006) and glucose metabolic clearance rate (MCR, P = 0.018) were higher. The [R.sub.a]-to-[R.sub.d] imbalance in EPI caused hyperglycemia (7.12 [+ or -] 0.22 vs. 5.59 [+ or -] 0.22 mM, P = 0.001) until minute 60 of recovery. A small and late IRG/IRI increase (P = 0.015 vs. CON) could not account for the [R.sub.a] increase. Norepinephrine (~4 X increase at peak) did not differ between EPI and CON. Thus Epi infusion during moderate exercise led to increments in [R.sub.a] and [R.sub.d] and caused rises of plasma glucose, lactate, and respiratory exchange ratio in fit individuals, supporting a regulatory role for Epi in IE. Epi's effects on [R.sub.d] and MCR during exercise may differ from its effects at rest. glucose turnover; catecholamines; insulin; glucagon

Stable isotopes have greatly contributed to our understanding of nitrogen metabolism and the urea cycle. The measurement of urea flux via isotopic methods has traditionally been utilized to determine total body protein synthesis in subjects with an intact urea cycle. However, isotopic studies of nitrogen metabolism are also a useful adjunct to conventional clinical investigations in the diagnosis and management of the inherited hyperammonemias. Such studies offer a safe non-invasive method of measuring the reduction of in vivo hepatic ureagenesis, and thus may provide a more accurate measure of phenotypic severity in affected patients. In addition, isotopic methods are ideally suited to evaluate the efficacy of novel therapies to augment urea production. [ABSTRACT FROM AUTHOR]

Identical studies using stable isotopes were performed before and after a 3-day trial of oral N-carbamyl-l-glutamate (NCG) in 5 subjects with late-onset carbamyl phosphate synthetase deficiency. NCG augmented ureagenesis and decreased plasma ammonia in 4 of 5 subjects. There was marked improvement in nitrogen metabolism with long-term NCG administration in 1 subject. [ABSTRACT FROM AUTHOR]

Introduction: Advancements in sequencing technologies have significantly improved clinical genetic testing, yet the diagnostic yield remains around 30-40%. Emerging sequencing technologies are now being deployed in the clinical setting to address the remaining diagnostic gap., Methods: We tested whether short-read genome sequencing could increase diagnostic yield in individuals enrolled into the UCI-GREGoR research study, who had suspected Mendelian conditions and prior inconclusive clinical genetic testing. Two other collaborative research cohorts, focused on aortopathy and dilated cardiomyopathy, consisted of individuals who were undiagnosed but had not undergone harmonized prior testing., Results: We sequenced 353 families (754 participants) and found a molecular diagnosis in 54 (15.3%) of them. Of these diagnoses, 55.5% were previously missed because the causative variants were in regions not interrogated by the original testing. In 9 cases, they were deep intronic variants, 5 of which led to abnormal splicing and cryptic exon inclusion, as directly shown by RNA sequencing. All 5 of these variants had inconclusive spliceAI scores. In 26% of newly diagnosed cases, the causal variant could have been detected by exome sequencing reanalysis., Conclusion: Genome sequencing overcomes multiple limitations of clinical genetic testing, such as inability to call intronic variants and technical limitations. Our findings highlight cryptic exon inclusion as a common mechanism via which deep intronic variants cause Mendelian disease. However, they also reinforce that reanalysis of exome datasets can be a fruitful approach., Competing Interests: Disclosures/Conflict of interest M.H, J.Z. and K.S. are currently employees of Labcorp Genetics Inc, formerly known as Invitae Corp, I.C. is a former employee of Invitae Corp. All other authors declare no conflicts of interest.

Background: Inherited metabolic disorders (IMDs) are individually rare but collectively common disorders that frequently require rapid or urgent therapy., Purpose: This article provides a generalized approach to IMDs, as well as some investigations and safe therapies that may be initiated pending the metabolic consult., Methods/search Strategy: An overview of the research supporting management strategies is provided. In addition, the newborn metabolic screen is reviewed., Findings/results: Caring for infants with IMDs can seem difficult because each of the types is rarely seen; however, collectively the management can be seen as similar., Implications for Practice: When an IMD is suspected, a metabolic specialist should be consulted for expert advice regarding appropriate laboratory investigations and management. Because rapid intervention of IMDs before the onset of symptoms may prevent future irreversible sequelae, each abnormal newborn screen must be addressed promptly., Implications for Research: Management can be difficult. Research in this area is limited and can be difficult without multisite coordination since sample sizes of any significance are difficult to achieve.