Marshall Summar

Neonatal pulmonary hypertension: Urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function

BACKGROUNDnEndogenous production of nitric oxide is vital for the decrease in pulmonary vascular resistance that normally occurs after birth. The precursor of nitric oxide is arginine, a urea-cycle intermediate. We hypothesized that low concentrations of arginine would correlate with the presence of persistent pulmonary hypertension in newborns and that the supply of this precursor would be affected by a functional polymorphism (the substitution of asparagine for threonine at position 1405 [T1405N]) in carbamoyl-phosphate synthetase, which controls the rate-limiting step of the urea cycle.nnnMETHODSnPlasma concentrations of amino acids and genotypes of the carbamoyl-phosphate synthetase variants were determined in 65 near-term neonates with respiratory distress. Plasma nitric oxide metabolites were measured in a subgroup of 10 patients. The results in infants with pulmonary hypertension, as assessed by echocardiography, were compared with those in infants without pulmonary hypertension. The frequencies of the carbamoyl-phosphate synthetase genotypes in the study population were assessed for Hardy-Weinberg equilibrium.nnnRESULTSnAs compared with infants without pulmonary hypertension, infants with pulmonary hypertension had lower mean (+/-SD) plasma concentrations of arginine (20.2+/-8.8 vs. 39.8+/-17.0 micromol per liter, P<0.001) and nitric oxide metabolites (18.8+/-12.7 vs. 47.2+/-11.2 micromol per liter, P=0.05). As compared with the general population, the infants in the study had a significantly skewed distribution of the genotypes for the carbamoyl-phosphate synthetase variants at position 1405 (P<0.005). None of the infants with pulmonary hypertension were homozygous for the T1405N polymorphism.nnnCONCLUSIONSnInfants with persistent pulmonary hypertension have low plasma concentrations of arginine and nitric oxide metabolites. The simultaneous presence of diminished concentrations of precursors and breakdown products suggests that inadequate production of nitric oxide is involved in the pathogenesis of neonatal pulmonary hypertension. Our preliminary observations suggest that the genetically predetermined capacity of the urea cycle--in particular, the efficiency of carbamoyl-phosphate synthetase--may contribute to the availability of precursors for nitric oxide synthesis.

Requirement of argininosuccinate lyase for systemic nitric oxide production

Nitric oxide (NO) is crucial in diverse physiological and pathological processes. We show that a hypomorphic mouse model of argininosuccinate lyase (encoded by Asl) deficiency has a distinct phenotype of multiorgan dysfunction and NO deficiency. Loss of Asl in both humans and mice leads to reduced NO synthesis, owing to both decreased endogenous arginine synthesis and an impaired ability to use extracellular arginine for NO production. Administration of nitrite, which can be converted into NO in vivo, rescued the manifestations of NO deficiency in hypomorphic Asl mice, and a nitric oxide synthase (NOS)-independent NO donor restored NO-dependent vascular reactivity in humans with ASL deficiency. Mechanistic studies showed that ASL has a structural function in addition to its catalytic activity, by which it contributes to the formation of a multiprotein complex required for NO production. Our data demonstrate a previously unappreciated role for ASL in NOS function and NO homeostasis. Hence, ASL may serve as a target for manipulating NO production in experimental models, as well as for the treatment of NO-related diseases.

Shift Work in Nurses: Contribution of Phenotypes and Genotypes to Adaptation

Background Daily cycles of sleep/wake, hormones, and physiological processes are often misaligned with behavioral patterns during shift work, leading to an increased risk of developing cardiovascular/metabolic/gastrointestinal disorders, some types of cancer, and mental disorders including depression and anxiety. It is unclear how sleep timing, chronotype, and circadian clock gene variation contribute to adaptation to shift work. Methods Newly defined sleep strategies, chronotype, and genotype for polymorphisms in circadian clock genes were assessed in 388 hospital day- and night-shift nurses. Results Night-shift nurses who used sleep deprivation as a means to switch to and from diurnal sleep on work days (∼25%) were the most poorly adapted to their work schedule. Chronotype also influenced efficacy of adaptation. In addition, polymorphisms in CLOCK, NPAS2, PER2, and PER3 were significantly associated with outcomes such as alcohol/caffeine consumption and sleepiness, as well as sleep phase, inertia and duration in both single- and multi-locus models. Many of these results were specific to shift type suggesting an interaction between genotype and environment (in this case, shift work). Conclusions Sleep strategy, chronotype, and genotype contribute to the adaptation of the circadian system to an environment that switches frequently and/or irregularly between different schedules of the light-dark cycle and social/workplace time. This study of shift work nurses illustrates how an environmental “stress” to the temporal organization of physiology and metabolism can have behavioral and health-related consequences. Because nurses are a key component of health care, these findings could have important implications for health-care policy.

The incidence of urea cycle disorders

A key question for urea cycle disorders is their incidence. In the United States two UCDs, argininosuccinic synthetase and lyase deficiency, are currently detected by newborn screening. We used newborn screening data on over 6million births and data from the large US and European longitudinal registries to determine how common these conditions are. The incidence for the United States is predicted to be 1 urea cycle disorder patient for every 35,000 births presenting about 113 new patients per year across all age groups.

Natural history of propionic acidemia.

Propionic acidemia is an organic acidemia that can lead to metabolic acidosis, coma and death, if not treated appropriately in the acute setting. Recent advancements in treatment have allowed patients with propionic acidemia to live beyond the neonatal period and acute presentation. The natural history of the disease is just beginning to be elucidated as individuals reach older ages. Recent studies have identified the genomic mutations in the genes PCCA and PCCB. However, as of yet no clear genotype-phenotype correlations are known. As patients age, the natural progression of propionic acidemia illuminates intellectual difficulties, increased risk for neurological complications, including stroke-like episodes, cardiac complications, and gastrointestinal difficulties, as well as a number of other complications. This article reviews the available literature for the natural history of propionic acidemia.

The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation.

BackgroundThe clinical presentation of patients with organic acidurias (OAD) and urea cycle disorders (UCD) is variable; symptoms are often non-specific.Aims/methodsTo improve the knowledge about OAD and UCD the E-IMD consortium established a web-based patient registry.ResultsWe registered 795 patients with OAD (nu2009=u2009452) and UCD (nu2009=u2009343), with ornithine transcarbamylase (OTC) deficiency (nu2009=u2009196), glutaric aciduria type 1 (GA1; nu2009=u2009150) and methylmalonic aciduria (MMA; nu2009=u2009149) being the most frequent diseases. Overall, 548 patients (69xa0%) were symptomatic. The majority of them (nu2009=u2009463) presented with acute metabolic crisis during (nu2009=u2009220) or after the newborn period (nu2009=u2009243) frequently demonstrating impaired consciousness, vomiting and/or muscular hypotonia. Neonatal onset of symptoms was most frequent in argininosuccinic synthetase and lyase deficiency and carbamylphosphate 1 synthetase deficiency, unexpectedly low in male OTC deficiency, and least frequently in GA1 and female OTC deficiency. For patients with MMA, propionic aciduria (PA) and OTC deficiency (male and female), hyperammonemia was more severe in metabolic crises during than after the newborn period, whereas metabolic acidosis tended to be more severe in MMA and PA patients with late onset of symptoms. Symptomatic patients without metabolic crises (nu2009=u200994) often presented with a movement disorder, mental retardation, epilepsy and psychiatric disorders (the latter in UCD only).ConclusionsThe initial presentation varies widely in OAD and UCD patients. This is a challenge for rapid diagnosis and early start of treatment. Patients with a sepsis-like neonatal crisis and those with late-onset of symptoms are both at risk of delayed or missed diagnosis.

Relationship Between Carbamoyl-Phosphate Synthetase Genotype and Systemic Vascular Function

Abstract—Endothelial cells can convert l-citrulline to l-arginine, the precursor of nitric oxide. The present study tests the hypothesis that a C-to-A nucleotide transversion (T1405N) in the gene-encoding carbamoyl-phosphate synthetase 1, the enzyme catalyzing the rate-limiting step in l-citrulline formation, influences nitric oxide metabolite concentrations or nitric oxide-mediated vasodilation in humans. Bradykinin (100, 200, and 400 ng/min) was infused via brachial artery in 106 (CC:AC:AA=40:54:12) healthy subjects. Sodium nitroprusside (1.6, 3.2, and 6.4 &mgr;g/min) was also infused in 87 (CC:AC:AA=31:46:10) subjects. Forearm blood flow was measured by plethysmography and blood samples were collected for tissue-type plasminogen activator antigen, nitric oxide metabolites, and cyclic GMP. There was a significant relationship between carbamoyl-phosphate synthetase 1 genotype and nitric oxide metabolites, such that nitric oxide metabolite concentrations were highest in individuals homozygous for the C allele (mean±SD, 14.0±8.5 &mgr;mol/L), lowest in individuals homozygous for the A allele (9.1±3.1 &mgr;mol/L), and intermediate (11.8±6.6 &mgr;mol/L) in heterozygotes (P =0.036). There was a significant effect of carbamoyl-phosphate synthetase 1 genotype on forearm blood flow during bradykinin (P =0.028), such that the vasodilator response was greatest in C allele homozygotes (22.2±9.1 mL/min/100 mL at 400 ng/min), least in A allele homozygotes (13.6±6.2 mL/min/100 mL), and intermediate (19.4±10.7 mL/min/100 mL) in heterozygotes. Similarly, carbamoyl-phosphate synthetase 1 genotype influenced forearm blood flow during nitroprusside (maximal flow 19.2±8.3, 18.1±8.3, and 11.5±4.9 mL/min/100 mL in the CC:AC:AA groups, respectively; P =0.022). In contrast, there was no effect of carbamoyl-phosphate synthetase 1 genotype on the nitric oxide–independent tissue-type plasminogen activator response to bradykinin (P =0.943). These data indicate that a polymorphism in the gene encoding carbamoyl-phosphate synthetase 1 influences nitric oxide production as well as vascular smooth muscle reactivity.

Establishing a consortium for the study of rare diseases: The Urea Cycle Disorders Consortium

The Urea Cycle Disorders Consortium (UCDC) was created as part of a larger network established by the National Institutes of Health to study rare diseases. This paper reviews the UCDCs accomplishments over the first 6years, including how the Consortium was developed and organized, clinical research studies initiated, and the importance of creating partnerships with patient advocacy groups, philanthropic foundations and biotech and pharmaceutical companies.

Acute management of propionic acidemia.

Propionic acidemia or aciduria is an intoxication-type disorder of organic metabolism. Patients deteriorate in times of increased metabolic demand and subsequent catabolism. Metabolic decompensation can manifest with lethargy, vomiting, coma and death if not appropriately treated. On January 28-30, 2011 in Washington, D.C., Childrens National Medical Center hosted a group of clinicians, scientists and parental group representatives to design recommendations for acute management of individuals with propionic acidemia. Although many of the recommendations are geared toward the previously undiagnosed neonate, the recommendations for a severely metabolically decompensated individual are applicable to any known patient as well. Initial management is critical for prevention of morbidity and mortality. The following manuscript provides recommendations for initial treatment and evaluation, a discussion of issues concerning transport to a metabolic center (if patient presents to a non-metabolic center), acceleration of management and preparation for discharge.

Chronic management and health supervision of individuals with propionic acidemia

Propionic acidemia is a relatively rare inborn error of metabolism. Individuals with propionic acidemia often have life-threatening episodes of hyperammonemia and metabolic acidosis, as well as intellectual disability. There are many reports of additional problems, including poor growth, stroke-like episodes of the basal ganglia, seizures, cardiomyopathy, long QTc syndrome, immune defects, pancreatitis and optic neuropathy; however, there is little information about the incidence of these problems in this rare disease. Additionally, there are no clear guidelines for medical or surgical management of individuals with propionic acidemia. Through a comprehensive and systematic review of the current medical literature and survey of expert opinion, we have developed practice guidelines for the chronic management of individuals with propionic acidemia, including dietary therapy, use of medications, laboratory monitoring, chronic health supervision, use of gastrostomy tubes and liver transplantation.