Cerebral defects and nephrogenic diabetes insipidus with the ARC syndrome: Additional findings or a new syndrome (ARCC-NDI)?

We report on 4 children from 2 unrelated families who appear to have the lethal ARC syndrome (arthrogryposis, renal tubular dysfunction, and cholestasis) together with the additional findings of nephrogenic diabetes insipidus and cerebral anomalies, including deafness. With increased survival time in our patients, paucity of the intrahepatic bile ductules and cholestasis progressed to cirrhosis, growth was severely impaired, and severe mental retardation became apparent. No evidence was found for peroxisomal, chromosomal, or mitochondrial disorders. We propose to amend the ARC mnemonic to ARCC-NDI (A-Arthrogryposis, R-renal Fanconi, C-cerebral, C-cholestasis, NDI-nephrogenic diabetes insipidus) to name the major manifestations of this syndrome, several of which have not been appreciated. Am. J. Med. Genet. 72:335–338, 1997. © 1997 Wiley-Liss, Inc.     

Genetic variation in the urea cycle: a model resource for investigating key candidate genes for common diseases

The urea cycle is the primary means of nitrogen metabolism in humans and other ureotelic organisms. There are five key enzymes in the urea cycle: carbamoyl-phosphate synthetase 1 (CPS1), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS1), argininosuccinate lyase (ASL), and arginase 1 (ARG1). Additionally, a sixth enzyme, N-acetylglutamate synthase (NAGS), is critical for urea cycle function, providing CPS1 with its necessary cofactor. Deficiencies in any of these enzymes result in elevated blood ammonia concentrations, which can have detrimental effects, including central nervous system dysfunction, brain damage, coma, and death. Functional variants, which confer susceptibility for disease or dysfunction, have been described for enzymes within the cycle; however, a comprehensive screen of all the urea cycle enzymes has not been performed. We examined the exons and intron/exon boundaries of the five key urea cycle enzymes, NAGS, and two solute carrier transporter genes (SLC25A13 and SLC25A15) for sequence alterations using single-stranded conformational polymorphism (SSCP) analysis and high-resolution melt profiling. SSCP was performed on a set of DNA from 47 unrelated North American individuals with a mixture of ethnic backgrounds. High-resolution melt profiling was performed on a nonoverlapping DNA set of either 47 or 100 unrelated individuals with a mixture of backgrounds. We identified 33 unarchived polymorphisms in this screen that potentially play a role in the variation observed in urea cycle function. Screening all the genes in the pathway provides a catalog of variants that can be used in investigating candidate diseases.     

Molecular and vascular targets in the pathogenesis and management of the hypertension associated with preeclampsia

Normal pregnancy is associated with significant hemodynamic changes and vasodilation of the uterine and systemic circulation in order to meet the metabolic demands of the mother and developing fetus. Preeclampsia (PE) is one of the foremost complications of pregnancy and a major cause of maternal and fetal mortality. The pathophysiological mechanisms of PE have been elusive, but some parts of the puzzle have begun to unravel. Genetic factors such as leptin gene polymorphism, environmental and dietary factors such as Ca(2+) and vitamin D deficiency, and co-morbidities such as obesity and diabetes may increase the susceptibility of pregnant women to develop PE. An altered maternal immune response may also play a role in the development of PE. Although the pathophysiology of PE is unclear, most studies have implicated inadequate invasion of cytotrophoblasts into the uterine artery, leading to reduced uteroplacental perfusion pressure (RUPP) and placental ischemia/hypoxia. Placental ischemia induces the release of biologically active factors such as growth factor inhibitors, anti-angiogenic factors, inflammatory cytokines, reactive oxygen species, hypoxia-inducible factors, and antibodies to vascular angiotensin II (AngII) receptor. These bioactive factors could cause vascular endotheliosis and consequent increase in vascular resistance and blood pressure, as well as glomerular endotheliosis with consequent proteinuria. The PE-associated vascular endotheliosis could be manifested as decreased vasodilator mediators such as nitric oxide, prostacyclin and hyperpolarizing factor and increased vasoconstrictor mediators such as endothelin-1, AngII and thromboxane A?. PE could also involve enhanced mechanisms of vascular smooth muscle contraction including intracellular Ca(2+), and Ca(2+) sensitization pathways such as protein kinase C and Rho-kinase. PE-associated changes in the extracellular matrix composition and matrix metalloproteinases activity also promote vascular remodeling and further vasoconstriction in the uterine and systemic circulation. Some of these biologically active factors and vascular mediators have been proposed as biomarkers for early prediction or diagnosis of PE, and as potential targets for prevention or treatment of the disease.     

Neurological implications of urea cycle disorders

Summary The urea cycle disorders constitute a group of rare congenital disorders caused by a deficiency of the enzymes or transport proteins required to remove ammonia from the body. Via a series of biochemical steps, nitrogen, the waste product of protein metabolism, is removed from the blood and converted into urea. A consequence of these disorders is hyperammonaemia, resulting in central nervous system dysfunction with mental status changes, brain oedema, seizures, coma, and potentially death. Both acute and chronic hyperammonaemia result in alterations of neurotransmitter systems. In acute hyperammonaemia, activation of the NMDA receptor leads to excitotoxic cell death, changes in energy metabolism and alterations in protein expression of the astrocyte that affect volume regulation and contribute to oedema. Neuropathological evaluation demonstrates alterations in the astrocyte morphology. Imaging studies, in particular ¹H MRS, can reveal markers of impaired metabolism such as elevations of glutamine and reduction of myoinositol. In contrast, chronic hyperammonaemia leads to adaptive responses in the NMDA receptor and impairments in the glutamate–nitric oxide–cGMP pathway, leading to alterations in cognition and learning. Therapy of acute hyperammonaemia has relied on ammonia-lowering agents but in recent years there has been considerable interest in neuroprotective strategies. Recent studies have suggested restoration of learning abilities by pharmacological manipulation of brain cGMP with phosphodiesterase inhibitors. Thus, both strategies are intriguing areas for potential investigation in human urea cycle disorders. Competing interests: None declared     

Acute expansion of a hospital-acquired methicillin-resistant Staphylococcus aureus-infected abdominal aortic aneurysm

Infected aortic aneurysms (IAAs) are rare but can have devastating outcomes, particularly if diagnosis and treatment are delayed. The incidence of IAA is between 0.65% and 2% of all aortic aneurysms. The disease has a poor prognosis because these aneurysms have an increased tendency to grow rapidly and to rupture, and patients often have severe comorbidities and coexisting sepsis. Typical microorganisms associated with IAA are Salmonella, Streptococci, and Staphylococcus aureus. Methicillin-resistant Staphylococcus aureus (MRSA) continues to emerge as a cause of serious infections, but its association with IAA is extremely rare. We present a rare case of infected abdominal aortic aneurysm caused by hospital-acquired (HA) MRSA. This case adds another presentation to the clinical spectrum of HA MRSA infections, and it highlights the problems encountered in the choice of the therapy of serious HA or health care-acquired infections in an era of increasing MRSA infections. We will discuss the clinical spectrum of HA MRSA infections as well as the problems encountered in the management of IAA, and will review the relevant literature.     

Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes

Abstract Aim: A large longitudinal interventional study of patients with a urea cycle disorder (UCD) in hyperammonaemic crisis was undertaken to amass a significant body of data on their presenting symptoms and survival. Methods: Between 1982 and 2003, as part of the FDA approval process, data were collected on patients receiving an intravenous combination of nitrogen scavenging drugs (Ammonul(R) sodium phenylacetate and sodium benzoate (10%, 10%)) for the treatment of hyperammonaemic crises caused by urea cycle disorders. Results: A final diagnosis of a UCD was made for 260 patients, representing 975 episodes of hospitalization. Only 34% of these patients presented within the first 30 days of life and had a mortality rate of 32%. The most common presenting symptoms were neurological (80%), or gastrointestinal (33%). This cohort is the largest collection of patients reported for these diseases and the first large cohort in the United States. Conclusion: Surprisingly, the majority (66%) of patients with heritable causes of hyperammonaemia present beyond the neonatal period (>30 days). Patients with late-onset presenting disorders exhibited prolonged survival compared to the neonatal-presenting group.     

The effect of deuterium oxide on the conformational stability and aggregation of bovine serum albumin

Abstract

Protein aggregation is a significant problem affecting the integrity of proteins, and is a major hindrance to the development of biopharmaceutical products. Deuterium oxide (D₂O), widely used in protein characterization studies, has been shown to promote protein aggregation when used as a substitute for water in most buffered protein solutions; however, a few studies have reported minor improvements in melting point temperatures for some proteins. Our study aims to investigate the effect of D₂O on protein stability, using bovine serum albumin (BSA) as a model. We performed accelerated stability studies at high temperatures and assessed the physical and conformational stability of BSA using fluorescence spectroscopy, dynamic light scattering (DLS) and size-exclusion high performance liquid chromatography. Our findings reveal that D₂O enhances the conformational stability of monomeric BSA, reducing monomer loss and formation of small aggregates at high temperatures. There is also an increase in the formation of larger aggregates probed by thioflavin T (ThT), however, the increase is not considered significant based on DLS results. Our findings demonstrate that exchanging water with D₂O can improve the stability of proteins in solution, by maintaining the stability of the monomeric form, which may be beneficial for the long-term storage of some biological products.     

Connecting the dots between genes, biochemistry, and disease susceptibility: systems biology modeling in human genetics

Understanding how DNA sequence variations impact human health through a hierarchy of biochemical and physiological systems is expected to improve the diagnosis, prevention, and treatment of common, complex human diseases. We have previously developed a hierarchical dynamic systems approach based on Petri nets for generating biochemical network models that are consistent with genetic models of disease susceptibility. This modeling approach uses an evolutionary computation approach called grammatical evolution as a search strategy for optimal Petri net models. We have previously demonstrated that this approach routinely identifies biochemical network models that are consistent with a variety of genetic models in which disease susceptibility is determined by nonlinear interactions between two or more DNA sequence variations. We review here this approach and then discuss how it can be used to model biochemical and metabolic data in the context of genetic studies of human disease susceptibility.