Amino acid synthesis deficiencies

In recent years the number of disorders known to affect amino acid synthesis has grown rapidly. Nor is it just the number of disorders that has increased: the associated clinical phenotypes have also expanded spectacularly, primarily due to the advances of next generation sequencing diagnostics. In contrast to the "classical" inborn errors of metabolism in catabolic pathways, in which elevated levels of metabolites are easily detected in body fluids, synthesis defects present with low values of metabolites or, confusingly, even completely normal levels of amino acids. This makes the biochemical diagnosis of this relatively new group of metabolic diseases challenging. Defects in the synthesis pathways of serine metabolism, glutamine, proline and, recently, asparagine have all been reported. Although these amino acid synthesis defects are in unrelated metabolic pathways, they do share many clinical features. In children the central nervous system is primarily affected, giving rise to (congenital) microcephaly, early onset seizures and varying degrees of mental disability. The brain abnormalities are accompanied by skin disorders such as cutis laxa in defects of proline synthesis, collodion-like skin and ichthyosis in serine deficiency, and necrolytic erythema in glutamine deficiency. Hypomyelination with accompanying loss of brain volume and gyration defects can be observed on brain MRI in all synthesis disorders. In adults with defects in serine or proline synthesis, spastic paraplegia and several forms of polyneuropathy with or without intellectual disability appear to be the major symptoms in these late-presenting forms of amino acid disorders. This review provides a comprehensive overview of the disorders in amino acid synthesis

Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature

Autosomal recessive cutis laxa (ARCL) is a connective tissue disorder characterized by wrinkled, inelastic skin, frequently associated with a neurologic involvement and multisystem disease. Next generation sequencing was performed in genetically unsolved patients with progeroid features, neurological and eye involvement to assess the underlying etiology. We describe an 6 month old child, diagnosed with a novel, homozygous nonsense mutation c.2339T>C in exon 18 of the ALDH18A1 gene, and reviewed all reported P5CS patients. So far 10 patients were described with mutations in ALDH18A1. Features of our patient that have been described in literature included cutis laxa on hands and feet, visible veins on thorax and abdomen, joint laxity, failure to thrive, short stature, microcephaly, and severe developmental and speech delay. Furthermore, abnormal fat distribution, retinal abnormalities, undescended testis, and retinitis pigmentosa have never been described in ALDH18A1. Some features described as unique in ALDH18A1 have been observed in PYCR1 patients, thus suggesting that the phenotypic overlap is higher than previously shown. In conclusion, the clinical phenotype caused by ALDH18A1 mutations is diverse, with variable degree of progeria in children, but always in association with neurologic disease. We suggest genetic testing for possible ALDH18A1 mutations in all patients with progeroid features, like wrinkled or parchment-like skin, abnormal growth, especially with central nervous system involvement and microcephaly.status: publishe

An EGF receptor/Ral-GTPase signaling cascade regulates c–Src activity and substrate specificity

c–Src is a membrane-associated tyrosine kinase that can be activated by many types of extracellular signals, and can regulate the function of a variety of cellular protein substrates. We demonstrate that epidermal growth factor (EGF) and β–adrenergic receptors activate c–Src by different mechanisms leading to the phosphorylation of distinct sets of c–Src substrates. In particular, we found that EGF receptors, but not β(2)–adrenergic receptors, activated c–Src by a Ral-GTPase-dependent mechanism. Also, c–Src activated by EGF treatment or expression of constitutively activated Ral–GTPase led to tyrosine phosphorylation of Stat3 and cortactin, but not Shc or subsequent Erk activation. In contrast, c–Src activated by isoproterenol led to tyrosine phosphorylation of Shc and subsequent Erk activation, but not tyrosine phosphorylation of cortactin or Stat3. These results identify a role for Ral–GTPases in the activation of c–Src by EGF receptors and the coupling of EGF to transcription through Stat3 and the actin cytoskeleton through cortactin. They also show that c–Src kinase activity can be used differently by individual extracellular stimuli, possibly contributing to their ability to generate unique cellular responses

Advances in ventilator-associated lung injury: prevention is the target.

Mechanical ventilation (MV) is the main supportive treatment in respiratory failure due to different etiologies. However, MV might aggravate ventilator-associated lung injury (VALI). Four main mechanisms leading to VALI are: 1) increased stress and strain, induced by high tidal volume (VT); 2) increased shear stress, i.e. opening and closing, of previously atelectatic alveolar units; 3) distribution of perfusion and 4) biotrauma. In severe acute respiratory distress syndrome patients, low VT, higher levels of positive end expiratory pressure, long duration prone position and neuromuscular blockade within the first 48 hours are associated to a better outcome. VALI can also occur by using high VT in previously non injured lungs. We believe that prevention is the target to minimize injurious effects of MV. This review aims to describe pathophysiology of VALI, the possible prevention and treatment as well as monitoring MV to minimize VALI

Genome-Wide Association Study of Staphylococcus aureus Carriage in a Community-Based Sample of Mexican-Americans in Starr County, Texas

Staphylococcus aureus is the number one cause of hospital-acquired infections. Understanding host pathogen interactions is paramount to the development of more effective treatment and prevention strategies. Therefore, whole exome sequence and chip-based genotype data were used to conduct rare variant and genome-wide association analyses in a Mexican-American cohort from Starr County, Texas to identify genes and variants associated with S. aureus nasal carriage. Unlike most studies of S. aureus that are based on hospitalized populations, this study used a representative community sample. Two nasal swabs were collected from participants (n = 858) 11-17 days apart between October 2009 and December 2013, screened for the presence of S. aureus, and then classified as either persistent, intermittent, or non-carriers. The chip-based and exome sequence-based single variant association analyses identified 1 genome-wide significant region (KAT2B) for intermittent and 11 regions suggestively associated with persistent or intermittent S. aureus carriage. We also report top findings from gene-based burden analyses of rare functional variation. Notably, we observed marked differences between signals associated with persistent and intermittent carriage. In single variant analyses of persistent carriage, 7 of 9 genes in suggestively associated regions and all 5 top gene-based findings are associated with cell growth or tight junction integrity or are structural constituents of the cytoskeleton, suggesting that variation in genes associated with persistent carriage impact cellular integrity and morphology