Computational approach to unravel the impact of missense mutations of proteins (D2HGDH and IDH2) causing D-2-hydroxyglutaric aciduria 2.

The 2-hydroxyglutaric aciduria (2-HGA) is a rare neurometabolic disorder that leads to the development of brain damage. It is classified into three categories: D-2-HGA, L-2-HGA, and combined D,L-2-HGA. The D-2-HGA includes two subtypes: type I and type II caused by the mutations in D2HGDH and IDH2 proteins, respectively. In this study, we studied six mutations, four in the D2HGDH (I147S, D375Y, N439D, and V444A) and two in the IDH2 proteins (R140G, R140Q). We performed in silico analysis to investigate the pathogenicity and stability changes of the mutant proteins using pathogenicity (PANTHER, PhD-SNP, SIFT, SNAP, and META-SNP) and stability (i-Mutant, MUpro, and iStable) predictors. All the mutations of both D2HGDH and IDH2 proteins were predicted as disease causing except V444A, which was predicted as neutral by SIFT. All the mutants were also predicted to be destabilizing the protein except the mutants D375Y and N439D. DSSP plugin of the PyMOL and Molecular Dynamics Simulations (MDS) were used to study the structural changes in the mutant proteins. In the case of D2HGDH protein, the mutations I147S and V444A that are positioned in the beta sheet region exhibited higher Root Mean Square Deviation (RMSD), decrease in compactness and number of intramolecular hydrogen bonds compared to the mutations N439D and D375Y that are positioned in the turn and loop region, respectively. While the mutants R140Q and R140QG that are positioned in the alpha helix region of the protein. MDS results revealed the mutation R140Q to be more destabilizing (higher RMSD values, decrease in compactness and number of intramolecular hydrogen bonds) compared to the mutation R140G of the IDH2 protein. This study is expected to serve as a platform for drug development against 2-HGA and pave the way for more accurate variant assessment and classification for patients with genetic diseases.

[Inborn errors of metabolism in adults]. / Les maladies héréditaires du métabolisme à l'âge adulte.

We present a simplified classification of treatable inborn errors of metabolism (IEM) in three groups with a special focus on those disorders observed at adult age. Group 1 includes inborn errors (IE) of intermediary metabolism which give rise to an acute or chronic intoxication. It encompasses aminoacidopathies, organic acidurias (OA), urea cycle disorders (UCD), sugar intolerances, metal storage disorders and porphyrias. Clinical expression can be acute, systemic or involves a specific organ, it can strike in the neonatal period or later and intermittently from infancy to late adulthood. Most of these disorders are treatable and require the emergency removal of the toxin by special diets, extracorporeal procedures, cleansing drugs or vitamins. Group 2 includes IE of intermediary metabolism which affect the cytoplasmic and mitochondrial energetic processes. Cytoplasmic defects encompass those affecting glycolysis, glycogenosis, gluconeogenesis, creatine and pentose phosphate pathways; the latter are untreatable. Mitochondrial defects include respiratory chain disorders, Krebs cycle and pyruvate oxidation defects, mostly untreatable, and disorders of fatty acid oxidation and ketone bodies that are treatable. Group 3 involves cellular organelles and include lysosomal, peroxisomal, glycosylation, and cholesterol synthesis defects. Among these, some lysosomal disorders can be efficiently treated by enzyme replacement or substrate reduction therapies. Physicians can be faced with the possibility of a treatable IE in emergency, either in the neonatal period or late in infancy to adulthood, or as chronic and progressive symptoms, general (failure to thrive), neurological, or specific for various organs or systems. These symptoms and the simplified classification of IEM are summarized in seven tables.

Clinical evaluation and emergency management of inborn errors of metabolism presenting in the newborn.

Close to 500 biochemically diverse genetic metabolic disorders have been identified. Despite their diversity, these diseases share a number of features. First, the majority of patients with an inborn error present clinically with one of five general phenotypes; acute encephalopathy, progressive encephalopathy, primary muscle disease, primary liver disease or primary renal disease. Encephalopathy is by far the most common clinical manifestation of inborn errors of metabolism, and may be acute, intermittent, chronic (progressive), or even non-progressive. Although the five major phenotypes are a useful clinical guide, other clinical presentations of course occur, and some are virtually specific to a single disease or group of disorders. Second, almost all inborn errors are recessive in inheritance, and most of these conditions map to one of the 22 autosomes. Third, specific and effective treatment of inborn errors is often made possible by our understanding of their biochemical bases. Because inborn errors are genetic diseases, families with affected children can be made aware of the risk of recurrence, through genetic counselling. In many instances, presymptomatic treatment of affected relatives, carrier testing, and prenatal diagnosis can be offered. The types of inborn errors and their mode of presentation in the newborn are discussed, along with a schema permitting their rapid diagnosis. The principles of emergency and long term management are also discussed, with particular emphasis on those disorders that present in the newborn period with an acute encephalopathy, the so-called "small molecule" disorders.

New proteins from old diseases provide novel insights in cell biology.

The lysosomal disease concept was developed by Hers in 1963. At the time, few could have imagined the breadth and depth of knowledge about cell biology that these disorders would reveal. With a collective hindsight of nearly four decades, it is fair to say that we have learned more about the lysosomal system of cells through the study of these rare diseases than by any other means. Given the advancements of the past year, it is apparent that some of the most significant insights are yet to come, as we delineate the last remaining and most enigmatic of these diseases.