Environmental influences on familial discordance of phenotype in people with homocystinuria: a case report

<p>Abstract</p> <p>Introduction</p> <p>Non-heritable factors may have an influence on the clinical expression of monogenic inherited metabolic diseases.</p> <p>Case presentation</p> <p>This is a case report of a man whose mother had been diagnosed late in childhood with pyridoxine responsive homocystinuria with lens dislocation and neurodevelopmental delay. These severe complications were not observed in her son who was pyridoxine unresponsive but who had been treated appropriately since early infancy.</p> <p>Conclusion</p> <p>The phenotype of people with homocystinuria can be discordant within a family, with variability in metabolic and clinical expression depending upon both the genotype and therapeutic interventions. Offspring of people with homocystinuria should be screened in early infancy and, if positive, treated appropriately whether they have pyridoxine responsive or unresponsive disease.</p

Mapping gene associations in human mitochondria using clinical disease phenotypes

Nuclear genes encode most mitochondrial proteins, and their mutations cause diverse and debilitating clinical disorders. To date, 1,200 of these mitochondrial genes have been recorded, while no standardized catalog exists of the associated clinical phenotypes. Such a catalog would be useful to develop methods to analyze human phenotypic data, to determine genotype-phenotype relations among many genes and diseases, and to support the clinical diagnosis of mitochondrial disorders. Here we establish a clinical phenotype catalog of 174 mitochondrial disease genes and study associations of diseases and genes. Phenotypic features such as clinical signs and symptoms were manually annotated from full-text medical articles and classified based on the hierarchical MeSH ontology. This classification of phenotypic features of each gene allowed for the comparison of diseases between different genes. In turn, we were then able to measure the phenotypic associations of disease genes for which we calculated a quantitative value that is based on their shared phenotypic features. The results showed that genes sharing more similar phenotypes have a stronger tendency for functional interactions, proving the usefulness of phenotype similarity values in disease gene network analysis. We then constructed a functional network of mitochondrial genes and discovered a higher connectivity for non-disease than for disease genes, and a tendency of disease genes to interact with each other. Utilizing these differences, we propose 168 candidate genes that resemble the characteristic interaction patterns of mitochondrial disease genes. Through their network associations, the candidates are further prioritized for the study of specific disorders such as optic neuropathies and Parkinson disease. Most mitochondrial disease phenotypes involve several clinical categories including neurologic, metabolic, and gastrointestinal disorders, which might indicate the effects of gene defects within the mitochondrial system. The accompanying knowledgebase (http://www.mitophenome.org/) supports the study of clinical diseases and associated genes

Nutrition education: a questionnaire for assessment and teaching

It is generally recognized that there is a need for improved teaching of nutrition in medical schools and for increased education of the general population. A questionnaire, derived in part from a study of physician knowledge, was administered to first year medical students in order to assess their knowledge of various aspects of nutrition and metabolism, and as a teaching tool to transmit information about the subject. The performance of first year students was consistent with a generally educated population but there were surprising deficits in some fundamental areas of nutrition. Results of the questionnaire are informative about student knowledge, and immediate reinforcement from a questionnaire may provide a useful teaching tool. In addition, some of the subject matter can serve as a springboard for discussion of critical issues in nutrition such as obesity and markers for cardiovascular disease. A major barrier to improved teaching of nutrition is the lack of agreement on some of these critical issues and there are apparent inconsistencies in recommendations of government and health agencies. It seems reasonable that improved teaching should address the lack of knowledge of nutrition, rather than knowledge of official guidelines. Student awareness of factual information should be the primary goal

Reduced Satellite Cell Numbers and Myogenic Capacity in Aging Can Be Alleviated by Endurance Exercise

Background: Muscle regeneration depends on satellite cells, myogenic stem cells that reside on the myofiber surface. Reduced numbers and/or decreased myogenic aptitude of these cells may impede proper maintenance and contribute to the age-associated decline in muscle mass and repair capacity. Endurance exercise was shown to improve muscle performance; however, the direct impact on satellite cells in aging was not yet thoroughly determined. Here, we focused on characterizing the effect of moderate-intensity endurance exercise on satellite cell, as possible means to attenuate adverse effects of aging. Young and old rats of both genders underwent 13 weeks of treadmill-running or remained sedentary. Methodology: Gastrocnemius muscles were assessed for the effect of age, gender and exercise on satellite-cell numbers and myogenic capacity. Satellite cells were identified in freshly isolated myofibers based on Pax7 immunostaining (i.e., exvivo). The capacity of individual myofiber-associated cells to produce myogenic progeny was determined in clonal assays (in-vitro). We show an age-associated decrease in satellite-cell numbers and in the percent of myogenic clones in old sedentary rats. Upon exercise, there was an increase in myofibers that contain higher numbers of satellite cells in both young and old rats, and an increase in the percent of myogenic clones derived from old rats. Changes at the satellite cell level in old rats were accompanied with positive effects on the lean-to-fat Gast muscle composition and on spontaneous locomotion levels. The significance of these data is that they suggest that the endurance exercise-mediated boost in bot

Therapeutic potential of transplanted placental mesenchymal stem cells in treating Chinese miniature pigs with acute liver failure

<p>Abstract</p> <p>Background</p> <p>Stem cell-based therapy to treat liver diseases is a focus of current research worldwide. So far, most such studies depend on rodent hepatic failure models. The purpose of this study was to isolate mesenchymal stem cells from human placenta (hPMSCs) and determine their therapeutic potential for treating Chinese experimental miniature pigs with acute liver failure (ALF).</p> <p>Methods</p> <p>hPMSCs were isolated and analyzed for their purity and differentiation potential before being employed as the donor cells for transplantation. ALF models of Chinese experimental miniature pigs were established and divided into four groups: no cell transplantation; hPMSCs transplantation via the jugular vein; X-ray-treated hPMSCs transplantation via the portal vein; and hPMSCs transplantation via the portal vein. The restoration of biological functions of the livers receiving transplantation was assessed via a variety of approaches such as mortality rate determination, serum biochemical analysis, and histological, immunohistochemical, and genetic analysis.</p> <p>Results</p> <p>hPMSCs expressed high levels of CD29, CD73, CD13, and CD90, had adipogenic, osteogenic, and hepatic differentiation potential. They improved liver functions <it>in vivo </it>after transplantation into the D-galactosamine-injured pig livers as evidenced by the fact that ALT, AST, ALP, CHE, TBIL, and TBA concentrations returned to normal levels in recipient ALF pigs. Meanwhile, histological data revealed that transplantation of hPMSCs via the portal vein reduced liver inflammation, decreased hepatic denaturation and necrosis, and promoted liver regeneration. These ameliorations were not found in the other three groups. The result of 7-day survival rates suggested that hPMSCs transplantation via the portal vein was able to significantly prolong the survival of ALF pigs compared with the other three groups. Histochemistry and RT-PCR results confirmed the presence of transplanted human cells in recipient pig livers (Groups III, IV).</p> <p>Conclusions</p> <p>Our data revealed that hPMSCs could not only differentiate into hepatocyte-like cells <it>in vitro </it>and <it>in vivo</it>, but could also prolong the survival time of ALF pigs. Regarding the transplantation pathways, the left branch of the portal vein inside the liver was superior to the jugular vein pathway. Thus, hPMSCs transplantation through the portal vein by B-ultrasonography may represent a superior approach for treating liver diseases.</p

Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway.

PURPOSE: The endoplasmic reticulum-associated degradation pathway is responsible for the translocation of misfolded proteins across the endoplasmic reticulum membrane into the cytosol for subsequent degradation by the proteasome. To define the phenotype associated with a novel inherited disorder of cytosolic endoplasmic reticulum-associated degradation pathway dysfunction, we studied a series of eight patients with deficiency of N-glycanase 1. METHODS: Whole-genome, whole-exome, or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data. RESULTS: All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypolacrima or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele. CONCLUSION: NGLY1 deficiency is a novel autosomal recessive disorder of the endoplasmic reticulum-associated degradation pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a broader range of mutations are detected

Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society

The purpose of this statement is to provide consensus-based recommendations for optimal management and care for patients with primary mitochondrial disease. This statement is intended for physicians who are engaged in the diagnosis and management of these patients. Working group members were appointed by the Mitochondrial Medicine Society. The panel included members with several different areas of expertise. The panel members utilized surveys and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve. Consensus-based recommendations are provided for the routine care and management of patients with primary genetic mitochondrial disease