Pathophysiology and targets for treatment in hereditary galactosemia: A systematic review of animal and cellular models.

Since the first description of galactosemia in 1908 and despite decades of research, the pathophysiology is complex and not yet fully elucidated. Galactosemia is an inborn error of carbohydrate metabolism caused by deficient activity of any of the galactose metabolising enzymes. The current standard of care, a galactose-restricted diet, fails to prevent long-term complications. Studies in cellular and animal models in the past decades have led to an enormous progress and advancement of knowledge. Summarising current evidence in the pathophysiology underlying hereditary galactosemia may contribute to the identification of treatment targets for alternative therapies that may successfully prevent long-term complications. A systematic review of cellular and animal studies reporting on disease complications (clinical signs and/or biochemical findings) and/or treatment targets in hereditary galactosemia was performed. PubMed/MEDLINE, EMBASE, and Web of Science were searched, 46 original articles were included. Results revealed that Gal-1-P is not the sole pathophysiological agent responsible for the phenotype observed in galactosemia. Other currently described contributing factors include accumulation of galactose metabolites, uridine diphosphate (UDP)-hexose alterations and subsequent impaired glycosylation, endoplasmic reticulum (ER) stress, altered signalling pathways, and oxidative stress. galactokinase (GALK) inhibitors, UDP-glucose pyrophosphorylase (UGP) up-regulation, uridine supplementation, ER stress reducers, antioxidants and pharmacological chaperones have been studied, showing rescue of biochemical and/or clinical symptoms in galactosemia. Promising co-adjuvant therapies include antioxidant therapy and UGP up-regulation. This systematic review provides an overview of the scattered information resulting from animal and cellular studies performed in the past decades, summarising the complex pathophysiological mechanisms underlying hereditary galactosemia and providing insights on potential treatment targets.

Change in total body water as a predictive tool for growth hormone treatment response.

BACKGROUND/AIMS: To investigate whether short-term changes in body composition as a result of growth hormone therapy could be used to predict its growth effect after 1 year in children with growth hormone deficiency (GHD) and children born small for gestational age (SGA). METHODS: 88 GHD children and 99 SGA children who started treatment with recombinant human growth hormone were included. Total body water (TBW) and height were measured. After 1 year, patients were divided into adequate and inadequate responders. RESULTS: In GHD and SGA children a sensitivity of 87 and 53%, respectively, and a specificity of 58 and 83%, respectively, were found. The positive predictive values for GHD and SGA children were 73 and 90%, respectively. The negative predictive values were 75 and 32%, respectively. CONCLUSION: Changes in body composition data measured by TBW are a valuable tool to correctly predict 75% of the GHD children and are only useful in SGA children when the change in TBW is above the cut-off value of 0.7 l/m(2).

Preconception care: preliminary estimates of costs and effects of smoking cessation and folic acid supplementation.

OBJECTIVE: To assess costs and effectiveness of preconception counseling for all women planning pregnancy in The Netherlands with regard to folic acid supplementation and smoking cessation counseling. STUDY DESIGN: Costs and effects were estimated based on 200,000 women approached yearly and uptake rates of 50% and 75%. Effectiveness and potential savings were based on hospital costs of neural tube defects, low birth weight, very low birth weight and perinatal death attributable to maternal smoking. RESULTS: Total costs were estimated at dollar 5.1 million and dollar 7.2 million at uptake rates of 50% and 75%, respectively. If 50% of women would seek preconception counseling, 22 neural tube defects, 98 low-birth-weight infants, 10 very-low-birth-weight infants and 7 perinatal deaths could be avoided. At 75% uptake, 33 neural tube defects, 146 low- and 15 very-low-birth-weight infants, and 11 perinatal deaths could be avoided. CONCLUSION: Net costs of preconception counseling amount to dollar 3.7 million and dollar 5.0 million when considering cases prevented and subsequent potential savings in costs of neural tube defects and smoking-related morbidity only. However, in light of many other preventable adverse outcomes and the potential of preconception counseling to prevent significant lifetime costs for affected children, the net costs may ultimately result in a favorable cost-savings balance. Moreover, the importance of a healthy child cannot be expressed in terms of costs and savings alone.