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Mitochondrial DNA (mtDNA)-depletion syndromes (MDS; OMIM 251880) are phenotypically heterogeneous, autosomal-recessive disorders characterized by tissue-specific reduction in mtDNA copy number. Affected individuals with the hepatocerebral form of MDS have early progressive liver failure and neurological abnormalities, hypoglycemia and increased lactate in body fluids. Affected tissues show both decreased activity of the mtDNA-encoded respiratory chain complexes (I, III, IV, V) and mtDNA depletion. We used homozygosity mapping in three kindreds of Druze origin to map the gene causing hepatocerebral MDS to a region of 6.1 cM on chromosome 2p13, between markers D2S291 and D2S2116. This interval encompasses the gene (DGUOK) encoding the mitochondrial deoxyguanosine kinase (dGK). We identified a single-nucleotide deletion (204delA) within the coding region of DGUOK that segregates with the disease in the three kindreds studied. Western-blot analysis did not detect dGK protein in the liver of affected individuals. The main supply of deoxyribonucleotides (dNTPs) for mtDNA synthesis comes from the salvage pathway initiated by dGK and thymidine kinase-2 (TK2). The association of mtDNA depletion with mutated DGUOK suggests that the salvage-pathway enzymes are involved in the maintenance of balanced mitochondrial dNTP pools.

Enteral nutrition support (ENS) involves both the delivery of nutrients via feeding tubes and the provision of specialised oral nutritional supplements. ENS is indicated in a patient with at least a partially functioning digestive tract when oral intake is inadequate or intake of normal food is inappropriate to meet the patients' needs. The aim of this comment by the Committee on Nutrition of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition is to provide a clinical practice guide to ENS, based on the available evidence and the clinical expertise of the authors. Statements and recommendations are presented, and future research needs highlighted, with a particular emphasis placed on a practical approach to ENS.Among the wide array of enteral formulations, standard polymeric feeds based on cow's-milk protein with fibre and age adapted for energy and nutrient content are suitable for most paediatric patients. Whenever possible, intragastric is preferred to postpyloric delivery of nutrients, and intermittent feeding is preferred to continuous feeding because it is more physiological. An anticipated duration of enteral nutrition (EN) exceeding 4 to 6 weeks is an indication for gastrostomy or enterostomy. Among the various gastrostomy techniques available, percutaneous endoscopic gastrostomy is currently the first option. In general, both patients and caregivers express satisfaction with this procedure, although it is associated with a number of well-recognised complications. We strongly recommend the development and application of procedural protocols that include scrupulous attention to hygiene, as well as regular monitoring by a multidisciplinary nutrition support team to minimise the risk of EN-associated complications.

MethodsLiterature search timeframe: The references cited in the previous guidelines [1] are not repeated here, except for some relevant publications, and only the previous guidelines are cited instead. All publications published after the previous guidelines (i.e., from January 2004 to December 2014), have been considered for the first draft of this manuscript. Randomized controlled trials (RCTs), review articles, prospective studies and meta-analyses published in 2015 and 2016, during the revision process, have also been considered.Type of publications: Original papers, meta-analyses and reviews.