The mitochondrial (mt) DNA depletion syndromes (MDDS) are genetic disorders characterized by a severe, tissue-specific decrease of mtDNA copy number, leading to organ failure. There are two main clinical presentations: myopathic (OMIM 609560) and hepatocerebral (OMIM 251880). Known mutant genes, including TK2, SUCLA2, DGUOK and POLG, account for only a fraction of MDDS cases. We found a new locus for hepatocerebral MDDS on chromosome 2p21-23 and prioritized the genes on this locus using a new integrative genomics strategy. One of the top-scoring candidates was the human ortholog of the mouse kidney disease gene Mpv17. We found disease-segregating mutations in three families with hepatocerebral MDDS and demonstrated that, contrary to the alleged peroxisomal localization of the MPV17 gene product, MPV17 is a mitochondrial inner membrane protein, and its absence or malfunction causes oxidative phosphorylation (OXPHOS) failure and mtDNA depletion, not only in affected individuals but also in Mpv17-/- mice.

T he insulin-like growth factors (IGFs; somatomedins) comprise a family of peptides that play important roles in mammalian growth and development. The principal members of this family are IGF1 and IGF2. IGF1 (somatomedin C), a 70 residue basic polypeptide, mediates many of the growth promoting actions of growth hormone (GH) and has metabolic and mitogenic effects.1 The major source of circulating IGF1 is the liver, but it is also produced in a wide variety of tissues and has endocrine and paracrine modes of action. The mature IGF1 peptide has A, B, C, and D domains with homology to insulin, and is highly conserved.2 It is produced as an inactive precursor, pre-pro-IGF1, with an additional carboxyterminal E region that plays an important role in the maturation of normal IGF1 peptide. This regulatory region is obtained by alternative splicing of the last two exons. IGF1 resides on the long arm of chromosome 12 (12q 22-24.1), 3 and several molecular studies have demonstrated that the structure of this gene is very complex. The gene contains six exons, which extend over more than 85 kb on chromosomal DNA. For human IGF1, two potential primary translation products exist: IGF1A and IGF1B, with sizes of 153 and 195 amino acids respectively. The two precursors are synthesised from distinct messenger RNAs produced by alternative splicing of the primary transcript. IGF1A mRNA contains exons 1, 2, 3, 4, and 6 of the human IGF1 gene while IGF1B is encoded by exons 1, 2, 3, 4, and 5. It has been speculated that IGF1B plays the major role during intrauterine growth, while the same function during postnatal growth is taken over by IGF1A. 4 Recent studies have focused attention on the genetic causes of growth alterations. Mutations involving the molecular structure of GH 5 or the function of the GH receptor 6 have been described. Recently, a partial deletion of the gene for IGF1, resulting in intrauterine growth failure plus severe post-natal growth retardation, sensorineural deafness, and mental retardation has been found. 7 In this study, we describe a new case of IGF1 deficiency associated with sensorineural deafness, severe pre-and post-natal growth failure, and delayed psychomotor development produced by a novel transversion TRA, which disrupts the normal consensus sequence for the polyadenylation site in the 39 untranslated region of exon 6 of IGF1, leading to altered mRNA processing, which could account for the extremely low IGF1 circulating levels and for the clinical findings. METHODS Case reportThe patient was born at 39 weeks' gestation by caesarean section because of poor fetal growth. The pregnancy had until then been uneventful. The birth weight was 1480 kg (24SD), length was 41 cm (26.5 SD), and the head circumference was 26.5 cm (,5th percentile). Hypoglycaemia and icterus were not reported. His parents were second cousins and the family history showed several miscarriages. His mother was 153 cm tall (5th percentile) and his father was 163 cm (5th percentile). His healthy sister, at the age of 9 years, was ...

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We found that 12% of Italian infants satisfied the Rome II criteria for infant regurgitation. Eighty-eight percent of 210 infants who had completed a 24-month follow-up period had improved at the age of 12 months. Only 1 patient later turned out to have gastroesophageal reflux disease. Use of breast milk was associated with a shorter time necessary to reach an Infant Gastroesophageal Reflux Questionnaire score of 0.

Aim: The aim of the study was to investigate the frequency of breastfeeding among children with Down syndrome. Methods: The mothers of 560 children with Down syndrome attending four university hospitals in Italy were interviewed and the neonatal clinical records retrieved. Information was collected on the type of infant feeding and on why some mothers had not breastfed their children. Two groups of healthy children whose feeding habits had been previously investigated were recruited as control subjects (1601 and 714, respectively). A paediatrician in each hospital was interviewed about the neonatal admission policy of children with Down syndrome. Results: Among the 560 Down children, 246 (44%) were admitted to the neonatal unit. Compared with the two control groups, children with Down syndrome were significantly more frequently bottle‐fed (57% vs 15% and 24%, respectively, odds ratio 7.5, 95% CI 6.0–9.4 and 4.2, 95% CI 3.3–5.4. respectively). Only 30% of infants admitted to the neonatal unit were breastfed. The main reasons reported by the mothers for not having breastfed were infants’illness in infants who had been admitted to the neonatal unit and frustration or depression, perceived milk insufficiency and difficulty with suckling for those babies who had not been admitted to the unit. The paediatricians reported that the admission of a baby with Down syndrome to the neonatal unit could sometimes take place not for medical reasons, but for diagnostic work‐up or for a more appropriate diagnosis and to maintain communication with the family. Conclusions: Down syndrome babies are less frequently breastfed compared with healthy children. Support in breastfeeding should become a relevant point of health supervision for children with Down syndrome.