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"One of the current debates in Genetics is the genomic sequencing in newborns. Thanks to the genomic technologies, it is currently possible to detect diseases that a newborn may suffer in the short, medium or long term. Genomic tests pose some important ethical issues. Those issues can be classified in three different types: those regarding the object of the screening (genes that must be analyzed), those related to the information (how it must be managed) and those regarding justice questions (economic costs, population to be included in some screening programs). This study is based on a previous study whose aim was to present a general view of those three ethical problems. This study aims to focus on one of these three problems: the information. We think that how to manage the information on the results of a genomic sequencing in newborns is perhaps the most important ethical issue in this topic. Hence this work aims to address these questions regarding information on genomic sequencing: How the genomic screening has to be explained to the parents in order to get the informed consent? Should the physician give them all the data or only the information related to some genes about which he is sure that they will cause a disease? How the genomic information has to be managed? Can we keep this information once we have finished the screening of a newborn? Should we destroy it after the screening? Is it ethical that parents, without a prescription or medical control, can do on their own a genomic screening on their newborn child? "

Vanishing white matter (VWM) leukoencephalopathy is one of the most prevalent hereditary white matter diseases. It has been associated with mutations in genes encoding eukaryotic translation initiation factor ( eIF2B). We have compiled a list of all the patients diagnosed with VWM in Spain; we found 21 children. The first clinical manifestation in all of them was spasticity, with severe ataxia in six patients, hemiparesis in one child, and dystonic movements in another. They suffered from progressive cognitive deterioration and nine of them had epilepsy too. In four children, we observed optic atrophy and three also had progressive macrocephaly, which is not common in VWM disease. The first two cases were diagnosed before the 1980s. Therefore, they were diagnosed by necropsy studies. The last 16 patients were diagnosed according to genetics: we found mutations in the genes eIF2B5 (13 cases), eIF2B3 (2 cases), and eIF2B4 (1 case). In our report, the second mutation in frequency was c.318A>T; patients with this mutation all followed a slow chronic course, both in homozygous and heterozygous states. Previously, there were no other reports to confirm this fact. We also found some mutations not described in previous reports: c.1090C>T in eIF2B4, c.314A>G in eIF2B5, and c.877C>T in eIF2B5.

Summary Background Some limited studies of coeliac disease have shown higher frequency of coeliac disease in infancy and adolescence than in adulthood. This finding has remained unnoticed and not adequately demonstrated. Aim To assess whether there are age and gender differences in coeliac disease prevalence. Methods A total of 4230 subjects were included consecutively (1 to ≥80 years old) reproducing the reference population by age and gender. Sample size was calculated assuming a population-based coeliac disease prevalence of 1:250. After an interim analysis, the paediatric sample was expanded (2010 children) due to high prevalence in this group. Anti-transglutaminase and antiendomysial antibodies were determined and duodenal biopsy was performed if positive. Log-linear models were fitted to coeliac disease prevalence by age allowing calculation of percentage change of prevalence. Differences between groups were compared using Chi-squared test. Results Twenty-one subjects had coeliac disease (male/female 1:2.5). Coeliac disease prevalence in the total population was 1:204. Coeliac disease prevalence was higher in children (1:71) than in adults (1:357) (P = 0.00005). A significant decrease of prevalence in older generations was observed [change of prevalence by age of −5% (95% CI: −7.58 to −2.42%)]. In the paediatric expanded group (1–14 years), a decrease of coeliac disease prevalence was also observed [prevalence change: −17% (95% CI: −25.02 to −6.10)]. Conclusions The prevalence of coeliac disease in childhood was five times higher than in adults. Whether this difference is due to environmental factors influencing infancy, or latency of coeliac disease in adulthood, remains to be demonstrated in prospective longitudinal studies.

Congenital disorder of glycosylation Ia (CDG-Ia) is a metabolic disease with a broad spectrum of clinical signs, including recently described mild phenotypes. Our aim was to describe the clinical presentation and follow-up of eight CDG-Ia patients highlighting atypical features and aspects of evolution of the disease. CDG diagnosis was confirmed by enzymatic analysis of phosphomannomutase (PMM2) and molecular studies of the PMM2 gene. Four neonates presented with cerebral haemorrhage (1), failure to thrive (2) and non-immune hydrops (1) and a fatal course to death (2); pathological examination of the brain in one case revealed olivopontocerebellar atrophy of prenatal origin. During infancy failure to thrive, coagulopathy and hepatopathy were the most significant causes of morbidity, but these disappeared after the first years of life in most patients. Three patients are currently in their 20s; they present mental retardation and severe motor impairment but no acute decompensations were noticed after the first decade of life. They do not present spinal or thoracic deformities otherwise observed in patients from northern countries. A 10-year-old patient who manifested gastrointestinal dysfunction in early childhood showed normal neurodevelopment. Mutation analysis of the PMM2 gene showed great variability, with all patients being compound heterozygous for two different mutations. Long-term evolution in our patients indicates that CDG-Ia is a stable systemic and neurological condition after the first decade of life. The diverse phenotypes and atypical manifestations in our series may be due to their genetic heterogeneity.

Resumen Introduccion La enfermedad celiaca (EC) y la diabetes mellitus tipo 1 son alteraciones cronicas que comparten susceptibilidad genetica, presencia de anticuerpos organo especificos e influencia de factores ambientales. Segun un estudio transversal realizado el ano 2001 en nuestro centro, el 8,3% de los pacientes diabeticos tiene anticuerpos especificos de la EC y el 4,9% presenta una lesion intestinal Marsh III. Con estos antecedentes, se instaura el cribado serologico sistematico para la EC en los pacientes que debutan diabetes mellitus de tipo 1 (DM1). El objetivo de este estudio es valorar el resultado de esta estrategia y caracterizar a los pacientes celiacos detectados. Material y metodos Se estudian los 202 pacientes diabeticos que debutan durante el periodo 2002–2007 controlados en la Unidad de Diabetes de nuestro hospital. Se determina la concentracion serica de anticuerpos antitransglutaminasa en el debut diabetico con controles anuales. Resultados y discusion El 6,4% (13/202) de los pacientes diabeticos debutantes tiene EC, siendo mas frecuente entre los que la debutan precozmente (p=0,016) y mostrando un orden de aparicion aleatorizado de ambas enfermedades. En estos pacientes, la EC es mayoritariamente asintomatica. La mitad de ellos muestra una respuesta serologica parcial a la dieta sin gluten, lo que sugiere una falta de motivacion para el tratamiento dietetico. Segun nuestra experiencia, el control metabolico de los pacientes diabeticos con EC puede ser complicado y una elevada proporcion de casos (p=0,013) requiere el uso de bombas de infusion continua de insulina.

Deregulation of intracellular calcium homeostasis is widely considered as one of the underlying pathophysiological mechanisms of hypoxic-ischemic brain injury. Whether this alteration can result in cerebral calcification was investigated in basal ganglia, cerebral cortex, and hippocampus of human premature and term neonates together with glial reaction. In all samples nonarteriosclerotic calcifications were observed, their number and size were area-specific and increased in term neonates. Basal ganglia always presented the highest degree of calcification and hippocampus the lowest, located mainly in the CA1 subfield. In all cases, neuronal damage was associated with astroglial reaction and calcium precipitates, with microglial reaction only in basal ganglia and cerebral cortex, and argues for the participation of excitatory amino acid receptors in hypoxia-ischemia damage. These data correlate with hypoxia-ischemia vulnerability in the perinatal period. The clinical relevance of these precipitates and the neuroprotective interest of non-NMDA receptor manipulation are discussed in the light of our results.

Pyruvate carboxylase deficiency is a rare metabolic disorder, with three different phenotypes. We aim to report the case of a newborn presenting the severe neonatal form of this deficiency (the B or “French” phenotype, hypokinesia and rigidity being the main features) and the results of the study of classic neurotransmitters involved in movement control. Hyperdopaminergic transmission (both in the cerebrospinal fluid and in the substantia nigra) and hypoGABAergic transmission (in the substantia nigra) were found. Both gamma-aminobutyric acid and dopamine markers were found coexisting in individual neurons of the substantia nigra. This is the first time this phenomenon has been reported in the literature. We discuss the possible role of GABAergic deficiency, its interaction with other neurotransmitters and its implication in neurotransmitter homeostasis. A better comprehension of that field would increase understanding of the pathophysiology of neurological symptoms and neurotransmitter plasticity.

A further case of pyruvate carboxylase deficiency, French type, with a particular clinical presentation and evolution is described. The initial neonatal symptoms started with respiratory distress, severe metabolic acidosis and a tendency to hypoglycemia. However, the clinical course was not rapidly deteriorating. At the age of 6 months he presented acute neurological symptoms, respiratory difficulty, lactic acidosis and hyperammonemia. Amino and organic acid abnormalities strongly suggested pyruvate carboxylase deficiency, which was confirmed by enzymatic studies in cultured fibroblasts and liver necropsy. Progressive deterioration and bronchopneumonia with cardiac failure and renal insufficiency led to death. Anatomic-pathologic studies revealed periventricular cysts and diffuse hypomyelination. Prenatal diagnosis of a further sibling was performed. The neonatal clinical presentation, biochemical abnormalities, and the presence of periventricular cysts suggested a French phenotype. However, the clinical course was less severe, suggesting a residual enzymatic activity and a possible milder mutation.

The levels of expression of the α1 and α3 subunits of the Na(+)/K(+)-ATPase (the NaK sodium pump) in medulloblastomas are unclear.This study investigated the expression of the NaK subunits using immunohistochemical methods in 29 medulloblastomas including 23 classic, three large-cell/anaplastic and three nodular/desmoplastic medulloblastomas, as well as in three atypical teratoid/rhabdoid tumors (AT/RTs).There was overexpression of the α1 or α3 NaK subunits in more than half of the medulloblastomas and atypical AT/RTs, with about one-third of these tumours displaying overexpression of both subunits.These preliminary data suggest that targeting these subunits in AT/RTs and medulloblastomas that overexpress these proteins may lead to therapeutic benefit. These findings warrant confirmation in larger numbers of patients than those used in this study. Moreover, it should be determined whether inhibition of the α1/α3 NaK subunits can be integrated into the risk stratification schemes already in use for medulloblastoma patients.

Quantification of mitochondrial DNA (mtDNA) content is an essential tool for the diagnosis of mtDNA depletion syndrome (MDS). Samples collected and processed for anatomopathology studies represent a unique source of archived biological material. Thus, the possibility to study mtDNA copy number in these specimens would be a useful way to screen for MDS. In this study, we designed and validated the methodology to determine mtDNA content by quantitative real-time polymerase chain reaction (qRT-PCR) in formalin-fixed paraffin-embedded (FFPE) muscle tissue. We studied 14 frozen muscle biopsies and compared the results with a portion of the same biopsy embedded in paraffin. Our results showed a similar variability among frozen and FFPE muscle biopsies. Patients with MDS detected in frozen muscle were also confirmed in their corresponding FFPE samples, which validate the usefulness of this approach. We conclude that the analysis of mtDNA copy number in FFPE muscle tissue by qRT-PCR is a useful method for the molecular screening of patients suspected to have MDS when frozen biopsies are not available. Analysis of these samples would facilitate retrospective studies and diagnostic procedures.

The role of chorioamnionitis in neurodevelopment of preterm infants is not fully understood.To examine the association between different indicators of intrauterine inflammation (clinical chorioamnionitis, histological chorioamnionitis and funisitis) and neurodevelopmental impairment in very preterm infants.Preterm infants with a birth weight of1500 g or a gestational age of32 weeks were included. Follow-up evaluation up to 2 years of age consisted of neurological examination, neurodevelopmental assessment and visual and audiologic tests. Outcome data were compared between the chorioamnionitis and the control groups, controlling for gestational age, birth weight and Apgar score at 5 min.One hundred seventy-seven patients comprised the study population (mean gestational age 29±2 weeks, mean birth weight 1167±344 g). Histological chorioamnionitis was present in 49% of placentas, whereas funisitis was observed in 25%. In 57% cases clinical maternal chorioamnionitis was suspected. Follow-up was available for 130 (82%) patients. Infants with funisitis, compared with controls, had a significantly higher incidence of moderate to severe disability (18% vs 5%, OR 4.07; 95% CI 1.10-15.09).The results of this study suggest that, unlike a broad definition of histological chorioamnionitis including inflammation of maternal or fetal placental tissues, funisitis may entail a higher risk of moderate to severe disability at 2 years of age in preterm infants.

Heat shock protein 60 (hsp60) is a mitochondrial matrix protein involved in the folding and correct assembly of polypeptides into complex mitochondrial enzymes. Its deficiency has recently been described as the most likely primary cause of congenital lactic acidaemia with multiple mitochondrial enzyme deficiencies in a female patient, We describe a new case of a girl with a substantially decreased amount of hsp60 in cultured fibroblasts. She presented from birth with hypotonia, unusual facial features, feeding difficulties and failure to thrive. Death occurred at age 4.5 years. Biochemical findings included metabolic acidosis with lactic acidaemia, hyperammonaemia and intermittent ketosis. In contrast to the previously reported case, organic acid analysis showed an altered profile throughout her life. In agreement with this profile, various mitochondrial enzyme activities were deficient in cultured fibroblasts, including enzymes of die respiratory chain and the Krebs cycle, the pyruvate dehydrogenase complex and the mitochondrial biotin-dependent carboxylases. Fibroblast mitochondria showed ultrastructural abnormalities, were swollen, and were mainly localized around the nucleus.The description of a second case of multiple mitochondrial enzyme deficiencies with reduced amount of hsp60 supports the idea that hsp60 deficiency might be a more common cause of mitochondrial disease. This opens new possibilities for the diagnosis and understanding of congenital lactic acidaemia.