Comprehensive cDNA study and quantitative analysis of mutant HADHA and HADHB transcripts in a French cohort of 52 patients with mitochondrial trifunctional protein deficiency.

BACKGROUND: Deficiency of mitochondrial trifunctional protein (MTP) is caused by mutations in the HADHA and HADHB genes, which have been mostly delineated at the genomic DNA level and have not been always elucidated. AIM: To identify mutations in a French cohort of 52 MTP deficient patients and the susceptibility of mutations generating premature termination codons (PTCs) to the nonsense mRNA mediated decay (NMD). METHODS: Mutation screening in fibroblasts was performed at the cDNA level and real-time RT-PCR was used to compare the levels of the different PTC-bearing mRNAs before and after a treatment of fibroblasts by emetine, a translation inhibitor. RESULTS: A mutation detection rate of 100% was achieved. A total of 22 novel mutations were identified, including a large-sized genomic deletion in HADHB gene. A high proportion of all identified mutations were non-sense, frameshift and splicing mutations, generating (PTCs), distributed essentially on HADHA coding regions. We could demonstrate that the majority of mutations resulting in PTCs conform to the established rules governing the susceptibility to NMD. CONCLUSION: Our results emphasize the value of cDNA analysis in the characterization of HADHA and HADHB mutations and further strengthen the model of haploinsufficiency as a major pathomechanism in MTP defects.

Satisfaction of mothers regarding human milk donation.

In France, human milk banks are in charge of the collection, analysis, processing, and distribution of human milk to neonatology centers for preterm infants. Knowledge of what motivates mothers to donate their milk could lead to better communication regarding human milk donation. A satisfaction survey was conducted among mothers who were donating their milk to a human milk bank. In total, 214 mothers answered a questionnaire in the presence of the collector during a home visit. The median age of the mothers was 31 years (18-46), mainly high school (19%) or university (65%) graduates, and the median duration of donation was 3 months (0.5-22). At the time of the study, the median age of infants was 3 months (0.5-25), and 88% of infants were exclusively breastfed. About three quarters of mothers were motivated by willingness to help others, a quarter of them being especially sensitive to premature neonatal care; 30% of mothers were motivated by having a high supply of milk. Around 25% of mothers were given information on human milk donation during pregnancy, and two thirds after delivery, mainly by the maternity ward midwives (53.4%) or by collectors during their visit (14.1%). Most mothers (72%) found the human milk donation process easy and most of them (92.5%) were willing to donate their milk again after their next pregnancy. This survey shows that more than 90% of mothers are satisfied with donation to human milk banks. However, efforts should be made to provide information on breastfeeding and human milk donation to the general population and health professionals.

[Prognostic value of MR in term neonates with neonatal hypoxic-ischemic encephalopath: MRI score and spectroscopy. About 26 cases]. / Apport pronostique de la résonance magnétique cérébrale dans l'encéphalopathie hypoxique-ischémique du nouveau-né à terme: score d'imagerie, spectroscopie. Etude de 26 cas.

UNLABELLED: Neonatal hypoxic-ischemic encephalopathy remains a major cause of chronic disability in childhood. Early diagnosis and prognosis are necessary for the clinician to adapt the treatment. However, there is yet no reliable test to predict the patient's evolution. OBJECTIVE: The aim of our study was to evaluate the predictive value of a personal magnetic resonance imaging (MRI) scoring system and of magnetic resonance spectroscopy (MRS). MATERIAL AND METHODS: We included 26 term newborns in condition of neonatal brain suffering. MR examination was performed during the first week of life for all patients and MRI and MRS data were collected. Standardised follow-up visits were made for all patients. Finally, prognostic value of the different criteria was evaluated with statistical tests. RESULTS: Our MRI scoring system proved to be linked to prognosis. A high MRI score, abnormal signal in the internal capsule, white matter or basal ganglia abnormalities with diffusion imaging were associated with unfavourable outcome. These results confirmed the data of the literature concerning the MRI predictive value. Our study also confirmed prognostic interest of MR: particularly, ratios using lactate were significantly linked to prognosis in our study. Specificity of the elevation of these ratios was interesting but sensibility was less optimal. CONCLUSION: We suggest using our MRI scoring system which associates standard MRI and diffusion imaging, which is significantly related to outcome. We confirm the prognostic value of MRS in this pathological situation. MR with diffusion sequence and spectroscopy, performed three to four days after birth appears to be an essential tool to manage these patients.

Transition from pediatric to adult care in adolescents with hereditary metabolic diseases: Specific guidelines from the French network for rare inherited metabolic diseases (G2M).

Inherited metabolic diseases (IMD) form a heterogeneous group of genetic disorders that surface primarily during childhood and result in significant morbidity and mortality. A prevalence of 1 in 2500-5000 live births is often reported. The transfer of adolescents from pediatric care to adult health facilities is often difficult for patients and their families and can lead to a breakdown in medical follow-up and therefore serious complications. Existing recommendations for the successful transition of patients with chronic disorders do not specifically address patients with IMDs associated with dietary treatment. Here, the French network for rare inherited metabolic diseases (G2M) presents its reflections and recommendations for a successful transition. Preparations for the transfer must be made well in advance. The transfer must aim for adolescents gaining autonomy by making them responsible and providing them with the knowledge that will enable them to manage their care themselves, know how to react appropriately if there is any change in their condition, and move comfortably within the adult healthcare system. This requires the active participation of the patient, his or her family, and pediatric and adult care teams. It involves multidisciplinary management plus the production and maintenance of an educational therapy program. Finally, the identification of physicians and dietitians trained in IMDs, relevant subspecialists, and even expert patients could improve the continuum of complete and appropriate care for these patients within adult medicine.

Major role for neuronal NO synthase in curtailing choroidal blood flow autoregulation in newborn pig.

We examined whether nitric oxide (NO) generated from neuronal NO synthase (nNOS) contributes to the reduced ability of the newborn to autoregulate retinal blood flow (RBF) and choroidal blood flow (ChBF) during acute rises in perfusion pressure. In newborn pigs (1-2 days old), RBF (measured by microsphere) is autoregulated over a narrow range of perfusion pressure, whereas ChBF is not autoregulated. N(G)-nitro-L-arginine methyl ester (L-NAME) or specific nNOS inhibitors 7-nitroindazole, 3-bromo-7-nitroindazole, and 1-(2-trifluoromethyl-phenyl)imidazole as well as ganglionic blocker hexamethonium, unveiled a ChBF autoregulation as observed in juvenile (4- to 6-wk old) animals, whereas autoregulation of RBF in the newborn was only enhanced by L-NAME. All NOS inhibitors and hexamethonium prevented the hypertension-induced increase in NO mediator cGMP in the choroid. nNOS mRNA expression and activity were three- to fourfold higher in the choroid of newborn pigs than in tissues of juvenile pigs. It is concluded that increased production of NO from nNOS curtails ChBF autoregulation in the newborn and suggests a role for the autonomic nervous system in this important hemodynamic function, whereas, for RBF autoregulation, endothelial NOS seems to exert a more important contribution in limiting autoregulation.

[Clinical presentation of inborn metabolic diseases in the neonatal period]. / Signes néonatals des maladies héréditaires du métabolisme.

Inborn metabolic diseases (IMDs) that can start in the neonatal period include various defects in numerous metabolic pathways. Such diseases are due to the genetic deficiency of an enzyme or a transporter. From a physiopathological point of view, the metabolic disorders can be divided into 3 diagnostically useful groups of diseases. The first group is due to the accumulation of endogenous toxic metabolites and includes inborn errors of amino acid metabolism, organic acidemias, urea cycle disorders, and sugar intolerances. The second one includes IMDs of intermediary metabolism causing a disturbance in energy production or utilization resulting from a defect in the liver, the muscles, the myocardium, or the brain (fatty acid oxidation defects, congenital lactic acidosis, etc.). The third group includes diseases that disturb the synthesis or the catabolism of complex molecules (lysosomal or peroxisomal disorders, etc.). IMDs are individually rare, but collectively numerous. Therefore, it is difficult to acquire extensive experience in the management of these diseases. However, the neonate has a limited repertoire of responses to severe illness and, at first, presents with nonspecific symptoms that could be easily attributed to infection or some other common cause. An IMD must be suspected in all situations of neonatal distress for which there is no apparent reason and that does not respond to symptomatic therapy. The priority is given to IMDs that are amenable to treatment, and emergency management has to be scheduled as soon as the diagnosis is suspected, even if the precise diagnosis is still unknown. In fact, emergency treatment must be undertaken in parallel with metabolic investigations, to prevent any delay in the management of the disease. The neonatologist must be able to recognize the neonatal distresses that suggest the possibility of an IMD. In such situations, an adequate diagnostic approach can be based on the proper use of only a few screening tests, which will also be useful to schedule adequate emergency treatment.

[Acute fatty liver in pregnancy: revealing fetal fatty acid oxidation disorders]. / Atteinte hépatique gravidique : mode de révélation d'une anomalie de la bêta-oxydation des acides gras chez l'enfant.

Acute fatty liver of pregnancy (AFLP) and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome are serious maternal illnesses occurring in the third trimester of pregnancy with significant perinatal and maternal mortality. AFLP may result from mitochondrial defects in the beta-oxidation of fatty acids, in particular a deficiency of the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) in the fetus. Clinical findings in AFLP vary and its diagnosis is complicated by a significant overlap in clinical and biochemical features with HELLP syndrome. We report the case of 2 siblings who died, the first one in the neonatal period of asphyxia with multivisceral presentation and the second one from sudden death at 7 months. Autopsy of the latter infant revealed hepatic steatosis associated with cardiomyopathy, which led to suspicion of a fatty acid oxidation deficiency. Mutation analysis demonstrated that both children were homozygous for the common mutation c.1528G>C and the parents were heterozygous for this same mutation. This case demonstrates the importance of screening mothers with acute fatty liver disease of pregnancy and their children at birth for a metabolic disease. This article proposes several metabolic tests for mother and child suspected of having beta-oxidation of a fatty acid disorder.