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Maple syrup urine disease (MSUD) is a rare inborn metabolic disorder, managed with a strict protein‐restricted diet. At any time or age patients may still experience metabolic decompensations, requiring administration of branched chain amino acid (BCAA)‐free formula to reduce leucine levels. This retrospective observational study of 126 decompensation episodes from 54 MSUD patients treated at five centers in France and Germany from 2010 to 2016, describes episodes and outcomes for patients stratified into groups who received enteral/oral or intravenous (IV) BCAA‐free formula, and by pediatric or adult age categories. IV administration of BCAA‐free formula was required in cases of gastric intolerance (33%), refusal to undergo nasogastric tubing (31%), “emergency” (14%) or coma patients (8%), and as prophylaxis before surgery (6%). Overall, mean duration of hospitalization was 6.6 days with oral/enteral BCAA‐free formula and 5.4 days with IV formula. Leucine levels at discharge decreased by a mean of 548.5 μmol/L (69.3%) in the oral/enteral group and 657.2 μmol/L (71.3%) in the IV group. In the pediatric subgroup, there were no marked differences between administration groups on any outcome. In the adult subgroup, mean time to episode resolution was 15.8 days in the oral/enteral group and 7.7 days in the IV group (P = .008); mean duration of hospitalization was 6 days in the oral/enteral group and 4.6 days in the IV group (P = NS). Overall, seven serious adverse events in two patients were reported, of which only nausea and vomiting were treatment related.

The objective of this study was to compare the quality of life (QoL) for parents of children with inborn errors of metabolism (IEMs) requiring a restricted diet with French population norms and investigate parental QoL determinants.This cross-sectional study included mothers and/or fathers of children18 years of age affected by IEMs requiring a restricted diet (except phenylketonuria) from January 2015 to December 2017. Parents' QoL was assessed using the World Health Organization Quality of Life BREF questionnaire and compared with age- and sex-matched reference values from the French general population. Linear mixed models were used to examine the effects of demographic, socioeconomic, disease-related, and psychocognitive factors on parental QoL, according to a 2-level regression model considering individuals (parents) nested within families.Of the 1156 parents invited to participate, 785 (68%) were included. Compared with the general population, parents of children with IEMs requiring a restricted diet reported a lower QoL in physical and social relationship domains but a higher QoL in the psychological domain. In the multivariate analysis, characteristics associated with poorer parental QoL included both parent-related factors (being a father, older age, more educated parent, nonworking parent, greater anxiety, seeking more social support, and using less positive thinking and problem-solving coping strategies) and family-related factors (disease complications, increased number of hospital medical providers, child's younger age, single-parent family, and lower family material wealth).Parents of children with IEMs requiring a restricted diet reported poorer QoL in physical and social relationship domains than population norms. Psychocognitive factors, beyond disease-specific and family-related characteristics, were the most important determinants influencing parental QoL and may represent essential aspects for interventions.ClinicalTrials.gov: NCT02552784.

Objective To investigate the determinants of quality of life (QoL) in children with inborn errors of metabolism with restricted diet (IEMRDs) using a single theory-based multidimensional model. Study design In this multicenter cross-sectional study, data from children with IEMRDs (except phenylketonuria) aged 8 to 17 years and their parents were collected from January 2015 to December 2017. Measurements included a child’s self-reported QoL, self-rated behavioral problems and anxiety, and parental anxiety. Based on hypotheses from a literature-built theoretical model linking demographic, clinical, family environment and psychosocial characteristics to QoL either directly or indirectly, associations of these factors with a child's self-rated QoL were examined using a structural equation modeling (SEM) approach. Results A total of 312 children (mean [SD] age, 12.2 [2.6] years; 160 [51%] boys) were included. Higher trait anxiety and behavioral problems in children were the most important factors associated with poorer QoL (standardized path coefficients = −0.71 and −0.23, respectively). Additionally, higher parent trait anxiety, younger age at diagnosis, and having a disease requiring an emergency diet were associated with poorer QoL in these children. The final model fit the data closely according to conventional goodness-of-fit statistics and explained 86% of QoL variance. Conclusions Psychosocial factors appear to be major determinants of QoL impairment in children with IEMRDs. These factors should be particularly addressed in clinical practice as part of the global treatment plan for a child with IEMRD. Future studies based on longitudinal design should consider coping strategies when exploring potential predictive factors of QoL.

Objective To describe the health status of young patients affected by inborn errors of metabolism that require adherence to a restricted diet (IEMRDs) and to describe and compare their self- and proxy (parent)-reported quality of life (QoL) with reference values. Study design A cross-sectional study was conducted in 2015-2017 in patients affected by IEMRDs (except phenylketonuria) younger than 18 years. Data collection was based on medical records, clinical examinations, parents' and children's interviews, and self-reported questionnaires. Measurements included clinical and healthcare data, child and family environment data, and self- and proxy (parent)-reported QoL. Results Of the 633 eligible participants, 578 were recruited (50.3% boys; mean age: 8.7 years); their anthropometric status did not differ from the general population. Approximately one-half of them had at least 1 complication of the disease. Their self-reported global QoL did not differ from that of the general population. However, relations with friends and leisure activities QoL domains were negatively impacted, whereas relations with medical staff, relations with parents, and self-esteem QoL domains were positively impacted. Their proxy (parent)-reported QoL was negatively impacted. Conclusions Young patients affected by IEMRDs present a high rate of clinical complications. Although their proxy (parent)-reported QoL was negatively impacted, their self-reported QoL was variably impacted (both positively and negatively). These results may inform counseling for those who care for affected patients and their families.

Maple syrup urine disease (MSUD), an inborn error of amino acids catabolism is characterized by accumulation of branched chain amino acids (BCAAs) leucine, isoleucine, valine and their corresponding alpha-ketoacids. Impact on the cognitive development has been reported historically, with developmental delays of varying degree. Currently, earlier diagnosis and improved management allow a better neurodevelopment, without requirement of special education. However, specific impairments can be observed, and so far, results of detailed neurocognitive assessments are not available. The aim of this study was to analyse neurocognitive profiles of French MSUD patients. This was a multicentre retrospective study on MSUD patients who underwent neurocognitive evaluation at primary school age. Twenty-one patients with classical neonatal onset MSUD were included. The patients’ mean age at the time of evaluation was 8.7 years. The mean intellectual quotient (IQ) score was in the normal range (95.1 ± 12.6). In a subset of eight patients, a consistent developmental pattern of higher verbal than performance IQ was observed (mean of the difference 25.7 ± 8.7, p

Background Feeding breast milk is associated with reduced morbidity and mortality, as well as improved neurodevelopmental outcome but does not meet the high nutritional requirements of preterm infants. Both plasma and urinary urea concentrations represent amino acid oxidation and low concentrations may indicate insufficient protein supply. This study assesses the effect of different levels of enteral protein on plasma and urinary urea concentrations and determines if the urinary urea-creatinine ratio provides reliable information about the protein status of preterm infants. Methods Sixty preterm infants (birthweight

International audience; 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.

Background:Long-chain polyunsaturated fatty acids (LC-PUFAs) are important for newborn neurosensory development. Supplementation of breastfeeding mothers’ diets with omega-3 PUFAs, such as alpha-linolenic acid (ALA), may increase their concentration in human milk.Research aim:This study aimed to assess human milk composition after 15-day supplementation regimens containing either omega-3 PUFAs or olive oil, which does not provide ALA.Methods:A multicenter factorial randomized trial was conducted with four groups of breastfeeding women, with each group containing 19 to 22 women. After a 15-day ALA washout period, three groups received supplementation with omega-3 precursors for 15 days: an enriched margarine (M), a rapeseed oil (R), and a margarine and rapeseed oil (MR). The fourth was unexposed to omega-3 precursors (olive oil control diet, O). After 15 days, blind determination of human milk fatty acid (FA) composition was assessed by gas chromatography, and the FA composition was compared among groups using variance analyses.Results:Alpha-linolenic acid content, expressed as the mean (standard deviation) total human milk FA percentage, was significantly higher after diet supplementation with omega-3 PUFAs, with values of 2.2% (0.7%) (MR), 1.3% (0.5%) (R), 1.1% (0.4%) (M), and 0.8% (0.3%) (O at D30) ( p < .003 for each comparison). The lowest LA–ALA ratio (5.5) was found in the MR group ( p < .001). Docosahexaenoic acid and trans FA concentrations did not differ among groups.Conclusion:In lactating women, omega-3 supplementation via the combination of enriched margarine and rapeseed oil increased the ALA content of human milk and generated the most favorable LA–ALA ratio for LC-PUFA synthesis.

International audience; Background and aim To improve the diagnostic work‐up of patients with diverse neurological diseases, we have elaborated specific clinical and CSF neurotransmitter patterns. Methods Neurotransmitter determinations in CSF from 1200 patients revealed abnormal values in 228 (19%) cases. In 54/228 (24%) patients, a final diagnosis was identified. Results We have reported primary (30/54, 56%) and secondary (24/54, 44%) monoamine neurotransmitter disorders. For primary deficiencies, the most frequently mutated gene was DDC (n = 9), and the others included PAH with neuropsychiatric features (n = 4), PTS (n = 5), QDPR (n = 3), SR (n = 1), and TH (n = 1). We have also identified mutations in SLC6A3, FOXG1 (n = 1 of each), MTHFR (n = 3), FOLR1, and MTHFD (n = 1 of each), for dopamine transporter, neuronal development, and folate metabolism disorders, respectively. For secondary deficiencies, we have identified POLG (n = 3), ACSF3 (n = 1), NFU1, and SDHD (n = 1 of each), playing a role in mitochondrial function. Other mutated genes included: ADAR, RNASEH2B, RNASET2, SLC7A2‐IT1 A/B lncRNA, and EXOSC3 involved in nuclear and cytoplasmic metabolism; RanBP2 and CASK implicated in post‐traductional and scaffolding modifications; SLC6A19 regulating amino acid transport; MTM1, KCNQ2 (n = 2), and ATP1A3 playing a role in nerve cell electrophysiological state. Chromosome abnormalities, del(8)(p23)/dup(12) (p23) (n = 1), del(6)(q21) (n = 1), dup(17)(p13.3) (n = 1), and non‐genetic etiologies (n = 3) were also identified. Conclusion We have classified the final 54 diagnoses in 11 distinctive biochemical profiles and described them through 20 clinical features. To identify the specific molecular cause of abnormal NT profiles, (targeted) genomics might be used, to improve diagnosis and allow early treatment of complex and rare neurological genetic diseases.

International audience; Background: Despite ACADS (aryl-CoA dehydrogenase, short-chain) gene susceptibility variants (c.511C \textgreater T and c.625G \textgreater A) are considered to be non-pathogenic, encoded proteins are known to exhibit altered kinetics. Whether or not, they might affect overall fatty acid beta-oxidation still remains, however, unclear. Methods: De novo biosynthesis of acylcarnitines by whole blood samples incubated with deuterated palmitate (16-H-2(3),15-H-2(2)-palmitate) is suitable as a fluxomic exploration to distinguish between normal and disrupted beta-oxidation, abnormal profiles and ratios of acylcarnitines with different chain-lengths being indicative of the site for enzymatic blockade. Determinations in 301 control subjects of ratios between deuterated butyrylcarnitine and sum of deuterated C2 to C14 acylcarnitines served here as reference values to state specifically functional SCAD impairment in patients addressed for clinical and/or biological suspicion of a beta-oxidation disorder. Results: Functional SCAD impairment was found in 39 patients. The 27 patients accepting subsequent gene studies were all positive for ACADS mutations. Twenty-six of 27 patients were positive for c.625G \textgreater A variant. Twenty-three of 27 patients harbored susceptibility variants as sole ACADS alterations (18 homozygous and 3 heterozygous for c.625G \textgreater A, 2 compound heterozygous for c.625G \textgreater A/c.511C \textgreater T). Conclusion: Our present fluxomic assessment of SCAD suggests a link between ACADS susceptibility variants and abnormal beta-oxidation consistent with known altered kinetics of these variants.

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.

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.

Objective To report the case of a child with severe autoimmune thrombotic thrombocytopenic purpura (TTP) resistant to plasma exchange and steroids who was successfully treated with rituximab. Design Case report and review of the literature on pediatric acquired TTP. The report was approved by an independent local ethics committee. Setting Pediatric intensive care unit in a tertiary care children's hospital. Patient A 10-yr-old boy was referred to the emergency unit with fever, vomiting, confusion, hemolytic anemia, thrombocytopenia, and mild acute renal failure. An atypical hemolytic uremic syndrome was suspected, and plasma exchange was started urgently. The patient was refractory to plasma therapy and presented critical complications. After a diagnosis of acquired TTP attributable to anti-ADAMTS13 autoantibodies had been made, he was treated with rituximab, which resulted in a stable clinical remission. Interventions Rituximab therapy. Measurements and main results Clinical remission. Conclusions TTP is a rare but life-threatening condition in children that is characterized by hemolytic anemia, thrombocytopenia, and signs of ischemic organ dysfunction. If renal involvement is present, TTP may be misdiagnosed as hemolytic uremic syndrome, but reliable screening for ADAMTS13 activity and anti-ADAMTS autoantibodies allow us to distinguish the two entities and provide adequate therapy.

Background and Purpose— Reduced endothelium-dependent vasorelaxation partly due to loss of nitric oxide (NO) bioavailability occurs in most cases of chronic hypertension. Intrauterine nutritional deprivation has been associated with increased risk for hypertension and stroke, associated with relaxant dysfunction and decreased vascular compliance, but the underlying mechanisms are not known. The present studies were undertaken to investigate whether endothelial dysfunction associated with altered NO-dependent vasodilatation pathways is also observed in a model of in utero programming of hypertension. Methods— Pregnant Wistar rats were fed a normal (18%), low (9%), or very low (6%) protein isocaloric diet during gestation. Vasomotor response of resistance cerebral microvessels (Ca channel expression were measured by Western blot. NO synthase (NOS) activity was measured enzymatically as well as in situ by NADPH diaphorase staining. Results— Litter size and survival to adulthood were not affected by the diets. Birth weights of offspring of dams fed the 6% diet were markedly lower than those of dams fed the 9% diet, which were marginally lower than those of controls. Systolic blood pressures of adult offspring of mothers in the 6% and 9% groups were comparably greater (156±2 and 155±1 mm Hg, respectively) than that of control offspring (137±1 mm Hg); we therefore focused on the 9% and 18% groups. Cerebral microvessel constriction to thromboxane A 2 mimetic and dilation to carba-prostaglandin I 2 did not differ between diet groups. In contrast, vasorelaxation to the NO-dependent agents substance P and acetylcholine was diminished by 50% in low protein-exposed offspring, but eNOS expression and activity were similar between the 2 diet groups. Vasorelaxant response to the NO donor sodium nitroprusside was also decreased and was associated with reduced (by 50% to 65%) cGMP levels and sGC expression. cGMP analogues caused comparable vasorelaxation in the 2 groups. Expression of K Ca (another important mediator of NO action) and relaxation to the K Ca opener NS1619 were unchanged by antenatal diet. Conclusions— Maternal protein deprivation, which leads to hypertension in the offspring, is associated with diminished NO-dependent relaxation of major organ (cerebral) microvasculature, which seems to be largely attributed to decreased sGC expression and cGMP levels. The study provides an additional explanation for abnormal vasorelaxation in nutrient-deprived subjects in utero.

Keywords Rhabdomyolysis.Acute kidney injury.Carnitine palmitoyltransferase II deficiencyAbbreviationsAKI acute kidney injuryacyl-CoAs acylcoenzyme A derivativesCPT II carnitine palmitoyltransferase II deficiencyFAO fatty acid β-oxidationAnswers1. Severe rhabdomyolysis related to a mild form ofcarnitine palmitoyltransferase II (CPT II) deficiency.Diagnosis was suspected clinically by the occurrence ofsevere and recurrent rhabdomyolysis and based on theacylcarnitine profile. The diagnosis was confirmed bythe measurement of CPT II enzyme activity andsubsequent molecular analysis.2. First, the patient had a genetic disorder of lipidmetabolism, namely, a mild form of CPT II deficiency,which was responsible for the severe rhabdomyolysis,which in turn can be triggered by fever, exercise, andcold. Furthermore, viral myositis is a common cause ofrhabdomyolysis in children [1], and rapid testing forInfluenza A was positive in our patient. Influenzainfection-related severe rhabdomyolysis has alreadybeen reported [2]. Life-threatening rhabdomyolysismay be a consequence of any Influenza infection inpatients with CPT II deficiency [3].3. The primary cause of acute kidney injury (AKI) inthis patient is the rhabdomyolysis. Rhabdomylolysismay not be the only cause of AKI. Indeed, ourpatient also presented with diarrhea and occasionalvomiting and was probably dehydrated. Finally, acumulative dose of 60 mg/kg body weight ofibuprofen was given as self-medication 1 day priorto admission. All of these elements may havecontributed to a deterioration of the renal functiondue to hypoperfusion and/or vasoconstriction.4. The management regimen includes the treatment ofrhabdomyolysis-induced AKI and the prevention offurther rhabdomyolysis episodes.Supportive treatment of rhabdomyolysis consists of theearly and aggressive repletion of fluids. Alkalinization of

Thrombotic microangiopathies comprise different entities, including hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), and several other conditions. TTP is characterized by hemolytic anemia, thrombocytopenia, and multiorgan failure. TTP is the result of severe von Willebrand factor multimer cleaving protease (ADAMTS13) deficiency that is either inherited or the result of acquired autoantibodies. We report a critically ill 2-year-old girl with invasive pneumococcal disease associated HUS (p-HUS) whose condition was complicated by severe ADAMTS13 deficiency, without detectable inhibitor, in a context of multiple organ failure. The patient recovered with supportive treatment, and ADAMTS13 activity normalized without plasmatherapy. Severe ADAMTS13 deficiency appears to be a manifestation of transient endothelial cell injury in the context of severe sepsis, including invasive p-HUS. The choice of appropriate therapy should not be based on this finding.

In neonates, proper positioning of the tip of intravenous long lines (LL) is essential in order to prevent potential life-threatening complications. The gold standard for the evaluation of LL position in neonates is the chest X-ray with or without contrast. We performed a prospective study to assess the use of transthoracic ultrasonography (US) for the positioning of LL in neonates and to compare it to plain radiography.Thirty-six consecutive neonates requiring percutaneous LL over a period of 3 months were included in the study. Immediately after LL insertion, the position of its tip was verified using transthoracic US, followed by plain radiography. The two techniques were compared in terms of adequate placement and length of time between insertion and radiographic evaluation of the correct position.The correlation between positioning by US and plain radiography was very good (r=0.97, r(2)=0.94, p0.0001). The time needed to verify LL placement by US was shorter by a mean 15 min compared to plain radiography.US can accurately guide LL tip positioning. We believe that because of the potential gain of time it offers and its lack of ionising radiation, it to be considered as an interesting tool for the positioning of LL in neonates. Yet more accurate results could be obtained with a better-trained staff.

A previously healthy 10-year-old boy presented to the Pediatric Emergency Unit during the winter with fever, myalgias, and muscular weakness since the previous day. The urine had turned a dark-brown color. The patient also had diarrhea and occasional vomiting for 2 days. The parents explained that a total dose of 2.1 g of ibuprofen (i.e., 60 mg/kg) had been administered as self-medication the day before. Upon admission, the patient’s blood pressure was 113/ 78 mmHg, and his heart rate was 123/min. Axillary temperature was 39.5°C. Physical examination showed muscular weakness in both legs and flank tenderness. The findings of the respiratory, cardiac, and neurological examinations were normal. The test results on admission were as follows: rapid testing for Influenza A was positive; urine dipstick was positive for bilirubin (3+), blood (3+), and protein (3+). Laboratory tests showed a creatine kinase level of 318,000 U/l, urea nitrogen 18 mmol/l, creatinine 214 μmol/l, bicarbonate 16 mmol/l, and potassium 5 mmol/l. A diagnosis of massive rhabdomyolysis with acute kidney injury (AKI) was made. Rhabdomyolysis progressed with a peak creatine kinase level of 348,000 U/l, lactate dehydrogenase 124,000 U/l, serum myoglobin 42,873 μg/l, aspartate aminotransferase 7,122 IU/l, alanine aminotransferase 1,462 IU/l, metabolic acidosis, hyperkalemia of 5.2 mmol/l, hypocalcemia of 1.5 mmol/l, and hyperphosphoremia of 2.7 mmol/l. Ultrasound imaging showed enlarged kidneys with a loss of corticomedular differentiation. Despite aggressive intravenous hydration with normal saline and urine alkalinization with sodium bicarbonate, urinary output decreased, and the patient developed anuric renal failure on day 2 with a creatinine level of 663 μmol/l and urea nitrogen level of 35 mmol/l. Hemodialysis was initiated on day 2. Nine hemodialysis sessions were necessary until day 16. The patient had no cardiac complication. His condition improved, with diuresis The answer to this question can be found at doi:10.1007/s00467-0111767-3.