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Mucopolysaccharidosis type I-H (MPS I-H) is a rare lysosomal storage disorder caused by α-L-Iduronidase deficiency. Early haematopoietic stem cell transplantation (HSCT) is the sole available therapeutic option to preserve neurocognitive functions. We report long-term follow-up (median 9 years, interquartile range 8–16.5) for 51 MPS I-H patients who underwent HSCT between 1986 and 2018 in France. 4 patients died from complications of HSCT and one from disease progression. Complete chimerism and normal α-L-Iduronidase activity were obtained in 84% and 71% of patients respectively. No difference of outcomes was observed between bone marrow and cord blood stem cell sources. All patients acquired independent walking and 91% and 78% acquired intelligible language or reading and writing. Intelligence Quotient evaluation (n = 23) showed that 69% had IQ ≥ 70 at last follow-up. 58% of patients had normal or remedial schooling and 62% of the 13 adults had good socio-professional insertion. Skeletal dysplasia as well as vision and hearing impairments progressed despite HSCT, with significant disability. These results provide a long-term assessment of HSCT efficacy in MPS I-H and could be useful in the evaluation of novel promising treatments such as gene therapy.

Purpose We aimed to identify prognostic factors for survival and long-term intellectual and developmental outcome in neonatal patients with early-onset urea cycle disorders (UCD) experiencing hyperammonaemic coma. Methods We retrospectively analysed ammonia (NH3) and glutamine levels, electroencephalogram and brain images obtained during neonatal coma of UCD patients born between 1995 and 2011 and managed at a single centre and correlated them to survival and intellectual and developmental outcome. Results We included 38 neonates suffering from deficiencies of argininosuccinate synthetase (ASSD, N = 12), ornithine transcarbamylase (OTCD, N = 10), carbamoylphosphate synthetase 1 (CPSD, N = 7), argininosuccinate lyase (ASLD, N = 7), N-acetylglutamate synthase (NAGS, N = 1) or arginase (ARGD, N = 1). Symptoms occurred earlier in mitochondrial than in cytosolic UCD. Sixty-eight percent of patients survived, with a mean (standard deviation-SD) follow-up of 10.4 (5.3) years. Mortality was mostly observed in OTCD (N = 7/10) and CPSD (N = 4/7) patients. Plasma NH3 level during the neonatal period, expressed as area under the curve, but not glutamine level was associated with mortality (p = .044 and p = .610). 62.1% of the patients had normal intellectual and developmental outcome. Intellectual and developmental outcome tended to correlate with UCD subtype (p = .052). No difference in plasma NH3 or glutamine level during the neonatal period among developmental outcomes was identified. EEG severity was linked to UCD subtypes (p = .004), ammonia levels (p = .037), duration of coma (p = .043), and mortality during the neonatal period (p = .020). Status epilepticus was recorded in 6 patients, 3 of whom died neonatally, 1 developed a severe intellectual disability while the 2 last patients had a normal development. Conclusion UCD subtypes differed by survival rate, intellectual and developmental outcome and EEG features in the neonatal period. Hyperammonaemia expressed as area under the curve was associated with survival but not with intellectual and developmental outcome whereas glutamine was not associated with one of these outcomes. Prognostic value of video-EEG monitoring and the association between status epilepticus and mortality should be assessed in neonatal hyperammonaemic coma in further studies.

Context A strictly controlled diet (often involving enteral tube feeding (ETF)) is part of the treatment of many inherited metabolic diseases (IMDs). Objective To describe the use of ETF in a large cohort of patients with IMDs. Design A retrospective analysis of ETF in patients with urea cycle disorders (UCDs), organic aciduria (OA), maple syrup disease (MSUD), glycogen storage diseases (GSDs) or fatty acid oxidation disorders (FAODs) diagnosed before the age of 12 months. Setting The reference center for IMDs at Necker Hospital (Paris, France). Results 190 patients born between January 1991 and August 2017 were being treated for OA (n = 60), UCDs (n = 55), MSUD (n = 32), GSDs (n = 26) or FAODs (n = 17). Ninety-eight of these patients (52%) received ETF (OA subgroup: n = 40 (67%); UCDs: n = 12 (22%); MSUD: n = 9 (28%); GSDs: n = 23 (88%); FAODs: n = 14 (82%)). Indications for ETF were feeding difficulties in 64 (65%) patients, cessation of fasting in 39 (40%), and recurrent metabolic decompensation in 14 (14%). Complications of ETF were recorded in 48% of cases, more frequently with nasogastric tube (NGT) than with gastrostomy. Among patients in whom ETF was withdrawn, the mean duration of ETF was 5.9 (SD: 4.8) years (range: 0.6–19.8 years). The duration of ETF was found to vary from one disease subgroup to another (p = 0.051). While the longest median duration was found in the GSD subgroup (6.8 years), the shortest one was found in the UCD subgroup (0.9 years). Conclusion ETF is an integral part of the dietary management of IMDs. The long duration of ETF and the specific risks of NGT highlights the potential value of gastrostomy. In this study at a French tertiary hospital, we documented the indications, modalities, duration and complications of enteral tube feeding in a cohort of patients with inherited metabolic diseases.

Propionic acidemia is the result of a deficiency in propionyl-CoA carboxylase activity. Chronic neurologic and cognitive complications frequently occur, but the psychiatric evolution of the disorder is not well documented. We conducted a pedopsychiatric evaluation of 19 children, adolescents and young adults, aged between 2 and 25 years, using ADI-R, CARS-T, as well as ADOS when autism spectrum disorder was suspected. Previous psychometric examinations were also taken into consideration. Thirteen patients had an IQ

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 Trimethylaminuria (TMAU) is a metabolic disorder characterized by the excessive excretion of the malodorous compound trimethylamine (TMA). The diagnosis of TMAU is challenging because this disorder is situated at the boundary between biochemistry and psychiatry. Here, we used nuclear magnetic resonance spectroscopy to assess TMAU in 13 patients. We also sequenced the FMO3 gene in 11 of these patients. Treatment with vitamin B2 was prescribed. Results Two patients (aged 3 and 9 years at the initial consultation) had a particularly unpleasant body odor, as assessed by their parents and the attending physicians. The presence of high urine TMA levels confirmed the presence of a metabolic disorder. The two (unrelated) children carried compound heterozygous variants in the FMO3 gene. In both cases, vitamin B2 administration decreased TMA excretion and reduced body odor. The 11 adults complained of an unpleasant body odor, but the physicians did not confirm this. In all adult patients, the urine TMA level was within the normal range reported for control (non-affected) subjects, although two of the patients displayed an abnormally high proportion of oxidized TMA. Seven of the 9 tested adult patients had a hypomorphic variant of the FMO3 gene; the variant was found in the homozygous state, in the heterozygous state or combined with another hypomorphic variant. All 11 adults presented a particular psychological or psychiatric phenotype, with a subjective perception of unpleasant odor. Conclusions The results present the clinical and biochemical data of patients complaining of unpleasant body odor. Contrary to adult patients, the two children exhibited all criteria of recessively inherited trimethylaminuria, suspected by parents in infancy. B2 vitamin treatment dramatically improved the unpleasant body odor and the ratio of TMA/Cr vs TMAO/Cr in the urine in the children. Other patients presented a particular psychological or psychiatric phenotype.

Propionic acidemia is an inborn deficiency of propionyl–coenzyme A (CoA) carboxylase activity, which leads to mitochondrial accumulation of propionyl-CoA and its by-products. Neurologic complications are frequent, but only a few cases presenting with psychiatric symptoms have been reported so far. We report 2 cases of children with chronic psychiatric symptoms who presented with an acute psychotic episode as teenagers. Both patients had hallucinations, panic and grossly disorganized behavior, for several weeks to several months. They had signs of moderate metabolic decompensation at the beginning of the episode, although the psychiatric symptoms lasted longer than the metabolic imbalance. We propose that these episodes were at least partially imputable to propionic acidemia. Such episodes require psychiatric examination and antipsychotic treatment, which may have to be adapted in case of cardiomyopathy or long QT syndrome.

X-linked cerebral creatine deficiency is caused by the deficiency of the creatine transporter (CTP) encoded by the SLC6A8 gene.We report here a series of six patients with severe CTP deficiency, four males and two females; clinical presentations include mild to severe mental retardation (6/6), associated with psychiatric symptoms (5/6: autistic behaviour, chronic hallucinatory psychosis), seizures (2/6) and muscular symptoms (2/4 males). Diagnosis was suspected upon elevated urinary creatine/creatinine (except in one of the female patients) and on a markedly decreased creatine peak on magnetic resonance spectroscopy (MRS). Diagnosis was confirmed by molecular analysis that identified four novel mutations not reported so far, including a mutation found twice in two male patients. All patients were treated successively and according to the same protocol by creatine alone then combined to its precursors, L-glycine and L-arginine for 42 months.In our patients, creatine supplementation alone or with its precursors L-glycine and L-arginine showed benefit only in the muscular symptoms of the disease and no improvement in the cognitive and psychiatric manifestations and did not modify brain creatine content on MRS of male and female CTP deficient patients. New treatment strategies are required including creatine derivatives transported independently from CTP or using alternative pathways and transporters.

Resume L’idee a longtemps prevalu que l’anxiete avait sur l’excitation sexuelle un effet essentiellement inhibiteur. Au cours des dernieres decennies, des recherches utilisant des techniques plethysmographiques ont demontre qu’il n’en allait pas toujours de la sorte. Selon les conditions, l’anxiete peut avoir un impact inhibiteur, neutre ou facilitant. L’articulation de ces donnees de recherche a des modeles et concepts developpes par ailleurs dans le champ de la psychologie cognitive permet de proposer une theorie coherente des relations anxiete–excitation. On peut l’enoncer en plusieurs points : l’effet inhibiteur de l’anxiete sur le fonctionnement sexuel se doit largement a un phenomene d’interference cognitive ; l’attention du sujet se porte sur des signaux de danger au detriment des stimuli erotiques. Dans ce cas, la memoire de travail du sujet est saturee par des signaux de danger, les ressources cognitives indispensables au traitement des stimuli erotiques s’en trouvent reduites avec pour consequence une alteration de ses reactions sexuelles. Une structure cognitive et emotionnelle nommee erotophobie predisposerait a ce processus. En l’absence du vecteur d’interference, l’anxiete aurait plutot tendance a favoriser l’excitation, cela parce qu’elle accroit l’attention allouee aux stimuli erotiques et/ou parce que les correlats psychophysiologiques de l’anxiete sont interpretes comme ayant une origine sexuelle.

Resume Depuis Wolpe, Masters et Johnson et Kaplan, qui consideraient l’anxiete et l’excitation sexuelle comme des etats incompatibles, la comprehension de l’influence du stress sur les reactions sexuelles a beaucoup evolue. En deux decennies, on est passe d’une theorie centree sur l’inhibition et les mecanismes physiologiques peripheriques a une theorie insistant davantage sur la complexite des relations anxiete – excitation et sur des explicateurs cognitifs. Cette evolution se doit largement a l’essor des techniques plethysmographiques et au developpement concomitant de modeles generaux du fonctionnement cognitif humain. Le present article en retrace les principaux jalons. En fournissant une mesure directe des reactions genitales a la presentation de stimuli erotiques, la plethysmographie a permis d’objectiver une influence non lineaire de l’anxiete sur l’excitation sexuelle : l’anxiete tantot inhibe, tantot facilite l’excitation. L’explication decisive de l’effet inhibiteur de l’anxiete semble etre l’interference cognitive dont elle s’accompagne chez certains sujets : leur attention se deplace vers des stimuli a caractere non erotique. En articulant les observations realisees a l’aide de techniques plethysmographiques a des modeles developpes par ailleurs dans le domaine de la psychologie cognitive, on parvient a la theorie suivante : l’erotophobie (disposition a associer des idees de danger a la sexualite) peut etre consideree comme un facteur de vulnerabilite a l’interference. En situation sexuelle, l’attention des sujets erotophobes tend a se porter sur des schemas de danger, ce qui provoque l’irruption massive en memoire de travail d’informations a caractere non erotique. La part de ressources cognitives allouables a l’execution de reactions sexuelles s’en trouve reduite, avec pour consequence l’inhibition de celles-ci. En l’absence de ce mecanisme d’interference, l’anxiete tend plutot a renforcer l’excitation, soit parce qu’elle accroit l’attention portee aux stimuli erotiques, soit parce que les modifications physiologiques qui l’accompagnent sont percues comme ayant une origine sexuelle.

The relations between public services and local public services are analysed. The local communities are now obliged to consider the requirements of sustainable development, with new constraints and new possibilities for the local public services. The objectives and means of action of the local public services are modified by the sustainable development. Classification JEL : H7, O1, Q0, R0, R5.

Neurological heterotopic ossification (NHO) is the abnormal formation of bone in soft tissues as a consequence of spinal cord or traumatic brain injury. NHO causes pain, ankyloses, vascular and nerve compression and delays rehabilitation in this high-morbidity patient group. The pathological mechanisms leading to NHO remain unknown and consequently there are no therapeutic options to prevent or reduce NHO. Genetically modified mouse models of rare genetic forms of heterotopic ossification (HO) exist, but their relevance to NHO is questionable. Consequently, we developed the first model of spinal cord injury (SCI)-induced NHO in genetically unmodified mice. Formation of NHO, measured by micro-computed tomography, required the combination of both SCI and localized muscular inflammation. Our NHO model faithfully reproduced many clinical features of NHO in SCI patients and both human and mouse NHO tissues contained macrophages. Muscle-derived mesenchymal progenitors underwent osteoblast differentiation in vitro in response to serum from NHO mice without additional exogenous osteogenic stimuli. Substance P was identified as a candidate NHO systemic neuropeptide, as it was significantly elevated in the serum of NHO patients. However, antagonism of substance P receptor in our NHO model only modestly reduced the volume of NHO. In contrast, ablation of phagocytic macrophages with clodronate-loaded liposomes reduced the size of NHO by 90%, supporting the conclusion that NHO is highly dependent on inflammation and phagocytic macrophages in soft tissues. Overall, we have developed the first clinically relevant model of NHO and demonstrated that a combined insult of neurological injury and soft tissue inflammation drives NHO pathophysiology.

International audience; Pyruvate carboxylase (PC) is a biotin-containing mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate, thereby being involved in gluconeogenesis and in energy production through replenishment of the tricarboxylic acid (TCA) cycle with oxaloacetate. PC deficiency is a very rare metabolic disorder. We report on a new patient affected by the moderate form (the American type A). Diagnosis was nearly fortuitous, resulting from the revision of an initial diagnosis of mitochondrial complex IV (C IV) defect. The patient presented with severe lactic acidosis and pronounced ketonuria, associated with lethargy at age 23 months. Intellectual disability was noted at this time. Amino acids in plasma and organic acids in urine did not show patterns of interest for the diagnostic work-up. In skin fibroblasts PC showed no detectable activity whereas biotinidase activity was normal. We had previously reported another patient with the severe form of PC deficiency and we show that she also had secondary C IV deficiency in fibroblasts. Different anaplerotic treatments in vivo and in vitro were tested using fibroblasts of both patients with 2 different types of PC deficiency, type A (patient 1) and type B (patient 2). Neither clinical nor biological effects in vivo and in vitro were observed using citrate, aspartate, oxoglutarate and bezafibrate. In conclusion, this case report suggests that the moderate form of PC deficiency may be underdiagnosed and illustrates the challenges raised by energetic disorders in terms of diagnostic work-up and therapeutical strategy even in a moderate form.

Introduction Patients with methylmalonic acidemia (MMA) may develop many complications despite medical treatment, in particular, severe central nervous system damage and chronic kidney disease (CKD). A kidney transplant may partially correct the metabolic dysfunctions. Liver, kidney and combined liver–kidney transplantations have been advocated but no guidelines are available to identify the most suitable organ to transplant. Patients and methods Four patients with MMA (mut° phenotype) received a kidney graft because of repeated metabolic decompensations, with progression to CKD in 3 patients (end-stage kidney disease in two patients and CKD stage III in one patient with an estimated glomerular filtration rate [eGFR] of 40ml/min/1.73m 2 ) but normal renal function in one (eGFR of 93ml/min/1.73m 2 ) before transplantation. Results The medium age at transplantation was 7.9y (5–10.2) and the median follow-up was 2.8years (1.8–4.6). Renal transplantation improved the relevant metabolic parameters in 4/4 patients and renal function in the patients with CKD. Plasma and urinary MMA levels immediately decreased and remained normal or subnormal (mean values of plasma MMA before transplantation 1530μmol/L versus 240μmol/L after transplantation, and mean values of urine MMA before transplantation 4700mmol/mol creatinine versus 2300mmol/mol creatinine after transplantation). No further acute metabolic decompensation was observed and protein-intake was increased from 0.60 to 0.83g/Kg/day. One patient transplanted at age 9.7years developed a hepatoblastoma at age 11years with subsequent neurological complications and eventually died. The three other patients are alive. Two of them remained neurologically stable. The 3rd patient who displayed choreoathetosis transiently improved his neurological condition immediately after transplantation and then remained stable. Conclusion Kidney transplantation represents an interesting alternative therapeutic option in methylmalonic aciduria, for renal complications but also as a "cellular therapy" that may significantly reduce metabolic decompensations and hospitalizations. However, further neurological impairment remains possible.

An important factor contributing to hematopoietic stem cell (HSC) mobilization is the ability of mobilizing cytokines and chemotherapy to disturb the cellular components of HSC niches, particularly osteoblasts and their progenitors, and to inhibit the production of HSC supportive cytokines and chemokines. Although the mechanisms by which niche cells are inhibited by mobilizing treatments is still incompletely understood, it has recently emerged that bone marrow macrophages play a critical role in maintaining osteoblasts, bone formation, and the expression of CXCL12, KIT ligand, and angiopoietin-1 necessary to HSC maintenance. In this chapter, we describe how to mobilize HSC into the blood in mice by depleting macrophages with clodronate-loaded liposomes and compare this mode of mobilization to mobilization induced by granulocyte colony-stimulating factor and cyclophosphamide. Detailed methods to analyze mobilization of phenotypic and functional reconstituting HSC are described with examples.

The hematopoietic system is highly proliferative in the bone marrow (BM) due to the short half-life of granulocytes and platelets in the blood. Analysis of cell cycling and cell proliferation in vivo in specific populations of the mouse BM has highlighted some key properties of adult hematopoietic stem cells (HSCs). For instance, despite their enormous proliferation and repopulation potential, most true HSC are deeply quiescent in G(0) phase of the cell cycle and divide very infrequently, while less potent lineage-restricted progenitors divide rapidly to replace the daily consumption of blood leukocytes, erythrocytes, and platelets. In response to stress, e.g., following ablative chemotherapy or irradiation, HSC must enter the cell cycle to rapidly repopulate the BM with progenitors. Due to their extreme rarity in the BM, at least five color flow cytometry for cell surface antigens has to be combined with staining for DNA content and nuclear markers of proliferation to analyze cell cycle and proliferation of HSC in vivo. In this chapter, we describe two methods to stain mouse HSC to (1) distinguish all phases of the cell cycle (G(0), G(1), S, and G(2)/M) and (2) analyze the divisional history of HSC in vivo by incorporation of the thymidine analog 5-bromo-2-deoxyuridine.

Identification of the precise location, where hematopoietic stem cells (HSCs) reside in the bone marrow, has made a great leap forward with the advance of live time-lapse video 2-photon fluorescent microscopy. These studies have shown that HSCs preferentially resides in the endosteal region of the BM, at an average of two cell diameters from osteoblasts covering endosteal bone surfaces. However, this equipment is very sophisticated and only a very few laboratories can perform these studies. To investigate functional attributes of these niches, we have developed a flow cytometry technique in which mice are perfused with the cell-permeable fluorescent dye Hoechst33342 in vivo before bone marrow cells are collected and antibody stained. This method enables to position phenotypic HSC, multipotent and myeloid progenitors, as well as BM nonhematopoietic stromal cells relative to blood flow in vivo. This technique enables prospective isolation of HSCs based on the in vivo perfusion of the niches in which they reside.

ContextCongenital hyperinsulinism (HI) is a common cause of hypoglycemia in infancy. The medical treatment of diazoxide-unresponsive HI is based on a somatostatin analogue.ObjectiveThis study aims at replacing three daily s.c. octreotide (Sandostatin, Novartis) injections by a single and monthly i.m. injection of long-acting release (LAR) octreotide (Sandostatin LP, Novartis) in HI patients.Subjects and methodLAR octreotide was injected every 4 weeks during 6 months and s.c. octreotide injections were stopped after the third injection of LAR octreotide. After this 6-month study, LAR octreotide was continued, with an average follow-up of 17 months. Ten HI pediatric patients unresponsive to diazoxide and currently treated with s.c. octreotide were included in the trial. Glycemias and other parameters (HbA1c, IGF1, height, weight, quality of life (QoL), and satisfaction) were monitored at each monthly visit.ResultsFor all ten patients, glycemias were maintained in the usual range, HbAlc (mean 5.5%; 95% CI: 4.6–6.2) and IGF1 (mean 89.7 ng/ml; 95% CI: 26–153) were unchanged. Patients gained height significantly (mean 2.7 cm; 95% CI: 1.9–3.4) and no side effect was noted during the study and the later follow-up. Plasma octreotide levels were stable under LAR octreotide. Parents' questionnaires of general satisfaction were highly positive whereas children's QoL evaluation remained unchanged.ConclusionIn these diazoxide-unresponsive HI patients, LAR octreotide was efficient, well tolerated and contributed to a clear simplification of the medical care.

Fumarase deficiency (FD), caused by biallelic alteration of the Fumarase Hydratase gene (FH), and a rare metabolic disorder that affects the Krebs cycle, causes severe neurological impairment and fumaric aciduria. Less than 30 unrelated cases are known to date. In addition, heterozygous mutations of the FH gene are responsible for hereditary leiomyomatosis and renal cell cancer (HLRCC). We report three additional patients with dramatically different clinical presentations of FD and novel missense mutations in the FH gene. One patient had severe neonatal encephalopathy, polymicrogyria

Stem cell transplantation is not appropriate first-line treatment for attenuated phenotypes of mucopolysaccharidosis type I (MPS I). In three patients with attenuated MPSA I treated by laronidase, Patients 2 and 3 displayed significant cognitive improvement within 2years; Patients 1 and 3 displayed improvement on MRI scans of the brain.

To better delineate the natural history of patients with methylmalonic aciduria (MMA).Thirty patients with vitamin-B12-unresponsive MMA (25 aged 1.5 to 22.0 years (y) at the end of the study and 5 who died during a metabolic crisis) were managed following standardized guidelines and studied retrospectively. The median follow-up was 8.3 y (range: 1.4-19.5). Patients were investigated with neuropsychological testing, brain MRIs, inulin clearances, biochemical and genetic studies.Fifteen patients had a neonatal onset. Thirteen patients (43%) had significant neurological impairment. Chronic renal disease (CRD) occurred in 14 patients (47%) with a median age of onset of 6.5 y (range 1.5-18.6). Renal function further deteriorated in 4 patients within a median period of 5.8 y (range 2-7.4). Of 25 patients investigated at the enzymatic level, 17 were classified mut(o), 3 mut- and 5 cblA. Mortality, number of acute decompensations (p=0.031), median MMA urinary excretion (p=0.006) and neurological impairment (p0.0001) were higher in mut degrees patients compared to mut-/cblA patients. Concerning the CRD, no difference incidence was found although the onset of CRD occurred earlier in mut(o) patients and was more severe.Our study provides unique data concerning the progression of renal disease in MMA. Patients with mut(o) phenotype have a more severe phenotype and probably an earlier and more severe CRD than patients with mut-/cblA phenotype.

Aims: Ornithine delta-aminotransferase (OAT) deficiency causes gyrate atrophy (GA) of the retina, as a consequence of high plasma ornithine concentrations. Because creatine synthesis requires the conversion of arginine and glycine into ornithine and guanidinoacetate, high ornithine concentration inhibits this reaction thus causing secondary creatine deficiency. The aim of this study was to evaluate the neuropsychological features and creatine metabolism in patients with GA. Methods: The study involved 7 GA patients, aged from 11 to 27 years who underwent neuropsychological evaluation and cerebral proton magnetic resonance spectroscopy (MRS). Results: Neurocognitive impairment was found in 5/7 patients, including mental retardation (3/7), school failure (1/7), major visuospatial dyspraxia (1/7), aggressive behavior (3/7) and epilepsy (2/7). Two patients had normal neuropsychological evaluation. Cerebral proton magnetic resonance spectroscopy revealed a profound creatine deficiency in all patients. MRS data were confirmed by decreased levels of creatine and/or guanidinoacetate in plasma and urine in all patients. Conclusions: In our group of patients with GA, we found a high prevalence of neurological impairment, not reported so far, and possibly related to secondary creatine deficiency and hyperornithinemia. We propose to treat mentally retarded GA patients with high doses of creatine, as it may normalize brain creatine levels and help to reduce ornithine levels.

The third generation of the regional healthcare organization plan (Sros III) proposes to develop the organisation of healthcare and its management according to evolution of its activities and the populations concerned. At the time of a strategic analysis of SROS III (what we refer to as its perinatal period), the question is whether promoters can move from an approach based on accessibility (egalitarian equity) to a needs-based approach (differential equity), which although more complicated in to apply and implement, was found be much better adapted to healthcare users. The research is derived from an analysis of documents from November 2004 to November 2006. A university public hospital developed the data which supported a proposal to shift from level I to level II. This proposition was retained in the territory's medical plan authorized by the regional health authorities. Health professionals and the architects of the healthcare plan have the capacity to new organizations responsible for taking into account the activities and healthcare needs of the population in order to initiate and establish differential equity.

Resume Le schema regional d’organisation sanitaire de troisieme generation (SROS III) propose de faire evoluer l’organisation sanitaire en fonction des besoins de sante de populations prises en charge et des evolutions d’activites. Lors de l’analyse strategique d’un SROS III « perinatalite », les promoteurs peuvent-ils passer d’une approche en termes d’accessibilite (equite egalitariste) a une approche par les besoins (equite differentielle), plus compliquee a mettre en œuvre, mais plus adaptee aux usagers dans un territoire de sante ? La recherche s’est appuyee sur l’analyse de documents de novembre 2004 a novembre 2006. Un centre hospitalier universitaire implante dans un quartier defavorise a elabore des donnees qui ont permis de proposer le passage d’une maternite de niveau I a II. Cette proposition est retenue dans le projet medical de territoire, puis est autorisee par l’ARH. Professionnels de sante et promoteurs de la planification sanitaire peuvent mettre en œuvre une equite differentielle.

Objective. To evaluate the neurologic outcomes of neonates and infants suffering from persistent hyperinsulinemic hypoglycemia of infancy (PHHI). Methods. The neurologic development of 90 PHHI patients was studied retrospectively. Sixty-three patients were treated surgically and 27 were treated medically. Fifty-four patients were neonates, of whom 8 were treated medically and 46 were operated on (19 for a focal adenomatous hyperplasia and 27 for diffuse hyperinsulinism). Thirty-six patients had infancy-onset hyperinsulinism, of whom 19 were treated medically and 17 underwent pancreatectomy (10 patients for a focal adenomatous hyperplasia and 7 for diffuse hyperinsulinism). Results. Severe psychomotor retardation was found in 7 patients, 6 with neonatal-onset PHHI. Intermediate psychomotor disability existed in 12 patients; epilepsy existed in 16. Neonatal-onset was the main risk factor for severe retardation or epilepsy. Medically treated patients were less severely affected than those treated by surgery, and there was no difference between the diffuse and focal forms of hyperinsulinism. Conclusion. Neonatal hyperinsulinemic hypoglycemia is still a severe disease with an important risk to rapidly develop severe mental retardation and epilepsy.

Background Classical organic acidurias including methylmalonic aciduria (MMA), propionic aciduria (PA) and isovaleric aciduria (IVA) are severe inborn errors of the catabolism of branched-chain amino acids and odd-numbered chain fatty acids, presenting with severe complications. Methods This study investigated the long-term outcome of 80 patients with classical organic aciduria (38 with MMA, 24 with PA and 18 with IVA) by integrating clinical, radiological, biochemical and genetic data. Results Patients were followed-up for a mean of 14 years [age 3.3-46.3 years]. PA included a greater number of patients with abnormal neurological examination (37% in PA, 24% in MMA and 0% in IVA), lower psychometric scores (abnormal evaluation at age 3 years in 61% of patients with PA versus 26% in MMA and 18% in IVA) and more frequent basal ganglia lesions (56% of patients versus 36% in MMA and 17% in IVA). All patients with IVA presented a normal neurological examination and only 1/3 presented cognitive troubles. Prognosis for MMA was intermediate. Biochemical metabolite analysis excluding acute decompensations revealed significant progressive increases of glycine, alanine and glutamine particularly in PA and possibly in MMA but no correlation with neurological outcome. A significant increase of plasma methylmalonic acid was found in MMA patients with intellectual deficiency (mean level of 199 μmol/L versus 70 μmol/L, p MMAA gene was better compared to patients with mutations involving the MUT gene. Conclusion Propionic aciduria had the most severe neurological prognosis. Our radiological and biochemical data are consistent with a mitochondrial toxicity mechanism. Follow-up plasma MMA and urinary 3-HP levels may have prognostic significance calling for greater efforts to optimize long-term management in these patients.

Background The principal aim of this study was to investigate the long-term outcomes of a large cohort of patients with ornithine transcarbamylase deficiency (OTCD) who were followed up at a single medical center. Methods We analyzed clinical, biochemical and genetic parameters of 90 patients (84 families, 48 males and 42 females) with OTCD between 1971 and 2011. Results Twenty-seven patients (22 boys, 5 girls) had a neonatal presentation; 52 patients had an “intermediate” late-onset form of the disease (21 boys, 31 girls) that was revealed between 1 month and 16 years; and 11 patients (5 boys, 6 girls) presented in adulthood (16 to 55 years). Patients with a neonatal presentation had increased mortality (90% versus 13% in late-onset forms) and peak plasma ammonium (mean value: 960 μmol/L versus 500 μmol/L) and glutamine (mean value: 4110 μmol/L versus 1000 μmol/L) levels at diagnosis. All of the neonatal forms displayed a greater number of acute decompensations (mean value: 6.2/patient versus 2.5 and 1.4 in infants and adults, respectively). In the adult group, some patients even recently died at the time of presentation during their first episode of coma. Molecular analyses identified a deleterious mutation in 59/68 patients investigated. Single base substitutions were detected more frequently than deletions (69% and 12%, respectively), with a recurrent mutation identified in the late-onset groups (pArg40 His; 13% in infants, 57% in adults); inherited mutations represented half of the cases. The neurological score did not differ significantly between the patients who were alive in the neonatal or late-onset groups and did not correlate with the peak ammonia and plasma glutamine concentrations at diagnosis. However, in late-onset forms of the disease, ammonia levels adjusted according to the glutamine/citrulline ratio at diagnosis were borderline predictors of low IQ (p = 0.12 by logistic regression; area under the receiver operating characteristic curve of 76%, p