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BackgroundThe key Alzheimer’s disease (AD) biomarkers are traditionally measured with techniques/exams that are either expensive (amyloid-positron emission tomography (PET) and tau-PET), invasive (cerebrospinal fluid Aβ42and p-tau181), or poorly specific (atrophy on MRI and hypometabolism on fluorodeoxyglucose-PET). Recently developed plasma biomarkers could significantly enhance the efficiency of the diagnostic pathway in memory clinics and improve patient care. This study aimed to: (1) confirm the correlations between plasma and traditional AD biomarkers, (2) assess the diagnostic accuracy of plasma biomarkers as compared with traditional biomarkers, and (3) estimate the proportion of traditional exams potentially saved thanks to the use of plasma biomarkers.MethodsParticipants were 200 patients with plasma biomarkers and at least one traditional biomarker collected within 12 months.ResultsOverall, plasma biomarkers significantly correlated with biomarkers assessed through traditional techniques: up tor=0.50 (pr=0.43 (p=0.002) among tau, andr=−0.23 (p=0.001) among neurodegeneration biomarkers. Moreover, plasma biomarkers showed high accuracy in discriminating the biomarker status (normal or abnormal) determined by using traditional biomarkers: up to area under the curve (AUC)=0.87 for amyloid, AUC=0.82 for tau, and AUC=0.63 for neurodegeneration status. The use of plasma as a gateway to traditional biomarkers using cohort-specific thresholds (with 95% sensitivity and 95% specificity) could save up to 49% of amyloid, 38% of tau, and 16% of neurodegeneration biomarkers.ConclusionThe implementation of plasma biomarkers could save a remarkable proportion of more expensive traditional exams, making the diagnostic workup more cost-effective and improving patient care.

International audience; Background and purpose: HIBCH and ECHS1 genes encode two enzymes implicated in the critical steps of valine catabolism, 3-hydroxyisobutyryl-coenzyme A (CoA) hydrolase (HIBCH) and short-chainenoyl-CoA hydratase (ECHS1), respectively. HIBCH deficiency (HIBCHD) and ECHS1 deficiency (ECHS1D) generate rare metabolic dysfunctions, often revealed by neurological symptoms. The aim of this study was to describe movement disorders spectrum in patients with pathogenic variants in ECHS1 and HIBC.Methods: We reviewed a series of 18 patients (HIBCHD: 5; ECHS1D: 13) as well as 105 patients from the literature. We analysed the detailed phenotype of HIBCHD (38 patients) and ECHS1D (85 patients), focusing on MDs.Results: The two diseases have a very similar neurological phenotype, with an early onset before 10 years of age for three clinical presentations: neonatal onset, Leigh-like syndrome (progressive onset or acute neurological decompensation), and isolated paroxysmal dyskinesia. Permanent or paroxysmal MDs were recorded in 61% of HIBCHD patients and 72% of ECHS1D patients. Patients had a variable combination of either isolated or combined MD, and dystonia was the main MD. These continuous MDs included dystonia, chorea, parkinsonism, athetosis, myoclonus, tremors, and abnormal eye movements. Patients with paroxysmal dyskinesia (HIBCHD: 4; ECHS1D: 9) usually had pure paroxysmal dystonia with normal clinical examination and no major impairment in psychomotor development. No correlation could be identified between clinical pattern (especially MD) and genetic pathogenic variants.Conclusions: Movement disorders, including abnormal ocular movements, are a hallmark of HIBCHD and ECHS1D. MDs are not uniform; dystonia is the most frequent, and various types of MD are combined in single patient.

Introduction Lipoprotein(a) [Lp(a)] is an LDL-like molecule that is likely causally related to cardiovascular events. Lp(a) levels are highly variable, by more two orders of magnitude, and most of this variability appears to be of genetic origin. Exogenous hormones (hormone replacement therapy) seem to influence Lp(a) levels, but the impact of the variation of endogenous hormone levels on Lp(a) is unknown. Purpose To investigate the association between Lp(a) levels and non-genetic factors, as endogenous steroid hormone levels, in contrast to genetic factors. Methods We investigated the association of 28 endogenous steroids with Lp(a) levels and compared the association to other non-genetic and genetic variables in a prospective, population-based sample (N=1,021). Results The average age of the participants was 51 years and 53% were female. Median Lp(a) levels were 62 (±204) mg/l and the 90th and 99th percentile of Lp(a) was 616mg/l and 1035 mg/l respectively. The prevalence of a Lp(a) elevation ≥700mg/l was 3.2% and Lp(a) varied greatly from undetectable to 1,690mg/l. Age explained 2.0% of Lp(a) variability (p Conclusion Our results confirm previous findings demonstrating that the majority of the Lp(a) variation in the general population is of genetic origin. Age and LDL-levels explain a further small part of Lp(a) variability. Endogenous hormone levels do not contribute significantly to the wide range of variability. Funding Acknowledgement Type of funding sources: None. Coefficient plot Lp(a) and variables

Background: Lipoprotein(a) [Lp(a)] is an LDL-like molecule that is likely causal for cardiovascular events and Lp(a) variability has been shown to be mostly of genetic origin. Exogenous hormones (hormone replacement therapy) seem to influence Lp(a) levels, but the impact of endogenous hormone levels on Lp(a) is still unknown. The aim of the study was to assess the effect of endogenous steroid hormone metabolites on Lp(a). Methods: Lipoprotein(a) levels were measured in 1,021 participants from the Swiss Kidney Project on Genes in Hypertension, a family-based, multicentre, population-based prospective cohort study. Endogenous levels of 28 steroid hormone precursors were measured in 24-h urine collections from 883 individuals. Of the participants with Lp(a) data, 1,011 participants had also genotypes available. Results: The participants had an average age of 51 years and 53% were female. Median Lp(a) levels were 62 mg/L, and the 90thpercentile was 616 mg/L. The prevalence of a Lp(a) elevation ≥700 mg/L was 3.2%. Forty-three per cent of Lp(a) variability was explained respectively by: age (2%, p-16). Of the 28 endogenous steroid hormones assessed, androstenetriol, androsterone, 16α-OH-DHEA and estriol were nominatively associated with serum Lp(a) levels in univariable analyses and explained 0.4%-1% of Lp(a) variability, but none of them reached significance in multivariable models. Conclusions: In this contemporary population-based study, the prevalence of a Lp(a) elevation ≥700 mg/L was 3.2%. The effect of endogenous steroid hormone levels of Lp(a) variability was small at best, suggesting a negligible impact on the wide range of Lp(a) variability.

In a consanguineous Pakistani family with two affected individuals, a homozygous variant Gly399Val in the eighth transmembrane domain of the taurine transporter SLC6A6 was identified resulting in a hypomorph transporting capacity of ~15% compared with normal. Three-dimensional modeling of this variant has indicated that it likely causes displacement of the Tyr138 (TM3) side chain, important for transport of taurine. The affected individuals presented with rapidly progressive childhood retinal degeneration, cardiomyopathy and almost undetectable plasma taurine levels. Oral taurine supplementation of 100 mg/kg/day resulted in maintenance of normal blood taurine levels. Following approval by the ethics committee, a long-term supplementation treatment was introduced. Remarkably, after 24-months, the cardiomyopathy was corrected in both affected siblings, and in the 6-years-old, the retinal degeneration was arrested, and the vision was clinically improved. Similar therapeutic approaches could be employed in Mendelian phenotypes caused by the dysfunction of the hundreds of other molecular transporters.

Background Central neurological gait abnormalities (CNGA) are frequently associated with parkinsonism in older adults. However, the neuropathological substrates and the clinical impact of parkinsonism have been not described in CNGA. Objective This cross-sectional study aims to compare the CSF total tau, Aβ1-42, and phosphorylated tau levels in non-Parkinson's disease (PD) patients with CNGA with and without parkinsonism and to study the clinical impact of parkinsonism on gait and cognition. Methods CSF biomarkers were measured by ELISA in 49 non-PD patients with CNGA (77.7±6.6 years; 32.7% women). Gait was quantified with an optoelectronic system and cognition with a comprehensive neuropsychological assessment. Parkinsonism was defined by presence of bradykinesia and at least one of the following signs among muscular rigidity, rest tremor, or postural instability. Results Parkinsonism was identified in 14 CNGA patients (28.6% ). CSF Aβ1-42 level was decreased in CNGA patients with parkinsonism (β: - 189.4; 95% CI [- 352.3; - 26.6]; p = 0.024) even after adjusting for age, gender, comorbidities, and total white matter burden; while CSF total tau and phosphorylated tau levels were similar between CNGA patients with and without parkinsonism. CNGA patients with parkinsonism presented decreased attentional and executive performances but similar gait parameters than those without parkinsonism. Conclusion Parkinsonism represents a phenotype related with amyloidopathy-decreased CSF Aβ1-42 level-in non-PD patients with CNGA. This phenotype is clinically associated with impaired cognition, but similar quantitative gait parameters in comparison to CNGA patients without parkinsonism.

Progressive myoclonic epilepsies are rare neurodegenerative diseases with a wide spectrum of clinical presentations and genetic heterogeneity that render their diagnosis perplexing. Discovering new imputable genes has been an ongoing process in recent years. We present two pediatric cases of progressive myoclonic epilepsy with SERPINI1 pathogenic variants that lead to a severe presentation; we highlight the importance of including this gene, previously known as causing an adult-onset dementia-epilepsy syndrome, in the genetic work-up of childhood-onset progressive myoclonic epilepsies.

BACKGROUND Minimal lipoprotein(a) [Lp(a)] target values are advocated for high-risk cardiovascular patients. We investigated the prognostic value of Lp(a) in the acute setting of patients with acute coronary syndromes (ACS). METHODS Plasma levels of Lp(a) were collected at time of angiography from 1711 patients hospitalized for ACS in a multicenter Swiss prospective cohort. Associations between elevated Lp(a) ≥ 30 mg/dL (cut-off corresponding to the 75 percentile of the assay) or Lp(a) tertiles at baseline, and major adverse cardiovascular events (MACE) at 1-year, defined as a composite of cardiac death, myocardial infarction or stroke were assessed using hazard ratios (HR) and 95% confidence intervals (CI) adjusting for traditional cardiovascular risk factors (age, sex, smoking, diabetes, hypertension, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C] and triglycerides. RESULTS Lp(a) levels range between 2.5 mg/dL to 132 mg/dL with a median value of 6 mg/dL and a mean value of 14.2 mg/dL. A total of 276 patients (23.0%) had Lp(a) plasma levels ≥ 30 mg/dL). Patients with elevated Lp(a) were more likely to be of female gender, and to have higher levels of total cholesterol, LDL-C, HDL-C and triglycerides. Higher Lp(a) was associated with failure to reach the LDL-C target < 1.8 mmol/l at 1-year (HR 1.71, 95% CI 1.13-2.58, P=0.01). No association was found between elevated Lp(a) and MACE at 1 year (HR 1.05, 95% CI 0.64-1.73), nor for Lp(a) tertiles (HR 0.82, 95% CI 0.52-1.28, P >0.20) or standardized continuous variables (0.98, 95% CI 0.82-1.19 for each increase of standard deviation). CONCLUSIONS Our real-world data suggest high Lp(a) levels at time of angiography are not predictive for cardiovascular outcomes in patients otherwise medically well controlled, but might be useful to identify patients who would not be on LDL-C targets one year after ACS. This article is protected by copyright. All rights reserved.

Identification of neurotoxic drugs and environmental chemicals is an important challenge. However, only few tools to address this topic are available. The aim of this study was to develop a neurotoxicity/developmental neurotoxicity (DNT) test system, using the pluripotent mouse embryonic stem cell line CGR8 (ESCs). The test system uses ESCs at two differentiation stages: undifferentiated ESCs and ESC-derived neurons. Under each condition, concentration–response curves were obtained for three parameters: activity of the tubulin alpha 1 promoter (typically activated in early neurons), activity of the elongation factor 1 alpha promoter (active in all cells), and total DNA content (proportional to the number of surviving cells). We tested 37 compounds from the ESNATS test battery, which includes polypeptide hormones, environmental pollutants (including methylmercury), and clinically used drugs (including valproic acid and tyrosine kinase inhibitors). Different classes of compounds showed distinct concentration–response profiles. Plotting of the lowest observed adverse effect concentrations (LOAEL) of the neuronal promoter activity against the general promoter activity or against cytotoxicity, allowed the differentiation between neurotoxic/DNT substances and non-neurotoxic controls. Reporter activity responses in neurons were more susceptible to neurotoxic compounds than the reporter activities in ESCs from which they were derived. To relate the effective/toxic concentrations found in our study to relevant in vivo concentrations, we used a reverse pharmacokinetic modeling approach for three exemplary compounds (teriflunomide, geldanamycin, abiraterone). The dual luminescence reporter assay described in this study allows high-throughput, and should be particularly useful for the prioritization of the neurotoxic potential of a large number of compounds. Electronic supplementary material The online version of this article (doi:10.1007/s00204-016-1690-2) contains supplementary material, which is available to authorized users.

Neuronal ceroid lipofuscinoses represent a heterogeneous group of early onset neurodegenerative disorders that are characterized by progressive cognitive and motor function decline, visual loss, and epilepsy. The age of onset has been historically used for the phenotypic classification of this group of disorders, but their molecular genetic delineation has now enabled a better characterization, demonstrating significant genetic heterogeneity even among individuals with a similar phenotype. The rare Congenital Neuronal Ceroid Lipofuscinosis (CLN10) caused by mutations in the CTSD gene encoding for cathepsin D is associated with a dramatic presentation with onset before or around birth. We report on a female born to consanguineous parents who presented at birth with severe neonatal encephalopathy with massive cerebral and cerebellar shrinking on magnetic resonance imaging. Whole exome sequencing with targeted bioinformatic analysis of a panel of genes associated with prenatal/perinatal onset of neurodegenerative disease was performed and revealed the presence of a novel homozygous in-frame deletion in CTSD. Additional functional studies further confirmed the pathogenic character of this variant and established the diagnosis of CLN10 in the patient.

Rare Diseases, defined by a prevalence of less than 1 per 2000 persons, affect 36 million people in Europe, 500 000 in Switzerland, corresponding to 6-8% of the general population. 7000 rare diseases are currently recorded.Mitochondrial diseases are a heterogeneous group of genetic diseases. They are characterized by intracellular failure of energy production and affect predominantly energy-dependent tissues. The clinical presentation is not always suggestive, particularly in adulthood. In order to reach the diagnosis, a prerequisite is to think of them. In this article, we will focus on the clinical aspects of mitochondrial disorders in order to give the internist simple tools on how not to miss those rare diseases in his daily practice.Les maladies rares, définies par une prévalence égale ou inférieure à 1 pour 2000 personnes, touchent 36 millions de personnes en Europe et 500 000 en Suisse, soit 6 à 8% de la population générale. On en dénombre quelque 7000 actuellement.Les maladies mitochondriales constituent un groupe hétérogène de maladies génétiques. Elles sont liées à des carences de production intracellulaire d’énergie et s’expriment principalement sur les tissus énergie-dépendants. L’expression phénotypique n’est pas toujours spontanément évocatrice, en particulier chez l’adulte. Nous proposons dans cet article une approche centrée sur la clinique des maladies mitochondriales permettant à l’interniste de les évoquer.

We report a four-year-old African boy referred for proximal muscle weakness, fatigability and episodic limb pain. Classical causes of structural and metabolic myopathy were initially considered before clinical and biological features of vitamin D deficiency rickets were identified. Prompt treatment with vitamin D and calcium supplementation led to a complete reversal of the muscle symptoms. Rickets-associated myopathy should be included in the differential diagnosis of proximal myopathy, especially in at-risk individuals. Vitamin D deficiency and its prevention remain important health issues in industrialized countries.

Introduction Les troubles de la marche du sujet âge sont souvent associes a un parkinsonisme. Toutefois, le substrat moleculaire et l’impact clinique de ce parkinsonisme n’ont pas ete etudies. Cette etude transversale vise a comparer les taux du liquide cephalorachidien (LCR) des proteines tau, Aβ1-42, et tau phosphoryle chez des sujets âges avec troubles de la marche et presence ou non d’un parkinsonisme ; et d’etudier l’impact clinique de ce parkinsonisme sur la marche et la cognition. Materiel et methodes Nous avons mesure les marqueurs du LCR chez 49 patients (77,7 ± 6,6 ans ; 32,7 % femmes). Les parametres spatiotemporels de la marche ont ete quantifies par un systeme optoelectronique et la cognition par une evaluation neuropsychologique. Le parkinsonisme etait defini par la presence d’une bradykinesie associee a l’un des signes suivants : rigidite, tremblement de repos ou instabilite posturale. Resultats Un parkinsonisme a ete retrouve chez 14 patients (28,6 %). Le taux d’Aβ1-42 etait diminue de facon significative chez les patients avec parkinsonisme (β : − 189,4 ; 95 %CI [−352,3 ; − 26,6] ; p = 0,024) meme apres ajustement sur âge, genre, comorbidites et anomalies de la substance blanche ; alors que les taux de total tau et tau phosphoryle etaient identiques entre patients avec et sans parkinsonisme. Les patients avec parkinsonisme presentaient une diminution des performances attentionnelles et executives, tandis qu’ils presentaient des parametres de marche comparable aux patients sans parkinsonisme. Discussion–conclusion La presence d’un parkinsonisme chez des sujets âges avec trouble de la marche represente un phenotype en lien avec une amyloidopathie.

Pyridoxal-5'-phosphate oxidase (PNPO) deficiency is a rare autosomal recessive, vitamin-responsive metabolic disorder causing refractory neonatal seizures that respond to the administration of pyridoxal-5'-phosphate (PLP). There are currently few case studies that have documented the functional outcome in PNPO deficiency, which remains poor in the majority of cases. We present the case of a male infant born at 35 weeks gestation who promptly responded to oral administration of PLP, following resistance to common anticonvulsive therapy and to a pyridoxine trial. Neurological outcome at 21 months is favorable and illustrates the importance of standardized vitamin trials in the acute setting of "therapy-resistant" neonatal seizures. Early recognition of PNPO deficiency and appropriate intervention might be associated with a more favorable outcome than initially considered.

Neural differentiation of embryonic stem cells (ESC) is considered a promising model to perform in vitro testing for neuroactive and neurotoxic compounds. We studied the potential of a dual reporter murine ESC line to identify bioactive and/or toxic compounds. This line expressed firefly luciferase under the control of the neural cell-specific tubulin alpha promoter (TUBA1A), and renilla luciferase under the control of the ubiquitous translation elongation factor 1-alpha-1 (EEF1A1) promoter. During neural differentiation, TUBA1A activity increased, while EEF1A1 activity decreased. We first validated our test system using the known neurotoxin methyl mercury. This compound altered expression of both reporter genes, with ESC-derived neural precursors being affected at markedly lower concentrations than undifferentiated ESCs. Analysis of a library of 1040 bioactive compounds picked up 127 compounds with altered EEF1A1 and/or TUBA1A promoter activity, which were classified in 4 clusters. Cluster 1 (low EEF1A1 and TUBA1A) was the largest cluster, containing many cytostatic drugs, as well as known neurodevelopmental toxicants, psychotropic drugs and endocrine disruptors. Cluster 2 (high EEF1A1, stable TUBA1A) was limited to three sulfonamides. Cluster 3 (high EEF1A1 and TUBA1A) was small, but markedly enriched in neuroactive and neurotoxic compounds. Cluster 4 (stable EEF1A1, high TUBA1A) was heterogeneous, containing endocrine disruptors, neurotoxic and cytostatic drugs. The dual reporter gene assay described here might be a useful addition to in vitro drug testing panels. Our two-dimensional testing strategy provides information on complex response patterns, which could not be achieved by a single marker approach.

Background The cblC defect is a rare inborn error of intracellular cobalamin metabolism. Biochemical hallmarks are elevated homocysteine and low methionine in plasma accompanied by methylmalonic aciduria. Due to the heterogeneous clinical picture, patients with the late-onset form of the disease (onset >12 months) come to the attention of diverse medical specialists, e.g. paediatricians, neurologists, nephrologists, psychiatrists or haematologists. The report reviews the published clinical data and adds three new cases to raise awareness for this severe but often treatable disease. Methods The Pubmed and the Cochrane databases were searched for clinical reports on cblC patients and three unreported cases are presented to illustrate the clinical spectrum. Results Reports on 58 cases (30 females, 22 males, 6 = no information) and the three new cases underlined the clinical heterogeneity of the disease. Time between first symptoms and diagnosis ranged from three months to more than 20 years. Haemolytic uraemic syndrome and pulmonary hypertension were main presenting symptoms in preschool children. In older children/adolescents, psychiatric symptoms, cognitive impairment, ataxia and myelopathy were frequently observed while thromboembolic events and glomerulopathies were almost exclusively seen in adults. Brain atrophy, white matter lesions and myelopathy were frequently encountered. The majority of patients showed marked biochemical and clinical response to treatment with parenteral hydroxocobalamin combined with oral betaine, folate, carnitine and rarely methionine. The course was less favourable in late treated or untreated patients. Conclusions The late-onset cblC defect is a rare disease and unfortunately, diagnosis is often delayed. Raising awareness for this disorder can significantly improve patients’ outcome and perspective by timely initiation of targeted treatment. Newborn screening (NBS) for the cblC defect might be of benefit especially for late-onset patients since treatment seems efficient when initiated before irreversible organ damage. In general, inborn errors of metabolisms should be considered in unexplained medical cases at any age, especially in patients with multisystemic disease. More specifically, total homocysteine in plasma and methylmalonic acid in urine/plasma should be measured in unexplained neurologic, psychiatric, renal, haematologic and thromboembolic disease.

OBJECTIVE: Sapropterin dihydrochloride, the synthetic form of 6R-tetrahydrobiopterin (BH4), is an approved drug for the treatment of patients with BH4-responsive phenylketonuria (PKU). The purpose of this study was to assess genotypes and data on the long-term effects of BH4/sapropterin on metabolic control and patient-related outcomes in 6 large European countries. METHODS: A questionnaire was developed to assess phenotype, genotype, blood phenylalanine (Phe) levels, Phe tolerance, quality of life, mood changes, and adherence to diet in PKU patients from 16 medical centers. RESULTS: One hundred forty-seven patients, of whom 41.9% had mild hyperphenylalaninemia, 50.7% mild PKU, and 7.4% classic PKU, were followed up over ≤12 years. A total of 85 different genotypes were reported. With the exception of two splice variants, all of the most common mutations were reported to be associated with substantial residual Phe hydroxylase activity. Median Phe tolerance increased 3.9 times with BH4/sapropterin therapy, compared with dietary treatment, and median Phe blood concentrations were within the therapeutic range in all patients. Compared with diet alone, improvement in quality of life was reported in 49.6% of patients, improvement in adherence to diet was reported in 47% of patients, and improvement in adherence to treatment was reported in 63.3% of patients. No severe adverse events were reported. CONCLUSIONS: Our data document a long-term beneficial effect of orally administered BH4/sapropterin in responsive PKU patients by improving the metabolic control, increasing daily tolerance for dietary Phe intake, and for some, by improving dietary adherence and quality of life. Patient genotypes help in predicting BH4 responsiveness.

Presentation of exogenous protein antigens to T lymphocytes is based on the intersection of two complex pathways: (a) synthesis, assembly, and transport of major histocompatibility complex (MHC) class II-invariant chain complexes from the endoplasmic reticulum to a specialized endosomal compartment, and (b) endocytosis, denaturation, and proteolysis of antigens followed by loading of antigenic peptides onto newly synthesized MHC class II molecules. It is believed that expression of MHC class II heterodimers, invariant chain and human leukocyte antigen-DM is both necessary and sufficient to reconstitute a functional MHC class II loading compartment in antigen-presenting cells. Expression of each of these essential molecules is under the control of the MHC class II transactivator CIITA. Unexpectedly, however, whereas interferon gamma stimulation does confer effective antigen-processing function to nonprofessional antigen presenting cells, such as melanoma cells, expression of the CIITA transactivator alone is not sufficient. Activation of antigen-specific T cells thus requires additional CIITA-independent factor(s), and such factor(s) can be induced by interferon gamma.

MHC-encoded HLA-DMA and -DMB molecules are atypical MHC chains that play an essential role in antigen presentation by MHC class II molecules. They resemble both MHC class I and II molecules but are not expressed at the cell surface. From the study of MHC class II regulatory mutants, it was found recently that two novel transactivators, CIITA and RFX5, are essential for the control of MHC class II gene expression. We report here that CIITA and RFX5, although operating at different levels of transcriptional control, are also both essential regulators of HLA-DMA and -DMB genes. This is true for both the constitutive and the inducible mode of DM gene expression. Indeed, both CIITA and RFX5 cDNA can correct the HLA-DMA and -DMB gene expression defect in the respective regulatory mutants. The involvement of these two transcription factors accounts for the coordinate expression of MHC class II and HLA-DM, two sets of molecules that perform quite different functions in the overall process of antigen presentation.

Considerable progress has been achieved in recent years in treating children affected by bone diseases. Advances in the understanding of the molecular pathophysiology of genetic bone diseases have led to the development of enzyme replacement therapies for various lysosomal storage diseases, following the breakthrough initiated in treating Gaucher disease. Clinical studies are underway with tailored molecules correcting bone fragility and alleviating chronic bone pain and other manifestations of hypophosphatasia, or promoting growth of long bones in achondroplasia patients. We further report our very encouraging experience with intravenous bisphosphonate treatment in children suffering from secondary osteopenia and the high prevalence of calcium and vitamin D deficits in these severely disabled children.

Background DNA polymerase γ (POLG) is the only known mitochondrial DNA (mtDNA) polymerase. It mediates mtDNA replication and base excision repair. Mutations in the POLG gene lead to reduction of functional mtDNA (mtDNA depletion and/or deletions) and are therefore predicted to result in defective oxidative phosphorylation (OXPHOS). Many mutations map to the polymerase and exonuclease domains of the enzyme and produce a broad clinical spectrum. The most frequent mutation p.A467T is localised in the linker region between these domains. In compound heterozygote patients the p.A467T mutation has been described to be associated amongst others with fatal childhood encephalopathy. These patients have a poorer survival rate compared to homozygotes. Methods mtDNA content in various tissues (fibroblasts, muscle and liver) was quantified using quantitative PCR (qPCR). OXPHOS activities in the same tissues were assessed using spectrophotometric methods and catalytic stain of BN-PAGE. Results We characterise a novel splice site mutation in POLG found in trans with the p.A467T mutation in a 3.5 years old boy with valproic acid induced acute liver failure (Alpers-Huttenlocher syndrome). These mutations result in a tissue specific depletion of the mtDNA which correlates with the OXPHOS-activities. Conclusions mtDNA depletion can be expressed in a high tissue-specific manner and confirms the need to analyse primary tissue. Furthermore, POLG analysis optimises clinical management in the early stages of disease and reinforces the need for its evaluation before starting valproic acid treatment.

Summary: Congenital disorders of glycosylation (CDG) are a family of multisystem inherited disorders caused by defects in the biosynthesis of N- or O-glycans. Among the many different subtypes of CDG, the defect of a mannosyltransferase encoded by the human ALG3 gene (chromosome 3q27) is known to cause CDG Id. Six patients with CDG Id have been described in the literature so far. We further delineate the clinical, biochemical, neuroradiological and molecular features of CDG Id by reporting an additional patient bearing a novel missense mutation in the ALG3 gene. All patients with CDG Id display a slowly progressive encephalopathy with microcephaly, severe psychomotor retardation and epileptic seizures. They also share some typical dysmorphic features but they do not present the multisystem involvement observed in other CDG syndromes or any biological marker abnormalities. Unusually marked osteopenia is a feature in some patients and may remain undiagnosed until revealed by pathological fractures. Serum transferrin screening for CDG should be extended to all patients with encephalopathy of unknown origin, even in the absence of multisystem involvement

International audience; BACKGROUND: Cirrhosis is associated with intestinal barrier failure, related in part to enterocytes oxidative damage via xanthine oxidase overactivity. Experimentally, allopurinol, a xanthine oxidase inhibitor, reduces enterocytes' damage and bacterial translocation. AIM: To assess the short-term effects of allopurinol on intestinal permeability, oxidative stress and endotoxin-dependent cytokines in patients with cirrhosis. METHODS: Nineteen patients with cirrhosis, in a stable condition (age: 56 years; Child A/B/C: 6/7/6; ascites: 12; alcoholic cirrhosis: 16/19; abstinence >2 weeks), were included. At baseline and day 10 of allopurinol 400 mg/day, intestinal permeability [lactulose/mannitol (Lac/Man) ratio test], oxidative stress (serum malondialdehyde), as well as TNF-soluble receptor-1, IL-6 and lipopolysaccharide-binding protein (which reflects exposition to endotoxin) were measured. RESULTS: Malondialdehyde decreased significantly (-23%, P

Tetrahydrobiopterin (BH4) is the cofactor for phenylalanine hydroxylase (PAH) and is essential to treat different forms of hyperphenylalaninaemia, i.e. patients with defects in the biosynthesis of BH4, but also in the PAH gene [1, 4,5]. Responsiveness of mutant PAH to BH4 administration relies on a chemical chaperon effect of BH4 preventing PAH from protein misfolding and inactivation [6], but several other mechanisms may also be involved [2]. Recently, we reported that sublingual administration of BH4 tablets in a single control person resulted in 58%–67% higher plasma BH4 concentrations than the usual oral route [3]. Drawbacks included rapid decomposition of tablets, acidic taste, and increased salivation. Since sublingual application could reduce therapy costs, orange flavoured artificially sweetened BH4 pastilles were tested on four healthy volunteers and a child with mild phenylketonuria (PKU). BH4 (Schircks, Switzerland) was administered to four healthy male volunteers (age 28–57 years) on 2 subsequent days either as tablets (50 mg) or pastilles (100 mg, containing 5 mg aspartame and orange aroma) with a 1 week wash-out between the two trials. Blood was collected before, and 1, 2, 3, and 4 h after administration. An 8-year-old patient with mild PKU (genotype P281L/R261Q) who was already on regular BH4 therapy was treated with BH4 pastilles (sublingually, 12 mg/kg/day; bid) in addition to P-AM 2 formula for 2 weeks. Written consensus was obtained from the family. In the four healthy male volunteers, total biopterin values before and up to 4 h after oral and sublingual administration were compared (Fig. 1A). No statistically significant difference between oral and sublingual administration was observed. Pterin concentrations increased after both oral and sublingual administration, reflecting instability of BH4 in blood. The ratio of pterin to cumulated biopterin and pterin ranged between 22.8% and 33.5%. Summing biopterin and pterin instead of total biopterin did not alter the ratio between oral and sublingual administration (data not shown). Changing from standard therapy to sublingual administration in a child with mild PKU resulted in almost unchanged plasma phenylalanine concentrations (Fig. 1B). After 2 weeks of twice daily sublingual BH4 administration, the patient complained of a painful prickling sensation at the tip of the tongue. He nevertheless continued the treatment for a further 10 days, moving the tablets in his mouth from one side to the other, which resulted in severe mucitis. His condition normalised rapidly upon discontinuation of the sublingual form. No mucitis appeared in healthy volunteers. A clinical trial with sublingual BH4 in a patient with mild PKU failed despite pharmacological effectiveness on blood phenylalanine levels because of an adverse pastille-related side-effect. Formulation of buffered tablets approaching neutral pH and further investigations on BH4 metabolism and pharmacokinetics are needed.

Aims. In the face of major tendency towards midwiferyled-care it was our purpose to investigate the extent of the influence of the midwife on the rates of obstetric procedures and perinatal outcome. Methods. 5384 consecutive deliveries at the Department of Obstetrics and Gynecology. University of Graz, were enrolled in the study. The following data were collected: mode of delivery, pH of umbilical artery, Apgar score. Firstly, data were investigated for interindividual differences and, secondly, for relationship with age of the midwife as a measure of experience. Results. Interindividual differences were significant for episiotomy rates (minimum: 31.6%; maximum 76.9%; p

Nat. Genet. 43, 189–196 (2011); published online 23 January 2011; corrected after print 29 March 2011 In the version of this article initially published, the authors should have acknowledged that the work was also funded by a grant from the European Union (EU-SYSCILIA) to E.E.D., C.A.J., P.L.B. and N.

Starting from a cohort of 50 NADH-oxidoreductase (complex I) deficient patients, we carried out the systematic sequence analysis of all mitochondrially encoded complex I subunits (ND1 to ND6 and ND4L) in affected tissues. This approach yielded the unexpectedly high rate of 20% mutation identification in our series. Recurrent heteroplasmic mutations included two hitherto unreported (T10158C and T14487C) and three previously reported mutations (T10191C, T12706C and A13514G) in children with Leigh or Leigh-like encephalopathy. The recurrent mutations consistently involved T-->C transitions (p

Contains fulltext : 87372.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To describe the current treatment; clinical, biochemical, and molecular findings; and clinical follow-up of patients with aromatic l-amino acid decarboxylase (AADC) deficiency. METHOD: Clinical and biochemical data of 78 patients with AADC deficiency were tabulated in a database of pediatric neurotransmitter disorders (JAKE). A total of 46 patients have been previously reported; 32 patients are described for the first time. RESULTS: In 96% of AADC-deficient patients, symptoms (hypotonia 95%, oculogyric crises 86%, and developmental retardation 63%) became clinically evident during infancy or childhood. Laboratory diagnosis is based on typical CSF markers (low homovanillic acid, 5-hydroxyindoleacidic acid, and 3-methoxy-4-hydroxyphenolglycole, and elevated 3-O-methyl-l-dopa, l-dopa, and 5-hydroxytryptophan), absent plasma AADC activity, or elevated urinary vanillactic acid. A total of 24 mutations in the DDC gene were detected in 49 patients (8 reported for the first time: p.L38P, p.Y79C, p.A110Q, p.G123R, p.I42fs, c.876G>A, p.R412W, p.I433fs) with IVS6+ 4A>T being the most common one (allele frequency 45%). CONCLUSION: Based on clinical symptoms, CSF neurotransmitters profile is highly indicative for the diagnosis of aromatic l-amino acid decarboxylase deficiency. Treatment options are limited, in many cases not beneficial, and prognosis is uncertain. Only 15 patients with a relatively mild form clearly improved on a combined therapy with pyridoxine (B6)/pyridoxal phosphate, dopamine agonists, and monoamine oxidase B inhibitors.

Auditory impairment in mitochondrial disorders are usually due to peripheral sensorineural dysfunction. Central deafness is only rarely reported. We report here an 11-year-old boy with MELAS syndrome who presented with subacute deafness after waking up from sleep. Peripheral hearing loss was rapidly excluded. A brain MRI documented bilateral stroke-like lesions predominantly affecting the superior temporal lobe, including the primary auditory cortex, confirming the central nature of deafness. Slow recovery was observed in the following weeks. This case serves to illustrate the numerous challenges caused by MELAS and the unusual occurrence of acute cortical deafness, that to our knowledge has not be described so far in a child in this setting.