Usefulness of analysis of cerebrospinal fluid for the diagnosis of neurotransmitters and pterin defects and glucose and folate transport deficiencies across blood brain barrier

Med Clin (Barc). 2006 Jun 17;127(3):81-5. [Usefulness of analysis of cerebrospinal fluid for the diagnosis of neurotransmitters and pterin defects and glucose and folate transport deficiencies across blood brain barrier] [Article in Spanish] Ormazabal A, García Cazorla A, Pérez Dueñas B, Pineda M, Ruiz A, López Laso E, García Silva M, Carilho I, Barbot C, Cormand B, Ribases M, Moller L, Fernández Alvarez E, Campistol J, Artuch R. Hospital Sant Joan de Déu, Esplugues, Barcelona, España. Abstract BACKGROUND AND OBJECTIVE: In the last few years, it has been described inborn errors of neurotransmitter and pterin metabolism and defects in folate and glucose transport across blood brain barrier. All these defects are classified as rare diseases and needs cerebrospinal fluid (CSF) sample analysis for diagnosis. Our aim was to evaluate the results of the application of a CSF analysis protocol in a pediatric population from Spain and Portugal presenting with neurological disorders of unknown origin. PATIENTS AND METHOD: We studied CSF samples from and 283 patients with neurological disorders of unknown origin and 127 controls. Neurotransmitters were analysed by HPLC with electrochemical detection, and pterins and 5-methyltetrahydrofolate were determined by HPLC with fluorescence detection. RESULTS: We diagnosed 3 patients with tyrosine hidroxylase deficiency, 2 with dopa responsive dystonia, 14 with GTP-ciclohydrolase deficiency, 2 with glucose transport deficiency and 43 with cerebral folate deficiency. CONCLUSIONS: This study allowed us to diagnose new patients, and more importantly, the establishment in all of them of a pharmacological or nutritional treatment. The most frequent defect found was CSF 5-methyltetrahydrofolate deficiency, which was present in different groups of patients. PMID: 16827996 [PubMed - indexed for MEDLINE

Insights into the expanding phenotypic spectrum of inherited disorders of biogenic amines

Inherited disorders of neurotransmitter metabolism are rare neurodevelopmental diseases presenting with movement disorders and global developmental delay. This study presents the results of the first standardized deep phenotyping approach and describes the clinical and biochemical presentation at disease onset as well as diagnostic approaches of 275 patients from the registry of the International Working Group on Neurotransmitter related Disorders. The results reveal an increased rate of prematurity, a high risk for being small for gestational age and for congenital microcephaly in some disorders. Age at diagnosis and the diagnostic delay are influenced by the diagnostic methods applied and by disease-specific symptoms. The timepoint of investigation was also a significant factor: delay to diagnosis has decreased in recent years, possibly due to novel diagnostic approaches or raised awareness. Although each disorder has a specific biochemical pattern, we observed confounding exceptions to the rule. The data provide comprehensive insights into the phenotypic spectrum of neurotransmitter disorders

Levodopa-refractory hyperprolactinemia and pituitary findings in inherited disorders of biogenic amine metabolism

Elevated serum prolactin concentrations occur in inherited disorders of biogenic amine metabolism because dopamine deficiency leads to insufficient inhibition of prolactin secretion. This work from the International Working Group on Neurotransmitter Related Disorders (iNTD) presents the results of the first standardized study on levodopa-refractory hyperprolactinemia (LRHP; >1000 mU/L) and pituitary magnetic resonance imaging (MRI) abnormalities in patients with inherited disorders of biogenic amine metabolism. Twenty-six individuals had LRHP or abnormal pituitary findings on MRI. Tetrahydrobiopterin deficiencies were the most common diagnoses (n = 22). The median age at diagnosis of LRHP was 16 years (range: 2.5-30, 1st-3rd quartiles: 12.25-17 years). Twelve individuals (nine females) had symptoms attributed to hyperprolactinemia: menstruation-related abnormalities (n = 7), pubertal delay or arrest (n = 5), galactorrhea (n = 3), and decreased sexual functions (n = 2). MRI of the pituitary gland was obtained in 21 individuals; six had heterogeneity/hyperplasia of the gland, five had adenoma, and 10 had normal findings. Eleven individuals were treated with the dopamine agonist cabergoline, ameliorating the hyperprolactinemia-related symptoms in all those assessed. Routine monitoring of these symptoms together with prolactin concentrations, especially after the first decade of life, should be taken into consideration during follow-up evaluations. The potential of slow-release levodopa formulations and low-dose dopamine agonists as part of first-line therapy in the prevention and treatment of hyperprolactinemia should be investigated further in animal studies and human trials. This work adds hyperprolactinemia-related findings to the current knowledge of the phenotypic spectrum of inherited disorders of biogenic amine metabolism

Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: data from the iNTD registry

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport or degradation of neurotransmitters or co-factors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (<70) compared to patients with a BH4 deficiency (mean IQ 84, range 40-129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self-stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter (DAT) deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self-injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6-pyruvoyltetrahydropterin synthase deficiency while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH4 deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: a) difference in IQ and subdomains of quality of life between BH4 deficiencies and primary neurotransmitter-related disorders, and b) previously underreported behavioral traits

Comparative study of paediatric prescription drug utilization between the spanish and immigrant population

<p>Abstract</p> <p>Background</p> <p>The immigrant population has increased greatly in Spain in recent years to the point where immigrants made up 12% of the infant population in 2008. There is little information available on the profile of this group with regard to prescription drug utilization in universal public health care systems such as that operating in Spain. This work studies the overall and specific differences in prescription drug utilization between the immigrant and Spanish population.</p> <p>Methods</p> <p>Use was made of the Aragonese Health Service databases for 2006. The studied population comprises 159,908 children aged 0-14 years, 13.6% of whom are foreign nationals. Different utilization variables were calculated for each group. Prescription-drug consumption is measured in Defined Daily Doses (DDD) and DDD/1000 persons/day/(DID).</p> <p>Results</p> <p>A total of 833,223 prescriptions were studied. Utilization is lower for immigrant children than in Spanish children for both DID (66.27 v. 113.67) and average annual expense (€21.55 v. €41.14). Immigrant children consume fewer prescription drugs than Spanish children in all of the therapy groups, with the most prescribed (in DID) being: respiratory system, anti-infectives for systemic use, nervous system, sensory organs. Significant differences were observed in relation to the type of drugs and the geographical background of immigrants.</p> <p>Conclusion</p> <p>Prescription drug utilization is much greater in Spanish children than in immigrant children, particularly with reference to bronchodilators (montelukast and terbutaline) and attention-disorder hyperactivity drugs such as methylphenidate. There are important differences regarding drug type and depending on immigrants' geographical backgrounds that suggest there are social, cultural and access factors underlying these disparities.</p

Obstetric history and mammographic density: a population-based cross-sectional study in Spain (DDM-Spain)

High mammographic density (MD) is used as a phenotype risk marker for developing breast cancer. During pregnancy and lactation the breast attains full development, with a cellular-proliferation followed by a lobular-differentiation stage. This study investigates the influence of obstetric factors on MD among pre- and post-menopausal women. We enrolled 3,574 women aged 45–68 years who were participating in breast cancer screening programmes in seven screening centers. To measure MD, blind anonymous readings were taken by an experienced radiologist, using craniocaudal mammography and Boyd’s semiquantitative scale. Demographic and reproductive data were directly surveyed by purpose-trained staff at the date of screening. The association between MD and obstetric variables was quantified by ordinal logistic regression, with screening centre introduced as a random effect term. We adjusted for age, number of children and body mass index, and stratified by menopausal status. Parity was inversely associated with density, the probability of having high MD decreased by 16% for each new birth (P value < 0.001). Among parous women, a positive association was detected with duration of lactation [>9 months: odds ratio (OR) = 1.33; 95% confidence interval (CI) = 1.02–1.72] and weight of first child (>3,500 g: OR = 1.32; 95% CI = 1.12–1.54). Age at first birth showed a different effect in pre- and post-menopausal women (P value for interaction = 0.030). No association was found among pre-menopausal women. However, in post-menopausal women the probability of having high MD increased in women who had their first child after the age of 30 (OR = 1.53; 95% CI = 1.17–2.00). A higher risk associated with birth of twins was also mainly observed in post-menopausal women (OR = 2.02; 95% CI = 1.18–3.46). Our study shows a greater prevalence of high MD in mothers of advanced age at first birth, those who had twins, those who have breastfed for longer periods, and mothers whose first child had an elevated birth weight. These results suggest the influence of hormones and growth factors over the proliferative activity of the mammary gland

A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-Negative Effect.

Gillespie syndrome (GS) is characterized by bilateral iris hypoplasia, congenital hypotonia, non-progressive ataxia, and progressive cerebellar atrophy. Trio-based exome sequencing identified de novo mutations in ITPR1 in three unrelated individuals with GS recruited to the Deciphering Developmental Disorders study. Whole-exome or targeted sequence analysis identified plausible disease-causing ITPR1 mutations in 10/10 additional GS-affected individuals. These ultra-rare protein-altering variants affected only three residues in ITPR1: Glu2094 missense (one de novo, one co-segregating), Gly2539 missense (five de novo, one inheritance uncertain), and Lys2596 in-frame deletion (four de novo). No clinical or radiological differences were evident between individuals with different mutations. ITPR1 encodes an inositol 1,4,5-triphosphate-responsive calcium channel. The homo-tetrameric structure has been solved by cryoelectron microscopy. Using estimations of the degree of structural change induced by known recessive- and dominant-negative mutations in other disease-associated multimeric channels, we developed a generalizable computational approach to indicate the likely mutational mechanism. This analysis supports a dominant-negative mechanism for GS variants in ITPR1. In GS-derived lymphoblastoid cell lines (LCLs), the proportion of ITPR1-positive cells using immunofluorescence was significantly higher in mutant than control LCLs, consistent with an abnormality of nuclear calcium signaling feedback control. Super-resolution imaging supports the existence of an ITPR1-lined nucleoplasmic reticulum. Mice with Itpr1 heterozygous null mutations showed no major iris defects. Purkinje cells of the cerebellum appear to be the most sensitive to impaired ITPR1 function in humans. Iris hypoplasia is likely to result from either complete loss of ITPR1 activity or structure-specific disruption of multimeric interactions

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Latest physics results of TJ-II flexible heliac

This paper is devoted to the presentation of the most relevant recent Physics results obtained in the TJ-II flexible heliac. Firstly ECRH modulation and plasma breakdown studies are summarised; then the particle control techniques used to obtain reproducible discharges with density under control are presented. Transport studies show internal heat transport barriers that reduce heat conductivity to neoclassical values, and ELM-like transport events, similar to those observed in tokamaks and in other stellarators before and during H mode transition. Evidence of ExB sheared has been observed both in the proximity of rational surfaces. Finally, a high resolution Thomsom Scattering system has shown Te and ne profile structures