DOCSLIB.ORG

(12) Patent Application Publication (10) Pub. No.: US 2016/0281166 A1 BHATTACHARJEE Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) Patent Application Publication (10) Pub. No.: US 2016/0281166 A1 BHATTACHARJEE Et Al US 20160281 166A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0281166 A1 BHATTACHARJEE et al. (43) Pub. Date: Sep. 29, 2016 (54) METHODS AND SYSTEMIS FOR SCREENING Publication Classification DISEASES IN SUBJECTS (51) Int. Cl. (71) Applicant: PARABASE GENOMICS, INC., CI2O I/68 (2006.01) Boston, MA (US) C40B 30/02 (2006.01) (72) Inventors: Arindam BHATTACHARJEE, G06F 9/22 (2006.01) Andover, MA (US); Tanya (52) U.S. Cl. SOKOLSKY, Cambridge, MA (US); CPC ............. CI2O 1/6883 (2013.01); G06F 19/22 Edwin NAYLOR, Mt. Pleasant, SC (2013.01); C40B 30/02 (2013.01); C12O (US); Richard B. PARAD, Newton, 2600/156 (2013.01); C12O 2600/158 MA (US); Evan MAUCELI, (2013.01) Roslindale, MA (US) (21) Appl. No.: 15/078,579 (57) ABSTRACT (22) Filed: Mar. 23, 2016 Related U.S. Application Data The present disclosure provides systems, devices, and meth (60) Provisional application No. 62/136,836, filed on Mar. ods for a fast-turnaround, minimally invasive, and/or cost 23, 2015, provisional application No. 62/137,745, effective assay for Screening diseases, such as genetic dis filed on Mar. 24, 2015. orders and/or pathogens, in Subjects. Patent Application Publication Sep. 29, 2016 Sheet 1 of 23 US 2016/0281166 A1 SSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSS S{}}\\93? sau36 Patent Application Publication Sep. 29, 2016 Sheet 2 of 23 US 2016/0281166 A1 &**** ? ???zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz??º & %&&zzzzzzzzzzzzzzzzzzzzzzz &Sssssssssssssssssssssssssssssssssssssssssssssssssssssssss & s s sS ------------------------------ Patent Application Publication Sep. 29, 2016 Sheet 3 of 23 US 2016/0281166 A1 23 25 20 FG, 2. Patent Application Publication Sep. 29, 2016 Sheet 4 of 23 US 2016/0281166 A1 : S Patent Application Publication Sep. 29, 2016 Sheet 5 of 23 US 2016/0281166 A1 - BS 25 SO Six F.G. 44 Patent Application Publication Sep. 29, 2016 Sheet 6 of 23 US 2016/0281166 A1 %. FG, 4 B Patent Application Publication Sep. 29, 2016 Sheet 7 of 23 US 2016/0281166 A1 {{Citi sexy-w yes werex xwyx 8.8 S.S. s 3: 8 sws: ixx 88: 1 | Ex. | & s Š. se Patent Application Publication Sep. 29, 2016 Sheet 9 of 23 US 2016/0281166 A1 is : x.ŠNSWNSSoxxs S. S$\ SS ^s. w Šss xsm : ES išYi'3: $888. Six:3: F.G. C. Patent Application Publication Sep. 29, 2016 Sheet 10 of 23 US 2016/0281166 A1 450000 prior 400000 in us WES 350000 383 . ::: Patent Application Publication Sep. 29, 2016 Sheet 11 of 23 US 2016/0281166 A1 B F.G. 6B Patent Application Publication Sep. 29, 2016 Sheet 12 of 23 US 2016/0281166 A1 Fassig is Fitters? * Protein impact e Aki faiiar: * Regis g Acq::se Zygosity is is: casgos at 38-83% of eac{s} ataxiase • variet Scoring Annotation Known polymorphism or predicted is rigin? Honozygous? (“ -: Ritai: ineface? ------------------------------------------------------ Sisectei isieterious base on No variant type of grediction algorithis? Yes Yes of 33 ygosioi ecessive disease geste & co;i&st site;t&ea? sS *Yes. Sompositi heterozygote with 88 2 is etects statis? F.C. 7 Patent Application Publication Sep. 29, 2016 Sheet 13 of 23 US 2016/0281166 A1 &pixes sixirst & S 8 if is-Seasies is Eat's as SS k is six S-SE expies & $ r. s s^YsaxxxWSWSWWWWWSWWWWWSWWWsixs 888 S. $88: Si: 88 Siges:8888 is {xy}ssfs&&. Patent Application Publication Sep. 29, 2016 Sheet 15 of 23 US 2016/0281166 A1 & Patent Application Publication Sep. 29, 2016 Sheet 17 of 23 US 2016/0281166 A1 A. six x: 8xxx x: FIG. I. IA Patent Application Publication Sep. 29, 2016 Sheet 18 of 23 US 2016/0281166 A1 : : : : S g : : S Patent Application Publication Sep. 29, 2016 Sheet 19 of 23 US 2016/0281166 A1 l Exome t is exixxx xxxx FIG. I.3 Patent Application Publication Sep. 29, 2016 Sheet 20 of 23 US 2016/0281166 A1 FC, i. Patent Application Publication Sep. 29, 2016 Sheet 21 of 23 US 2016/0281166 A1 Patent Application Publication Sep. 29, 2016 Sheet 22 of 23 US 2016/0281166 A1 C3A&G 33 & C SCCs F.G. 64 Patent Application Publication Sep. 29, 2016 Sheet 23 of 23 US 2016/0281166 A1 BTD OGCDH OGALT FIG. I.6B US 2016/0281166 A1 Sep. 29, 2016 METHODS AND SYSTEMIS FOR SCREENING sample, a cord blood sample, single blood drop, saliva, oral DISEASES IN SUBJECTS swab, other body fluid or other tissue; (b) sequencing the sample to generate a sequencing product, wherein the CROSS-REFERENCE sequencing product is determined by a sequencing method selected from a group consisting of next-generation 0001. This application claims priority to U.S. Provisional sequencing (NGS), targeted next-generation sequencing Patent Application 62/136,836, filed Mar. 23, 2015, and U.S. (TNGS) and whole-exome sequencing (WES); and (c) ana Provisional Patent Application 62/137,745, filed Mar. 24, lyzing the sequencing product to determine a presence of 2015, which are entirely incorporated herein by reference. absence of or predisposition to the pathogen. In some cases, GOVERNMENT RIGHTS the methods and systems further comprise providing a sample previously obtained from a relative of the subject. 0002. The invention described herein was made with 0007. The methods and systems disclosed herein can also government support under phase I SBIR NIH grants from be used for detecting a hearing loss condition in a Subject, NIDCD (1R43DC013012-01) and NICHD comprising: (a) providing a sample previously obtained (1R43HD076544-01) awarded by the National Institutes of from the Subject, wherein the sample comprises a dried Health. The United States Government has certain rights in blood spot (DBS) sample, a cord blood sample, single blood the invention. drop, saliva, oral Swab, other body fluid or other tissue; (b) sequencing the sample to generate a sequencing product, BACKGROUND wherein the sequencing product is determined by a sequenc 0003 For newborns with genetic disorders, a rapid diag ing method selected from a group consisting of next-gen nosis of diseases can make the difference between life and eration sequencing (NGS), targeted next-generation death and reduce length of stay in the neonatal intensive care sequencing (TNGS) and whole-exome sequencing (WES); unit (NICU). However, current single gene sequencing and (c) analyzing the sequencing product to determine a methods used for confirmatory diagnosis can be impractical presence of absence of or predisposition to the hearing loss in newborns. They can be costly, time consuming and condition. In some cases, the methods and systems further require a large blood Volume that cannot be easily or safely comprise providing a sample previously obtained from a obtained from an infant. relative of the subject. 0004 Two compelling forces are expected to drive adop 0008. In an aspect, the subject disclosed herein is a fetus, tion of genetic testing in newborns. First is the need for a newborn, an infant, a child, an adolescent, a teenager or an rapid, minimally invasive diagnosis to treat and minimize adult. In some cases, the Subject is a newborn. In some cases, adverse outcomes. Second is the financial incentive to the subject is within 28 days after birth. In some cases, the shorten length of stay and reduce overall patient-manage subject is a relative of a newborn. ment costs associated with delayed or inaccurate diagnosis. 0009. In another aspect, the methods and systems dis The methods and systems disclosed herein can provide a closed herein use less than 1000 uL of the sample (e.g. fast-turnaround, minimally invasive, and cost-effective DBS). For example, less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, assay for Screening diseases, such as genetic disorders 30, 40, 50, 60, 70, 80,90, 100, 150, 200, 250, 300, 350, 400, and/or pathogens, in newborns. It demonstrates that turn 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or around and sample requirements for newborn genetic cases 1000 uL of the sample (e.g. DBS) can be used. can be achieved using Targeted Next-Generation Sequenc 0010. In another aspect, the sample disclosed herein is a ing (TNGS), and that combining genetic etiology (via blood sample. In some cases, the blood sample is a dried TNGS) with phenotype can allow a prompt and comprehen blood spot (DBS) sample. In some cases, the sample con sive clinical understanding. tains less than 1000 uL of blood. For example, less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, SUMMARY 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 0005. The methods and systems disclosed herein can be 750, 800, 850,900, 950 or 1000 uL of the sample (e.g. DBS) used for detecting a genetic condition in a Subject, compris is contained within the sample. In some cases, the sample ing: (a) providing a sample previously obtained from the contains less than 50 uL of blood. Subject, wherein the sample comprises a dried blood spot 0011. In another aspect, providing a sample further com (DBS) sample, a cord blood sample, single blood drop, prise purifying and/or isolating a DNA from the sample. In saliva, oral swab, other bodily fluid or other tissue; (b) another aspect, providing a sample does not comprise puri sequencing the sample to generate a sequencing product, fying and/or isolating a DNA from the sample. In some wherein the sequencing product is determined by a sequenc cases, the sample is a whole blood sample. In some cases, ing method selected from a group consisting of next-gen the sample is a whole blood sample without purification. In eration sequencing (NGS), targeted next-generation Some cases, the sample is a purified sample.
Load more

Recommended publications
  • Centronuclear Myopathies Under Attack: a Plethora of Therapeutic Targets Hichem Tasfaout, Belinda Cowling, Jocelyn Laporte
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Archive Ouverte en Sciences de l'Information et de la Communication Centronuclear myopathies under attack: A plethora of therapeutic targets Hichem Tasfaout, Belinda Cowling, Jocelyn Laporte To cite this version: Hichem Tasfaout, Belinda Cowling, Jocelyn Laporte. Centronuclear myopathies under attack: A plethora of therapeutic targets. Journal of Neuromuscular Diseases, IOS Press, 2018, 5, pp.387 - 406. 10.3233/JND-180309. hal-02438924 HAL Id: hal-02438924 https://hal.archives-ouvertes.fr/hal-02438924 Submitted on 14 Jan 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Journal of Neuromuscular Diseases 5 (2018) 387–406 387 DOI 10.3233/JND-180309 IOS Press Review Centronuclear myopathies under attack: A plethora of therapeutic targets Hichem Tasfaouta,b,c,d, Belinda S. Cowlinga,b,c,d,1 and Jocelyn Laportea,b,c,d,1,∗ aDepartment of Translational Medicine and Neurogenetics, Institut de G´en´etique et de Biologie Mol´eculaire et Cellulaire (IGBMC), Illkirch, France bInstitut National de la Sant´eetdelaRechercheM´edicale (INSERM), U1258, Illkirch, France cCentre National de la Recherche Scientifique (CNRS), UMR7104, Illkirch, France dUniversit´e de Strasbourg, Illkirch, France Abstract.
    [Show full text]
  • Effect of Propionic Acid on Fatty Acid Oxidation and U Reagenesis
    Pediat. Res. 10: 683- 686 (1976) Fatty degeneration propionic acid hyperammonemia propionic acidemia liver ureagenesls Effect of Propionic Acid on Fatty Acid Oxidation and U reagenesis ALLEN M. GLASGOW(23) AND H. PET ER C HASE UniversilY of Colorado Medical Celller, B. F. SlOlillsky LaboralOries , Denver, Colorado, USA Extract phosphate-buffered salin e, harvested with a brief treatment wi th tryps in- EDTA, washed twice with ph os ph ate-buffered saline, and Propionic acid significantly inhibited "CO z production from then suspended in ph os ph ate-buffe red saline (145 m M N a, 4.15 [I-"ejpalmitate at a concentration of 10 11 M in control fibroblasts m M K, 140 m M c/, 9.36 m M PO" pH 7.4) . I n mos t cases the cells and 100 11M in methyl malonic fibroblasts. This inhibition was we re incubated in 3 ml phosph ate-bu ffered sa lin e cont aining 0.5 similar to that produced by 4-pentenoic acid. Methylmalonic acid I1Ci ll-I4Cj palm it ate (19), final concentration approximately 3 11M also inhibited ' 'C0 2 production from [V 'ejpalmitate, but only at a added in 10 II I hexane. Increasing the amount of hexane to 100 II I concentration of I mM in control cells and 5 mM in methyl malonic did not impair palmit ate ox id ation. In two experiments (Fig. 3) the cells. fibroblasts were in cub ated in 3 ml calcium-free Krebs-Ringer Propionic acid (5 mM) also inhibited ureagenesis in rat liver phosphate buffer (2) co nt ain in g 5 g/ 100 ml essent iall y fatty ac id slices when ammonia was the substrate but not with aspartate and free bovine se rum albumin (20), I mM pa lm itate, and the same citrulline as substrates.
    [Show full text]
  • Moderate the MAOA-L Allele Expression with CRISPR/Cas9 System
    Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 23 April 2018 doi:10.20944/preprints201804.0275.v1 1 Review 2 Moderate the MAOA-L Allele Expression with CRISPR/Cas9 System 3 Martin L. Nelwan 4 Department of Animal Science – Other 5 Nelwan Institution for Human Resource Development 6 Jl. A. Yani No. 24 7 Palu, Sulawesi Tengah, Indonesia 8 Email: [email protected] 9 Abstract: Antisocial behavior is a behavior disorder inherited according to the inheritance of X-linked 10 chromosome. Mutations in the MAOA gene can cause different behaviors in humans. These can comprise 11 violent behavior or antisocial behavior. Low MAOA (MAOA-L) allele activity can cause antisocial 12 behavior in both healthy and unhealthy people. Antisocial from healthy males can originate from 13 maltreatment during childhood. There are no drugs for the treatment of antisocial behavior permanently 14 at this time. MAOA inhibitor can reverse antisocial behavior in animal models. To cure antisocial 15 behavior in the future, the CRISPR/Cas9 system in combination with iPSCs or ssODN methods for 16 instance can be used. This system has succeeded to correct erroneous segments in the F8 gene and F9 17 gene. Both genes occupy the X chromosome. The MAOA gene also occupies the X chromosome. It seems 18 that CRISPR/Cas9 system may be a beneficial tool to edit erroneous segments in the MAOA gene to treat 19 antisocial behavior. 20 Keywords: advanced therapy, aggressive, antisocial, behavior, MAOA. 21 22 1. Introduction 23 Antisocial behavior is a hereditary disorder inherited through an X-linked recessive inheritance 24 pattern.
    [Show full text]
  • Propionic Acidemia: an Extremely Rare Cause of Hemophagocytic Lymphohistiocytosis in an Infant
    Case report Arch Argent Pediatr 2020;118(2):e174-e177 / e174 Propionic acidemia: an extremely rare cause of hemophagocytic lymphohistiocytosis in an infant Sultan Aydin Kökera, MD, Osman Yeşilbaşb, MD, Alper Kökerc, MD, and Esra Şevketoğlud, Assoc. Prof. ABSTRACT INTRODUCTION Hemophagocytic lymphohystiocytosis (HLH) may be primary Hemophagocytic lymphohistiocytosis (inherited/familial) or secondary to infections, malignancies, rheumatologic disorders, immune deficiency syndromes (HLH) is a life-threatening disorder in and metabolic diseases. Cases including lysinuric protein which there is uncontrolled proliferation of intolerance, multiple sulfatase deficiency, galactosemia, activated lymphocytes and histiocytes. The Gaucher disease, Pearson syndrome, and galactosialidosis have diagnosis of HLH is based on fulfilling at least previously been reported. It is unclear how the metabolites trigger HLH in metabolic diseases. A 2-month-old infant five of eight criteria (fever, splenomegaly, with lethargy, pallor, poor feeding, hepatosplenomegaly, bicytopenia, hypertriglyceridemia and/ fever and pancytopenia, was diagnosed with HLH and the or hypofibrinogenemia, hemophagocytosis, HLH-2004 treatment protocol was initiated. Analysis for low/absent natural killer cell activity, primary HLH gene mutations and metabolic screening tests were performed together; primary HLH gene mutations were hyperferritinemia, and high soluble interleukin- negative, but hyperammonemia and elevated methyl citrate 2-receptor levels). HLH includes both familial were detected. Propionic acidemia was diagnosed with tandem and reactive disease triggered by infection, mass spectrometry in neonatal dried blood spot. We report this immunologic disorder, malignancy, or drugs. case of HLH secondary to propionic acidemia. Both metabolic disorder screening tests and gene mutation analysis may be Clinical presentations of patients with primary performed simultaneously especially for early diagnosis in (familial) and secondary (reactive) HLH are infants presenting with HLH.
    [Show full text]
  • Genetic Syndromes with an Increased Risk of Developing Cancer As an Example of the Use of New Technologies
    Genetics and Molecular Biology, 37, 1 (suppl), 241-249 (2014) Copyright © 2014, Sociedade Brasileira de Genética. Printed in Brazil www.sbg.org.br Review Article Impact of NGS in the medical sciences: Genetic syndromes with an increased risk of developing cancer as an example of the use of new technologies Pablo Lapunzina1,2, Rocío Ortiz López3,4, Lara Rodríguez-Laguna2, Purificación García-Miguel5, Augusto Rojas Martínez3,4 and Víctor Martínez-Glez1,2 1Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain. 2Instituto de Genética Médica y Molecular, Hospital Universitario la Paz, Madrid, Spain. 3Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León. Monterrey, Nuevo León, México. 4Centro de Investigación y Desarrollo en Ciencias de la Salud, Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, México. 5Unidad de Oncología Pediátrica, Hospital Infantil La Paz, Madrid, Spain. Abstract The increased speed and decreasing cost of sequencing, along with an understanding of the clinical relevance of emerging information for patient management, has led to an explosion of potential applications in healthcare. Cur- rently, SNP arrays and Next-Generation Sequencing (NGS) technologies are relatively new techniques used to scan genomes for gains and losses, losses of heterozygosity (LOH), SNPs, and indel variants as well as to perform com- plete sequencing of a panel of candidate genes, the entire exome (whole exome sequencing) or even the whole ge- nome. As a result, these new high-throughput technologies have facilitated progress in the understanding and diagnosis of genetic syndromes and cancers, two disorders traditionally considered to be separate diseases but that can share causal genetic alterations in a group of developmental disorders associated with congenital malformations and cancer risk.
    [Show full text]
  • Childhood Cerebral X-Linked Adrenoleukodystrophy with Atypical Neuroimaging Abnormalities and a No…
    9/28/2018 Journal of Postgraduate Medicine: Childhood cerebral X-linked adrenoleukodystrophy with atypical neuroimaging abnormalities and a no… Open access journal indexed with Index Medicus & EMBASE Home | Subscribe | Feedback [Download PDF] CASE REPORT Year : 2018 | Volume : 64 | Issue : 1 | Page : 59-63 Childhood cerebral X-linked adrenoleukodystrophy with atypical neuroimaging abnormalities and a novel mutation M Muranjan1, S Karande1, S Sankhe2, S Eichler3, 1 Department of Pediatrics, Seth GS Medical College and KEM Hospital, Parel, Mumbai, Maharashtra, India 2 Department of Radiology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, Maharashtra, India 3 Centogene AG, Schillingallee 68, Rostock, Germany Correspondence Address: Dr. M Muranjan Department of Pediatrics, Seth GS Medical College and KEM Hospital, Parel, Mumbai, Maharashtra India Abstract Childhood cerebral X-linked adrenoleukodystrophy (XALD) typically manifests with symptoms of adrenocortical insufficiency and a variety of neurocognitive and behavioral abnormalities. A major diagnostic clue is the characteristic neuroinflammatory parieto-occipital white matter lesions on magnetic resonance imaging. This study reports a 5-year 10-month old boy presenting with generalized skin hyperpigmentation since 3 years of age. Over the past 9 months, he had developed right-sided hemiparesis and speech and behavioral abnormalities, which had progressed over 5 months to bilateral hemiparesis. Retrospective analyses of serial brain magnetic resonance images revealed an unusual pattern of lesions involving the internal capsules, corticospinal tracts in the midbrain and brainstem, and cerebellar white matter. The clinical diagnosis of childhood cerebral adrenoleukodystrophy was confirmed by elevated basal levels of adrenocorticotropin hormone and plasma very long chain fatty acid levels. Additionally, sequencing of the ABCD1 gene revealed a novel mutation.
    [Show full text]
  • Affected Female Carriers of MTM1 Mutations Display a Wide Spectrum
    Acta Neuropathol DOI 10.1007/s00401-017-1748-0 ORIGINAL PAPER Afected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues Valérie Biancalana1,2,3,4,5 · Sophie Scheidecker1 · Marguerite Miguet1 · Annie Laquerrière6 · Norma B. Romero7,8 · Tanya Stojkovic8 · Osorio Abath Neto9 · Sandra Mercier10,11,12 · Nicol Voermans13 · Laura Tanner14 · Curtis Rogers15 · Elisabeth Ollagnon‑Roman16 · Helen Roper17 · Célia Boutte18 · Shay Ben‑Shachar19 · Xavière Lornage2,3,4,5 · Nasim Vasli2,3,4,5 · Elise Schaefer20 · Pascal Laforet21 · Jean Pouget22 · Alexandre Moerman23 · Laurent Pasquier24 · Pascale Marcorelle25,26 · Armelle Magot12 · Benno Küsters27 · Nathalie Streichenberger28 · Christine Tranchant29 · Nicolas Dondaine1 · Raphael Schneider2,3,4,5,30 · Claire Gasnier1 · Nadège Calmels1 · Valérie Kremer31 · Karine Nguyen32 · Julie Perrier12 · Erik Jan Kamsteeg33 · Pierre Carlier34 · Robert‑Yves Carlier35 · Julie Thompson30 · Anne Boland36 · Jean‑François Deleuze36 · Michel Fardeau7,8 · Edmar Zanoteli9 · Bruno Eymard21 · Jocelyn Laporte2,3,4,5 Received: 9 May 2017 / Revised: 24 June 2017 / Accepted: 2 July 2017 © Springer-Verlag GmbH Germany 2017 Abstract X-linked myotubular myopathy (XLMTM), a females and to delineate diagnostic clues, we character- severe congenital myopathy, is caused by mutations in the ized 17 new unrelated afected females and performed a MTM1 gene located on the X chromosome. A majority of detailed comparison with previously reported cases at the afected males die in the early postnatal period, whereas clinical, muscle imaging, histological, ultrastructural and female carriers are believed to be usually asymptomatic. molecular levels. Taken together, the analysis of this large Nevertheless, several afected females have been reported. cohort of 43 cases highlights a wide spectrum of clini- To assess the phenotypic and pathological spectra of carrier cal severity ranging from severe neonatal and generalized weakness, similar to XLMTM male, to milder adult forms.
    [Show full text]
  • Clinical Issues in Neonatal Care
    Linda Ikuta , MN, RN, CCNS, PHN , and Ksenia Zukowsky, PhD, APRN, NNP-BC ❍ Section Editors Clinical Issues in Neonatal Care 2.5 HOURS Continuing Education Deconstructing Black Swans An Introductory Approach to Inherited Metabolic Disorders in the Neonate Nicholas Ah Mew , MD ; Sarah Viall , MSN, PPCNP ; Brian Kirmse , MD ; Kimberly A. Chapman , MD, PhD ABSTRACT Background: Inherited metabolic disorders (IMDs) are individually rare but collectively common disorders that frequently require rapid or urgent therapy. Purpose: This article provides a generalized approach to IMDs, as well as some investigations and safe therapies that may be initiated pending the metabolic consult. Methods/Search Strategy: An overview of the research supporting management strategies is provided. In addition, the newborn metabolic screen is reviewed. Findings/Results: Caring for infants with IMDs can seem difficult because each of the types is rarely seen; however, collectively the management can be seen as similar. Implications for Practice: When an IMD is suspected, a metabolic specialist should be consulted for expert advice regarding appropriate laboratory investigations and management. Because rapid intervention of IMDs before the onset of symptoms may prevent future irreversible sequelae, each abnormal newborn screen must be addressed promptly. Implications for Research: Management can be difficult. Research in this area is limited and can be difficult without multisite coordination since sample sizes of any significance are difficult to achieve. Key Words:
    [Show full text]
  • Inherited Metabolic Disease
    Inherited metabolic disease Dr Neil W Hopper SRH Areas for discussion • Introduction to IEMs • Presentation • Initial treatment and investigation of IEMs • Hypoglycaemia • Hyperammonaemia • Other presentations • Management of intercurrent illness • Chronic management Inherited Metabolic Diseases • Result from a block to an essential pathway in the body's metabolism. • Huge number of conditions • All rare – very rare (except for one – 1:500) • Presentation can be non-specific so index of suspicion important • Mostly AR inheritance – ask about consanguinity Incidence (W. Midlands) • Amino acid disorders (excluding phenylketonuria) — 18.7 per 100,000 • Phenylketonuria — 8.1 per 100,000 • Organic acidemias — 12.6 per 100,000 • Urea cycle diseases — 4.5 per 100,000 • Glycogen storage diseases — 6.8 per 100,000 • Lysosomal storage diseases — 19.3 per 100,000 • Peroxisomal disorders — 7.4 per 100,000 • Mitochondrial diseases — 20.3 per 100,000 Pathophysiological classification • Disorders that result in toxic accumulation – Disorders of protein metabolism (eg, amino acidopathies, organic acidopathies, urea cycle defects) – Disorders of carbohydrate intolerance – Lysosomal storage disorders • Disorders of energy production, utilization – Fatty acid oxidation defects – Disorders of carbohydrate utilization, production (ie, glycogen storage disorders, disorders of gluconeogenesis and glycogenolysis) – Mitochondrial disorders – Peroxisomal disorders IMD presentations • ? IMD presentations • Screening – MCAD, PKU • Progressive unexplained neonatal
    [Show full text]
  • Liver Glucose Metabolism in Humans
    Biosci. Rep. (2016) / 36 / art:e00416 / doi 10.1042/BSR20160385 Liver glucose metabolism in humans Mar´ıa M. Adeva-Andany*1, Noemi Perez-Felpete*,´ Carlos Fernandez-Fern´ andez*,´ Cristobal´ Donapetry-Garc´ıa* and Cristina Pazos-Garc´ıa* *Nephrology Division, Hospital General Juan Cardona, c/ Pardo Bazan´ s/n, 15406 Ferrol, Spain Synopsis Information about normal hepatic glucose metabolism may help to understand pathogenic mechanisms underlying obesity and diabetes mellitus. In addition, liver glucose metabolism is involved in glycosylation reactions and con- nected with fatty acid metabolism. The liver receives dietary carbohydrates directly from the intestine via the portal vein. Glucokinase phosphorylates glucose to glucose 6-phosphate inside the hepatocyte, ensuring that an adequate flow of glucose enters the cell to be metabolized. Glucose 6-phosphate may proceed to several metabolic path- ways. During the post-prandial period, most glucose 6-phosphate is used to synthesize glycogen via the formation of glucose 1-phosphate and UDP–glucose. Minor amounts of UDP–glucose are used to form UDP–glucuronate and UDP– galactose, which are donors of monosaccharide units used in glycosylation. A second pathway of glucose 6-phosphate metabolism is the formation of fructose 6-phosphate, which may either start the hexosamine pathway to produce UDP-N-acetylglucosamine or follow the glycolytic pathway to generate pyruvate and then acetyl-CoA. Acetyl-CoA may enter the tricarboxylic acid (TCA) cycle to be oxidized or may be exported to the cytosol to synthesize fatty acids, when excess glucose is present within the hepatocyte. Finally, glucose 6-phosphate may produce NADPH and ribose 5-phosphate through the pentose phosphate pathway.
    [Show full text]
  • Megalencephaly and Macrocephaly
    277 Megalencephaly and Macrocephaly KellenD.Winden,MD,PhD1 Christopher J. Yuskaitis, MD, PhD1 Annapurna Poduri, MD, MPH2 1 Department of Neurology, Boston Children’s Hospital, Boston, Address for correspondence Annapurna Poduri, Epilepsy Genetics Massachusetts Program, Division of Epilepsy and Clinical Electrophysiology, 2 Epilepsy Genetics Program, Division of Epilepsy and Clinical Department of Neurology, Fegan 9, Boston Children’s Hospital, 300 Electrophysiology, Department of Neurology, Boston Children’s Longwood Avenue, Boston, MA 02115 Hospital, Boston, Massachusetts (e-mail: [email protected]). Semin Neurol 2015;35:277–287. Abstract Megalencephaly is a developmental disorder characterized by brain overgrowth secondary to increased size and/or numbers of neurons and glia. These disorders can be divided into metabolic and developmental categories based on their molecular etiologies. Metabolic megalencephalies are mostly caused by genetic defects in cellular metabolism, whereas developmental megalencephalies have recently been shown to be caused by alterations in signaling pathways that regulate neuronal replication, growth, and migration. These disorders often lead to epilepsy, developmental disabilities, and Keywords behavioral problems; specific disorders have associations with overgrowth or abnor- ► megalencephaly malities in other tissues. The molecular underpinnings of many of these disorders are ► hemimegalencephaly now understood, providing insight into how dysregulation of critical pathways leads to ►
    [Show full text]
  • Genes in Eyecare Geneseyedoc 3 W.M
    Genes in Eyecare geneseyedoc 3 W.M. Lyle and T.D. Williams 15 Mar 04 This information has been gathered from several sources; however, the principal source is V. A. McKusick’s Mendelian Inheritance in Man on CD-ROM. Baltimore, Johns Hopkins University Press, 1998. Other sources include McKusick’s, Mendelian Inheritance in Man. Catalogs of Human Genes and Genetic Disorders. Baltimore. Johns Hopkins University Press 1998 (12th edition). http://www.ncbi.nlm.nih.gov/Omim See also S.P.Daiger, L.S. Sullivan, and B.J.F. Rossiter Ret Net http://www.sph.uth.tmc.edu/Retnet disease.htm/. Also E.I. Traboulsi’s, Genetic Diseases of the Eye, New York, Oxford University Press, 1998. And Genetics in Primary Eyecare and Clinical Medicine by M.R. Seashore and R.S.Wappner, Appleton and Lange 1996. M. Ridley’s book Genome published in 2000 by Perennial provides additional information. Ridley estimates that we have 60,000 to 80,000 genes. See also R.M. Henig’s book The Monk in the Garden: The Lost and Found Genius of Gregor Mendel, published by Houghton Mifflin in 2001 which tells about the Father of Genetics. The 3rd edition of F. H. Roy’s book Ocular Syndromes and Systemic Diseases published by Lippincott Williams & Wilkins in 2002 facilitates differential diagnosis. Additional information is provided in D. Pavan-Langston’s Manual of Ocular Diagnosis and Therapy (5th edition) published by Lippincott Williams & Wilkins in 2002. M.A. Foote wrote Basic Human Genetics for Medical Writers in the AMWA Journal 2002;17:7-17. A compilation such as this might suggest that one gene = one disease.
    [Show full text]