DOCSLIB.ORG

Genetic Testing in Spinocerebellar Ataxias Defining a Clinical Role

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Genetic Testing in Spinocerebellar Ataxias Defining a Clinical Role NEUROLOGICAL REVIEW Genetic Testing in Spinocerebellar Ataxias Defining a Clinical Role Eng-King Tan, MD; Tetsuo Ashizawa, MD lthough genetic tests for known spinocerebellar ataxia (SCA) genes are increasingly available, their exact clinical role has received much less attention. Currently avail- able DNA tests can define the genotypes of up to two thirds of patients with domi- nantly inherited SCAs. Certain characteristic clinical features and ethnic predilection Aof some of the SCA subtypes may help prioritize specific SCA gene testing. Available data on genotype- phenotype correlation suggest that currently available DNA tests cannot accurately predict age of onset or prognosis. Because of the mostly adult-onset symptoms and the absence of effective treat- ment, genetic counseling is essential for addressing ethical, social, legal, and psychological issues associated with SCA DNA testing. Arch Neurol. 2001;58:191-195 GENETIC CLASSIFICATION lated region of the SCA8 gene that produces antisense messenger RNA to the Spinocerebellar ataxias (SCAs) are a group KLHL1 gene on the complementary of neurodegenerative diseases character- strand.6 In SCA10, the disease-causing ex- ized by cerebellar dysfunction alone or in pansion occurs in the ATTCT penta- combination with other neurological ab- nucleotide repeat of intron 9 of SCA10, a normalities. Spinocerebellar ataxias have gene of unknown function widely ex- become a focus of human genetics re- pressed in the brain.7 Five additional SCA search since expansions of coded CAG tri- loci have been mapped: SCA4 to 16q24- nucleotide repeats were shown to cause qter,8 SCA5 to 11q13,9 SCA11 to 15q1- several dominantly inherited SCAs (SCAs q21.3,10 SCA13 to 19q13.3-q13.4,11 and 1, 2, 3, 6, and 7) and dentatorubral pal- SCA14 to 19q13.4-qter.12 Episodic ataxia lidoluysian atrophy (DRPLA).1-3 Another types 1 and 2 are also dominantly inher- dominant ataxia with an expanded CAG ited cerebellar ataxias; they are caused by repeat in the TATA box binding protein point mutations within a voltage-gated po- (TBP) gene has been added recently to this tassium channel gene (KCNA1) and the ce- group of disorders.4 In these disorders, the rebral P/Q-type calcium channel a 1 sub- CAG triple repeat expansion gives rise to unit gene (CACNL1A4), respectively.13,14 an elongated polyglutamine tract in the re- The most common recessively inherited spective proteins, leading to a gain in func- ataxia is Friedreich ataxia (FRDA), which tion that is toxic to neurons. However, un- is caused by an expansion of the GAA re- translated repeat expansions also cause peat in intron 1 of the FRDA gene.15 Other dominantly inherited ataxic disorders. Spi- recessive ataxias include vitamin E defi- nocerebellar ataxia type 12 shows an ex- ciency (due to a- tocopherol transfer pro- panded CAG repeat in the 59 untrans- tein deficiency or abetalipoproteinemia), lated region of PPP2R2B, a gene coding for ataxia telangiectasia, infantile-onset a brain-specific regulatory subunit of the spinocerebellar ataxia (IOSCA), Mari- protein phosphatase PP2A.5 Spinocerebel- nesco-Sjo¨gren syndrome, spastic ataxia lar ataxia type 8 is associated with an ex- of Charlevoix-Saguenay, Refsum disease, pansion of a CTG repeat in the 39 untrans- carbohydrate-deficiency ataxia, and Cay- man Island ataxia, among others3 (also see From the Departments of Neurology, Baylor College of Medicine (Drs Tan and the Washington University ataxia clas- Ashizawa), and the Veterans Affairs Medical Center (Dr Ashizawa), Houston, Tex. sification16). Wilson disease may mimic (REPRINTED) ARCH NEUROL / VOL 58, FEB 2001 WWW.ARCHNEUROL.COM 191 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Inherited Spinocerebellar Ataxias (SCAs) for Which Commercial DNA Testing Is Available* Age at Pattern of Gene (Repeat) Disease Main Target Main Clinical Features Onset Range, y Inheritence Gene and Product Location SCA1 Cerebellum, brainstem ADCAI 5-70 AD with anticipation SCA1, ataxin 1 6p22-p23 (exon) SCA2 Cerebellum, brainstem ADCAI with slow saccade, 9-44 AD with anticipation SCA2, ataxin 2 12q24.1 (exon) areflexia MJD/SCA3 Cerebellum, brainstem ADCAI wih dystonia, rigidity, 17-72 AD with anticipation SCA3, ataxin 3 14q32.1 (exon) bulged eyes in MJD 2+ SCA6 Cerebellum ADCAIII with occasional 28-50 AD with anticipation? CACNAIA, a1A-Ca 19p13 (exon) dyskinesia and abnormal channel reflex SCA7 Cerebellum, brainstem, ADCAII 28-50 AD with anticipation SCA7, ataxin 7 3p21.1-p12 (exon) retina SCA8 Cerebellum ADCAIII 28-50 AD SCA8 19p13 (39 UTR) SCA10 Cerebellum, cerebral cortex Ataxia, seizure 12-45 AD with anticipation SCA10, E46 22q13.3 (intron 9) SCA12 Cerebellum, cerebral cortex Ataxia, upper body tremor, 8-55 AD PPP2R2B, PP2ABb 5p31-p33 (59 UTR) hyperreflexia, paucity of movements, dementia DRPLA Dentatorubral pallidoluysian Progressive myoclonus, seizure, 10-70 AD with anticipation DRPLA, atrophin 1 12p12 (exon) systems ataxia, and dementia FRDA DRG, spinal cord, Progressive ataxia and ,20 AR FRDA, frataxin 9p13 (intron 1) cerebellum, peripheral proprioceptive sensory loss, 3-70 nerve areflexia, cardiomyopathy, diabetes *ADCA indicates autosomal dominant cerebellar ataxia, ADCAI; cerebellar ataxia plus other neurologic abnormalities; ADCAII, ADCA with macular degeneration; and ADCAIII, pure cerebellar ataxia17; AD, autosomal dominant; AR, autosomal recessive; MJD, Machado-Joseph disease; DRPLA, dentatorubral pallidoluysian atrophy; FRDA, Friedreich ataxia; DRG, dorsal root ganglia; UTR, untranslated region; and question mark, anticipation has been reported but not confirmed. †Normal alleles 40-44 are interrupted by 1 or 2 CATs and disease alleles 40-44 are not. Ellipses indicate intermediate alleles have not been reported in these diseases. ‡Disease alleles show reduced penetrance. features of SCAs. Genetic testing is a powerful way of con- testing for point mutations may also be available on a re- firming the diagnosis and distinguishing various SCA sub- search basis for ataxia telangiectasia, ataxia of vitamin E types, although there have been previous attempts to clas- deficiency, mitochondrial disorders, Wilson disease, Ref- sify them according to their clinical presentations.17 sum disease, and episodic ataxia types 1 and 2. How- ever, screening of point mutations in these diseases are TYPES OF GENETIC TESTS generally not cost-effective because each family can carry a different mutation, and their diagnoses should be based Although genetic testing for known SCA genes are in- on clinical and other laboratory findings at present creasingly available, their exact clinical role has re- (Figure). New technologies, such as DNA microchip ar- ceived much less attention. Currently available commer- rays,19 may make DNA testing for these diseases com- cial DNA tests can define the genotypes of up to two thirds mercially feasible in the near future. of patients with dominantly inherited SCAs10 (Table; see also Web site www.genetests.org,18 which catalogs ge- CHOICE OF GENETIC TEST netic testing). As the list of these DNA tests grows, the variable and overlapping phenotypic manifestations of In general, these tests should be done in SCAs that dem- the SCA subtypes make it difficult to choose which spe- onstrate a clear mode of inheritance (Figure). For those cific SCA DNA test to order initially. Although a posi- without family history, secondary causes, especially treat- tive DNA test result provides the unequivocal diagnosis able ones, should be excluded first. However, testing in at a cost comparable to magnetic resonance imaging stud- apparent “sporadic” cases might be worthwhile if the fam- ies, a negative test result has little diagnostic value other ily history is unreliable or ambiguous because about 5% than exclusion of certain diseases. It might not be cost- of sporadic cases have been found to be autosomal domi- effective to order blanket genetic tests for all patients with nant.20 A positive family history may not always be avail- SCA, especially with the availability of an increasing num- able for patients with SCA6 and recessive ataxias such ber of DNA tests for ataxic disorders (a single SCA di- as FRDA. A de novo mutation, ie, an expansion of an in- agnostic test costs approximately $300). Some laborato- termediate allele into a full mutant allele, may cause the ries offer less expensive rates when many SCA DNA tests disease with clearly negative family history. Early paren- are done at the same time, and such a battery might be tal deaths, nonpaternity, and adoption should also be useful in cases in which there are few clues for prioriti- taken into consideration. By the same reasons, domi- zation of the SCA DNA testing. At present, DNA testing nant ataxias may mimic recessive inheritance. Although that can directly detect mutations is commercially avail- it is not easy to prioritize the screening order of SCA sub- able for SCAs 1, 2, 3, 6, 7, and 8; FRDA; and DRPLA and types on clinical grounds alone, the ethnic origin and the may become available for SCAs 10 and 12 and the ataxia presence of certain suggestive clinical signs may pro- with the TBP CAG expansion in the near future. DNA vide some guidance.1-3 Machado-Joseph disease (MJD) (REPRINTED) ARCH NEUROL / VOL 58, FEB 2001 WWW.ARCHNEUROL.COM 192 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Patient With Cerebellar Syndrome Positive Detailed History Negative Repeat Normal Intermediate Disease Family History and Examination Family History (Cryptic Sequence) Range Range Range CAG (CAT) 6-44 . .† 40-82 Autosomal Genetic Autosomal Recessive or CAG (CAA) 14-31 34-35 34-59 Dominant Counseling Uncertain Inheritance CAG (none) 12-40 . 55-200 Testing for Recessive Disorders if Compatible Exclude Secondary With Observed Manifestations Causes, CAG (none) 4-20 . 21-33 Disease Test Disease Test Negative eg, Neuroacanthocytosis, FRDA (GAA)>120 Refsum Phytanic Acid Paraneoplastic Syndrome, AVED Vitamin E Wilson Ceruloplasmin Hypothyroidism, Alcoholism, AT α-Fetoprotein and Antigliadin Antibody CAG (none) 4-19 28-35 37-.300 CTG (complex) 16-34 .
Load more

Recommended publications
  • Rehabilitating Individuals with Spinocerebellar Ataxia: Experiences from Impairment-Based Rehabilitation Through Multidisciplinary Care Approach
    Neurology Asia 2020; 25(1) : 75 – 80 Rehabilitating individuals with spinocerebellar ataxia: Experiences from impairment-based rehabilitation through multidisciplinary care approach 1,2Fatimah Ahmedy MBBCh MRehabMed, 1Yuen Woei Neoh MBBS, MRehabMed, 1Lydia Abdul Latiff MBBS MRehabMed 1Department of Rehabilitation Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur; 2Department of Surgery, Faculty of Medicine & Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Sabah, Malaysia Abstract Spinocerebellar ataxia (SCA) is a rare neurodegenerative disease with progressive course and poor expected outcomes. Therefore, rehabilitation remains the principal form of management especially in advanced disease. Impairment-based rehabilitation through multidisciplinary care approach has proven benefits for functional improvement in individuals with advancing SCA. This concept is based on comprehensive assessments of individualised impairments and functional limitations while exploring contributing environmental and personal factors affecting the person as a whole. From this assessment, individualised rehabilitation goals can be formulated through a multidisciplinary care approach. Neurologists, rehabilitation physicians, physiotherapists, occupational therapists and speech and language pathologists are key individuals involved in the multidisciplinary care for individuals with SCA rehabilitation. Two cases of individuals at different stages of SCA are presented to highlight the rehabilitation approach in providing focused interventions
    [Show full text]
  • The Genetic Background of Anticipation P Teisberg MD
    JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Volume 88 April 1995 The genetic background of anticipation P Teisberg MD J R Soc Med 1995;88:185-187 Keywords: genetics; anticipation; triplet repeats; neurological disorders Anticipation was controversial impairment and increased infant mortality were observed. Anticipation may be defined as the occurrence of a genetic The sequence of events often ends in congenital MD with its disorder at progressively earlier ages in successive severe clinical manifestation of mental retardation and generations. The disease moreover occurs with increasing muscular dystrophy. Later, clinical studies confirmed these severity. The concept emerged early in this century mainly observations and described a dominant inheritance pattern through descriptive dinical studies ofmyotonic dystrophy1'2. which could not be explained by classical Mendelian Later studies have added other disease entities to a list of mechanisms8. states showing anticipation, the most notable being Another phenomenon which did not fit easily into the Huntington's disease3. In one form of inherited mental concepts of genetics was the finding that congenital MD was retardation, the fragile X syndrome, the term 'the Sherman transmitted almost exclusively via affected mothers9. paradox' describes a very similar phenomenon4. In the fragile X syndrome, anticipation is manifested in a Towards the middle of this century, basic research in different manner. This is the most common cause of familial genetics had given us a much clearer understanding of mental retardation. It segregates in families as an X-linked Mendelian inheritance. It became increasingly difficult to dominant disorder with reduced penetrance. When reconcile the originally described phenomenon of chromosomes are stained a fragile site on the X anticipation with a concept of genes as stable elements chromosome may be seen in a proportion of cells taken only changed by the rare mutation.
    [Show full text]
  • Original Articles Anticipation Resulting in Elimination of the Myotonic
    J7 Med Genet 1994;31:595-601 595 Original articles J Med Genet: first published as 10.1136/jmg.31.8.595 on 1 August 1994. Downloaded from Anticipation resulting in elimination of the myotonic dystrophy gene: a follow up study of one extended family C E M de Die-Smulders, C J Howeler, J F Mirandolle, H G Brunner, V Hovers, H Bruggenwirth, H J M Smeets, J P M Geraedts Abstract muscular manifestations, it is characterised by We have re-examined an extended myo- multiple systemic effects including cataract, tonic dystrophy (DM) family, previously mental retardation, cardiac involvement, and described in 1955, in order to study the testicular atrophy. Extreme variability is one of long term effects of anticipation in DM the hallmarks of the disease; clinical studies and in particular the implications for have led to the recognition of four disease types families affected by this disease. This fol- on the basis of age at onset and core symptoms: low up study provides data on 35 gene late onset (mild) type, adult onset (classical) carriers and 46 asymptomatic at risk type, childhood, and congenital type.'"3 family members in five generations. Anticipation, increasing severity and earlier Clinical anticipation, defined as the cas- age at onset in successive generations, has been cade ofmild, adult, childhood, or congen- observed in DM since the beginning of this ital disease in subsequent generations, century, but remained unexplained and contro- appeared to be a relentless process, oc- versial until recently."- With the discovery of curring in all affected branches of the an unstable CTG trinucleotide repeat in the 3' family.
    [Show full text]
  • Spinocerebellar Ataxia Genetic Testing
    Lab Management Guidelines V1.0.2020 Spinocerebellar Ataxia Genetic Testing MOL.TS.311.A v1.0.2020 Introduction Spinocerebellar ataxia (SCA) genetic testing is addressed by this guideline. Procedures addressed The inclusion of any procedure code in this table does not imply that the code is under management or requires prior authorization. Refer to the specific Health Plan's procedure code list for management requirements. Procedures addressed by this Procedure codes guideline ATXN1 gene analysis, evaluation to detect 81178 abnormal (eg,expanded) allele ATXN2 gene analysis, evaluation to detect 81179 abnormal (eg,expanded) allele ATXN3 gene analysis, evaluation to detect 81180 abnormal (eg,expanded) allele ATXN7 gene analysis, evaluation to detect 81181 abnormal (eg,expanded) allele ATXN8 gene analysis, evaluation to detect 81182 abnormal (eg, expanded) alleles ATXN10 gene analysis, evaluation to 81183 detect abnormal (eg, expanded) alleles CACNA1A gene analysis; evaluation to 81184 detect abnormal (eg, expanded) alleles CACNA1A gene analysis; full gene 81185 sequence CACNA1A gene analysis; known familial 81186 variant PPP2R2B gene analysis, evaluation to 81343 detect abnormal (eg, expanded) alleles TBP gene analysis, evaluation to detect 81344 abnormal (eg, expanded) alleles Unlisted molecular pathology procedure 81479 © 2020 eviCore healthcare. All Rights Reserved. 1 of 15 400 Buckwalter Place Boulevard, Bluffton, SC 29910 (800) 918-8924 www.eviCore.com Lab Management Guidelines V1.0.2020 What is spinocerebellar ataxia Definition Spinocerebrallar ataxias (SCA) are a group of autosomal dominant ataxias that have a range of phenotypes. There are various subtypes of SCA, which are denoted by numbers (e.g. SCA1, SCA3, etc.) Incidence and Prevalence The prevalence of autosomal dominant cerebellar ataxias, as a whole, is 1-5:100,000.1 SCA3 is the most common autosomal dominant form of ataxia.
    [Show full text]
  • Fact Sheet 54| FRAGILE X SYNDROME This Fact Sheet
    11111 Fact Sheet 54| FRAGILE X SYNDROME This fact sheet describes the condition Fragile X and includes a discussion of the symptoms, causes and available testing. In summary Fragile X is a condition caused by a change in the FMR-1 gene, on the X chromosome It is characterised by particular physical features, varying degrees of learning difficulties and behavioural and emotional problems Fragile X affects around 1 in 4,000 males and between 1 in 5,000 and 1 in 8,000 females. WHAT IS FRAGILE X SYNDROME? WHAT CAUSES FRAGILE X SYNDROME? Fragile X syndrome is the most common known Fragile X syndrome is caused by a variation in the cause of inherited intellectual disability. genetic information in the FMR-1 gene. Genes are Intellectual problems in people with fragile X made up of a string of three letter ‘words’, or syndrome can vary from mild learning difficulties triplets, using the letters A,T, C & G. The FMR-1 through to severe intellectual disability. gene codes for a protein called FMRP that is necessary for usual brain development and/or Emotional and behavioural problems may also be function. In the FMR-1 gene, the triplet word present. ‘CGG’ can be repeated many times. When the Females with fragile X syndrome show varying number of ‘CGG’ repeats in the FMR-1 gene degrees of the condition, but are usually less increases over a critical number, the gene severely affected than males. becomes so long that it becomes faulty and the production of the FMRP is disrupted. The features of the condition, and their severity, are related to the genetic information in the faulty gene causing the condition.
    [Show full text]
  • Amino Acid Disorders 105
    AMINO ACID DISORDERS 105 Massaro, A. S. (1995). Trypanosomiasis. In Guide to Clinical tions in biological fluids relatively easy. These Neurology (J. P. Mohrand and J. C. Gautier, Eds.), pp. 663– analyzers separate amino acids either by ion-ex- 667. Churchill Livingstone, New York. Nussenzweig, V., Sonntag, R., Biancalana, A., et al. (1953). Ac¸a˜o change chromatography or by high-pressure liquid de corantes tri-fenil-metaˆnicos sobre o Trypanosoma cruzi in chromatography. The results are plotted as a graph vitro: Emprego da violeta de genciana na profilaxia da (Fig. 1). The concentration of each amino acid can transmissa˜o da mole´stia de chagas por transfusa˜o de sangue. then be calculated from the size of the corresponding O Hospital (Rio de Janeiro) 44, 731–744. peak on the graph. Pagano, M. A., Segura, M. J., DiLorenzo, G. A., et al. (1999). Cerebral tumor-like American trypanosomiasis in Most amino acid disorders can be diagnosed by acquired immunodeficiency syndrome. Ann. Neurol. 45, measuring the concentrations of amino acids in 403–406. blood plasma; however, some disorders of amino Rassi, A., Trancesi, J., and Tranchesi, B. (1982). Doenc¸ade acid transport are more easily recognized through the Chagas. In Doenc¸as Infecciosas e Parasita´rias (R. Veroesi, Ed.), analysis of urine amino acids. Therefore, screening 7th ed., pp. 674–712. Guanabara Koogan, Sa˜o Paulo, Brazil. Spina-Franc¸a, A., and Mattosinho-Franc¸a, L. C. (1988). for amino acid disorders is best done using both South American trypanosomiasis (Chagas’ disease). In blood and urine specimens. Occasionally, analysis of Handbook of Clinical Neurology (P.
    [Show full text]
  • Spinocerebellar Ataxia 17 (SCA17) and Huntington’S Disease-Like 4 (HDL4)
    Spinocerebellar ataxia 17 (SCA17) and Huntington’s disease-like 4 (HDL4). Giovanni Stevanin, Alexis Brice To cite this version: Giovanni Stevanin, Alexis Brice. Spinocerebellar ataxia 17 (SCA17) and Huntington’s disease-like 4 (HDL4).. The Cerebellum, Springer, 2008, 7 (2), pp.170-8. 10.1007/s12311-008-0016-1. inserm- 00293796 HAL Id: inserm-00293796 https://www.hal.inserm.fr/inserm-00293796 Submitted on 26 Mar 2009 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. Stevanin & Brice, SCA7 and HDL4 1 SPINOCEREBELLAR ATAXIA 17 (SCA17) AND HUNTINGTON’S DISEASE-LIKE 4 (HDL4) GIOVANNI STEVANIN1,2,3 & ALEXIS BRICE1,2,3 1INSERM, U679, 75013 Paris, France; 2Université Pierre et Marie Curie – Paris 6, UMR S679, Institut Fédératif de Recherche en Neurosciences, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France; 3APHP, Groupe Hospitalier Pitié-Salpêtrière, Département de Génétique et Cytogénétique, 75013 Paris, France Correspondence: Giovanni Stevanin, PhD, INSERM U679, Groupe Pitié-Salpêtrière, 47 Boulevard de l’Hôpital, 75651 Paris Cedex 13, France. E-mail: [email protected] Running title: SCA7 and HDL4 Stevanin & Brice, SCA7 and HDL4 2 Abstract Spinocerebellar ataxia 17 (SCA17) or Huntington's disease-like-4 is a neurodegenerative disease caused by the expansion above 44 units of a CAG/CAA repeat in the coding region of the TATA box binding protein (TBP) gene leading to an abnormal expansion of a polyglutamine stretch in the corresponding protein.
    [Show full text]
  • Inherited Renal Tubulopathies—Challenges and Controversies
    G C A T T A C G G C A T genes Review Inherited Renal Tubulopathies—Challenges and Controversies Daniela Iancu 1,* and Emma Ashton 2 1 UCL-Centre for Nephrology, Royal Free Campus, University College London, Rowland Hill Street, London NW3 2PF, UK 2 Rare & Inherited Disease Laboratory, London North Genomic Laboratory Hub, Great Ormond Street Hospital for Children National Health Service Foundation Trust, Levels 4-6 Barclay House 37, Queen Square, London WC1N 3BH, UK; [email protected] * Correspondence: [email protected]; Tel.: +44-2381204172; Fax: +44-020-74726476 Received: 11 February 2020; Accepted: 29 February 2020; Published: 5 March 2020 Abstract: Electrolyte homeostasis is maintained by the kidney through a complex transport function mostly performed by specialized proteins distributed along the renal tubules. Pathogenic variants in the genes encoding these proteins impair this function and have consequences on the whole organism. Establishing a genetic diagnosis in patients with renal tubular dysfunction is a challenging task given the genetic and phenotypic heterogeneity, functional characteristics of the genes involved and the number of yet unknown causes. Part of these difficulties can be overcome by gathering large patient cohorts and applying high-throughput sequencing techniques combined with experimental work to prove functional impact. This approach has led to the identification of a number of genes but also generated controversies about proper interpretation of variants. In this article, we will highlight these challenges and controversies. Keywords: inherited tubulopathies; next generation sequencing; genetic heterogeneity; variant classification. 1. Introduction Mutations in genes that encode transporter proteins in the renal tubule alter kidney capacity to maintain homeostasis and cause diseases recognized under the generic name of inherited tubulopathies.
    [Show full text]
  • Episodic Ataxias
    REVIEW ARTICLE http://dx.doi.org/10.14802/jmd.16028 / J Mov Disord 2016;9(3):129-135 pISSN 2005-940X / eISSN 2093-4939 Episodic Ataxias: ABSTRACT Episodic ataxia (EA) is a clinically heterogeneous group of disorders that are characterized by recur- Clinical and Genetic rent spells of truncal ataxia and incoordination last- ing minutes to hours. Most have an autosomal do- minant inheritance pattern. To date, 8 subtypes Features have been defined according to clinical and genet- ic characteristics, and five genes are known to be linked to EAs. Both EA1 and EA2, which are caus- ed by mutations in KCNA1 and CACNA1A, account Kwang-Dong Choi,1 Jae-Hwan Choi2 for the majority of EA, but many patients with no identified mutations still exhibit EA-like clinical fea- 1 Department of Neurology, College of Medicine, Pusan National University Hospital, tures. Furthermore, genetically confirmed EAs have Pusan National University School of Medicine and Biomedical Research Institute, Busan, Korea mostly been identified in Caucasian families. In this 2Department of Neurology, Pusan National University School of Medicine, article, we review the current knowledge on the Research Institute for Convergence of Biomedical Science and Technology, clinical and genetic characteristics of EAs. Addition- Pusan National University Yangsan Hospital, Yangsan, Korea ally, we summarize the phenotypic features of the genetically confirmed EA2 families in Korea. Key Words Episodic ataxia; KCNA1; CACNA1A. Received: June 30, 2016 Revised: July 25, 2016 Accepted: August 1,
    [Show full text]
  • The Bio Revolution: Innovations Transforming and Our Societies, Economies, Lives
    The Bio Revolution: Innovations transforming economies, societies, and our lives economies, societies, our and transforming Innovations Revolution: Bio The Executive summary The Bio Revolution Innovations transforming economies, societies, and our lives May 2020 McKinsey Global Institute Since its founding in 1990, the McKinsey Global Institute (MGI) has sought to develop a deeper understanding of the evolving global economy. As the business and economics research arm of McKinsey & Company, MGI aims to help leaders in the commercial, public, and social sectors understand trends and forces shaping the global economy. MGI research combines the disciplines of economics and management, employing the analytical tools of economics with the insights of business leaders. Our “micro-to-macro” methodology examines microeconomic industry trends to better understand the broad macroeconomic forces affecting business strategy and public policy. MGI’s in-depth reports have covered more than 20 countries and 30 industries. Current research focuses on six themes: productivity and growth, natural resources, labor markets, the evolution of global financial markets, the economic impact of technology and innovation, and urbanization. Recent reports have assessed the digital economy, the impact of AI and automation on employment, physical climate risk, income inequal ity, the productivity puzzle, the economic benefits of tackling gender inequality, a new era of global competition, Chinese innovation, and digital and financial globalization. MGI is led by three McKinsey & Company senior partners: co-chairs James Manyika and Sven Smit, and director Jonathan Woetzel. Michael Chui, Susan Lund, Anu Madgavkar, Jan Mischke, Sree Ramaswamy, Jaana Remes, Jeongmin Seong, and Tilman Tacke are MGI partners, and Mekala Krishnan is an MGI senior fellow.
    [Show full text]
  • Genome As a Tool of Genetic Engineering: Application in Plant and Plant Derived Medicine
    International Journal of Biotech Trends and Technology (IJBTT) – Volume 8 Issue 1- Jan - March 2018 Genome as a Tool of Genetic Engineering: Application in Plant and Plant Derived Medicine A.B.M. Sharif Hossain1,2 Musamma M. Uddin2 1Department of Biology, Faculty of Science, Hail University, Hail, KSA 2Biotechnology Program, Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603, Kuala Lumpur, Malaysia introduce point mutations. Genetically modified Abstract organism (GMO) is considered as an organism that The study was conducted from different is generated through genetic engineering. The first modern research data to review the innovative GMOs were bacteria in 1973, GM mice were generated in 1974 [4]. Insulin-producing bacteria latest technology in the genomics and its were commercialized in 1982 and genetically application in Agriculture, biomedicinae and modified food has been sold since 1994. Glofish, the plant derived medicine. Application of genome first GMO designed as a pet, was first sold in the in genetic engineering and molecular United States December in 2003 [4]. Genetic biotechnology have been exhibited well. engineering biotechnology has been applied in Genetically Modified Organism (GMO), numerous fields including agriculture, industrial Agrobacterium mediated recombination (T- biotechnology, and medicine. Enzymes used in DNA) and genetic engineering using molecular laundry detergent and medicines such as insulin and Biotechnology in plant, medicine and human growth hormone are now manufactured in biomedicine have been highlighted from GM cells, experimental GM cell lines and GM animals such as mice or zebra fish are being used for technology based different research data. research purposes, and genetically modified Moreover, molecular biotechnology in crops have been commercialized [4].
    [Show full text]
  • Review of the Current State of Genetic Testing - a Living Resource
    Review of the Current State of Genetic Testing - A Living Resource Prepared by Liza Gershony, DVM, PhD and Anita Oberbauer, PhD of the University of California, Davis Editorial input by Leigh Anne Clark, PhD of Clemson University July, 2020 Contents Introduction .................................................................................................................................................. 1 I. The Basics ......................................................................................................................................... 2 II. Modes of Inheritance ....................................................................................................................... 7 a. Mendelian Inheritance and Punnett Squares ................................................................................. 7 b. Non-Mendelian Inheritance ........................................................................................................... 10 III. Genetic Selection and Populations ................................................................................................ 13 IV. Dog Breeds as Populations ............................................................................................................. 15 V. Canine Genetic Tests ...................................................................................................................... 16 a. Direct and Indirect Tests ................................................................................................................ 17 b. Single
    [Show full text]