A. GABRIELE

A. MAGARIELLO

A. PATITUCCI

A. QUATTRONE

A. TESSITORE

C. UNGARO

F. BONO

FL CONFORTI

G. MAJORANA

G. TEDESCHI

IL SIMONE

L. CITRIGNO

LA BELLA, Vincenzo

M. MUGLIA

MR MONSURRÒ

P. VALENTINO

R. MAZZEI

S. ZOCCOLELLA

T. SPROVIERI

Archivio istituzionale della ricerca - Università di Palermo

  PLEASE SCROLL DOWN FOR ARTICLEThis article was downloaded by: [Fondazione Salvatore Maugeri]On: 27 February 2009Access details: Access Details: [subscription number 788991605]Publisher Informa HealthcareInforma Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,37-41 Mortimer Street, London W1T 3JH, UKAmyotrophic Lateral SclerosisPublication details, including instructions for authors and subscription information:http://www.informaworld.com/smpp/title~content=t713656198Further evidence that D90A-SOD1 mutation is recessively inherited in ALSpatients in ItalyFrancesca Luisa Conforti a; Teresa Sprovieri a; Rosalucia Mazzei a; Alessandra Patitucci a; Carmine Ungaro a;Stefano Zoccolella b; Angela Magariello a; Vincenzo La Bella c; Alessandro Tessitore d; Gioacchino Tedeschi d;Isa Laura Simone b; Giovanni Majorana e; Paola Valentino f; Luigi Citrigno a; Annalia Gabriele a; FrancescoBono f; Maria Rosaria Monsurrò d; Maria Muglia a; Aldo Quattrone afa From the Institute of Neurological Sciences, National Research Council, Mangone, Cosenza b Department ofNeurological and Psychiatric Sciences, University of Bari, Bari c Department of Neurology and Psychiatry,University of Palermo, Palermo d Second Division of Neurology, Second University of Naples, Naples eDepartment of Neurosciences, Psychiatric and Anaesthesiological Sciences, University of Messina, Messina fInstitute of Neurology, University Magna Graecia, Catanzaro, ItalyFirst Published:February2009To cite this Article Luisa Conforti, Francesca, Sprovieri, Teresa, Mazzei, Rosalucia, Patitucci, Alessandra, Ungaro, Carmine,Zoccolella, Stefano, Magariello, Angela, Bella, Vincenzo La, Tessitore, Alessandro, Tedeschi, Gioacchino, Simone, Isa Laura,Majorana, Giovanni, Valentino, Paola, Citrigno, Luigi, Gabriele, Annalia, Bono, Francesco, Monsurrò, Maria Rosaria, Muglia, Mariaand Quattrone, Aldo(2009)'Further evidence that D90A-SOD1 mutation is recessively inherited in ALS patients in Italy',AmyotrophicLateral Sclerosis,10:1,58 — 60To link to this Article: DOI: 10.1080/17482960802163853URL: http://dx.doi.org/10.1080/17482960802163853Full terms and conditions of use: http://www.informaworld.com/terms-and-conditions-of-access.pdfThis article may be used for research, teaching and private study purposes. Any substantial orsystematic reproduction, re-distribution, re-selling, loan or sub-licensing, systematic supply ordistribution in any form to anyone is expressly forbidden.The publisher does not give any warranty express or implied or make any representation that the contentswill be complete or accurate or up to date. The accuracy of any instructions, formulae and drug dosesshould be independently verified with primary sources. The publisher shall not be liable for any loss,actions, claims, proceedings, demand or costs or damages whatsoever or howsoever caused arising directlyor indirectly in connection with or arising out of the use of this material.SHORT NOTEFurther evidence that D90A-SOD1 mutation is recessively inherited inALS patients in ItalyFRANCESCA LUISA CONFORTI1, TERESA SPROVIERI1, ROSALUCIA MAZZEI1,ALESSANDRA PATITUCCI1, CARMINE UNGARO1, STEFANO ZOCCOLELLA2,ANGELA MAGARIELLO1, VINCENZO LA BELLA3, ALESSANDRO TESSITORE4,GIOACCHINO TEDESCHI4, ISA LAURA SIMONE2, GIOVANNI MAJORANA5,PAOLA VALENTINO6, LUIGI CITRIGNO1, ANNALIA GABRIELE1,FRANCESCO BONO6, MARIA ROSARIA MONSURRO`4, MARIA MUGLIA1 &ALDO QUATTRONE1,6From the 1Institute of Neurological Sciences, National Research Council, Mangone, Cosenza, 2Department of Neurologicaland Psychiatric Sciences, University of Bari, Bari, 3Department of Neurology and Psychiatry, University of Palermo,Palermo, 4Second Division of Neurology, Second University of Naples, Naples, 5Department of Neurosciences, Psychiatric andAnaesthesiological Sciences, University of Messina, Messina, and 6Institute of Neurology, University Magna Graecia,Catanzaro, ItalyAbstractMutations in the Cu/Zn superoxide dismutase 1 (SOD1) gene have been reported to cause adult-onset autosomal dominantamyotrophic lateral sclerosis (FALS). In sporadic cases (SALS), de novo mutations in the SOD1 gene have occasionallybeen observed. All the SOD1 mutations are autosomal dominantly inherited with the exception of D90A. To date, in Italy,only two sporadic ALS cases carrying the D90A mutation have been reported in a homozygous state. We investigated for thepresence of this mutation in 169 unrelated ALS patients from southern Italy. The genetic analysis revealed three ALSpatients (1.8%) with mild phenotype carrying the homozygous D90A mutation.IntroductionAbout 3% of cases of amyotrophic lateral sclerosis(ALS), a fatal adult-onset motor neuron degenera-tion, are due to mutations in the Cu/Zn superoxidedismutase (SOD1) gene. All the SOD1 mutationsare autosomal dominantly inherited with the excep-tion of Asp90Ala (D90A), very common in theScandinavian population, and Asp96Asn (D96N)which can act as recessive (1,2). Only a few cases ofD90A heterozygous ALS in non-Scandinavian pa-tients have been reported, all of them inherited as adominant trait (3,4). To date, only two Italiansporadic ALS (SALS) cases associated with thehomozygous D90A mutation, one from Tuscanyand one from southern Italy, have been reported(3). The aim of this study is to investigate further thepresence of the D90A mutation in ALS patients insouthern Italy.Materials and methodsOne hundred and sixty-three unrelated CaucasianALS patients (eight familial ALS and 155 sporadiccases, 84 men and 79 women; mean age 54.52 years,SD 12.14), from southern Italy were screened forD90A-SOD1 mutations in exon 4. All studiedpatients were diagnosed with ALS according torevised El Escorial criteria. Samples were also takenfrom 150 controls, matched for age, sex andgeographical region. All participants gave theirwritten informed consent, and DNA extraction andgenotyping was performed by standard protocols.Results and discussionIn our study, of all patients investigated three ALScases (1.8%, 2 FALS and 1 SALS) showed thehomozygous D90A mutation in the SOD1 geneCorrespondence: F. L. Conforti, Institute of Neurological Sciences, CNR, C. da Burga, Mangone, 87050 (Cosenza), Italy. Fax: 39 0984 969306. E-mail:fl.conforti@isn.cnr.itAmyotrophic Lateral Sclerosis. 2009; 10: 5860ISSN 1748-2968 print/ISSN 1471-180X online # 2009 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS)DOI: 10.1080/17482960802163853Downloaded By: [Fondazione Salvatore Maugeri] At: 14:43 27 February 2009(Figure 1). In particular, two out of three patientsshared the over-represented D90A Scandinavianhaplotype (4) for three markers (D21S223,D21S63 and D21S261).Furthermore, the screening for D90A-SOD1mutations in more than 150 healthy subjects didnot reveal any heterozygous individual. This findingis in accordance with the data of the low frequency ofthe D90A mutation (0.05%) previously reportedelsewhere (4).The phenotype of D90A-SOD1-ALS describedin the previous studies seems to be associated withits mode of transmission because all ALS patientshomozygous for the D90A showed a phenotypecharacterized by slow progression of the disease,mean survival of 13 years, with a predominantlylower motor neuron and lower limb form of ALS atonset of the disease. By contrast, when D90A ispathogenic in the heterozygous state, the firstsymptoms can occur in any territory and diseaseprogression can be more rapid (1,4). Consistent withprevious findings, our patients showed a mildphenotype (clinical description in Table I).A previous study suggested an explanation forthe recessive and the dominant inheritance of theD90A mutation, and the different expressed pheno-type (4). A single ancient founder was shown forboth D90A-SOD1 recessive and dominant ALSfamilies and it was proposed that a second disease-modifying mutation arose in a more restricted regionacross the SOD1 gene in the recessive allele. Thisdisease modifier could reduce the transcription ofD90A SOD1 in motor neurons and, probably, insubjects carrying the recessive haplotype two copiesare required to cause disease. On this basis, it isconceivable that D90A homozygotes can showprolonged survival in contrast to the dose dependentprogression of disease demonstrated in mutantSOD1 transgenic mice.In conclusion, our study gives further evidencefor autosomal recessive ALS in Italian patients,confirming that the phenotypic characteristics ofthe homozygous D90A associated ALS closelyresemble those already described in recessiveD90A patients from Sweden and Finland.Declaration of interest: The authors report noconflicts of interest. The authors alone are respon-sible for the content and writing of the paper.Figure 1. Sequence electropherograms of the PCR products ofexon 4. The arrows in the figures indicate: A) Normal sequence;B) D90A heterozygous sequence; C) D90A homozygoussequence. D) Fnu4HI digestion of the PCR product of exon4: lane 1 undigested PCR product, lanes 23 normal subjects, lane4 heterozygous unaffected subject, and lane 5 homozygousaffected subject.Figure 1 (Continued)D90A mutation and ALS 59Downloaded By: [Fondazione Salvatore Maugeri] At: 14:43 27 February 2009References1. Andersen PM, Nilsson P, Ala-Hurula V, Kera¨nen ML,Tarvainen I, Haltia T, et al. Amyotrophic lateral sclerosisassociated with homozygosity for an Asp90Ala mutation in Cu/Zn superoxide dismutase. Nat Genet. 1995;10:616.2. Gellera C, Castellotti B, Riggio MC, Silani V, Morandi L,Testa D, et al. Superoxide dismutase gene mutations in Italianpatients with familial and sporadic amyotrophic lateral sclero-sis: identification of three novel missense mutations. Neuro-muscul Disord. 2001;11:40410.3. Battistini S, Giannini F, Greco G, Bibbo` G, Ferrera L, MariniV, et al. SOD1 mutations in amyotrophic lateral sclerosis.Results from a multicentre Italian study. J Neurol. 2005;252:7828.4. Parton MJ, Broom W, Andersen PM, Al-Chalabi A, NigelLeigh P, Powell JF, et al. D90A-SOD1 mediated amyotrophiclateral sclerosis: a single founder for all cases with evidence fora cis-acting disease modifier in the recessive haplotype. HumMutat. 2002;20:473.Table I. Clinical features of ALS patients carrying D90A SOD1-gene mutation.Patients SexFALS/SALSAge atonsetSite ofonsetPredomiance of upper/lower motor neuronsALS/FRS NEE NCSDiseasecourse1 M FALS 49 Weakness of distallower limbsCompulsivelaughing andcryingLower motor neuron 16/40 f/psw in upperand lower limbmusclesNormal Slowlyprogressive2 F FALS 68 Weakness of distallower limbsLower motor neuron 20/40 f/psw in upperand lower limbmusclesNormal Slowlyprogressive3 M SALS 32 Weakness of distallower limbsLower motor neuron 25/40 f/psw in upperand lower limbmusclesNormal SlowlyprogressiveFALS, familial amyotrophic lateral sclerosis; SALS, sporadic amyotrophic lateral sclerosis; ALS/FRS, ALS functional rating scale scores;NEE, needle electrode examination; f, fibrillation; psw, positive sharp wave; NCS, nerve conduction studies.60 F. L. Conforti et al.Downloaded By: [Fondazione Salvatore Maugeri] At: 14:43 27 February 2009

FURTHER EVIDENCE THAT D90A-SOD1 MUTATION IS RECESSIVELY INHERITED IN
ALS PATIENTS IN ITALY

https://iris.unipa.it/retrieve/handle/10447/50642/22349/ALS%20other%20MND%20-%202009.pdf

FURTHER EVIDENCE THAT D90A-SOD1 MUTATION IS RECESSIVELY INHERITED IN ALS PATIENTS IN ITALY

Abstract

Similar works

Full text

Available Versions

Archivio istituzionale della ricerca - Università di Palermo