intergenerational contractions of the CTG repeat - ResearchGate

INTERGENERATIONAL CONTRACTION OF THE CTG REPEATS IN 2FAMILIES WITH MYOTONIC DYSTROPHY TYPE 1Jack Puymirat, Yves Giguère, Jean Mathieu and Jean-Pierre BouchardNeurology 2009;73;2126-2127DOI: 10.1212/WNL.0b013e3181c677e1This information is current as of January 5, 2010The online version of this article, along with updated information and services, islocated on the World Wide Web at:http://www.neurology.org/cgi/content/full/73/24/2126Neurology® is the official journal of the American Academy of Neurology. Published continuouslysince 1951, it is now a weekly with 48 issues per year. Copyright © 2009 by AAN Enterprises, Inc.All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.Downloaded from www.neurology.org at CHUQ PAV ST FRANCOIS D'ASSISE on January 5, 2010

carrying a splice acceptor site mutation (IVS9-2AT) inALS2 causes infantile-onset ascending spastic paralysis(IAHSP). Neurogenetics 2009;10:59–64.5. Mintchev N, Zamba-Papanicolaou E, Kleopa KA, et al. Anovel ALS2 splice-site mutation in a Cypriot juvenileonsetprimary lateral sclerosis family. Neurology 2009;72:28–32.6. Kress JA, Kuhnlein P, Winter P, et al. Novel mutation inthe ALS2 gene in juvenile amyotrophic lateral sclerosis.Ann Neurol 2005;58:800–803.7. Eymard-Pierre E, Yamanaka K, Haeussler M, et al. Novelmissense mutation in ALS2 gene results in infantile ascendinghereditary spastic paralysis. Ann Neurol 2006;59:976–980.Jack Puymirat, MD, PhDYves Giguère, MD, PhDJean Mathieu, MD, MScJean-Pierre Bouchard,MD, FRCPCINTERGENERATIONAL CONTRACTION OF THECTG REPEATS IN 2 FAMILIES WITH MYOTONICDYSTROPHY TYPE 1Myotonic dystrophy type 1 (DM1) is an autosomaldominant multisystemic disorder caused by the expansionof an unstable CTG trinucleotide repeat atchromosome region 19q13.3. 1 The number of CTGrepeats is unstable in the abnormal range and usuallyincreases in size in successive generations, in associationwith anticipation. 2,3 A decrease in the CTG repeatsize during transmission from parents to childcan also occur in about 6.4% of transmissions,most frequently during paternal transmissions(10%). 4 In the French-Canadian DM1 population,intergenerational contractions occur in about7.4% of transmissions, all in cases of paternaltransmission. We report here 2 French-CanadianDM1 families with paternal transmission, bothoriginating from the Saguenay-Lac St-Jean, inwhich all affected children display CTG contractions.Although it was already reported that intergenerationalcontractions could be observed inseveral sibs in a same family, it was not notedwhether this occurred in all affected sibs. 4 Overall,these observations support the existence of a paternalfactor that prevents CTG expansion.Case reports. The pedigree of the 2 families andSouthern blot analysis are shown in the figure.Family A. No clinical information was available forI-1. II-4 was diagnosed with DM1 at age 38. He hadthe classic manifestations of the disease with distalmuscle weakness and wasting, myotonia, and cataracts,with a Muscular Impairment Rating Scale(MIRS) of 3. 5 Molecular analysis by Southern blotrevealed a CTG repeat size of about 500. His son anddaughter were evaluated at age 32 and 36. The sonFigureFamily tree and Southern blotPedigree of family (A, B). (C, D) Southern blot analysis. The DNA (3–5 g) was digested with EcoRV/HindIII, electrophoresed on 0.8% agarose gels, transferredonto nylon membrane (Hybond, Amersham), and probed overnight with radiolabeled FNU428 probe, as previously described. 7 The sizes of hybridizedfragments were determined from the autoradiographs containing the 1 kb DNA ladder (N32325, New England Biolabs) as markers.2126 Neurology 73 December 15, 2009Downloaded from www.neurology.org at CHUQ PAV ST FRANCOIS D'ASSISE on January 5, 2010

had myotonia and hypersomnia but no muscle weakness,whereas the daughter was clinically asymptomatic,with an MIRS of 1. Molecular analysis revealeda CTG repeat size of 360 and 260 repeats for theson and the daughter. The brother of II-4, II-5was diagnosed with DM1 at age 48. He had muscleweakness and wasting, myotonia, a first-degreeheart block, and cataracts, which had been extractedat age 30. The MIRS was 4. Molecularanalysis revealed a CTG repeat size of 630. His sonand daughter were diagnosed with DM1 at age 25and 27. Both were clinically asymptomatic, with aMIRS of 1. Molecular analysis revealed a CTGrepeat size of 260 repeats for both children. A newevaluation of the daughter at age 42 revealed thatshe was still clinically asymptomatic.Family B. I-1 was diagnosed with DM1 at age 50.He had the classic manifestations of the disease withdistal muscle weakness and wasting, myotonia, cataracts,and an MIRS of 3. Molecular analysis revealeda CTG repeat size of 500. I-1 had 4 affected childrenwho were diagnosed with DM1 at age 30, 34, 35,and 36. All were clinically asymptomatic with anMIRS of 1. Molecular analysis revealed a CTGrepeat size of 250 for all 4 children. Subjects II-5and II-6 both have 2 affected children. All wereclinically asymptomatic with a CTG repeat size of210 at age 10 (III-9), 5 (III-10), 7 (III-12), and 5(III-13).Discussion. We report 2 DM1 families with paternaltransmission in which a CTG repeat size contractionwas observed in all affected descendants. Infamily A, the contraction was observed in all affectedchildren from 2 branches and, in family B, a contractionwas observed in all affected children and hasremained stable in the next generation. There is onlyone reported case in which a CTG repeat size contractionin one child was associated with a concomitantexpansion in the brother, during paternaltransmission. 6 In this latter study, however, a possiblebias may exist because of the weak differences inthe size of the CTG repeats between the father andthe children (833 for the father and 500, 667, and1,000 for the children) and because the molecularanalysis was performed at different times.This observation raises the possibility that, incases of paternal transmission, when a contraction isobserved in a sibling, intergenerational contractionscould be observed in all affected sibs, in differentbranches of the same family, and could remain stableacross further generations. Because this is of majorimportance for genetic counseling, this needs to beconfirmed in a large number of similar families.From the Departments of Human Genetics (J.P.) and Medical Biology(Y.G.), Centre Hospitalier Universitaire de Quebec; NeuromuscularClinic (J.M.), Carrefour de Santé de Jonquière, Quebec; andthe Department of Neurological Sciences (J.-P.B.), Hôpital del’Enfant-Jésus, Quebec, Canada.Disclosure: Dr. Puymirat reports no disclosures. Dr. Bouchardserved on a scientific advisory board for Merck Serono; served as aconsultant for Teva Pharmaceutical Industries Ltd.; and has receivedresearch support from Sanofi-Aventis and Biogen Idec. Drs.Mathieu and Giguere report no disclosures.Received January 12, 2009. Accepted in final form September 23, 2009.Address correspondence and reprint requests to Dr. Jack Puymirat,Department of Human Genetics, CHUQ, 2705 Blvd Laurier,Quebec, G1V4G2, Canada; Jack.Puymirat@crchul.ulaval.caCopyright © 2009 by AAN Enterprises, Inc.1. Harper PS. Myotonic Dystrophy. London: W.B. Saunders;2001.2. Hunter A, Tsilfidis C, Mettler G, et al. The correlation ofage of onset with CTG trinucleotide repeat amplificationin myotonic dystrophy. J Med Genet 1992;29:774–779.3. de Die-Smulders CE, Höweler CJ, Mirandolle JF, et al.Anticipation resulting in elimination of the myotonic dystrophygene: a follow up study of one extended family.J Med Genet 1994;31:595–601.4. Ashizawa T, Anvret M, Baiget M, et al. Characteristics ofintergenerational contractions of the CTG repeat in myotonicdystrophy. Am J Hum Genet 1994;54:414–423.5. Mathieu J, Boivin H, Meunier D, Gaudreault M, Bégin P.Assessment of a disease-specific muscular impairment ratingscale in myotonic dystrophy. Neurology 2001;56:336–340.6. López de Munain A, Cobo AM, Sáenz A, et al. Frequencyof intergenerational contractions of the CTG repeats inmyotonic dystrophy. Genet Epidemiol 1996;13:483–487.7. Arsenault E, Prevost C, Lescault A, Laberge C, Puymirat J,Mathieu J. Clinical characteristics of myotonic dystrophytype 1 patients with small CTG expansions. Neurology2006;66:1248–1250.H. Cario, MDH. Bode, MDK.-M. Debatin, MDT. Opladen, MDK. Schwarz, MDSupplemental data atwww.neurology.orgCONGENITAL NULL MUTATIONS OF THEFOLR1 GENE: A PROGRESSIVE NEUROLOGICDISEASE AND ITS TREATMENTFolate-receptor alpha (FOLR1) is of central importancefor folate transport across the blood–brain barrier viathe choroid plexus. Autoantibodies against folate receptorswere identified as the cause of the infantile-onsetcerebral folate deficiency (CFD) syndrome. 1 In addition,FOLR1 is important for neural tube closure duringembryogenesis. 2,3 Here we report siblings withcompound heterozygosity for 2 FOLR1 mutationscausing congenital CFD.Clinical presentation. A 5-year-old boy developednormally until the age of 30 months. Thereafter,resting and intention tremor evolved, followed byataxia, progressive speech disturbances and loss ofmotor capabilities, general hypotonia, apathy, andNeurology 73 December 15, 2009 2127Downloaded from www.neurology.org at CHUQ PAV ST FRANCOIS D'ASSISE on January 5, 2010

INTERGENERATIONAL CONTRACTION OF THE CTG REPEATS IN 2FAMILIES WITH MYOTONIC DYSTROPHY TYPE 1Jack Puymirat, Yves Giguère, Jean Mathieu and Jean-Pierre BouchardNeurology 2009;73;2126-2127DOI: 10.1212/WNL.0b013e3181c677e1This information is current as of January 5, 2010Updated Information& ServicesSubspecialty CollectionsPermissions & LicensingReprintsincluding high-resolution figures, can be found at:http://www.neurology.org/cgi/content/full/73/24/2126This article, along with others on similar topics, appears in thefollowing collection(s):All Neuromuscular Diseasehttp://www.neurology.org/cgi/collection/all_neuromuscular_disease Muscle diseasehttp://www.neurology.org/cgi/collection/muscle_disease Naturalhistory studies (prognosis)http://www.neurology.org/cgi/collection/natural_history_studies_prognosis All Geneticshttp://www.neurology.org/cgi/collection/all_geneticsTrinucleotide repeat diseaseshttp://www.neurology.org/cgi/collection/trinucleotide_repeat_diseasesInformation about reproducing this article in parts (figures, tables)or in its entirety can be found online at:http://www.neurology.org/misc/Permissions.shtmlInformation about ordering reprints can be found online:http://www.neurology.org/misc/reprints.shtmlDownloaded from www.neurology.org at CHUQ PAV ST FRANCOIS D'ASSISE on January 5, 2010