HSPHSPand clinically heterogeneous group of disorders with aprevalence - PDF document

HSPHSPand clinically heterogeneous group of disorders with aprevalence ranging from 2.0 to 9.6 /100, 000. One form of HSPtransmitted in an autosomal dominant fashion and unassociatedwith other clinical features has been genetically linked to 2p21-p22. This disorderSPGSPGcause of HSP. instability of these repeats during intergenerational transmission. ABSTRACT: Clinical and genetic analysis of this family and the deletionmutation. In this family, the age of onset, which ranges from 3 to 50 years shows an averagemultiple family members indicates that all affected members carry the same c.1340_1344delTATAA In this family, other molecular mechanisms may PossibilitŽ dÕanticipation dans la paraplŽgie spastique hŽrŽditairPSG4PSG4 Objectif : PSHPSHnon compliquŽe et ce qui semble tre un phŽnomne dÕanticipation. LÕanalyse gŽnŽtique chez le cas index a montrŽdŽlŽtion de 5 paires de basesdŽlŽtion de 5 paires de basesՏspastine. Nous avons Žmis lÕhypothse que cette dŽlŽtion puisse tre dynamique et que la variabilitŽ de la taille de MŽthodes : Analyse clinique et gŽnŽtique de cettefamille et de sa mutation. RŽsultats : transmission sur trois gŽnŽrations, lÕ‰ge de dŽbut variant de 3 ˆ 50 ans. LÕanalyse gŽnŽtique effectuŽe chez plusieursc.1340_1344delTATAAqui nÕest pas dynamique. Conclusion : Il est possible quÕun autre mŽcanisme molŽculaire Can. J. Neurol. Sci. 2007; 34: 208-210 Possible Anticipation in HereditarySpastic Paraplegia TSPG4SPG4 P. Leema Reddy, William K. Seltzer, Raji P. Grewal PLR, RPGPLR, RPG,Edison, New Jersey; WKSWKSWorcester, Massachusetts, 21, 2006. A CCEPTEDINFINALFORM EBRUARY 9, 2007. Reprint requests to: Neuroscience Institute/JFK Medical Center, 65 James Street, Edison, New Jersey, RIGINALARTICLE We present a family with a genetically confirmed EPORT III-1, FigureIII-1, Figure-old woman who was KWWSVGRLRUJ6 3XEOLVKHGRQOLQHE\&DPEULGJH8QLYHUVLW\3UHVV symptoms. HoweverCase 3Case 3stiffness progressively worsened. Family history revealed thatdiplopia or difficulties with her bowel or bladder. Clinicalat the ankles. The plantar reflexes were extensor bilaterally andIII-3, FigureIII-3, Figure-old brother of the index,he was asymptomatic. He had worked as a roofer, an occupationflexors with no sensory disturbance. The re

flexes were brisk inCase 3 (IV-1, Figure), is 23-years-old and the only child ofwalk, his gait was clumsy. Further evaluation was performed atage three and he was diagnosed with spastic paraplegia. As hegrew older, he was unable to keep up with any physical activityaffected and their age of onset. Two members of generation II areIn addition, another member of generation IVis affected withage of onset in the first decade (Figure, IV-6). Although there isreliable family history of affected individuals earlier than Genetic analysis Direct testing of highly purified DNAsamples was performedautomated sequencing of both genomic DNAstrands for theGT/AG) for all exons in the SPG4 gene. Analysis of the SPG4TAA)mutation in exon 9 of the SPG4 gene. The DNAsequencing The affected members of this family have the typicalTAA) mutation in the SPG4 gene. ThismRNAresulting in premature protein truncation. Spasticparaplegia type 4 normally possesses 17 exons. This deletionalker motif B and the AAAminimal 1 It isunknown if this mutant spastin protein is stable, or is degradedimmediately upon translation. In either case, the spastin proteinis unlikely to be functional and therefore this mutation is a loss-of-function mutation leading to the above described phenotype.Previously reported deletion mutations of the SPG4 gene aredistributed throughout the gene and account for approximately23% of all spastin mutations. This is the fourth family that hasbeen reported with this specific mutation. Genetic anticipation with an earlier age of onset has beenobserved in some families with familial spastic paraparesis. Priorto the discovery of the SPG4 gene, a number of articles hadreported the possible existence of anticipation in SPG4 linked Pedigree of family with c.1340_1344delTATAAmutation with 7indicated. Squares represent males, circles females, diamonds unknown LE JOURNALCANADIEN DES SCIENCES NEUROLOGIQUES Volume 34, No. 2 Ð May 2007 KWWSVGRLRUJ6 3XEOLVKHGRQOLQHE\&DPEULGJH8QLYHUVLW\3UHVV CANADIAN JOURNALOF NEUROLOGICALSCIENCES There have also been some reports with thediscussion of anticipation in families with specific mutations inthis gene. this family, there is strong historical clinical evidence to supportits presence. In this family, the age of onset ranges between 3 toFigureFigureThe genetic analysis demonstrates that thec.1340_1344delTATAAmutation is not dynamic and does notHowever, there are other molecular mechanisms which couldcontribut

e to the development of anticipation. These include thepresence of intronic DNArepeat sequences that are often highlyexpression to varying degrees. Alternatively, other genes couldanticipation exists in this disorder. Confirmation of the presence 1.Silva MC, Coutinho P, Pinheiro CD, Neves JM, Serrano P.2.Polo JM, Calleja J, Combarros O, Berciano J. Hereditary ataxiasand paraplegias in Cantabria, Spain. An epidemiological andclinical study. Brain. 1991; 1Pt 2Pt 23.Hazan J, Fontaine B, Bruyn RP, Lamy C, van Deutekom JC, Rime4.Hazan J, Fonknechten N, Mavel D, Paternotte C, Samson D,Artiguenave F, et al. Spastin, a new AAAprotein, is altered in theFonknechten N, Mavel D, Byrne P, Davoine CS, Cruaud C, Bonsch7.Bruyn RP, van Deutekom J, Frants RR, Padberg GW. Hereditaryspastic paraparesis. Clinical and genetic data from a large Dutchfamily. Clin Neurol Neurosur228.Durr A, Davoine CS, Paternotte C, von Fellenberg J, CogiliniceanS, Coutinho P, et al. Phenotype of autosomal dominant spasticaraplegia linked to chromosome 2. Brain. 1996; 1Pt 5Pt 59.Nielsen JE, Koefoed P, Abell K, Hasholt L, Eiberg H, Fenger K, et1997; 6(11):1811-16. 10.Thurmon TF, He C, Haskell C, Thorpe P, Thurmon SG, Rosen DR.Genetic anticipation in a large family with pure autosomalominant hereditary spastic paraplegia. Am J Med Genet. 1999;11.Burger J, Fonknechten N, Hoeltzenbein M, Neumann L, Bratanoff E, Hazan J, et al. Hereditary spastic paraplegia caused12.Raskind WH, Pericak-Vance MA, Lennon F, Wolff J, Lipe HP, Birdheterogeneity, anticipation, and haplotype mapping of the SPG4locus on the short arm of chromosome 2. Am J Med Genet. 1997;13.Scott WK, Gaskell PC, Lennon F, Wolpert CM, Menold MM,Aylsworth AS, et al. Locus heterogeneity, anticipation and14.Matsuura T, Sasaki H, Wakisaka A, Hamada T, Moriwaka F, TashiroK. Autosomal dominant spastic paraplegia linked to chromo-some 2p: clinical and genetic studies of a large Japanese15.Namekawa M, Takiyama Y, Sakoe K, Nagaki H, Shimazaki H,Yoshimura M, et al. AJapanese SPG4 family with a novelage at onset and clinical severity. Acta Neurol Scand. 2002;16.Morita M, Ho M, Hosler BA, McKenna-Yasek D, Brown RH Jr. A17.Orlacchio A, Gaudiello F, Totaro A, Floris R, St George-Hyslop PH,Bernardi G, et al. Anew SPG4 mutation in a variant form ofspastic paraplegia with congenital arachnoid cysts. Neurology.18.Bonsch D, Schwindt A, Navratil P, Palm D, Neumann C, Klimpe S KWWSVGRLRUJ6 3XEOLVKHGRQOLQHE\&DPEULGJH8QLYHUVLW\3UHVV