|
Published online before print October 11, 2006, doi:10.1212/01.wnl.0000244413.49258.f5)
© 2006 American Academy of Neurology High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegiaFrom the Institut für Klinische Chemie und Laboratoriumsdiagnostik (C.B., J.S., T.D.), Universitätsklinikum Jena, Germany; MRC-Holland (A.N.), the Netherlands; Zentrum für Medizinische Forschung (M.A.), Medizinische Universität Graz, Austria; Institut für Hirnforschung (K.B.), Universität Tübingen, Germany; Klinik für Neurologie (G.H., O.W.), Universitätsklinikum Jena, Germany; Klinik und Poliklinik für Neurologie (S.K.), Johannes–-Gutenberg-Universität Mainz, Germany; Neurologische Klinik am Klinikum Großhadern (T.K.), Ludwig-Maximilians-Universität München, Germany; Klinikum Chemnitz GmbH (F.K.), Germany; Klinik für Neurologie (S.O.), Ruhr-Universität Bochum, Germany; Neurologische Klinik und Hertie-Institut für Klinische Hirnforschung (R.S., L.S.), Universität Tübingen, Germany; and Neurologische Klinik und Poliklinik (J.K, A.S.), Universität Ulm, Germany. Address correspondence and reprint requests to Dr. T. Deufel, Institut für Klinische Chemie und Laboratoriumsdiagnostik, Universitätsklinikum Jena, D-07740 Jena, Germany; e-mail: thomas.deufel{at}med.uni-jena.de Background: Hereditary spastic paraplegia (HSP) is a genetically heterogeneous neurodegenerative disease. The most frequent cause of autosomal dominant HSP is mutation of SPAST (SPG4 locus), but additional pedigrees remain mutation negative by conventional screening despite linkage to SPG4. Objective: To determine the frequency of genomic copy number aberrations of SPAST in autosomal dominant HSP. Methods: We developed and validated a multiplex ligation-dependent probe amplification assay targeting SPAST and SPG3A, another gene frequently involved in autosomal dominant HSP. In a multicenter study we subsequently investigated 65 index patients with autosomal dominant HSP, all of whom had previously been screened negative for SPAST mutations. Independent secondary samples, additional family members, and cDNA were analyzed to confirm positive findings. Results: Aberrant MLPA profiles were identified in 12 cases (18%). They exclusively affect SPAST, represent deletions, segregate with the disease, and are largely pedigree specific. Internal SPAST deletions entail expression of correspondingly shortened transcripts, which vary in stability. Age at onset in SPAST deletion carriers does not differ from that associated with other SPAST mutations. Conclusions: Partial SPAST deletions, but not SPAST amplifications and SPG3A copy number aberrations, represent an underestimated cause of autosomal dominant hereditary spastic paraplegia. Partial SPAST deletions are likely to act via haploinsufficiency.
Editorial, see page 1912 This article was previously published in electronic format as an Expedited E-Pub on October 11, 2006, at www.neurology.org. *These authors contributed equally to this work. Supported by the Bundesministerium für Bildung und Forschung (grant 01GM0304-GeNeMove), the European Union (grant FP6-2002-LIFESCIHEALTH, Spastic Models), the Interdisziplinäres Zentrum für Klinische Forschung of Medizinische Fakultät der Friedrich-Schiller-Universität Jena (grants T.P.1.10 and T.P.3.8), and the Tom-Wahlig-Stiftung (grant AZ JenaPROJ). Disclosure: The authors report no conflicts of interest. Received April 25, 2006. Accepted in final form July 28, 2006.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
