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Published online before print October 11, 2006, doi:10.1212/01.wnl.0000244413.49258.f5)
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Received April 25, 2006
Accepted July 28, 2006

High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegia

C. Beetz PhD, A. O.H. Nygren , J. Schickel PhD, M. Auer-Grumbach MD, K. Bürk MD, G. Heide MD, J. Kassubek MD, S. Klimpe MD, T. Klopstock MD, F. Kreuz MD, S. Otto MD, R. Schüle MD, L. Schöls MD, A.-D. Sperfeld MD, O. W. Witte MD, and T. Deufel MD*

From 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 Gro{beta}hadern (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.


* To whom correspondence should be addressed. 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.




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