A Novel Splice Site Mutation in the SPG7 Gene Causing Widespread Fiber Damage in Homozygous and Heterozygous Subjects Tobias Warnecke, MD, 1 * Thomas Duning, MD, 1 Anja Schirmacher, PhD, 1 Siawoosh Mohammadi, PhD, 1 Wolfram Schwindt, MD, 2 Hubertus Lohmann, PhD, 1 Rainer Dziewas, MD, 1 Michael Deppe, PhD, 1 E. Bernd Ringelstein, MD, 1 and Peter Young, MD 1 * 1 Department of Neurology, University Hospital of Mu¨nster, Mu¨nster, Germany 2 Department of Clinical Radiology, University Hospital of Mu¨nster, Mu¨nster, Germany Abstract: Hereditary spastic paraplegias (HSP) are geneti- cally and clinically heterogeneous neurodegenerative disorders. The purpose of this study was to assess the genotype and phe- notype in a family with a complicated form of autosomal re- cessive hereditary spastic paraplegia (ARHSP). Neurological and neuropsychological evaluation, neurophysiologic studies, fiberoptic endoscopic evaluation of swallowing (FEES), neuro- imaging analysis including diffusion tensor imaging (DTI), and mutation analysis of SPG4 and SPG7 gene were per- formed. The index case (mother) was affected by an adult- onset form of complicated ARHSP due to the homozygous splice site mutation c.155211G>T in the SPG7 gene. This mutation leads to an abnormally spliced mRNA lacking exon 11. Additional clinical features were bilateral ptosis and subtle deficits in executive function. All three asymptomatic daugh- ters carried the sequence variation c.155211G>T in hetero- zygous state. DTI of the mother revealed disturbance of white matter (WM) integrity in the left frontal lobe, the left cortico- spinal tract and both sides of the brainstem. DTI of the daugh- ters showed subtle WM alteration in the frontal corpus cal- losum. The novel mutation is the first splice site mutation found in the SPG7 gene. It removes part of the AAA domain of paraplegin protein, probably leading to a loss-of-function of the paraplegin-AFG3L2 complex in the mitochondrial inner membrane. The pattern of WM damage in the homozygote index case may be specific for SPG7-HSP. The detection of cerebral WM alterations in the corpus callosum of asymptom- atic heterozygote carriers confirms this brain region as the most prominent and early location of fiber damage in ARHSP. Ó 2010 Movement Disorder Society Key words: hereditary spastic paraplegia; SPG7; splice site mutation; white matter damage; diffusion tensor imaging Hereditary spastic paraplegias (HSP) are a group of clinically and genetically heterogeneous neurodegener- ative disorders. 1,2 HSP phenotypes are clinically di- vided in pure and complicated forms. The pure forms are defined by the presence of a progressive spastic paraparesis optionally accompanied by urinary urgency and minor sensory findings in the lower limbs. In case of additional clinical features such as dementia, dys- arthria, dysphagia, muscular atrophy, or epileptic seiz- ures HSP is classified as complicated. 3 HSP can be inherited as an autosomal dominant, recessive, or X- linked recessive trait and at least 45 genetic loci (SPG1-45) have been mapped and 17 genes identified so far. 4,5 Mutations in the SPG7 gene, mapped to Chromo- some 16q24.3, are responsible for autosomal recessive HSP (ARHSP) forms leading to both pure and compli- cated phenotypes. 6 SPG7 comprises 17 exons spanning 52 kilobases and encodes the protein paraplegin, which is a mitochondrial metalloprotease belonging to the AAA (ATPases associated with diverse cellular activities) family that shares a common ATPase do- main and plays an important role in diverse cellular processes including membrane trafficking, intracellular motility, organelle biogenesis, protein folding, and pro- *Correspondence to: Dr. Peter Young, Department of Neurology, University Hospital of Mu ¨nster, Albert-Schweitzer-Strasse 33, 48129 Mu ¨nster, Germany. E-mail: young@uni-muenster.de The first two authors contributed equally to this work. Potential conflict of interest: Nothing to report. Received 23 September 2009; Revised 4 November 2009; Accepted 12 November 2009 Published online 27 January 2010 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22949 413 Movement Disorders Vol. 25, No. 4, 2010, pp. 413–420 Ó 2010 Movement Disorder Society