Hereditary Spastic Paraplegia (HSP) refers to a group of disorders characterized by progressive lower extremity spastic weakness. Beginning in childhood, adolescence, or adulthood, walking becomes progressively impaired, wheelchairs are often required, and urinary bladder disturbance and other neurologic deficits may occur. Neuropathologic studies show degeneration at the distal ends of the longest axons in the central nervous system: the descending terminals of the corticospinal tracts and ascending terminals of fasciculus gracilus. HSP may be inherited as an autosomal dominant, recessive, or X-linked trait, each of which is genetically heterogeneous. Until recently, the cause of autosomal dominant and autosomal recessive HSP was completely unknown. In Preliminary Data, we present the discovery of a gene for autosomal recessive spastic paraplegia. Co-Investigator, Dr. Ballabio and his colleagues discovered mutations in a novel gene (paraplegin) on chromosome l6q in patients with """"""""pure"""""""" and """"""""complicated"""""""" autosomal recessive HSP as well as in many patients with """"""""apparently sporadic HSP"""""""". This landmark discovery greatly advances our understanding of this degenerative spinal cord disease. We present in Preliminary Data, for example, that paraplegin is homologous to yeast mitochondrial metalloproteases AFG3, RCA1, and YME1 and that abnormal mitochondrial histochemistry is evident in muscle biopsy in patients with paraplegin gene mutations. Dr. Ballabio and his colleagues also identified structurally similar paraplegia-related genes. These are candidate genes for autosomal recessive HSP not linked to chromosome 16q and for """"""""apparently sporadic HSP"""""""". We will extend these discoveries by addressing the following questions. 1) How frequent are paraplegin gene mutations in autosomal recessive and """"""""apparently sporadic HSP""""""""? 2) Do different paraplegin gene mutations produce different clinical patterns? 3) Are there mutations in paraplegin-related genes in autosomal recessive and apparently sporadic HSP? 4) Is abnormal mitochondria structure or function a common feature of genetically diverse types of HSP? This proposal unites three groups of investigators with diverse expertise. The Principal Investigator, Dr. John Fink, has extensive experience evaluating HSP, has ascertained more than 140 HSP kindreds, and has expertise identifying mutations in genes responsible for inherited neurologic disorders. Co-investigator Dr. Ballabio identified not only the paraplegin gene but 3 other structurally homologous members of this gene family. Dr. Ballabio will determine the precise genetic location, complete cDNA sequence, and genomic organization of these candidate genes. Dr. Fink will determine the presence of paraplegin and paraplegin-related gene mutations in HSP subjects and correlate these mutations with phenotypic patterns. Co-investigator Dr. Salvatore DiMauro, an expert in clinical and biochemical analysis of mitochondrial abnormalities, will perform biochemical, histologic, and ultrastructural analysis of mitochondria in skin fibroblast and muscle biopsies from HSP patients. These findings will be correlated with paraplegin and paraplegin-related gene analysis and with phenotypic patterns of HSP. Through this collaborative project, we will learn not only the frequency of paraplegin and paraplegin-related gene mutations in HSP, but also whether mitochondrial disturbance is a common mechanism underlying genetically diverse types of HSP. This insight will facilitate identification of candidate genes for other genetic forms of HSP. Currently, paraplegin gene analysis can be used to diagnose some forms of autosomal recessive HSP. Our research will extend this ability to diagnose HSP (by muscle biopsy and/or by the presence of paraplegin-related gene mutation). Greater understanding of HSP's pathophysiology will provide insights into possible therapy for this paralyzing disorder and hopefully into the molecular basis and ultimately treatments for other degenerative neurologic disorders including amyotrophic lateral sclerosis.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Mammalian Genetics Study Section (MGN)
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Gwinn, Katrina
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
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Fink, John K (2006) Hereditary spastic paraplegia. Curr Neurol Neurosci Rep 6:65-76
Rainier, Shirley; Sher, Carron; Reish, Orit et al. (2006) De novo occurrence of novel SPG3A/atlastin mutation presenting as cerebral palsy. Arch Neurol 63:445-7
Moretti, Paolo; Hedera, Peter; Wald, John et al. (2005) Autosomal recessive primary generalized dystonia in two siblings from a consanguineous family. Mov Disord 20:245-7
Hedera, P; Eldevik, O P; Maly, P et al. (2005) Spinal cord magnetic resonance imaging in autosomal dominant hereditary spastic paraplegia. Neuroradiology 47:730-4
Lorincz, Matthew T; Rainier, Shirley; Thomas, Donald et al. (2005) Cerebrotendinous xanthomatosis: possible higher prevalence than previously recognized. Arch Neurol 62:1459-63
Chen, Dong-Hui; Matsushita, Mark; Rainier, Shirley et al. (2005) Presence of alanine-to-valine substitutions in myofibrillogenesis regulator 1 in paroxysmal nonkinesigenic dyskinesia: confirmation in 2 kindreds. Arch Neurol 62:597-600
Rainier, Shirley; Thomas, Donald; Tokarz, Debra et al. (2004) Myofibrillogenesis regulator 1 gene mutations cause paroxysmal dystonic choreoathetosis. Arch Neurol 61:1025-9
Meredith, Christopher; Herrmann, Ralf; Parry, Cheryl et al. (2004) Mutations in the slow skeletal muscle fiber myosin heavy chain gene (MYH7) cause laing early-onset distal myopathy (MPD1). Am J Hum Genet 75:703-8
Ferreirinha, Fatima; Quattrini, Angelo; Pirozzi, Marinella et al. (2004) Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport. J Clin Invest 113:231-42
Hedera, Peter; Petty, Elizabeth M; Bui, Melanie R et al. (2003) The second kindred with autosomal dominant distal myopathy linked to chromosome 14q: genetic and clinical analysis. Arch Neurol 60:1321-5

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