This investigation will advance our knowledge of inherited and degenerative brain and spinal cord disorders. Familial Spastic Paraparesis (FSP) includes a group of clinically and genetically diverse disorders that share progressive lower extremity spasticity beginning in childhood, adolescence or adulthood. Walking is progressively impaired, wheelchairs are often required, and urinary bladder disturbance and other neurologic deficits may occur. Neuropathologic studies show greatest degeneration in distal portions of the longest axons in the central nervous system: descending terminals of corticospinal tracts and ascending terminals of fasciculus gracilus. The underlying molecular basis of FSP is not known and specific treatments are not available. Genetic linkage analysis and positional cloning hold exciting promise for understanding the pathophysiology of FSP and related neurodegenerative disorders. Recently, autosomal dominant FSP was shown to be genetically heterogeneous. The disorder was tightly linked to chromosome 14q 11.2 in an extended French kindred. This locus was in other FSP families. We established an inter- institutional, multidisciplinary investigation aimed at defining the phenotypic spectrum of FSP and genetic mapping and positional cloning of FSP genes. We have evaluated more than 10 FSP kindreds in our Neurogenetic Disorders Clinic. This investigation will define the clinical spectrum of autosomal dominant FSP by performing detailed neurologic, neuro-ophthalmologic, electrophysiologic and neuro-imaging evaluations of FSP patients from a total of 22 kindreds. 126 members of one autosomal dominant FSP kindred including 32 living affected subjects were examined and videotaped. Using genetic linkage analysis, chromosome l4ql I .2 (the F5P1 locusl was excluded as the disease locus. A genome- wide search for the disease locus in this family was initiated in collaboration with the University of Utah Human Genome Center. Identifying the chromosomal locus and subsequently the gene responsible for FSP in this kindred will greatly advance our understanding of FSP. This information will permit accurate genetic counseling and diagnosis and facilitate the rationale design of treatments to prevent, retard or reverse this debilitating condition. Moreover, understanding the molecular basis of FSP will provide important insight into the pathophysiology of other inherited and degenerative brain and spinal cord disorders particularly those characterized by axonal degeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS033645-03
Application #
2333010
Study Section
Neurology A Study Section (NEUA)
Program Officer
Spinella, Giovanna M
Project Start
1995-03-01
Project End
1999-01-31
Budget Start
1997-02-01
Budget End
1998-01-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Neurology
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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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
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
Fink, John K (2003) The hereditary spastic paraplegias: nine genes and counting. Arch Neurol 60:1045-9
Rainier, Shirley; Chai, Jing-Hua; Tokarz, Debra et al. (2003) NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6). Am J Hum Genet 73:967-71

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