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Bibliografia
1) Bouslam, N.; Benomar, A.; Azzedine, et al.. Mapping of a new form of pure autosomal recessive spastic paraplegia (SPG28). Ann. Neurol. 57: 567-571, 2005.
2) Blumen SC, Bevan S, Abu-Mouch S, et al. A locus for complicated hereditary spastic paraplegia maps to chromosome 1q24-q32. Ann Neurol 2003;54:796-803.
3) Casali C, Valente EM, Bertini E, et al. Clinical and genetic studies in Hereditary spastic paraparesis with thin corpus callosum. Neurology 2004;62:262-268.
4) Casari G, De Fusco M, Ciarmatori S, et al. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 1998;93:973-983
5) Crosby AH, Proukakis C. Is the transportation highway the right road for hereditary spastic paraplegia? Am J Hum Genet. 2002 ;71:1009-1016
6) De Michele G, De Fusco M, Cavalcanti F, et al. A new locus for autosomal recessive hereditary spastic paraplegia maps to chromosome 16q24.3. Am J Hum Genet 1998;63:135-139
7) De Stefano N, Matthews PM, Arnold DL (1995) Reversible decreases in N-Acetylaspartate after acute brain injury. Magn. Reson. Med. 34, 721-727
8) Filla A, De Michele G, Marconi R, et al. Prevalence of hereditary ataxias and spastic paraplegias in Molise, a region of Italy. J Neurol 1992;239:351-3
9) Fink JK. Hereditary spastic paraplegia. Neurol Clin 2002;20: 711-726
10) Fu L, Wolfson C, Worsley KJ, De Stefano N, Collins DL, Narayanan S, Arnold DL. Statistics for investigation of multimodal MR imaging data and an application to multiple sclerosis patients. NMR Biomed. 1996;9:339-46.
11) Hentati A, Pericak-Vance MA, Hung WY, et al. Linkage of 'pure' autosomal recessive familial spastic paraplegia to chromosome 8 markers and evidence of genetic locus heterogeneity. Hum Mol Genet 1994;3:1263-7
12) Hodgkinson CA, Bohlega S, Abu-Amero SN, et al. A novel form of autosomal recessive pure hereditary spastic paraplegia maps to chromosome 13q14. Neurology 2002;59:1905-1909
13) Hughes CA, Byrne PC, Webb S, et al. SPG15, a new locus for autosomal recessive complicated HSP on chromosome 14q. Neurology 2001;56:1230-1233
14) Klebe S, Azzedine H, Durr A, et al. Autosomal recessive spastic paraplegia (SPG30) with mild ataxia and sensory neuropathy maps to chromosome 2q37.3. Brain. 2006.
15) Lossos A, Stevanin G, Meiner V, et al. 2006. Hereditary spastic paraplegia with thin corpus callosum: reduction of the SPG11 interval and evidence for further genetic heterogeneity. Arch Neurol in press
16) Martinez Murillo F, Kobayashi H, Pegoraro E, et al. Genetic localization of a new locus for recesive familial spastic paraparesis to 15q13-15. Neurology 1999;53:50-56
17) Meijer IA, Cossette P, Roussel J, et al. A novel locus for pure recessive hereditary spastic paraplegia maps to 10q22.1-10q24.1. Ann Neurol. 2004;56:579-82
18) Orlacchio A, Kawarai T, Totaro A, et al.. Hereditary spastic paraplegia: clinical genetic study of 15 families. Arch Neurol 2004;61: 849-855
19) Patel H, Cross H, Proukakis C, et al. SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia Nat Genet 2002;31:347-348
20) Reddy H. Narayanan S, Woolrich M et al. (2002)Functional brain reorganization for hand movement in patients with multiple sclerosis: defining distinct effects of injury and disability. Brain 125:2646-2657
21) Reid E. Many pathways lead to hereditary spastic paraplegia. Lancet Neurol 2003;2:210
Seri M, Cusano R, Forabosco P, et al. Genetic mapping to 10q23.3-q24.2, in a large Italian pedigree, of a new syndrome showing bilateral cataracts, gastroesophageal reflux, and spastic paraparesis with amyotrophy. Am J Hum Genet 1999;64:586-593
22) Shibasaki Y, Tanaka H, Iwabuki K, et al. Linkage of autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum to chromosome 15q13-15. Ann Neurol 2000;48:108-112.
23) Simpson MA, Cross H, Proukakis C, et al. Maspardin is mutated in mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia. Am J Hum Genet 2003;73:1147-56.
24) Smith SM, Zhang Y, Jenkinson M, Chen J, Matthews PM, Federico A, De Stefano N. (2002). Accurate, robust and automated longitudinal and cross-sectional brain change analysis. Neuroimage 17 , 479-489
25) Stevanin G, Montagna G, Azzadine H, et al. 2006. Spastic paraplegia with thin corpus callosum: description of 20 new families, refinement of the SPG11 locus, candidate gene analysis and evidence of genetic heterogeneity. Neurogenetics in press
26) Tang BS, Chen X, Zhao GH, et al. 2004. Clinical features of hereditary spastic paraplegia with thin corpus callosum: report of 5 Chinese cases. Chin Med J (Engl). 117:1002-1005
27) Teive HA, Iwamoto FM, Della Coletta MV, et al. 2001. Hereditary spastic paraplegia associated with thin corpus callosum. Arq Neuropsiquiatr 59:790–792
28) Vazza G, Zortea M, Boaretto F, et al. A new locus for autosomal recessive spastic paraplegia associated with mental retardation and distal motor neuropathy, SPG14, maps to chromosome 3q27-q28. Am J Hum Genet 2000;67:504-509
29) Wilkinson PA, Simpson MA, Bastaki L, et al. A new locus for autosomal recessive complicated hereditary spastic paraplegia (SPG26) maps to chromosome 12p11.1-12q14. J Med Genet. 2005;42:80-2
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Keywords
HEREDITARY SPASTIC PARAPLEGIA, SPG11, DATABASE AND DNA BANK, LINKAGE ANALYSIS, MUTATIONAL ANALYSIS, NEUROIMAGING, FUNCTIONAL STUDIES OF SPATACSIN, GENOTYPE-PHENOTYPE RELATIONSHIP

Hereditary spastic paraplegias: a genetic, functional and clinical study

Università degli Studi di Napoli "Federico II"
Abstract
Hereditary spastic paraplegias are a heterogeneous group of neurodegenerative disorders clinically characterized by progressive weakness and spasticity at lower limbs, and, from a pathologic point of view from axonal degeneration of the longest descending and ascending tracts in the spinal cord. The molecular genetics demonstrated an unexpected genetic heterogeneity. Fourtheen autosomal recessive, 12 autosomal dominant and three X-linked forms have been identified. Moreover, eleven genes have been cloned (three for the AR HSP, six for AD HSP and two for the X-linked forms).
The third locus to be identified for autosomal recessive spastic paraplegia (ARHSP), SPG11, was initially mapped on chromosome 15q13-15 in a group of families with heterogeneous origins and forms of spastic paraplegia, including two families with thin corpus callosum (TCC, Martinez-Murillo et al 1999). Subsequent reports confirmed that this region on chromosome 15 contained at least one disease-gene for ARHSP-TCC in families from various ethnic origins, initially from Japan (Shibasaki et al 2000), and then from southern Europe and the Mediterranean basin (Casali et al 2004; Winner et al 2004; Lossos et al 2006 in press) or elsewhere (Tang et al 2004, Teive et al 2001). We have further narrowed the SPG11 chromosomal interval (Stevanin et al 2006, unpublished) and very recently identified the disease gene in this clinical entity (Santorelli and Stevanin, unpublished).
Specific objectives are >>>

Principal Investigator
Alessandro Filla Università degli Studi di NAPOLI "Federico II"
Research Objectives
The third locus to be identified for autosomal recessive spastic paraplegia (ARHSP), SPG11, was initially mapped on chromosome 15q13-15 in a group of families with heterogeneous origins and forms of spastic paraplegia, including two families with thin corpus callosum (TCC, Martinez-Murillo et al 1999). Subsequent reports confirmed that this region on chromosome 15 contained at least one disease-gene for ARHSP-TCC in families from various ethnic origins, initially from Japan (Shibasaki et al 2000), and then from southern Europe and the Mediterranean basin (Casali et al 2004; Winner et al 2004; Lossos et al 2006 in press) or elsewhere (Tang et al 2004, Teive et al 2001). We have further narrowed the SPG11 chromosomal interval (Stevanin et al 2006, unpublished) and very recently identified the disease gene in this clinical entity (Santorelli and Stevanin, unpublished). Our goals involve clinical and molecular genetic studies in order to identify the spectrum and frequency of mutations in the SPG11 gene, and to establish more complete genotype/phenotype correlations.
The project will thus be based on the pursuit of following aims:
1) Identification and sampling of further patients with ARHSP-TCC, and their clinical assessment.
2) Database and DNA bank for ARHSP-TCC patients.
3) Linkage study of new ARHPSP-TCC to SPG11.
4) Molecular analyses to determine the relative frequencies and the spectrum of SPG11 mutations in ARHSP-TCC families, in other >>>

Timescale
24 months
National and international background
The hereditary spastic paraplegias (HSP), also referred to as Strümpell-Lorrain disease, are a heterogeneous group of neurodegenerative disorders characterized by progressive weakness and spasticity at the lower limbs.
The pathological hallmark of the disease is the degeneration of the corticospinal tract. These axons are exceptionally long, in some cases over one meter, with axonal volumes that can be up to one thousand times the volume of the cell body. Corticospinal tract neurones therefore provide an extreme example of the difficulties encountered in diverse cellular processes, such as trafficking, transport, and energy metabolism.
HSP are clinically and genetically heterogeneous. From a clinical point of view progressive spasticity may occur isolated (pure or uncomplicated HSP) or associated with other neurologic and extra-neurologic abnormalities (complicated HSP), including optic neuropathy, retinopathy, cataract, extrapyramidal features, dementia, mental retardation, epilepsy, ataxia, deafness, skin pigmentation abnormalities, ichthyosis, gastroesophageal reflux, and skeletal abnormalities.
Molecular genetics demonstrated an unexpected heterogeneity in SPastic paraplegia (SPG). Fourteen segregate as AR (SPG5A, 7, 11, 14-15, 20-21, 23-28, 30), 12 as AD (SPG3A, 4, 6, 8-10, 12-13, 17, 19, 29, 12q), and three as X-linked (SPG1-2, 16; Reid 2003). The prevalent phenotype in AD-HSP is that of pure spastic paraplegias, whereas the AR and the X-linked >>>