Hereditary Spastic Paraparesis: Phenotypic Heterogeneity and Confirmation of the SPG11 Locus

Herediter spastik paraplejiler (HSP) üst motor nöron hastalıklarının genetik ve klinik olarak heterojen bir grubudur. HSP' nin temel özelliği alt eksremite güçsüzlüğü olmasına rağmen (komplike olamayan tip), bu hastalığın sekelleri ve klinik özellikleri demans, nöropati, retinopati, mental retardasyon ve nöbetler gibi diğer nörolojik bozuklukları kapsayabilir (komplike tip). Günümüze kadar, HSP'nin sorumlu nedeni olarak otozomal resesif, otozomal dominant veya X' e bağlı 56' dan fazla farklı genetik bölge ve 41 HSP ilişkili gen tanımlanmıştır. Kromozon 15q daki aynı zamanda SPG11 (OMIM 604360) olarak bilinen bir çeşit bölgenin, hastalığın ince korpus kallozumlu HSP ( HSP-TCC) olarak bilinen komplike otozomal resesif formuyla bağlantılı olduğu gösterilmiştir.Bu araştırmada, mental gerilik, epilepsi ve MRG' de ince korpus kallozumun eşlik ettiği otozomal resesif kalıtım gösteren HSP li Türkiyenin doğusundan yeni bir aile tanımlanmış ve klinik özellikleri tarif edilmiştir. Chip temelli SNP genotiplemesi kullanarak, kromozon 15q13-15' da SPG11 bölgesine bağlantı saptanmıştır. Aynı zamanda chip temelli kopya sayısı değişkenliği (CNV) analizi uygulanmıştır. Sonuçlarımız sadece SPG11 bölgesi ile ilişkili erken yaşta epilepsi ile başlayan fenotipik heterojeniteyi genişletmemiş, aynı zamanda 15q kromozomunun 13 Mbp aralığına bağlantıyıda doğrulamıştır. Bu veri, daha önceki çalışmalara eklendiğinde, SGP11'in fenotipik ve genotipik olarak heterojen hastalık olduğu gerçeğini desteklemektedir.

Herediter spastik paraparezi:Fenotipik heterojenite ve SPG11 lokusunun doğrulanması

Hereditary spastic paraplegias (HSPs) are a genetically and clinically heterogeneous group of upper motor neuron disorders. Although the primary feature of HSP is lower extremity weakness ("uncomplicated" form), sequelae and clinical features of this disorder may include other neurological deficits such as dementia, neuropathy, retinopathy, mental retardation, and seizures ("complicated" form). To date, more than 56 different genetic loci and 41 HSP-related genes have been described as causative for autosomal dominant, recessive or X-linked HSP. One such locus on chromosome 15q, also known as locus SPG11 (OMIM 604360), has been shown to link to a complicated autosomal recessive form of disease known as HSP with thin corpus callosum (HSP-TCC). Herein we describe the identification and clinical presentation of a new family from Eastern Turkey with autosomal recessive HSP associated with mental retardation, epilepsy and a thinned corpus callosum on MRI. Using array-based SNP genotyping, we demonstrate linkage to the SPG11 locus on chromosome 15q13-15. Array-based copy number variation (CNV) analysis was also performed. Our results not only expand the phenotypic heterogeneity associated with the SPG11 locus to include an earlier age of onset with epilepsy, but also confirm the linkage to a 13 Mbp interval on chromosome 15q. This data, when added to those previously reported, support the notion that SPG11 is a phenotypically and genetically heterogeneous disorder.

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Reid E. Many pathways lead to hereditary spastic paraplegia. Lancet neurology 2003;2(4):210.
Fink J.K. Hereditary spastic paraplegia. Current neurology and neuroscience reports 2006;6(1):65-76.
Fink J.K. The hereditary spastic paraplegias: nine genes and counting. Archives of neurology ;60(8):1045-9.
Gigli G.L, Diomedi M, Bernardi G, et al. Spastic paraplegia, epilepsy, and mental retardation in several members of a family: a novel genetic disorder. Am J Med Genet 1993;45(6):711-6.
Lo Nigro C, Cusano R, Gigli G.L, et al. Genetic heterogeneity in inherited spastic paraplegia associated with epilepsy. Am J Med Genet A 2003;117(2):116-21.
Stevanin G, Montagna G, Azzedine H, et al. 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 2006;7(3):149-56.
Olmez A, Uyanik G, Ozgul R.K, et al. Further clinical and genetic characterization of SPG11: hereditary spastic paraplegia with thin corpus callosum. Neuropediatrics 2006;37(2):59-66.
Lossos A, Stevanin G, Meiner V, et al. Hereditary spastic paraplegia with thin corpus callosum: reduction of the SPG11 interval and evidence for further genetic heterogeneity. Archives of neurology 2006;63(5):756-60.
Winner B, Uyanik G, Gross C, et al. Clinical progression and genetic analysis in hereditary spastic paraplegia with thin corpus callosum in spastic gait gene (SPG11). Archives of neurology 2004;61(1):117-21.
Casali C, Valente E.M, Bertini E, et al. Clinical and genetic studies in hereditary spastic paraplegia with thin corpus callosum. Neurology 2004;62(2):262-8.
Shibasaki Y, Tanaka H, Iwabuchi K, et al. Linkage of autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum to chromosome 15A13- 15. Ann Neurol 2000;48(1):108-12.
Martinez Murillo F, Kobayashi H, Pegoraro E, et al. Genetic localization of a new locus for recessive familial spastic paraparesis to 15q13-15. Neurology ;53(1):50-6.
Bell G.I, Karam J.H, Rutter W.J. Polymorphic DNA region adjacent to the 5' end of the human insulin gene. Proc Natl Acad Sci U S A 1981;78(9):5759-63.
Laurans M.S, DiLuna M/L, Shin D, et al. Mutational analysis of 206 families with cavernous malformations. Journal of neurosurgery 2003;99(1):38-43.
Nahed B.V, Seker A, Guclu B, et al. Mapping a Mendelian form of intracranial aneurysm to 1p34.3- p36.13. American journal of human genetics ;76(1):172-9.
Gudbjartsson D.F, Jonasson K, Frigge M.L, Kong A. Allegro, a new computer program for multipoint linkage analysis. Nature genetics 2000;25(1):12-3.
Elston R.C, Guo X, Williams L.V. Two-stage global search designs for linkage analysis using pairs of affected relatives. Genet Epidemiol 1996;13(6):535-58.
Workman C, Jensen L.J, Jarmer H, et al. A new non- linear normalization method for reducing variability in DNA microarray experiments. Genome biology 2002;3 (9):research0048.
Olshen A.B, Venkatraman E.S, Lucito R, Wigler M. Circular binary segmentation for the analysis of array- based DNA copy number data. Biostatistics: Oxford, England 2004;5(4):557-72.
Dixon W.J. Analysis of extreme values. Annals of Mathmatics and Statistics 1950;21(4):488-506.
Nakamura A, Izumi K, Umehara F, et al. Familial spastic paraplegia with mental impairment and thin corpus callosum. J Neurol Sci 1995;131(1):35-42.
Ueda M, Katayama Y, Kamiya T, et al. Hereditary spastic paraplegia with a thin corpus callosum and thalamic involvement in Japan. Neurology 1998;51(6):1751-4.
Iwabuchi K, Kubota Y, Hanihara T, Nagatomo H. [Three patients of complicated form of autosomal recessive hereditary spastic paraplegia associated with hypoplasia of the corpus callosum]. No to shinkei 1994;46(10):941-7.
Kallioniemi A, Kallioniemi O.P, Sudar D, et al. Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science ;258(5083):818-21.
Pinkel D, Segraves R, Sudar D, et al. High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nature genetics ;20(2):207-11.
Pollack J.R, Perou C.M, Alizadeh A.A, et al. Genome- wide analysis of DNA copy- number changes using cDNA microarrays. Nature genetics 1999;23(1):41-6.
Solinas-Toldo S, Lampel S, Stilgenbauer S, et al. Matrix-based comparative genomic hybridization: biochips to screen for genomic imbalances. Genes, chromosomes & cancer 1997;20(4):399-407.
Hentati A, Ouahchi K, Pericak-Vance M.A, et al. Linkage of a commoner form of recessive amyotrophic lateral sclerosis to chromosome 15q15-q22 markers. Neurogenetics 1998;2(1):55-60.
Eymard-Pierre E, Lesca G, Dollet S, et al. Infantile- onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene. American journal of human genetics 2002;71(3):518-27.