Herediter spastik paraparezi:Fenotipik heterojenite ve SPG11 lokusunun doğrulanması

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.

Anahtar Kelimeler:

Herediter spastik paraparezi, Mikro-chip-SPG11-kromozom 15, Bağlantı analizi

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

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 HSPwith 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.

Keywords:

SPG11, Chromosome 15 Linkage analysis, hereditary spastic paraparesis, Microarray,

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