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

Year 2015, Volume: 12 Issue: 2, 230 - 239, 30.08.2015

Zülfikar Arlier

Abstract

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

Herediter spastik paraparezi:Fenotipik heterojenite ve SPG11 lokusunun doğrulanması

Abstract

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.

Keywords

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

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