Hereditary Spastic Paraplegias (HSP) are a clinically and genetically heterogeneous group of neurodegenative disorders. The predominant symptom of HSP is the degeneration of upper motoneurons and their corticospinal tract axons. They are classified genetically into autosomal dominant (AD-HSP), autosomal recessive (AR-HSP), and X-linked HSP forms. The clinical classification may distinguish between pure and complicated forms of HSP based on the presence of neurological or non neurological symptoms associated to spasticity. The most common mutated gene in AR-HSP with Thin Corpus Callosum (TCC) cases is SPG11. Mutations in SPG4 gene are most common in AD-HSP but HSP-TCC and HSP with dementia too, while SPG7 gene is studied in AR-HSP pure or complicated with dementia. Alzheimer’s disease (AD), the most common form of dementia, is neuropathologically characterized by two types of brain lesions: neuritic plaques and neurofibrillary tangles. The amyloid β peptide (Aβ), the main component of the neuritic plaques, is generated by β- and γsecretase cleavage of the amyloid precursor protein (APP). There are two kinds of the onset: Alzheimer: Early Onset Alzheimer Disease (EOAD) and Late Onset Alzheimer Disease (LOAD), but exists.cases of family Alzheimer’s disease (FAD) inherited in an autosomal dominant pattern These patients carry mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2) genes. This study aims at genetic-molecular investigation of affected families by a complicated form of AR-HSP with thin corpus callosum (ARHSP-TCC), or dementia, apparently sporadic cases complicated with thin corpus callosum or dementia, cases of AD-HSP with dementia or TCC, affected families by Alzheimer’disease (EOAD and LOAD), and sporadic cases of Alzheimer’disease with SP phenotype. SPG11, SPG4, SPG7, PSEN1, PSEN2 and APP genes were studied to correlate AD and SP. The genetic-molecular-screening of SPG11 gene was based on HRM, CSCE, and direct sequencing techniques. These techniques was also used for the screening of other genes. The screening of the SPG11 gene on probands of the families ARHSP-TCC revealed 6 mutations already reported in literature. After that, the remaining families with AR-HSP, the apparently sporadic with dementia or TCC, and all described sporadic cases were analyzed for SPG7 gene. AD-HSP families, complicated by TCC, or dementia and negative apparently sporadic for AR-HSP were screened for SPG4 gene. Three probands’s AD-HSP were positive to mutational screening of the SPG4 gene: one complicated by dementia, one apparently sporadic HSP with dementia and one apparently sporadic HSP patient were positive to mutational screening of the gene SPG4; four identified mutations already reported in literature. The genetic-molecular-screening of SPG11 gene was based on HRM, CSCE, and direct sequencing techniques. These techniques was also used for the screening of other genes. The screening of the SPG11 gene on probands of the families ARHSP-TCC revealed 6 mutations already reported in literature. After that, the remaining families with AR-HSP, the apparently sporadic with dementia or TCC, and all described sporadic cases were analyzed for SPG7 gene. AD-HSP families, complicated by TCC, or dementia and negative apparently sporadic for AR-HSP were screened for SPG4 gene. Three probands’s AD-HSP were positive to mutational screening of the SPG4 gene: one complicated by dementia, one apparently sporadic HSP with dementia and one apparently sporadic HSP patient were positive to mutational screening of the gene SPG4; four identified mutations already reported in literature.
Le Paraparesi Spastiche Ereditarie (HSP) sono un gruppo di disordini neurodegenerativi clinicamente e geneticamente eterogeneo, che hanno come fattore comune il danneggiamento dei motoneuroni superiori e delle loro proiezioni assonali. Sulla base del meccanismo di trasmissione genetica le HSP possono essere classificate in autosomiche dominanti (AD-HSP), autosomiche recessive (AR-HSO) o X-linked. Dal punto di vista clinico, invece, le HSP possono essere suddivise in forme pure e complicate in base alla presenza o meno di sintomi neurologici o non neurologici associati alla spasticità. Il gene più comunemente mutato nei casi di AR-HSP con assottigliamento del corpo calloso (TCC) è SPG11, mutazioni nel gene SPG4 sono le cause più comuni di AD-HSP ma può essere associato anche a HSP-TCC e HSP associato a demenza, mentre il gene SPG7 è studiato per i casi di AR-HSP puri o complicati di demenza. La malattia di Alzheimer (AD) è la forma più comune di demenza, dal punto di vista neuropatologico è caratterizzata da due tipi di lesioni cerebrali: le placche neuritiche ed i grovigli neurofibrillari. Il peptide β amiloide (Aβ), il principale componente delle placche neuritiche, deriva dal taglio del precursore della proteina amiloide (APP) da parte della β- e γ-secretasi. Esistone due differenti tipi di esordio: malattia di Alzheimer ad esordio precoce (EOAD) e malattia di Alzheimer ad esordio tardivo (LOAD) ma esistono anche casi con storia familiare (FAD). Questi pazienti hanno mutazioni nel gene del precursore della proteina amiloide (APP), presenilina 1 (PSNE1) o presenilina 2 (PSEN2). Mutazioni del gene PSNE1 sono associate con malattia di Alzheimer, ma alcune famiglie sviluppano AD e SP con danni cerebrali caratterizzati da placche senili ed accumulo del peptide patogeno Aβ42. Il progetto di ricerca svolto prevedere tra gli obiettivi l'analisi genetico-molecolare di famiglie affette da una forma complicata di AR-HSP con assottigliamento del corpo calloso (ARHSP-TCC) o demenza; casi apparentemente sporadici complicati con TCC e demenza, casi di AD-HSP associati a demenza o a TCC, famiglie affette da malattia di Alzheimer ad esordio precoce e tardivo e casi sporadici di malattia di Alzheimer associati ad un fenotipo di Paraparesi Spastica sono stati studiati i geni geni SPG11, SPG4, SPG7, PSEN1, PSEN2 e APP. Lo screening genetico-molecolare del gene SPG11 è stato messo a punto con l’ausilio dell’ High Resolution Melting (HRM), la Conformation Sensitive Capillary Elettrophoresis (CSCE) e del sequenziamento diretto. Queste tecniche sono state applicate anche per lo screening degli altri geni. Lo screening del gene SPG11 sui probandi di famiglie ARHSP-TCC ha rivelato 6 mutazioni, di cui una non riportata in letteratura. In seguito, le restanti famiglie AR-HSP, i casi apparentemente sporadici con demenza e TCC, insieme a tutti i casi sopracitati sono stati analizzati per il geni SPG7, mentre le famiglie AD-HSP con fenotipo complicato da TCC o demenza e i casi apparentemente sporadici negativi all’indagine genetica dei geni causativi delle forme recessive di HSP, sono stati analizzati per il gene SPG4. Tre probandi di famiglie AD-HSP, di cui uno complicato da TCC, e un individuo con HSP apparentemente sporadica e HSP apparentemente sporadica complicata da demenza, sono risultati positivi allo screening mutazionale del gene SPG4; le quattro mutazioni identificate sono riportate in letteratura. Contrariamente, l’indagine per il gene SPG7 non ha evidenziato mutazioni patogenetiche, ma solo polimorfismi già noti in letteratura. Infine, i pazienti risultati negativi per i geni SPG11, SPG4 ed SPG7, ed i pazienti con diagnosi di malattia di Alzheimer con storia familiare e sporadici, con fenotipo riconducibile a Paraparesi Spastica, sono stati analizzati per i geni PSEN1, PSEN2 e APP. Questo screening ha evidenziato una mutazione del gene PSEN1, non riportata in letteratura, in un paziente FAD con fenotipo riconducibile ad SP, ad esordio tardivo per entrambe le malattie. L’indagine per il gene PSEN2 ha evidenziato solo polimorfismi noti, mentre lo screening del gene APP ha evidenziato una mutazione nota in letteratura, ma per la prima volta associata in un paziente con un fenotipo AD/SP. Il presente studio, conferma il ruolo eterogeneo delle HSP, in particolare, nel caso delle forme complicate e l’identificazione per la prima volta di una mutazione nel gene APP (V717I) in un paziente con Alzheimer e Paraparesi, suggerisce lo screening del gene APP nelle casistiche di AD con HSP.
Studi genetici in pazienti con malattia di Alzheimer e paraparesi spastica ereditaria
VARLESE, MARIA LAURA
2011
Abstract
Hereditary Spastic Paraplegias (HSP) are a clinically and genetically heterogeneous group of neurodegenative disorders. The predominant symptom of HSP is the degeneration of upper motoneurons and their corticospinal tract axons. They are classified genetically into autosomal dominant (AD-HSP), autosomal recessive (AR-HSP), and X-linked HSP forms. The clinical classification may distinguish between pure and complicated forms of HSP based on the presence of neurological or non neurological symptoms associated to spasticity. The most common mutated gene in AR-HSP with Thin Corpus Callosum (TCC) cases is SPG11. Mutations in SPG4 gene are most common in AD-HSP but HSP-TCC and HSP with dementia too, while SPG7 gene is studied in AR-HSP pure or complicated with dementia. Alzheimer’s disease (AD), the most common form of dementia, is neuropathologically characterized by two types of brain lesions: neuritic plaques and neurofibrillary tangles. The amyloid β peptide (Aβ), the main component of the neuritic plaques, is generated by β- and γsecretase cleavage of the amyloid precursor protein (APP). There are two kinds of the onset: Alzheimer: Early Onset Alzheimer Disease (EOAD) and Late Onset Alzheimer Disease (LOAD), but exists.cases of family Alzheimer’s disease (FAD) inherited in an autosomal dominant pattern These patients carry mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2) genes. This study aims at genetic-molecular investigation of affected families by a complicated form of AR-HSP with thin corpus callosum (ARHSP-TCC), or dementia, apparently sporadic cases complicated with thin corpus callosum or dementia, cases of AD-HSP with dementia or TCC, affected families by Alzheimer’disease (EOAD and LOAD), and sporadic cases of Alzheimer’disease with SP phenotype. SPG11, SPG4, SPG7, PSEN1, PSEN2 and APP genes were studied to correlate AD and SP. The genetic-molecular-screening of SPG11 gene was based on HRM, CSCE, and direct sequencing techniques. These techniques was also used for the screening of other genes. The screening of the SPG11 gene on probands of the families ARHSP-TCC revealed 6 mutations already reported in literature. After that, the remaining families with AR-HSP, the apparently sporadic with dementia or TCC, and all described sporadic cases were analyzed for SPG7 gene. AD-HSP families, complicated by TCC, or dementia and negative apparently sporadic for AR-HSP were screened for SPG4 gene. Three probands’s AD-HSP were positive to mutational screening of the SPG4 gene: one complicated by dementia, one apparently sporadic HSP with dementia and one apparently sporadic HSP patient were positive to mutational screening of the gene SPG4; four identified mutations already reported in literature. The genetic-molecular-screening of SPG11 gene was based on HRM, CSCE, and direct sequencing techniques. These techniques was also used for the screening of other genes. The screening of the SPG11 gene on probands of the families ARHSP-TCC revealed 6 mutations already reported in literature. After that, the remaining families with AR-HSP, the apparently sporadic with dementia or TCC, and all described sporadic cases were analyzed for SPG7 gene. AD-HSP families, complicated by TCC, or dementia and negative apparently sporadic for AR-HSP were screened for SPG4 gene. Three probands’s AD-HSP were positive to mutational screening of the SPG4 gene: one complicated by dementia, one apparently sporadic HSP with dementia and one apparently sporadic HSP patient were positive to mutational screening of the gene SPG4; four identified mutations already reported in literature.| File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.14242/197710
URN:NBN:IT:UNIROMA2-197710