Correlating Familial Alzheimer's Disease Gene Mutations with Clinical Phenotype

Ryan, Natalie S.; Rossor, Martin N.

doi:10.2217/bmm.09.92

Cited by 157 publications

(147 citation statements)

References 79 publications

(94 reference statements)

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“…Mutaciones en el cromosoma 1, como las Y231C, M239V y T122R 24 , son causales de EA, y los afectados pueden presentar un cuadro demencial en el que se hay alteraciones neuroconductuales y parkinsonismo, al igual que en las mutaciones PS2A85V y A85V 25 .…”

Section: Enfermedad De Alzheimer Familiar Precozunclassified

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Descripción genotípica y fenotípica de la enfermedad de Alzheimer tardía y familiar precoz: revisión

Castrillón¹,

Jiménez²,

Restrepo³

et al. 2015

MedUPB

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RESUMENLa demencia es la pérdida de varias áreas del funcionamiento cognitivo respecto al nivel premórbido, con deterioro significativo en la funcionalidad. La más común es ocasionada por la enfermedad de Alzheimer, que se define como un trastorno neurodegenerativo que produce una alteración progresiva de la memoria y de otras habilidades mentales, por una pérdida de volumen en los lóbulos temporales, en especial en las áreas mediales como el hipocampo y la corteza entorrinal. Menos del 5% de los pacientes con esta enfermedad presenta formas hereditarias que pueden tener un inicio precoz (antes de los 65 años) o tardío (después de dicha edad). La EA precoz presenta un patrón de herencia autosómico dominante y puede ser causado por mutaciones en el gen de la proteína precursora de amiloide, en presenilina-1 o presenilina-2. Los casos de EA tardía, están influenciados por una genética compleja, con múltiples factores de susceptibilidad y el alelo ApoE4 es el principal y más reconocido. La EA es una enfermedad heterogénea tanto en su genotipo como en su fenotipo que varían en cuanto a intensidad y tipo de síntomas, edad de inicio y severidad de la demencia, de acuerdo con las mutaciones que el paciente presenta y su interacción con factores ambientales.

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Section: Enfermedad De Alzheimer Familiar Precozunclassified

“…Sumado a los trastornos cognitivos, es frecuente encontrar alteraciones neuroconductuales y parkinsonismo 24 .…”

Section: Descripción Fenotípicaunclassified

Descripción genotípica y fenotípica de la enfermedad de Alzheimer tardía y familiar precoz: revisión

Castrillón¹,

Jiménez²,

Restrepo³

et al. 2015

MedUPB

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“…Clinical studies indicated that many patients with FAD mutations in PS1 display significant phenotypic heterogeneity, including variable age of onset, penetrance, myoclonus and seizures, Parkinsonism, apraxia/ataxia, FTD and psychiatric symptoms [73][74][75]. There are also variations in PS1-FAD neuropathology.…”

Section: Er Ca 2+ Leak and Variant Admentioning

confidence: 99%

“…There are also variations in PS1-FAD neuropathology. For instance, greater NFT formation, altered amyloid β plaque composition, hippocampal sclerosis, the appearance of Pick bodies and neuropathological involvement of the basal ganglia and/or brainstem [73][74][75]. An intriguing subset of PS1-FAD patients manifest symptoms of spastic paraparesis (SP, known as variant AD), or progressive spasticity of the lower limbs [73][74][75][76].…”

Section: Er Ca 2+ Leak and Variant Admentioning

confidence: 99%

“…It is believed that the accumulation of CWP plaques in the basal ganglia, brainstem and spinal cord is responsible for the Parkinsonism and spastic phenotypes clinically observed in these patients. The reasons for these unique clinical and pathological phenotypes observed in these PS1-FAD pedigrees are not understood [8,[73][74][75]80,81]. Could this variant AD somehow be explained by the altered ER Ca 2+ signaling caused by PS1-FAD mutations?…”

Section: Er Ca 2+ Leak and Variant Admentioning

confidence: 99%

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Presenilins as endoplasmic reticulum calcium leak channels and Alzheimer’s disease pathogenesis

Supnet

Bezprozvanny

2011

Sci. China Life Sci.

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Alzheimer disease (AD) is the most common neurodegenerative disorder worldwide and is at present, incurable. The accumulation of toxic amyloid-beta (Aβ) peptide aggregates in AD brain is thought to trigger the extensive synaptic loss and neurodegeneration linked to cognitive decline, an idea that underlies the 'amyloid hypothesis' of AD etiology in both the familal (FAD) and sporadic forms of the disease. Genetic mutations causing FAD also result in the dysregulation of neuronal calcium (Ca 2+ ) handling and may contribute to AD pathogenesis, an idea termed the 'calcium hypothesis' of AD. Mutations in presenilin proteins account for majority of FAD cases. Presenilins function as catalytic subunit of γ-secretase involved in generation of Aβ peptide Recently, we discovered that presenilns function as low-conductance, passive ER Ca 2+ leak channels, independent of γ-secretase activity. We further discovered that many FAD mutations in presenilins result in loss of ER Ca 2+ leak function activity and Ca 2+ overload in the ER. These results provided potential explanation for abnormal Ca 2+ signaling observed in FAD cells with mutations in presenilns. Our latest work on studies of ER Ca 2+ leak channel function of presenilins and implications of these findings for understanding AD pathogenesis are discussed in this article.

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Functional Connectivity in Autosomal Dominant and Late-Onset Alzheimer Disease

et al. 2014

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IMPORTANCE Autosomal dominant Alzheimer disease (ADAD) is caused by rare genetic mutations in 3 specific genes in contrast to late-onset Alzheimer disease (LOAD), which has a more polygenetic risk profile.OBJECTIVE To assess the similarities and differences in functional connectivity changes owing to ADAD and LOAD. DESIGN, SETTING, AND PARTICIPANTSWe analyzed functional connectivity in multiple brain resting state networks (RSNs) in a cross-sectional cohort of participants with ADAD (n = 79) and LOAD (n = 444), using resting-state functional connectivity magnetic resonance imaging at multiple international academic sites. MAIN OUTCOMES AND MEASURESFor both types of AD, we quantified and compared functional connectivity changes in RSNs as a function of dementia severity measured by the Clinical Dementia Rating Scale. In ADAD, we qualitatively investigated functional connectivity changes with respect to estimated years from onset of symptoms within 5 RSNs. RESULTSA decrease in functional connectivity with increasing Clinical Dementia Rating scores were similar for both LOAD and ADAD in multiple RSNs. Ordinal logistic regression models constructed in one type of Alzheimer disease accurately predicted clinical dementia rating scores in the other, further demonstrating the similarity of functional connectivity loss in each disease type. Among participants with ADAD, functional connectivity in multiple RSNs appeared qualitatively lower in asymptomatic mutation carriers near their anticipated age of symptom onset compared with asymptomatic mutation noncarriers. CONCLUSIONS AND RELEVANCEResting-state functional connectivity magnetic resonance imaging changes with progressing AD severity are similar between ADAD and LOAD. Resting-state functional connectivity magnetic resonance imaging may be a useful end point for LOAD and ADAD therapy trials. Moreover, the disease process of ADAD may be an effective model for the LOAD disease process.

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Correlating Familial Alzheimer's Disease Gene Mutations with Clinical Phenotype

Cited by 157 publications

References 79 publications

Descripción genotípica y fenotípica de la enfermedad de Alzheimer tardía y familiar precoz: revisión

Descripción genotípica y fenotípica de la enfermedad de Alzheimer tardía y familiar precoz: revisión

Presenilins as endoplasmic reticulum calcium leak channels and Alzheimer’s disease pathogenesis

Functional Connectivity in Autosomal Dominant and Late-Onset Alzheimer Disease

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