A Novel Presenilin-1 Mutation (Leu85Pro) in Early-Onset Alzheimer Disease With Spastic Paraparesis

Ataka, Suzuka; Tomiyama, Takami; Takuma, Hiroshi; Yamashita, Takenari; Shimada, Hiroyuki; Tsutada, Tsuyoshi; Kawabata, Koichi; Mori, Hiroshi; Miki, Takami

doi:10.1001/archneur.61.11.1773

Cited by 46 publications

(27 citation statements)

References 19 publications

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“…Typical sporadic AD rarely shows cerebellar ataxia and signs of pyramidal tract disturbances. Patients bearing presenilin-1 (PS-1) mutations exhibited spasticity of their legs, but they did not exhibit cerebellar ataxia [17]. Patients with spinocerebellar ataxia (SCA) showed not only spasticity and cerebellar ataxia, but also dementia [18,19,20,21,22].…”

Section: Discussionmentioning

confidence: 99%

Clinical Course of Patients with Familial Early-Onset Alzheimer’s Disease Potentially Lacking Senile Plaques Bearing the E693Δ Mutation in Amyloid Precursor Protein

Shimada

Ataka

Tomiyama

et al. 2011

Dement Geriatr Cogn Disord

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Background/Aims: Oligomeric amyloid β (Aβ) is currently considered to induce Alzheimer’s disease (AD). We examined 2 patients with familial AD who possessed the Osaka (E693Δ) mutation in amyloid precursor protein. To the best of our knowledge, these patients are the first AD cases presumably affected with Aβ oligomers in the absence of senile plaques, and they support the Aβ oligomer hypothesis. Methods: We evaluated the clinical course, neuropsychological data, cerebrospinal fluid biomarker levels, magnetic resonance imaging (MRI) scans, fluorodeoxyglucose-positron emission tomography (PET) scans, and Pittsburgh compound B (PiB)-PET images of these patients. Results: In the early stages, these patients developed memory disturbances in a similar rate to patients with sporadic AD. Despite their memory disturbances, both patients showed only limited brain atrophy on MRI and little amyloid accumulation on PiB-PET. Subsequent to the development of memory disturbances, both patients suffered from motor dysfunction, probably due to cerebellar ataxia, and, within a few years, the patients fell into an apallic state. Conclusions: Familial AD patients with Osaka (E693Δ) mutation show severe dementia, cerebellar ataxia, and gait disturbances.

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Section: Discussionmentioning

confidence: 99%

Clinical Course of Patients with Familial Early-Onset Alzheimer’s Disease Potentially Lacking Senile Plaques Bearing the E693Δ Mutation in Amyloid Precursor Protein

Shimada

Ataka

Tomiyama

et al. 2011

Dement Geriatr Cogn Disord

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“…There are also some family members with the mutation p.P117A [74,75], p.P117L [76][77][78] and p.L173W [79] have recently been recorded with onset at 24 years. Very early onset of cognitive decline, before age 30 years, has been noted with the following PSEN-1 mutations: p.L85P [80], p.T116N [81][82][83][84], p.P117S [77], p.I143T [82,83,[85][86][87], InsFI [82,88], p.L166H [89], p.S169L [90,91], p.S170F [92][93][94], p.G209V [95], p.M233V [96], p.M233I [97], p.L235Pr [98], p.Y256S [99], p.A260V [39,100], p.V272A [84,101], p.L381V [102], p.G384A [85], p.L424R [103], and p.A434C [82]. PSEN-1 mutations show almost complete penetrance by the age of 60 years.…”

Section: Aao and Penetrancementioning

confidence: 99%

“…Most patients with the exon 9 genomic deletion (Δ9) in the PSEN-1 gene shared this phenotype, however, there is an exception, the Δ9 (g.58304G>T) mutation [6,44,45]. Other PSEN-1 mutations with dementia and spastic paraparesis have subsequently been described: ΔI83/M84 [6,152], p.L85P [80], p.N135S [46,153], p.Y154N [154], InsFI [82,88], p.Q223R [155], p.F237I [156], p.V261L [157], p.V261P [82], p.P264L [158], p.G266S [159], p.R278K [160], p.R278S [161], p.E280G [83], p.P284S [162], p.L381V [102], and p.P436Q [6]. No family with mutations in either the APP gene or PSEN-2 gene was reported to have spastic paraparesis.…”

Section: Spastic Paraparesis/variant Admentioning

confidence: 99%

The Correlation between Genotype and Phenotype of Alzheimer's Disease

Li¹,

Jiang²,

Wu³

2018

J Alzheimers Dis Parkinsonism

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“…Otra mutación de la PS1 causante de EA precoz es la Leu85Pro, que se manifiesta por trastornos visuoespaciales y paraparesia espástica 19 . En Irlanda se encontró una mutación en el exón 8 E280G en la que tres miembros de una misma familia presentaban leucoaraiosis, paraparesia o cuadriparesia espástica, oftalmoplejía, ataxia, y angiopatía amiloide 20 .…”

Section: Enfermedad De Alzheimer Familiar Precozunclassified

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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A Novel Presenilin-1 Mutation (Leu85Pro) in Early-Onset Alzheimer Disease With Spastic Paraparesis

Abstract: To our knowledge, this is the first report of very early-onset Alzheimer disease with spastic paraparesis and with the visual variant form of the disease, which is associated with visuospatial cognitive disorder. The Leu85Pro mutation in PSEN1 was pathogenic.

Cited by 46 publications

References 19 publications

Clinical Course of Patients with Familial Early-Onset Alzheimer’s Disease Potentially Lacking Senile Plaques Bearing the E693Δ Mutation in Amyloid Precursor Protein

Clinical Course of Patients with Familial Early-Onset Alzheimer’s Disease Potentially Lacking Senile Plaques Bearing the E693Δ Mutation in Amyloid Precursor Protein

The Correlation between Genotype and Phenotype of Alzheimer's Disease

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

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