Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene

Poorkaj, Parvoneh; Sharma, Vikram; Anderson, Leojean; Nemens, Ellen; Alonso, Ma Elias; Orr, Harry T.; White, June A.; Heston, Leonard L.; Bird, Thomas D.; Schellenberg, Gerard D.

doi:10.1002/(sici)1098-1004(1998)11:3<216::aid-humu6>3.0.co;2-f

Cited by 54 publications

(19 citation statements)

References 34 publications

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“…A further sequence variant, C263F, occurred at a residue where mutations have previously been reported. 29 The level of penetrance and mechanism of pathogenicity remain to be determined for the novel sequence variants described here. 21 Mutations of APP and PSEN1 show almost complete penetrance by the age of 60 years with the exception of four PSEN1 missense mutations: A79V, 11 I143F, 27 H163Y, 28 and H163R.…”

Section: Methodsmentioning

confidence: 99%

Early onset familial Alzheimer’s disease

Janssen

Beck²,

Campbell³

et al. 2003

Neurology

283

179

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Section: Methodsmentioning

confidence: 99%

Early onset familial Alzheimer’s disease

Janssen

Beck²,

Campbell³

et al. 2003

Neurology

283

179

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“…e A426P mutation kindred (Poorkaj et al, 1998). AP-C indicates the noncarrier sibling control subject.…”

Section: Human Subjectsmentioning

confidence: 99%

“…In this study, we used PiB-PET amyloid imaging to study both asymptomatic and mildly symptomatic individuals from two unrelated pedigrees who carry different mutations in the PS1 gene [i.e., a cysteine to tyrosine mutation at position 410 of the PS1 protein (C410Y) (Campion et al, 1995;Sherrington et al, 1995) or an alanine to proline mutation at position 426 (A426P) (Poorkaj et al, 1998)]. This baseline data are intended to serve as the initial time point in a longitudinal natural history study.…”

Section: Introductionmentioning

confidence: 99%

Amyloid Deposition Begins in the Striatum of Presenilin-1 Mutation Carriers from Two Unrelated Pedigrees

Klunk¹,

Price²,

Mathis³

et al. 2007

Journal of Neuroscience

374

333

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The amyloid cascade hypothesis suggests that the aggregation and deposition of amyloid-␤ protein is an initiating event in Alzheimer's disease (AD). Using amyloid imaging technology, such as the positron emission tomography (PET) agent Pittsburgh compound-B (PiB), it is possible to explore the natural history of preclinical amyloid deposition in people at high risk for AD. With this goal in mind, asymptomatic (n ϭ 5) and symptomatic (n ϭ 5) carriers of presenilin-1 (PS1) mutations (C410Y or A426P) that lead to early-onset AD and noncarrier controls from both kindreds (n ϭ 2) were studied with PiB-PET imaging and compared with sporadic AD subjects (n ϭ 12) and controls from the general population (n ϭ 18). We found intense and focal PiB retention in the striatum of all 10 PS1 mutation carriers studied (ages 35-49 years). In most PS1 mutation carriers, there also were increases in PiB retention compared with controls in cortical brain areas, but these increases were not as great as those observed in sporadic AD subjects. The two PS1 mutation carriers with a clinical diagnosis of early-onset AD did not show the typical regional pattern of PiB retention observed in sporadic AD. Postmortem evaluation of tissue from two parents of PS1C410Y subjects in this study confirmed extensive striatal amyloid deposition, along with typical cortical deposition. The early, focal striatal amyloid deposition observed in these PS1 mutation carriers is often is not associated with clinical symptoms.

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“…4 5 Surprisingly, the P264L mutation found in our family has been described in several families with Alzheimer's disease, but never in association with spastic paraparesis. 9 10 It seems unlikely, however, that this association resulted from random association in four family members. Alternatively, two gene defects, the P264L PSEN1 mutation and another mutation responsible for spastic paraplegia, might segregate in the family.…”

mentioning

confidence: 99%

Spastic paraparesis and atypical dementia caused by PSEN1 mutation (P264L), responsible for Alzheimer's disease

Jacquemont¹

2002

Journal of Medical Genetics

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A lzheimer's disease, the most common cause of dementia in later life, is genetically heterogeneous. Mutations in three genes encoding the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are responsible for autosomal dominant early onset cases. A few families have been described in which PSEN1 mutations, usually exon 9 deletions, cause progressive dementia associated with spastic paraparesis. [1][2][3][4][5] We present a family in which another PSEN1 mutation causes disease that begins with spastic paraparesis and is associated with dementia that is not of the Alzheimer type.The index case first presented at the age of 54 with lower back pain and gait difficulties; he was unable to squat unaided and walked with caution. He complained of a memory deficit that he attributed to the Algerian war, 34 years ago. On examination, he had brisk reflexes in all four limbs and normal muscle tone. Blood cell counts, CSF glucose and protein levels, electromyography, and nerve conduction velocity were unremarkable. A lumbar CT scan and cervicothoracic MRI showed no signs of spinal compression. Brain MRI showed mild cortical atrophy.One year later, the patient had a bilateral extensor plantar reflex, with clonus of the patella and proximal muscle weakness in the lower limbs. There was no sign of cerebellar ataxia, and sensory modalities of the trunk and limbs were not affected. A second brain MRI showed mild cortico-subcortical atrophy. He was referred to our clinic at the age of 55 with the diagnosis of spastic paraparesis. He could not walk for more than one mile and complained of frequent falls. Gait was markedly spastic, but muscle tone at rest was normal. In addition to the pyramidal syndrome, there was gaze evoked nystagmus, saccadic ocular pursuit, and marked orthostatic hypotension. Dementia was evident, with a Mini Mental Status Examination (MMSE) score of 18/30 with deficits in visuospatial organisation and memory but no signs specific for Alzheimer's disease. Somatosensory evoked potentials and VLCFA (very long chain fatty acids) dosage were normal.At the age of 57, the neurological examination was stable. The patient had a single generalised tonic-clonic seizure when he was 58, a brain CT scan showed global atrophy, and EEG was normal. Examination at the age of 60 showed additional signs: fasciculations of the tongue, facial hypomimia, and cramps during the night. There was gestural apraxia without dressing apraxia and a sustained nasopalpebral reflex. A detailed neuropsychological examination was performed, showing decreased global efficiency, with an MMSE score of 14/30 (temporospatial subscore 2/10).There was a deficit in long term memory, without impairment of recognition capacity, but no short term anterograde memory with no alteration of retrograde memory. There was no aphasia, ideomotor apraxia, or agnosia. Only visuospatial abilities were affected. Finally, neither anosognosia nor frontal behaviour was evident.At the age of 61, he was able to walk with a walker and was able to...

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Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene

Cited by 54 publications

References 34 publications

Early onset familial Alzheimer’s disease

Early onset familial Alzheimer’s disease

Amyloid Deposition Begins in the Striatum of Presenilin-1 Mutation Carriers from Two Unrelated Pedigrees

Spastic paraparesis and atypical dementia caused by PSEN1 mutation (P264L), responsible for Alzheimer's disease

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