A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1

Abstract

We describe a novel variant of Alzheimer's disease (AD) in a Finnish pedigree with 17 affected individuals of both sexes in three generations. The disease is characterized by progressive dementia which is, in most cases, preceded by spastic paraparesis. Neuropathological investigations revealed numerous, distinct, large, round and eosinophilic plaques as well as neurofibrillary tangles and amyloid angiopathy throughout the cerebral cortex. The predominant plaques resembled cotton wool balls and were immunoreactive for Abeta but lacked a congophilic dense core or marked plaque-related neuritic pathology. Molecular genetic analysis revealed that the disease was caused by a deletion of exon 9 (delta9) of the presenilin 1 (PS1) gene from the mRNA: unlike previous examples of the delta9 variant, the deletion was not caused by a splice acceptor site mutation.

P2‐203: Phenotypic Similarities between Late‐Onset Autosomal Dominant and Sporadic Alzheimer Disease: A Single‐Family Case‐Control Study

“…Hallucinations and delusions were reported more frequently in PSEN1 A79V MCs from this family, as has been noted previously in individuals with ADAD. 44,45 These findings demonstrate that the clinical phenotypes of late-onset ADAD and LOAD can overlap, and suggest that previously reported clinical (e.g., seizures, early myoclonus, spastic paraparesis, dysarthria, and rapid decline [9][10][11][12][13][14][15][16][17][18] ) and neuropathological differences (e.g., altered cerebral Aβ 42 and neurofibrillary tangle deposition, increased prevalence of cerebral amyloid angiopathy, and formation of "cotton wool" plaques 6,12,16,[19][20][21][22][23][24][25][26][27] ) may reflect age-or mutation-dependent effects.…”

“…7,8 Also, ADAD may be characterized by clinical features that are unusual in LOAD, including pyramidal signs, hypo/hyperkinetic movement disorders, ataxia, and early myoclonus and seizures. [9][10][11][12][13][14][15][16][17][18] Additional differences in the pattern of cerebral Aβ 42 deposition are reported in some ADAD cases, including 6,16,19,20 higher Aβ 42 burden and greater densities of neurofibrillary tangles; [21][22][23] increased Aβ 42 deposition within the cerebellum [24][25][26] and basal ganglia; 19,20 ; and higher prevalence of cerebral amyloid angiopathy and large diffuse so-called "cotton wool" plaques. 12,22,24,27 Such clinical and pathological differences may challenge whether findings from studies of early-onset ADAD, including current trials of anti-amyloid therapies, 28 can be extrapolated to the understanding of the far more common LOAD.…”

The Correlation between Genotype and Phenotype of Alzheimer's Disease

“…The clinical phenotype was characterized by memory impairment associated with spastic paraparesis. The pathological basis of this distinctive phenotype is Aβ positive "cotton wool" plaques without a congophilic core [151].…”

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

“…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 . La deleción del exón 9 (delta9) del gen de la PS1 fue descrita en una familia de Finlandia, mutación causante de una demencia caracterizada por paraparesia espástica y hallazgos de angiopatía amiloide y ovillos neurofibrilares en los estudios de patología 21 . La mutación por inserción en el exón 3 de la PS1 causa deterioro cognitivo, distonía, disartría y paraplejía espástica 22 .…”