A novel presenilin 1 mutation (V261L) associated with presenile Alzheimer's disease and spastic paraparesis

Background and purpose:  We report a novel mutation in exon 8 of the presenilin 1 (PSEN1) gene (V261L) associated with early-onset autosomal dominant Alzheimer's disease and spastic paraparesis.
Methods and results:  The proband was a woman who developed insidious cognitive decline with predominant memory loss and gait disorder secondary to spasticity at the age of 40. Her brother and her mother had a similar disease in the fifth decade of life. The feature of amnestic presentation with spastic paraparesis is consistent with the majority of mutations in the exon 8 of the PSEN1 1 gene.
Conclusions:  Screening for PSEN1 mutations is especially likely to be productive when directed toward persons with positive family history and with age at onset of under 60.     

New V272A presenilin 1 mutation with very early onset subcortical dementia and parkinsonism

In this report, we present the clinical and pathological details of a kindred of four individuals with a novel missense mutation (V272A) of the presenilin 1 gene (PSEN1) that experienced a subcortical dementia. The age of onset of symptoms ranged 26-36-year old, with an age at death of 36-46 years. Initial symptom was a marked mood disorder, with prominent parkinsonism in one case. The neuropsychological study, as well as the neuroimaging and PET in the proband were concordant with a subcortical dementia. The cerebral pathology showed in this patient, aside from the classical lesions of Alzheimer disease, Lewy bodies in cortex and substantia nigra, and widespread subcortical neuritic lesions. This clinical pattern and pathology expands the clinical spectrum of familial Alzheimer's disease and compel to include mutations of PSEN1 gene in the genetic study of subcortical dementia.     

A novel PSEN1 mutation (K239N) associated with Alzheimer’s disease with wide range age of onset and slow progression

Objective: To describe a novel mutation (K239N) in the PSEN1 associated with familial Alzheimer’s disease (AD). Methods and results: The proband was a man who developed cognitive decline with marked behavioural abnormalities at age 57. At age 70, he was admitted into a psychiatric facility because of aggressiveness and a suicide attempt. Family history was consistent with autosomal dominant AD. One of the two other family members studied presented also with prominent behavioural symptoms at age 42 and has also been forced into a psychiatric facility because of aggressiveness at age 56. The remainder patient has presented a prototypical AD, but starting at age 71. Direct sequencing of PSEN1 in the three living affected members disclosed a heterozygous G to C transition in exon 7 of PSEN1 leading to the K239N mutation. Conclusion: The K239N mutation is associated with autosomal dominant AD with a wide range of age of onset and incomplete penetrance at the age of 65, prominent behavioural features and slow progression.     

Very early-onset familial Alzheimer's disease: a novel presenilin 1 mutation

BACKGROUND: Early-onset familial Alzheimer's disease (EOFAD) is linked to mutations in three autosomal dominant genes: PS1, PS2 and APP. The clinical presentation and age of onset of mutations is variable. OBJECTIVES: The aim of this report is to describe a novel PS1 mutation believed to be causal for a very early onset of AD. METHODS: This is a case history using information from medical records, relative interviews and genetic testing results to describe the pre-clinical prodrome and clinical course of a patient with EOFAD. RESULTS: A previously undescribed G206V mutation in PS1 was found in the proband. CONCLUSION: The G206V mutation in PS1 is probably causal of a case of EOFAD with significant premorbid features.     

A novel mutation in the PSEN1 gene (L286P) associated with familial early-onset dementia of Alzheimer type and lobar haematomas

The aim of this study was to describe a novel mutation in exon 8 of the presenilin gene (L286P) associated with early-onset autosomal dominant Alzheimer's disease (AD) and lobar haematomas. The proband was a woman who developed cognitive decline with predominant memory loss at the age of 35 years. The patient died at the age of 54 years and the neuropathological examination confirmed the diagnosis of AD. Three of her four siblings, one parent and one sibling of her parent had suffered from cognitive decline at ages between 35 and 42 years. Three of them also presented lobar haematomas. The neuropathological examination, available in one of them, disclosed the presence of severe amyloid angiopathy as the cause of the haematoma. The study of PSEN1 gene with single strand conformation polymorphism technique failed to show abnormalities suggestive of mutations. Direct sequencing disclosed the presence of a missense mutation in codon 286 (L286P) in the proband and her already affected descendent, which was absent in the healthy sibling. L286P is a novel mutation in PSEN1 that causes familial early-onset AD and brain haematomas related to amyloid angiopathy.     

A novel mutation (Thr116Ile) in the presenilin 1 gene in a patient with early-onset Alzheimer''s disease

We report a novel presenilin 1 (PSN1) mutation (Thr116Ile) in a woman with early onset Alzheimer's disease (AD). This mutation was not found in 100 healthy controls, indicating that this is not a common polymorphism. The patient presented with forgetfulness at age 45, followed over the next 3 years by a worsening of the memory loss and frequent episodes of confusion and spatial disorientation. Neuroimaging studies were consistent with AD. The analysis of the family's pedigree showed that the proband was apparently the only member affected. Because the early death of several close relatives (i.e. the mother and the grandmother) and the demonstration that the father is not a mutation carrier, it is suggested that either a de novo mutation or a censor effect might have occurred. Our finding supports the indication that PSN1 mutations should be searched for in early-onset AD, particularly when a censor effect precludes a precise genetic analysis.     

A novel presenilin 1 mutation (L174 M) in a large Cuban family with early onset Alzheimer disease

We studied a Cuban family with presenile dementia (autosomal dominant) consisting of 281 members within six generations, the proband descended from a Spanish founder. Mean age at onset was 59 years of age. Memory impairment was the main symptom in all patients, additionally, ischemic episodes were described in 4 (n=18) patients. Neuropathological examination of brain material (1 patient) revealed neuronal loss, amyloid plaques, and neurofibrillary tangles. Thirty DNA samples were genotyped (regions on chromosome 1, 3, 10, 12, 14, 17, 19, 20, and 21). A maximum Lod score of 3.79 at θ=0 was obtained for marker D14S43, located in a 9-cM interval in which all patients shared the same haplotype. Sequencing of the PSEN1 gene revealed a heterozygous base substitution, C520A (exon 6), which is predicted to cause an amino acid change from leucine to methionine in the TMIII of the presenilin 1 protein. The mutation was found to co-segregate with the disease phenotype and the associated disease haplotype. The C→A change was not observed in 80 control chromosomes from the Cuban population. Leucine at position 174 is highly conserved among species and is identical in presenilin 1 and presenilin 2 proteins. We propose the L174 M mutation might lead to an abnormal N-terminal and probably C-terminal fragments and malfunction of the protein complex. In conclusion, we found a novel PSEN1 mutation in a large family with clinical and pathological diagnosis of early onset familial Alzheimer disease, which may be relevant for other Hispanic populations. Electronic Publication     

A novel presenilin1 mutation (Q223R) associated with early onset Alzheimer’s disease,dysarthria and spastic paraparesis and decreased Abeta levels in CSF

Background and purpose: A novel presenilin1 (PSEN1) mutation associated with dementia and spastic paraplegia in a family with five affected individuals is described. The index patient was a 35‐year‐old man presenting with cognitive decline, behavioural symptoms, dysarthria, and gait disorder due to spasticity. Methods and results: Genetic analysis revealed a missense mutation Gln223Arg in exon 7. Initial CSF analysis revealed drastically decreased Abeta42 level despite marginally decreased FDG metabolism. Conclusion: Cerebrospinal fluid biomarker analysis might point towards genetic analysis of PSEN1 in patients with positive family history and age of onset below 60 years.     

A presenilin 1 mutation (Arg278Ser) associated with early onset Alzheimer's disease and spastic paraparesis

Early onset familial Alzheimer’s disease (EOFAD) has been associated with mutations in three genes, of which presenilin 1 (PSEN1) mutations are the most frequent. Several families with an association of progressive dementia and spastic paraplegia caused by PSEN1 mutations have been described. Here we described a novel PSEN1 mutation that was associated with dementia and spastic paraplegia in a family with 5 affected individuals in three generations. The proband was a 44-year-old woman who presented with 5 years history of progressive difficulties in walking, cognition and visuospatial impairment. Her maternal grandmother, mother and two maternal aunts also had similar neurological presentation. Molecular genetic analysis showed a missense mutation predicted to substitute an arginine residue for a serine residue at position 278 in the PSEN1 polypeptide (Arg278Ser). The novel PSEN1 mutation identified in this patient adds to the diverse list of existing mutations causing EOFAD associated with spastic paraparesis.     

A novel presenilin 1 mutation (Leu166Arg) associated with early-onset Alzheimer disease

BACKGROUND: Pathogenic mutations in the presenilin 1 (PS1) gene leading to early-onset Alzheimer disease have been described in various populations. The different mutations are not distributed randomly in the PS1 protein but are clustered in some PS1 exons. OBJECTIVE: To screen the PS1 gene in search of a potential mutation in a Spanish family with early-onset Alzheimer disease. METHODS: Single-stranded conformational polymorphism and heteroduplex analyses of all exons were used to search for a potential mutation. Subsequent sequencing of the DNA samples with an abnormal heteroduplex pattern was performed to identity the mutation in the sense strand and in the complementary strand. RESULTS: We found a novel mutation in exon 6 of the PS1 gene at a site that, so far, had not been described as a cluster of mutations. The mutation (an A to C change) causes a substitution of leucine for arginine at position 166 of the PS1 protein and is located adjacent to the transmembrane domain III, where few mutations have been found. In this family, the disease follows an autosomal inheritance pattern with early onset (range, 32-44 years). CONCLUSION: A novel missense mutation (Leu166Arg) at an atypical site associated with early-onset Alzheimer disease has been identified in a Spanish family.     

Laminar specific loss of isocortical presenilin 1 immunoreactivity in Alzheimer's disease. Correlations with the amyloid load and the density of tau-positive neurofibrillary tangles

Presenilin 1 has been shown to be mutated in a high proportion of cases of familial Alzheimer's disease. Immunoreactive epitopes of the protein have been found mainly in neurones devoid of neurofibrillary tangles - an observation that has led to the conclusion that presenilin 1 could have a protective role. In this study, the relationship between deposits of Abeta peptide (both the 40 and 42 isoforms), tau positive neurofibrillary tangles and presenilin 1-positive neuronal profiles were analysed in three cases of presenilin 1 mutation, four cases of sporadic Alzheimer's disease and five controls. Immunohistochemistry was performed in a sample from the supramarginal gyrus. The proportion of volume occupied by the Abeta1-40 and Abeta1-42 deposits (amyloid load) was evaluated by a point-counting technique. Tau-positive neurofibrillary tangles, and presenilin 1-positive neuronal profiles were directly counted. The location of the lesions in the thickness of the cortex was recorded. The density of PS1-positive neuronal profiles in Alzheimer's disease cases was lower than in the controls. The deficit was significant only in the upper layers of the cortex. The density of presenilin 1 neuronal profiles was negatively correlated with Abeta1-40 and Abeta1-42 loads, and with the density of tau-positive neurofibrillary tangles. Multivariate analysis showed that the Abeta1-42 load was the best determinant of the decrease in presenilin 1-positive neuronal profiles. Presenilin 1-positive neurones appear to be lost rather than protected in the course of Alzheimer disease.     

Neuropsychological profiles of familial Alzheimer's disease associated with mutations in the presenilin 1 and amyloid precursor protein genes

Patients with familial Alzheimer's disease and a subset known to have presenilin mutations were compared with sporadic cases on a comprehensive battery of cognitive tests. These included measures of memory, intelligence, language and perception. The three group were very comparable, in terms of severity, on global measures of dementia. However, their profiles/patterns of cognitive impairment differed in two respects; the group with sporadic Alzheimer's disease were significantly more impaired on tests of object naming and object perception than either the group with familial Alzheimer's disease or group with familial Alzheimer's disease and presenilin mutations, yet they scored at a significantly higher level on the measure of verbal intelligence. This study provides further evidence of the heterogeneity of the disease process. Received: 25 April 2000 / Received in revised form: 26 June 2000 / Accepted: 14 July 2000     

No association between presenilin 1 (PS1) intronic polymorphism and sporadic Alzheimer's disease in Koreans

Summary. To investigate the possible involvement of an intronic polymorphism in the presenilin 1 (PS1) gene and its interactions with the aplolipoprotein E (APOE) or alpha-1 antichymotrypsin (ACT) polymorphisms in the manifestation of AD, we analyzed the PS1, APOE and ACT genotypes of 100 sporadic AD patients and 199 normal elderly controls in Koreans. The genotypic (χ² = 0.92, df = 2, P > 0.1) and allelic (χ² = 0.01, df = 1, P > 0.1) frequencies of the PS1 polymorphism in the late- and early-onset sporadic AD patients did not differ from those in the controls. And the occurrence of the APOE ε4 allele and ACT A allele did not influence the distribution of the PS1 intronic polymorphism. The PS1 intronic polymorphism didn't influence the age-at-onset of AD (F = 0.02, df = 2, P > 0.1). In conclusion, the PS1 intronic polymorphism did not modify the risk for sporadic AD, neither independently nor synergistically with the APOE ε4 allele or ACT A allele, in Koreans. Received December 24, 1999; accepted March 18, 2000     

Relationship between neuronal loss and 'inflammatory plaques' in early onset Alzheimer's disease

We have previously described a novel 'inflammatory plaque' in the cortex of early onset Alzheimer's disease (EOAD) cases with presenilin 1 mutations (PS1). These plaques are associated with a significant inflammatory infiltrate consisting of reactive microglia and astrocytes. We speculated that these inflammatory plaques might be responsible for the more severe disease process seen in EOAD. In the present study using the superior frontal cortex, 63 EOAD cases with mutations in PS1, presenilin 2 (PS2) and amyloid precursor protein (APP) were categorized as either having inflammatory plaques (13 cases, two APP and 11 PS1) or not. To determine the impact on cell loss, seven EOAD cases with inflammatory plaques (EOIP) and seven EOAD cases without (EONIP) were selected and neuronal cell counts performed. These were compared with neuronal counts taken from the same cortical region of seven control and six sporadic AD cases. Cases with EOAD had significantly less neurones per field compared with sporadic AD and control cases (EOAD = 19.5 +/- 0.8 neurones/field, spAD = 23.7 +/- 1.2 neurones/field, controls = 30.37 +/- 1.2 neurones/field). However, no significant difference in the number of neurones per field was seen in EOAD cases with or without inflammatory plaque pathology (EOIP = 19.2 +/- 1.4, EONIP = 19.7 +/- 0.8). These data demonstrate that EOAD cases exhibit greater neuronal cell loss in the superior frontal cortex than sporadic AD and that this effect is independent of the presence or absence of inflammatory plaque pathology.     

A presenilin 1 mutation (L420R) in a family with early onset Alzheimer disease,seizures and cotton wool plaques,but not spastic paraparesis

Over 100 mutations in the presenilin‐1 gene (PSEN1) have been shown to result in familial early onset Alzheimer disease (EOAD), but only a relatively few give rise to plaques with an appearance like cotton wool (CWP) and/or spastic paraparesis (SP). A family with EOAD, seizures and CWP was investigated by neuropathological study and DNA sequencing of the PSEN1 gene. Aβ was identified in leptomeningeal vessels and in cerebral plaques. A single point mutation, p.L420R (g.1508T > G) that gives rise to a missense mutation in the eighth transmembrane (TM8) domain of PS1 was identified in two affected members of the family. p.L420R (g.1508T > G) is the mutation responsible for EOAD, seizures and CWP without SP in this family.     

A novel presenilin 2 mutation (V393M) in early‐onset dementia with profound language impairment

Background: Mutations in the Presenilin 2 gene (PSEN2) are rare causes of Alzheimer’s disease (AD). Pathogenic mutations in the genes associated with autosomal dominant inherited AD have been shown to alter processing of the amyloid precursor protein (APP) resulting in a relative increase of the amount of Aβ42 peptide. Methods and results: We present a patient with neuropathologically confirmed early‐onset AD characterized by profound language impairment. The patient was heterozygous for a novel missense mutation in exon 11 of the PSEN2 gene leading to a predicted amino acid substitution from valine to methionine in position 393, a conserved residue. However, in vitro expression of PSEN2 V393M cDNA did not result in detectable increase of the secreted Aβ42/40 peptide ratio. The mutation was not found in 384 control individuals tested. Conclusions: The possible pathogenic nature of the mutation is not clarified. We discuss the limitations of functional PSEN2 studies and the challenges associated with genetic counselling of family members at risk.     

A novel mutation (L250V) in the presenilin 1 gene in a Japanese familial Alzheimer's disease with myoclonus and generalized convulsion

This study reports a novel presenilin 1 (PS1) gene mutation in a Japanese family with Alzheimer's disease (AD). Two patients developed progressive memory disorder with disorientation around 50 years of age and showed myoclonus with frequent tonic-clonic seizures several years later. Direct sequencing of the proband's PS1 gene revealed a novel mis-sense mutation (leucine-to-valine at residue 250 (L250V)). This mutation was found in both patients, but not in a normal family member or normal Japanese control subjects. Thus, L250V is a novel PS1 gene mutation responsible for familial AD (FAD) in Japan.     

Association between presenilin 1 intronic polymorphism and late onset Alzheimer's disease in the North Chinese population

The association between presenilin 1 intronic polymorphism (rs165932) and late onset Alzheimer's disease (LOAD) has been a matter of controversy. Within China, varied results have been reported. Therefore, we collected a large sample from the North Chinese population to test the association of the PS1 polymorphism with LOAD. AD patients (467 total, mean age=75.3+/-7.3, age at onset=70.2+/-5.1) and age-matched normal elderly controls (480 total) were recruited. Genotypes of PS1 and apolipoprotein E (APOE) were determined by PCR and RFLP. The results showed that there were significant differences in the distributions of both alleles (chi(2)=45.305, P<10(-5)) and genotypes (chi(2)=53.055, P<10(-5)) of PS1 gene between the AD and control groups. The APOE epsilon4 allele was more prevalent in patients than in controls (chi(2)=46.389, P<10(-5)). It was significantly different when PS1 alleles and genotypes were compared between AD and controls with APOE epsilon4 negative. However, no significance was found when PS1 alleles or genotypes were compared between AD and controls with APOE epsilon4 positive. Furthermore, with PS1 2/2 genotype as a reference, the odds ratios (ORs) of LOAD with PS1 1/2, 1/1+1/2 and 1/1 genotypes gradually increased allele 1 copy number, suggesting that allele 1 is a crucial risk for LOAD. In summary, we found an association between presenilin 1 intronic polymorphism and LOAD, but no influence of APOE epsilon4 on the distribution of the PS1 intronic polymorphism. In addition, the larger sample size raises the possibility that ethnic and regional differences in China may explain the differences in reported results.