Objective. This study compared the frequencies of genetic and functional coagulation abnormalities in children with arterial ischemic stroke or porencephaly with frequencies in previously published studies.Methods. A series of 59 children ( age 0-18 years) with arterial ischemic stroke or porencephaly were referred to the National Institutes of Health. A blood sample, buccal smear sample, questionnaire, and pedigree were requested for each child. Blood samples were analyzed for protein C (PC); protein S; antithrombin (AT); activated PC resistance (APCR); lipoprotein ( a) [Lp(a)]; lupus anticoagulant; anticardiolipin antibodies; and the methylenetetrahydrofolate reductase C677T (MTHFR), factor V G1619A, factor II G20210A (PT), plasminogen activator inhibitor-1 4G6755G, and tissue factor pathway inhibitor C536T mutations. The frequency of each coagulation abnormality was compared with published international pediatric stroke case and control rates.Results. At least 1 prothrombotic abnormality was identified in 63% (36 of 57) of children studied, including plasminogen activator inhibitor-1 4G6755G (15 of 56), MTHFR (12 of 56), elevated Lp(a) (12 of 59), APCR (11 of 58), factor V G1619A (5 of 57), PT (3 of 57), PC deficiency (1 of 59), and AT deficiency (1 of 59). The MTHFR mutation, elevated Lp(a), the PT mutation, and AT deficiency rates were similar to rates in cases and more common than control subjects in previously published studies. The rate of children with APCR or multiple abnormalities was higher than in previous pediatric stroke studies. A family history of early thrombosis was identified in one third of the children with a prothrombotic abnormality.Conclusions. Two thirds of children in this study had at least 1 of the prothrombotic risk factors tested, and several children had multiple risk factors. These results provide additional evidence that prothrombotic abnormalities are common among children with AIS or porencephaly.

Objective: To identify the genetic mutation responsible for autosomal dominant spastic paraplegia (HSP) in a large family with a "pure" form of the disorder. Background: The disease locus in most families with HSP is genetically linked to the SPG4 locus on chromosome 2p21-p22. Some of these families have mutations in the splice-site or coding regions of the spastin gene (SPAST). Methods: Linkage and mutational analyses were used to identify the location and the nature of the genetic defect causing the disorder in a large family. After the disease phenotype was linked to the SPG4 locus, all 17 coding regions and flanking intronic sequences of SPAST were analyzed by single-strand conformation polymorphism analysis (SSCP) and compared between affected and normal individuals. Direct sequencing and subcloning methods were used to investigate incongruous mobility shifts. Results: The genomic sequence of SPAST showed a heterozygous four-base pair deletion (deITAAT) near the 3 ' splice-site of exon three in all 11 affected individuals but not in 21 normal family members or in 50 unrelated controls (100 chromosomes). Conclusions: This study identifies an atypical intronic microdeletion in SPAST that causes HSP and widens the spectrum of genetic abnormalities that cause the disorder.

Both APP and PS-1 are causal genes for early-onset familial Alzheimer’s disease (AD) and their mutation effects on cerebral Aβ deposition in the senile plaques were examined in human brains of 29 familial AD (23 PS-1, 6 APP) cases and 14 sporadic AD cases in terms of Aβ40 and Aβ42. Aβ isoform data were evaluated using repeated measures analysis of variance which adjusted for within-subject measurement variation and confounding effects of individual APP and PS-1 mutations, age at onset, duration of illness and APOE genotype. We observed that mutations in both APP and PS-1 were associated with a significant increase of Aβ42 in plaques as been documented previously. In comparison to sporadic AD cases, both APP717 and PS-1 mutation cases had an increased density (measured as the number of plaques/mm2) and area (%) of Aβ42 plaques. However, we found an unexpected differential effect of PS-1 but not APP717 mutation cases. At least some of PS-1 but not APP717 mutation cases had the significant increase of density and area of Aβ40-plaques as compared to sporadic AD independently of APOE genotype. Our results suggest that PS-1 mutations affect cerebral accumulation of Aβ burden in a different fashion from APP717 mutations in their familial AD brains.

Alzheimer's disease (AD) is caused by multiple genetic and/or environmental etiologies. Because differences in the genetically determined pathogenesis may cause differences in the phenotype, we examined age at onset and age at death in 90 subjects with dominantly inherited AD due to different mutations (amyloid precursor protein, presenilin-1, and presenilin-2 genes). We found that among patients with dominantly inherited AD, genetic factors influence both age at onset and age at death.

Objective: To assess AMY expression in familial AD (FAD). Background: The discovery of non beta-amyloid (A beta), plaque-like deposits composed of a 100-kd protein (AMY) in sporadic AD (SAD) brains prompted us to determine whether these plaques (AMY plaques) also occur in AD due to mutations of the presenilin-1 (PS-1), presenilin-2 (PS-2), or the amyloid precursor protein (APP) genes. Methods. We used immunohistochemistry and confocal laser scanning microscopy to probe the brains of 22 patients with FAD (13 with PS-1, 5 with PS-2, and 4 with APP mutations) and 14 patients with SAD. Results: AMY plaques were present in all SAD and FAD brains, including an FAD/PS-1 brain from an individual with preclinical disease. The morphology of AMY plaques in SAD and FAD brains was indistinguishable, but they differed from A beta deposits because AMY plaques lacked an immunoreactive core. AMY plaques sometimes colocalized with A beta(x-42) deposits, but they did not colocalize with A beta(x-40) plaque cores in either SAD or FAD brains. The percent of cortical area occupied by AMY was greater in FAD than in SAD brains (mean percent area = 9.8% and 5.9%, t = 2.487, p = 0.018). In particular, APP and PS-1 cases had more AMY deposition than PS-2 or SAD cases (12.9%, 10.5%, 6.2% in APP, PS-1, and PS-2 AD). Conclusions: AMY plaques are consistently present in familial AD due to presenilin-1 (PS-1), PS-2, and amyloid precursor protein mutations, and they can begin to accumulate before the emergence of dementia.

It is unclear how tau gene mutations cause frontotemporal dementia (FTD) with parkinsonism linked to chromosome 17 (FTDP-17), but those in exon 10 (E10) or the following intron may be pathogenic by altering E10 splicing, perturbing the normal 1:1 ratio of four versus three microtubule-binding repeat tau (4R:3R tau ratio) and forming tau inclusions. We report on a 55-year old woman with frontotemporal dementia and a family history of FTDP-17 in whom we found a novel E12 (Glu342Val) tau gene mutation, prominent frontotemporal neuron loss, intracytoplasmic tau aggregates, paired helical tau filaments, increased 4R tau messenger RNA, increased 4R tau without E2 or E3 inserts, decreased 4R tau with these inserts, and a 4R:3R tau ratio greater than 1 in gray and white matter. Thus, this novel Glu342Val mutation may cause FTDP-17 by unprecedented mechanisms that alter splicing of E2, E3, and E10 to preferentially increase 4R tau without amino terminal inserts and promote aggregation of tau filaments into cytopathic inclusions.

Presenilin 1 (PS1) is the causative gene for an autosomal dominant familial Alzheimer's disease (AD) mapped to chromosome 14. Here we show that QM/Jun-interacting factor (Jif)-1, a negative regulator of c-Jun, is a candidate to mediate the function of PS1 in the cell. We screened for proteins that bind to PS1 from a human embryonic brain cDNA library using the two-hybrid method and isolated one clone encoding the QM/Jif-1 gene. The binding of QM/Jif-1 to full-length PS1 was confirmed in vitro by pull-down assay, and in vivo by immunoprecipitation assays with human samples, including AD brains. Immunoelectronmicroscopic analysis showed that QM/Jif-1 and PS1 are colocalized at the endoplasmic reticulum, and the nuclear matrix in human brain neurons. Chloramphenicol acetyltransferase assays in F9 cells showed that PS1 suppresses transactivation by c-Jun/c-Jun but not by c-Jun/c-Fos heterodimers, consistent with the reported function of QM/Jif-1. By monitoring fluorescent recombinant protein and by gel mobility shift assays, PS1 was shown to accelerate the translocation of QM from the cytoplasm to the nucleus and to thereby suppress the binding of c-Jun homodimer to 12-O-tetradecanoylphorbol-13- acetate (TPA)-responsive element (TRE). PS1 suppressed c-jun–associated apoptosis by retinoic acid in F9 embryonic carcinoma cells, whereas this suppression of apoptosis is attenuated by mutation in PS1. Collectively, the novel function of PS1 via QM/Jif-1 influences c-jun–mediated transcription and apoptosis.

We obtained follow-up data on 22 sets of twins where at least one twin had Alzheimer's disease (AD). The concordance rate for monozygotic twins (n = 17 pairs) was 59%, whereas that for dizygotic twins was 40%. In our series 8 monozygotic twins had hysterectomies; all had AD. The twins with hysterectomies also had a tendency to develop AD at an earlier age than their co-twin. Five twins with serious systemic infection developed AD, and they tended to have earlier onset than their corresponding twin. We found no strong evidence that head injury predisposed to AD.

Linkage disequilibrium studies suggest that progressive supranuclear palsy (PSP) is an autosomal recessive condition that maps to a polymorphism in the tau gene. These results provide evidence that homozygous mutations in the tau gene may cause PSP. Recently, a missense mutation in exon 13 of one tare allele (R406W) was found in a single family with an atypical clinicopathologic form of dominantly inherited PSP. The authors report that the R406W mutation is lacking in 25 unrelated individuals with PSP and in six unrelated individuals with another tauopathy-corticobasal degeneration.

Missense mutations in the alpha-synuclein gene cause familial Parkinson's disease (PD), and alpha-synuclein is a major component of Lewy bodies (LBs) in sporadic PD, dementia with LBs (DLB), and the LB variant of Alzheimer's disease (AD). To determine whether alpha-synuclein is a component of LBs in familial AD (FAD) patients with known mutations in presenilin (n = 65) or amyloid precursor protein (n = 9) genes, studies were conducted with antibodies to alpha-, beta-, and gamma-synuclein. LBs were detected with alpha- but not beta- or gamma-synuclein antibodies in 22% of FAD brains, and alpha-synuclein-positive LBs were most numerous in amygdala where some LBs co-localized with tau-positive neurofibrillary tangles. As 12 (63%) of 19 FAD amygdala samples contained alpha-synuclein-positive LBs, these inclusions may be more common in FAD brains than previously reported. Furthermore, alpha-synuclein antibodies decorated LB filaments by immunoelectron microscopy, and Western blots revealed that the solubility of alpha-synuclein was reduced compared with control brains. The presence of alpha-synuclein-positive LBs was not associated with any specific FAD mutation. These studies suggest that insoluble alpha-synuclein aggregates into filaments that form LBs in many FAD patients, and we speculate that these inclusions may compromise the function and/or viability of affected neurons in the FAD brain.

To determine whether similar abnormalities of various soluble full-length and N-terminal truncated Aβ peptides occur in postmortem cerebral cortex of affected PS1 mutation carriers, we examined the amounts of two amyloid species ending at residue 40 or at residues 42(43) using sandwich ELISA systems. Our results indicate that PS1 mutations effect a dramatic accumulation in brain of the highly insoluble potentially neurotoxic long-tailed isoforms of the Aβ peptide such as Aβ1-42(43) and Aβx-42(43). This enhancing effect of PS1 mutation on Aβx-42(43) deposition was highly similar to that of a βAPP mutation (Val717Ile) but the effects on Aβx-40 production were significantly different between these two causal genes. In contrast to previous studies of soluble Aβ in plasma and in supernatants from cultured fibroblasts of subjects with PS1 mutations, our studies also show that there is an increase in insoluble Aβx-40 peptides in brain of subjects with PS1 mutations.

The sequence of events which result in β-amyloid (Aβ) plaques and tau-rich neurofibrillary tangles (NFT) in the tau-rich brain, the signature lesions of Alzheimer's disease, are incompletely understood. We know that metabolic breakdown of the amyloid precursor protein (APP) within the endoplasmic reticulum and the Golgi apparatus results in formation of different length Aβ peptides (Aβ−42 and the shorter Aβ−40). 1 Cook DG Forman MS Sung JC et al. Alzheimer's Aβ(1–42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells. Nat Med. 1997; 3: 1021-1023 Crossref PubMed Scopus (430) Google Scholar Because elderly people with Down's syndrome develop Alzheimer's disease, the occurrence of Aβ−42 plaques before other changes in trisomy 21 2 Iwatsubo T Mann DMA Odaka et al. Amyloid β protein (Aβ) deposition: Aβ42(43) precedes Aβ40 in Down syndrome. Ann Neurol. 1995; 37: 294-299 Crossref PubMed Scopus (338) Google Scholar suggests that Aβ−42 deposition is the earliest event in Alzheimer's disease. Aβ−42 and Aβ−40 are present in older people with Down's syndrome and in Alzheimer's disease. 2 Iwatsubo T Mann DMA Odaka et al. Amyloid β protein (Aβ) deposition: Aβ42(43) precedes Aβ40 in Down syndrome. Ann Neurol. 1995; 37: 294-299 Crossref PubMed Scopus (338) Google Scholar However, in trisomy 21 there is an extra copy of the APP gene with overexpression of APP, so the early occurence of Aβ cannot be generalised to all people with Alzheimer's disease. To define the initial pathological features in Alzheimer's disease due to genetic abnormalities that do not involve the APP gene we report here the neuropathology of a presymptomatic carrier of the FAD1 presenilin-1 (PS-1) Alzheimer-disease mutation on chromosome 14. 3 Nee LE Polinsky RJ Eldridge R et al. A family with histologically confirmed Alzheimer's disease. Arch Neurol. 1983; 40: 203-208 Crossref PubMed Scopus (135) Google Scholar This mutation causes the disease in all carriers with an average age of onset of dementia at 53 and of death at 61. Because PS-1 is a transmembrane protein located in the Golgi apparatus and endoplasmic reticulum, PS-1 mutations may cause Alzheimer's disease by an interaction with the APP protein in these sites.

We report the results of linkage analysis in a large American family of Czech descent with dominantly inherited ''pure'' essential tremor (ET) and genetic anticipation. Genetic loci on chromosome 2p22-p25 establish linkage to this region with a maximum LOD score (Z(max)) = 5.92 for the locus, D2S272. Obligate recombinant events place the ETM gene in a 15-cM candidate interval between the genetic loci D2S168 and D2S224. Repeat expansion detection analysis suggests that expanded CAG trinucleotide sequences are associated with ET. These findings will facilitate the search for an ETM gene and may further our understanding of the human motor system.

Cerebral presenilin-1 protein (PS-1) is normally composed of the amino-terminal fragment (NTF) with Mr 28 kDa and the carboxy-terminal fragment (CTF) with 18 kDa. We analyzed human PS-1 in brains with early-onset familial Alzheimer's disease (FAD) with and without PS-1 mutations to study whether mutated PS-1 was abnormally metabolized. Cerebral PS-1 were found to be cleaved into two fragments of NTF and CTF independently of the occurrence of PS-1 mutation in human brains. A small portion of PS-1 was recently found to suffer another processing by caspase-3, an apoptosis-related cysteine protease. In contrast to the recent finding that the Volga-German mutation on presenilin-2 (PS-2) affects the increasing caspase-3 PS-2 fragment, the PS-1 mutation did not cause a significant change in PS-1 fragmentation. We conclude that PS-1 fragmentation and other (probably caspase-3-mediated) digestion following apoptosis occur independently of PS-1 mutations.

In the past few years, genetic characterization has assigned seven chromosomal loci-designated as spinocerebellar ataxia (SCA) types 1-5 (OMIM 164400, 183090, 183085, 600223, 600224), SCA type 7 (OMIM 164500), and dentatorubropallidoluysian atrophy (OMIM 125370)-to a group of dominantly inherited ataxias.1 The locus for a benign adult-onset form of dominantly inherited ataxia has been linked to the centromeric region of chromosome 11 in a family descended from the grandparents of President Abraham Lincoln.2 During our investigation of a family with dominantly inherited ataxia that has lived in Rockingham County, Virginia, since colonial times, we uncovered several interesting historical facts about President Lincoln's family that cast doubt that the SCA5 gene was inherited through the Lincoln lineage. As part of this investigation, we constructed a family pedigree of President Lincoln's ancestors based on several historical sources3-6(figure 1). Figure 1. A partial pedigree of President Abraham Lincoln's family. Nine generations and 29 individuals from the president's family are shown. The names of family members whose signatures are found infigures 2 and 3 are followed by an asterisk (*). The known birth and death years are below each individual's name. Males are squares and females are circles. The dark symbols represent individuals with ataxia as cited by Ranum et al.2 The gray symbol representing individual VI-10 denotes that she had evidence of a tremor in her handwritten line. Our 16th president's paternal grandfather, Captain Abraham Lincoln(individual VI-9, figure 1), was born in Berks County, Pennsylvania, on May 13, 1744, and later moved to northwest Virginia. Captain Lincoln was a wealthy landowner and a distinguished figure in the American militia during the Revolutionary War. His wife, Bathsheba (individual VI-10,figure 1), was born in Bridgewater, Virginia, …

We report an autosomal recessive form of ataxia that is not allelic to Friedreich's disease in six individuals from a large kindred with family origins traced to a common founder of German-Swiss descent. The disorder begins during early childhood with a concentric contraction of the visual fields and proprioceptive loss. Eventually blindness, a severe sensory ataxia, achalasia, scoliosis, and inanition develop by the third decade. Inversion recovery MRIs of the spinal cord in affected individuals demonstrate a hyperintense signal in the posterior columns. Finding the gene responsible for this disorder may aid in our understanding of the mechanisms that cause sensory neuronal degeneration.