Familial Alzheimer's disease: progress and problems

This paper reexamines recent epidemiologic and molecular genetic studies on the genetic basis of Alzheimer's Disease (AD). Careful analysis of the available epidemiologic data strongly suggests that at least a proportion of AD results from the inheritance of an autosomal dominant gene defect. However, studies of isolated families, of concordance rates in twins, and of risk for AD in relatives of AD probands yield conflicting data. While it is likely that much of the conflict can be ascribed to methodologic differences, it remains premature to conclude that all AD is transmitted as an autosomal dominant trait. Molecular genetic techniques hold the promise of isolation and characterization of the genetic defect(s) in familial AD (FAD). Recently, chromosome 21 has been implicated as the potential site of an autosomal dominant defect in some but not necessarily all FAD pedigrees. However, the results of recent genetic epidemiologic studies suggest that progress in the molecular genetic approach to AD will be difficult.     

Does autosomal dominant pseudoxanthoma elasticum exist?

Pseudoxanthoma elasticum (PXE) is a progressive disorder of elastic fibers in skin, eyes, and arterial walls. It is caused by mutations in the ABCC6 gene. Most patients are sporadic cases. The majority of familial cases show autosomal recessive (AR) inheritance, but autosomal dominant (AD) inheritance has also been reported. We reviewed the literature on AD PXE and we studied in detail, both clinically and by DNA studies, a selection of potentially AD pedigrees from our patient population consisting of 59 probands and their family members. Individuals were considered to have definite PXE if they had two of the following three criteria: characteristic ophthalmologic signs, characteristic dermatologic signs, and a positive skin biopsy. In the literature we found only three families with definite PXE in two successive generations and no families with definite PXE in three or more generations. Our own data set comprised three putative AD families. Extensive DNA studies revealed a mutation in only one ABCC6 allele in the patients of these families. Only one of our families showed definite PXE in two generations. Linkage studies revealed that pseudodominance was unlikely in this family. In the other two families AD PXE could not be confirmed after extensive clinical examinations and application of our criteria, since definite PXE was not present in two or more generations. Conclusion: the inheritance pattern in PXE usually is AR. Part of the phenotype in family members of PXE patients might be due to expression in heterozygous carriers of an AR disease. AD inheritance in PXE may exist, but is both after careful literature study and in our patient material much rarer than previously thought.     

Female sex preponderance for idiopathic familial premature ovarian failure suggests an X chromosome defect: opinion

Premature ovarian failure (POF) is defined as ovarian failure occurring before the age of 40 years. A genetic aetiology is suggested by the occurrence of families with two or more affected females. We have characterised the pattern of inheritance of 41 cases of familial POF and compared them to published pedigrees. In eleven families a clear genetic association of POF could be identified. In the remaining 30 families the mechanism of inheritance was obscure. We found a female sex preponderance in the siblings of 30 families with idiopathic POF and in previously published series of idiopathic familial POF. In contrast, other known causes of POF, such as blepharophimosis ptosis epicanthus and inversus and autosomal recessive gonadal dysgenesis, had no altered sex ratio. One of our series of 30 pedigrees demonstrated transmission of POF susceptibility through fathers, which we believe is the first to be described in the literature. We present a group of five consanguineous families where we assume the mode of inheritance is autosomal recessive and where there was no female sex preponderance. Female sex preponderance for idiopathic familial POF suggests an X chromosome defect is inherited as a major cause of ovarian failure.     

SMN gene analysis of the spinal form of Charcot-Marie-Tooth disease.

The spinal form of Charcot-Marie-Tooth disease (spinal CMT) is a rare genetic disorder of the peripheral nervous system, the genetic basis of which remains unknown. To test the hypothesis that a defect of survival motor neuron (SMN), the determining gene for spinal muscular atrophy (SMA), would result in spinal CMT, 18 unrelated spinal CMT patients were studied. Nine of them were sporadic cases and the other nine belonged to unrelated autosomal dominant pedigrees. None of the 18 patients showed deletions involving SMN exons 7 or 8, the most frequent gene alteration found in SMA. In addition, haplotype analysis in two large autosomal dominant pedigrees showed that the 5q13 locus was not segregating with the spinal CMT locus. Therefore, neither the sporadic nor the familial cases of spinal CMT are associated with a SMN gene deletion, nor are the familial cases linked to the 5q13 region, indicating that this neuropathy is genetically different from SMA.     

Initial report of a genome search for the affective disorder predisposition gene in the old order Amish pedigrees: Chromosomes 1 and 11

Family data have suggested that some forms of major affective disorder are genetic. Certain of the Old Order Amish pedigrees have a familial form of the disease. In this report we present the results of genetic analyses under autosomal dominant mode of transmission with reduced pentrance and three different disease hierarchies. The pedigrees were genotyped with 28 markers from chromosome 1 and 23 markers from chromosomes 11. None of the markers result in a significantly positive lod score. © 1994 Wiley-Liss, Inc.     

Familial thoracic aortic aneurysm/dissection with patent ductus arteriosus: genetic arguments for a particular pathophysiological entity

Thoracic aortic aneurysm and aortic dissection (TAA and AD) are an important cause of sudden death. Familial cases could account for 20% of all cases. A genetic heterogeneity with two identified genes (FBN1 and COL3A1) and three loci (3p24-25 or MFS2/TAAD2, 5q13-q14 and 11q23.2-24) has been shown previously. Study of a single family composed of 179 members with an abnormally high occurrence of TAA/AD disease. A total of 40 subjects from three generations were investigated. In addition to five cases of stroke and three cases of sudden death, there were four cases of AD and four cases of TAA in adults. In all, 11 cases of patent ductus arteriosus (PDA) were observed, two of which were associated with TAA and one with AD. Segregation analysis showed that the distribution of these vascular abnormalities was more likely compatible with a single genetic defect with an autosomal dominant pattern of inheritance. There were no clinical signs of Marfan, Elhers-Danlos vascular type or Char syndromes. Genetic linkage analysis was performed for seven genes or loci implicated in familial TAA/AD disease (COL3A1, FBN1, 3p24-25 or MFS2/TAAD2, 5q13-q14 and 11q23.2-q24), Char syndrome (TFAP2B) or autosomal recessive PDA (12q24). Using different genetic models, linkage with these seven loci was excluded. Familial TAA/AD with PDA is likely to be a particular heritable vascular disorder, with an as yet undiscovered Mendelian genetic basis.     

特发性癫痫遗传方式的研究

目的为了探讨特发性癫痫（ＩＥＰ）的遗传方式。方法采用家系分析、多基因分析和分离分析的方法，对山东省遗传病群体调查中发现的２１０个ＩＥＰ家系进行了研究。结果ＩＥＰ不符合多基因遗传，而主要为常染色体隐体遗传。分离分析结果显示，Ｕ×Ｕ多发家庭组和Ｕ×Ａ家庭组可以接受常染色体隐性遗传的假设；部分Ｕ×Ｕ组的家庭可以接受常染色体隐性遗传的假设，但是大多数Ｕ×Ｕ组的家庭为散发病例，散发病例比例为７８．５％。结论散发病例和Ｕ×Ｕ（ｆ）家庭组可能存在遗传异质性，其原因有待进一步的研究。     

Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease

Two closely related genes, the presenilins ( PS ), located at chromosomes 14q24.3 and 1q42.1, have been identified for autosomal dominant Alzheimer disease (AD) with onset age below 65 years (presenile AD). We performed a systematic mutation analysis of all coding and 5'-non-coding exons of PS -1 and PS -2 in a population-based epidemiological series of 101 unrelated familial and sporadic presenile AD cases. The familial cases included 10 patients of autosomal dominant AD families sampled for linkage analysis studies. In all patients mutations in the amyloid precursor protein gene ( APP ) had previously been excluded. Four different PS -1 missense mutations were identified in six familial cases, two of which where autosomal dominant cases. Three mutations resulted in onset ages above 55 years, with one segregating in an autosomal dominant family with mean onset age 64 years (range 50-78 years). One PS -2 mutation was identified in a sporadic case with onset age 62 years. Our mutation data provided estimates for PS -1 and PS -2 mutation frequencies in presenile AD of 6 and 1% respectively. When family history was accounted for mutation frequencies for PS -1 were 9% in familial cases and 18% in autosomal dominant cases. Further, polymorphisms were detected in the promoter and the 5'-non-coding region of PS -1 and in intronic and exonic sequences of PS -2 that will be useful in genetic association studies.      

Problems in detecting etiological heterogeneity in genetic disease illustrated with retinitis pigmentosa

Simulated data were generated under four etiologic mechanisms for each of 20 different pedigree structures drawn from a study of families ascertained through a proband with retinitis pigmentosa. These simulated data were then used to identify subgroups of pedigrees which best supported each of three genetic mechanisms (autosomal dominant, autosomal recessive, X-linked recessive with 10% penetrance of disease in heterozygous females) and a non-genetic, sporadic mechanism. Results of these studies show that pedigrees identified as supporting one genetic model in a 'model choice' approach tend to be etiologically homogeneous, but are not truly representative of all the phenotypic combinations possible under that mechanism. The problem of etiologic heterogeneity is most acute when dealing with pedigrees less than size 10. Pedigrees lumped under a non-genetic, sporadic mechanism are extremely heterogeneous and studies of the natural history of diseases where both genetic and non-genetic mechanisms may be operating (such as with retinitis pigmentosa) should avoid using this group of largely simplex pedigrees.     

Linkage of familial alzheimer disease to chromosome 14 in two large early-onset pedigrees: Effects of marker allele frequencies on lod scores

Alzheimer disease (AD) is a devastating neurodegenerative disease leading to global dementia. In addition to sporadic forms of AD, familial forms (FAD) have been recognized. Mutations in the amyloid precursor protein (APP) gene on chromosome (CHR) 21 have been shown to cause early-onset AD in a small number of pedigrees. Recently, linkage to markers on CHR 14 has been established in several early-onset FAD pedigrees. We now report lod scores for CHR 14 markers in two large early-onset FAD pedigrees. Pairwise linkage analysis suggested that in these pedigrees the mutation is tightly linked to the loci D14S43 and D14S53. However, assumptions regarding marker allele frequencies had a major and often unpredictable effect on calculated lod scores. Therefore, caution needs to be exercised when single pedigrees are analyzed with marker allele frequencies determined from the literature or from a pool of spouses. © 1993 Wiley-Liss, Inc.     

Major gene and multifactorial inheritance of mandibular prognathism

Mandibular prognathism typically shows familial aggregation. Various genetic models have been described and it is assumed to be a multifactorial and polygenic trait, with a threshold for expression. Our goal was to examine specific genetic models of the familial transmission of this trait. The study sample comprised of 2,562 individuals from 55 families. Complete family histories for each proband were ascertained and the affection status of relatives were confirmed by lateral cephalograms, photographs, and dental models. Pedigrees were drawn using PELICAN and complex segregation analysis was performed using POINTER. Parts of some pedigrees were excluded to create one founder pedigrees, so the total N was 2,050. Analysis showed more affected females than males (P = 0.030). The majority of the pedigrees suggest autosomal dominant inheritance. Incomplete penetrance was demonstrated by the ratio of affected/unaffected parents and siblings. The heritability of mandibular prognathism was estimated to be 0.316. We conclude that there is a major gene that influences the expression of mandibular prognathism with clear signs of Mendelian inheritance and a multifactorial component.     

Gene diagnosis of Alzheimer's disease and Parkinson's disease

Alzheimer's disease(AD) is the most common form of neurodegenerative diseases that causes intellectual dysfunction. AD is a genetically heterogenous disorder. Over 100 mutations have been identified in three causative genes, i.e. amyloid protein precursor(APP), presenilin 1(PS1) and presenilin 2(PS2) genes, for early-onset autosomal dominant familial AD(FAD). Apolipoprotein E(APOE) gene has been identified as susceptibility gene for late-onset FAD. The missense mutations in the causative genes lead to abnormal APP processing with overproduction of total A beta protein or A beta 42(43) isoform. The epsilon 4 allele of APOE gene is a genetic risk factor for sporadic AD as well as FAD. Parkinson's disease(PD) is another common form of neurodegenerative disease that causes movement dysfunction. Three genes, i.e. alpha-synuclein (SNCA), parkin(PARK2), and ubiquitin carboxy-terminal hydrolase L1(UCHL1) genes, have been identified as causative genes for familial PD. The B mutation of CYP2D6 gene(CYP2D6*4 allele) is a genetic risk factor for PD. Lewy body(LB), that is an intracellular inclusion body characteristic of PD, is widely distributed in the cerebral cortex of 20 to 30% of AD patients. This disease entity is called as Lewy body variant(LBV) of AD. LBV shares the genetic risk factor with AD and PD, i.e. APOE epsilon 4 allele and CYP2D6 B mutation. Gene diagnosis is possible for familial AD and PD. APOE and CYP2D6 genotyping is also applicable to the future prediction of AD and PD, respectively.     

SPG4基因的遗传学研究

遗传性痉挛性截瘫(hereditary spastic paraplegia,HSP),又称为家族性Strümpell-Lorrain病,是一种具有临床及遗传高度异质性的神经系统遗传病,患病率为2/10万～9.6/10万,表现为缓慢进展的双下肢无力及痉挛性截瘫.根据遗传方式不同HSP可分为常染色体显性遗传、常染色体隐性遗传和X-连锁隐性遗传,以常染色体显性遗传最常见.目前已经发现40个HSP基因位点,已克隆19个疾病基因.其中spastin基因突变所致的遗传性痉挛性截瘫4型(spastic paraplegia-4,SPG4)约占常染色体显性遗传的HSP的40%.基因检测是诊断该病的金标准,有助于早期诊断、症状前诊断及产前诊断.动物模型的研究对揭示HSP的分子病理机制有重要作用,本文就SPG4基因的遗传学研究作一概述.     

Systematic genetic study of Alzheimer disease in Latin America: mutation frequencies of the amyloid beta precursor protein and presenilin genes in Colombia

Nearly all mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid beta precursor protein (APP) genes lead to early-onset Alzheimer disease (EOAD, onset age at or before 65 years). In order to assess the genetic contribution of these genes in a series of Colombian AD cases, we performed a systematic mutation analysis in 11 autosomal dominant, 23 familial, and 42 sporadic AD patients (34% with age of onset < or = 65 years). No APP missense mutations were identified. In three autosomal dominant cases (27.2%), two different PSEN1 missense mutations were identified. Both PSEN1 mutations are missense mutations that occurred in early-onset autosomal AD cases: an I143T mutation in one case (onset age 30 years) and an E280A mutation in two other cases (onset ages 35 and 42 years). In addition, a novel PSEN1 V94M mutation was present in one early-onset AD case without known family history (onset age 53 years) and absent in 53 controls. The E318G polymorphism was present in five AD cases and absent in controls. In PSEN2, two different silent mutations were detected, including one not reported elsewhere (P129). The majority of the Colombian AD cases, predominantly late-onset, were negative for PSEN and APP mutations.     

Age of onset in familial early onset Alzheimer's disease correlates with genetic aetiology

Age of onset is the most robust clinical feature demarcating aetiologic subtypes of familial Alzheimer's disease. It has previously been noted that early onset disease (arbitarily below the age of 65 years) conforms to an autosomal dominant pattern of transmission. Late onset disease is generally thought to have a more complex aetiology. We present data here suggesting that early onset disease can be subdivided by genetic aetiology with which age of onset correlates. In general, those pedigrees showing linkage to the chromosome 14 locus have a mean age of onset in the forties whereas those pedigrees with an APP mutation have an age of onset in the fifties. © 1993 Wiley-Liss, Inc.     

Discriminating among single locus models using small pedigrees

Simulated small pedigrees (2 parents, 4 offspring) were used to illustrate the applications and limitations of a “model choice” approach designed to detect genetic heterogeneity in familial diseases. While it is possible to identify groups of pedigrees which have different genetic causes for quantitative phenotypic trait(s), theoretical limitations on discriminating between 4 single locus models exist for certain pedigree structures. These limitations originate from the overlapping phenotypic predictions of the various genetic models. Such limitations must be carefully considered in the design of genetic studies. Studies aimed at detecting genetic heterogeneity in familial diseases should limit the different genetic models being considered and tailor the sampling strategy to avoid collecting pedigrees which are non-informative for certain comparisons.     

Genetic testing in familial and young-onset Alzheimer's disease: mutation spectrum in a Serbian cohort

Alzheimer's disease (AD) is the most common form of dementia. To date, more than 200 mutations in three genes have been identified as cause of early-onset autosomal dominant inherited AD. The aim of this study was to characterize the mutation spectrum and describe genotype-phenotype correlations in Serbian patients with positive family history of AD or/and early-onset AD. We performed a genetic screening for mutations in the coding regions of Presenilins 1 and 2 (PSEN1 and PSEN2), as well as exons 16 and 17 of the Amyloid Precursor Protein gene (APP) in a total of 47 patients from Serbia with a clinical diagnosis of familial and/or early-onset AD (mean age at onset of 60.3 years; range 32-77). We found one novel mutation in PSEN1, one novel variant in PSEN2, and three previously described variants, one in each of the analyzed genes. Interestingly, we identified one patient harboring two heterozygous mutations: one in APP (p.L723P) and one in PSEN1 (p.R108Q).     

Familial Scheuermann disease: a genetic and linkage study.

Scheuermann juvenile kyphosis or Scheuermann disease is the most frequent cause of kyphosis in adolescence. However, the natural history and genetic basis is still unknown. Reports of identical radiological changes in monozygotic twins, sib recurrence, and transmission over three generations suggest underlying heritability. In this study, 12 probands were referred to us. Upon radiological examination of the proband's parents and sibs, seven were shown to have familial Scheuermann disease with an autosomal dominant pattern of inheritance. Of the remaining five probands, four had chromosomal anomalies. The three largest pedigrees were subjected to linkage analysis with three candidate genes: Duffy, COL1A1, and COL1A2. Linkage of Scheuermann disease was excluded with Duffy (lod score = -2.195 at theta = 0.10) and COL1A2 (lod score = -2.750 at theta = 0.05) in these families.     

Familial Alzheimer Dementia: a prevalent disorder with specific clinical features

The early literature on Alzheimer Dementia (AD) describes the clinical features aphasia, apraxia and agraphia as characteristic. We investigated the hypothesis that these features would specifically identify the familial form of AD (FAD). Since pedigree studies had suggested that FAD is an autosomal dominant genetic disorder, we hypothesized that the first-degree relatives of language-disordered or apractic AD probands would show at least 50% lifetime risks of dementia. Using standardized methods, we screened 3500 nursing home beds for stringently defined AD cases and controls, tested for agraphia, and obtained probands' clinical and family histories from multiple informants. Language disorder and apraxia were found in 78% of AD cases. They strongly predicted familial aggregation of dementia, with a 90-year lifetime incidence among relatives exceeding 50%, or 7 times the control values. The results suggest that language disorder and apraxia specifically identify a distinct clinical entity, Familial Alzheimer Dementia, that is among the commonest forms of senile dementia.     

Analysis of the butyrylcholinesterase gene and nearby chromosome 3 markers in Alzheimer disease

The K-variant of butyrylcholinesterase (BCHE-K) recently has been reported to be associated with Alzheimer disease (AD) in carriers of the epsilon4 allele of the apolipoprotein E (APOE) gene. We have re- examined the frequency of the BCHE-K allele in a large data set of both sporadic and familial cases of AD disease, and we have also examined the segregation of three genetic markers on chromosome 3 near BCHE . Our data neither support an association of BCHE-K with sporadic or familial AD, nor do they suggest the existence of another gene nearby on chromosome 3 as a common cause of familial AD.