摘要:

The presenilin‐1 (PS‐1)/S 182gene at chromosome 14q24.3 is, when mutated, the most common disease gene in autosomal dominant early‐onset Alzheimer's disease. Substitution of methionine 146 of the gene product for either valine or leucine co‐segregates with Alzheimer's disease with the age of onset in the late thirties or early forties. Here we describe a new substitution of methionine 146 for isoleucine that co‐segregates with Alzheimer's disease with age of the onset in the early forties. All identified missense mutations in methionine codon 146 replace one hydrophobic amino acid (Met) with another (Val, Leu, Ile) and correspond to any nucleotide change at the first or third position of the codon. Second position mutations invariably lead to replacement of the hydrophobic methionine with a hydrophilic amino acid that may severely affect the function of the protein. The fact that no second position mutations have been identified so far may support the hypothesis that the protein product ofPS‐1plays a crucial role during

ISSN:0009-9163    

DOI:10.1111/j.1399-0004.1996.tb02375.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Metachromatic leukodystrophy (MLD) is an autosomal, recessively inherited, lysosomal storage disease caused by arylsulfatase A (ASA) activity deficit. Arylsulfatase A initiates the degradation of sulfatide (cerebroside sulfate), which is an essential component of myelin. The main clinical symptoms are caused by progressive demyelination. At least 37 MLD‐related ASA mutations are known to date. I179S (E3P799) is a disease‐related mutation, described for the first time by Fluharty in 1991. This aberration appears to substantially reduce, but not completely eliminate ASA activity, and was detected in individuals with late‐onset (juvenile or adult) forms of MLD. This paper deals with the peculiar clinical course in three unrelated juveniles with late‐onset MLD carrying the I179S mutation on one allele. In the three described patients with the I179S mutation, psychiatric disturbances and intellectual impairment dominated the clinical picture, while the neurological lesions progressed more slowly. Although the symptoms appeared rather early, making it possible to classify this as the juvenile type of MLD, the clinical picture was more that of the adult type. Although the mutations on the second allele in our patients are unknown, one can speculate, that the mutation I179S plays an important role in the characteristic clinical course (psychiatric impairment, slower neurological deterioration, but relatively early onset). It seems that I179S mutation on one allele with another mutation on the other allele reduces ASA activity, but the enzyme can still cope with a part of the substrate influx, leading to late‐juvenile‐onset MLD with such strikingly similar phenotypes remaining a little bit of the adult (psychiatric) type. This could be one more argument in favour of phenotype‐genotype correlation in pati

ISSN:0009-9163    

DOI:10.1111/j.1399-0004.1996.tb02376.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

The presence of the apolipoprotein E e4 allele has been considered to be a risk factor for Alzheimer's disease and vascular dementia. We therefore used demanding neuropsychologic testing and brain MRI to determine if elderly normals with at least one e4 allele demonstrate subclinical changes in cognition and a higher frequency of brain atrophy or silent ischemic brain damage. The study population consisted of 214 randomly selected individuals aged 50 to 75 years without neuropsychiatric or general disease. There were 175 (81.8%) subjects without and 39 (18.2%) with at least one e4 allele. The two groups were comparable for age, length of education, verbal intelligence, mood and major vascular risk factors. Apolipoprotein E e4 carriers performed significantly worse than non‐carriers when assessed for learning and memory abilities, while there were no differences in test results of conceptualization, attention, speed of mental processing and visuopractical skills. There were no between‐group differences for thromboembolic and lacunar infarcts, white matter hyperintensity grading and the semiautomatically measured white matter hyperintensity area. The extent of sulcal and ventricular widening as well as hippocampal and parahippocampal volumes were also similar between the comparative subsets. We conclude that the apolipoprotein E e4 allele is associated with subtle learning and memory deficits in normal elderly persons and may therefore be suggested a marker for accelerated cognitive aging. In this group of subjects it was not associated with brain parenchymal changes as demonstrated by

ISSN:0009-9163    

DOI:10.1111/j.1399-0004.1996.tb02377.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Cytogenetic analysis of amniotic fluid cells from a 31‐week‐old fetus suffering from polyhydramnios revealed that there were two cell lines, each with either trisomy 13 or trisomy 18. We studied the origin and mechanism of formation of this unique mixoploidy by tracing chromosomal heteromorphisms as genetic markers, and showed no discordance of parent‐child transmission between the two cell lines in any of the heteromorphisms examined. The result indicated that the mixoploidy is not chimerism but mosaicism and that the mechanism of mosaic development is most likely due to two non‐disjunctional events which had occurred independently at the two‐cell stage of the zygote. A girl was born at the 38th gestational week and her clinical features were mainly those for trisomy 13. Chromosome analysis of the newborn confirmed +13/+18 mosaicism in fibroblasts from the skin and chorionic plate, while cord blood lymphocytes and chorionic villus cells showed only the +18

ISSN:0009-9163    

DOI:10.1111/j.1399-0004.1996.tb02378.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

We have studied a family with autosomal dominant osteogenesis imperfecta (OI) type IV. Electrophoresis of collagen produced by cultured fibroblasts revealed a slower migrating population of collagen I. Cyanogen bromide peptide mapping localised the structural defect to the area of the αl(l)CB3 peptide. Subsequent sequencing revealed a deletion of nucleotides 1964–1966 in exon 27 of COL1A1. By means of restriction enzyme analysis, the deletion could be detected in all affected family members. This in‐frame deletion resulted in the removal of alanine‐438 and a Glu437Asp substitution in the proαl (I) collagen chain. Clinical variation was considerable among affected family members. The most consistent clinical features were reduced height and extraosseous manifestation

ISSN:0009-9163    

DOI:10.1111/j.1399-0004.1996.tb02379.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

In a large five‐generation Polish family, late‐onset ornithine transcarbamylase (OTC) deficiency in males segregated with the missense mutation Ala208Thr (A208T), and all heterozygous females were asymptomatic. No other mutations were found in the coding sequences and intron‐exon boundaries of the OTC gene. Surprisingly, the mutation originated from the great‐grandfather of the index patient who died at age 59 of liver carcinoma. He never had dietary restrictions or hyperammonemic spells throughout life and appears to be the oldest male reported with OTC deficiency. The index patient had a severe OTC deficiency (3% of normal). Eight males died suddenly at ages 4 months to 23 years (average 14 years) after a foudroyant episode triggered by a common infection. The patients remained undiagnosed for 28 years because a metabolic defect was not considered to be the cause of the acute episodes. Recognition of the familial pattern of inheritance was initially unnoticed since the patients were admitted to eight different hospitals. DNA analysis predicted that two ‘healthy’ boys also had OTC deficiency, which was confirmed by abnormal results of allopurinol challenge tests. Initial suspicion of OTC deficiency in such families is complicated, since symptoms can develop at any age, or even remain absent. This obscures the typical pattern of X‐linked inheritance in s

ISSN:0009-9163    

DOI:10.1111/j.1399-0004.1996.tb02380.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Seventy‐one children with Down syndrome who were admitted consecutively to Hacettepe University Children's Hospital Genetics Department were examined for skin disorders. None of the patients suffered directly from skin disorders. All were living with their families and had approximately similar living conditions. There were 29 children with palmoplantar hyperkeratosis (40.8%), seven with xerosis (9.8%), 22 with seborrheic dermatitis (30.9%), 14 with fissured tongue (20%), eight with geographic tongue (11.2%), and nine with cutis marmorata (12.6%). Nine had normal skin findings. Since palmoplantar hyperkeratosis may be a result of vitamin A deficiency, the serum vitamin A levels of these patients were evaluated. There was no statistical difference between vitamin A levels of the children with Down syndrome and the control grou

ISSN:0009-9163    

DOI:10.1111/j.1399-0004.1996.tb02381.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Chromosome aberrations, mendelian mutations and exogenous agents can cause holoprosencephaly. Therefore, etiologic evaluation of holoprosencephaly is necessary for obstetricians and genetic counselors, once a prenatal diagnosis of holoprosencephaly has been made. We present four pregnancies in three women in which routine sonographic examinations led to the prenatal diagnosis of holoprosencephaly. Prenatal cytogenetic analysis and fluorescencein situhybridization demonstrated a 46, XY, del(7)(pter→q32:) and a 46, XY, der(2)t(2;3)(q37;p21)pat karyotype respectively in two fetuses with cyclopia, and a 46, XX, der(2)t(2;3)(q37;p21)pat and a 46, XX, der(7)t(3;7)(p23;q36) karyotype respectively in two fetuses with premaxillary agenesis. In conclusion, terminal deletion 7q and partial trisomy 3p in holoprosencephalic fetuses indicates that genes contributing to craniofacial development reside in these critical regions. Proper prognostic evaluation in further pregnancies requires expertise in cytogenetics and genetic counselin

ISSN:0009-9163    

DOI:10.1111/j.1399-0004.1996.tb02382.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Accurate carrier determination is an important aspect in providing prenatal diagnosis and genetic counselling to families with Duchenne/Becker muscular dystrophy patients. Using quantitative polymerase chain reaction, we have analyzed the carrier status of 31 mothers (8 familial and 23 sporadic) who have an affected son with known deletion in the dystrophin gene. Only four out of 23 mothers of sporadic cases turned out to be heterozygous for the deleted exons. The lower number of carrier mothers in sporadic cases suggests a higher frequency of new mutations in North Indian DMD/BMD patients.

ISSN:0009-9163    

DOI:10.1111/j.1399-0004.1996.tb02383.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Genetic and environmental factors have been implicated in the etiology of atopy and of serum IgE levels. In order to eliminate post‐natal environmental influences we measured IgE in cord blood (CB‐IgE) from a cohort of unselected, like‐sexed twins. IgE determination was performed with a sensitive radioimmunoassay with a detection limit of 0.01 kU/l. Samples with contamination by maternal blood were identified by IgA determination and excluded. CB‐IgE was evaluated in 29 monozygotic (MZ) and 28 dizygotic (DZ) twin pairs. The means and variances for IgE values were comparable for MZ and DZ twins when sex was controlled for. Placental anatomy (MZ twins with mono‐and dichorial placenta and DZ twins with one or two placentae) had no significant influence on the IgE levels. In an analysis of variance with subsampling the among‐pair, within‐pair and analytical variance components were calculated. The analytical variance was well below the biological variances. Biometrical analysis showed that the best model by Akaike Information Criteria was a model including only additive genetic and non‐shared environmental factors. With this model the heritability estimate was 0.8. These data suggest that the majority of the variation in CB‐IgE is accounted for by genetic factors, but a substantial effect of a common environment cannot be excluded with the pr

ISSN:0009-9163    

DOI:10.1111/j.1399-0004.1996.tb02384.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY