Significant changes in the tau A0 and A3 alleles in progressive supranuclear palsy and improved genotyping by silver detection.

BACKGROUND: Progressive supranuclear palsy (PSP) is characterized by intraneuronal inclusions of neurofibrillary tangles formed by aggregated tau protein. A significant association between the tau gene A0/A0 genotype and PSP recently has been reported. OBJECTIVES: To determine if a significant association between the tau gene A0/A0 genotype and PSP could be found in an independent population with a genetic background different from that in which the initial association was reported, and to standardize a nonradioactive method for tau gene genotyping. SETTING: Hospital and university research laboratories. SUBJECTS AND METHODS: To facilitate genotyping of the tau gene, we standardized the conditions for silver-based detection of the tau gene dinucleotide polymorphism. Thirty patients from Spain clinically diagnosed as having probable PSP were included in the study and compared with different control groups. RESULTS: A highly significant overrepresentation of the A0/A0 genotype (P<.001) and a decrease in the frequency of the A0/A3 genotype were found in the Spanish patients with PSP compared with the control group. A method based on silver detection was standardized for the genotyping of the tau gene. CONCLUSIONS: The detection of a significant association between the tau gene A0/A0 genotype and PSP in 2 independent populations rules out genetic stratification as an explanation for the association and indicates that the presence of the tau A0/A0 genotype is a risk factor for developing PSP independent of genetic background. Alternatively, the results could be interpreted as a protective effect of the A3 allele.

A presenilin 1 mutation (Ser169Pro) associated with early-onset AD and myoclonic seizures.

OBJECTIVE: To characterize the mutation responsible for early-onset AD in a large Spanish kindred. BACKGROUND: Mutations in the presenilin 1 (PS1) gene have been identified and are known to be responsible for 18 to 50% of familial early-onset AD cases. METHODS: Patients were characterized clinically. The proband was further studied with EEG, CSF analysis, CT, brain biopsy, and histology. Other members were studied using EEG, CT, MRI, and SPECT. Genetic analysis of PS1 was performed using PCR amplification of PS1 exons and direct sequencing followed by PS1 modeling of the normal and mutant PS1 proteins. RESULTS: A novel mutation (Ser169Pro) in exon 6 of the PS1 gene was identified in different affected members. The Ser169Pro mutation is located at a site of the PS1 protein that is not a cluster of mutations. The mutation was not present in 100 general population controls and in 50 unrelated sporadic AD cases. The Ser169Pro mutation is associated with generalized myoclonic seizures several years after the initial symptoms of AD, a very early AD onset (< or =35 years), and a rapidly progressive cognitive decline. CONCLUSIONS: The absence of the PS1 Ser169Pro mutation in the general population and in sporadic AD cases together with its detection in the affected members of this kindred suggests that it is a pathogenic mutation. The serine to proline change predicts a kink in the alpha-helix of the transmembrane domain of the PS1 protein that could radically disrupt its normal structure. Further characterization of the effect of this mutation could help identify the function of the PS1 protein and the pathogenic mechanisms of AD.

Alpha1-antichymotrypsin gene polymorphism and susceptibility to Parkinson's disease.

OBJECTIVE: To determine whether the alpha1-antichymotrypsin AA genotype (ACT-AA) confers susceptibility for developing Parkinson's disease (PD) in the Spanish population. BACKGROUND: A correlation between the ACT-AA genotype and the risk of developing PD has been recently reported in the Japanese population. METHODS: The ACT genotypes of 71 patients diagnosed with clinically definite PD were compared with those of 109 age-matched healthy control subjects. RESULTS: The authors found that the ACT-AA polymorphism frequency was not increased significantly in the PD group (31%) compared with the control group (28.4%). The ACT allelic distribution was also similar for familial and sporadic PD, for female and male patients, and for the different clinical subtypes of PD. The age at onset of PD was significantly lower in the ACT-AA patients compared with non-ACT-AA patients. When the actual age was considered, the ACT-AA frequency was higher in PD patients < or =50 years old (50%) compared with that present in patients >50 years old (26.8%), but the same effect was found in control subjects. CONCLUSIONS: The ACT-AA polymorphism is not related to an increased risk of developing PD in the Spanish population. The ACT-AA overrepresentation in PD and control subjects < or =50 years old suggests that this polymorphism could be associated with life-threatening conditions other than PD.

Nager anomaly with severe facial involvement, microcephaly, and mental retardation.

A girl is reported who has severe facial abnormalities with preaxial anomalies of upper and lower limbs indicative of Nager syndrome. Additional findings include marked microcephaly, mental retardation, and normal hearing.

SRY gene transferred to the long arm of the X chromosome in a Y-positive XX true hermaphrodite.

Yp-specific sequences, including the testicular determinant gene SRY, have been detected and located in a 46,XX true hermaphrodite individual, using PCR amplification and fluorescent in situ hybridization (FISH). Among different Y chromosome loci tested, it was only possible to detect Yp sequences. The Y-centromere and Yq sequences were absent. Unexpectedly, the Y fragment was translocated to the long arm of one of the X chromosomes, at the Xq28 level, and the derivative (X) chromosome of the patient lacked q-telomeric sequences. To our knowledge, this is the first Yp/Xq translocation reported. The coexistence of testicular and ovarian tissue in the patient may have arisen by differential inactivation of the Y-bearing X chromosome, in which Xq telomeric sequences are missing. The possible origin of the Yp/Xq translocation, during paternal meiosis or in somatic paternal cells, is discussed.

Paternal isodisomy 13 in a normal newborn infant after trisomy rescue evidenced by prenatal diagnosis.

Maternal and paternal uniparental disomy of chromosome 13 have been associated with normal phenotypes. We report on a new case of paternal isodisomy 13 in a phenotypically normal girl. Prenatal diagnosis had shown a 46,XX,-13,der(13;13) karyotype in chorionic villi and a 45,XX,der(13;13) karyotype in amniocytes and fetal blood. Molecular studies demonstrated that the de novo der(13;13) was an isochromosome 13 of paternal origin. This observation supports the lack of imprinting effects on chromosome 13 and trisomy rescue as a mechanism leading to uniparental disomy in cases involving isochromosomes.

Analysis of the polymorphic (GT)(n) repeat at the dopamine beta-hydroxylase gene in Spanish patients affected by schizophrenia.

The presence of a polymorphic (GT)(n) repeat, a microsatellite repeat, at the human dopamine beta-hydroxylase (DBH) gene had been previously investigated in healthy people and in schizophrenic patients. The different DBH genotypes had been found to be associated to different DBH biochemical function, but no differences were found in the allelic and genotype frequencies between schizophrenic and control groups. To further clarify the potential involvement of the variation at the DBH gene in schizophrenia we have studied the DBH (GT)(n) repeat in a sample of 47 Spanish schizophrenic patients, in their healthy relatives (n = 72), and in a control population (n = 74). We have been able to identify five different variants of the DBH gene (A1, A2, A3, A4, A5) in the different groups. Subsequent statistical analysis revealed that the genotypes as well as the allele frequencies did not differ significantly among schizophrenic patients and the control population. Interestingly, the allelic variant A2 and the genotype A4/A2 were significantly more frequent in schizophrenic patients as compared with their healthy relatives. However, the association of the A2 allele with schizophrenia was not supported by the haplotype relative risk analysis of transmitted versus nontransmitted alleles. Therefore, although it will be important to extend the present analysis in a larger sample of schizophrenic patients and controls, our results suggest that the (GT)(n) does not seem to play a major role in the genetics of schizophrenia at least in this group of Spanish schizophrenic patients. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:88-92, 2000.

Cytogenetic studies in blast crisis of Ph-positive chronic granulocytic leukemia: results and prognostic evaluation in 52 patients.

Bone marrow cytogenetic (G-banding) studies were carried out in 52 patients with Ph-positive chronic granulocytic leukemia (CGL) at the time of diagnosis of blast crisis. In all cases, the Ph chromosome was due to the standard (9;22) translocation. Eighteen patients displayed the 46,Ph cell line unchanged, whereas additional chromosome abnormalities were observed in the remaining 34 patients (65.4%). Among the latter, numerical karyotypic changes were found in 31 patients and structural changes in 8 patients. Five patients displayed numerical and structural changes simultaneously. The most common chromosome numerical changes were an extra #8 (14 cases) and additional Ph chromosomes (11 patients); an i(17q) was the most frequently observed structural change (3 cases). These three aberrations were often combined; at least one of them was present in 21 patients, constituting 62% of the cases with new cytogenetic abnormalities at blast crisis. When comparing the clinical and hematologic characteristics, as well as the survival, of patients retaining the unchanged 46,Ph cell line and patients showing additional chromosome changes, no differences were found between the two groups of patients. However, a minority displaying a hypodiploid modal chromosome number survived significantly longer than the remaining patients.

Prevalence of Y chromosome microdeletions in oligospermic and azoospermic candidates for intracytoplasmic sperm injection.

OBJECTIVE: To determine the prevalence and type of Y chromosome microdeletions in 136 consecutively seen intracytoplasmic sperm injection (ICSI) candidates and in 50 consecutively seen azoospermic men attending an infertility clinic. DESIGN: Controlled clinical study. SETTING: Genetics laboratory and infertility clinic at a University hospital. PATIENT(S): One hundred eighty-six men who were seen at an infertility clinic and who were referred to a genetics counseling service for genetic assessment before ICSI. INTERVENTION(S): Collection of semen and blood samples. MAIN OUTCOME MEASURE(S): Semen analysis; serum FSH, LH, and T levels; karyotype analysis; and presence or absence of several single tagged site markers along the Y chromosome (sY274, sY238, sY276, sY84, sY102, sY143, sY153, sY254, sY269, sY202, sY158, sY160). RESULT(S): Yq chromosome microdeletions were detected in 10 (5.4%) of 186 consecutively seen ICSI candidates. The number of microdeletions was much higher in azoospermic patients (16%; 8 of 50) than in oligospermic patients (1.5%; 2 of 136). Two of the azoospermic patients with a Yq microdeletion also had sex chromosome aneuploidy mosaicism. No microdeletions were detected in 100 consecutively seen fathers who were included as controls. CONCLUSION(S): The prevalence of Yq microdeletions in the azoospermic group was much higher than in the oligospermic group and was consistent with the prevalence of Yq microdeletions detected in other series of azoospermic men in different geographic areas. All Yq microdeletions found in our patients belong to the AZFc region, indicating that microdeletions of the AZFa and AZFb regions are infrequent among oligospermic ICSI candidates or azoospermic males in our population.

Alpha-antichymotrypsin gene polymorphism and risk for Alzheimer's disease in the Spanish population.

The alpha-antichymotrypsin (ACT) and the ApoE polymorphisms have been determined in 136 Alzheimer's disease (AD) patients and in 92 age-matched controls. Only a borderline significant difference is found when comparing the overall ACT/AA genotype frequency between AD patients and controls (chi2, P = 0.08). However this difference is attributable entirely and significantly to the ApoE epsilon4 non-carrier AD group (chi2, P = 0.004). No differences are found in the ACT/AA genotype frequency of the ApoE epsilon4 AD carrier group as compared controls (chi2, P = 0.98) in contrast with previous works. These findings support that the presence of the ACT/AA genotype is a genetic risk factor for developing AD in non-ApoE epsilon4 carriers subjects in our population.

Identification of Spanish familial Parkinson's disease and screening for the Ala53Thr mutation of the alpha-synuclein gene in early onset patients.

We initiated the present work in order to determine if the Ala53Thr mutation of the alpha-synuclein gene previously described by Polymeropoulos et al. [Science, 276 (1997) 2045-2047] could be detected in Spanish early onset Parkinson's disease (PD) patients. Thirty-four PD patients were evaluated. Of these, 13 were considered early onset patients (six familial and seven sporadic) and were included in the genetic study. We detected the presence of genetic anticipation in four kindreds with early onset PD members. The Ala53Thr mutation of the alpha-synuclein gene was absent in all patients. The results do not support a role for this mutation in our patients with early onset PD and, in agreement with the results previously reported, indicate that the Ala53Thr mutation of the alpha-synuclein gene is a rare cause of PD.

The genotype 2/2 of the presenilin-1 polymorphism is decreased in Spanish early-onset Alzheimer's disease.

We have found a significantly lower frequency of the presenilin-1 (PS-1) intronic polymorphism 2/2 genotype in early-onset Alzheimer's disease (AD) patients without APOE epsilon4 alleles (2/2 = 0.054; P = 0.009) as compared to age matched non-epsilon4 controls (2/2 = 0.227). Moreover the average age of onset in AD patients with the PS-1 2/2 genotype is older than that in AD patients with a 1/2 genotype or with a 1/1 genotype. This data suggest a protective effect of the 2/2 genotype which would delay the age of onset in AD. Our results do not support an association between the 1/1 genotype and AD. However, a non-significant increase of the 1/1 genotype is found in non-epsilon4 AD patients (P = 0.20).

Apolipoprotein E epsilon 4 alleles and meiotic origin of non-disjunction in Down syndrome children and in their corresponding fathers and mothers.

An increased risk of Alzheimer disease (AD) has been reported in young mothers of Down syndrome (DS) probands. Subsequently, an increased frequency of the apolipoprotein E (apoE) allele epsilon 4 has been found in mothers (< or = 32 years) of DS children due to meiosis II (MII) errors providing a potential explanation for the increased risk of AD in DS mothers. In the present study we genotyped apoE and determined the origin of non-disjunction of 132 mothers and the corresponding fathers and DS children from Spain. Unexpectedly no epsilon 4 alleles have been detected in MII mothers of < or = 32 years of age (P = 0.02). Thus our study not only fails to find the effect previously reported, but it detects an opposite correlation. An increase in the epsilon 4 frequency (0.227) is detected in MI mothers <28 as compared to the epsilon 4 frequency present in MI mothers >28 years of age (0.089), although the differences are not significant if correction for multiple comparisons is applied. The simplest overall interpretation of the previously reported and present findings is that the detected associations are due to random statistical variation rather than to some real effect of the epsilon 4 allele. However the important potential implications of alternative explanations imply that this issue deserves further clarification in independent studies in other populations.

[Clinical characterization, molecular and FISH studies in 80 patients with clinical suspicion of Williams-Beuren syndrome]. / Caracterización clínica y genética de 80 pacientes con sospecha clínica de síndrome de Williams-Beuren.

BACKGROUND: Williams-Beuren syndrome is a developmental disorder affecting vascular and connective tissues and central nervous system. The syndrome is caused by a submicroscopic deletion in the chromosome 7 implicating the 7q11.23 region. Fluorescence in situ hybridization (FISH) and molecular studies allow us to confirm the clinical suspicion of this syndrome. PATIENTS AND METHODS: We report clinical evaluation, FISH using Elastin Williams/D7S427 probe and molecular study with markers: D7S672, D7S653, D7S489B, D7S2476, D7S1870 and D7S489A, in 80 patients referred to test for Williams-Beuren syndrome. RESULTS: We found hemizygosity for the critical region in 36 patients. From 69 cases studied by FISH, 28 showed the deletion. Molecular studies in 78 cases showed loss of heterozygosity (LOH) in 26 patients. The patients presented the deletion from the paternal or maternal chromosome at equal frequency. Clinical evaluation of mental retardation, facial features, esotopia dental, malocclusion, hoarse voice, supravalvular aortic stenosis (SVAS), hernias, join limitation, WBS personality and mental retardation from positive and negative patients showed estatistical significant differences for all items except mental retardation and joint limitation. The most significant item was the presence of SVAS. CONCLUSION: This study confirms the usefulness of genetic studies as a diagnostic tool for William-Beuren Syndrome.

[Transient cerebral oedema associated to hypoglycaemia]. / Edema cerebral transitorio asociado a hipoglucemia.

INTRODUCTION: In the adult, hypoglycaemia is documented as a consequence of overdose of insulin or oral hypoglycaemic agents. Neonatal hypoglycaemia is common but rarely symptomatic due to protective mechanisms. Very few reports on hypoglycaemic injury are available in adults and most of them in patients with poor outcome. CASE REPORT: Woman, 45 years old. She is referred to emergency room due to insulin overdose and coma of unknown duration. Glucose level was 15 mg% without other metabolic anomalies. Computerized tomography revealed brain oedema most obvious in the parieto-occipital lobes. Therapy with manitol and glucose was started with total functional recovery. CONCLUSIONS: Brain imaging in neonatal hypoglycaemia shows similar findings. In the acute phase oedema in the parieto-occipital cortex and underlying white matter and atrophy or malacic cysts in the chronic phase have been described. Chronic changes are related to long-term sequelae that vary from development delay and epilepsy to persistent vegetative state. In adults lesions involve hippocampus and basal ganglia. The reasons of different sensitivity of these regions are not fully clear. Differences in regional blood flow autoregulation or in excitotoxins receptors of aspartate have been postulated. Hypoglycaemia may induce blood-brain-barrier permeability and subsequently brain oedema.

Mutation analysis of Wilson disease in the Spanish population -- identification of a prevalent substitution and eight novel mutations in the ATP7B gene.

Wilson disease (WD) is a copper metabolism disorder characterized by hepatic and/or neurological damage. More than 200 mutations in the ATP7B gene causing this autosomal recessive defect have been reported. In certain populations, a high prevalence of particular mutations allows rapid screening and diagnosis of the disease. We identified the ATP7B alterations in Spanish patients with WD. Mutations in the ATP7B gene were analysed in a total of 64 individuals from 40 different WD families by PCR amplification, single-strand conformation polymorphism (SSCP) analysis and sequencing. Twenty-one different ATP7B gene mutations were identified, eight of which were novel. 74% of the disease alleles were characterized among the 40 unrelated probands. We identified a prevalent mutation in our population (Met645Arg), present in 55% of this 40 patients. The frequency of the remaining ATP7B alterations was low. In addition, 17 different polymorphic variants were found. There is remarkable allele heterogeneity in WD in the Spanish population. Nevertheless, SSCP screening for the most frequent mutations in our population is feasible and leads to the detection of about 74% of the mutated chromosomes. Molecular diagnosis of WD is very useful in clinical practice to confirm or support clinical suspicion.

[Genetics and allergy]. / Genética y alergia.

Complex diseases, including diseases of allergic origin (asthma, rhinitis, dermatitis), tend to cluster in families, suggesting the existence of a genetic predisposition that has been confirmed by the family and twin studies. However, it is difficult to establish a clear Mendelian pattern of inheritance and it is accepted that multiple genes exist which have an additive effect (polygeny) and interact with environmental factors (multifactorial polygenic mechanism) to cause not only the atopic constitution but also the pathology that derives from it. Advances in genetics and molecular biology, through linkage studies in chosen family nuclei and different population groups, are facilitating the location of chromosomal regions related with allergic pathology. The genes situated in these regions are considered candidate genes, and the genes themselves and the functions that they control are studied in relation to allergic disease. Although there are regions and candidate genes distributed throughout the genome, chromosomes 5, 6, 11, and 14 contain genes whose responsibility for susceptibility to atopy, asthma and bronchial hyperreactivity is accepted and whose polymorphisms could be risk factors. The study of these genes and many other candidate genes may clarify some etiopathogenic aspects of diseases of allergic origin and improve their prophylaxis and therapy.