Neuropsychological deficits in obligatory heterozygotes for metachromatic leukodystrophy

Summary Two groups of heterozygotes, one for metachromatic leukodystrophy (MLD) and the other for Tay-Sachs disease, were given a battery of neuropsychological tests, a standard neurological examination, and an EEG. Neurological and EEG findings were unremarkable for both groups. The MLD heterozygotes showed deficits in the neuropsychological tests involving spatial or constructional components, but not in tests involving language skills. The Tay-Sachs heterozygotes showed no consistent deficit on any component of the neuropsychological tests.     

Multiple mutations are responsible for the high frequency of metachromatic leukodystrophy in a small geographic area.

Metachromatic leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulfatase A. The disease occurs panethnically, with an estimated frequency of 1/40,000. Metachromatic leukodystrophy was found to be more frequent among Arabs living in two restricted areas in Israel. Ten families with affected children have been found, three in the Jerusalem region and seven in a small area in lower Galilee. Whereas all patients from the Jerusalem region are homozygous for a frequent mutant arylsulfatase A allele, five different mutations were found in the families from lower Galilee. In patients of Muslim Arab origin, we have found a G86-->D, a S96-->L, and a Q190-->H substitution. Two different defective arylsulfatase A alleles, characterized by a T274-->M and a R370-->W substitution, respectively, have been found among the Christian Arab patients. All mutations were introduced into the wild-type arylsulfatase A cDNA. No enzyme activity could be expressed from the mutagenized cDNAs after transfection into heterologous cells. In all instances, the patients were found to be homozygous for the mutations, and four of the five mutations occurred on different haplotypes. The clustering of this rare lysosomal storage disease in a small geographic area usually suggests a founder effect, so the finding of five different mutations is surprising.     

Metachromatic leukodystrophy: a 12-bp deletion in exon 2 of the arylsulfatase A gene in a late infantile variant

Sequencing of the arylsulfatase A gene in a late infantile metachromatic leukodystrophy patient showed the presence of a 12-bp deletion in exon 2. This deletion was found in a compound heterozygous state with the previously described 287 CT transition.     

Campora: a young genetic isolate in South Italy

Genetic isolates have been successfully used in the study of complex traits, mainly because due to their features, they allow a reduction in the complexity of the genetic models underlying the trait. The aim of the present study is to describe the population of Campora, a village in the South of Italy, highlighting its properties of a genetic isolate. Both historical evidence and multi-locus genetic data (genomic and mitochondrial DNA polymorphisms) have been taken into account in the analyses. The extension of linkage disequilibrium (LD) regions has been evaluated on autosomes and on a region of the X chromosome. We defined a study sample population on the basis of the genealogy and exogamy data. We found in this population a few different mitochondrial and Y chromosome haplotypes and we ascertained that, similarly to other isolated populations, in Campora LD extends over wider region compared to large and genetically heterogeneous populations. These findings indicate a conspicuous genetic homogeneity in the genome. Finally, we found evidence for a recent population bottleneck that we propose to interpret as a demographic crisis determined by the plague of the 17th century. Overall our findings demonstrate that Campora displays the genetic characteristics of a young isolate.     

Twenty-year outcome analysis of genetic screening programs for Tay-Sachs and beta-thalassemia disease carriers in high schools.

Programs for education, screening, and counseling of senior-high-school students, in populations at high risk for Tay-Sachs and beta-thalassemia diseases, have existed for >20 years in Montreal. Four process and outcome variables are reported here: (i) voluntary participation rates in the high-school cohort; (ii) uptake rates for the screening test; (iii) origin of carrier couples seeking the prenatal diagnosis option in the programs; and (iv) change in incidence of the two diseases. Between 1972 and 1992, we screened 14,844 Ashkenazi-Jewish students, identified 521 HexA-deficient carriers (frequency 1:28), reached 89% of the demographic cohort in the educational component of the program, and achieved 67% voluntary participation in the subsequent screening phase. The corresponding data for the beta-thalassemia program are 25,274 students (mainly of Mediterranean origin) representing 67% of the cohort with 61% voluntary participation in the screening phase (693 carriers; frequency 1:36). From demographic data, we deduce that virtually all the carriers identified in the high-school screening program remembered their status, had their partner tested if they did not already know they were a carrier couple, and took up the options for reproductive counseling/prenatal diagnosis. In Montreal, the current origin of all couples using prenatal diagnosis for Tay-Sachs and beta-thalassemia diseases is the corresponding genetic screening/testing program, whereas, at the beginning of the programs, it was always because there was a history of an affected person in the family. Incidence of the two diseases has fallen by 90%-95% over 20 years; the rare new cases are born (with two exceptions) outside the target communities or to nonscreened couples.     

The genetic bases for syndromic and nonsyndromic deafness among Jews

There are hundreds of different mutated genes associated with hearing loss. However, recent findings indicate that a large proportion of both syndromic and nonsyndromic forms of deafness in some Jewish populations is caused by a small number of founder mutations. This review is focused on genetic disorders such as nonsyndromic deafness, Usher syndrome and Alport syndrome, in which hearing loss is a major part of the phenotype and in which the underlying prevalent founder mutations have been recently identified in different Jewish populations. These and other examples of common mutations within a distinct population allow for sensitive and specific use of genetic testing for carrier screening and diagnosis, and are an impetus for development of therapeutic strategies.     

Study on a Brazilian isolate. I. Population structure and random genetic drift

A number of parameters were evaluated in order to determine the level of isolation of a small Brazilian community existing in partial geographic isolation and thereby evaluate the random genetic drift potential in the population. On a theoretical basis, it is concluded that the probability of genetic drift is low but cannot be excluded. The relatively small proportion of migrants (26%), the limited individual mobility, as given by marital distance (29 +/- 7 km), the mean migrational distance (46 +/- 11 km), the small effective size (122), and the value of the product Neme (26) agree with the possibility of genetic drift in this population. The observed coefficient of inbreeding (0.00239) is lower than that expected (0.0066) for random mating, suggesting some pressures against consanguineous marriage.     

Tay-Sachs disease: high gene frequency in a non-Jewish population.

A non-Amish "Pennsylvania Dutch" semi-isolate was found to have a high frequency of Tay-Sachs gene. This high frequency could be ascribed to founder effect and may represent, in microcosm, how this mechanism could have produced the high gene frequency among Ashkenazi Jews.     

新疆杨高效遗传转化系统的建立

选择新疆杨(Populus alba L.var．pyramidalis Bge．)为遗传转化受体材料,为建立根癌农杆菌介导新疆杨高效遗传转化系统,从预培养时间、侵染时间、共培养时间、添加乙酰丁香酮(AS)的时机、共培养培养基中添加乙酰丁香酮浓度、侵染菌液的制备方法、外植体继代方式等7个方面优化筛选。结果显示较合适的转化系统为：预培养8h,农杆菌菌液(OD600=0．4)侵染15min,共培养5d,侵染菌液的最优制备方法是液体培养活化农杆菌2次加离心收集菌体重悬,共培养培养基中添加乙酰丁香酮80μmol／L。新疆杨叶盘转化频率可达38．10％。     

Non-disjunction frequency in male complex Robertsonian heterozygotes of the common shrew

Common shrews display two types of Robertsonian (Rb) heterozygosity: simple (where CIII configurations are formed at meiosis I) and complex (which have longer meiotic chains or rings). Based on an analysis of large sample sizes (over 100) of MII cells per specimen, we estimated the non-disjunction frequency in seven Rb homozygotes and 21 complex Rb heterozygotes (CIV and CV) of Sorex araneus Linnaeus, 1758. The analysis showed high betweenindividual variability. The mean level of non-disjunction in homozygotes (2.01%) was significantly lower than in CIV and CV heterozygotes (4.27% and 5.78%, respectively). The study demonstrated that non-disjunction frequency in male CIV and CV heterozygotes was similar to that in simple heterozygotes in the common shrew.     

Ethnic communities in Israel: The genetic blood markers of the Moroccan Jews

One hundred and ninety-six Moroccan Jews now settled in Israel were typed for 7 blood groups, 12 red cell enzymes and 2 plasma protein systems. Their blood group picture is in agreement with results previously obtained on different samples of Moroccan Jews: rather high B in ABO, somewhat elevated frequencies of cDE and cDe in Rh and K in Kell. Differences in various blood markers exist between them and other North African Jewish communities. This fact, together with data on disease distribution and HLA frequencies, supports our assumption that Jews in the North African diaspora lived as small secluded isolates even within the same geographical zones. Comparisons with meager data on the neighboring non-Jewish populations do not disclose any resemblance to either Arab or Berber inhabitants of Morocco.     

Ethnic communities in Israel: The genetic blood markers of the Babylonian Jews

One hundred eighty-eight Jewish individuals who either they or whose both parents were born in Iraq were typed for 7 blood groups (ABO, MNS, Rh, Kell, Duffy, P and Kidd), 12 red cell enzyme systems and 2 serum proteins. Iraqi Jews are characterized by a high frequency of A (in ABO), N (in MNS), low cde (Rh) and low Hp-1. Several rare electrophoretic variants were encountered: PGM₁ 6-1, PHI 3-1 and PHI 2-1, and an unidentified AK phenotype. No evidence of Negroid admixture was found in their gene pool. Comparisons with results previously obtained in Iraqi Jews show general similarities in frequencies while comparisons with neighboring non-Jewish populations suggest divergence in most systems investigated. The difficulties of assessing relationships on the basis of a few selected differences and the need for careful interpretations of similarities are emphasized.     

Sandhoff disease in Cyprus: population screening by biochemical and DNA analysis indicates a high frequency of carriers in the Maronite community

In the last 15 years, four patients with the infantile form of Sandhoff disease were diagnosed in four different families in Cyprus (population 703,000, birth rate 1.7%). Three of these cases came from the Christian Maronite community (less than 1% of the population) and one from the Greek community (84% of the population). This relatively large number of patients prompted us to initiate an epidemiological study in order to establish the frequency of the mutant allele in Cyprus. Carrier detection was initially based on the measurement of beta-hexosaminidase A and B in both leucocytes and serum. Using the enzyme test, 35 carriers were identified among 244 random Maronite samples and 15 among 28 Maronites with a family history of Sandhoff disease, but only one carrier was found out of 115 random samples from the Greek community. In parallel to the biochemical screening, DNA studies were undertaken in one of the three Maronite patients and in a Greek carrier related to the Greek patient. These studies resulted in the identification of two novel mutations, a deletion of A at nt76 and a G to C transversion at position 5 of the 5'-splice site of intron 8, which have been published. We subsequently screened the carriers detected in the biochemical study for these two mutations using PCR-based tests. Of 50 Maronite carriers examined, 42 were found to have the nt76 deletion. Eight Maronite samples, designated carriers from the biochemical results, were negative for both mutations. It is possible that these individuals were incorrectly classified as carriers since their enzyme values are equivocal, although the presence of another mutation has not been excluded. Two Greek Cypriot carriers and two obligate Lebanese carriers were negative for both mutations. We conclude that there is a high frequency of Sandhoff disease carriers in the Maronite community of Cyprus, approximately 1 in 7, and that a single mutation predominates in this population.