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PubMed2001

Ocular oscillations induced by shifts of the direction and depth of visual fixation.

Shifts of the point of fixation between two targets aligned on one eye that are located near and far (Müller paradigm) stimulates a combined saccadic-vergence movement. In normal subjects, this test paradigm often induces saccadic oscillations of about 0.3 degrees at 20 to 30 Hz. We measured eye movements using the magnetic search coil technique in 2 patients recovering from viral opsoclonus-myoclonus syndrome, comparing saccadic-vergence responses to the Müller paradigm with conjugate saccades between distant targets. Both patients exhibited intermittent conjugate ocular oscillations of about 4 to 5 degrees amplitude at about 10 Hz. Combined saccadic-vergence movements induced these oscillations twice as often as did conjugate saccades. One patient also exhibited disjunctive ocular oscillations at 10 Hz while sustaining fixation on the near target. The Müller paradigm provides a useful clinical and experimental technique for inducing saccadic oscillations. The probable mechanism is that pontine omnipause neurons, which normally gate saccades, are inhibited during the sustained vergence movement that follows the saccadic component of the response to the Müller paradigm.

Adult↗

PubMed1989

Epidemiology of genetically determined cancer.

Dominantly heritable susceptibility is known for virtually every cancer. Susceptibility is typically restricted to one or a few tumours. For some tumours there appear to be at least two different predisposing conditions. Some mutant gene carriers survive to old age without developing the expected tumour(s). Some cases are new germline mutations. None of the conditions is very common, because of natural selection against gene carriers. Two questions arise: What is inherited? What is the relationship between the hereditary and non-hereditary forms of the same tumour? Retinoblastoma is a prototypic tumour. Penetrance in humans is nearly complete by the age of five years in the heritable form, which usually affects both eyes. Rare cases in which there is a constitutional deletion of chromosomal band 13q14 permitted localization of the responsible gene. Tumour formation is clearly a rare event at the cellular level, suggesting the necessity of a second, somatic, event. The difference in ages at diagnosis between unilateral and bilateral cases also suggests that two somatic events occur in non-hereditary cases. One explanation is that the gene is recessive and the second event involves loss of the remaining normal allele by mutation, non-disjunction, deletion or somatic recombination. The normal allele may be regarded as anti-oncogenic.

Disease Susceptibility↗

PubMed1992

Protein phosphatases and cell division cycle control.

Fission yeast has at least ten protein phosphatase genes that appear to play distinct roles in cell cycle control. Because of functional overlap, a clear lethal phenotype can be obtained only after multiple genetic alterations. Cells that have lost the protein phosphatase 1 (PP1)-like dis2/sds21 phosphatase activities prematurely enter mitosis and remain in a defective mitotic state with high H1 kinase activity and without sister chromatid disjunction. The same phenotype can be obtained in the presence of hydroxyurea. Overexpression of PP1-like phosphatase, on the other hand, delays the entry into mitosis. Cells that have lost PP2A-like ppa2 phosphatase activity also prematurely enter mitosis with a reduction in cell size. This semi-wee phenotype is enhanced in delta ppa2 mutants treated with the phosphatase inhibitor, okadaic acid. Genetic interactions between ppa2 and mitotic regulators suggest that ppa1/ppa2 phosphatase may directly or indirectly inhibit p34cdc2/cyclin kinase. Thus both PP1- and PP2A-like phosphatases in fission yeast may negatively regulate entry into mitosis. The major property of the dis2/sds21 mutant which is distinct from those of the ppa2/ppa1 mutant is its failure to inactivate the p34cdc2/cyclin complex after entry into mitosis. A novel phosphatase regulator encoded by sds22+ binds to dis2 phosphatase and controls the substrate specificity which appears to become essential in the progression from metaphase to anaphase.

Cell Division↗

PubMed1997

Space-time statistics for decision support to smart farming.

This paper summarizes statistical procedures which are useful for precision farming at different scales. Three topics are addressed: spatial comparison of scenarios for land use, analysis of data in the space-time domain, and sampling in space and time. The first study compares six scenarios for nitrate leaching to ground water. Disjunctive cokriging reduces the computing time by 80% without loss of accuracy. The second study analyses wind erosion during four storms in a field in Niger measured with 21 devices. We investigated the use of temporal replicates to overcome the lack of spatial data. The third study analyses the effects of sampling in space and time for soil nutrient data in a Southwest African field. We concluded that statistical procedures are indispensable for decision support to smart farming.

Agriculture↗

PubMed1999

In search of spatial extremes.

In environmental studies attention increasingly focuses on identification of spatial extremes: locations with observations that are apparently higher than either a preset background threshold or neighbouring observations. We consider various procedures for identifying values and locations of these extremes: extreme value theory, conditionally simulated fields and disjunctive kriging. In a recent research project we studied the distribution of nine environmental pollutants (heavy metals, polyaromatic hydrocarbons and mineral oil) in a large industrial estate in the southern Netherlands. This area is interesting as it is influenced by three contaminating processes: inundation by the river Meuse, anthropogenic heightening with contaminated materials and local industrial activities. Concentrations are measured. In this paper the peaks over threshold method was useful for finding extremes for spatially uncorrelated variables, whereas conditional simulations applied in particular to areas with spatial dependence.

Animals↗

PubMed1982

Meiotic segregation in familial reciprocal translocation t(8q;22q).

We studied the chromosomes of a mentally retarded boy with minor anomalies and of his parents using a G-band stained high-resolution chromosome method. This documented dup (8q24.1 = to 8qter) and dup(22pter = to 22q11.2) in the boy due to a maternal balanced reciprocal translocation of chromosomes 8 and 22 and 3:1 disjunction during meiosis I. The karyotype of the boy is 47,XY, +der(22) (22pter = to 22q11.2::8q24.1 = to 8qter). The der(22) was involved in satellite associations and stained positively with AgNO3 in mother and child. The case is compared to similar cases in the literature and the function of the small acrocentric marker chromosome during meiosis is discussed.

Child, Preschool↗

PubMed1983

Reproductive risks for translocation carriers: cytogenetic study and analysis of pregnancy outcome in 58 families.

Here we report on studies of the reproductive risks for heterozygous carriers of chromosome translocations. Pregnancy outcome, breakpoints, mode of segregation of the translocated chromosomes, and resulting chromosome imbalance were analyzed in 58 families (46 with reciprocal and 12 with Robertsonian translocations) ascertained for birth of a malformed child, recurrent spontaneous abortion, or hypogonadism. These families include a total of 122 informative sibships. The analysis of the data, after correction for ascertainment bias, showed that the incidence of spontaneous abortion is nearly 50% in reciprocal and between 20 and 25% in Robertsonian translocation families ascertained for malformed child or recurrent abortion. The risk of malformed infants with unbalanced genome is approximately 6% among the liveborn offspring of reciprocal translocation carriers and 23% among the liveborn offspring of carrier mothers of t(14q21q). The distribution of the breakpoints on the chromosomes involved in reciprocal translocations ascertained through a malformed child is nonrandom, with an excess on chromosomes 5, 9, 13, and 15. The study of chromosome imbalance, expressed as gain or loss of a portion of genetic information relative to the total haploid autosome length (percent HAL), shows that among the common types of disjunction-segregation leading to unbalanced gametes, adjacent 1 seems to be the one producing on the average the least level of genome imbalance. This explains why it is the most frequently observed type of segregation giving rise to gametes from which subjects with a chromosome imbalance compatible with life can be generated.

Abortion, Habitual↗

PubMedDate not supplied

Sex chromosome aneuploidy in fragile X carriers.

Not few reports of sex chromosome aneuploidy in association with the fragile site at Xq28 have appeared, suggesting other factors than pure coincidence. In the present report lymphocyte cultures from 23 obligate and 45 potential carriers have been examined cytogenetically. As expected, an increase in sex chromosome aneuploidy with increasing age was observed. However, it seemed that the increase of hyperdiploid cells was far in excess of the expected, and a difference between obligate and potential carriers was apparently also present. Hence, a disposition to non-disjunction of the fragile X chromosome is suggested.

Adult↗

PubMed1987

Partial duplication 16p resulting from a 3:1 segregation of a maternal reciprocal translocation.

We report on a male infant with a duplication 9p (pter----q13) and duplication 16p (p13----pter) resulting from a 3:1 meiotic disjunction of a maternal reciprocal translocation. In this case, the mode of segregation fits to the Pachytene-Diagram Model of Jalbert et al [1980]. The infant showed clinical features that have been described both in dup(16p) and in dup(9p). To our knowledge, this is the first time that this unbalanced karyotype has been reported.

Abnormalities, Multiple↗

PubMed1990

Incidence, survival, and mortality in Down syndrome in Denmark.

The incidence of Down syndrome (DS) has been studied intensively for the two periods 1960-1972 and 1980-1985. The age distribution of birth-giving mothers has changed to older age at child birth from the first to the second period. Non-disjunction studies were carried out in 328 families. Most cases were first maternal meiotic division failures (43%). Nearly 12% were paternal meiotic failures, half of them in first meiosis and half in second. Both newborn infants and fetuses were studied. There was an excess of males, especially among newborn DS children, which was related to a failure at paternal first meiosis. A positive sex ratio was found in all newborn infants as well as in free trisomics as in those with de novo translocations. Survival was studied in the cohort of 278 infants born 1980 to 1985. The highest death-rate occurred between 22 days to 1 year (10.4%), 30 times more than the death probability in the Danish population. There was a significant difference between DS cases with congenital heart defect and those without. The probability of infants without heart disease of reaching the first year was 93.1% and the age of 6 years 88.0%. The probability of survival of children with congenital heart defect was 71.7% and 45.2%, respectively, reflecting also the increasing number of infants born prematurely with low birth weight or small-for-date infants. The predominant heart problems were atrio-ventricular canal defects. Infections and malformations added to the high mortality rate. Three cases of leukemia were significantly more than expected.

Child↗

PubMed1990

The origin of aneuploidy: bivalent instability and the maternal age effect in trisomy 21 Down syndrome.

The mechanism behind the high rate of maternal first meiotic non-disjunction and the maternal age effect in trisomy 21 is unknown. Much attention has been paid to the causal role of univalence 21 by lack of chiasma formation. Here I suggest that not only achiasmatic bivalents may be susceptible to nondisjunction, but the chiasmatic bivalent shape per se may play an important role. Considering the topology of the chiasmata and the orientation of the bivalent at first meta- and anaphase, some bivalent shapes may have a greater segregational potential than others. For any one chromosome there may at first meta- and anaphase be an optimal balance between chromosome coiling/condensation on the one hand and chiasma frequency distribution on the other. Chromosome coiling/condensation may play an interesting dual role in both determining bivalent flexibility and dictating chiasma formation. I propose that the higher rate of double- and triple-chiasma bivalents 21 in oocytes contributes to its higher rate of spontaneous first meiotic nondisjunction; and the maternal age effect is associated with chromosome laxity, secondary to an impairment of appropriate chromosome coiling/condensation in oocytes of older women. In spermatocytes of older men some compensatory increase in chiasma frequency with a shift towards double- and triple-chiasma bivalents 21 might take place, i.e., if a general age-related chromosome decondensation is counteracted by an auto-regulatory "length effect" remaining intact in pachytene spermatocytes.

Aneuploidy↗

PubMed1995

Clinical and molecular studies in full trisomy 22: further delineation of the phenotype and review of the literature.

Trisomy 22 is commonly found among spontaneous abortions, second in frequency of occurrence only to trisomy 16. Most earlier reports of surviving trisomy 22 cases in the literature are thought to represent the product of unbalanced 11;22 translocations or the result of undetected mosaicism, since this condition is thought to manifest early embryonic or fetal lethality. We present two strikingly similar cases of non-mosaic trisomy 22 surviving to late gestation. In this paper we emphasize the unique phenotype of this trisomy which included intrauterine growth retardation, microcephaly, broad flat nasal bridge with epicanthal folds and ocular hypertelorism, microtia, variable cleft palate, webbed neck, congenital heart defects involving anomalous great vessels, anorectal and renal anomalies, and hypoplastic distal digits with thumb anomalies. We also explore why some cases survive to late gestation. Confined placental mosaicism, a frequent finding in other lethal trisomies, has been ruled out in one of the cases. Molecular studies done to assess the parental origin of the extra chromosome in the other case showed that the non-disjunction originated during maternal meiosis II. Parental origin of the extra chromosome does not seem to play a role in late survival for trisomy 22.

Abnormalities, Multiple↗

PubMed2001

Abnormal folate metabolism and genetic polymorphism of the folate pathway in a child with Down syndrome and neural tube defect.

The association of neural tube defects (NTDs) with Down syndrome (trisomy 21) and altered folate metabolism in both mother and affected offspring provide a unique opportunity for insight into the etiologic role of folate deficiency in these congenital anomalies. We describe here the case of a male child with trisomy 21, cervical meningomyelocele, agenesis of corpus callosum, hydrocephaly, cerebellar herniation into the foramen magnum, and shallow posterior cranial fossa. Molecular analysis of the methylenetetrahydrofolate (MTHFR) gene revealed homozygosity for the mutant 677C-->T polymorphism in both the mother and child. The plasma homocysteine of the mother was highly elevated at 25.0 micromol/L and was associated with a low methionine level of 22.1 micromol/L. Her S-adenosylhomocysteine (SAH) level was three times that of reference normal women, resulting in a markedly reduced ratio of S-adenosylmethionine (SAM) to SAH and significant DNA hypomethylation in lymphocytes. The child had low plasma levels of both homocysteine and methionine and a reduced SAM/SAH ratio that was also associated with lymphocyte DNA hypomethylation. In addition, the child had a five-fold increase in cystathionine level relative to normal children, consistent with over-expression of the cystathionine beta synthase gene present on chromosome 21. We suggest that altered folate status plus homozygous mutation in the MTHFR gene in the mother could promote chromosomal instability and meiotic non-disjunction resulting in trisomy 21. Altered folate status and homozygous TT mutation in the MTHFR gene in both mother and child would be expected to increase the risk of neural tube defects. The presence of both trisomy 21 and postclosure NTD in the same child supports the need for an extended periconceptional period of maternal folate supplementation to achieve greater preventive effects for both NTD and trisomy 21.

Amino Acids, Sulfur↗

PubMed2006

Pre- and postnatal findings in trisomy 17 mosaicism.

Trisomy 17 mosaicism is one of the rarest autosomal trisomies in humans. Thus far, only 23 cases have been described, most of them detected prenatally. In only five instances has mosaicism been demonstrated in lymphocytes and/or fibroblasts postnatally, and only in these have multiple congenital anomalies (MCA), facial dysmorphisms, and mental retardation been reported. Patients with trisomy 17 mosaicism at amniocentesis and a normal karyotype in blood and fibroblasts (n = 17) were always healthy. Here, we report on pre- and postnatal clinical, cytogenetic, molecular-cytogenetic, and molecular findings in four patients with trisomy 17 mosaicism. The first case was detected in cultured but not in short-term chorionic villi and amniocytes. Due to MCA on prenatal ultrasound examination the pregnancy was terminated. The second patient is a 13-month-old healthy boy, in whom low level trisomy 17 mosaicism was detected in cultured chorionic villi only. The third patient is a 2-year-old girl with growth retardation, developmental delay, MCA, and trisomy 17 mosaicism in amniocytes, fibroblasts, and placenta, but not in blood and buccal smear. The fourth patient is a 9-year-old boy with growth and mental retardation, sensoneurinal hearing loss, and MCA. Cytogenetic analyses showed trisomy 17 mosaicism in amniocytes, skin fibroblasts, and urinary sediment cells, whereas in blood and buccal smear a 46,XY karyotype was found. Molecular investigations in all four cases indicated biparental inheritance of chromosome 17. Formation of trisomy was most likely due to a maternal meiosis I error in Patient 1 and a postzygotic non-disjunction of the paternal chromosome 17 in Patient 4. Cerebellar malformations, reported in two cases from the literature and in two reported here may be a specific feature of trisomy 17 mosaicism. Since the aberration has rarely been reported in lymphocytes, chordocentesis is not indicated in prenatal diagnosis. Prenatal genetic counseling for trisomy 17 mosaicism in chorionic villi or amniocytes should consider that the clinical significance remains uncertain.

Adult↗

PubMed2006

A father of four consecutive trisomic pregnancies with elevated frequencies of associated aneuploid sperm.

A couple with normal somatic karyotypes had four consecutive trisomic pregnancies, each involving a different chromosome, of which two children were liveborn with confirmed paternal-origin trisomies. The apparently healthy father produced abnormally high frequencies of disomic sperm for each of the four chromosomes involved in the trisomic pregnancies (P< 0.003, by sperm fluorescence in situ hybridization (FISH)). His elevated sperm aneuploidies persisted over a 2-year period and affected all chromosomes evaluated, suggesting that he had a genome-wide defect in meiotic disjunction. He also had the highest frequencies of aneuploid sperm reported for any healthy man to date. His frequencies of aneuploid sperm were comparable to the peak frequencies of the transient responses reported in some cancer patients after receiving aneugenic chemotherapies. These findings indicate that apparently healthy men can produce abnormally high frequencies of sperm aneuploidies that suggest that this condition may contribute to recurrent trisomic pregnancies.

Adult↗

PubMed2007

X-chromosome inactivation patterns in females with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder caused by loss of paternally expressed genes from the 15q11-q13 region generally due to a paternally-derived deletion of the 15q11-q13 region or maternal disomy 15 (UPD). Maternal disomy 15 is usually caused by maternal meiosis I non-disjunction associated with advanced maternal age and after fertilization with a normal sperm leading to trisomy 15, a lethal condition unless trisomy rescue occurs with loss of the paternal chromosome 15. To further characterize the pathogenesis of maternal disomy 15 process in PWS, the status of X-chromosome inactivation was calculated to determine whether non-random skewing of X-inactivation is present indicating a small pool of early embryonic cells. We studied X-chromosome inactivation in 25 females with PWS-UPD, 35 with PWS-deletion, and 50 controls (with similar means, medians, and age ranges) using the polymorphic androgen receptor (AR) gene assay. A significant positive correlation (r = 0.5, P = 0.01) was seen between X-chromosome inactivation and age for only the UPD group. Furthermore, a significantly increased level (P = 0.02) of extreme X-inactivation skewness (>90%) was detected in our PWS-UPD group (24%) compared to controls (4%). This observation could indicate that trisomy 15 occurred at conceptus with trisomy rescue in early pregnancy leading to extreme skewness in several PWS-UPD subjects. Extreme X-inactivation skewness may also lead to additional risks for X-linked recessive disorders in PWS females with UPD and extreme X-chromosome skewness.

Adolescent↗

PubMed2006

Complete maternal uniparental isodisomy of chromosome 4 in a subject with major depressive disorder detected by high density SNP genotyping arrays.

Uniparental isodisomy (iUPD) is a rare genetic condition caused by non-disjunction during meiosis that ultimately leads to a duplication of either the maternal or paternal chromosome in the affected individual. Two types of disorders can result, those due to imprinted genes and those due to homozygosity of recessive disease-causing mutations. Here, we describe the third known case of complete chromosome 4 iUPD of maternal origin. This condition became apparent during whole genome linkage studies of psychiatric disorders in the Portuguese population. The proband is an adult female with normal fertility and no major medical complaints, but a history of major depressive disorder and multiple suicide attempts. The proband's siblings and parents had normal chromosome 4 genotypes and no history of mood disturbance. A brief review of other studies lends support for the possibility that genes on chromosome 4 might confer risk for mood disorders. We conclude that chromosome 4 maternal uniparental disomy (UPD) is a rare disorder that may present with a major depressive phenotype. The lack of a common disease phenotype between this and two other cases of chromosome 4 iUPD [Lindenbaum et al. [1991] Am J Med Genet 49(Suppl 285):1582; Spena et al. [2004] Eur J Hum Genet 12:891-898) would suggest that there is no vital maternal gene imprinting on chromosome 4. However, since there is no reported case of paternal chromosome 4 UPD, paternal gene imprinting on chromosome 4 cannot be excluded.

Adult↗

PubMed1984

Variation in the pattern of cranial venous sinuses and hominid phylogeny.

In 1967 Tobias noted that Australopithecus boisei cranium O.H.5 exhibited a cranial venous sinus pattern in which the occipital sinus and the marginal sinuses of the foramen magnum appeared to have replaced the transverse-sigmoid sinuses as the major venous outflow track. Specimens of A. robustus and several more recently recovered A. boisei crania also show evidence of enlarged occipital-marginal sinuses. In contrast, A. africanus and H. habilis retain a dominant transverse-sigmoid system that characterizes the great majority of extant apes and modern human cadaver samples. Pliocene A. afarensis exhibits a high frequency of occipital-marginal drainage systems. An examination of several series of precontact North American Indian crania shows that the frequency distribution of the occipital-marginal sinus pattern is spatiotemporally disjunct , ranging from 7.5% to 28%. The Late Pleistocene sample from P redmost , Czechoslovakia, also shows a very high incidence of occipital-marginal sinus patterns (approximately 45%). These observations suggest that occipital-marginal and transverse-sigmoid sinus patterns are adaptively equivalent character states. This conclusion is supported by the fact that enlarged occipital-marginal and transverse-sigmoid sinus systems often coexist on the same and/or contralateral sides of the head. It is well known that the frequencies of such adaptively neutral traits are often heavily influenced by population-specific epistatic interactions. The utilization of such traits in phylogenetic reconstruction entails a substantial risk of mistaking parallelism for synapomorphy . It is concluded that using functional-adaptive criteria in the definition of morphologic characters is a more reliable method to guide phylogeny reconstruction. In light of this, the distribution of venous sinus variants in Plio -Pleistocene hominids gives little or no basis for revising the phylogenetic scheme of Johanson and White (1979), or the functional-adaptive interpretation offered by White et al. (1981).

Animals↗