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D A Hay

Publications and source records attributed to D A Hay.

At least 37 records · Page 2Linked to original sources
PubMed1994

Does IQ decline with age in fragile-X? A methodological critique.

The recent claims for a decline in intelligence test performance in males and females with fragile-X (fra(X)) syndrome have implications both clinically and in evaluating the underlying neurological basis. This commentary identifies three key issues in evaluating evidence for a decline and in planning future, more co-ordinated efforts. These are (1) problems in combining data across different intelligence tests and/or different ages with potentially incompatible norms, task demands, and models of the structure of intelligence; (2) limitations in applying to low ability persons tests designed to discriminate best around the population average; and (3) specific cognitive deficits and behavioral problems in fra(X) individuals which may be confounded with the task demands of particular IQ tests at particular ages. While the decline in ability may be a real phenomenon rather than an artifact, recommendations are made about the psychometric requirements for a larger and more definitive collaborative study.

Age Factors↗
PubMed1994

Transmitting males and carrier females in fragile X--revisited.

Fragile X "transmitting males" have customarily been defined as phenotypically normal hemizygotes, who show very few or no fragile sites, and who transmit the fragile X premutation to phenotypically normal daughters. However, an objective justification of this definition was lacking. The discovery of an unstable CCG repeat as the genetic basis of fragile X further emphasized the apparent distinction between the "normal transmitting males" with short repeat and expression of the FMR1 gene, and the affected males with larger repeats (delta > 0.6 kb) and a complete lack of FMR1 transcription. We have recently shown that the transition between these two groups in phenotypic expression of fragile X is gradual, mainly on account of methylation mosaicism. However, there were insufficient data on the phenotype within the short repeat (0.0 < delta < 0.6) range. In this paper we approach this problem by comparing some clinical, anthropometric, and psychometric data from a sample of normal transmitting males with those from their non-fragile X male relatives. Moreover, female carriers with short repeat are compared for the same traits with their non-fragile X female relatives. The results have shown that both males and females with a short repeat differed significantly from normal on several psychometric and physical measurements, and males only showed differences in typical facial traits. Further studies of genotype-phenotype correlations within the short repeat range, including the estimate of FMR1 gene function and a more exact estimate of repeat size, is required before genetic explanation for the clinical findings can be provided.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Between-generation differences in ascertainment and penetrance: relevance to genetic hypotheses in fragile X.

Between-generation differences in ascertainment were examined in 54 extended fragile X pedigrees, where all available members were clinically, psychometrically, and cytogenetically investigated. In 24 families a diagnosis was verified by molecular characterization using the pfxa3 fragile X-specific probe. We found considerable differences between generations in relative proportions of affected fragile X subjects versus 'non-penetrant' carriers. We also found deviation in the segregation ratio in unbiased samples of relatives in pedigrees. We claim that these irregularities are influenced by different rates of ascertainment, depending on the clinical expression of the condition (penetrance) and the fertility of fragile X individuals in a pedigree, as well as by the thoroughness of clinical investigation in individual families. Penetrance and fertility were estimated in fragile X females assessed by psychometric tests, and they were compared with earlier estimates based on a subjective judgement of their intellectual status. We suggest that the standard correction for ascertainment bias, such as has been applied in segregation analysis of this condition, is not sufficient to adjust for all types of bias.

Family Health↗
PubMed1993

Twin birth is not a risk factor for seizures.

There is a belief that perinatal factors are a major cause of epilepsy. We studied a community-based sample of twins, a group with a marked excess of adverse perinatal events. The observed number of non-twin siblings with seizures did not differ from that predicted by the age-specific cumulative incidence rate of seizures (4.2% at age 10 years) in the twins. The types of epilepsies in the twins were largely benign and self-limited and not those associated with brain damage. Zygosity, birth order, and birth weight did not predict affected status. Within affected sibships, the frequency of seizures in co-twins of dizygotic probands (9%) was not different from the frequency in non-twin siblings (12%) but was much less than the frequency in co-twins of monozygotic probands (38%; p < 0.001), reflecting a major genetic component to certain epilepsies. These data show that twins do not have an increased risk of seizures and strongly suggest that perinatal factors have little bearing on the etiology of the common epilepsies in the community.

Adolescent↗
PubMed1993

Genotype-phenotype relationships in fragile X syndrome: a family study.

Relationships between the measures of intellectual and physical status in the fragile X syndrome and the size of amplification of the fragile X-specific fragment, equivalent to the number of CCG repeats within the FMR1 locus, were studied by a maximum-likelihood scoring technique for analysis of pedigree data. This allows for estimation of random effects (genetic and environmental variance) concurrently with other (fixed) effects in a quantitative trait. FMR1 expression is usually shut down in males penetrant for the fragile X syndrome who have hypermethylated CCG amplifications of > or = 0.6 kb. The assumption of the step versus curvilinear function representing this relationship was tested by the likelihood-ratio criterion. The maximum-likelihood parameters were based on the most appropriate model for each measure. The results were indicative of the presence of a curvilinear relationship between the amplification size and the two intellectual scores, the Peabody Picture Vocabulary Test and Block Design Test, measuring verbal and spatial abilities, respectively. Reasons for the unexpected curvilinear regression between the amplification size and intellectual scores were explained further by methylation analysis of fragile X males with amplifications of 0.6 < delta < or = 1.2 kb who appeared to be responsible for the curvilinearity of the relationship. Four of these showed unmethylated status of the amplified bands in lymphocytes, which were presumably transcriptionally active. Removal of the aberrant individuals led to the anticipated step function between amplification and intellectual scores. For the combined anthropometric score, as well as for several single physical measures, the step function was the most appropriate model regardless of the inclusion or omission of the aberrant individuals in the pedigree sample.

Adolescent↗
PubMed1992

Fragile X family with unusual digital and facial abnormalities, cleft lip and palate, and epilepsy.

We present a fragile X family with unusual clinical manifestations. These findings, which often occur in the X-linked FG syndrome, include minor limb anomalies, cleft lip and palate, characteristic facial appearance, gastrointestinal problems and epilepsy, and intellectual disability. In a total sample of 54 fra(X) families, the frequency of minor limb anomalies was estimated to be 32% in the affected males and 19% in the female heterozygotes. These anomalies tend to occur in several members of the same family, where some craniofacial abnormalities reported as characteristic of the FG syndrome have also been encountered. Possible mechanisms for the occurrence of these unusual manifestations in the fra(X) families are discussed.

Abnormalities, Multiple↗
PubMed1992

Selective breeding for increased cholinergic function: biometrical genetic analysis of muscarinic responses.

Biometric genetic analyses of behavioral and physiologic responses known to be related to muscarinic cholinergic receptors (hypothermia, hypoactivity, inhibited avoidance, and reduced responding for water) were studied in genetic crosses and backcrosses of the Flinders sensitive line (FSL) and Flinders resistant line (FRL) of rats. The FSL rats were more sensitive to the direct muscarinic agonists, arecoline and oxotremorine, and to the indirect agonist, physostigmine, than any other group. The next most sensitive group was the F1 x FSL backcross, followed by the F2, F1, F1 x FRL backcross, and the FRL, in that order. These differences between the genetic groups could be accounted for completely by either solely additive or additive plus dominance genetic factors. When dominance genetic factors contributed to the differences among groups (6 out of 15), the F1 responded like the FRL rats. The variance of the responses measured made it impossible to obtain reliable estimates of the number of genes involved in many instances; when such estimates were possible, several genes (greater than or equal to 3) appeared to be involved. We conclude that muscarinic sensitivity in rats is under genetic control, with the greatest contribution coming from additive genetic factors. Because the FSL rat appears to be a genetic animal model of depression, the finding of several genes influencing muscarinic responses may help account for the difficulties investigators have had in locating a single major gene or biological marker for human depressive disorders.

Analysis of Variance↗
PubMed1991

Problems in ascertainment of transmitting males in Martin-Bell syndrome.

The difficulty of assigning families affected with the Martin-Bell syndrome (MBS) into the category of male transmission is emphasised and illustrated by examples of 3 MBS families. These examples demonstrate how the ability to detect transmitting males depends on the number of generations available for investigation, and also on the "spread" of clinical investigation across many branches of the family regardless of what appears to be an unremarkable family history. Some unusual properties of male transmission are shown, and the problem of selective ascertainment of the particular MBS male individuals in different generations in a set of pedigrees is discussed.

Face↗
PubMed1990

Neuropsychological dimensions of the fragile X syndrome: support for a non-dominant hemisphere dysfunction hypothesis.

This study contends that males with the fragile X syndrome feature problems in the visuospatial sphere as compared with Down syndrome males matched on vocabulary ability. Fragile X males suffer impairments of constructional functions, as demonstrated by their poor performance on block construction tests and on drawing tasks. These problems exist in association with visuoperceptive impairments, including the inability to reliably estimate angular relationships (Judgement of Line Orientation). They have shortened Digit and Corsi spans, and may feature some deficits in left hand co-ordination. The observation of a pervasive non-verbal deficit may also apply to carrier females, who despite functioning at an overall higher level, feature a similar pattern of deficits. It is possible that the deficit in non-dominant hemisphere functioning may be a pathognomonic feature of the chromosomal abnormality.

Adolescent↗
PubMed1990

"Twins in school". An Australia-wide program.

The multiple birth family is more likely to have a dispute with the education system than with any other service. So many potential areas of conflict exist over the abilities and behaviour of multiples and over such issues as separation or keeping back one twin. One reason for disputes is the lack of good data to adequately reflect the different perspectives of parents and teachers and the differing needs of families: the same solution does not apply to all. To provide the first large-scale data base and building upon an initial survey of 85% of all primary school teachers in South Australia, the LaTrobe Twin Study and AMBA worked with Education Departments to set-up in each state Education Research Teams (ERTs) of parents of multiples who were also teachers. The ERTs were crucial in three phases. 1) Developing and circulating questionnaires and publicising the nationwide survey. 784 families and 1264 teachers of their children completed these questionnaires, many reporting that simply having to address the issues raised in the questionnaire was a valuable learning experience. 2) Exploring the data base. Issues arising included the very different bases on which parents and teachers judged separation desirable, with teachers emphasising the unsubstantiated claim that separation is essential to individual development. Separation became more common over the first three years of schooling but 20-25% of twins separated one year were back together the next. 3) Running regional meetings of parents, teachers and administrators to discuss the results and to pool experiences and plan policies at the local level. A need clearly exists to improve the level of consultation between families and school personnel and to ensure the widespread availability of information which identifies key issues in making decisions for that multiple birth family.

Anxiety, Separation↗
PubMed1990

What information should the multiple birth family receive before, during and after the birth?

Advances in the management of the multiple pregnancy and delivery must be accompanied by corresponding improvements in service access outside key centres and especially in the information families receive about what may happen during or after the pregnancy. A major review of birthing services in Victoria has focussed attention on four areas where the quality of information is often inadequate. 1) Prepregnancy and the standard of counselling about the incidence of multiples as a result of fertility drugs and in vitro fertilization procedures and about problems which may accompany a multiple birth. 2) Antenatal: At what stage of the pregnancy should parents be told of the multiple pregnancy and how should monitoring of the mother and procedures such as bedrest take into account what are often conflicting demands within the family? 3) Perinatal: Families are frequently illprepared for a cesarean delivery and for the procedures for premature multiples. The problem is often compounded by separation of the mother from one or both twins. While bereavement services are improving, much still needs to be learned about handling congenital abnormalities in one or more multiples. 4) Postnatal: Irrespective of the level of prenatal advice, families greatly underestimate the workload with multiples. The resulting stress contributes to the incidence of postnatal depression, child abuse and divorce now being reported from multiple birth families. Some suggestions are made from social psychology and genetic counselling about how families can best handle risk information to achieve the goal of neither under- nor overestimating the risks at these different stages of the multiple pregnancy.

Adaptation, Psychological↗
PubMed1990

Twin children in volunteer registries: biases in parental participation and reporting.

The biases in voluntary participation by adult twins are well known but less attention has been paid to twin children where parents decide on participation and provide much of the information. Several aspects of reporting including the assessment of zygosity are compared in four large Australian data bases: 1) a nationwide compulsory (and hence representative) survey of literacy and numeracy; 2) a nationwide "Twins in School" survey of parents and teachers of twins run through Education Departments and AMBA, the parents organisation in conjunction with LaTrobe; 3) the LaTrobe Twin Study which is a longitudinal program involving frequent interactions between families and researchers, and 4) the Australian NHMRC Twin Registry which has surveyed a large sample of their families with twin children by mail. One potential bias comes when recruitment is on a continuing basis as in the LaTrobe Twin Study and the Australian Twin Registry when differences between "early" and "late" enrolling families arise. One difference between the four samples arose from parents being much more likely to contrast their twins and to report problems in one but not the other, whereas teachers' and psychologists' assessments of these same children generally reported much smaller intrapair differences. Future studies should have some common questions to provide comparative data on such biases. Key questions are proposed for this area, mainly on the perceived need for different forms of remediation, together with other recommendations about the minimal essential baseline data set for a registry.

Attitude↗
PubMed1989

The relevance of the health belief model to Australian smokers.

The Health Belief Model is one of the few models predicting health behavior which explicitly evaluates the role of cues to action from the doctor or others. Rarely have such cues to action been examined formally by the comparison of groups receiving different interventions. Initial and follow-up data covering a wide range of sociopsychological variables were gathered from typical smokers among family-practice patients participating in an Australian quit-smoking program. Patients were randomly assigned either to a control or experimental group, the latter receiving the Give-Up Smoking (GUS) kit, and quit-smoking advice from their doctor. Factor analysis of the initial data largely confirmed the clusters of the Health Belief Model. At follow-up, after the experimental and control group treatment, a totally different factor structure emerged, comprising some very specific sociopsychological variables and cues to action. Implications are discussed for the Health Belief Model relative to other health behavior models.

Attitude to Health↗
PubMed1988

Clinical features and reproductive patterns in fragile X female heterozygotes.

Clinical findings are presented on 113 fragile X female heterozygotes from 44 families, based on physical examination, behavioural assessment, and reproductive history. In 85% of a subsample of 92 adult females non-verbal IQ score derived from the Block Design test was 85 or less. Verbal ability deficits were much less common. Typical facial characteristics, irregular teeth, and hypermobility of finger joints occurred in approximately 40% of adult females, but facial abnormalities were less common in children. Some physical anomalies and the level of intellectual impairment were, in adult carriers, associated with the presence of fragile X sites. The commoner physical anomalies or typical facial characteristics and intellectual abilities differed significantly between the known female heterozygotes and their 40 presumed normal relatives. Frequency of miscarriages was increased in fragile X females; in spite of this, a moderate increase in the number of children has been encountered in female carriers with borderline intellectual impairment. This important problem has genetical implications and needs further investigation. The importance is emphasised of a more detailed clinical examination of the females at risk in fragile X families.

Abortion, Spontaneous↗
PubMed1987

Phenotypic variation in male-transmitted fragile X: genetic inferences.

Three families with confirmed and one family with suspected male transmission of the fragile X are presented, with psychological and physical assessment of all available members. The psychological tests used were the Peabody Picture Vocabulary test and Block Design which measured verbal and non-verbal abilities, respectively. Physical status was assessed by recording dysmorphic features and by anthropometric measurements. This study demonstrated that there are appreciable differences in mental and physical status within sibships of daughters of male carriers, as well as recognizable physical alterations and intellectual impairment in the transmitting males. These findings contradict the concept that there are two distinct categories of fragile X carriers: phenotypically normal as opposed to affected. They suggest instead that the defect may be graded and emphasize the importance of intellectual deficits and physical alterations in defining the fragile X phenotype, both in low-penetrant males and female heterozygotes.

Child↗
PubMed1987

Individual variation and specific cognitive deficits in the fra(X) syndrome.

Mental retardation has been associated with fra(X) but comprehensive psychological evaluation has rarely been applied to 2 major behavioral questions 1) the extent of individual variation in IQ among fra(X) males and the possibility of some fra(X) males being of normal IQ; and 2) whether there is a depression in general IQ or whether specific abilities are impaired. The problems of developing an effective battery of tests for assessing fra(X) are discussed. These questions were examined in 54 individuals, comprising fra(X) males, their obligate carrier mothers and those sisters shown to have the fra(X). Among noninstitutionalised males nonverbal IQ as measured on a Block Design test ranged from 100 to 0, and vocabulary scores while generally higher, ranged from 79-33. The males scored low on a digit span memory task, while performance on a memory of objects task was adequate. Despite lower overall scores, a similar pattern and variability emerged in institutionalised males. Daughters were extremely variable in performance and the mothers performed much better, supporting the view that women who have children are a selected subset of fra(X) syndrome individuals. The performance of one male is discussed in detail. His vocabulary and nonverbal IQ scores were normal, despite his having other specific cognitive deficits. The pattern of abilities and behavior seen in fra(X) may result in an overestimation of intelligence and underestimation of penetrance when based on clinical impressions rather than formal psychological assessment. The implications of this for molecular and for population genetic approaches to fra(X) are discussed.

Adolescent↗
PubMed1987

Birthweight differences, the transfusion syndrome and the cognitive development of monozygotic twins.

Monochorionic twins may differ from dichorionic monozygotic (MZ) twins because of the transfusion syndrome and the timing of the cleavage of the zygote. Intrapair birthweight differences may be an indicator of these intrauterine variables. Previous evidence concerning weight differences and intellectual ability in MZ twins is reviewed with recommendations that future research also incorporates full placental data. Poorer scores on a nonverbal test are found for the lighter male twin of pairs with large intrapair differences in birthweight. Co-twin concordance rates for test scores are also highest for this group indicating that they vary consistently from other groups. Some evidence is presented from the present and earlier studies implicating anomalies of asymmetry or the transfusion syndrome as possible causes of these differences in brain functioning. The study adds further doubts as to the validity of any assumption of developmental equivalence between MZ twins and the general population.

Adolescent↗