Biomedical subjects

D Z Loesch

Publications and source records attributed to D Z Loesch.

At least 37 records · Page 2Linked to original sources

PubMed1995

Use of robust statistical methods to determine the effect of fragile X on means and variance components of a quantitative trait.

Owing to the presence of outliers, an estimated 3.5% in the ridge breadth data and 1.7% in the height data, the effect of fragile X on height and ridge breadth was examined using robust statistical techniques for data collected from 54 families afflicted with this disorder. It is shown that fragile X affects ridge breadth and height in a different manner. Fragile X women had a greater mean ridge breadth than normal women, whereas there was a similar trend, but no significant difference, between normal and fragile X men. Fragile X men were shorter than normal men, but no significant difference between the mean height of normal and fragile X women was observed. However, fragile X girls were shown to grow more quickly and to stop growing earlier than normal girls. An examination of the covariance between relatives classified according to fragile X status showed that for both traits the effect of fragile X was to reduce the covariance between parents and offspring, which produced the effect of departure from an additive polygenic model of inheritance.

Adolescent↗

PubMed1995

FRAXE and mental retardation.

Mental impairment and instability of the CCG repeat at FRAXE is described in six kindreds. Cosegregation of FRAXA and FRAXE was found within one of these kindreds. Cytogenetic expression of FRAXE was shown to skip a generation when associated with a reduction in size of the CCG expansion when transmitted through a male; however, in general, transmission occurred through females and a copy number increased from one generation to the next. In these respects the behaviour of FRAXE paralleled that of FRAXA. A relationship between FRAXE and non-specific mental impairment is strongly suggested by the occurrence in these families of more mentally impaired male and female carriers, after removal of index cases, than could reasonably be expected by chance.

Adolescent↗

PubMed1995

Timing and genetic rapport between growth in skeletal maturity and height around puberty: similarities and differences between girls and boys.

We have analyzed longitudinal twin data by using a multivariate normal model to identify and quantify genetic effects over time on two main aspects of growth, height and skeletal maturity. The largest genetic contribution to the variance in both height and skeletal maturity coincided with the respective ages of peak growth velocity. The highest genetic covariance between these two traits coincided with the age of greatest acceleration of growth in height. These findings imply the existence of regulatory or structural genes that influence growth in both height and skeletal maturity. We also found sex differences in the rapport between velocities for height and skeletal maturity. These are consistent with a predominant role of estrogen in accelerating skeletal maturation in females, and the existence of additional mechanisms in males which may promote growth in height independently of the effects of gonadal sex steroids.

Adolescent↗

PubMed1995

Expansion of the CGG repeat in fragile X in the FMR1 gene depends on the sex of the offspring.

Analysis of 139 mother-to-offspring transmissions of fragile X CGG triplet repeats revealed that the repeat expansion is enhanced in mother-to-son transmissions compared with mother-to-daughter transmissions. Evidence has been based on analysis of mother-offspring differences in the size of repeat (in kb), as well as on comparisons between proportions of male and female offspring with premutations, and full mutations, inherited from mothers carrying a premutation. Mean difference in the repeat size from mother-son transmissions was 1.45 kb, compared with mother-daughter transmissions of 0.76 kb. The difference is due primarily to a greater proportion of male than female offspring with full mutation from the premutation mothers and also to a higher frequency of reduction in repeat size from mothers to daughters than from mothers to sons. Our findings suggest the possibility of an interaction of the normal X homologue in a female zygote with the FMR1 sequence on the fragile X during replication to account for the lower level of expansion in mother-to-daughter transmissions relative to mother-to-son transmissions.

Female↗

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

Effect of fragile X on physical and intellectual traits estimated by pedigree analysis.

A maximum likelihood scoring technique for analysis of pedigree data, which allows for estimation of random effects (variance components) concurrently with other "fixed" effects in a quantitative trait, was applied to establish the effect of the fragile X condition in the variation of intellectual and physical traits. In 52 fragile X families, intellectual status was represented by measures of vocabulary knowledge (PPVT) and of nonverbal visuospatial skills (BDT), and physical status by a combined physical (anthropometric) score, and jaw length. The fixed effects included fragile X and sex and their interaction on the mean and covariances between relatives for the intellectual and physical scores. The random effects included environmental (common and individual) and genetic (additive and dominance) components. Different genetic models were tested by the likelihood ratio criterion, and the maximum likelihood parameters for each of the three scores were based on the most appropriate models. The effect of fragile X on the mean values was found to be significant for all the traits, and much more conspicuous in male than in female individuals, the effects in the PPVT and the anthropometric score being intercorrelated. The effect of fragile X on growth of a single physical trait relative to height was demonstrated using jaw length as an example. We have also demonstrated an effect of fragile X on genetic (additive) variance, as well as on the mean of the BDT score, and the effect of age on the nongenetic variance of PPVT, and jaw length.

Anthropometry↗

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

Effect of the fragile X anomaly on body proportions estimated by pedigree analysis.

The purpose of this study was to determine the effect of the fragile X syndrome on limb (upper limb length) and facial (ear length) measurements in relation to body height, which was considered as a covariate. The analysis was performed in 52 fragile X Caucasian families, including affected individuals as well as their normal relatives. The maximum likelihood analysis of complex pedigrees, under the assumption of multivariate normality, was used to select the best genetic model and to estimate model parameters. This method allowed us to test various assumptions concerning the effect of normal hereditary variation, as well as of genetic anomaly and other relevant factors, in the mean and variance of a quantitative trait, and to obtain the maximum likelihood parameters for these effects. The results demonstrated that, if the family factor is accounted for in a model, the fragile X condition affects growth of both upper limb length and ear length, disproportionately to body height.

Adult↗

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

Fixed and random effects in the variation of the finger ridge count: a study of fragile-X families.

A maximum-likelihood scoring technique for analysis of pedigree data allows for the concurrent estimation of random and of fixed effects in a quantitative trait. We included both types of effects in genetic models, to study the sources of variation in finger ridge count in 54 large families affected with the fragile-X disorder. The fixed effects were represented by fragile X and sex, and the random effects by environmental and genetic variance. We found a significant effect of fragile X in the mean of the finger ridge count on the thumb (finger 1) and index finger (finger 2), which had the lowest heritability and a negligible nonadditive component of genetic variance. This was in contrast with ridge counts on fingers 3 and 4, which showed little fragile-X effect, but high heritability and a significant nonadditive component. A contrast in genetic properties for ridge counts on fingers 1 and 2, compared with these counts on the remaining three fingers, may be relevant to increased selection pressures on functions of the thumb and of the index finger in evolution of modern man. We have also demonstrated an important effect of fragile X in increasing the additive variance in covariance, especially between male pairs. These findings suggest that the effect of the fragile-X genotype in finger ridge count is additive and superimposed on the normal hereditary variations in this trait.

Dermatoglyphics↗

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

Relationships of epidermal ridge patterns with body measurements and their possible evolutionary significance.

It is commonly believed that in humans epidermal ridge patterns are in regression relative to nonhuman primates, and they play no role in adaptive processes. In contrast with this we have found relationships between anthropometric and dermatoglyphic measurements in a sample of 61 normal males. Anthropometric variables included limb, trunk, head, and face measures. Dermatoglyphic variables included finger ridge counts and pattern intensities and ridge breadth in the palmar interdigital area II. The strongest relationship is between the type and size of pattern on the thumb and the breadth of ridges, and wrist width, which accounts for nearly 30% of the total variance in these traits. These findings identify previously unknown sources of variation in dermatoglyphic patterns and indicate that the dermatoglyphic-anthropometric relationships might have resulted from selection pressures in evolution of modern man.

Anthropometry↗

PubMed1990

Hand locomotor functions, body structure, and epidermal ridge patterns: preliminary study.

The purpose of this study was to determine whether any relationships exist between hand locomotor functions and dermatoglyphic characteristics and body structure. The pilot sample consisted of 71 adult normal individuals (30 males and 41 females). The locomotor function tests included a power grip and two precision grips; dermatoglyphic features were represented by finger and palmar pattern intensities and ridge counts, and body structure by 35 head, face, trunk, and limb anthropometric measurements. Univariate and multivariate correlation analyses reveal that on average half of the variance in the locomotor hand-function tests can be accounted for by a set of body and/or dermatoglyphic variables in males; this contribution is appreciably lower in females. Body longitudinal measurements and some facial measures, such as jaw length, were found to be the main correlates of either a power grip or a simple thumb-index squeeze, especially in males; head and face measurements and the size and intensity of patterns on fingers 1 and 2 were the main correlates of more complex precision tests involving complicated manipulation of objects using the thumb and index finger. These preliminary results identify some previously unknown sources of variation in dermatoglyphic patterns and contribute to a better understanding of the evolutionary aspects of the relationships between specific functional and morphologic traits in humans.

Adolescent↗

PubMed1989

Multivariate analysis of body shape in fragile X (Martin-Bell) syndrome.

Human body shape measures can be more informative in studies of developmental abnormalities than distances between body landmarks. Such measures were obtained by an appropriate transformation of 34 distances between trunk/limbs and head/face landmarks in 43 men and 72 women with the Martin-Bell Syndrome (MBS), and in 99 and 103 normal men and women, respectively. The transformation of the original distances was performed by adjusting individual measures for an overall size measure using regression analysis. Thus obtained body shape variables were used in discriminant analysis in order to obtain unbiased classification probabilities of individuals having the MBS or being normal. The average percent correctly classified male and female individuals was high (93 and 87, respectively). Moreover, the body shape variables were used to obtain shape dimensions by means of principal component analysis. There was no difference between the MBS and normal individuals in the first (most important) principal component (shape dimension). This component represents the relative proportions between trunk and limb lengths and widths, or between midfacial lengths and widths. However, there were appreciable differences in some succeeding components. The problem of interpretation of shape dimensions as derived from principal component analysis and of their relevance to abnormal development in the MBS individuals is discussed.

Adolescent↗

PubMed1989

Application of the anthropometric discriminant functions in estimation of carrier probabilities in Martin-Bell syndrome.

A method of estimating the likelihood ratio and the risk of an individual being affected with Martin Bell syndrome (MBS) from anthropometric measurements is described. The procedure is based on the discriminant functions (one for each sex), generated in our previous study in order to separate the individuals with MBS from the normal individuals. The procedure is illustrated by the examples of estimating the likelihood and the likelihood ratio in four individuals of either sex, belonging to MBS families, where the discriminant score value obtained from each individual is compared with the empirical (normalized) distribution of discriminant scores from the known MBS and normal subjects of a corresponding sex. The ways in which the risk of an individual being MBS is estimated in the general population or in members of the MBS families are indicated. The limitations of the discriminant diagnosis based on body measurements, as well as its particular applications in studies of the Martin-Bell syndrome, are discussed.

Anthropometry↗

PubMed1988

Dermatoglyphic variation and weight and length at birth.

Relationships between dermatoglyphic variables, including finger ridge counts and finger, palmar, and plantar pattern intensities, and weight and length at birth, were tested in a sample of 184 boys and 202 girls from Warsaw schools. No convincing evidence for such relationships has been obtained from the results of correlations and one-way analysis of variance, although there are indications that some palmar traits may be related to length at birth in females. The data agree with the common belief that birth weight and birth length are mainly determined by influences operating in later stages of pregnancy, that is, after the 20th gestational week.

Birth Weight↗

PubMed1988

Discriminant analysis of dermatoglyphic measurements in fragile X males and females.

Two hundred and eight fragile X subjects (92 males and 116 females) and matched Australian (60 males and 32 females) and British (122 males and 118 females) normal samples were used to calculate 4 discriminant functions, based on dermatoglyphic measurements. The most efficient discriminating variables between fragile X and normal males, selected by means of the Wilk's stepwise method, included: ridge counts on fingers 1-3, the hallucal (f) count on soles, the atd angle, and pattern intensities in palmar areas 2, 4 and 5 as well as on fingers 4 and 5. In females, the ridge breadth, the hallucal (e) count, the atd angle and pattern intensities in palmar areas 3-5 as well as on fingers 1, 3 and 5 comprised the final discriminant. The misclassification rate based on distributions of individual discriminant scores in each pair of samples, and on prior probabilities, was lowest (16.8%) in fragile X males compared with the Australian normal subjects. In both female comparisons, this rate approached 44%. A bias to misclassification rates resulting from various analytical procedures and some properties of the data are discussed. We conclude that the discriminant function based on dermatoglyphic measured variables alone is not good enough for assessing carrier probabilities for fragile X, especially in females. However, we have been able to select the best discriminators which may be used, together with other measured body characteristics, to obtain a more powerful discriminant function. Moreover, a consideration of discriminant scores based on dermatoglyphic traits only may help in estimating carrier probabilities.(ABSTRACT TRUNCATED AT 250 WORDS)

Dermatoglyphics↗