M G Linden

University of Colorado, Denver, CO, United States

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Publications (26)64.62 Total impact

  • Mary G. Linden, Bruce G. Bender
    American Journal of Medical Genetics Part A 01/2004; · 2.30 Impact Factor
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    ABSTRACT: Sex chromosome abnormalities (SCAs) are the most frequently occurring chromosomal abnormalities encountered at both prenatal diagnosis and at birth. Approximately 1/400 newborns has an SCA, and incidence at prenatal diagnosis is even greater, 1/250 to 1/300. Physicians and health providers from various specialties are encountering diagnoses of SCAs with increased frequency as more individuals are becoming identified, both prenatally and postnatally. Because these conditions generally have relatively few serious physical implications and because they are extremely variable, genetic counseling is often more complex and challenging than that occurring with an autosomal abnormality. It is imperative that health professionals have the knowledge of content and methodology to provide appropriate counseling to such individuals and their families. During the period from 1964 to 1975, seven international groups (including the Denver group) screened a total of 199,898 consecutive births and identified 307 individuals with SCA. The Denver group has followed more than 40 such individuals from birth to adulthood. In addition, the Denver group has experience in counseling over 1,000 families with a prenatal diagnosis of SCA. Based on these studies and contacts, guidelines for the counseling of individuals and families with SCA are provided. Accurate information must be presented and the variability and imprecise prognosis recognized. Successful counseling strategies include interfamily contact, viewing photographs, and utilizing support groups. Issues of disclosure, follow-up, and anticipatory guidance should be addressed.
    American Journal of Medical Genetics 07/2002; 110(1):3-10.
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    Mary G Linden, Bruce G Bender
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    ABSTRACT: Children with sex chromosome abnormalities (SCA) are known to be at risk for developmental delays. These risks were identified 2 decades ago by seven international research groups who prospectively followed children ascertained after birth. Subsequently, some of these investigators suggested the course of prenatally identified children with SCA may be different from children in earlier studies. The first such evidence was published by Robinson et al. [1992: Am J Med Genet 44:365-368], who compared 20 prenatally diagnosed children to the original postnatally diagnosed cohort. The following report presents an update and expansion of that research and includes 51 children and adolescents prenatally diagnosed with SCA, now 7-18 years of age. Results confirm that this cohort of prenatally diagnosed children has a milder developmental course than children ascertained postnatally. The study provides new information to health professionals counseling families faced with prenatal diagnosis of SCA.
    American Journal of Medical Genetics 07/2002; 110(1):11-8.
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    ABSTRACT: The excess of 47,XXX and 47,XXY karyotypes found in cytogenetic screening studies of individuals with schizophrenia has given support for an increased risk of psychiatric illness among men and women with sex chromosomal aneuploidy (SCA). Mesial temporal lobe structures, including the amygdala and hippocampus, are thought to be associated with abnormalities of mood and behavior in humans and in the neurobiology of schizophrenia. This study focuses on variations in volumes of mesial temporal lobe structures in men and women with SCA. Utilizing an unselected birth cohort of subjects with SCA and high-resolution magnetic resonance imaging (MRI), we investigated the neuroanatomical consequences of a supernumerary X chromosome on the morphology of the amygdala and hippocampus. Regional and total brain volumes were measured in 10 subjects with 47,XXY, 10 subjects with 47,XXX, and 20 euploid controls. Amygdala volumes were significantly reduced in men with 47,XXY, compared to control men, while the decrease in women with 47,XXX was not as pronounced. Hippocampus volumes were preserved in both groups, compared to same-gender controls. Longitudinal studies of SCA individuals have shown an increased incidence of mild psychopathology and behavioral dysfunction in men with 47,XXY and more overt psychiatric illness in women with 47,XXX, compared to control populations. The alteration in amygdala volumes in individuals with a supernumerary X chromosome may provide a neuroanatomic basis for these findings.
    American Journal of Medical Genetics 02/2002; 114(1):93-8.
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    ABSTRACT: This report presents data defining the neuropsychological and cognitive phenotypes of a group of adults with sex chromosome abnormalities identified at birth through the chromosome screening of 40,000 consecutive newborns between 1964 and 1974. In all three nonmosaic groups, reading skills were impaired and intelligence quotients were on average reduced more than 20 points relative to controls. The 47,XXX women demonstrated greatest overall impairment, including reduced scores on tests of conceptualization and problem solving. 45,X women demonstrated impairment in spatial thinking skills, and 47,XXY men in verbal processing skills. No reduced scores were found in the female mosaic group. Marked variability in scores was seen in all groups; some propositi have been unable to hold any job, whereas others have completed college and are professionally employed.
    American Journal of Medical Genetics 10/2001; 102(4):309-13.
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    B G Bender, M G Linden, R J Harmon
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    ABSTRACT: This report from the last phase of the 36-year Denver Study provides information about the adult life adaptation of 35 men and women with sex chromosome abnormalities (SCA) followed since their identification at birth. Sex chromatin screening of 40,000 consecutive newborns between 1964 and 1974 resulted in the cohort of 35 SCA men and women followed to date since birth. Sixteen chromosomally normal siblings served as controls. Data constituting this report was obtained from formal and informal interviews and psychological testing conducted in the final year of this study. The nonmosaic SCA propositi had lower mean intelligence quotients and psychosocial adjustment scores than did siblings. Consistent with these results, propositi also had lower levels of educational achievement and career success, although most have completed school, married, hold full-time employment, and are financially independent. While the SCA adults demonstrated lower levels of cognitive and psychosocial competence, their overall adaptation has been positive, particularly given an early literature suggesting a high rate of psychopathology and severe dysfunction.
    Genetics in Medicine 06/2001; 3(3):187-91. · 5.56 Impact Factor
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    ABSTRACT: This study focuses on variation in brain morphology associated with supernumerary X chromosome and Klinefelter syndrome (KS). Using an unselected birth cohort of KS subjects and high-resolution MRI, the authors investigated the neuroanatomic consequences of the 47,XXY karyotype in the presence and absence of exogenous testosterone supplementation. Regional brain volumes were measured in 10 subjects with KS and 10 age-matched control men. Five of the KS subjects had received testosterone supplementation since puberty (KS+T) and five had not (KS-T). KS subjects showed significant (p < 0.01) reduction in left temporal lobe gray matter volumes compared with normal control subjects. Differences in left temporal gray volumes were also significant between the KS+T and KS-T groups (p < 0.01). Verbal fluency scores were significantly different between the KS+T and KS-T groups as well. Supernumerary X chromosome material in men is associated with a reduction in left temporal lobe gray matter, a finding that is consistent with the verbal and language deficits associated with KS. Also, relative preservation of gray matter in the left temporal region is associated with exposure to exogenous androgen during development. A history of testosterone supplementation also appears to be associated with increased verbal fluency scores in KS patients.
    Neurology 07/2000; 54(12):2218-23. · 8.30 Impact Factor
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    ABSTRACT: Very little is known about the adult adaptation of individuals with sex chromosome abnormalities (SCA) except for a few reports based upon biased samples of clinically identified patients. This first report from the Denver SCA study on the adult psychosocial adaptation of 36 unselected propositi, identified at birth, shows a continuation of mild psychological and social problems. Psychiatric interviews and self-reported information revealed that adaptation is quite variable, with many of the nonmosaic propositi not faring as well as their siblings, but in a few instances exceeding the success of brothers and sisters. Within this group of SCA subjects a subset demonstrated more marked pathology and a tendency to over-rate their social adaptation relative to the psychiatric interviewer, suggesting that the exclusive use of self-report questionnaires may not provide accurate assessment of psychological characteristics in this and other special populations. The full adult SCA behavioral phenotype has not yet been established but is emerging through additional reports from this and other studies of unselected SCA adults.
    American Journal of Medical Genetics 05/1999; 88(2):200-6.
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    ABSTRACT: Very little is known about the adult adaptation of individuals with sex chromosome abnormalities (SCA) except for a few reports based upon biased samples of clinically identified patients. This first report from the Denver SCA study on the adult psychosocial adaptation of 36 unselected propositi, identified at birth, shows a continuation of mild psychological and social problems. Psychiatric interviews and self-reported information revealed that adaptation is quite variable, with many of the nonmosaic propositi not faring as well as their siblings, but in a few instances exceeding the success of brothers and sisters. Within this group of SCA subjects a subset demonstrated more marked pathology and a tendency to overrate their social adaptation relative to the psychiatric interviewer, suggesting that the exclusive use of self-report questionnaires may not provide accurate assessment of psychological characteristics in this and other special populations. The full adult SCA behavioral phenotype has not yet been established but is emerging through additional reports from this and other studies of unselected SCA adults. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:200–206, 1999. © 1999 Wiley-Liss, Inc.
    American Journal of Medical Genetics 04/1999; 88(2):200 - 206.
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    ABSTRACT: To investigate the adolescent and early adult adaptation of a group of 47,XXX women as compared with their siblings, addressing developmental differences in adaptation and psychiatric status. Subjects included eleven 47,XXX women and nine female sibling controls. Interviews during adolescence and during early adulthood were semistructured and included a psychiatric evaluation. Four areas of inquiry were (1) relationships with other family members, (2) sense of self-esteem, (3) sexual identity and preference, and (4) responses to life stressors. A DSM-IV psychiatric diagnosis was assigned where appropriate. The Schedule for Affective Disorders and Schizophrenia-Lifetime version was also administered, and assessments of overall functioning and adaptation were completed. The 47,XXX women during adolescence and young adulthood were less well adapted; had more stress; had more work, leisure, and relationship problems; had a lower IQ; and showed more psychopathology when contrasted with the comparison group. However, most of the 47,XXX women were self-sufficient and functioning reasonably well, albeit less well than their siblings. This longitudinal study has clarified that previously reported outcomes of severe psychopathology and antisocial behavior in individuals with sex chromosome anomalies are rare and variability in the behavioral phenotype is much larger than originally appreciated.
    Journal of the American Academy of Child & Adolescent Psychiatry 03/1998; 37(3):286-91. · 6.97 Impact Factor
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    M G Linden, B G Bender, A Robinson
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    ABSTRACT: To provide current information on sex chromosome aneuploidies to obstetricians who encounter such diagnoses and who counsel prospective parents faced with the prenatal diagnosis of a sex chromosome aneuploidy. Unbiased information about the natural course of sex chromosome aneuploidy has become available only in the last few years. Current knowledge is based on seven prospective studies on unselected individuals with sex chromosome aneuploidy identified 20-30 years ago. All literature on sex chromosome aneuploidy was reviewed. Karyotypes specifically addressed included the following: 47,XXY, 47,XXX, 47,XYY, 45,X, 45,X/46,XX, 46,XX/47,XXX, and 46,XY/47,XXY. The international studies followed the affected subjects from birth to young adulthood. All published reports, case studies, and articles were reviewed. All prospective studies were included in the course of determining necessary information for obstetricians and prospective parents. Points addressed for each of the aneuploid karyotypes included expected phenotype, reproductive competence, developmental risks, and intervention therapies. Information about sex chromosome aneuploidy can assist obstetricians in providing accurate and comprehensive genetic counseling to parents of affected fetuses, and thereby facilitate the process of making an informed decision about pregnancy management.
    Obstetrics and Gynecology 04/1996; 87(3):468-75. · 4.80 Impact Factor
  • M G Linden, B G Bender, A Robinson
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    ABSTRACT: Sex chromosome abnormalities occur in at least 1 in 400 births and include the well-described 47,XXX, 47,XXY, 47,XYY, and 45,X karyotypes. The addition of more than one extra X or Y chromosome occurs rarely, and little information is available in the medical literature. Individual case reports make up most of this body of knowledge, and all are based on subjects who identified themselves postnatally. Many were ascertained through screenings of institutions and hospitals; thus, there is no unbiased information on the natural history of poly X and Y karyotypes. A direct relationship between the number of additional sex chromosomes and the severity of the phenotype is generally assumed. The purpose of this article is to summarize what is known about these conditions and to present 10 additional cases. The karyotypes include, 48,XXXX, 49,XXXXX, 48,XXYY, 48,XXXY, 49,XXXXY, 49,XXXYY, 48,XYYY, 49,XYYYY, and 49,XXYYY.
    Pediatrics 11/1995; 96(4 Pt 1):672-82. · 5.12 Impact Factor
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    ABSTRACT: Children with sex chromosome abnormalities (SCA) are known to be at increased risk for neuromotor, language, learning, and behavioral problems, but little is known of psychosocial adaptation of SCA adolescents. This study was conducted to evaluate psychologic characteristics of unselected SCA adolescents, including socialization, educational progress, separation from family, and incidence and severity of psychiatric disturbance. Thirty-nine propositi identified through the screening of 40,000 consecutive Denver newborns, including boys with 47,XXY karyotypes and girls with 47,XXX, 45,X, and partial X monosomy, or SCA mosaic karyotypes, have been followed longitudinally into adolescence. Twenty-seven siblings served as controls. Between 12 and 19 years of age, all participated in blind psychiatric interviews and were administered standardized intelligence and achievement tests. SCA propositi demonstrated a mean IQ score 21 points lower than that of control subjects. In addition, lower mean scores were seen on achievement test results as well as lower overall psychosocial adaptation scores and increased incidence of psychiatric disturbance. Depression was the most frequent psychiatric diagnosis. Propositi were more likely to receive special education assistance in high school and were less likely to graduate from high school than were controls. Of the three nonmosaic propositi groups, the 47,XXX girls demonstrated the poorest overall psychosocial adaptation and highest degree of psychiatric disturbance. Mosaic girls were indistinguishable from control subjects. Marked variability was found among all three nonmosaic groups, with some individuals in each group demonstrating relatively strong psychosocial adaptation. The presence of nonmosaic sex chromosome abnormality increases the risk for impeded cognitive skills, learning abilities, and psychosocial adaptation in adolescence. The factors that allow for stronger adaptation in some of these adolescents include the presence of a stable and supportive family environment. The outlook for adaptation in unselected SCA adults remains uncertain.
    Pediatrics 09/1995; 96(2 Pt 1):302-8. · 5.12 Impact Factor
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    Bruce G. Bender, Mary G. Linden, Arthur Robinson
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    ABSTRACT: Sixty-seven adolescents participated in this protocol, including 42 with sex chromosome abnormalities and 25 controls. Results from a battery of neuropsychological tests indicated karyotype specific patterns of neuropsychological impairment: (1) 47,XXY boys had unimpaired intelligence but reduced abilities in verbal fluency and reading; (2) 47,XXX girls experienced reduced general intelligence accompanied by impaired scores on individual tests of attention, concept formation, spatial thinking, verbal fluency, and academic skills, while retention of memorized information was a relative strength; (3) among the 45,X girls average intelligence level was also reduced along with scores on tests of attention, concept formation, verbal fluency, spatial thinking, and academic skills, and an atypical pattern of hand dominance was identified; (4) test scores in the group of mosaic females did not differ from those of controls. Test scores and patterns of personal adaptation were quite variable in all groups; while eight nonmosaic propositi required intensive special education assistance in their public schooling, eight others have attended college.
    American Journal of Medical Genetics 11/1993; 48(3):169-73.
  • Arthur Robinson, Bruce G. Bender, Mary G. Linden
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    ABSTRACT: Sex chromosome aneuploidy (SCA) occurs in about 1/250 amniocenteses, and the significance of the long-term prognosis of fetuses with SCA is of concern to prospective parents and health care providers. Longitudinal studies in an unselected group of newborn infants with SCA diagnosed postnatally have refuted allegations of mental retardation but have documented an increased risk for developmental problems. Of the 530 phone consultations with parents faced with a prenatal diagnosis of SCA, 68% continued the pregnancy. Twenty of the oldest subsequently born children (now 7-14 years old) were available for follow-up. In this small sample and age group, the propositi are progressing developmentally at a rate comparable to their sibs and are doing better at school and in peer relations than the SCA group diagnosed postnatally. Only 2 have documented IQs as low as 90. The documented IQs of the remainder, none of whom are sex chromosome mosaics, are all over 110. The parent population in this prenatally diagnosed group is unique and different from that of the postnatally diagnosed group in that over 85% of them are college graduates, often professionals, and upper socioeconomic individuals. The developmental competence of this SCA sample may be attributable to the supportive environment provided by these families, all of whom made a conscious decision to continue the pregnancy.
    American Journal of Medical Genetics 11/1992; 44(3):365-8.
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    ABSTRACT: Forty-six unselected children with various sex chromosome abnormalities (14 boys with 47,XXY, 4 boys with 47,XYY, 11 girls with 47,XXX, 9 girls with 45,X, and 8 girls with SCA mosaicism), identified through the consecutive chromosome screening of 40,000 Denver newborns, have been followed developmentally and evaluated in a protocol that included intellectual, language, and achievement testing. Controls consisted of 12 chromosomally normal males and 13 chromosomally normal females who were siblings of various propositi. While most SCA children were not mentally retarded, most of the nonmosaic propositi (31/37) received special education help for learning problems. In general, nonmosaic males were less severely affected than nonmosaic females, who demonstrated significantly reduced mean IQ scores on both Wechsler IQ tests. The inference that learning disorders were genetically mediated in this group was further supported by karyotype-specific findings. 47,XXY boys tended to demonstrate lower verbal skills and a specific reading disability. 47,XXX girls, while more globally impaired, demonstrated evidence of a specific weakness in language skills. 45,X girls tended to be globally impaired, but demonstrated a contrasting specific deficit in spatial thinking skills. Mosaic girls were not significantly different than controls on any measure, an outcome likely occurring because of the low percentage of aneuploid cells in these propositae. Variability was present in each group, and no single profile can characterize all children with any specific SCA. The presence of SCA, therefore, must be viewed as a risk factor creating a tendency towards LD but interacting with a host of other genetic and environmental forces to create a range of phenotypic outcomes.
    Reading and Writing 01/1991; 3(3):315-327. · 1.44 Impact Factor
  • M G Linden, B G Bender, A Robinson
    Comprehensive Therapy 06/1990; 16(5):3-10.
  • Birth defects original article series 02/1990; 26(4):59-115.
  • A Robinson, B G Bender, M G Linden
    Birth defects original article series 02/1990; 26(4):225-8.
  • A Robinson, B G Bender, M G Linden
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    ABSTRACT: This is a report of 327 phone calls to our center concerning the intrauterine diagnosis of sex chromosome abnormalities (SCA). The first author (A.R.) responded to each by counseling either the parents or the referring professional. Sixty-two percent continued the pregnancy. When the parents were counseled directly, the percentage continuing the pregnancy was significantly higher than when the information was transmitted through the professionals. Our results are different from most reports in these situations, and suggest that well-informed couples, counseled by geneticists, are more likely to continue these pregnancies. The possible occurrence of SCA should be considered in preamniocentesis counseling.
    American Journal of Medical Genetics 01/1990; 34(4):552-4.

Publication Stats

703 Citations
64.62 Total Impact Points

Institutions

  • 1998
    • University of Colorado
      • Department of Psychiatry
      Denver, CO, United States
  • 1990–1992
    • University of Colorado Hospital
      • Department of Pediatrics
      Denver, Colorado, United States