Elsevier

The Lancet Neurology

Volume 13, Issue 3, March 2014, Pages 306-318
The Lancet Neurology

Review
Cognitive and neurological aspects of sex chromosome aneuploidies

https://doi.org/10.1016/S1474-4422(13)70302-8Get rights and content

Summary

Sex chromosome aneuploidies are a common group of disorders that are characterised by an abnormal number of X or Y chromosomes. However, many individuals with these disorders are not diagnosed, despite established groups of core features that include aberrant brain development and function. Clinical presentations often include characteristic profiles of intellectual ability, motor impairments, and rates of neurological and psychiatric disorders that are higher than those of the general population. Advances in genetics and neuroimaging have substantially expanded knowledge of potential mechanisms that underlie these phenotypes, including a putative dose effect of sex chromosome genes on neuroanatomical structures and cognitive abilities. Continuing attention to emerging trends in research of sex chromosome aneuploidies is important for clinicians because it informs appropriate management of these common genetic disorders. Furthermore, improved understanding of underlying neurobiological processes has much potential to elucidate sex-related factors associated with neurological and psychiatric disease in general.

Introduction

Sex chromosome aneuploidies are characterised by an atypical variation in the number or function of sex chromosomes. They are some of the most common genetic disorders in human beings, and include Klinefelter's syndrome (47,XXY; one in 600 male livebirths), Turner's syndrome (45,X; one in 2000 female livebirths) and XYY syndrome (47,XYY; one in 1000 male livebirths). However, by comparison with other chromosomal abnormalities, such as trisomy 21 (one in 600 livebirths), clinicians have relatively little awareness about diagnosis or management of associated cognitive, psychiatric, and neurological symptoms. These circumstances create a potential gap in clinical practice, with risk of missed diagnoses and high disease burden for patients who might otherwise receive treatments that would improve outcomes. As an example, about 50–85% of individuals with Klinefelter's syndrome and XYY syndrome are not identified.1, 2, 3 Taken together with evidence that earlier detection could positively affect psychosocial, cognitive, physiological, and reproductive outcomes,4, 5, 6, 7 it is imperative for health professionals to increase their familiarity with this group of disorders.

In addition to improvements in clinical practice, increased understanding of sex chromosome aneuploidies provides an important opportunity to advance knowledge of sex-related differences in clinical disease in general. Advances in genomics and neuroimaging research have made it increasingly possible that genotype–phenotype links will be established in the foreseeable future. Sex chromosome aneuploidies are ideal models for investigation of genotype–phenotype correlations because of their well defined genetic basis and relatively well described phenotypic characteristics. Targeted research can elucidate how disrupted expression of sex chromosome genes and aberrant sex hormone production specifically affects cognitive and neurological function, and how this disruption can affect sex differences in clinical pathophysiology in general. Many immunological, cognitive, and motor features associated with sex chromosome aneuploidies are also commonly associated with disease states that have highly skewed sex differences in prevalence and symptomatology. As such, improved knowledge of the inter-relation between genetics and nervous system function in sex chromosome aneuploidies can provide clinicians with an expanded understanding of mechanisms underlying sex differences in the nervous system.

In this Review, we summarise the major clinical features of sex chromosome aneuploidies, focusing mainly on Turner's syndrome, Klinefelter's syndrome, and XYY syndrome, although we also briefly review other supernumerary sex chromosome disorders. We present cognitive, motor, and other neurological outcomes associated with these disorders, and mechanistic models and treatment frameworks that are used. Additionally, we delineate clinical features for each of these disorders, and discuss how continuing research in this area has broad implications for future understanding of sex differences in cognitive and neurological functioning in human beings.

Section snippets

Pathophysiology

X-chromosome monosomy (ie, Turner's syndrome) is a common disorder that occurs in one in 2000 female livebirths8 and is characterised by the partial or complete absence of an X chromosome. Roughly 50% of individuals with Turner's syndrome have complete monosomy (ie, 45,X karyotype), rather than the full complement of 46 chromosomes.9 The other 50% have a range of different disorders, including deletions along the short or long arm of the X chromosome, ring X-chromosome formations, and mosaic

Pathophysiology

Sex chromosome aneuploidies also include disorders characterised by supernumerary sex chromosomes, the most common of which is Klinefelter's syndrome. The disorder occurs as frequently as one in 600 male livebirths.64 Individuals with Klinefelter's syndrome typically have an additional X chromosome resulting in a 47,XXY karyotype. As with Turner's syndrome, variations on this karyotype are noted, including mosaicism with 46,XY, or other karyotypes, including additional X chromosomes (eg,

Pathophysiology

XYY syndrome is another common supernumerary sex chromosome aneuploidy with an incidence of one in 1000 male livebirths.3 The genetic mechanism for XYY syndrome also stems from nondisjunction; however, given that the karyotype is two Y chromosomes, errors exclusively result from the paternal gamete, typically during the second stage of meiosis.10 Other than early and controversial reports of behavioural features of XYY syndrome, there is a notable paucity of research on the disorder, despite

Other sex chromosome aneuploidies

Published work on other sex chromosome aneuploidies is scarce. Some early studies have been done of triple X or 47,XXX syndrome, which occurs in roughly one in 1000 female livebirths; however, the paucity of recent investigations is probably due to the lack of knowledge of phenotypic traits associated with this disorder, other than increased stature.109, 135 Interestingly, neuropsychological studies of women with 47,XXX indicate a cognitive profile similar to other sex chromosome trisomies

Similarities across disorders

Sex chromosome aneuploidies create a broad range of observed phenotypes, with substantial variability in associated cognitive and neurological features. This variability might be partly due to ascertainment biases associated with these disorders, including the fact that girls with Turner's syndrome are more likely to present with a prominent physical phenotype, resulting in earlier detection and enrolment in services, whereas boys with sex chromosome trisomies frequently are not detected until

Future directions

Future research in this area has profound implications for clinical and research domains in its potential to clarify the effect of sex chromosome genes on neurocognitive functions. Genomic technologies provide powerful methods to elucidate the genetic mechanisms associated with sex chromosome function. Mammalian studies have already shown that processes moderating X-chromosome inactivation and dose compensation between the X chromosome and autosomes are more complicated than was previously

Search strategy and selection criteria

We searched PubMed using a search string of the names of sex chromosome aneuploidies (“Turner syndrome”, “Klinefelter syndrome”, etc). We restricted results to only reports of human clinical studies published from Jan 1, 2003, to Jan 1, 2014, and relevant studies from earlier years. We considered only original studies published in peer-reviewed journals in English. We generated the final reference list on the basis of relevance to the topics in this Review.

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