X-Linked Mental Retardation
Total Page：16
File Type：pdf, Size：1020Kb
REVIEWS X-LINKED MENTAL RETARDATION H.-Hilger Ropers* and Ben C. J. Hamel‡ Abstract | Genetic factors have an important role in the aetiology of mental retardation. However, their contribution is often underestimated because in developed countries, severely affected patients are mainly sporadic cases and familial cases are rare. X-chromosomal mental retardation is the exception to this rule, and this is one of the reasons why research into the genetic and molecular causes of mental retardation has focused almost entirely on the X-chromosome. Here, we review the remarkable recent progress in this field, its promise for understanding neural function, learning and memory, and the implications of this research for health care. Mental retardation is one of the main reasons for refer- subject (by Chelly and Mandel7) was published. Pro- ral in paediatric, child-neurological and clinical genetic gress has been particularly spectacular for so-called practice. Often, however, despite extensive investiga- non-syndromic or ‘pure’ forms of XLMR, consisting of tions, an aetiological diagnosis cannot be made, leaving numerous disorders that are clinically indistinguishable families without accurate genetic counselling or repro- because cognitive impairment is their only manifestation. ductive options, such as prenatal diagnosis. The preva- In this review, we describe the strategies used to iden- lence of mental retardation in developed countries is tify all genes that have been implicated in XLMR so far, thought to be on the order of 2–3% (REF.1), although emphasizing the crucial importance of large cohorts of estimates vary widely, particularly for mild mental retar- well-characterized families. We provide a brief summary dation. In central Europe, about 8% of health-care of what is currently known about the physiological and expenditure is spent on ‘mental handicaps’ as defined by pathophysiological functions of XLMR genes, and exam- the International Classification of Disease (ICD) (BOX 1), ine the evidence for a role of these genes in cognition. which by far exceeds the costs that are related to all other Taking into account the possibility that XLMR might be ICD categories2.Together with its high burden for soci- less common than indicated by the observed excess of ety and families, this renders mental retardation one of males with the condition, we discuss the potential of this the most important unsolved problems in medicine. research to provide new possibilities for the diagnosis, X-linked gene defects have long been considered to prevention and therapy of mental retardation. We con- be important causes of mental retardation, on the basis clude by discussing the importance of autosomal mental of the observation that mental retardation is significantly retardation genes and the challenges that will need to be more common in males than in females3–5.Clinical overcome to identify them. *Max-Planck-Institute for observations and linkage studies in families revealed that Molecular Genetics, X-linked mental retardation (XLMR) is a highly het- Syndromic and non-syndromic forms of XLMR Ihnestrasse 73, erogeneous condition. The most common form of XLMR is subdivided into syndromic (S-XLMR) and D-14195 Berlin, XLMR — the Fragile X (Fra(X)) mental-retardation non-syndromic (NS-XLMR) forms, depending on Germany. syndrome — is associated with a cytogenetic marker in whether further abnormalities (in addition to mental ‡University Medical Centre Nijmegen, Department of the distal region of the long arm of the X chromosome, retardation) are found on physical examination, labora- Human Genetics, Geert which was shown to coincide with the map position of tory investigation and brain imaging. Roughly two thirds Grooteplein 10, 6525 GA the underlying gene defect, and eventually this led to the of XLMR cases are thought to be non syndromic8;how- Nijmegen, The Netherlands. cloning of the FMR1 gene6. Since then, the number of ever, as the possibilities for classifying families through Correspondence to H.-H.P. e-mail: cloned XLMR genes has been increasing exponentially. molecular studies improve, and as patients are exam- [email protected] No fewer than 23 of the currently known XLMR genes ined in more detail, it is likely that the proportion of doi:10.1038/nrg1501 have been identified since a previous review on this syndromic cases that are diagnosed will increase, with a 46 | JANUARY 2005 | VOLUME 6 www.nature.com/reviews/genetics © 2005 Nature Publishing Group REVIEWS Box 1 | Definition and classification of mental retardation Mental retardation is a complex disorder, which is not easily defined in a comprehensive way. The most widely used definition118 comprises three criteria: significantly sub-average general intellectual functioning (Intelligence quotient (IQ) <70); significant limitations in adaptive functioning in at least two of the following skill areas — communication, self-care, ability to live independently, social and interpersonal skills, use of public services, decision making, functional academic skills, work, leisure, and health and Terminology Intelligence quotient safety; and onset before the age of 18 years. On the basis of Profound <20 IQ, mental retardation is subdivided into several classes. Most commonly, the WHO (World Health Organization) Severe 20–35 classification and terminology (see table) are used119, but Moderate 35–50 numerous studies distinguish only between mild (IQ 70–50) Mild 50–70 and severe mental retardation (IQ <50). Borderline 70–85 concomitant decrease in the non-syndromic cases. This to the identification of the 20 NS-XLMR genes is illustrated by the Fra(X) syndrome, which was initially identified so far (TABLE 2). described as non syndromic and is now considered to Different strategies led to the identification of these be the most frequent example of S-XLMR. Moreover, genes. For example, FMR2 was found because of its asso- mutations in several XLMR genes can give rise to both ciation with a fragile site, FRAXE, which is analogous to non-syndromic and syndromic forms (TABLES 1,2), the association of FMR1 with another such site, FRAXA, indicating that there is no reliable molecular basis for in mentally retarded males9,10.Other genes were identified strictly distinguishing between genes for S-XLMR and by breakpoint mapping and cloning in mentally retarded NS-XLMR. However, for pragmatic reasons and in patients with BALANCED REARRANGEMENTS that involve the agreement with others (see the XLMR Genes Update X chromosome, or by molecular characterization of web site in the Online links box), we found it useful to small X-chromosomal deletions. maintain this separation in this review. The study of chromosomal rearrangements has About 140 syndromic forms of XLMR have been proved to be particularly informative in the identifica- described so far. In 66 of these, including several that tion of genes that are involved in XLMR. Through the have since been found to be allelic, the causative systematic characterization of patients with balanced genetic defects have been identified (TABLE 1;see X-chromosomal rearrangements, several additional online supplementary information S1 (table) for a full genes were found to be truncated (see for example, version), and in about 50 others, the underlying defect REFS 11,12; FIG. 2). However, these genes are not listed in has been mapped to a specific region of the X chromo- TABLE 2 because subsequent screening of unrelated some. By contrast, for NS-XLMR, less than 50% of the NS-XLMR patients failed to identify further mutations causative gene defects have been identified, as discussed in these genes. This might be because patients with clin- below. Although progress has been made in identifying ically complex developmental disorders are more likely genes that are involved in NS-XLMR in the past few years to undergo karyotyping than patients with NS-XLMR, (FIG. 1), the identification of other genes that are involved and so more balanced rearrangements will be identified in these cases remains an important task. that are associated with syndromic rather than with non-syndromic XLMR. Indeed, screening for mutations Large-scale identification of XLMR genes of the CDKL5 (STK9) gene — previously identified by Searching for genetic defects that underlie clinically breakpoint cloning in two severely affected females13 well-defined syndromic forms of XLMR is not different — was unsuccessful in large cohorts of families with from gene hunting in any other monogenic condition. It NS-XLMR,but several mutations of this gene were later has been greatly facilitated by the availability of the found in patients with atypical Rett syndrome14,15 (a syn- annotated human genome sequence and the increase in dromic form of XLMR; TABLE 1). Therefore, many of the our knowledge about gene function. Between 2002 and truncated genes that were identified by studying mentally 2004, causative mutations in 15 genes have been iden- retarded patients with balanced X-chromosomal tified in 18 clinically different syndromic forms of rearrangements might still be bona fide XLMR genes, XLMR, and it is safe to predict that before long, most of even if no mutations are detectable in unrelated patients the 50 syndromic forms of XLMR for which mapping with NS-XLMR. information is already available will also be elucidated. Mapping the causative gene defect to a defined Finding molecular causes of NS-XLMR is intrinsi- X-chromosomal interval, followed by mutation screening cally more difficult owing to its high level of genetic het- in unrelated families, is another successful strategy for BALANCED REARRANGEMENTS Chromosomal rearrangements erogeneity, which precludes the pooling of linkage identifying novel XLMR genes, particularly if the size of that change the chromosomal information from unrelated families and greatly com- the relevant interval is small. For example, ARX — gene order but do not remove or plicates the search for mutations. To overcome these mutations in which are now known to be a common duplicate any of the DNA from obstacles and to study the molecular basis of NS-XLMR cause of syndromic and non-syndromic XLMR — was the chromosomes.