Download Genetics of Mental Retardation

MEDICINE
REVIEW ARTICLE
Genetics of Mental Retardation
Andreas Tzschach, Hans-Hilger Ropers
SUMMARY
Introduction: Mental retardation (MR) has a prevalence of about 2% and constitutes one of the
major unsolved medical problems. MR arises from genetic defects in more than 50% of
patients. Methods: Selected literature review. Results: Chromosomal aberrations are a major
cause of MR. New molecular genetic and molecular cytogenetic techniques allow even
submicroscopic chromosomal aberrations to be detected. The gene defects underlying many
syndromic forms of MR have been elucidated in recent years, whereas insight into non-specific
(non-syndromic) MR is restricted almost exclusively to the X-chromosome. The Fragile X syndrome
is the most frequent monogenic cause of MR in males. A more broadly based search for
autosomal gene defects in non-syndromic MR has recently begun. Discussion: The elucidation of
gene defects in MR improves the diagnosis and management of patients and facilitates genetic
counselling of their parents. In the long run, this research will also have therapeutic
implications.
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Key words: mental retardation, chromosomal aberration, submicroscopic chromosome aberrations,
monogenic disorders, X-linked mental retardation
M
ental retardation (MR) is among the more significant public health problems
because of its prevalence (ca. 2%), the few therapeutic options that are currently
available, and the resulting life-long harm to the affected persons, their families, and
society as a whole (1). Persons with an intelligence quotient (IQ) below 70 are considered
mentally retarded; milder forms of mental retardation, with IQ between 50 and 70 (overall
prevalence ca. 1.5%), are more common than moderate and severe forms with IQ below 50
(prevalence 0.4%). Mental retardation is characterized by impaired cognitive, linguistic,
and social abilities. It is sometimes already manifest in infancy (with muscular hypotonia,
poor visual contact, and diminished motor activity) or early childhood, e.g., with abnormal
play and delayed attainment of developmental milestones.
Mental retardation can be caused by genetic or non-genetic factors: for example, infection
or intoxication during pregnancy, complications of delivery, or postnatal infection or trauma
(table 1). Genetic causes are present in more than 50% of severely mentally retarded
TABLE
Causes of congenital mental retardation and their
prevalence
Cause
%
Chromosomal anomalies
4–28
Identifiable dysmorphic syndromes
3–7
Known monogenetic diseases
3–9
Structural malformations of the CNS
7–17
Complications of premature birth
2–10
Environmental and teratogenic causes
5–13
"Cultural/familial" causes
3–12
Metabolic/endocrine causes
1–5
Unknown
30–50
Modified from Curry et al. 1997.
Max-Planck-Institut für molekulare Genetik, Berlin: Dr. med. Tzschach; Prof. Dr. med. Ropers
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persons (2). Most mild forms of MR, however, represent the tail end of the normal distribution
of intelligence in the population at large and are due to a complex interaction of genetic
predispositions and environmental factors.
For many persons with MR, it is unclear whether a genetic cause or an unknown, exogenous
cause is present. This is, however, a question of major importance to parents, if they wish to
have more children, as well as to other members of the family: the etiology of MR determines
the risk of MR in any subsequently born children, as well as the measures that can be taken to
prevent it, if any.
In this article, the authors provide an overview of the known genetic defects and diagnostic
possibilities, as well as prospects for further developments in the field. Emphasis is placed on
the common non-syndromic types of MR, i.e., those that cannot be classified among the known
MR syndromes because of the absence of any accompanying deformities or abnormalities.
Syndromic and non-syndromic types of MR are not always clearly distinguishable, and some
syndromes can only be diagnosed from a certain age onward (e.g., fragile X syndrome).
Chromosomal aberrations
Some 15% of all mentally retarded persons harbor chromosomal aberrations that can be
detected under the light microscope (3). The majority of cases involve trisomy 21 (karyotype
47,XX,+21 or 47,XY,+21; prevalence 1 : 700 to 1 : 1 000), which is clinically expressed as
Down syndrome (4). Other chromosomal aberrations are much rarer and are usually associated
with further clinical manifestations; among these, for example, are deletions (loss of
chromosomal material) in chromosome 5 (cri du chat syndrome) and chromosome 4
(Wolf-Hirschhorn syndrome). With the exception of sex chromosome abnormalities, nearly
all unbalanced chromosomal aberrations that can be seen under the light microscope cause
mental impairment. Because chromosomal aberrations are so common, all patients with
mental retardation of unknown cause should undergo chromosomal analysis.
Submicroscopic chromosomal aberrations
Chromosomal aberrations that are too small to be seen under the light microscope (i.e.,
smaller than ca. 5 megabases [Mb]) are a further important cause of mental retardation.
DIAGRAM 1
Example of a submicroscopic 2.7 Mb deletion on chromosome 14 detected by array CGH (with the kind permission of R. Ullmann). The ca.
32 000 DNA fragments used for hybridization are represented as single points. Deleted BACs are illustrated to the left of the midline.
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Microdeletions can be detected with molecular cytogenetic techniques, such as fluorescent
in situ hybridization (FISH). FISH is performed when there is concrete clinical suspicion of
a particular microdeletion syndrome, e.g., Williams-Beuren syndrome (deletions in 7q11),
22q11 deletion syndrome, 1p36 deletion syndrome, or Smith-Magenis syndrome (deletions
in 17p11) (5).
Often, in mentally retarded persons with additional deformities or signs of dysmorphism
that cannot be clearly assigned to any known syndrome, a search will also be made for
deletions located immediately before the ends of chromosomes (telomeres). Subtelomer
screening reveals abnormalities in 2% to 3% of patients studied (7).
DIAGRAM 2
Partial chromosome ideogram representing
a balanced translocation between
chromosomes X and 7 and the
homologous normal chromosomes in
a severely mentally retarded female
patient. The breakpoint in the
X chromosome was found to lie within
the STK9/CDKL5 gene. Mutations in the
same gene were subsequently found in
other female patients with similar clinical
manifestations (13, e4).
Array CGH (comparative genomic hybridization) is a new technique enabling detection
of very small, unbalanced chromosomal aberrations anywhere in the genome (8, 9). It
employs arrays of cloned DNA fragments which together incorporate the entire human
genome, with a resolution of ca. 100 kilobases (kb) at present. This is a major improvement
over conventional chromosomal analysis or CGH (maximal resolution 2 to 3 Mb). An example
of a submicroscopic deletion is depicted in diagram 1.
Initial studies have shown that high-resolution CGH can reveal causative chromosomal
changes in ca. 7% of patients with non-specific MR and in about 15% to 20% of patients
with additional clinical abnormalities (10) (Ullmann, Kirchoff, et al, Max Planck
Institute for Molecular Genetics, Berlin: unpublished data). This method enables the
detection of almost twice as many unbalanced aberrations as conventional chromosomal
analysis. Thus, the demonstration or exclusion of submicroscopic changes ought to be
just as important a part of standard diagnostic testing in idiopathic mental retardation as
conventional chromosomal analysis. At present, there are only a few laboratories in the
world that can perform array CGH testing at the 100 kb resolution level. Soon, however,
commercial variants of this technique (oligonucleotide array CGH, single nucleotide
polymorphism chips) are likely to be introduced that will reduce the cost to less than
500 euros per analysis. A remaining impediment to the routine diagnostic use of array
CGH is the difficulty of distinguishing functionally relevant changes from neutral
variations or polymorphisms. The variability of the human genome at the submicroscopic
level is unexpectedly high, and the pathological relevance of many of the changes that
are seen will only become clear once many patients and many normal controls have
been studied.
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Balanced chromosomal rearrangements
Not only unbalanced chromosomal aberrations, in which genetic material is lost or added,
but also balanced chromosomal rearrangements can lead to mental retardation if they cause
genes to be interrupted or less than fully expressed. There are two types of balanced
rearrangement, translocation (an exchange of genetic material between different
chromosomes) and inversion (a rearrangement within a chromosome). About 6% of all
newly arising rearrangements are associated with disease; in half of these cases, the disease
is thought to be due to the interruption of a gene (11). The molecular characterization of
changes of this type furnishes information about the function of the gene or genes involved
and is thus an important way of improving our understanding of the mechanisms leading to
mental retardation in humans (diagram 2) (12–14).
X-chromosomal mental retardation
The prevalence of mental retardation is significantly higher in boys than in girls, with a sex
ratio of 1.4 : 1 for severe MR and 1.9 : 1 for mild MR (16). The higher prevalence in boys
is partly due to X-chromosomal genetic defects, which, according to current estimates, are
the cause of mental retardation in about 10% of affected boys (17).
Fragile X syndrome is the most common X-chromosomal type of MR. Patients with this
syndrome have a large head circumference, big ears, a prominent chin, and enlarged
testicles. The manifestations of the syndrome are variable, however, and do not reach their
full extent till puberty. Fragile X syndrome should, therefore, be included in the differential
DIAGRAM 3
Localization of the XLMR genes on the X chromosome. Left side: genes in which mutations lead to syndromic types of XLMR. Right side: genes
in which mutations have been found in patients with non-syndromic types of XLMR.
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DIAGRAM 4
Family tree of a consanguineous (inbred) kindred with multiple children affected by autosomal
recessive mental retardation and microcephaly (dark symbols). Linkage studies in this family
led to the demonstration of a homozygous mutation in the MCPH1 gene (23).
diagnosis of all boys with mental retardation, particularly those with a positive family
history. Girls, too, can suffer from fragile X syndrome, though the characteristic features of
the syndrome are less commonly observed in girls. The underlying genetic defect
(a trinucleotide repeat expansion of the FMR1 gene) has been known since 1991 and can be
detected with a simple molecular genetic test (18).
Fragile X syndrome is found in approximately 25% of all families suffering from familial
mental retardation with a clearly X-chromosomal inheritance pattern. Recent years have seen
the identification of the genetic defects underlying many types of X-chromosomal retardation,
both syndromic (e.g., Coffin-Lowry syndrome, ATRX syndrome) and non-syndromic
(diagram 3) (19). Many clinically distinguishable syndromic types of X-linked mental
retardation (XLMR) are due to a defect in a single gene. Non-syndromic types, in contrast, can
be due to defects in many different genes, of which more than 20 are currently known. In practice,
however, it is unlikely that a defect will be found in any of these genes, even in patients with
familial mental retardation. Therefore, routine diagnostic testing for the exclusion of specific
genetic defects can hardly be justified, in view of the high cost of the tests currently in use.
Soon, however, newer and cheaper diagnostic techniques will be available. Alternative
techniques of (re-)sequencing are now being developed that ought to enable mutation
screening at considerably lesser expense. The European Mental Retardation Consortium
(EUROMRX; www.euromrx.com) has set itself the goal of detecting at least 90% of all genetic
defects causing XLMR by the systematic identification and study of families with Xchromosomal MR. At present, more than 500 families have been studied. The genes that are
known to date are collectively responsible for about 50% of all cases of non-syndromic XLMR.
Autosomal recessive genetic defects
Metabolic defects are the best studied cause of mental retardation of autosomal recessive
inheritance. Phenylketonuria (PKU) is the most common inborn error of metabolism in
Germany, with an incidence of 1 in 10 000 births. In PKU, there is impaired degradation of
the amino acid phenylalanine, and, if the disorder remains untreated, the accumulation of
toxic metabolites impairs brain development. Nearly all PKU patients in Germany are
identified in the first few days of life by neonatal screening, and strict adherence to a
low-phenylalanine diet enables them to undergo normal mental development. PKU is thus
one of the few monogenic diseases that can be successfully treated (20).
There are also many other autosomal recessive MR syndromes (including Bardet-Biedl
syndrome and Cohen syndrome) whose underlying genetic defects have been identified in
recent years. These defects cause abnormalities in multiple organs (21, 22). To date,
however, only a few of the genes responsible for the common non-syndromic (non-specific)
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types of mental retardation are known. An investigation of more than 100 consanguineous
(inbred) Iranian families with MR revealed a marked degree of genetic heterogeneity
(diagram 4) (23, 24). Just as is the case for X-chromosomal defects, testing for individual
gene defects will be possible as a part of routine diagnostic evaluation only when cheaper
methods of mutation screening become available.
Autosomal dominant mental retardation
The genetic defects that have so far been found to cause mental retardation of autosomal
dominant inheritance are almost exclusively connected to syndromic types of MR. Non-specific
autosomal dominant MR is more difficult to study, because the affected persons usually do
not procreate, and thus no large family trees are available for linkage studies. Most of these
mutations presumably arise de novo. Nearly all of the genes that have been found to date
have been identified through the analysis of balanced chromosomal aberrations or of very
small chromosomal deletions.
Genetic diagnosis of MR patients
Once any evident non-genetic causes have been ruled out, patients with mental retardation
should be referred to a physician specializing in human genetics or to a pediatrician
specializing in medical genetics. The specialist will first perform a clinical genetic
examination enabling diagnosis of the known syndromic types of MR, if one of these is present.
If the clinical evidence points to a particular syndrome, directed cytogenetic, molecular
genetic, or biochemical testing may follow, to the extent that such tests are available.
Many patients, however, display no additional dysmorphisms or other abnormalities, or else
these abnormalities are so non-specific that they cannot be connected to any particular known
syndrome. Families in Germany tend to be small; thus, mental retardation usually arises
sporadically, and family trees only rarely provide evidence of a particular inheritance pattern.
All patients with non-syndromic (non-specific) mental retardation should undergo
chromosomal analysis. It is reasonable to test boys for fragile X syndrome even if they do not
(yet) display any of the typical clinical features. In families that can be identified as suffering
from X-chromosomal mental retardation (at least two affected males, with inheritance through
a healthy mother), testing for the detection or exclusion of all known X-chromosomal genetic
defects can be considered; for financial reasons, this may best be done in the setting of the
international research projects that are currently in progress (the authors can provide further
information on request). Even when all of the available diagnostic techniques are applied, a
cause can now be clearly identified in only about 50% of patients with severe MR; in those with
mild MR, the percentage is even lower (2). Although no causal therapy is yet available for most
types of genetically determined MR, the effort to make a diagnosis is justifiable, even aside
from the question of family counseling with regard to prognosis, risk of recurrence in future
children, etc. The identification of a genetic defect helps parents accept the illness and actively
contend with it, e.g., by participating in self-help groups.
Genetic counseling and the risk of recurrence
The parents of a mentally retarded child often ask about the risk of recurrence in future
children. If the patient is suffering from an identifiable syndrome, the risk of recurrence can
usually be stated fairly precisely. If a genetic defect has been found, the opportunity for
prenatal diagnosis exists. For children with non-syndromic MR as well, the demonstration
of a genetic defect allows a precise statement of the risk of recurrence and enables prenatal
genetic testing. In most cases, however, no genetic defect can be found. If there is no
positive family history, then the risk of mental retardation in each future child is ca. 8%, as
long as the ill child has a non-specific type of mental retardation (25, e1). This risk is
elevated in relation to the baseline risk level of 2% and often leads parents to choose not to
have any more children. A more precise estimation of the risk will be possible only after
more MR genes have been characterized and more comprehensive tests have been developed
to diagnose or exclude defects within them.
Summary and prospects
The diagnostic possibilities for genetically determined mental retardation have considerably
expanded in recent years because of the introduction of new techniques for chromosomal
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analysis with higher resolution and the identification of the genetic defects underlying
many monogenic diseases. Nonetheless, the etiology of genetically determined MR can
still only be found in about half of all patients. The greatest problem lies in the area of nonsyndromic mental retardation, which, though very common, has not been very intensively
investigated to date. Many different genetic abnormalities can cause non-syndromic MR.
The study of individual MR-related genes is hindered by the rarity of large enough kindreds
for linkage analysis and by the fact that chromosomal aberrations are either rare
(e.g., translocations) or rarely diagnosed (e.g., microdeletions). It is, therefore, all the more
important that patients and families who are suitable for study should be referred to
specialized research centers. This is the decisive step that must be taken if new MR genes
are to be identified.
Studying the molecular causes of MR will be important, in future, not only for the
purposes of genetic counseling and diagnosis; the knowledge gained can be expected to
further our understanding of the central nervous system. Successful experimental drug
trials in animal models of MR give hope that long-term, effective treatment will one day be
possible for human beings as well. In a Drosophila model of fragile X syndrome, treatment
with antagonists of metabotropic glutamate receptors led to correction of structural
neuronal changes as well as of pathological behavior patterns (e2). Behavioral studies have
shown that a stimulating environment has a beneficial effect on cognitive ability in murine
models of Down syndrome and fragile X syndrome (e3). These observations imply that
mentally retarded children stand to benefit from intensive special education that is provided
to them as early as possible; this, in turn, underscores the importance of early diagnosis.
Conflict of Interest Statement
The authors state that they have no conflict of interest as defined by the Guidelines of the International Committee of Medical
Journal Editors.
Manuscript received on 27 June 2006, final version accepted on 12 December 2006.
Translated from the original German by Ethan Taub, M.D.
REFERENCES
For e-references please refer to the additional references listed below.
1. Leonard H, Wen X: The epidemiology of mental retardation: challenges and opportunities in the new millennium.
Ment Retard Dev Disabil Res Rev 2002; 8: 117–34.
2. Chelly J, Khelfaoui M, Francis F et al.: Genetics and pathophysiology of mental retardation. Eur J Hum Genet
2006; 14: 701–13.
3. Chiurazzi P, Oostra BA: Genetics of mental retardation. Curr Opin Pediatr 2000; 12: 529–35.
4. Roizen NJ, Patterson D: Down's syndrome. Lancet 2003; 361: 1281–9.
5. Carpenter NJ: Molecular cytogenetics. Semin Pediatr Neurol 2001; 8: 135–46.
6. Horsthemke B, Buiting K: Imprinting defects on human chromosome 15. Cytogenet Genome Res 2006; 113:
292–9.
7. Ravnan JB, Tepperberg JH, Papenhausen P et al.: Subtelomere FISH analysis of 11 688 cases: an evaluation of
the frequency and pattern of subtelomere rearrangements in individuals with developmental disabilities. J Med
Genet 2006; 43: 478–89.
8. Solinas-Toldo S, Lampel S, Stilgenbauer S et al.: Matrix-based comparative genomic hybridization: biochips to
screen for genomic imbalances. Genes Chromosomes and Cancer 1997; 20: 399–407.
9. Pinkel D, Segraves R, Sudar D et al.: High resolution analysis of DNA copy number variation using comparative
genomic hybridization to microarrays. Nat Genet 1998; 20: 207–11.
10. de Vries BB, Pfundt R, Leisink M et al.: Diagnostic genome profiling in mental retardation. Am J Hum Genet 2005;
77: 606–16.
11. Warburton D: De novo balanced chromosome rearrangements and extra marker chromosomes identified at
prenatal diagnosis: clinical significance and distribution of breakpoints. Am J Hum Genet 1991; 49: 995–1013.
12. Bugge M, Bruun-Petersen G, Brondum-Nielsen K et al.: Disease associated balanced chromosome
rearrangements: a resource for large scale genotype-phenotype delineation in man. J Med Genet 2000;
37: 858–65.
13. Kalscheuer VM, Tao J, Donnelly A et al.: Disruption of the serine/threonine kinase 9 gene causes severe X-linked
infantile spasms and mental retardation. Am J Hum Genet 2003; 72: 1401–11.
14. Shoichet SA, Hoffmann K, Menzel C et al.: Mutations in the ZNF41 gene are associated with cognitive deficits:
identification of a new candidate for X-linked mental retardation. Am J Hum Genet 2003; 73: 1341–54.
15. Stankiewicz P, Lupski JR: Genome architecture, rearrangements and genomic disorders. Trends Genet 2002;
18: 74–82.
16. Penrose L: A clinical and genetic study of 1280 cases of mental defect. London: Medical Research Council, 1938.
Dtsch Arztebl 2007; 104(20): A 1400–5 ⏐ www.aerzteblatt.de
7
MEDICINE
17. Ropers HH: X-linked mental retardation: many genes for a complex disorder. Curr Opin Genet Dev 2006;
16: 260–9.
18. Vincent A, Heitz D, Petit C et al.: Abnormal pattern detected in fragile-X patients by pulsed-field gel electrophoresis.
Nature 1991; 349: 624–6.
19. Ropers HH, Hamel BC: X-linked mental retardation. Nat Rev Genet 2005; 6: 46–57.
20. Kahler SG, Fahey MC: Metabolic disorders and mental retardation. Am J Med Genet C Semin Med Genet 2003;
117: 31–41.
21. Kolehmainen J, Black GC, Saarinen A et al.: Cohen syndrome is caused by mutations in a novel gene, COH1,
encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein
transport. Am J Hum Genet 2003; 72: 1359–69.
22. Beales PL: Lifting the lid on Pandora's box: the Bardet-Biedl syndrome. Curr Opin Genet Dev 2005; 15: 315–23.
23. Garshasbi M, Motazacker MM, Kahrizi K et al.: SNP array-based homozygosity mapping reveals MCPH1 deletion
in family with autosomal recessive mental retardation and mild microcephaly. Hum Genet 2006; 118: 708–15.
24. Najmabadi H, Motatzacker MM, Garshasbi M et al.: Homozygosity mapping in consanguineous families reveals
extreme heterogeneity of non-syndromic autosomal recessive mental retardation and identifies 8 novel gene loci.
Hum Genet 2007; 121: 43-8.
25. Basel-Vanagaite L, Attia R, Yahav M et al.: The CC2D1A, a member of a new gene family with C2 domains, is
involved in autosomal recessive non-syndromic mental retardation. J Med Genet 2006; 43: 203–10.
ADDITIONAL REFERENCES
e1. Van Naarden Braun K, Autry A, Boyle C: A population-based study of the recurrence of developmental
disabilities-Metropolitan Atlanta Developmental Disabilities Surveillance Program, 1991–94.
Paediatr Perinat Epidemiol 2005; 19: 69–79.
e2. McBride SM, Choi CH, Wang Y et al.: Pharmacological rescue of synaptic plasticity, courtship behavior,
and mushroom body defects in a Drosophila model of fragile X syndrome. Neuron 2005; 45: 753–64.
e3. Nithianantharajah J, Hannan AJ: Enriched environments, experience-dependent plasticity and disorders of the
nervous system. Nat Rev Neurosci 2006; 7: 697–709.
e4. Tao J, Van Esch H, Hagedorn-Greiwe M et al.: Mutations in the X-linked cyclin-dependent kinase-like 5
(CDKL5/STK9) gene are associated with severe neurodevelopmental retardation. Am J Hum Genet 2004;
75: 1149–54.
Corresponding author
Dr. med. Andreas Tzschach
Max-Planck-Institut für molekulare Genetik
Ihnestr. 73
14195 Berlin, Germany
[email protected]
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