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Mental 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

Dtsch Arztebl 2007; 104(20): A 14005 www.aerzteblatt.de 1

M E D I C I N E

SUMMARYIntroduction: 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 geneticcounselling of their parents. In the long run, this research will also have therapeutic

implications. Dtsch Arztebl 2007; 104(20): A 14005.

Key words: mental retardation, chromosomal aberration, submicroscopic chromosome aberrations,

monogenic disorders, X-linked mental retardation

Max-Planck-Institut fr molekulare Genetik,Berlin: Dr.med. Tzschach; Prof. Dr.med. Ropers

REVIEW ARTICLE

Genetics of Mental Retardation

Andreas Tzschach, Hans-Hilger Ropers

Modified from Curry et al.1997.

TABLE

Causes of congenital mental retardation and theirprevalence

Cause %Chromosomal anomalies 428

Identifiable dysmorphic syndromes 37

Known monogenetic diseases 39

Structural malformations of the CNS 717

Complications of premature birth 210

Environmental and teratogenic causes 513

"Cultural/familial" causes 312

Metabolic/endocrine causes 15

Unknown 3050

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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 aberrationsSome 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 aberrationsChromosomal 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.


M E D I C I N E

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.

DIAGRAM 1

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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).

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 patientswith 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 thatare seen will only become clear once many patients and many normal controls have

been studied.


M E D I C I N E

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).

DIAGRAM 2

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Balanced chromosomal rearrangementsNot 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) (1214).

X-chromosomal mental retardationThe 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


M E D I C I N E

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.

DIAGRAM 3

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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 X-

chromosomal MR. At present, more than 500 families have been studied. The genes that areknown to date are collectively responsible for about 50% of all cases of non-syndromic XLMR.

Autosomal recessive genetic defectsMetabolic 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 inrecent 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)


M E D I C I N E

Family tree of a consanguineous (inbred) kindred with multiple children affected by autosomalrecessive mental retardation and microcephaly (dark symbols). Linkage studies in this family

led to the demonstration of a homozygous mutation in the MCPH1 gene (23).

DIAGRAM 4

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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 retardationThe 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 patientsOnce 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 futurechildren. 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 prospectsThe diagnostic possibilities for genetically determined mental retardation have considerably

expanded in recent years because of the introduction of new techniques for chromosomal


M E D I C I N E

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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 non-

syndromic 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 StatementThe authors state that they have no conflict of interest as defined by the Guidelines of the International Committee of MedicalJournal Editors.

Manuscript received on 27 June 2006, final version accepted on 12 December 2006.

Translated from the original German by Ethan Taub, M.D.

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Corresponding authorDr.med. Andreas TzschachMax-Planck-Institut fr molekulare Genetik

Ihnestr. 7314195 Berlin, [email protected]


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