Syndromal mental retardation

Single genes

Molecular analysis of syndromal mental retardation has identified numerous genes, but has not cast much light on the pathogenesis of the condition. A division into conditions due to mutations in a single gene and those due to chromosomal rearrangements is helpful for descriptive purposes, but this probably does not reflect a major distinction in pathogenesis.

Perhaps the most disappointing result comes from the cloning of the FMR1 gene, mutations in which give rise to the fragile X syndrome, a common heritable cause of mental retardation (see ChapteLi0.4). The mechanism of gene inactivation has turned out to be extremely interesting (amplification of a CGG repeat in the first exon of the gene), but although the gene was cloned in 1991, its function is still a mystery. (26,45,46) In normal brain, the protein is found in nearly all neurones but is absent from non-neuronal cells. The protein can bind RNA, including its own transcript, and it has been postulated that FMR protein has a role in the machinery of translation/4 d8,49,,5,0and51> FMR1 knockout mice have macro-orchidism and impaired spatial learning abilities, but nothing more to tell us what the gene does. (52)

We know more about a gene for a much rarer mental retardation syndrome, ATRX.(6) The disorder is X linked and patients have an anaemia (a-thalassaemia), a characteristic facial appearance, profound developmental delay, neonatal hypotonia, and genital abnormalities. The gene contains sequence motifs indicating that it belongs to a group of proteins that bind to chromatin. ATRX may be involved in chromatin remodelling (see Fig..., . 2). Possibly it regulates expression of a restricted class of genes, accounting for the pleiotropic effects of the mutant.

The final example is Optiz G/BBB syndrome, an X-linked multiple-organ disorder which includes developmental delay. Mutations have been found in a gene called MID1 whose features suggest that it is involved in developmental regulation by protein-protein interactions. Again, this has not (yet) been helpful in advancing our understanding of pathogenesis of mental retardation.

Segmental aneusomy syndromes

A number of syndromes associated with mental retardation have been found to be due to chromosomal rearrangements among which Down syndrome (trisomy 21) is by far the most common (accounting for about a third of all cases with moderate to severe retardation). Chromosomal rearrangements can be extremely complex, as can the nomenclature used to describe them. Abnormalities of the number of chromosomes result in aneuploidy. Deletion of part or an entire chromosome is termed monosomy (or haploinsufficiency); an extra copy of either part of or an entire chromosome is called trisomy. A general term to describe either loss or excess of chromosomal material is aneusomy.

The phenotypes of chromosomal rearrangements are thought to arise because of the loss, in the case of monosomy, or addition, in the case of trisomy, of dosage-sensitive genes, of unrelated function, that happen to lie next to each other on the chromosome. Most chromosomal abnormalities involve small regions of aneusomy and consequently are known as segmental aneusomy syndromes(54) (see T§ble,,3.). The small size of some of the aneusomic regions has enabled a search for dosage-sensitive genes, and there are currently two examples where this approach appears to have been successful. Unfortunately, in neither case can it be said that the discovery has led to an understanding of the pathogenesis of mental retardation.

In Williams syndrome (see Chapt,eL10 4) it has been possible to identify genes that contribute to different components of the syndrome, one of which is cognitive impairment. Families have been found with a mutation affecting the elastin gene and presenting with supravalvular aortic stenosis and facial features typical of Williams syndrome, but normal intelligence. Other, very rare, families have some facial features, supravalvular aortic stenosis, verbal ability, and short-term memory similar to unaffected members, but marked impairment of visuoconstructive skills. Molecular characterization of these individuals showed that the chromosomal deletion was small (only 84 kb, compared with more than 500 kb found in the majority of Williams syndrome patients) which permitted the researchers to isolate a candidate gene, LIMK1 kinase.(55) The LIM domain, first identified in three homeodomain (developmental) proteins, is a zinc finger motif believed to function as protein-protein binding module in neural development.(56) LIMK1 binds to several isoforms of protein kinase C and to neuregulin.(57) Transmembrane neuregulins interact with LIMK1 and co-localize at the neuromuscular synapse, suggesting that the two proteins have a role in synapse formation and maintenance, although how this explains the defect in visuospatial cognition in Williams syndrome patients is a mystery.

Rubinstein-Taybi syndrome is characterized by abnormal craniofacial features, broad thumbs, and mental retardation. It arises from monosomy of a small region on 16p13.3, where mutations have been documented in the Cbp gene.(58) The protein product of the Cbp gene binds to the cyclic adenosine monophosphate ( cAMP) response element binding protein, and to several elements of the basal transcriptional machinery, suggesting that mutations will disturb the transcription of numerous genes. Thus, as is the case with the ATRX syndrome, the molecular basis of Rubinstein-Taybi syndrome lies in a gene with effects on many different systems.

Non-Mendelian disorders

Two clinically distinct disorders, Prader-Willi syndrome ( PWS) and Angelman syndrome (AS), arise from abnormalities of a small region of 15q11-q13.(59) The two syndromes have characteristic and distinct neurobehavioural profiles. In AS the retardation is severe (very few affected individuals can talk) and there is ataxia, seizures, an abnormal electroencephalogram, microcephaly, facial dysmorphism, hyperactivity, and paroxysmal laughter. In contrast, in PWS the mental retardation may be only mild. There is a characteristic facial appearance and a specific behavioural abnormality: hyperphagia resulting in severe obesity.

Despite the phenotypic differences, the basic defect is the same in both disorders—a failure of parent-of-origin-specific gene expression. Normally one chromosome 15 is inherited from the mother and the other from the father. If both derive from the mother, the individual will have PWS; if both derive from the father, the phenotype is AS. In both cases the DNA sequence is the same as in a normal individual, yet the phenotype is abnormal, showing that the chromosomes bear an additional molecular signal that affects gene expression and indicates their parent of origin. The signal is termed an imprint and is believed to be DNA methylation.

The majority (about 70 per cent) of cases of AS and PWS arise because there is a deletion within a 1.5-Mb region of 15q11-q13. A deletion on the maternal chromosome leaves only paternally expressed genes, resulting in AS, and conversely a deletion on the paternal chromosome leads to PWS. About a quarter of cases of PWS and 2 per cent of AS are due to uniparental disomy, i.e. inheritance of both chromosome 15s from one parent.

Mutations in a ubiquitin protein ligase gene (UBE3A) have been found in a few rare families with AS (69 and it has been proposed that the UBE3A gene is maternally expressed. If the mutations are the cause of AS, then it is unlikely to tell us much about the origin of the phenotype. The gene product is part of a widely used ubiquitin-mediated protein degradation pathway. The deletion almost certainly has pleiotropic effects that will be difficult, if not impossible, to disentangle.

PWS is probably not the result of a defect in a single gene. Seven genes (and candidate genes) have been identified in the PWS region, all of which appear to be brain specific. The function of these genes is not known; one, IPW, does not even code for a protein. Potentially, therefore, the phenotype arises from deficits in all these genes. Again, it is not known how the specific behavioural abnormalities can be explained by the genetic defect.

Similar problems beset attempts to understand how deletions of 22q11 give rise to cognitive disabilities. DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes are different manifestations of deletions of 22q11. DiGeorge and velocardiofacial syndromes are associated with mental retardation; additionally psychosis is found in some patients with 22q11 deletions.(62) The region most consistently deleted is large (> 1.5 megabases), containing at least 14 genes. Cloning and sequencing of the entire region has not identified any obvious candidates for the cognitive defect and it now seems likely that the syndromes arise from combined monosomy of more than one gene.(54) For example, one gene in this region, HIRA, encodes a protein similar to yeast transcriptional repressors. Potentially HIRA, like ATRX, remodels chromatin locally, altering the expression of many genes.


Both Down syndrome and Turner syndrome are due to an abnormal number of chromosomes, an extra chromosome 21 in the case of Down syndrome and a single X (without a Y) in the case of Turner syndrome. Epstein has argued that the phenotypes of the aneuploid syndromes (of which these are just two examples) cannot be due to non-specific effects of chromosome imbalance because the phenotypic features are distinct.(64) This view is not without its critics,(65) and there certainly are some common phenotypic features of chromosome abnormalities, for instance small stature, microcephaly, and mental retardation. Nevertheless Turner and Down syndrome have sufficient specific features to encourage a search for dosage-sensitive genes that determine the syndromal phenotype.

Candidate genes for some of the somatic features of Turner syndrome have been proposed: SHOX/PHOG encodes a homeodomain protein that may explain the short stature; RPS4Y (which encodes an isoform of a ribosomal small subunit protein) and ZFY (which encodes a transcription factor of unknown function) may have pleiotropic effects.(66) There are no candidates for the unusual cognitive profile. However, there is one report that Turner syndrome patients with a paternally derived X chromosome have superior verbal abilities and skills involved in social interactions. (67) Therefore there may be an imprinted gene on the X chromosome that mediates some cognitive abilities.

Attempts have been made in Down syndrome to correlate regions of trisomy with different phenotypic abnormalities and hence infer the location of specific genes. While no genes have been identified solely on this basis, the information has been crucial in driving attempts to make a mouse model of Down syndrome. First, mice with three copies of chromosome 16 (the mouse homologue of human chromosome 21) show many of the features of Down syndrome.(68) Astrocytosis, craniofacial abnormalities, and seizures in trisomy 16 mice mimic the phenotype of Down syndrome. Second, attention has been focused on 21q22.2 as a potential site for dosage-sensitive genes that affect learning and behaviour. By putting pieces of human DNA from 21q22.2 into mice, and testing the mice for deficits in memory, one gene has been identified/69) It is a human homologue of the Drosophila minibrain gene, a tyrosine/serine kinase expressed in developing neuroblasts. The use of transgenic mice to isolate minibrain demonstrates how complex phenotypes may be dissected down to their molecular basis, but there is as yet no proof that minibrain in humans is either dosage sensitive or a critical determinant of mental retardation in Down syndrome.

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