It is generally accepted that 10% to 15% of individuals with autism have other known genetic diseases. Many of these diseases are developmental disorders leading to other phenotypes of intellectual or learning disability, which may overlap with autism.
Intellectual disability is generally defined as measurable intelligence substantially below the population mean that is associated with significant limitations in adaptive functioning before the age of 18 years. Adaptive functioning is defined as how well one copes, at a given age, with common demands of life and includes such things as communication, social and interpersonal skills, and self-care.
Intelligence is usually defined by the intelligence quotient (or IQ), as determined by a variety of standardized tests, such as the Stanford-Binet or Wechsler Scales. These tests, in the general population, produce a range of scores that define a bell curve with the mean at 100 points. By definition an IQ below 2 standard deviations (below 70 points) is considered in the range of intellectual disability. Besides an IQ below 70, a person with intellectual disability also shows deficits in adaptive functioning. Like IQ, adaptive functioning is measured by standardized tests.
Fragile X syndrome is a common form of chromosome X-linked intellectual disability. Patients show many similarities to autism, such as poor eye contact, a dislike of being touched, and repetitive behaviors. Its prevalence is approximately one in 4,000 boys and one in 8,000 girls. Estimates of the concurrence of autism and fragile X syndrome vary widely. In some early studies up to 25% of boys with autism were incorrectly diagnosed as having the fragile X syndrome. With the discovery of the gene for fragile X, diagnostic tests based on the genetic abnormality became available, lowering the percentage to approximately 3%. However, among children with fragile X syndrome, nearly 30% meet standard diagnostic criteria for autism.
The fragile X mutation is quite remarkable. The FMR1 gene on the X chromosome includes the nucleotide triplet CGG. In normal individuals this triplet is repeated in approximately 30 copies. In fragile X syndrome patients the number of repeats is more than 200, with approximately 800 repeats being most common. As we have seen in Chapters 3 and 43, this expansion of trinucleotide repeats has since been recognized in other genes leading to neurological diseases, such as Huntington disease. When the number of CGG repeats exceeds 200, the FMR1 gene becomes heavily methylated, and gene expression is shut off. Consequently, the fragile X mental retardation protein (FMRP) is lacking.
Lack of functional FMRP is considered responsible for fragile X syndrome. FMRP is a selective RNA-binding protein that renders messenger RNA dormant by blocking translation until protein synthesis is required. It is found at the base of dendritic spines together with ribosomes, where it regulates local dendritic protein synthesis that is needed both for synaptogenesis and for certain forms of long-lasting synaptic changes associated with learning and memory (see Chapters 66 and 67). Interestingly, a form of long-lasting synaptic change that requires local protein synthesis, the long-term depression of excitatory synaptic transmission, is actually enhanced in a mouse model of fragile X syndrome in which the gene encoding FMRP has been deleted. Loss of FMRP may enhance long-term depression by allowing excess translation of messenger RNAs (mRNAs) important for synaptic plasticity.
Indeed, mice lacking FMRP do not require new protein synthesis for the induction of long-term synaptic depression. An exciting implication of these data is that chemical antagonists of the type 5 metabotropic glutamate receptor, mGluR5, activation of which is required for this form of long-term depression, may lessen the excess protein translation and thus perhaps have a therapeutic benefit.
Another single-gene disorder sometimes confused with autism is Rett syndrome, a devastating disorder that affects girls primarily. Affected children appear normal from birth until 6 to 18 months of age, when they regress, losing speech and hand skills that they had acquired. Rett syndrome is progressive, and initial symptoms are followed by repetitive hand movements, a loss of motor control, and intellectual retardation. Girls with Rett syndrome can live into adulthood but never regain speech or the ability to use their hands. Its prevalence is approximately one in 15,000 girls.
Rett syndrome is an X-linked inherited disease caused by mutations in the MeCP2 gene, which normally encodes a transcription factor that binds to methylated cytosine bases in DNA, thus regulating gene expression and chromatin remodeling. Although loss of MeCP2 alters expression of a wide range of genes, an important contributing factor to the Rett syndrome phenotype may be the result of the reduced expression of the gene that codes for brain-derived neurotropic factor (BDNF). In mice reduced expression of this secreted neurotrophic factor leads to a phenotype much like the mouse model of Rett syndrome; overexpression of BDNF can substantially improve the phenotype in MeCP2 mutant mice.
One might think that such a global abnormality in gene expression would lead to an even more severe phenotype than that of Rett syndrome. It turns out that one copy of MeCP2 is essential for survival. Boys who have a single X chromosome and thus a single copy of MeCP2 die prenatally or soon after birth of encephalopathy if they carry a mutant form of MeCP2. Although girls carry two X chromosomes, only one is active in any given cell. Because the choice of which X chromosome is active is random, girls with a MeCP2 mutation on one X chromosome are mosaics: Some of their cells express the normal protein whereas others express the abnormal form. The cells with the normal protein compensate and thus the phenotype develops into the Rett syndrome rather than the early lethal disease.
Down syndrome is the most common cause of birth defects in the United States and a major cause of intellectual disability. Each year approximately 100,000 infants worldwide are born with Down syndrome—approximately one in 1,000 births. Approximately 7% of children with Down syndrome also have autism.
Besides manifesting a characteristic set of facial and physical features, hypotonia, and congenital heart defects, Down syndrome is associated with cognitive defects and with early-onset Alzheimer disease. Among the cognitive deficits are poor spatial memory and difficulties in converting short-term to long-term memory. These memory defects are consistent with the fact that in individuals with Down syndrome the hippocampus is smaller than in typical development. The deficits are also the opposite of the exceptional short-term and long-term memory of many individuals with autism.
What are the specific genes that contribute to the cognitive symptoms of Down syndrome? Down syndrome results from the presence of an extra copy of chromosome 21 (trisomy of chromosome 21). Approximately 88% of these extra chromosomes are maternal in origin, 9% are paternal, and 3% occur at mitosis after fertilization. Studies of rare cases of partial trisomy of chromosome 21 suggest that the entire extra copy of the chromosome does not need to be expressed to have the full-blown syndrome.
A considerable part of the Down syndrome phenotype results from duplication of a 2-Mb region at segment 21q22.2 that contains 50 to 70 genes called the critical Down region. Examination of 27 transcripts that cover 80% of this region reveals several genes of potential interest for the cognitive deficit. These include a gene for two inwardly rectifying K+ channels (KCNJ6, Homo sapiens potassium inwardly rectifying channel, subfamily J, member 6, also know as Kir3.2 or GIRK2) that are expressed in the developing and adult central nervous system, the gene for a kainate-type glutamate receptor mGluR5 (GRM5) which regulates a form of plasticity implicated in fragile X syndrome, the single-minded gene 2 (SIM2), and the gene for a dual-functioning protein kinase called minibrain kinase (Mnbk).
Prader-Willi and Angelman Syndrome and Other Disorders
Few errors that involve an entire chromosome are compatible with life. Among the autosomes, in addition to Down syndrome, only trisomy 18 and trisomy 13, each leading to severe intellectual disability, occur in an appreciable frequency, with a prevalence of one in 3,000 and one in 20,000 live births, respectively. Various numerical errors of the sex chromosomes occur but usually do not cause a significant degree of delay in cognitive development.
The only exception is Turner syndrome, which occurs in females missing an X chromosome. Girls who carry only the maternal X chromosome display a much higher prevalence of social-interaction difficulties similar to autism than do girls who carry the paternal X chromosome. This suggests genetic imprinting, where maternal and paternal copies of a gene are differentially expressed.
With imprinted genes, which represent only a small fraction (< 1%) of the genome, only one copy of the gene is expressed. In contrast, both the paternal and maternal alleles of nonimprinted genes are expressed. With paternally imprinted genes only the maternal allele is expressed. With maternally imprinted genes the opposite is true; only the paternally inherited allele is active. For example, with a maternally imprinted gene, either of the father's two alleles can be expressed in his children whereas the mother's alleles are silent. However, imprinting is reversible and is erased in the germ cells. Thus the same maternal alleles that are silenced in a mother's offspring can be active when they are transmitted by her son to his children.
Prader-Willi syndrome and Angelman syndrome, two related disorders with intellectual disability and possible connections with autism, are classic examples of imprinting. These two syndromes are usually caused by a specific deletion of the same region of chromosome 15 (Figure 64–7). However, individuals with Prader-Willi syndrome inherit the defective chromosome 15 from their father, whereas individuals with Angelman syndrome inherit the defective gene from their mother (see Chapter 3). Despite involving the same genetic mutation, the two syndromes have different symptoms. Prader-Willi syndrome is associated with mild intellectual disability, hypogonadism, and a hypothalamic abnormality that results in the inability to feel satiated from hunger, leading to morbid obesity. In contrast, Angelman syndrome is characterized by profound intellectual disability and an inappropriately happy demeanor with frequent laughing and smiling.
Imprinting in Prader-Willi and Angelman syndrome. Approximately 70% of Prader-Willi and Angelman syndrome patients inherit chromosome 15 from one parent with spontaneous (noninherited) deletions of the q11–13 interval.
This interval contains imprinted genes with alleles that are either expressed or not depending on whether the chromosome was inherited from the father or mother. If the chromosome with the deletion is from the father, Prader-Willi syndrome occurs because maternally imprinted genes on the corresponding interval of the intact maternal chromosome (gene B, for example) are not expressed. If the chromosome with the deletion is from the mother, the gene for ubiquitin ligase (UBE3A) will not be expressed in offspring because of its normal inactivation on the paternal chromosome caused by imprinting; loss of expression of this gene leads to Angelman syndrome.
How can the same genetic deletion produce such different behavioral and physical changes? The answer lies in the differential patterns of imprinting of the paternal and maternal alleles of certain genes in this region of chromosome 15. If the paternal chromosome contains the deletion, as occurs in Prader-Willi syndrome, only the maternal alleles are present. Thus any maternal alleles that are normally turned off because of imprinting will not be expressed in the offspring. Similarly, if the maternal chromosome contains the deletion, as occurs in Angelman syndrome, those genes that are normally turned off because of paternal imprinting will not be expressed in the offspring. Because different sets of genes are imprinted in males and females, individuals with Prader-Willi syndrome and Angelman syndrome have defects in expression of distinct sets of genes. Therefore, despite having similar deletions of chromosome 15, individuals with Prader-Willi and Angelman syndromes have completely different phenotypes.
Although Prader-Willi syndrome likely involves the loss of more than one imprinted gene on chromosome 15, the cause of Angelman syndrome has been narrowed to a single gene encoding the E3 ubiquitin ligase enzyme. Imprinted genes on chromosome 15 may also predispose for autism, as linkage studies have shown some positive signal from the proximal long arm of chromosome 15. Indeed, a significant number of individuals with autism, perhaps as many as 1%, have maternal duplications of a portion of proximal chromosome 15 immediately adjacent to the Prader-Willi/Angelman syndrome region.
Other chromosome deletions that produce cognitive changes do not involve imprinted genes. Such deletions simply reduce the normal level of that gene's protein product by approximately 50%, because of the loss of one of the two alleles. Half the normal amount of some proteins is insufficient to support normal cellular function (known as haploinsufficiency), resulting in a particular behavioral phenotype. Most often these deletions involve varying degrees of intellectual disability and sometimes produce striking neuropsychiatric phenotypes.
One such example is Smith-Magenis syndrome, which results from the deletion of a single band on the short arm of chromosome 17. The syndrome is characterized by mild to moderate intellectual disability and marked hypersomnolence. Smith-Magenis syndrome patients engage in a variety of unusual self-mutilations that they seem unable to resist, such as onychotillomania (self-mutilation of the finger and toe nails) and polyembolokoilomania (insertion of foreign objects into body orifices). They also repeat two stereotypic behaviors, spasmodically squeezing their upper body ("self hug") and hand licking and page flipping ("lick and flip"). What is most remarkable is that although most patients with Smith-Magenis syndrome have a 4-Mb deletion, four patients have been identified recently with a mutation in only one of the genes in this interval, RAI1, which is expressed in neurons. Once the function of RAI1 becomes understood, it will be fascinating to consider how haploinsufficiency leads to the bizarre behaviors of Smith-Magenis syndrome.
Williams syndrome is also a segmental deletion but on the long arm of chromosome 7. Although no specific gene of the 25 to 30 genes within the deletion is singly responsible, the phenotype is nevertheless intriguing. Williams syndrome patients show specific dissociations of cognitive function, such as severe deficits in construction of visuospatial relations, yet have good language capabilities and do well in face recognition tests. However, the cognitive processes underlying these achievements differ from those used by typically developing children. Interestingly, Williams syndrome patients, regardless of family background and ethnicity, share somewhat similar personality traits marked by empathy and overfriendliness, making this syndrome in many ways the opposite of the stereotype of autism.
Probably hundreds of genes can lead to intellectual disability when mutated. Many of them encode proteins whose roles are central to brain development and function. For example, a form of lissencephaly ("smooth brain"), the loss of convolutions and gyri in the cerebral cortex, results from the mutation or deletion of the gene LIS1, which encodes a protein that normally participates in the regulation of cytoplasmic dynein heavy chains, which are essential for axonal transport (see Chapters 4 and 53). Intellectual disability also results from mutations of at least three genes with products that interact with Rho GTPases, leading to disruptions in signaling from the cell surface to the actin cytoskeleton that presumably alter neurite outgrowth. Mutations in Rab GTPases, which participate in vesicle fusion, also can lead to severe intellectual disability.
Other gene defects have much more subtle impacts on the nervous system and behavior. For example, Tony Monaco and co-workers studied an extended family, KE, in which a severe speech and language disorder is transmitted as an autosomal dominant condition because of a mutation in the gene FOXP2, which codes for a transcription factor. The FOXP2 mutation causes faulty selection and sequencing of fine orofacial movements necessary for articulation, resulting in deficiencies in language processing and grammatical skills. FOXP2 mutations have also been found in unrelated individuals with similar language deficits. Interestingly, nucleotide substitution rates in the FOXP2 gene between species, a measure of evolutionary change, are accelerated in primates, suggesting that this gene had been a target of natural selection, possibly playing a significant role in the evolution of language in humans.