Autism is a complex, behaviorally defined, static disorder of the immature brain that is of great concern to the practicing pediatrician because of an astonishing 556% reported increase in pediatric prevalence between 1991 and 1997, to a prevalence higher than that of spina bifida, cancer, or Down syndrome. This jump is probably attributable to heightened awareness and changing diagnostic criteria rather than to new environmental influences. Autism is not a disease but a syndrome with multiple nongenetic and genetic causes. By autism (the autistic spectrum disorders [ASDs]), we mean the wide spectrum of developmental disorders characterized by impairments in 3 behavioral domains: 1) social interaction; 2) language, communication, and imaginative play; and 3) range of interests and activities. Autism corresponds in this article to pervasive developmental disorder (PDD) of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and International Classification of Diseases, Tenth Revision. Except for Rett syndrome—attributable in most affected individuals to mutations of the methyl-CpG-binding protein 2 (MeCP2) gene—the other PDD subtypes (autistic disorder, Asperger disorder, disintegrative disorder, and PDD Not Otherwise Specified [PDD-NOS]) are not linked to any particular genetic or nongenetic cause. Review of 2 major textbooks on autism and of papers published between 1961 and 2003 yields convincing evidence for multiple interacting genetic factors as the main causative determinants of autism. Epidemiologic studies indicate that environmental factors such as toxic exposures, teratogens, perinatal insults, and prenatal infections such as rubella and cytomegalovirus account for few cases. These studies fail to confirm that immunizations with the measles-mumps-rubella vaccine are responsible for the surge in autism. Epilepsy, the medical condition most highly associated with autism, has equally complex genetic/nongenetic (but mostly unknown) causes. Autism is frequent in tuberous sclerosis complex and fragile X syndrome, but these 2 disorders account for but a small minority of cases. Currently, diagnosable medical conditions, cytogenetic abnormalities, and single-gene defects (eg, tuberous sclerosis complex, fragile X syndrome, and other rare diseases) together account for <10% of cases. There is convincing evidence that “idiopathic” autism is a heritable disorder. Epidemiologic studies report an ASD prevalence of ∼3 to 6/1000, with a male to female ratio of 3:1. This skewed ratio remains unexplained: despite the contribution of a few well characterized X-linked disorders, male-to-male transmission in a number of families rules out X-linkage as the prevailing mode of inheritance. The recurrence rate in siblings of affected children is ∼2% to 8%, much higher than the prevalence rate in the general population but much lower than in single-gene diseases. Twin studies reported 60% concordance for classic autism in monozygotic (MZ) twins versus 0 in dizygotic (DZ) twins, the higher MZ concordance attesting to genetic inheritance as the predominant causative agent. Reevaluation for a broader autistic phenotype that included communication and social disorders increased concordance remarkably from 60% to 92% in MZ twins and from 0% to 10% in DZ pairs. This suggests that interactions between multiple genes cause “idiopathic” autism but that epigenetic factors and exposure to environmental modifiers may contribute to variable expression of autism-related traits. The identity and number of genes involved remain unknown. The wide phenotypic variability of the ASDs likely reflects the interaction of multiple genes within an individual's genome and the existence of distinct genes and gene combinations among those affected. There are 3 main approaches to identifying genetic loci, chromosomal regions likely to contain relevant genes: 1) whole genome screens, searching for linkage of autism to shared genetic markers in populations of multiplex families (families with >1 affected family member); 2) cytogenetic studies that may guide molecular studies by pointing to relevant inherited or de novo chromosomal abnormalities in affected individuals and their families; and 3) evaluation of candidate genes known to affect brain development in these significantly linked regions or, alternatively, linkage of candidate genes selected a priori because of their presumptive contribution to the pathogenesis of autism. Data from whole-genome screens in multiplex families suggest interactions of at least 10 genes in the causation of autism. Thus far, a putative speech and language region at 7q31-q33 seems most strongly linked to autism, with linkages to multiple other loci under investigation. Cytogenetic abnormalities at the 15q11-q13 locus are fairly frequent in people with autism, and a “chromosome 15 phenotype” was described in individuals with chromosome 15 duplications. Among other candidate genes are the FOXP2, RAY1/ST7, IMMP2L, and RELN genes at 7q22-q33 and the GABAA receptor subunit and UBE3A genes on chromosome 15q11-q13. Variant alleles of the serotonin transporter gene (5-HTT) on 17q11-q12 are more frequent in individuals with autism than in nonautistic populations. In addition, animal models and linkage data from genome screens implicate the oxytocin receptor at 3p25-p26. Most pediatricians will have 1 or more children with this disorder in their practices. They must diagnose ASD expeditiously because early intervention increases its effectiveness. Children with dysmorphic features, congenital anomalies, mental retardation, or family members with developmental disorders are those most likely to benefit from extensive medical testing and genetic consultation. The yield of testing is much less in high-functioning children with a normal appearance and IQ and moderate social and language impairments. Genetic counseling justifies testing, but until autism genes are identified and their functions are understood, prenatal diagnosis will exist only for the rare cases ascribable to single-gene defects or overt chromosomal abnormalities. Parents who wish to have more children must be told of their increased statistical risk. It is crucial for pediatricians to try to involve families with multiple affected members in formal research projects, as family studies are key to unraveling the causes and pathogenesis of autism. Parents need to understand that they and their affected children are the only available sources for identifying and studying the elusive genes responsible for autism. Future clinically useful insights and potential medications depend on identifying these genes and elucidating the influences of their products on brain development and physiology.
Comments
Re: Genetic Complexity, Evolution, and Autism
Dear Editor, I found the hypotheses contained in Dr. Casanova's letter quite intriguing. It occurred to me that Tuberous Sclerosis Complex is a single- gene disorder that is associated with localised areas of loss of normal hexalaminar cortical organization(1) which might be seen as an exaggerated example of the minicolumnopathies that he discusses. The high prevalence of autism spectrum disorders in TSC affected individuals would help support this premise(2,3,4,5,6,7). As far as I know, TSC 2 and TSC1 gene product tubulin or hamartin abnormalities have not yet been linked to other minicolumnar pathologies.
1 Genotype and psychological phenotype in tuberous sclerosis Lewis et al. J Med Genet.2004; 41: 203-207. 2 Baker P, Piven J, Sato Y (1998) Autism and tuberous sclerosis complex: prevalence and clinical features. J Autism Dev Disord 28:279-85 3 Gutierrez GC, Smalley SL, Tanguay PE (1998) Autism in tuberous sclerosis complex. J Autism Dev Disord 28:97-103 4 Hunt A and Dennis J (1987) Psychiatric disorder among children with tuberous sclerosis. Dev Med Child Neurol 29:190-8 5 Hunt A and Shepherd C (1993) A prevalence study of autism in tuberous sclerosis. J Autism Dev Disord 23:323-39 6 Curatolo P, Cusmai R, Cortesi F, Chiron C, Jambaque I, Dulac O (1991) Neuropsychiatric aspects of tuberous sclerosis. Ann N Y Acad Sci 615:8-16 7 Smalley SL, Tanguay PE, Smith M, Gutierrez G (1992) Autism and tuberous sclerosis. J Autism Dev Disord 22:339-55
Genetic Complexity, Evolution, and Autism
Dear Sir or Madame,
A recent article by Muhle et al. in this journal (1) summarizes available evidence on the genetics of autism. In general, single-gene disorders (e.g., Fragile X, Rett, and Zellweger’s syndrome) in psychiatry are rare. Arguably, a corollary to this observation is the scant evidence of behavioral abnormalities when single genes are “knocked-out” in mice models. The majority of mental disorders, including autism, are defined by a large number of interactions between multiple predisposing gene variants and the environment. This concept is now subsumed under the concept of a “complex trait”. This is an important concept to bear in mind when instituting putative medical interventions and analyzing association/linkage studies.
Thus far there have been no speculations as to why mental disorders, and more specifically, autism, tend to be complex traits. We propose that genetic complexity is a consequence of encephalization and evolution. Encephalization is a measure of brain size corrected for body size. In humans, encephalization quotients are higher than in the case of other mammalian species of similar body size. Brain size is therefore a marker of the fast pace at which genetic novelties have been introduced into the Homo lineage. Genetic variability is mandatory for rapid evolution to occur (2).
The brain is a complicated organ consisting of some 1010 neurons, 103–104 connections per neuron, and about 50 different neurotransmitters. Furthermore humans, as other larger mammals, have long generation cycles and few offsprings. At first glance large mammals and complex brains should lag in the evolutionary race. How has our species been able to evolve at such a rapid pace? A possible answer is that large brains serve to accumulate genetic variation (3). Novel genetic changes introduced into a receptive brain (e.g., one with appropriate connectivity or number of neurons) can be easily appropriated by natural selection. Genetic variability thus allows the brain to adapt in unison to changing environmental conditions. This may help explain a contrasting fact between megalencephaly and micrencephaly: cognitive impairment is more commonly seen in conditions related to smaller rather than larger brains.
According to the radial unit hypothesis, the neocortex consists of arrays of ontogenetic columns (4). Brain growth (cortical expansion) has occurred through the addition of supernumerary ontogenetic columns. For normal function, once these (mini)columns have been established, connectivity among them approximates the order of 1000. Encephalization has consequently provided for a disproportionate increase in white matter as compared to gray matter. There may be a functional asymptote to overall cortical expansion (5). This suggests that pathology may flourish as we approach the limits of cortical expansion.
We think that minicolumnopathies constitute a suite of mental disorders that are the consequence of cortical expansion. It is therefore noteworthy that in autism, brains are on average larger than normal and have an increased white:gray matter ratio. Unsurprisingly, recent neuropathological studies have reported minicolumnar abnormalities in the brains of autistic patients (6). In these cases minicolumns have been noted to be more numerous and narrower while preserving normal cellular density.
Another potential sequel of encephalization characterized by plasticity and redundancy of neuronal networks is generalized relaxation of selective pressures for genetic components expressed in the brain. This model predicts an accumulation of selectively neutral or slightly deleterious genetic factors (3). The significance of this for understanding the origin of autism, is that due to population history (7) or cultural practices, there can be an increase in the frequency of individuals carrying gene complexes in similar environments: It follows that any estimate of a parameter measuring genetic association may be inflated.
References
1. Muhle R, Trentacoste SV, Rapin I. The genetics of autism. Pediatrics 2004; 113(5):472-486.
2. Lipp H-P. Non-mental aspects of encephalization: the brain as a playground of mammalian evolution. Hum Evol 1989; 4:45-53.
3. Lipp H-P, Wolfer DP. Big brains for bad genes: nonmental correlates of encephalization. Evolutionary Anthropology 2003; Suppl 1: 126-131.
4. Rakic P, Kornack DR. Neocortical expansion and elaboration during primate evolution: a view from neuroembryology. In Dean Falk and Kathleen R. Gibson editors: Evolutionary Anatomy of the Primate Cerebral Cortex. Cambridge University Press, New York, NY, 2001; chapter 2, pages 30-56.
5. Ringo JL. Neuronal interconnection as a function of brain size. Brain, Behavior & Evolution 1991;38:1-6.
6. Casanova MF, Buxhoeveden D, Switala A, Roy E. Minicolumnar pathology in autism. Neurology 2002; 58:428-432.
7. Wang N, Akey JM, Zhang K, Chakraborty R, Jin L. Distribution of recombination crossovers and the origin of haplotype blocks: the interplay of population history, recombination, and mutation. Am J Hum Genet 2002; 71(5):1227-34.