Elliott W. Simon, Ph.D.; Brenda Finucane, MS
The behavioral nature of psychiatric diagnoses is no more apparent than in the collection of symptoms that we have come to term autistic disorder. The DSM-IV (American Psychiatric Association, 1994) defines this disorder as being manifested by abnormalities in communication and socialization, with restricted patterns of behavior and interests. An individual must have a certain number of symptoms in each area to meet the diagnostic criteria for autistic disorder. Delays or functional abnormalities must be present by the age of three years in at least language, social skills, or imaginative play. The disturbance may not be better accounted for by Rett syndrome or childhood disintegrative disorder.
The exclusion of individuals with Rett syndrome from the diagnosis of autistic disorder highlights the difference between traditional psychiatry and an etiology-based genetic approach. Rett syndrome is a well known disorder with a highly characteristic developmental course. Individuals with Rett syndrome meet the behavioral criteria for autistic disorder. As Rett syndrome was initially identified behaviorally, it is included in the DSM- IV as a pervasive developmental disorder. The genetic basis for Rett syndrome has only recently been determined (Amir et al., 1999). Like many other genetic disorders associated with developmental delay, the etiology of Rett syndrome is now known. As these other disorders, such as Down syndrome and fragile X, are not included in the DSM-IV, presumably, the next version of the DSM will no longer include Rett syndrome.
It is becoming increasingly apparent that there is a large genetic component to the etiology of autistic disorder in many individuals (Simonoff, Bolton, & Rutter, 1996). Studies of genetic influences on autistic disorder take one of two general approaches (Smalley, 1991). The first approach examines the prevalence of chromosomal and genetic anomalies among groups of individuals meeting the behavioral criteria for autistic disorder. This approach also investigates the heritability and prevalence of autism within the families of individuals with autism. Much of the behavioral genetic research in autism has taken this phenotype-to-genotype approach. Because of this, there is a large literature which examines recurrences of autism among family members, concordance rates among monozygotic and dizygotic twins, and prevalence rates of chromosomal and genetic anomalies among groups of individuals with autism. A review of studies using this methodology (Folstein, Bisson, Santangelo, & Piven, 1998) concluded that a fairly large number of genes may be involved in the autistic phenotype.
The second approach to the question of genetic factors in autistic disorder evaluates groups of individuals with known genetic disorders for the presence of autism. This genotype-to-phenotype approach delineates the behavioral characteristics of people with a given genetic disorder and compares them to accepted criteria for autistic disorder. This approach has uncovered several genetic conditions that can result in an autistic behavioral phenotype. A recent review by Gilberg (1998) found that autistic disorder or severe autistic-like behavior have been associated with structural abnormalities involving all chromosomes except numbers 14 and 20. Abnormalities involving the X chromosome and the long arm of chromosome 15 accounted for the vast majority of these cases.
The association of X chromosome disorders, such as Rett syndrome, and most specifically fragile X syndrome, with autistic symptoms has been well documented (Hagerman, Jackson, Levitas, Rimland, & Braden, 1986). Recent reviews have called the autism/fragile X connection into question (Dykens & Volkmar, 1997; Feinstein & Reiss, 1998), and it is generally accepted that most individuals with fragile X syndrome do not meet the full DSM-IV criteria for autistic disorder. Rather, the majority of young children with fragile X syndrome show symptoms consistent with PDD-NOS (Hagerman, 1996).
Evidence is mounting that abnormalities of chromosome 15, most notably supernumerary isodicentric 15 [idic(15)], result in a clinically recognizable syndrome which in most cases meets the DSM-IV criteria for autistic disorder. Idic(15) was first determined by examining karyotypes (Schreck, Breg, Erlanger, & Miller, 1977) and then defining the behavioral phenotype of affected individuals. Because of this, idic(15) was excluded from the DSM. The characterization of the autistic disorder phenotype of idic(15) is described below.
An association between chromosome 15 and autism has been recognized for some time. Recent work by the South Carolina Autism project, (Schroer et al., 1998) found abnormalities of chromosome 15 to be the single most common cause of autism. Deletion of a specific short arm region of chromosome 15 (q11-13) is known to result in either Prader-Willi or Angelman syndrome, dependent upon maternal (Angelman) or paternal (Prader-Willi) origin of the deletion. An inverted duplication of this same region, as opposed to a deletion, is the basis for the majority of so-called supernumerary marker chromosomes (Schreck et al., 1977). On karyotype analysis, a small extra chromosome is visible which is made up of a duplicated piece of the 15q11-13 region . The extent of the duplication of this region is correlated with the severity of symptoms that make up the idic(15) syndrome (Cheng, Spinner, Zackai, & Knoll, 1994). In all cases studied, the supernumerary chromosome has been determined to be maternally derived (Cheng et al., 1994; Martinsson et al., 1996). Small duplications containing no active genetic material result in an unaffected individual; larger duplications result in a constellation of nonspecific features which include hypotonia, minor facial dysmorphia, mental retardation, seizure disorders, and behavioral problems (Wisniewski, Hassold, Heffelfinger, & Higgins, 1979). These symptoms in association with the supernumerary isodicentric 15 chromosome have become known as the idic(15) syndrome.
Gillberg et al. (1991) reported on six males with idic(15), five of whom met a strict DSM III-R (American Psychiatric Association, 1987) definition of autistic disorder. The other individual met criteria on all counts except for the restricted behavior domain with no stereotypies, preoccupations, or insistence on routines present. In a later review article, Gillberg (1998) noted 15 individuals with idic(15) who had met either DSM III-R or DSM-IV criteria for autistic disorder. Ghaziuddin, Sheldon, Venkataraman, Tsai, and Ghaziuddin (1993) reported a male and female with moderate mental retardation, autistic disorder and idic(15). Other studies which have described individuals with confirmed idic(15) meeting standardized criteria for autistic disorder include Baker, Piven, Schwartz, and Patil (1994) and Hotopf and Bolton (1995). Interestingly, there are also individuals with Prader Willi and Angelman syndromes who meet the DSM -IV criteria for autistic disorder. Each of these syndromes, however, clearly has its own developmental course, physical characteristics and specific behavioral phenotype. Idic(15), of these three chromosome 15 disorders, appears to be the most highly associated with a behavioral phenotype of autistic disorder.
We (Rineer, Finucane, & Simon, 1998) have recently completed the largest standardized assessment of autistic disorder yet done in individuals with confirmed idic(15). Through the U.S.-based idic(15) support group called IDEAS (Inverted Duplication Exchange, Advocacy and Support), we were able to assess 29 individuals with confirmed duplications of chromosome 15 on the Gilliam Autism Rating Scale (GARS) (Gilliam, 1995). The GARS is based on the DSM-IV criteria for autistic disorder. One advantage of the GARS is that it has norms for individuals with mental retardation who do not have autistic disorder. It thus allows one to distinguish individuals with mental retardation who do not have autistic disorder from those who do. Three subscales, matching the DSM-IV diagnostic categories of communication, social interaction, and stereotypical behavior include 42 behaviorally stated items. Additionally, a developmental sub scale assesses the respondents knowledge of development during the first 3 years of life. An autism quotient (AQ) is able to be determined from the GARS. This scale has a mean of 100 and a standard deviation of 15. An AQ of 100 therefore means that an individual has scored the same as the average person with autism. Each subscale has a standard score of 10 and a standard deviation of 3.
Of our cohort of 29 individuals (MAGE = 98.76 months, Range = 36 to 253 months), 14 were male and 15 were female. It is well known that among individuals with autistic disorder unselected for etiology, there is a higher preponderance of males. As idic(15) is an autosomal chromosome disorder, one would expect an even split between males and females. As a group, these 29 individuals were indistinguishable from the GARS autistic disorder norm group. Their mean AQ was 95.66 (sd=13.58), which is significantly higher than the GARS norm group of non-autistic individuals with mental retardation. Of the nine individuals in our sample who scored below an AQ of 90, eight were younger than 66 months of age. We examined this age-related trend in some detail and determined that the younger individuals with idic(15) were significantly more social than the autistic disorder norm group for the GARS. We concluded that children with idic(15) who do not meet the full DSM- IV criteria for autistic disorder are likely to be young. We are currently collecting longitudinal data to determine if there is a developmental course to the autistic disorder in idic(15) syndrome.
The Rineer, Finucane, and Simon (1998) article highlights the advantages of a genotype-to-phenotype approach. A relatively homogeneous group can be examined for the presence or absence of DSM-IV criteria symptoms, and the developmental course of a psychiatric disorder can be charted. It may be that idic(15) is a relatively minor cause of autistic disorder in the overall autistic population (Salmon et al., 1999); however, autism is a major clinical feature in the majority of people with idic(15). Continued investigations into the behavioral phenotypes of other genetic disorders will elucidate more of the multiple causes of autistic disorder. Recent research has identified promising areas on chromosomes 13 and 7 (Barrett et al., 1999) along with the already known associations of the 15th and X chromosomes. As specific behavioral phenotypes of genetic disorders are further delineated and genetic loci are determined for other developmental disorders, the specificity of behavioral/psychiatric disorders will increase.
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Addresses: Elliott W. Simon, Ph.D.
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Brenda Finucane, M.S.
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