The syndrome of autism: a critical review.

The authors review the clinical features and behavioral characteristics of autism; differential diagnosis of the syndrome; clinical, neurophysiological, and biochemical research; and its medical management and treatment. They conclude that autism is a behaviorally defined, specific syndrome that is manifested at birth or shortly thereafter. Its symptoms are expressive of an underlying neuropathophysiological process that affects developmental rate; modulation of perception; language, cognitive, and intellectual development; and the ability to relate. The long-term prognosis is guarded; almost all patients manifest severe symptomatology throughout their lives. Further basic research into the neuropathophysiological process underlying the syndrome is necessary in order to reach the ultimate goal of developing etiologically specific treatment programs.

Magnetic resonance imaging of the posterior fossa in autistic adults.

Magnetic resonance imaging measurements were obtained for 12 adults with DSM-III-defined autism and a matched group of 12 normal subjects. No significant differences were found for mean midsagittal areas of pons, fourth ventricle, cerebellar vermis, or vermis lobules. No significant brain abnormalities were observed in either group.

Concordance for the syndrome of autism in 40 pairs of afflicted twins.

The UCLA Registry for Genetic Studies in Autism was established in 1980 to test the hypothesis that genetic factors may be etiologically significant in subsets of patients. To date 61 pairs of twins have enrolled and 40 meet research diagnostic criteria for autism. The authors found a concordance for autism in these 40 pairs of 95.7% in the monozygotic twins (22 of 23) and 23.5% in the dizygotic twins (four of 17).

Behavioral characteristics of high- and low-IQ autistic children.

The authors are developing the Behavior Observation Scale to objectively differentiate autistic, normal, and mentally retarded children aged 30--60 months. They describe operational definitions and procedures and report data on the frequency of selected behaviors among 114 children. Prior studies have revealed that to assess the clinical significance of behaviors in autistic children, both frequency of occurrence per subject and the number of children exhibiting the behaviors must be considered concurrently. This study confirms the hypothesis that it is critical to consider the IQ of the child when assessing the clinical significance of individual behaviors and groups of behaviors.

Lower Purkinje cell counts in the cerebella of four autistic subjects: initial findings of the UCLA-NSAC Autopsy Research Report.

As part of an autopsy research project, the brains of four autistic subjects were examined and compared with those of three comparison subjects without CNS pathology and one with phenytoin toxicity. The cerebellum was selected for initial investigation because pathognomonic symptoms and neurophysiological measures suggest that pathology may exist in the cerebellar-vestibular axis in certain patients. Total Purkinje cell counts were significantly lower in the cerebellar hemisphere and vermis of each autistic subject than in the comparison subjects.

Evidence for autosomal recessive inheritance in 46 families with multiple incidences of autism.

The authors ascertained 46 families with multiple incidences of autism (41 with two and five with three autistic probands). Classical segregation analyses revealed a maximum likelihood estimate of the segregation ratio of p = 0.19 +/- 0.07. This is not significantly less than 0.25, the expected value for autosomal recessive inheritance. However, it is significantly less than 0.50, the expected value for autosomal dominant inheritance. The polygenic threshold model was tested and rejected over a full range of values of heritability and ascertainment probability for these families. These results are most consistent with the hypothesis of autosomal recessive inheritance in this subset of 46 families with multiple incidences of autism.

A magnetic resonance imaging study of autism: normal fourth ventricle size and absence of pathology.

Magnetic resonance imaging did not diagnose neuropathology in 15 autistic patients. Measurements of the midsagittal area and volume of the fourth ventricle did not differ between these patients and matched control subjects.

Electroretinograms in autism: a pilot study of b-wave amplitudes.

The authors recorded electroretinograms for 27 autistic patients and 20 age- and sex-matched healthy volunteers. Thirteen (48%) of the autistic patients demonstrated subnormal b-wave amplitudes, which may indicate abnormal retinal function. One patient was tested serially at two sites; his low b-wave amplitude did not vary over time or between the two sites. If this retinal finding can be confirmed at other laboratories and in larger samples of autistic patients, it might provide a marker for a specific subtype of autism.

Psychometric assessment of first-degree relatives of 62 autistic probands in Utah.

The Wechsler Intelligence Scales, Wide Range Achievement Test, and the Shipley-Hartford Test were administered to 122 parents and 153 siblings of 62 autistic probands in Utah. Scores were distributed as expected within the published normative ranges for each scale. Parents' scores correlated with those of their nonautistic children, but neither parents' nor siblings' scores correlated with the IQ level of the autistic probands. These results do not confirm prior reports from England and the United States of a high rate of cognitive and learning problems in the siblings of autistic individuals, nor the aggregation of such problems in the siblings of probands with high or low levels of cognitive function.

The UCLA-University of Utah epidemiologic survey of autism: the etiologic role of rare diseases.

Twelve rare diseases known to cause CNS pathology were found in 26 (11%) of 233 autistic probands identified during a recent epidemiologic survey of Utah. These 26 probands had significantly lower mean IQs than the remaining patients (43 versus 60) but similar sex distribution and prevalence of abnormal EEGs and seizures. The rarity and diversity of these 12 diseases make it highly unlikely that they randomly occurred with autism. Their presence in this epidemiologic survey is the most compelling evidence to date to support the hypothesis that different diseases producing different types of CNS pathology can play an etiologic role in autism.

The UCLA-University of Utah epidemiologic survey of autism: recurrence risk estimates and genetic counseling.

The authors recently reported, in this journal, an epidemiologic survey of autism in Utah. Twenty (9.7%) of the 207 families ascertained had more than one autistic child. Analyses of these data revealed that autism is 215 times more frequent among the siblings of autistic patients than in the general population. The overall recurrence risk estimate (the chance that each sibling born after an autistic child will develop autism) is 8.6%. If the first autistic child is a male the recurrence risk estimate is 7%, and if a female 14.5%. These new recurrence risk estimates should be made available to all individuals who have autistic children and are interested in family planning.

The UCLA-University of Utah epidemiologic survey of autism: prevalence.

The authors conducted an epidemiologic survey in Utah using a four-level ascertainment system, blind current diagnostic assessments, and DSM-III criteria. Of 483 individuals ascertained, 241 were diagnosed as having autism. The best estimate for the prevalence rate was 4 per 10,000 population. Autism was not associated with parental education, occupation, racial origin, or religion. Sixty-six percent of the autistic subjects scored below 70 on standardized IQ tests, and females scored proportionately lower than males. Twenty (9.7%) of 207 families had more than one autistic sibling, which supports the authors' previous finding that there may be a familial subtype of autism.

The UCLA-University of Utah epidemiologic survey of autism: prenatal, perinatal, and postnatal factors.

In a recent epidemiologic survey conducted in Utah, 241 autistic patients (DSM-III criteria) were found. Medical records of 233 autistics were surveyed for the presence of 36 potentially pathologic prenatal, perinatal, and postnatal factors. These results were compared with those of an identical survey of 62 of their nonautistic siblings, with the results of four previously published surveys, and with normative data. No potentially pathologic factor or group of factors occurred significantly more frequently among the autistic patients. Also, previous observations of significant differences in the occurrence of certain factors in the histories single vs multiple siblings with autism were not confirmed, with the exception of increased viral-type illness during gestation in single-incidence cases. Thus, the etiology of the brain pathology that characteristically disrupts normal development and produces the syndrome of autism remains obscure. Other data from the epidemiologic survey, however, suggest that the role of genetic factors needs to be explored further.

The UCLA-University of Utah epidemiologic survey of autism: genealogical analysis of familial aggregation.

To assess familial aggregation of autism, 86 autistic subjects were linked to the Utah Genealogical Database. Kinship coefficients were estimated for all possible pairs of autistic subjects and then averaged. Fifty replicate sets of matched control subjects (86 members in each set) were drawn randomly from the database, and the average kinship coefficient was computed for all possible pairs of individuals in each set. The average kinship coefficient for the autistic subjects was approximately 1/1,000, while the average kinship coefficients for the 50 control groups ranged from 4/100,000 to 1.6./10,000. These results indicate a strong tendency for autism to cluster in families. When kinship was analyzed by specific degrees of relationship, it was shown that the familial aggregation of autism is confined exclusively to sib pairs and does not extend to more remote degrees of relationship. This finding indicates that a single-gene model is unlikely to account for most cases of autism.

Effects of chronic fenfluramine on blood serotonin, cerebrospinal fluid metabolites, and behavior in monkeys.

The effects of long term (70 days) fenfluramine treatment on selected physiological and behavioral measures were examined in four adult male vervet monkeys (Cercopithecus aethiops sabaeus). Relative to pretreatment baseline values, whole blood serotonin (WBS) and cerebrospinal fluid 5-hydroxyindole acetic acid (5-HIAA) were reduced, cerebrospinal fluid homovanillic acid (HVA) was unaltered, and aggressive and locomotor behavior were increased. Both physiological and behavioral effects were reversible: all measures returned to baseline values in the 35 day post-treatment period, with WBS resuming pretreatment values more rapidly than CSF 5-HIAA. At the relatively low doses (1-4 mg/kg/day) employed in the present study fenfluramine produced behavioral effects similar to those resulting from PCPA and opposite to those following tryptophan administration. Thus the behavioral effects of long-term fenfluramine may involve reductions in serotonergic transmission.

The stability of cognitive and behavioral parameters in autism: a twelve-year prospective study.

Sixty-two autistic patients enrolled in a prospective study an average of 12 years ago. Current retesting results are now available on 53 of the original 62 patients (85.5%). Results indicate that 36 (67.9%) achieved scores within their original IQ group. Twelve (22.6%) moved up IQ groups and five (9.4%) moved down. Of particular clinical importance is the observation that Vineland Adaptive Behavior Scores were consistently lower than cognitive scores, and maladaptive behaviors occurred with equal frequency in the high, medium, and low IQ groups. The implications of this new data for understanding the natural history of autism, educational and vocational planning, and future research are discussed.

Objectively defined linguistic parameters in children with autism and other developmental disabilities.

The language of children with autism and other developmental disabilities was examined systematically according to a set of objectively defined linguistic parameters. These criteria were drawn from clinical observations reported in the literature and from developmental norms of language acquisition. Data analysis identified sets of parameters that were correlated with psychiatrists' clinical diagnoses but failed to isolate individual parameters (such as echolalia or noncommunicativeness) that have been suggested to be pathonomic.

Genetic and immunohematologic factors in autism.

The present study is being conducted to explore the hypothesis that genetic and/or congenital factors are etiologically significant in certain persons with the syndrome of autism. To initiate the project, the UCLA Registry for Genetic Studies in Autism was established in 1980. To date 254 families have enrolled. Extensive clinical material and past medical data are being gathered from each family. Information presented in this preliminary report is based solely upon parental reports and prior medical and school evaluations, as the diagnoses have not yet been verified by the authors. Clinical data and family pedigrees will be analyzed by computer-based methods. Blood studies including chromosomes, gene markers, T-cell and B-cell functions, and antibody levels are being conducted on families meeting specific research criteria.

Hyperserotoninemia and antiserotonin antibodies in autism and other disorders.

This study examined the linkage between elevated blood serotonin in autism and the presence of circulating autoantibodies against the serotonin 5HT1A receptor. Information was also obtained on the diagnostic and receptor specificity of these autoantibodies. Blood serotonin was measured as was inhibition of serotonin binding to human cortical membranes by antibody-rich fractions of blood from controls and from patients with childhood autism, schizophrenia, obsessive-compulsive disorder, Tourette's, and multiple sclerosis. The results showed elevated blood serotonin was not closely related to inhibition of serotonin binding by antibody-rich blood fractions. Inhibition of binding was highest for patients with multiple sclerosis and was not specific to the 5HT1A receptor as currently defined. Although inhibition was not specific to autism, the data were insufficient to establish if people with autism differed from normal controls on this measure.

Fenfluramine effects on serotonergic measures in vervet monkeys.

Chronic fenfluramine treatment reduced whole blood serotonin and CSF 5-hydroxyindoleacetic acid, but increased aggressive and locomotor behavior, in adult male vervet monkeys (Cercopithecus aethiops sabaeus). Following a drug-free washout period to monitor the drug recovery course, we initiated a second period of fenfluramine treatment in the same animals. When whole blood serotonin concentrations were reduced by about 40% from predrug baseline levels, we examined 11 cortical and subcortical brain regions for their content of 5-hydroxytryptamine, 5-hydroxyindoleacetic acid, norepinephrine, and dopamine. We observed correspondence between the reduction in whole blood serotonin and the reduction in brain 5-hydroxytryptamine. Similarly, there was a correspondence between the reduced 5-hydroxyindoleacetic acid levels observed in CSF and brain. No alterations were noted in the concentrations of norepinephrine or dopamine. These observations suggest that the behavioral effects observed in monkeys after chronic fenfluramine treatment result from reduced central serotonin.