Catecholamines metabolism in infantile autism: A controlled study of 22 autistic children

In a group of 22 autistic children aged 5 to 16 years and a group of normal controls matched for age and sex, catecholamines metabolism was investigated in plasma, platelets, and urine. This investigation was part of a research project in which several biological parameters (including serotonin) were explored simultaneously in the same children. In the autistic group, epinephrine and norepinephrine were significantly elevated in plasma, while epinephrine, norepinephrine, and dopamine were significantly lower in isolated platelets. No significant difference was found between the two groups for the urinary excretion of epinephrine, norepinephrine, dopamine, DOPAC, and MHPG. Other differences between the two groups in the statistical correlations of several biochemical parameters also suggest abnormalities of bioamine metabolism in the platelets of autistic children.This work was supported by a grant of the Institut National de la Santé et de la Recherche Médicale (INSERM-ATP n 73.79.105). We are indebted to Prof. M. Da Prada, Pharmaceutical Research Department, Hoffman-La Roche, Basel, for his continuous help throughout this work, and to Ms. D. Pasques, Hôpital Saint-Louis, Paris, for her excellent technical assistance.     

Disorders of catecholamine metabolism in infantile autism. Comparative study of 22 autistic children

In a group of 22 autistic children aged 5 to 16 y., and a group of normal controls matched for age and sex, catecholamines metabolism has been investigated in plasma, platelets and urine. This investigation was part of a research project in which several biological parameters (including serotonin) were simultaneously explored in the same children. In the autistic group, epinephrine and norepinephrine and dopamine were significantly lower in isolated platelets, and no significant difference was found between the two groups for the urinary excretion of epinephrine, norepinephrine, dopamine, DOPAC and MHPG. Other differences between the two groups in the statistical correlations of several biochemical parameters (plasma norepinephrine and dopamine with platelet MAO activity, platelet norepinephrine with platelet dopamine, platelet dopamine, platelet dopamine with platelet serotonin) also suggest abnormalities of bioamine metabolism in the platelets of autistic children.     

A biochemical study of early infantile autism

A pilot study designed to determine whether patients with a diagnosis of infantile autism excreted N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine and bufotenin, as do some chronic adult schizophrenic patients, is presented and discussed. Twenty-four-hour urinary collections from 12 children and adolescents, 10 boys and 2 girls, were made at their homes. Subsequently, 24-hour samples were also collected during 14 consecutive days from the 6 children who were possibly autistic and on controlled diet at the hospital. At home, samples of the normal controls and of 2 possibly autistic patients were negative for bufotenin. In the hospital, those of 5 of the 6 were positive. It is suggested that some patients with a diagnosis of early infantile autism excrete bufotenin, an ability they share with schizophrenic patients.The authors wish to thank Dr. Newell C. Kephart for his recommendations and data related to the initial subjects selected for this study, and Dr. Bernard Rimland for his clinical evaluations of the patients. We are also grateful to Drs. D. Wilson Taylor, James B. Ebersole, and Quentin R. Petersen for serving as medical and technical consultants, to Dr. Angelo F. Zocchi who has helped to smooth our way, to Dr. Margaret A. Ohlson for formulating the diets and to Rowena Ginther for supervising their preparation. The intelligent and dedicated cooperation received from the Department of Nursing Services is greatly appreciated and the following members of the nursing staff of the Galesburg State Reserach Hospital deserve our special thanks: Ilaine Pedersen, Esther Vatthauer, Delores Adcock, Blanche Andrews, Lula Cochran, Neona Cooper, Dorothy McDowell, Marjorie Miller, Mary Pickering, Barbara Price, Hester Rask, and Pat Reisinbigler.     

A controlled crossover study of triiodothyronine in autistic children

A placebo-controlled crossover study of behavioral effects of triiodothyronine (T₃) was conducted in 30 young clinically euthyroid autistic children. Multiple independent raters and multiple rating scales were used. Except for a few symptoms that were reduced on T₃, the drug did not differ from placebo. Time itself accounted for most of the improvement in the whole sample. As a group, the lower IQ children responded to T₃. The individual children who were responders could not be defined by any parameter.This study was supported in part by Public Health Service Grant No. MH04665 from the National Institute of Mental Health. The authors wish to express their gratitude to Dr. Nancy Branom (Department of Radiology) and Dr. Ralph David (Department of Pediatrics) for their collaboration, to Mrs. Kathleen Nash, R.N., and Mrs. Sara Sol for their efforts in this study, and to Smith, Kline & French Laboratories for the medication supply.     

Serotonin and amino acid content in platelets of autistic children

The platelet levels of serotonin and the amino acids aspartic acid, glutamine, glutamic acid and gamma-aminobutyric acid were measured in 18 drug-free autistic (DSM-III criteria) and 14 age-matched healthy children. Serotonin was significantly increased while the amino acids aspartic acid, glutamine, glutamic acid and gamma-aminobutyric acid were significantly decreased in comparison with the controls. It is suggested that the decline of the amino acids in platelets from autistic children represents a biochemical marker related to infantile autism.     

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. This research was supported in part by MH 29248 awarded to B. J. Freeman, Ph.D.; by MH 30897 awarded to Peter Tanguay, M.D., for Clinical Research Center for the Study of Childhood Psychosis; by Maternal and Child Health Project No. 927 awarded to James Q. Simmons, III, M.D., Chief of Child Psychiatry, all of the Division of Mental Retardation and Child Psychiatry, University of California, Los Angeles, California. Computing was done at Health Sciences Computing Facility, University of California, Los Angeles.     

Evidence of altered energy metabolism in autistic children.

1. In this pilot study, the authors investigated the hypotheses there are increased concentrations of lactate in brain and plasma and reduced brain concentrations of N-acetyl-aspartate (NAA) in autistic children. 2. NAA and lactate levels in the frontal lobe, temporal lobe and the cerebellum of 9 autistic children were compared to 5 sibling controls using MRS. Plasma lactate levels were measured in 15 autistic children compared to 15 children with epilepsy. 3. Preliminary results show lower levels of NAA cerebellum in autistic children (p = 0.043). Lactate was detected in the frontal lobe in one autistic boy, but was not detected any of the other autistic subjects or siblings. 4. Plasma lactate levels were higher in the 15 autistic children compared to 15 children with epilepsy (p = 0.0003). 5. Higher plasma lactate in the autistic group is consistent with metabolic changes in some autistic children. The findings of altered brain NAA and lactate in autistic children suggest that MRS may be useful characterizing regional neurochemical and metabolic abnormalities in autistic children.     

A follow-up study of infantile autism in Hong Kong

All 87 autistic children referred to the Department of Psychiatry from 1976 to 1986 were included as subjects. Their demographic, family, medical, and psychiatric characteristics were described. Sixty-six (75.9%) were traced for follow-up assessment. There was a striking similarity between the characteristics of our sample and those reported in other countries (e.g., sex ratio, intelligence, language ability, behavioral characteristics, and outcome). The finding of less family history of language delay, epilepsy, and sex difference are discussed.This research was funded by the Committee on Research and Conference Grants, University of Hong Kong.     

Serotonin transporter gene and autism: a haplotype analysis in an Irish autistic population

The role of the serotonin transporter (5-HTT) in the development of neuropsychiatric disorders has been widely investigated. Two polymorphisms, an insertion/deletion in the promoter region and a 12 repeat allele in a variable nucleotide tandem repeat (VNTR) in intron 2, drive higher expression of the 5-HTT gene. Four studies have shown nominally significant excess transmission of alleles of the 5-HTT gene in autism, while three studies have reported no excess transmission. This present study investigates the role of 5-HTT in the genetically homogenous Irish population. In all, 84 families were genotyped for five polymorphisms (three SNPs, a VNTR and an in/del). The analysis of allele transmissions using the transmission disequilibrium test (TDT) was undertaken and indicated preferential transmission of the short promoter allele (TDT P-value=0.0334). Linkage disequilibrium between markers was calculated and haplotypes were assessed for excess transmission and odds ratios (ORs) to affected children. A number of haplotypes, especially those involving and surrounding SNP10, showed evidence of association. The ORs ranged from 1.2 to 2.4. The most significant haplotype associated with transmission to affected probands was the SNP10-VNTR-SNP18 haplotype (chi(2)=7.3023, P=0.0069, odds ratio=1.8). This haplotype included the 12 repeat allele of the VNTR, which is associated with increased expression and may play a subtle role in the early development of the brain in affected probands.     

A controlled study of prednisone therapy in infantile spasms.

A controlled study of 12 patients with infantile spasms was performed to determine the effectiveness of prednisone treatment. Patients were monitored serially, using a time-synchronized polygraphic and video system. Three patients (25%) showed prompt reduction in seizure frequency and normalization of the EEG after institution of treatment. The remaining patients showed no improvement in seizure frequency or significant change in the EEG.     

Immune status in infantile autism. Correlation between the immune status, autistic symptoms and levels of serotonin

In sixteen autistic children high values of IgG and a high level of lymphocyte stimulation with PHA were observed. Principal component analysis showed: 1) a significant correlation between basic lymphocyte mitogenic activity and the clinical symptoms opposition and hyperactivity, 2) a significant correlation between high Ig levels, high PHA stimulation responses and the main autistic symptoms (withdrawal, inaffectivity, hypoactivity, mannerism, stereotypy and negatively echolalia), 3) a significant correlation with serotonin uptake by platelets and high immunological responses. Such correlations are strongly in favor of an immunologic component in autistic disease.     

The presence or absence of certain behaviors associated with infantile autism in severely retarded autistic and nonautistic retarded children and very young normal children

The modified Behavior Observation Scale adapted from Freeman et al. was used to compare normal, retarded, and autistic children with very low developmental ages and to determine the types of behavior that could differentiate these three diagnostic categories of children. Examination of the data revealed that there was much more overlap between autistic and retarded children than between autistic and normal children. However, a behavioral pattern of autism could be delineated and very retarded autistic children could be distinguished from the nonautistic retarded children. The autistic behavioral pattern included subclusters of symptoms that might be interpreted as disturbances of sensory modulation and motility.This study was supported by C.N.R.S. (UA596), Biology and Neuropsychiatry, Sécurité Sociale 1982, and Fondation Langlois. We thank B. Baron, E. Vaudelon, J. Beurier-Charriere, P. Colombel, S. Roux, D. Lioret, and J. Sapede for their assistance.     

Autoimmune diseases in parents of children with infantile autism: a case-control study

This register study compared the rates and types of autoimmune disease in the parents of 111 patients (82 males, 29 females; mean age at diagnosis 5y 5mo [SD 2y 6mo]) with infantile autism (IA) with a matched control group of parents of 330 children from the general population. All parents were screened through the nationwide Danish National Hospital Register. We inquired about 35 autoimmune diseases during an observation period of 27 years. At follow-up the case and control mothers were identical in age (65y 7mo [SDs 9y 7mo and 9y respectively]). For case and control fathers the figures were 70 years 2 months (SD 10y 2mo) and 69 years 1 month (SD 10y 1mo) respectively. A similar proportion of case and control mothers had a diagnosis of any autoimmune disease: 10.8% versus 9.1%. For case fathers the proportion was 8.6% versus 4.6%. Two autoimmune conditions were associated with IA: ulcerative colitis in mothers (p=0.05) and type 1 diabetes in fathers (p=0.02). Additional studies are required to determine whether there is a true association between a parental history of autoimmune disease and pervasive developmental disorder in their offspring.     

Psychiatric morbidity in disintegrative psychosis and infantile autism: A long-term follow-up study.

In order to study the validity of disintegrative psychosis (DP), the authors compared 13 patients given this diagnosis in childhood with a control group of 39 patients with infantile autism (IA) matched for sex, age, IQ and social class on measures of psychiatric morbidity. Almost the same proportion of the two groups had been admitted to a psychiatric hospital during a 22-year follow-up period. However, there was a slight tendency (statistically nonsignificant) for the DP group to utilize the psychiatric health care system more frequently than the IA group. They had more admissions and stayed longer in hospital than patients with IA suggesting that they had more psychiatric symptoms than the IA group. The original IA diagnoses were confirmed fairly consistently during the follow-up period, while the DP group was given more heterogenous diagnoses. No diagnosis of schizophrenia was made in either group.     

Season of birth in infantile autism and other types of childhood psychoses

Season of birth in 328 children with infantile autism and other types of childhood psychoses born between 1945 and 1980 was compared with that of a control population born in the same period. For some parts of the period (the years 1951–56, 1963–68 and 1975–80 combined) an excess of March born boys with infantile autism was found. For boys with autistic-like disorders, born in the same period a maximum occurred in November, while no seasonality was observed for a borderline sample.The authors wish to thank Jones, Ford & Hamman for supplying the seasonality program and the Snedkermester Axel Wichman and Fru Else Wichmanns Fond for technical support.     

A follow-up study of high-functioning autistic children

It is well known that IQ is an important prognostic variable in the outcome of autistic children. There are, however, very few data available on the outcome of nonretarded autistic children as adults. We identified 16 such probands from records and followed them up between 11 and 27 years since discharge from a center specializing in the assessment of autistic children. There were 12 males and 4 females, average age was 26, and mean IQ was 92 (range 68–110). Although the majority were functioning poorly in terms of occupational-social outcome and psychiatric symptoms, a surprising number (4) had a very good outcome and might be considered recovered. The severity of early autistic behavior was a poor predictor of outcome, but neuropsychologic measures of nonverbal problem solving were highly correlated with outcomes. The results of the study indicate that a small percentage of nonretarded autistic children can be expected to recover to a substantial degree.We are very grateful to the staff of the West End Creche, Toronto, Ontario for all their help in conducting this study. Special thands must go to Dr. Milada Havelkova, without whose support and assistance the study could not have been completed. The project was funded by the Medical Research Council of Canada, and Dr. Szatmari was supported by the Council under the Fellowship program.     

Serotonin 2A receptor gene polymorphism and clinical efficacy of fluvoxamine in children with autistic disorder

Fluvoxamine, a selective serotonin reuptake inhibitor which modulates serotoninergic activities, is a useful drug for patients with an autistic disorder. Genetic variation of the serotonin receptor may influence the efficacy of fluvoxamine treatment. We studied the correlation between clinical responses to fluvoxamine and serotonin receptor gene polymorphism (5-HT2AR) in children with an autistic disorder. Eighteen patients completed a 12-week double-blind, placebo-controlled, randomized crossover study. Clinical global impression (CGI) by child neurologists and interviews for parents were assessed after 12 weeks of fluvoxamine treatment. Behavioral assessments consisting of 20 items by newly created Behavioral Assessment Scale (BAS) were obtained before as well as 6 and 12 weeks after treatment. For genotyping of 5-HT2AR, 102 T/C polymorphism was analyzed by the PCR method. Seven cases of T/T, 6 of T/C and 5 of C/C were identified. The patients with the genotype T/C responded more favorably when estimated by CGI and parents' report at 12 weeks of treatment. Although not significant statistically (p = 0.0578), the number of improved BAS items in these patients were larger after fluvoxamine than placebo treatment. On analyses of individual BAS items, the patients with the genotype C/C showed improvement of unnatural facial expression, which was significant at 6 weeks, but not at 12 weeks, of fluvoxamine treatment. In the patients with the genotype T/C, eye movements and emotional changes were significantly improved at 12 weeks of treatment. Our results suggested that genetic polymorphism of 102 T/C in the 5-HT2AR gene may have influence on the response to fluvoxamine treatment for patients with an autistic disorder. Because of the small numbers of subject studied here, further studies are needed. The methods of fluvoxamine treatment, such as appropriate dosage and treatment duration, should also be clarified.     

Cerebral glucose metabolism in autistic children. Study and positron emission tomography

Brain glucose metabolism was measured in 18 autistic children, using high resolution positron emission tomography (PET Scan), with fluorodeoxyglucose (FDG) as tracer. Measurements were performed on an ECAT III tomograph (CTI). Global brain glucose utilization in the autistic population was slightly more elevated than in young adult volunteers, particularly in frontal cortical regions, an observation previously reported for adult autists (Rumsey et al., 1985). However, mean brain glucose metabolism did not differ significantly from that of control children. Regional metabolic maps were also normal, although there was evidence for heterogeneities, particularly at the level of prefrontal and parieto-occipital association areas: 6 children showed a relative hyperfrontality whilst hypofrontality was found in 2 cases. These data suggest that PET might be useful for a better definition of subsets of autistic syndrome in children.