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Autism, a neurodevelopmental disorder first described in 1943, is reviewed. The signs and symptoms of the disorder are described together with the etiological factors. The evidence for a genetic etiology of autism and its association with other genetic disorders are discussed. Possible candidate genes for autism are described.
Prenatal alcohol use is a threat to healthy pregnancy outcomes for many U.S. women. During 1999, approximately 500,000 pregnant women reported having one or more drinks during the preceding month, and approximately 130,000 reported having seven or more alcohol drinks per week or engaging in binge drinking (i.e., five or more drinks in a day). These heavier drinking patterns have been associated with fetal alcohol syndrome (FAS) and alcohol-related neurodevelopmental disorders (ARND). Lower levels of alcohol consumption (i.e., fewer than seven drinks per week) also have been associated with measurable effects on children's development and behavior. Although the majority of women reduce their alcohol use substantially when they realize they are pregnant, a large proportion do not realize they are pregnant until well into the first trimester and, therefore, might continue to drink alcohol during this critical period of fetal development. To reduce alcohol-exposed pregnancies, CDC initiated a multisite pilot study (phase I clinical trial) in 1997 to investigate the use of a dual intervention focused on both alcohol-use reduction and effective contraception among childbearing-aged women at high risk for an alcohol-exposed pregnancy (Project CHOICES). This report describes the association between baseline drinking measures and the success women have achieved in reducing their risk for an alcohol-exposed pregnancy. The analysis compares the impact of the motivational intervention at 6-month follow-up on women drinking at high-, medium-, and low-risk drinking levels. The findings indicate that although 69% of the women in the study reduced their risk for an alcohol-exposed pregnancy, women with the lowest baseline drinking measures achieved the highest rates of outcome success, primarily by choosing effective contraception and, secondarily, by reducing alcohol use. Women with higher baseline drinking measures chose both approaches equally but achieved lower success rates for reducing their risk for an alcohol-exposed pregnancy. A randomized controlled trial of the motivational intervention is under way to further investigate outcomes of the phase I study.
INTRODUCTION: Progressive encephalopathy with oedema, hypsarrhythmia and optic atrophy (PEHO syndrome) is a pathological process that begins in the first months of life and quickly leads to a very serious encephalopathy. We report the case of an infant suffering from PEHO syndrome and discuss its pathogenesis. CASE REPORT: A 4 year old male, the son of parents who were not blood related, with no pre or perinatal background of interest, who, from the first month, was seen to have a moderate retardation in psychomotor development and generalised hypotonia. These clinical signs increased progressively over the next months. From the age of 6 months onwards infantile spasms were observed, together with an EEG displaying hypsarrhythmic characteristics, slight facial oedema as well as in the hands, abnormal ocular movements and loss of vision with optic atrophy. In the neuroimaging serial studies, MRI showed a progressive atrophy of the brain stem and the cerebellum associated with cortical atrophy, hypoplasia of the corpus callosum and retarded myelination. CONCLUSIONS: Diagnosis of PEHO syndrome is essentially clinical with the help of neuroimaging, since there is no biological or genetic marker. The case described fulfils the criteria required for diagnosis of PEHO syndrome. The existence of cases in the family suggests that PEHO syndrome is due to a genetically based neurodevelopmental disorder. To our knowledge this is the first case reported in Spain.
BACKGROUND: The purpose of the study was to evaluate the effects of MMR immunization and mercury from thimerosal-containing childhood vaccines on the prevalence of autism. MATERIAL/METHODS: Evaluations of the Biological Surveillance Summaries of the Centers for Disease Control and Prevention (CDC), the U.S. Department of Education datasets, and the CDC's yearly live birth estimates were undertaken RESULTS: It was determined that there was a close correlation between mercury doses from thimerosal--containing childhood vaccines and the prevalence of autism from the late 1980s through the mid-1990s. In contrast, there was a potential correlation between the number of primary pediatric measles-containing vaccines administered and the prevalence of autism during the 1980s. In addition, it was found that there were statistically significant odds ratios for the development of autism following increasing doses of mercury from thimerosal-containing vaccines (birth cohorts: 1985 and 1990-1995) in comparison to a baseline measurement (birth cohort: 1984). The contribution of thimerosal from childhood vaccines (>50% effect) was greater than MMR vaccine on the prevalence of autism observed in this study. CONCLUSIONS: The results of this study agree with a number of previously published studies. These studies have shown that there is biological plausibility and epidemiological evidence showing a direct relationship between increasing doses of mercury from thimerosal-containing vaccines and neurodevelopmental disorders, and measles-containing vaccines and serious neurological disorders. It is recommended that thimerosal be removed from all vaccines, and additional research be undertaken to produce a MMR vaccine with an improved safety profile.
Alcohol consumption during pregnancy causes a major risk of Fetal Alcohol Syndrome (FAS). This article defines the three syndromes linked to alcohol consumption during pregnancy: (1) FAS, with or without confirmed maternal alcohol exposure; (2) alcohol-related birth defect (ARBD) (3) and alcohol-related neurodevelopmental disorder (ARND). The article also reviews data on alcohol use in pregnant women and in women of child-bearing age. The literature indicates that between 6% and 45% pregnant women have an at-risk alcohol use, and suggests that brief counseling interventions designed to prevent at-risk alcohol use are effective. Studies assessing alcohol use and brief intervention efficacy in pregnant women in Switzerland are needed.
In neurodevelopmental disorders, the characteristic symptoms appear age-dependently along with the functional and morphological development of the affected neurons and the neuronal pathways. Most of them have the primary lesion in the subcortical structures as these mature earlier, which include the aminergic neurons of the brainstem and the midbrain having important roles for development of the higher cortical function (HCF). Thus, to clarify the pathophysiologies of the symptoms appearing age-dependently makes it possible to demonstrate the process of development of the HCF. Here, I reviewed the characteristic symptoms and their pathophysiologies of Rett syndrome, DYT-1, autosomal dominant GTP cyclohydrolase I (ADGCH I) deficiency, Tourette syndrome (TS) and Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH), and suggested that the brainstem aminergic neurons modulating the locomotion have roles for development of the frontal cortex, the dopaminergic neurons and basal ganglia pathways involving in the action dystonia for motor execution and the serotonergic and the dopaminergic neurons projectioning to the nonmotor basal ganglia thalamocortical circuits for development of the frontal area, the targets of the circuits. While, postural dystonia, tics in GTS and symptoms in EAOH reflect the development of the causative neurons and the neuronal systems.
OBJECTIVE: Rett syndrome (RTT) is a neurodevelopmental disorder which causes severe mental retardation. This study aimed at elucidating clinical features of 66 Chinese RTT cases diagnosed by The Department of Pediatric Neurology, Peking University First Hospital since 1987, and at analysis of the MeCP2 genotype / phenotype correlation. METHODS: Sixty-six RTT cases were followed up every one to two years to get the information of their clinical manifestations and the response to the L-carnitine treatment which was administered to the patients at a dose of 80-100 mg/(kg d). MeCP2 mutation analysis by PCR and sequencing were performed on 39 cases. RESULTS: In this cohort of cases, the onset of the disease occurred between 3 and 38 months of age, 89% of the cases lost their purposeful hand use at 7 months to six years of age, all the cases had stereotype hand movement which presented at 1 to 5 years of age, 85% of the cases lost language ability at 11 months to eight years of age, 21% of the cases lost the ability of walking at ages of 2 years and 9 months to 15 years. The symptoms/signs such as small head circumference, seizures, breathing irregularities, teeth grinding, scoliosis/ kyphosis were presented in many of the cases. The clinical manifestations were improved in 6 cases after L-carnitine treatment. MeCP2 gene mutation was found in 64% of the cases. Two cases with non-sense mutation C502t (amino acid change R168X) died, two cases with missense mutation C397T (amino acid change R133C) and one case with missense mutation A398T (amino acid change R133H) preserved several words. CONCLUSION: Deceleration of the head growth, loss of acquired purposeful hand use, stereotype hand movement and language deterioration were the main characteristics of RTT. L-carnitine could improve the clinical manifestation of some cases. There are some correlations between MeCP2 genotype and phenotype.
INTRODUCTION: Rett syndrome is an X-linked neurodevelopmental disorder characterized by loss of acquired skills and stereotypical hand movements. Mutations in the gene encoding methyl-CpG-binding protein 2 have been identified as cause of Rett syndrome in 1999. AIM: The authors initialized mutation screening of this gene in Hungarian patients identified on the base of clinical manifestation in various institutes. So far 25 patients were examined who were supposed to have Rett syndrome. METHOD: Total genomic DNA was extracted from peripheral blood with routine desalting method for mutation analysis. The three coding regions of the gene were amplified with primer pairs described. The PCR products were analysed by direct sequencing. RESULTS: Mutations in methyl-CpG-binding protein 2 gene were found in 17/25 cases (68%). This rate of mutation among Rett patients corresponds well with the findings of other studies. Two novel mutations were found. In the first patient whose history was characterized by a slower than normal progression, a G insertion at the base position 276 of exon 3 was detected, while in the second child a double deletion (191, and 9 bases, resp.) in exon 4 was identified.
AIM: We review the ability of head circumference (HC) at birth and head growth during the neonatal period to predict neurodevelopmental outcome, putting emphasis on new knowledge in this area. DEVELOPMENT: During infancy HC correlates closely with intracranial volume and constitutes an accurate predictor of cerebral volume. Both an abnormal head size at birth and an abnormal head growth during the neonatal period, can express brain damage or the presence of entities that involve varied degrees of neurological dysfunction in childhood. In general, the influence of head size or growth abnormalities on neurodevelopment is more related to the underlying etiology and/or the presence of structural diseases of the brain than with the HC alteration itself. HC evaluation is of particular interest in sick neonates, specially very low birth weight infants, regardless of whether they are normal or small for gestational age, and both during admission an during the first months of life. In these patients, HC catch-up within the first months of life represents a favorable neurodevelopmental prognostic factor. CONCLUSION: HC measuring and head growth evaluation constitute the most simple, inexpensive and quick available tools to assess the development of the central nervous system and identify neonates at risk of neurodevelopmental disorders.
AIMS: Our aim was to evaluate the presence, type and severity of neurological sequelae in infants born prematurely. SUBJECTS AND METHODS: A descriptive, retrospective study was conducted in which we reviewed the patient records of 179 patients with a history of prematurity who visited the Child Neurology clinic at COLSANITAS in Bogota between 1st January 2000 and 31st July 2004. Data was collected concerning demographic aspects, maternal and foetal risk factors, perinatal complications, age at the last Child Neurology control, type of sequela and severity. The variables and their relation to neurodevelopmental disorders were analysed. RESULTS: Of the 179 patients analysed, 51% were males and the remaining 49% were females. The average gestational age was 31.8 weeks. Average weight at birth was 1,690 g. No statistically significant associations were found among the variables that were analysed. CONCLUSIONS: The results obtained differ from those reported in the literature from around the world. This is due to the fact that the sample population belongs to a minority living in privileged socioeconomic conditions, which does not represent the real situation of the Columbian population. In addition, the high percentage of patients who drop out of the follow-up programmes makes it difficult to check the sequelae. With the data obtained we are considering the possibility of extending the neurological follow-up until the age of 6 years or up to the age at which the patient is completely adapted to full-time education.
The causes of autism and neurodevelopmental disorders are unknown. Genetic and environmental risk factors seem to be involved. Because of an observed increase in autism in the last decades, which parallels cumulative mercury exposure, it was proposed that autism may be in part caused by mercury. We review the evidence for this proposal. Several epidemiological studies failed to find a correlation between mercury exposure through thimerosal, a preservative used in vaccines, and the risk of autism. Recently, it was found that autistic children had a higher mercury exposure during pregnancy due to maternal dental amalgam and thimerosal-containing immunoglobulin shots. It was hypothesized that children with autism have a decreased detoxification capacity due to genetic polymorphism. In vitro, mercury and thimerosal in levels found several days after vaccination inhibit methionine synthetase (MS) by 50%. Normal function of MS is crucial in biochemical steps necessary for brain development, attention and production of glutathione, an important antioxidative and detoxifying agent. Repetitive doses of thimerosal leads to neurobehavioral deteriorations in autoimmune susceptible mice, increased oxidative stress and decreased intracellular levels of glutathione in vitro. Subsequently, autistic children have significantly decreased level of reduced glutathione. Promising treatments of autism involve detoxification of mercury, and supplementation of deficient metabolites.
Autism is a neurodevelopmental disorder characterized by impairments in social skills, language, and behavior. It is now clear that autism is not a disease, but a syndrome characterized by phenotypic and genetic complexity. The etiology of autism is still poorly understood. Available evidence from a variety of sources strongly suggests that many genetic disorders are frequently associated with autism for their similar phenotypes. Based on this fact, this review begins by highlighting several principal genetic syndromes consistently associated with autism (fragile X, tuberous sclerosis, Angelman syndrome, Pader-Willi syndrome, Rett syndrome, Down syndrome and Turner syndrome). These genetic disorders include both chromosome disorders and single gene disorders. By comparing the similar phenotype, protein marker and candidate genes, we might make some breakthrough in the mechanism of autism and other genetic disorders.
Autism is a lifelong neurodevelopmental disorder characterized by early onset of impairments in social interaction and communication and unusual, stereotyped behaviors. Autism (i.e., autistic disorder) often is classified with two related, although less severe, developmental disorders: Asperger disorder and pervasive developmental disorder--not otherwise specified. These three constitute the autism spectrum disorders (ASDs). Diagnosis of ASDs is based exclusively on developmental pattern and behavioral observation. Two population-based studies conducted by CDC in selected U.S. locations reported ASD prevalence of 3.4 and 6.7 per 1,000 children, respectively. CDC also conducts two nationally representative surveys, the National Health Interview Survey (NHIS) and the National Survey of Children's Health (NSCH), in which parents are asked whether their child ever received a diagnosis of autism. Because of similarities in methodology used by the two surveys, CDC analyzed 2003-2004 data from NHIS and data from the first-ever NSCH (collected during January 2003-July 2004) to 1) estimate the population-based prevalence of parental report of diagnosed autism in the United States and 2) assess parental reporting of child social, emotional, and behavioral strengths and difficulties and special-health care needs among children with and without reported autism. This report describes the results of that analysis, which indicated that the prevalence of parent-reported diagnosis of autism was 5.7 per 1,000 children in NHIS and 5.5 per 1,000 children in NSCH. Prevalence estimates in the two studies were similar across age, sex, and racial/ethnic populations. The consistency in estimates between the two surveys suggests high reliability for parental report of autism. These estimates suggest that, as of 2003-2004, autism had been diagnosed in at least 300,000 U.S. children aged 4-17 years. In addition, parental reports of autism were associated with reported social, emotional, and behavioral symptoms and specialized needs. Thus, these surveys might be useful to assess health, education, and social service needs of children with autism.
Autism is a complex neurodevelopmental disorder characterized by qualitative impairments in social interaction and communication, with restricted, repetitive, stereotyped patterns of behavior, interests and activities. These behaviors manifest along a wide spectrum and commence before 36 months of age. Diagnosis of autism is made by ascertaining whether the child's specific behaviors meet the Diagnostic and Statistical Manual of Mental Disorders-IV-Revised criteria. Its etiology is still unclear but recent studies suggest that genetics plays a major role in conferring susceptibility. Recent neuroimaging research studies indicate that autism may be caused by atypical functioning in the central nervous system, particularly in the limbic system: amygdala and hippocampus. In a third of autistic children, loss of language and/or social skills occurs during the second year of life, usually between 15 and 21 months of age. Comorbidity with mental retardation, epilepsy, disruptive behaviors and learning difficulty is not uncommon. Although there is currently no known cure for autism there is evidence to suggest that early intervention therapy can improve functioning of autistic children. Judicious use of psychotropic drugs is necessary to manage associated aggression, hyperactivity, self-mutilation, temper tantrums; but drugs are not a substitute for behavioral and educational interventions. The family physician can play an important role in detecting autism early, coordinating its assessment and treatment, counseling the parents and classroom teacher, and monitoring the child's progress on a long term basis.
BACKGROUND AND PURPOSE: Iodine deficiency and hypothyroxinemia have a negative effect on the development of the central nervous system during fetal and early postnatal life. MR spectroscopy is a sensitive technique for detecting the changes of brain metabolites in various neurodevelopmental disorders. By using MR spectroscopy, we aimed to show the decrease in N-acetylaspartate (NAA) levels in neonates with hypothyroidism who were born in iodine-deficient areas and its normalization with early thyroxine therapy. METHODS: Eight congenital hypothyroid and 8 healthy full-term neonates were chosen as study and control groups, respectively. Serum thyroid hormones and median urinary iodine concentration of the neonates and their mothers were measured. Measurements of NAA, choline (Cho), and creatine (Cr) were made in frontal white matter, parietal white matter (PWM), and the thalamus with MR spectroscopy, first at 5-7 days of life and after 8 weeks of thyroxine therapy in the study group and at the same time in the control group. RESULTS: The patient group had significantly lower NAA/Cr ratios in PWM and the thalamus (P < .05, for each), whereas the difference between Cho/Cr ratios of the 2 groups before therapy was not significant. After 8 weeks of thyroxine therapy, measurements did not show significant difference between study and control groups. CONCLUSION: MR spectroscopy performed in neonates with hypothyroidism reveals that intrauterine hypothyroxinemia due to iodine deficiency results in significant decrease in NAA levels in PWM and the thalamus and that the normalization of NAA levels is achieved with early thyroxine therapy.
OBJECTIVE: Rett syndrome (RTT) is a severe childhood neurodevelopmental disorder mainly affecting females. The pathogenic gene is located at Xq28, which codes for the methyl-CpG-binding protein 2. MECP2 gene is affected by X chromosome inactivation (XCI). The different XCI patterns of females could affect the expression ratios of pathogenic gene, causing changes in clinical symptoms. In order to understand the XCI patterns in RTT patients and the relationship between XCI pattern, genotype and phenotype, the XCI patterns in patients with RTT and their mothers, the parental origin of the priority inactive X chromosome in RTT, and the relations of XCI patterns with genotype and phenotype in RTT cases were analyzed. METHODS: Genomic DNA was extracted from peripheral blood of 55 cases with RTT (52 with MECP2 mutations, 3 without mutations), 53 mothers of RTT cases and 48 normal female controls. DNA was digested with methylation sensitive restriction endonuclease Hpa II. Then the undigested and digested DNAs were amplified via PCR for the first exon of human androgen receptor (AR) gene. PCR products were analyzed by Genescan. RESULTS: The heterozygotic rates of AR gene were 82%, 77% and 83% in RTT patients, mothers and controls, respectively. XCI distribution pattern of RTT was different from that of the mothers and control, P < 0.05. More mothers and controls than RTT patients were in the area of XCI 50:50 - 59:41. The differences between them were statistically significant (P < 0.05). No significant difference in XCI distribution patterns between mothers and the control groups was found (P > 0.05). Non-random XCI rates in the areas of XCI >or= 65:35 and >or= 80:20 were 53.35% and 17.8%, respectively, in RTT patients, compared with the mothers group (36.6%, 7.3%) and control group (35%, 10%), it was higher in RTT patients, but the difference was not statistically significant (P > 0.05). In 18 of 21 cases with XCI >or= 65:35, the priority inactive X chromosome was of paternal origin (85.7%). Variable XCI patterns were observed in the same gene mutation patients. The highly skewed XCI as well as the random XCI were found in patients with mild, severe and typical phenotype. The rate of highly skewed XCI in atypical patients was higher than that in typical RTT patients. The rate of highly skewed XCI in T158M was higher than the other type mutations. No highly skewed XCI was observed in cases with R133C mutation. CONCLUSION: The XCI distribution pattern of RTT patients was different from that of RTT mother and control groups. There was no significant difference in XCI distribution patterns between mothers and the control groups. It was not a main genetic pattern in RTT that mothers as the carriers to transmit the pathogenic gene to the patients. Non-random XCI was not the main XCI pattern in RTT patients. The priority inactive X chromosome was mainly of paternal origin. XCI could modify the clinical phenotype of RTT, but had limitations in explaining all the phenotypes manifested in RTT cases.
Autism is now generally considered to be an organic neurodevelopmental disorder. This review considers the current understanding of genetic factors and associated medical conditions, together with a discussion of some aspects of management and treatment of affected children and adolescents.
The initial assumptions as to the existence of neurodevelopmental disorders have been confirmed by almost a century of studies focused on the nature and causes of reading disability. Dyslexia is an umbrella term for the various manifestations of reading disabilities, each of which is related to its own complex of neuropsychological dysfunctions, sometimes accompanied by neurological symptoms that can be indicative of the specific location involved. Electro-physiology and neuro-imaging in relation to metabolic activity have also confirmed that, to some extent, there is dysfunction in various cerebral areas, more frequently in the left than in the right hemisphere, less often between the hemispheres (corpus callosum) and outside the classical language areas. The rather rare subtype referred to as visual dyslexia and the inter-modal disconnection type resembling alexia are eclipsed by dyslexias related to spoken language: the dysphonemic (auditory-phonological) subtype and the subtypes that are concerned with the production of speech (fluency, word-finding, syntax, sequences), semantics (language comprehension) and linguistic memory. Although it is considered that there are basic brain dysfunctions in dyslexics such as deficits in sequential information processing, there is no "grand unified theory" of dyslexia. There are some new insights as regards the aetiology. In addition to indications of such possible causes as perinatal brain damage, genetic or chromosomal anomalies that manifest themselves in the substrate in an unclear manner, there is also the possibility that the cortical language areas can be disturbed in their development (migration disorders and abnormal asymmetry) due to genetic or epigenetic hormonal and/or immunological factors, so that the normal left hemispheric dominance does not develop. The diagnosis and treatment of dyslexia should begin at an early age and should be acknowledged as being of great social importance.