Being adults with cerebral palsy: results of a multicenter Italian study on quality of life and participation.

Cerebral palsy (CP) is still the most common cause of disability developing in infancy. How such a complex disorder affects adult life raises important questions on the critical issues to consider and the most appropriate care pathway right from early childhood. We conducted a multicenter study on a sample of 109 individuals with CP followed up from infancy and recalled for an assessment at ages ranging between 18 and 50 years (mean age 26 years). Semi-structured interviews and specific questionnaires (SF36, LIFE-H and Hollingshead Index) were conducted to assess general psychological state, quality of life, and socio-economic conditions. Our findings showed a globally positive perception of quality of life, albeit with lower scores for physical than for mental health. Our cases generally showed good scores on participation scales, though those with more severe forms scored lower on parameters such as mobility, autonomy, and self-care. These findings were investigated in more depth in interviews, in which our participants painted a picture showing that gradual improvements have been made in several aspects over the years, in the academic attainment and employment, for instance. On the downside, our sample reported persistent limitations on autonomy in daily life. As for the more profound psychological domain, there was evidence of suffering due to isolation and relational difficulties in most cases that had not emerged from the questionnaires. Our data have possible implications for the management of CP during childhood, suggesting the need to avoid an exclusive focus on motor function goals, and to promote strategies to facilitate communication, participation, autonomy, and social relations.

Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives.

OBJECTIVES: Intestinal permeability (IPT) was investigated in patients with autism as well as in their first-degree relatives to investigate leaky gut hypothesis. Faecal calprotectin (FC) was also measured in patients with autism, either with or without gastrointestinal symptoms, and in their first-degree relatives. PATIENTS AND METHODS: IPT results, assessed by means of the lactulose/mannitol test, were compared with adult and child controls and with FC values. RESULTS: A high percentage of abnormal IPT values were found among patients with autism (36.7%) and their relatives (21.2%) compared with normal subjects (4.8%). Patients with autism on a reported gluten-casein-free diet had significantly lower IPT values compared with those who were on an unrestricted diet and controls. Gastrointestinal symptoms were present in 46.7% of children with autism: constipation (45.5%), diarrhoea (34.1%), and others (alternating diarrhoea/constipation, abdominal pain, etc: 15.9%). FC was elevated in 24.4% of patients with autism and in 11.6% of their relatives; it was not, however, correlated with abnormal IPT values. CONCLUSIONS: The results obtained support the leaky gut hypothesis and indicate that measuring IPT could help to identify a subgroup of patients with autism who could benefit from a gluten-free diet. The IPT alterations found in first-degree relatives suggest the presence of an intestinal (tight-junction linked) hereditary factor in the families of subjects with autism.

A double-blind, parallel, multicenter comparison of L-acetylcarnitine with placebo on the attention deficit hyperactivity disorder in fragile X syndrome boys.

Attention deficit hyperactivity disorder (ADHD) is a frequent behavioral problem in young boys with fragile X syndrome (FXS), and its treatment is critical for improving social ability. The short-term efficacy of stimulant medications like methylphenidate (MPH) is well established in children with ADHD. FXS boys treated with MPH have improved attention span and socialization skills; however their mood becomes unstable at higher doses. Therefore, alternative pharmacological treatment of ADHD symptoms is desirable. A recent study showed that carnitine has a beneficial effect on the hyperactive-impulsive behavior in boys with ADHD without side effects. Our previous placebo-controlled trial indicated that L-acetylcarnitine (LAC) reduces hyperactivity in FXS boys. The objective of this study was to determine the efficacy of LAC in a larger sample of FXS boys with ADHD. The study design was randomized, double blind placebo controlled, parallel, and multicenter (with eight centers involved in Italy, France, and Spain). Sixty-three FXS males with ADHD (aged 6-13 years) were enrolled; 7 patients dropped out, 56 completed the one-year treatment, and 51 were included in the statistical analysis. Both groups improved their behavior, showing that psychosocial intervention has a significant therapeutic effect. However, we observed a stronger reduction of hyperactivity and improvement of social behavior in patients treated with LAC, compared with the placebo group, as determined by the Conners' Global Index Parents and the Vineland Adaptive Behavior Scale. Our results show that LAC (20-50 mg/kg/day) represents a safe alternative to the use of stimulant drugs for the treatment of ADHD in FXS children.

Clinical, morphological, and biochemical correlates of head circumference in autism.

BACKGROUND: Head growth rates are often accelerated in autism. This study is aimed at defining the clinical, morphological, and biochemical correlates of head circumference in autistic patients. METHODS: Fronto-occipital head circumference was measured in 241 nonsyndromic autistic patients, 3 to 16 years old, diagnosed according to DSM-IV criteria. We assessed 1) clinical parameters using the Autism Diagnostic Observation Schedule, Autism Diagnostic Interview-Revised, Vineland Adaptive Behavioral Scales, intelligence quotient measures, and an ad hoc clinical history questionnaire; 2) height and weight; 3) serotonin (5-HT) blood levels and peptiduria. RESULTS: The distribution of cranial circumference is significantly skewed toward larger head sizes (p < .00001). Macrocephaly (i.e., head circumference >97th percentile) is generally part of a broader macrosomic endophenotype, characterized by highly significant correlations between head circumference, weight, and height (p < .001). A head circumference >75th percentile is associated with more impaired adaptive behaviors and with less impairment in IQ measures and motor and verbal language development. Surprisingly, larger head sizes are significantly associated with a positive history of allergic/immune disorders both in the patient and in his/her first-degree relatives. CONCLUSIONS: Our study demonstrates the existence of a macrosomic endophenotype in autism and points toward pathogenetic links with immune dysfunctions that we speculate either lead to or are associated with increased cell cycle progression and/or decreased apoptosis.

Case-control and family-based association studies of candidate genes in autistic disorder and its endophenotypes: TPH2 and GLO1.

BACKGROUND: The TPH2 gene encodes the enzyme responsible for serotonin (5-HT) synthesis in the Central Nervous System (CNS). Stereotypic and repetitive behaviors are influenced by 5-HT, and initial studies report an association of TPH2 alleles with childhood-onset obsessive-compulsive disorder (OCD) and with autism. GLO1 encodes glyoxalase I, the enzyme which detoxifies alpha-oxoaldehydes such as methylglyoxal in all living cells. The A111E GLO1 protein variant, encoded by SNP C419A, was identified in autopsied autistic brains and proposed to act as an autism susceptibility factor. Hyperserotoninemia, macrocephaly, and peptiduria represent some of the best-characterized endophenotypes in autism research. METHODS: Family-based and case-control association studies were performed on clinical samples drawn from 312 simplex and 29 multiplex families including 371 non-syndromic autistic patients and 156 unaffected siblings, as well as on 171 controls. TPH2 SNPs rs4570625 and rs4565946 were genotyped using the TaqMan assay; GLO1 SNP C419A was genotyped by PCR and allele-specific restriction digest. Family-based association analyses were performed by TDT and FBAT, case-control by chi2, endophenotypic analyses for 5-HT blood levels, cranial circumference and urinary peptide excretion rates by ANOVA and FBAT. RESULTS: TPH2 alleles and haplotypes are not significantly associated in our sample with autism (rs4570625: TDT P = 0.27, and FBAT P = 0.35; rs4565946: TDT P = 0.45, and FBAT P = 0.55; haplotype P = 0.84), with any endophenotype, or with the presence/absence of prominent repetitive and stereotyped behaviors (motor stereotypies: P = 0.81 and 0.84, verbal stereotypies: P = 0.38 and 0.73 for rs4570625 and rs4565946, respectively). Also GLO1 alleles display no association with autism (191 patients vs 171 controls, P = 0.36; TDT P = 0.79, and FBAT P = 0.37), but unaffected siblings seemingly carry a protective gene variant marked by the A419 allele (TDT P < 0.05; patients vs unaffected siblings TDT and FBAT P < 0.00001). CONCLUSION: TPH2 gene variants are unlikely to contribute to autism or to the presence/absence of prominent repetitive behaviors in our sample, although an influence on the intensity of these behaviors in autism cannot be excluded. GLO1 gene variants do not confer autism vulnerability in this sample, but allele A419 apparently carries a protective effect, spurring interest into functional correlates of the C419A SNP.

Impact of malnutrition on gastrointestinal disorders and gross motor abilities in children with cerebral palsy.

UNLABELLED: Children with cerebral palsy (CP) often demonstrate abnormal feeding behaviours, leading to reduced food consumption and malnutrition. Moreover, most of them present with gastrointestinal disorders, such as gastroesophageal reflux disease (GERD) and/or chronic constipation (CC), and poor motor function rehabilitation. The aim of our study was to assess the possible relationship between malnutrition and gastrointestinal problems and to evaluate the role of nutrition on their gross motor abilities in a population of children with CP and mental retardation. PATIENTS: Twenty-one consecutive children (10 boys; mean age: 5.8+/-4.7 years; range: 1-14 years) with CP and severe mental retardation. METHODS: Nutritional assessment included the measurement of body mass index (BMI=W/H2), fat body mass (FBM) and fat free mass (FFM). Children with symptoms suggesting GERD underwent prolonged 24h intraesophageal pH monitoring and/or upper GI endoscopy with biopsies before and after a 6 months of pharmaceutical (omeprazole) and nutritional (20% increment of daily caloric intake) treatments. The motor function was evaluated by "The Gross Motor Function Measure" (GMFM) before and after the 6 months on nutritional rehabilitation. RESULTS: BMI for age was or=25 degrees percentile, five of nine (55.5%) patients had persistent GERD when they were taken off the medication. CONCLUSIONS: Malnutrition and gastrointestinal disorders are very common in children with cerebral palsy. Improved nutritional status, particularly fat free mass gain, appears to have an impact on motor function in children with CP.

Pediatric selective mutism therapy: a randomized controlled trial.

BACKGROUND: Selective mutism (SM) is a rare disease in children coded by DSM-5 as an anxiety disorder. Despite the disabling nature of the disease, there is still no specific treatment. AIM: The aims of this study were to verify the efficacy of six-month standard psychomotor treatment and the positive changes in lifestyle, in a population of children affected by SM. DESIGN: Randomized controlled trial registered in the European Clinical Trials Registry (EuDract 2015-001161-36). SETTING: University third level Centre (Child and Adolescent Neuropsychiatry Clinic). POPULATION: Study population was composed by 67 children in group A (psychomotricity treatment) (35 M, mean age 7.84±1.15) and 71 children in group B (behavioral and educational counseling) (37 M, mean age 7.75±1.36). METHODS: Psychomotor treatment was administered by trained child therapists in residential settings three times per week. Each child was treated for the whole period by the same therapist and all the therapists shared the same protocol. The standard psychomotor session length is of 45 minutes. At T0 and after 6 months (T1) of treatments, patients underwent a behavioral and SM severity assessment. To verify the effects of the psychomotor management, the Child Behavior Checklist questionnaire (CBCL) and Selective Mutism Questionnaire (SMQ) were administered to the parents. RESULTS: After 6 months of psychomotor treatment SM children showed a significant reduction among CBCL scores such as in social relations, anxious/depressed, social problems and total problems (P<0.001), Withdrawn (P=0.007) and Internalizing problems (P=0.020). Regarding SM severity according to SMQ assessment, children of group A showed a reduction of SM symptoms in all situations (school, P=0.003; family, P=0.018; and social, P=0.030 situations) and in SMQ total score (P<0.001). CONCLUSIONS: Our preliminary results suggest the positive effect of the psychomotor treatment in rehabilitative program for children affected by selective mutism, even if further studies are needed. CLINICAL REHABILITATION IMPACT: The present study identifies in psychomotricity a safe and efficacy therapy for pediatric selective mutism.

No evidence for association between dyslexia and DYX1C1 functional variants in a group of children and adolescents from Southern Italy.

Recently, DYX1C1, a candidate gene for developmental dyslexia, encoding a nuclear tetratricopeptide repeat domain protein dynamically regulated in brain, has been characterized through a translocation breakpoint in a Finnish family. Two putatively functional variants, -3G/A and 1249G/T, have been reported to be significantly associated with dyslexia in this population. Further studies, conducted on different ethnic groups (English and Canadian), have not confirmed a role for DYX1C1 variants in increasing the risk for dyslexia. We investigated the role of these variants in dyslexic children and adolescents from Southern Italy. No significant evidence for association between dyslexia and these DYX1C1 putative functional variants has been shown. We argue that the different DYX1C1 allele frequencies shown among Italian and Finnish subjects with dyslexia could be attributable to the different linkage disequilibrium structure of these populations.

Association between the HOXA1 A218G polymorphism and increased head circumference in patients with autism.

BACKGROUND: The HOXA1 gene plays a major role in brainstem and cranial morphogenesis. The G allele of the HOXA1 A218G polymorphism has been previously found associated with autism. METHODS: We performed case-control and family-based association analyses, contrasting 127 autistic patients with 174 ethnically matched controls, and assessing for allelic transmission disequilibrium in 189 complete trios. RESULTS: A, and not G, alleles were associated with autism using both case-control (chi(2) = 8.96 and 5.71, 1 df, p <.005 and <.025 for genotypes and alleles, respectively), and family-based (transmission/disequilibrium test chi(2) = 8.80, 1 df, p <.005) association analyses. The head circumference of 31 patients carrying one or two copies of the G allele displayed significantly larger median values (95.0th vs. 82.5th percentile, p <.05) and dramatically reduced interindividual variability (p <.0001), compared with 166 patients carrying the A/A genotype. CONCLUSIONS: The HOXA1 A218G polymorphism explains approximately 5% of the variance in the head circumference of autistic patients and represents to our knowledge the first known gene variant providing sizable contributions to cranial morphology. The disease specificity of this finding is currently being investigated. Nonreplications in genetic linkage/association studies could partly stem from the dyshomogeneous distribution of an endophenotype morphologically defined by cranial circumference.

A novel mutation in the CLN1 gene in a patient with juvenile neuronal ceroid lipofuscinosis.

We describe the clinical, neuropathological and molecular findings from a patient affected with neuronal ceroid lipofuscinosis with a juvenile onset (JNCL). She was a 9-year-old right-handed girl with a normal birth and early developmental milestones. At the age of 4 the early symptoms began. Skin biopsy showed granular osmiophilic deposits (GRODs). Because JNCL with GRODs is caused by mutations in the CNL1 gene, we performed a molecular investigation by direct sequencing of nine exons of the CNL1 gene. This analysis revealed a novel mutation in homozygous form in the exon 7 that caused an aminoacid substitution at codon 222 (Leu --> Pro). Direct sequencing of the exon 7 in both parents showed the same substitution in heterozygous form.

Effect of different starting doses of levothyroxine on growth and intellectual outcome at four years of age in congenital hypothyroidism.

To evaluate the effect of different initial levothyroxine (LT4) replacement doses on growth and intellectual outcome in patients with congenital hypothyroidism (CH) detected by neonatal screening program, the longitudinal growth and intelligence quotient (IQ) were assessed and compared at 4 years of age in 83 patients with CH. The patients were divided into three groups according to the initial LT4 dose used: (1) group 1 (n = 42) received the previously recommended dose of 6.0-8.0 microg/kg per day; (2) group 2 (n = 21) received a dose of 8.1-10.0 microg/kg per day; (3) Group 3 (n = 20) a dose of 10.1-15.0 microg/kg per day. The IQ, evaluated by the Wechsler Preschool and Primary Scale of Intelligence test at 4 years of age, was significantly higher in group 3 (IQ 98 +/- 9) compared to group 1 (IQ 88 +/- 13; p < 0.05) but not compared to group 2 (IQ 94 +/- 13). However, the IQs were below the normal range (< 85) in six patients from group 2 (28%), but in none of the patients from group 3 (p = 0.03). Patients from group 3, with severe CH at diagnosis, had an IQ (97 +/- 9) at 4 years of age, which was not different from that of patients from the same group with moderate CH at diagnosis (IQ 99 +/- 9). Similar results were also observed in patients from group 2 however, mean IQ scores in these patients (93 +/- 12) were several points lower than those observed in patients from group 3 (95 +/- 15). After the first month of treatment, optimal serum levels of thyroxine (T4) and free thyroxine (FT4) were achieved in all groups, however, only patients from group 3 were able to normalize thyrotropin (TSH) (group 1, 16.0 +/- 12.0; group 2, 9.2 +/- 10.0; and group 3, 2.4 +/- 3.3 mU/L; p < 0.0001). Twelve patients from group 2 treated with an initial LT4 dose above 9 microg/kg per day were able to normalize TSH levels within the first 3 months of life and this resulted in a better IQ (97 +/- 16) compared to the remaining patients from the same group (IQ 90 +/- 9). In the whole group of 83 patients the IQ at 4 years of age was positively correlated to both initial LT4 dosage (r = 0.27, p < 0.02) and FT4 concentrations after the first month of treatment (r = 0.29, p < 0.02), and negatively correlated to TSH concentrations after the first month of treatment (r = -0.27, p < 0.02). No significant differences were observed in height, weight, head circumference, and bone age maturation among the three groups of patients. No clinical signs or symptoms of overtreatment were observed during follow-up in patients receiving the higher LT4 dosage. Our results indicate that high LT4 starting doses rapidly normalize serum TSH concentrations resulting in an improvement of the IQ at 4 years of age, even in patients with severe CH at diagnosis. Growth and bone age maturation are not affected by such a high dose.

Etiopathogenesis of autism spectrum disorders: fitting the pieces of the puzzle together.

Autism spectrum disorders (ASD) are disorders of the central nervous system characterized by impairments in communication and social reciprocity. Despite thousands of studies on this topic, the etiopathogenesis of these disorders remains unclear, apart from a general belief that they derive from an interaction between several genes and the environment. Given the mystery surrounding the etiopathogenesis of ASD it is impossible to plan effective preventive and treatment measures. This is of particular concern due to the progressive increase in the prevalence of ASD, which has reached a figure as high as 1:88 children in the USA. Here we present data corroborating a novel unifying hypothesis of the etiopathogenesis of ASD. We suggest that ASD are disorders of the immune system that occur in a very early phase of embryonic development. In a background of genetic predisposition and environmental predisposition (probably vitamin D deficiency), an infection (notably a viral infection) could trigger a deranged immune response which, in turn, results in damage to specific areas of the central nervous system. If proven, this hypothesis would have dramatic consequences for strategies aimed at preventing and treating ASD. To confirm or refute this hypothesis, we need a novel research approach, which unlike former approaches in this field, examine the major factors implicated in ASD (genetic, infections, vitamin D deficiency, immune system deregulation) not separately, but collectively and simultaneously.

Family-based association study of ITGB3 in autism spectrum disorder and its endophenotypes.

The integrin-ß 3 gene (ITGB3), located on human chromosome 17q21.3, was previously identified as a quantitative trait locus (QTL) for 5-HT blood levels and has been implicated as a candidate gene for autism spectrum disorder (ASD). We performed a family-based association study in 281 simplex and 12 multiplex Caucasian families. ITGB3 haplotypes are significantly associated with autism (HBAT, global P=0.038). Haplotype H3 is largely over-transmitted to the affected offspring and doubles the risk of an ASD diagnosis (HBAT P=0.005; odds ratio (OR)=2.000), at the expense of haplotype H1, which is under-transmitted (HBAT P=0.018; OR=0.725). These two common haplotypes differ only at rs12603582 located in intron 11, which reaches a P-value of 0.072 in single-marker FBAT analyses. Interestingly, rs12603582 is strongly associated with pre-term delivery in our ASD patients (P=0.008). On the other hand, it is SNP rs2317385, located at the 5' end of the gene, that significantly affects 5-HT blood levels (Mann-Whitney U-test, P=0.001; multiple regression analysis, P=0.010). No gene-gene interaction between ITGB3 and SLC6A4 has been detected. In conclusion, we identify a significant association between a common ITGB3 haplotype and ASD. Distinct markers, located toward the 5' and 3' ends of the gene, seemingly modulate 5-HT blood levels and autism liability, respectively. Our results also raise interest into ITGB3 influences on feto-maternal immune interactions in autism.

Candidate gene study of HOXB1 in autism spectrum disorder.

BACKGROUND: HOXB1 plays a major role in brainstem morphogenesis and could partly determine the cranial circumference in conjunction with HOXA1. In our sample, HOXA1 alleles significantly influence head growth rates both in autistic patients and in population controls. An initial report, suggesting that HOXB1 could confer autism vulnerability in interaction with HOXA1, was not confirmed by five small association studies. METHODS: Our sample includes 269 autistic individuals, belonging to 219 simplex and 28 multiplex families. A mutational analysis of the two exons and flanking intronic sequences of the HOXB1 gene was carried out in 84 autistic patients by denaturing high performance liquid chromatography, followed by DNA sequencing. Identified rare variants were then searched by a restriction analysis in 236 autistic patients and 325-345 controls. Case-control and family-based association studies were performed on two common variants in 169 Italian patients versus 184 Italian controls and in 247 trios. RESULTS: We identified three common polymorphisms, rs72338773 [c.82insACAGCGCCC (INS/nINS)], rs12939811 [c.309A>T (Q103H)], and rs7207109 [c.450G>A (A150A)] and three rare variants, namely IVS1+63G>A, rs35115415 [c.702G>A (V234V)] and c.872_873delinsAA (S291N). SNPs rs72338773 and rs12939811 were not associated with autism, using either a case-control (alleles, exact P = 0.13) or a family-based design [transmission/disequilibrium test (TDT)chi2 = 1.774, P = 0.183]. The rare variants, all inherited from one of the parents, were present in two Italian and in two Caucasian-American families. Autistic probands in two families surprisingly inherited a distinct rare variant from each parent. The IVS1+63A allele was present in 3/690 control chromosomes, whereas rare alleles at rs35115415 and c.872_873delinsAA (S291N) were not found in 662 and 650 control chromosomes, respectively. The INS-T309 allele influenced head size, but its effect appears more modest and shows no interaction with HOXA1 alleles. The INS-T309 allele is also associated with more severe stereotypic behaviours, according to ADI-R scores (N = 60 patients, P < 0.01). CONCLUSIONS: HOXB1 mutations do not represent a common cause of autism, nor do HOXB1 common variants play important roles in autism vulnerability. HOXB1 provides minor, albeit detectable contributions to head circumference in autistic patients, with HOXA1 displaying more prominent effects. HOXB1 variants may modulate the clinical phenotype, especially in the area of stereotypic behaviours.

Principal pathogenetic components and biological endophenotypes in autism spectrum disorders.

Autism is a complex neurodevelopmental disorder, likely encompassing multiple pathogenetic components. The aim of this study is to begin identifying at least some of these components and to assess their association with biological endophenotypes. To address this issue, we recruited 245 Italian patients with idiopathic autism spectrum disorders and their first-degree relatives. Using a stepwise approach, patient and family history variables were analyzed using principal component analysis ("exploratory phase"), followed by intra- and inter-component cross-correlation analyses ("follow-up phase"), and by testing for association between each component and biological endophenotypes, namely head circumference, serotonin blood levels, and global urinary peptide excretion rates ("biological correlation phase"). Four independent components were identified, namely "circadian & sensory dysfunction," "immune dysfunction," "neurodevelopmental delay," and "stereotypic behavior," together representing 74.5% of phenotypic variance in our sample. Marker variables in the latter three components are positively associated with macrocephaly, global peptiduria, and serotonin blood levels, respectively. These four components point toward at least four processes associated with autism, namely (I) a disruption of the circadian cycle associated with behavioral and sensory abnormalities, (II) dysreactive immune processes, surprisingly linked both to prenatal obstetric complications and to excessive postnatal body growth rates, (III) a generalized developmental delay, and (IV) an abnormal neural circuitry underlying stereotypies and early social behaviors.

HOXA1 gene variants influence head growth rates in humans.

We previously described a significant association between the HOXA1 G218 allele and increased head circumference in autism [Conciatori et al. (2004); Biol Psychiatry 55:413-419]. The present study reveals identical effects also in normal children. HOXA1 A218G alleles and sex explain as much as 10.9 and 6.8% of the variance in head circumference in 142 pediatric controls and in 191 autistic children, aged 3-16 years (F = 6.777, 3 and 141 df, P < 0.001 and F = 5.588, 3 and 190 df, P < 0.01, respectively). Instead, no association is found in 183 adult controls and in 35 pediatric fragile-X patients. Therefore HOXA1 A218G alleles significantly influence head growth rates, but not final head size, in normal human development. This influence does not differ between normal and autistic children, whereas the lack of FMRP seemingly overwhelms HOXA1 effects in fragile-X patients.

A genetic variant that disrupts MET transcription is associated with autism.

There is strong evidence for a genetic predisposition to autism and an intense interest in discovering heritable risk factors that disrupt gene function. Based on neurobiological findings and location within a chromosome 7q31 autism candidate gene region, we analyzed the gene encoding the pleiotropic MET receptor tyrosine kinase in a family based study of autism including 1,231 cases. MET signaling participates in neocortical and cerebellar growth and maturation, immune function, and gastrointestinal repair, consistent with reported medical complications in some children with autism. Here, we show genetic association (P = 0.0005) of a common C allele in the promoter region of the MET gene in 204 autism families. The allelic association at this MET variant was confirmed in a replication sample of 539 autism families (P = 0.001) and in the combined sample (P = 0.000005). Multiplex families, in which more than one child has autism, exhibited the strongest allelic association (P = 0.000007). In case-control analyses, the autism diagnosis relative risk was 2.27 (95% confidence interval: 1.41-3.65; P = 0.0006) for the CC genotype and 1.67 (95% confidence interval: 1.11-2.49; P = 0.012) for the CG genotype compared with the GG genotype. Functional assays showed that the C allele results in a 2-fold decrease in MET promoter activity and altered binding of specific transcription factor complexes. These data implicate reduced MET gene expression in autism susceptibility, providing evidence of a previously undescribed pathophysiological basis for this behaviorally and medically complex disorder.

Repetitive behaviors in autistic disorder.

INTRODUCTION: Repetitive behaviors are common in autistic disorder, as in other developmental disabilities. Behaviors as diverse as stereotypies, cognitive inflexibility, and a need for sameness are grouped together under DSM IV classification, even though they are diverse in phenomenology, underlying neural circuitry, and possible clinical significance. In order to better define repetitive behaviors, we studied the relationship between such behaviors and chronological age, developmental level, estimated IQ, presumed mood state, severity of illness, as well as behavior reactivity to environmental stimuli, in a group of 121 consecutive autistic children, aged 2-4 and 7-11 years. RESULTS: Younger autistic children displayed more motor and sensory repetitive behaviors. Older children had more complex behaviors. Children with higher IQ scores, likewise, demonstrated more complex repetitive behaviors. Most motor behaviors and self injury showed features of reactivity. CONCLUSIONS: Certain "repetitive" activities may not represent core features of autistic disorder and may be equivalent to normal motor and cognitive behaviors, as seen during typical development.