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P F Bolton

Publications and source records attributed to P F Bolton.

14 recordsLinked to original sources
PubMed2002

FOXP2 is not a major susceptibility gene for autism or specific language impairment.

The FOXP2 gene, located on human 7q31 (at the SPCH1 locus), encodes a transcription factor containing a polyglutamine tract and a forkhead domain. FOXP2 is mutated in a severe monogenic form of speech and language impairment, segregating within a single large pedigree, and is also disrupted by a translocation in an isolated case. Several studies of autistic disorder have demonstrated linkage to a similar region of 7q (the AUTS1 locus), leading to the proposal that a single genetic factor on 7q31 contributes to both autism and language disorders. In the present study, we directly evaluate the impact of the FOXP2 gene with regard to both complex language impairments and autism, through use of association and mutation screening analyses. We conclude that coding-region variants in FOXP2 do not underlie the AUTS1 linkage and that the gene is unlikely to play a role in autism or more common forms of language impairment.

Alleles↗
PubMed2001

The phenotypic manifestations of interstitial duplications of proximal 15q with special reference to the autistic spectrum disorders.

This study investigated the phenotypic manifestations of interstitial duplications of chromosome 15 that involve the Prader-Willi/Angelman syndrome critical region (PWACR). Twenty-one affected individuals from six families were evaluated in detail, using standardized and semi-standardized measures of intelligence, psychopathology, and physical anomalies. Special attention was placed on determining the prevalence of autism spectrum disorders as well as the relationship between the parental origin of the duplication and the phenotypic effects. Assessments of the affected individuals were compared with evaluations of the unaffected relatives from the same families. Results indicated that duplications in the region were associated with variable degrees of intellectual impairments and motor coordination problems. Four of the subjects received a diagnosis of pervasive developmental disorder. Three of these cases were probands and only one met criteria for classic autism. There was very little evidence of the duplication cosegregating with autism spectrum disorder diagnosis. Paternally inherited duplications were significantly less likely to give rise to phenotypic effects. The findings indicate that duplications in the PWACR give rise to developmental delay but not necessarily autism spectrum disorders. They also suggest that phenotypic expression is dependent on the parental origin of the duplication and implicate maternally active genes in the pathogenesis of the developmental impairments. Further research will be required to clarify the range and basis of the phenotypic manifestations.

Adult↗
PubMed2001

Association between idiopathic infantile macrocephaly and autism spectrum disorders.

We conducted a case-controlled, catch-up study of a cohort of boys born with macrocephaly in order to determine whether infantile macrocephaly is a risk marker for the later development of autism spectrum disorders. Our results show that infantile macrocephaly was associated with an increased risk of developing autism spectrum disorders (odds ratio 5.44, 95% CI 1.11-52.15; p=0.03). These findings suggest that neurobiological differences during infancy may predict behavioural manifestations of autism spectrum disorders.

Autistic Disorder↗
PubMed2001

Widespread anatomical abnormalities of grey and white matter structure in tuberous sclerosis.

BACKGROUND: Neuroimaging studies of tuberous sclerosis complex (TSC) have previously focused mainly on tubers or subependymal nodules. Subtle pathological changes in the structure of the brain have not been studied in detail. Computationally intensive techniques for reliable morphometry of brain structure are useful in disorders like TSC, where there is little prior data to guide selection of regions of interest. METHODS: Dual-echo, fast spin-echo MRI data were acquired from 10 TSC patients of normal intelligence and eight age-matched controls. Between-group differences in grey matter, white matter and cerebrospinal fluid were estimated at each intracerebral voxel after registration of these images in standard space; a permutation test based on spatial statistics was used for inference. CSF-attenuated FLAIR images were acquired for neuroradiological rating of tuber number. RESULTS: Significant deficits were found in patients, relative to comparison subjects, of grey matter volume bilaterally in the medial temporal lobes, posterior cingulate gyrus, thalamus and basal ganglia, and unilaterally in right fronto-parietal cortex (patients -20%). We also found significant and approximately symmetrical deficits of central white matter involving the longitudinal fasciculi and other major intrahemispheric tracts (patients -21%); and a bilateral cerebellar region of relative white matter excess (patients +28%). Within the patient group, grey matter volume in limbic and subcortical regions of deficit was negatively correlated with tuber count. CONCLUSIONS: Neuropathological changes associated with TSC may be more extensive than hitherto suspected, involving radiologically normal parenchymal structures as well as tubers, although these two aspects of the disorder may be correlated.

Adult↗
PubMed2001

Pervasive developmental disorder and obstetric complications in children and adolescents with tuberous sclerosis.

Children with autism have an increased risk for obstetric complications but it is not known whether these are of primary aetiological significance. It is also unclear whether obstetric complications play a secondary role in shaping phenotypic expression in individuals at genetic risk for autism. We investigated this question by studying the role of obstetric complications in determining phenotypic manifestations in tuberous sclerosis, a single gene disorder frequently associated with autism spectrum disorders. Obstetric histories of 43 children with non-familial TS and 40 unaffected siblings were obtained using a structured parent interview. ADI-R, ADOS-G and IQ evaluations were undertaken. Children with TS experienced more obstetric complications than their unaffected siblings, but these were related to mild rather than severe adversities. No differences in obstetric complications were found in children with and without autism spectrum disorders and there was no positive correlation between obstetric adversities and severity of autism spectrum disorders or intellectual impairments.

Adolescent↗
PubMed2000

Identification of a novel gene on chromosome 7q31 that is interrupted by a translocation breakpoint in an autistic individual.

The results of genetic linkage studies for autism have suggested that a susceptibility locus for the disease is located on the long arm of chromosome 7 (7q). An autistic individual carrying a translocation, t(7;13)(q31.3;q21), with the chromosome 7 breakpoint located in the region of 7q implicated by genetic studies was identified. A novel gene known as "RAY1" (or "FAM4A1") was found to be directly interrupted by the translocation breakpoint. The gene, which was found to be encoded by 16 exons with evidence of alternative splicing, spanned > or =220 kb of DNA at 7q31.3. Mutation screening of the entire coding region in a set of 27 unrelated autistic individuals failed to identify phenotype-specific variants, suggesting that coding region mutations are unlikely to be involved in the etiology of autism. Apparent homologues of RAY1 have also been identified in mouse, rat, pig, chicken, fruit fly, and nematode. The human and mouse genes share similar splicing patterns, and their predicted protein products are 98% identical.

Alternative Splicing↗
PubMed2000

Personality traits of the relatives of autistic probands.

BACKGROUND: There is substantial evidence that the genetic liability to autism confers a risk for a range of more subtle social and communication impairments, as well as stereotyped and repetitive behaviours. Recent research suggests that increased expression of particular personality traits may be a manifestation of the liability to autism. METHODS: To investigate this we examined the personality traits of the adult relatives of 99 autistic and 36 Down's syndrome probands, using the informant version of the Modified Personality Assessment Schedule. RESULTS: There was significantly increased expression of the traits anxious, impulsive, aloof, shy, over-sensitive, irritable and eccentric among the autism relatives with evidence of different profiles for male and female relatives and for parents and adult children. Factor analysis revealed three broad groups of traits, two of which ('withdrawn' and 'difficult') appeared to reflect impairments in social functioning and a third group of anxiety related traits ('tense'). Each of these factors differed in their pattern of associations with the factor we termed 'withdrawn' showing a similar pattern of association to that found for other autism related conditions. The 'tense' factor appeared in part to be related to the burden of caring for an autistic child. CONCLUSIONS: This study confirms the finding that particular personality traits may aggregate in the family members of autistic individuals and furthermore that some of these traits may be a manifestation of the liability to autism.

Adult↗
PubMed1999

Cognitive deficits in normally intelligent patients with tuberous sclerosis.

Webb, Thomson, and Osborne [1991: Arch Dis Child 66:1375-1377] reported on the pattern of cerebral lesions found in an epidemiological sample of patients with tuberous sclerosis (TS) and clinically judged to be of normal intellect. Varying numbers of tubers and subependymal nodules were found, but clinically there appeared to be few associated neuropsychological impairments. Our objectives in this study were to conduct a detailed neuropsychological assessment to determine whether these patients were indeed free of cognitive deficits. We report the results of a detailed neuropsychological assessment in this sample and a matched comparison group. Although of average intelligence, most TS individuals had a significant cognitive deficit of one sort or another, and in a number of cases the pattern of cognitive impairments matched that seen in other neurological disorders. Additionally, the overall rate of cognitive deficits was significantly greater than in the controls. We conclude that normally intelligent individuals with TS are prone to specific cognitive difficulties. Further research will be required to clarify the nature of the links between the brain abnormalities and type of neuropsychological dysfunction. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:642-646, 1999.

Adolescent↗
PubMed1998

Autism, affective and other psychiatric disorders: patterns of familial aggregation.

BACKGROUND: The liability to autism confers a risk for a range of more subtle autistic-like impairments, but it remains unclear whether it also confers a risk for other psychiatric disturbances. METHODS: To investigate this, we studied the pattern of familial aggregation of psychiatric disorders in relatives of 99 autistic and 36 Down's probands, using family history and direct interview measures. RESULTS: Family history data showed that motor tics, obsessive-compulsive (OCD) and affective disorders were significantly more common in relatives of autistic probands and that individuals with OCD were more likely to exhibit autistic-like social and communication impairments. Direct interview data confirmed the increased rate of affective disorders (especially major depressive disorder) in the first-degree relatives. There was no evidence to indicate significant co-morbidity between affective disorders and the broadly defined phenotype of autism. Moreover, the characteristics of the probands' and the relatives' that were associated with the liability to familiarity of the broader phenotype of autism differed from those that predicted the liability to the familiarity of affective disorders. Examination of the onset of affective disorders suggested that the increased risk was not confined to the period following the birth of the child with autism. CONCLUSIONS: Overall, the results indicated that OCD, but not affective disorders, may index an underlying liability to autism. They also indicated that the increased risk of affective disorders was not solely the consequence of the stress of raising a child with autism and that further research will be required to clarify the mechanisms involved.

Adolescent↗
PubMed1997

Association of tuberous sclerosis of temporal lobes with autism and atypical autism.

BACKGROUND: Tuberous sclerosis (TS) is a multisystem genetic disorder that is associated with mental retardation, autism, and atypical autism. We investigated the basis for these associations by examining whether the liability to mental retardation and autism or atypical autism is related to the number and distribution of hamartomatous brain growths (cortical tubers) that characterise TS. METHODS: 18 patients consecutively referred to our clinic were assessed for the presence of autism or atypical autism, and their IQs were estimated (without awareness of brain-scan results). Brain scans were reviewed by a neuroradiologist (unaware of clinical diagnoses), and the number and location of cortical tubers was examined in relation to the liability to psychopathology. FINDINGS: Nine of the 18 patients had autism or atypical autism (two with IQ > or = 70; four with IQ 51-69, three with IQ < or = 50; eight with a history of epilepsy). The remaining patients had various other psychiatric disorders (five with IQ > or = 70; four with IQ 51-69; seven had a history of epilepsy). In the group as a whole, the number of tubers was significantly greater (p = 0.005) in patients with mental retardation (median 6 [IQR 4-9]) than in those of normal intelligence (1 [0-3]), and the degree of mental retardation was significantly correlated with the number of brain tubers (rs = 0.64; p = 0.008). Similarly, the number of tubers was significantly greater (p = 0.02) in individuals with a diagnosis of autism or atypical autism (6 [4-8]) than in those without this diagnosis (2 [1-4]). Eight of the nine patients with autism or atypical autism, but none of the non-autistic individuals, had tubers located in the temporal lobes (p = 0.0004). Otherwise, no particular distribution of cortical tubers was associated with a diagnosis of autism or atypical autism. INTERPRETATION: Our investigation provides evidence of an association between a gross, focal brain abnormality detectable on neuroimaging and autism or atypical autism. The results show the importance of scan findings in the prognosis of TS, and also suggest that temporallobe neurodevelopmental abnormalities may create a risk for autism or atypical autism.

Adolescent↗
PubMed1997

Obstetric complications in autism: consequences or causes of the condition?

OBJECTIVE: To determine whether and why obstetric complications are associated with autism. METHOD: Obstetric histories, obtained at maternal interview and coded as an optimality score (OS), were compared in two groups: 78 families containing an autistic proband (ICD-10 criteria) and 27 families containing a down syndrome (DS) proband. The OS was examined in relation to offspring diagnosis, proband characteristics, and familial loading for autism and its phenotypic variants. RESULTS: Autistic and DS probands had a significantly elevated OS compared with unaffected siblings, regardless of birth order position. The elevation was mainly due to an increase in mild as opposed to severe obstetric adversities. In autistic probands, the OS was best predicted by familial loading for autism and its phenotypic variants, but in the absence of this measure by the number of autistic symptoms. Among siblings of autistic probands affected with autism or its variants, the OS was best predicted by the probands' OS, and in its absence, by the measure of familial loading. In DS probands and siblings the OS was associated with increased maternal age, although this did not account for the OS elevation in DS probands. CONCLUSIONS: Rather than playing any principal etiological role, the obstetric adversities associated with autism either represent an epiphenomenon of the condition or derive from some shared risk factor(s).

Adolescent↗
PubMedDate not supplied

Molecular and cytogenetic investigations of the fragile X region including the Frax A and Frax E CGG trinucleotide repeat sequences in families multiplex for autism and related phenotypes.

We undertook molecular and cytogenetic analyses in 25 families multiplex for autism and related disorders. Three of the multiplex families exhibited fragile X, and the affected offspring all exhibited CGG triplet repeat insertion mutations in the FMR-1 gene. One of these families contained an affected pair of monozygotic female twins. Both had similar-sized CGG triplet repeat expansions, but different phenotypic manifestations. One suffered from autism and the other from mild mental retardation and marked social anxiety. PCR and Southern hybridization analysis of the CGG repeat sequences characterizing fragile X A (Frax A) and E and the methylation status of FMR-1 showed no evidence of abnormal CGG repeat expansion or FMR-1 hypermethylation in the remaining 22 multiplex families. Moreover, there was no correlation between the Frax A or E (CGG)n repeat length with affected status, nor any association with the low-level (< 3 %) expression of cytogenetic fragility at Xq27 previously reported in these families. Our findings indicate that most instances of recurrence in families multiplex for autism and related disorders are not accounted for by Frax A and E. They also indicate that the phenotypic manifestations of Frax A may be influenced by stochastic, environmental and other biological factors.

Autistic Disorder↗