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Biomedical subjects

W M McMahon

Publications and source records attributed to W M McMahon.

At least 19 recordsLinked to original sources
PubMed2006

Evidence for multiple loci from a genome scan of autism kindreds.

We performed a genome-wide linkage scan using highly polymorphic microsatellite markers. To minimize genetic heterogeneity, we focused on sibpairs meeting the strict diagnosis of autism. In our primary analyses, we observed a strong linkage signal (P=0.0006, 133.16 cM) on chromosome 7q at a location coincident with other linkage studies. When a more relaxed diagnostic criteria was used, linkage evidence at this location was weaker (P=0.01). The sample was stratified into families with only male affected subjects (MO) and families with at least one female affected subject (FC). The strongest signal unique to the MO group was on chromosome 11 (P=0.0009, 83.82 cM), and for the FC group on chromosome 4 (P=0.002, 111.41 cM). We also divided the sample into regression positive and regression negative families. The regression-positive group showed modest linkage signals on chromosomes 10 (P=0.003, 0 cM) and 14 (P=0.005, 104.2 cM). More significant peaks were seen in the regression negative group on chromosomes 3 (P=0.0002, 140.06 cM) and 4 (P=0.0005, 111.41 cM). Finally, we used language acquisition data as a quantitative trait in our linkage analysis and observed a chromosome 9 signal (149.01 cM) of P=0.00006 and an empirical P-value of 0.0008 at the same location. Our work provides strong conformation for an autism locus on 7q and suggestive evidence for several other chromosomal locations. Diagnostic specificity and detailed analysis of the autism phenotype is critical for identifying autism loci.

Adolescent↗
PubMed2001

A comparison of individual and family psychology of adolescents with chronic fatigue syndrome, rheumatoid arthritis, and mood disorders.

Chronic fatigue syndrome (CFS) is a controversial diagnosis with unknown cause. Adult studies indicate high rates of psychosocial dysfunction and psychiatric comorbidity. The authors compared three groups of pediatric patients selected by diagnosis-(1l) CFS (n = 15), (2) juvenile rheumatoid arthritis (n = 15), and (3) mood disorders (n = 15)-across many psychological measures. CFS subjects had dramatic elevation of the Somatic Complaints subscale (mean T score = 75), whereas the mood disorders group had higher externalizing scores (mean T score = 68) on the Child Behavior Checklist. The CFS subjects missed significantly more school compared with the two control groups. After the onset of CFS, 13 of 15 of the CFS patients required significant educational accommodation. Only 4 of the 15 CFS patients had an Axis I psychiatric diagnosis, as determined by the Computerized Diagnostic Interview for Children. Despite a low rate of psychiatric diagnosis in the CFS sample, these data attest to their psychosocial and school dysfunction.

Adolescent↗
PubMed2000

Tryptophan hydroxylase polymorphisms in suicide victims.

Both environmental and genetic factors appear to contribute to the risk for suicide. The serotonergic system has been implicated in depression, impulsivity and suicidality. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin. Suicide has been associated with polymorphisms in intron 7 of the TPH gene. These alleles were studied in samples from 47 deceased Caucasian males as part of the Utah Youth Suicide Study. A 918 base pair fragment spanning the region of interest was amplified. The A218C polymorphism was visualized by restriction fragment length polymorphism (RFLP) and the A779C was sequenced. Neither A218C nor A779C appeared to be associated with suicide in this population. These results did not change when the sample was stratified by age (10-21 years, 22-31 years) or when violent suicides were selected. The complexity of the phenotype of suicide may reflect multiple biological and social etiologic factors, and poses a worthy challenge for genetic studies.

Adolescent↗
PubMed1999

Exclusion of linkage to the HLA region in ninety multiplex sibships with autism.

Several studies have suggested a role for the histocompatibility complex of loci (HLA) in the genetic susceptibility to autism. We have tested this hypothesis by linkage analysis using genetic marker loci in the HLA region on chromosome 6p in multiplex families with autism. We have examined sharing of alleles identical by descent in 97 affected sib pairs from 90 families. Results demonstrate no deviation from the null expectation of 50% sharing of alleles in this region; in fact, for most marker loci, the observed sharing was less than 50%. Thus, it is unlikely that loci in this region contribute to the genetic etiology of autism to any significant extent in our families.

Adolescent↗
PubMed1998

Privacy and confidentiality in the publication of pedigrees: a survey of investigators and biomedical journals.

CONTEXT: Pedigree diagrams efficiently communicate family information to genetics investigators; however, the publication of pedigrees poses a risk to the privacy and confidentiality of individuals depicted in the diagrams. Two sets of authoritative guidelines have been published to protect the privacy and confidentiality of subjects, but the influence of these guidelines on publication practices for pedigrees is unknown. OBJECTIVE: To determine the attitudes, practices, and experiences of investigators and journals with respect to privacy and confidentiality concerns in the publication of pedigrees. DESIGN: Investigators who have published pedigrees and editors of 26 biomedical journals were surveyed. Journals were reviewed for content in their "information for authors" sections and for documentation of informed consent in articles containing pedigrees. OUTCOME MEASURES: Practices regarding confidentiality and privacy reported by investigators and editors. RESULTS: Of 226 surveys sent to investigators, 177 were returned (78% response rate). Sixty-one investigators (36%) stated that family members were not informed that their pedigree would be published; 131 (78%) do not obtain informed consent specifically for pedigree publication and only 12 (28%) of the 43 who obtained consent obtained consent from all family members depicted. Thirty-two individuals (19%) reported having altered published pedigrees and 14 (45%) of 31 who had altered pedigrees stated that alterations were not disclosed to journals. Of the 14 journals that responded (54% response rate), only 3 reported written policies for managing potentially identifying information. Two journals reported having asked authors to alter pedigrees and 3 stated they had permitted alterations. A review of 5 genetics journals over a 2-year period revealed no documentation of consent for pedigree publication. CONCLUSIONS: Current practices in the publication of pedigrees do not conform with established recommendations and risk the privacy and confidentiality of subjects, often without informed consent. Attempts to address this problem through the alteration of data are being used, although this practice impairs the integrity of scientific communication.

Confidentiality↗
PubMed1998

Inhibitory deficits in Tourette syndrome: a function of comorbidity and symptom severity.

This study examined central inhibitory function in children with Tourette syndrome (TS; N = 46) and normally developing controls (N = 22) matched on age, gender, and IQ. A negative priming task measured the ability to inhibit processing of irrelevant distractor stimuli presented on a visual display. Initial analyses indicated that participants with Tourette syndrome did not differ significantly in inhibitory function from controls. However, when the large Tourette syndrome sample was separated into subgroups, one without evidence of comorbidity (N = 23) and the other meeting research criteria for either AD/HD, OCD, or both (N = 23), it became evident that individuals with Tourette syndrome with comorbid conditions tended to perform less well than the control group, whereas those without comorbidity performed much like controls. Similarly, when the large Tourette syndrome sample was divided into two subgroups on the basis of severity of symptomatology (N = 23 in each), those with more numerous and severe symptoms of Tourette syndrome, AD/HD, and OCD performed significantly less well than both controls and Tourette syndrome subjects with fewer and less severe symptoms. This suggests that neuropsychological impairment occurs as a function of comorbidity and symptom severity in Tourette syndrome. It also suggests that categorical diagnoses alone may be less useful than dimensional methods for predicting cognitive impairment in individuals with Tourette syndrome.

Adolescent↗
PubMed1996

Male-to-male transmission in extended pedigrees with multiple cases of autism.

Despite strong genetic influences in autism, the true mode of inheritance remains unknown. Sex differences in autism have been described in both singleton and multiplex families [Lord et al., 1982; Volkmar et al., 1993; McLennan et al., 1993; Lord, 1992]: Boys outnumber girls by 3 or 4 to 1, and so a sex-linked mode of transmission must also be considered. The key characteristic of X-linkage is that all sons of affected men are unaffected (no male-to-male transmission). In the present study, which is part of an ongoing linkage project in autism, we describe 77 multiplex autism families, 11 of who are affected cousin or half-sibling families. By using these families, it is possible to trace the path of genetic transmission and observe whether the hypothesis of X-linkage is tenable. Of 11 extended pedigrees from 77 multiplex families, six show male-to-male transmission; in these families, X-linkage can be excluded as the genetic basis for their autism. The data from the other five families are compatible with either an autosomal or an X-linked mode of transmission. The key point to emerge, then, is that autism cannot be exclusively an X-linked disorder; there must be an autosomal mode of transmission at least in some families. Thus we must consider the alternative hypotheses that autism is either entirely autosomal, or it is genetically heterogeneous, involving at least one autosomal locus with genderspecific expression, as well as a possible locus on the X-chromosome.

Autistic Disorder↗
PubMed1996

Autism and the X chromosome. Multipoint sib-pair analysis.

BACKGROUND: Genetic factors undoubtedly play a major etiologic role in autism, but how it is inherited remains unanswered. The increased incidence in males suggests possible involvement of the X chromosome. METHODS: Using data from 38 multiplex families with autism (2 or more autistic siblings), we performed a multipoint sib-pair linkage analysis between autism and 35 microsatellite markers located on the X chromosome. The model included a single parameter, the risk ratio lambda xs (i.e., ratio of risk to siblings compared with the population prevalence), owing to an X-linked gene. Different lambda xs values were assumed and regions of exclusion were established. RESULTS: The entire X chromosome could be excluded for a lambda xs value of 4. The ability to exclude an X-linked gene decreased with smaller lambda xs values, and some positive evidence was obtained with smaller values. A maximum lod score of 1.24 was obtained at locus DXS424 with a lambda xs value of 1.5. CONCLUSIONS: We were able to exclude any moderate to strong gene effect causing autism on the X chromosome. Smaller gene effects (lambda xs < 4) could not be excluded, in particular, a gene of small effect located between DXS453 and DXS1001.

Adolescent↗
PubMed1996

Bilineal transmission and phenotypic variation of Tourette's disorder in a large pedigree.

OBJECTIVE: Variability in the clinical phenotype of Tourette's disorder (TD) was assessed in a single large family, with a focus on the influence of bilineal transmission. METHOD: Tics, obsessive-compulsive symptoms, and attention-deficit symptoms were evaluated through interview and standardized checklists for 175 descendants and 16 spouses who married into a single four-generation pedigree. RESULTS: Some form of tic disorder was diagnosed in 67% of descendants and 44% of married-in spouses. TD was found in 36% of descendants and in 31% of married-in spouses. Impairment was minimal in most cases, but age at onset and location and number of tics were typical of TD described in clinic samples. Obsessive-compulsive symptoms were found in 38% of descendants and 62% of those with current TD, but obsessive-compulsive disorder was found in only four individuals. Attention-deficit hyperactivity disorder occurred in 25% of children. Multivariate analysis indicated that offspring of two parents with tic disorders manifested significantly more lifetime tics, more severe categories of tic disorders, and an earlier age at onset for TD compared with offspring of one or no affected parents. CONCLUSIONS: TD in this family is most often a mild disorder but otherwise similar to published clinical cases. Increased morbidity is significantly associated with bilineality. The frequency and impact of bilineality raise questions about possible assortative mating, the prevalence of TD, and assumed mechanisms of transmission and etiology.

Adolescent↗
PubMed1995

Effects of methylphenidate on reward strength in boys with attention-deficit hyperactivity disorder.

OBJECTIVE: To test the hypothesis that methylphenidate reduces thresholds for reward in children with attention-deficit hyperactivity disorder (ADHD). METHOD: A double-blind crossover design was used in which 16 ADHD boys, aged 8 to 13 years, received methylphenidate on one testing occasion and placebo on another. On each occasion, subjects performed a task that required progressively greater numbers of button presses to earn a fixed monetary payoff. RESULTS: The "breaking point" above which the hyperactive child was unwilling to continue with the task was significantly higher during drug than placebo trials. CONCLUSIONS: The results support an assumption that underlies the reward system dysfunction hypothesis of ADHD, and they suggest that reward mechanisms may underlie the therapeutic effects of stimulants observed across a wide range of tasks and settings.

Adolescent↗
PubMed1995

Intermediate inheritance of Tourette syndrome, assuming assortative mating.

Segregation analysis incorporating assortative mating was used to test for major locus inheritance of Tourette syndrome in a single large pedigree containing 182 members. The analysis provided evidence of a major locus with an intermediate inheritance pattern for which the penetrance was estimated from the data as 28% in heterozygotes and 98%-99% in homozygotes. A significant assortative mating correlation was estimated from the data as 70%-79%. In contrast, when assortative mating was not included in the model, intermediate inheritance was not inferred. If, in addition, constancy of the allele frequencies across generations was not assumed, Mendelian transmission was rejected. Each subject, affected or unaffected, was assigned a score reflecting the presence and severity of symptoms. Higher means scores in affected homozygotes than in affected heterozygotes suggested greater severity in homozygotes: genotype information was obtained from genotype probabilities computed assuming intermediate inheritance.

Adolescent↗
PubMed1994

Executive function abilities in autism and Tourette syndrome: an information processing approach.

This study used information processing paradigms to provide a detailed examination of executive function abilities in autism. The performance of non-retarded autistic children was compared with that of two matched control groups, one with Tourette Syndrome and the other developmentally normal. Autistic subjects performed as well as controls on tasks requiring global-local processing and inhibition of neutral responses. In contrast to both control groups, however, the autistic sample was significantly impaired on a measure of cognitive flexibility. The performance of children with Tourette Syndrome did not differ from that of normal controls on any task. These results refine our knowledge about executive dysfunction in autism and suggest a new conceptual framework and general method for investigating the cognitive underpinnings of neurodevelopmental disorders.

Adolescent↗
PubMed1993

Searching for human epilepsy genes: a progress report.

Application of new genetic techniques has brought remarkable discoveries in the study of genetic diseases. The potential benefits from applying such technology to idiopathic epilepsies include improved understanding of cellular mechanisms and potential new methods of prevention and treatment. The complex problems involved in studying the hereditary epilepsies include: defining of specific phenotypes; detecting genetic and non-genetic heterogeneity; and specifying the appropriate mode of inheritance and penetrance. The gene loci for three primary epilepsies have been localized to specific chromosomal regions, and serve to demonstrate the process used in generalized linkage studies of hereditary epilepsy syndromes. Benign familial neonatal convulsions (BFNC) and Unverricht-Lundborg progressive myoclonus epilepsy are rare single-gene disorders that are sufficiently localized to chromosomal regions that positional cloning studies are likely to succeed. Juvenile myoclonic epilepsy (JME), a common hereditary syndrome with an uncertain mode of inheritance, has been reported to be linked to chromosome 6p. JME presents a challenge for generalized linkage methodology that may be overcome by attending to potential problems reviewed here. The candidate-gene method, combined with studies using animal models, holds promise for understanding these as well as other hereditary epilepsies.

Animals↗
PubMed1993

Contracting to lower precaution status for child psychiatric inpatients.

1. Contracting will reduce high-risk precaution incidents. 2. Children are capable of understanding, writing, and adhering to contracting procedures. 3. Contracting performed according to established procedures that use specified criteria for advancement is effective. 4. Nurses should listen carefully and critically examine the child's statements, avoiding making inferences about the child's intentions.

Adolescent↗
PubMed1991

Complex segregation analysis of autism.

A complex segregation analysis of autism in 185 Utah families was carried out using the mixed model. The 209 affected individuals in these families represent nearly complete ascertainment of the autistic cases born in Utah between 1965 and 1984. The sibling recurrence risk for autism was 4.5% (95% confidence limits 2.8%-6.2%). Likelihoods were maximized for major-gene models, a polygenic model, a sibling-effect model, and a mixed model consisting of major-gene and shared-sibling effects. The analysis provided no evidence for major-locus inheritance of autism. Subdivision of the sample according to the probands' IQ levels showed that sibling recurrence risk did not vary consistently with IQ level. A segregation analysis of families in which the proband had an IQ less than 50 also failed to provide evidence for a major locus. However, because of the etiologic heterogeneity of this disorder, genetic analysis of other meaningful subsets of families could prove informative.

Autistic Disorder↗
PubMed1990

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

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

Autistic Disorder↗
PubMed1990

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

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

Adult↗