Neuropsychiatric genetics: misclassification in linkage studies of phenotype-genotype research.

Research on neuropsychiatric disorders has produced a number of very important findings in the last few decades. However, several problems continue to hinder research in this area. One problem area has been the appropriate classification of disease status for probands and extended family members in linkage studies. In this article, we examine rates of misclassification in a 12-year follow-up study of children previously diagnosed with Tourette syndrome. At the 12-year follow-up, we found a 5 to 12% rate of misclassification of previously diagnosed cases. We present a model of a linkage study with three classification steps. The model demonstrates that an error rate of 5% would result in misclassification of 20% of true cases by step three. Adding additional steps to improve diagnostic accuracy may increase rather than decrease classification error.

A 15-year follow-up of a boy with pyridoxine (vitamin B6)-dependent seizures with autism, breath holding, and severe mental retardation.

Pyridoxine (vitamin B6) (2q31) dependency is a rare autosomal-recessive disorder that causes a severe seizure disorder of prenatal or neonatal onset. The abnormality appears to inhibit the binding of vitamin B6 to the enzyme glutamic acid decarboxylase-1, which is needed for the biosynthesis of gamma-aminobutyric acid (GABA). Most patients with pyridoxine-dependent seizures require lifelong treatment with pyridoxine. The full range of associated symptomatology is unknown since fewer than 100 cases have been reported. A majority of cases are mentally retarded. We report a 15-year-old boy with pyridoxine-dependent seizures, nonpyridoxine-dependent seizures, severe mental retardation, autistic disorder, aerophagia, breath holding, and self-injury. This complex outcome should alert clinicians to the wide range of neuropsychiatric outcomes associated with this disorder.

Asperger's syndrome, X-linked mental retardation (MRX23), and chronic vocal tic disorder.

Pervasive developmental disorders are severe disorders of development with no consistent neurobiologic etiology and most often an idiopathic etiology. We report a 12-year-old male who met criteria for a pervasive developmental disorder (Asperger's syndrome) and a chronic tic disorder. The child also has an X-linked cognitive impairment (MRX23). The presence of tic symptomatology, pervasive developmental disorder, and fragile X syndrome has previously been reported. Since no singular etiology for Asperger's syndrome has been found, the possibility of other cases of Asperger's syndrome occurring with concurrent abnormalities on the X chromosome should be considered by clinicians, especially if tic symptomatology is present.

An international perspective on Tourette syndrome: selected findings from 3,500 individuals in 22 countries.

We have established a multisite, international database of 3,500 individuals diagnosed with Tourette syndrome (TS). The male:female ratio is 4.3:1 for the total sample, with wide variation among sites; the male excess occurs at every site. Anger control problems, sleep difficulties, coprolalia, and self-injurious behavior only reach impressive levels in individuals with comorbidity. Anger control problems are strongly correlated with comorbidity, regardless of site, region, or whether assessed by neurologists or psychiatrists. The mean age at onset of tics is 6.4 years. At all ages, about 12% of individuals with TS have no reported comorbidity. The most common reported comorbidity is attention-deficit-hyperactivity disorder. Males are more likely to have comorbid disorders than females. The earlier the age at onset, the greater the likelihood of a positive family history of tics. An understanding of the factors producing these and other variations might assist in better subtyping of TS. Because behavioral problems are associated with comorbidity, their presence should dictate a high index of suspicion of the latter, whose treatment may be at least as important as tic reduction. The established database can be used as the entry point for further research when large samples are studied and generalizability of results is important.

A prevalence methodology for mental illness and developmental disorders in rural and frontier settings.

A prevalence study methodology developed for use in rural and frontier settings is described. The general method was developed over a 15 year period and has been successfully adapted and used in studies of 14 different childhood onset developmental disorders. Subjects were the 168,000 school aged children from North Dakota who were first surveyed for cases of autism--pervasive developmental disorders in 1985 and 1986. The results of the prevalence study were compared with the results of a 12-year ongoing surveillance of the cohort. The 12-year ongoing surveillance identified one case missed by the original prevalence study. Thus the original prevalence study methodology identified 98% of the cases of autism-pervasive developmental disorder in the population. This methodology may also be useful for studies of other developmental disorders in rural and frontier settings.

Comorbid Down's syndrome, Tourette syndrome and intellectual disability: registry prevalence and developmental course.

The co-occurrence of Tourette syndrome (TS) and Down's syndrome (DS) has been previously reported in the literature. In the present study, a retrospective record review was conducted using the North Dakota TS registry in order to ascertain the number of cases of TS and DS, and to develop case descriptions. We identified five cases from North Dakota. Two of these patients were simply comorbid for TS and DS. One was additionally comorbid for bipolar disorder, another for childhood disintegrative disorder and a third had a D/G group translocation. The association between DS and TS occured in 2% of TS patients. Contrary to the situation in patients with pervasive developmental disorders, the presence of TS in DS may be a negative prognostic indicator.

Peek-a-boo fragile site at 16d associated with Tourette syndrome, bipolar disorder, autistic disorder, and mental retardation.

Five patients with a fragile site at 16q22-23 and neuropsychiatric disorders are reported. Three of five had Tourette disorder, three had mental retardation, two had bipolar disorder, and one had autistic disorder. During our attempts to study the fragile sites in more detail we were unable to reproduce the fragile sites found several years earlier. The potential relationship between the fragile sites and the neuropsychiatric disorders in these patients is discussed. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:69-73, 2000.

Prenatal and perinatal risk factors for Tourette disorder.

AIMS: To identify pre- and perinatal risk factors for Tourette disorder. METHODS: Case control study. We matched names of patients who met DSM criteria for Tourette disorder with their birth certificates. For each case five controls were selected. The controls were matched by sex, year and month of birth. RESULTS: Univariate analysis of the 92 cases and the 460 matched controls identified 4 risk factors; one categorical variable--trimester prenatal care begun and 3 continuous variables--apgar score at 5 minutes, month prenatal began and number of prenatal visits. Logistic modeling to control for confounding produced a three variable model (apgar score at 5 minutes (OR = 1.31), number of prenatal visits (OR = .904) and fathers age (OR = .909). The model parameters were: chi 2 = 19.76; df = 3; p < .001. CONCLUSIONS: This is an inexpensive methodology to identify potential risk factors of patients with Tourette disorder and other mental illness.

Recognition and management of Tourette's syndrome and tic disorders.

Tic disorders and Tourette's syndrome are conditions that primary care physicians are likely to encounter. Up to 20 percent of children have at least a transient tic disorder at some point. Once believed to be rare, Tourette's syndrome is now known to be a more common disorder that represents the most complex and severe manifestation of the spectrum of tic disorders. Tourette's syndrome is a chronic familial disorder with a fluctuating course; the long-term outcome is generally favorable. Although the exact underlying pathology has yet to be determined, evidence indicates a disorder localized to the frontal-subcortical neural pathways. Tourette's syndrome is commonly associated with attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, behavior problems and learning disabilities. These comorbid conditions make the management of Tourette's syndrome more challenging. Management of Tourette's syndrome should include timely and accurate diagnosis, education, and behavior or pharmacologic interventions. Use of neuroleptic medications and dopamine D2 antagonist drugs can be effective but may be associated with significant side effects.

Prenatal and perinatal risk factors for autism.

AIM: To identify pre- and perinatal risk factors for autism. METHOD: Case control study. We matched names of patients from North Dakota who met DSM criteria for autism, a pervasive developmental disorder, and autistic disorder with their birth certificates. Five matched controls were selected for each case. RESULTS: Univariate analysis of the 78 cases and 390 controls identified seven risk factors. Logistic modeling to control for confounding produced a five variable model. The model parameters were chi 2 = 36.6 and p < 0.001. The five variables in the model were decreased birth weight, low maternal education, later start of prenatal care, and having a previous termination of pregnancy. Increasing father's age was associated with increased risk of autism. CONCLUSION: This methodology may provide an inexpensive method for clinics and public health providers to identify risk factors and to identify maternal characteristics of patients with mental illness and developmental disorders.

The FAS Screen: a rapid screening tool for fetal alcohol syndrome.

Fetal alcohol syndrome (FAS) is an important cause of mental retardation and developmental disabilities. A population based screening tool would allow for early diagnosis and entry into intervention programs. The aim of the study was to develop a brief screening tool for use in population-based settings to improve the identification of children with FAS. The FAS Screen was developed and tested in six sites. These were sites that served children and all were located in North Dakota. Screening was completed on 1013 children, 65 were found to have a positive screening score and were referred for further investigation. Forty were seen for evaluation by a medical geneticist and six were diagnosed with FAS. The estimated values for the screening tool were: specificity 94.1%, sensitivity 100%, positive predictive value 9.1% and negative predictive value 100%. The cost of screening was $13.00 per child and the cost per case identified was $4,100. The FAS Screen is a brief screening test with acceptable performance characteristics and is cost effective.

Two males with childhood disintegrative disorder: a prospective 14-year outcome study.

A prospective 14-year outcome study of two children meeting DSM-IV criteria for childhood disintegrative disorder is presented. Their ages at first evaluation were 4 years 7 months and 6 years 3 months. Both are now adults and continue to have a severe pervasive developmental disorder, mental retardation, seizure disorder, and are non-verbal. Both require residential care.

The brain-mind quiddity: ethical issues in the use of human brain tissue for therapeutic and scientific purposes.

The use of human brain tissue in neuroscience research is increasing. Recent developments include transplanting neural tissue, growing or maintaining neural tissue in laboratories and using surgically removed tissue for experimentation. Also, it is likely that in the future there will be attempts at partial or complete brain transplants. A discussion of the ethical issues of using human brain tissue for research and brain transplantation has been organized around nine broadly defined topic areas. Criteria for human brain tissue transplantation and laboratory use of brain tissue are proposed.

Prevalence of psychotropic and anticonvulsant drug use among North Dakota group home residents.

In a previous study, the present authors reported on the prevalence of psychoactive (psychotropic and anticonvulsant) medication use among people with intellectual disability residing in community settings in the state of North Dakota, USA. The present study replicates the earlier survey. A questionnaire was sent to all group homes serving people with developmental disabilities. Questionnaires were obtained for 100% of North Dakota group home residents. Psychoactive medications (anticonvulsants included) were used by 38% of the 1384 residents represented. The results are discussed in relation to the previous study from North Dakota.

Case study: comorbidity among Tourette's syndrome, autistic disorder, and bipolar disorder.

OBJECTIVE: Several studies report a greater than expected concurrence for Tourette's syndrome (TS) with autistic disorder (AD). TS and bipolar disorder (BD) also may co-occur at a greater than expected rate. The authors assess whether there is a greater than expected concurrence for TS+AD+BD. METHOD: Four patients who had at some time in their lives diagnoses of TS, AD, and BD were identified. Three of these had concurrent TS+AD+BD. Diagnoses were made according to DSM-III-R criteria. Each of these patients was living in North Dakota and was in the authors' care at the time of this study. RESULTS: The point prevalence (risk) for concurrent TS+AD+BD in North Dakota is not less than 4.6 x 10(-6). The developmental sequence of syndromes in these four patients was AD, then TS and then BD. Data from the authors' previously published, population-based prevalence studies indicate that TS+AD+BD co-occur at a greater than chance expectation. CONCLUSIONS: Common etiological factors may be involved in the greater than chance concurrence of TS+AD+BD.

Comorbid Tourette's disorder and bipolar disorder: an etiologic perspective.

OBJECTIVE: Using an epidemiologic approach, the authors attempt to elucidate relationships between Tourette's disorder and bipolar disorder. METHOD: Of 205 patients with Tourette's disorder in the North Dakota Longitudinal Tourette Syndrome Surveillance Project, 15 had comorbid bipolar disorder. A subset of the patients with Tourette's disorder had been included in earlier population-based prevalence studies of Tourette's disorder in children, adolescents, and adults. Minimal risk ratios were calculated for the patients with Tourette's disorder plus bipolar disorder by age group (children/adolescents and adults). This information was used to estimate genetic risk indicators for comorbid Tourette's disorder and bipolar disorder. RESULTS: The estimated risk of developing bipolar disorder among the study group of children, adolescents, and adults with Tourette's disorder was more than four times higher than the level expected by chance, but this finding did not reach statistical significance. It was indicative of trends, however. CONCLUSIONS: Comorbidity between Tourette's disorder and bipolar disorder does not appear to be due to chance co-occurrence of the two disorders. Although a genetic mechanism may play a causal role, in the absence of family studies an explanatory model involving the concept of canalization of basal-ganglia-mediated dysfunctions is offered. In such a construct, Tourette's disorder would be a likely accompaniment to other conditions, including bipolar disorder, whose pathogenic determinants might channel through neural pathways involving the basal ganglia. The presence of significant developmental disabilities may further enhance factors culminating in comorbid Tourette's disorder and bipolar disorder.

Tourette syndrome and learning disabilities.

We reviewed the records of 42 consecutive cases of children with Tourette Syndrome (TS) who had IQs above 70, and contrasted the reading, reading comprehension, math, and spelling quotients with IQ scores to determine how many would meet criteria for a learning disability. The mean IQ of the 35 males and 7 females was 94.4 and was higher than the mean math score (82.8), spelling score (90.4), reading score (87.4), and reading comprehension score (85.3). Using a 1.5 standard deviation discrepancy, 51% met criteria for learning disability in at least one academic area; 21% had a 2-standard-deviation discrepancy. Children with TS frequently have learning disabilities, and assessment of academic achievement should be a routine aspect in the evaluation of such children.