First-degree Relatives Of Probands Research Articles

Psychotic (delusional) major depression: should it be included as a distinct syndrome in DSM-IV?

To review data supporting or not supporting the designation of unipolar psychotic major depression as a distinct syndrome in DSM-IV, the authors used computerized literature searches to identify reports of studies that have directly compared the characteristics, biology, familial transmission, course/outcome, and response to treatment of psychotic and nonpsychotic major depression. The review showed that statistically significant differences between the two types of depression have been found on each of these dimensions. There are greater guilt feelings and psychomotor disturbance, among other features, in psychotic depression. Studies have found significant differences between patients with psychotic and nonpsychotic depression in glucocorticoid activity, dopamine beta-hydroxylase activity, levels of dopamine and serotonin metabolites, sleep measures, and ventricle-to-brain ratios. Family studies show higher rates of bipolar disorder in first-degree relatives of probands with psychotic major depression than of probands with nonpsychotic major depression. Greater morbidity and residual impairment have also been reported in patients with psychotic major depression, and they respond more poorly to placebo and to tricyclic antidepressants. Differences between patients with psychotic and nonpsychotic major depression on many of these measures were not due to differences in severity or endogenicity. Since the data indicate that psychotic and nonpsychotic major depression can be separated, the frequency with which the diagnosis of psychotic major depression is missed and its unique course and response to treatment point to the practical importance of a separate diagnosis for this disorder. However, further studies are needed to resolve important methodological issues and to develop an optimal set of operational criteria.

Schizophrenia: Gender and familial risk

The morbid risks for schizophrenia and any nonaffective psychosis in the first degree relatives of male and female schizophrenic probands were compared utilizing Cox proportional hazards models. The schizophrenic probands (275 male; 106 female) were drawn from a larger sample of hospitalized patients obtained by systematically screening all psychiatric admissions to 15 facilities over a six-year period. Proband diagnoses (DSM-III) were based on a direct assessment of the patient and a review of medical records. The family history method was used to obtain information about the first degree relatives of the probands. Cox proportional hazards models were adjusted for duration of illness of the proband and gender of the relatives. First degree relatives of female probands had significantly higher morbid risks for schizophrenia and nonaffective phychosis than relatives of male probands. The differential risk for schizophrenia in the relatives of male and female probands demonstrated in this study, as well as others, suggests that males and females may be at different risk for subtypes of the disorder.

Epidemiology of congenital eye malformations in 131,760 consecutive births.

The epidemiology of eye malformations was studied in the geographical area covered by the authors' registry of congenital malformations. For each of the 78 new cases studied during the period 1979 to 1988, more than 50 factors were compared in probands and in controls. The prevalence rate of congenital eye malformations was 7.5 per 10,000 with microphthalmia 1.8, anophthalmia 0.3, cataract 2.3 and coloboma 0.7 respectively. Sex ratio was 0.82. Prenatal diagnosis was performed in ten cases and three cases were induced abortions. The more common types of associated malformations in the 42 affected cases (53.8%) with at least one anomaly other than an eye malformation were clubfeet, microcephaly, hydrocephaly and facial dysmorphia. At birth infants with eye malformations and other malformations were smaller, weighed less and their head circumference was lower than in controls. Placental weight was also lower than in controls. Pregnancies with eye malformations were more often complicated by threatened abortion, oligoamnios and polyhydramnios. Mothers of children with congenital eye malformations took more often drugs during pregnancy than mothers of controls. Fathers of children with congenital eye malformations were more often exposed to occupational hazards than fathers of controls. There was a significant association between eye malformation and consanguinity of parents. First degree relatives of probands had more than three times the prevalence of non-eye malformations than controls. These results are of relevance to genetic counseling.

The use of conditional probabilities to examine age-period-cohort data: further evidence for a period effect in major depressive disorder

There is growing evidence that rates of major depression have been increasing over this century, with successive birth cohorts showing increased lifetime risks and earlier ages of onset. In this paper, we describe and compare onset rates in six birth cohorts of first degree relatives of probands with affective disorders from the NIMH Collaborative Study, using graphs of conditional probabilities of first onset. There is evidence of a period effect and age-period interaction for both men and women.

Interrater reliability of the structured clinical interview for DSM-III-R, Axis II: Schizophrenia spectrum and affective spectrum disorders

Three interviewers (second raters) blindly rated 15 audiotapes each of the Structured Clinical Interview for DSM-III-R, Axis II (SCID-II) administered to the first degree relatives of probands with either DSM-III-R schizophrenia, schizoaffective disorder, or bipolar disorder, for a total of 45 second ratings. Interrater reliability was determined using the intraclass correlation coefficient and ranged from 0.60 to 0.84. The previous studies of the reliability of structured interviews for diagnosing personality disorders are summarized and compared to the present findings. We conclude that the SCID-II can be reliably used to diagnose schizophrenia-spectrum and affective spectrum disorders in the first degree family members of probands with schizophrenic or bipolar affective disorders.

Phenotypic Correlations between Oculomotor Functioning and Schizophrenia‐Related Characteristics in Relatives of Schizophrenic Probands

Abnormalities of visual pursuit tracking are frequent in the first-degree relatives of probands with schizophrenia. The relationship between oculomotor abnormalities and schizophrenia-related characteristics in those family members, however, has received little attention. Fifty-three first-degree relatives of 24 probands with schizophrenia were evaluated for the presence of schizophrenia-related characteristics using both interview (Schedule for Schizotypal Personalities) and questionnaire (Chapman scales). The family members also had their eye movements recorded during pursuit tracking tasks and scored for gain in both the frequency and time domains, and saccadic intrusions. Social-interpersonal schizophrenia-related features were significantly related to both time- and frequency-domain gain calculations. It appears that abnormalities in the smooth-pursuit oculomotor system may be associated with symptoms conjectured to be most closely related to a genetic diathesis for schizophrenia. These findings provide further evidence that oculomotor abnormalities may be related to risk for this disorder.

Schizophrenia and Affective Disorder: Are They Genetically Linked?

The relationship between schizophrenic 'spectrum' disorders and affective illness was studied in the nuclear families of 90 chronic schizophrenic probands. An increased risk of schizophrenia and related disorders was demonstrated among the first-degree relatives of probands with a family history of major affective disorders. Conversely, relatives of probands with a family history of schizophrenic 'spectrum' disorders were at a greater risk of affective illness (major depression) than relatives of probands with no family history. These results lend support to the notion that a subset of affective disorders is associated with the liability to schizophrenia.

Epidemiological and genetic study in 207 cases of oral clefts in Alsace, north-eastern France.

The epidemiology of oral clefts was studied in the geographical area covered by our registry of congenital malformations. For each of the 207 new cases studied during the period 1979 to 1987, more than 50 factors were compared in probands and controls. The incidence of oral clefts was 1.75 per 1000, with cleft lip/palate (CL(P] 0.98 and cleft palate only (CP) 0.77 per 1000. A total of 8.2% of cleft cases were stillbirths and 5.3% were induced abortions. The more common types of associated malformations in the 76 affected cases (36.7%) with at least one anomaly other than oral cleft were neural tube defects and skeletal malformations. At birth, infants with oral clefts and other malformations were smaller, weighed less, and their head circumference was lower than in controls. Placental weight was also lower than in controls. Pregnancies with oral clefts were more often complicated by threatened abortion, polyhydramnios, and arterial hypertension. There was a significant association between clefting and consanguinity; heritability of CL(P) was 81% and first degree relatives of probands had more than three times the prevalence of noncleft malformations as controls. These results are of relevance to genetic counselling.

Pursuit gain and saccadic intrusions in first-degree relatives of probands with schizophrenia.

Pursuit gain and saccadic intrusions in first-degree relatives of probands with schizophrenia.

Hypoplastic Left Heart Syndrome: Natural History in a Geographically Defined Population

Advances in surgical treatment of hypoplastic left heart syndrome with the Norwood procedure and cardiac transplantation have made essential the understanding of the natural history of hypoplastic left heart syndrome. In a geographically defined population, we ascertained the prevalence of hypoplastic left heart syndrome in children born in Oregon from 1971 through 1986. Clinical and anatomic data were extracted from the charts of the 98 affected children and the survival rate was calculated. Hypoplastic left heart syndrome occurred in 0.162 per 1000 live births in Oregon during this period. No syndrome complex was prevalent and 84% were free of other congenital malformations. However, there was an increased occurrence of congenital heart defects in first-degree relatives of probands with hypoplastic left heart syndrome. Of the affected children 15 +/- 4% died on the first day of life, 70 +/- 5% died within the first week, and 91 +/- 3% died within 30 days. No secular change in survival occurred during the study. Palliation with the Norwood procedure was performed in 20 children. Although survival was significantly improved with this surgery (P = .01), the effect was observed principally through 30 days of life and only one of these children remains alive. Hypoplastic left heart syndrome is a lethal congenital heart defect in children and poses management and ethical dilemmas.

Pursuit gain and saccadic intrusions in first-degree relatives of probands with schizophrenia.

Oculomotor functioning of 26 probands with schizophrenia, 12 spectrum and 46 nonspectrum first-degree relatives, and 38 nonpsychiatric control subjects was evaluated. Spectrum relatives had more anticipatory saccades (ASs) and lower pursuit gain than nonspectrum relatives, who had more ASs and lower pursuit gain than control subjects. Probands also had lower pursuit gain than nonspectrum relatives and control subjects but did not differ from other groups on AS frequency. Control subjects had more globally accurate pursuit tracking (root mean square [RMS] error deviation) than both relative groups, whereas probands had the poorest RMS scores. Square wave jerk frequency did not differentiate the groups. Attention enhancement affected the frequency of ASs but did not affect either the other intrusive saccadic event or RMS scores. These results offer evidence that eye-movement dysfunction may serve as a biological marker for schizophrenia.

Cardiac malformations in relatives of infants with hypoplastic left-heart syndrome.

In a pilot study of relatives of infants with hypoplastic left-heart syndrome (HLHS), we obtained a medical history, cardiovascular examination, and echocardiogram in 48 first-degree relatives of 11 probands with isolated HLHS and 3 with HLHS and noncardiac malformations. Echocardiography confirmed heart defects in 5 of 41 relatives of patients with isolated HLHS. In four instances, the cardiac abnormality was unrecognized. Among 7 relatives of infants with HLHS and extracardiac anomalies, no heart defects were detected. Cardiac defects occurred in first-degree relatives of probands at a frequency higher than previously predicted by an additive multifactorial model of inheritance. These findings suggest that first-degree relatives of HLHS probands may have an increased risk for subclinical cardiac defects and that genetic factors likely contribute to the cause of left-heart blood-flow lesions.

Psychiatric disorders in the first-degree relatives of probands with bulimia nervosa.

Data from a family study of psychiatric disorders showed higher rates of major affective disorders, eating disorders, and alcoholism in first-degree relatives of 40 bulimic probands than in first-degree relatives of 24 control subjects. More importantly, the data showed higher rates of major affective disorders in relatives of bulimic probands who themselves had no history of major affective disorders than in relatives of control subjects. This significant finding indicates a familial relationship between bulimia nervosa and major affective disorders, which suggests the possibility of a common diathesis.

Eye movement dysfunction (EMD) and schizotypy in first-degree relatives of probands with schizophrenia

It has been consistently reported that first-degree relatives of probands with schizophrenia have “global” EMD. Whicker et al. (1985) found that six of eight such relatives had a specific EMD called “anticipatory saccades (AS).” This is the only published study suggesting AS may be a specific EMD for schizophrenia. Additionally, a study investigating the relationship between EMD and schizotypy in these relatives has not been published. The frequency of specific EMD in 38 relatives of 19 probands with RDC schizophrenia and 20 normals is reported. Subjects were studied with IR while watching a target travelling at .4 Hz subtending 20 degrees of visual angle. Sixtyeight percent of the family members had macro-square wave jerks (SWJ) and 62% had AS. Only ten percent of the normals had such large intrusive events. Furthermore, the presence of both macro-SWJ and AS was highly correlated with schizotypy in the family members (0.51-0.57, p’s .005). These results document a high prevalence of large saccadic intrusions in family members of probands with schizophrenia, and suggest that their presence is associated with schizophrenia-related symptomatology.

Multiple sclerosis. Updated risks for relatives

Two important characteristics of multiple sclerosis (MS) are familial clustering and a variable age of onset. There is increasing evidence for a genetically influenced susceptibility in MS. Because of this, patients and their relatives are increasingly asking about the risk for relatives of developing MS. In the MS Clinic in Vancouver, genetic histories are taken routinely for all patients and are updated annually. Patients do not attend the clinic specifically to participate in genetic studies, which could result in over-representation of familial cases. Data were available for 815 MS index cases and 11,345 of their relatives. Age-specific MS risks were calculated for first-, second-, and third-degree relatives of probands and are presented in an easy-reference format. In general, first-degree relatives of probands have a risk that is 30-50 times greater than the 0.1% risk for the general population.

Estimating the age-at-onset function using life-table methods.

In the analysis of dominantly inherited diseases, the age-at-onset function is often estimated from the observed age-at-onset distribution of cases. This estimate is confounded with the age distribution of the population from which the cases were sampled and is accurate only if there are no competing causes of death. In this paper, we present a straightforward method for calculating a more accurate age-at-onset function under etiologic heterogeneity. We use the life-table approach and survival analysis methods. This method is illustrated using data on first-degree relatives of probands from two sets of families with high cancer incidence: one with breast/ovarian cancer and the other with colon cancer. A comparison of the estimated age-at-onset function obtained by the two methods is presented. In both cases, colon cancer as well as breast/ovarian cancer, the estimates of onset probabilities based on proportion of cases, are consistently higher than those obtained by the life-table method. For breast/ovarian cancer, this difference is not as striking as it is in the case of colon cancer; nevertheless, the method using proportion of cases tends to give a lower estimate of the age-at-onset function (higher probability of being affected at lower age) than the life-table approach.

Family study of platelet membrane fluidity in Alzheimer's disease.

The fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene in labeled platelet membranes, an index of membrane fluidity, identifies a prominent subgroup of patients with Alzheimer's disease who manifest distinct clinical features. In a family study, the prevalence of this platelet membrane abnormality was 3.2 to 11.5 times higher in asymptomatic, first-degree relatives of probands with Alzheimer's disease than in neurologically healthy control subjects chosen without regard to family history of dementia. The pattern of the platelet membrane abnormality within families was consistent with that of a fully penetrant autosomal dominant trait. Thus, this abnormality of platelet membranes may be an inherited factor that is related to the development of Alzheimer's disease.

A family study of generalized anxiety disorder.

The frequency of generalized anxiety disorder was higher among first-degree relatives of probands with generalized anxiety (N = 20) than among the relatives of control subjects (N = 20), but it was not higher among relatives of probands with panic disorder (N = 40) or agoraphobia (N = 40). Also, the frequency of panic disorder was higher among relatives of probands with panic disorder than among control relatives but was not higher among relatives of generalized anxiety probands. Relatives of probands with generalized anxiety who had the same disorder had a mild, stress-related illness. The results confirm the separation between generalized anxiety disorder and panic disorder but challenge the distinction between generalized anxiety and adjustment disorders.

Hazard, heredity and depression. A family study

The relationship between proband characteristics and familial aggregation of depression was assessed in an interview study of 83 families ascertained via probands who had a recent onset of depression. Contrary to expectations and to previous reports in the literature there were no differences between the frequencies of depression in the first degree relatives of probands who had or had not experienced adversity prior to the onset of their illness. Depression was actually slightly more common among the first degree relatives of probands who had experienced a threatening life event compared with the relatives of those who had not. Early onset of depression (before 32 yr) and a neurotic pattern of symptoms in probands were associated with significantly higher rates of current illness in relatives. However, both these differences disappeared when lifetime prevalence or morbid risk to age 65 were considered. Indeed the morbid risk of severe depression in the relatives of endogenously depressed probands was nearly twice that in the relatives of neurotic probands.

Increased Familial Risk for Lung Cancer

For the determination of whether lung cancer clusters in families, an analysis was conducted on demographic and morbidity-mortality data, occupational and industrial experiences, and tobacco use practices for family members of 336 deceased lung cancer probands and 307 controls (probands' spouses). First-degree relatives of probands, compared with first-degree relatives of controls, showed a strong excess risk for lung cancer. Overall, male relatives of probands had a greater risk for lung cancer than did their female counterparts, and the risk was fourfold for parents of probands as compared with parents of spouses. Female relatives of probands over 40 years old were at nine times higher risk than similarly aged female controls, even among those who were non-smokers and who had not reported excessive exposure to hazardous occupations; the risk was fourfold to sixfold for heavy smokers. After control for the confounding effects of age, sex, cigarette smoking, and occupational and industrial exposures, relationship to proband remained a significant determinant of lung cancer, with a 2.4-fold greater risk among relatives of probands.