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The Genain Quadruplets, a genetically identical group of sisters, all developed schizophrenia by their early 20s. Beginning in the 1950s, under the direction of David Rosenthal, they have been studied extensively with a number of neurobiological, neuroradiological and neurobehavioral measures at the Intramural Program of the National Institute of Mental Health (NIMH). A major focus of research interest has been the fact that they varied greatly in the severity of their illness. The present report emphasizes the important role that Monte Buchsbaum had in their evaluation, especially with respect to neuroradiology, during their second period of study at NIMH in the 1980s. It is of special interest that Buchsbaum et al. (1984) concluded "No strong relationship is shown between these (radiological) measures and illness severity or drug responsivity." The inference, therefore, is that the differences in illness severity among the sisters were not readily attributable to differences in the amount of damaged brain, at least as could be determined by the imaging methods available in the 1980s. The current report also summarizes the results of the other studies performed on the sisters in the 1980s, to which Monte Buchsbaum contributed.

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Our primary objective in this study was to test the multiple birth hypothesis, which asserts that multiple gestation and delivery, per se, entail a greater likelihood of adverse outcome than for singletons. Our second objective was to assess the power of various neonatal risk indicators to predict developmental status at school age. In particular, we sought to weigh multiple birth as an indicator of outcome against brain lesions visualized by ultrasonography. Additional neonatal indicators included birth weight, gestational age, weight relative to gestational age, and gender. At 6 years of age, children were assessed on selected aspects of perceptuo-motor competence and verbal ability. Previous findings favoring the multiple birth hypothesis have been mostly confined to comparisons of unmatched groups of twins and singletons. This study limited investigation to children born prematurely (before 35 weeks gestation) and included comparison of multiplet-singleton pairs, matched on type and extent of any lesions, gestational age, and birth weight. The full sample comprised 124 singletons and 45 multiplets (twins, triplets, and quadruplets). About half exhibited brain lesions in the neonatal period. In this population, there was no tendency for singletons to do better than multiplets, either in the unmatched or matched samples, at 6 years of age. Lesions, supplemented by gestational age, were highly predictive of outcome on the selected measures. In contrast, the multiple birth factor was of no predictive utility.

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The Genains, a unique group of monozygotic female quadruplets, all developed a schizophrenic disorder by age 24. They have been studied since the 1950s, because of the rarity of this occurrence (estimated to be one in 1.5 billion) and because their illnesses varied in severity. The identical inheritance would tend to rule out genetic differences as the cause of the neuropsychological differences; however, we cannot disentangle the effects of early brain injury and harsh punitive treatment as factors accounting for the differences in the severity of their disorders. We conducted neuropsychological examinations of the Genains at age 66, compared their test profiles, and contrasted certain test scores at 66 with those at ages 27 and 51. Test results indicate generally stable (or even improved) performance over time and support the notion that cognitive decline is not a degenerative process in schizophrenia. The Genains remind us of the exquisite interaction among variables that must be understood before additional, satisfactory progress can be made in preventing the development and predicting the course of schizophrenia.

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Noncontingent reinforcement (NCR), a response-independent schedule for the delivery of reinforcement, has been found to be effective in reducing behavior when the reinforcer delivered is responsible for behavioral maintenance. In this study, dense and lean schedules of response-independent attention were compared to determine whether it is necessary to begin with a dense schedule before fading to a lean schedule, or whether treatment would be as effective using a lean schedule at the outset. The subjects were 5-year-old identical quadruplets diagnosed with mental retardation and pervasive developmental disorder who displayed destructive behavior that was maintained by social attention. NCR was selected partially because it is not very labor intensive and could be implemented by a single mother simultaneously with all 4 children. Using a combination multielement and multiple baseline design, it was found that (a) a dense schedule of response-independent reinforcement (i.e., fixed-time 10 s) resulted in immediate and dramatic reductions in destructive behavior with no evidence of an extinction burst, and (b) an equivalent reduction in destructive behavior was achieved with a lean schedule of response-independent reinforcement (fixed-time 5 min) only after a systematic fading procedure was implemented. The findings suggest that the effectiveness of NCR may be dependent on the use of a dense schedule initially, and that systematic fading can increase the effectiveness of a lean schedule.

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A case of successful quadruplet pregnancy followed from date of diagnosis, through delivery, and to the third year of life is presented. The emotional, social, and economic problems encountered by the parents and hospital personnel are examined with a detailed analysis of the financial burden placed on all parties. Individual, voluntary donations made at the time of delivery have proved insufficient to cover the care involved before, during, and after the birth of multiples. A more concrete commitment on the part of government in the form of legislation or subvention is suggested in order to ease some of the stress on the parents of multiples.

PIP: A case of a quadruplet pregnancy in a 22-year old primigravida who required hospitalization for premature labor and a cesarean section, and whose premature infants needed special care, in a small mission hospital in Nnewi, Nigeria, is presented. The women had been treated with Clomid after 2 years of infertility. She presented to the antenatal clinic at 31 weeks' gestation in distress because of a large, pendulous abdomen and preterm labor. She was treated with iv salbutamol and bedrest. 24 hours later the developed pre-eclampsia managed with sedation, alpha-methyldopa and bedrest. At 35 weeks a cesarean delivery produced a male and 3 females weighing 1.35 to 2.4 kg. The infants stayed in the premature unit for 7 weeks. After discharge the family was followed monthly. The economics of the situation are described in detail. For the hospital 124 visits by the obstetric house officer were required, and an extra nurse was added full time to care for the infants, with extra visits by a pediatrician. The family incurred expenses of $771 for the hospitalization, and will need $420 monthly for daily expenses. Average hospital deliveries here cost $25, and the average monthly household income is $22, although this family is a relatively well off urban couple with an income of $150 monthly. Some of the expenses were defrayed by donations. It is suggested that in the absence of health insurance here, wealthy individuals and organizations should start trust funds for use in catastrophic medical cases. The government should subsidize such infants' care.

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The Genain quadruplets are a unique set of monozygous women who are concordant for schizophrenia but discordant for the severity of their disorder. They were studied by David Rosenthal and colleagues at the National Institute of Mental Health in the late 1950's when they were in their twenties and again in 1981 when they were 51. They are faring about as well now as they ever have in their adult lives. The results of psychological tests, some of which were repeated more than 20 years apart, are discussed, as are the effects of medication on attention and memory. The differential response of the Genains to neuroleptic drugs, as well as certain other findings in the 1981 study, leads to a different conclusion about the discordant severity of their disorder from that reached in 1963 by Rosenthal and Quinn. These observations emphasize the value of long-term followup studies in genetically related individuals, with repeated assessments of the same functions.

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A group of related new technologies has made it possible to study the brain's regional changes in metabolism, blood flow, electrical activity, and neurochemistry. Positron emission tomography (PET) produces slice images of radioisotope density--brain metabolism or receptor concentration can be quantitated. Studies in schizophrenia have indicated relative metabolic underactivity of the frontal lobes of schizophrenics. Decreased activity in the basal ganglia, which can be reversed with neuroleptic treatment, is also seen in schizophrenia. PET studies are in the early stages; standard methodology for isotope selection, task during tracer uptake, and quantitative analysis is still developing. Cerebral blood flow studies have shown similar patterns in the cortical surface. The electroencephalogram provides a short time resolution approach which can assess attention and arousal, but lacks some of the anatomic exactness and depth capabilities of PET. Magnetic resonance imaging furnishes anatomical images of gray and white matter previously unavailable with x-ray computed tomography. Advances in methodology and clinical studies with imaging are making neuroanatomic theories of schizophrenia more directly testable than ever before.

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A series of behavioral studies is reported on the Genain Quadruplets. These monozygous women, all of whom have suffered or are suffering from schizophrenia, were studied previously at the National Institute of Mental Health (1955-1958) and were the subject of an extensive report by Rosenthal (1963). Although the Genains are genetically identical, the expression of the schizophrenic disorder is unequal among the quads, and this circumstance has led to speculation about the relative contributions of nature and nurture (or diathesis and stress in Rosenthal's terminology) in the development of this disease. Two goals were pursued in this investigation: one concerned a comparison of the status of the Genains in 1981 as compared with 1958; the other concerned whether data from the armamentarium of newer behavioral and neurobiological techniques invented and employed since 1958 might shed some light on the unequal expression of schizophrenia among the quadruplets. We conclude that the Genains are functioning about as well as they ever have in their adult lives, and scores on attentional tests show improvement as compared to 1958 measures. This is probably attributable to the medication (primarily neuroleptics) and other supportive treatments they have received over the years. With respect to the varying degrees of illness seen in the Genains, scrutiny of the biochemical, physiological, neuroradiological, immunogenetic, and behavioral test data leads to speculation that certain unique biochemical findings interacting with differing types and amounts of cerebral pathology constitute a major cause of the variable expression of the schizophrenic diathesis.

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Four 51-year-old monozygotic quadruplets concordant for schizophrenia, originally studied at the National Institute of Mental Health 25 years ago, were restudied with topographic electroencephalography (EEG), evoked potentials (EPs), computed tomography (CT scans), polysomnographic sleep recordings, and positron emission tomography (PET) with 18F-2-deoxyglucose. EEG and EP findings were consistent with those from other groups of patients with schizophrenia and showed great similarity within the quadruplets. CT scans revealed uniformly small lateral ventricles. PET scans replicated earlier findings of relatively low glucose use in the frontal lobes but did not show strong familial concordance.

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A biological and clinical followup of the Genain Quadruplets was initiated as a multilaboratory collaborative effort at the National Institute of Mental Health (NIMH). The quadruplets are 51-year-old monozygotic women previously studied with a battery of psychological and physiological tests 25 years ago at the NIMH. The present article (the first of a series of three) details the clinical history and course of the schizophrenic illness in each of the quadruplets and describes the biochemical measures determined. The findings of elevated urinary phenylethylamine excretion, decreased plasma dopamine-beta-hydroxylase activity, and increased alpha-adrenergic receptor concentrations in all quadruplets warrant further genetic studies.

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