Unaffected Twin Research Articles

Counter clockwise scalp hair whorl in schizophrenia

Recent work has suggested that schizophrenia may be a neurodevelopmental disorder (Weinberger !987; Murray and Lewis 1987; Benes et al 1986). Evidence for this hypothesis includes epidemiologic studies indicating that e~:posure to a physical insult during the second trimester of gestation may be associated with schizophrenia in later life (Torrey et al 1975; Huttunen and Niskanen 1978; Mednick et al 1988). In addition, several structures reported to be deviant in schizophrenia, ineluding the hippocampus, thalamus and basal ganglia, are formed during the second trimester (Lyon et al 1989). Braeha et al ( 1991), noting that development of the distal upper limb occurs in the second trimester, studied hand anomalies in a group of monozygotic twin pairs discordant for schizophrenia and found a higher frequency of hand maldevelopment scores in the schizophrenic twins than in the unaffected twins, implicating a second trimester insult in these patients. Scalp hair patterning is determined during

Evidence of dysfunction of a prefrontal-limbic network in schizophrenia: a magnetic resonance imaging and regional cerebral blood flow study of discordant monozygotic twins.

The authors previously reported that in monozygotic twins discordant for schizophrenia the affected twin almost invariably had a smaller anterior pes hippocampus, measured with magnetic resonance imaging (MRI), and invariably had less regional cerebral blood flow (rCBF) in the dorsolateral prefrontal cortex during performance of the Wisconsin Card Sorting Test. The present study was an investigation of the relationship between hippocampal pathology and prefrontal hypofunction in the same twin pairs. Nine pairs of monozygotic twins discordant for schizophrenia underwent MRI scanning for determination of anterior hippocampal volume and xenon-inhalation rCBF testing for determination of prefrontal physiological activation associated with the Wisconsin Card Sorting Test. The differences within twin pairs on the MRI and rCBF measures were strongly and selectively correlated. Specifically, the more an affected twin differed from the unaffected twin in left hippocampal volume, the more they differed in prefrontal physiological activation during the Wisconsin Card Sorting Test. In the affected twins as a group, prefrontal activation was strongly related to both left and right hippocampal volume. These relationships were not found in the group of unaffected twins. This finding is consistent with the notion that schizophrenia involves pathology of and dysfunction within a widely distributed neocortical-limbic neural network that has been implicated in, among other activities, the performance of cognitive tasks requiring working memory.

Serologic studies of monozygotic twins with systemic lupus erythematosus

The goal of these studies was to assess the role of genetic factors and disease expression in the pattern and titer of autoantibodies to several RNA protein antigens in patients with systemic lupus erythematosus (SLE) by studying identical twins concordant and discordant for disease expression. Autoantibodies to Ro/SS-A, La/SS-B, U1 RNP, and Sm were measured by quantitative enzyme-linked immunosorbent assay using affinity-purified antigens. Detailed serologic studies were performed in 7 pairs of identical twins, 3 of whom were concordant and 4 of whom were discordant for disease expression. Autoantibody titers were higher in affected than in unaffected twins from discordant pairs, but in 3 of 4 pairs, the profile of anti-RNA proteins (e.g., Ro/SS-A, La/SS-B, U1 RNP, and Sm) was virtually identical. In the SLE pairs concordant for disease expression, the autoantibody titers were very similar, as were the anti-RNA protein profiles. When the identical twins were matched by sex, race, and age to pairs of nontwin SLE patients, the 6 white twins shared an average of 2.5 (+/- 1.05 SD) anti-RNA proteins, while the control SLE pairs shared only 0.33 (+/- 0.82), P less than 0.01 (t = 4.0, P less than 0.01). In addition, in the white SLE twins, all had elevated levels of anti-U1 RNP while in white nontwin SLE patients, the frequency of anti-U1 RNP was 30%. These data point to a dominant role for genetic factors in the determination of specific autoantibody profiles.

Neuropsychological Performance in the Unaffected Twin-Reply

In Reply.— As Dr Green implies, the interpretation of the comparison of unaffected and normal monozygotic twins is complex and open to a number of interpretations. We have examined the issue in more detail in an unpublished manuscript. To summarize our conclusion, it appears that the emotional burden of having an ill cotwin, differences in cooperation and anxiety level, and small differences in parental socioeconomic status might have contributed to the effect sizes that we observed. How- ever, as Dr Green correctly notes, differences were consistently in the predicted direction (unaffected twins performed worse than normal twins). Moreover, they were most marked for those key variables that yielded prominent differences in the contrast between the unaffected and affected groups. This pattern is not inconsistent with the notion that there are cognitive markers for the genetic component of schizophrenia. 1-3 In fact, the socioemotional and the cognitive marker viewpoints are not mutually

Pigmented Paravenous Retinochoroidal Atrophy

We studied a 43-year-old woman affected with pigmented paravenous retinochoroidal atrophy and her unaffected monozygotic twin. The affected twin had stable visual acuity (20/25), typical fundus findings, markedly constricted visual fields, abnormal color vision, and an abnormal electroretinogram, all consistent with pigmented paravenous retinochoroidal atrophy. Results of examinations and studies in her twin were entirely normal. Fingerprinting for DNA performed on the twins strongly supported monozygosity. Our findings suggest that either our patient did not inherit pigmented paravenous retinochoroidal atrophy or that an unusual (nonmendelian) genetic mechanism occurred.

First‐trimester prenatal diagnosis in quintuplets: A practical approach using step‐by‐step embryo reduction

A multiple pregnancy of high rank may occur in a couple at risk for a Mendelian disorder. Prenatal diagnosis is hampered by the difficulty of (1) obtaining chorionic villi from each zygote and (2) unequivocally relating each sample to the corresponding embryo. The calculation of the genetic risk according to the number of zygotes led us to propose a diagnostic strategy based on embryo reduction, a technique initially designed to improve the perinatal outcome of multiple pregnancies with normal embryos. We report a case in which this approach allowed rational use of first-trimester chorionic villus sampling in a quintuplet pregnancy at risk for non-ketotic hyperglycinaemia, resulting in the selective birth of unaffected twins.

Detection of preclinical Parkinson's disease with PET

Putamen 18F-dopa uptake of patients with Parkinson's disease (PD) is reduced by at least 35% at onset of symptoms; therefore, positron-emission tomography (PET) can be used to detect preclinical disease in clinically unaffected twins and relatives of patients with PD. Three out of 6 monozygotic and 2 out of 3 dizygotic unaffected PD co-twins have shown reduced putamen 18F-dopa uptake to date. In addition, an intact sibling and a daughter of 1 of 4 siblings with PD both had low putamen 18F-dopa uptake. These preliminary findings suggest there may be a familial component to the etiology of PD. PET can also be used to detect underlying nigral pathology in patients with isolated tremor and patients who become rigid taking dopamine-receptor blocking agents (DRBAs). Patients with familial essential tremor have normal, and those with isolated rest tremor have consistently low, putamen 18F-dopa uptake. Drug-induced parkinsonism is infrequently associated with underlying nigral pathology.

Extracranial primitive neuroectodermal tumors. The memorial sloan-kettering cancer center experience

The clinical data of 54 patients (57% males) with extracranial primitive neuroectodermal tumors (PNET) seen over a 20-year period at Memorial Sloan-Kettering Cancer Center were reviewed. The age at diagnosis ranged from 1 month to 81 years (median, 17 years). One PNET arose in a previously irradiated site. One patient had an unaffected identical twin. Primary sites were thoracopulmonary (n = 25), pelvis (n = 12), retroperitoneum or abdomen (n = 10), limbs (n = 5), neck (n = 1), and unknown (n = 1). At diagnosis, epidural extension was present in 13 patients with truncal primaries, and 11 patients had distant metastases. All of the latter died with disease. Progression-free survival (PFS) among the 43 patients with localized tumors (all greater than 5 cm) was 25% at 24 months. Two of 13 patients who relapsed after more than 12 months without therapy were long-term survivors. Patients with localized PNET who had resection of all gross disease within 3 months of diagnosis had a significantly longer PFS (P = 0.0003). Radiation therapy caused tumor shrinkage but was not curative of measurable disease. A dose-response effect was evident with the most commonly used drug, cyclophosphamide. Myeloablative regimens using melphalan (n = 8) or thiotepa (n = 1) with autologous bone marrow rescue were not clearly beneficial. The treatment results favor: (1) early surgical removal, (2) dose-intensive use of drugs active against PNET (especially cyclophosphamide), and (3) radiation therapy to ablate residual microscopic disease.

Anatomic, Metabolic, Neuropsychological, and Molecular Genetic Studies of Three Pairs of Identical Twins Discordant for Dementia of the Alzheimer's Type

Three pairs of twins, each with proved monozygosity, were shown to be discordant for dementia of the Alzheimer's type and to have remained discordant for periods of 8 to 11 years. Dementia of the Alzheimer's type was demonstrated by history; serial clinical examinations; serial measurements of cerebral glucose utilization using positron emission tomography and of cerebral ventricular volumes and of rates of change of volumes using quantitative computed tomography; and by serial neuropsychological tests. The results of each of these measures showed no evidence of clinical abnormality in any unaffected twin. DNA markers from the proximal long arm of chromosome 21 did not distinguish between the affected and the unaffected member of any pair of identical twins. Family pedigrees were negative for Alzheimer's disease. The results suggest that environmental or other nongenetic factors contribute to Alzheimer's disease in discordant monozygotic twins, or that some cases arise by a postzygotic somatic mutation.

Neuropsychological Assessment of Monozygotic Twins Discordant for Schizophrenia

A comparison of monozygotic twins discordant for schizophrenia controls for genetic variance and reduces variance due to environmental circumstances, thus serving to highlight differences due to phenotypic-related variables. In this study, we assessed 16 such twin pairs on a wide range of neuropsychological tests. The affected twins tended to perform worse than their unaffected counterparts on most of the tests. Deficits were especially severe on tests of vigilance, memory, and concept formation, suggesting that dysfunction is greatest in the frontotemporal cortex. While manifest symptoms were not highly associated with neuropsychological scores, global level of functioning was. To address the issue of genetic liability, we also compared the sample of discordant unaffected twins with a sample of seven pairs of normal monozygotic twins. No significant differences between the groups were found for any neuropsychological test. In fact, the results suggest that neuropsychological dysfunction is a consistent feature of schizophrenia and that it is related primarily to the clinical disease process and not to genetic or nonspecific environmental factors.

Steroid Responsive Familial Neuropathy with Liability to Pressure Palsies

Autosomal dominant motor and sensory neuropathy with liability to pressure palsies was studied in three members of the same family. Only one of two monozygotic twin sisters was clinically affected. She developed unilateral peroneal palsy twenty minutes following local pressure. Electromyography revealed a weak intermediate innervation pattern with very rapid action potentials in the right anterior lower leg muscle. A 25-70 per cent reduction of motor and sensory conduction velocity was recorded in the clinically unaffected twin sister and in the father. The electrophysiological findings in the mother were normal. The sural nerve biopsy revealed "sausage-like" formations. The palsy persisted for two months and disappeared after eight weeks of fluocortolon treatment. It is possible that the myelin sheaths acted as antigen.

Morphometry of the corpus callosum in monozygotic twins discordant for schizophrenia: a magnetic resonance imaging study.

The corpus callosum (CC) has been the focus of several morphometric studies of patients with schizophrenia, but the results of these studies have been contradictory. In an attempt to improve the reliability of morphometric measurements of the corpus callosum, a computerised image analysis system was used to measure the shape, area, thickness and length of the CC on magnetic resonance imaging (MRI) in 12 pairs of monozygotic twins discordant for schizophrenia (SC). No differences in CC area (anterior, middle, posterior thirds and total), length or vertical thickness of the CC body (at three levels) were demonstrated by t test comparisons of the affected SC and unaffected twins. Statistical analysis of a Fourier expansion series suggested differences in shape between normal and SC cotwins in the second harmonic of the anterior and middle segments and effects of gender on posterior CC shape. These results fail to replicate previous findings of altered length, thickness and area in the schizophrenic CC, but implicate disease-related shape differences in the anterior and middle segment of the corpus callosum and gender-related differences in splenium shape. The disease-related shape distortion suggest ventriculomegaly rather than an intrinsic abnormality of the corpus callosum.

MATERNAL SERUM ALPHA‐FETOPROTEIN SCREENING FOR OPEN NEURAL TUBE DEFECTS IN TWIN PREGNANCIES

Data on maternal serum alpha-fetoprotein (AFP) levels at 13-24 weeks' gestation in 46 twin pregnancies with open neural tube defects (22 with anencephaly, 24 with open spina bifida) and 169 unaffected twins were used to estimate the detection and false-positive rates associated with different cut-off levels. Using the conventional cut-off level of 2.5 multiples of the median (MoM) for unaffected singleton pregnancies of the same gestation and laboratory, the detection rate in twins was 99 per cent for anencephaly and 89 per cent for open spina bifida, with a false-positive rate of 30 per cent. Using a 5.0 MoM cut-off level to maintain a similar false-positive rate to that found among singleton pregnancies at 16-18 weeks' gestation (about 3 per cent), the detection rate was 83 per cent for anencephaly and 39 per cent for open spina bifida. Estimates are provided of the odds of having an affected twin pregnancy given a positive AFP result as well as the odds for individual women with a raised AFP level.

Monozygotic twins discordant for Alzheimer's disease.

We identified 3 pairs of monozygotic twins discordant for probable Alzheimer's disease from a twin register and found no systematic differences in potential risk factor exposures between affected and unaffected twins. Such cases predict a role for environmental factors in the etiology or clinical onset of Alzheimer's disease.

Prenatal diagnosis of infantile sialic acid storage disease in a twin pregnancy

A diagnosis of infantile sialic acid storage disease was made in an infant who died aged 17 months. In the mother's next pregnancy no morphological or biochemical abnormality was found in chorionic villi, amniotic fluid, cultured amniotic fluid cells or fetal blood and a normal boy was born. In the subsequent pregnancy an ultrasound scan revealed a twin pregnancy. Chorionic villus samples were obtained from both twins and microscopic and biochemical analysis indicated one twin to be affected with sialic acid storage disease. Selective fetocide was performed. The unaffected twin proceeded to term.

Amniotic fluid α-fetoprotein concentrations in twin gestations: Dependence on placental membrane anatomy

Placental membrane anatomy was evaluated after delivery in 65 twin pregnancies undergoing genetic amniocentesis with amniotic fluid α-fetoprotein and acetylcholinesterase determinations when indicated. Each twin member in the 57 uncomplicated twin pregnancies was found to have an amniotic fluid α-fetoprotein concentration similar to that of singleton pregnancies of an equivalent gestational age. Eight twin pregnancies were found to be discordant for fetal anomalies associated with an elevated amniotic fluid α-fetoprotein and acetylcholinesterase level. The amniotic fluid α-fetoprotein concentration in the unaffected fetus in these eight cases was found to be dependent on placental membrane structure. Of the five discordant twin pregnancies with diamnionic-dichorionic placentas, all unaffected twins demonstrated an amniotic fluid α-fetoprotein concentration within the normal range for gestational age with a normal acetylcholinesterase level. In three twin pairs with diamnionic-monochorionic placentas, the unaffected twin member had significantly elevated amniotic fluid α-fetoprotein and acetylcholinesterase levels, which suggested diffusion of α-fetoprotein and acetylcholinesterase through the amnion-amnion interface.

Abnormal lymphocyte function in scleroderma: A study on identical twins

This paper describes immunologic studies on a set of identical twins discordant for the presence of scleroderma. The affected twin had a low absolute T-cell count, low numbers of T4 helper/inducer cells, and an increase in the T8 suppressor/cytotoxic cell count. The T cells of the patient responded poorly to mitogens and to allogeneic and autologous stimuli. By contrast, T-cell-helper activity for pokeweed mitogen-induced IgM synthesis was markedly enhanced in the patient. Furthermore, activated mononuclear cell supernatants from the patient markedly enhanced the synthesis of collagen by normal cultured fibroblasts. The unaffected twin by contrast displayed normal responses in these assays. The results suggest that the immunologic defects in scleroderma are not entirely genetically determined.

Method for First Trimester Selective Abortion in Multiple Pregnancy

PIP: The new potential for diagnosing fetal genetic diseases in the first trimester of pregnancy raises the issue of selective abortion in twin pregnancies. If only 1 twin fetus is affected, it is generally necessary to also abort the unaffected twin or to wait until the second trimester and perform selective feticide through use of the air embolism technique. The authors of this paper describe a method that permits selective abortion in multiple pregnancy during the first trimester. An aspirative cannula is introduced through the cervix, guided by ultrasound, and its tip is placed just under the embryo to be aspirated. A 50-ml syringe is linked to the cannula and sudden suction is applied. The embryo is aspirated into the cannula with the amniotic fluid, while the trophoblast is left in place. To date, this method has been applied in 15 cases of multiple pregnancy resulting from ovarian hyperstimulations. It was successful in 12 of these cases. In 2 of the 3 cases where this technique failed, the surrounding trophoblast was also aspirated and spontaneous abortion occurred. Indications for this technique of selective abortion are: 1) pregnancies involving more than 3 fetuses, and 2) an affected cotwin after a positive early prenatal diagnosis.

Characterization of antigen-specific T cells in multiple sclerosis twins with elevated proliferative responses to measles virus.

The proliferative response to measles virus in normal individuals is low compared with the response to mumps virus. This is probably due to a low precursor frequency of OKT4+, IL 2-secreting helper cells. The presence of a measles high-responder state has previously been identified in some twin individuals with multiple sclerosis. Further characterization of the measles response in these high-responder individuals has demonstrated that the enhanced measles responses are due to a greater response by OKT4+ cells, which secrete higher levels of IL 2; this contrasting with the low levels of IL 2 secretion and OKT4+ cell proliferation seen in the unaffected twins. No evidence for suppression by either accessory or T cells, which would account for the quantitative differences between the high responders with multiple sclerosis and their unaffected low-responder twin siblings, was detected. The results indicate that a clonally expanded population of measles-specific responder cells is responsible for the high-responder state in these twins with multiple sclerosis. The mechanism producing this state may have relevance to possible immunoregulatory abnormalities producing autoimmunity in multiple sclerosis.

A case-control study of twin pairs discordant for Parkinson's disease: a search for environmental risk factors.

A previous study of twins with Parkinson's disease (PD) revealed low concordance, suggesting that genetic factors play a minor role in the etiology of PD. To identify possible environmental determinants of PD while maximally controlling for hereditary factors, 31 monozygotic twin pairs discordant for PD were interviewed by telephone. Information about possible risk factors was obtained from systematic and uniform interviews with cases and controls. The only statistically significant result was less cigarette smoking by PD patients (p less than 0.05). Thirteen dizygotic discordant twin pairs were evaluated with the same techniques, but there were no statistically significant differences between affected and unaffected twins.