Autonomic regulation in fragile X syndrome

Autonomic reactivity was studied in individuals with fragile X syndrome (FXS), a genetic disorder partially characterized by abnormal social behavior. Relative to age-matched controls, the FXS group had faster baseline heart rate and lower amplitude respiratory sinus arrhythmia (RSA). In contrast to the typically developing controls, there was a decrease in RSA with age within the FXS group. Moreover, within the FXS group heart rate did not slow with age. The FXS group also responded with an atypical increase in RSA to the social challenge, while the control group reduced RSA. In a subset of the FXS group, the autonomic profile did not change following 2 months and 1 year of lithium treatment. The observed indices of atypical autonomic regulation, consistent with the Polyvagal Theory, may contribute to the deficits in social behavior and social communication observed in FXS.     

Physiological arousal in females with fragile X or Turner syndrome

Physiological arousal was measured in 12- to 22-year-old females with either fragile X, Turner syndrome, or neither disorder to explore potential differences in the manifestation of arousal and anxiety in adolescents and young women. Physiological arousal was measured at baseline and during performance on mental arithmetic, divided attention, and risk-taking tasks. Contrary to prediction, females with fragile X rarely exhibited higher arousal than females in either the Turner syndrome or comparison groups. On the Divided Attention Task, both the fragile X and Turner syndrome groups exhibited higher arousal relative to one another based on different physiological indices. Relative to the comparison group, the fragile X group presented with a heightened state of arousal at baseline, based on mean skin conductance range, which may account for little increase in arousal on the cognitive tasks for females with fragile X. Females with Turner syndrome exhibited higher arousal relative to the comparison group on all cognitive tasks, but not for all physiological measures. Factors potentially associated with heightened arousal in fragile X and Turner syndrome are discussed.     

Prader-Willi-like phenotype in fragile X syndrome

Henk Meyer¹
A 3-year-old boy was referred to the pediatric department because of unexplained extreme obesity. Height and occipitofrontal circumference were just above the 90th centile. Endocrine studies failed to show any significant abnormality. Motor and speech development were generally delayed. On clinical-cytogenetic-molecular grounds, Prader-Willi syndrome was excluded. Fragile X syndrome was diagnosed by the presence of the classical FMR-1 mutation and confirmed by cytogenetic studies, revealing 20% fragile X positive cells. We compare the clinical features in the present patient with the nine reported patients with fra(X) syndrome and extreme obesity. In pathogenesis, hypothalamic dysregulation is hypothesized. In differential diagnosis of Prader-Willi syndrome, fragile X has to be considered, especially when laboratory workup for Prader-Willi syndrome is negative. Clinical behavior can be of help.     

Prevalence of fragile X syndrome

The much-quoted prevalence figure of 1:1,000 males for fragile X syndrome is an overestimate in a mixed ethnic population. A reexamination of the individuals from whom those data were derived using molecular diagnostic techniques demonstrates a more realistic figure of 1:4,000 males. © 1996 Wiley-Liss, Inc.     

Children's narratives and patterns of cardiac reactivity

The present study examines the associations between narrative processing, narrative production, and cardiac rate and variability in children. Heart period (HP) and vagal tone (VT) were computed for fifty-eight 7-year-olds (29 males) during a resting baseline and during epochs in which the children listened to and completed a selected set of story-stems from the MacArthur Story-Stem Battery (I. Bretherton, D. Oppenheim, H. Buchsbaum, R. N. Emde, & the MacArthur Narrative Group, 1990). Significant decreases in HP and VT were observed between a resting baseline and epochs of story-stem presentation by the experimenter. In addition, HP was shorter and VT lower during children's narrative production to emotionally laden story-stems compared with narration to a neutral story-stem. Furthermore, narrative and cardiac responses to stories containing separation-reunion themes reflected increased emotional and cognitive load compared with responses to stories that did not contain such themes. Finally, children who showed VT suppression in response to emotion-laden stories produced more coherent and adaptive narratives compared to those of children who did not show VT suppression. The findings suggest interplay between the cognitive-emotional processes associated with narrative processing and production and cardiac activation patterns.     

Vagal regulation during bottle feeding in low-birthweight neonates: Support for the gustatory-vagal hypothesis

The gustatory-vagal hypothesis proposes that gustatory stimulation elicits a coordinated vagal response manifested as an increase in ingestive behaviors (e.g., sucking) and a decrease in nucleus ambiguus vagal tone measured by decreases in the amplitude of respiratory sinus arrhythmia (RSA). The current study tested the gustatory-vagal hypothesis in a bottle feeding paradigm with 29 clinically stable, high-risk, low-birthweight neonates. The amplitude of respiratory sinus arrhythmia (RSA) was collected before, during, and after bottle feeding. Consistent with the gustatory-vagal hypothesis, RSA decreased during bottle feeding. In a longitudinal subsample of subjects, the pattern of RSA changes during the feeding paradigm was stable across two test sessions. © 1997 John Wiley & Sons, Inc. Dev Psychobiol 30: 225–233, 1997     

Infant regulation of the vagal “brake” predicts child behavior problems: A psychobiological model of social behavior

Cardiac vagal tone is a construct that describes the functional relationship between the brainstem and the heart. Cardiac vagal tone is measured by quantifying the amplitude of respiratory sinus arrhythmia, a component of heart rate variability reflecting the functional output of vagal pathways on the heart. Although there is an extensive literature evaluating baseline vagal tone and its relation to behavior, the relation between individual differences in the ability to regulate cardiac vagal tone and behavior has been theoretically vague. This article introduces a theoretical model to explain the relation between vagal tone during steady states and vagal reactivity (i.e., the vagal brake) in response to environmental challenges. Based upon the proposed model, it was hypothesized that infants who had difficulties in regulating the vagal brake (i.e., decreasing cardiac vagal tone) during social/attention tasks would have difficulties developing appropriate social interactions requiring reciprocal engagement and disengagement strategies. Data from 24 infants are presented. The findings support the model and demonstrate that infants with difficulties in decreasing vagal tone during a social/attention task at 9 months of age had significantly more behavioral problems at 3 years of age. © 1996 John Wiley & Sons, Inc.     

Reverse mutations in the fragile X syndrome

Three females were identified who have apparent reversal of fragile X premutations. Based on haplotype analysis of nearby markers, they were found to have inherited a fragile X chromosome from their premutation carrier mothers, and yet had normal size FMR1 repeat alleles. The changes in repeat sizes from mother to daughter was 95 to 35 in the first, 145 to 43 in the second, and 82 to 33 in the third. In the first family, mutations of the nearby microsatellites FRAXAC2 and DXS548 were also observed. In the other two, only mutations involving the FMR1 repeats were found. We suggest differing mutational mechanisms such as gene conversion versus DNA replication slippage may underlie such reversions. We estimate that such revertants may occur among 1% or less of premutation carrier offspring. Our results indicate that women identified to be carriers by linkage should be retested by direct DNA analysis. © 1996 Wiley-Liss, Inc.     

Dilemmas in counselling females with the fragile X syndrome

The dilemmas in counselling a mildly retarded female with the fragile X syndrome and her retarded partner are presented. The fragile X syndrome is an X linked mental retardation disorder that affects males and, often less severely, females. Affected females have an increased risk of having affected offspring. The counselling of this couple was complicated by their impaired comprehension which subsequently impaired their thinking on the different options. The woman became pregnant and underwent CVS, which showed an affected male fetus. The pregnancy was terminated. Whether nondirective counselling for this couple was the appropriate method is discussed and the importance of a system oriented approach, through involving relatives, is stressed.     

Prenatal diagnosis of 30 fetuses at risk for fragile X syndrome

The results of 30 prenatal diagnoses for fragile X syndrome are reported. Amniotic fluid cells were examined in 1 case, fetal blood in 4, and chorionic villi samples in the others. Of the 5 fetuses analyzed by cytogenetic methods, 1 had showed 4% of fraXq27.3 expression sites and the pregnancy was terminated. For 1 diagnosis, linkage analysis was used: the female fetus turned out to be normal. In 24 fetuses, the direct analysis of the mutation by StB12.3 probe was performed: 6 female and 3 male fetuses were found to carry a full mutation and 1 female fetus was found to carry a premutation. In 3 cases, the diagnoses were verified on fetal blood samples. Several tissues of 2 aborted male fetuses were analyzed for the fragile X mutation. The results are reported and discussed. © 1996 Wiley-Liss, Inc.     

Affected sibs with fragde X syndrome exhibit an age-dependent decrease in the size of the fragile X full mutation

The sizes of the fragile X mutation in 33 sib pairs affected with fragile X syndrome were determined by Southern blot analysis. An age-dependent decrease in the size of the mutation was found, suggesting positive selection of blood cells carrying small mutations during life or maternal imprinting.     

Effect of folic acid treatment in the fragile X syndrome

The effect of folic acid intake on the frequency of fragile X positive cells and some behavioural characteristics were evaluated in 5 boys and 4 adult males with the fragile X syndrome. The expression of fragile X was nullified in 6 and decreased in 3 of the 9 patients. Behavioural and motor ability were considered to have improved in 4 of the 5 boys but not in the 4 adults with fragile X syndrome.     

Applicability of a checklist for clinical screening of the fragile X syndrome

In a population of 340000 in Southern Häme, Finland, there were 541 intellectually disabled adult males (> 16 years) known to the District Organisation for the Care of the Mentally Retarded in August 1993. Of these, 197 already had a confirmed etiological diagnosis, with 20 having the fragile X syndrome. The other 344 males were screened for the fragile X syndrome using a three-step method: a clinical checklist used by a specialist nurse, a clinical examination by a physician who was very familiar with the fragile X syndrome, and the FRAXA-locus gene test. Six new fragile X males were found. The minimum prevalence of the fragile X syndrome in the district was calculated to be 1:4400.     

Influence of inspiratory threshold load on cardiovascular responses to controlled breathing at 0.1 Hz

Slow, deep breathing is being used as a self‐management intervention for various health conditions including pain and hypertension. Stimulation of the arterial baroreceptors and increased vagal modulation are among the proposed mechanisms for the therapeutic effects of slow, deep breathing. We investigated whether adding inspiratory threshold load can enhance the cardiovascular responses to controlled breathing at the frequency of 0.1 Hz, a common form of slow, deep breathing. Healthy volunteers (N = 29) performed controlled breathing at 0.1 Hz (6 breaths/minute) without load and with inspiratory threshold loads of 5 cmH₂O and 10 cmH₂O. Respiratory airflow, heart rate, and blood pressure were continuously recorded. The amplitude of the systolic blood pressure variation during respiratory cycles increased with increasing loads. Respiratory sinus arrhythmia was higher during controlled breathing at 0.1 Hz with the load of 10 cmH₂O compared to without load. Baroreflex sensitivity was not affected by loads. The effect of loads on respiratory sinus arrhythmia was mediated by increasing the amplitude of systolic blood pressure variation during respiratory cycles. These results suggest that applying small inspiratory threshold loads during controlled breathing at 0.1 Hz increases cardiac vagal modulation by this breathing exercise. This effect seems to be mediated by stronger stimulation of the arterial baroreceptors because of larger systolic blood pressure swings along the respiratory cycle. The potential benefit of long‐term practice of controlled breathing at 0.1 Hz with inspiratory threshold loads on baroreflex function and cardiac vagal control needs to be investigated, particularly in pain and hypertension patients.     

Short-term stability of physiological measures in kindergarten children: respiratory sinus arrhythmia, heart period, and cortisol

The short-term stability of measures of respiratory sinus arrhythmia (RSA), heart period, and salivary cortisol and the relation of these variables to one another and to measures of social competence in kindergartners were examined. Physiological measures were collected during multiple individual sessions with 30 kindergarten children, ages 5 to 6 years. Three sessions were scheduled at 2-week intervals and included a negative affect task as a challenge. Cardiovascular and cortisol responses to the challenge were assessed. Results indicated that baseline measures of RSA and heart period were stable across time. Baseline cortisol levels were not stable. The change in RSA in response to a task that elicited emotional responses was not stable over time. Consistent with findings observed in adults and older children, changes in RSA were related to the cortisol response. Children who increased cortisol over the course of Session 1 exhibited larger decreases in RSA than children who did not show increased cortisol levels. In addition, the children who had larger decreases in RSA had higher ratings of sociability on the Colorado Childhood Temperament Inventory. Greater decreases in heart period during the task were associated with lower ratings of shyness. The relation of RSA measures to ratings of social competence supports the Polyvagal Theory (Porges, 1995, 2001), which suggests that the ability to engage and disengage with objects and people in one's environment, necessary for social competence, is related to the regulation of vagal control of the heart.