Inheritance of migraine investigated by complex segregation analysis

Migraine is the most common neurological disorder, affecting about 20% of adults. The mode of inheritance was analyzed in the two main types of migraine, migraine without aura (MO) and migraine with aura (MA), by complex segregation analysis using the computer program POINTER. We included 126 probands with MO and 127 probands with MA from the general population. Firstdegree relatives and spouses were blindly interviewed by a neurological research fellow. The complex segregation analysis indicated that both MO and MA have multifactorial inheritance without generational difference.     

A genetic study of Hirschsprung disease

Hirschsprung disease, or congenital aganglionic megacolon, is commonly assumed to be a sex-modified multifactorial trait. To test this hypothesis, complex segregation analysis was performed on data on 487 probands and their families. Demographic information on probands and the recurrence risk to relatives of probands are presented. An increased sex ratio (3.9 male:female) and an elevated risk to sibs (4%), as compared with the population incidence (0.02%), are observed, with the sex ratio decreasing and the recurrence risk to sibs increasing as the aganglionosis becomes more extensive. Down syndrome was found at an increased frequency among affected individuals but not among their unaffected sibs, and the increase was not associated with maternal age. Complex segregation analysis was performed on these family data. The families were classified into separate categories by extent of aganglionosis. For cases with aganglionosis beyond the sigmoid colon, the mode of inheritance is compatible with a dominant gene with incomplete penetrance, while for cases with aganglionosis extending no farther than the sigmoid colon, the inheritance pattern is equally likely to be either multifactorial or due to a recessive gene with very low penetrance. A model of gene action with random effects during morphogenesis is compatible with our observations.     

Biofeedback Treatment for Headache Disorders: A Comprehensive Efficacy Review

The aim of the present review was to critically evaluate the documented evidence regarding the efficacy of biofeedback for the two most prevalent headache conditions––migraine and tension-type headache. Drawing upon two recently published meta-analyses, data from 150 outcome studies, including randomized controlled trials as well as uncontrolled quasi-experimental designs, were screened. Of these, 94 studies were selected for inclusion according to predefined criteria. Meta-analytic integrations were carried out separately for the two conditions of interest. The main results were medium-to-large mean effect sizes for biofeedback in adult migraine and tension-type headache patients. Treatment effects remained stable over an average follow-up period of 14 months, both in completer and intention-to-treat analyses. Headache frequency was the primary outcome variable and showed the largest improvements. Further significant effects were shown for perceived self-efficacy, symptoms of anxiety and depression, and medication consumption. Reduced muscle tension in pain related areas was observed in electromyographic feedback for tension-type headache. Biofeedback was more effective than waiting list and headache monitoring conditions in all cases, while electromyographic feedback for tension-type headache showed additional significant effects over placebo and relaxation therapies. Levels of efficacy (migraine: efficacious, level 4; tension-type headache: efficacious and specific, level 5) and recommendations for future research are provided.

Learning from Our Treatment Failures

Barton and Blanchard's report that multicomponent behavioral treatment fails to modify chronic daily headaches is discussed with reference to the effectiveness of behavioral and drug treatments for chronic tension-type headache, the distinction between chronic tension-type headache and chronic migraine, and the psychophysiology of episodic vs. persistent pain (K. A. Barton & E. B. Blanchard, 2001). It is suggested that the treatment of chronic daily headache can be improved through research on the benefits of combined behavioral and drug therapy, the psychophysiology of persistent pain, and methods of preventing episodic headaches from evolving to daily headaches.     

Segregation analysis of cleft lip with or without cleft palate in the First Nations (Amerindian) people of British Columbia and review of isolated cleft palate etiologies

BACKGROUND: The First Nations (Amerindian) population of British Columbia, Canada, has the highest reported birth prevalence in the world of cleft lip with or without cleft palate (CL/P) at nearly 3 per 1000 births. In addition, a substantial proportion of cleft palate only (CPO) cases in this population has been reported to be X‐linked. The aims of this study were to perform complex segregation analysis to investigate the mode of inheritance of CL/P in the First Nations people of British Columbia and to review the etiology of the CPO cases. METHODS: All First Nations children born in British Columbia between 1952 and 1971 with an orofacial cleft were included in the study. Multiple sources of ascertainment were used, so that nearly 100% of live births were identified and included during this time. No stillbirths were found but would likely have been ascertained. Extended pedigrees were constructed from these probands and examination of immediate family members, e.g., parents and siblings, was done wherever possible. Complex segregation analysis included all family members. In addition, a CPO case review was conducted. RESULTS: Complex segregation analysis supports the hypothesis that the most likely mode of inheritance of CL/P in this population is a mixed model; that is, an autosomal major gene with polygenic component. The review of 26 CPO cases showed that a substantial proportion are syndromic. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

Complex segregation analysis of non-myoclonic idiopathic generalized epilepsy in families ascertained from probands affected with idiopathic epilepsy with tonic-clonic seizures in Antioquia,Colombia

In an attempt to identify the possible role of major genes, multifactorial inheritance, and cohort effects in the susceptibility to idiopathic epilepsy with generalized tonic-clonic seizures of the awakening type (GTCS), complex segregation analysis was performed in 196 nuclear families ascertained through affected probands with idiopathic epilepsy with GTCS belonging to the Paisa community of Antioquia (Colombia). Models postulating no transmission, single major locus (dominant and recessive) only, and multifactorial component only, were rejected. Since the codominant single major locus model could not be rejected and models that assign no major locus to transmission, no polygenic component to transmission, and no transmission of the major effect were rejected, complex segregation analysis suggested that a major autosomal codominant allele together with a multifactorial component (mixed model) best explained clustering of idiopathic epilepsy with GTCS in families of the Paisa community. The deficit of transmission of heterozygotes (0.17) is compatible with the existence of epistasis acting on a major gene whose frequency was estimated to be 0.0211. Its transmission variance accounts for 81% of the susceptibility to idiopathic epilepsy with GTCS. The complementary variance (19%) is due to the polygenic component. Received: 19 January 1996 / Revised: 11 March 1996     

Complex segregation analysis of hypospadias

Hypospadias, when the urethra opens on the ventral side of the penis, is a common malformation seen in about 3 per 1000 male births. It is considered a complex disorder with both genetic and environmental factors involved in the pathogenesis. Low birth weight is known to be an important risk factor for hypospadias, but several observations speak in favour of genetic factors as well. In order to delineate the relative contribution of the genetic factors behind hypospadias, we performed a complex segregation analysis of 2005 pedigrees in Sweden. The probands were ascertained through the departments of paediatric surgery and departments of plastic surgery and urology in Sweden where boys with hypospadias undergo surgery. In 7% of the ascertained families one or more additional cases of hypospadias were present. The complex segregation analysis showed a heritability of 0.99 and evidence for multifactorial inheritance. The results suggest that hypospadias might be due to monogenic effects in a small proportion of the families, but that there is a multifactorial cause for the majority of the cases.     

A preliminary analysis of EMG variance as an index of change in EMG biofeedback treatment of tension-type headache

The effectiveness of EMG biofeedback training for tension headache has been well established. Previous studies evaluating changes in an average EMG activity score from pre- to posttreatment have not consistently found a relationship between a reduction in average EMG activity and headache improvement at posttreatment. The current study is a preliminary analysis of the utility of EMG variance as another possible mechanism of change. Frontalis EMG average activity and variances from 6 chronic tension-type headache sufferers who demonstrated significant improvement in headache activity at posttreatment (at least 70%) and 6 chronic tension-type headache sufferers who did not demonstrate improvement (less than 30%) were examined across 6 sessions of biofeedback treatment. The improved group demonstrated larger time-specific EMG variance in relation to mean EMG amplitudes during all treatment sessions. A dramatic decline in time-specific variance was observed during the later treatment sessions for improved participants; this pattern was not observed in the group who demonstrated little or no improvement. Results from the current study suggest that the inclusion of both average EMG activity and EMG variance may provide a more comprehensive measure to evaluate possible physiological changes responsible for improvement in headache activity following EMG biofeedback training.     

Segregation analysis of idiopathic torsion dystonia in Ashkenazi Jews suggests autosomal dominant inheritance.

The results of segregation analysis applied to a family study of idiopathic torsion dystonia in Ashkenazi Jews are reported. The study is based on 43 probands (with age at onset prior to 27 years) from 42 nuclear families; pedigrees were extended systematically through all available first- and second-degree relatives, who were directly examined and videotaped. Final diagnoses were based on exam information and blinded videotape review. Segregation analysis demonstrated that the data are consistent with autosomal dominant inheritance with 30% penetrance. Recessive and polygenic inheritance were strongly rejected. There was no evidence for sporadic cases or new mutations. The high incidence and dominant inheritance of early-onset idiopathic torsion dystonia in Ashkenazi Jews suggests genetic homogeneity within this population, making it especially useful for linkage studies of this disorder.     

Classification and Clinical Features of Headache Disorders in Pakistan: A Retrospective Review of Clinical Data

Background

Morbidity associated with primary headache disorders is a major public health problem with an overall prevalence of 46%. Tension-type headache and migraine are the two most prevalent causes. However, headache has not been sufficiently studied as a cause of morbidity in the developing world. Literature on prevalence and classification of these disorders in South Asia is scarce. The aim of this study is to describe the classification and clinical features of headache patients who seek medical advice in Pakistan.

Methods and Results

Medical records of 255 consecutive patients who presented to a headache clinic at a tertiary care hospital were reviewed. Demographic details, onset and lifetime duration of illness, pattern of headache, associated features and family history were recorded. International Classification of Headache Disorders version 2 was applied.66% of all patients were women and 81% of them were between 16 and 49 years of age. Migraine was the most common disorder (206 patients) followed by tension-type headache (58 patients), medication-overuse headache (6 patients) and cluster headache (4 patients). Chronic daily headache was seen in 99 patients. Patients with tension-type headache suffered from more frequent episodes of headache than patients with migraine (p<0.001). Duration of each headache episode was higher in women with menstrually related migraine (p = 0.015). Median age at presentation and at onset was lower in patients with migraine who reported a first-degree family history of the disease (p = 0.003 and p<0.001 respectively).

Conclusions/Significance

Patients who seek medical advice for headache in Pakistan are usually in their most productive ages. Migraine and tension-type headache are the most common clinical presentations of headache. Onset of migraine is earlier in patients with first-degree family history. Menstrually related migraine affects women with headache episodes of longer duration than other patients and it warrants special therapeutic consideration. Follow-up studies to describe epidemiology and burden of headache in Pakistan are needed.     

Computer Animated Relaxation Therapy in Children Between 7 and 13 Years with Tension-Type Headache: A Pilot Study

This pilot study evaluated the effect of computer animated relaxation therapy in children between 7 and 13 years with tension-type headache and the children’s experiences with the therapy. The therapy consisted of an uncontrolled nine-session course in modified progressive relaxation therapy assisted by computer animated surface EMG provided from the trapezius muscles and with the physiotherapist as a participant observer. Outcome measures were (a) headache frequency and intensity, (b) pericranial tenderness, (c) tension patterns, and (d) evaluations assessed at baseline and at 3 months follow up. Nine children, mean age 10.9 (SD 1.7) years, diagnosed with frequent episodic or chronic tension-type headache completed the course. The results showed a mean improvement of 45% for headache frequency at 3 months follow up versus baseline and a significant reduction in headache frequency for all participants and in Total Tenderness Score for children with frequent episodic tension-type headache. The children expressed a growing understanding of body reactions and an acquired ability to deactivate and regulate these reactions. Computer animated SEMG seems an applicable learning strategy for young headache sufferers. This study suggests that children below the age of 13 need both the dialog and guidance from a participant observer in order to achieve body awareness.     

Application of ICHD-II Criteria in a Headache Clinic of China

Background

China has the huge map and the largest population in the world. Previous studies on the prevalence and classification of headaches were conducted based on the general population, however, similar studies among the Chinese outpatient population are scarce. This study aimed to analyze the characteristics of 1843 headache patients enrolled in a North China headache clinic of the General Hospital for Chinese People''s Liberation Army from October 2011 to May 2012, with the International Classification of Headache Disorders, 2nd Edition (ICHD-II).

Methods and Results

Personal interviews were carried out and a detailed questionnaire was used to collect medical records including age, sex and headache characteristics. Patients came from 28 regions of China with the median age of 40.9 (9–80) years and the female/male ratio of 1.67/1. The primary headaches (78.4%) were classified as the following: migraine (39.1%), tension-type headache (32.5%), trigeminal autonomic cephalalgias (5.3%) and other primary headache (1.5%). Among the rest patients, 12.9% were secondary headaches, 5.9% were cranial neuralgias and 2.5% were unspecified or not elsewhere classified. Fourteen point nine percent (275/1843) were given an additional diagnosis of chronic daily headache, including medication-overuse headache (MOH, 49.5%), chronic tension-type headache (CTTH, 32.7%) and chronic migraine (CM, 13.5%). The visual analogue scale (VAS) score of TTH with MOH was significantly higher than that of CTTH (6.8±2.0 vs 5.6±2.0, P<0.001). The similar result was also observed in VAS score between migraine with MOH and CM (8.0±1.5 vs 7.0±1.5, P = 0.004). The peak age at onset of TTH for male and female were both in the 3^rd decade of life. However, the age distribution at onset of migraine shows an obvious sex difference, i.e. the 2^nd decade for females and the 1^st decade for males.

Conclusions/Significance

This study revealed the characteristics of the headache clinic outpatients in a tertiary hospital of North China that migraine is the most common diagnosis. Furthermore, most headaches in this patient population can be classified using ICHD-II criteria.     

Clinico-genetical analysis of colonic cancer. I. Occurrence, frequency in families and segregation analysis

The data on clinico-genealogic studies of colon cancer are presented. 694 families were examined with 432 probands having rectal and 262 colonic carcinoma among them. Clear family accumulation of colon cancer (2.4 +/- 0.35%) as well as other malignant tumors (6.8 +/- 0.6%) (p less than 0.01) was shown among the relatives of the first degree of relation. The values of segregation rates obtained for clinical forms of colon cancer were lower than theoretically expected for simple monogenic types of inheritance. The analysis of incomplete penetration of genotypes showed that, though formally the inheritance of colon cancer and its clinico-anatomical forms may be described by quasi-dominant types of inheritance, the penetration values are very low: from 4.3 to 13.3% for homozygotes and from 2.1 to 6.6% for heterozygotes. It shows that the supposition about the monogenic types of the colon cancer inheritance is doubtful and suggests that the colon cancer is to be regarded on the basis of the multifactorial model.     

Migraine: Intelligence,Social Class,and Familial Prevalence

Groups of individuals with headache, unilateral headache, and migraine, and a fourth group who had not had a headache in the previous year, were identified by questionnaire from a random sample of adults in the general population. Intelligence and social class were assessed in about 400 individuals. There was no evidence that individuals with migraine were more intelligent or of higher social class. There was, however, a suggestion that the more intelligent individuals with migraine, and those in social classes I and II, were more likely to consult a doctor for their headaches. This trend might explain the origin of the hypotheses associating migraine with intelligence and with social class.Random samples of individuals with migraine with headache and without headache in the previous year were the probands for a family study. There were 524 first-degree relatives over 21 years of age who lived in South Wales. Headache histories, obtained “blindly” from over 99% of these relatives with a standard questionnaire, were classified as migraine, possible migraine, headache, or without headache in the previous year. The prevalence of migraine in the families of the migrainous probands was nearly twice as high as the prevalence in the other families, but this difference was not statistically significant. It is suggested that family history should not be included in the definition of migraine and that heredity is much less important in migraine than is usually supposed.     

Evidence for major gene inheritance of Alzheimer disease in families of patients with and without apolipoprotein E epsilon 4.

Apolipoprotein E (APOE) genotype is the single most important determinant to the common form of Alzheimer disease (AD) yet identified. Several studies show that family history of AD is not entirely accounted for by APOE genotype. Also, there is evidence for an interaction between APOE genotype and gender. We carried out a complex segregation analysis in 636 nuclear families of consecutively ascertained and rigorously diagnosed probands in the Multi-Institutional Research in Alzheimer Genetic Epidemiology study in order to derive models of disease transmission which account for the influences of APOE genotype of the proband and gender. In the total group of families, models postulating sporadic occurrence, no major gene effect, random environmental transmission, and Mendelian inheritance were rejected. Transmission of AD in families of probands with at least one epsilon 4 allele best fit a dominant model. Moreover, single gene inheritance best explained clustering of the disorder in families of probands lacking epsilon 4, but a more complex genetic model or multiple genetic models may ultimately account for risk in this group of families. Our results also suggest that susceptibility to AD differs between men and women regardless of the proband's APOE status. Assuming a dominant model, AD appears to be completely penetrant in women, whereas only 62%-65% of men with predisposing genotypes develop AD. However, parameter estimates from the arbitrary major gene model suggests that AD is expressed dominantly in women and additively in men. These observations, taken together with epidemiologic data, are consistent with the hypothesis of an interaction between genes and other biological factors affecting disease susceptibility.     

Diurnal variation of tension-type headache intensity and exacerbation: An investigation using computerized ecological momentary assessment

ABSTRACT: BackgroundsTension-type headache is a common psychosomatic disease. However, diurnal variation of headache is yet to be clarified, perhaps due to the lack of an appropriate method to investigate it. Like other painful diseases, it would be helpful to know if there is diurnal variation in tension-type headaches, both for managing headaches and understanding their pathophysiology. The aim of this study was to determine if there is diurnal variation in the intensity and exacerbation of tension-type headache. METHODS: Patients (N = 31) with tension-type headache recorded for one week their momentary headache intensity several times a day and their acute headache exacerbations using a watch-type computer as an electronic diary (computerized ecological momentary assessment). Multilevel modeling was used to test the effects of time of day on momentary headache intensity and on the occurrence of acute exacerbations. RESULTS: A significant diurnal variation in momentary headache intensity was shown (P = 0.0005), with the weakest headaches in the morning and a peak in the late afternoon. A between-individual difference in the diurnal pattern was suggested. On-demand medication use was associated with a different diurnal pattern (P = 0.025), suggesting that headache intensity decreases earlier in the evening in subjects who used on-demand medication, while headache subtype, prophylactic medication use, and sex were not associated with the difference. The occurrence of acute headache exacerbation also showed a significant diurnal variation, with a peak after noon (P = 0.0015). CONCLUSIONS: Tension-type headache was shown to have a significant diurnal variation. The relation to pathophysiology and psychosocial aspects needs to be further explored.     

Case-control study of whether subfertility in men is familial.

OBJECTIVE--To test the hypothesis that subfertility in men is familial and to examine the distribution of subfertility within families for consistency with a genetic cause. DESIGN--Case-control study and segregation analysis. SETTING--Two teaching hospitals in Leeds. SUBJECTS--Cases (probands) were men with an abnormal sperm count who attended a subfertility clinic and whose partners had no major factor contravening fertility. Controls were fathers of two or more children recruited through vasectomy clinics or a maternity department. MAIN OUTCOME MEASURES--The incidence of involuntary childlessness among brothers with partners and among sisters and second and third degree male relatives. When possible clinical and laboratory details were obtained from involuntarily childless brothers. RESULTS--Seventeen of the 148 (11.5%) brothers of probands but none of the 169 brothers of controls had sought medical advice for childlessness (P < 0.0005). Four probands had more than one involuntarily childless brother. There were six further brothers whose childlessness was thought to be involuntary bringing the total prevalence of subfertility among brothers of probands to 16%. Segregation analysis was consistent with an autosomal recessive mode of inheritance accounting for 60% of subfertility in men. Seventeen of the 346 (4.9%) uncles of probands and 10 of 420 (2.8%) uncles of controls were reported to be involuntarily childless (P = 0.09), but there was no difference in childlessness among sisters. In three families sperm counts from "affected" brothers confirmed the diagnosis and showed considerable similarities within but not between families. CONCLUSION--Subfertility in men has a familial component, and the observations are consistent with an autosomal recessive mode of inheritance in over half the cases. Several different genes are probably involved.     

病理性近视的家系研究

为了探讨我国病理性近视的遗传模式,对90个病理性近视大家系进行了分离分析。简单分离分析采用先验法和SEGRAN-B软件,进行拟合优度卡方检验,比较实际分离比与理论分离比的符合程度;复合分离分析运用SAGE-REGD软件进行孟德尔遗传模型(主基因、显性、隐性、共显性)和非孟德尔遗传模型(非传递、环境、一般)的拟合。结果显示,婚配类型为A*N的家系符合常染色体显性遗传,散发概率为13．8％,婚配类型为N*N的家系符合常染色体隐性遗传,散发概率为16．3％,但常染色体显性遗传不能除外,复合分离分析接受孟德尔遗传的显性、隐性、共显性和主基因模型,共显性模型的可能性最大,基因频率为0．21442999。因此,我国病理性近视存在常染色体显性和隐性遗传模式,并有一定比例的散发病例,具有遗传异质性。     

The effects of conditioning on probands to correct for multiple ascertainment.

Cannings and Thompson suggested conditioning on the phenotypes of the probands to correct for ascertainment in the analysis of pedigree data. The method assumes single ascertainment and can be expected to yield asymptotically biased parameter estimates except in this specific case. However, because the method is easy to apply, we investigated the degree of bias in the more typical situation of multiple ascertainment, in the hope that the bias might be small and that the method could be applied more generally. To explore the utility of conditioning on probands to correct for multiple ascertainment, we calculated the asymptotic value of the segregation ratio for two versions of the simple Mendelian segregation model on sibship data. For both versions, we found that this asymptotic value decreased approximately linearly as the ascertainment probability increased. When ascertainment was complete, the segregation-ratio estimates were zero, not just asymptotically but for finite sample size as well. In some cases, conditioning on probands actually resulted in greater parameter bias than no ascertainment correction at all. These results hold for a variety of sibship-size distributions, several modes of inheritance, and a wide range of population prevalences of affected individuals.     

The effect of proband designation on segregation analysis

In many family studies, it is often difficult to know exactly how the families were ascertained. Even if known, the circumstances under which the families came to the attention of the study may violate the assumptions of classical ascertainment bias correction. The purpose of this work was to investigate the effect on segregation analysis of violations of the assumptions of the classical ascertainment model. We simulated family data generated under a simple recessive model of inheritance. We then ascertained families under different "scenarios." These scenarios were designed to simulate actual conditions under which families come to the attention of-and then interact with-a clinic or genetic study. We show that how one designates probands, which one must do under the classical ascertainment model, can influence parameter estimation and hypothesis testing. We demonstrate that, in some cases, there may be no "correct" way to designate probands. Further, we show that interactions within the family, the conditions under which the genetic study must function, and even social influences can have a profound effect on segregation analysis. We also propose a method for dealing with the ascertainment problem that is applicable to almost any study situation.