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PubMed1985

[Narcolepsy].

First described as a separate entity by Gelineau in 1880 and later considered as a symptom, narcolepsy has eventually been recognized as a disease on clinical and polygraphic grounds. Its prevalence stays between 0.04 and 0.06 percent. Age at onset varies from 5 to 50 with a peak in the second decade. Clinical symptoms include excessive daytime somnolence, overwhelming daytime sleep episodes, attacks of cataplexy, hypnagogic hallucinations, sleep paralysis and disturbed nocturnal sleep; sleep onset REM episodes are the main polygraphic feature. Natural history varies with the different symptoms. Excessive daytime somnolence never subsides completely. Cataplexy may disappear spontaneously. Hypnagogic hallucinations and sleep paralysis are not present in all patients and tend to be more transitory. A positive diagnosis of narcolepsy requires a minimum of one major symptom, daytime sleep episodes or cataplexy, together with documented sleep onset REM episodes. Prolonged polygraphic recordings or multiple sleep latency test are of special interest in difficult cases. Clinical variants can be grouped under three headings, incomplete, symptomatic and associated narcolepsies. The etiology of narcolepsy is not well understood. However the discovery of natural animal models of narcolepsy, mainly dogs, has prompted genetic, pharmacological and biochemical studies. The breeding of narcoleptic canine colonies has led to the evidence of a possible autosomal recessive model of inheritance in some species. Pharmacological and neurochemical analysis has shown an imbalance between monoaminergic and cholinergic mechanism. In man, extensive family studies suggest either a two-threshold multifactorial model of inheritance or a dominant mode of inheritance and immunologic studies have recently shown a strong association between HLA-DR2 and narcolepsy. Assays of CSF biogenic amines suggest a decreased bioavailability of dopamine to explain sleepiness and an imbalance between monoamines and acetylcholine to explain cataplexy. A disturbance of circadian rhythms has not been evidenced in narcoleptics. Treatment is still purely symptomatic. Amphetamines and tricyclic antidepressants have been extensively used. However they are not free of side-effects hence the need for alternative treatments.

Adolescent↗

PubMed1998

Genetics of psoriasis.

Non-pustular psoriasis consists of two disease subtypes, type I and type II, which demonstrate distinct characteristics. Firstly the disease presents in different decades of life, in type I before the age of 40 years and later in type II. Secondly, contrasting frequencies of HLA alleles are found: type I patients express predominantly HLA-Cw6, -B57, and -DR7, whereas in type II patients HLA-Cw2 is overrepresented. Finally, familial inheritance is found in type I but not in type II psoriasis. The study of concomitant diseases in psoriasis contributes to deciphering the distinct patterns of the disease. Defence against invading microorganisms seems better developed in psoriatics than in controls. This evolutionary benefit may have caused the overall high incidence of psoriasis of 2%. Psoriasis is a multifactorial and heterogenetically inherited disease. The heterogeneity is evident by the diversity of genetically linked markers. The multifactorial component results from the observation of external trigger mechanisms, such as the Koebner phenomenon, stress and the intake of certain drugs. Twin studies have shown that environmental factors contribute to the onset of the disease. In type I psoriasis, special extended haplotypes such as EH57.1 (HLA-Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303) and EH65.1 (HLA-Cw8-B65-DRB1*0102-DQB1*0501) have been found to be increased. The application of microsatellite techniques has identified distinct positions on several chromosomes at which putative psoriasis genes may be located. Disease susceptibility genes are thought to be present on chromosomes 4q, 6p, 16q, 17q and 20p. Moreover, on chromosome 1q, genes regulating epidermal differentiation have been identified. Linkage to this area has been proposed. Furthermore, psoriasis gene loci on chromosomes 2, 8 and 20 have been suggested.

HLA Antigens↗

PubMed1999

Heritability and segregation analysis of immune responses to specific malaria antigens in Papua New Guinea.

Familial patterns of inheritance of immune responses to specific Plasmodium falciparum antigens were studied in 214 adults in an area of Papua New Guinea highly endemic for malaria. Preliminary variance component analysis indicated familial aggregation in both humoral and cellular immune responses against the ring-infected erythrocyte surface antigen (RESA) and the FC27 allele of the Merozoite surface antigen 2 (MSA-2). Including a term for sharing houses in the models affected only the antibody response to RESA. Segregation analysis of the antibody responses against RESA indicated inheritance via a multifactorial model and analysis of the proliferation response suggested a possible recessive major gene. The best fitting models for the immune responses against MSA-2 (FC27) postulated dominant major gene inheritance. We found no significant associations between HLA class I or II alleles and these two antigens in this population. Although there was evidence of familial aggregation of antibody responses to MSA-2 (3D7), the segregation analysis failed to identify a mode of inheritance. There was little or no heritability of either humoral or cellular immune responses against the NANP repeats of the Circumsporozoite protein (NANP), the synthetic malaria vaccine SPf66, or a preparation of MSA-2 (3D7) from which the repetitive part was deleted (MSA-2 (d3D7)). Although it is often difficult to separate genetic effects from the effects of living in the same environment, it appears that some immune responses against certain malaria antigens may be partly influenced by genetic factors.

Adult↗

PubMed2005

Genetic basis of common diseases: the general theory of Mendelian recessive genetics.

Common diseases tend to appear sporadically, i.e., they appear in an individual who has no first or second degree relatives with the disease. Yet diseases are often associated with a slight but definite increase in risk to the children of an affected individual. This weak pattern of inheritability cannot be explained by conventional interpretations of Mendelian genetics, and it is therefore commonly held that there is "incomplete penetrance" of a gene, or that there are polygenic, or multifactorial modes of inheritance. However, such arguments are heuristic and lack predictive power. Here, we explore the possibility that "incomplete penetrance" means the existence of a second, disease-related, gene. By examining in detail a specific common condition, Parkinson's disease (PD), we show that the sporadic form of the disease can be fully explained by a compact fully penetrant genotype involving an interaction between two, and only two, genes. In this model, therefore PD is fundamentally genetic. Our digenic model is complementary to Mendelian recessive genetics, but taken together with the latter forms a complete description for recessive genetics on one chromosome. It explains the slight increase in risk to the children if one parent has sporadic PD, and makes strict predictions where both parents coincidentally have sporadic PD. These predictions were verified in two large and carefully selected kindred, where the data also argue against other genetic models, including oligogenic and polygenic schemes. Since the inheritance patterns of sporadic PD are reminiscent of what is seen in many common diseases, it is plausible that similar genetic forms could apply to other diseases. Seen in this light, diseases wash in and out of every family, so that in a sense, over time every human family is equally at risk for most diseases.

Family Health↗

PubMed1975

[Incidence and etiology of omphaloceles (author's transl)].

Omphaloceles are congenital malformations with herniation of the abdominal viscera into the umbilical cord. The incidence in newborns is 1:4300, the sex ratio 1.24:1 in favour to boys. Children with this malformation are neither more frequent at the beginning nor at the end of the sibship; the average maternal age is not increased. In about 50% other different malformations are found. All those omphaloceles, which are found as an obligatory symptom in the EMG syndrome (Wiedemann-Beckwith syndrome) to be probably in most cases autosomal recessively inherited or which are seen within a chromosomal malformation syndrome are of etiologically known origin. Omphaloceles without other malformations are mainly sporadic, less frequent in sibs, possibly due to a polygenic or multifactorial mode of inheritance. Findings in population genetics and animal experiments suggest that exogenous factors, too, can be the cause of malformation syndromes with omphaloceles.

Abdominal Muscles↗

PubMed1993

The genetics of migraine without aura and migraine with aura.

Studies of twins, spouses and familial aggregation strongly suggest that migraine without aura (MO) and migraine with aura (MA) are genetically determined. The mode of inheritance is most likely multifactorial in both MO and MA. However, autosomal dominant inheritance with reduced penetrance cannot be excluded in either MO or MA. At present the only evidence for genetic heterogeneity of MA is familial hemiplegic migraine with slowly progressive ataxia. This phenomenon can also be explained by linkage of different genes. All existing studies have been characterized by one or more of the following methodologic shortcomings: selection of probands from clinic populations, information obtained by questionnaire, family history obtained through probands, insufficient description of the attacks, lack of distinction between MO and MA. Useful strategies for future studies of migraine genetics are discussed.

Humans↗

PubMedDate not supplied

[Genetic aspects of asthma].

Asthma is a complex disease associated with bronchial hyperreactivity and atopy, making asthma a disease with a phenotype that has been clinically difficult to define. Despite intense research, prevalence of asthma remain relatively high. The key reason for the high prevalence and morbility is that the fundamental mechanisms predisposing individuals to the development of asthma are not understood. Familial aggregation observed in this pathology has prompted for the search of an involved genetic component. This task is difficult due to the complex nature of asthma. A universally accepted definition for this disease is not available, clinical expression can be modulated by environmental factors, and inheritance does not follow a clear Mendelian pattern. Establishment of more precise clinical and laboratory criteria has improved the design and interpretation of genetic studies. Twin analysis and segregation studies have demonstrated an important genetic component with a probably multifactorial pattern of inheritance. "Sib pair" studies and familial segregation analyses have shown linkage between some chromosomal regions and asthma, including chromosome 5, 6, 7, 11 and 14. The search for major genes in these chromosomal segments has been focused on loci involved in the allergic process. Among these, the loci for IL-9 and IL-13 in chromosome 5 seem to play an important role in the pathogenesis of asthma. Understanding the fundamental gene-environmental interactions in the development of asthma should lead to earlier identification of susceptible individuals and more effective approaches for disease prevention.

Adult↗

PubMed1995

The search for genetic mechanisms of congenital heart disease.

Identification of the genetic basis for congenital heart defects has been a topic of inquiry for pediatric cardiologists for many years. Any genetic model proposed must account for three often puzzling features of congenital heart diseases, namely the high population incidence, the less than Mendelian recurrence risk, and low concordance rates of heart lesions within individual families. A multifactorial or polygenic inheritance model has been used to explain these observations. Although this model has been serviceable, it does not adequately explain the phenotypic variability within families. Further, the emphasis on teratogenic influences has not led to the elucidation of pathogenetic mechanisms. The multifactorial model should be modified to include the role of chance as originally proposed by Kurnit. Once the role of chance is acknowledged, the phenotypic variability of congenital heart diseases becomes less problematic, and the multifactorial model gives way to a model in which single genes are capable of producing congenital heart disease. Through recent work in animal models and humans, it is now clear that single congenital heart disease genes can be identified that produce phenotypic variability in families that is similar to that seen in the population as a whole. Examples demonstrating recent progress in the search for major congenital heart disease genes are discussed.

Animals↗

PubMed1994

Cephalometric evidence for a dominantly inherited predisposition to cleft lip-cleft palate in a single large kindred.

Several studies have demonstrated an association between facial shape in parents and the presence of oral clefts in their offspring. However, these observations have been of little practical value because it has been assumed that facial shape was just one predisposing component among many in a multifactorial model of inheritance. Cephalometric analysis of a large family with 5 generations of affected individuals suggests that facial shape can be used to identify presumed carriers of a major gene associated with an increased risk for oral clefts. Discriminant function analysis indicates that such at risk individuals can be recognized effectively through a combination of increased midfacial and nasal cavity widths, reduced facial height, and a flat facial profile. The ability to identify minimally affected gene carriers within families would provide critical information needed in the search for molecular markers that segregate with the genetic risk for clefting.

Cephalometry↗

PubMed1995

[Mode of genetic inheritance of abdominal aortic aneurysm: still no clear answers].

Clear evidence has not yet come concerning the genetics of abdominal aortic aneurysms (AAA). There are circumstantial proof for a hereditary predisposition. In a retrospective study of sixty patients consecutively underwent a surgical repair for AAA, showed that one third of them knew a first-degree relative with the same disease. Environmental factors, such as smoking, ageing or hypertension, must be taken into account. A multifactorial mode of inheritance is under discussion due to both multiple genes with different expressivity and diverse environmental factors. Linkage-analysis or DNA sequencing of the different gene loci in population studies or sibbling-analysis are the tools in search for candidate genes for inheritance of AAA. Mutations in those genes encoding structural components of the aortic wall, such as collagen-type-III, fibrillin or elastin, are not taken to be the underligned genetic cause. Mutations in genes encoding enzymes for the turnover of the aortic wall components, such as alpha-1-antitrypsin or matrix-metalloproteinase-2, may play an important role.

Aortic Aneurysm, Abdominal↗

PubMedDate not supplied

Genetic analysis of triploidy in a selected line of chickens.

We investigated the pattern of inheritance of maternal meiotic errors responsible for a high frequency of triploid progeny in a selected line of chickens. For the genetic analysis, F1 and backcross populations were produced from crosses between normal diploid individuals of the triploidy line and a control line. Triploid embryos were produced by 35% and 67% of reciprocal F1 females and by 24% and 67% of reciprocal backcross females. These results exclude autosomal recessive and sex-linked recessive or sex-linked dominant inheritance. A single autosomal dominant gene is also not likely to be responsible. However, the results are consistent with the determination of triploidy by a single autosomal gene with no dominance, and an even better fit is obtained by two loci, an autosomal gene with no dominance and a sex-linked gene. The results cannot exclude a multifactorial mode of inheritance, but the rapid response to selection for triploidy and consistent expression of the meiotic errors in different genotypes suggest that meiotic mutations at one or two loci are the most plausible genetic basis for the trait.

Animals↗

PubMed1982

Estimating genetic and non-genetic components of variance for fasting glucose levels in pedigrees ascertained through non-insulin dependent diabetes.

Fasting glucose levels measured on 337 individuals in 14 pedigrees ascertained through a proband with non-insulin dependent diabetes were used to estimate genetic and non-genetic components of variance under a multifactorial model of inheritance. In this sample genetic factors were important in controlling variation in basal carbohydrate metabolism, as represented by age-adjusted log-fasting glucose. There was no evidence that arbitrary sib common environments or arbitrary parent common environments accounted for significant portions of the variability in fasting glucose in these data. An arbitrary environment shared by parent and offspring, however, had a marginally significant impact on the likelihood. Parameter estimates obtained from multifactorial models analysed in this manner are sensitive to extreme phenotypic values, however, and caution must be exercised in estimating total genetic variation. While additive genetic factors did account for a significant proportion of the total variation in fasting glucose, a large proportion remained unexplained.

Adolescent↗

PubMed1995

Indirect DNA/gene diagnoses via electrophoresis--an obsolete principle?

In principle, gene defects can be investigated directly or indirectly via informative polymorphisms in their vicinity. But because many defects are not yet defined molecularly, these inherited diseases can only be diagnosed indirectly via analysis of informative family situations. Since (multiple) mutation analyses, e.g. via DNA sequencing, are time-consuming and expensive, indirect analysis may still be performed initially--particularly in diseases caused by heterogenous mutations. We focus on diagnoses of neurological and (auto)immune diseases by polymerase chain reaction and separation of the DNA fragments via gel electrophoreses. Even after gene defects have been identified, indirect analysis might be necessary, for example in Huntington's chorea. Although this genetic defect has been characterized as a trinucleotide disease, indirect DNA diagnosis is still performed in particular cases for psychological reasons. The causes of autoimmune diseases are multifactorial and the inheritance is complex, involving several genes. Genome-wide screening programs may involve indirect approaches via analyses of polymorphic microsatellites. Large parts of the immunological genome can be covered when 20 or more genes are investigated simultaneously. Thus the genetic bases of autoimmune diseases are disclosed. Microsatellites themselves could have a biological meaning. We therefore discuss also DNA/protein interactions for simple tandem repeats, the major targets for indirect gene diagnoses. Only indirect evidence exists that certain simple repeats influence genomic (in)stability. Taken together, indirect gene diagnoses supplement direct approaches in a variety of different purposes and in combination with standard electrophoresis techniques.

Animals↗

PubMed2001

Exfoliation syndrome: clinical and genetic features.

We have ascertained a large number of individuals and families with exfoliation syndrome in order to clarify the disorder's mode of inheritance. Patients with exfoliation syndrome and their relatives were recruited from the practices of a group of ophthalmologists in Maritime Canada. The degree to which the subjects were affected was graded according to a standardized 1-4-point clinical scheme. Pedigrees were constructed from information supplied by family members and from genealogical sources. A total of 782 patients and relatives participated, of whom 467 were definitely affected. The mean age of affected males and females did not differ significantly, but females appeared to be more severely affected at ascertainment than males. More than half of the affected subjects had definite exfoliation in only one eye. Approximately 30 multiplex families were discovered, including one containing 23 affected members among a total of 137 examined individuals that constitutes the largest exfoliative pedigree thus far described. We observed well-documented paternal transmission of the trait, a finding that has not to our knowledge been previously reported. Clustering of cases in the families provides evidence for the involvement of genetic factors. The possibility of homozygosity is suggested in a few patients by the earlier or more frequent presentation of the disorder in the offspring of two affected parents or consanguineous pairings. Although a multifactorial mode of inheritance cannot be excluded, exfoliation syndrome appears to be inherited as an autosomal dominant trait whose late onset and incomplete penetrance poses a significant but not insuperable obstacle to pedigree construction.

Aged↗

PubMed1998

Assessment of bone in Ehlers Danlos syndrome by ultrasound and densitometry.

OBJECTIVE: Ehlers Danlos syndrome (EDS) is an inherited disorder of connective tissue characterised by hyperextensible skin, joint laxity, and easy bruising. There are phenotypic similarities with osteogenesis imperfecta, but in EDS a tendency to fracture or altered bone mass has not previously been considered to be a cardinal feature. METHOD: This case-control design study investigates whether 23 patients with EDS had differences in fracture rates, bone mass, and calcaneal ultrasound parameters compared with age and sex matched controls. RESULTS: 23 cases of EDS (mean (SD) age 38.5 (15.5)) were compared with 23 controls (mean age 37.8 (14.5)). A significant reduction in bone density measured by dual energy x ray absorptiometry was found at the neck of femur by 0.9 SD, p = 0.05, and lumbar spine by 0.74 SD, p = 0.02. At the calcaneum, broad band ultrasound attenuation and speed of sound were significantly reduced compared with controls by 0.95 SD (p = 0.004) and 0.49 SD (p = 0.004) for broad band ultrasound attenuation and speed of sound respectively. Broad band ultrasound attenuation and speed of sound remained significantly reduced after adjusting for bone mineral density (BMD). After adjusting for functional status (HAQ), age and sex, hypermobility was inversely correlated with broad band ultrasound attenuation and SOS, but not BMD at hip or spine. Previous fracture was 10 times more common in EDS (p < 0.001), with 86.9% of patients reporting a total of 47 low impact fractures, compared with 8.7% of controls. CONCLUSION: This study has identified a tendency of EDS patients to fracture, have low bone mass and abnormal bone structure. The aetiology is likely to be multifactorial, with an inherited structural element, accentuated by immobility or reduced exercise. This is one of the first clinical studies to suggest ultrasound can detect structural differences in bone, independent of dual energy x ray absorptiometry.

Absorptiometry, Photon↗

PubMed1980

Familial pulmonary atresia. Its occurrence with a ventricular septal defect.

To our knowledge, this is the first reported case of pulmonary atresia with a ventricular septal defect that occurred in a father and his son. A multifactorial mode of determination that resulted from an interaction between genetic predisposition and environmental factors was assumed, since the family history did not show other members with congenital heart defects. Based on the background and on information from the multifactorial theory of inheritance, a counseling plan was formulated for these parents. A similar approach is recommended for the many surgical survivors of previously uncorrectable complex congenital heart defects as they approach reproductive age.

Abnormalities, Multiple↗

PubMed1989

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.

Family↗

PubMed2003

Parental consanguinity and congenital heart malformations in a developing country.

The association between isolated congenital heart defects and consanguinity was examined in 759 Lebanese patients with different types of congenital heart malformations. The subjects were patients of the Children's Cardiac Registry Center (CCRC) at the American University of Beirut Medical Center. The proportion of first-cousin marriages among cardiac subjects was compared to that of the National Collaborative Perinatal Neonatal Network (NCPNN), after adjusting for the subjects' geographic distribution, and to the highest proportion reported by NCPNN. In general, the proportion of overall parental consanguinity and first-cousin matings among CCRC subjects (34.7 and 20.2%, respectively) were significantly higher than the highest proportion of first-cousin marriages reported by NCPNN (Bekaa subjects; 13.2%) (P < 0.0001). Comparison with the NCPNN-adjusted first-cousin mating proportion revealed a significantly increased rate of consanguinity in all categories of cardiac malformations except great vessel and coronary artery lesions (P < 0.05). The following lesions were significantly associated with increased parental consanguinity: aortic anomalies (aortic insufficiency, aortic stenosis, bicuspid aortic valve), atrial septal defect, double-outlet right ventricle, pulmonary atresia, patent ductus arteriosus, pulmonic stenosis, tetralogy of Fallot, and ventricular septal defect (P < 0.05). Higher maternal education was the only variable that was negatively correlated with parental consanguinity (P = 0.037). Our study emphasizes the role of homozygous recessive genes in the causation of different types of isolated congenital heart malformations, known to follow a multifactorial pattern of inheritance. There is an urgent need for educating the public on the deleterious effects of inbreeding, especially in developing countries with high overall consanguinity rates and limited financial resources.

Adult↗