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Erythrokeratoderma variabilis is a rare genodermatosis conventionally regarded as autosomal dominant in inheritance. We describe the clinical features and light and electron microscopic findings in two affected siblings born to unaffected parents and suggest an autosomal recessive mode of inheritance in this family. We also briefly review the literature on this disorder.
A general method has been developed which, in theory, will make it possible to follow the inheritance of virtually all genes in human families. This method, based on genetic linkage, envisions the use of cloned single copy human deoxyribonucleic acid probes to reveal restriction fragment length polymorphisms as genetic markers. Such markers can be assembled into a linkage map which can be applied to analysis of inherited diseases. It is speculated that such a map might help to clarify the role that heredity plays in the etiology of epilepsy.
To revive the appreciation of the importance of genetic studies for the understanding of neurologic diseases inherited in a monogenic fashion. After a description of the basic patterns of monogenic inheritance, the importance of linkage studies for the mapping of a disease gene is mentioned. Furthermore, the term linkage disequilibrium is introduced. Finally, several procedures used in current linkage analyses are briefly mentioned, with the aim of identifying the disease gene. The importance of genetic studies of disease families with many members, preferably from isolated surroundings to favor homogeneity, is stressed. However, such analyses can be performed only as a consequence of a close cooperation between clinicians and research scientists.
Idiopathic epilepsies account for approximately 40% of all epileptic diseases. For a long time, it has been known that genetic factors play a major role in the etiology of these diseases. Although oligogenic or polygenic inheritance is suspected in most of the common syndromes, a few rare idiopathic epilepsies are single-gene disorders. They offer a chance to identify candidate genes that also may be involved in epilepsies with complex inheritance. In recent years, major progress has been made regarding the analysis of genetic factors in idiopathic epilepsy. For the first time, gene defects could be linked to two idiopathic epilepsies. Mutations in the CHRNA4 gene, which codes for the alpha4 subunit of the neuronal nicotinic acetylcholine receptor, lead to autosomal dominant nocturnal frontal lobe epilepsy, a rare idiopathic partial epilepsy syndrome. Two highly homologous voltage-gated potassium channels, KCNQ2 and KCNQ3, were found to be mutated in benign familial neonatal convulsions.
A significant proportion of the childhood epilepsies have a genetic component. Therefore, animal models that can be bred for seizure expression may provide important information regarding the mechanisms by which molecular defects result in the neuronal hyperexcitability states collectively termed "epilepsy." Because of the rate and ease of breeding, rodent models are the most commonly used. The genetically epilepsy-prone rat has motor seizures in response to auditory stimuli. It is likely that the seizures are generated in the inferior colliculus because of an abnormality in the noradrenergic system. The seizure predisposition is inherited as an autosomal dominant trait. The genetic absence epilepsy rat has age-related spontaneous seizures characterized by motor arrest and head drops that are correlated with generalized spike-wave on the electroencephalogram (EEG). The seizure generating mechanism appears to be located in the lateral thalamic nuclei. The epileptic mongolian gerbil demonstrates behavioral arrest followed by myoclonic, tonic, and tonic-clonic seizures in response to unfamiliar environments. The underlying neuroanatomy involves hippocampal-cortical interactions indicative of a partial epilepsy. The tottering mouse has absence and myoclonic seizures, a 6- to 7-Hz ictal spike-wave EEG, and noradrenergic hyperinnervation that are linked to a mutation on chromosome 8. Hippocampal network hyperexcitability has been found with normal neuronal intrinsic properties. Stargazer is a mouse mutant with almost identical clinical and electrographic features as found in tottering. However, the genetic defect is located on chromosome 15 and no abnormalities of norepinephrine have been discovered. The El mouse demonstrates ictal automatisms in response to vestibular stimulation. Metabolic and structural abnormalities have been found in the hippocampus. Linkage to chromosomes 9 and 2 have been reported recently. The dilute brown agouiti mouse demonstrates motor seizures in response to auditory stimuli. Chromosomes 4 and 17 are linked to seizure expression. Thus, a variety of models exist to study the genetic, biochemical, structural and electrophysiological mechanisms that underlie the predisposition and expression of the inherited epilepsies.
INTRODUCTION: Dogs with an inherited predisposition to sudden death display ventricular arrhythmias having certain characteristics, such as pause dependence, that are suggestive of early afterdepolarization-induced triggered activity. We hypothesized that alpha-adrenergic stimulation may facilitate the development of these arrhythmias by inducing a reflex bradycardia and by exerting a direct myocardial effect. METHODS AND RESULTS: Twenty affected dogs and 7 unaffected dogs were studied. The incidence and severity of ventricular arrhythmias were determined after administration of phenylephrine (0.01 mg/kg IV), with or without pretreatment with propranolol (0.1 to 0.3 mg/kg IV), atropine (0.04 mg/kg IV), or prazosin (0.5 mg/kg IV). Third-degree heart block was induced by AV nodal ablation in 4 affected dogs. Phenylephrine increased ventricular arrhythmias in affected dogs, with or without pretreatment with propranolol, but did not induce ventricular arrhythmias in unaffected dogs. In dogs with intact AV nodal conduction, atropine increased sinus rate, which suppressed baseline and phenylephrine-induced arrhythmias. In dogs with heart block, arrhythmias were increased during baseline and after phenylephrine, with or without pretreatment with atropine. Prazosin and overdrive ventricular pacing suppressed phenylephrine-induced arrhythmias. CONCLUSION: Phenylephrine increases ventricular arrhythmias in dogs with inherited sudden death via both an induction of reflex bradycardia and a direct myocardial effect. Superimposition of heightened alpha-adrenergic and vagal tone may facilitate the development of sudden death in these animals.
Sudden cardiac death (SCD) at youth is rare and is often caused by inherited cardiac disorders. This review focuses on the genetic background of inherited primary electrical diseases, the so-called "channelopathies." Following a short clinical description of each syndrome, the recent findings in the genetics of long QT syndrome, short QT syndrome, isolated cardiac conduction defect, familial sick sinus syndrome, familial atrial fibrillation, cathecholaminergic polymorphic ventricular tachycardia, familial Wolff-Parkinson-White (WPW) syndrome, and Brugada syndrome are discussed. The currently proposed theoretical model of overlapping phenotypes in SCN5A sodium channel mutations is presented. The recent data indicate that advances in molecular genetics, experimental and clinical electrophysiology shed some light on the genetic background of primary electrical diseases. However, it is also becoming clear that the process from a mutation of a gene to the clinical presentation of a patient is currently only partially understood and extremely complex.
BACKGROUND: The implanted cardioverter-defibrillator (ICD) has been shown to improve survival in adult patients with high risk acquired cardiac disease, with a cost-effectiveness ratio in the range of $30,000 to $185,000 per quality-adjusted-life-year saved. However, data on the benefit and cost-effectiveness of device therapy in high-risk patients with inherited cardiac disorders are limited. METHODS: We developed two separate computer-based analytical models to compare non-ICD with ICD therapy in patients (age range: 10-75 years) with long QT syndrome (LQTS) and hypertrophic cardiomyopathy (HCM). In each disease entity patients were stratified into low-risk (no known risk factors); high-risk (known risk factors [primary prevention]); and very high-risk (prior near-fatal events [secondary prevention]). Net costs were defined as the difference between costs resulting from treatment of the disease and savings due to gained productivity attributable to prevention of sudden cardiac death. Outcome was defined as costs per quality-adjusted life-years saved. RESULTS: In LQTS, defibrillator therapy was shown to be cost effective in high-risk male patients (incremental cost-effectiveness ratio [ICER]=$3328 per quality-adjusted-life-year saved), and cost saving in high-risk females (ICER=$7102 gained per quality-adjusted-life-year saved) and very high-risk males and females (ICER=$15,483 and 19,393 gained per quality-adjusted-life-year saved, respectively). In HCM, defibrillator therapy was cost saving in both male and female high-risk (ICER=$17,892 and $17,526 gained per quality-adjusted-life-year saved, respectively) and very high-risk (ICER $22,944 and $22,329 gained per quality-adjusted-life-year saved, respectively) patients. Defibrillator therapy was not shown to be cost effective in low-risk patients with either LQTS or HCM (ICER in the range of $400,000 to $600,000 lost per quality-adjusted-life-year saved). Sensitivity analyses were consistent with the results in each risk group. CONCLUSIONS: In appropriately selected patients with inherited cardiac disorders, early intervention with ICD therapy is cost-effective to cost saving due to added years of gained productivity when the lifespan of an individual at risk is considered.
Individuals with inflammatory bowel disease frequently experience increased systemic thromboembolic complications, which represent an important cause of morbidity and mortality. Risk factors for thrombosis can be inherited or acquired. The most common inherited risk factors for thromboembolism are factor V Leiden mutation, G20210A mutation in the prothrombin gene, and homozygous C677T mutation in the methylenetetrahydrofolate reductase gene. In the last few years, a great amount of literature has focused on the prevalence of such genetic mutations and their role in determining thrombosis in IBD patients. In this review, we summarize the results of these studies.
BACKGROUND: Inflammatory bowel diseases (IBD) are characterized by an increased risk for venous and arterial thrombosis. Although the pathogenetic mechanisms of this predisposition are unclear, a possible role of inherited risk factors for thrombosis in determining this predisposition has been suggested. AIM: To evaluate the role of factor V Leiden (G1691A) and G20210A prothrombin gene mutations in determining the occurrence of thrombosis in IBD patients. PATIENTS AND METHODS: Forty-seven IBD patients (30 ulcerative colitis and 17 Crohn's disease) with a positive history for thrombosis (9 at arterial sites and 38 at venous sites) were enrolled in the study. For each patient, two non-IBD subjects matched for sex and age, type, and site of thrombosis were used as controls. Peripheral blood DNA specimens were amplified by PCR using appropriate primers and analyzed by restriction analysis on agarose gel electrophoresis. Statistical analysis was performed by means of Fisher's exact test. RESULTS: The total number of subjects with one or both mutations was significantly lower in IBD patients with thrombosis than in control subjects (12.8%vs 29.8%, respectively; p= 0.035, OR = 0.34, 95% CI 0.13-0.90). The total frequency of the mutated alleles was also significantly lower in IBD than in controls (7.4%vs 16.5%, respectively; p= 0.041, OR = 0.40, 95% CI 0.17-0.96). Prothrombotic mutations were particularly unfrequent in IBD patients with active disease at the time of thrombosis compared with patients with quiescent disease (8.0%vs 36.4%, respectively; p= 0.057, OR = 0.15, 95% CI 0.02-1.01). CONCLUSIONS: The major inherited risk factors for thrombosis are significantly less frequent in thrombotic IBD patients than in thrombotic non-IBD subjects, suggesting that acquired risk factors play the most relevant role in determining thromboembolic events observed in IBD patients, particularly during active phases of the disease.
The 1.6 and 1.8 kbp dsRNAs have been found in the rice blast fungus, Magnaporthe grisea strain MG01. These dsRNA molecules are located in cytoplasm of the fungal cells and maintained stably during vegetative growth. Three crosses between dsRNA free and dsRNA containing strains including a parental cross, sib-mating and back cross were made to follow the inheritance of dsRNAs during sexual reproduction. Approximately 10% of ascospore progenies (11 out of 105) contained dsRNAs from all three crosses. These data indicate that dsRNAs of M. grisea are inherited at a low frequency and not in a Mendelian fashion.
The frequency of psychotics among sibs of index cases with a functional psychosis was found by Odegaard (1972) to be positively associated with the number of psychotics in the parents' generation. Odegaard considered this correlation to be indicative of polygenic inheritance. However, an attempt at replicating this fascinating finding in a sample of schizophrenic families was not successful. Although this discrepancy in results might have been due to chance, the importance of the problem of the mode of inheritance induced a search for biases that might have obscured the comparison of the two samples. Unfortunately, the discrepancy remained unexplained, but certain structural and diagnostic differences were brought up and discussed. The very existence of such incongruities, together with the contrasting main results, seems to caution against definite genetic conclusions until further evidence is available.
A better understanding of the role of genetic factors in affective disorders is likely to result from investigating more homogeneous populations. To achieve this goal, we have systematically studied patients who are excellent responders to long-term lithium treatment and their relatives. In the families of 71 such probands, we have analyzed the mode of inheritance by comparing the observed morbidity risks with the risks expected under different genetic models. The results demonstrate major-gene effects in the transmission of primary affective disorders; the polygenic model with sex-specific thresholds could be rejected. Discrimination between the autosomal and X-chromosome models was not possible, but the autosomal recessive model predicts more realistic, gender-specific frequencies of affective disorders in the general population. These results suggest that autosomal recessive inheritance deserves serious consideration in molecular genetic investigations.
Size distribution curves of red blood cells were used to detect the presence of microcytes in peripheral blood of members of a Dutch family with hereditary sideroblastic anaemia. 22 of 49 members of this family have a bimodal erythrocyte volume distribution curve and a dimorphic blood picture. The pattern of inheritance of this morphological abnormality is clearly autosomal. It is suggested that the study of red blood cell size distribution curves may add valuable information on the pattern of inheritance in other families with hereditary sideroblastic anaemia.
Vac8p, an armadillo (ARM) repeat protein, is required for multiple vacuolar processes. It functions in vacuole inheritance, cytoplasm-to-vacuole protein targeting pathway, formation of the nucleus-vacuole junction and vacuole-vacuole fusion. These functions each utilize a distinct Vac8p-binding partner. Here, we report an additional Vac8p function: caffeine resistance. We show that Vac8p function in caffeine resistance is mediated via a newly identified Vac8p-binding partner, Tco89p. The interaction between Vac8p and each binding partner requires an overlapping subset of Vac8p ARM repeats. Moreover, these partners can compete with each other for access to Vac8p. Furthermore, Vac8p is enriched in three separate subdomains on the vacuole, each with a unique binding partner dedicated to a different vacuolar function. These findings suggest that a major role of Vac8p is to spatially separate multiple functions thereby enabling vacuole inheritance to occur concurrently with other vacuolar processes.
An 11-year-old girl presented with permanent elevation of serum alkaline phosphatase activity (AP) exceeding 4 times the upper normal limit. Family investigations revealed a persistent increment of AP activity in the father and one of the two sisters, indicating a dominant form of inheritance. Physical examination and laboratory results were normal; isoenzyme studies revealed that the raised serum AP activity was mainly due to an increase of the bone isoenzyme. No disturbance of calcium or phosphate metabolism or morphological alterations of the skeleton could be demonstrated. This indicates an inherited abnormality in the metabolism of bone AP in the absence of disease.
The study of complement deficiency states and their influence on immune function has generated new insights and still provides a challenge to continued investigation. The association of classical pathway deficiencies (C1, C4, C2 or C3) with immunological diseases such as SLE and glomerulonephritis has contributed to current knowledge concerning complement-dependent immune complex handling and elimination. Susceptibility to systemic infection with encapsulated bacteria is encountered in most forms of inherited complement deficiency. Recurrent neisserial infection is the only clinical manifestation clearly associated with defects of the membranolytic sequence C5-C9, while deficiency of properdin, a component of the alternative activation pathway, appears to predispose to nonrecurrent meningococcal disease. Inherited complement deficiency is rare, but the perspective is widened by the more common occurence of acquired defects in immunological diseases, and the apparent requirement for efficient complement recruitment in host defense. Another aspect is the possibility that complement deficiency might alleviate or prevent inflammatory symptoms. Notably, complement deficiency has not been reported in classical rheumatoid arthritis. Considerations of this kind would be refuted or modified by findings of complement deficiency in single patients.
A hereditary, non-inflammatory myopathy occurring in young great Danes with distinctive histological features in muscle biopsy specimens is reviewed. Onset of clinical signs is usually before one year of age and both sexes are affected. Clinical signs are characterised by exercise intolerance, muscle wasting, and an exercise-induced tremor. Although most affected dogs have a severe form of the disease, occasional dogs may have a less pronounced form and survive into adulthood with an acceptable quality of life. Litters containing affected puppies are born to clinically unaffected parents, and an autosomal recessive pattern of inheritance is likely. All recorded cases have had fawn or brindle coat coloration. Elevated serum creatinine kinase concentrations and spontaneous electrical activity in skeletal muscles are frequently found. While originally reported (Targett and others 1994) as a central core myopathy in this breed, the histochemical characteristics of the distinct cytoarchitectural structures differ from those of the well-characterised central core myopathy in human beings. In fact, these structures differ from any known myopathy in human beings and likely represents a unique non-inflammatory myopathy affecting dogs. Until this myopathy is characterised further, the name inherited myopathy in great Danes is suggested.