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PubMed1995

Inherited disorders of coagulation appear to protect against inflammatory bowel disease.

BACKGROUND/AIMS: Crohn's disease and ulcerative colitis seem to be rarely associated with inherited diseases of coagulation. Histological and hematologic studies suggest that thrombotic mesenteric microvascular occlusion is involved in the pathogenesis of inflammatory bowel disease. The aim of this study was to perform a national survey to determine the prevalence of inflammatory bowel disease among patients with inherited disorders of coagulation. METHODS: Using a postal and telephone questionnaire survey sent to directors of all 129 hemophilia centers in the United Kingdom, the number of patients with inflammatory bowel disease and either hemophilia or von Willebrand's disease was determined. The expected number of cases of inflammatory bowel disease in this population was estimated using published data. RESULTS: Of 6433 patients with hemophilia and 3129 patients with von Willebrand's disease, 4 cases of Crohn's disease were reported compared with expected 11.97-16.58 cases (standardized morbidity ratio, 0.33-0.24; 95% confidence interval, 0.90-0.01; P < 0.05). Ulcerative colitis also occurred significantly less frequently than expected: 9 observed cases in comparison with expected 19.43-31.35 cases (standardized morbidity ratio, 0.46-0.29; 95% confidence interval, 0.91-0.01; P < 0.025). CONCLUSIONS: This epidemiological study provides further evidence that thrombosis and vascular occlusion may be important in the pathogenesis of inflammatory bowel disease.

Adolescent↗
PubMed1989

Inherited changes in concentrations of retinal and serum melatonin in the chicken.

Concentrations of melatonin in the retina, serum, and pineal gland were studied in genetically blind chicks carrying an autosomal recessive mutation, rc, characterized by the degeneration of photoreceptors in the retina after hatching. Blind homozygous (rc/rc) and sighted heterozygous (Rc+/rc) chicks were housed under 12:12 light:dark cycles. They were decapitated at 4, 6, 8, and 10 weeks of age at midlight and middark. Retinas, pineal glands, and serum samples were collected, and the resultant tissue melatonin was extracted and determined by radioimmunoassay. Retinal and pineal melatonin were also identified and quantified by gas chromatography-mass spectrometry (GC-MS). Good correlations were demonstrated between the values obtained by GC-MS and levels of quantified by radioimmunoassay. In all the tissues studied, there were age-related changes and diurnal variations in melatonin levels with high levels in the dark period. Melatonin levels in the retina and serum of rc/rc chicks were also significantly lower than those of Rc+/rc control birds. However, storages of melatonin in the pineal gland were similar between the two groups of chicks studied. These results suggest that (1) retinal melatonin is synthesized in the photoreceptor, (2) the phototransduction process which produces neural signals (i.e., electroretinogram) may be different from the phototransduction process which initiated the rhythmic melatonin synthesis and production in the retina, (3) the inherited degeneration of retinal photoreceptors with lower retinal melatonin levels correlates with an inherited abnormality of the pineal melatonin synthesis and/or secretion resulting in lower serum melatonin levels (pleiotropism), (4) levels of pineal melatonin (an indicator of the rate of synthesis and/or storage) and that of serum melatonin (an indicator of the rate of release) may not be directly correlated, and (5) the chicken pineal secretes melatonin not only by simple diffusion but also from a bound pool of melatonin in the gland.

Animals↗
PubMed1987

In inherited porphyrias, lead intoxication is a toxogenetic disorder.

1. delta-Aminolevulinic acid dehydratase (ALA-D), blood lead and several enzymes and metabolites of the heme biosynthetic pathway were measured in a number of symptomatic porphyric patients, 22 with acute intermittent porphyria, three with hereditary hepatic coproporphyria, 10 with hereditary porphyria cutanea tarda, two with erythropoietic protoporphyria and two with congenital erythropoietic porphyria and in 84 lead intoxicated persons. 2. In the 39 individuals suffering from the inherited porphyrias and in 32 lead poisoned patients with a 30-50% reduced deaminase, blood lead content was not sufficiently increased (average 28 micrograms%) to account for the greatly decreased activity of ALA-D (average 36% of controls). 3. After a relatively trifling lead exposure they developed the signs of acute lead intoxication. 4. A second group of lead intoxicated patients showing low ALA-D activity and corresponding high concentration of lead in blood, exhibited no other physiologic deviation in the enzymes and metabolites of porphyrin biosynthesis. 5. Individuals with inherited porphyrias are ultrasensitive to low level lead exposure and that lead would also act as a triggering factor. In these patients, lead intoxication can be considered a toxogenetic disorder. 6. An inversely linear correlation between ALA-D activity and blood lead content was obtained for both groups of lead intoxicated patients, however, a different constant (k) for each was obtained, which we have taken as a measure of lead toxogeneticity: k = 10 +/- 1 for lead intoxicated individuals with otherwise normal heme metabolism and k = 5 +/- 0.5 for lead intoxicated symptomatic porphyric patients. 7. Determination of erythrocytic ALA-D, besides blood lead, will be a valuable indicator for preventive medical care for these patients, when they are expected to be exposed to lead either environmentally or in their professional life.

Heme↗
PubMed1986

Genetic and cultural inheritance of serum lipids, low and high density lipoprotein cholesterol and serum apolipoproteins A-I, A-II and B.

The genetic and cultural heritability of serum cholesterol and triglyceride concentrations, as well as of the concentrations of low and high density lipoprotein cholesterol and serum apolipoproteins A-I, A-II and B, were estimated by path analysis in families selected through probands with premature myocardial infarction and in families randomly selected from the general population. Genetic heritability was high for serum cholesterol (0.64) and low density lipoprotein cholesterol (0.67) concentrations, whereas it was lower for high density lipoprotein cholesterol level (0.42). Cultural inheritance was of less importance than genetic inheritance for all cholesterol variables. For serum triglyceride concentration genetic (0.33) and cultural (0.23) heritability was of similar significance. The results for serum apolipoproteins A-I and A-II parallelled those for HDL cholesterol. A marked intergenerational difference was found in the genetic heritability for apolipoprotein B concentration. The parental genetic heritability was 0.14, whereas the genetic heritability was 0.51 among siblings.

Adult↗
PubMed1987

Minicore myopathy with dominant inheritance.

Minicore disease (multicore disease) is a benign myopathy characterized by segmental muscle fibre degeneration with disruption of myofibrils and loss of mitochondria. The disease is generally thought to occur either sporadically or follow an autosomal recessive mode of inheritance. We describe 2 patients, a mother and her son, with essentially non-progressive weakness of both proximal and distal muscles. Biopsies from both patients showed focal defects of oxidative enzyme activity as well as focal disturbances of cross-striation typical of minicore myopathy. Normal fibre type differentiation was lacking. Three other families reported in the literature suggest dominant inheritance of minicore myopathy or closely related disease.

Adolescent↗
PubMed1977

Inheritance of type-III hyperlipoproteinemia. Lipoprotein patterns in first-degree relatives.

The lipoprotein (LP) patterns were studied in the families of 19 index cases with type-III hyperlipoproteinemia (HLP). Seventy adult first-degree relatives (93% ascertainment) to the 19 probands were analyzed. The diagnosis of HLP type III among the first-degree relatives was based on three criteria, all of which had to be fulfilled to make the diagnosis: (1) presence of a slow-moving band in very-low-density LP (VLDL) on agarose gel electrophoresis migrating in beta or close to beta position; (2) A cholesterol/triglyceride ratio (mg/100 ml: mmoles/liter) in VLDL greater than 29.0; and (3) A "III-index" [cholesterol/triglycerides in VLDL x 10 divided by cholesterol/triglycerides in low-density LP (LDL)] greater than 1.30. When defined according to these criteria there was a marked over-representation of HLP type III among the relatives (27%). There was also an increased frequency of hypertriglyceridemia (28% against expected 15%), mainly because of a high prevalence of HLP type IV (24%). On agarose gel electrophoresis a "late pre-beta" band, probably indicative of an increased amount of intermediary LP particles, was frequently present (47%) among relatives not classified as HLP type III. Type-III patients with hypertriglyceridemia were characterized by a significantly higher body weight than those with normotriglyceridemic type III. However, there was no qualitative difference in the composition of the lipoproteins in normotriglyceridemic and hypertriglyceridemic type-III patients. A genetic analysis of the LP patterns within the families showed several examples of vertical transmission of HLP type III. There was no sex linkage. Six of thirteen analyzed parents showed LP patterns classified as HLP type III. Another two parents were most probably carriers of the gene. Of the siblings to the probands, 23% showed a type-III pattern and another four (7%) showed LP patterns very similar to type III, fulfilling two of three criteria for HLP type III. The data support the concept that HLP type III is inherited as an autosomal dominant gene. It was indicated that HLP type IV with a late pre-beta band in VLDL may represent another expression of the gene for HLP type III. It is suggested that HLP type III may be a pathogenetically heterogenous group of lipid disorders. A separation of type III into two subgroups with low or normal and high LDL cholesterol concentration, respectively, may facilitate the understanding of the inheritance of type III as well as of the pathogenesis behind this LP abnormality.

Adult↗
PubMed1994

Inherited protein S deficiency: clinical manifestations and laboratory findings in 63 patients.

To further characterize inherited heterozygous protein S (PS) deficiencies, we studied 63 patients belonging to 33 families. Diagnosis of PS deficiency was based on protein S activity (PS Act) and/or free PS antigen (FPS Ag) levels below the lower limit of the normal range in patients not on oral anticoagulation. Depending on the level of total PS antigen (TPS Ag), two subpopulations could be distinguished: in the first one (25 patients belonging to 11 families) level of TPS Ag was reduced whereas in the second one (38 patients belonging to 22 families), TPS Ag was normal. In none of the families studied the two types of PS deficiency coexisted suggesting that they are different entities. In the 63 patients, thromboembolic events occurred in 57% of cases and were recurrent in 36.5% of patients. Age at the time of the first thrombosis ranged from 14 to 74 years, and was below 40 years in 69% of symptomatic cases. Thrombotic events were spontaneous in 64% of cases, and were associated with other risk factors in 36%. There was no apparent relationship between clinical status, symptomatic or asymptomatic, and the type or degree of the PS deficiency. Long-term anticoagulation prevented the recurrence of thrombosis in every case but one, and led to a decrease in circulating levels of C4b-binding protein suggesting the existence of a regulation between C4b-BP and PS concentrations. Together with previous reports, these findings underline the clinical and biological heterogeneity of inherited protein S deficiency.

Adolescent↗
PubMed1995

Central retinal vein and branch artery occlusion associated with inherited plasminogen deficiency and high lipoprotein(a) levels: a case report.

We describe a case of central retinal vein and branch artery occlusion associated with inherited type I plasminogen deficiency (68%) and permanent elevation of Lp(a) (460 mg/l, S2 phenotype) in a 45 year old white woman with no associated local or systemic risk factors. Pedigree analysis revealed inheritance of plasminogen deficiency from the deceased father and of high Lp(a) levels from the mother. Both the patient's sons had plasminogen deficiency, but they had normal Lp(a) levels. In a series of 40 consecutive patients with central retinal vein occlusion we previously reported the observation of high Lp(a) levels--consistently associated with the S2 phenotype--in 30% of the patients as compared to a 10% incidence in controls. This case emphasizes the importance of screening patients with occlusion of the retinal vessels and no associated risk factors for coagulation abnormalities predisposing to thrombosis.

Female↗
PubMed1995

A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel.

Mutations in HERG cause an inherited cardiac arrhythmia, long QT syndrome (LQT). To define the function of HERG, we expressed the protein in Xenopus oocytes. The biophysical properties of expressed HERG are nearly identical to the rapidly activating delayed rectifier K+ current (IKr) in cardiac myocytes. HERG current is K+ selective, declines with depolarizations above 0 mV, is activated by extracellular K+, and is blocked by lanthanum. Interestingly, HERG current is not blocked by drugs that specifically block IKr in cardiac myocytes. These data indicate that HERG proteins form IKr channels, but that an additional subunit may be required for drug sensitivity. Since block of IKr is a known mechanism for drug-induced cardiac arrhythmias, the finding that HERG encodes IKr channels provides a mechanistic link between certain forms of inherited and acquired LQT.

Animals↗
PubMed1990

Non-inherited maternal HLA antigens and protection against sensitisation.

To test the hypothesis that non-inherited maternal antigens (NIMAs), which reportedly afford protection against sensitisation by random transfusions, can provide protection against repetitive antigenic exposure of donor-specific transfusion (DST), 140 DST patients whose donors were mismatched for NIMAs and 71 whose donors were mismatched for non-inherited paternal antigens (NIPAs) were studied. The rate of sensitisation in the two groups of patients was similar (22.1% vs 15.5%). There was no difference in sensitisation to NIMAs and NIPAs between patients who received azathioprine and those who did not. The formation of donor specific HLA antibody was comparable in the two groups. After kidney transplantation there were no differences in 1-year graft survival or the incidence of rejection episodes. These findings suggest that NIMAs do not provide lifelong protection against subsequent repetitive antigen challenge and sensitisation.

Adult↗
PubMed1993

Recessive inheritance of von Willebrand's disease type I.

The inheritance of type I von Willebrand's disease is thought to be autosomally dominant. The laboratory profile may, however, vary between affected people, even within a single family. There is also a large variation in the severity of clinical symptoms. To see if there is an association between the von Willebrand factor genotype, the laboratory profile, and the severity of the clinical symptoms we did a genetic analysis of four families with type I von Willebrand's disease. The proband of each family proved to be a compound heterozygote for defects in the von Willebrand factor gene. Simple heterozygotes in these families were either symptomless or only mildly affected. One of the identified mutations, which was shared by the probands of three of the four families, may have a carrier prevalence of 1:50 in the general population. These results suggest that the inheritance of von Willebrand's disease is often recessive rather than dominant and so have important implications for diagnosis and genetic counselling.

Female↗
PubMed1981

Familial patterns and possible modes of inheritance of primary affective disorders.

A logistic model was used to analyze the pattern of affected relatives of probands with primary affective disorders (PAD). The sample consisted of 242 patients, diagnosed as either unipolar (UP, 107) or bipolar (BP, 135) and 430 control nonpsychiatric inpatients and all first degree relatives of both groups. Age correction was applied to both groups. The analysis showed a significant baseline increase in frequency of PAD among relatives of PAD probands with siblings more likely to be affected than parents. The difference in frequency of PAD according to sex of relative almost reached significance. Specific diagnosis (UP or BP) of proband did not significantly affect the probability of relatives becoming ill. Genetic models incorporating sex-specific thresholds were able to explain the data satisfactorily as resulting from either Single-Major-Locus inheritance or Multifactorial-Polygenic inheritance.

Bipolar Disorder↗
PubMed1995

Evidence against unusual sex concordance and pseudoautosomal inheritance in the catatonic subtype of schizophrenia.

The study is based on sibships with multiply afflicted members derived from a family study of consecutively admitted probands with catatonic schizophrenia. As shown recently, the clinical subtype of periodic catatonia, as defined by Leonhard, is compatible with a major gene effect and genetic anticipation; that is, the age of illness onset of the probands is significantly earlier than that of their parents. In the present study, 83 probands with the clinical subtype of periodic catatonia had 26 afflicted siblings that were distributed among 23 families. We analyzed sex-concordance and pseudoautosomal inheritance patterns. Stratifying the 26 afflicted siblings by sibship size and by the proband's sex, we did not find unusual sex-concordance rates in sibships afflicted with periodic catatonia. Further, there was no association between sex concordance and maternal or paternal origin of the disease. Thus, our results provide strong evidence against pseudoautosomal inheritance or sex-linked transmission in affected sibships in the obviously familial schizophrenic subtype of periodic catatonia.

Adult↗
PubMed1987

Inherited deficiencies of complement components in man.

Isolated inherited deficiency states of almost every complement protein have been recognized. Almost all are autosomal recessive traits. Deficiency of the early-acting components C1, C4 and C2 is associated with increased risk of immune complex disease, particularly systemic lupus erythematosus. Patients with deficiency of C3, factor I or factor H have increased susceptibility to infection by pyogenic bacteria, whereas those with deficiencies of properdin, C5, C6, C7 or C8 are prone to systemic neisserial infection. Inherited deficiency of C1 inhibitor is transmitted as an autosomal dominant trait, is genetically heterogeneous, and is associated with attacks of angioedema and consumption of C4 and C2. There is evidence that a plasmin-modified fragment of C2 is responsible for the angioedema in this disorder. Administration of androgens tends to correct the biochemical abnormalities of hereditary angioedema and to prevent attacks.

Angioedema↗
PubMed1994

Non-Mendelian mitochondrial inheritance as a cause of progressive genetic sensorineural hearing loss.

Awareness of non-Mendelian mitochondrial inheritance and of its role as an agent of genetic sensorineural hearing loss (SNHL) is recent. Mitochondria are passed on exclusively from the ovum to all the offspring of both sexes, a novel pattern of inheritance. Owing to the critical role of mitochondria in cellular energy metabolism, deletions or point mutations of the mitochondrial DNA often cause progressive SNHL and a variety of disorders in other organ systems (mitochondrial cytopathies). The clinical expression of mitochondrial diseases varies and depends on the proportion of mutated mitochondria in various body tissues, as well as the nature of the mutation or deletion. In order to determine how often SNHL occurs in mitochondrial diseases and what is its presenting symptom, and also whether SNHL is a marker for particular phenotypes, we carried out a review of published case reports of patients with an established diagnosis of mitochondrial disease. The review indicates that SNHL occurs at all ages and in virtually all variants of mitochondrial diseases. It is not clear whether SNHL is a marker for a more severe and more rapid course of disease; the lower prevalence of SNHL in descriptions of live patients than of those who had died may be an artifact of case selection reported in the literature. Mitochondrial disease needs to be considered in progressive hearing loss and better longitudinal audiometric study of established cases will be required to answer these questions.

Age of Onset↗
PubMed1985

Ethyl methanesulfonate-induced mutations of major genes for quantitative phenotypes: mutant alleles for altered activity of brain or liver enzymes in C57BL/6J mice and their inheritance across several generations.

We recently identified and confirmed 8 induced mutations in the N2 and N3 progeny of ethyl methanesulfonate (EMS) treated C57BL/6J mice. Each of these mutations altered specific enzyme activities. These separate mutant sublines have been maintained through several generations as heterozygous mutant carriers. The percent decrease of the specific enzyme activity from normal in each subline was calculated for each generation. Additionally, the percentage of breeders within each mutant subline producing abnormal progeny and the fraction of such breeders' total progeny possessing abnormal activity were determined. The aberrant activity values observed in progeny of a confirmed mutant carrier were all lower than normal. 4 of the mutant sublines had decreases in enzyme activities which were constant across the generations analyzed. 3 of the mutant sublines had decreases in activities which were consistent over early generations but changed significantly in later generations. Another subline with decreased enzyme activity was lost. For 7 of the sublines, the number of progeny having altered activity and the number of breeders producing mutant progeny approximated that expected for single gene inheritance. In the remaining subline, a change in the decrease in enzyme activity probably accounts for the deviation from expected inheritance. Although the phenotypes for these quantitative traits are considered to be quasi-continuous, the data indicate that the mutations are probably of major genes.

Alleles↗
PubMed1992

Dermatopathia pigmentosa reticularis: a report of a family demonstrating autosomal dominant inheritance.

Dermatopathia pigmentosa reticularis is a rare heritable disorder consisting of a triad of cutaneous findings including reticulate hyperpigmentation, noncicatricial alopecia, and onychodystrophy. In addition to this triad, other variable features of dermatopathia pigmentosa reticularis have been described, including adermatoglyphia, hypohidrosis or hyperhidrosis, and palmoplantar hyperkeratosis. Only 10 cases have been described in the world literature to date, and no clear inheritance pattern has been demonstrated. We present a patient with the classic features of the dermatopathia pigmentosa reticularis triad, along with adermatoglyphia, hypohidrosis, and punctate hyperkeratosis of the palms and soles. A family pedigree demonstrates the autosomal dominant inheritance of dermatopathia pigmentosa reticularis.

Adult↗
PubMed1991

HLA and IDDM: facts and speculations on the disease gene and its mode of inheritance.

1. The mode of inheritance of the DR3- and DR4-associated susceptibility genotype is essentially recessive, based on both the segregation data and the existence of Hardy-Weinberg equilibrium in Ashkenazi Jewish and possibly in patients of other populations. 2. Maternal effects may alter the expressivity of IDDM in some susceptible offspring, depending on the maternal DR genotype. Thus, the number of susceptible DR4 types inherited from the mothers may be decreased in certain population samples. Conceivably, these maternal effects also account for the smaller proportion of diabetic children born to diabetic women than to diabetic men. Conversely, maternal DRw6 may raise this risk. 3. The locus of the susceptibility gene is most likely in the DQ region. While specific DQA1 and DQB1 alleles are very closely associated with IDDM in some populations, neither is completely associated with it in DR4 haplotypes and neither accounts for the differences in IDDM susceptibility associated with DR3 haplotypes. 4. Linkage disequilibrium between DR and DP alleles in affected haplotypes indicates the existence of subsets of DR3 and DR7, which account for all or most of the risk to those haplotypes. The possibility of direct DP effects is less likely because the respective DP alleles are different and because DR4 does not maintain disequilibrium with DP alleles in either affected or unaffected haplotypes. 5. The DQA2-BglII-7.2Kb polymorphism in complete association with affected B8,DR3 haplotypes suggests the possible involvement of DQA2.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗