Asymptomatic Parents Research Articles

Genetic Heterogeneity in Erythropoietic Protoporphyria: A Study of the Enzymatic Defect in Nine Affected Families

Erythropoietic protoporphyria (EPP) is associated with a deficiency of protohaem ferrolyase. We have used a novel assay for this enzyme based on its ability to utilize zinc as a substrate to investigate the inheritance of EPP in nine affected families. Zinc chelatase activity was markedly reduced in peripheral blood mononuclear cells from 14 EPP patients (mean, 3.3 nmol Zn protohaem/h/mg protein; range, 0.3-8.0) when compared with 41 controls (16.8 +/- 3.6) p less than 0.01. In three families with parent-to-child transmission of disease, the asymptomatic parent had an enzymatic activity within the normal range. In three pedigrees where the parents were asymptomatic, enzymatic activities were below the 95% confidence limits in both. Zinc chelatase activity was below the mean control value in 17 of the 18 parents in nine affected pedigrees, and six of seven asymptomatic offspring of patients with protoporphyria. The findings suggest that EPP is not transmitted as a simple dominant trait and that inheritance of more than one gene may be required for disease expression.

Severe recessive poikilocytic anaemia with a new spectrin α chain variant

A severe neonatal haemolytic anaemia was observed in a propositus from the West Indies. Frequent blood transfusions were required until complete splenectomy was carried out. Blood smears showed predominant poikilocytosis with spherocytes and microcytes as observed in hereditary pyropoikilocytosis. Erythrocytes were completely fragmented after incubation at 45 degrees C. The two asymptomatic parents had normal haematological profiles. The erythrocyte membrane electrophoretic patterns of the splenectomized propositus and her parents were normal. The propositus had a moderate defect in the spectrin (Sp) dimer self-association. Limited tryptic digestion of the propositus' Sp under standard conditions (0 degrees C, 20 h, enzyme-substrate ratio of 1/100) revealed an increased sensitivity to tryptic digestion. The major features detected by one- and two-dimensional electrophoresis gels of Sp tryptic digests were the absence of high molecular weight peptides from the Sp alpha II (48 kDa and 35 kDa peptides) and Sp alpha III (52 kDa peptide) domains with increased amounts of the lower molecular weight peptides from the Sp alpha II and Sp alpha III (29 kDa peptide and 47 kDa peptide) domains respectively. Kinetic studies of Sp tryptic digestion (10 min to 36 h) confirmed the increased tryptic susceptibility of Sp. Immunodetection with specific anti-alpha-chain domain antibodies showed that the highest molecular weight peptides from the alpha II and alpha III domains are released early in digestion, but disappear quickly, with an increase in their corresponding smaller peptides. The molecular weights of the peptides corresponding to the 48 kDa and 35 kDa peptides from the alpha II domain are slightly modified. Peptides from the alpha I and alpha IV domains showed no significant abnormalities. The Sps of both parents were normal. These results indicate that the patient has a novel Sp alpha chain defect, which is probably located in the region of the alpha II domain which adjoins the alpha III domain.

Antenatal Diagnosis of Bilateral Renal Agenesis in One of a Twin Pair

DOI: http://dx.doi.org/10.5915/22-1-13543 Bilateral renal agenesis (BRA) was diagnosed antenatally in one of like-sexed (probably monozygotic) twins. This is the first report of such a diagnosis. The difficulties of certain sonographic diagnosis of BRA are outlined and are possibly compounded in twin pregnancy in the presence of growth retardation/oligohydramnios of one of the twins. Recent evidence suggests that BRA is inherited in an autosomal dominant pattern with reduced penetrance and variable expressivity. The discordance for BRA in twins, even mono.zygotic twins, has been relatively frequent suggesting a possible role of environmental influences in the expression of the anomaly. Genetic counseling should include renal evaluation of asymptomatic parents and siblings and early detailed ultrasound evaluation of fetal kidneys in all subsequent pregnancies.

Mapping the Gene for Juvenile Myoclonic Epilepsy

The practice of epileptology at a molecular level, where gene products are identified by gene mapping, will soon be possible for a growing number of epilepsies. Juvenile myoclonic epilepsy (JME) is the first of such epilepsies to be mapped to a chromosome, namely chromosome 6p21.3. Family studies of 68 JME probands from California revealed 50% of all families reported seizures in first- or second-degree relatives. Twelve percent of all family members other than the proband had epileptic seizures. Eighty percent of symptomatic siblings and 6% of asymptomatic siblings had diffuse 4- to 6-Hz multispike-wave complexes. Twelve percent of asymptomatic parents had diffuse, nonspecific slow waves mixed with spikes or sharp waves. JME is tightly linked to the Bf-HLA loci in chromosome 6. No matter what mode of inheritance is assumed, linkage to the clinical manifestations of JME and its associated EEG traits is indicated by lod scores over 3.0, as long as "EEG affected" but clinically asymptomatic family members are counted as affected during LIPED analysis. Studies are now being done to further localize the JME site. At the same time, further linkage studies should decide if JME is heterogeneous within itself and whether the same JME site in 6p21.3 underlies absence and grand mal epilepsies.

Homozygous and heterozygous deletions of the von Willebrand factor gene in patients and carriers of severe von Willebrand disease.

Severe von Willebrand disease is characterized by undetectable or trace quantities of von Willebrand factor in plasma and tissue stores. We have studied the genomic DNA of 10 affected individuals from six families with this disorder using probes from the 5' and 3' ends of the vWF cDNA and with a probe extending from the 5' end into the central region. Southern blots of restriction endonuclease digests and gene dosage analysis measurements carried out with quantitative slot blots of undigested genomic DNA separated these patients into three groups. The first group consisted of a family with complete homozygous deletions of the vWF gene in the four probands. Gene dosage analysis was consistent with heterozygous deletions in both of the asymptomatic parents and four asymptomatic siblings of this kindred (P less than 0.01). The second group was comprised of a family in which there was a complete heterozygous deletion of the vWF gene in the proband and one asymptomatic parent, suggesting that a different type of genetic abnormality was inherited from the other parent. Thus, the patient appeared to be doubly heterozygous for interacting genetic abnormalities affecting vWF expression. In the third group, no gene deletions could be detected. Alloantibodies developed only in the kindred with homozygous deletions. These techniques should prove useful in identifying carriers of severe von Willebrand disease and also in defining patients predictably at risk of developing alloantibodies to vWF.

Abnormal procollagen synthesis in fibroblasts from three patients of the same family with a severe form of osteogenesis imperfecta (type III)

Dermal fibroblast cultures from three siblings with a severe form of osteogenesis imperfecta were established in order to analyze their procollagen and collagen synthesis. Cell strains from clinically normal consanguineous parents (first cousins), were also obtained for comparison. Total collagen production in culture media was diminished by 55% in the patients fibroblasts and to a lesser extent in the parents. This decrease was specific for collagenous proteins. From polyacrylamide gel electrophoresis, it appeared that the three children had not only the same defective secretion of pro α 1(I) molecules but that their pro α 1(I) migrated slightly faster than the parental and control counterparts. Analysis of secretion confirmed a reduced rate in procollagen synthesis and the absence of intracellular storage. Upon pepsin treatment, extracellular α 1(I) and α 2(I) chains were found in the expected ratio of 2:1 and migrated normally, suggesting that the altered mobility of pro α 1(I) chains was related to COOH or NH 2 terminal propeptides. In agreement with the reduced type I collagen production, an increase in the α 1( III) α 1( I) ratio was also detected. Furthermore, after a 2.5-h labelling followed by alkylation with iodoacetamide, free intracellular pro α 2(I) and α 1(I) chains were detected in the absence of reduction, consistent with an abnormal intracellular ratio of pro α 1( I) pro α 2( I) that was measured after dithiothreitol reduction. Analysis of intracellular collagen chains from parental strains following a 4-h incubation demonstrated that pro α 1(I) appeared as a doublet, one band with normal mobility and a less intense band migrating faster and corresponding to the defective chain found in the patients. Absence of the abnormal molecules in culture media was related to the demonstration of a defective collagen secretion by parental fibroblasts. Correlation between these biochemical findings and clinical data strongly support a recessive inheritance of the disease that could be classified as a type III form of osteogenesis imperfecta. Patients would be homozygous for the same defective allele and the asymptomatic parents would most likely be heterozygous carriers of the mutation. Although the exact location of the alteration is not yet elucidated, a splicing mutation is suggested.

Identification of minimal expression of myotonic dystrophy using electroretinography

The electroretinograms (ERGs) of patients with definite myotonic dystrophy were studied as well as neurologically asymptomatic patients with minimal expression of myotonic dystrophy. Children in 4 families exhibited definite myotonic dystrophy when neither parent exhibited clinical or electromyographic signs of myotonic dystrophy. Myotonic dystrophy is dominantly inherited. We were able to identify the asymptomatic parent with the gene in these families. This study suggests that ERG testing, which includes scotopically balanced dim blue and red flashes, will identify some asymptomatic adults minimally expressing the gene for myotonic dystrophy.

All in the family: matrimonial mitral valve clicks.

Mitral valve clicks with or without late systolic murmurs were detected in genetically unrelated marital partners of 5 families. The first family represented 2 successive nonconsanguineous marital unions with 3 generations of mitral valve clicks. The second family included 1 natural and 2 adopted children with clinical and echographic evidence of mitral valve prolapse. The third family was comprised of asymptomatic parents, both with nonejection clicks and mitral valve prolapse, whose daughter presented 3 years previously with syncope, palpitations, and combined mitral and tricuspid valve prolapse. The fourth family had 3 members with auscultatory and ultrasonic manifestations of billowing mitral valve, whereas the fourth member had "silent mitral valve prolapse." The fifth family represented a mother with auscultatory and echographic evidence of mitral valve prolapse; her 14-year-old daughter had both mitral and tricuspid valve prolapse, whereas the son had a bicuspid aortic valve. Both children were products of a prior marriage, and her husband has symptomatic mitral valve prolapse. We conclude that matrimonial mitral valve prolapse probably reflects the purported (6--10%) prevalence of this disorder in the general population. The consequences of such marital union on progeny is currently unclear and warrants future investigation.

Presumed vitelliform dystrophy with perimacular flecks and retinal detachment

Seven of eight siblings of asymptomatic non-consanguineous parents were investigated. Two of them had atrophic cystoid macular degeneration and flat or subnormal electro-oculograms suggesting the diagnosis of vitelliform dystrophy. In one eye the central cystoid lesion was surrounded by atypical small whitish hyperfluorescent flecks resembling fundus flavimaculatus. In the other eye of this patient cystoid macular degeneration progressed to shallow non-rhegmatogenous detachment of the retina. One of the asymptopmatic siblings had a mild colour vision defect of tritan-type and some fleckish hyperfluorescence around the macula and another sister showed abnormal EOG responses. These patients are probably carriers of the pathological gene responsible for the disease.

Late-Infantile Neuronal Ceroid-Lipofuscinosis

Ultrastructural study of peripheral blood from two patients with late-infantile neuronal ceroid-lipofuscinosis with curvilinear bodies, demonstrated in brain biopsies revealed curvilinear bodies in lymphocytes. These findings indicate that ultrastructural investigation of circulating lymphocytes may be useful in the diagnosis of late-infantile neuronal ceroid-lipofuscinosis and may circumvent the need for brain biopsy. Curvilinear bodies were also present in the lymphocytes of a neurologically normal younger female sibling of patient 1, who has had a single seizure, leading to speculation that she may be in the early stages of the same disease. This case suggests the possibility of early detection of this disorder and indicates the importance of screening lymphocytes of siblings of affected patients. Tubular cytoplasm inclusions were present in a high percentage of lymphocytes of the asymptomatic parents and a younger sibling of these patients.

Analysis of peroral jejunal biopsies in clinically asymptomatic parents of children with celiac sprue.

Peroral jejunal biopsies were performed in both clinically asymptomatic parents of 15 children with c.s. Histological, histochemical and biochemical exanimation revealed various alterations in 24 parents. Irregular configuration of villi, increased quantity of cytoplasmic RNA in enterocytes and decreased activities of membrane enzymes, shift of LDH-monomers in favor of the H-form and a decrease of total activity of lactase and cellobiase were found. The origin of changes, particularly their relation to the ingestion of gluten or to other injuries of the jejunal mucosa as well as to some hereditary mechanism, remains unknown at the present time.

Red-cell transport defect in patients with cystic fibrosis and in their parents.

The ouabain-sensitive and the ethacrynic acid-sensitive sodium efflux from erythrocytes of patients with cystic fibrosis are both decreased. Furthermore, the ouabain-sensitive adenosine triphosphatase activity is diminished in the red blood cell ghosts of these patients. Perhaps of greater significance is the fact that ethacrynic acid-sensitive sodium efflux is clearly diminished in the erythrocytes of the asymptomatic parents of these sick children. This defect in sodium transport may be valuable for detecting the heterozygous carrier state.

Familial growth retardation, renal aminoaciduria and cor pulmonale: I. Description of a new syndrome, with case reports

A syndrome, apparently previously undescribed, characterized by growth retardation, poor muscular development, scanty adipose tissue, recurrent pulmonary infection, atelectasis and right ventricular hypertrophy has been found in three of six children of asymptomatic parents. Two children died suddenly in the first decade. The survivor has, in addition, aminoaciduria without hyperaminoacidemia, increased plasma unesterified fatty acid concentration, a low basal respiratory quotient and evidence of alveolar hypoventilation with resultant cor pulmonale.