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Biomedical subjects

L D Notarangelo

Publications and source records attributed to L D Notarangelo.

At least 19 recordsLinked to original sources
PubMed1992

Wiskott-Aldrich syndrome carrier detection with the hypervariable marker M27 beta.

Whole-blood cells of obligate carriers of the X-linked Wiskott-Aldrich syndrome (WAS) exhibit nonrandom inactivation of the X-chromosomes. However, because of the limited polymorphism of the probes available, the X-methylation pattern can only be determined in a restricted proportion of females. We thus analysed a large set of normal females and members of WAS families, using the recently described marker M27 beta, which detects the hyperpolymorphic locus DXS255. The probe was used to detect differences in methylation between the active and inactive X-chromosome, and the findings were compared with the pattern obtained using the well-documented probes from the 5' end of the PGK and HPRT genes. All the normal females were found to use either X-chromosome randomly, and there was complete correlation between the three probes in the populations studied. Segregation analysis performed with M27 beta and other related markers in the WAS families was fully in accordance with the X-inactivation data. The use of M27 beta, for both X-inactivation and segregation analysis of WAS kindreds, provides a basis for genetic counselling in the majority of families, including those with no surviving males.

DNA Probes↗
PubMed1992

Insulin-dependent diabetes mellitus and severe atopic dermatitis in a child with adenosine deaminase deficiency.

We report a 2.3-year-old girl with complete lack of adenosine deaminase (ADA) activity who presented with severe atopic dermatitis and insulin-dependent diabetes mellitus but only mild recurrent infections. Abnormalities of immune function included profound depletion of CD8+ lymphocytes, hyperimmunoglobulinaemia E, and very low in vitro proliferative response to mitogens. Treatment with polyethylene glycol-conjugated ADA was followed by rapid amelioration of clinical and immunological conditions. The immunological and clinical features of this child suggest that the clinical spectrum of ADA deficiency may be broader than originally supposed.

Adenosine Deaminase↗
PubMed1992

Carrier detection in X-linked adrenoleukodystrophy by determination of very long chain fatty acid levels and by linkage analysis.

Diagnosis of X-linked adrenoleukodystrophy is based upon demonstration of high levels of very long chain fatty acids. More recently, in addition to biochemical analysis, closely linked DNA probe St14 has been used for prenatal diagnosis in informative families. Identification of heterozygotes is particularly important, both in order to specifically address only carrier females to prenatal diagnosis, and because appropriate dietary therapy is now available to treat those heterozygotes presenting with neurological symptoms. We report two pedigrees in which carrier detection was performed by a combination of biochemical and molecular genetic analysis. Such approach should allow extremely high accuracy in carrier detection.

Adrenoleukodystrophy↗
PubMed1992

Identification of novel RFLPs in the vicinity of CpG islands in Xq28: application to the analysis of the pattern of X chromosome inactivation.

Probes for CpG islands were cloned from the distal long arm of the human X chromosome; three of them were found to be polymorphic. A HindIII RFLP was identified by the probe 2-25 (DXS606), and it was mapped to the Xq27-Xq28 boundary. Probes 2-19 (DXS605) and 2-55 (DXS707), which identify EcoRI and MspI polymorphisms, respectively, have been mapped to the distal part of Xq28, in the G6PD-RCP/GCP gene region. Probe 2-19 has been further localized about 16 kb from the 3' end of the G6PD gene. The new RFLPs may be useful for the precise mapping of the many disease genes localized in this part of the human X chromosome. Probe 2-19 is highly informative, and it has been studied in greater detail. Using the methylation-sensitive rare-cutter enzyme EagI in conjunction with the polymorphic EcoRI site, we were able to demonstrate that the RFLP may be used both to study randomness of X chromosome inactivation and for carrier detection in X-linked syndromes where nonrandom X inactivation occurs. It is conceivable that the combined use of 2-19 and of the probes described so far (pSPT-PGK and M27 beta) will make analysis of X inactivation feasible in virtually every female.

Alleles↗
PubMed1992

Immunodeficiency with hyper-IgM (HIM).

Immunodeficiency with hyper-IgM (HIM) is a rare disorder characterized by recurrent infections associated with low IgG and IgA, and normal to increased IgM serum levels. Both primary and secondary forms of HIM syndrome have been reported. Among primary HIM syndrome, evidence for genetic heterogeneity is provided by the occurrence of the disease as X-linked, autosomal recessive, or autosomal dominant trait. The most common clinical manifestations include upper and lower respiratory tract infections, otitis, diarrhoea, oral ulcers, lymphoid hyperplasia, and autoimmunity. Recurrent neutropaenia is a frequent finding. Immunological abnormalities consist of lack of IgG and IgA secretion, and failure to respond to vaccination. Lymph nodes show absence of germinal centres. Few patients with a concurrent T-cell defect, and clinical expression of combined immune deficiency, have been reported. The gene responsible for the X-linked HIM syndrome (HIGM1) has been tentatively assigned to Xq24-27. However, carrier detection and prenatal diagnosis are not yet possible. Pathogenetic hypotheses include failure of B-cell differentiation, and defective regulation of immunoglobulin isotype switching due to abnormal T-cell-mediated signals. Treatment is mainly based upon regular administration of intravenous immunoglobulins. Steroids may be useful in the treatment of neutropaenia and of severe autoimmune manifestations.

Chromosome Mapping↗
PubMed1991

Analysis of X-chromosome inactivation in X-linked immunodeficiency with hyper-IgM (HIGM1): evidence for involvement of different hematopoietic cell lineages.

The pattern of X-chromosome inactivation was analyzed, by means of two different DNA probes (pSPT-PGK and M27 beta), in several cell lineages derived from females belonging to a pedigree with X-linked immunodeficiency with hyper-IgM (HIGM1). Non-random X-chromosome inactivation was demonstrated in T cells, B cells, and neutrophils, but not in fibroblasts, of obligate carriers, suggesting that different hematopoietic cell lineages are primarily involved in HIGM1. Preferential inactivation of the paternally derived X-chromosome was demonstrated by analysis of segregation of the alleles defined by the pSPT-PGK and M27 beta probes. The possibility that the HIGM1 mutation may confer a proliferative and/or differential advantage to hematopoietic precursors carrying the mutated allele on the active X-chromosome is discussed.

B-Lymphocytes↗
PubMed1991

Analysis of X-chromosome inactivation and presumptive expression of the Wiskott-Aldrich syndrome (WAS) gene in hematopoietic cell lineages of a thrombocytopenic carrier female of WAS.

We report on a thrombocytopenic female belonging to a pedigree with the Wiskott-Aldrich syndrome (WAS). Restriction fragment length polymorphism (RFLP) analysis with probe M27 beta, closely linked to the WAS gene, demonstrated that she is a carrier of WAS. Both small-sized and normal-sized platelets were present, suggesting that, unlike the vast majority of WAS carriers, she does not manifest nonrandom X-chromosome inactivation in the thrombopoietic cell lineage. Study of X-chromosome inactivation by means of RFLP and methylation analysis demonstrated that the pattern of X-chromosome inactivation was nonrandom in T lymphocytes, but random in granulocytes. While this is the first complete report on the occurrence of thrombocytopenia in a carrier female of WAS as the result of atypical lyonization, it also suggests that expression of the WAS gene occurs at (or extends up to) a later stage than the multipotent stem cell along the hematopoietic differentiation pathway.

Dosage Compensation, Genetic↗
PubMed1990

Immunology of Down syndrome: a review.

Subjects with Down syndrome (DS) have a high mortality due to infections and a high risk of developing malignancies. These observations, together with the demonstration of a frequent occurrence of HBsAg carrier state and of autoantibodies, have prompted investigations of the immune function in DS. Thymic morphological and functional abnormalities have been demonstrated. Peripheral blood mononuclear cells of DS subjects have been shown to include a high number of T lymphocytes with low avidity for sheep erythrocytes and a very high percentage of cells with an NK phenotype. However, NK activity is low in DS. Production of some important cytokines, such as IL-2, is depressed, thus contributing to T-cell derangement. Abnormalities of the B-cell compartment were also demonstrated, with a tendency towards high IgG and low IgM serum levels. Controversial results have been obtained with regard to antigen-specific antibody response. Also phagocytes of DS subjects display some characteristic functional impairments, with low chemotactic ability and reduced production of oxygen radicals. Despite the clearly established and rather detailed evidence of immune derangements, therapeutic trials have been anecdotal and resulted in marginal effects. HBV vaccination is highly advisable in DS because of the high risk of becoming chronic HBV carriers once infected.

Adolescent↗
PubMed1989

Close linkage of probe p212 (DXS178) to X-linked agammaglobulinemia.

Segregation analysis was performed in three families affected in X-linked agammaglobulinemia (XLA) with five polymorphic DNA probes linked to the disease locus. In agreement with previous studies, no recombination was observed with either pXG12 (DXS94) or S21 (DXS17). Segregation analysis was also performed with a marker, p212 (DXS178), which has been shown to be closely linked to pXG12 in normal families. No cross-over with XLA was observed in these three families and in five additional families previously analyzed with DXS17 and DXS94 (z = 5.92 at theta = 0). These data provide evidence against genetic heterogeneity in XLA and indicate the value of probe p212 for carrier detection and prenatal diagnosis of XLA. We were able to estimate the carrier status of six females (out of six) in the three previously unreported families.

Agammaglobulinemia↗
PubMed1989

[RAST positivity for food in atopic dermatitis].

In 113 children with atopic dermatitis RAST results for 9 food mixtures were analyzed. Sixty-eight children (60%) were RAST positive (greater than or equal to ++) for one or more mixture and 87% of those RAST positive had specific IgE for egg and/or cereals and/or legumes. Sensitization to egg, cow milk and meat was more frequent in the first years of life. RAST for the mixture of cereals and each single cereal, performed in 37 children, gave concordant results in 76%; agreement for the positive results was 88%, but only 54% for the negative ones. Breast versus cow milk feeding in the first months of life was not found to affect intensity of the skin manifestations or frequency of RAST positivity for the food mixtures or the respiratory symptoms.

Child↗
PubMed1988

Neonatal T4+ lymphocytes: analysis of the expression of 4B4 and 2H4 antigens.

Using monoclonal antibodies anti-2H4 and anti-4B4 we investigated by double immunofluorescence and immunorosette technique the presence of cells displaying the helper-inducer and the inducer of suppression phenotype among T4+ cord blood cells. The analysis of the estimated frequencies of subpopulations of T4+ cells shows that a high percentage of T4+ cord blood cells can coexpress both antigens in comparison to adult. Furthermore the percentage of T4+ cells with helper-inducer phenotype (2H4-4B4+) is significantly lower than that in the adult, while the percentage of T4+ cells with suppressor-inducer phenotype (2H4+4B4-) although higher, is not significantly different. These findings suggest that the relative immunoincompetence observed in the newborn may result from a variety of mechanisms including a low percentage of helper-inducer (4B4+2H4-) T4+ lymphocytes possibly also associated to an increased number of suppressor-inducer T4+ cells (2H4+4B4-).

Antibodies, Monoclonal↗
PubMed1986

IgG subclass serum levels in juvenile chronic arthritis.

IgG subclass levels of sera from 26 patients with juvenile chronic arthritis (JCA) were determined by means of mouse monoclonal antibodies. Patients were divided into three groups according to clinical activity of the disease: active disease, partial remission, and remission. One hundred and sixty four age matched, healthy children served as controls. IgG subclass concentrations were log transformed, and a robust regression method was applied to obtain expected values for the different ages. We found a significant increase of IgG3 (p less than 0.0001), IgG1 (p less than 0.002), and IgG2 (p less than 0.035) in JCA sera, while IgG4 values did not differ significantly from those of controls. When patients were divided according to clinical activity significant increases of IgG2 and IgG4 were observed in the patients in partial remission. Our data suggest that differential increase of IgG subclasses during the courses of JCA may be of relevance to the pathogenesis of the disease.

Adolescent↗
PubMed1986

Enhanced interleukin 1 and depressed interleukin 2 production in juvenile arthritis.

Blood mononuclear cells from a total of 23 children with juvenile arthritis were stimulated in vitro to produce interleukin 1 (IL-1) and interleukin 2 (IL-2) and compared with age matched healthy controls. Peripheral blood monocytes from patients with juvenile arthritis produced a higher amount of IL-1 than controls, whereas peripheral blood lymphocytes from the same patients produced lower amount of IL-2 than controls. These findings could not be explained by concurrent therapy. The increase of IL-1 production was more marked in patients with active disease and therefore may have been secondary to the pathological process. However, the decrease of IL-2 production did not depend on disease activity, thus suggesting an immunoregulatory abnormality.

Adolescent↗
PubMed1986

Lymphocyte subpopulations in the neonate: in vitro proliferation, IL-1 and IL-2 production by a subset of HNK-1-, OKT3-, OKT8+ lymphocytes displaying NK activity.

Neonatal lymphocytes include a subset of E-, OKT3-, OKT4-, OKT8+, HNK-1-, OKM1- cells displaying natural killer (NK) activity. More than 50% of these cells react with the B73.1 monoclonal antibody, moreover most of them bear the DR antigen, the receptor for Peanut agglutinin (PNA) and react with the OKT10 monoclonal antibody. This neonatal subset displays a higher NK activity than unseparated cord blood lymphocytes (CBL) and the present study shows that it is sensitive to boosting effect of IFN-B preincubation. When stimulated with T cell mitogens E-, OKT3-, OKT8+ CBL both produce Interleukin-2 (IL-2) and proliferate. Moreover this neonatal subset produces Interleukin-1 (IL-1) both spontaneously and in response to lipopolysaccharide (LPS). It has been previously suggested that these neonatal cells include a common precursor of NK and T cells. The present study further strengthen this hypothesis.

Antibodies, Monoclonal↗
PubMed1985

Henoch-Schönlein syndrome and selective IgA deficiency.

A 9 year old girl presented with clinical manifestations of Henoch-Schönlein syndrome and macroscopic haematuria. Laboratory investigations showed selective IgA deficiency and renal biopsy showed mesangial proliferative glomerulonephritis with diffuse granular deposits of C3 on immunofluorescence. IgA deposits were absent.

Child↗