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Results for “Chediak-Higashi Syndrome”

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At least 19 recordsLinked to original sources
PubMed2025

Comprehensive analysis of a novel LYST mutation in a Tunisian patient with Chediak-Higashi syndrome.

BACKGROUND: Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism, recurrent infections, bleeding tendencies, and progressive neurological impairment. The syndrome is caused by mutations in the LYST gene, which plays a crucial role in lysosomal trafficking. OBJECTIVE: This study aims to characterize the molecular basis of CHS in a Tunisian patient by identifying mutations in the LYST gene and analyzing their impact on the protein function, correlating these findings with the patient's clinical presentation. METHODS: A comprehensive clinical assessment was conducted on the patient, followed by biochemical, hematological, and microbiological analyses. Additionally, LYST protein levels were quantified in the patient and their parents using an ELISA assay. Genomic DNA was extracted from the patient's blood, and Whole Exome Sequencing (WES) was performed to identify mutations in the LYST gene. The findings were confirmed through Sanger sequencing, and bioinformatic tools were employed to predict the functional consequences of the detected mutations. RESULTS: The patient presented with classical symptoms of CHS, including silver hair, hypopigmented skin, recurrent infections, and neurological decline, with an unusually late onset at 18 years. ELISA results demonstrated significantly reduced LYST levels in the patient (1.8 ng/ml) compared to heterozygous parents (7.8 ng/ml and 8.1 ng/ml) and controls (9.2 ng/ml). Genetic analysis revealed a novel homozygous deletion, c.10269_10275del (p.Gly3424SerfsTer15), in the LYST gene, leading to a frameshift mutation and premature termination of the protein. Bioinformatic analysis demonstrated that this mutation leads to the deletion of five out of sven WD40 repeats in the protein's C-terminal region, which are critical for protein-protein interactions and lysosomal trafficking. CONCLUSION: The study identifies a novel LYST mutation in a Tunisian patient with CHS, expanding the spectrum of known genetic variants associated with the disease. The findings highlight the importance of genetic screening in populations with high consanguinity and underscore the need for targeted therapies to address the molecular defects in CHS.

Adolescent↗
PubMed1979

The Chediak-Higashi syndrome: quantitation of a deficiency in maximal bactericidal capacity.

The maximum bactericidal capacity of neutrophils from a patient with the Chediak-Higashi syndrome (CHS) was measured by a quantitative assay in which the neutrophils were challenged with increasing multiples of Staphylococcus aureus, 502A. At various bacterial challenges from 0.5 to 65 bacteria per neutrophil, the CHS cells killed normal numbers of bacteria in 60 minutes. However, at higher ratios with a mean of 118 bacteria per neutrophil, the percentage of bacteria killed in 60 minutes by CHS neutrophils (8.1 +/- 2.3%) was significantly less (P < 0.001) than that killed by normal neutrophils (44 +/- 2.3%). The CHS neutrophils lagged in their ability to kill low challenges of bacteria (0.5 or 1.2 bacteria per neutrophil) only at 20 minutes. A hydrogen-peroxide-producing strain of Streptococcus faecalis was killed normally by the CHS neutrophils at 60 minutes, with all ratios of challenge up to 114 to 1. Electron microscopic examination of 60-minute specimens from high ratios of challenge that were stained for myeloperoxidase activity revealed a failure of many bacteria-laden phagosomes to display this marker of degranulation. The results of this study indicate that the maximal bactericidal capacity of CHS neutrophils is saturated by a significantly lower challenge of bacteria than is required to saturate normal cells. This appears to be the result of sequestration of a significant portion of these cells' bactericidal resources in the giant granules that do not participate appreciably in degranulation.

Adolescent↗
PubMed1975

Defective lysosomal enzyme secretion in kidneys of Chediak-Higashi (beige) mice.

The beige mouse is an animal model for the human Chediak-Higashi syndrome, a disease characterized by giant lysosomes in most cell types. In mice, treatment with androgenic hormones causes a 20-50-fold elevation in at least one kidney lysosomal enzyme, beta-glucuronidase. Beige mice treated with androgen had significantly higher kidney beta-glucuronidase, beta-galactosidase, and N-acetyl-beta-D-glucosaminidase (hexosaminidase) levels than normal mice. Other androgen-inducible enzymes and enzyme markers for the cytosol, mitochondria, and peroxisomes were not increased in kidney of beige mice. No significant lysosomal enzyme elevation was observed in five other organs of beige mice with or without androgen treatment, nor in kidneys of beige females not treated with androgen. Histochemical staining for glucuronidase together with subcellular fractionation showed that the higher glucuronidase content of beige mouse kidney is caused by a striking accumulation of giant glucuronidase-containing lysosomes in tubule cells near the corticomedullary boundary. In normal mice lysosomal enzymes are coordinately released into the lumen of the kidney tubules and appreciable amounts of lysosomal enzymes are present in the urine. Levels of urinary lysosomal enzymes are much lower in beige mice than in normal mice. It appears that lysosomes may accumulate in beige mice because of defective exocytosis resulting either from decreased intracellular motility of lysosomes or from their improper fusion with the plasma membrane. A similar defect could account for characteristics of the Chediak-Higashi syndrome.

Alcohol Oxidoreductases↗
PubMed1979

Albinism.

There are seven forms of oculo-cutaneous albinism, which are all autosomal recessive: three are tyrosinase-negative (complete oculo-cutaneous albinism, Amish albinism, Hermansky-Pudlak syndrome) and four are tyrosinase-positive (incomplete oculo-cutaneous albinism, Chediak-Higashi syndrome, Cross syndrome, Bergsma's albinism). There are three forms of sex-linked albinism: ocular albinism, which is intermediary sex-linked, François-De Rouck syndrome and Ziprkowski syndrome, which show a generalized albinism and are recessive sex-linked. There are two principal forms of cutaneous albinism, one without deafness and the other with deafness (Waardenburg-Klein syndrome).

Albinism↗
PubMed1977

Large granules and lysosomal fusion in human Chediak-Higashi white blood cells.

The phenomenon of giant anomalous lysosome formation in human Chediak-Higashi syndrome leukocytes was analyzed. Ultrastructure findings combined with cytochemical procedures for visualizing acid phosphatase and peroxidase activity showed giant anomalous granules in addition to normal, small and enlarged granules. Massive granules in lymphocytes had an appearance and structure different from those found in other leukocytes. The giant granules seem to be a product of an active fusion between primary and secondary normal sized or enlarged lysosomes. This fusion occurs in polymorphonuclear neutrophils, eosinophils and in monocytes. No fusion was found in lymphocyte granules.

Acid Phosphatase↗
PubMed1978

The mouse gut T lymphocyte, a novel type of T cell. Nature, origin, and traffic in mice in normal and graft-versus-host conditions.

Lymphocytes of the mouse intestinal mucosa, identified in tissue sections or purified suspensions of intraepithelial lymphocytes as T cells (gut T lymphocytes [GTL]), were studied in normal mice or in beige mice (the equivalent of the Chediak-Higashi syndrome in man, characterized by giant granules in various cell types, including mast cells). Mice were studied in normal or in germ-free conditions, or during a graft versus host (GVH) reaction resulting from the injection of parental thymocytes into lethally irradiated F1 mice, a condition leading to massive accumulation of T lymphocytes of donor origin in the host gut mucosa. In normal as well as in GVH conditions, a high percentage of the gut IE lymphocytes contain granules (up to 80% in the beige mouse). These granules have ultrastructural, hostochemical and other features resembling those of mast cell granules; in beige mice, up to 50% of them can be shown to contain histamine. Granulated T cells are also found in the lamina propria. It appears that the GTL may progressively lose their surface T antigens when the granules become more developed. Kinetics of [3H]TdR labeling of the GTL, transfer experiments with T cells of various origins, selective [3H]TdR labeling and selective irradiation of the Peyer's patches (PP), and effect of thoraic duct (TD) drainage led to the conclusion that GTL are the progeny of T cells stimulated to divide in the PP microenvironment, which endows them with a gut-homing tendency. From the PP, these cells follow a cycle, migrating to the TD and to the blood to colonize the whole intestinal mucosa, the majority of them as dividing cells undergoing a single round of traffic, with some probably able to recirculate and becoming a more long-lived variety. Antigenic stimulation within the PP is necessary for the emergence of GTL progenitors, but their gut-homing property is unrelated to the antigen as shown with fetal gut grafts, notably in GVH where grafts syngeneic to the host or donor become similarly infiltrated by GTL. On the basis of their properties and of further evidence to be reported elsewhere, it is proposed that GTL belong to a special class of T lymphocytes, related to the immune defenses of the mucosal systems in general, and capable of acting as progenitors of mucosal mast cells.

Animals↗
PubMed1975

Abnormal mast cell granules in the beige (Chédiak-Higashi syndrome) mouse.

Mast cells of beige (C57BL/6J) (bg-j/bg-j) mice were examined histochemically and ultrastructurally. Mast cell granules in the beige mice were markedly enlarged and irregular in shape. Granule contents stained uniformly with acidified toluidine blue, but with ruthenium red and Alcian Blue-safranin, two components were evident. The rims of the abnormal granules stained with ruthenium red and with Alcian Blue; the centers of the granules were clear with ruthenium red and stained with safranin. Mast cell granules thus represent another abnormal organelle in the Chédiak-Higashi syndrome.

Animals↗
PubMed1978

The ultrastructure of defective human platelets.

Much of our current knowledge about the physiology of hemostasis has come from intensive study of platelets from patients with inherited and acquired bleeding disorders or an increased risk of thrombotic disease. Appreciation of the role of plasma proteins in platelet stickiness, of platelet surface membrane glyco-proteins in aggregation, of the substances stored in platelet organelles in cell-cell interaction, vascular injury and atherosclerosis, and of endoperoxides and thromboxanes in platelet intercellular communication have resulted largely from investigations on various types of defective platelets. While the techniques of physiology and biochemistry have generated critical details about abnormal platelets, electron microscopy and ultrastructural cytochemistry have provided an improved morphological framework in which to integrate the new discoveries. The present review has attempted to correlate physiological, biochemical and ultrastructural concepts as they relate to the current understanding of inherited platelet disorders.

Blood Platelet Disorders↗
PubMed1978

Immunocytochemical identification of azurophilic and specific granule markers in the giant granules of Chediak-Higashi neutrophils.

We used immunofluorescent microscopy to characterize the abnormal granules in neutrophils from five patients with Chediak-Higashi disease. Monospecific antiserums to the azurophilic markers myeloperoxidase, elastase, cathepsin G and lysozyme, and to the specific granule markers lactoferrin and lysozyme, were labeled with fluorescein and rhodamine and were used to demonstrate two antigens in the same cell simultaneously. The abnormal granules in Chediak-Higashi neutrophils contained both azurophilic and specific granule markers. Normal-appearing lactoferrin-positive granules were also present, but normal azurophilic granules were not seen. Analysis of bone-marrow samples from two of these patients suggested that the abnormal granules were formed during granulocyte maturation by the progressive aggregation and fusion of normally formed azurophilic and specific granules. These results are consistent with a membrane abnormality or a defect of microtubular function leading to inappropriate granule fusion, and suggest that the granular abnormality is more generalized than previously appreciated.

Acid Phosphatase↗
PubMed1977

Disorders of phagocyte function: biochemical aspects.

Intensive laboratory investigation of patients with recurrent infections, and with infections with microbial species not usually considered to be pathogenic, have led to the identification of several defects in granulocyte function. The two functions of granulocytes which have received most attention in the past decade have been locomotion (especially response to chemotactic stimulation) and microbicidal activity. Defective granulocyte chemotaxis has been demonstrated in patients with clinical manifestations suggesting abnormalities related to vasoactive amines, i.e., patients with eczema and extreme IgE hyperimmunoglobulinemia. The depressed granulocyte chemotactic responsiveness found in these patients can be reproduced in vitro when histamine and beta adrenergic agents are incubated with control granulocytes. Since these compounds have been shown to increase levels of intracellular cyclic AMP in other cells, there appears to be an association between cyclic nucleotide metabolism and regulation of granulocyte locomotion. Defective granulocyte microbicidal activity is found in patients with chronic granulomatous disease and it has been shown that there is little increase in oxidative metabolism during phagocytosis by these cells. Methods for quantitating the oxidative metabolism of granulocytes and monocytes include oxygen uptake, reduction of nitroblue tetrazolium, formate oxidation, and chemiluminescence response during phagocytosis. Since products of oxygen metabolism, i.e., hydrogen peroxide, superoxide or singlet oxygen do not accumulate in granulocyte phagocytic vacuoles, intracellular microbes are not killed (except bacterial species that produce hydrogen peroxide). The biochemical basis for defective oxidative metabolism in granulocytes from patients with chronic granulomatous disease appears to be associated with abnormal nucleotide oxidase activity.

Blood Bactericidal Activity↗