Hereditary Myeloperoxidase Deficiency: Study of 12 Cases

12 cases of hereditary myeloperoxidase (MPO) deficiency are reported. Histochemical stainings, lysosomal enzyme determinations, electron microscopic study of MPO and granulocytic function were performed. Family studies on 2 generations were carried out in 5 patients and histochemical stainings and biochemical lysosomal enzyme determinations were done. MPO deficiency was found to follow autosomal recessive inheritance and only rarely to have clinical effects.     

Impaired Neutrophil Function and Myeloperoxidase Deficiency in Pregnancy

The ability of neutrophils to phagocytose and kill Candida guilliermondii was investigated in 28 pregnant women and compared wtih 29 healthy controls. Phagocytosis was normal, but the ability to kill and digest Candida was reduced to 65% of normal. Quantitative myeloperoxidase measurement revealed a considerable reduction of this enzyme (55% of normal) while neutrophil alkaline phosphatase levels were nearly twice as high as in normals. It is suggested that both lack of myeloperoxidase and impaired candidacidal ability result from the discharge of the neutrophil's granules during previous phagocytosis of antibody-antigen complexes in the circulation.     

Partial Myeloperoxidase Deficiency in a Case of Preleukaemia

A patient with a refractory anaemia preceding acute myeloblastic leukaemia had an increased susceptibility to infection due to Staphylococcus aureus. 36% of neutrophils lacked myeloperoxidase (MPO) activity and, in vitro, these polymorphonuclear neutrophils (PMN) had a defect of bactericidal activity against Staphylococcus aureus. Cytochemical studies of phagocytosis with the electron miscroscope have shown that the degranulation of primary granules (MPO+ or MPO-) was normal after phagocytosis of Escherichia coli which were normally lysed. A defective destruction of Staphylococcus aureus and Candida albicans was observed in some PMN with or without MPO activity, suggesting that MPO deficiency itself was not the only cause of this defect. In PMN which appeared normal, most MPO(+) granules were unable to fuse with the phagocytic vacuole containing intact germs even after 90 min of contact. There was, therefore, in addition to a partial MPO deficiency, a defect in cellular degranulation. This defect, the mechanism of which is unknown, may be in part responsible for the defective bacterial degradation.     

Partial Myeloperoxidase Deficiency in a Case of Preleukaemia

The ultrastructural localization of peroxidase activity has been studied in the circulating neutrophils and in a neutrophilic series of bone marrow cells from a patient with preleukaemia. Light microscopic examination showed 36% of the polymorphonuclear leucocytes to be totally devoid of myeloperoxidase, while 50% were normally stained and 14% were slightly positive for this enzyme. Electron microscopic studies revealed considerable heterogeneity in the promyelocyte population, since the number of peroxidase-deficient azurophil granules was seen to vary from 0 to 100% in these cells. Thus, several types of promyelocytes were identified. One cell type, which resembled that seen in normal subjects, contained myeloperoxidase within its azurophil granules and also within the cisternae of the rough endoplasmic reticulum and Golgi complex. A second type of promyelocyte, which was at an early stage of development, lacked myeloperoxidase in its secretory apparatus. These cells contained two species of azurophil granules, the first of which was devoid of peroxidase activity whereas the other reacted positively. These observations suggest that the premature arrest of myeloperoxidase synthesis in the promyelocytes from a preleukaemic patient may give rise to several populations of circulating neutrophils which can exhibit varying contents of myeloperoxidase.     

Impaired Neutrophil Function and Myeloperoxidase Deficiency in Myeloid Metaplasia

The ability of neutrophils to phagocytose and kill Candida guilliermondii was investigated in 12 patients with myeloid metaplasia (MM). Following ingestion there was a considerable impairment in the ability of MM neutrophils to kill and digest Candida which was not explained by the very mild impairment in phagocytosis. Quantitative myeloperoxidase measurement revealed an overall deficiency of this enzyme in MM neutrophils and a highly significant correlation between low myeloperoxidase levels and impaired candidacidal activity. Neutrophils from patients with myeloid metaplasia show a pattern of defective microbial killing, high alkaline phosphatase activity and low myeloperoxidase activty which is similar to that seen in severe infections and distinct from chronic granulocytic leukaemia. The cells of one patient with particularly low myeloperoxidase and defective microbial killing were further studied both cytochemically and by electron microscopy. The azurophilic granules of his neutrophils were present in normal numbers and contained normal amounts of acid phosphatase but they lacked myeloperoxidase.     

Molecular Characterization of Glucose-6-Phosphate Dehydrogenase Deficiency among Jordanians

Background/Aims: In Jordan, glucose-6-phosphate dehydrogenase (G6PD) deficiency is a significant health problem, and the incidence was reported to be about 3.6%. The aims of this study are to investigate the most common molecular mutations of the G6PD gene among Jordanians in northern Jordan and to examine the correlation between the genotype and phenotype of this enzyme deficiency. Methods: Seventy-five blood samples were collected from patients attending King Abdullah University Hospital and Princess Rahma Teaching Hospital. The G6PD gene was scanned for mutations using a DNA sequencing technique. Results: Our results showed 11 variations (7 exonic and 4 intronic) as follows: c.202 G>A (rs1050828), c.376 A>G (rs1050829), c.404 A>C (CM962574 single-nucleotide polymorphism), c.542 A>T (rs5030872), c.563 C>T (rs5030868), c.1003 G>A (rs5030869), c.1311 C>T (rs2230037), c.486-90 C>T, c.486-60 C>G (rs2515904), c.770+175 C>T (rs2515905) and c.1311 C>T (rs2230037). Among these, G6PD Mediterranean (c.563 C>T) was the most common in our patients, with a frequency of 76.2%, followed by G6PD A- (c.202 G>A + c.376 A>G) with 19%, and an equal frequency of 1.6% was found for G6PD Chatham (c.1003 G>A), G6PD Santamaria (c.542 A>T + c.376 A>G) and G6PD Cairo (c.404 A>C). Conclusion: This is the first report of G6PD Santamaria and Cairo among our Jordanian population.     

Hereditary Factor-VII Deficiency in the Beagle

S ummary . Hereditary factor-VII deficiency is identified in another large colony of beagles. Evidence is presented to suggest that this trait may be relatively widespread in colonies in Great Britain.     

Hereditary Nonspherocytic Hemolysis With Erythrocyte Phosphofructokinase Deficiency

Hereditary nonspherocytic hemolysisassociated with abnormal erythrocytephosphofructokinase activity was demonstrated in a young man. Enzymeactivity in the propositus, his mother,and maternal grandmother was approximately 60% of normal controls. Therewas markedly increased lability ofenzyme activity on in vitro storage.Kinetic studies revealed increased sensitivity to adenosine triphosphate inhibition. Erythrocyte adenosine triphosphate levels were depressed. Theabsence of muscle disease and thepresence of normal in vivo lactateproduction following ischemic exercisedifferentiated this kindred from thosewith Type VII glycogen storagedisease.

Submitted on July 16, 1971 Revised on August 24, 1971 Accepted on August 31, 1971     

Red Cell Aldolase Deficiency in Hereditary Spherocytosis

Red cell aldolase activity decreases normally with cell age at a mathematically predictable rate. Compared to aldolase activity so predicted for red cells of the same age, activity of this glycolytic enzyme was 35 per cent deficient (range 18–53 per cent) in 20 splenectomized patients from eight unrelated families with typical hereditary spherocytosis. In two unsplenectomized patients with hereditary spherocytosis red cell age was estimated from measurement of their diisopropyl-fluorophosphate (DF³²P)-labelled red cell survivals, and deficiencies of 62 and 55 per cent in red cell aldolase activity observed. The rates of glycolysis in intact cells and haemolysates measured under conditions designed to produce maximum rates of lactate formation were 20–30 per cent less than expected for the red cell age in the splenectomized subjects. Since patients with hereditary spherocytosis are probably heterozygous for the genetic defect presumed to be present in this disease, the magnitude of deficiency was compared to those reported in heterozygotes for inherited red cell abnormalities such as sickle haemoglobinopathy, glucose-6-phosphate dehydrogenase deficiency and pyruvate kinase deficiency and it was found to be similar. This suggests that a deficiency in red cell aldolase activity may be the basic biochemical lesion in hereditary spherocytosis. One of the products of the aldolase reaction, dihydroxyacetone phosphate, is known to be an important precursor for phospholipid in other tissues, suggesting a possible relationship between red cell aldolase deficiency and the known red cell membrane abnormalities of hereditary spherocytosis.     

Molecular Characterization of Hereditary Persistence of Fetal Hemoglobin in the Karen People of Thailand

Hereditary persistence of fetal hemoglobin (HPFH) is the condition whereby a continuously active γ‐globin gene expression leads to elevated fetal hemoglobin (Hb F) levels in adult life [Stamatoyannopoulos G, Grosveld F. Hemoglobin switching. In: Stamatoyannopoulos G, Majerus PW, Perlmutter RM, Varmus H, eds. The Molecular Basis of Blood Diseases. Philadelphia: W.B. Saunders, 2001:135–182; Wood WG. Hereditary persistence of fetal hemoglobin and δβ thalassemia. In: Steinberg MH, Forget BG, Higgs DR, Nagel RL, eds. Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. Cambridge: Cambridge University Press, 2001:356–388; and Weatherall DJ, Clegg JB. Hereditary persistence of fetal hemoglobin. In: Weatherall DJ, Clegg JB, eds. The Thalassaemia Syndromes. Oxford: Blackwell Scientific Publishers, 1981:450–507]. The condition is caused either by mutation of the β‐ and γ‐globin genes, or the γ‐gene controlled region on other chromosomes. Several families with this condition have been reported from Vietnam, Cambodia and China, and the Southeast Asian mutation (or HPFH‐6), a 27 kb deletion, was demonstrated. Here we report on a mother and her daughter of the Karen ethnic group with high levels of Hb F, living in the Suan Pueng District on the border of Thailand and Myanmar. Genotyping showed a heterozygosity for the 27 kb deletion of the β‐globin gene. Their conditions have been confirmed by gap polymerase chain reaction (PCR) with three oligonucleotide primers recently developed by Xu et al. [Xu X‐M, Li Z‐Q, Liu Z‐Y, Zhong X‐L, Zhao Y‐Z, Mo Q‐H. Molecular characterization and PCR detection of a deletional HPFH: application to rapid prenatal diagnosis for compound heterozygotes of this defect with β‐thalassemia in a Chinese family. Am J Hematol 2000; 65:183–188.], and a DNA sequencing method. Thus far there has been no official report of the HPFH‐6 anomaly from Thailand. The compound heterozygosity of β‐thalassemia (thal) and hereditary persistence of Hb F causes the phenotype of thalassemia intermedia; in contrast, homozygotes for this anomaly show only mild microcytic anemia. Hence, genetic counseling for hereditary persistence of Hb F carriers is needed for family planning.     

Hereditary Factor VII Deficiency in a Chinese Family

Hereditary deficiency of factor VII is demonstrated in a Chinese family. The proposita was a 32-year-old female with bleeding diathesis consisting of spontaneous ecchymosis, menorrhagia and recurrent haemarthrosis. The prothrombin time was prolonged and the prothrombin and proconvertin test was 10% of normal. The activated partial thromboplastin time and the Stypven-cephalin clotting time were normal. The prolonged prothrombin time could be corrected by the addition of normal serum, but not by adsorbed normal or coumadin plasma. The factor VII level was 3.6% of normal. One of her brothers had bleeding symptoms and died at age 25, suggesting that factor VII deficiency might have been present. 13 of her family members had partial deficiency of factor VII with plasma levels ranging from 24 to 50%. These results suggest an autosomal recessive inheritance with a homozygous state occurring in the proposita and possibly in her brother, and a heterozygous state occurring in 13 of her family members. Our study marks an extensive survey of factor VII deficiency in an Oriental family.     

Hereditary Antithrombin III Deficiency in an English Family

S ummary . A family including four members with decreased antithrombin III (ATIII) measured by a biological and an immunological method is described. Immunologically measured levels of other coagulation inhibitors were normal. In the antithrombin III deficient family members there was a history of thrombotic disease. Turnover of ¹²⁵I-antithrombin III in a deficient individual showed the lower plasma levels probably to be due to a deficiency in the rate of synthesis rather than to an increased catabolic rate.     

Atypical Hereditary Spherocytosis: Biochemical Studies and Sites of Erythrocyte Destruction

A family with hereditary spherocytosis has been investigated and found to have the following unusual features: atypical pre- and post-incubation red cell osmotic fragility and absence of splenic sequestration of red cells. Ouabain, an inhibitor of active cation transport, was found not to inhibit the corrective effect of glucose on the rate of autohaemolysis of whole blood, a finding present in some cases of known hereditary spherocytosis, but not in others. The red cells of the propositi showed evidence of increased A.T.P.-ase activity as well as increased utilization of A.T.P. for purposes other than for active cation transport, and are metabolically similar to hereditary spherocytic cells in this respect. The reason for the absence of splenic sequestration of red cells was not established.