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PubMed2004

Cribra orbitalia visualized in computed tomography.

Cribra orbitalia are sieve-like lesions of the orbital roof. While common in historic skulls, they have long been absent in those examined in the last decades. Only recently we found low-grade cribra orbitalia in some contemporary cases. Though of unknown origin, this lesion is often attributed to anemia and deficiency diseases. It is theoretically possible to visualize cribra orbitalia in living subjects by computed tomography and thus study their etiology. The aim of our study was to investigate the possibilities of computed tomography for visualizing cribra orbitalia. We used multislice computed tomography (MSCT) in the spiral and sequential mode to image medium-grade cribra orbitalia of moderate severity in a human skull. Virtual endoscopic and 3-D images were produced by post-processing. The best results were obtained by the sequential mode and 3-D reconstruction. Given a thin slice thickness and a wide slice angle between slice plane and the orbital roof, the threshold level seems to be the most important factor influencing realistic reproduction and should be finely adjusted according to bone density. Clinical research may now begin by examining relevant patients undergoing CT.

Bone Diseases↗
PubMed2007

Genetics, biology and clinical management of myeloid cell primary immune deficiencies: chronic granulomatous disease and leukocyte adhesion deficiency.

PURPOSE OF REVIEW: Chronic granulomatous disease and leukocyte adhesion deficiency are the major primary immune deficiencies affecting phagocytic blood cells. Major advances in clinical diagnosis and development of novel treatments for these disorders merit review. RECENT FINDINGS: Clinically beneficial gene therapy correction of X-linked chronic granulomatous disease in two adult patients was reported. Nonmyeloablative busulfan conditioning before administration of gene corrected autologous hematopoietic stem cells was likely an essential maneuver to achieve successful gene therapy. There is an increased association of autoimmune disorders with chronic granulomatous disease. Preimplantation genetic diagnosis of leukocyte adhesion deficiency-I led to the birth of a normal child. A canine model of leukocyte adhesion deficiency-I facilitated development of new nonmyeloablative hematopoietic stem cell transplant and gene therapy approaches to leukocyte adhesion deficiency. Nonmyeloablative transplantation may provide an effective, but less toxic approach for leukocyte adhesion deficiency in children. There have been advances in understanding the basis of leukocyte adhesion deficiency-II and III. SUMMARY: The most important subjects reviewed in this chapter include new advances in development of gene therapy for chronic granulomatous disease and leukocyte adhesion deficiency-I; transplantation for leukocyte adhesion deficiency-I; prenatal diagnosis of leukocyte adhesion deficiency-I; and association of autoimmune diseases with chronic granulomatous disease.

Animals↗
PubMed1982

[Clinical aspects of monoclonal gammopathies in diseases of the lympho-plasmacytic cell system].

Paraproteinemias can be subdivided in 1. obligatory paraproteinemias (myeloma, macroglobulinemia, heavy chain diseases); 2. accompanying paraproteinemias (Non-Hodgkin's lymphomas, myeloproliferative diseases, immune deficiency diseases, autoimmune diseases, transitory paraproteinemias after infection, paraproteinemias in association with nonlymphatic neoplasms); 3. benign paraproteinemias: a) with symptoms (primary amyloidosis, chronic cold agglutinin disease, paraproteinemias with further autoantibody function, monoclonal cryoglobulinemia); b) asymptomatic forms. Myeloma is the most common type of obligatory paraproteinemias. Characteristic findings are: Paraproteinemia and/or paraproteinuria in 98%, increase of plasma cells in the bone marrow in 84%, alterations in the roentgenograms of the skeleton in 79%. Clinical staging is of importance for the prognosis (amount of paraproteins, Hb level, renal disease, hypercalcemia, lytic lesions of bone). Neurologic complications, hemostasis dysfunction, cryopathies may be other symptoms. The terminal phase of the disease is determined by plasma cell proliferation, immune deficiency and renal disease or myelomonocytic leukemia. As to Non-Hodgkin's lymphomas the accompanying paraproteinemia is to be found in immunocytomas and in CLL. At last it has to be mentioned that B-cell disorders will influence the T-cell populations and vice versa.

Antibodies, Monoclonal↗
PubMed1990

Central MHC genes, IgA deficiency and autoimmune disease.

IgA deficiency is a common immunological disorder that is sometimes associated with an immunodeficiency syndrome, allergic disease, autoimmune disease and gluten enteropathy. Many subjects with this deficiency, however, are healthy, at least for many decades. Analysis of the immunological and genetic abnormalities found in IgA deficiency and in some of the associated disorders has led to the postulate that a genetically determined defect of immunoregulation underlies all of these diseases. Here, Martyn French and Roger Dawkins propose that the products of genes located within the central region of the major histocompatibility complex (MHC) regulate B cells and/or antibody production. Particular MHC ancestral haplotypes contain specific alleles and arrangements of these genes, thereby explaining associations with either increased or decreased production of immunoglobulin isotypes by B cells.

Agammaglobulinemia↗
PubMed2004

[From gene to disease; Krabbe disease and galactosylceramidase deficiency].

Krabbe disease is a devastating lysosomal storage disease with autosomal recessive inheritance. Early symptoms of leukodystrophy, such as irritability and hypertonicity, appear at 3 to 6 months of age, but progress rapidly to severe mental and motor deterioration and death in the second year. The disease is caused by the deficiency of the lysosomal enzyme galactosylceramidase, which is in turn caused by mutations in the GALC gene. The incidence of the infantile form of the disease in the Netherlands is estimated at 1.3 per 100,000 births; 50% of the patients' alleles show the large 30-kb deletion. Early diagnosis by enzyme assay in leukocytes or skin fibroblasts permits timely genetic counselling and prenatal diagnosis, which is reliably made by enzyme or mutation analysis in the chorionic villi.

Galactosylceramidase↗
PubMed2001

Mitochondria deficient in complex I activity are depolarized by hydrogen peroxide in nerve terminals: relevance to Parkinson's disease.

Deficiency of complex I in the respiratory chain and oxidative stress induced by hydrogen peroxide occur simultaneously in dopaminergic neurones in Parkinson's disease. Here we demonstrate that the membrane potential of in situ mitochondria (Delta Psi m), as measured by the fluorescence change of JC-l (5,5',6,6'-tetrachloro-1,1,3,3'-tetraethylbezimidazolyl-carbocyani ne iodide), collapses when isolated nerve terminals are exposed to hydrogen peroxide (H(2)O(2), 100 and 500 microM) in combination with the inhibition of complex I by rotenone (5 nM-1 microM). H(2)O(2) reduced the activity of complex I by 17%, and the effect of H(2)O(2) and rotenone on the enzyme was found to be additive. A decrease in Delta Psi m induced by H(2)O(2) was significant when the activity of complex I was reduced to a similar extent as found in Parkinson's disease (26%). The loss of Delta Psi m observed in the combined presence of complex I deficiency and H(2)O(2) indicates that when complex I is partially inhibited, mitochondria in nerve terminals become more vulnerable to H(2)O(2)-induced oxidative stress. This mechanism could be crucial in the development of bioenergetic failure in Parkinson's disease.

Animals↗
PubMed1992

Corneal opacity in LCAT disease.

Deficiency of lecithin:cholesterol acyltransferase, LCAT disease, is one of the dyslipoproteinemias with characteristic lipid deposits in the cornea. The present report documents the clinicopathologic abnormalities of one case in which a full-thickness corneal specimen was obtained at the time of corneal transplantation. The characteristic clinical abnormality was a progressive corneal opacification with a peripheral arcus that extended into the sclera. The pathologic abnormality consisted of vacuoles prevalent in the anterior corneal stroma by light microscopy and containing extracellular, membranous deposits by electron microscopy. These observations confirm and supplement the previous six pathologic reports of corneal changes in LCAT disease and demonstrate, for the first time, histopathologic evidence of unesterified cholesterol in the corneal stroma of LCAT disease.

Corneal Opacity↗
PubMed1983

[Familial hypoalphalipoproteinemia. Vergani's disease].

Deficiencies of lipoproteins occur as genetic disorders or may be presenting features of underlying disease. Familial high density lipoprotein (HDL), or alpha-lipoprotein, deficiency so far described includes Tangier disease, Lecithin: cholesterol acyltransferase (LCAT) deficiency, A-I Variants syndrome and Fish-eye disease. In 1981 Vergani described a familial aggregation of low HDL-cholesterol (less than 33 mg/dl) and Apo A (about 50% of normal levels) in the presence of normal VLDL and LDL-cholesterol. LCAT and lipoprotein lipase activities, both extrahepatic and hepatic, were normal. By zonal ultracentrifugation HDL2 subclass was found to be reduced. HDL apoproteins, examined by isoelectric focusing in polyacrylamide gel, were qualitatively normal. No disorders to which low levels of HDL might be secondary (e.g., overweight, cigarette smoking, nephropathy, liver disease) are present in the affected members. The underlying biochemical defect is unknown but probably involves altered synthesis or catabolism of HDL. Familial hypo-alpha-lipoproteinemia is accompanied by a high prevalence of premature myocardial infarction and sudden death. The genetic analysis of the disorder is consistent with autosomal inheritance. The criteria for the definition of familial hypo-alpha-lipoproteinemia are, therefore, as follows: 1) low HDL-cholesterol level in the presence of normal VLDL and LDL-cholesterol levels; 2) absence of diseases or factors to which hypo-alpha-lipoproteinemia might be secondary; 3) presence of a similar lipoprotein pattern in a first degree relative.

Adult↗
PubMed1998

Mutation analysis in myophosphorylase deficiency (McArdle's disease).

Inherited deficiency of myophosphorylase leads to glycogen storage disease type V (McArdle's disease). We performed mutation analysis in 9 patients of eight unrelated families from Germany with typical clinical presentation of myophosphorylase deficiency. Beside previously described mutations we identified four novel mutations in the myophosphorylase gene. Four patients were homozygous for a nonsense mutation Arg49Stop that has been reported to be the most common mutation in white patients. Two affected siblings were compound heterozygotes for a novel missense mutation Gly685Arg and the nonsense mutation Arg49Stop. One patient carried a novel nonsense mutation Arg575Stop and a previously identified missense mutation Gly204Ser. In another patient, we identified a novel missense mutation Gln665Glu and a single-base deletion delA in Lys753. One patient of Turkish ancestry carried a newly identified homozygous A-to-G transition (ATG to GTG) abolishing the translation initiation codon of the myophosphorylase gene. These results suggest that Arg49Stop also is the most common genetic error associated with myophosphorylase deficiency in the German population. Our findings further demonstrate molecular heterogeneity of myophosphorylase deficiency among the clinically homogeneous patients we studied.

Adolescent↗
PubMed2004

Enhanced stimulus contrast normalizes visual processing of rapidly presented letters in Alzheimer's disease.

Deficient perception and cognition in Alzheimer's disease (AD) has been attributed to slow information processing and attentional disturbance, but an additional explanation may be reduced signal strength. In 21 individuals with probable AD, 29 healthy older and 54 younger adults, we enhanced the contrast level of rapidly-flashed masked letters. The AD group reached identification criterion (80% accuracy), but required significantly higher contrast than the control groups. A source of the prevalent masking deficit may be reduced signal strength arising from dysfunction of retina or visual cortex. Increasing stimulus contrast may be an effective means of enhancing cognitive performance in AD.

Aged↗
PubMed2002

Signaling pathway for radiation-induced apoptosis in the lymphoblasts from neuronopathic (type A) and non-neuronopathic (type B) forms of Niemann-Pick disease.

Deficient activity of human lysosomal hydrolase, acid sphingomyelinase (ASM), results in the neuronopathic (type A) and non-neuronopathic (type B) forms of Niemann-Pick disease (NPD). A deficiency of ASM is known to deprive lymphoblasts of their response to apoptotic induction by X-ray irradiation. To elucidate the genetic heterogeneity of apoptotic induction in NPD cells, we investigated radiation-induced apoptosis of lymphoblasts in patients with type A (genotype: IVS3-2A-G/IVS3-2A-G) and type B (genotype: S436R/S436R) NPD. Epstein-Barr virus (EBV)-transformed lymphoblasts established from a patient with type A NPD, a patient with type B NPD and a normal control were irradiated with 20 Gy and incubated for 24 h. The cells were harvested and the morphological features of apoptosis were observed with DNA-specific fluorochrome bis-benzimide. Exposure of lymphoblasts to 20 Gy of radiation resulted in 25-30% apoptosis of total cells in normal lymphoblasts, 8-9% apoptosis in type A NPD and 20-27% apoptosis in type B NPD. The radiation-induced apoptotic response in the lymphoblasts of type A NPD was significantly different from that of the normal lymphoblasts (P<0.0005). On the other hand, the radiation-induced apoptotic response in type B NPD was not markedly different from that in normal lymphoblasts (P=0.624). In the patient with type B NPD, the signaling pathway for radiation-induced apoptosis was preserved in lymphoblasts, which suggests that the extent of cell signaling system disturbance due to ASM deficiency may be related to the phenotypes in types A and B NPD.

Amino Acid Substitution↗
PubMed1987

The spectrum of human immunodeficiency virus infection in patients with factor IX deficiency (Christmas disease)

Early reports suggested that hemophiliacs with factor IX deficiency (Christmas Disease) may be at less risk for developing the acquired immunodeficiency syndrome (AIDS) than patients with classic hemophilia. We evaluated 12 factor IX deficient patients for clinical and immunologic abnormalities related to infection with the human immunodeficiency virus (HIV). Antibody to HIV was not detected in these patients prior to 1982. By 1985, 66 percent (eight of 12) patients were seropositive. All three concentrates available commercially before 1985 were associated with seropositivity. Furthermore, seropositive hemophiliacs had received on average significantly more factor IX concentrate than seronegative hemophiliacs (27,825 +/- 17,976 (S.D.) versus 1,250 +/- 1,500 factor units/year, (p less than 0.02). Half of the seropositive individuals had generalized lymphadenopathy with splenomegaly. Two seropositive patients have developed AIDS, one with cryptococcal meningitis and another with a large cell immunoblastic lymphoma. Infection with HIV has occurred with high frequency in hemophiliacs who received unmodified factor IX concentrates.

AIDS-Related Complex↗
PubMed1998

New lysosomal acid lipase gene mutants explain the phenotype of Wolman disease and cholesteryl ester storage disease.

Deficiency of lysosomal acid lipase (LAL) leads to either Wolman disease (WD) or the more benign cholesteryl ester storage disease (CESD). To identify the molecular basis of the different phenotypes we have characterised the LAL gene mutations in three new patients with LAL deficiency. A patient with WD was homozygote for a null allele Y303X. The other two patients, with CESD, presented either homozygosity for T267I or compound heterozygosity consisting of Q64R and an exon 8 donor splice site substitution (G-->A in position -1). The mutants T267I and Q64R and the previously reported L273S, G66V, and H274Y CESD substitutions, overexpressed in stable clones, were found to be fully glycosylated and show an enzymatic activity of 3-8% of that of normal LAL. On the other hand, the delta254-277 mutant protein derived from exon 8 skipping and the Y303X protein were totally inactive. By transient transfection of hybrid minigene constructs, the CESD G-->A (-1) substitution resulted in partial exon inclusion, thus allowing the production of a small amount of normal LAL mRNA and hence of a functional enzyme. In contrast, a G-->A substitution observed in WD at position + 1 of the same exon 8 donor site resulted in complete exon skipping and the sole production of an inactive delta254-277 protein. In conclusion, LAL genotypes determine the level of residual enzymatic activity, thus explaining the severity of the phenotype.

Amino Acid Substitution↗
PubMed1981

Plasma apolipoprotein concentrations in familial apolipoprotein A-I and A-II deficiency (Tangier disease).

Familial apolipoprotein A-I and A-II deficiency (Tangier disease) is characterized by cholesterol ester deposition in histiocytes, decreased plasma cholesterol and low density lipoprotein cholesterol (C-LDL), and a striking deficiency of high density lipoproteins (HDL). We measured plasma lipid, lipoprotein cholesterol, and plasma apolipoprotein (apo) A-I, A-II, B, C-I, C-II, C-III, D, and E concentrations in 7 Tangier homozygotes, 2 obligate heterozygotes, and 50 normal subjects. Heterozygotes had modest reductions in high density lipoprotein cholesterol (C-HDL), plasma apoA-I, and apoA-II levels. Mean concentrations (+/- SD) of plasma C-HDL and apolipoproteins A-I, A-II, B, C-I, C-II, C-III, D, and E in mg% in normals were: 50 +/- 14, 134 +/- 24, 68 +/- 18, 98 +/- 20, 7 +/- 2, 3.7 +/- 2, 13 +/- 5, 10 +/- 4, and 10 +/- 4, respectively; and in homozygotes were: 1 +/- 1, 1.3 +/- 0.7, 4.8 +/- 2.5, 82.6 +/- 18, 4.1 +/- 1.7, 2.3 +/- 0.9, 6.5 +/- 3.8, 2.2 +/- 0.5, +/- 3.1, respectively. Homozygotes had C-HDL, apoA-I and apoA-II levels which were 2%, 1%, and 7% (p less than .001) of normal, respectively, and mean levels of apolipoproteins B, C-I, C-II, C-III, D, and E which were 84%, 59%, 62%, 50%, 22%, and 54% of normal, respectively. There was heterogeneity of these latter apolipoprotein concentrations among homozygotes. Mean apoC-I, apoC-III, apoD, and apoE levels were significantly less than normal (pp less than .05) in homozygotes. These data indicate that homozygotes have variable but generally decreased apoC and apoE levels, a deficiency of apoD, and a striking reduction in plasma apoA-I and apoA-II concentrations.

Adolescent↗
PubMed2000

Genotype-phenotype correlation in two frequent mutations and mutation update in type III glycogen storage disease.

Deficiency of glycogen debranching enzyme (AGL) activity causes glycogen storage disease type III (GSD-III). Generalized loss of AGL activity results in GSD-IIIa, and muscle-specific retention of AGL activity results in GSD-IIIb. To date, no common mutation has been described among GSD-III patients, except for three alleles; two linked specifically with GSD-IIIb, and the third found only in North African Jews with GSD-IIIa. Here we report two frequent mutations, each of which was found in the homozygous state in multiple patients, and each of which was associated with a subset of clinical phenotype in those patients with that mutation. A novel point mutation of a single T deletion at cDNA position 3964 (3964delT) was first detected in an African American patient, who has a severe phenotype and early onset of clinical symptoms. The second mutation was an A to G transition at position -12 upstream of the 3' splice site of intron 32 (IVS32-12A > G). This lesion, previously implicated as a IIIb mutation in a Japanese patient, was identified in a confirmed GSD-IIIa Caucasian patient presenting with mild clinical symptoms. These two mutations together account for more than 12% of the molecular defects in the GSD-III patients tested. Our molecular and clinical data suggest a genotype-phenotype correlation for each of these mutations. Furthermore, this current study, coupled with our previous reports, describes the molecular tools necessary for the development of a DNA-based diagnostic test for GSD-III.

Adult↗
PubMedDate not supplied

Secondary metabolic changes in von Gierke's disease (Type I glycogen storage disease).

Deficiency of glucose-6-phosphatase in Type I glycogen storage disease (GSD) results in hypoglycemia and excessive accumulation of glucose-6-phosphate. As a result, lactic acid, uric acid, and lipids are formed as end-products. The formation of these metabolites are discussed with an emphasis on monitoring therapeutic progress. In addition, hyperlipidemia and associated changes in apolipoproteins are considered as indices of the clinical course.

Glycogen Storage Disease Type I↗