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1.
Inherited diseases and metabolism inborn errors with hematologic abnormalities such as cytopenias are observed early in the infant or childhood. Most of them require an acute observation of the bone marrow to determine quantitative and qualitative morphological peculiarities of each cell line in order to charatherize cytological signs of these childhood hereditary diseases and differentiate them from acquired disorders, which are particularly frequent in pediatric. So, after a brief review of hematopoietic physiology in healthy neonates and infant, we'll consider the physiopathology and bone marrow aspect of the erythroid (Blackfan-Diamond anemia, congenital dyserythropoietic...), megacaryocytic (Wiskott-Aldrich syndrome, congenital amegakaryocytic thrombocytopenia...) and granulocytic cell line (Kostmann syndrome, WHIM syndrome...) in hereditary disorder. Considering the hematologic consequences of metabolism inborn errors and storage diseases, the last part of this review will be dedicated to the examination of the bone marrow encountered in those diseases such as mitochondrial cytopathy, orotic aciduria or lysinuric aciduria intolerance. 相似文献
2.
Pilot study of gas chromatographic-mass spectrometric screening of newborn urine for inborn errors of metabolism after treatment with urease. 总被引:5,自引:0,他引:5
T Kuhara T Shinka Y Inoue M Ohse X Zhen-wei I Yoshida T Inokuchi S Yamaguchi M Takayanagi I Matsumoto 《Journal of chromatography. B, Biomedical sciences and applications》1999,731(1):141-147
Gas chromatographic-mass spectrometric (GC-MS) techniques for urinary organic acid profiling have been applied to high-risk screening for a wide range of diseases, mainly for inborn errors of metabolism (IEM), rather than to low-risk screening or mass screening. Using a simplified procedure with urease-pretreatment and the GC-MS technique, which allows simultaneous determination of organic acids, amino acids, sugars and sugar acids, we performed a pilot study of the application of this procedure to neonatal urine screening for 22 IEM. Out of 16,246 newborns screened, 11 cases of metabolic disorders were chemically diagnosed: two each of methylmalonic aciduria and glyceroluria, four of cystinuria, and one each of Hartnup disease, citrullinemia and alpha-aminoadipic aciduria/alpha-ketoadipic aciduria. The incidence of IEM was thus one per 1477, which was higher than the one per 3000 obtained in the USA in a study targeting amino acids and acylcarnitines in newborn blood spots by tandem mass spectrometry. Also, 227 cases were found to have transient metabolic abnormalities: 108 cases with neonatal tyrosinuria, 99 cases with neonatal galactosuria, and 20 cases with other transient metabolic disorders. Two hundred and thirty-eight cases out of 16,246 neonates (approximately 1/68) were thus diagnosed using this procedure as having either persistent or transient metabolic abnormalities. 相似文献
3.
Over the past few years, the number of identified inborn errors of cholesterol biosynthesis has increased significantly. The first inborn error of cholesterol biosynthesis to be characterized, in the mid 1980s, was mevalonic aciduria. In 1993, Irons et al. ( 1 ) (M. Irons, E. R. Elias, G. Salen, G. S. Tint, and A. K. Batta, Lancet 341:1414, 1993) reported that Smith-Lemli-Opitz syndrome, a classic autosomal recessive malformation syndrome, was due to an inborn error of cholesterol biosynthesis. This was the first inborn error of postsqualene cholesterol biosynthesis to be identified, and subsequently additional inborn errors of postsqualene cholesterol biosynthesis have been characterized to various extent. To date, eight inborn errors of cholesterol metabolism have been described in human patients or in mutant mice. The enzymatic steps impaired in these inborn errors of metabolism include mevolonate kinase (mevalonic aciduria as well as hyperimmunoglobulinemia D and periodic fever syndrome), squalene synthase (Ss-/- mouse), 3beta-hydroxysteroid Delta14-reductase (hydrops-ectopic calcification-moth-eaten skeletal dysplasia), 3beta-hydroxysteroid dehydrogenase (CHILD syndrome, bare patches mouse, and striated mouse), 3beta-hydroxysteroid Delta8,Delta7-isomerase (X-linked dominant chondrodysplasia punctata type 2, CHILD syndrome, and tattered mouse), 3beta-hydroxysteroid Delta24-reductase (desmosterolosis) and 3beta-hydroxysteroid Delta7-reductase (RSH/Smith-Lemli-Opitz syndrome and Dhcr7-/- mouse). Identification of the genetic and biochemical defects which give rise to these syndromes has provided the first step in understanding the pathophysiological processes which underlie these malformation syndromes. 相似文献
4.
Struys EA Verhoeven NM Salomons GS Berthelot J Vianay-Saban C Chabrier S Thomas JA Tsai AC Gibson KM Jakobs C 《Molecular genetics and metabolism》2006,88(1):53-57
Succinic semialdehyde dehydrogenase (SSADH) deficiency and D-2-hydroxyglutaric aciduria (D-2-HGA) are rare inborn errors of metabolism primarily revealed by urinary organic acid screening. Three patients with proven SSADH deficiency excreted, in addition to GHB considerable amounts of D-2-HG. We examined whether these patients suffered from two inborn errors of metabolism by measuring D-2-HG concentrations in the culture medium of cells from these patients. In addition, mutation analysis of the D-2-hydroxyglutarate dehydrogenase gene was performed. Normal concentrations of D-2-HG were measured in the culture media of fibroblasts or lymphoblasts derived from the three patients. In one patient, we found a heterozygous likely pathogenic mutation in the D-2-hydroxyglutarate dehydrogenase gene. These combined results argue against the hypothesis that the patients are affected with "primary" D-2-HGA in combination with their SSADH deficiency. Moderately increased levels of D-2-HG were also found in urine, plasma, and cerebrospinal fluid samples derived from 12 other patients with SSADH deficiency, revealing that D-2-HG is a common metabolite in this disease. The increase of D-2-HG in SSADH deficiency can be explained by the action of hydroxyacid-oxoacid transhydrogenase, a reversible enzyme that oxidases GHB in the presence of 2-ketoglutarate yielding SSA and D-2-HG. 相似文献
5.
Engelke UF Kremer B Kluijtmans LA van der Graaf M Morava E Loupatty FJ Wanders RJ Moskau D Loss S van den Bergh E Wevers RA 《NMR in biomedicine》2006,19(2):271-278
A diagnosis of 3-methylglutaconic aciduria type I (OMIM: 250950) based on elevated urinary excretion of 3-methylglutaconic acid (3MGA), 3-methylglutaric acid (3MG) and 3-hydroxyisovaleric acid (3HIVA) was made in a 61-year-old female patient presenting with leukoencephalopathy slowly progressing over more than 30 years. The diagnosis was confirmed at the enzymatic and molecular level. In vivo brain MR spectroscopic imaging (MRSI) was performed at 3.0 T, and one-dimensional and two-dimensional in vitro NMR spectroscopy of body fluids of the patient was performed at 11.7 T. Additionally, we measured 1D (1)H-NMR spectra of urine of seven patients with a total of four different inborn errors of leucine metabolism. Increased concentrations of 3HIVA, 3MGA (cis and trans) and 3MG were observed in the NMR spectra of the patient's urine. In the cerebrospinal fluid, the 3HIVA concentration was 10 times higher than in the plasma of the patient and only the cis isomer of 3MGA was observed. In vivo brain MRSI showed an abnormal resonance at 1.28 ppm that may be caused by 3HIVA. Comparison of (1)H-NMR spectra of urine samples from all eight patients studied, representing five different inborn errors of leucine metabolism, showed that each disease has typical NMR characteristics. Our leukoencephalopathy patient suffers from a late-onset form of 3-methylglutaconic aciduria type I. In the literature, only very few adult patients with this conditions have been described, and 3HIVA accumulation in white matter in the brain has not been presented before in these patients. Our data demonstrate that (1)H-NMR spectroscopy of urine can easily discriminate between the known inborn errors of leucine metabolism and provide the correct diagnosis. 相似文献
6.
Severe liver fibrosis in argininosuccinic aciduria 总被引:3,自引:0,他引:3
A Zimmermann C Bachmann R Baumgartner 《Archives of pathology & laboratory medicine》1986,110(2):136-140
Hepatomegaly is an important clinical finding in patients with argininosuccinic aciduria (a hereditary defect of the urea cycle enzyme, argininosuccinate lyase [argininosuccinase]). A severe degree of liver fibrosis, almost corresponding to cirrhosis, was observed in liver biopsy material obtained from a boy with this disorder. This observation is of interest in light of the fact that liver fibrosis or cirrhosis are hallmarks of many inheritable phenotypes, and especially of inborn errors of metabolism. Variable degrees of liver fibrosis are noted in other inborn defects of the urea cycle, eg, in ornithine transcarbamylase and carbamoylphosphate synthetase deficiencies. These findings appear to indicate that inheritable defects of urea synthesis may form a group of metabolic disorders prone to cause hepatic fibrosis, or even cirrhosis, as shown in our patient. 相似文献
7.
A D Colevas J L Edwards R H Hruban G A Mitchell D Valle G M Hutchins 《Archives of pathology & laboratory medicine》1988,112(11):1133-1139
Glutaric acidemia type II (GA II) is a metabolic disorder caused by deficiency of electron transport flavoprotein or its oxyreductase. It is characterized by acidosis, hypoglycemia, hyperammonemia, organic aciduria, and "sweat-sock" odor. Neonatal GA II differs from most inborn metabolic errors in that there are prominent congenital malformations. We recently observed two infants at autopsy with GA II whose malformations included: subcortical renal glomerular cysts, renal medullary dysplasia, cerebral pachygyria, pulmonary hypoplasia, and facial dysmorphism. In addition, there was lipid accumulation in liver, heart, and renal tubular epithelium, tissues that use fatty acids as a primary source of energy. Review of previous reports of 12 patients showed that these lesions are typical of neonatal GA II. The pattern of lesions, in particular the striking localization of renal dysplasia to the medulla, suggests that the malformations may be the consequence of an accumulation of toxic metabolites that is not corrected by placental transfer. 相似文献
8.
P P Kamoun 《Annales de biologie clinique》1992,50(2):63-70
This article is a review of the animal models which have been described until now for the inborn errors of amino acid metabolism and urea cycle. Two approaches have been explored to obtain such animal models: firstly oral or parenteral administration of the amino acid(s) accumulated in some enzymatic defects of the amino acid catabolism or urea cycle--specific enzymatic inhibitors have sometimes been used; secondly, the genetic approach, which is often the best method. Systematic screening of rat or mouse mutants obtained by experimental mutagenesis was performed in some cases. The relationships between the metabolic disturbances observed either in the inborn errors of metabolism or in the experimental models are discussed as well as the origin of the discrepancies often observed between human and animal syndromes. 相似文献
9.
The experience of a specialized laboratory for the biological diagnosis of inborn errors of metabolism in selected pediatrics patients is reported. The strategy starts with a wide testing of blood and urine, as many inborn errors of metabolism can be detected through testing of blood and urine for increased concentration of specific metabolites known to be associated with the genetic defect. Then enzymatic or DNA studies are performed to confirm the diagnosis. The mutant cells mostly fibroblasts are stored in a cell bank and available for other research. 相似文献
10.
Transcobalamin receptor defect: Identification of two new cases through positive newborn screening for propionic/methylmalonic aciduria and long‐term outcome
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Fady Hannah‐Shmouni Vivian Cruz Andreas Schulze Saadet Mercimek‐Andrews 《American journal of medical genetics. Part A》2018,176(6):1411-1415
11.
D T Forman 《Annals of clinical and laboratory science》1991,21(2):85-93
Clinical signs and symptoms of organic acidurias are usually subtle and non-specific. Laboratory evaluation, therefore, is usually the only conclusive way to reach a definitive diagnosis. Defects of amino acid catabolism generally caused by diminished activity or complete absence of specific enzymes usually occurs at the later stages of a pathway and results in organic aciduria. Most of these acids are effectively cleared from the blood by the kidneys, resulting in their concentration in urine to exceed greatly that in serum. Therefore, the detection of increased organic acids is greatly facilitated by a urine assay. The use of dual capillary column gas chromatography should allow the unambiguous determination of all known organic aciduria. Using this method provides a cost-effective alternative to gas chromatography-mass spectrometry. 相似文献
12.
Liver transplantation is an important therapeutic option for many individuals with metabolic liver disease. Nevertheless, the invasive nature of surgery and limitations of donor organ availability have led to the search for alternatives to whole-organ transplantation. Cell-based therapies have been a particularly active area of investigation in recent years. Hepatocyte transplantations have been performed for a variety of indications, including acute liver failure, end-stage liver disease, and inborn errors of metabolism. Individuals with inborn errors of metabolism who have undergone hepatocyte transplantation have shown clinical improvement and partial correction of the underlying metabolic defect. In most cases, sustained benefits have not been observed. This may be related to inadequate cell dose, variations in the quality of hepatocyte preparations, rejection of the transplanted cells, or senescence of transplanted hepatocytes. Though initial proof of concept with hepatocyte transplantation has been demonstrated by a number of investigators, wide application of this technology has been hindered by the inability to secure a reliable and well-characterized cell source(s) for transplantation and by the challenges of sustained engraftment and expansion of transplanted cells in vivo. Cell-based therapies, including those based on stem cells or more differentiated progenitor cells, may represent the future of cell transplantation for treatment of metabolic liver disease. 相似文献
13.
Tristan Barnes Preston Parry Iris Hart Carol Jones Michele Minet David Patterson 《Somatic Cell and Molecular Genetics》1993,19(4):405-411
De novo UMP synthesis is a critical metabolic pathway for nucleic acid synthesis and for a variety of metabolic pathways. The pathway is a target for many widely used cancer chemotherapy agents, several of which are pyrimidine analogs. Humans and cattle have been described with mutations in UMP synthesis that lead to serious inborn errors of metabolism. Dihydroorotate dehydrogenase (EC 1.3.3.1) (DHODH) carries out the fourth committed step in the pathway and may also be important for mitochondrial electron transport and oxygen radical metabolism. We report here that the gene encoding this enzyme in humans is located in the chromosomal region 16q22. With the mapping of DHODH, the mapping of all the steps of UMP synthesis is complete. All three genes involved map to different human chromosomes. This information is important in consideration of regulation of UMP synthesis in mammals, including humans. 相似文献
14.
Neven B Valayannopoulos V Quartier P Blanche S Prieur AM Debré M Rolland MO Rabier D Cuisset L Cavazzana-Calvo M de Lonlay P Fischer A 《The New England journal of medicine》2007,356(26):2700-2703
Mevalonic aciduria is a rare, inborn error of isoprene biosynthesis characterized by severe, periodic attacks of fever and inflammation, developmental delay, ataxia, and dysmorphic features. This autosomal recessive disease is caused by a mutation in the mevalonate kinase gene that severely reduces mevalonate kinase activity. A 3-year-old boy with mevalonic aciduria whose condition had failed to improve with antiinflammatory treatment underwent allogeneic bone marrow transplantation from an HLA-identical sister who was a heterozygous carrier of the mutant gene. We observed sustained remission of febrile attacks and inflammation during a 15-month follow-up period. 相似文献
15.
van Kuilenburg AB Meinsma R Beke E Assmann B Ribes A Lorente I Busch R Mayatepek E Abeling NG van Cruchten A Stroomer AE van Lenthe H Zoetekouw L Kulik W Hoffmann GF Voit T Wevers RA Rutsch F van Gennip AH 《Human molecular genetics》2004,13(22):2793-2801
beta-Ureidopropionase deficiency is an inborn error of the pyrimidine degradation pathway, affecting the cleavage of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid. In this study, we report the elucidation of the genetic basis underlying a beta-ureidopropionase deficiency in four patients presenting with neurological abnormalities and strongly elevated levels of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid in plasma, cerebrospinal fluid and urine. No beta-ureidopropionase activity could be detected in a liver biopsy obtained from one of the patients, which reflected the complete absence of the beta-ureidopropionase protein. Analysis of the beta-ureidopropionase gene (UPB1) of these patients revealed the presence of two splice-site mutations (IVS1-2A>G and IVS8-1G>A) and one missense mutation (A85E). Heterologous expression of the mutant enzyme in Escherichia coli showed that the A85E mutation resulted in a mutant beta-ureidopropionase enzyme without residual activity. Our results demonstrate that the N-carbamyl-beta-amino aciduria in these patients is due to a deficiency of beta-ureidopropionase, which is caused by mutations in the UPB1 gene. Furthermore, an altered homeostasis of beta-aminoisobutyric acid and/or increased oxidative stress might contribute to some of the clinical abnormalities encountered in patients with a beta-ureidopropionase deficiency. An analysis of the presence of the two splice site mutations and the missense mutation in 95 controls identified one individual who proved to be heterozygous for the IVS8-1G>A mutation. Thus, a beta-ureidopropionase deficiency might not be as rare as is generally considered. 相似文献
16.
Vivian E. Shih Roseann Mandell Harvey L. Levy John W. Littlefield 《Clinical genetics》1975,7(5):421-425
In the search for a simple screening test for prenatal diagnosis of amino acid metabolic disorders, we compared the free amino acid contents in the extract of cultured skin fibroblasts from normal individuals with that from patients with 10 metabolic disorders: maple-syrup urine disease; homocystinuria due to cystathionine synthase deficiency; homocystinuria due to N5, 10-methylene-tetrahydrofolate reductase deficiency; citrullinemia; argininosuccinic acidemia: propionic acidemia; hyperprolinemia Type II; non-ketotic hyperglycinemia; hydroxyprolinemia; and hyperonithinemia. An accumulation of abnormal metabolites was not found in any of the disorders except argininosuccinic aciduria. Argininosuccinic acid anhydrides were detected in cell extracts from all four patients only after the extract was boiled at acid pH for 2 1/2 h. Thus, it is concluded that the measurement of free amino acids in extracts from cultured fibroblasts is not a useful screening technique in the diagnosis of inborn errors of amino acid metabolism. 相似文献
17.
Kenneth Lee Jones Dennis E. Carey John M. Opitz 《American journal of medical genetics. Part A》1982,11(4):449-452
We report the first known patient with a del(18p) and Graves disease. This deletion has previously been reported to be associated with autoimmune thyroid disease and, perhaps, with inborn errors of thyroxin biosynthesis. We present the clinical and histological information on this patient and review the literature in an attempt to clarify the relationship between abnormalities of chromosome 18 and thyroid disease. 相似文献
18.
O M Rennert 《Annals of clinical and laboratory science》1975,5(3):153-160
During the past decade, a vast methodology has been developed for the study and antenatal diagnosis of genetic disorders. The cytogenetic antenatal diagnosis of chromosome abnormalities is possible through the application of new methods for chromosome visualization in cultured amniotic fluid cells. A variety of inborn errors of metabolism may be diagnosed prenatally by the study of amniotic fluid, amniotic fluid cells and cultivated fibroblasts from this biologic fluid. Additionally, morphologic malformations such as neural tube defects and fetal catastrophies may be diagnosed during gestation by the study of alpha fetoprotein and beta trace protein levels. In the past few years, the application of methods for the visualization of the intrauterine fetus has been made possible by the use of techniques such as sonography, contrast radiography and fetoscopy. 相似文献
19.
7-dehydrocholesterol reductase (7-Dhcr) catalyses the final step in the pathway of cholesterol biosynthesis. Human patients with inborn errors of 7-Dhcr (Smith-Lemli-Opitz-Syndrome) have elevated serum levels of 7-dehydrocholesterol but low levels of cholesterol, which in phenotypical terms can result in growth retardation, craniofacial abnormalities including cleft palate, and reduced metal abilities. This study reports the isolation and molecular characterisation of 7-dehydrocholesterol reductase (Xdhcr7) from Xenopus laevis. During early embryonic development, the expression of Xdhcr7 is first of all spatially restricted to the Spemann's organizer and later to the notochord. In both tissues, Xdhcr7 is coexpressed with Sonic hedgehog (Shh), which itself is cholesterol-modified during autoproteolytic cleavage. Data from Xdhcr7 overexpression and knockdown experiments reveals that a tight control of cholesterol synthesis is particularly important for proper development of the central and peripheral nervous system. 相似文献