scholarly journals Confounding factors in the diagnosis and clinical course of rare congenital hemolytic anemias

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Bruno Fattizzo ◽  
Juri Alessandro Giannotta ◽  
Nicola Cecchi ◽  
Wilma Barcellini
Keyword(s):  
Iron Overload ◽  
Triosephosphate Isomerase ◽  
Metabolic Diseases ◽  
De Novo ◽  
Hereditary Hemochromatosis ◽  
Phosphoglycerate Kinase ◽  
Clinical Findings ◽  
Diagnostic Tools ◽  
Biochemical Tests ◽  
Hepatic Diseases

AbstractCongenital hemolytic anemias (CHAs) comprise defects of the erythrocyte membrane proteins and of red blood cell enzymes metabolism, along with alterations of erythropoiesis. These rare and heterogeneous conditions may generate several difficulties from the diagnostic point of view. Membrane defects include hereditary spherocytosis and elliptocytosis, and the group of hereditary stomatocytosis; glucose-6-phosphate dehydrogenase and pyruvate kinase, are the most common enzyme deficiencies. Among ultra-rare forms, it is worth reminding other enzyme defects (glucosephosphate isomerase, phosphofructokinase, adenylate kinase, triosephosphate isomerase, phosphoglycerate kinase, hexokinase, and pyrimidine 5′-nucleotidase), and congenital dyserythropoietic anemias. Family history, clinical findings (anemia, hemolysis, splenomegaly, gallstones, and iron overload), red cells morphology, and biochemical tests are well recognized diagnostic tools. Molecular findings are increasingly used, particularly in recessive and de novo cases, and may be fundamental in unraveling the diagnosis. Notably, several confounders may further challenge the diagnostic workup, including concomitant blood loss, nutrients deficiency, alterations of hemolytic markers due to other causes (alloimmunization, infectious agents, rare metabolic disorders), coexistence of other hemolytic disorders (autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria, etc.). Additional factors to be considered are the possible association with bone marrow, renal or hepatic diseases, other causes of iron overload (hereditary hemochromatosis, hemoglobinopathies, metabolic diseases), and the presence of extra-hematological signs/symptoms. In this review we provide some instructive clinical vignettes that highlight the difficulties and confounders encountered in the diagnosis and clinical management of CHAs.

Four New Mutations in the Erythroid-Specific 5-Aminolevulinate Synthase (ALAS2) Gene Causing X-Linked Sideroblastic Anemia: Increased Pyridoxine Responsiveness After Removal of Iron Overload by Phlebotomy and Coinheritance of Hereditary Hemochromatosis

Blood ◽  
1999 ◽  
Vol 93 (5) ◽  
pp. 1757-1769 ◽  
Author(s):  
Philip D. Cotter ◽  
Alison May ◽  
Liping Li ◽  
A.I. Al-Sabah ◽  
Edward J. Fitzsimons ◽  
...  
Keyword(s):  
Iron Overload ◽  
De Novo ◽  
Normal Population ◽  
Hereditary Hemochromatosis ◽  
Refractory Anemia ◽  
Missense Mutations ◽  
Sideroblastic Anemia ◽  
Aminolevulinate Synthase ◽  
C282y Homozygote ◽  
New Mutations

X-linked sideroblastic anemia (XLSA) in four unrelated male probands was caused by missense mutations in the erythroid-specific 5-aminolevulinate synthase gene (ALAS2). All were new mutations: T647C, C1283T, G1395A, and C1406T predicting amino acid substitutions Y199H, R411C, R448Q, and R452C. All probands were clinically pyridoxine-responsive. The mutation Y199H was shown to be the first de novo XLSA mutation and occurred in a gamete of the proband’s maternal grandfather. There was a significantly higher frequency of coinheritance of the hereditary hemochromatosis (HH)HFE mutant allele C282Y in 18 unrelated XLSA hemizygotes than found in the normal population, indicating a role for coinheritance ofHFE alleles in the expression of this disorder. One proband (Y199H) with severe and early iron loading coinherited HH as a C282Y homozygote. The clinical and hematologic histories of two XLSA probands suggest that iron overload suppresses pyridoxine responsiveness. Notably, reversal of the iron overload in the Y199H proband by phlebotomy resulted in higher hemoglobin concentrations during pyridoxine supplementation. The proband with the R452C mutation was symptom-free on occasional phlebotomy and daily pyridoxine. These studies indicate the value of combined phlebotomy and pyridoxine supplementation in the management of XLSA probands in order to prevent a downward spiral of iron toxicity and refractory anemia.

Four New Mutations in the Erythroid-Specific 5-Aminolevulinate Synthase (ALAS2) Gene Causing X-Linked Sideroblastic Anemia: Increased Pyridoxine Responsiveness After Removal of Iron Overload by Phlebotomy and Coinheritance of Hereditary Hemochromatosis

Blood ◽  
1999 ◽  
Vol 93 (5) ◽  
pp. 1757-1769 ◽  
Author(s):  
Philip D. Cotter ◽  
Alison May ◽  
Liping Li ◽  
A.I. Al-Sabah ◽  
Edward J. Fitzsimons ◽  
...  
Keyword(s):  
Iron Overload ◽  
De Novo ◽  
Normal Population ◽  
Hereditary Hemochromatosis ◽  
Refractory Anemia ◽  
Missense Mutations ◽  
Sideroblastic Anemia ◽  
Aminolevulinate Synthase ◽  
C282y Homozygote ◽  
New Mutations

Abstract X-linked sideroblastic anemia (XLSA) in four unrelated male probands was caused by missense mutations in the erythroid-specific 5-aminolevulinate synthase gene (ALAS2). All were new mutations: T647C, C1283T, G1395A, and C1406T predicting amino acid substitutions Y199H, R411C, R448Q, and R452C. All probands were clinically pyridoxine-responsive. The mutation Y199H was shown to be the first de novo XLSA mutation and occurred in a gamete of the proband’s maternal grandfather. There was a significantly higher frequency of coinheritance of the hereditary hemochromatosis (HH)HFE mutant allele C282Y in 18 unrelated XLSA hemizygotes than found in the normal population, indicating a role for coinheritance ofHFE alleles in the expression of this disorder. One proband (Y199H) with severe and early iron loading coinherited HH as a C282Y homozygote. The clinical and hematologic histories of two XLSA probands suggest that iron overload suppresses pyridoxine responsiveness. Notably, reversal of the iron overload in the Y199H proband by phlebotomy resulted in higher hemoglobin concentrations during pyridoxine supplementation. The proband with the R452C mutation was symptom-free on occasional phlebotomy and daily pyridoxine. These studies indicate the value of combined phlebotomy and pyridoxine supplementation in the management of XLSA probands in order to prevent a downward spiral of iron toxicity and refractory anemia.

scholarly journals Fructose and Mannose in Inborn Errors of Metabolism and Cancer

Metabolites ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 479
Author(s):  
Elizabeth L. Lieu ◽  
Neil Kelekar ◽  
Pratibha Bhalla ◽  
Jiyeon Kim
Keyword(s):  
Metabolic Disease ◽  
Inborn Errors Of Metabolism ◽  
Metabolic Diseases ◽  
Treatment Options ◽  
Biochemical Properties ◽  
Biological Molecules ◽  
Diagnostic Tools ◽  
Inborn Errors ◽  
Mannose Metabolism

History suggests that tasteful properties of sugar have been domesticated as far back as 8000 BCE. With origins in New Guinea, the cultivation of sugar quickly spread over centuries of conquest and trade. The product, which quickly integrated into common foods and onto kitchen tables, is sucrose, which is made up of glucose and fructose dimers. While sugar is commonly associated with flavor, there is a myriad of biochemical properties that explain how sugars as biological molecules function in physiological contexts. Substantial research and reviews have been done on the role of glucose in disease. This review aims to describe the role of its isomers, fructose and mannose, in the context of inborn errors of metabolism and other metabolic diseases, such as cancer. While structurally similar, fructose and mannose give rise to very differing biochemical properties and understanding these differences will guide the development of more effective therapies for metabolic disease. We will discuss pathophysiology linked to perturbations in fructose and mannose metabolism, diagnostic tools, and treatment options of the diseases.

Effects of iron overload on chronic metabolic diseases

2014 ◽  
Vol 2 (6) ◽  
pp. 513-526 ◽  
Author(s):  
José Manuel Fernández-Real ◽  
Melania Manco
Keyword(s):  
Iron Overload ◽  
Metabolic Diseases

An intronic variant disrupts mRNA splicing and causes FGFR3-related skeletal dysplasia

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Ting Xu ◽  
Liang Shi ◽  
Weiqian Dai ◽  
Xuefan Gu ◽  
Yongguo Yu ◽  
...  
Keyword(s):  
De Novo ◽  
Clinical Findings ◽  
Recurrent Mutation ◽  
Mrna Splicing ◽  
Additional Patient ◽  
Missense Mutations ◽  
Splicing Variant ◽  
Amino Acid Insertion ◽  
Whole Exome ◽  
Minigene Assay

Abstract Objectives Achondroplasia and hypochondroplasia are the most common forms of disproportionate short stature, of which the vast majority of cases can be attributed to the hotspot missense mutations in the gene FGFR3. Here we presented cases with a novel cryptic splicing variant of FGFR3 gene and aimed to interrogate the variant pathogenicity. Case presentaiton In whole exome sequencing of two patients with hypochondroplasia-like features, a de novo intronic variant c.1075 + 95C>G was identified, predicted to alter mRNA splicing. Minigene assay showed that this intronic variant caused retention of a 90-nucleotide segment of intron 8 in mRNA, resulting in a 30-amino acid insertion at the extracellular domain of the protein. This is the first likely pathogenic splicing variant identified in the FGFR3 gene and was detected in one additional patient among 26 genetically unresolved patients. Conclustions Our results strongly suggest that c.1075 + 95C>G is a recurrent mutation and should be included in genetic testing of FGFR3 especially for those patients with equivocal clinical findings and no exonic mutations identified.

Possible Protective Role of Deferoxamine in Ameliorating Osteoporosis in a Rat Model of Liver Cirrhosis via Iron Metabolism Regulation

QJM ◽  
2021 ◽  
Vol 114 (Supplement_1) ◽  
Author(s):  
Shereen Helmy ◽  
Doaa I Mohamed ◽  
Wesam Elbakly ◽  
Lobna F Abd Elaziz ◽  
Eman Khairy ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Iron Overload ◽  
Rat Model ◽  
Bone Fractures ◽  
Bone Mineralization ◽  
Treated Group ◽  
Disease Etiology ◽  
Iron Storage ◽  
Metabolism Regulation ◽  
Hepatic Diseases

Abstract Background Liver cirrhosis is considered the terminal stage of many hepatic diseases of different etiologies. Liver cirrhosis was associated with increased incidence rates of some extrahepatic manifestations such as osteoporosis. Regardless of the liver disease etiology, the presence of cirrhosis implies a twofold risk of bone fractures higher than non-cirrhotic patients. The liver is the main storage depot for iron and is the primary organ that is responsible for clearing excess iron in conditions of iron overload. When the iron storage and antioxidant capacity of the liver is overwhelmed, iron overload can lead to marked oxidantmediated liver and bone injury and iron overload was a risk factor for osteoporosis via affecting osteoblast survival. Aim of the work to examine the possible protective effect of Deferoxamine (DFO) on liver cirrhosis rat model induced osteoporosis. Material and Method rats was divided into 4 groups Animal Groups: Naïve control, DFO-treated group, TAA-treated group received Thioacetamide (TAA) ip (200 mg/kg/rat) twice weekly for 12 weeks, TAA+DFO treated group received TAA intra-peritoneal in addition to DFO intraperitoneal injections (300 mg/kg/3 times/week, for the last 4 weeks of TAA injections. Results and Conclusion Deferoxamine produced significant improvement in bone mineralization alongside its significant effect on liver function test in a rat model of liver cirrhosis induced osteoporosis.

scholarly journals The relation of the pleural thickening in tuberculosis pleurisy with the activity of adenosine deaminase

2005 ◽  
Vol 63 (2) ◽  
Author(s):  
B. Uskul ◽  
H. Turker ◽  
C. Ulman ◽  
M. Ertugrul ◽  
A. Selvi ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Adenosine Deaminase ◽  
Pleural Fluid ◽  
Clinical Findings ◽  
X Rays ◽  
Biochemical Tests ◽  
Pleural Thickening ◽  
Group I ◽  
Immunological Mechanisms ◽  
Tuberculosis Pleurisy

Selvi, A. Kant, S. Arslan, M. Ozgel. Background: Residual pleural thickening (RPT) still occurs in most patients with tuberculosis pleurisy despite advances in the treatment of tuberculosis. The aim of this study was to evaluate the significance of RPT in tuberculosis pleurisy with the patients clinical findings, biochemical and microbiological properties of pleural effusion and with the total adenosine deaminase (ADA) and isoenzymes levels. Methods: 121 tuberculosis pleurisy patients were evaluated retrospectively. According to posteroanterior chest x-rays, the 63 (52%) cases with the thickness 2 mm or more in lower lateral hemithorax were grouped as I and the 58 (48%) cases without pleural thickness were grouped as II. The amount of pleural effusion was classified into small, medium or massive according to their chest x-rays. In both groups; sex, age, symptoms score, bacteriological and biochemical tests and ADA levels were recorded. Results: 81 (67%) male and 40 (33%) female, overall 121 patients were enrolled into the study. RPT was found higher in males (p=0.014) and the increase ran parallel with the amount of cigarette smoking (p=0.014). RPT was found to be lower in small effusions (p=0.001). The group with RPT, the serum albumin was found lower (p=0.002), pleural fluid total protein (p=0.047) and the ratio of pleural fluid protein to serum protein (p=0.002) were found higher. In group I, total ADA: 69.5±38.9 IU/L and ADA2: 41.3±31.6 IU/L were higher than the cases without RPT (p=0.032, p=0.017, respectively). Conclusions: We suggest that the immunological mechanisms are effective in the development of pleural thickening.

scholarly journals Treatment of iron overload syndrome: a general review

2019 ◽  
Vol 65 (9) ◽  
pp. 1216-1222 ◽  
Author(s):  
Tadeu Gonçalves de Lima ◽  
Fernanda Luna Neri Benevides ◽  
Flávio Lima Esmeraldo Filho ◽  
Igor Silva Farias ◽  
Diovana Ximenes Cavalcante Dourado ◽  
...  
Keyword(s):  
Life Expectancy ◽  
Oxidative Damage ◽  
Iron Overload ◽  
Hereditary Hemochromatosis ◽  
Treatment Strategies ◽  
Iron Chelators ◽  
Pharmacological Targets ◽  
Pubmed Database ◽  
Toxic Drugs ◽  
Oral Chelators

SUMMARY INTRODUCTION Iron overload is a broad syndrome with a large spectrum of causative etiologies that lead to iron deposition. When iron exceeds defenses, it causes oxidative damage and tissular disfunction. Treatment may prevent organ dysfunction, leading to greater life expectancy. METHODS Literature from the last five years was reviewed through the use of the PubMed database in search of treatment strategies. DISCUSSION Different pharmacological and non-pharmacological strategies are available for the treatment of iron overload and must be used according to etiology and patient compliance. Therapeutic phlebotomy is the basis for the treatment of hereditary hemochromatosis. Transfusional overload patients and those who cannot tolerate phlebotomy need iron chelators. CONCLUSION Advances in the understanding of iron overload have lead to great advances in therapies and new pharmacological targets. Research has lead to better compliance with the use of oral chelators and less toxic drugs.

scholarly journals Evaluation of Children's Appendicitis Score Compared With Pediatric Appendicitis Score in Diagnosis of Pediatric Appendicitis

2020 ◽  
Author(s):  
Mohammad Khaasteh ◽  
Fariba Heidari ◽  
Akram Motamedi ◽  
Kafieh Aslani ◽  
Masoud Jamshidi ◽  
...  
Keyword(s):  
Acute Appendicitis ◽  
Clinical Findings ◽  
Diagnostic Methods ◽  
Diagnostic Tools ◽  
Diagnostic Challenge ◽  
Diagnostic Features ◽  
Surgical Field ◽  
Us Findings ◽  
Pathology Reports ◽  
Appendicitis Score

Introduction: Identification and promotion of diagnostic methods has been a continuous effort to reduce disease and its complications and reduce costs associated with treatment. Despite all these efforts and improving our knowledge of diseases and diagnostic tools, pediatric appendicitis remains part of the diagnostic challenge in the surgical field. The aim of this is to compare the two diagnostic criteria of appendicitis (Children's Appendicitis Score [PAS] Versus Pediatric Appendicitis Score [CAS]) and evaluation of the diagnostic features of them. Methods: A retrospective cohort study was conducted on all children admitted to the hospital's emergency center with a possible diagnosis of appendicitis (270 patients) during 2018 and 2019 at Tabriz Pediatric Hospital. Based on the clinical examinations and para-clinical findings some of the patients were underwent the surgical intervention (220 cases) and some discharged and followed up for a period of 2 and 4 weeks later (50 cases). The data were analyzed through SPSS ver. 16 software. Results: The results of the present study indicated that if CAS was associated with ultrasound, the specificity of these criteria would improve and could be more acceptable compared with the PAS. In addition, it was revealed that WBC≥11000, as well as PMN≥65% and guarding were very specific for diagnosis and complication of acute appendicitis. There was a significant relationship between US findings and pathology reports (P<0.05). Conclusion: In conclusion, the CAS criteria were more sensitive and the PAS was more specific in diagnosing pediatric acute appendicitis.

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