History

Fact Explanation
Family history of sideroblastic anaemia [3] There are two forms of sideroblastic anemia: congenital sideroblastic anemia and acquired sideroblastic anemia. [2] Hereditary sideroblastic anaemia is a condition characterized by anemia with the emergence of ring sideroblasts in the bone marrow. Its inheritance is X linked recessive [6] affecting mainly males and manifestation of the disease may be early or late during the first 3 decades of life. This is due to the mutations in the erythroid-specific ALA synthase gene (ALAS) . [3]
Shortness of breath on exertion on exertion [7] malaise, fatigue These are symptoms of anemia, Anaemia cause low oxygenation of the blood, Hypoxia can be sensed by the carotid chemoreceptors and it will increase the depth of respiration. If the patient has heart failure [7] anemia can worsen the symptoms. Anaemia causes low oxygenation of the blood leading to reduced energy production, and lack of energy.
Complications due to haemasiderosis [8] -Shortness of breath, right hypochondrial pain In sideroblastic anaemia there is increased absorption of iron and increased storage. Iron, nitrogen, and protein are the content of the hemosiderin granules. [5] Excess iron can be deposited in the liver, heart and endocrine organs causing organ failures.
Problems with balance and gait [1] There is an association between spinocerebellar disorder and hereditary sideroblastic anaemia which is characterised by progressive ataxia and incoordination. [1] Ataxic form of the disease is mostly inherited as autosomal recessive and dominant. [4]
Speech problems [3] Dysarthria is seen in spinocerebellar disorders. [3]
References
  1. PAGON RA, BIRD TD, DETTER JC, PIERCE I. Hereditary sideroblastic anaemia and ataxia: an X linked recessive disorder. J Med Genet [online] 1985 Aug, 22(4):267-273 [viewed 31 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1049446
  2. OHBA R, FURUYAMA K, YOSHIDA K, FUJIWARA T, FUKUHARA N, ONISHI Y, MANABE A, ITO E, OZAWA K, KOJIMA S, OGAWA S, HARIGAE H. Clinical and genetic characteristics of congenital sideroblastic anemia: comparison with myelodysplastic syndrome with ring sideroblast (MDS-RS) Ann Hematol [online] 2013 Jan, 92(1):1-9 [viewed 31 July 2014] Available from: doi:10.1007/s00277-012-1564-5
  3. CAZZOLA M, INVERNIZZI R. Ring sideroblasts and sideroblastic anemias Haematologica [online] 2011 Jun, 96(6):789-792 [viewed 31 July 2014] Available from: doi:10.3324/haematol.2011.044628
  4. RASKIND WH, WIJSMAN E, PAGON RA, COX TC, BAWDEN MJ, MAY BK, BIRD TD. X-linked sideroblastic anemia and ataxia: linkage to phosphoglycerate kinase at Xq13. Am J Hum Genet [online] 1991 Feb, 48(2):335-341 [viewed 31 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1683027
  5. RICHTER GW. THE NATURE OF STORAGE IRON IN IDIOPATHIC HEMOCHROMATOSIS AND IN HEMOSIDEROSIS : ELECTRON OPTICAL, CHEMICAL, AND SEROLOGIC STUDIES ON ISOLATED HEMOSIDERIN GRANULES J Exp Med [online] 1960 Sep 30, 112(4):551-570 [viewed 06 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2137244
  6. COTTER PD, MAY A, FITZSIMONS EJ, HOUSTON T, WOODCOCK BE, AL-SABAH AI, WONG L, BISHOP DF. Late-onset X-linked sideroblastic anemia. Missense mutations in the erythroid delta-aminolevulinate synthase (ALAS2) gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts. J Clin Invest [online] 1995 Oct, 96(4):2090-2096 [viewed 06 August 2014] Available from: doi:10.1172/JCI118258
  7. MOTTRAM PM, MARWICK TH. Assessment of diastolic function: what the general cardiologist needs to know Heart [online] 2005 May, 91(5):681-695 [viewed 10 September 2014] Available from: doi:10.1136/hrt.2003.029413
  8. CARTWRIGHT GE, EDWARDS CQ, SKOLNICK MH, AMOS DB. Association of HLA-linked hemochromatosis with idiopathic refractory sideroblastic anemia. J Clin Invest [online] 1980 May, 65(5):989-992 [viewed 10 September 2014] Available from: doi:10.1172/JCI109785

Examination

Fact Explanation
Pallor Due to the anaemia. [2]
Dyspnea [4] Anaemia leading to hypoxia may be the aetiology for exertional dyspnea. [4]
Murmers [5] Due to the anaemia patient can develop flow murmurs, [5] as a result of the hyperdynamic circulation.
Features of cardiac failure: exrtional dyspnea, [4] elevated jugular venous pressure, tender hepatomegally, peripheral oedema Patients with existing heart disease may have aggravation due to anaemia. [6]
Spasticity This is usually mild, and there is no sensory impairment. [2]
Incoordination and ataxia [3] Sideroblastic anaemia is associated with non-progressive spinocerebellar syndrome in an X linked recessive manner. [1]
Failure of growth [3] Males affected by sideroblastic anemia shows retardation of growth. [3]
References
  1. PAGON RA, BIRD TD, DETTER JC, PIERCE I. Hereditary sideroblastic anaemia and ataxia: an X linked recessive disorder. J Med Genet [online] 1985 Aug, 22(4):267-273 [viewed 31 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1049446
  2. RASKIND WH, WIJSMAN E, PAGON RA, COX TC, BAWDEN MJ, MAY BK, BIRD TD. X-linked sideroblastic anemia and ataxia: linkage to phosphoglycerate kinase at Xq13. Am J Hum Genet [online] 1991 Feb, 48(2):335-341 [viewed 31 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1683027
  3. PRASAD AS, TRANCHIDA L, KONNO ET, BERMAN L, ALBERT S, SING CF, BREWER GJ. Hereditary sideroblastic anemia and glucose-6-phosphate dehydrogenase deficiency in a negro family J Clin Invest [online] 1968 Jun, 47(6):1415-1424 [viewed 06 August 2014] Available from: doi:10.1172/JCI105833
  4. MOTTRAM PM, MARWICK TH. Assessment of diastolic function: what the general cardiologist needs to know Heart [online] 2005 May, 91(5):681-695 [viewed 10 September 2014] Available from: doi:10.1136/hrt.2003.029413
  5. JAYAWARDENA SURIYA, ANANDACOOMARASWAMY DHARSHAN, BURZYANTSEVA OLGA, ABDULLAH MUHAMMAD. Isolated diffuse hyperplastic gastric polyposis presenting with severe anemia. Array [online] 2008 December [viewed 10 September 2014] Available from: doi:10.1186/1757-1626-1-130
  6. CROMIE N, LEE C, STRUTHERS AD. Anaemia in chronic heart failure: what is its frequency in the UK and its underlying causes? Heart [online] 2002 Apr, 87(4):377-378 [viewed 15 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1767058

Differential Diagnoses

Fact Explanation
Thalassemia [1] Ineffective erythropoiesis, due to excess production of free alpha (α) globin chains is the major abnormality in thalassemia. Thalassemia patients have anemia that requires chronic blood transfusions and chelation therapies to prevent iron overload. [7] Beta-thalassemia intermedia, is relatively a mild disease that does not require chronic blood transfusions. On examination they will have thalassemic facies maxillary hyperplasia, splenomegaly etc. These patients will also have the microcytic hypochromic anaemia as in sideroblastic anaemia . Red cell distribution width is normal in thalassemia.
Iron deficiency [6] This also has a microcytic hypochromic anaemia. It is associated with certain clinical features that are specifically seen in iron deficiency such as picca (desire to eat substances that are not suitable for consumption), koilonychia and glossitis. They may also have a history of poor diet, excessive loss of iron [6] or malabsorption. Sideroblastic anemia differs from the iron deficiency anaemia as they will have almost complete saturation of the serum transferrin, when compared to iron deficiency. [2]
Lead poisoning [4] Lead poisoning will have characteristic signs and symptoms of lead poisoning such as abdominal pain, confusion, headache, anemia, irritability, and in severe cases seizures, coma, and death. Blood lead concentration is the commonly used marker and Zinc protoporphyrin (ZPP) concentration in blood can be used to detect the lead exposure over the prior 3 months. [5]
Myelodysplastic syndrome [3] Refractory anemia with ring sideroblasts is found in some patients with myelodysplastic syndrome characterized by isolated anemia and erythroid dysplasia with 15% or more ring sideroblasts in the bone marrow. [2]
References
  1. RECHAVI G, RIVELLA S. Regulation of Iron Absorption in Hemoglobinopathies Curr Mol Med [online] 2008 Nov, 8(7):646-662 [viewed 27 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3722362
  2. CAZZOLA M, INVERNIZZI R. Ring sideroblasts and sideroblastic anemias Haematologica [online] 2011 Jun, 96(6):789-792 [viewed 31 July 2014] Available from: doi:10.3324/haematol.2011.044628
  3. BERGMANN AK, CAMPAGNA DR, MCLOUGHLIN EM, AGARWAL S, FLEMING MD, BOTTOMLEY SS, NEUFELD EJ. Systematic Molecular Genetic Analysis of Congenital Sideroblastic Anemia: Evidence for Genetic Heterogeneity and Identification of Novel Mutations Pediatr Blood Cancer [online] 2010 Feb, 54(2):273-278 [viewed 10 September 2014] Available from: doi:10.1002/pbc.22244
  4. GOLDSTEIN GW. Lead poisoning and brain cell function. Environ Health Perspect [online] 1990 Nov:91-94 [viewed 10 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1567775
  5. GORDON JN, TAYLOR A, BENNETT PN. Lead poisoning: case studies Br J Clin Pharmacol [online] 2002 May, 53(5):451-458 [viewed 10 September 2014] Available from: doi:10.1046/j.1365-2125.2002.01580.x
  6. ZHU A, KANESHIRO M, KAUNITZ JD. Evaluation and Treatment of Iron Deficiency Anemia: A Gastroenterological Perspective Dig Dis Sci [online] 2010 Mar, 55(3):548-559 [viewed 10 September 2014] Available from: doi:10.1007/s10620-009-1108-6
  7. WOOD JC. CARDIAC COMPLICATIONS IN THALASSEMIA MAJOR Hemoglobin [online] 2009, 33(Suppl 1):S81-S86 [viewed 10 September 2014] Available from: doi:10.3109/03630260903347526

Investigations - for Diagnosis

Fact Explanation
Full blood count [1] Will show anaemia with low haemoglobin. Red cell indices such as mean corpuscular haemoglobin and mean corpuscular volume are reduced as this is a microcytic hypochromic anaemia. [4]
Blood picture [1] Shows microcytic hypochromic anaemia, anisocytosis, cigar shaped cells and a dimorphic peripheral blood smear with normocytic and microcytic picture. [1,5]
Serum free erythrocyte protoporphyrin [1] Raised serum free erythrocyte protoporphyrin is seen. [1]
Bone marrow examination Bone marrow examination shows erythroblastic hyperplasia, ring sideroblasts, and marrow with increased iron. [1,2] Erythroblasts with iron-loaded mitochondria visualized by Prussian blue staining (Perls’ reaction), they are seen as a perinuclear ring of blue granules and are known as ring sideroblasts. [3]
Serum iron [2] Serum iron is usually elevated. [2] There is low Fe incorporation into erythrocytes, but normal erythrocyte survival is seen.
Iron-binding capacity [2] Decreased unsaturated iron-binding capacity is seen. [2]
Erythrocyte survival (51 Cr) [2] Erythrocyte survival is normal. [2]
References
  1. PAGON RA, BIRD TD, DETTER JC, PIERCE I. Hereditary sideroblastic anaemia and ataxia: an X linked recessive disorder. J Med Genet [online] 1985 Aug, 22(4):267-273 [viewed 31 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1049446
  2. PRASAD AS, TRANCHIDA L, KONNO ET, BERMAN L, ALBERT S, SING CF, BREWER GJ. Hereditary sideroblastic anemia and glucose-6-phosphate dehydrogenase deficiency in a negro family J Clin Invest [online] 1968 Jun, 47(6):1415-1424 [viewed 27 July 2014] Available from: doi:10.1172/JCI105833
  3. CAZZOLA M, INVERNIZZI R. Ring sideroblasts and sideroblastic anemias Haematologica [online] 2011 Jun, 96(6):789-792 [viewed 31 July 2014] Available from: doi:10.3324/haematol.2011.044628
  4. COTTER PD, MAY A, FITZSIMONS EJ, HOUSTON T, WOODCOCK BE, AL-SABAH AI, WONG L, BISHOP DF. Late-onset X-linked sideroblastic anemia. Missense mutations in the erythroid delta-aminolevulinate synthase (ALAS2) gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts. J Clin Invest [online] 1995 Oct, 96(4):2090-2096 [viewed 10 September 2014] Available from: doi:10.1172/JCI118258
  5. BERGMANN AK, CAMPAGNA DR, MCLOUGHLIN EM, AGARWAL S, FLEMING MD, BOTTOMLEY SS, NEUFELD EJ. Systematic Molecular Genetic Analysis of Congenital Sideroblastic Anemia: Evidence for Genetic Heterogeneity and Identification of Novel Mutations Pediatr Blood Cancer [online] 2010 Feb, 54(2):273-278 [viewed 10 September 2014] Available from: doi:10.1002/pbc.22244

Investigations - Fitness for Management

Fact Explanation
Echocardiography [2] Hemosiderosis can be due to excess iron deposition, that can affects cardiac function. [1]
References
  1. CAZZOLA M, INVERNIZZI R. Ring sideroblasts and sideroblastic anemias Haematologica [online] 2011 Jun, 96(6):789-792 [viewed 06 August 2014] Available from: doi:10.3324/haematol.2011.044628
  2. MOTTRAM PM, MARWICK TH. Assessment of diastolic function: what the general cardiologist needs to know Heart [online] 2005 May, 91(5):681-695 [viewed 10 September 2014] Available from: doi:10.1136/hrt.2003.029413

Investigations - Followup

Fact Explanation
Haemoglobin level [1] Haemoglobin level need to assess the response to therapy. Usually with the pyridoxine therapy, there will be 2-4g/100ml of improvement in the level of haemoglobin. [1]
Blood picture [2] Microcytic hypochromic anaemia can be reversed with the pyridoxine treatment. [2]
References
  1. PRASAD AS, TRANCHIDA L, KONNO ET, BERMAN L, ALBERT S, SING CF, BREWER GJ. Hereditary sideroblastic anemia and glucose-6-phosphate dehydrogenase deficiency in a negro family J Clin Invest [online] 1968 Jun, 47(6):1415-1424 [viewed 31 July 2014] Available from: doi:10.1172/JCI105833
  2. COTTER PD, MAY A, FITZSIMONS EJ, HOUSTON T, WOODCOCK BE, AL-SABAH AI, WONG L, BISHOP DF. Late-onset X-linked sideroblastic anemia. Missense mutations in the erythroid delta-aminolevulinate synthase (ALAS2) gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts. J Clin Invest [online] 1995 Oct, 96(4):2090-2096 [viewed 06 August 2014] Available from: doi:10.1172/JCI118258

Investigations - Screening/Staging

Fact Explanation
Magnetic Resonance Imaging[1] MRI shows cerebellar atrophy. [1]
Genomic analysis (PCR) [3] Mutation (ALAS) detection is helpful for the early diagnosis of those affected, targeted education of families, early treatment with pyridoxine and prevention of iron overload. [2]
References
  1. RASKIND WH, WIJSMAN E, PAGON RA, COX TC, BAWDEN MJ, MAY BK, BIRD TD. X-linked sideroblastic anemia and ataxia: linkage to phosphoglycerate kinase at Xq13. Am J Hum Genet [online] 1991 Feb, 48(2):335-341 [viewed 31 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1683027
  2. MAY A, BISHOP DF. The molecular biology and pyridoxine responsiveness of X-linked sideroblastic anaemia. Haematologica [online] 1998 Jan, 83(1):56-70 [viewed 06 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/9542324
  3. COTTER PD, MAY A, FITZSIMONS EJ, HOUSTON T, WOODCOCK BE, AL-SABAH AI, WONG L, BISHOP DF. Late-onset X-linked sideroblastic anemia. Missense mutations in the erythroid delta-aminolevulinate synthase (ALAS2) gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts. J Clin Invest [online] 1995 Oct, 96(4):2090-2096 [viewed 10 September 2014] Available from: doi:10.1172/JCI118258

Management - General Measures

Fact Explanation
Blood transfusion [4] Severe symptomatic anaemia require blood transfusion. [4]
Supportive management If complications like liver, heart failure occur due to hemosiderosis, [3] they need supportive treatment. Phlebotomy can be used to prevent and treat iron overload. [1]
Genetic councelling [2] This is needed specially when a carrier state is diagnosed by DNA screening. Prenatal diagnosis is unnecessary unless there is a pyridoxine refractory severe anaemia. [2]
References
  1. CAZZOLA M, INVERNIZZI R. Ring sideroblasts and sideroblastic anemias Haematologica [online] 2011 Jun, 96(6):789-792 [viewed 06 August 2014] Available from: doi:10.3324/haematol.2011.044628
  2. COTTER PD, MAY A, FITZSIMONS EJ, HOUSTON T, WOODCOCK BE, AL-SABAH AI, WONG L, BISHOP DF. Late-onset X-linked sideroblastic anemia. Missense mutations in the erythroid delta-aminolevulinate synthase (ALAS2) gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts. J Clin Invest [online] 1995 Oct, 96(4):2090-2096 [viewed 06 August 2014] Available from: doi:10.1172/JCI118258
  3. CARTWRIGHT GE, EDWARDS CQ, SKOLNICK MH, AMOS DB. Association of HLA-linked hemochromatosis with idiopathic refractory sideroblastic anemia. J Clin Invest [online] 1980 May, 65(5):989-992 [viewed 10 September 2014] Available from: doi:10.1172/JCI109785
  4. BERGMANN AK, CAMPAGNA DR, MCLOUGHLIN EM, AGARWAL S, FLEMING MD, BOTTOMLEY SS, NEUFELD EJ. Systematic Molecular Genetic Analysis of Congenital Sideroblastic Anemia: Evidence for Genetic Heterogeneity and Identification of Novel Mutations Pediatr Blood Cancer [online] 2010 Feb, 54(2):273-278 [viewed 10 September 2014] Available from: doi:10.1002/pbc.22244

Management - Specific Treatments

Fact Explanation
Pyridoxine therapy [2] Pyridoxine 100 mg daily for 6 months will usually given to increase the haemoglobin level at a rate of 2-4g/100ml. [1] There can be an incomplete response in some patients. [2]
References
  1. PRASAD AS, TRANCHIDA L, KONNO ET, BERMAN L, ALBERT S, SING CF, BREWER GJ. Hereditary sideroblastic anemia and glucose-6-phosphate dehydrogenase deficiency in a negro family J Clin Invest [online] 1968 Jun, 47(6):1415-1424 [viewed 31 July 2014] Available from: doi:10.1172/JCI105833
  2. COTTER PD, MAY A, FITZSIMONS EJ, HOUSTON T, WOODCOCK BE, AL-SABAH AI, WONG L, BISHOP DF. Late-onset X-linked sideroblastic anemia. Missense mutations in the erythroid delta-aminolevulinate synthase (ALAS2) gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts. J Clin Invest [online] 1995 Oct, 96(4):2090-2096 [viewed 06 August 2014] Available from: doi:10.1172/JCI118258