What is Sideroblastic Anemia
Sideroblastic anemia is a heterogeneous group of inherited and acquired disorders characterized by defective heme synthesis leading to pathological iron accumulation in the mitochondria of developing red blood cells, creating characteristic "ring sideroblasts" visible on bone marrow examination. 1, 2
Core Pathophysiology
The fundamental defect involves disrupted heme biosynthesis within erythroid precursors, causing iron to accumulate in perinuclear mitochondria rather than being incorporated into hemoglobin. 2, 3 This creates the diagnostic hallmark: ring sideroblasts, which are erythroid precursors with iron-laden mitochondria forming a ring-like pattern around the nucleus. 1, 4
The paradoxical feature of sideroblastic anemia is that patients develop microcytic hypochromic anemia despite having adequate or excessive total body iron stores, because the iron cannot be properly utilized for hemoglobin synthesis. 2, 5 This makes iron supplementation contraindicated in most forms. 2
Classification and Genetic Causes
Congenital Forms
Congenital sideroblastic anemia results from genetic mutations affecting different steps in heme synthesis or iron metabolism: 1, 3
X-linked sideroblastic anemia (XLSA):
- Most common genetic form, caused by ALAS2 gene mutations affecting erythroid-specific δ-aminolevulinate synthase. 2, 6
- Impairs pyridoxal phosphate (vitamin B6) cofactor binding, disrupting the first step of heme synthesis. 2
- Typically presents with mild to moderate microcytic hypochromic anemia in hemizygous males. 6
- Many patients respond to pyridoxine (vitamin B6) supplementation at 50-200 mg daily. 5, 6
Autosomal recessive forms:
- SLC25A38 mutations cause severe congenital sideroblastic anemia by disrupting mitochondrial glycine import or ALA exchange. 1, 2 Patients present in childhood with severe, often transfusion-dependent microcytic anemia clinically similar to thalassemia major. 1
- GLRX5 mutations impair Fe-S cluster biosynthesis, leading to repression of ALAS2 and reduced heme synthesis. 2
- ABCB7 mutations cause X-linked sideroblastic anemia with ataxia by disrupting mitochondrial Fe-S complex export. 1
Iron metabolism defects:
- SLC11A2 (DMT1) mutations cause defective enterocyte and erythroid iron uptake, yet paradoxically lead to systemic iron loading through alternative heme absorption pathways or low hepcidin levels. 1, 2
- STEAP3 mutations impair ferroreductase activity, preventing Fe³⁺ to Fe²⁺ reduction in erythroblast endosomes. 1, 2
Acquired Forms
Acquired sideroblastic anemia is more common than congenital forms and includes: 3
- Myelodysplastic syndrome with ring sideroblasts (MDS-RS): Over 90% carry somatic SF3B1 mutations affecting RNA splicing machinery, causing misrecognition of splice sites and multifactorial pathogenesis. 6 This is rare in pediatric populations but represents the most common acquired form in adults. 7
- Secondary causes: Drugs, toxins, copper deficiency, chronic neoplastic disease, or alcohol. 3, 4
Clinical Consequences
Microcytic hypochromic anemia occurs due to reduced hemoglobin synthesis, with severity ranging from mild anemia in XLSA to severe transfusion-dependent anemia in SLC25A38 defects. 2, 5
Systemic iron overload affects liver, heart, and endocrine organs despite the presence of anemia, with increased transferrin saturation and ferritin reflecting iron loading despite impaired erythroid iron utilization. 2 This iron overload develops even before transfusions in many genetic forms. 1
Ineffective erythropoiesis is a hallmark feature, where developing red blood cells fail to mature properly and undergo apoptosis in the bone marrow. 3, 6
Diagnostic Approach
Bone marrow examination with Perls' Prussian blue stain is essential for diagnosis, revealing ring sideroblasts (type 3 sideroblasts with >5 iron-laden mitochondria encircling at least one-third of the nucleus). 5, 7 The presence of >15% ring sideroblasts is diagnostic. 7
Genetic testing is crucial for definitive diagnosis in cases with extreme microcytosis and for characterizing congenital forms. 5, 7 Testing should be guided by clinical presentation, family history, and inheritance pattern. 3
Critical Clinical Pitfall
The most important pitfall is the paradoxical iron overload with microcytic anemia, where iron cannot be properly utilized for heme synthesis despite adequate or excessive body iron stores. 2 This makes iron supplementation contraindicated in most forms of sideroblastic anemia, with the notable exception of SLC11A2 defects where oral iron may actually improve hemoglobin and lead to transfusion independence in some patients. 1, 5