Multi-organ iron overload in an African-American man with ALAS2 R452S and SLC40A1 R561G

Acta Haematol. 2008;120(3):168-73. doi: 10.1159/000181183. Epub 2008 Dec 10.


Background: X-linked sideroblastic anemia (XLSA) is associated with iron overload and mutations in ALAS2, which encodes 5-aminolevulinate synthase. There are few reports of XLSA in persons of sub-Saharan African descent.

Methods: A 47-year-old African-American man had microcytic anemia, elevated iron measures, cardiomyopathy, hepatic cirrhosis, diabetes mellitus, a history of cocaine use and hepatitis C. We amplified and directly sequenced his genomic DNA to detect mutations of SLC40A1, HFE, TFR2, HAMP, HJV and ALAS2.

Results: The subject's transferrin saturation was 100% and his serum ferritin was 2,960 ng/ml. An MRI scan revealed diffusely decreased T(2) signals of the heart, liver and pancreas. Transjugular right endomyocardial and liver biopsy specimens revealed marked iron deposition in cardiac myocytes and hepatocytes, and cirrhosis. He died of progressive cardiomyopathy. He was hemizygous for ALAS2 R452S (exon 9; c.1354C-->A) and heterozygous for SLC40A1 R561G (exon 8; c.1681A-->G). He did not have coding region mutations in HFE, TFR2, HAMP or HJV.

Conclusions: ALAS2 R452S largely explains this patient's microcytic anemia and multi-organ iron overload and dysfunction. SLC40A1 R561G may have increased his iron absorption and overload further. Acquired factors, especially cocaine use and hepatitis C, may have contributed to his clinical phenotype.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Aminolevulinate Synthetase / genetics*
  • 5-Aminolevulinate Synthetase / metabolism
  • Amino Acid Substitution
  • Anemia, Sideroblastic / genetics*
  • Anemia, Sideroblastic / metabolism
  • Anemia, Sideroblastic / pathology
  • Black or African American*
  • Cardiomyopathies / genetics
  • Cardiomyopathies / metabolism
  • Cardiomyopathies / pathology
  • Cation Transport Proteins / genetics*
  • Cation Transport Proteins / metabolism
  • Genetic Diseases, X-Linked / genetics*
  • Genetic Diseases, X-Linked / metabolism
  • Genetic Diseases, X-Linked / pathology
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Humans
  • Iron Overload / genetics*
  • Iron Overload / metabolism
  • Iron Overload / pathology
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology
  • Male
  • Middle Aged
  • Mutation, Missense*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology


  • Cation Transport Proteins
  • metal transporting protein 1
  • 5-Aminolevulinate Synthetase
  • ALAS2 protein, human