Multi-organ iron overload in an African-American man with ALAS2 R452S and SLC40A1 R561G.
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.
Sussman
Norman L
NL
Department of Medicine, Baylor College of Medicine, Houston, Tex., USA.
Lee
Pauline L
PL
Dries
Andrew M
AM
Schwartz
Mary R
MR
Barton
James C
JC
D000624:5-Aminolevulinate Synthetase / Q000235:genetics* / Q000378:metabolism; D001741:Black or African American; D019943:Amino Acid Substitution; D000756:Anemia, Sideroblastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019190:Iron Overload / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D000098742:Ferroportin
D027682:Cation Transport Proteins; D000098742:Ferroportin; D000624:5-Aminolevulinate Synthetase; C480079:ALAS2 protein, human