Albertine Donker

Chapter 3 118 Table 1. Continued 3D. Sideroblastic anemia due to defects in GLRX5 Clinical presentation and diagnosis • In patients presenting with microcytic sideroblastic anemia and iron loading (among others) defects in GLRX5 should be considered. • In case of microcytic sideroblastic anemia without ALAS2 , or SLC25A38 defects a lymphoblastic culture should be considered. Decreased activity of mitochondrial acitonase and succinate dehydrogenase (complex I-IV) as a manifestation of a defective Fe-S cluster synthesis, is suggestive for a GLRX5 defect. Treatment • In patients with sideroblastic anemia and iron loading due to GLRX5 defects, monitoring of the iron status and possible complications of iron overload is recommended. Iron loading should be treated with chelation therapy. Severe anemia with blood transfusions. Family screening* • Recommendations are identical to those described in 1C. 3E. Erythropoietic ProtoPorphyria due to defects in FECH and gain-of-function mutations in ALAS2 (XLDPP) Clinical presentation and diagnosis • In patients with an unexplained mild normo- to microcytic anemia, a low to normal serum ferritin and cutaneous protoporphyria, a painful photosensitivity in childhood, EPP has to be considered, both in men and women. • The diagnosis EPP should be confirmed by fluorescent erythrocytes in an unstained smear, and/or enhanced protoporphyrin in plasma and/or erythrocytes. • To prove autosomal recessive EPP FECH activity should be measured or FECH mutations determined. • In case EPP is not explained by the FECH genotype, the ALAS2 gene should be investigated for the presence of gain-of-function mutations. Treatment • In case anemia in EPP is present, it is mild, and treatment is not recommended. Family screening* • Because of complex genetics, influenced by genetic background, we recommend referral to a clinical geneticist in case of EPP. Family screening for a proband with XLDPP due to and ALAS2 gain-of-function mutation should initially include phenotyping and genotyping of all first-degree family members (including women): mother in case of a male proband, both parents in case of a female proband, siblings and children.