INTRODUCTION
The congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited disorders of erythropoiesis characterized by pathologic deposits of iron in the mitochondria of developing erythroblasts (Cartwright & Deiss, 1975). The genetically defined CSAs can be attributed to defects in three interrelated mitochondrial pathways: heme biosynthesis, iron-sulfur cluster assembly, and mitochondrial protein synthesis and respiration (Ducamp & Fleming, 2019). CSAs due to primary heme biosynthesis defects are the most prevalent. The most common CSA, X-linked sideroblastic anemia (XLSA), is caused by mutations in the first and rate-limiting enzyme in erythroid heme synthesis, 5-aminolevulinate synthase 2 (ALAS2), which catalyses the condensation of glycine with succinyl coenzyme A to form 5-aminolevulinic acid (ALA) in the mitochondrial matrix. More than 200 families with XLSA have been described in the literature (Bottomley & Fleming, 2014). ALAS2 is extraordinarily dependent upon high levels of glycine to ensure sufficient heme synthesis, as it has a very highKm (9.3 ± 1.2 mM) for this substrate (Bishop, Tchaikovskii, Nazarenko, & Desnick, 2013).
An autosomal recessive form due to loss-of-function mutations in SLC25A38 is the second most common form of CSA (Guernsey et al., 2009). SLC25A38 is a member of the Mitochondrial Solute Carrier Family 25 (SLC25) family of transporters (Kunji, 2004; Ruprecht & Kunji, 2020), is encoded on chromosome 3p22, and is highly and selectively expressed in erythroblasts (Guernsey et al., 2009). The yeast ortholog of SLC25A38 (yDL119c) is essential for efficient heme biosynthesis and knockdown of the orthologous proteins in zebrafish results in anemia; each of these phenotypes can be rescued by the addition of glycine or ALA (Fernandez-Murray et al., 2016; Guernsey et al., 2009). Transport studies show that yDL119c is a high affinity mitochondrial glycine importer (Lunetti et al., 2016).
While the severity of the anemia is generally far more profound than XLSA, consistent with the shared interruption of heme synthesis, the morphologic features of the blood and bone marrow in the SLC25A38 anemia are highly reminiscent of XLSA and characterized by a reticulocytopenic, hypochromic, microcytic anemia with a very wide red blood cell distribution width (RDW) and ring sideroblasts (RS) predominantly found in later erythroid precursors. To date, 69 families and a total of 36 different causative SLC25A38 mutations have been described (W. An et al., 2015; W. B. An et al., 2019; Andolfo et al., 2020; Fouquet et al., 2019; Guernsey et al., 2009; Kakourou et al., 2016; Kannengiesser et al., 2011; Kim, Shah, Bottomley, & Shah, 2018; Kucerova et al., 2011; Le Rouzic et al., 2017; Liu et al., 2013; Mehri et al., 2018; Ravindra et al., 2020; Shefer Averbuch et al., 2018; Ulirsch et al., 2019; Uminski et al., 2020; Wong et al., 2015). Here we describe the clinical phenotypes and genotypes of an additional 31 individuals from 24 families, including 11 novel mutations. We also review the spectrum of mutations and genotypes associated with the disease, including describing the unique localization of missense (MS) mutations in transmembrane (TM) domains and account for the reoccurrence of several alleles in different populations.