ALAS is involved in the conversion of glycine and succinyl-coenzyme A into delta-aminolevulinic acid in a pyridoxal 5-phosphate (PLP)-dependent manner [5]. Therefore, pathogenic variants in ALAS2 lead to the deficiency of heme biosynthesis, which results in anemia. More than 100 pathogenic variants in ALAS2 gene have been reported to date, and most of them are missense variants and mainly in exon5 to exon11 [6]. In our case, a novel missense pathogenic variant was identified in Exon 5 which resulted in the amino acid substitution of Leucine for Arginine at codon 204.

The differentiation of CSA from other causes of microcytic hypochromic anemia in pediatric and young adult patients is crucial. A bone marrow examination should be done for ring sideroblasts in all patients with normal Hb electrophoresis and serum iron studies. If an ALAS2 pathogenic variant is found, pyridoxine supplementation may reduce any transfusion burden and iron overload.

Some XLSA patients can present later in their lives because of mild, chronic anemia which may not be detected due to of lack of symptoms. One oldest case was an 81-year-old male with chronic renal failure in whom pyridoxine deficiency developed on maintenance hemodialysis and occult XLSA was uncovered [7]. Other reports had also described older individuals with XLSA and a prior misdiagnosis of myelodysplastic syndrome with ring sideroblasts [8]. Women with XLSA mostly have normocytic or macrocytic anemia and they develop symptomatic XLSA later in life due to acquired skewing of X chromosome inactivation in hematopoietic cells leading to predominance of an active X which bears an ALAS2 pathogenic variant.

In the process of ALA synthesis, pyridoxal 5′-phosphate (PLP) is a cofactor which reversibly binds to Lysine 391. This interaction is required for enzymatic activity. All reported ALAS2 pathogenic variants in male XLSA patients were missense pathogenic variants, often located at the domains important for pyridoxal phosphate co-factor binding or catalysis Pyridoxine can enhance the activity of ALAS2 enzyme [9]. We hypothesize that the presence of Leu at the R204 location destabilizes the enzyme’s structure and that additional PLP cofactor supply stabilizes.

Patients with XLSA are prone to iron overload irrespective of red blood cell transfusions and pyridoxine-responsiveness. Iron overload is attributed to reduced hepcidin level secondary to ineffective erythropoiesis, which promotes intestinal iron absorption [10]. It is necessary to regularly monitor patients’ clinical, laboratory, and radiological parameters to detect long-term complications