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X-linked sideroblastic anemia (XLSA) is a hypochromic, microcytic anemia caused by germline mutations in the erythroid‐specific 5-aminolevulinate synthase gene (ALAS2) on Xp11.21. Hemizygous males present with ringed sideroblasts, iron overload, and variable pyridoxine responsiveness, whereas heterozygous females may be asymptomatic or show macrocytic anemia depending on X-chromosome inactivation. The disorder follows an X-linked recessive inheritance pattern with full penetrance in males and variable expression in females.
Genetic evidence for ALAS2–XLSA is definitive. Over 100 distinct ALAS2 mutations have been reported in more than 240 families worldwide, including missense, nonsense, splice-site, promoter, frameshift, and deep intronic variants, with consistent segregation in X-linked pedigrees and multiple de novo events ([PMID:40195342]). Early case reports identified a missense c.475G>T (p.Asp159Tyr) in two brothers and their mother, confirming familial segregation in an X-linked pattern ([PMID:12031592]). Multi‐patient studies describe late-onset pyridoxine-responsive cases with variants such as c.514G>A (p.Ala172Thr) and c.895A>C (p.Lys299Gln) in unrelated probands ([PMID:7560104]).
Variant spectrum is broad: missense substitutions account for the majority of pathogenic alleles, with several hotspots at Arg411, Arg452, and Arg559. Frameshift and nonsense mutations in exon 11 (e.g., c.1743_1753del (p.Gln581HisfsTer35)) result in loss of function and longer polypeptides prone to degradation. Promoter mutations (c.-206C>G) reduce ALAS2 transcription by 94% in luciferase assays, and intronic GATA site mutations (c.-15-2187T>C) abolish enhancer activity. Recurrent founder variants include p.Arg452Cys and p.Arg452His, which disrupt protein–protein interactions.
Segregation analyses report at least 19 affected male relatives across multiple families, with additional obligate carriers in female lineages showing skewed X-inactivation ([PMID:11110715]). Penetrance in males is essentially complete, while females exhibit variable expressivity depending on lyonization, sometimes presenting with macrocytic anemia or iron overload. Carrier detection enables genetic counseling and anticipatory management.
Functional studies demonstrate that pathogenic missense mutations reduce ALAS2 enzyme activity to 7–25% of wild-type and alter pyridoxal 5′-phosphate affinity, consistent with pyridoxine responsiveness ([PMID:9858242]). Frameshift truncations in the C-terminal tail impair binding to the β-subunit of succinyl-CoA synthetase (SUCLA2), further compromising heme biosynthesis ([PMID:22740690]). Recombinant expression and cellular models confirm that loss‐of‐function variants cause mitochondrial iron accumulation and ring sideroblast formation, while gain‐of‐function deletions in the same region underlie X-linked protoporphyria.
Integration of genetic and experimental data establishes ALAS2 mutations as the definitive cause of XLSA. Genetic testing of ALAS2—including coding, promoter, and enhancer regions—is recommended for patients with unexplained microcytic anemia or ring sideroblasts. Pyridoxine supplementation and iron chelation remain cornerstone therapies. Key take-home: ALAS2 mutation analysis provides conclusive diagnosis of XLSA, guiding tailored treatment and family counseling.
Gene–Disease AssociationDefinitiveMultiple unrelated families with >240 mutation-positive pedigrees, consistent X-linked recessive inheritance, and extensive functional characterization Genetic EvidenceStrongIdentification of >100 distinct ALAS2 mutations across >240 families with segregation in X-linked pedigrees and recurrent founder alleles Functional EvidenceStrongIn vitro assays show reduced enzyme activity and altered cofactor binding for missense and truncating variants; disrupted SUCLA2 interaction and cellular models recapitulate ring sideroblast phenotype |