Genetic and phenotypic characteristics of SA
| . | Inheritance . | Syndromic . | Gene . | Mutations . | Frequency* . | Age at presentation . | Anemia severity . | MCV . | Associated abnormalities . |
|---|---|---|---|---|---|---|---|---|---|
| CSA | |||||||||
| Heme synthesis defects | |||||||||
| XLSA | X | No | ALAS2 | MS/R♂ | 100s | Infancy to adulthood | Mild to severe | ↓♂ N/↑♀ | Iron overload in the absence of transfusions |
| MS/NS/FS♀ | |||||||||
| SLC25A38 deficiency | AR | No | SLC25A38 | NS/FS/SPL/MS | ∼40 | Infancy | Severe | ↓ | Transfusional iron overload |
| EPP | AR/PSD | No | FECH | SPL/MS/NS/FS | 100s | Childhood | Mild | ↓ | Acute photosensitivity |
| Fe-S biogenesis defects | |||||||||
| GLRX5 deficiency | AR | No | GLRX5 | MS | 2 | Adulthood | Mild to severe | ↓ | Iron overload |
| HSPA9 deficiency | AR/PSD | No | HSPA9 | MS/FS/NS/SPL | 12 | Childhood | Mild to severe | N/↓ | Retinitis pigmentosa |
| HSCB deficiency | AR | No | HSCB | FS/R | 1 | Childhood | Moderate | N | None |
| XLSA/A | X | Yes | ABCB7 | MS | 5 | Childhood | Mild to moderate | ↓ | Cerebellar ataxia and hypoplasia, delayed motor development |
| Mitochondrial protein synthesis defects | |||||||||
| PMPS | SP/M | Yes | mtDNA | DEL (heteroplasmic) | 100s | Early childhood | Severe | ↑ | Lactic acidosis, exocrine pancreatic insufficiency, failure to thrive, hepatic/renal failure |
| MLASA1 | AR | Yes | PUS1 | MS, NS | ∼10 | Childhood | Mild to severe | N/↑ | Myopathy, lactic acidosis, facial dysmorphism |
| MLASA2 | AR | Yes | YARS2 | MS, FS, NS, DEL, SPL | ∼40 | Childhood | Mild to severe | N/↑ | Myopathy, lactic acidosis, cardiomyopathy |
| LARS2 deficiency | AR | Yes | LARS2 | MS | 1 | Infancy | Severe | ↑ | Lactic acidosis, cardiomyopathy, hepatopathy, seizures |
| SIFD | AR | Yes | TRNT1 | MS/FS/NS/ SPL | ∼30 | Infancy | Severe | ↓ | Immunodeficiency (B>T), aseptic febrile episodes, developmental delay, seizures, cardiomyopathy, retinitis pigmentosa, other |
| Mitochondrial respiratory protein mutations | |||||||||
| MT-ATP6-SA | SP/M | Yes | MT-ATP6 | p.Ser148Asn | 4 | Infancy to early childhood | Moderate to severe | N/↑ | Lactic acidosis, myopathy, neurological abnormalities |
| NDUFB11-SA | X | Yes | NDUFB11 | p.Phe90del | 5 | Early childhood | Moderate | N | Lactic acidosis, myopathy |
| Multifactorial | |||||||||
| TRMA | AR | Yes | SLC19A2 | NS/FS/SPL/MS | ∼50 | Early childhood | Mild to severe | ↑ | Sensorineural deafness, non-type I diabetes mellitus, optic atrophy, stroke-like episodes |
| Acquired clonal SA | |||||||||
| MDS-RS-SLD/MDS-RS-MLD | SOM | N/A | SF3B1 | Recurrent HEAT domain MS | 1000s | Adulthood | Mild to moderate | ↑/N | Iron overload, other cytopenias (MDS-RS-MLD) |
| MDS/MPN-RS-T | SOM | N/A | SF3B1 + JAK2, MPL, CALR | Recurrent HEAT domain MS + recurrent TK-activating MS | 100s | Adulthood | Mild | ↑/N | Thrombocytosis |
| . | Inheritance . | Syndromic . | Gene . | Mutations . | Frequency* . | Age at presentation . | Anemia severity . | MCV . | Associated abnormalities . |
|---|---|---|---|---|---|---|---|---|---|
| CSA | |||||||||
| Heme synthesis defects | |||||||||
| XLSA | X | No | ALAS2 | MS/R♂ | 100s | Infancy to adulthood | Mild to severe | ↓♂ N/↑♀ | Iron overload in the absence of transfusions |
| MS/NS/FS♀ | |||||||||
| SLC25A38 deficiency | AR | No | SLC25A38 | NS/FS/SPL/MS | ∼40 | Infancy | Severe | ↓ | Transfusional iron overload |
| EPP | AR/PSD | No | FECH | SPL/MS/NS/FS | 100s | Childhood | Mild | ↓ | Acute photosensitivity |
| Fe-S biogenesis defects | |||||||||
| GLRX5 deficiency | AR | No | GLRX5 | MS | 2 | Adulthood | Mild to severe | ↓ | Iron overload |
| HSPA9 deficiency | AR/PSD | No | HSPA9 | MS/FS/NS/SPL | 12 | Childhood | Mild to severe | N/↓ | Retinitis pigmentosa |
| HSCB deficiency | AR | No | HSCB | FS/R | 1 | Childhood | Moderate | N | None |
| XLSA/A | X | Yes | ABCB7 | MS | 5 | Childhood | Mild to moderate | ↓ | Cerebellar ataxia and hypoplasia, delayed motor development |
| Mitochondrial protein synthesis defects | |||||||||
| PMPS | SP/M | Yes | mtDNA | DEL (heteroplasmic) | 100s | Early childhood | Severe | ↑ | Lactic acidosis, exocrine pancreatic insufficiency, failure to thrive, hepatic/renal failure |
| MLASA1 | AR | Yes | PUS1 | MS, NS | ∼10 | Childhood | Mild to severe | N/↑ | Myopathy, lactic acidosis, facial dysmorphism |
| MLASA2 | AR | Yes | YARS2 | MS, FS, NS, DEL, SPL | ∼40 | Childhood | Mild to severe | N/↑ | Myopathy, lactic acidosis, cardiomyopathy |
| LARS2 deficiency | AR | Yes | LARS2 | MS | 1 | Infancy | Severe | ↑ | Lactic acidosis, cardiomyopathy, hepatopathy, seizures |
| SIFD | AR | Yes | TRNT1 | MS/FS/NS/ SPL | ∼30 | Infancy | Severe | ↓ | Immunodeficiency (B>T), aseptic febrile episodes, developmental delay, seizures, cardiomyopathy, retinitis pigmentosa, other |
| Mitochondrial respiratory protein mutations | |||||||||
| MT-ATP6-SA | SP/M | Yes | MT-ATP6 | p.Ser148Asn | 4 | Infancy to early childhood | Moderate to severe | N/↑ | Lactic acidosis, myopathy, neurological abnormalities |
| NDUFB11-SA | X | Yes | NDUFB11 | p.Phe90del | 5 | Early childhood | Moderate | N | Lactic acidosis, myopathy |
| Multifactorial | |||||||||
| TRMA | AR | Yes | SLC19A2 | NS/FS/SPL/MS | ∼50 | Early childhood | Mild to severe | ↑ | Sensorineural deafness, non-type I diabetes mellitus, optic atrophy, stroke-like episodes |
| Acquired clonal SA | |||||||||
| MDS-RS-SLD/MDS-RS-MLD | SOM | N/A | SF3B1 | Recurrent HEAT domain MS | 1000s | Adulthood | Mild to moderate | ↑/N | Iron overload, other cytopenias (MDS-RS-MLD) |
| MDS/MPN-RS-T | SOM | N/A | SF3B1 + JAK2, MPL, CALR | Recurrent HEAT domain MS + recurrent TK-activating MS | 100s | Adulthood | Mild | ↑/N | Thrombocytosis |
↓, decreased; ↑, increased; AR, autosomal recessive; DEL, deletion; EPP, erythropoietic protoporphyria; FS, frameshift; M, maternal; MCV, mean red blood cell volume; MDS/MPN, myelodysplastic syndrome/myeloproliferative neoplasm; MDS/MPN-RS-T, MDS/MPN with ring sideroblasts and thrombocytosis; MDS-RS-MLD, MDS with ring sideroblasts and multilineage dysplasia; MDS-RS-SLD, MDS with ring sideroblasts and single-lineage dysplasia; MS, missense; N, normal; N/A, not applicable; NS, nonsense; PMPS, Pearson marrow-pancreas syndrome; PSD, pseudodominant; R, regulatory; SIFD, SA, immunodeficiency, fevers, and developmental delay; SOM, somatic; SP, sporadic; SPL, splicing; TK, tyrosine kinase signaling pathway; TRMA, thiamine-responsive megaloblastic anemia; X, X-linked; XLSA, X-linked SA; XLSA/A, X-linked CSA associated with cerebellar ataxia.
Number of reported families with CSA or patients with clonal SA.