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. 2018 Nov 6;133(1):59–69. doi: 10.1182/blood-2018-08-815951

Table 1.

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

↓, 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.