Skip to main content
PMC home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2022 Nov 1.
Published in final edited form as: Hum Mutat. 2021 Aug 5;42(11):1367–1383. doi: 10.1002/humu.24267

MUTATION UPDATE SLC25A38

SLC25A38 Congenital Sideroblastic Anemia: Phenotypes and genotypes of 31 individuals from 24 families, including 11 novel mutations, and a review of the literature

Matthew M Heeney 1,#, Simon Berhe 2,#, Dean R Campagna 2,#, Joseph H Oved 3, Peter Kurre 4, Peter J Shaw 5, Juliana Teo 6, Mayada Abu Shanap 7, Hoda M Hassab 8, Bertil E Glader 9, Sanjay Shah 10, Ayami Yoshimi 11, Afshin Ameri 12, Joseph H Antin 13, Jeanne Boudreaux 14, Michael Briones 14, Kathryn E Dickerson 15, Conrad V Fernandez 16, Roula Farah 17, Henrik Hasle 18, Sioban B Keel 19, Timothy S Olson 20, Jacquelyn M Powers 21, Melissa J Rose 22, Akiko Shimamura 1, Sylvia S Bottomley 23, Mark D Fleming 2
PMCID: PMC8511274  NIHMSID: NIHMS1727268  PMID: 34298585

Abstract

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. Mutations in the mitochondrial glycine carrier SLC25A38 cause the most common recessive form of CSA. Nonetheless, the disease is still rare, there being fewer than 70 reported families. Here we describe the clinical phenotype and genotypes of 31 individuals from 24 families, including 11 novel mutations. We also review the spectrum of reported mutations and genotypes associated with the disease, describe the unique localization of missense mutations in transmembrane domains and account for the presence of several alleles in different populations.

Keywords: Sideroblastic anemia, Genetics, Iron, Erythropoiesis, Hematopoietic Stem Cell Transplantation

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 high Km (9.3 ± 1.2 mM) for this substrate (Bishop et al., 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 (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 disturbance in 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. 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.

METHODS

Patients with a diagnosis of CSA or an aregenerative congenital anemia were referred for clinical consultation or research testing to M.D.F., M.M.H, or S.S.B., as a part of human subjects research protocols approved at Boston Children’s Hospital and the University of Oklahoma. All subjects or their guardians provided written informed consent to participate in the study. Data were assembled from routine clinical testing and/or consented research specimens and stored in a custom RedCap database (Harris et al., 2009). The patients described here are a subset of 253 CSA probands referred to M.D.F., M.M.H., and S.S.B., which, in addition to the 24 families described here, includes 12 families described in the initial report of the SLC25A38 anemia (Guernsey et al., 2009). Most mutations were discovered by research Sanger sequencing of SLC25A38 exons. Several were identified by commercial inherited anemia sequencing panels. In most cases, mutations were proven to be biallelic based on sequencing of parental and/or sibling DNA samples.

Mutational and splicing analysis on all variants was performed with Alamut Visual (Sophia Genetics, https://www.interactive-biosoftware.com/doc/alamut-visual/2.7/splicing.html). Protein alignment and conservation analysis was performed using the Clustal Omega (https://www.ebi.ac.uk/Tools/msa/clustalo/) set of multiple sequence alignment tools and the sequences described in Suppl. Tables S1 and S2. Statistical analysis was performed with Prism 9 for macOS (GraphPad Software, LLC).

SLC25A38 CSA patients described in the literature accessible through PubMed and available online are reviewed and are current as of June 1, 2021.

CLINICAL FEATURES

We identified 31 patients (16 males and 15 females) from 24 families with proven or presumptive biallelic SLC25A38 rare variants predicted to be functionally deleterious (Tables 1 and 2). Using Sanger or whole exome sequencing in 70 additional CSA probands without a specific genetic diagnosis, we did not identify an individual with even a single SLC25A38 allele present in reference databases at a frequency of <0.1, nor did we find evidence of a deletion of all or part of the gene. This suggests that pathogenic SLC25A38 alleles that are occult to sequencing exons are unusual.

Table 1.

Demographic, Hematologic and Clinical Characteristics of SLC25A38 CSA Patients.

Patient Relation to Proband Sex Year of Birth Age at Presentation Referral Country Ancestry Race/Ethnicity Consanguinity Age at CBC TX Prior to CBC HGB (g/dL) MCV (fL) RDW (%) Abs Retic (M/μL) WBC (K/μL) ANC (cells/μL) PLT
(K/μL)		 Bone marrow findings RS (%) Other Clinical Features
1.1 Self M 2005 Infant Lebanon Lebanese Arab Yes Infant No 8.1 68 23.7 0.008 7.55 1480 484 ↓M:E 17 None
2.1 Self M 1996 Birth US Mexican Hispanic No 16 Yes 9.2 92 14.1 0.004 8.09 — 803 NP — DD,S/P splenectomy C/B thrombocytosis
2.2 Sibling F 1997 Infant US Mexican Hispanic No 15 Yes 9.1 93 12.6 0.006 9.11 — 738 NP — None
3.1 Self M 2000 Birth Denmark Danish Caucasian No Infant No 8.6 62 — — 18.3 1010 562 Erythroid hypoplasia, Dyserythropoiesis 20 None
4.1 Self F 1997 4 yrs. US Mexican/Filipino Hispanic/Asian No 14 No 8.4 67 27.7 0.028 3.6 1584 574 Initially normal, then normocellular with ↓M:E and RS 27 None
5.1 Self M — — UK — — — — Yes 11.7 82 14.7 — — — — NP — —
6.1 Self M 2004 Birth Germany — Caucasian No Infant Yes 6.2 70 — 0.010 5500 1320 405 Normocellular, ↓M:E 50 CM and IDDM improved after chelation therapy
7.1 Self M 1999 Birth Germany — Caucasian No 1 No 5.1 61 — — 8.1 1530 365 Normocellular, Erythroid hypoplasia 55 None
8.1 Self M 1992 Birth Australia Lebanese Caucasian Yes Infant No 6.2 57 — — 13.4 — 145 Dyserythropoiesis >90 Phlebotomy post-HSCT
8.2 Sibling M 1993 Birth Australia Lebanese Caucasian Yes Infant No 6.2 61 — — 11.3 — 598 ↓M:E >90 Macrocephaly, Phlebotomy post-HSCT
9.1 Self M 1986 14 yrs. Kuwait Arab Arab No 29 Yes 7.0 77 37.3 — 5.47 2850 375 Hypercellular, ↓M:E, Dyserythropoiesis 58 ID
10.1 Self F 2005 Infant Australia Nepalese South Asian No Infant No 3.3 67 20.3 — 9.7 2100 677 ↓M:E 12 No
11.1 Self F 2017 Infant Canada Acadian Caucasian No Infant No 2.7 54 34.5 0.014 6.79 1.54 295 ↓M:E 37 No
12.1 Self F 1979 Infant US Northern European/ Native American Caucasian/Native American Yes 36 Yes 7.8 86 — — 17.1 4340 820 Hypercellular, ↓M:E, Mild fibrosis 29 Cushingoid without history of excessive steroid use , DVT and thrombophlebitis, post-splenectomy
13.1 Self F 2014 Prenatal US Northern European Caucasian No Infant Yes 3.3 75 16.4 — 2.6 600 480 Hypercellular, ↓M:E, Dyserythropoiesis 32 Unilateral corneal clouding, FTT, Congenital hypothyroidism, Congenital pulmonary hypertension requiring ECMO
14.1 Self F 2011 Infant Jordan Jordanian Arab Yes 6 Yes 8.6 91 12.9 0.008 5.4 — 502 ↓M:E, Hypercellular, erythroid hypoplasia 30 Box-shaped skull with hyperostotic calvarium
15.1 Self F 2014 Birth Egypt Egyptian Arab Yes 3 Yes 6.0 86 35.1 — 13.5 — 717 Normocellular, Erythroid hypoplasia Increased Congenital pneumonia
16.1 Self M 2008 Infant Egypt Egyptian Arab Yes Infant Yes 2.5 64 23.5 — 9.25 — 143 Hypercellular, ↓M:E, Dyserythropoiesis 37 None
17.1 Self M 2015 Birth Jordan Jordanian Arab Yes 2 Yes 7.6 75 14.8 — 15.6 — 159 Normocellular >50 Macrocephaly, Meningomyelocele, Club foot
17.2 Sibling F 2017 Birth Jordan Jordanian Arab Yes 1 Yes 9.3 96 14.7 0.021 17.13 — 227 Normocellular >90 None
18.1 Self M 2006 Birth US Northern European Caucasian No Infant Yes 8.2 75 30.9 0.010 8.2 2378 280 Normocellular, Erythroid hypoplasia None Microphallus, Bicuspid aortic valve, ASD with aggressive behaviors, Speech delay, IVF conception
19.1 Self M 2004 Infant US African American Black — 4 No 4.8 59 28 — 4 — 388 Hypercellular, ↓M:E, Dyserythropoiesis, Moderate fibrosis Rare —
20.1 Self F 2009 Birth US Mexican Hispanic No Infant No 3.3 57 31.1 — Normal — Normal Hypercellular, ↓M:E 5-10 Phlebotomy post-HSCT
20.2 Sibling F 2019 Birth US Mexican Hispanic No Infant No 5.9 70 37.6 0.078 5.8 1400 404 Hypercellular Rare PDA, LVH at birth. Coronary fistula.
21.1 Self M 2010 Infant US European Caucasian — 1 No 1.3 60 — — 1.8 — 142 Hypercellular, ↓M:E Numerous ASD, S/P splenectomy C/B thrombocytosis,
22.1 Self F 2011 Birth US Guatemalan Hispanic No Infant No 2.7 — — — 52 2.23 100 Hypercellular <10 DD, Syndromic facies, Behavioral outbursts/ASD, HSM, Pulmonary HTN, CM, Respiratory failure @ birth requiring ECMO
22.2 Sibling F 2012 Birth US Guatemalan Hispanic No DOL 0 Yes 9.1 74 32.2 — 20.2 8.7 326 Normocellular, Erythroid hypoplasia Rare Aortic root dilation
22.3 Sibling M 2015 Birth US Guatemalan Hispanic No — — — — — — — — — NP — Hypospadias; PDA, Aortic root dilation
22.4 Sibling M 2018 Prenatal US Guatemalan Hispanic No DOL 0 Yes 13.8 77 24.7 0.220 32.5 14.95 585 NP — Hypospadias, In utero TX x 5
23.1 Self F 2015 Birth Australia Pakistani South Asian Yes 2 Yes 8.5 77 — — 9.2 — 189 Hypercellular, ↓M:E >15 Asymptomatic b-ureidopropionase deficiency,UPB1, (homozygous c.873+1G>A),
24.1 Self F 2019 Infant US European/Indian Caucasian/South Asian No 1 No 5.1 61 37.3 0.033 8.3 — 343 ↓M:E 70 Frontal Bossing, “Box-Shaped” Head
Open in a new tab

—, Unknown; ↓M:E, Decreased Myeloid:Erythroid Ratio; Abs Retic, Absolute Reticulocyte Count; ANC, Absolute Neutrophil Count; ASD, Autism Spectrum Disorder; C/B, CBC, Complete Blood Count; Complicated by; DD, Developmental Delay; DOL, Day of Life; DVT, Deep Venous Thrombosis; ECMO, Extracorporeal Membrane Oxygenation; F, Female; FTT, Failure to Thrive; GHD, Growth Hormone Deficiency; HGB, Hemoglobin; HTN, Hypertension; ID, Intellectual Disability; IVF, In Vitro Fertilization; LVH, Left Ventricular Hypertrophy; M, Male; MCV, Mean Corpuscular Volume; NP, Not Performed; PDA, Patent Ductus Arteriousus; PLT, Platelets; RDW, Red Cell Distribution Width; RS, Ring Sideroblasts; S/P, Status-Post; TX, Transfusion; WBC, White Blood Cell. *Reported by Kim MH et al. Clin Case Rep 2018; 6:1841-1844.

Table 2:

Genetic Characteristics of SLC25A38 CSA Patients in this Report.

Patient SLC25A38 Mutations (NM_17875.3) Homozygous
Allele 1 Allele 2
cDNA Protein Type cDNA Protein Type
1.1 c.276+1G>A p.? SPL c.276+1G>A p.? SPL Yes
2.1 c.832C>T p.Arg278X X c.832C>T p.Arg278X X Yes
2.2 c.832C>T p.Arg278X X c.832C>T p.Arg278X X Yes
3.1 c.324_325del p.Tyr109Leufs*43 FS c.324_325del p.Tyr109Lfs*43 FS Yes
4.1 c.70-2A>C p.? SPL c.70-2A>C p.? SPL Yes
5.1 c.669_682del p.Cys223Trpfs*67 FS c.913T>C p.X305Argext*28 EXT No
6.1 c.277-2A>C p.? SPL c.277-2A>C p.? SPL Yes
7.1 c.207_214del p.Met70Cysfs*80 FS c.362del p.Pro121Glnfs*26 FS No
8.1 c.388G>A p.Gly130Arg MS c.389G>A p.Gly130Glu MS Yes
8.2 c.388G>A p.Gly130Arg MS c.389G>A p.Gly130Glu MS Yes
9.1 c.792+5G>C p.? SPL c.792+5G>C p.? SPL Yes
10.1 c.480dup p.Ile161TyArgfs*12 FS c.480dup p.Ile161Tyrfs*12 FS No
11.1 c.349C>T p.Arg117X X c.349C>T p.Arg117X X Yes
12.1 c.324_325del p.Tyr109Leufs*43 FS c.324_325del p.Tyr109Leufs*43 FS Yes
13.1 c.324_325del p.Tyr109Leufs*43 FS c.324_325del p.Tyr109Lfs*43 FS Yes
14.1 c.400C>T p.Arg134Cys MS c.400C>T p.Arg134Cys MS Yes
15.1 c.175C>T p.Gln59X X c.175C>T p.Gln59X X Yes
16.1 c.809dup p.Phe271Leufs*24 FS c.809dup p.Phe271Leufs*24 FS Yes
17.1 c.672delinsTT p.Ile225Tyrfs*70 FS c.672delinsTT p.Ile225Tyrfs*70 FS Yes
17.2 c.672delinsTT p.Ile225Tyrfs*70 FS c.672delinsTT p.Ile225Tyrfs*70 FS Yes
18.1 c.324_325del p.Tyr109Leufs*43 FS c.400C>T p.Arg134Cys MS No
19.1 c.305G>A p.Gly102Glu MS c.349C>T p.Arg117X X No
20.1 c.832C>T p.Arg278X X c.832C>T p.Arg278X X Yes
20.2 c.832C>T p.Arg278X X c.832C>T p.Arg278X X Yes
21.1 c.349C>T p.Arg117X X c.[161G>A;349C>T] p.[Arg54His;Arg117X] MS & X No
22.1 c.457-1G>T p.? SPL c.457-1G>T p.? SPL Yes
22.2 c.457-1G>T p.? SPL c.457-1G>T p.? SPL Yes
22.3 c.457-1G>T p.? SPL c.457-1G>T p.? SPL Yes
22.4 c.457-1G>T p.? SPL c.457-1G>T p.? SPL Yes
23.1 c.475del p.Glu159Argfs*7 FS c.475del p.Glu159Argfs*7 FS Yes
24.1 c.401G>A p.Arg134His MS c.560G>A p.Arg187Gln MS No
Open in a new tab

EXT, Extension/Stop-Lost; FS, Frameshift; MS, Missense; SPL, Splicing; X, Nonsense/Stop-Gained alleles

Two patients (13.1 and 22.4) presented with hydrops fetalis in utero. Sixteen presented in the neonatal period (<1 week of life), 10 in infancy (<12 months), and one each at 4- (4.1) and 14-years of age (14.1); the age of clinical presentation of one patient is unknown. In 10 of 23 families where the family history was known, there was defined consanguinity. Five (5) of the remaining 13 families were not known to be consanguineous but originated from genetically isolated populations or populations with known founder effects (e.g., Acadians from the Canadian Maritime Provinces).

All patients presented with reticulocytopenic, microcytic anemia (Table 1). In the 13 individuals in whom pre-transfusion CBC data are available, most of whom were neonates or infants at the time, the mean hemoglobin (HGB) was 5.1 ± 2.4 g/dL (generalized normal range 10.5-13.0 g/dL), mean cell volume (MCV) 61.9 ± 4.9 fL (generalized normal range 79.6-83.3 fL), and absolute reticulocyte count 0.032 ± 0.032 x 106/μL (generalized normal range 0.037-0.104 x106/μL). In 20 of 24 families the diagnosis of CSA was made in the proband by bone marrow aspiration where ring sideroblasts generally constituted >15% of nucleated erythroblasts. In several cases, RS were absent or only rare. In most, but not all, cases, there was an erythroid hyperplasia in the bone marrow; in some there was an erythroid hypoplasia. Conspicuous dyserythropoiesis and variable fibrosis were present in a minority of samples. Anemic siblings were sometimes diagnosed with CSA by genetic testing alone, as was the case with patient 20.2, whose older sibling (20.1), has previously been reported (Kim et al., 2018). Three patients from two families (patients 2.1, 2.2, and 18.1) were initially regarded as having an atypical form of Diamond-Blackfan anemia (DBA). In family 2, the eventual identification of rare siderocytes in the peripheral blood suggested CSA, which was confirmed by candidate gene sequencing. Because of the unusual, apparently syndromic features in patient 14.1, this patient’s diagnosis was established by whole exome sequencing. In patient 18.1, SLC25A38 mutations were identified by whole exome sequencing years after successful hematopoietic stem cell transplantation for “DBA.” Most patients did not have abnormalities in other organ systems that were not attributable to chronic anemia or iron overload (e.g. growth failure, endocrine abnormalities, liver disease, cardiomyopathy), but several potentially syndromic features were observed in a number of patients (Table 1): unilateral corneal clouding (13.1), a “box-shaped” hyperostotic skull (14.1, 24.1), macrocephaly (8.2, 17.1), syndromic facies (22.1), meningomyelocoele/club foot (17.1), genital abnormalities (18.1, 22.3, 22.4), behavioral issues (18.1 and 22.1), and aortic root/coronary abnormalities (20.2, 22.2, 22.3).

THERAPY

All of the patients have required transfusions, most chronically, beginning in the neonatal period or infancy (Table 3). Of the 28 patients in whom data are available, 2 patients received their first transfusions in utero (13.1 and 22.4), 12 in the neonatal period, 11 in infancy, and 3 between age 4- and 8-years. All but one was maintained on regular transfusions with a transfusion interval of between 2 and 8 weeks. In 20 of 20 patients for whom oral pyridoxine was prescribed, there was no improvement in the hemoglobin (HGB). All patients surviving early childhood have developed secondary iron overload and have required chelation. A variety of agents including deferoxamine, deferisirox, deferiprone alone or in combination have been employed. One patient (2.1), poorly compliant with chelation, died at age 18 from cardiomyopathy. Another (17.1), age 3, died of central venous line-associated sepsis. Three patients who were status-post splenectomy experienced thrombocytosis and/or thrombotic events. The median age of patients alive at the time of last follow-up is 11 years (range 1-39 years).

Table 3:

Iron Status, Chelation Therapy and Outcomes of SLC25A38 CSA Patients.

Patient TX Age at First TX TX interval (wks) TfSat (%) Ferritin (mg/L) Iron overload Anemia/Iron Complications Chelator(s) HSCT? Status Cause of Death Age at Last Follow-Up or Death
1.1 Yes Infant 3 — 557 ND None DFX No Alive NA 15
2.1 Yes Neonate 3-5 — — Yes, Liver, Pancreas, Pituitary & Heart (MRI) CM, PHP, IDDM, SS DFX No Dead CM 18
2.2 Yes Neonate 3-5 — 1092 Yes None DFO, DFX, DFP No Alive NA 23
3.1 Yes Neonate 3-4 — — Yes None DFO or DFX Yes Alive NA 21
4.1 Yes 8 yrs. 4 44 63 Yes, Liver, Pancreas and Heart (MRI) SS DFX & DFO No Alive NA 21
5.1 Yes — 3-5 — — — — — — — — 15
6.1 Yes Neonate 3-5 95 882 Yes, Liver and Heart CM, IDDM DFO No Alive NA 14
7.1 Yes Neonate 3-5 92 405 Yes, Liver (MRI) None DFO No Alive NA 3
8.1 Yes Neonate 4 — — Yes, Liver (BX) None DFO Yes Alive NA 26
8.2 Yes 4 yrs. 4 — — Yes, Liver (BX) None DFO Yes Alive NA 23
9.1 Yes — Rarely — 2893 ND SS DFX Yes Alive NA 32
10.1 Yes Infant 4 — 1037 Yes, Liver (MRI) None DFX & DFP No Alive 15
11.1 Yes Infant 3-4 — 269 Yes, Liver (MRI), No, Heart (MRI) None DFX No Alive 3
12.1 Yes Infant 2 — 1373 Yes, Liver (MRI), No, Heart (MRI) HE DFX No Alive NA 39
13.1 Yes In utero 2 — — ND None DFX & DFO→ DFP & DFO No Alive NA 6
14.1 Yes Infant 2-3 116 832 Yes, Liver (BX) None DFX Yes Alive NA 9
15.1 Yes Neonate 6 — 362 ND None DFX No Alive NA 6
16.1 Yes Infant 4 — 596 ND None DFX Yes Alive NA 12
17.1 Yes Neonate 2-3 — — ND None No No Dead Sepsis 3
17.2 Yes Neonate 3 70 770 ND None No Yes Alive NA 3
18.1 Yes Neonate 2-3 — ~1000 Yes, Liver (BX and MRI) SS, GHD DFO→ DFX Yes Alive NA 14
19.1 Yes 4 yrs. 4 100 1050 ND None DFX + IV DFO No Alive NA 14
20.1* Yes Neonate 4-8 60 1817 Yes, Liver (MRI), No, Heart (MRI) None DFX Yes Alive NA 11
20.2 Yes Neonate 4-5 84 938 ND None DFX No Alive 1
21.1 Yes Infant 4 62 945 Yes, Liver and Heart (MRI) None DFX & DFO→DFX & DFP No Alive NA 10
22.1 Yes Infant 2 95 1303 Yes, Liver (MRI), None DFX & DFO No Alive NA 9
22.2 Yes Infant 3 101 1431 Yes, Liver (MRI), None DFX & DFO No Alive NA 8
22.3 Yes Infant 3 95 1586 Yes, Liver (MRI), None DFX & DFO No Alive NA 5
22.4 Yes In utero 3 86 859 ND None No No Alive NA 2
23.1 Yes Neonate 4-5 — 500 ND None DFX No Alive NA 5
24.1 Yes Infant 4 91 632 ND None None No Alive NA 2
Open in a new tab

BX; Biopsy; CM, Cardiomyopathy; DFO, Deferoxamine; DFP, Deferiprone; DFX, Deferisirox; HE, Hepatic Encephalopathy; HSCT, Hematopoietic Stem Cell Transplantation; IDDM, Insulin-Dependent Diabetes Mellitus; MRI, Magnetic Resonance Imaging; NA, Not Applicable; ND, Not Determined; PHP, Panhypopituitarism; SS, Short Stature TX, Transfusion. All patients were previously transfused at the time of iron overload assessment.

Nine patients have undergone allogeneic hematopoietic stem cell transplantation (Table 4) with a median follow up of 7 years (range 6 mos. to 17 yrs.). All transplanted patients are alive; 8 of 9 had full engraftment and became transfusion independent. One patient (14.1) had secondary graft failure at 18-months post-transplant with auto recovery and became transfusion dependent; a second transplant with the same donor failed to engraft. Four patients received myeloablative conditioning, and 4 others received reduced intensity conditioning. Donors were matched unrelated donor (n=4), matched related donors (one matched family donor and three were matched sibling donors), and one patient had one antigen mismatch sibling donor. Methotrexate and a calcineurin inhibitors were the most common graft versus host disease prophylaxis. Acute and chronic graft versus host disease were seen in 1 and 3 patients, respectively. One patient developed chronic post-transplant autoimmune hemolytic anemia requiring transfusion.

Table 4.

Hematopoietic Stem Cell Transplantation Outcomes of SLC25A38 CSA Patients.

Patient Year of HSCT Age at HSCT (yrs.) Pre-HSCT Ferritin Donor type Stem cell source Conditioning Intensity Conditioning GVHD PPX Most Recent Chimerism (%) aGVHD cGVHD Other HSCT Complications Follow up (yrs.)
3.1 2012 12 1500 MUD BM MAC Bu/Cy CsA/MTX 100 None None None 8
8.1 2009 7 1825 MSD BM MAC Bu/Cy/ATG CsA/MTX ND None Lung None 11
8.2 2003 9 1700 MUD BM MAC Bu/Cy/TT/ATG CsA/MTX 100 None Lung, Skin, Liver None 17
9.1 2017 31 11,154 MUD BM RIC Flu/Bu TAC/MTX 97 None None None 3
14.1-1* 2018 8 900 MMSD (1 Ag) PB RIC Flu/Bu/ATG/TLI PT-Cy/CsA/MMF 40 @12 mos.
4 @18 mos.		 None None Graft failure 2
14.1-2* 2021 10 ND MMSD (1 Ag) PB MAC ATG/Flu/TT Melphalan Flu/Dex x1 Recipient NA NA Primary graft failure 0.5
16.1 2018 11 750 MSD PB MAC Bu/Cy/ATG CsA 100 None None None 2
17.2 2020 3 800 MRD BM MAC ATG/Bu/Cy CsA/MTX 98 None NA None 1 mo.
18.1 2012 6 342 MUD BM RIC Flu/Treo/ATG TA/MTX 100 Skin Gut,Oral TX-dependent post-HSCT AIHA, splenectomy 8
20.1 2013 4 783 MSD BM RIC Flu/Bu/CAM TAC/MTX 100 None None None 7
Open in a new tab

Ag, HLA-Antigen; AIHA, Autoimmune Hemolytic Anemia; BM, Bone Marrow; Bu, Busulfan; BX, Biopsy; CAM; Campath; CsA; Cyclosporine A; Cy, Cytoxan; Dex, Dexamethasone; Flu, Fludarabine; aGVHD, Acute Graft vs. Host Disease; cGVHD, Chronic Graft vs. Host Disease; HSCT, Hematopoietic Stem Cell Transplantation; MRD, Matched Related Donor; MMSD, Mismatched Sibling Donor; MTX, Methotrexate; MUD, Matched Unrelated Donor; NA, Not Applicable; ND, Not Determined; PB, peripheral blood; PPX, Prophylaxis; PT, Post-Transplant; RIC, Reduced Intensity Conditioning; SD, Sibling Donor; TLI, Total Lymphoid Irradiation; Treo, Treosulfan; TT, Thiotepa; TX; Transfusion.

*

Patient 14.1 was retransplanted with the same donor following secondary graft failure

MUTATION ANALYSIS

The 24 families carry 27 distinct SLC25A38 mutations (Table 2). Sixteen (16) of these mutations have been described by us and others previously. Eleven (11) mutations are novel, including one MS allele (c.388G>A; p.Gly130Arg), 5 frameshift (FS) alleles (c.207_214del, p.Met70Cysfs*80; c.362del, p.Pro121Glnfs*26; c.475del, p.Glu159Argfs*7; c.669_682del, p.Cys223Trpfs*67; and c.809dup, p.Phe271Leufs*24), and 5 variants predicted to interrupt splicing (c.70-2A>C, c.276+1G>A, c.277-2A>C, c.457-1G>T, and c.792+5G>C). In contrast to many of the previously reported pathogenic alleles, which are generally more common (see below), only one of these variants occurs in a sequence with a predisposition to mutation: the c.207_214del involves a deletion of a 7 base-pair repeat. Furthermore, only two of the novel mutations, c.457-1G>T (rs1448237170, MAF 4.00x10−6) and c.669_682del (rs781372292, MAF 1.77x10−5), are recorded in references databases such as gnomAD (gnomad.broadinstitute.org).

As expected in a rare recessive disease, 19 of the 24 families (79%) are homozygous for the pathogenic mutation. In the patients with homozygous mutations, 10 are known to be consanguineous and 5 are from geographically or ethnically restricted populations that may be genetically less diverse.

In this cohort, we detected no difference in age of onset of anemia, age at initial transfusion, pre-transfusion HGB, or transfusion interval among patients with two null alleles, two splicing alleles, or at least one MS mutation (data not shown).

THE SLC25A38 MUTATION SPECTRUM

There are 16 publications, including the current one, describing, a total of 92 SLC25A38 CSA families from diverse geographic and ethnic backgrounds (Table 5). As is true of our sample, approximately three-quarters (77%) of the reported probands carry homozygous mutant alleles (Figure 1A). In one case, homozygosity is the result of constitutional uniparental isodisomy (Andolfo et al., 2020). MS (36%), frameshift (27%) and stop-gained (27%) alleles each constitute one-quarter to one-third of alleles detected in probands (Figure 1B). Variants predicted to affect splicing (9%) or cause a stop-loss (EXT, 1%) are comparatively rare. Two MS variants, c.560G>C; p.Arg187Pro and c.625G>C; p.Asp209His, are also predicted to affect splicing, the former likely activating a cryptic splice acceptor site within exon 5 and the latter altering the conserved G at the last base pair of exon 5. Patients homozygous for MS mutations are most common, constituting approximately one-third (31%) of all reported probands (Figure 1C). Whereas 42% of patients bear at least one MS allele and may retain some transport function, 46% have two stop-gained or frameshift (or a combination of both) presumptive null alleles, and another 12% have two splicing alleles or a splicing allele in trans of a frameshift or stop-loss allele, also likely to retain little transport activity (Figure 1D).

Table 5:

The SLC25A38 Mutation Spectrum.

cDNANM_017875.3 Sequence Feature Protein MS in TM? Exon Type Number of Families Number of Mutations @ Codon SNP ID gnomAD MAF References
c.70-2A>C — p.? NA 2 SPL 1 1 — — Current
c.166C>A CpG p.Gln56Lys Yes 2 MS 3 1 — — Fouquet et al., 2019; Kannengiesser et al., 2011
c.175C>T — p.Gln59X NA 2 X 2 1 — — Current; W. B. An et al., 2019
c.207_214del Repeat p.Met70Cysfs*80 NA 3 FS 1 1 — — Current
c.227_236del — p.Lys76Thrfs*17 NA 3 FS 1 1 — — Shefer Averbuch et al., 2018
c.260G>A — p.Trp87X NA 3 X 1 1 — — W. An et al., 2015; W. B. An et al., 2019
c.276+1G>A — p.? NA 3 SPL 1 1 — — Current
c.276+1G>T — p.? NA 3 SPL 1 1 — — Ulirsch et al., 2019
c.277-1G>A — p.? NA 4 SPL 1 1 — — Guernsey et al., 2009
c.277-2A>C — p.? NA 4 SPL 1 1 — — Current
c.281T>A — p.Ile94Asn Yes 4 MS# 1 1 — — Liu et al., 2013
c.305G>A — p.Gly102Glu Yes 4 MS 2 1 — — Current; Guernsey et al., 2009
c.324_325del CT Repeat p.Tyr109Leufs*43 NA 4 FS 12 2 rs755447127 1.66E-04 Current; Fouquet et al., 2019; Guernsey et al., 2009; Kannengiesser et al., 2011; Le Rouzic et al., 2017
c.324_330del CT Repeat p.Tyr109X NA 4 X 1 2 — — Mehri et al., 2018
c.336_346del — p.Lys112Asnfs*37 NA 4 FS 1 1 rs1301033567 — Guernsey et al., 2009
c.349C>T† CpG p.Arq117X NA 4 X 15* 1 rs121918330 1.59E-05 Current; Fouquet et al., 2019; Guernsey et al., 2009; Kakourou et al., 2016; Kannengiesser et al., 2011; Le Rouzic et al., 2017; Ravindra et al., 2020
c.362del — p.Pro121Glnfs*26 NA 4 FS 1 1 — — Current
c.388G>A — p.Gly130Arq Yes 4 MS 1 2 — — Current
c.389G>A — p.Gly130Glu Yes 4 MS 1 2 rs762562272 3.98E-06 Guernsey et al., 2009
c.400C>T CpG p.Arq134Cys Yes 4 MS 6 2 rs1293528130 3.98E-06 Current ; W. An et al., 2015; W. B. An et al., 2019; Fouquet et al., 2019; Kannengiesser et al., 2011; Le Rouzic et al., 2017
c.401G>A CpG p.Arq134His Yes 4 MS 4 2 — — Current; Fouquet et al., 2019; Guernsey et al., 2009; Le Rouzic et al., 2017
c.409dup — p.Ala137Glyfs*16 NA 4 FS 6 1 — — Ravindra et al., 2020
c.429_431deilinsAG — p.Ile144Alafs*3 NA 4 FS 1 1 — — W. An et al., 2015; W. B. An et al., 2019
c.440T>A — p.Ile147Asn Yes 4 MS 2 1 — — Fouquet et al., 2019; Kannengiesser et al., 2011
c.457-1G>T — p.? NA 4 SPL 1 1 rs1448237170 4.00E-06 Current
c.469G>C — p.Gly157Arg No 4 MS 1 1 — — Liu et al., 2013
c.475del CpG p.Glu159Arqfs*7 NA 4 FS 1 1 — — Current
c.480dup — p.Ile161Tyrfs*12 NA 5 FS 2 1 — — Current; Wong et al., 2015
c.560G>A CpG p.Arq187Gln Yes 5 MS 6 2 rs121918331 7.96E-06 Current; W. An et al., 2015; W. B. An et al., 2019 Kannengiesser et al., 2011; Ravindra et al., 2020; Uminski et al., 2020
c.560G>C^ CpG p.Arq187Pro or p.? Yes 5 MS-SPL 1 2 rs121918331 7.96E-06 Guernsey et al., 2009
c.562G>C — p.Asp188His Yes 5 MS 2 1 — — Ravindra et al., 2020
c.569C>G — p.Pro190Arq Yes 5 MS 1 1 — — Kannengiesser et al., 2011
c.587T>C — p.Leu196Pro Yes 5 MS 2 1 — — Fouquet et al., 2019; Le Rouzic et al., 2017
c.625G>C‡ CpG p.Asp209His or p.? No 5 MS-SPL 4 1 rs1372117091 3.98E-06 Guernsey et al., 2009; Kannengiesser et al., 2011; Ravindra et al., 2020
c.626-2A>T — p.? NA 6 SPL 1 1 — — Ravindra et al., 2020
c.669_682del — p.Cys223Trpfs*67 NA 6 FS 1 1 rs781372292 1.77E-05 Current
c.672delinsTT — p.Ile225Tyrfs*70 NA 6 FS 2 1 — — Current; Shefer Averbuch et al., 2018
c.683G>T — p.Gly228Val Yes 6 MS 4 1 rs755205622 3.98E-06 Kannengiesser et al., 2011; Mehri et al., 2018
c.689T>C — p.Leu230Pro Yes 6 MS 1 1 — — Liu et al., 2013
c.790A>T — p.Lys264X NA 6 X 5 1 — — Fouquet et al., 2019; Guernsey et al., 2009; Le Rouzic et al., 2017; Ulirsch et al., 2019
c.792+5G>C — p.? NA 6 SPL 1 1 — — Current
c.809dup — p.Phe271Leufs*24 NA 6 FS 1 1 — — Current
c.832C>G CpG p.Arq278Gly Yes 6 MS 2 2 rs147431446 — Kannengiesser et al., 2011; Le Rouzic et al., 2017
c.832C>T CpG p.Arq278X NA 6 X 5 2 rs147431446 3.18E-05 Current; Andolfo et al., 2020; Fouquet et al., 2019; Guernsey et al., 2009
c.858del — p.Ala287Glnfs*10 NA 6 FS 1 1 — — Mehri et al., 2018
c.879T>G — p.Tyr293X NA 6 X 3 1 — — Fouquet et al., 2019; Guernsey et al., 2009; Le Rouzic et al., 2017
c.913T>C — p.*305Arqext*28 NA 6 EXT 2 1 rs1218815001 3.18E-05 Current; Guernsey et al., 2009
Open in a new tab

EXT, Extension/Stop-Lost; FS, Frameshift; MS, Missense; SPL, Splicing; X, Nonsense/Stop-Gained. MS in TM, Missense in predicted transmembrane amino acid.

†

In at least two cases rs121918330 is in cis with rs144319567: c.161G>A; p.Arg64His.

‡

Last base pair of exon predicted to affect splicing.

^

Predicted to create a new splice acceptor site.

*

The family reported by Kakourou et al. and family E in Guernsey et al. are both Greek and are likely distantly related.

One patient is homozygous due to uniparental disomy.

#

MS mutation also predicted to disrupt an exonic splice enhancer.

Figure 1. Review of SLC25A38 Mutation Types and Genotypes.

Figure 1.

Open in a new tab

A. Mutation types. B. Genotypic combinations by mutation type. C. Genotypic combination zygosity. D. Genotypic combination by function. Cmpd, Het, Compound Heterozygous; EXT, Extension; FS, Frameshift; Hom, Homozygous; SPL, Splicing; X, Premature stop.

Of the 47 reported disease-associated mutations, 12 occur at sequences prone to recurrence, including 9 at CpG dinucleotides and 3 at a direct or simple repeat. Of the 21 apparently recurrent mutations, 9 are at a CpG or repeat (Figure 2).

Figure 2. Distribution of SLC25A38 mutations in relation to structural and genetic features.

Figure 2.

Open in a new tab

Vertical bars depict the number of independent occurrences of missense (green), stop-gained (red), frameshift (yellow), splicing (blue), and stop-loss (purple) pathogenic SLC25A38 mutations at that codon. Horizontal bars: transmembrane (TM) segments are indicated in black. The relative frequency of loss-of-function (LOF: stop-gained, frameshift, and splicing) and missense (MS) variants in gnomAD are depicted in red and green heat maps. Absolute conservation of amino acid in 16 SLC25A38 orthologues from 15 diverse species (Suppl. Table S2) and 53 H. sapiens SLC25 protein family members in magenta and blue heat maps. Short tandem (aqua) and direct (light green) repeats and CpG dinucleotides (navy blue) are indicated, demonstrating clustering of disease-associated mutations at these sequences. The first 23 amino acids, approximately corresponding to the mitochondrial targeting sequence, are not shown; no pathogenic mutations are found in this region. Each block of sequences corresponds to one mitochondrial carrier family repeat unit containing two TM domains.

Pathogenic MS mutations are distributed nearly exclusively in the transmembrane (TM) domains. Of the 18 pathogenic MS mutations, 16 are located in amino acids within a predicted TM domain (Table 5 and Figure 2). One of the remaining two, c.625G>C; p.Asp209His, is also predicted to affect splicing (Suppl. Table 3). The remaining variant, c.469G>C; p.Gly157Arg, in addition to be located between TM3 and TM4, is conserved neither in SLC25 family members, nor in SLC25A38 orthologues. There is no difference in the relative conservation of amino acids in TM and non-TM regions of SLC25A38 orthologues (Mann-Whitney P=0.385) whereas there is an unexpected predominance of disease-causing mutations present in TMs (χ2 P<0.001). Of the TM residues with pathogenic mutations, there is a trend toward being relatively conserved compared to other TM amino acids (Mann-Whitney P=0.085).

DISCUSSION

This is the largest series of patients with SLC25A38 associated CSA yet reported, describing 31 individuals from 24 different families and 11 novel mutations, expanding the total number of reported families and pathogenic alleles to 92 and 47, respectively. Notably, nearly all of the MS mutations are located within TM domains. It has been suggested that TM MS mutations, particularly those that substitute a polar for a hydrophobic residue, lead to protein instability and malfunction and are disproportionately associated with human disease (Partridge et al., 2004).

Despite the diversity of mutations, there are several unexpected aspects of the SLC25A38 anemia revealed by these studies worth noting. First is the very limited evidence that there is a genotype-phenotype correlation. Essentially all patients present at birth or infancy with a severe hypochromic, microcytic anemia that eventually requires chronic transfusion. This is in stark contrast with the most common form of hypochromic microcytic, non-syndromic CSA, XLSA, which is the major differential diagnosis. Male patients with XLSA may present at birth to older adulthood. The most severe XLSA cases tend to present at an earlier age, but it is unusual for a patient to have transfusion dependent anemia as is typical of SLC25A38 disease. Indeed, the anemia in XLSA is frequently incidental and may be discovered only by screening or as a result of investigation of unexplained iron overload. There are, however, several exceptional cases of patients with SLC25A38 disease coming to medical attention in their teens or twenties. Three of these patients had homozygous mutations at codon 134 [p.Arg134His or p.Arg134Cys] (Fouquet et al., 2019; Hanina et al., 2018; Le Rouzic et al., 2017). However, two other patients homozygous for the p.Arg134Cys allele presented at age 2 months and 2 years (An et al., 2015; An et al., 2019; Kannengiesser et al., 2011). In our own cohort, a patient with a homozygous variant at the only incompletely conserved +5 position of a splice donor site (c.792+5G>C) presented in his mid-teens. It is certainly possible that other genotype-phenotype correlations are masked by the clinical imperative to initiate transfusions in a patient with a HGB less than ~9 g/dL. Indeed, in the publications in which an initial diagnostic HGB is reported, only one individual, a neonate, had a hemoglobin >9 g/dL (Guernsey et al., 2009; Hanina et al., 2018; Kannengiesser et al., 2011; Liu et al., 2013; Wong et al., 2015).

Although the SLC25A38 anemia is typically sideroblastic, in one patient, RS were not detected and in several they were not a prominent feature. Why this is the case, is not entirely clear, but may be attributed to a number of factors, one of which, may be ambient iron levels at the time of sampling; RS development might “require” iron overload or at least iron sufficiency. Alternatively, we have seen patients with other forms of sideroblastic anemia in which the RS present on some samples, but not others. Indeed, even some anemic patients with ALAS2 mutations are reported not to be sideroblastic (Sankaran et al., 2015) and mutations in other “CSA genes” are even more inconsistently associated with RS (Bergmann et al., 2009) or even with anemia (Riley et al., 2018; Sommerville et al., 2017). Although we reviewed all the iron-stained aspirate slides that were available, in some cases, we had to rely upon the existing pathology report(s), and while RS are usually abundant in this disorder, it is certainly possible that they were missed by the hematologists/pathologists reviewing the specimens.

Although clinical practice to transfuse these patients may disguise the subtle differences between SLC25A38 genotypes, it is abundantly evident that an SLC25A38 null genotype does not preclude some mitochondrial glycine being available for heme synthesis. This may be due to other transporters, possibly including the highly homologous orphan mitochondrial carrier protein SLC25A39, or pathways that produce glycine from other amino acids, such as serine (Amelio et al., 2014; Kory et al., 2018). Leveraging these pathways may provide an avenue for therapy. However, based on limited data, it is unlikely that glycine supplementation alone will suffice (Fernandez-Murray et al., 2016; LeBlanc et al., 2016).

The SLC25A38 anemia is regarded as non-syndromic. Nevertheless, twelve of the 31 patients described here had developmental or intellectual disabilities. Similar abnormalities, including psychomotor delay, hypotonia, facial dysmorphism (Fouquet et al., 2019), Hypospadias (An et al., 2015), congenital myelomeningocele, patent ductus arteriosus and ventricular septal defects (Wong et al., 2015) have been reported in several other patients, but no abnormality is unusually prevalent across multiple families to suggest a specific syndromic association. The relative abundance of diverse developmental defects might be attributable to the high prevalence of consanguinity in the cohort and reflect other recessive Mendelian disorders segregating in the families.

Three patients who underwent splenectomy developed thrombocytosis and/or recurrent thrombosis, further supporting the notion that splenectomy may be contraindicated in SLC25A38 CSA as has generally been advocated in other patients with microcytic CSAs (Bottomley & Fleming, 2014; Fouquet et al., 2019).

The 47 described SLC25A38 pathogenic mutations occur at 40 different codons. However, nearly one-third (27 of 92) families carry at least one copy of either the c.324_325del or the c.349C>T allele. The latter has been identified in families of Acadian (Guernsey et al., 2009), African American (current report), South Asian (Ravindra et al., 2021), Greek (Guernsey et al., 2009), and Northern European (current report) origin, suggesting that it has reoccurred on multiple occasions. In fact, in one case (21.1), the patient is homozygous for the c.349C>T;p.Arg117X allele, but one chromosomal copy also carries a MS variant in a non-conserved residue in cis (c.[161G>A;349C>T]; p.[Arg54His;Arg117X]). Reanalysis of other SLC25A38 anemia patients previously reported by us (Guernsey et al., 2009) identified one other patient having this compound mutant chromosome (data not shown). Both of these variants occur at hypermutable cytosine-guanosine (CpG) dinucleotides. This would support the notion that the c.349C>T;p.Arg117X allele has occurred on multiple occasions and that homozygosity for a disease-associated variant in SLC25A38 should not necessarily be taken as evidence of identity by descent. However, we were unable to verify this further by analyzing SLC25A38 haplotypes because, remarkably, each of the diverse mutations in our patients has occurred on the same, rs35616367C/rs67035835A/rs12991T, haplotype.

Because of the severity and great similarity of the disorder to transfusion-dependent β-thalassemia (thalassemia major), all of the patients in our cohort were at one time managed with transfusion and iron chelation in a like manner. This is concordant with nearly all SLC25A38 CSA patients described in the literature. Just as we identified no consistent, distinctive syndromic aspects of the disease outside the anemia, we did not observe any complications or undue toxicity as a result of transfusion or iron overload. The oldest patient in this cohort is 39 years of age, and we are aware of at least two patients in their early fifties (Guernsey et al., 2009), suggesting that modern transfusion and chelation regimens support long-term survival.

Nonetheless, 9 of our patients underwent allogenic HSCT at varying times during their disease course. Ten other patients (Guernsey et al., 2009; Kannengiesser et al., 2011; Uminski et al., 2020) as well as the sibling of one patient included in this series (Kim et al., 2018) are reported to have been transplanted. Comprehensive details are unavailable for most of these patients, but when stated, similar to those described here, HSCT regimens have variously included matched-related and matched unrelated donors with fully myeloablative or reduced intensity conditioning regimens. In many cases, aggressive chelation was employed to reduce the iron burden pre-transplant and phlebotomy was often used post-HSCT to further normalize iron stores. In all, of 18 patients receiving HSCT, 14 have achieved transfusion independence, 3 grafts failed, and one patient died in the immediate post-transplant period with follow up ranging from months to 19 years. In no case has an unusual disease-specific transplant-related morbidity been reported. Thus, allogeneic HSCT provides a curative option in SLC25A38 CSA, and may be considered in young patients with appropriate donors prior to the development of sequelae of chronic transfusions such as hemosiderosis and alloimmunization.

CONCLUSION

Although it is uncommon, SLC25A38 CSA is a clinically distinctive entity nearly always associated with transfusion-dependent microcytic, hypochromic sideroblastic anemia from infancy. Although it is presently managed in a manner similar to other severe anemias, such as β-thalassemia major, with chronic transfusion and iron chelation, HSCT may be an increasingly attractive option for definitive therapy. Furthermore, as disease-specific metabolic and genetic therapies for rare diseases emerge, SLC25A38 CSA will be increasingly important to distinguish genetically.

Supplementary Material

supinfo

ACKNOWLEDGMENTS

The authors thank the patients and their families for participating. Susan Wong is acknowledged for administration of human subjects research protocols.

Funding sources:

R01 DK087992 and American Society of Hematology Bridge Grant (M.D.F) and RC2 DK122533 (M.D.F. and A.S.)

Footnotes

CONFLICT OF INTEREST STATEMENT

The authors declare no competing interests

DATA AVAILABILITY STATEMENT

All primary sequence data are available upon request. Novel variant sequence data have been submitted to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/).

REFERENCES

  1. Amelio I, Cutruzzola F, Antonov A, Agostini M, & Melino G (2014). Serine and glycine metabolism in cancer. Trends Biochem Sci, 39(4), 191–198. 10.1016/j.tibs.2014.02.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. An W, Zhang J, Chang L, Zhang Y, Wan Y, Ren Y, Niu D, Wu J, Zhu X, & Guo Y (2015). Mutation analysis of Chinese sporadic congenital sideroblastic anemia by targeted capture sequencing. J Hematol Oncol, 8, 55. 10.1186/s13045-015-0154-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. An WB, An WB, Liu C, Wan Y, Guo Y, Wang SC, Zhang YC, & Zhu XF (2019). [Clinical features and gene mutation spectrum in children with sideroblastic anemia]. Zhongguo Dang Dai Er Ke Za Zhi, 21(10), 1016–1021. https://www.ncbi.nlm.nih.gov/pubmed/31642437 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Andolfo I, Martone S, Ribersani M, Bianchi S, Manna F, Genesio R, Gambale A, Pignataro P, Testi AM, Iolascon A, & Russo R (2020). Apparent recessive inheritance of sideroblastic anemia type 2 due to uniparental isodisomy at the SLC25A38 locus. Haematologica, 105(12), 2883–2886. 10.3324/haematol.2020.258533 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bergmann AK, Sahai I, Falcone JF, Fleming J, Bagg A, Borgna-Pignati C, Casey R, Fabris L, Hexner E, Mathews L, Ribeiro ML, Wierenga KJ, & Neufeld EJ (2009). Thiamine-responsive megaloblastic anemia: identification of novel compound heterozygotes and mutation update [Research Support, N.I.H., Extramural]. The Journal of pediatrics, 155(6), 888–892 e881. 10.1016/j.jpeds.2009.06.017 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bishop DF, Tchaikovskii V, Nazarenko I, & Desnick RJ (2013). Molecular expression and characterization of erythroid-specific 5-aminolevulinate synthase gain-of-function mutations causing X-linked protoporphyria. Mol Med, 19, 18–25. 10.2119/molmed.2013.00003 [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bottomley SS, & Fleming MD (2014). Sideroblastic anemia: diagnosis and management. Hematol Oncol Clin North Am, 28(4), 653–670, v. 10.1016/j.hoc.2014.04.008 [DOI] [PubMed] [Google Scholar]
  8. Cartwright GE, & Deiss A (1975). Sideroblasts, siderocytes, and sideroblastic anemia. N Engl J Med, 292(4), 185–193. 10.1056/nejm197501232920405 [DOI] [PubMed] [Google Scholar]
  9. Ducamp S, & Fleming MD (2019). The molecular genetics of sideroblastic anemia. Blood, 133(1), 59–69. 10.1182/blood-2018-08-815951 [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fernandez-Murray JP, Prykhozhij SV, Dufay JN, Steele SL, Gaston D, Nasrallah GK, Coombs AJ, Liwski RS, Fernandez CV, Berman JN, & McMaster CR (2016). Glycine and Folate Ameliorate Models of Congenital Sideroblastic Anemia. PLoS Genet, 12(1), e1005783. 10.1371/journal.pgen.1005783 [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fouquet C, Le Rouzic MA, Leblanc T, Fouyssac F, Leverger G, Hessissen L, Marlin S, Bourrat E, Fahd M, Raffoux E, Vannier JP, Jakel N, Knoefler R, Triolo V, Pasquet M, Bayart S, Thuret I, Lutz P, Vermylen C, Touati M, Rose C, Matthes T, Isidor B, Kannengiesser C, & Ducassou S (2019). Genotype/phenotype correlations of childhood-onset congenital sideroblastic anaemia in a European cohort. Br J Haematol, 187(4), 530–542. 10.1111/bjh.16100 [DOI] [PubMed] [Google Scholar]
  12. Guernsey DL, Jiang H, Campagna DR, Evans SC, Ferguson M, Kellogg MD, Lachance M, Matsuoka M, Nightingale M, Rideout A, Saint-Amant L, Schmidt PJ, Orr A, Bottomley SS, Fleming MD, Ludman M, Dyack S, Fernandez CV, & Samuels ME (2009). Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, Non-P.H.S.]. Nature genetics, 41(6), 651–653. 10.1038/ng.359 [DOI] [PubMed] [Google Scholar]
  13. Hanina S, Bain BJ, Clark B, & Layton DM (2018). Congenital sideroblastic anemia in a female. Am J Hematol, 93(9), 1181–1182. 10.1002/ajh.25196 [DOI] [PubMed] [Google Scholar]
  14. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, & Conde JG (2009). Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform, 42(2), 377–381. 10.1016/j.jbi.2008.08.010 [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kannengiesser C, Sanchez M, Sweeney M, Hetet G, Kerr B, Moran E, Fuster Soler JL, Maloum K, Matthes T, Oudot C, Lascaux A, Pondarre C, Sevilla Navarro J, Vidyatilake S, Beaumont C, Grandchamp B, & May A (2011). Missense SLC25A38 variations play an important role in autosomal recessive inherited sideroblastic anemia [Research Support, Non-U.S. Gov’t]. Haematologica, 96(6), 808–813. 10.3324/haematol.2010.039164 [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kim MH, Shah S, Bottomley SS, & Shah NC (2018). Reduced-toxicity allogeneic hematopoietic stem cell transplantation in congenital sideroblastic anemia. Clin Case Rep, 6(9), 1841–1844. 10.1002/ccr3.1667 [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kory N, Wyant GA, Prakash G, Uit de Bos J, Bottanelli F, Pacold ME, Chan SH, Lewis CA, Wang T, Keys HR, Guo YE, & Sabatini DM (2018). SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism. Science, 362(6416). 10.1126/science.aat9528 [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Le Rouzic MA, Fouquet C, Leblanc T, Touati M, Fouyssac F, Vermylen C, Jakel N, Guichard JF, Maloum K, Toutain F, Lutz P, Perel Y, Manceau H, Kannengiesser C, & Vannier JP (2017). Non syndromic childhood onset congenital sideroblastic anemia: A report of 13 patients identified with an ALAS2 or SLC25A38 mutation. Blood Cells Mol Dis, 66, 11–18. 10.1016/j.bcmd.2017.07.003 [DOI] [PubMed] [Google Scholar]
  19. LeBlanc MA, Bettle A, Berman JN, Price VE, Pambrun C, Yu Z, Tiller M, McMaster CR, & Fernandez CV (2016). Study of Glycine and Folic Acid Supplementation to Ameliorate Transfusion Dependence in Congenital SLC25A38 Mutated Sideroblastic Anemia. Pediatr Blood Cancer, 63(7), 1307–1309. 10.1002/pbc.25981 [DOI] [PubMed] [Google Scholar]
  20. Liu G, Guo S, Kang H, Zhang F, Hu Y, Wang L, Li M, Ru Y, Camaschella C, Han B, & Nie G (2013). Mutation spectrum in Chinese patients affected by congenital sideroblastic anemia and a search for a genotype-phenotype relationship. Haematologica, 98(12), e158–160. 10.3324/haematol.2013.095513 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lunetti P, Damiano F, De Benedetto G, Siculella L, Pennetta A, Muto L, Paradies E, Marobbio CM, Dolce V, & Capobianco L (2016). Characterization of Human and Yeast Mitochondrial Glycine Carriers with Implications for Heme Biosynthesis and Anemia. J Biol Chem, 291(38), 19746–19759. 10.1074/jbc.M116.736876 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Partridge AW, Therien AG, & Deber CM (2004). Missense mutations in transmembrane domains of proteins: phenotypic propensity of polar residues for human disease. Proteins, 54(4), 648–656. 10.1002/prot.10611 [DOI] [PubMed] [Google Scholar]
  23. Ravindra N, Athiyarath R, S E, S S, Kulkarni U, N AF., Korula A, Shaji RV, George B, & Edison ES. (2021). Novel frameshift variant (c.409dupG) in SLC25A38 is a common cause of congenital sideroblastic anaemia in the Indian subcontinent. J Clin Pathol, 74(3), 157–162. 10.1136/jclinpath-2020-206647 [DOI] [PubMed] [Google Scholar]
  24. Riley LG, Heeney MM, Rudinger-Thirion J, Frugier M, Campagna DR, Zhou R, Hale GA, Hilliard LM, Kaplan JA, Kwiatkowski JL, Sieff CA, Steensma DP, Rennings AJ, Simons A, Schaap N, Roodenburg RJ, Kleefstra T, Arenillas L, Fita-Torro J, Ahmed R, Abboud M, Bechara E, Farah R, Tamminga RYJ, Bottomley SS, Sanchez M, Huls G, Swinkels DW, Christodoulou J, & Fleming MD (2018). The phenotypic spectrum of germline YARS2 variants: from isolated sideroblastic anemia to mitochondrial myopathy, lactic acidosis and sideroblastic anemia 2. Haematologica, 103(12), 2008–2015. 10.3324/haematol.2017.182659 [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ruprecht JJ, & Kunji ERS (2020). The SLC25 Mitochondrial Carrier Family: Structure and Mechanism. Trends Biochem Sci, 45(3), 244–258. 10.1016/j.tibs.2019.11.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sankaran VG, Ulirsch JC, Tchaikovskii V, Ludwig LS, Wakabayashi A, Kadirvel S, Lindsley RC, Bejar R, Shi J, Lovitch SB, Bishop DF, & Steensma DP (2015). X-linked macrocytic dyserythropoietic anemia in females with an ALAS2 mutation. J Clin Invest, 125(4), 1665–1669. 10.1172/JCI78619 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sommerville EW, Ng YS, Alston CL, Dallabona C, Gilberti M, He L, Knowles C, Chin SL, Schaefer AM, Falkous G, Murdoch D, Longman C, de Visser M, Bindoff LA, Rawles JM, Dean JCS, Petty RK, Farrugia ME, Haack TB, Prokisch H, McFarland R, Turnbull DM, Donnini C, Taylor RW, & Gorman GS (2017). Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy. JAMA Neurol, 74(6), 686–694. 10.1001/jamaneurol.2016.4357 [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Uminski K, Houston DS, Hartley JN, Liu J, Cuvelier GDE, & Israels SJ (2020). Clinical characterization and hematopoietic stem cell transplant outcomes for congenital sideroblastic anemia caused by a novel pathogenic variant in SLC25A38. Pediatr Blood Cancer, 67(10), e28623. 10.1002/pbc.28623 [DOI] [PubMed] [Google Scholar]
  29. Wong WS, Wong HF, Cheng CK, Chang KO, Chan NP, Ng MH, & Wong KF (2015). Congenital sideroblastic anaemia with a novel frameshift mutation in SLC25A38. J Clin Pathol, 68(3), 249–251. 10.1136/jclinpath-2014-202211 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

supinfo
NIHMS1727268-supplement-supinfo.docx (20.9KB, docx)

Data Availability Statement

All primary sequence data are available upon request. Novel variant sequence data have been submitted to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/).

RESOURCES