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X-Linked Sideroblastic Anemia and Ataxia

, , MD, and , MD, PhD.

Author Information
Rouen University Hospital
Rouen, France
, MD
Department of Neurology
Hospital St Jan
Bruges, Belgium
, MD, PhD
University Hospital Louvain
Louvain, Belgium

Initial Posting: ; Last Update: April 3, 2014.

Summary

Disease characteristics. X-linked sideroblastic anemia and ataxia (XLSA/A) is characterized by moderate anemia and early-onset spinocerebellar syndrome in males, manifest primarily as delayed walking, ataxia evident in early childhood, dysmetria, and dysdiadochokinesis. When present the intention tremor is mild and the dysarthria is mild to moderately severe. The ataxia has been described to be either non-progressive or slowly progressive. Upper motor neuron (UMN) signs in the legs, manifest by brisk deep tendon reflexes, unsustained ankle clonus, and equivocal or extensor plantar responses, are present in some males. Need for crutches or a wheelchair has been reported. Strabismus is seen in some males. Nystagmus and hypometric saccades may occur. Mild learning disability and depression are seen. The moderate hypochromic and microcytic anemia does not cause symptoms. Carrier (heterozygous) females have a normal neurologic examination and may show mild hematologic abnormalities.

Diagnosis/testing. The diagnosis of XLSA/A is suspected in males with characteristic neurologic findings and the presence of moderate hypochromic and microcytic anemia, elevated whole blood total erythrocyte protoporphyrin (TEP) and zinc erythrocyte protoporphyrin (ZnEP), and ring sideroblasts on bone marrow examination. Pappenheimer bodies are seen in peripheral blood smear. The diagnosis is confirmed in a male by identification of a hemizygous pathogenic variant in ABCB7.

Females have a normal neurologic examination and may have a dimorphic blood smear with both hypochromic microcytic red blood cells and normal red blood cells; they may have ring sideroblasts on bone marrow examination.

Management. Treatment of manifestations: Males with XLSA/A benefit from early physical therapy to facilitate acquisition of gross motor skills. Adaptive devices such as ankle fixation orthoses and walkers may be needed. Weighted eating utensils may help promote independent skills in childhood. Speech therapy may improve intelligibility problems from dysarthria. Difficulty with handwriting may be managed with computers for word processing.

Genetic counseling. XLSA/A is inherited in an X-linked manner. Heterozygous females have a 50% chance of transmitting the pathogenic variant in each pregnancy. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will usually not be affected. Males with XLSA/A will pass the pathogenic variant to all of their daughters and none of their sons. Carrier testing of at-risk female relatives and prenatal testing of pregnancies at increased risk are possible if the ABCB7 pathogenic variant in the family is known.

Diagnosis

Males with X-linked sideroblastic anemia and ataxia (XLSA/A) exhibit the following signs:

  • Ataxia and incoordination. Note: Pagon et al [1985] described non-progressive ataxia; Hellier et al [2001] described ataxia that was possibly slowly progressive.
  • Upper motor neuron (UMN) signs (i.e., brisk deep tendon reflexes, unsustained ankle clonus, and equivocal or extensor plantar responses) in the legs (present in some males)
  • Mild asymptomatic hypochromic, microcytic anemia
    • Hematocrit ranges from 26% to 35%.
    • Mean corpuscular volume (MCV fl) is low (Table 1).
    • Peripheral blood smears show in affected males: (1) microcytic and hypochromic red cells with marked poikilocytosis, reticulocytosis, and heavy stippling; (2) Pappenheimer bodies (iron inclusions in more mature erythrocytes). These siderocytes are present in the peripheral blood of affected males and in some heterozygous females.
    • Bone marrow examination shows increased iron stores with ring sideroblasts (Figure 1). Note: Serum iron parameters are normal.
    • High levels of whole blood total erythrocyte protoporphyrin (TEP) and zinc erythrocyte protoporphyrin (ZnEP) further support the diagnosis [Pagon et al 1985, Bekri et al 2000, Hellier et al 2001, Maguire et al 2001, D’Hooghe et al 2012].

      Note: (1) Whole blood TEP may be used as a screening tool [Piomelli et al 1975, Hart & Piomelli 1981]. (2) If no ABCB7 pathogenic variant is identified (see The diagnosis of XLSA/A below), the presence of characteristic bone marrow changes and high levels of TEP identified in at least one affected family member with a family history consistent with X-linked inheritance strongly suggests the diagnosis of XLSA/A.
Figure 1

Figure

Figure 1. Ringed sideroblast

Prussian blue staining of the bone marrow aspirate (x1000) showing a normal erythroid precursor (straight arrow) and a ringed sideroblast containing many iron granules around the nucleus (curved arrow).

From (more...)

Table 1. Mean Corpuscular Volume (MCV fl) in XLSA/A

GroupMean Corpuscular Volume (MCV fl)
Normal male89.1 ± 5.01
Normal female87.6 ± 5.5
Affected male58 to 68
Carrier female83 to 90

Heterozygous females have a normal neurologic examination and may show mild hematologic abnormalities, including Pappenheimer bodies in peripheral blood smear [Hellier et al 2001] and ringed sideroblasts in bone marrow aspirate [Pagon et al 1985]. Some heterozygous females also have increased levels of whole blood TEP and ZnEP [Pagon et al 1985].

The diagnosis of XLSA/A is confirmed in a male by presence of a hemizygous pathogenic variant in ABCB7.

  • One genetic testing strategy is molecular genetic testing of ABCB7, the only gene in which pathogenic variants are known to cause XLSA/A. Sequence analysis should be performed first; if no pathogenic variant is identified, deletion/duplication analysis may be considered.
  • An alternative genetic testing strategy is use of a multi-gene panel that includes ABCB7 and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Table 2. Summary of Molecular Genetic Testing Used in X-Linked Sideroblastic Anemia and Ataxia

Gene 1 Test MethodProportion of Male Probands with a Pathogenic Variant Detectable by this Method
ABCB7Sequence analysis 2, 3 4/4 families tested 4
Deletion/duplication analysis 5Unknown, none reported 6

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

2. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3. Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.

4. Allikmets et al [1999], Bekri et al [2000], Hellier et al [2001], Maguire et al [2001], D'Hooghe et al [2012]

5. Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6. No deletions/duplications of ABCB7 have been reported to cause XLSA/A.

Clinical Description

To date, four unrelated families with X-linked sideroblastic anemia and ataxia (XLSA/A) have been reported [Allikmets et al 1999, Bekri et al 2000, Hellier et al 2001, Maguire et al 2001, D'Hooghe et al 2012].

Pagon et al [1985] reported two families with a non-progressive spinocerebellar syndrome and sideroblastic anemia, both segregating in an X-linked recessive mode of inheritance. Four males in two generations and a fifth male from an unrelated family were affected. Bekri et al [2000] reported two affected brothers with XLSA/A. Maguire et al [2001] reported another family with two affected brothers and two affected maternal uncles. D’Hooghe et al [2012] reported a boy with XLSA/A.

Ataxia/neurologic findings. Males have an early-onset spinocerebellar syndrome manifesting primarily as delayed walking, ataxia evident from early childhood, dysmetria, and dysdiadochokinesis. When present, intention tremor is mild and dysarthria is mild to moderately severe.

In some, but not all, affected members of one family, the ataxia appeared to improve with time, such that truncal titubation decreased and walking became progressively easier [Pagon et al 1985]. However, in older patients slow deterioration of walking can be seen in the fifth or sixth decade [Pagon et al 1985, Bekri et al 2000, Hellier et al 2001].

Need for crutches and/or a wheel chair have been reported.

Upper motor neuron (UMN) signs in the legs, manifest by brisk deep tendon reflexes, unsustained ankle clonus, and equivocal or extensor plantar responses are present in some males.

Strabismus is seen in some males. Extraocular movements are normal; however, nystagmus and hypometric saccades may occur.

Intellectual abilities are generally within the normal range. Mild learning disability and depression have been seen [Pagon & Bird, personal communication] and one person was reported to have "schizophrenia" [Hellier et al 2001].

Pes cavus, scoliosis, and muscle wasting are not present.

Impairment of visual acuity either from optic atrophy or retinal dystrophy is not seen.

In most cases brain MRI shows cerebellar atrophy/hypoplasia [Raskind et al 1991].

Anemia. The anemia is mild and does not cause symptoms.

Iron storage. Despite the finding of increased iron stores and ring sideroblasts on bone marrow examination, systemic iron overload has not been described. Serum iron studies including serum concentration of iron, total iron binding capacity (TIBC), per cent TIBC saturation, and serum concentration of ferritin were normal in the families reported by Pagon et al [1985] and Hellier et al [2001].

Heterozygotes. Carrier females have a normal neurologic examination.

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known.

Prevalence

Four families and one male who was a simplex case (i.e., a single occurrence in a family) have been reported to date [Pagon et al 1985, Bekri et al 2000, Hellier et al 2001, D’Hooghe et al 2012]. The prevalence of the disorder is probably underestimated because of failure to recognize the mild anemia in males with the characteristic ataxia.

Differential Diagnosis

Sideroblastic anemia. The sideroblastic anemias are a heterogeneous group of acquired and heritable anemias characterized by ringed sideroblasts (erythroid precursors - present in the bone marrow - that have pathologic iron overload in the mitochondria); the perinuclear location of mitochondria leads to the characteristic ringed appearance [Camaschella 2008, Bergmann et al 2010]. Iron inclusions, called Pappenheimer bodies, may also be observed in more mature erythrocytes [Sears & Udden 2004, Camaschella 2008] (Figure 1).

The most common congenital sideroblastic anemia is X-linked sideroblastic anemia (XLSA) caused by mutation of ALAS2. XLSA is characterized by hepatic and systemic iron overload but not ataxia (as expression of ALAS2 is confined to erythroid tissues) [Napier et al 2005].

Other causes of congenital sideroblastic anemia include mutation of genes that encode proteins affecting mitochondrial metabolism [Bergmann et al 2010, Fujiwara & Harigae 2013] and/or affect iron-sulfur (Fe-S) cluster protein biosynthesis, assembly, or function. Fe-S proteins, which are essential for fundamental metabolic processes such as respiration and gene expression, are synthesized in the mitochondria and are either associated with mitochondrial apoprotein to form mitochondrial Fe/S proteins or exported to the cytosol (via the ABCB7 transporter) to assist in the formation of cytosolic and nuclear Fe-S proteins [Sheftel et al 2010]. These genes include the following:

  • SLC25A38 (encoding an erythroid specific mitochondrial transporter) [Guernsey et al 2009]
  • SLC19A2 (encoding a high-affinity thiamine transporter)
  • PUS1 (RNA-modifying enzyme pseudouridine synthase 1) [Bykhovskaya et al 2004]
  • ABCB7 (encoding mitochondrial ATP-binding cassette transporter), the cause of XLSA/A
  • GLRX5 (encoding monothiol glutaredoxin 5) [Camaschella et al 2007], associated with a Fe-S cluster biosynthetic defect (the assembly of mitochondrial Fe/S proteins). The deregulation of mitochondrial iron metabolism results in sideroblastic anemia.
  • YARS2 (mitochondrial tyrosyl-tRNA synthase) [Riley et al 2010]
  • Mitochondrial DNA deletions, duplications and rearrangements (Pearson marrow-pancreas syndrome) [Fleming 2002]

Another ataxia linked to Fe-S cluster protein is Friedreich ataxia (FRDA), caused by mutation of FXN, which encodes the mitochondrial protein frataxin whose main role is to supply iron in a bioavailable form for mitochondrial Fe-S cluster synthesis (Figure 2) [Ye & Rouault 2010b]. In persons with FRDA excess iron accumulation is observed in mitochondria of cardiac myocytes and neurons [Rouault & Tong 2008, Ye & Rouault 2010b]; however, persons with FRDA do not demonstrate significant anemia, suggesting either that frataxin is not essential for heme synthesis and erythropoiesis or that frataxin deficiency does not compromise erythropoietic tissues [Stemmler et al 2010, Ye & Rouault 2010a].

Figure 2

Figure

Figure 2. Fe-S cluster biogenesis, heme synthesis and hypothetic effects of defects in ABCB7

Adapted from D’Hooghe et al [2012] with permission

Of note, in murine cultured fibroblasts with decreased levels of frataxin, some Fe-S cluster proteins are deficient, iron accumulates in mitochondria, and oxidant sensitivity is observed as in the human disease [Calmels et al 2009]. The causal links among these effects are not well defined [Stemmler et al 2010].

Ataxia. The diagnostic approach to the numerous heritable ataxias can be quite challenging. Some hereditary ataxias typically present before age three years, including ataxia-telangiectasia, infantile-onset spinocerebellar ataxia, X-linked sideroblastic anemia with ataxia (XLSA/A), congenital disorders of glycosylation, and cerebellar malformations (e.g., Dandy-Walker malformation) [Bernard & Shevell 2008].

X-linked spinocerebellar ataxia has been reported, but is rare (see Hereditary Ataxia Overview). None has been associated with anemia. Mutation of ABCB7 should be considered in any unexplained X-linked spinocerebellar ataxia, even in the absence of clear hematologic changes.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with sideroblastic anemia and ataxia (XLSA/A), the following evaluations are recommended:

  • Neurologic examination
  • Brain CT or MRI
  • Psychological testing if indicated
  • Medical genetics consultation

Treatment of Manifestations

There is no effective treatment for XLSA/A.

Males with ataxia benefit from early physical therapy to facilitate acquisition of gross motor skills. Adaptive devices such as ankle fixation orthoses and walkers may be needed.

Weighted eating utensils may help promote independent skills in childhood.

Speech therapy may improve intelligibility problems resulting from dysarthria.

Difficulty with handwriting may be managed with computers for word processing.

The anemia is usually mild and asymptomatic and does not require treatment; hepatic and systemic iron overload does not occur.

Surveillance

It is debated whether monitoring for possible iron overload is warranted in older individuals through routine screening of serum iron concentration, total iron binding capacity (TIBC), and serum ferritin concentration; iron overload is theoretically possible but has not been reported.

Evaluation of Relatives at Risk

See Related Genetic Counseling Issues for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

One possible therapeutic approach to some of the disorders involving iron misdistribution is drug-mediated iron relocation. Deferiprone (DFP), an iron chelator used to treat iron overload, has iron-relocating abilities when used to treat disorders of regional iron accumulation. Because of their possible side effects, siderophores (small, high-affinity iron chelating compounds secreted by microorganisms) and other chelators must be administered with care; thus, the potential use of iron-redistributing agents in some iron-misdistribution diseases (such as XLSA/A) warrants rigorous investigation [Boddaert et al 2007, Camaschella 2008, Kakhlon et al 2010].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

X-linked sideroblastic anemia and ataxia (XLSA/A) is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

  • The father of an affected male will not have the disease nor will he be a carrier of the pathogenic ABCB7 allelic variant.
  • In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
  • If pedigree analysis reveals that a male proband is the only affected family member, his mother may be a carrier or the pathogenic variant may be de novo in him (in which case the mother is not a carrier).
  • If a woman has more than one affected son and the pathogenic variant cannot be detected in her DNA, she has germline mosaicism. To date germline mosaicism has not been reported in XLSA/A.

Sibs of a proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother of the proband is a carrier, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Male sibs who inherit the pathogenic ABCB7 variant will be affected; female sibs who inherit the pathogenic variant will be carriers and will not be affected.
  • If the pathogenic variant cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Males with XLSA/A will pass the pathogenic variant to all of their daughters and none of their sons.

Other family members. The proband's maternal aunts may be at risk of being carriers and the aunt's offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Heterozygous females (carriers) are asymptomatic.

  • They have a normal neurologic examination with no cerebellar dysfunction.
  • They have a normal hematocrit, but may have a dimorphic blood smear with hypochromic microcytic red blood cells and normal red blood cells, sideroblasts on bone marrow examination. Some also have increased levels of whole blood total erythrocyte protoporphyrin (TEP) and zinc erythrocyte protoporphyrin (ZnEP) [Pagon et al 1985, D’Hooghe et al 2012].

Carrier testing of at-risk female relatives is possible if the pathogenic variant has been identified in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the pathogenic ABCB7 variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Requests for prenatal testing for conditions such as XLSA/A are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for families in which the pathogenic ABCB7 variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • euro-ATAXIA (European Federation of Hereditary Ataxias)
    Ataxia UK
    9 Winchester House
    Kennington Park
    London SW9 6EJ
    United Kingdom
    Phone: +44 (0) 207 582 1444
    Email: marco.meinders@euro-ataxia.eu
  • International Network of Ataxia Friends (INTERNAF)
    Email: internaf-owner@yahoogroups.com
  • Medline Plus
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. X-Linked Sideroblastic Anemia and Ataxia: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for X-Linked Sideroblastic Anemia and Ataxia (View All in OMIM)

300135ATP-BINDING CASSETTE, SUBFAMILY B, MEMBER 7; ABCB7
301310ANEMIA, SIDEROBLASTIC, AND SPINOCEREBELLAR ATAXIA; ASAT

Molecular Genetic Pathogenesis

ABCB7 encodes a mitochondrial adenosine triphosphate (ATP)-binding cassette (ABC) transporter protein involved in iron homeostasis. The family of ABC transporters consists of a large group of ATP-dependent transmembrane proteins that specifically transport a wide variety of substrates across cell and organelle membranes [Holland 2011, Moitra & Dean 2011]. The human genome contains 49 ABC genes. Compared to bacteria, human mitochondria surprisingly harbor a very small number (≤4) of ABC transporters [Burke & Ardehali 2007, Zutz et al 2009]. Mitochondrial ABC transporters belong to the subfamily B and assemble as homodimers of half-transporters [Zutz et al 2009]. ABCB7 is found in the inner mitochondrial membrane.

The substrate transported by the ABCB7 transporter is not fully characterized. Initially, ABCB7 was thought to be involved in transport of heme from the mitochondria to the cytosol [Shimada et al 1998]. Recent studies in different species suggest relationships between heme biosynthetic pathways, iron-sulfur (Fe–S) cluster biogenesis, and mitochondrial iron homeostasis. The most common Fe–S clusters in eukaryotes are the [2Fe–2S] and [4Fe–4S] clusters. Fe–S clusters are ancient biologic prosthetic groups essential for numerous biologic processes, including mitochondrial respiratory chain activity and various other enzymatic and regulatory functions. Mitochondrial iron overload is a prominent feature of the human Fe–S cluster assembly disorders [Rouault & Tong 2008, Sheftel et al 2010]. It is possible that ABCB7 transports Fe-S clusters or/and an as-yet-unknown regulatory molecule from mitochondria to convey the signal that mitochondria have sufficient iron (Figure 2). Then, if either Fe-S cluster synthesis or heme synthesis is disrupted, the cytosolic/nuclear compartment would perceive mitochondrial iron deficiency and could respond by significantly increasing mitochondrial iron stores.

See Additional information on pathogenesis (pdf).

Gene structure. ABCB7 comprises 16 exons [Shimada et al 1998, Bekri et al 2000]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table 2 and Table 3. Only four unrelated families with XLSA/A have been reported, each with a distinct missense mutation. It is worth noting that the identified pathogenic variants are missense mutations with intermediate severity.

  • Pagon et al [1985] reported four males in two generations and a fifth male from an unrelated family were affected. In the four members of the first kindred, Allikmets et al [1999] found a hemizygous missense pathogenic variant in exon 9 (c.1203T>G; p.Ile401Met) resulting in a substitution in the fifth putative transmembrane region of the ABCB7 protein. This pathogenic variant was identified in the heterozygous state in female obligate carriers.
  • Bekri et al [2000] reported two affected brothers with XLSA/A and found a hemizygous missense pathogenic variant in exon 10 (c.1300G>A; p.Glu434Lys) causing a substitution adjacent to the sixth putative transmembrane region of the ABCB7 protein; this variant was present in one allele in their mother.
  • Maguire et al [2001] reported a family with two affected brothers and two affected maternal uncles. In the two brothers and in one uncle who was still alive, Maguire et al [2001] found a hemizygous missense pathogenic variant in exon 10 (c.1234G>C; p.Val412Leu) leading to a substitution in the last of six putative transmembrane regions of the ABCB7 protein. The mother was heterozygote for this variant.
  • D’Hooghe et al [2012] reported a male child with a novel hemizygous missense pathogenic variant in exon 6 (c.627A>T; p.Glu209Asp) causing a substitution adjacent to the second transmembrane domain at the mitochondrial side; his mother was heterozygous for the same variant.

Table 3. ABCB7 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.627A>Tp.Glu209AspNM_004299​.3
NP_004290​.2
c.1203T>Gp.Ile401Met
c.1234G>Cp.Val412Leu
c.1300G>Ap.Glu434Lys

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

See Additional information on genetics of XLSA/A (pdf).

Normal gene product. The ATP-binding cassette, subfamily B, member 7 protein (ABCB7) belongs to the adenosine triphosphate-binding cassette transporter superfamily; its yeast ortholog, Atm1p, plays a central role in the maturation of cytosolic iron-sulfur (Fe-S) cluster-containing proteins [Bekri et al 2000]. ABCB7 contributes to the production of heme during the differentiation of erythroid cells [Taketani et al 2003]. It is also thought to transport a component required for the maturation of cytosolic Fe-S clusters from the mitochondrion to the cytosol [Napier et al 2005]. Thus, the mitochondrion appears to be important in both heme synthesis and in the biogenesis of Fe-S clusters.

ABCB7 is highly expressed in bone marrow as well as in the cerebellum, which may explain why males with ABCB7 deficiency have ataxia [Allikmets et al 1999, Ye & Rouault 2010a, Ye & Rouault 2010b]. The ataxia observed in XLSA/A may be related to the damage mediated by the iron loading in the mitochondrion and/or disruption to mitochondrial iron homeostasis in neural cells [Napier et al 2005].

Abnormal gene product. Complementation studies in yeast suggest that the human mutant ATP-binding cassette, subfamily B, member 7 proteins (ABCB7) are caused by mild, partial loss-of-function alleles [Allikmets et al 1999, Bekri et al 2000] that result in diminished cytosolic Fe-S cluster protein.

Pondarre et al [2006] created a conditional knockout allele of the murine ortholog Abcb7 and formally demonstrated that XLSA/A is caused by partial loss of function mutations that directly or indirectly inhibit heme biosynthesis [Pondarré et al 2007]. Indeed, mutation leading to a significant loss of protein function must be lethal as illustrated by a knock out mouse model [Pondarre et al 2006].

References

Literature Cited

  1. Allikmets R, Raskind WH, Hutchinson A, Schueck ND, Dean M, Koeller DM. Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A). Hum Mol Genet. 1999;8:743–9. [PubMed: 10196363]
  2. Bekri S, Kispal G, Lange H, Fitzsimons E, Tolmie J, Lill R, Bishop DF. Human ABC7 transporter: gene structure and mutation causing X-linked sideroblastic anemia with ataxia with disruption of cytosolic iron-sulfur protein maturation. Blood. 2000;96:3256–64. [PubMed: 11050011]
  3. Bergmann AK, Campagna DR, McLoughlin EM, Agarwal S, Fleming MD, Bottomley SS, Neufeld EJ. Systematic molecular genetic analysis of congenital sideroblastic anemia: evidence for genetic heterogeneity and identification of novel mutations. Pediatr Blood Cancer. 2010;54:273–8. [PMC free article: PMC2843911] [PubMed: 19731322]
  4. Bernard G, Shevell M. The wobbly child: an approach to inherited ataxias. Semin Pediatr Neurol. 2008;15:194–208. [PubMed: 19073328]
  5. Boddaert N, Le Quan Sang KH, Rötig A, Leroy-Willig A, Gallet S, Brunelle F, Sidi D, Thalabard JC, Munnich A, Cabantchik ZI. Selective iron chelation in Friedreich ataxia: biologic and clinical implications. Blood. 2007;110:401–8. [PubMed: 17379741]
  6. Boultwood J, Pellagatti A, Nikpour M, Pushkaran B, Fidler C, Cattan H, Littlewood TJ, Malcovati L, Della Porta MG, Jädersten M, Killick S, Giagounidis A, Bowen D, Hellström-Lindberg E, Cazzola M, Wainscoat JS (2008) The role of the iron transporter ABCB7 in refractory anemia with ring sideroblasts. PLoS ONE 3:e1970. [PMC free article: PMC2276313] [PubMed: 18398482]
  7. Burke MA, Ardehali H. Mitochondrial ATP-binding cassette proteins. Transl Res. 2007;150:73–80. [PubMed: 17656326]
  8. Bykhovskaya Y, Casas K, Mengesha E, Inbal A, Fischel-Ghodsian N. Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA). Am J Hum Genet. 2004;74:1303–8. [PMC free article: PMC1182096] [PubMed: 15108122]
  9. Calmels N, Schmucker S, Wattenhofer-Donzé M, Martelli A, Vaucamps N, Reutenauer L, Messaddeq N, Bouton C, Koenig M, Puccio H. The first cellular models based on frataxin missense mutations that reproduce spontaneously the defects associated with Friedreich ataxia. PLoS One. 2009;4:e6379. [PMC free article: PMC2710521] [PubMed: 19629184]
  10. Camaschella C. Recent advances in the understanding of inherited sideroblastic anaemia. Br J Haematol. 2008;143:27–38. [PubMed: 18637800]
  11. Camaschella C, Campanella A, De Falco L, Boschetto L, Merlini R, Silvestri L, Levi S, Iolascon A. The human counterpart of zebrafish shiraz shows sideroblastic-like microcytic anemia and iron overload. Blood. 2007;110:1353–8. [PubMed: 17485548]
  12. D'Hooghe M, Selleslag D, Mortier G, Van Coster R, Vermeersch P, Billiet J, Bekri S. X-linked sideroblastic anemia and ataxia: a new family with identification of a fourth ABCB7 gene mutation. Eur J Paediatr Neurol. 2012;16:730–5. [PubMed: 22398176]
  13. Fleming MD. The genetics of inherited sideroblastic anemias. Semin Hematol. 2002;39:270–81. [PubMed: 12382202]
  14. Fujiwara T, Harigae H. Pathophysiology and genetic mutations in congenital sideroblastic anemia. Pediatr Int. 2013;55:675–9. [PubMed: 24003969]
  15. 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. Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia. Nat Genet. 2009;41:651–3. [PubMed: 19412178]
  16. Hart D, Piomelli S. Simultaneous quantitation of zinc protoporphyrin and free protoporphyrin in erythrocytes by acetone extraction. Clin Chem. 1981;27:220–2. [PubMed: 7460270]
  17. Hellier KD, Hatchwell E, Duncombe AS, Kew J, Hammans SR. X-linked sideroblastic anaemia with ataxia: another mitochondrial disease? J Neurol Neurosurg Psychiatry. 2001;70:65–9. [PMC free article: PMC1763461] [PubMed: 11118249]
  18. Holland IB. ABC transporters, mechanisms and biology: an overview. Essays Biochem. 2011;50:1–17. [PubMed: 21967049]
  19. Kakhlon O, Breuer W, Munnich A, Cabantchik ZI. Iron redistribution as a therapeutic strategy for treating diseases of localized iron accumulation. Can J Physiol Pharmacol. 2010;88:187–96. [PubMed: 20393584]
  20. Maguire A, Hellier K, Hammans S, May A. X-linked cerebellar ataxia and sideroblastic anaemia associated with a missense mutation in the ABC7 gene predicting V411L. Br J Haematol. 2001;115:910–7. [PubMed: 11843825]
  21. Moitra K, Dean M. Evolution of ABC transporters by gene duplication and their role in human disease. Biol Chem. 2011;392:29–37. [PubMed: 21194360]
  22. Napier I, Ponka P, Richardson DR. Iron trafficking in the mitochondrion: novel pathways revealed by disease. Blood. 2005;105:1867–74. [PubMed: 15528311]
  23. Nikpour M, Scharenberg C, Liu A, Conte S, Karimi M, Mortera-Blanco T, Giai V, Fernandez-Mercado M, Papaemmanuil E, Högstrand K, Jansson M, Vedin I, Stephen Wainscoat J, Campbell P, Cazzola M, Boultwood J, Grandien A, Hellström-Lindberg E. The transporter ABCB7 is a mediator of the phenotype of acquired refractory anemia with ring sideroblasts. Leukemia. 2013;27:889–96. [PMC free article: PMC3794445] [PubMed: 23070040]
  24. Pagon RA, Bird TD, Detter JC, Pierce I. Hereditary sideroblastic anaemia and ataxia: an X linked recessive disorder. J Med Genet. 1985;22:267–73. [PMC free article: PMC1049446] [PubMed: 4045952]
  25. Piomelli S, Lamola AA, Poh-Fitzpatrick MF, Seaman C, Harber LC. Erythropoietic protoporphyria and lead intoxication: the molecular basis for difference in cutaneous photosensitivity. I. Different rates of disappearance of protoporphyrin from the erythrocytes, both in vivo and in vitro. J Clin Invest. 1975;56:1519–27. [PMC free article: PMC333130] [PubMed: 1202082]
  26. Pondarre C, Antiochos BB, Campagna DR, Clarke SL, Greer EL, Deck KM, McDonald A, Han AP, Medlock A, Kutok JL, Anderson SA, Eisenstein RS, Fleming MD. The mitochondrial ATP-binding cassette transporter Abcb7 is essential in mice and participates in cytosolic iron-sulphur cluster biogenesis. Hum Mol Genet. 2006;15:953–64. [PubMed: 16467350]
  27. Pondarré C, Campagna DR, Antiochos B, Sikorski L, Mulhern H, Fleming MD. Abcb7, the gene responsible for X-linked sideroblastic anemia with ataxia, is essential for hematopoiesis. Blood. 2007;109:3567–9. [PMC free article: PMC1852240] [PubMed: 17192398]
  28. Raskind WH, Wijsman E, Pagon RA, Cox TC, Bawden MJ, May BK, Bird TD. X-linked sideroblastic anemia and ataxia: linkage to phosphoglycerate kinase at Xq13. Am J Hum Genet. 1991;48:335–41. [PMC free article: PMC1683027] [PubMed: 1671320]
  29. Riley LG, Cooper S, Hickey P, Rudinger-Thirion J, McKenzie M, Compton A, Lim SC, Thorburn D, Ryan MT, Giegé R, Bahlo M, Christodoulou J. Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia--MLASA syndrome. Am J Hum Genet. 2010;87:52–9. [PMC free article: PMC2896778] [PubMed: 20598274]
  30. Rouault TA, Tong WH. Iron-sulfur cluster biogenesis and human disease. Trends Genet. 2008;24:398–407. [PMC free article: PMC2574672] [PubMed: 18606475]
  31. Sears DA, Udden MM. Pappenheimer bodies: a brief historical review. Am J Hematol. 2004;75:249–50. [PubMed: 15054821]
  32. Sheftel A, Stehling O, Lill R. Iron-sulfur proteins in health and disease. Trends Endocrinol Metab. 2010;21:302–14. [PubMed: 20060739]
  33. Shimada Y, Okuno S, Kawai A, Shinomiya H, Saito A, Suzuki M, Omori Y, Nishino N, Kanemoto N, Fujiwara T, Horie M, Takahashi E. Cloning and chromosomal mapping of a novel ABC transporter gene (hABC7), a candidate for X-linked sideroblastic anemia with spinocerebellar ataxia. J Hum Genet. 1998;43:115–22. [PubMed: 9621516]
  34. Stemmler TL, Lesuisse E, Pain D, Dancis A. Frataxin and mitochondrial FeS cluster biogenesis. J Biol Chem. 2010;285:26737–43. [PMC free article: PMC2930671] [PubMed: 20522547]
  35. Taketani S, Kakimoto K, Ueta H, Masaki R, Furukawa T. Involvement of ABC7 in the biosynthesis of heme in erythroid cells: interaction of ABC7 with ferrochelatase. Blood. 2003;101:3274–80. [PubMed: 12480705]
  36. Ye H, Rouault TA. Erythropoiesis and iron sulfur cluster biogenesis. Adv Hematol 2010a;2010. [PMC free article: PMC2939393] [PubMed: 20862391]
  37. Ye H, Rouault TA. Human iron-sulfur cluster assembly, cellular iron homeostasis, and disease. Biochemistry. 2010b;49:4945–56. [PMC free article: PMC2885827] [PubMed: 20481466]
  38. Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, Sato Y, Sato-Otsubo A, Kon A, Nagasaki M, Chalkidis G, Suzuki Y, Shiosaka M, Kawahata R, Yamaguchi T, Otsu M, Obara N, Sakata-Yanagimoto M, Ishiyama K, Mori H, Nolte F, Hofmann WK, Miyawaki S, Sugano S, Haferlach C, Koeffler HP, Shih LY, Haferlach T, Chiba S, Nakauchi H, Miyano S, Ogawa S. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011;478:64–9. [PubMed: 21909114]
  39. Zutz A, Gompf S, Schagger H, Tampe R. Mitochondrial ABC proteins in health and disease. Biochim Biophys Acta. 2009;1787:681-90. [PubMed: 19248758]

Chapter Notes

Author History

Soumeya Bekri (2014-present)
Marc D’Hooghe, MD (2014-present)
Thomas D Bird, MD; University of Washington, Seattle (1998-2014)
Roberta A Pagon, MD; University of Washington, Seattle (1998-2014)
Pieter Vermeersch (2014-present)

Revision History

  • 3 April 2014 (me) Comprehensive update posted live
  • 7 April 2009 (me) Comprehensive update posted live
  • 1 May 2008 (cd) Revision: sequencing of exons 5-16 and the intron/exon junctions available clinically
  • 24 March 2008 (cd) Revision: clinical testing not available
  • 1 March 2006 (me) Review posted to live Web site
  • 12 November 1998 (bp) Original submission
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