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Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-.
Bookshelf ID: NBK1321PMID: 20301496
Summary
Disease characteristics. Sideroblastic anemia and ataxia (XLSA/A) is characterized by moderate anemia and early-onset spinocerebellar syndrome in males manifesting primarily as ataxia, dysmetria, and dysdiadochokinesis. Dysarthria and intention tremor are mild when present. 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 anemia is mild and does not cause symptoms. Carrier females have a normal neurologic examination.
Diagnosis/testing. The diagnosis of XLSA/A is made in males by neurologic examination and presence of moderate hypochromic and microcytic anemia, ring sideroblasts on bone marrow examination, and elevated free erythrocyte protoporphyrin levels. Brain MRI shows cerebellar atrophy/hypoplasia. Females 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. Molecular genetic testing of ABCB7, the only gene known to be associated with XLSA/A, is available clinically.
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. Carrier females have a 50% chance of transmitting the mutation in each pregnancy. Males who inherit the mutation will be affected; females who inherit the mutation will be carriers and will usually not be affected. Males with XLSA/A will pass the disease-causing mutation to all of their daughters and none of their sons. Carrier testing of at-risk female relatives is possible if the disease-causing mutation in the family is known. Prenatal testing may be available through laboratories offering custom prenatal testing if the disease-causing mutation in the family is known.
Diagnosis
Clinical Diagnosis
Males with X-linked sideroblastic anemia and ataxia (XLSA/A) have the following:
Moderate hypochromic, microcytic anemia, ring sideroblasts on bone marrow examination, and elevated serum concentration of free erythrocyte protoporphyrin
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 in the legs (present in some males)
Testing
Males
Hematocrit ranges from 26% to 35%.
Mean corpuscular volume (MCV fl) is low (Table 1).
Table 1. Mean Corpuscular Volume (MCV fl) in XLSA/A
| Group | Mean Corpuscular Volume (MCV fl) |
|---|---|
| Normal Male | 89.1±5.01 |
| Normal Female | 87.6±5.5 |
| Affected Male | 58 to 68 |
| Carrier Female | 83 to 90 |
Pagon et al [1985] (4 affected males and 3 obligate carrier females)
Peripheral blood smears show microcytic and hypochromic red cells with marked poikilocytosis, reticulocytosis, and heavy stippling. 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.
Free erythrocyte protoporphyrin (FEP) serum concentrations are generally elevated.
Females. Females have a normal hematocrit, but may have a dimorphic blood smear with both hypochromic microcytic red blood cells and normal red blood cells, sideroblasts on bone marrow examination, and normal serum concentration of free erythrocyte protoporphyrin (FEP).
Molecular Genetic Testing
Gene. ABCB7 is the only gene known to be associated with X-linked sideroblastic anemia and ataxia.
Clinical testing
Sequence analysis of the exons 5-16 and the intron/exon junctions detects mutations in an unknown percentage of affected males.
Table 2. Summary of Molecular Genetic Testing Used in X-Linked Sideroblastic Anemia and Ataxia
| Gene Symbol | Test Method | Mutations Detected | Mutation Detection Frequency by Test Method | Test Availability |
|---|---|---|---|---|
| ABCB7 | Sequence analysis of select exons | Sequence variants in exons 5-16 and the intron/exon junctions | Unknown | Clinical |
Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Testing Strategy
Confirming the diagnosis in a proband. Because the hematologic findings are so mild, it is reasonable to require that characteristic bone marrow changes or an ABCB7 mutation be identified in at least one affected family member to establish the diagnosis of X-linked sideroblastic anemia and ataxia.
Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: (1) Carriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis and then, if no mutation is identified, by methods to detect gross structural abnormalities.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.
Genetically Related (Allelic) Disorders
No other phenotypes are known to be associated with germline mutations in ABCB7.
In investigations of individuals with refractory anemia with ring sideroblasts (RARS), an acquired myelodysplastic syndrome (MDS) characterized by an excess iron accumulation in the mitochondria of erythroblasts, Boultwood et al [2008] identified a strong relationship between an increasing percentage of bone marrow ring sideroblasts and decreasing ABCB7 gene expression levels, suggesting that ABCB7 is a candidate gene for RARS.
Clinical Description
Ataxia/neurologic
Males have an early-onset spinocerebellar syndrome manifesting primarily as ataxia, dysmetria, and dysdiadochokinesis. Dysarthria and intention tremor are mild when present. 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]. In another family, progression of ataxia after the fifth decade was reported [Hellier et al 2001]. Need for crutches and/or a wheel chair has 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.
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.
Prevalence
Three families and one male who was a simplex case (i.e., a single occurrence in a family) have been reported to date. The prevalence of the disorder is probably underestimated because of failure to recognize the mild anemia in males with the characteristic ataxia.
Differential Diagnosis
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Both X-linked spinocerebellar ataxia and X-linked spastic paraparesis have been reported, but are rare. (See Hereditary Ataxia Overview and Hereditary Spastic Paraplegia Overview.) None has been associated with anemia.
The term sideroblastic anemia refers to a heterogeneous group of anemias in which immature red cells accumulate pathologic intramitochondrial iron, which is in some cases secondary to a defect in heme synthesis. There are several acquired forms of sideroblastic anemia and several other hereditary types, including a genetically distinct X-linked recessive type not associated with ataxia [Fleming 2002].
X-linked sideroblastic anemia (without ataxia) is a hypochromic, microcytic anemia that is usually mild to moderate, but considerable variability is observed even within a family. Males with X-linked hereditary sideroblastic anemia can have histologic and clinical evidence of parenchymal iron overload by the second or third decade even without exogenous iron therapy or previous transfusions. In these individuals, the serum iron concentration and percentage transferrin saturation are abnormally high in childhood. Mutations in ALAS2 are causative [Fleming 2002].
Sideroblastic anemia with deficiency of glutaredoxin 5 encoded by GLRX5 has been reported in one middle-aged male with anemia and iron overload with a low number of ringed sideroblasts [Camaschella et al 2007].
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
Treatment of Manifestations
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 from dysarthria.
Difficulty with handwriting may be managed with computers for word processing.
Testing 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
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.
Other
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.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
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 mutation.
In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
If pedigree analysis reveals that the proband is the only affected family member, the mother may be a carrier or the affected male may have a de novo gene mutation, in which case the mother is not a carrier.
If a woman has more than one affected son and the disease-causing mutation cannot be detected in her DNA, she has germline mosaicism. To date germline mosaicism has not been reported.
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, and a normal serum concentration of free erythrocyte protoporphyrin (FEP).
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 disease-causing mutation in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will not be affected.
If the disease-causing mutation 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 disease-causing mutation 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
Carrier testing of at-risk female relatives is possible if the disease-causing mutation has been identified in the family.
Related Genetic Counseling Issues
Family planning
The optimal time for determination of genetic risk and clarification of carrier status 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 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.
Prenatal Testing
No laboratories offering molecular genetic testing for prenatal diagnosis of XLSA/A are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering custom prenatal testing, see .
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 available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .
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
| Gene Symbol | Chromosomal Locus | Protein Name | Locus Specific | HGMD |
|---|---|---|---|---|
| ABCB7 | Xq13 | ATP-binding cassette sub-family B member 7, mitochondrial | ABCB7 @ LOVD | ABCB7 |
Table B. OMIM Entries for X-Linked Sideroblastic Anemia and Ataxia (View All in OMIM)
Normal allelic variants. The ABCB7 gene comprises 16 exons [Shimada et al 1998, Bekri et al 2000].
Pathologic allelic variants. See Table 3. Mutations have been identified in several families: p.Ile400Met [Allikmets et al 1999], p.Lys433Glu [Bekri et al 2000], p.Val411Leu [Maguire et al 2001].
Table 3. Selected ABCB7 Pathologic Allelic Variants
| DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequence |
|---|---|---|
| c.1200T>G | p.Ile400Met | NM_004299 NP_004290 |
| c.1231G>T | p.Val411Leu | |
| c.1297G>A | p.Lys433Glu |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (http://www
.hgvs.org).
Normal gene product. The ATP-binding cassette, subfamily B, member 7 protein 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.
Frataxin, the protein product of the gene that is altered in Friedreich ataxia (FRDA), is also involved in the mitochondrial biosynthesis of Fe-S clusters.
Abnormal gene product. Complementation studies in yeast suggest that the human mutant ATP-binding cassette, subfamily B, member 7 proteins are 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 of ABCB7 and formally demonstrated that XLSA/A is caused by partial loss of function mutations in Abcb7 that directly or indirectly inhibit heme biosynthesis [Pondarré et al 2007].
Resources
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
References
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page. 
Literature Cited
- 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]
- 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]
- 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.
- 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]
- Fleming MD. The genetics of inherited sideroblastic anemias. Semin Hematol. 2002;39:270–81. [PubMed: 12382202]
- 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]
- 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]
- Napier I, Ponka P, Richardson DR. Iron trafficking in the mitochondrion: novel pathways revealed by disease. Blood. 2005;105:1867–74. [PubMed: 15528311]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
Published Statements and Policies Regarding Genetic Testing
No specific guidelines regarding genetic testing for this disorder have been developed.
Suggested Reading
- Camaschella C. Recent advances in the understanding of inherited sideroblastic anaemia. Br J Haematol. 2008;143:27–38. [PubMed: 18637800]
- Rouault TA, Tong WH. Iron-sulfur cluster biogenesis and human disease. Trends Genet. 2008;24:398–407. [PMC free article: PMC2574672] [PubMed: 18606475]
Chapter Notes
Revision History
GeneReviews™ [Internet].
Pagon RA, Bird TD, Dolan CR, et al., editors.
Seattle (WA): University of Washington, Seattle; 1993-.
-
Mucopolysaccharidosis Type II
[GeneReviews™. 1993]
Mucopolysaccharidosis Type IIScarpa M. GeneReviews™. 1993
-
Phosphorylase Kinase Deficiency
[GeneReviews™. 1993]
Phosphorylase Kinase DeficiencyGoldstein J, Austin S, Kishnani P, Bali D. GeneReviews™. 1993
-
Fanconi Anemia
[GeneReviews™. 1993]
Fanconi AnemiaAlter BP, Kupfer G. GeneReviews™. 1993
-
Dystrophinopathies
[GeneReviews™. 1993]
DystrophinopathiesDarras BT, Miller DT, Urion DK. GeneReviews™. 1993
-
Ocular Albinism, X-Linked
[GeneReviews™. 1993]
Ocular Albinism, X-LinkedLewis RA. GeneReviews™. 1993
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Shprintzen-Goldberg Syndrome - GeneReviews™
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Simpson-Golabi-Behmel Syndrome Type 1 - GeneReviews™
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Sialuria - GeneReviews™
Sialuria - GeneReviews™Bookshelf
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X-Linked Spondyloepiphyseal Dysplasia Tarda - GeneReviews™
X-Linked Spondyloepiphyseal Dysplasia Tarda - GeneReviews™Bookshelf
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