Alternative titles; symbols
SNOMEDCT: 719816006; ORPHA: 2802; DO: 0050554;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq13.3 | Anemia, sideroblastic, with ataxia | 301310 | X-linked | 3 | ABCB7 | 300135 |
A number sign (#) is used with this entry because of evidence that X-linked spinocerebellar ataxia-6 with or without sideroblastic anemia (SCAX6) is caused by hemizygous mutation in the ABCB7 gene (300135) on chromosome Xq13.
X-linked spinocerebellar ataxia-6 with or without sideroblastic anemia (SCAX6) is an X-linked recessive disorder characterized by delayed motor development apparent in infancy with delayed walking (often by several years) due to ataxia and poor coordination. Additional features may include dysmetria, dysarthria, spasticity of the lower limbs, hyperreflexia, dysdiadochokinesis, strabismus, and nystagmus. The disorder is slowly progressive, and patients often lose ambulation. Brain imaging usually shows cerebellar atrophy. Most affected individuals have mild hypochromic, microcytic sideroblastic anemia, which may be asymptomatic. Laboratory studies show increased free erythrocyte protoporphyrin (FEP) and ringed sideroblasts on bone marrow biopsy. Female carriers do not have neurologic abnormalities, but may have subtle findings on peripheral blood smear (Pagon et al., 1985; D'Hooghe et al., 2012).
For a discussion of genetic heterogeneity of X-linked spinocerebellar ataxia (SCAX), see SCAX1 (302500).
Pagon et al. (1985) reported 4 males from a single family (family 1) and an unrelated male (family 2) with early-onset spinocerebellar ataxia and sideroblastic anemia. Affected males had a moderate hypochromic microcytic anemia with ring sideroblasts on bone marrow examination as in typical X-linked sideroblastic anemia (300751) but had raised, rather than normal or low, free erythrocyte protoporphyrin (FEP) levels and no excessive parenchymal iron storage in adulthood. The ataxia and incoordination were evident by age 1 year, were nonprogressive, and were accompanied by long motor tract signs (hyperactive deep tendon reflexes, positive Babinski sign, clonus) in the younger affected males. Some of the obligate heterozygotes had ring sideroblasts on bone marrow examination, dimorphic peripheral blood smear, and raised free red cell protoporphyrin. The ataxia did not conform to any reported X-linked form (302500, 302600); thus, the possibility was raised of a 'new' disorder as the pleiotropic effects of a single mutant gene.
Bekri et al. (2000) described a family in which affected males had sideroblastic anemia with ataxia. In the older brother, congenital ataxia had been diagnosed at the age of 4. The ataxia was nonprogressive, and computed tomography of the brain at age 18 showed striking, selective cerebellar hypoplasia. The mother's blood film showed dimorphism, consistent with an X-linked defect. The anemia was refractory to treatment with pyridoxine.
Hellier et al. (2001) reported a large family in which 2 brothers and their 2 maternal uncles had early-onset cerebellar ataxia associated with mild sideroblastic anemia. The patients, who ranged from 50 to 78 years of age, had motor delay with delayed walking (at 3 to 11 years of age), ataxic and unsteady gait, dysarthria, hypometric saccades, nystagmus, and dysdiadochokinesia. Some lost ambulation. Brain imaging in 2 patients showed cerebellar atrophy. Hematologic examination in 3 patients as adults showed mild anemia, increased FEP, and Pappenheimer bodies; ringed sideroblasts on bone marrow biopsy were observed in 1 patient. The obligate female carrier had no neurologic symptoms or anemia, but peripheral blood smear showed Pappenheimer bodies.
D'Hooghe et al. (2012) reported a 5-year-old boy who had early normal developmental milestones, but lost the ability to stand around 2 years of age. He had coordination abnormalities of the upper and lower limbs, dysarthria, poor balance, and strabismus. Brain imaging at age 2 years was normal. Hematologic studies showed hypochromic microcytic anemia with anisocytosis and Pappenheimer bodies; bone marrow showed 5 to 10% ringed sideroblasts. Total erythrocyte protoporphyrin (TEP) was elevated. His mother had no signs or symptoms of a neurologic or hematologic disease, but peripheral blood smear showed anisocytosis and Pappenheimer bodies; TEP was increased.
Xiong et al. (2021) reported a 5-year-old Chinese boy who presented at 4 years of age with recurrent seizures and growth retardation. He showed nystagmus soon after birth and had impaired motor development with poor coordination and ataxia. He also was noted to have mild normochromic anemia without clinical symptoms. At age 5, he had severe global developmental delay with autistic features, poor overall growth, cryptorchidism, and ataxic wide-based gait. Brain imaging showed a lacunar infarct in the left basal ganglia, but the cerebellum was normal. His mother and maternal aunt had mild anemia that was not treated.
Clinical Variability
Illarioshkin et al. (1996) reported a large 5-generation kindred with 7 males from 3 generations affected with X-linked recessive nonprogressive congenital ataxia. Blood smear examination in 3 affected individuals revealed no evidence of sideroblastic anemia. The kindred originated from the Russian province of Buryatia and were ethnic Buryats, a historically nomadic people who represent a branch of the Mongolian people. Linkage analysis assigned a locus for the disorder to a large genetic interval (54 cM) on Xp11.21-q24.
The transmission pattern of SCAX6 in the family reported by Pagon et al. (1985) and Allikmets et al. (1999) was consistent with X-linked recessive inheritance. Carrier females may have mild hematologic abnormalities on blood smear, but they do not show neurologic deficits.
Raskind et al. (1991) showed linkage of the disorder to PGK1 (311800) with a lod score of at least 2.60 at a recombination fraction of 0. ALAS2 (301300) and ERYF1 (305371) showed no detectable alteration of restriction patterns in DNA from affected males. Raskind et al. (1991) expressed the opinion that clinically and genetically this disorder is distinct from that in previously reported families with X-linked hereditary ataxia or spastic paraparesis. Cox et al. (1992) found close linkage with no recombination between ALAS2 and DXS14, whereas Raskind et al. (1991) reported negative lod scores which excluded linkage within 5 to 10 cM of DXS14 with the sideroblastic anemia/ataxia syndrome.
In affected males from a family with SCAX6 originally reported by Pagon et al. (1985), Allikmets et al. (1999) identified a hemizygous missense mutation in the ABCB7 gene (I400M; 300135.0001). The mutation, which occurred in a predicted transmembrane segment of the protein, was found to segregate with the disease in the family. Introduction of the corresponding mutation into the orthologous Saccharomyces cerevisiae gene resulted in a partial loss of function of the yeast ATM1 protein. In addition, the human wildtype ABCB7 protein was able to complement ATM1 deletion in yeast. The ABCB7 gene encodes an ATP-binding cassette (ABC) transporter that localizes to the mitochondrial inner membrane and is involved in iron homeostasis. The data indicated that ABCB7 is the causal gene of SCAX6 and that SCAX6 is a mitochondrial disease caused by mutation in the nuclear genome.
Bekri et al. (2000) identified a second missense mutation in the ABCB7 gene (E433K; 300135.0002) as the cause of SCAX6 in a family.
In 2 brothers with SCAX6, originally reported by Hellier et al. (2001), Maguire et al. (2001) identified a hemizygous missense mutation in the ABCB7 gene (V411L; 300135.0003). The mother was heterozygous for the mutation, and a maternal uncle with ataxia was hemizygous for the mutation. Functional studies of the variant were not performed.
In a 5-year-old boy with SCAX6, D'Hooghe et al. (2012) identified a hemizygous missense mutation in the ABCB7 gene (E209D; 300135.0004). Functional studies of the variant and studies of patient cells were not performed.
In a 5-year-old Chinese boy with SCAX6, Xiong et al. (2021) identified a hemizygous missense mutation in the ABCB7 gene (D675G; 300135.0005). The mutation, which was found by whole-exome sequencing, was inherited from the mother, who had only subtle anemia. The variant was not present in the gnomAD database. Functional studies of the variant were not performed.
In affected members of the Buryat family with ataxia without sideroblastic anemia (Illarioshkin et al., 1996), Protasova et al. (2016) identified a hemizygous missense mutation (G682S) in exon 16 of the ABCB7 gene, as well as a 41.4-kb deletion encompassing exon 2 of the ATP7A gene (300011) and including complete deletion of the PGAM4 retrogene (300567) located in an intronic region of the ATP7A gene. No clinical signs of a copper-related disorder were seen in individuals with these mutations.
Allikmets, R., Raskind, W. H., Hutchinson, A., Schueck, N. D., Dean, M., Koeller, D. M. Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A). Hum. Molec. Genet. 8: 743-749, 1999. [PubMed: 10196363] [Full Text: https://doi.org/10.1093/hmg/8.5.743]
Bekri, S., Kispal, G., Lange, H., Fitzsimons, E., Tolmie, J., Lill, R., Bishop, D. F. Human ABC7 transporter: gene structure and mutation causing X-linked sideroblastic anemia with ataxia with disruption of cytosolic iron-sulfur protein maturation. Blood 96: 3256-3264, 2000. [PubMed: 11050011]
Cox, T. C., Kozman, H. M., Raskind, W. H., May, B. K., Mulley, J. C. Identification of a highly polymorphic marker within intron 7 of the ALAS2 gene and suggestion of at least two loci for X-linked sideroblastic anemia. Hum. Molec. Genet. 1: 639-641, 1992. [PubMed: 1301172] [Full Text: https://doi.org/10.1093/hmg/1.8.639]
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. Europ. J. Paediat. Neurol. 16: 730-735, 2012. [PubMed: 22398176] [Full Text: https://doi.org/10.1016/j.ejpn.2012.02.003]
Hellier, K. D., Hatchwell, E., Duncombe, A. S., Kew, J., Hammans, S. R. X-linked sideroblastic anaemia with ataxia: another mitochondrial disease? J. Neurol. Neurosurg. Psychiat. 70: 65-69, 2001. [PubMed: 11118249] [Full Text: https://doi.org/10.1136/jnnp.70.1.65]
Illarioshkin, S. N., Tanaka, H., Markova, E. D., Nikolskaya, N. N., Ivanova-Smolenskaya, I. A., Tsuji, S. X-linked nonprogressive congenital cerebellar hypoplasia: clinical description and mapping to chromosome Xq. Ann. Neurol. 40: 75-83, 1996. [PubMed: 8687195] [Full Text: https://doi.org/10.1002/ana.410400113]
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. Brit. J. Haemat. 115: 910-917, 2001. [PubMed: 11843825] [Full Text: https://doi.org/10.1046/j.1365-2141.2001.03015.x]
Pagon, R. A., Bird, T. D., Detter, J. C., Pierce, I. Hereditary sideroblastic anaemia and ataxia: an X linked recessive disorder. J. Med. Genet. 22: 267-273, 1985. [PubMed: 4045952] [Full Text: https://doi.org/10.1136/jmg.22.4.267]
Protasova, M. S., Grigorenko, A. P., Tyazhelova, T. V., Andreeva, T. V., Reshetov, D. A., Gusev, F. E., Laptenko, A. E., Kuznetsova, I. L., Goltsov, A. Y., Klyushnikov, S. A., Illarioshkin, S. N., Rogaev, E. I. Whole-genome sequencing identifies a novel ABCB7 gene mutation for X-linked congenital cerebellar ataxia in a large family of Mongolian ancestry. Europ. J. Hum. Genet. 24: 550-555, 2016. [PubMed: 26242992] [Full Text: https://doi.org/10.1038/ejhg.2015.139]
Raskind, W. H., Wijsman, E., Pagon, R. A., Cox, T. C., Bawden, M. J., May, B. K., Bird, T. D. X-linked sideroblastic anemia and ataxia: linkage to phosphoglycerate kinase at Xq13. Am. J. Hum. Genet. 48: 335-341, 1991. [PubMed: 1671320]
Xiong, S., Jia, Y., Li, S., Huang, P., Xiong, J., Mao, D., He, Q., Liu, L. The first case report of X-linked sideroblastic anemia with ataxia of Chinese origin and literature review. Front. Pediat. 9: 692459, 2021. [PubMed: 34354969] [Full Text: https://doi.org/10.3389/fped.2021.692459]