Anemia, Sideroblastic, And Spinocerebellar Ataxia

A number sign (#) is used with this entry because of evidence that sideroblastic anemia with spinocerebellar ataxia (ASAT) is caused by mutation in the ABCB7 gene (300135) on chromosome Xq13.

Clinical Features

Pagon et al. (1985) reported 2 apparently unrelated families with this combination and concluded that they could not distinguish between close linkage (e.g., small deletion) and pleiotropic effects of a mutant allele at a single locus. 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 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 of a 'new' disorder as the pleiotropic effects of a single mutant gene.

Mapping

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.

Molecular Genetics

In a family with 5 affected males with ASAT, Allikmets et al. (1999) identified a missense mutation (I400M; 300135.0001) in the ABCB7 gene. The gene in question, an ATP-binding cassette (ABC) transporter, encodes a protein that localizes to the mitochondrial inner membrane and is involved in iron homeostasis. Thus, ASAT is a mitochondrial disease caused by a mutation in the nuclear genome.

In affected members of a family with ASAT, Bekri et al. (2000) identified a missense mutation (E433K; 300135.0002) in the ABCB7 gene.