Spherocytosis, Type 3

A number sign (#) is used with this entry because hereditary spherocytosis-3 is caused by mutation in the alpha-spectrin gene (SPTA; 182860) on chromosome 1q21.

For a general description and a discussion of heterogeneity of spherocytosis, see 182900.

Clinical Features

Agre et al. (1982) reported 2 daughters, of related but normal parents, who had nearly fatal hemolytic anemia requiring early splenectomy. Both improved strikingly thereafter but spherocytosis persisted. Red cell membranes were at least 50% deficient in spectrin, with band 1 reduced more than band 2. No defect was found in membrane binding of spectrin or in membrane binding sites (ankyrin). The parents were fourth cousins. Parentage was confirmed by HLA typing. Extensive hematologic studies showed no abnormality in the parents and other close relatives. Agre et al. (1986) found that distally related homozygotes showed different clinical severities and different spectrin levels as determined by radioimmunoassay.

Agre et al. (1985) demonstrated deficiency of red cell spectrin in cases of several different types of spherocytosis. A number of observations indicated that deficiency of spectrin is a primary factor in the pathogenesis of spherocytosis. Studies in both mice and men indicated that a variety of mutations affecting spectrin synthesis or stability can underlie spherocytosis.

Agre et al. (1986) found that spectrin levels in all patients with spherocytosis were inversely related to osmotic fragility and were also correlated with the clinical response to splenectomy.

Inheritance

In the patients with spherocytosis reported by Agre et al. (1982), inheritance was autosomal recessive.

Molecular Genetics

In the kindred with autosomal recessive spherocytosis reported by Agre et al. (1986), Marchesi et al. (1989, 1989) identified a missense mutation in the alpha-II domain of the SPTA gene (182860.0005).

In a patient with severe spherocytic hemolytic anemia, Wichterle et al. (1996) identified compound heterozygosity for 2 mutations in the SPTA gene (182860.0022; 182860.0023).

Animal Model

A morphologically comparable disorder in the deer mouse Peromyscus is inherited as a recessive (Anderson et al., 1960). The defect in autosomal recessive spherocytosis of the laboratory mouse is a deficiency of spectrin (Greenquist et al., 1978; Shohet, 1979). The homozygous mice have less than 50% of the normal amount of spectrin and heterozygotes have normal levels of spectrin. That the defect resides in alpha-spectrin is indicated by the close linkage of the spherocytosis and alpha-spectrin genes on chromosome 1 (Birkenmeier et al., 1988).