Biology of Disease

care. However, associated stress means that a support group where members

pool common experiences and problems can be of use. Genetic counseling

is advisable, especially if there is a family history of the disorders. Note that

sons of a man with BMD (or DMD) will not develop the disease but daughters

can be carriers. An amniocentesis and appropriate genetic studies means that

DMD is detectable with an approximately 95% accuracy during pregnancy.

Hereditary Elliptocytosis and Spherocytosis

Two relatively common disorders associated with the erythrocyte cytoskeleton

are hereditary elliptocytosis (HE) and spherocytosis (HS). Their incidences

are variable. For example, in the USA, HS is the commonest of the hereditary

hemolytic anemias (Chapter 13) among people of Northern European descent,

with an incidence of approximately one in 5000, although many regard this

as an underestimation. The prevalence of HE is thought to be one in 2000 to

4000. Like sickle cell anemia, which was described in Chapter 13, the condi-
      tion shows a much higher incidence in areas endemic for malaria, in equato-
      rial Africa, for instance the incidence is approximately six per 1000.

Patients with HE or HS synthesize lower amounts of cytoskeletal proteins

than normal, or the proteins themselves are defective. Most cases of heredi-

tary spherocytosis are caused by mutations in the ANK1,SPTB,SLC4A1,

EPB42 and SPTA1 genes that encode ankyrin, spectrin P-chain, band 3, pro-

tein 4.2 and @-spectrin respectively (Figure 16.17). The mutations responsi-

ble for hereditary elliptocytosis occur in the SPTB and SPTA1 and the EPB41

gene encoding protein 4.1. These mutations mean that the erythrocytes are

misshapen (Figure 16.18) and less deformable and so become trapped in

the spleen where they are prematurely degraded. The consequent excessive

release of bilirubin leads to jaundice and gallstones (Chapter 11). The anemia

caused by reduced numbers of circulating erythrocytes results in the release

of immature erythrocytes from the bone marrow.

Diagnosis and treatment of hereditary elliptocytosis and spherocytosis

The simplest way to test for HE and HS is the microscopic examination of

peripheral blood smears to observe the misshapen erythrocytes (Figure

16.18). Other tests include demonstration of the increased resistance of the

erythrocytes to osmotic shock using the osmotic fragility test, observation

of reduced fluorescence following staining with eosin-5-maliemide and

determination of the amounts of cytoskeletal proteins present following their

separation by electrophoresis.

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Figure 16.18 Light micrographs of misshapen

erythrocytes in (A) hereditary spherocytosis and

(B) elliptocytosis. In (A) the abnormal spherocytes

(examples highlighted) lack the usual biconcave

shape (N) and appear a uniform dark color.

Note the presence in (B) of abnormal elliptical

erythrocytes (example highlighted). Courtesy of A.

Will, Royal Manchester Children’s Hospital, UK.

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