that attend the disorder of a structural protein. The
impairment in glycosylphosphatidylinositol (GPI)
anchoring that occurs in paroxysmal nocturnal
hemoglobinuria, for example, leads to a partial
deficiency of the membrane-bound proteins that
modulate membrane lysis by complement. Conse-
quently, the red cells have a heightened sensitivity to
complement that can be demonstrated very reliably
by a laboratory study of complement-mediated
hemolysis, the Ham test.
The specialized proteins of blood cell function
include red cell hemoglobin, the membrane adhesion
proteins and granule proteins of phagocytes and
platelets, and the immunoglobulins of lymphocytes.
The genetic disorders of hemoglobin consist of
the hemoglobinopathies and the thalassemias. The
hemoglobinopathies are disorders with variant hemo-
globin products. They are diagnosed by protein
phenotyping using hemoglobin electrophoresis. The
thalassemias are disorders with reduced synthesis of
β
hemoglobin chains (
β
-thalassemia) or
α
hemoglo-
bin chains (
α
-thalassemias). Their diagnosis
depends, in part, upon the demonstration of a
reduced production of hemoglobin chain products.
In
β
-thalassemia there is a decrease in the intracellu-
lar concentration of hemoglobin A (
α
2
β
2
) but a
normal concentration of hemoglobin A
2
(
α
2
δ
2
) and
hemoglobin F (
α
2
γ
2
). This is shown by semiquantita-
tive hemoglobin electrophoresis. In
α
-thalassemia
the intracellular concentrations of hemoglobin A, F,
and A
2
are all decreased. This alone is not diagnos-
tic of
α
-thalassemia, however, as a number of
acquired disorders, most notably iron deficiency,
share this finding. The presence of hemoglobin H
(
β
4
), which forms in red cells deficient in
α
hemoglobin chains, is highly suggestive of
α
-thal-
assemia. It is demonstrated by supravital staining.
Deficiencies of blood cell membrane adhesion
proteins are evaluated by i
n vitro
adhesion studies.
The assessment of granule protein deficiencies is
guided by the function of the protein believed to be
deficient. Disorders of granule proteins that mediate
adhesion processes are evaluated using i
n vitro
adhesion studies; disorders of granule enzymes are
evaluated using i
n vitro
assays of enzyme activity.
Deficiencies of immunoglobulins are assessed
semiquantitatively by protein electrophoresis and
quantitatively by mass assay using immunologic
methods.
SCREENING FOR GENETIC DISEASE
Screening studies are performed to detect
serious, treatable disorders before they are clinically
manifest. Early detection allows for the early insti-
tution of therapy, thereby minimizing any serious or
irreversible consequences that may arise during the
preclinical stage of the disorder.
Typically, screening studies for genetic disease
are designed as dichotomous diagnostic tests. They
have a critical value which separates screen-positive
results from screen-negative results. Individuals
who are found to be screen-positive undergo further
diagnostic evaluation. To be useful for screening, a
laboratory study must have a diagnostic performance
that satisfies two criteria. First, the screen-positive
study values must have likelihood ratios that exceed
the threshold likelihood ratio for followup,
Genetic Disease
10-10
Figure 10.5
Schematic depiction of the isoelectric focusing band patterns for the major variants of
α
1
-antitrypsin. Each
allelic product has two major and three minor forms that differ in their isoelectric points. The different forms arise from
heterogeneity in the post-translational processing of the protein.
Only the major form bands are shown.
4.4
4.5
4.6
4.7
MM SS
ZZ
pH
MS
MZ
SZ
Genotype
Phenotype
