Biology of Disease

and generally failure to thrive. Hernias, hepatomegaly, joint limitation and hip
dislocations are common. Patients experience frequent upper respiratory tract
infections with recurrent attacks of pneumonia, bronchitis and otitis media
(Chapter 3). Cardiac murmurs from pathologies of heart valves are common
and survival beyond the age of five years is unusual.

Diagnosis and Treatment of Lysosomal Storage Disorders

Experienced laboratory practitioners using relatively simple methods can
accurately diagnose patients exhibiting the typical traits of LSDs. However,
atypical patients usually require more detailed investigations. An early
diagnosis is important to prevent serious damage to the nervous and skeletal
systems. Almost all lysosomal storage diseases can be diagnosed using samples
of leukocytes or plasma. Diagnosis is based upon assays that determine the
reduced activities of lysosomal enzymes or an increase in substrate in skin
fibroblasts, plasma or urine. For example, Gaucher’s and I-cell diseases can
be confirmed by demonstrating deficiencies in B-glucocerebrosidase and
N-acetylglucosylaminyl-1-phosphotransferase activities in leukocytes or
fibroblasts respectively.

The prognosis for adult Gaucher’s disease patients is relatively good. The
hypersplenism is usually relieved by splenectomy although this may has-
ten bone deterioration. Symptomatic treatment includes analgesics for the
bone pains, blood transfusions to relieve the anemia and orthopedic relief
for fractures and degeneration of the hip joints. Enzyme replacement therapy,
involving intravenous administration of purified A-glucocerebrosidase, is now
common. Receptors on the surfaces of macrophages selectively bind man-
nose residues on the enzyme and allow it to be absorbed by the cells. Within
the macrophages, the enzyme is delivered to the lysosomes where it cata-
lyzes the breakdown of the accumulated glucosylceramide. In the majority of
cases this is an effective and safe treatment, reducing the sizes of the liver and
spleen and allowing them and the bone marrow to function effectively. Again,
bone marrow transplants (Chapter 6) may be useful. Gene therapy, in which
a functional gene for A-glucocerebrosidase is inserted into stem cells in the
bone marrow, may in the future provide a complete cure.

Treatment for I-cell disease is limited. Bone marrow transplants can potentially
replace the defective hemopoietic system with stem cells from a healthy donor,
providing a replacement for the defective enzymes. In a limited number of
cases, bone marrow transplants have normalized lysosomal enzyme activities,
but the preexisting clinical damage from the disease is usually so extensive by
this stage that this option is of questionable long-term benefit. In addition,
bone marrow transplants can fail and the problems of finding compatible
donors are immense.

Genetic counseling and prenatal diagnosis (Chapter 15) have roles in relation
to LSDs. In cases where the likelihood of a lysosomal storage disease being
present in a fetus is high, prenatal diagnosis is possible and a therapeutic
abortion can be offered. Methods for screening all newborns without a family
history of such conditions have been proposed but such screening programs
would require a large amount of effort for comparatively little gain.

16.7 Cytoskeletal Disorders

The cytoplasm of nucleated cells is supported by a cytoskeleton consisting
of three types of fibers and a number of associated proteins. The functions
of the fibers are to resist forces that would deform the cell, to allow the cell
to change shape and move and some types of intracellular transport. The
three types of fibers are microfilaments (MF), intermediate filaments (IF)

CYTOSKELETAL DISORDERS

CZhhVg6]bZY!BVjgZZc9Vlhdc!8]g^hHb^i]:YLddY )+*

Inclusion

Figure 16.15 Schematic of an I cell based on

several light and electron micrographs. Note the

numerous vesicles (inclusion bodies) containing

undigested material that has accumulated

because of deficiencies in lysosomal enzyme

activities.