Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 24 Lysosomal Storage Diseases
FIGURE 24-11 An electron micrograph of the lysosomes in a neuron
from a cat with MPS I showing the lamellar inclusions. These inclusions
are not typical of glycosaminoglycans but rather may represent glycolipids,
which accumulate secondary to the primary substrate storage.
Bar 0.5u.
( Fig. 24-11 ). The pathogenesis of the CNS lesions includes
the development of meganeurites and neurite sprouting,
which appear correlated to alterations in ganglioside
metabolism ( Purpura and Baker, 1977, 1978 ; Purpura et al. ,
1978 ; Siegel and Walkley, 1994 ; Walkley, 1988 ; Walkley
et al. , 1988, 1990, 1991 ). Gangliosides, whether stored as
a primary substrate (in G M1 and G M2 gangliosidosis) or
secondarily (in MPS I and III), appear to stimulate the
development of neurite sprouts with synapses. The presence
of new neurites and their synapses apparently plays
a role in the CNS dysfunction of these diseases ( Walkley,
2003 ).
Mucolipidosis II, also known as I-cell disease (named
for the inclusions seen in cultured fibroblasts ( Tondeur
et al. , 1971 ), is an exception to the usual pathogenesis of
LSDs (reviewed in Kornfeld and Sly [2001] ). Studies of
fibroblasts from patients with this disease were seminal in
providing insight into the M6P transport system ( Hickman
and Neufeld, 1972 ). This disorder results from a failure in
the first enzyme in the pathway responsible for the posttranslational
phosphorylation of the mannose moiety of
most lysosomal hydrolases ( Hasilik et al. , 1981 ; Reitman
et al. , 1981 ). The consequence of a defect in this phosphotransferase
enzyme is to produce lysosomal enzymes
that lack the signal responsible for efficiently directing
the enzymes to the lysosome by the M6P receptor-mediated
pathway. Thus, little amounts of the enzymes reach
the lysosomes, whereas large amounts are secreted extracellularly
into the plasma. Because the phosphotransferase
activity has been difficult to measure, the diagnosis of I-
cell disease has usually been reached by demonstrating the
low intracellular activity of most lysosomal enzymes and
consequent high enzyme activity in serum. The gene for
this phosphotransferase has been cloned for both humans
and cats, and mutations have been identified (Giger et al.,
2006; Kudo et al. , 2006 ). Although a clinical and pathological
phenotype that combines all of the lysosomal storage
diseases would be expected in I-cell disease, this does
not occur. Although I-cell is a severe disease in children
and cats, most of the pathology is found in mesenchymally
derived cells; Kupffer cells and hepatocytes are essentially
normal ( Martin et al. , 1975, 1984 ; Mazrier et al. , 2003 ).
Although mental retardation is present in children, and
death occurs before adulthood, there is relatively little
CNS pathology ( Martin et al. , 1984 ; Nagashima et al. ,
1977 ). All cell types examined to date have been deficient
in phosphotransferase activity, yet many organs (including
liver, spleen, kidney, and brain) still have near normal intracellular
lysosomal enzyme activities. This observation indicates
that there is either an intracellular M6P-independent
pathway to lysosomes, or that secreted enzymes are internalized
by cell surface receptors that recognize other
carbohydrates on enzymes, such as nonphosphorylated
mannose ( Waheed et al. , 1982 ). An M6P-independent
pathway to the lysosome has been demonstrated for betaglucocerebrosidase
and acid phosphatase ( Peters et al. ,
1990 ; Williams and Fukuda, 1990 ).
IV . CLINICAL SIGNS
As a group, LSDs are chronic, progressive disorders generally
with an early age of onset and characteristic clinical
signs. The predominant clinical signs are related to
the CNS, skeleton, joints, eye, cardiovascular system, and
organomegaly. Most LSDs can be divided clinically into
those with or without CNS involvement. Head and limb
tremors that progress to gait abnormalities, spastic quadriplegia,
seizures, and death are commonly observed.
The disorders in animals with marked CNS signs include
fucosidosis, galactosylceramide lipidosis, gangliosidosis,
mannosidosis, MPS III, and sphingomyelinosis.
Non-CNS clinical signs associated with lysosomal storage
disorders include failure to thrive, growth retardation
(Fig. 24-12 ), umbilical hernia, corneal clouding, hepatosplenomegaly,
cardiac murmurs, renal dysfunction, and skeletal
abnormalities including facial dysmorphia and vertebral,
rib, and long bone deformities ( Fig. 24-13 ). The MPS disorders,
in general, have more organ systems affected than the
other diseases. The age of onset and severity of clinical signs
are usually relatively consistent for a particular disease in
animals; however, some variability can exist even in a family
having the same disease-causing mutation. In research
colonies of dogs and cats with LSDs kept in a relatively consistent
environment, the explanation for variation in clinical
signs rests with the variable genetic background (modifying
genes) on which the mutation is expressed.
Most LSDs are manifest within a few months after birth,
with some evident at birth or before weaning and fewer
with adult onset (canine MPS IIIA and B). In severely