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

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Chapter | 24 Lysosomal Storage Diseases
( Crawley et al. , 1998 ). Affected individuals can be either
homozygous for the same mutation in both alleles (typical
of most LSDs in animals) or heteroallelic (having
one mutation in the allele on one chromosome and a different
mutation in the allele on the other chromosome
[ Crawley et al. , 1998] , common in humans with LSDs).
In addition, if the substrates being stored in different diseases
have similar pathological effects, defects in different
lysosomal enzymes may produce similar diseases, as has
been described in humans and animals with MPS III A-D
( Aronovich et al. , 2001 ; Bhaumik et al. , 1999 ; Ellinwood
et al. , 2003 ; Fischer et al. , 1998 ; Jones et al. , 1998 ;
Neufeld and Meunzer, 2001 ; Yogalingam et al. , 2002 ).
Furthermore, it is now recognized that the expression of
lysosomal genes, similar to other inborn errors of metabolism,
is also influenced by other (modifying) genes and
the environment, which explains the phenotypic variation
in animals homozygous for the same mutation. Finally,
the clinical features and disease course of animals with all
types of LSDs closely resemble their human counterparts.
Animals of several species were diagnosed clinically
and pathologically as having an LSD before recognizing
that the group of diseases were caused by deficiencies in
hydrolase activity. Because of the distinctive central and
peripheral nervous system lesions, the first of these diseases
to be described was globoid cell leukodystrophy in
Cairn and West highland white terriers ( Fankhauser et al. ,
1963 ) . These two related dog breeds (primarily a color
variation) are now known to have the same mutation in
the gene coding for galactosylceramidase ( Victoria et al. ,
1996 ), which apparently originated in the 19th century
from an ancestor common to these two breeds that diverged
around the beginning of the 20th century. The first definitive
discovery of an enzyme deficiency in a nonhuman
mammal was GM1 gangliosidosis in a Siamese cat by
Baker and colleagues in 1971 ( Baker et al. , 1971 ). Since
then, naturally occurring LSDs defined by a deficiency in
lysosomal enzyme activity have been recognized in cats,
cattle, dogs, goats, mice, pigs, rats, horses, sheep, and two
avian species, emus and flamingos ( Table 24-1 ).
Additional storage diseases do not involve lysosomal
enzymes and, thus, are not strictly LSDs, but some have
been included in Table 24-1 . These include glycogen
storage disease IV Niemann-Pick disease C, and ceroid
lipofuscinoses. Many mouse models of LSDs have been
created by gene knockout technology, but have not been
included in Table 24-1 . In creating murine knockouts,
the phenotype has ranged from essentially the same as
in humans, to no disease, to being fatal soon after birth.
New knockout models of LSDs will continue to be created
in mice to learn more about the pathogenesis of these
debilitating disorders and to evaluate therapy. However,
companion animals appear often to be better disease homologues
and are important to translating novel therapies to
humans.
III . PATHOGENESIS
In LSDs, the continued presentation of substrates to the
cell and their lack of degradation result in their storage
and swelling of the lysosomes. By electron microscopy,
lysosomes within the cytoplasm can be seen as membranebound
inclusions containing the stored substrate ( Fig. 24-4 ).
As the lysosomes become larger, they can be seen with
light microscopy ( Fig. 24-5 ). However, in some LSDs, the
accumulated substrate may be lost during tissue processing,
leaving empty vacuolar artifacts. The accumulation of
the primary substrate for a particular enzyme pathway may
also interfere with other lysosomal hydrolases necessary
for different catabolic pathways ( Kint et al. , 1973 ), thereby
leading to the secondary accumulation of additional substrates.
As more substrates accumulate, the lysosomes
occupy more of the cytoplasm ( Fig. 24-6 ). This increase in
the number and size of lysosomes may obscure the other
FIGURE 24-4 An electron micrograph of a polymorphonuclear leukocyte
from a cat with MPS VI showing the enlarged lysosomes containing
granular material (dermatan sulfate). Bar 1u.
FIGURE 24-5 A light micrograph of a polymorphonuclear leukocyte
from a dog with MPS VII showing the cytoplasmic granules, which
represent the lysosomes containing GAG, which stain metachromatically
with toluidine blue. Bar 10um.