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

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Chapter | 15 Skeletal Muscle Function
at 2 months of age, and the disorder is progressive with
death by 10 to 15 months.
3 . Branching Enzyme Defi ciency (GSD IV)
Glycogen storage associated with branching enzyme deficiency
has been reported in a family of Norwegian forest
cats ( Fyfe, 1995 ; Fyfe et al. , 1992 ) and in quarter horses
(Render et al. , 1999 ; Valberg et al. , 2001 ). Clinical signs and
involved organs include skeletal muscle, heart, and the central
nervous system. Abnormal glycogen is evident in tissues
at birth and abortion or stillbirths are common. GSD-IV is an
autosomal recessive disorder in both species. Eight percent
of quarter horses are carriers of the mutation, and at least 3%
of abortions can be attributed to the disease (Wagner et al. ,
2006). Diagnosis in foals is made by identifying characteristic
amylase-resistant PAS-positive globular inclusions in tissues
and, in horses, was confirmed by DNA testing for the
point mutation in exon 1 ( Ward et al. , 2004 ).
4 . Myophosphorylase Defi ciency (GSD V)
Myophosphorylase deficiency (McArdle’s disease) is an
inherited, autosomal recessive, glycogenosis in humans
( DiMauro et al. , 1995 ; Tsujino et al. , 2000 ), Charolais cattle
( Angelos et al. , 1995 ), and sheep ( Tan et al. , 1997 ). In
cattle, clinical signs include recumbency and fatigue with
forced exercise and elevated serum CK and AST activity.
Muscle glycogen concentrations are elevated 1.6 times
higher than controls, and histopathological changes are
modest with some vacuolated myofibers that do not appear
to contain glycogen. A rapid diagnosis is possible by
genetic testing for the autosomal recessive point mutation
in the myophosphorylase gene ( Bilstrom et al. , 1998 ).
5 . Phosphofructokinase Defi ciency (GSD VII)
Phosphofructokinase (PFK) is a key enzyme of the
Embden-Meyerhof pathway in all tissues, and inherited
deficiencies of this enzyme in humans are expressed primarily
as a myopathy in which it is designated as type
VII glycogen storage disease (GSD-VII). There is a partial
expression of hemolysis, and the deficiency is otherwise
quite heterogeneous ( Giger et al. , 1988a ; Harvey and
Reddy, 1989 ). Deficiency of PFK was reported in springer
spaniel dogs that presented a clinical picture remarkably
similar to that seen in humans. The dogs presented with
a history of intermittent severe hemolytic episodes, and
total erythrocyte PFK activity was 10% of normal controls
( Giger et al. , 1985 ). The disorder is inherited as an autosomal
recessive trait ( Giger et al. , 1986 ).
Mammalian PFK is present in different tissues as tetramers
of three subunits: PFK-M (muscle), PFK-L (liver),
and PFK-P (platelets). Human muscle and liver contain
homogeneous tetrameric PFK-M4 and PFK-L4, respectively.
The erythrocytes contain an admixture of PFK-M
and PFK-L tetramers. In normal dogs, a similar isoenzymic
distribution pattern exists except in the erythrocytes where
the PFK tetramers consist of an admixture of PFK-M and
PFK-P subunits. As in humans, PFK deficiency was found
to be a deficiency of the PFK-M subunits, and the erythrocytic
hybrids consisted of the PFK-L and PFK-P subunits.
Giger et al. (1985) speculated that exertional stresses
inducing hyperventilation and respiratory alkalosis in turn
directly or indirectly enhance the alkaline fragility of their
erythrocytes and subsequent hemolysis.
Early reports suggested that affected dogs did not
manifest severe muscle-related signs, which were possibly
masked by signs referable to hemolysis. However, biochemical
studies have revealed reduced glycolysis in muscle
(Giger et al. , 1988a, 1988b ), and pathological studies have
established the presence of a myopathy that included the
presence of PAS-positive polysaccharide storage vacuoles
in up to 10% of the myofibers ( Harvey et al. , 1990 ). Lack
of M-PFK enzyme activity is caused by a nonsense mutation
in the penultimate exon of the M-PFK gene, leading to
rapid degradation of a truncated (40 amino acids) and therefore
unstable M-PFK protein. A genetic test can identify
M-PFK-deficient and carrier animals ( Smith et al. , 1996 ).
6 . Polysaccharide Storage Myopathy
An inherited polysaccharide storage myopathy (PSSM) has
been described in quarter horses, quarter horse crossbreeds,
American paints, and Appaloosa horses ( Valberg et al. , 1992 ).
The horses have chronic episodes of exertional rhabdomyolysis
and myoglobinuria. In addition, draft horse breeds and
their derivatives also have polysaccharide storage myopathy
(Firshman et al. , 2005 ). Up to 30% of the type 2 muscle fibers
have subsarcolemmal vacuoles as well as cytoplasmic vacuoles
that contained acid mucopolysaccharide inclusions that
are brilliantly stained with the periodic-acid Schiff’s (PAS)
stain and resistant to amylase digestion. These inclusions
consisted of β -g1ycogen particles and filamentous material.
Glycogen concentrations are approximately 1.5 times higher
in the muscles of horses with these polysaccharide inclusions
( Annandale et al. , 2004 ). Glycogen accumulation in
PSSM quarter horses appears to have a novel basis related to
enhanced insulin sensitivity, muscle glucose uptake, and glycogen
synthesis ( Annandale et al. , 2004 ; De La Corte et al. ,
1999 ). An arginine to histidine mutation in the gene encoding
glycogen synthase (GYS1) was recently identified (McCue
et al. , 2008). The connection between increased synthesis of
glycogen and rhabdomyolysis has yet to be fully explained
but appears to be related to decreased energy generation in
individual muscle fibers ( Annandale et al. , 2005 ). A genetic
test can identify this disease.
E . Mitochondrial Myopathies
A large number of complex mitochondrial myopathies have
been described in humans ( DiMauro and Bonilla, 2004 ),