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

IX. Selected Neuromuscular Disorders of Domestic Animals
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include the following presentations: acute quadriplegia,
degrees of exercise-related weakness, gait abnormalities,
no apparent limb muscle weakness with dysphagia,
or regurgitation associated with a megaesophagus. There
appears to be a bimodal distribution in the onset of this disease
in dogs (early and late onset). Dogs are rarely affected
before 1 year of age and peak frequencies were found at
3 and 10 years of age; the prevalence did not appear to be
gender related ( Dewey et al. , 1997 ; Shelton et al. , 1988 ).
Frequently, overt signs may be limited to esophageal dysfunction.
In a study of 152 dogs afflicted with idiopathic
megaesophagus, 40 to 57 dogs (26% to 38%) had MG
( Shelton et al. , 1990 ).
A definitive diagnosis of MG is provided by detection
of circulating antibodies to the AChR. Additional diagnostic
tests that provide for a presumptive diagnosis include clinical,
pharmacological, electrodiagnostic, and immunocytochemical
methods of evaluation ( Dewey et al. , 1997 ; Shelton,
2002 ). When clinical signs permit the objective assessment
of strength, pharmacological testing can be employed
through the intravenous administration of 1 to 10 mg of edrophonium
chloride, an ultra-short-acting anticholinesterase
agent. Improved strength with edrophonium provides a presumptive
diagnosis of MG. A presumptive diagnosis of MG
is also suggested when the application of low-frequency (2 to
10 Hz), repetitive nerve stimulation results in the reduced
amplitude of the first few evoked compound MAPs (decrementing
response). Immunocytochemical procedures provide
presumptive tests for MG. In muscle biopsies of human and
canine MG patients that contain neuromuscular junctions, it
is possible to localize the IgG bound to the PSM using the
immunoreagent ( Engel and Hohfield, 2004 ; Pflugfelder et al. ,
1981 ). A more specific diagnosis can be established by measuring
acetylcholine receptor antibody titer in serum samples
from affected animals ( Dewey et al. , 1997 ; Shelton, 2002 ).
b . Congenital Myasthenia Gravis
Congenital MG is a developmental disorder of humans and
dogs ( Dickinson et al. , 2005 ; Engel et al. , 2004 ; Shelton,
2002 ). In the dog, the synthesis of AChRs appears to be
normal, and degradation does not appear to be accelerated.
The reduced AChR density is believed to be due to a low
insertion rate of AChRs into the PSM ( Engel et al. , 2004 ).
In humans, several congenital myasthenic syndromes are
recognized, which result from a number of inherited defects
that may be presynaptic (7% of cases), synaptic basal lamina-associated
(14%), or postsynaptic (79%) defects ( Engel
et al. , 2004 ). Because congenital MG is not immune mediated,
the immunodiagnostic tests used in acquired MG are
of no value in establishing the diagnosis of congenital MG.
2 . Sodium Ion Channels and Periodic Paralysis
Hyperkalemic periodic paralysis (HyPP) is a dominantly
inherited disorder of muscle in quarter horses, American
paint horses, Appaloosas, and quarter horse crossbred animals
that causes episodes of tremors, myotonia, weakness,
or paralysis in association with elevated serum potassium
( Naylor, 1997 ; Spier et al. , 1990 ). Weakness or paralysis
can be induced by the ingestion of potassium. HyPP
is caused by a single base pair sequence defect within the
gene encoding the voltage-dependent equine skeletal muscle
sodium channel α-subunit (Rudolph et al. , 1992 ). The point
mutation produces a Phe to Leu substitution in the transmembrane
domain IVS3. Patients are usually heterozygous
and express both normal and mutant α-subunits, although
homozygous HyPP horses have been identified. The primary
physiological defect in the mutant sodium channels is
impaired inactivation ( Cannon et al. , 1995 ). This results in
a resting membrane potential that is closer to firing than in
normal horses. Sodium channels are normally briefly activated
during the initial phase of the muscle action potential.
The HyPP mutation results in a failure of a subpopulation of
sodium channels to inactivate when serum potassium concentrations
are increased. As a result, an excessive inward
flux of sodium and outward flux of potassium ensues, resulting
in persistent depolarization of muscle cells and temporary
weakness. It appears likely that the clinical variability
and severity of signs are associated with the ratio of mutantto-normal
sodium ion channels expressed in the skeletal
muscles of heterozygous horses ( Zhou et al. , 1994 ). This disorder
in horses is similar to HyPP in humans in which there
are also a number of mutations involving the gene encoding
the sodium ion channel α-subunit (Lehmann-Horn et al. ,
2002 ). A definitive diagnosis is possible by base-pair analysis
of the DNA sequence responsible for encoding of the
α -subunit ( Rudolph et al. , 1992 ).
3 . Chloride Ion Channels and Myotonia
Myotonia is a clinical sign in which uncontrolled, prolonged,
and painless contraction of skeletal muscles occurs. The
condition is due to hyperexcitability of the sarcolemma and
the abnormal production of repetitive depolarizations of the
sarcolemma followed by delayed repolarization and relaxation.
Affected patients exhibit varying degrees of muscle
stiffness with the onset of exercise. The stiffness will often
subside with continued exercise or repeated movements and
is not aggravated by cold. Muscles may be grossly hypertrophied
with well-defined muscle groups. Percussion of muscles
results in local contractions that create dimpling of the
surface overlying the contracting muscles.
Two principal myotonic disorders occur in humans: (1)
myotonia congenita and (2) myotonic dystrophy ( Harper
and Monckton, 2004 ). Myotonia congenita is a nonprogressive
childhood disorder in which there is a diminished
chloride conductance across the sarcolemma caused
by mutations of the skeletal muscle chloride ion channel
( Heine et al. , 1994 ). A similar form of myotonia congenita
occurs as a recessive trait in miniature schnauzers