NEUROMUSCULAR DISEASES 0195–5616/02 $15.00
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NEUROMUSCULAR
COMPLICATIONS IN ENDOCRINE
AND METABOLIC DISORDERS
Simon R. Platt, BVM&S, MRCVS

Skeletal muscle not only provides the power for locomotion but is
also the largest protein store in the body.41 Abnormalities in interactions
between the force-generating and metabolic functions of skeletal muscle
resulting from endocrine and metabolic disorders result in poor muscle
performance. Many endocrinologic disorders, endogenous and iatro-
genic, result in muscle and likely peripheral nerve disease. Endocrine
myopathies are a relatively common occurrence in geriatric animals and
may present with a variety of clinical syndromes ranging from mild
weakness or stiffness to complete collapse. In most affected dogs and
cats, muscle involvement may be an incidental finding or may be sub-
clinical.44 In other cases, muscle weakness or stiffness may be the pre-
senting clinical sign and lead to the diagnosis of an underlying endocrine
disorder.44

NEUROMUSCULAR DISEASES WITH ADRENAL

DYSFUNCTION

Glucocorticoid Excess States

Myopathy secondary to glucocorticoid excess occurs in Cushing’s

disease and as a result of chronic exogenous corticosteroid therapy
(iatrogenic steroid myopathy).41, 44 Between 50% and 80% of human

From the Neurology/Neurosurgery Unit, The Animal Health Trust, Centre for Small
Animal Studies, Newmarket, Suffolk, England

VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE

VOLUME 32 • NUMBER 1 • JANUARY 2002 125

126 PLATT

patients with endogenous glucocorticoid excess develop severe proximal

muscle wasting and weakness.67 Although it is not known what percent-
age of veterinary patients are similarly affected with muscle weakness
and wasting, it is likely to be a common phenomenon based on the
number of muscle biopsy specimens with typical pathologic changes of
steroid excess at a busy neuromuscular diagnostic laboratory (G.D. Shel-
ton, DVM, PhD, unpublished observations).
A number of mechanisms have been proposed to explain how
corticosteroids (exogenous or endogenous) produce muscle weakness
and wasting. Glucocorticoids are highly lipid-soluble and easily partition
through the cell membrane into the cytosol.1 Inside the cell, these hor-
mones bind to specific cytoplasmic receptors which act by modifying
transcription. The major actions of glucocorticoids are to increase muscle
protein catabolism and inhibit synthesis of myofibrillar proteins.1 These
effects are accentuated when accompanied by reduced protein intake.53
Protein synthesis is inhibited in a dose-dependent manner primarily in
type 2 muscle fibers.1, 76, 79 This is consistent with the finding of type 2
fiber atrophy associated with Cushing’s syndrome and exogenous ste-
roid myopathy (Fig. 1).
Glucocorticoid excess is also associated with alterations of muscle
carbohydrate metabolism.77 Insulin has an anabolic influence on muscle,
and part of the effect of glucocorticoids may result from induction of
an insulin-resistant state.1 Mitochondrial structure is altered in human
patients and laboratory animals.1 Corticosteroid treatment interferes with
muscle oxidative capacity but does not deplete the muscle of adenosine
triphosphate (ATP).1 The resistance of individual fibers to glucocorticoids
depends in part on the ability to compensate for blockade of glycolytic

Figure 1. Type 2 fiber atrophy is demonstrated in a muscle biopsy specimen from a dog
chronically treated with corticosteroids. The atrophic type 2 fibers are light staining and the
type 1 fibers are dark staining. This pattern of muscle fiber atrophy is typically found
associated with endocrine disorders and chronic corticosteroid therapy (ATPase reaction
with preincubation at pH 4.3). (Courtesy of Diane Shelton, DVM, PhD, University of
California, San Diego, La Jolla, CA)
 COMPLICATIONS IN ENDOCRINE AND METABOLIC DISORDERS 127

activity by converting to oxidative metabolism.1 Type 1 fibers (oxidative)

are more resistant than type 2 (glycolytic) fibers.
The weakness and muscle atrophy resulting from corticosteroid
therapy is not likely a result of motor nerve damage. Motor nerve
conduction velocity and histologic studies of nerve were normal in
corticosteroid-treated animals. The experimental and clinical evidence
also indicates that chronic glucocorticoid therapy does not interfere with
neuromuscular transmission.1

Steroid Myopathy

Steroid myopathy can occur in any animal at any age but is more
commonly seen in dogs treated with glucocorticoids for a variety of
chronic diseases. Weakness and muscle atrophy may be profound. The
actual incidence of steroid-induced severe muscle weakness is unknown
in veterinary medicine but has been estimated to be up to 21% in human
medicine.1, 67 The diagnosis of steroid myopathy could conceivably be
overlooked in patients receiving steroid treatment for disorders that
produce weakness such as inflammatory myopathies or central nervous
system diseases. It is often difficult to decide whether deterioration in
the strength of an animal with inflammatory myopathy treated with
steroids is the result of steroid myopathy or worsening of the inflamma-
tory disease. Animals with steroid myopathy may have other clinical
signs of glucocorticoid excess, and skin and hair coat changes are typi-
cal.22
In human patients with steroid myopathy, there is wide variation
in the dose and duration of steroid treatment associated with the onset
of weakness.1 This has not been evaluated in dogs, but the author’s
clinical experience would suggest that a similar situation exists. Animals
rarely develop a severe clinical steroid myopathy with less than 4 weeks
of steroid administration. A study evaluating the effects of prednisolone
administration (4 mg/kg/d) on the muscles of 23 dogs demonstrated
mild morphologic alterations that included focal fiber necrosis and
phagocytosis after 1 week of the drug.5 Type 2 fibers became atrophic
after 2 weeks of treatment. In dogs that were treated for 28 days, there
was a significant reduction in mean muscle fiber diameters.5 In a study
evaluating cats treated with triamcinolone acetonide (3–4 mg/kg per
body weight for 10–16 days), atrophy was seen preferentially in the fast-
twitch type 2 fibers, suggesting that the condition also occurs in cats.64
It has been reported that steroid myopathy is more common after admin-
istration of the fluorinated corticosteroids such as triamcinolone, beta-
methasone, and dexamethasone.67
The treatment of choice for iatrogenic steroid myopathy is steroid
dose reduction. Obviously, this can only be done if the condition that
warranted treatment with corticosteroids is safely controlled. Conversion
to a nonfluorinated steroid preparation with alternate-day treatment is
recommended. Improvement usually follows but can take many weeks
128 PLATT

to months. Because of the catabolic effect of corticosteroids, optimizing

nutritional status is important. Protein supplementation in patients with
a loss of muscle mass is recommended. Inactivity worsens the myopathy,
and exercise may prevent the development of weakness.37 Physical ther-
apy may be useful in the prevention and treatment of muscle weakness
and wasting in patients receiving glucocorticoids. Androgens can par-
tially antagonize the catabolic actions of glucocorticoids.52

Cushing’s Syndrome (Spontaneous

Hyperadrenocorticism)

A myopathy has been described in dogs with spontaneous hyper-

adrenocorticism.7, 31 Most affected dogs are middle-aged, and female
dogs are predisposed. Poodles and the smaller breeds are overrepre-
sented. Affected dogs often have characteristic signs of hyperadrenocor-
ticism, including polyuria and polydipsia; bilaterally symmetric alopecia;
and abdominal distention in addition to generalized muscle atrophy and
weakness (Fig. 2). A long history suggestive of hyperadrenocorticism
(up to 6 years in one report) may be described before presentation for
gait abnormalities.31 As a result, it has been suggested that the prevalence
of subclinical myopathy in hyperadrenocorticism in the dog may be
high. Of the cats that have been reported with Cushing’s syndrome,

Figure 2. A 9-year-old male mixed-breed dog diagnosed with Cushing’s syndrome. The
dog exhibited a severe form of calcinosis cutis associated with the disease. The dog also
exhibited moderate pelvic limb weakness and muscle atrophy due to the underlying endo-
crine abnormality. (Courtesy of Steve Shaw, BVetMed, PhD, The Animal Health Trust,
Suffolk, England)
 COMPLICATIONS IN ENDOCRINE AND METABOLIC DISORDERS 129

most are middle-aged or older (on average, 10–11 years old) and are
usually of mixed breeding.24 Approximately 70% of the cats are female.
A distinct myopathy has not been reported in these cats; however,
muscle wasting is listed as a prominent finding.24
The clinical manifestations of Cushing’s myopathy are similar to
that of exogenous steroid myopathy with muscle atrophy and weakness.
Unilateral pelvic limb stiffness has been described as a frequent initial
sign, with other limbs becoming gradually involved over time.31 Severe
pelvic limb rigidity (Fig. 3) and clinical myotonia have been found in a
subset of dogs with chronic Cushing’s disease.
Serum creatinine kinase (CK) activity may be elevated in some
dogs.31 Complex repetitive discharges may be observed on electromyo-
graphic examination. Affected muscle groups are variable, but proximal
appendicular muscles have more consistently been affected.31 Clinical
signs may resolve in some dogs over a period of months when treated
for the primary disease, but deficits can persist.31 Improvement in motor
function seems to be inversely related to the duration of disease before
therapy.
Type 2 fiber atrophy is a consistent abnormality in muscle biopsies
from dogs affected with Cushing’s myopathy (see Fig. 1). Deposition of
perimysial and endomysial fat has been described. Although increased
amounts of connective tissue in muscle of dogs with chronic hyperadren-
ocorticism have been reported to produce irreversible muscle stiffness,5, 7, 31
another laboratory has not found significant endomysial or perimysial
fibrosis in muscle biopsies from affected dogs (G.D. Shelton, DVM, PhD,

Figure 3. A 10-year-old female spayed Jack Russell Terrier with hindlimb extensor spasticity
and proximal muscle hypertrophy associated with Cushing’s syndrome. Electrophysiology
was consistent with a myotonia associated with this endocrine disorder. (Courtesy of Mark
Jackson, University of Bristol.)
130 PLATT

unpublished observations). Using the modified Gomori trichrome stain,

‘‘ragged red fibers’’ may be found predominantly in type 1 fibers, sup-
porting a mitochondrial abnormality.5 Ultrastructural evaluation of mus-
cle has been performed in some cases. Increased amounts of intermyofi-
brillar lipid droplets and glycogen have been found, and structural
mitochondrial abnormalities and accumulations have been identified in
some patients.5, 7, 31 In one published study, a muscle biopsy from a 13-
year-old castrated male Poodle with rear limb muscle stiffness and
pseudomyotonia associated with Cushing’s syndrome showed numer-
ous lobulated type 1 fibers containing nemaline rods.14 Nemaline rods
have been described in association with several congenital and acquired
myopathies in human beings and dogs.14 Denervation has also been
associated with Cushing’s syndrome in a small number of cases (G.D.
Shelton, DVM, PhD, unpublished observations).7
With the possible exception of muscle rigidity secondary to Cush-
ing’s myotonia (see Fig. 3), the myopathy found in Cushing’s syndrome
has been attributed to glucocorticoid excess, because the weakness usu-
ally reverses when the glucocorticoid levels normalize.1 It has been
suggested that elevated levels of adrenocorticotropic hormone may also
be myopathic.1 Corticotropin administration to rabbits resulted in focal
necrosis of muscle fibers with extensive deposition of fat. This lipid
excess is not characteristic of steroid myopathy. Corticotropin excess
may also impair neuromuscular transmission by decreasing the quantal
content of the end plate potential. Corticotropin excess may have myo-
pathic actions that are separate from those of glucocorticoids. The exact
pathogenic mechanisms of corticotropin remain obscure.

Adrenal Insufficiency

Muscle weakness occurs frequently in association with hypoadreno-

corticism (Addison’s disease) in cats and dogs.44 The weakness is usually
generalized and may involve the pharyngeal or esophageal musculature.
Hypoadrenocorticism classically includes mineralocorticoid and gluco-
corticoid deficiency. Adrenal insufficiency impairs muscle carbohydrate
metabolism, water and electrolyte balance, muscle blood flow, and ad-
renergic sensitivity, which are all factors that contribute to the weakness
associated with Addison’s disease. Hyperkalemia develops with deple-
tion of muscle intracellular potassium, decreased membrane sodium-
potassium–adenosine triphosphatase activity, and diminished ␤-adrener-
gic stimulation of the sodium-potassium pump.21 Correction of the elec-
trolyte imbalance and glucocorticoid deficiency usually corrects the clini-
cal weakness.
An atypical form of Addison’s disease has been described in 11%
to 26% of dogs with hypoadrenocorticism in which there is a deficiency
of glucocorticoids alone, without concurrent mineralocorticoid defi-
ciency. Serum concentrations of sodium, potassium, or both were within
reference ranges.2, 46, 63, 66, 69, 84 Because reversible megaesophagus has been
 COMPLICATIONS IN ENDOCRINE AND METABOLIC DISORDERS 131

associated with this atypical form, all dogs with unexplained mega-
esophagus should be tested for glucocorticoid deficiency.

NEUROMUSCULAR DISORDERS WITH THYROID

DYSFUNCTION

The thyroid gland functions as a metabolic regulatory center with

effects on many organ systems. In general, hypothyroidism affects carbo-
hydrate, protein, and lipid metabolism. Hypothyroidism reduces oxygen
consumption and basal metabolic rate by decreasing mitochondrial oxi-
dation capacity, muscle oxidative enzyme activity, and glucose uptake.1
As a result of decreased numbers of ␤-adrenergic receptors on muscle
cells, muscle glycogenolysis is impaired, resulting in fasting hypoglyce-
mia and possibly glycogen accumulation.12 The impaired muscle glyco-
genolysis may contribute to muscle cramps and fatigability. Hypothy-
roidism impairs growth and the normal pattern of protein expression
during development and decreases protein turnover.68 Protein synthesis
and degradation are reduced with net protein catabolism. Hypothyroid-
ism also produces an insulin-resistant state and frequently is associated
with hypercholesterolemia, which may result from reduced cholesterol-
esterase activity and may be associated with impaired muscle uptake of
triglycerides. Thyroid regulation is done through the secretion of two
hormones: L-thyroxine (T4) and 3,5,3⬘-triiodo-L-thyroxine (T3).70 Mea-
surement of endogenous canine thyroid-stimulating hormone and se-
rum-free T4 levels by dialysis provides an excellent diagnostic screen for
thyroid gland dysfunction.70

Hypothyroidism

Myopathy and peripheral neuropathy have been reported to occur

in dogs affected with hypothyroidism.6, 44 Classic clinical signs of hypo-
thyroidism, including lethargy, weight gain, seborrhea, and alopecia,
may or may not be obvious. In fact, weakness, stiffness, and myalgia
may be the only clinical signs described. Clinical signs suggestive of
neuromuscular dysfunction in hypothyroid dogs include weakness, stiff-
ness, myalgia, reluctance to move, and muscle wasting (Fig. 4). A sub-
clinical myopathy has also been reported to occur in adult dogs with
primary hypothyroidism, although the prevalence of this condition is
not documented.6 In newly diagnosed hypothyroid human patients, as
many as 38% have clinical muscular weakness, and 80% have complaints
suggestive of muscle dysfunction.20
Serum CK activity is elevated in most human hypothyroid patients,
regardless of whether evidence of muscle disease is present clinically.35
This has also been reported in dogs, although dogs with histologically
confirmed hypothyroid myopathy can have normal muscle enzyme ac-
tivity.6 In human beings, elevated CK activity corrects rapidly with
132 PLATT

Figure 4. A 7-year-old female spayed Boxer diagnosed with hypothyroidism is pictured.

Although the dog appeared well muscled, a weak pelvic limb stance was observed that
resolved after correction of hypothyroidism. Muscle biopsies from this dog revealed a
myopathy compatible with hypothyroidism.

thyroid replacement.35 Electrophysiologic abnormalities are extremely

variable in people with this myopathy, although they have been reported
in over 70% of patients.1 Bizarre high-frequency discharges have been
reported in dogs with hypothyroidism.4 Light microscopic evaluation of
muscle biopsy sections shows a reduction in the mean diameter of type
II myofibers.6 A type 1 fiber predominance (Fig. 5A), nemaline rods (see
Fig. 5B), and glycogen accumulation have also been observed in fresh-
frozen muscle biopsy specimens in some cases.9, 10, 14
The prognosis for recovery in hypothyroid myopathy is excellent
once the dog is restored to a euthyroid state. Although there are no
long-term studies of the response of neuropathy to thyroid replacement,
it is the belief of the author that the prognosis for recovery is not as
favorable.

Feline Hyperthyroidism

Approximately 60% of all hyperthyroid people have clinical evi-

dence of muscular weakness or muscle wasting.20 Weakness and fatiga-
bility are reported less frequently in cats. In a clinical study of 202
hyperthyroid cats, it was noted that 12% were reported as weak by the
owners but that only 1% exhibited a ventral neck flexion characteristic
of muscle weakness in cats.60 In another report, 30% of affected cats had
a history of muscle tremors, 17% had historical evidence of generalized
 COMPLICATIONS IN ENDOCRINE AND METABOLIC DISORDERS 133

Figure 5. A, A type 1 fiber predominance is demonstrated in this biopsy specimen from

the vastus lateralis muscle in a dog with confirmed hypothyroid myopathy (ATPase reaction
with preincubation at pH 4.3). B, The modified Gomori trichrome stain highlights the
presence of accumulations of nemaline rods within the muscle fibers. (Courtesy of Diane
Shelton, DVM, PhD, University of California, San Diego, La Jolla, CA)
134 PLATT

weakness, and 3% had ventroflexion of the neck.44 With more advanced

disease, owners report a decreased ability to jump and fatigue associated
with physical exertion such that cats may lie down or rest when moving
from one place to another, with breathlessness not uncommon. In some
cats with extreme weakness, hypokalemia is a possible complicating
factor.55, 60 This is seen more commonly in human beings and is known
as thyrotoxic periodic paralysis.67 In this condition, patients can have
recurrent attacks of weakness, which can be precipitated by a carbohy-
drate challenge or rest after exercise.67
The prognosis is good for resolution of muscle weakness with
treatment to achieve a euthyroid state. A possible side effect of the
antithyroid drug methimazole (Tapazole) has been observed in a sub-
population of cats that developed muscle weakness and acetylcholine
receptor antibodies diagnostic of acquired myasthenia gravis 2 to 4
months after initiation of therapy.73 It was suggested that tolerance
to self–acetylcholine receptor was broken by a pharmacologic agent.
Weakness resolved and acetylcholine receptor antibodies returned to the
normal range after discontinuation of therapy.

NEUROMUSCULAR DISORDERS WITH PITUITARY

DYSFUNCTION

Acromegaly (Growth Hormone Excess)

In studies of human patients with acromegaly, proximal muscle

weakness, wasting, and hypotonia were evident.35 The patients showed
increased muscle bulk and strength but then became increasingly weak
with progression of disease. It is now recognized that approximately
50% of acromegalic patients may demonstrate insidious proximal muscle
weakness, minimal muscle wasting, and decreased exercise tolerance.1
Similar signs have not been noted as prominent features of the disease
in cats and dogs.59

Hypopituitarism

Pituitary failure and associated loss of thyroid and adrenal cortical

hormones cause severe weakness and fatigability with disproportionate
preservation of muscle mass in adult human beings.67 T3 and growth
hormone act in synergy to maintain normal protein synthesis, and loss
of growth hormone may contribute to weakness.35 Adults and children
with this disease have a gross reduction in muscle cell number that
reverses with growth hormone treatment, suggesting that this hormone
is necessary for muscle cell replication.67 Only one case report is found
in the veterinary literature of a cat with hypothalamic dysfunction and
fluctuating muscular weakness possibly secondary to hypodipsia-in-
duced alterations in serum sodium concentrations.16
 COMPLICATIONS IN ENDOCRINE AND METABOLIC DISORDERS 135

NEUROMUSCULAR DISORDERS AND PARATHYROID

GLAND DYSFUNCTION

Hyperparathyroidism

The essential disorder in primary hyperparathyroidism (PHPTH)

is the excessive synthesis and secretion of parathyroid hormone by
abnormal autonomously functioning parathyroid chief cells, which is
almost always associated with hypercalcemia. PHPTH is typically diag-
nosed in older dogs and seems to be much less common in cats. The
syndrome of neuromuscular disease in PHPTH consists of rapid tiring,
symmetric muscle weakness, and muscle atrophy. These myopathic fea-
tures are associated with gait abnormalities, shivering, trembling, and
twitching. Electromyography can demonstrate small polyphasic poten-
tials. Muscle biopsy can reveal atrophy of type II myofibers. These
findings are reversible with successful treatment for the primary dis-
ease.22
Parathyroid hormone has effects on skeletal muscle; however, the
exact pathophysiologic profile is unknown. With so many variables
(calcium, phosphorus, parathyroid hormone, and vitamin D), it is diffi-
cult to elucidate the exact source of the muscle weakness.35

Hypoparathyroidism

Hypoparathyroidism is most often the result of accidental surgical

removal of the glands during thyroid or neck surgery. Primary forms
can occur but are rare.23 The condition develops as a result of an absolute
or relative deficiency of parathyroid hormone, which causes various
physiologic problems. The final common pathway to clinical signs in-
volves those neurologic and neuromuscular disturbances resulting from
hypocalcemia.23 Most owners report that their pets were tense or ner-
vous, and these features can be accompanied by intense facial rubbing.
Muscular signs can include cramping and tonic spasm of leg muscles.
Focal muscle twitching, generalized tremors, fasciculations, or trembling
is frequently observed, as is a stiff, stilted, hunched, or rigid gait.23 Most
of these signs can be attributed to hypocalcemia rather than to a specific
myopathy.

Diabetic Mellitus

Peripheral neuropathy is a well-recognized debilitating complica-

tion of feline diabetes mellitus but a rare complication in canine diabetes.
Current theories on the etiology and pathogenesis of diabetic neuropathy
are discussed elsewhere in this issue. Diabetes mellitus is a common
endocrinopathy in the cat, with an incidence of 1 in 400 animals.43, 54
Most cats (72%) develop diabetes at approximately 7 years of age or
136 PLATT

greater, with no definitive breed predisposition.54 Classically, cats show

a pelvic limb distal symmetric polyneuropathy with a plantigrade stance
(Fig. 6), progressive paraparesis, distal muscle atrophy, and pelvic limb
hyporeflexia. Signs may progress to involve the thoracic limbs.47, 58, 78 The
reported clinical incidence of neurologic signs is 8%,47, 58 although the
true incidence may be much higher. Although strict glycemic control
reverses the clinical signs of neuropathy in some cats, many cats con-
tinue to show degrees of clinical weakness and muscle atrophy even
with specific therapy with either oral hypoglycemic agents or insulin.
Acetyl-L-carnitine has been shown to be of benefit in experimental
models of diabetes48, 49 and has been used in a few cats with persistent
clinical signs of neuropathy with subjectively good results (G.D. Shelton,
DVM, PhD, unpublished observations).

Hyperinsulinism Secondary to Pancreatic Islet Cell

Tumors

Pancreatic islet cell tumors (insulinoma) are generally reported in

middle-aged to older dogs. Peripheral neuropathy secondary to this
neoplasia is described elsewhere in this issue.

Figure 6. A 9-year-old male neutered Abyssinian cat with a 5-month history of tetraparesis
progressing to a plantigrade stance in the tarsi and carpi as a complication of diabetes
mellitus is pictured. While this stance is typical of neuropathy associated with diabetes
mellitus in cats, a similar stance may be observed associated with other peripheral neuropa-
thies affecting cats. (Courtesy of Susan Wagner, Ohio State University, Columbus, OH)
 COMPLICATIONS IN ENDOCRINE AND METABOLIC DISORDERS 137

METABOLIC MYOPATHIES

Metabolic myopathies are a diverse group of muscle disorders

caused by biochemical defects of the skeletal muscle energy system,
resulting in inefficient muscle performance and clinical weakness, myal-
gia, atrophy, cramping, or myoglobinuria. Signs of central nervous sys-
tem dysfunction may also be present in some disorders. The biochemical
defects primarily affect ATP production. Skeletal muscles have three
major sources of ATP: phosphocreatine, glycogen, and free fatty acids.
In recent years, a number of specific metabolic myopathies have been
identified in human beings and animals; however, mitochondrial myopa-
thies and other defects of oxidative metabolism are generally considered
rare conditions, and precise biochemical defects may be difficult to
confirm.

Mitochondrial Disorders

Over the past decade, a considerable body of evidence has accumu-

lated in human beings implicating defects in the mitochondrial energy-
generating pathway in a wide variety of degenerative diseases, including
myopathy and encephalopathy.81 A striking feature of mitochondrial
abnormalities is their clinical heterogeneity, ranging from single organ
involvement to severe multisystem disease. The same mutation or differ-
ent mutations in the same mitochondrial DNA gene may present with
different clinical manifestations, although the same clinical phenotype
may be caused by different mutations.45 The degree of organ dysfunction
depends on a tissue’s energy requirement; for instance, brain and muscle
are highly dependent on oxidative phosphorylation, and combined neu-
rologic illness and myopathy are common features of mitochondrial
DNA mutations.45 A clinical presentation for a combination of muscle
disease and brain disease should alert the clinician to the potential
diagnosis of a mitochondrial disorder.
Mitochondrial myopathies may be difficult to diagnose; however,
two important testing procedures may greatly aid in arriving at a pre-
sumptive diagnosis. Evaluation of resting and postexercise plasma lac-
tate and pyruvate concentrations should be performed as a screening
test in all animals with either neuromuscular disease or combined neuro-
muscular–central nervous system abnormalities. Blood for lactate con-
centration should be collected into sodium fluoride/potassium oxalate
tubes, and the plasma should be separated and stored at 20C until
analyzed. Blood for pyruvate analysis should be mixed at a 1:1 ratio
with 10% perchloric acid and centrifuged; the supernatant should be
removed and frozen at 20C. Samples should be analyzed for pyruvate
within 30 days.50
Lactic acid is the product of anaerobic metabolism of glucose, and
lactic acidemia results from a defect in the anabolic metabolism of
pyruvate.65 Lactic acidemia is found in several of the mitochondrial
138 PLATT

disorders described in human beings65 and also has been identified in

dogs with mitochondrial myopathy.8, 34, 36, 56, 75 In people, lactic acidemia
develops in association with deficiencies in pyruvate dehydrogenase or
pyruvate carboxylase, defects in the mitochondrial respiratory chain, or
defects in the Kreb’s cycle involving ␣-ketoglutarate dehydrogenase
complex or fumarase.65 Documentation of high serum lactate and py-
ruvate concentrations with a normal lactate-to-pyruvate ratio is con-
sistent with a defect in pyruvate dehydrogenase or one of the glu-
coneogenic enzymes.65 Lactic acidosis in association with a high
lactate-to-pyruvate ratio is found in association with defects involving
the mitochondrial electron transport chain, pyruvate carboxylase defi-
ciency, or mitochondrial myopathies.65 Lactate concentrations increase in
normal animals after strenuous anaerobic exercise.51 Resting lactic acide-
mia or lactic acidemia that seems disproportional to the degree of exer-
cise performed may be an indication of an underlying disorder of muscle
metabolism, however.
The second important diagnostic procedure is evaluation of a mus-
cle biopsy specimen. Human patients with severe mitochondrial myopa-
thy show a massive proliferation of abnormal mitochondria, apparently
resulting from a futile attempt to compensate for the energy deficiency.81
Similar abnormalities have been identified in canine myopathies.8, 56 The
aggregates of abnormal mitochondria stain red with the Gomori modi-
fied trichrome stain in frozen biopsy sections, creating the pathologic
representation of ragged-red muscle fibers (Fig. 7). Abnormal paracrys-
talline inclusions may also be identified ultrastructurally.
Few confirmed cases of mitochondrial myopathies have been re-
ported in dogs and cats, although mitochondrial dysfunction has been
suspected in a larger number of cases.56, 71, 74 Deficiency of pyruvate
dehydrogenase, a mitochondrial enzyme, has been confirmed in
Clumber and Sussex Spaniels.34, 36, 75 A mitochondrial myopathy with
altered cytochrome c oxidase activities and reduced mitochondrial
mRNA has been described in Old English Sheepdog littermates with
exercise intolerance.8, 80 A Jack Russell terrier presenting with progressive
exercise intolerance and elevated lactate and pyruvate concentrations
has more recently been reported with the tentative diagnosis of mito-
chondrial myopathy.56 The definitive diagnosis of a mitochondrial myop-
athy requires sophisticated biochemical and molecular testing available
only at few specialized neuromuscular centers. Even at these specialized
centers, arriving at a specific diagnosis may prove difficult and expen-
sive. With an increased awareness of these metabolic disorders, new
mitochondrial myopathies and encephalopathies are likely to be diag-
nosed in our animal patients.
At present, there is no specific therapy for disorders of mitochon-
dria, although cofactor therapy, vitamin supplementation, dietary
changes, and, in some cases, supplementation with L-carnitine may
improve muscle strength.45 As with all heritable diseases, affected ani-
mals should not be used for breeding.
 COMPLICATIONS IN ENDOCRINE AND METABOLIC DISORDERS 139

Figure 7. Modified Gomori trichrome stain of a muscle biopsy specimen from a dog
with suspected mitochondrial myopathy. Subsarcolemmal and intermyofibrillar deposits of
membranous material stains red with the trichrome stain. The membranous material repre-
sents the accumulation of mitochondria beneath the sarcolemma and between the myofi-
brils. (Courtesy of Diane Shelton, DVM, PhD, University of California, San Diego, La
Jolla, CA)

Lipid Storage Myopathy

Lipid storage myopathy has been described in the dog, but the
precise biochemical defect(s) has not yet been characterized.13, 61, 74 The
clinical presentation is variable and includes muscle atrophy, weakness,
and, in some cases, dramatic myalgia.13, 61, 74 Lactic acidemia is found in
most dogs with lipid storage myopathy. Diagnosis is made by evaluation
of a muscle biopsy specimen. After the diagnosis, further investigations,
including evaluation of urinary organic acid quantification by gas chro-
matography–mass spectrometry57; plasma amino acid concentrations;
and quantification of total, free, and esterified carnitine in plasma urine
and muscle, should be performed to try to determine a specific metabolic
abnormality.
Therapy for lipid storage myopathy in human beings and dogs
has included supplementation with L-carnitine (50 mg/kg twice daily),
coenzyme Q10 (100 mg daily), and B vitamins.15, 71, 74 Dramatic improve-
ments have been observed in some but not all dogs (G.D. Shelton, DVM,
PhD, unpublished observations). L-Carnitine is a carrier for long-chain
fatty acids from the cytosol into the mitochondrial matrix, where they
undergo ␤-oxidation.15 Carnitine also acts as a buffer against abnormal
organic acid accumulation to produce acylcarnitines, which can then be
shuttled out of the mitochondria and excreted in the urine, preventing
their local toxicity. L-Carnitine is neuroprotective in that it has antioxidiz-
140 PLATT

ing actions and is membrane stabilizing.15 Coenzyme Q10 is biosynthe-

sized in the body, functioning in the mitochondria as a carrier of elec-
trons between the flavoproteins and the cytochromes of the electron
transfer chains.3 Exogenously administered coenzyme Q10 has been
shown to be incorporated in the inner membrane of the mitochondria
and increases the activity of mitochondrial enzymes.3 Riboflavin is the
precursor of the prosthetic group of flavoproteins, and its administration
has been shown to decrease lipid storage in muscle in 3 to 6 months
when the myopathy is accompanied by organic acidurias.15

Defects of Glycogen Metabolism

These relatively uncommon disorders result from inborn errors of

glycogen metabolism with accumulation of glycogen-like material within
muscle and other tissues.44, 72 The enzyme defects result in inadequate
glycogen utilization and, frequently, fasting hypoglycemia. Clinical signs
include muscular weakness, exercise intolerance, collapse, and occa-
sional seizures. The diagnosis of a glycogen storage disorder is usually
made by the finding of periodic acid–Schiff (PAS)–positive vacuoles
within muscle biopsy sections. In fact, evaluation of a muscle biopsy
specimen with the finding of PAS-positive deposits may be the first
indication of an underlying disorder of the glycolytic pathway.25, 40 The
PAS-positive deposits may be glycogen or polysaccharide storage mate-
rial and may be further differentiated after further incubation with
amylase. Specific biochemical assays are necessary for a precise determi-
nation of the enzyme defect.

Glycogenosis Type II in Lapland Dogs

A glycogen storage disease caused by ␣-1,4-glucosidase (acid mal-
tase) deficiency (human glycogenosis type II) has been reported to occur
in related Lapland dogs.83 The disease is fatal, with the dogs dying
before 2 years of age. A gradually progressive generalized weakness
occurring after 6 months of age was reported, which was also accompa-
nied by dysphagia, frequent vomiting, and dyspnea. Massive glycogen
accumulations were confirmed in most organs by means of histopatho-
logic examination, with skeletal muscles severely affected. The precise
biochemical defect has been confirmed by the demonstration of greatly
reduced acid ␣-glucosidase activities in various tissues, including cul-
tured fibroblasts.82

Glycogenosis Type III in German Shepherd and Akita

Dogs
A defect of the glycogen-debranching enzyme amylo-1,6-glucosi-
dase (glycogenosis type III) similar to Cori’s disease in human beings
has been reported in German Shepherd and Akita dogs, with muscular
 COMPLICATIONS IN ENDOCRINE AND METABOLIC DISORDERS 141

weakness evident at 2 months of age.11, 62 Abdominal distention may

also be present as a result of hepatomegaly caused by deposition of
glycogen-like material.

Glycogenosis Type IV in Norwegian Forest Cats

A deficiency of the glycogen-branching enzyme has been reported
in young related Norwegian forest cats.26, 27 Clinical signs included gener-
alized muscle tremors and weakness progressing to tetraplegia that
became apparent at about 5 months of age. Severe generalized muscle
atrophy and contractures were present at the time of euthanasia. Accu-
mulations of abnormal glycogen and severe degeneration were found in
the central nervous sytem, peripheral nervous system, skeletal muscle,
and heart. A polymerase chain reaction (PCR)–based genetic test is now
available for the diagnosis of this disorder.

Glycogenosis Type VII in English Springer Spaniels and

American Cocker Spaniels
An autosomal recessive inherited form of phosphofructokinase de-
ficiency (PFK) (type VII glycogen storage disease) has been described in
young English Springer Spaniels at approximately 8 months of age.28
Affected animals almost completely lacked muscle PFK activity and had
low erythrocyte PFK activity.30 Presenting clinical signs were composed
predominantly of compensated hemolytic anemia, intravascular hemoly-
sis, and hemoglobinuria without overt muscle weakness. Although se-
rum CK concentrations may be mildly elevated, the lack of prominent
muscle weakness and morphologic evidence of a myopathy most likely
reflect the highly oxidative nature of canine skeletal muscle, with less
dependence on anaerobic glycolysis during exercise when compared
with human beings.30 An 11-year-old English Springer Spaniel has also
been reported with a progressive myopathy and associated exercise
intolerance.33 Morphologic and staining characteristics of abnormal poly-
saccharide deposits in muscle fibers were similar to those reported in
muscles of human patients with PFK deficiency.33 An inherited PFK
deficiency has also been reported in an American Cocker Spaniel; how-
ever, muscle wasting and weakness were not evident in this dog.29 PCR
studies confirmed that the mutation leading to PFK deficiency in this
breed is identical to that responsible in the English Springer Spaniel
breed.29 A PCR-based genetic test is now available to identify PFK-
deficient and carrier animals.

Electrolyte Disorders

Electrolyte disorders are an important cause of muscular weakness,

particularly in cats. The most important electrolyte disorders that result
in muscular weakness are abnormalities of potassium or phosphorus.42
142 PLATT

Hypokalemic Myopathy
Several reports of a polymyopathy in cats associated with potassium
depletion and hypokalemia are included in the literature.17–19 An acute
onset of generalized weakness, apparent muscular pain, and persistent
ventroflexion of the neck were described. The clinical signs were associ-
ated with a low serum potassium concentration and markedly elevated
serum CK activity. Signs of polymyopathy resolved, and CK activities
returned to the normal range after parenteral and oral potassium admin-
istration. It was subsequently shown that certain diet types and diseases
were associated with increased occurrence of hypokalemia.19 Renal loss
of potassium associated with chronic renal failure is the most important
of these causes in cats. Multiple conditions, including thyrotoxicosis,
diuretic therapy, chronic vomiting or diarrhea, and hepatic disease, may
result in hypokalemia in cats, however.55 A congenital form of hypoka-
lemia has been described in Burmese kittens from 2 to 6 months of age.39
This condition bears many similarities to hypokalemic periodic paralysis
in human beings, a condition that is thought to be related to a calcium
channel disorder. The condition has a familial and inherited basis, with
affected kittens being produced in specific lines of this breed.39 Low
potassium intake has also been a crucial inciting factor in the etiopatho-
genesis of this disease. More recently, the formulation of feline diets has
been altered to reduce this problem.
A myopathy suspected to be caused by hypokalemia has been
reported in a 6-year-old dog.32 A generalized flaccid paralysis associated
with hypokalemia after furosemide administration for suspected conges-
tive heart failure was reported. After treatment of the hypokalemia, the
dog was clinically normal.

Miscellaneous Electrolyte Disorders

Episodic weakness, collapse, and paralysis have been reported in a

dog with hyperkalemia precipitated by exercise or excitement.38 Muscle
weakness associated with increased serum potassium concentrations
may also occur in association with adrenocortical insufficiency, diabetes
mellitus, acute renal failure, or severe acidosis. Ventral neck flexion has
also been observed in a hydrocephalic cat with hypodipsic hyperna-
tremia.16 Signs of polymyopathy that resolved with restoration of euna-
tremia and recurred in association with hypernatremia were seen.

SUMMARY

Many of the endocrine and metabolic myopathies have no unique

features, and for most clinicians, it is not possible to remember the
clinical nuances of all the specific abnormalities and deficiencies respon-
sible for these myopathies. This can make this group of diseases difficult
 COMPLICATIONS IN ENDOCRINE AND METABOLIC DISORDERS 143

to suspect. It is more important to recognize the general features of

myopathic disease and to consider muscle biopsies as a preliminary
diagnostic technique, with the potential for further investigation if a
myopathy is confirmed.

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Address reprint requests to

Simon R. Platt, BVM&S, MRCVS
Neurology/Neurosurgery Unit
The Animal Health Trust
Centre for Small Animal Studies
Lanwades Park, Kentford
Newmarket, Suffolk
England

e-mail: simon.platt@aht.org.uk