Channelopathies (Myotonias and Periodic Paralysis)

Channelopathies
= disorders of ion channels that result in altered excitability of cellular membranes.
Most of channelopathies are disorders of muscle membrane ion channels.
Results in muscle membrane hyper excitability leading to sustained contraction =
myotonia
May result in muscle membrane hypoexcitability leading to weakness seen in periodic
paralysis
Muscle channelopathies are sodium, calcium, and chloride channel disorders
May be Inherited channelopathies OR
Acquired channelopathies (Acquired channelopathies are autoimmune)
myotonias
dystrophic
nondystrophic disorders.
In dystrophic myotonia, myotonia is one of several muscle symptoms
with muscle atrophy and weakness being most prominent.
These include
dystrophia myotonica
proximal myotonic myopathy
in nondystrophic myotonias the most prominent symptom is myotonia
periodic paralyses - divided into those associated
with a high or normal serum potassium concentration (i.e., hyperkalemic periodic
paralysis)
those associated with a low serum potassium concentration (i.e., hypokalemic periodic
paralysis).
the abnormal serum potassium concentration is the consequence rather than the cause of
the periodic paralysis.

Skeletal Muscle Channelopathies

Channel and disease are SODIUM
Hyperkalemic penodic paralysis
With myotonia
Without myotonia
With paramyotonia congenita
Paramyotonia congenita
Sodium channel myotonia
Myotonia fluctuans
Myotonia permanens
Acetazolamide-responsive myotonia
CALCIUM
Skeletal muscle calcium channel alpha-1 subunit
Hypokalemic periodic paralysis
CHLORIDE
Skeletal muscle chloride channel
AD myotonia congenita (Thomsen's)
AR myotonia congenita (Beeker's)

Pathogenesis and Pathophysiology of Sodium Channelopathies

sodium channelopathies result from point mutations in a gene, situated on the long arm of
chromosome 17.
reduced inactivation of the sodium channel, followed by
either increased muscle excitability with myotonia

or increased muscle inexcitability with hyperkalemic periodic paralysis.

Pathogenesis and Pathophysiology of Chloride Channelopathies.
reduced muscle membrane chloride conductance ( i.e.rate of flow of chloride is
decreased) resulting in muscle membrane hyper excitability repetitive firing, leads
to the myotonia.
Eg -Thomsen's and Becker's diseases
Pathogenesis and Pathophysiology of Calcium Channelopathies.
In hypokalemic periodic paralysis, the weakness is related to the calcium channel.
There is an influx of potassium into the muscle fiber with an accompanying influx of
extracellular water.
influx of potassium may account for the precipitation of hypokalemic periodic paralysis
with large carbohydrate meals.
influx of potassium in hypokalemic periodic paralysis causes the muscle fibers to become
depolarized and inexcitable.
Clinical Features and Associated Disorders of Sodium Channelopathies.
paramyotonia congenita
hyperkalemic periodic paralysis
sodium channel myotonias.
Paramyotonia Congenita.
The predominant symptom is paradoxical myotonia, which is present from birth
and persists throughout life.
The myotonia is paradoxical because unlike classic myotonia, it increases with
repetitive movements.
It is exacerbated by cold temperatures, which cause weakness.
In warm environment, patients may have no symptoms
attacks are precipitated by potassium ingestion
Hyperkalemic Periodic Paralysis.
appears in infancy or early childhood

paresis - brief and mild

lasting 15 minutes to 4 hours
precipitated by rest following exercise
by ingestion of potassium-rich foods
by administration of potassium compounds
attacks commonly start in the morning before breakfast
stress provokes them more easily
Weakness is mainly proximal
no ocular or respiratory muscle weakness
flaccid quadriplegia with absent reflexes and normal sensory examination.
The potassium level may rise during the attack
May cause cardiac dysrhythmias.
between attacks- patient has normal strength of muscles
Sodium Channel Myotonias.
myotonia becomes worse with cold,
not associated with weakness
responds to acetazolamide (acetazolamide-responsive myotonia
Clinical Features and Associated Disorders of Chloride Channelopathies.
two forms
autosomal dominant disease (Thomsen's disease)
autosomal recessive disease (Becker's disease).
Autosomal Dominant Myotonia Congenita (Thomsen's Disease).
painless generalized myotonia,
looks like muscle stiffness.
first and second decades of life
provoked by exertion following rest.

ask the patient to rise from a chair after a period of quiet sitting.
improves with exercise
well-developed muscles with particular hypertrophy of the lower limbs, giving
them an athletic appearance.
Muscle strength may be normal, or even stronger than normal.
normal reflexes,
eyelid, grip, and percussion-induced myotonia can be demonstrated.
Autosomal Recessive Myotonia Congenita (Becker's Disease).
similar to Thomsen's disease except that myotonia appears later in the first
decade.
Becker's disease -muscles are initially weak
a period of activity is required before full strength returns.
may have muscle hypertrophy, of the legs and buttocks,
Hypokalemic Periodic Paralysis.
autosomal dominant disorder
common in males
begin at adolescence
occur at night,
the patient awakens with weakness.
episodes may be precipitated by
carbohydrate or alcohol intake,
rest after exercise,
emotional stress.
attacks 1 to 4 hours, may persist for up to 3 days.
Prodromal symptoms of muscle stiffness, heavy limbs, or sweating
followed by proximal lower limb weakness,

spreads to become a tetraparesis.

Ocular or bulbar involvement is rare.
Fatalities are rare = injudicious treatment or hypokalemia-induced cardiac
dysrhythmias.
D

uring severe attacks patients are flaccid and areflexic.

Differential Diagnosis Myotonias.

The principal symptom of myotonia is
muscle stiffness
inability to relax contracted muscle
sodium channel myotonia is not painful
Stiffness may be confused with spasticity or rigidity.
Muscle cramps, is a feature of a peripheral nerve disorder
Dystonia results in abnormal postures
Painless contractures may be a feature of metabolic myopathy such as McArdle's
disease
withdrawl of levodopa = muscle rigidity or stiffness with fever, an elevated
creatine kinase (CK) level, and a high white blood cell count.
pseudomyotonia = impaired relaxation without electrical evidence of myotonia
= acid maltase deficiency and Brody's disease
Differential diagnosis of Periodic Paralysis.
causes of a flaccid, areflexic tetraparesis without sensory signs like
Hypercalcemia
Hypocalcemia
Hypophosphatemia
Hypomagnesemia
rhabdomyolysis

Guillain-Barre syndrome
myasthenic syndrome
acute poliomyelitis
Secondary hypokalemic periodic paralysis
intracellular potassium depletion from either renal, endocrine,
gastrointestinal, or drug-induced mechanisms
Thyrotoxic periodic paralysis
hyperthyroidism.
Evaluation Myotonias.
Laboratory evaluations
Serum CK level, - elevated in Thomsen's and Becker's diseases
EMG - spontaneous myotonic discharges
Periodic Paralysis.
blood tests for potassium, calcium, magnesium, phosphate, and CK should be
obtained during an episode of weakness.
electrocardiogram (ECG) may show changes consistent with hypokalemia or
hyperkalemia
EMG
Nerve conduction studies are normal.
Muscle biopsy
Management Myotonias.
anesthesia should be planned
potassium administration can exacerbate myotonia, potassium supplements should
be given only when necessary
myotonia congenita = membrane-stabilizing drugs such as procainamide and
quinine
Phenytoin is useful for chronic administration

Periodic Paralysis.
Hypokalemic prevented by a low-carbohydrate, low-sodium diet. A
cetazolamide prevents paralytic attacks
ECG for cardiac dysrhythmias.
hyperkalemic periodic paralysis,
thiazide diuretics
Carbohydrate-containing foods and fluid may aggravate the weakness,
Inhaled beta-adrenergic agonists such as salbutamol are effective treatments in
acute situations