Channelopathies (Myotonias and Periodic Paralysis)

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 à repetitive firing, à 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
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Learning and attention deficit disorders and mental retardation managed by a psychologist and educator.

Strabismus, nystagmus, and optic atrophy –consult with  ophthalmologist - in the initial assessment.

Lower urinary tract dysfunction should receive prompt assessment and treatment.

Several drugs have been used to treat Spasticity, including dantrolene sodium, the benzodiazepines, and baclofen.

            Intrathecal baclofen - used - in selected children with severe spasticity.

            Botulinum toxin - management of spasticity in specific muscle groups, - positive response in - patients studied.

            Patients with incapacitating athetosis occasionally respond to levodopa, and       children with dystonia may benefit from carbamazepine or trihexyphenidyl.

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Palpation

Applying the palm of the hand to the chest

Thrills

increased precordial pulsation (apical in left ventricular hypertrophy and basal and right sided in right ventricular hypertrophy)

diastolic shock (in the pulmonary area in pulmonary hypertension)

The apex beat, normally in the fourth or fifth intercostal space within the mid-clavicular line

pulse wrist (radial) or inguinal region (femoral).

Sinus arrhythmia (increase in rate on inspiration with decrease on expiration)

bounding pulse

weak pulse

collapsing (

femoral pulses may be absent, or delayed

Percussion

right cardiac border does not extend beyond the right sternal edge

the upper border is at the level of the second intercostal space

determine cardiac size

Diminished or absent cardiac dullness is found in emphysema and pneumothorax.

Auscultaition

The ranges for heart rate in infancy and childhood are:

Newborn          70/120  

Infant               80/160              

Preschool child 75/120  

School child 70/110

Auscultate areas -

Mitral

Tricuspid

Pulmonary

Aortic

3^rd & 4^th left intercostal spaces,below left clavicle.

Auscultatory assessment

cardiac rhythm

heart sounds

murmurs.

Third heart sound

ejection click

intensity of heart sounds

Description of murmurs should include

1)   site,

2)   intensity (graded 0—6) with point of maximum intensity,

3)   timing (systolic: pan, early or late; or diastolic: early diastolic, mid-diastolic or presystolic,

4)   propagation (mitral systolic murmurs radiate to the left axilla, aortic systolic to the neck, aortic regurgitant down the left sternal edge) and

5)   variation with position. Coarctation of the aorta may produce a murmur audible over the back.

6)  Variation with respiration

venous hum

pericardial friction rub

to his ear.

other systems, e.g. by hepatic enlargement in cardiac failure.