Channelopathies PDF

Channelopathies Swaiman Ch 49, 151  Pain Gene Type Epilepsy Headache Ataxia Channelopathies Syndrome...

Channelopathies Swaiman Ch 49, 151  Pain Gene Type Epilepsy Headache Ataxia Channelopathies Syndrome SCN1a SCN1b SCN9A Result from genetically Sodium SCN2a SCN1A SCN11A SCN2A1 SCN10A SCN9a determined defect in ion- Chloride GABAa CLCN2 channel function CLCN2 KCNQ2 Heterogeneous KCNQ3 Potassium KCNJ11 KCNK18 KCNA1 KCNC3 Ion channels control KCNJ10 KCNMA1 KCND3 excitability of neurons by Calcium CACNA1A CACNB4 CACN1A CACN1A mediating flow of charged GABRG2 ions in and out of cells GABRB3 GABRD GABRA1 Ligand- EFHC1 PRRT2 gated LGI1 ITPR1 ATP1A2 channels CHRNA4 CHRNA7 GRIN2A GPR98 CHRNB2 Epilepsy Syndromes  Dravet Syndrome Mutation in SCN1A (Na channel), most de novo Clinical: Seizures in 1st yr of life with fever, often prolonged with hemiconvulsions Other seizure types occur at 2yr with absence, myoclonic, GTC, and partial seizures w/o fever Tonic seizures are rare and tend to be brief and nocturnal Obtundation status: nonconvulsive status with intermixed myoclonus Sodium channel blockers (carbamazepine, phenytoin, fosphenytoin, oxcarbazepine, lamotrigine) exacerbate seizures Normal development in 1st yr followed by cessation of development, hyperactivity as toddler which turns to slowed behaviour as adolescent Dx: genetic; EEG (generalized & multifocal abn, photoconvulsive, diffuse slowing), MRI usually normal Tx: AEM (topiramate, valproic acid, benzos and levetiracetam work well) Cannabidiol (CBD) can help (?controversial) Avoidance of hot temperature (environmental and illness) Generalized Epilepsy with Febrile Seizures Plus (GEFS+) SCN1A/SCN1B/SCN2A (Na channel) Clinical: febrile seizures in childhood which often continues to adulthood + afebrile seizures; variable penetrance Seizure types: GTC, myoclonic, absence, atonic Seizure resolution often occurs by age 12yr, normal development and IQ Tx: avoid Na channel blockers Broad spectrum AEM Benign Familial Neonatal Seizures AD, KCNQ2/KCNQ3 (K channel) As neonate K channels play critical role in inhibition (replaced by action of GABA in first few months of life).: when mutated more likely to seize Clinical: seizures in 1-2 wk of life, usually on day 2-3, and resolve after 4-5mo; 15% develop epilepsy later in life Usually multifocal clonic or focal Normal development Ix: EEG – normal interictal features; MRI – normal R/o other causes of seizure (e.g., infection, metabolic) KCNQ2 Encephalopathy De novo KCNQ2 (K channel) – mutation present in highly conserved area leading to loss of function Clinical: Presents in first days of life with poorly controlled seizures, which may resolve in 1st year; residual and profound intellectual impairment Recognized as severe neonatal encephalopathy and overlaps with Ohtahara and West syndrome Seizures are tonic and focal with associated autonomic changes Ix: EEG burst suppression which is eventually replaced with diffuse slowing and multifocal epileptiform discharges MRI often shows thinning of CC, frontal lobe atrophy & non-specific WM changes Tx: some children respond to sodium channel blockers Developmental Delay, Epilepsy and Neonatal Diabetes (DEND) KCNJ11 gene (K channel) Found in pancreatic islet cells and in neurons Presents with neonatal diabetes, developmental delay, seizures, mild dysmorphic features (downturned mouth, bilateral ptosis, prominent metopic suture, contractures) Refractory spasms, tonic-clonic and myoclonic seizures Patients are responsive to sulfonylurea mediation (glibenclamide) which improves diabetes, developmental outcome and seizures  Other Genetic Generalized Epilepsies Autosomal-Dominant Nocturnal Frontal Lobe Epilepsy – nocturnal frontal lobe seizures and waking up with bizarre hypermotor behaviour such as spinning, thrashing, rocking Nicotinic receptor mutations (allow Na and K to cross cell membrane) Respond to carbamazepine and phenytoin Benign Familial Infantile-Neonatal Seizures – similar to benign neonatal seizures but slightly older age SCN2A1 mutation Childhood Absence Epilepsy – mutations in GABA receptors (GABRA1/GABRA2), chloride channels (CLCN2) and calcium channel (CACNA1H) – polygenic disorder Juvenile Myoclonic Epilepsy – mutations inf GABA receptors (GABRA1/GABRD), calcium channels (CACNB4) and chloride channels (CLCN2) – polygenic disorder Familial Pain Syndromes Inherited (Primary) Erythromelalgia Mutations in SCN9A Allows channel to be activated by smaller-than-normal depolarizations and remains open longer after activation Episodes of redness and swelling of hands and feet, associated with burning pain Triggered by mild warmth or exercise Can become constant Age of onset varies from childhood to adulthood Familial (AD) or sporadic Tx: sodium channel blockers Lidocaine, mexiletine, carbamazepine  Paroxysmal Extreme Pain Disorder Aka familial rectal pain Mutation in SCN9A Prolonged action potentials and repetitive neuronal firing when stimulated Episodic severe pain, commonly occurring in perirectal region, but can also involve genitals, limbs, face (periorbital region) Acute onset, usually lasts seconds to minutes Stimulation of region by bowel movement, contact in perianal region, eating or sudden changes in temperature can induce pain episodes Flushing, harlequin skin changes, pupillary abnormalities and cardiac abnormalities can occur at time of pain episodes Non-epileptic tonic episodes can occur with pain episode Following pain resolution, weakness can be present for 24hr Tx: carbamazepine No response to topiramate and gabapentin Congenital Indifference to Pain (CIP) Mutation in SCN9A Leads to loss of function Insensitivity to pain +/- loss of smell Some associated with anhidrosis, ID, hypotonia Can feel stimulus and differentiate from hot and cold but can’t feel extremes Signs of peripheral neuropathy on clinical exam or neurophysiological testing and autonomic nervous system abnormalities are lacking Tx: observe for injuries Migraine and Ataxia Syndromes  Familial Hemiplegic Migraines FHM1: CACNA1A (Ca channel) – more likely to have ataxia and coma and delayed cerebral edema after minor head injury; FHM2: ATP1A2 (Na-K ATPase) & PRRT2; FHM3: SCN1A (Na channel) Present in first/second decade w/ severe headache (often unilateral) with unilateral weakness, paresthesia or hemianopsia Extreme symptoms of prolonged duration (30 days) and coma are rare Usually duration is hours to days Must have one first or second degree relative w/ similar sx to make dx Can have features of basilar migraine including vertigo, visual sx, tinnitus, dysarthria and ataxia Dx: MRI can show cerebellar atrophy; EEG during event shows slowing in affected hemisphere Can have mild asymmetry and slowing in between episodes Tx: acetazolamide, verapamil (Ca channel blocker) Flunarazine ICHD 3 Diagnostic criteria Episodic Ataxia Intermittent periods of ataxia; EA type 1 & 2 are most common EA type 1 – frequent, brief episodes of ataxia (gait) and slurred speech Precipitated by strong emotional outbursts, sudden movements, exercise Can last seconds to minutes and occur multiple times per day Muscle hyperexcitability – myokymia; some family members report seizures and isolated myotonia KCNA1 (K channel), AD EA type 2 – truncal ataxia lasting hours to days +/- eye mvmt abn Episodes can be induced by stress or exercise Migraines more common Slow progressive cerebellar features CACNA1A (Ca channel), AD Dx: EMG (EA type 1 – myokymia); MRI (EA type 2 - cerebellar vermis atrophy) Tx: acetazolamide and carbamazepine Episodic ataxia Spinocerebellar Ataxia type 6 SCA6 is the only one that is a channelopathy Triplet repeats in CACNA1A gene (Ca channel) Unclear if symptoms are related to channel dysfunction or cytotoxic effects of repeat Slowly progressive cerebellar degeneration Ataxia, dysmetria, other prominent clinical features Spasticity, CN neuropathies are NOT common Dx: genetic MRI can show cerebellar atrophy Tx: supportive Muscle Disorders Myotonic Dystrophy AD inheritance Anticipation (earlier onset of more severe symptoms in successive generations) occurs in DM1 Congenital myotonic dystrophy (CDM) occurs almost exclusively through maternal transmission Myotonia = disturbance in muscle relaxation following contraction  DM1 DMPK gene; CTG expansion, the greater the length of expansion the more severe and earlier onset of symptoms Clinical: Early congenital form: respiratory failure, poor feeding hypotonia, clubfoot, increased risk of intracerebral hemorrhage Reduced fetal movements and polyhydramnios; placenta previa Cognitive deficits, hearing loss, facial weakness (delayed speaking until middle childhood) Childhood form: ID, difficulty with speech/hearing, clumsiness, cardiac dysrhythmia, postop apnea Classic Adult: Frontal balding, cataracts, cognitive dysfunction (not dementia) Facial weakness: long and thin due to temporal and masseter muscle wasting, droopy eyelids and mouth corners; dysphagia, dysarthria Myotonia, distal weakness Cardiac arrythmias Endocrinopathies: infertility, testicular atrophy, diabetes, hypothyroidism Percussion myotonia and prolonged hand grip on exam DM1 Ix & Tx Dx: genetic; EMG (myotonia); CK usually normal (mild elevated); GGT very high Slit-lamp – Christmas tree cataracts Tx: Mexiletine and tonic water (quinine) for myotonia Other membrane-stabilizing agents: procainamide, carbamazepine Cong: ventilatory support, feeding tube, bracing for club foot Cardiac monitoring Endocrine monitoring Succinylcholine contraindicated DM2 CNBP gene; CCTG expansion, no clear relationship between number of repeats and disease phenotype Clinical: presents as adults Early onset cataracts ( distal); myotonia of eye closure Myotonic stiffness occurs with sudden physical exertion after period of rest Warm up phenomenon: repeated muscle contractions ameliorate stiffness Becker – transient weakness after period of inactivity (muscle strength improves after several strong contractions) Muscle hypertrophy Dx: genetic, NCS/EMG, short/long exercise tests Does not have worsening with exposure to cold (soak hand in cold water for 15 min, if weakness = sodium channel) Tx: mexiletine (get baseline ECG), carbamazepine Clinical AD Myotonia Congenita or AR Generalized Myotonia of Becker Features Thomsen Inheritance Dominant Recessive Gene defect Chromosome 7; mutation in Chromosome 7; mutation in skeletal skeletal muscle chloride channel muscle chloride channel Age of onset Infancy to early childhood Late childhood, occasionally starts earlier or begins in teens Myopathy Muscle hypertrophy frequent; no Occasional muscle wasting and weakness myopathy, although variants can occur late; hypertrophy of muscles uncommonly develop weakness frequently occurs in legs Myotonia Generalized stiffness, especially Generalized stiffness, especially after after rest; improves with exercise; rest; transient weakness is prominent prominent myotonia of eye closure, after complete relaxation for several but not paradoxical myotonia minutes; myotonia occurs in eyes; no paradoxical myotonia Provocative Prolonged rest or maintenance of Prolonged rest or maintenance of same stimuli posture posture Therapy Exercise; antimyotonia therapy Exercise; especially avoiding prolonged (mexiletine); Achilles’ tendon rest; antimyotonia therapy (mexiletine); stretching helps prevent need for transient weakness does not improve heel cord-lengthening surgery after mexiletine Acetazolamide-Responsive Sodium Channel Myotonia and Myotonia Fluctuans Sodium channel; mimics myotonia congenita Clinical ARSCM: AD in first decade; clumsiness, frequent falls, lazy eye, growing pains, muscle spasm, stridor; paradoximal eyelid myotonia (eyes get stuck after crying) Myotonia most prominent in face, eyes, larynx  limbs and hands in middle childhood Muscle hypertrophy; pain is common and severe MF: similar to above but with more fluctuations (some days no myotonia) Exercise-induced delayed onset myotonia – after a period of rest following vigorous exercise, if they resume exercise severe muscle stiffness may develop Will not occur if time of rest is a few minutes or over an hour Dx: Genetic testing, EMG Tx: acetazolamide for ARSCM Mexiletine Avoid high K+ diet Clinical Features Acetazolamide-resp Na Channel Myotonia Fluctuans Myotonia Inheritance Dominant Dominant Gene defect Ch17; mutation in skeletal muscle Ch17; mutation in skeletal sodium channel muscle sodium channel Age of onset First decade First or second decade Myopathy Rare Rare, muscle hypertrophy common Myotonia Face, paraspinal muscles, Face, limbs, eyelids; paradoxical myotonia of eyelids, frequently fluctuates in grip limbs, varies in severity and severity; especially after often pain with myotonia exercise Provocative stimuli Fasting, cold, oral potassium, Exercise-rest-exercise, oral infection potassium Therapy Acetazolamide, mexiletine; avoid Mexiletine; avoid high high potassium diet; monitor post- potassium diet; monitor op for rigidity and rhabdo post-op for rigidity and rhabdo Malignant Hyperthermia RYR1 gene; sometimes CACNA1S; AD Causes Ca channel to open earlier and stay open longer causing rhabdo Clinical: Hypermetabolic reaction to volatile anesthetics and neuromuscular blocking agents Tachypnea, tachycardia, hyperthermia, rigidity, rhabdo, acidosis Dx: genetics Tx: Pre-treat with dantrolene In acute setting: immediate discontinuation of anesthetics, core cooling, dantrolene (inhibits Ca release from sarcoplasmic reticulum)  Hyperkalemic Periodic Paralysis AD, high penetrance; SCN4A, sodium channel Attacks begin in childhood; brief +/- myotonia, can be painful at onset of attack; diurnal variation, attacks usually occur in AM Triggers: exercise, K+ foods Dx: hyperkalemia during attack ECG during attack to assess for dysrhythmia R/o causes of secondary hyperkalemic weakness (insulin deficiency, adrenal insufficiency, medication side effect [beta-adrenergic antagonists, alpha- adrenergic agonists, digitalis intoxication, succinylcholine]) Oral potassium load or exercise followed by potassium challenge NCS/EMG short and long exercise Tx: oral glucose (+ crystalline insulin subQ) speeds up recovery during acute attack; calcium gluconate Avoid fasting, exposure to cold, overexertion Diuretics that promote kaluresis (hydrochlorothiazide) Paramyotonia Congenita SCN4A, sodium channel, AD Clinical: sx in first decade of life; facial, lingual, neck/hand muscles Attacks of increased muscle stiffness followed by paralysis occur on exposure to cold followed by exercise Paradoxical myotonia – worsens with repeated muscle contraction; most prominent with eye closure; can have lid lag and diplopia Dx: immersion of hand in cold water for 15 minutes followed by exercise should provoke stiffness NCS RNS before and after cold exposure Tx: mexiletine Thiazide diuretic/acetazolamide if associated with hyperK PP  Hyperkalemic Periodic Clinical Features Paramyotonia Congenita Paralysis Inheritance AD, SCN4A AD, SCN4A Age of onset First decade First decade Myopathy Very rare Rare Paradoxical myotonia of the Paradoxical myotonia of the Myotonia eyelids eyelids Grip myotonia Grip myotonia Oral potassium load Cold exposure followed Rest after exercise mainly in by exercise leads to focal morning (hyperkalemic Triggers paralysis; weakness) Occasionally exercise Cold exposure followed by provokes stiffness exercise (focal paralysis) Mexiletine, mild exercise, Mild exercise, acetazolamide, Treatment keep patient warm sodium restriction Hypokalemic Periodic Paralysis AD, calcium channel gene – CACNA1S (60%), sodium channel – SCN4A (15%) Clinical: onset in first-second decade (teens); rarely in infancy Attacks start rarely but eventually can become daily; during major attacks, potassium decreases but may not decrease below normal; attacks last hours; triggers: carb load, rest after intense exercise Urinary retention of Na, K, Cl and H2O; oliguria or anuria; bradycardia Attacks become less frequent around 4th or 5th decade; repeated attacks can leave permanent residual weakness; diurnal fluctuations in strength (greatest weakness at night or early morning) Dx: lytes/ECG during attack; genetics Muscle bx not usually necessary but can show vacuoles R/o secondary causes – hyperthyroidism, beta-adrenergic stimulation, excessive insulin, alkalemia, barium poisoning, poor potassium intake (anorexia, alcoholic), excessive potassium excretion (diarrhea, laxative abuse, profuse sweating during training) and renal loss Tx: acute = oral potassium chloride, ECG Low sodium/low carb diet, avoidance of exposure to cold/overexertion, supplemental doses of potassium chloride taken 2-4x/day Daily acetazolamide; dichlorphenamide (carbonic anhydrase inhibitor – produce metabolic acidosis & work on skeletal muscles to stabilize K flux) Periodic Paralysis with Cardiac Arrhythmia (Andersen-Tawil syndrome) KCNJ2 mutation (K channel), AD Clinical: characterized by periodic paralysis (with hyper & hypoK), long QT syndrome, ventricular dysrhythmias & skeletal developmental abnormalities (low set ears, widely spaced eyes, scoliosis, short stature, small mandibles, fifth-digit clinodactyly) Attacks vary in severity; can have sudden death with syncopal attack – cardiac arrhythmias improve with increased K level (worsen with hypoK) Dx: ECG monitoring; genetic R/o secondary forms; muscle bx Tx: Acetazolamide, dichlorphenamide Thyrotoxic Periodic Paralysis 95% sporadic Attacks develop in late teens; more frequent in Asian males Recurrent attacks of weakness can occur when not euthyroid state Triggers: sleep, hot weather, excessive physical activity Associated with cardiac problems Dx: TSH Tx: antithyroid therapy Propanolol to prevent attacks Acetazolamide can worsen Channelopathies with hypokalemic periodic paralysis and w/o myotonia Andersen-Tawil Clinical Calcium Channel Sodium Channel Potassium PP with Thyroid Syndrome: PP with Features PP PP Channel PP Disease Arrhythmia Inheritanc Dominant Dominant Dominant Dominant Sporadic e Age of Childhood-teens Childhood-20s Childhood-20s Unknown Males age 20s onset Myopathy Short stature, Clinical Myopathy Vacuoles dysmorphic features No clear myopathy No clear myopathy Infrequent myopathy features on biopsy Prolonged QT Dysrhythmias High-carb meals, High-carb meals, High-carb meals, rest Rest after exercise, oral rest after exercise, rest after exercise, Triggers Rest after exercise after exercise, glucose cold, emotional cold, emotional acetazolamide stress/excitement stress/excitement Acetazolamide, Mild exercise, Potassium, Propranolol, restoration Treatment potassium, Acetazolamide acetazolamide spirinolactone of euthyroid state spirinolactone 5 conditions associated with SCN1A Febrile seizures GEFS+ Dravet syndrome Familial hemiplegic migraine FHM3 Doose syndrome 5 conditions with CACNA1A FHM1 EA2 SCA6 Benign paroxysmal torticollis HHE (hemiconvulsive hemiplegia epilepsy syndrome) Conditions with SCN4A Paramyotonia congenita Hyperkalemic periodic paralysis Conditions with SCN9A Erythromelalgia Paroxysmal extreme pain disorder