channelopathies in neurological disorders: Sodium channelopathy

The author: Professor Yasser Metwally

http://yassermetwally.com


INTRODUCTION

February  9, 2010 — The past decade has witnessed exciting developments in the understanding of the pathogenesis of neurologic disease. The recognition that diverse neurologic disorders are caused by dysfunction of ion channels in excitable tissue has epitomized this molecular biologic advance in clinical neurology. The role of ion channels in neurologic disease began with the discovery that skeletal muscle diseases are linked to missense mutations of calcium, sodium, and chloride channels. This entire group of periodic paroxysmal neurologic diseases is termed “channelopathies” [1]. Availability of new molecular genetic tools has led to a rapidly increasing number of recognized channelopathies that reflect abnormalities in the structure and function of the various ion channels. Disorders as diverse as cardiac arrhythmias, epilepsy, myotonia, malignant hyperthermia, and cystic fibrosis have been linked to mutations in genes encoding for ion channels.

Channelopathies have surprisingly similar clinical features. Typically, neurologic channelopathies manifest as paroxysmal attacks of paralysis, myotonia, headache, or ataxia and are precipitated by physiologic stresses. Symptoms attributed to channelopathies may represent an abnormal gain of function (such as myokymia, myotonia, or epilepsy) or an abnormal loss of function (such as weakness) depending on whether or not the defect leads to increased membrane excitability or inexcitability.

Mutations in a specific ion channel gene can be associated with heterogeneous phenotypes. Conversely, mutations in different channel genes can produce similar clinical phenotypes. Given such clinical and genetic heterogeneity, any attempt at classification of channelopathies based solely on clinical signs and symptoms has limitations. Accordingly, this review is based on the particular ion channel involved rather than clinical manifestations.

Two types of sodium channelopathy exist as follows

Skeletal muscle Sodium channelopathy 1- Hyperkalemic periodic paralysis
2- Paramyotonia congenita
3- Potassium-aggravated myotonia
Neuronal Sodium channelopathy 1- Generalized epilepsy with febrile seizures plus
  • Ion channel structure

Cell membranes are impermeable to charged ions. Resultant ion concentration differentials are the source of an electrical potential difference across cell membranes. Membranes have protein pores or “channels” that allow ions to pass through. These channels display ion selectivity and have “gates” that open or close in response to specific stimuli, such as a change in the transmembrane voltage or the binding of a specific ligand.

Video 1. The Ion channel

Structurally, ion channels are composed of individual subunits or groups of subunits, each subunit containing six hydrophobic transmembrane regions, S1 through S6. The sodium and calcium channels are composed of a single a subunit containing four repeats of the six transmembrane-spanning segments. Voltage-gated potassium channels are composed of four distinct subunits, each subunit containing different six transmembrane-spanning segments. The subunits are assembled to form the central pore in a process that also determines the basic properties of gating and selective permeability characteristic of the channel type. The peptide chain (H5 or P loop) between the membrane-spanning segments S5 and S6 projects into and lines the water-filled channel pore. Mutations in this region alter the permeability properties of the channel. The S4 segment contains a cluster of positively charged amino acids (lysine and arginine) and is the major voltage sensor of the ion channel. Voltage-dependent “fast inactivation” of the channel is mediated by a tethered amino-terminal-blocking particle (the “ball and chain”) that swings in to occlude the permeation pathway. Most gain-of-function (myokymia, myotonia, or epilepsy) ion channel mutations affect the gating process by preventing channel closure.

Video 2. The ion channels structure and function

Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell’s plasma membrane.[1] They are classified according to the trigger that opens the channel for such ions, i.e. either a voltage-change (voltage-gated sodium channels) or binding of a substance (a ligand) to the channel (ligand-gated sodium channels).

In excitable cells such as neurons, myocytes, and certain types of glia, sodium channels are responsible for the rising phase of action potentials.

      • Voltage-gated sodium channel

Voltage-sensitive sodium channel a-subunit. G – glycosylation, P – phosphorylation, S – ion selectivity, I – inactivation, positive (+) charges in S4 are important for transmembrane voltage sensing, See fig.1 .[3] Sodium channels consist of a large a subunit that associates with other proteins, such as ß subunits. An a subunit forms the core of the channel and is functional on its own. When the a subunit protein is expressed by a cell, it is able to form channels that conduct Na+ in a voltage-gated way, even if ß subunits or other known modulating proteins are not expressed. When accessory proteins assemble with a subunits, the resulting complex can display altered voltage dependence and cellular localization.

Click to magnify figure

Figure 1. Voltage-sensitive sodium channel α-subunit. G – glycosylation, P – phosphorylation, S – ion selectivity, I – inactivation, positive (+) charges in S4 are important for transmembrane voltage sensing. (Click to enlarge figure)

The a-subunit has four repeat domains, labeled I through IV, each containing six membrane-spanning regions, labeled S1 through S6. The highly conserved S4 region acts as the channel’s voltage sensor. The voltage sensitivity of this channel is due to positive amino acids located at every third position. When stimulated by a change in transmembrane voltage, this region moves toward the extracellular side of the cell membrane, allowing the channel to become permeable to ions. The ions are conducted through a pore, which can be broken into two regions. The more external (i.e., more extracellular) portion of the pore is formed by the "P-loops" (the region between S5 and S6) of the four domains. This region is the most narrow part of the pore and is responsible for its ion selectivity. The inner portion (i.e., more cytoplasmic) of the pore is formed by the combined S5 and S6 regions of the four domains. The region linking domains III and IV is also important for channel function. This region plugs the channel after prolonged activation, inactivating it.

        • Gating of sodium channel

Voltage-gated sodium channels have three types of states: deactivated (closed), activated (open), and inactivated (closed). Channels in the deactivated state are thought to be blocked on their intracellular side by an "activation gate", which is removed in response to stimulation that opens the channel. The ability to inactivate is thought to be due to a tethered plug (formed by domains III and IV of the alpha subunit), called an inactivation gate, that blocks the inside of the channel shortly after it has been activated. During an action potential the channel remains inactivated for a few milliseconds after depolarization. The inactivation is removed when the membrane potential of the cell repolarizes following the falling phase of the action potential. This allows the channels to be activated again during the next action potential. Genetic diseases that alter sodium channel inactivation can cause muscle stiffness or epileptic seizures because of the introduction of a so-called window current, during which sodium channels are tonically active, causing muscle and/or nerve cells to become over-excited.

The temporal behaviour of sodium channels can be modeled by a Markovian scheme or by the Hodgkin-Huxley-type formalism. In the former scheme, each channel occupies a distinct state with differential equations describing transitions between states; in the latter, the channels are treated as a population that are affected by three independent gating variables. Each of these variables can attain a value between 1 (fully permeant to ions) and 0 (fully non-permeant), the product of these variables yielding the percentage of conducting channels.

  • Skeletal muscle Sodium channelopathy

The muscle disorders caused by defective sodium channels include hyperkalemic periodic paralysis, paramyotonia congenita, and potassium-aggravated myotonia. These disorders are caused by mutations in the voltage-gated skeletal muscle sodium ion channel gene (SCN4A) located on chromosome 17q [8–14]. Reported SCN4A mutations have been in domains 2, 3, and 4 of the sodium channel a subunit. These disorders display autosomal dominant inheritance and result from a common underlying defect of muscle membrane excitability. Linkage of malignant hyperthermia to the SCN4A gene in some families suggests that patients with sodium channel disease have a risk of malignant hyperthermia when exposed to certain anesthetic and muscle relaxing agents.

    • Hyperkalemic periodic paralysis

Hyperkalemic periodic paralysis was recognized as a distinct entity in 1955 [15]. The onset of attacks of weakness typically is in late childhood or early adolescence. Complete limb paralysis during attacks is rare. The episodes of weakness are brief, lasting 30 minutes to a few hours. Focal weakness is common. Attacks are precipitated by skipping meals and can be prevented by frequent high carbohydrate snacks. Common precipitants include rest after a period of exercise, stress, or cold. With increasing age, the frequency of attacks declines and interictal weakness may develop. Muscle biopsy may show vacuoles or tubular aggregates. Serum potassium during an attack may be elevated to approximately 6.0 mEq/L or can be normal (particularly if measured late in an attack). EMG can show interictal myotonic discharges or electrical silence during an attack. Genetic analysis yields diagnosis and obviates the need for potassium loading tests, which can be dangerous. Because attacks are brief, treatment may not be required. Prompt ingestion of carbohydrates at the onset of weakness often aborts attacks. Acetazolamide is an effective prophylaxis and may act through hypokalemia or acidosis. Thiazide diuretics often are preferable and appear to be equally effective.

    • Paramyotonia congenita

Described by Eulenburg in 1886, paramyotonia congenita is an autosomal dominant disorder characterized by myotonia that worsens with activity (paradoxical myotonia) [15]. This type of myotonia distinguishes paramyotonia congenita from the classical myotonia seen in myotonia congenita. Classical myotonia improves with repetitive movements, a feature known as the “warm-up” phenomenon. The myotonia and weakness in paramyotonia congenita are dramatically worsened by cold exposure. The onset of myotonia occurs in infancy. Attacks of periodic paralysis may develop in adolescence and may be associated with either hypokalemia or hyperkalemia. Stiffness after cooling in paramyotonia is not the result of myotonia, but rather contractures. Paradoxical myotonia is secondary to increasing membrane failure. The underlying membrane defect leads to increased sodium permeability, which is further increased with cooling. A similar effect seen in hyperthyroidism may explain marked worsening of exercise-induced weakness in paramyotonia congenita associated with hyperthyroidism. EMG reveals myotonic discharges. Muscle biopsy usually does not demonstrate any specific abnormalities, although some biopsy specimens show increased variation in myofiber size and reduced numbers of type 2B myofibers. Tocainide is an effective treatment, although mexiletine is preferred because of less toxicity. Acetazolamide may precipitate weakness but improve myotonia. Chorthiazide may improve weakness and myotonia.

    • Potassium-aggravated myotonia

Potassium-aggravated myotonia previously was known as myotonia fluctuans, myotonia permanens, and acetazolamide-sensitive myotonia [15]. The myotonia in this disorder is induced by potassium ingestion and rest after exercise [16]. Phenotypic variation exists. The mild cases show extremely variable muscle stiffness with symptom-free periods lasting days or weeks (myotonia fluctuans) [17]. The severe phenotype includes permanent and profound muscle stiffness with hypertrophy of neck and shoulder muscles. Painful myotonia is a clue to this diagnosis, but also is seen in patients with myotonia that results from chloride channel abnormalities. Acetazolamide may be helpful.

  • Neuronal Sodium channelopathy

Sodium channels are prevalent throughout the nervous system [22]. Many anticonvulsants are believed to exert their therapeutic response by modulation of neuronal sodium channels [18].

    • Generalized epilepsy with febrile seizures plus

Generalized epilepsy with febrile seizures plus is a recently described benign childhood-onset epileptic syndrome with autosomal dominant inheritance. This disorder is associated with mutations in a gene encoding a voltage-gated subunit of a neuronal sodium channel [19].The most common phenotype is febrile seizures and generalized tonic-clonic seizures that are not associated with fever. In approximately one third of patients, additional seizure types occur, including absence, myoclonic, or atonic seizures [20,21].


References

1. Griggs RC, Nutt JG. Episodic ataxias as channelopathies. Ann Neurol. 1995;37:285-287

2. Lorenz C, Meyer-Kleine C, Steinmeyer K, Koch MC, Jentsch TJ. Genomic organization of the human muscle chloride channel CIC-1 and analysis of novel mutations leading to Becker-type myotonia. Hum Mol Genet. 1994;3:941-946

3. Barchi RL. Ion channel mutations and diseases of skeletal muscle. Neurobiol Dis. 1997;4:254-264

4. Koch MC, Steinmeyer K, Lorenz C, et al. The skeletal muscle chloride channel in dominant and recessive human myotonia. Science. 1992;257:797-800

5. George Jr. AL, Crackower MA, Abdalla JA, Hudson AJ, Ebers GC. Molecular basis of Thomsen’s disease (autosomal dominant myotonia congenita). Nat Genet. 1993;3:305-310

6. George Jr. AL, Sloan-Brown K, Fenichel GM, Mitchell GA, Spiegel R, Pascuzzi RM. Nonsense and missense mutations of the muscle chloride channel gene in patients with myotonia congenita. Hum Mol Genet. 1994;3:2071-2072

7. Becker PE. Genetic approaches to the nosology of muscular disease: myotonias and similar diseases. Birth Defects. 1971;7:52-62

8. George Jr. AL. Hereditary dysfunction of voltage-gated sodium channels: from clinical phenotype to molecular mechanisms. Nephrol Dial Transplant. 1996;11:1730-1737

9. Ptacek LJ, Tawil R, Griggs RC, et al. Sodium channel mutations in acetazolamide-responsive myotonia congenita, paramyotonia congenita and hyperkalemic periodic paralysis. Neurology. 1994;44:1500-1503

10. Ptacek LJ, Trimmer JS, Agnew WS, Roberts JW, Petajan JH, Leppert M. Paramyotonia congenita and hyperkalemic periodic paralysis map to the same sodium-channel gene locus. Am J Hum Genet. 1991;49:851-854

11. Heine R, Pika U, Lehmann-Horn F. A novel SCN4A mutation causing myotonia aggravated by cold and potassium. Hum Mol Genet. 1993;2:1349-1353

12. Ptacek LJ, Tyler F, Trimmer JS, Agnew WS, Leppert M. Analysis in a large hyperkalemic periodic paralysis pedigree supports tight linkage to a sodium channel locus. Am J Hum Genet. 1991;49:378-382

13. Fontaine B, Khurana TS, Hoffman EP, et al. Hyperkalemic periodic paralysis and the adult muscle sodium channel alpha-subunit gene. Science. 1990;250:1000-1002

14. Ptacek LJ, Tawil R, Griggs RC, Storvick D, Leppert M. Linkage of atypical myotonia congenita to a sodium channel locus. Neurology. 1992;42:431-433

15. Riggs JE. The periodic paralyses. Neurol Clin. 1988;6:485-498

16. Trudell RG, Kaiser KK, Griggs RC. Acetazolamide-responsive myotonia congenita. Neurology. 1987;37:488-491

17. Ricker K, Moxley RT, Heine R, Lehmann-Horn F. Myotonia fluctuans. A third type of muscle sodium channel disease. Arch Neurol. 1994;51:1095-1102

18. Catterall WA. Molecular properties of brain sodium channels: an important target for anticonvulsant drugs. Adv Neurol. 1999;79:441-456

19. Wallace RH, Scheffer IE, Parasivam G, et al. Generalized epilepsy with febrile seizures plus: mutation of the sodium channel subunit SCN1B. Neurology. 2002;58:1426-1429

20. Scheffer IE, Berkovic SF. Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes. Brain. 1997;120:479-490

21. Singh R, Scheffer IE, Crossland K, Berkovic SF. Generalized epilepsy with febrile seizures plus: a common childhood-onset genetic epilepsy syndrome. Ann Neurol. 1999;45:75-81

22. Greenberg DA. Calcium channels in neurological disease. Ann Neurol. 1997;42:275-282

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Bladder dysfunction: Overflow incontinence

The author: Professor Yasser Metwally

http://yassermetwally.com


INTRODUCTION

February  8, 2010 — Overflow incontinence is related most commonly to bladder neuropathy. Diabetes mellitus is a common etiology of the neurogenic bladder. Lumbosacral nerve disease from tumors, meningomyelocele, MS, and prolapsed intravertebral disks also can result in bladder neuropathy and overflow incontinence. High spinal cord injuries are another etiology. Severe cases of outlet obstruction ultimately can cause severe retention, local neurologic injury, and overflow. In most cases, both sensory and motor neuropathy are present. The maximal physical capacity of the bladder is reached, often times without the individual realizing that this has occurred.

Incontinence occurs off the top of a chronically over-filled bladder. Effective emptying is not possible because of an acontractile detrusor muscle. In early bladder neuropathy, DI may coexist with a hypofunctioning detrusor muscle. Early in the course of diabetes-related bladder neuropathy, symptoms and the functioning of the detrusor may wax and wane. The result is periods when urinary retention and overflow incontinence are severe and periods when detrusor function and voiding effectiveness temporarily improve.


References

1. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 10.1a January 2010 [Click to have a look at the home page]

2. Acute and Chronic Bladder Effects of L-Dopa Differ in Parkinson’s Patients [Full text]

3. Incontinence medication and Cognition in the Elderly [Full text]

4. Voiding dysfunction in spinal cord disorders [Full text]

5. Iatrogenic voiding (Bladder) dysfunction [Full text]

6. Neurogenic bladders due to Supraspinal lesions (Detrusal hyperreflexia) [Full text]

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Bladder dysfunction: Detrusor hyperreflexia

The author: Professor Yasser Metwally

http://yassermetwally.com


INTRODUCTION

February  8, 2010 —  Detrusor hyperreflexia is a condition of uninhibited detrusor contractions (resulting in frequency, urgency and urge incontinence) in the presence of a neurologic lesion believed to be causative. In these cases, the pathophysiology of the incontinence can be traced back to a pathologic process involving the suprasacral spinal cord or CNS (Pyramidal or extrapyramidal lesions). Such disorders include spinal cord injuries, MS, cerebrovascular disease, stroke, Parkinson disease, dementia, and CNS/spinal neoplasia. (Click for more details)

  • Definition of detrusor hyperreflexia & Detrusor instability and Urge incontinence

The International Continence Society (ICS), describes the unstable bladder as one that has been shown objectively to contract spontaneously during the filling phase of cystometry, while the patient is inhibiting or attempting to inhibit voiding. If these contractions result in urinary leakage, then the term urge incontinence is used. In the patient who is nonneuropathic, this disorder is called Detrusor instability (DI). In situations where a definable causative neuropathic disorder exists, the coexisting urinary incontinence disorder is termed detrusor hyperreflexia. These disorders can be quite debilitating. Recently, a study using a quality of life assessment of women with incontinence showed that women with Detrusor instability (DI) consistently had a worse quality of life than did women with other urodynamic diagnoses. In light of such data, understanding the pathophysiology of urge incontinence takes on great importance.

  • Aetiology of Detrusor hyperreflexia

Spinal cord injuries interrupt the sacral reflex arc from the suprasacral spinal cord, cerebral cortex, and higher centers. These pathways are crucial for voluntary and involuntary inhibition. In the initial phase of spinal cord injury, the bladder is areflexic and overflow incontinence results. Later, detrusor hyperreflexia usually is found upon urodynamic evaluation.

The pathophysiology of MS is that of demyelinating plaques in the white matter of the cerebral cortex, cerebellum, brain stem, spinal cord, and optic nerve. Plaques involving the frontal lobe or lateral columns can produce lower urinary tract disorders. Incontinence may be the presenting symptom of MS in about 5% of the cases. Approximately 90% of individuals with MS experience urinary tract dysfunction during the course of the disease. A summary of the published series of urodynamic findings in MS demonstrated that in patients with lower urinary tract dysfunction, the most common urodynamic diagnosis is detrusor hyperreflexia (62%). Detrusor-sphincter dyssynergia (25%) and detrusor hyporeflexia (20%) also are common. Obstructive findings are much more common in males. Of note, the urodynamic diagnosis may change over time as the disease progresses.

Hemorrhage, infarction, or vascular compromise to certain areas of the brain can result in lower urinary tract dysfunction. The frontal lobe, internal capsule, brainstem, and cerebellum commonly are involved sites. Initially, urinary retention due to detrusor areflexia is observed. This may be followed by detrusor hyperreflexia.

Approximately 40-70% of patients with Parkinson disease have lower urinary tract dysfunction. Controversy exists as to whether specific neurologic problems in patients with Parkinson disease lead to bladder dysfunction or if bladder symptoms simply are related to aging. The extrapyramidal system is believed to have an inhibitory effect on the micturition center; theoretically, loss of dopaminergic activity in this area could result in loss of detrusor inhibition.

In patients with dementia, incontinence and urinary tract dysfunction may be due to specific involvement of the areas of the cerebral cortex involved in bladder control. Alternatively, incontinence may be related to global deterioration of memory, intellectual capacity, and behavior. Urodynamically, both detrusor hyperreflexia and areflexia have been found. In the case of neoplasms, CNS tumors of the superior medial frontal lobe, spinal cord tumors above the conus medullaris, and cervical spondylosis can cause detrusor hyperreflexia.


References

1. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 10.1a January 2010 [Click to have a look at the home page]

2. Acute and Chronic Bladder Effects of L-Dopa Differ in Parkinson’s Patients [Full text]

3. Incontinence medication and Cognition in the Elderly [Full text]

4. Voiding dysfunction in spinal cord disorders [Full text]

5. Iatrogenic voiding (Bladder) dysfunction [Full text]

6. Neurogenic bladders due to Supraspinal lesions (Detrusal hyperreflexia) [Full text]

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Bladder dysfunction: A quick guide

The author: Professor Yasser Metwally

http://yassermetwally.com


INTRODUCTION

February  8, 2010 — Bladder dysfunction: A quick guide

dsfs

Spastic bladder

Atonic bladder

Sphincter dyssynergia

Anatomy

Upper motor neuron lesions

Lower motor neuron lesions

Varies

Causes

Brain or spinal cord problem (upper motor neuron lesions)

Conus medullaris, cauda equina, plexus, peripheral nerve dysfunction

ds

Symptoms

Incontinence with urgency (Frequency with urgency and urge incontinence)..Detrusar hyperreflexia

Overflow incontinence

Increased residue urine 

Urodynamic findings

Decreased capacity, reduced compliance, uninhibited detrusor contractions

Increased capacity, increased compliance, low voiding pressure & flow rate

fluctuating voiding pressure, intermittent flow rate

Management

Timed bladder emptying, intermittent catherization

Crede’s  or Valsalva’s maneuver, intermittent catherization

 

dsfs

Medication

Anticholinergics, musculotropics, calcium antagonists, beta agonists

Cholinergic med, limited by side effects

 

dsfs


References

1. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 10.1a January 2010 [Click to have a look at the home page]

2. Acute and Chronic Bladder Effects of L-Dopa Differ in Parkinson’s Patients [Full text]

3. Incontinence medication and Cognition in the Elderly [Full text]

4. Voiding dysfunction in spinal cord disorders [Full text]

5. Iatrogenic voiding (Bladder) dysfunction [Full text]

6. Neurogenic bladders due to Supraspinal lesions (Detrusal hyperreflexia) [Full text]

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    Case of the week……Focal midbrain glioma

    The author: Professor Yasser Metwally

    http://yassermetwally.com


    INTRODUCTION

    February 7, 2010 — In this case record professor Metwally discusses a case presented with the clinical diagnosis of Focal midbrain glioma. The case is presented online and in downloadable PDF format.

    Click here to download the case record in PDF format (1350 KB)

    Click here to download the short case version of this case record in PDF format (846 K)

    The patient is a 44 years old male patient, who presented clinically at the age of 10 years complaining of clinical manifestations of increased intracranial pressure. MRI at that time revealed a focal midbrain glioma inducing compression of the aqueduct of Sylvius and producing hydrocephalic changes. The patient was shunted and the operation produced marked improvement and the patient became symptom free. The patient was not given any further treatment. He was examined by MRI at regular intervals (every two years). After 34 years (now…February 2010) the patient is symptom free and the last MRI examination of the brain did not show any changes of the midbrain tumor.

    Online case. Focal midbrain glioma

    Slide show 1. Case radiology

    Click here to download the case record in PDF format (1350 KB)

    Click here to download the short case version of this case record in PDF format (846 K)


    References

    1. Lázaro BC, Landeiro JA. Tectal plate tumours. Arq Neuropsiquiatr 2006; 64:432-436.

    2. Selvapaudian S, Rajshekhar V, Chandy MJ. Brainstem glioma: comparative study of clinico-radiological presentation, pathology and outcome in children and adults. Acta Neurochir (Wien) 1999;141:721-726; discussion 726-727.

    3. Daniel CB, Christos G, Leslie JA, et al. Tectal gliomas: natural history of an indolent lesion in pediatric patients. Pediatr Neurosurg 2000;32:24-29.

    4. Section of Pediatric Neurosurgery of the American Association of Neurological Surgeons (ed.). Pediatric neurosurgery. New York: Greene and Stratton, 1982.

    5. Packer RJ, Nicholson HS, Vezina LG, et al. Brain stem gliomas. Neurosurg Clin N Am 1992;3:863-879.

    6. Sun B, Wang CC, Wang J. MRI characteristics of midbrain tumours. Rev Neurol 1996;24:73-76.

    7. Bowers DC, Georgiadis C, Burger PC, Melhem E, Cohen KJ. Tectal gliomas: radiographic progression does not mandate clinical intervention. Meeting abstract – 1999 ASCO Annual Meeting

    8. Bognar L, Turjman F, Villanyi E, et al. Tectal plate gliomas. Part II: CT scans and MR imaging of tectal gliomas. Acta Neurochir 1994;127:48-54.

    9. Lapras C, Bognar L, Turjman F, et al. Tectal plate gliomas. Part II: CT scans and MR imaging of tectal gliomas. Acta Neurochir 1994;126:76-83.

    10. Hood TW, McKeever PE. Stereotactic management of cystic gliomas of the brain stem. Neurosurgery 1989;24:373-378.

    11. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 10.1a January 2010 [Click to have a look at the home page]

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    Muscle Chloride channel (CLCN1) gene

    The author: Professor Yasser Metwally

    http://yassermetwally.com


    INTRODUCTION

    February 6, 2010 —  A number of mutations have been identified in CLCN1 gene in patients with Becker and Thomsen myotonia congenita. The chloride channel is responsible for the high resting membrane potential of skeletal muscle cells. Current data suggests that both the recessive (Becker) and dominant (Thomsen) forms may have complete or near-complete loss of chloride conductance. The reduced chloride conductance results in delayed repolarization of the muscle fiber membrane, resulting in a prolonged hyperexcitability and generation of repeated action potentials.

    Only 1 mutant monomer is found in most of the patients with dominant (Thomsen) Myotonic congenita. The mutant monomer complexes with normal monomers to destroy the function of the tetrameric chloride channel (dominant negative effect). In recessive (Becker) Myotonic congenita, homozygous or compound heterozygous mutations result in 100% loss of function of the chloride channel while carriers with only 50% loss of function are asymptomatic.


    References

    1. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 11.1a January 2010 [Click to have a look at the home page]

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    Muscle Calcium channel gene

    The author: Professor Yasser Metwally

    http://yassermetwally.com


    INTRODUCTION

    February 6, 2010 —  The calcium channel (CACNL1A3) gene is a complex of 5 subunits (alpha-1, alpha-2, beta, gamma, and delta). The skeletal muscle dihydropyridine (DHP) receptor is located primarily in the transverse tubular membrane. The alpha-1 subunit has binding sites for dihydropyridine drugs (DHP receptor) and conducts the slow L-type Ca++ current. It also participates in excitation-contraction (EC) coupling and acts as a voltage sensor through its linkage with the ryanodine receptor of sarcoplasmic reticulum (calcium release channel). Any changes in the membrane potential are linked to intracellular calcium release, enabling excitation-contraction coupling. Point mutations in DHP receptor/calcium channel alpha 1 subunit cause hypokalemic periodic paralysis.

    The physiological basis of disease is still not understood, but is more likely due to a failure of excitation rather than a failure of EC coupling. However, hypokalemia-induced depolarization may reduce calcium release, directly affecting the voltage control of the channel or indirectly through inactivation of sodium channel. Insulin and adrenaline may act in a similar manner. There are some similarities as compared to SCN4A mutations. Mutations modify channel inactivation but not voltage-dependent activation. Recordings from myotube cultures from the patients revealed a 30% reduction in the DHP-sensitive L-type calcium current. Channels are inactivated at low membrane potentials. It is not understood how this inactivation is related to hypokalemia-induced attacks.


    References

    1. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 11.1a January 2010 [Click to have a look at the home page]

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    Muscle sodium channel (SCN4A) gene

    The author: Professor Yasser Metwally

    http://yassermetwally.com


    INTRODUCTION

    February 6, 2010 — The sodium channel has an alpha subunit and a beta subunit. The alpha subunit of sodium channel is a 260 kDa glycoprotein with about 1800-2000 amino acids. There is a high degree of evolutionary conservation of this channel from Drosophila to human. It has 4 homologous domains that fold to form central pore, each with 225-325 amino acids. Each domain consists of 6 hydrophobic segments (S1-S6) traversing the cell membrane. The main functions of the channel include voltage-sensitive gating, inactivation, and ion selectivity. The extracellular loop between S5 and S6 dips into the plasma membrane and participates in the formation of the pore. The S4 segment contains positively charged amino acids at every third position and functions as a voltage sensor. Conformation changes may occur during depolarization resulting in activation and inactivation of the channel. The cellular loop between domain III-S6 and domain IV-S1 acts as an inactivating gate.

    The sodium channel has 2 gates (activation and inactivation) and can exist in 3 states. At rest with the membrane polarized, the activation gate is closed and the inactivation gate is opened. With depolarization, the activation gate opens allowing sodium ions to pass through the ion channel and also exposing a docking site for the inactivation gate. With continued depolarization, the inactivation gate closes blocking the entry of sodium into the cell and causing the channel to enter the fast inactivation state. This inactivation of the channel allows the membrane to become repolarized resulting in a return to the resting state with the activation gate closed and the inactivation gate opened.

    There are several general features of sodium channel mutations. Most of the mutations are in the "inactivating" linker between repeats III and IV, in the "voltage-sensing" segment S4 of repeat IV or at the inner membrane where they could impair the docking site for the inactivation gate. The clinical phenotype differs based on the amino acid substitution and while there may be some overlap between hyperkalemic Periodic paralysis, paramyotonia congenita, and Potassium-aggravated myotonias (PAM), the 3 phenotypes are generally distinct (as described below). Nearly all mutant channels have impaired fast-inactivation of sodium current. Most of the patients are sensitive to systemic potassium or to cold temperature.

    Keeping in mind that there are 2 populations of channels, mutant and wild-type, the impaired fast inactivation results in prolonged depolarization of the mutant muscle fiber membranes and can explain the 2 cardinal symptoms of these disorders, myotonia and weakness. Mild depolarization (5-10 mV) of the myofiber membrane that may be caused by increased extracellular potassium concentrations, results in the mutant channels being maintained in the noninactivated mode. The persistent inward sodium current causes repetitive firing of the wild-type sodium channels, which is perceived as stiffness (myotonia).

    If a more severe depolarization (20-30 mV) is present, both normal and abnormal channels are fixed in a state of inactivation, causing weakness or paralysis. Thus, subtle differences in severity of membrane depolarization may make the difference from myotonia versus paralysis. Temperature sensitivity is a hallmark of paramyotonia congenita. Cold exacerbates myotonia and induces weakness. A number of mutations are associated with this condition and 3 of them at the same site (1448) in the S4 segment. These mutations replace arginine with other amino acids and neutralize this highly conserved S4 positive charge. Mutations of these residues are the commonest cause of paramyotonia congenita. Some of the possible mechanisms responsible for temperature sensitivity include the following:

    1. Temperature may differentially affect the conformational change in the mutant channel
    2. Lower temperatures may stabilize the mutant channels in an abnormal state
    3. Mutations may alter the sensitivity of the channel to other cellular processes, such as phosphorylation or second messengers

    References

    1. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 11.1a January 2010 [Click to have a look at the home page]

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    Periodic paralysis

    The author: Professor Yasser Metwally

    http://yassermetwally.com


    INTRODUCTION

    February 6, 2010 —  This heterogeneous group of muscle diseases is characterized by episodes of flaccid muscle weakness occurring at irregular intervals. Most of the conditions are hereditary and they are more episodic than periodic. They can be conveniently divided into primary and secondary.  General characteristics of primary periodic paralyses (PP) include (1) hereditary, (2) most of them are associated with alteration in the serum potassium levels, (3) myotonia sometimes coexists, and (4) both myotonia and periodic paralysis result from defective ion channels.

    Primary Periodic Paralyses

    Sodium Channel

    1- Hyperkalemic PP
    2- Paramyotonia congenita (PC)
    3- Potassium-aggravated myotonias (PAM)

    Calcium channel

    Hypokalemic PP

    Chloride channel

    1- Becker myotonia congenita
    2-Thomsen myotonia congenita

    • Hyperkalemic periodic paralyses

    Age at onset is before 10 years. Patients usually describe a sense of heaviness or stiffness in the muscles. Weakness starts in the thighs and calves, which then spreads to arms and neck. Proximal weakness predominates; distal muscles may become involved after vigorous exercise.

    In children, a myotonic lid lag (lagging of upper eyelid on downward gaze) may be the earliest symptom. Complete paralysis is rare and some residual mobility remains. Respiratory muscle involvement is rare. The attacks last less than 2 hours and in the majority, the duration is less than 1 hour. Sphincters are not involved and any bowel and bladder dysfunction is due to abdominal muscle weakness.

    Weakness occurs during rest after a period of strenuous exercise or during fasting. It may also be provoked by potassium, cold, ethanol, carbohydrates, or stress. It may be relieved by mild prolonged exercise or carbohydrate intake. Patients may also complain of muscle pains and paresthesias. Between attacks, clinical and electrical myotonia is present in the majority of patients. Some families show no myotonia. Interictal weakness, if present, is not as severe as in hypokalemic PP.

  1. Hypokalemic periodic paralyses

    Severe cases present in early childhood and mild cases may present as late as the third decade. Majority of cases present before the age of 16 years. Weakness may range from slight transient weakness of an isolated muscle group to severe generalized weakness. Severe attacks begin in the morning often with strenuous exercise or a high carbohydrate meal on the preceding day. Patients wake up with severe symmetrical weakness often with truncal involvement. Mild attacks are frequent and involve only a particular group of muscles, and may be unilateral, partial, or monomelic. Predominantly, this may affect legs, and, sometimes, extensor muscles are affected more than the flexors. Duration varies from a few hours to almost 8 days; but, typically, it seldom exceeds 72 hours. The attacks are intermittent and infrequent in the beginning but may increase in frequency with almost daily attacks. The frequency starts diminishing by age 30 years; it rarely occurs after age 50 years.

    Urinary output is decreased during the attack, because water accumulates intracellularly in muscles.

    Interictal myotonia is not as frequent as in hyperkalemic PP. Myotonic lid lag is observed between the attacks. Permanent muscle weakness may be seen later in the course of the disease and may become severe. Hypertrophy of the calves has been observed. Proximal muscle wasting, rather than hypertrophy, may be seen in patients with permanent weakness.

  2. Potassium-aggravated myotonia

    These autosomal dominant disorders have been divided into 3 categories, myotonia fluctuans, myotonia permanens, and acetazolamide-responsive myotonia congenita. Weakness is rare in these disorders, but episodic muscle pain and stiffness due to myotonia is present in myotonia fluctuans and acetazolamide-responsive myotonia congenita while it is continuous in myotonia permanens. Attacks begin at rest soon after exercise in myotonia fluctuans but are more common with exercise in acetazolamide-responsive myotonia congenita. Potassium and cold aggravate the myotonia in all 3 disorders.

  3. Paramyotonia congenita

    In this autosomal dominant disorder, myotonia worsens with activity (paradoxical myotonia), or cold temperatures. Symptoms are most pronounced in the face. Episodic weakness may also develop after exercise or cold temperatures and usually lasts only a few minutes, but may be up to days. Potassium loading usually worsens the symptoms, but in some cases, lowering the serum potassium precipitates the attacks.

  4. Thyrotoxicosis periodic paralyses

    This is the most common secondary hypokalemic periodic paralysis. It is most common in the 20-40 years age group. Hyperinsulinemia, a carbohydrate load and exercise are important in precipitating paralytic attacks. Weakness is proximal and, if severe, may involve respiratory or bulbar muscles. Attacks last hours to days. The prevalence of thyrotoxicosis periodic paralyses (TPP) in thyrotoxicosis patients is estimated to be 0.1-0.2% in Caucasians and 13-14% in Chinese. Ninety-five percent of TPP cases are sporadic. As it is more common in Orientals, a genetic predisposition is strongly suspected. Familial clustering of TPP indicates unmasking of an inherited disease (which is sporadic) by thyrotoxicosis.

    Table 1. Distinguishing Features Among the Common Forms of Periodic Paralyses  (Click to download table in PDF format)


    References

    1. Metwally, MYM: Textbook of neuroimaging, A CD-ROM publication, (Metwally, MYM editor) WEB-CD agency for electronic publication, version 11.1a January 2010 [Click to have a look at the home page]

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    Potassium channalopathy: Benign familial neonatal convulsions

    The author: Professor Yasser Metwally

    http://yassermetwally.com


    INTRODUCTION

    February 6, 2010 — Benign familial neonatal convulsions (BFNC) is an autosomal dominant condition characterized by neonatal seizures in otherwise healthy newborns. Seizures usually begin between the first and fourteenth days of life and typically remit spontaneously by 6 weeks of age. The risk of subsequent epilepsy is about 15%. The seizures are clinically heterogeneous and include eye deviation, tonic posturing, focal clonic activity and apnea with evolution to generalized convulsions. [1-3]

    Early studies demonstrated BFNC to be genetically heterogeneous. The two genes on chromosomes 20q and 8q encode highly homologous potassium channel subunits, KCNQ2 and KCNQ3. [2–3] Expression of either subunit alone in Xenopus oocytes results in small currents, but co-expression of the two genes yields a channel with currents 10–50 times larger, [4] and with the gating properties of the neuronal M-channel. [24] In-situ hybridization has demonstrated overlapping patterns of expression of KCNQ2 and KCNQ3. [4,5] These data cohere to suggest that KCNQ2 and KCNQ3 coassemble in vivo to form the M-channel. This molecular mechanism would explain why patients with BFNC linked to the loci on chromosomes 20q and 8q are clinically indistinguishable.

    Functional expression of the disease causing missense mutations in these subunits are associated with a variable reduction (20–95%) in current magnitude. [3,6] Coexpression of mutant and wild-type subunits yielded potassium currents of similar amplitude, essentially excluding a dominant negative effect. [6,7] Rather, these results are consistent with neuronal excitability being critically dependent on the absolute magnitude of KCNQ2/KCNQ3 potassium channel current.

    Reduced activity of the M-channel would be expected to cause neurons to become slightly depolarized and to fire multiple action potentials rhythmically after receiving excitatory inputs. The known functional effects of the KCNQ2 and KCNQ3 mutations are thus consistent with the clinical phenotype of seizures. It is unclear, however, why these mutations preferentially lead to seizures in the neonatal period. Possibilities include that the neonatal brain simply has a lower seizure threshold, or that potassium channel subunit expression is developmentally regulated, with neuronal excitability more dependent on the M-channel than on other voltage-sensitive potassium channels in the neonatal period.


    References

    1. Ronen G, Rosales T, Connolly M, Anderson V, Leppert M. Seizure characteristics in chromosome 20 benign familial neonatal convulsions. Neurology1993; 43:1355–60.

    2. Charlier C, Singh N, Ryan S, Lewis T, Reus B, Leach R, Leppert M. A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nature Genet1998; 18:53–5.

    3. Singh N, Charlier C, Stauffer D, DuPont B, Leach R, Melis R, Ronene G, Bjerre I, Quattlebaum T, Murphy J. A novel potassium channel gene, KNQ2, is mutated in an inherited epilepsy of newborns. Nature Genet1998; 18:25–9.

    4. Biervert C, Schroeder B, Kubisch C, Berkovic S, Propping P, Jentsch T, Steinlein O. A potassium channel mutation in neonatal human epilepsy. Science1998; 279:403–6.

    5. Schroeder B, Kubisch C, Stein V, Jentsch T. Moderate loss of function of cyclic-AMP modulated KCNQ2/KCNQ3 K+ channels cause epilepsy. Nature1998; 396:687–90.

    6. Wang H, Pan Z, Shi W, Brown B, Wymore R, Cohen I, Dixon J, McKinnon D. KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science1998; 282:1890–3.

    7. Lerche H, Biervert C, Alekov A, Schleithoff L, Lindner M, Klingler W, Bretschneider F, Mitrovic N, Jurkat-Rott K, Bode H, Lehmann-Horn F, Steinlein O. A reduced K+ current due to a novel mutation in KCNQ2 causes neonatal convulsions. Ann Neurol1999; 46:305–12.

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