Ion channel diseases

Ion channel diseases" are a heterogeneous group, predominantly hereditary, often autosomal-dominantly inherited, less frequently acquired diseases, which are based on defects in ion channels. Ion channelsare membrane-bound proteins that form selectively effective pores for sodium, chloride, potassium and calcium ions. The undisturbed physiological functionality of these ion channels is an important prerequisite for the undisturbed activity of muscles or the nervous system. Ion channels mediate the conversion of sensory stimuli and transmit this information via action potentials and synaptic transmission processes.

Mutations in genes that code for channel proteins lead to a changed "switching behaviour" of the ion channels. Increased or decreased openings of the membrane-bound channel proteins cause a pathological excitation potential of the affected tissue. The diagnosis should be confirmed by molecular genetic diagnostics

Neurogenic and muscular ion channel diseases.

• Nocturnal autosomal dominant frontal lobe epilepsy (Steinlein et al 1995): CHRNA4 (20q) gene encoding the a-4 portion of the ligand-gated neuronal nicotinic acetylcholine receptor.
• Nocturnal autosomal dominant frontal lobe epilepsy (De Fusco et al 2000): CHRNB2 (1q) gene encoding the b-2 subsection of the nicotinic acetylcholine receptor.
• Benign neonatal convulsions (Singh et al 1998): KCNQ2 (20q) gene encoding the voltage-gated potassium channel.
• Benign neonatal convulsions (Charkier et al 1998): KCNQ3 (8q) gene encoding the voltage-gated potassium channel.
• Generalized epilepsy and febrile convulsions (Wallace et al 1998): SCN1B (19q)-gene encoding the b-1 and a-1 portions of the voltage-gated neuronal sodium channel.
• Generalized epilepsy and febrile convulsions (Escayg et al 2000): SCN1A (2q) gene encoding the b-1 and a-1 portion of the voltage-gated neuronal sodium channel.
• Generalized epilepsy and febrile convulsions (Baulac et al 2001): GABRG2 (5q) gene encoding the g-2 portion of the GABA-A receptor.
• Febrile convulsions/absence epilepsy of childhood (Wallace et al 2001): GABRG2 (5q) gene encoding the g-2 portion of the GABA-A receptor.
• Periventricular heterotopia (Fox et al 1998): Filamin (Xq28) Filamin gene.
• Episodic ataxia with myokymia (EA-1): KCNA1. Gene encoding a potassium channel.
• Episodic ataxia (EA-2): KCNA1. Gene encoding a calcium channel.
• Hemiplegic migraine: CACNL1A4. Gene encoding a calcium channel.
• Stratle disease (hyperekpexia): GLTA1. Gene encoding the alpha1 subfamily of the glycine receptor.
• Autosomal dominant deafness (DFNA 2) KCNQ4

Skeletal muscle ion channel diseases

• Potassium-sensitive myotonia (hypokalemic periodic paralysis type I) SCN4A . Gene encoding the alpha subunit of the sodium ion channel.
• Paramyotonia congenita: SCN4A. Gene encoding the alpha subunit of the sodium ion channel.
• Hyperkalemic myotonia: SCN4A. Gene encoding the alpha subunit of the sodium ion channel.
• Hypokalemic periodic paralysis: CACNL1A3. Gene encoding a calcium ion channel and the dihydropyridine receptor.
• A.R. (Becker`s) myotonia: CLCN1. Gene encoding a chloride ion channel.
• A.D.(Thomson`s) myotonia: CLCN1. Gene encoding a chloride ion channel
• Malignant hypertension: RYR1, SCNA4; CACNL2A, CACNL1A3. Different genes
• Central Core disease: RYR1. Gene encoding calcium release channel (ryanodine receptor).
• Congenital myasthenia syndrome: CHRNA1; CHRNB1, CHRNE. Rare only 1-4% of all forms of myasthenia.

Cardiac ion channel diseases

• Cardiac ion channel diseases are due to mutations in ion channels and other functional proteins that can lead to bradycardic and tachycardic supraventricular arrhythmias, ventricular arrhythmias, syncope, and sudden cardiac death. Cardiac ion channel diseases can be classified based on the function of the mutant proteins. For clinical practice, the classification according to clinical and ECG criteria is particularly important.
• Long QT syndrome: KCNQ1- KCNQ2; SCN5A. Genes encoding the slow and fast potassium channels. The mutations are associated with loss of function. Furthermore, mutations in the cardiac sodium channel gene with gain of function underlie this syndrome.
• Romano-WRD syndrome: LQTS1-6.
• Jervell and Lange-Nelsen syndrome: KVLQT1, KCNQ1, KCNA8.
• Andersen-Tavil syndrome: LQTS7 gene. Gene encoding potassium channels.
• Short QT syndrome: KCNH1 gene; KCNQ1 gene KCNJ2 gene.
• Brugada syndrome: SCN5 gene. Gene encoding a protein of a potassium channel.
• Catecholaminergic polymorphic ventricular tachycardia (CPVT): Ryanodine receptor organ (RyR2)/calcisequestrin (CASQ2) gene. These genes encode the proteins that control calcium release from the sarcoplasmic reticulum. Patients with CPVT have a normal resting ECG and structurally and functionally unremarkable echo findings. Pathognomonic features include polymorphic ventricular extrasystoles and bidirectional or polymorphic ventricular tachycardia (VT), which are detectable on exercise and long-term ECG and on loop recorders or with drug provocation with epinephrine or isoproterenol. In addition, adrenergic-mediated atrial tachycardia may occur.

Nephrogenic ion channel diseases

• DeToni-Debré-Fanconi syndrome: EHHADH. Gene encoding the eponymous enzyme in mitochodrial fatty acid metabolism. Enzyme deficiency leads to tubule dysfunction.
• Bartter syndrome (different variants I-V -SLC12A; KCNJ1, CLCNKB, BSND). These genes lead to disruptions in Na and Ca ion channels in the renal tubules, resulting in renal tubular dysfunction.
• Liddle syndrome: mutations in a constitutively active Na channel with increased Na reabsorption.
• EAST syndrome (epilepsy, ataxia, hearing loss, tubulopathy): KCNJ10. Gene encoding a potassium channel localized in kidneys here in the distal nephron, brain and stria vascularis of the inner ear.

Other:

• Cystic fibrosis (pleiotropic ion channel disease with substantial lung involvement):Cystic fibrosis monogenic disease is caused by mutations in the cystic fibrosis transmembrane conductance regulator(CFTR) gene.

Nerves, muscle and sensory cells need a sufficient electrical charge state to fulfil their function (comparable to a battery). Ion channels provide for an electrical homeostasis of the cells. Genetic or autoimmunologically induced changes in the composition of the channel proteins can temporarily or permanently lead to a discharge of this "cell battery" and thus cause diseases. Changes in ion channels are associated with the following diseases:

• Chloride channels: Disturbances of the chloride channels are responsible for Myotonia congenita Thomson and Myotonia congenita Becker.
• Sodium channels: Disorders of the sodium channels are responsible for Eulenburg's paramyotonia congenita, myotonia fluctuans, myotonia permanent, acetazolamide sensitive myotonia and hyperkalemic periodic paralysis.
• Potassium channels: Disturbances of the potassium channels are believed to be responsible for familial benign neonatal convulsions, episodic ataxia type 1, paroxysmal choreoathetosis, and a form of hereditary deafness.
• Calcium channels: Disorders of calcium channels seem to be responsible for hypokalemic periodic paralysis, malignant hyperthermia, and central-core myopathy, congenital deafness (KCNQ4), and certain forms of night blindness. Schizophrenia is also suspected of having a dysfunction of KCNN3, a calcium-dependent potassium channel.
• Autoimmunological channelopathies: Isaacs syndrome (acquired neuromyotonia) is an antibody-mediated potassium ion channel disease. The "target channel proteins of these antigens are so-called "voltage-gated potassium channels (VGKCs), especially dendrotoxin-sensitive fast potassium channels or the ganglionic nicotinic acetylcholine receptors (AChR). Here, the suppression of the outwardly directed potassium flow leads to hyperexcitability of the peripheral nerves.
• Mutations in several ion channels: central nervous excitation disorders such as episodic ataxias, familial hemiplegic migraine and 3 forms of dominant hereditary epilepsies. There is evidence that some epilepsies are ion channel disorders. Various ion channels can be affected (potassium, sodium and calcium channels). In the group of idiopathic-generalised epilepsies, an interaction of different genes seems to occur.

Ion channels are membrane proteins that form selective pores for Na+, K+, Cl- or Ca2+ ions. They are the basis of the electrical excitability of nerve and muscle cells. Ion channels mediate communication with the environment by transforming different stimuli into receptor potentials. At muscular effector organs such as heart or skeletal muscle, they convert the electrical action potential into a mechanical muscle contraction. In the transmission of the action potential, it is the electrical membrane voltage that controls the switching behaviour of sodium and potassium channels via specific conformational changes of the proteins; in synaptic transmission processes, it is ligands such as acetylcholine and its receptors that transmit information.

Ion channel diseases are clinically characterized by an episodic occurrence of various functional disorders of the skeletal or cardiac muscles and the central nervous system (more rarely other tissues, e.g. the kidney). During a seizure there is usually an involuntary disturbance of excitation of the affected tissue. Depending on the type and location of the ion channel, this can manifest itself as cardiac arrhythmia, muscle stiffness, paralysis, ataxia, migraine or epileptic seizures. In organs that are not primarily excitable, such as the kidney, mutations in ion channels can cause electrolyte disorders.

Often the symptoms can be provoked by certain triggers, such as physical exertion or intake of carbohydrate-rich food. In the seizure-free interval, patients are often inconspicuous. However, in the course of some diseases, degeneration of the affected tissue may develop, leading to slowly progressive muscle atrophies, ataxia or nystagmus, for example.

The family history plays a key role in the analysis of an ion channel disease.

If a genetic defect is known, the pathophysiology of ion channel diseases can be elucidated in detail using electrophysiological techniques (voltage clamp, patch clamp - see below ion channels), which allow an exact functional analysis of the mutated ion channels down to the molecular level.

In clinically identified familial syndromes with typically episodic central or peripheral excitation disorders, such as epileptic seizures, episodic ataxias, paroxysmal dystonia or migraine, cardiac arrhythmia, the disease is additionally confirmed by molecular genetic investigations.

Treatment can also be based on the knowledge of the pathophysiological mechanism. Drugs, changes in the concentration of the ions can alter the threshold of activation of the ion channels or inactivate them, an action potential and the transmission of a nerve impulse is thus either facilitated or prevented.

Due to the fundamental importance of ion channels, it would actually be expected that mutations in these highly conserved and functionally important regions with changes in specific proteins would not allow for viability. Often, however, the measurable changes in the switching behaviour of the sodium channel are only very small and lead to only minor disturbance over a long period of time. Only when an additional trigger is added, e.g. a membrane depolarization due to an increase in potassium in the serum after muscle work, can the system become unbalanced. The disturbance becomes clinically manifest.

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