Download Ion channel disorders by Dr Susan Tomlinson

Name of Disorder: Ion Channel Disorders
Essay Title: Ion Channel Disorders
Author: Dr Susan Tomlinson
Institution: University of Sydney
Date: 27 June, 2014
Nerve and muscle cell membranes have the unique feature of being
electrically active. Ion channels are membrane-bound proteins which allow the
passage of charged particles (ions) across the membrane of nerve cells and
maintain the electrical activity of the membrane. Dysfunction of ion channels (either
genetic or acquired) can result in abnormal nerve excitability. The symptoms of ion
channel dysfunction in the nervous system are widely varied and depend upon the
site of the specific channel affected, and the role of that channel in the membrane.
For example, if a dysfunctional channel is expressed in the hippocampus in the
brain, a patient may develop seizures. If a different channel situated in muscle is
dysfunctional, muscle paralysis may ensue.
Neurological features caused by ion channel dysfunction include seizures,
ataxia, migraine, pain, muscle weakness, epilepsy and stroke-like symptoms. Such
disorders may be due to mutations in a single ion channel gene, or due to
development of an autoimmune antibody directed against an ion channel. Genetic
channelopathies are ideal disease models in which to study the effect of a single
channel in vivo. For example, almost all single-gene epilepsies are due to mutations
in genes which encode ion channels and great insights into the seizure generation
has been achieved through study of these conditions. While single-gene epilepsies
are still rare, it is likely that susceptibility to idiopathic epilepsy is due to complex
inheritance of ion channel genes, with the nett result being instability of nerve
membrane. Furthermore, a significant proportion of medications prescribed by
neurologists exert effects by modifying ion channel function. Many of these
pharmacologic agents were developed prior to our understanding of how channel
dysfunction can result in neurological symptoms. Hence, an understanding of ion
channel function and disorders is relevant to every subspecialty in neurology.
A clinical feature often seen in channelopathies is that symptoms may be
episodic or paroxysmal, and the patient may return to normal between episodes.
This can pose a challenge to doctors when assessing the patient, as the sufferer
may have no deficit between episodes. Historically, patients with channelopathies
were often diagnosed with hysteria or malingering because of this feature of
paroxysmal episodes from which they would fully recover, sometimes very quickly.
In contrast, some channelopathies have a progressive course, which may evolve
after initially starting with episodic symptoms. This interplay between paroxysmal
and progressive features in channelopathies is not well understood.
A further challenge in the diagnosis of channelopathies is that the underlying
disorder produces abnormal muscle or nerve function, whereas structurally the
muscle and nerves are intact. This means the clinician must always have the
thought of a channelopathy on their radar, and choose investigations appropriately.
Tests that assess structure of the nervous system (e.g. MRI, biopsy) may be entirely
normal and unhelpful with achieving a diagnosis. In the assessment of
channelopathies, it is imperative that tests assess function. Tools used to test for
abnormal membrane excitability include EEG, TMS, nerve conduction studies and
EMG. These tests can provide indications of instability of muscle or nerve
membrane electrical activity, however, have limited scope to provide data regarding
specific, single-channel function. For example, a patient with epilepsy may have a
normal MRI (structural assessment) but an abnormal EEG (functional assessment).
The EEG will not be able to determine if the electrical instability pertains to a specific
channel.
Assessment of a specific, single ion channel type previously relied on in vitro
expression of single channels. This cannot factor in the complex cascade of
interactions that occur in vivo and stemming from channel dysfunction. Therefore a
tool to sensitively measure ion channel function in vivo is critically needed in order to
define pathophysiology, aid diagnosis, monitor progress and assess treatment
outcomes. The TROND protocol of nerve excitability studies is a non-invasive test
performed in a similar fashion to nerve conduction studies. It provides information
regarding channel function in peripheral nerve and can provide helpful information
about peripheral nerve ion channels and membrane potential in vivo. While the
central nervous system cannot be directly interrogated in this way, peripheral nerves
carry many similarities and can provide a surrogate marker of channel function in the
CNS in some (but not all) patients with ion channel disorders.