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Intro (Underlined words are from the current wikipedia stub)

EAST syndrome is a syndrome consisting of epilepsy, ataxia (a movement disorder), sensorineural deafness (deafness because of problems with the hearing nerve) and salt-wasting renal tubulopathy (salt loss caused by kidney problems). The tubulopathy (renal tubule abnormalities) in this condition predispose to hypokalemic (low potassium) metabolic alkalosis with normal blood pressure. Hypomagnesemia (low blood levels of magnesium) may also be present.

EAST syndrome is an autosomal recessive genetic disorder caused by mutations in the KCNJ10 gene, as discovered by Bockenhauer and co-workers.[1] The KCNJ10 gene encodes the K+ channel Kir.4 (allowing K+ to flow into a cell rather than out) and is present in the brain, ear, and kidney.

Symptoms

Mutations

Many mutations that are found within EAST syndrome lead to a change in pH sensitivity and a modification in the IC50 value to the alkaline range, which is a higher pH reading. A specific KCNJ10 mutation, R65P, is affected by this shift. Its activity is greatly decreased when exposed to the intracellular pH. This causes more H+ sensitivity within humans, which means that the pH level is then shifted into the basic range.  There are still many other mutations such as R175Q, T164I, and R297C that also cause changes in the pH sensitivity. These mutations also have decreased sensitivity when they are exposed to physiological intracellular pH.

Epilepsy

Epilepsy is caused by the mutation KCNJ10 within EAST syndrome.  Glial cells express KCNJ10, which establishes the neuronal cells resting membrane potential.  Therefore, through repolarization, a neuron constantly takes up sodium, which causes the membrane potential to decrease because potassium is no longer being taken up intracellularly. So, because the KCNJ10 decreases the potassium uptake and increases the sodium uptake the protective barrier of potassium is no longer there, which is why seizures occur.

Ataxia

Ataxia is a non-specific condition characterized by a lack of voluntary movements to some degree. Rather than involving damage to the cerebellum, ataxia in EAST syndrome is due to the KCNJ10 mutation. In the brain, KCNJ10 is expressed in glial cells surrounding synapses and blood vessels as a K+ ion buffer. K+ is necessary to maintain a neuronal cell’s membrane potential, and these glial cells are responsible for transferring K+ ions from sites of excess K+ to sites with deficient K+. KCNJ10 is a major potassium channel in these glial cells, and when this gene is mutated, these glial cells cannot properly clear K+ from the extracellular space and deliver K+ ions to places that need it. Excess K+ in these areas of synapse disturbs physiological excitability, resulting in symptoms of ataxia.

Sensorineural Deafness

The S in EAST syndrome stands for Sensorineural Deafness, which indicates that the patient has difficulty hearing not due to environmental factors, but through genetic mutation in the KCNJ10 gene. This gene affects the potassium channel count and their productivity in several parts of the body.

Since the main mutation for EAST syndrome is in the KCNJ10 gene, it affects the potassium channels found in the inner ear cells. This includes the stria vascularis region of the inner ear, which is the upper portion of the fluid filled spiral ligament of the cochlea. The cochlea is the main region that translates sound waves into neurological signals to be interpreted by the brain. Without properly functioning potassium channel, the potassium conductance is reduced, which is critical for maintaining the endocochlear functioning properly. This implies that more potassium ions leave rather than going into the cell. This causes a lack of sound wave translation into neurological signals, which the brain is unable to understand or interpret. Potassium is also necessary on hair cells, which are mainly under concentration in the endolymph, which is an inner ear fluid membrane. Without the use of potassium channels or entry of potassium in appropriate regions, there is a lack of signal transduction that help with processing sounds.

Tubulopathy

Tubulopathy is represented by the T in the acronym EAST syndrome. This is a renal salt wasting tubulopathy involved in the kidneys. The mutation involved in EAST syndrome causes subnormal absorption of certain ions such as Na+, Ca2+, and Mg2+. The KCNJ10 gene is associated with a K+ channel in the distal convoluted tubule and the connecting tubule, two specific regions of the kidneys. These regions play a role in the excretion and absorption of salts. The KCNJ10 is an inwardly rectifying potassium channel which means it is important in the recycling of K+  believed to further be useful in building a gradient for Na+/K+ - ATPase’s. In addition to diminishing Na+/K+ - ATPase’s inadequate KCNJ10 functioning leads to depolarization of the basolateral membrane which reduces electrogenic transporters driving force. The lack of Na+ typically leads to the low blood pressure typical of EAST syndrome patients. The salt wasting tubulopathy of EAST syndrome most closely resembles that of Gitelman syndrome which is the most common syndrome affecting the distal convoluted tubule.

Prevention/Screening

EAST syndrome is an autosomal recessive disorder; therefore, it cannot necessarily be prevented. Presence of the four symptoms (epilepsy, ataxia, sensorineural deafness, and salt-wasting renal tubulopathy) and detection of a mutation in the KCNJ10 gene would indicate the presence of this disorder.

Management

There is not yet one method to help EAST syndrome as a whole, but hopefully with continued research, there could be one day.