EAST syndrome

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EAST syndrome
Other namesSeSAME syndrome [1]
Pronunciation

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). [2] 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.[ citation needed ] [3]

Contents

EAST syndrome is also called SeSAME syndrome, [1] as a syndrome of seizures, sensorineural deafness, ataxia, intellectual disability (mental retardation), and electrolyte imbalances. It is an autosomal recessive genetic disorder caused by mutations in the KCNJ10 gene, as discovered by Bockenhauer and co-workers. [4] The KCNJ10 gene encodes the K+ channel Kir4.1 (allowing K+ to flow into a cell rather than out) and is present in the brain, ear, and kidney.

Symptoms and signs

Mutations

Representation of autosomal recessive disease Autosomal recessive inheritance.gif
Representation of autosomal recessive disease

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. [5]

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. Seizures occur because the KCNJ10 mutation increases the sodium uptake and decreases the potassium uptake, which means the protective barrier of potassium is no longer there. [6]

Some signs of epilepsy can be temporary confusion, a staring spell, or uncontrollable movements of the arms and legs. A person may also experience a loss of consciousness or psychic symptoms. Someone with epilepsy typically has the same type of seizure each time one occurs and so the symptoms are also similar each time. [7]

The treatments of epilepsy vary depending on the case. Some treatments include medications, surgery, therapies, or a ketogenic diet.[ citation needed ]

Ataxia

Ataxia can develop very abruptly or it can develop over time. Some signs and symptoms of ataxia are loss of balance, loss of muscle coordination in an arm, hand, or leg, difficulty walking, slur of speech, or difficulty swallowing. [8] 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. [9]

The treatment of ataxia depends on the cause, and there is not current research for EAST syndrome specific treatment; however, there are some general ways to improve disability from ataxia. The movement disorders associated with ataxia can be managed by pharmacological treatments and through physical therapy and occupational therapy to reduce disability. [10] Physical therapy treatment is highly dependent on each individual and varies. A recent review states that physical therapy is effective, however, there is only moderate evidence to support this. [11]

Sensorineural deafness

When a person shows signs of sensorineural deafness there is usually muffling of speech, difficulty understanding words, especially against background noise or in a crowd of people. A person might also frequently ask others to speak more slowly, clearly and loudly. They might also withdraw from conversations or avoid some social settings because everything sounds muffled, even when there are loud noises. [12] Sensorineural Deafness 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.[ citation needed ]

Cochlea crossection Cochlea-crosssection.svg
Cochlea crossection

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. [13]

Even though sensorineural deafness is irreversible, one treatment are cochlear implants, which includes a microphone and electronic devices that sit externally to the head. When sound is emitted to the microphone, it converts the sound waves into electrical impulses. In contrast to hearing aids, which amplify sound, cochlear implants are designed to stimulate the auditory nerve. [14]

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. [6]

Diagnosis

Management

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.[ citation needed ]

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

See also

Related Research Articles

<span class="mw-page-title-main">Wolfram syndrome</span> Human disease

Wolfram syndrome, also called DIDMOAD, is a rare autosomal-recessive genetic disorder that causes childhood-onset diabetes mellitus, optic atrophy, and deafness as well as various other possible disorders including neurodegeneration. Symptoms can start to appear as early as childhood to adult years. There is a 25% recurrence risk in children.

<span class="mw-page-title-main">Jervell and Lange-Nielsen syndrome</span> Medical condition

Jervell and Lange-Nielsen syndrome (JLNS) is a rare type of long QT syndrome associated with severe, bilateral sensorineural hearing loss. Those with JLNS are at risk of abnormal heart rhythms called arrhythmias, which can lead to fainting, seizures, or sudden death. JLNS, like other forms of long QT syndrome, causes the cardiac muscle to take longer than usual to recharge between beats. It is caused by genetic variants responsible for producing ion channels that carry transport potassium out of cells. The condition is usually diagnosed using an electrocardiogram, but genetic testing can also be used. Treatment includes lifestyle measures, beta blockers, and implantation of a defibrillator in some cases. It was first described by Anton Jervell and Fred Lange-Nielsen in 1957.

<span class="mw-page-title-main">Gitelman syndrome</span> Genetic kidney disorder

Gitelman syndrome (GS) is an autosomal recessive kidney tubule disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH. It is the most frequent hereditary salt-losing tubulopathy. Gitelman syndrome is caused by disease-causing variants on both alleles of the SLC12A3 gene. The SLC12A3 gene encodes the thiazide-sensitive sodium-chloride cotransporter, which can be found in the distal convoluted tubule of the kidney.

<span class="mw-page-title-main">Channelopathy</span> Diseases caused by dysfunction of ion channels or related proteins

Channelopathies are a group of diseases caused by the dysfunction of ion channel subunits or their interacting proteins. These diseases can be inherited or acquired by other disorders, drugs, or toxins. Mutations in genes encoding ion channels, which impair channel function, are the most common cause of channelopathies. There are more than 400 genes that encode ion channels, found in all human cell types and are involved in almost all physiological processes. Each type of channel is a multimeric complex of subunits encoded by a number of genes. Depending where the mutation occurs it may affect the gating, conductance, ion selectivity, or signal transduction of the channel.

<span class="mw-page-title-main">Inward-rectifier potassium channel</span> Group of transmembrane proteins that passively transport potassium ions

Inward-rectifier potassium channels (Kir, IRK) are a specific lipid-gated subset of potassium channels. To date, seven subfamilies have been identified in various mammalian cell types, plants, and bacteria. They are activated by phosphatidylinositol 4,5-bisphosphate (PIP2). The malfunction of the channels has been implicated in several diseases. IRK channels possess a pore domain, homologous to that of voltage-gated ion channels, and flanking transmembrane segments (TMSs). They may exist in the membrane as homo- or heterooligomers and each monomer possesses between 2 and 4 TMSs. In terms of function, these proteins transport potassium (K+), with a greater tendency for K+ uptake than K+ export. The process of inward-rectification was discovered by Denis Noble in cardiac muscle cells in 1960s and by Richard Adrian and Alan Hodgkin in 1970 in skeletal muscle cells.

<span class="mw-page-title-main">Metabolic alkalosis</span> Abnormally high tissue pH due to metabolic dysfunction

Metabolic alkalosis is an acid-base disorder in which the pH of tissue is elevated beyond the normal range (7.35–7.45). This is the result of decreased hydrogen ion concentration, leading to increased bicarbonate, or alternatively a direct result of increased bicarbonate concentrations. The condition typically cannot last long if the kidneys are functioning properly.

<span class="mw-page-title-main">Renal tubular acidosis</span> Higher blood acidity due to failure of the kidneys to fully acidify urine

Renal tubular acidosis (RTA) is a medical condition that involves an accumulation of acid in the body due to a failure of the kidneys to appropriately acidify the urine. In renal physiology, when blood is filtered by the kidney, the filtrate passes through the tubules of the nephron, allowing for exchange of salts, acid equivalents, and other solutes before it drains into the bladder as urine. The metabolic acidosis that results from RTA may be caused either by insufficient secretion of hydrogen ions into the latter portions of the nephron or by failure to reabsorb sufficient bicarbonate ions from the filtrate in the early portion of the nephron. Although a metabolic acidosis also occurs in those with chronic kidney disease, the term RTA is reserved for individuals with poor urinary acidification in otherwise well-functioning kidneys. Several different types of RTA exist, which all have different syndromes and different causes. RTA is usually an incidental finding based on routine blood draws that show abnormal results. Clinically, patients may present with vague symptoms such as dehydration, mental status changes, or delayed growth in adolescents.

<span class="mw-page-title-main">Liddle's syndrome</span> Medical condition

Liddle's syndrome, also called Liddle syndrome, is a genetic disorder inherited in an autosomal dominant manner that is characterized by early, and frequently severe, high blood pressure associated with low plasma renin activity, metabolic alkalosis, low blood potassium, and normal to low levels of aldosterone. Liddle syndrome involves abnormal kidney function, with excess reabsorption of sodium and loss of potassium from the renal tubule, and is treated with a combination of low sodium diet and potassium-sparing diuretics. It is extremely rare, with fewer than 30 pedigrees or isolated cases having been reported worldwide as of 2008.

<span class="mw-page-title-main">Bartter syndrome</span> Medical condition

Bartter syndrome (BS) is a rare inherited disease characterised by a defect in the thick ascending limb of the loop of Henle, which results in low potassium levels (hypokalemia), increased blood pH (alkalosis), and normal to low blood pressure. There are two types of Bartter syndrome: neonatal and classic. A closely associated disorder, Gitelman syndrome, is milder than both subtypes of Bartter syndrome.

<span class="mw-page-title-main">Sodium-chloride symporter</span> Protein-coding gene in the species Homo sapiens

The sodium-chloride symporter (also known as Na+-Cl− cotransporter, NCC or NCCT, or as the thiazide-sensitive Na+-Cl− cotransporter or TSC) is a cotransporter in the kidney which has the function of reabsorbing sodium and chloride ions from the tubular fluid into the cells of the distal convoluted tubule of the nephron. It is a member of the SLC12 cotransporter family of electroneutral cation-coupled chloride cotransporters. In humans, it is encoded by the SLC12A3 gene (solute carrier family 12 member 3) located in 16q13.

Dravet syndrome (DS), previously known as severe myoclonic epilepsy of infancy (SMEI), is an autosomal dominant genetic disorder which causes a catastrophic form of epilepsy, with prolonged seizures that are often triggered by hot temperatures or fever. It is very difficult to treat with anticonvulsant medications. It often begins before one year of age, with six months being the age that seizures, char­ac­ter­ized by prolonged convulsions and triggered by fever, usually begin.

Hypomagnesemia with secondary hypocalcemia (HSH) is an autosomal recessive genetic disorder that affects the absorption of magnesium in the intestines. It is characterized by reduced reabsorption of magnesium from our diet in the intestines, leading to decreased levels of magnesium in the bloodstream. This, in turn, causes a decrease in the production of parathyroid hormone (PTH) by the parathyroid gland. Consequently, there is a decrease in both PTH and serum calcium levels, resulting in secondary hypocalcemia.

<span class="mw-page-title-main">Pendrin</span> Anion exchange protein

Pendrin is an anion exchange protein that in humans is encoded by the SLC26A4 gene . Pendrin was initially identified as a sodium-independent chloride-iodide exchanger with subsequent studies showing that it also accepts formate and bicarbonate as substrates. Pendrin is similar to the Band 3 transport protein found in red blood cells. Pendrin is the protein which is mutated in Pendred syndrome, which is an autosomal recessive disorder characterized by sensorineural hearing loss, goiter and a partial organification problem detectable by a positive perchlorate test.

<span class="mw-page-title-main">Dent's disease</span> Medical condition

Dent's disease is a rare X-linked recessive inherited condition that affects the proximal renal tubules of the kidney. It is one cause of Fanconi syndrome, and is characterized by tubular proteinuria, excess calcium in the urine, formation of calcium kidney stones, nephrocalcinosis, and chronic kidney failure.

Progressive Myoclonic Epilepsies (PME) are a rare group of inherited neurodegenerative diseases characterized by myoclonus, resistance to treatment, and neurological deterioration. The cause of PME depends largely on the type of PME. Most PMEs are caused by autosomal dominant or recessive and mitochondrial mutations. The location of the mutation also affects the inheritance and treatment of PME. Diagnosing PME is difficult due to their genetic heterogeneity and the lack of a genetic mutation identified in some patients. The prognosis depends largely on the worsening symptoms and failure to respond to treatment. There is no current cure for PME and treatment focuses on managing myoclonus and seizures through antiepileptic medication (AED).

<span class="mw-page-title-main">KCNJ10</span> Protein-coding gene in the species Homo sapiens

ATP-sensitive inward rectifier potassium channel 10 is a protein that in humans is encoded by the KCNJ10 gene.

<span class="mw-page-title-main">BSND</span> Protein-coding gene in the species Homo sapiens

Bartter syndrome, infantile, with sensorineural deafness (Barttin), also known as BSND, is a human gene which is associated with Bartter syndrome.

<span class="mw-page-title-main">Donnai–Barrow syndrome</span> Medical condition

Donnai–Barrow syndrome is a genetic disorder first described by Dian Donnai and Margaret Barrow in 1993. It is associated with LRP2. It is an inherited (genetic) disorder that affects many parts of the body.

<span class="mw-page-title-main">Distal renal tubular acidosis</span> Medical condition

Distal renal tubular acidosis (dRTA) is the classical form of RTA, being the first described. Distal RTA is characterized by a failure of acid secretion by the alpha intercalated cells of the distal tubule and cortical collecting duct of the distal nephron. This failure of acid secretion may be due to a number of causes. It leads to relatively alkaline urine, due to the kidney's inability to acidify the urine to a pH of less than 5.3.

CAPOS syndrome is a rare genetic neurological disorder which is characterized by abnormalities of the feet, eyes and brain which affect their normal function. These symptoms occur episodically when a fever-related infection is present within the body. The name is an acronym for "cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss".

References

  1. 1 2 Orphanet, EAST syndrome (ORPHA199343) , retrieved 2016-06-23.
  2. ↑ OMIM, Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance; SeSAMES (OMIM #612780) , retrieved 2016-06-23.
  3. ↑ Abdelhadi, O.; Iancu, D.; Stanescu, H.; Kleta, R.; Bockenhauer, D. (2016). "EAST syndrome: Clinical, pathophysiological, and genetic aspects of mutations in KCNJ10". Rare Diseases (Austin, Tex.). 4 (1): e1195043. doi:10.1080/21675511.2016.1195043. PMC   4961265 . PMID   27500072.
  4. ↑ Bockenhauer D, Feather S, Stanescu HC, et al. (May 2009). "Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations". N. Engl. J. Med. 360 (19): 1960–70. doi:10.1056/NEJMoa0810276. PMC   3398803 . PMID   19420365.
  5. ↑ Reichold M, Zdebik AA, Lieberer E, Rapedius M, Schmidt K, Bandulik S, Sterner C, Tegtmeier I, Penton D, Baukrowitz T, Hulton SA, Witzgall R, Ben-Zeev B, Howie AJ, Kleta R, Bockenhauer D, Warth R (2010). "KCNJ10 gene mutations causing EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function". Proc. Natl. Acad. Sci. U.S.A. 107 (32): 14490–5. Bibcode:2010PNAS..10714490R. doi: 10.1073/pnas.1003072107 . PMC   2922599 . PMID   20651251.
  6. 1 2 Bandulik, Sascha (2011). "The salt- wasting phenotype of EAST syndrome, a disease with multifaceted symptoms linked to the KCNJ10 K+ channel". Pflügers Archiv: European Journal of Physiology. 461 (4): 423–435. doi:10.1007/s00424-010-0915-0. PMID   21221631. S2CID   13484948.
  7. ↑ Mayo Clinic Staff. "Epilepsy- Symptoms and Causes". Mayo Clinic. Retrieved 25 April 2016.
  8. ↑ "Diagnosis of Ataxia". National Ataxia Foundation. Archived from the original on 30 July 2017. Retrieved 25 April 2016.
  9. ↑ Bandulik, Sascha (April 2011). "The salt-wasting phenotype of EAST syndrome, a disease with multifaceted symptoms linked to the KCNJ10 K+ channel". Pflügers Archiv: European Journal of Physiology. 461 (4): 423–435. doi:10.1007/s00424-010-0915-0. PMID   21221631. S2CID   13484948.
  10. ↑ Perlman SL (November 2006). "Ataxias". Clin. Geriatr. Med. 22 (4): 859–77, vii. doi:10.1016/j.cger.2006.06.011. PMID   17000340.
  11. ↑ Martin CL, Tan D, Bragge P, Bialocerkowski A (January 2009). "Effectiveness of physiotherapy for adults with cerebellar dysfunction: a systematic review". Clinical Rehabilitation. 23 (1): 15–26. doi:10.1177/0269215508097853. PMID   19114434. S2CID   25458915.
  12. ↑ "Hearing Loss Signs and Symptoms". UCSF Medical Center. Retrieved 25 April 2016.
  13. ↑ Moody, Antonio; Stransnick, Barry; A. M.D, Stephanie. "Genetic Sensorineural Hearing Loss". Medscape. FACS. Retrieved 3 February 2016.
  14. ↑ "Cochlear Implants". National Institute of Deafness and Other Communication Disorders. U.S. Department of Health and Human Services. Retrieved August 18, 2014.
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