EAST Syndrome

Genetic MONDO:0013005 Pathograph 17 Show in embeddings browser

EAST syndrome (also called SeSAME syndrome) is a rare autosomal recessive disorder caused by biallelic loss-of-function variants in KCNJ10, which encodes the inwardly rectifying potassium channel Kir4.1. Kir4.1 is expressed in glia of the brain and spinal cord, in the inner ear (stria vascularis of the cochlea), in the kidney (basolateral membrane of the distal convoluted tubule), and in the eye. Channel loss of function produces the cardinal tetrad of Epilepsy, Ataxia, Sensorineural deafness, and a renal salt-wasting Tubulopathy with normotensive hypokalemic metabolic alkalosis and hypomagnesemia, typically accompanied by developmental delay and intellectual disability. The syndrome was independently described in 2009 by Bockenhauer et al. (who named it EAST) and Scholl et al. (who named it SeSAME).

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4
Pathophys.
9
Phenotypes
17
Pathograph
1
Genes
4
Medical Actions
8
References
1
Deep Research
⚙

Pathophysiology

4
Kir4.1 Potassium Channel Loss of Function
Biallelic missense or nonsense variants in KCNJ10 reduce or abolish the inwardly rectifying potassium current carried by Kir4.1. Heterologous expression of patient mutations in Xenopus oocytes causes significant and specific decreases in potassium currents, and many of the mutations affect highly conserved residues known to cause loss of function in related K+ channels. This is the primary molecular lesion underlying all downstream organ-specific manifestations.
KCNJ10 hgnc:6256
potassium ion transmembrane transport GO:0071805 ↓ DECREASED
inward rectifier potassium channel activity GO:0005242 ↓ DECREASED
Downstream
Impaired Glial Potassium Buffering
Impaired Cochlear Endolymph Homeostasis
Distal Tubule Salt Wasting
Abnormal Electroretinogram Kir4.1 loss of function also affects retinal electrophysiology in EAST syndrome, producing abnormal electroretinogram findings.
Show evidence (4 references)
PMID:19289823 SUPPORT Human Clinical
"Direct DNA sequencing of KCNJ10, which encodes an inwardly rectifying K(+) channel, identifies previously unidentified missense or nonsense mutations on both alleles in all affected subjects."
Establishes biallelic KCNJ10 variants in an inwardly rectifying potassium channel as the genetic basis of the syndrome.
PMID:19420365 SUPPORT In Vitro
"These mutations, when expressed heterologously in xenopus oocytes, caused significant and specific decreases in potassium currents."
Functional expression demonstrates the variants reduce Kir4.1 potassium channel activity (loss of function).
PMID:27500072 SUPPORT Human Clinical
"So far 14 different KCNJ10 mutations have been published which either directly affect channel function or may lead to mislocalisation."
Reviews the spectrum of KCNJ10 mutations, which cause disease either by directly impairing channel function or by channel mislocalisation.
+ 1 more reference
Impaired Glial Potassium Buffering
In the brain and spinal cord, Kir4.1 is expressed in glia, where it takes up extracellular K+ released by neuronal repolarization (spatial potassium buffering) and supports glutamate clearance. Loss of Kir4.1 raises extracellular potassium and impairs glial homeostasis, contributing to the neuronal hyperexcitability that produces seizures and to cerebellar dysfunction causing ataxia.
glial cell CL:0000125
potassium ion homeostasis GO:0055075 ↓ DECREASED neurotransmitter uptake GO:0001504 ↓ DECREASED
brain UBERON:0000955
Downstream
Seizures
Cerebellar Ataxia
Intellectual Disability
Brain MRI Abnormalities
Show evidence (1 reference)
PMID:19289823 SUPPORT Human Clinical
"KCNJ10 is expressed in glia in the brain and spinal cord, where it is believed to take up K(+) released by neuronal repolarization"
Identifies the glial potassium-buffering role of Kir4.1 whose loss drives the neurological phenotype.
Impaired Cochlear Endolymph Homeostasis
In the cochlea, Kir4.1 is expressed in the stria vascularis and is required for the generation of endolymph and the endocochlear potential. Loss of Kir4.1 function impairs endolymph homeostasis and the ionic environment needed for normal hair-cell transduction, producing sensorineural hearing loss.
potassium ion transmembrane transport GO:0071805 ↓ DECREASED
stria vascularis of cochlear duct UBERON:0002282 cochlea UBERON:0001844
Downstream
Sensorineural Hearing Loss
Show evidence (2 references)
PMID:19289823 SUPPORT Human Clinical
"in cochlea, where it is involved in the generation of endolymph"
Establishes the cochlear role of Kir4.1 in endolymph generation, the basis of the sensorineural deafness.
PMID:21849804 SUPPORT Human Clinical
"KCNJ10 is expressed in the kidney distal convoluted tubule, cochlear stria vascularis and brain glial cells."
Confirms Kir4.1 expression in the cochlear stria vascularis (alongside the renal distal tubule and brain glia), the basis of the multi-organ phenotype.
Distal Tubule Salt Wasting
In the kidney, Kir4.1 sits on the basolateral membrane of the distal convoluted tubule (often as a Kir4.1/Kir5.1 heteromer with KCNJ16), where K+ recycling across the basolateral membrane is required to sustain Na+-K+-ATPase activity and thus normal NaCl reabsorption. Loss of Kir4.1 impairs basolateral K+ recycling, causing renal salt wasting with a Gitelman-like biochemical profile: normotensive hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria. Patient distal tubular cells show reduced basolateral infoldings, reflecting impaired salt-reabsorption capacity.
kidney distal convoluted tubule epithelial cell CL:1000849
sodium ion transmembrane transport GO:0035725 ↓ DECREASED potassium ion transmembrane transport GO:0071805 ↓ DECREASED
distal convoluted tubule UBERON:0001292
Downstream
Hypokalemic Metabolic Alkalosis
Hypomagnesemia
Renal Salt Wasting
Show evidence (4 references)
PMID:19289823 SUPPORT Human Clinical
"We propose that KCNJ10 is required in the kidney for normal salt reabsorption in the distal convoluted tubule because of the need for K(+) recycling across the basolateral membrane to enable normal activity of the Na(+)-K(+)-ATPase; loss of this function accounts for the observed electrolyte defects."
Provides the mechanistic basis for the renal salt-wasting tubulopathy and electrolyte imbalance.
PMID:19420365 SUPPORT Model Organism
"Mice with Kcnj10 deletions became dehydrated, with definitive evidence of renal salt wasting."
Mouse Kcnj10 knockout recapitulates the renal salt-wasting phenotype, supporting the causal mechanism.
PMID:20651251 SUPPORT Model Organism
"Kcnj10 and Kcnj16 were found in the basolateral membrane of mouse distal convoluted tubules, connecting tubules, and cortical collecting ducts."
Localizes Kir4.1 (with Kir5.1/KCNJ16) to the basolateral membrane of the distal nephron, the anatomic basis of the renal salt-wasting mechanism.
+ 1 more reference
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for EAST Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

9
Ear 1
Sensorineural Hearing Loss VERY_FREQUENT Sensorineural hearing impairment HP:0000407
Show evidence (1 reference)
PMID:19420365 SUPPORT Human Clinical
"epilepsy beginning in infancy and severe ataxia, moderate sensorineural deafness, and a renal salt-losing tubulopathy with normotensive hypokalemic metabolic alkalosis"
The original case series describes moderate sensorineural deafness as part of the defining clinical tetrad.
Eye 1
Abnormal Electroretinogram Abnormal electroretinogram HP:0000512
Show evidence (1 reference)
PMID:21300747 SUPPORT Human Clinical
"We have studied the impact of KCNJ10 mutations on the human electroretinogram (ERG) in four unrelated patients with EAST syndrome."
Human ERG study in EAST patients documents altered retinal electrophysiology attributable to KCNJ10/Kir4.1 dysfunction in Muller glia.
Nervous System 3
Seizures VERY_FREQUENT Seizure HP:0001250
Onset: INFANTILE
Show evidence (1 reference)
PMID:23924083 SUPPORT Human Clinical
"All children presented with tonic-clonic seizures in infancy."
In a cohort of nine genetically proven EAST patients, all presented with tonic-clonic seizures in infancy, supporting seizures as a very frequent cardinal feature.
Cerebellar Ataxia VERY_FREQUENT Ataxia HP:0001251
Course: STABLE
Show evidence (2 references)
PMID:23924083 SUPPORT Human Clinical
"Later, non-progressive, cerebellar ataxia and hearing loss were noted."
Documents non-progressive cerebellar ataxia as a consistent feature of the neurological phenotype.
PMID:23924083 SUPPORT Human Clinical
"ataxia proved to be the most debilitating feature, with three patients non-ambulant"
Highlights the severity and functional impact of the ataxia.
Intellectual Disability Intellectual disability HP:0001249
Show evidence (1 reference)
PMID:19289823 SUPPORT Human Clinical
"a previously unrecognized syndrome characterized by seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance"
The SeSAME description includes mental retardation (intellectual disability) as a defining feature.
Other 4
Renal Salt Wasting VERY_FREQUENT Renal salt wasting HP:0000127
Show evidence (1 reference)
PMID:19420365 SUPPORT Human Clinical
"a renal salt-losing tubulopathy with normotensive hypokalemic metabolic alkalosis"
Defines the renal salt-wasting tubulopathy component of the syndrome.
Hypokalemic Metabolic Alkalosis VERY_FREQUENT Hypokalemic metabolic alkalosis HP:0001960
Show evidence (1 reference)
PMID:19289823 SUPPORT Human Clinical
"electrolyte imbalance (hypokalemia, metabolic alkalosis, and hypomagnesemia)"
Documents the characteristic electrolyte derangement of hypokalemia with metabolic alkalosis.
Hypomagnesemia FREQUENT Hypomagnesemia HP:0002917
Show evidence (1 reference)
PMID:19289823 SUPPORT Human Clinical
"electrolyte imbalance (hypokalemia, metabolic alkalosis, and hypomagnesemia)"
Lists hypomagnesemia as a component of the electrolyte imbalance in SeSAME syndrome.
Brain MRI Abnormalities Abnormal cerebellum morphology HP:0001317
Show evidence (1 reference)
PMID:23924083 SUPPORT Human Clinical
"All available magnetic resonance imaging (MRI) revealed subtle symmetrical signal changes in the cerebellar dentate nuclei."
Documents consistent cerebellar/dentate MRI abnormalities that may aid diagnosis.
🧬

Genetic Associations

1
KCNJ10 loss of function
Gene: KCNJ10 hgnc:6256 relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:19420365 SUPPORT Human Clinical
"This region contained the KCNJ10 gene, which encodes a potassium channel expressed in the brain, inner ear, and kidney. Sequencing of this candidate gene revealed homozygous missense mutations in affected persons in both families."
Linkage and sequencing identify homozygous KCNJ10 missense mutations as the cause in the original consanguineous families.
PMID:19289823 SUPPORT Human Clinical
"These findings demonstrate that loss-of-function mutations in KCNJ10 cause this syndrome, which we name SeSAME."
Independent confirmation that KCNJ10 loss-of-function mutations cause the syndrome.
💊

Medical Actions

4
Electrolyte Replacement
Action: potassium supplementation MAXO:0001123
Oral potassium and magnesium supplementation to correct the hypokalemia and hypomagnesemia of the renal salt-wasting tubulopathy.
Target Phenotypes: Hypokalemia HP:0002900
Show evidence (1 reference)
PMID:29722015 SUPPORT Human Clinical
"The treatment is based on antiepileptic drugs, electrolyte replacement, hearing aids and mobility devices."
Review of reported patients identifies electrolyte replacement as a mainstay of management.
Magnesium Supplementation
Action: magnesium supplementation MAXO:0001149
Oral magnesium supplementation to correct hypomagnesemia associated with the distal tubulopathy.
Target Phenotypes: Hypomagnesemia HP:0002917
Show evidence (1 reference)
PMID:29722015 SUPPORT Human Clinical
"The treatment is based on antiepileptic drugs, electrolyte replacement, hearing aids and mobility devices."
Electrolyte replacement, which includes magnesium for the hypomagnesemia, is a core component of management.
Antiepileptic Drug Therapy
Action: anticonvulsant agent therapy MAXO:0000167
Anticonvulsant therapy to control the infantile-onset seizures, which generally respond well to treatment.
Target Phenotypes: Seizure HP:0001250
Show evidence (1 reference)
PMID:23924083 SUPPORT Human Clinical
"Whilst seizures mostly responded well to treatment"
Seizures in EAST syndrome typically respond well to antiepileptic treatment.
Hearing Aids
Action: hearing aid usage MAXO:0009030
Hearing aids and supportive audiologic management for the sensorineural hearing loss.
Target Phenotypes: Sensorineural hearing impairment HP:0000407
Show evidence (1 reference)
PMID:29722015 SUPPORT Human Clinical
"The treatment is based on antiepileptic drugs, electrolyte replacement, hearing aids and mobility devices."
Hearing aids are part of standard supportive management for the sensorineural deafness.
{ }

Source YAML

click to show 
name: EAST Syndrome
creation_date: "2026-06-03T00:00:00Z"
category: Genetic
description: >-
  EAST syndrome (also called SeSAME syndrome) is a rare autosomal recessive
  disorder caused by biallelic loss-of-function variants in KCNJ10, which encodes
  the inwardly rectifying potassium channel Kir4.1. Kir4.1 is expressed in glia
  of the brain and spinal cord, in the inner ear (stria vascularis of the
  cochlea), in the kidney (basolateral membrane of the distal convoluted tubule),
  and in the eye. Channel loss of function produces the cardinal tetrad of
  Epilepsy, Ataxia, Sensorineural deafness, and a renal salt-wasting
  Tubulopathy with normotensive hypokalemic metabolic alkalosis and
  hypomagnesemia, typically accompanied by developmental delay and intellectual
  disability. The syndrome was independently described in 2009 by Bockenhauer
  et al. (who named it EAST) and Scholl et al. (who named it SeSAME).
disease_term:
  preferred_term: EAST syndrome
  term:
    id: MONDO:0013005
    label: EAST syndrome
synonyms:
- SeSAME syndrome
- seizures, sensorineural deafness, ataxia, intellectual disability and electrolyte imbalance
- seizures-sensorineural deafness-ataxia-intellectual disability-electrolyte imbalance syndrome
references:
- reference: PMID:19420365
  title: "Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations."
- reference: PMID:19289823
  title: "Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10."
- reference: PMID:20651251
  title: "KCNJ10 gene mutations causing EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function."
- reference: PMID:21300747
  title: "Altered electroretinograms in patients with KCNJ10 mutations and EAST syndrome."
- reference: PMID:21849804
  title: "KCNJ10 mutations disrupt function in patients with EAST syndrome."
- reference: PMID:23924083
  title: "Neurological features of epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome."
- reference: PMID:27500072
  title: "EAST syndrome: Clinical, pathophysiological, and genetic aspects of mutations in KCNJ10."
- reference: PMID:29722015
  title: "EAST/SeSAME syndrome: Review of the literature and introduction of four new Latvian patients."
pathophysiology:
- name: Kir4.1 Potassium Channel Loss of Function
  description: >-
    Biallelic missense or nonsense variants in KCNJ10 reduce or abolish the
    inwardly rectifying potassium current carried by Kir4.1. Heterologous
    expression of patient mutations in Xenopus oocytes causes significant and
    specific decreases in potassium currents, and many of the mutations affect
    highly conserved residues known to cause loss of function in related K+
    channels. This is the primary molecular lesion underlying all downstream
    organ-specific manifestations.
  gene:
    preferred_term: KCNJ10
    term:
      id: hgnc:6256
      label: KCNJ10
  molecular_functions:
  - preferred_term: inward rectifier potassium channel activity
    term:
      id: GO:0005242
      label: inward rectifier potassium channel activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: potassium ion transmembrane transport
    term:
      id: GO:0071805
      label: potassium ion transmembrane transport
    modifier: DECREASED
  evidence:
  - reference: PMID:19289823
    reference_title: "Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Direct DNA sequencing of KCNJ10, which encodes an inwardly rectifying K(+) channel, identifies previously unidentified missense or nonsense mutations on both alleles in all affected subjects."
    explanation: >-
      Establishes biallelic KCNJ10 variants in an inwardly rectifying potassium
      channel as the genetic basis of the syndrome.
  - reference: PMID:19420365
    reference_title: "Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These mutations, when expressed heterologously in xenopus oocytes, caused significant and specific decreases in potassium currents."
    explanation: >-
      Functional expression demonstrates the variants reduce Kir4.1 potassium
      channel activity (loss of function).
  - reference: PMID:27500072
    reference_title: "EAST syndrome: Clinical, pathophysiological, and genetic aspects of mutations in KCNJ10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "So far 14 different KCNJ10 mutations have been published which either directly affect channel function or may lead to mislocalisation."
    explanation: >-
      Reviews the spectrum of KCNJ10 mutations, which cause disease either by
      directly impairing channel function or by channel mislocalisation.
  - reference: PMID:20651251
    reference_title: "KCNJ10 gene mutations causing EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "When expressed in CHO and HEK293 cells, the KCNJ10 mutations R65P, G77R, and R175Q caused a marked impairment of channel function. R199X showed complete loss of function."
    explanation: >-
      Functional electrophysiology of specific patient mutations confirms loss
      of Kir4.1 channel function, ranging from marked impairment to complete
      loss.
  downstream:
  - target: Impaired Glial Potassium Buffering
    causal_link_type: DIRECT
  - target: Impaired Cochlear Endolymph Homeostasis
    causal_link_type: DIRECT
  - target: Distal Tubule Salt Wasting
    causal_link_type: DIRECT
  - target: Abnormal Electroretinogram
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Kir4.1 loss of function also affects retinal electrophysiology in EAST
      syndrome, producing abnormal electroretinogram findings.
- name: Impaired Glial Potassium Buffering
  description: >-
    In the brain and spinal cord, Kir4.1 is expressed in glia, where it takes up
    extracellular K+ released by neuronal repolarization (spatial potassium
    buffering) and supports glutamate clearance. Loss of Kir4.1 raises
    extracellular potassium and impairs glial homeostasis, contributing to the
    neuronal hyperexcitability that produces seizures and to cerebellar
    dysfunction causing ataxia.
  cell_types:
  - preferred_term: glial cell
    term:
      id: CL:0000125
      label: glial cell
  biological_processes:
  - preferred_term: potassium ion homeostasis
    term:
      id: GO:0055075
      label: potassium ion homeostasis
    modifier: DECREASED
  - preferred_term: neurotransmitter uptake
    term:
      id: GO:0001504
      label: neurotransmitter uptake
    modifier: DECREASED
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:19289823
    reference_title: "Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KCNJ10 is expressed in glia in the brain and spinal cord, where it is believed to take up K(+) released by neuronal repolarization"
    explanation: >-
      Identifies the glial potassium-buffering role of Kir4.1 whose loss drives
      the neurological phenotype.
  downstream:
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cerebellar Ataxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Brain MRI Abnormalities
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Cochlear Endolymph Homeostasis
  description: >-
    In the cochlea, Kir4.1 is expressed in the stria vascularis and is required
    for the generation of endolymph and the endocochlear potential. Loss of
    Kir4.1 function impairs endolymph homeostasis and the ionic environment
    needed for normal hair-cell transduction, producing sensorineural hearing
    loss.
  biological_processes:
  - preferred_term: potassium ion transmembrane transport
    term:
      id: GO:0071805
      label: potassium ion transmembrane transport
    modifier: DECREASED
  locations:
  - preferred_term: stria vascularis of cochlear duct
    term:
      id: UBERON:0002282
      label: stria vascularis of cochlear duct
  - preferred_term: cochlea
    term:
      id: UBERON:0001844
      label: cochlea
  evidence:
  - reference: PMID:19289823
    reference_title: "Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in cochlea, where it is involved in the generation of endolymph"
    explanation: >-
      Establishes the cochlear role of Kir4.1 in endolymph generation, the basis
      of the sensorineural deafness.
  - reference: PMID:21849804
    reference_title: "KCNJ10 mutations disrupt function in patients with EAST syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KCNJ10 is expressed in the kidney distal convoluted tubule, cochlear stria vascularis and brain glial cells."
    explanation: >-
      Confirms Kir4.1 expression in the cochlear stria vascularis (alongside the
      renal distal tubule and brain glia), the basis of the multi-organ
      phenotype.
  downstream:
  - target: Sensorineural Hearing Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Distal Tubule Salt Wasting
  description: >-
    In the kidney, Kir4.1 sits on the basolateral membrane of the distal
    convoluted tubule (often as a Kir4.1/Kir5.1 heteromer with KCNJ16), where K+
    recycling across the basolateral membrane is required to sustain Na+-K+-ATPase
    activity and thus normal NaCl reabsorption. Loss of Kir4.1 impairs basolateral
    K+ recycling, causing renal salt wasting with a Gitelman-like biochemical
    profile: normotensive hypokalemic metabolic alkalosis, hypomagnesemia, and
    hypocalciuria. Patient distal tubular cells show reduced basolateral
    infoldings, reflecting impaired salt-reabsorption capacity.
  cell_types:
  - preferred_term: kidney distal convoluted tubule epithelial cell
    term:
      id: CL:1000849
      label: kidney distal convoluted tubule epithelial cell
  biological_processes:
  - preferred_term: sodium ion transmembrane transport
    term:
      id: GO:0035725
      label: sodium ion transmembrane transport
    modifier: DECREASED
  - preferred_term: potassium ion transmembrane transport
    term:
      id: GO:0071805
      label: potassium ion transmembrane transport
    modifier: DECREASED
  locations:
  - preferred_term: distal convoluted tubule
    term:
      id: UBERON:0001292
      label: distal convoluted tubule
  evidence:
  - reference: PMID:19289823
    reference_title: "Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We propose that KCNJ10 is required in the kidney for normal salt reabsorption in the distal convoluted tubule because of the need for K(+) recycling across the basolateral membrane to enable normal activity of the Na(+)-K(+)-ATPase; loss of this function accounts for the observed electrolyte defects."
    explanation: >-
      Provides the mechanistic basis for the renal salt-wasting tubulopathy and
      electrolyte imbalance.
  - reference: PMID:19420365
    reference_title: "Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice with Kcnj10 deletions became dehydrated, with definitive evidence of renal salt wasting."
    explanation: >-
      Mouse Kcnj10 knockout recapitulates the renal salt-wasting phenotype,
      supporting the causal mechanism.
  - reference: PMID:20651251
    reference_title: "KCNJ10 gene mutations causing EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Kcnj10 and Kcnj16 were found in the basolateral membrane of mouse distal convoluted tubules, connecting tubules, and cortical collecting ducts."
    explanation: >-
      Localizes Kir4.1 (with Kir5.1/KCNJ16) to the basolateral membrane of the
      distal nephron, the anatomic basis of the renal salt-wasting mechanism.
  - reference: PMID:20651251
    reference_title: "KCNJ10 gene mutations causing EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EM of distal tubular cells of a patient with EAST syndrome showed reduced basal infoldings in this nephron segment, which likely reflects the morphological consequences of the impaired salt reabsorption capacity."
    explanation: >-
      Patient ultrastructural pathology (reduced basal infoldings in the distal
      tubule) corroborates impaired salt reabsorption.
  downstream:
  - target: Hypokalemic Metabolic Alkalosis
    causal_link_type: DIRECT
  - target: Hypomagnesemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Renal Salt Wasting
    causal_link_type: DIRECT
phenotypes:
- category: Phenotypic
  name: Seizures
  description: >-
    Epilepsy with onset in infancy; affected children typically present with
    tonic-clonic seizures. Seizures generally respond well to antiepileptic
    treatment.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
    onset:
      onset_category: INFANTILE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:23924083
    reference_title: "Neurological features of epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All children presented with tonic-clonic seizures in infancy."
    explanation: >-
      In a cohort of nine genetically proven EAST patients, all presented with
      tonic-clonic seizures in infancy, supporting seizures as a very frequent
      cardinal feature.
- category: Phenotypic
  name: Cerebellar Ataxia
  description: >-
    Severe, typically non-progressive cerebellar ataxia. Ataxia is often the
    most debilitating feature; some patients become non-ambulant.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
    clinical_course: STABLE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:23924083
    reference_title: "Neurological features of epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Later, non-progressive, cerebellar ataxia and hearing loss were noted."
    explanation: >-
      Documents non-progressive cerebellar ataxia as a consistent feature of the
      neurological phenotype.
  - reference: PMID:23924083
    reference_title: "Neurological features of epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ataxia proved to be the most debilitating feature, with three patients non-ambulant"
    explanation: >-
      Highlights the severity and functional impact of the ataxia.
- category: Phenotypic
  name: Sensorineural Hearing Loss
  description: >-
    Moderate sensorineural deafness due to impaired Kir4.1-dependent endolymph
    homeostasis in the cochlea.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:19420365
    reference_title: "Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "epilepsy beginning in infancy and severe ataxia, moderate sensorineural deafness, and a renal salt-losing tubulopathy with normotensive hypokalemic metabolic alkalosis"
    explanation: >-
      The original case series describes moderate sensorineural deafness as part
      of the defining clinical tetrad.
- category: Phenotypic
  name: Renal Salt Wasting
  description: >-
    A renal salt-losing tubulopathy of the distal convoluted tubule, clinically
    resembling Gitelman syndrome, with normotensive electrolyte imbalance.
  phenotype_term:
    preferred_term: Renal salt wasting
    term:
      id: HP:0000127
      label: Renal salt wasting
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:19420365
    reference_title: "Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a renal salt-losing tubulopathy with normotensive hypokalemic metabolic alkalosis"
    explanation: >-
      Defines the renal salt-wasting tubulopathy component of the syndrome.
- category: Phenotypic
  name: Hypokalemic Metabolic Alkalosis
  description: >-
    Hypokalemia with metabolic alkalosis resulting from distal tubule salt
    wasting, characteristically with normal blood pressure.
  phenotype_term:
    preferred_term: Hypokalemic metabolic alkalosis
    term:
      id: HP:0001960
      label: Hypokalemic metabolic alkalosis
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:19289823
    reference_title: "Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "electrolyte imbalance (hypokalemia, metabolic alkalosis, and hypomagnesemia)"
    explanation: >-
      Documents the characteristic electrolyte derangement of hypokalemia with
      metabolic alkalosis.
- category: Phenotypic
  name: Hypomagnesemia
  description: >-
    Low serum magnesium due to impaired distal tubule magnesium handling, part
    of the Gitelman-like biochemical profile.
  phenotype_term:
    preferred_term: Hypomagnesemia
    term:
      id: HP:0002917
      label: Hypomagnesemia
  frequency: FREQUENT
  evidence:
  - reference: PMID:19289823
    reference_title: "Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "electrolyte imbalance (hypokalemia, metabolic alkalosis, and hypomagnesemia)"
    explanation: >-
      Lists hypomagnesemia as a component of the electrolyte imbalance in SeSAME
      syndrome.
- category: Phenotypic
  name: Abnormal Electroretinogram
  description: >-
    Altered electroretinogram (ERG) findings reflecting Kir4.1 expression in
    retinal Muller glia; reported as reduced photopic negative response
    amplitudes and reduced retinal sensitivity in EAST patients.
  phenotype_term:
    preferred_term: Abnormal electroretinogram
    term:
      id: HP:0000512
      label: Abnormal electroretinogram
  evidence:
  - reference: PMID:21300747
    reference_title: "Altered electroretinograms in patients with KCNJ10 mutations and EAST syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have studied the impact of KCNJ10 mutations on the human electroretinogram (ERG) in four unrelated patients with EAST syndrome."
    explanation: >-
      Human ERG study in EAST patients documents altered retinal
      electrophysiology attributable to KCNJ10/Kir4.1 dysfunction in Muller glia.
- category: Phenotypic
  name: Intellectual Disability
  description: >-
    Intellectual disability / developmental delay (the "mental retardation"
    component captured in the SeSAME acronym).
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:19289823
    reference_title: "Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a previously unrecognized syndrome characterized by seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance"
    explanation: >-
      The SeSAME description includes mental retardation (intellectual
      disability) as a defining feature.
- category: Phenotypic
  name: Brain MRI Abnormalities
  description: >-
    Consistent neuroimaging abnormalities, including subtle symmetrical signal
    changes in the cerebellar dentate nuclei, and in some patients a small
    corpus callosum and brainstem hypoplasia.
  phenotype_term:
    preferred_term: Abnormal cerebellum morphology
    term:
      id: HP:0001317
      label: Abnormal cerebellum morphology
  evidence:
  - reference: PMID:23924083
    reference_title: "Neurological features of epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All available magnetic resonance imaging (MRI) revealed subtle symmetrical signal changes in the cerebellar dentate nuclei."
    explanation: >-
      Documents consistent cerebellar/dentate MRI abnormalities that may aid
      diagnosis.
genetic:
- name: KCNJ10 loss of function
  gene_term:
    preferred_term: KCNJ10
    term:
      id: hgnc:6256
      label: KCNJ10
  relationship_type: CAUSATIVE
  notes: >-
    Biallelic (homozygous or compound heterozygous) missense and nonsense
    variants in KCNJ10 (Kir4.1) cause EAST/SeSAME syndrome in an autosomal
    recessive manner. The original families harbored homozygous missense
    mutations identified by linkage to chromosome 1q23.2.
  evidence:
  - reference: PMID:19420365
    reference_title: "Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This region contained the KCNJ10 gene, which encodes a potassium channel expressed in the brain, inner ear, and kidney. Sequencing of this candidate gene revealed homozygous missense mutations in affected persons in both families."
    explanation: >-
      Linkage and sequencing identify homozygous KCNJ10 missense mutations as
      the cause in the original consanguineous families.
  - reference: PMID:19289823
    reference_title: "Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings demonstrate that loss-of-function mutations in KCNJ10 cause this syndrome, which we name SeSAME."
    explanation: >-
      Independent confirmation that KCNJ10 loss-of-function mutations cause the
      syndrome.
treatments:
- name: Electrolyte Replacement
  description: >-
    Oral potassium and magnesium supplementation to correct the hypokalemia and
    hypomagnesemia of the renal salt-wasting tubulopathy.
  treatment_term:
    preferred_term: potassium supplementation
    term:
      id: MAXO:0001123
      label: potassium supplementation
  target_phenotypes:
  - preferred_term: Hypokalemia
    term:
      id: HP:0002900
      label: Hypokalemia
  evidence:
  - reference: PMID:29722015
    reference_title: "EAST/SeSAME syndrome: Review of the literature and introduction of four new Latvian patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The treatment is based on antiepileptic drugs, electrolyte replacement, hearing aids and mobility devices."
    explanation: >-
      Review of reported patients identifies electrolyte replacement as a
      mainstay of management.
- name: Magnesium Supplementation
  description: >-
    Oral magnesium supplementation to correct hypomagnesemia associated with the
    distal tubulopathy.
  treatment_term:
    preferred_term: magnesium supplementation
    term:
      id: MAXO:0001149
      label: magnesium supplementation
  target_phenotypes:
  - preferred_term: Hypomagnesemia
    term:
      id: HP:0002917
      label: Hypomagnesemia
  evidence:
  - reference: PMID:29722015
    reference_title: "EAST/SeSAME syndrome: Review of the literature and introduction of four new Latvian patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The treatment is based on antiepileptic drugs, electrolyte replacement, hearing aids and mobility devices."
    explanation: >-
      Electrolyte replacement, which includes magnesium for the hypomagnesemia,
      is a core component of management.
- name: Antiepileptic Drug Therapy
  description: >-
    Anticonvulsant therapy to control the infantile-onset seizures, which
    generally respond well to treatment.
  treatment_term:
    preferred_term: anticonvulsant agent therapy
    term:
      id: MAXO:0000167
      label: anticonvulsant agent therapy
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:23924083
    reference_title: "Neurological features of epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whilst seizures mostly responded well to treatment"
    explanation: >-
      Seizures in EAST syndrome typically respond well to antiepileptic
      treatment.
- name: Hearing Aids
  description: >-
    Hearing aids and supportive audiologic management for the sensorineural
    hearing loss.
  treatment_term:
    preferred_term: hearing aid usage
    term:
      id: MAXO:0009030
      label: hearing aid usage
  target_phenotypes:
  - preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:29722015
    reference_title: "EAST/SeSAME syndrome: Review of the literature and introduction of four new Latvian patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The treatment is based on antiepileptic drugs, electrolyte replacement, hearing aids and mobility devices."
    explanation: >-
      Hearing aids are part of standard supportive management for the
      sensorineural deafness.
📚

References & Deep Research

References

8
PMID:19420365
Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations.
No top-level findings curated for this source.
PMID:19289823
Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10.
No top-level findings curated for this source.
PMID:20651251
KCNJ10 gene mutations causing EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function.
No top-level findings curated for this source.
PMID:21300747
Altered electroretinograms in patients with KCNJ10 mutations and EAST syndrome.
No top-level findings curated for this source.
PMID:21849804
KCNJ10 mutations disrupt function in patients with EAST syndrome.
No top-level findings curated for this source.
PMID:23924083
Neurological features of epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome.
No top-level findings curated for this source.
PMID:27500072
EAST syndrome: Clinical, pathophysiological, and genetic aspects of mutations in KCNJ10.
No top-level findings curated for this source.
PMID:29722015
EAST/SeSAME syndrome: Review of the literature and introduction of four new Latvian patients.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 21 citations 2026-06-03T23:20:10.432967

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: EAST Syndrome
  • MONDO ID: (if available)
  • Category: Genetic

Research Objectives

Please provide a comprehensive research report on EAST Syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
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  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
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  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
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  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

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  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
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  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
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  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive Research Report: EAST Syndrome (EAST/SeSAME)

Target disease

  • Disease name: EAST syndrome
  • Synonyms/alternative names: SeSAME syndrome; “Epilepsy–ataxia–sensorineural deafness–tubulopathy syndrome” (EAST); “Seizures–sensorineural deafness–ataxia–(intellectual disability/mental retardation)–electrolyte imbalance syndrome” (SeSAME) (fracaro2024roleofkir4.1 pages 11-12, nadella2019identificationandfunctional pages 11-12)
  • Category: Genetic, ion channelopathy (K+ channel)
  • MONDO ID: Not retrieved from available full-text sources in this tool run (requires dedicated ontology lookup).

1. Disease information (overview and identifiers)

Definition and current understanding. EAST syndrome is a rare multisystem disorder caused by biallelic loss-of-function variants in KCNJ10, encoding the inwardly rectifying potassium channel Kir4.1. It is clinically defined by a characteristic tetrad: epilepsy/seizures, ataxia, sensorineural deafness, and renal salt-wasting tubulopathy (reichold2010kcnj10genemutations pages 1-2). The term SeSAME emphasizes frequent additional neurodevelopmental impairment and electrolyte imbalance (fracaro2024roleofkir4.1 pages 11-12, nadella2019identificationandfunctional pages 11-12).

Key identifiers (available from retrieved sources). - OMIM (disease): #612780 (EAST syndrome / SeSAME) (thimm2024untanglingtheuncertain pages 6-6, roesch2021geneticdeterminantsof pages 9-10) - OMIM (gene): KCNJ10 = *602208 (roesch2021geneticdeterminantsof pages 9-10) - ICD-10/ICD-11, MeSH, Orphanet: Not present in the retrieved full texts; would require explicit database querying.

Evidence source type. Most clinical characterization is derived from case reports/series and small family studies plus mechanistic/functional electrophysiology in heterologous systems and animal models (e.g., channel function testing in Reichold et al.) (reichold2010kcnj10genemutations pages 1-2, reichold2010kcnj10genemutations pages 3-4).

2. Etiology

2.1 Disease causal factors

Primary cause: biallelic pathogenic variants in KCNJ10 (Kir4.1) leading to loss of Kir4.1 channel function across relevant tissues (brain glia, distal nephron, cochlea) (fracaro2024roleofkir4.1 pages 11-12, reichold2010kcnj10genemutations pages 1-2).

Direct abstract quote (primary literature): - Reichold et al. (PNAS, 2010) states: “Mutations of the KCNJ10 (Kir4.1) K+ channel underlie autosomal recessive epilepsy, ataxia, sensorineural deafness, and (a salt-wasting) renal tubulopathy (EAST) syndrome.” (reichold2010kcnj10genemutations pages 1-2)

2.2 Risk factors

  • Genetic risk factor: autosomal recessive inheritance implies increased risk in families with carrier parents and in settings of consanguinity (reported in some families) (fracaro2024roleofkir4.1 pages 12-14, reichold2010kcnj10genemutations pages 1-2).
  • Environmental risk factors: no robust disease-triggering environmental factors were identified in the retrieved evidence; phenotype is primarily genetically determined.

2.3 Protective factors / gene–environment interactions

  • No specific protective variants or environmental protective factors were identified in the retrieved evidence.
  • A mechanistically plausible modifier is systemic/renal pH: certain Kir4.1 variants show alkaline-shifted pH sensitivity, implying that the biochemical milieu (metabolic alkalosis typical of the tubulopathy) may modulate residual channel function (reichold2010kcnj10genemutations pages 1-2, reichold2010kcnj10genemutations pages 3-4).

3. Phenotypes (clinical spectrum)

3.1 Core phenotype domains

1) Neurologic: seizures/epilepsy; ataxia; variable neurodevelopmental impairment/intellectual disability (fracaro2024roleofkir4.1 pages 11-12, reichold2010kcnj10genemutations pages 1-2). 2) Renal tubulopathy: salt wasting resembling Gitelman syndrome with characteristic electrolyte/acid–base pattern (below) (reichold2010kcnj10genemutations pages 1-2). 3) Auditory: sensorineural hearing loss (variable severity) (fracaro2024roleofkir4.1 pages 11-12). 4) Ophthalmic physiology (functional): altered electroretinogram findings have been demonstrated in affected patients (thompson2011alteredelectroretinogramsin pages 1-2).

3.2 Renal biochemical abnormalities (disease-defining)

Reichold et al. (2010) describes the renal phenotype as Gitelman-like and comprising: - urinary Na+ loss - RAAS activation - hypokalemic metabolic alkalosis - hypomagnesemia - hypocalciuria (reichold2010kcnj10genemutations pages 1-2)

3.3 Age of onset, severity, progression

Recent review-level summary (2024) indicates: - “Seizures generally occur at the beginning of childhood” and “degree of hearing impairment ranges from mild to severe” with variable intrafamilial expressivity (fracaro2024roleofkir4.1 pages 11-12).

3.4 Suggested HPO terms (examples; not exhaustive)

  • Seizures: HP:0001250
  • Epilepsy: HP:0001250 (often used interchangeably in HPO annotations)
  • Ataxia: HP:0001251
  • Sensorineural hearing impairment: HP:0000407
  • Hypokalemia: HP:0002900
  • Metabolic alkalosis: HP:0001943
  • Hypomagnesemia: HP:0002917
  • Hypocalciuria: HP:0003106
  • Renal salt wasting: HP:0000128 (broader; often “abnormality of renal tubular function”)
  • Intellectual disability / developmental delay (subset): HP:0001249, HP:0001263

3.5 Quality-of-life impact

Not quantified in retrieved studies; expected burdens include refractory seizures, balance/gait impairment, hearing loss requiring assistive technology, and lifelong electrolyte management (inferred from phenotype definition and supportive treatment approaches used in salt-wasting disorders) (thimm2024untanglingtheuncertain pages 6-6, reichold2010kcnj10genemutations pages 1-2).

4. Genetic / molecular information

4.1 Causal gene

  • KCNJ10 (Kir4.1) is the causal gene; it encodes an inwardly rectifying K+ channel expressed in kidney distal segments, brain glia, and the cochlea (reichold2010kcnj10genemutations pages 1-2, fracaro2024roleofkir4.1 pages 11-12).

4.2 Pathogenic variants and functional consequences

Landmark functional testing (Reichold et al., PNAS 2010). Variants tested included R65P, G77R, R175Q, R199X, all showing partial or complete loss-of-function in electrophysiology assays (reichold2010kcnj10genemutations pages 3-4, reichold2010kcnj10genemutations pages 1-2). - Open probability (single channel): WT ~70–80%; R65P ~20–30%; R175Q ~10–15%; G77R ~0.5% (nearly inactive) (reichold2010kcnj10genemutations pages 3-4). - pH sensitivity: WT IC50 ~pH 6.3; R65P shifted to ~7.8; R175Q shifted to ~9.35 (strong alkaline shift) (reichold2010kcnj10genemutations pages 3-4). - PIP2 affinity: R175Q showed markedly reduced PIP2 affinity (poly-Lys inhibition time constant 0.47 ± 0.1 s vs WT 17.89 ± 3.1 s) (reichold2010kcnj10genemutations pages 4-5).

Additional variants mentioned in later summaries. Reviews and variant-focused analyses cite additional missense and truncating variants (e.g., A167V, R297C, T164I, G83V, L166Q, and truncating frameshifts such as Asn232Glnfs*14 and Gly275Valfs*7) and interpret many as loss-of-function with variable severity (fracaro2024roleofkir4.1 pages 12-14, gur2025bioinformaticanalysisof pages 2-4).

Variant type classes (from evidence base): missense and nonsense/truncating variants are reported (fracaro2024roleofkir4.1 pages 11-12, fracaro2024roleofkir4.1 pages 12-14).

Allele frequency (gnomAD etc.): not available from retrieved evidence; requires database access.

4.3 Modifier genes / oligogenic context

No validated modifier genes for EAST syndrome were identified in the retrieved evidence. However, mechanistic overlap is highlighted with other Kir subunits (e.g., Kir5.1/KCNJ16 forming heteromers with Kir4.1), relevant to renal transport physiology and differential diagnosis (gondra2026typelocationand pages 1-2, gondra2026typelocationand pages 8-9).

5. Environmental information

No specific environmental toxins, pathogens, or lifestyle factors were identified as causal or modifying factors in the retrieved EAST-specific evidence. The disorder is primarily a genetic ion-channel disorder (reichold2010kcnj10genemutations pages 1-2, fracaro2024roleofkir4.1 pages 11-12).

6. Mechanism / pathophysiology

6.1 Unifying causal chain (multi-organ)

Trigger: biallelic KCNJ10 loss-of-function → reduced Kir4.1 channel-mediated K+ conductance.

Kidney (distal convoluted tubule and related segments): Kir4.1 (often with Kir5.1) is localized to basolateral membranes where it supports a hyperpolarized membrane potential and “pump–leak coupling,” enabling Na+/K+-ATPase-dependent transport and linked electrolyte handling. Loss-of-function leads to impaired salt reabsorption and a Gitelman-like tubulopathy with RAAS activation and characteristic electrolyte pattern (reichold2010kcnj10genemutations pages 1-2, gondra2026typelocationand pages 1-2).

Cochlea/inner ear: Kir4.1 is required for endolymph K+ homeostasis and generation of the endocochlear potential; loss disrupts cochlear ionic homeostasis and contributes to sensorineural hearing loss (fracaro2024roleofkir4.1 pages 11-12).

Brain (glia/astrocytes): Kir4.1 in glia supports extracellular K+ buffering; loss-of-function is mechanistically linked to neuronal hyperexcitability and seizures, and contributes to broader neurologic phenotype (fracaro2024roleofkir4.1 pages 11-12, reichold2010kcnj10genemutations pages 1-2).

6.2 Mechanistic statistics/data points (functional electrophysiology)

Quantitative channel dysfunction measures (open probability changes; pH IC50 shifts; PIP2 affinity differences) are provided above from the PNAS 2010 functional study (reichold2010kcnj10genemutations pages 3-4, reichold2010kcnj10genemutations pages 4-5).

6.3 Suggested pathway / ontology mappings

GO Biological Process (examples): - potassium ion transport; potassium ion homeostasis - regulation of membrane potential - renal sodium ion transport / salt reabsorption

CL Cell types (examples): - CL:0000127 astrocyte - cochlear stria vascularis intermediate cells (cell ontology term availability varies; often annotated via tissue/cell-type strings) - distal convoluted tubule epithelial cell (kidney epithelial cell subtypes)

UBERON anatomy (examples): - kidney distal convoluted tubule - cochlea; stria vascularis - brain (astroglial compartment)

7. Anatomical structures affected

  • Primary organ systems: nervous system (brain); kidney distal nephron; inner ear/cochlea (reichold2010kcnj10genemutations pages 1-2, fracaro2024roleofkir4.1 pages 11-12).
  • Tissue/cell-level: renal tubular epithelium in distal segments (basolateral membrane localization); cochlear supporting/strial cells; retinal Müller glia are implicated in functional phenotype (ERG) (reichold2010kcnj10genemutations pages 1-2, thompson2011alteredelectroretinogramsin pages 1-2).

8. Temporal development

  • Typical seizure onset described as early childhood in review-level summary (fracaro2024roleofkir4.1 pages 11-12).
  • Disease course is lifelong; severity is variable and can differ even among family members (fracaro2024roleofkir4.1 pages 11-12).

9. Inheritance and population

  • Inheritance: autosomal recessive (reichold2010kcnj10genemutations pages 1-2, fracaro2024roleofkir4.1 pages 11-12).
  • Epidemiology (prevalence/incidence): not quantified in retrieved evidence; the syndrome is repeatedly described as “rare,” and literature largely comprises case reports/series (fracaro2024roleofkir4.1 pages 11-12).
  • Founder effects/carrier frequency: not available from retrieved evidence.

10. Diagnostics

10.1 Clinical and laboratory evaluation

  • Identify the tetrad (seizures/epilepsy, ataxia, sensorineural deafness, renal tubulopathy) (reichold2010kcnj10genemutations pages 1-2).
  • Laboratory evaluation consistent with a salt-wasting tubulopathy: serum electrolytes (K+, Mg2+, Cl−), acid–base status, urine electrolytes, and evidence of RAAS activation (reichold2010kcnj10genemutations pages 1-2).

10.2 Genetic testing

  • Confirmatory testing: “identified by sequencing the KCNJ10 gene” (fracaro2024roleofkir4.1 pages 11-12).
  • Molecular diagnosis is particularly important because the renal phenotype resembles other tubulopathies (e.g., Gitelman/Bartter spectrum), and overlapping hearing-loss syndromes exist (reichold2010kcnj10genemutations pages 1-2, roesch2021geneticdeterminantsof pages 9-10).

10.3 Functional/adjunct tests (real-world implementations)

  • Electroretinography (ERG): Thompson et al. (2011) studied four unrelated EAST patients and demonstrated measurable ERG alterations. Abstract quote: “We have studied the impact of KCNJ10 mutations on the human electroretinogram (ERG) in four unrelated patients with EAST syndrome.” (thompson2011alteredelectroretinogramsin pages 1-2)
  • The study reports reduced photopic negative response amplitudes and reduced retinal sensitivity in some patients, supporting ERG as a functional assessment of Kir4.1-related retinal physiology in humans (thompson2011alteredelectroretinogramsin pages 1-2).

11. Outcome / prognosis

No robust survival/life expectancy data were identified in retrieved sources. Prognosis is expected to depend on seizure control, neurodevelopmental impairment, and chronic electrolyte disturbances. Phenotypic variability is documented (fracaro2024roleofkir4.1 pages 11-12).

12. Treatment

Evidence base limitation: A 2024 review on sodium-wasting disorders notes that for rare syndromes, “there is only limited clinical information on treatment,” and management is largely supportive (thimm2024untanglingtheuncertain pages 6-6).

12.1 Supportive renal/electrolyte management (current practice patterns)

Supportive approaches used for salt-wasting tubulopathies (applied in related contexts and plausibly relevant to EAST’s Gitelman-like phenotype) include: - Fluid and electrolyte replacement, with careful volume management in newborns to prevent pre-renal injury (thimm2024untanglingtheuncertain pages 6-6). - Potassium supplementation (e.g., potassium chloride) as initial symptomatic therapy for hypokalemia (thimm2024untanglingtheuncertain pages 6-6). - Potassium-sparing agents (spironolactone, eplerenone, amiloride) to increase serum potassium and counteract metabolic alkalosis (thimm2024untanglingtheuncertain pages 6-6). - NSAIDs/prostaglandin inhibitors (e.g., indomethacin) in selected salt-wasting disorders (thimm2024untanglingtheuncertain pages 6-6). - ACE inhibitors may be used in some contexts to correct low K+ levels or counteract proteinuria (thimm2024untanglingtheuncertain pages 6-6).

Mechanism-linked therapeutic hypothesis (not established as standard of care): Because certain Kir4.1 variants show alkaline-shifted pH sensitivity, the PNAS 2010 study notes that altered pH sensitivity “may therefore have implications for the treatment” of mutation carriers, though no protocol is provided (reichold2010kcnj10genemutations pages 1-2, reichold2010kcnj10genemutations pages 3-4).

12.2 Seizure, ataxia, hearing interventions

Specific anti-seizure medication regimens, rehabilitation approaches, and hearing interventions (hearing aids/cochlear implant outcomes) were not detailed in the retrieved EAST-focused evidence and would require additional clinical guideline retrieval.

12.3 Suggested MAXO terms (examples)

  • Potassium supplementation: MAXO:0000647 (electrolyte supplementation; exact term may vary)
  • Magnesium supplementation (if used): electrolyte supplementation term
  • Genetic testing: MAXO:0000057 (genetic test)
  • Hearing aid/cochlear implant: assistive device / cochlear implantation terms

13. Prevention

  • Primary prevention: not applicable (genetic disorder).
  • Secondary prevention: early recognition + genetic diagnosis enables early hearing and neurodevelopmental interventions and proactive electrolyte monitoring (fracaro2024roleofkir4.1 pages 11-12, reichold2010kcnj10genemutations pages 1-2).
  • Genetic counseling: recommended by implication due to autosomal recessive inheritance and the value of molecular diagnosis (reichold2010kcnj10genemutations pages 1-2).

14. Other species / natural disease

Cross-species Kir4.1 biology and disease modeling has been leveraged in research (e.g., Drosophila irk2 modeling of Kir4.1-associated neurobehavioral phenotypes has been reported in preprint literature) (nadella2018novelkcnj10mutation pages 13-15).

15. Model organisms / experimental systems

  • Heterologous expression systems: CHO/HEK293 and Xenopus oocytes for Kir4.1 (KCNJ10) functional studies (reichold2010kcnj10genemutations pages 3-4, reichold2010kcnj10genemutations pages 2-3).
  • Mouse models: renal localization studies and mechanistic inference from Kir4.1 biology are supported by murine kidney segment expression and functional physiology framing (reichold2010kcnj10genemutations pages 1-2).

Recent developments and latest research (prioritizing 2023–2024)

1) Updated physiologic integration (2024): Review discussions continue to place EAST/SeSAME within the spectrum of salt-wasting tubulopathies and emphasize supportive electrolyte/volume management strategies used in these syndromes (thimm2024untanglingtheuncertain pages 6-6). 2) Auditory pathophysiology synthesis (2024): A 2024 review highlights Kir4.1’s cochlear expression (e.g., stria vascularis intermediate cells, root cells, supporting/glial cells) and its role in endocochlear potential maintenance, and summarizes EAST/SeSAME as a key Kir4.1-associated syndrome with variable hearing loss severity and early-childhood seizure onset (fracaro2024roleofkir4.1 pages 11-12).

Current applications / real-world implementations

  • Clinical diagnosis is increasingly genotype-driven: sequencing of KCNJ10 is emphasized as the key confirmatory diagnostic step in clinically suspected cases (fracaro2024roleofkir4.1 pages 11-12).
  • Functional testing in humans: ERG is a demonstrated clinical physiology tool showing measurable abnormalities in KCNJ10-mutated patients, providing a real-world functional correlate to Kir4.1 Müller glial function (thompson2011alteredelectroretinogramsin pages 1-2).

Clinical trials and registries

No EAST syndrome–specific interventional trials were identified in the retrieved ClinicalTrials.gov searches; the only directly relevant entry retrieved was a broad rare kidney disease registry: - National Registry of Rare Kidney Diseases (NCT06065852; recruiting; observational; target enrollment 35,000) (clinical trial metadata retrieved in this run; no EAST-specific outcome data available).

Key visual evidence (mutation/function mapping)

Reichold et al. (2010) includes figures mapping Kir4.1 mutations and showing electrophysiology effects (channel schematics and functional traces), supporting variant-to-function conclusions (reichold2010kcnj10genemutations media 4e065939, reichold2010kcnj10genemutations media 5b951dbe, reichold2010kcnj10genemutations media 0b7ee06e).

Evidence summary table

Topic Key facts Source (year) DOI / URL Evidence citation
Definition / core phenotype EAST syndrome = Epilepsy, Ataxia, Sensorineural deafness, Tubulopathy; SeSAME = Seizures, Sensorineural deafness, Ataxia, Mental/Intellectual disability, Electrolyte imbalance. Rare multisystem disorder with neurologic, renal, and auditory involvement. Reichold et al. 2010; Fracaro et al. 2024 https://doi.org/10.1073/pnas.1003072107 ; https://doi.org/10.3390/app14124985 (reichold2010kcnj10genemutations pages 1-2, fracaro2024roleofkir4.1 pages 11-12)
Causative gene / protein Caused by biallelic loss-of-function variants in KCNJ10, encoding the inwardly rectifying potassium channel Kir4.1; gene located on chromosome 1q22-23. Reichold et al. 2010; Fracaro et al. 2024 https://doi.org/10.1073/pnas.1003072107 ; https://doi.org/10.3390/app14124985 (reichold2010kcnj10genemutations pages 1-2, fracaro2024roleofkir4.1 pages 11-12)
Inheritance Autosomal recessive disorder; several reported families are consanguineous. Reichold et al. 2010; Fracaro et al. 2024 https://doi.org/10.1073/pnas.1003072107 ; https://doi.org/10.3390/app14124985 (reichold2010kcnj10genemutations pages 1-2, fracaro2024roleofkir4.1 pages 12-14, fracaro2024roleofkir4.1 pages 11-12)
Key renal electrolyte abnormalities Gitelman-like salt-wasting tubulopathy with urinary Na+ loss, RAAS activation, hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria. Reichold et al. 2010 https://doi.org/10.1073/pnas.1003072107 (reichold2010kcnj10genemutations pages 1-2)
Renal mechanism Kir4.1/KCNJ10 is expressed in the basolateral membrane of distal convoluted tubule (DCT), connecting tubule, and cortical collecting duct; with KCNJ16/Kir5.1 it supports K+ recycling / pump-leak coupling, sustaining Na+/K+-ATPase activity and distal transport. Loss reduces reabsorptive capacity and causes salt wasting. Reichold et al. 2010; Gondra et al. 2026 preprint https://doi.org/10.1073/pnas.1003072107 ; https://doi.org/10.64898/2026.01.07.25343066 (reichold2010kcnj10genemutations pages 1-2, reichold2010kcnj10genemutations pages 2-3, gondra2026typelocationand pages 1-2)
Renal structural correlate Patient renal biopsy EM showed reduced basolateral infoldings (and decreased mitochondria in DCT cells in summarized evidence), consistent with impaired salt reabsorption. Reichold et al. 2010 https://doi.org/10.1073/pnas.1003072107 (reichold2010kcnj10genemutations pages 2-3, reichold2010kcnj10genemutations pages 1-2)
Auditory mechanism Kir4.1 is critical for cochlear K+ recycling and generation/maintenance of the endocochlear potential; loss in strial intermediate cells disrupts endolymph homeostasis and contributes to sensorineural hearing loss. Hearing loss severity ranges from mild to severe. Fracaro et al. 2024 https://doi.org/10.3390/app14124985 (fracaro2024roleofkir4.1 pages 11-12, fracaro2024roleofkir4.1 pages 12-14)
Neurologic mechanism Kir4.1 dysfunction in brain glia/astrocytes impairs extracellular K+ spatial buffering, promoting neuronal hyperexcitability and epilepsy/ataxia. Fracaro et al. 2024; contextual mechanistic evidence https://doi.org/10.3390/app14124985 (fracaro2024roleofkir4.1 pages 11-12)
Ophthalmic / physiologic implementation Human ERG studies in 4 unrelated EAST patients showed reduced photopic negative response and reduced retinal sensitivity, confirming Kir4.1 contribution to human retinal physiology. Thompson et al. 2011 https://doi.org/10.1113/jphysiol.2010.198531 (thompson2011alteredelectroretinogramsin pages 1-2)
Variant set studied functionally in landmark paper R65P, G77R, R175Q, R199X were tested in heterologous systems; all caused partial or complete channel dysfunction, with R199X complete loss-of-function. Reichold et al. 2010 https://doi.org/10.1073/pnas.1003072107 (reichold2010kcnj10genemutations pages 2-3, reichold2010kcnj10genemutations pages 1-2, reichold2010kcnj10genemutations pages 3-4)
Single-channel functional results WT open probability ~70–80%; R65P ~20–30%, R175Q ~10–15%, G77R ~0.5% / nearly inactive. Mutants showed flickering and reduced mean open time; whole-cell Ba2+-sensitive currents were markedly reduced. Reichold et al. 2010 https://doi.org/10.1073/pnas.1003072107 (reichold2010kcnj10genemutations pages 3-4, reichold2010kcnj10genemutations pages 4-5)
pH sensitivity shift WT KCNJ10 pH IC50 ~6.3; R65P shifted to ~7.8 and R175Q to ~9.35, indicating a marked alkaline shift in pH sensitivity. Authors note metabolic alkalosis in R65P patients might partially improve residual function. Reichold et al. 2010 https://doi.org/10.1073/pnas.1003072107 (reichold2010kcnj10genemutations pages 1-2, reichold2010kcnj10genemutations pages 3-4)
PIP2 affinity defect R175Q showed markedly reduced PIP2 affinity, with poly-Lys inhibition time constant 0.47 ± 0.1 s vs WT 17.89 ± 3.1 s. Reichold et al. 2010 https://doi.org/10.1073/pnas.1003072107 (reichold2010kcnj10genemutations pages 4-5)
Additional notable variants in later reviews / summaries Additional EAST/SeSAME-associated variants discussed include A167V, R297C, T164I, G83V, L166Q, and frameshifts Asn232Glnfs*14 and Gly275Valfs*7. Fracaro et al. 2024; Gür et al. 2025 https://doi.org/10.3390/app14124985 ; https://doi.org/10.1186/s43042-025-00800-w (fracaro2024roleofkir4.1 pages 12-14, gur2025bioinformaticanalysisof pages 2-4)
Functional notes for additional variants R65P, T164I, R297C alter pH sensing/pore gating; G77R likely alters channel structure/gating; A167V may reduce surface expression (especially with R297C); G83V and L166Q are reported to reduce or abolish channel activity in cited functional work. Truncating variants Asn232Glnfs*14 and Gly275Valfs*7 are predicted to cause more severe consequences, including severe epilepsy/tubulopathy. Fracaro et al. 2024; Gür et al. 2025 https://doi.org/10.3390/app14124985 ; https://doi.org/10.1186/s43042-025-00800-w (fracaro2024roleofkir4.1 pages 12-14, gur2025bioinformaticanalysisof pages 2-4)
Mutation burden / phenotypic variability Review summary notes 16 KCNJ10 mutations reported, with variable intrafamilial phenotypes; seizures typically begin in early childhood, hearing loss ranges mild to severe. Fracaro et al. 2024 https://doi.org/10.3390/app14124985 (fracaro2024roleofkir4.1 pages 11-12)
Diagnostic implication KCNJ10 sequencing is central for diagnosis in individuals with the EAST/SeSAME phenotype; real-world differential diagnosis often overlaps with Gitelman/Bartter-like tubulopathies and syndromic deafness. Fracaro et al. 2024; Reichold et al. 2010 https://doi.org/10.3390/app14124985 ; https://doi.org/10.1073/pnas.1003072107 (fracaro2024roleofkir4.1 pages 11-12, reichold2010kcnj10genemutations pages 1-2)

Table: This table condenses the core clinical, genetic, mechanistic, and variant-function evidence for EAST/SeSAME syndrome from the retrieved literature. It is designed as a quick reference for disease definition, Kir4.1 biology, hallmark electrolyte abnormalities, and mutation-specific functional effects.

Notes on evidence gaps and limitations

  • This tool run retrieved strong mechanistic and functional genetics evidence (especially PNAS 2010) and 2024 review-level synthesis for hearing and tubulopathy, but did not retrieve comprehensive epidemiology, standardized ICD/MeSH/MONDO mappings, or detailed treatment outcomes for seizures/hearing interventions.
  • For a knowledge base entry requiring those fields, dedicated queries to OMIM/Orphanet/MeSH/MONDO and clinical guideline resources are needed.

References

  1. (fracaro2024roleofkir4.1 pages 11-12): Silvia Fracaro, Filippo Hellies, Gino Marioni, Davide Brotto, Sebastiano Franchella, Elisabetta Zanoletti, Giovanna Albertin, and Laura Astolfi. Role of kir4.1 channel in auditory function: impact on endocochlear potential and hearing loss. Applied Sciences, 14:4985, Jun 2024. URL: https://doi.org/10.3390/app14124985, doi:10.3390/app14124985. This article has 6 citations.

  2. (nadella2019identificationandfunctional pages 11-12): Ravi K. Nadella, Anirudh Chellappa, Anand G. Subramaniam, Ravi Prabhakar More, Srividya Shetty, Suriya Prakash, Nikhil Ratna, V. P. Vandana, Meera Purushottam, Jitender Saini, Biju Viswanath, P. S. Bindu, Madhu Nagappa, Bhupesh Mehta, Sanjeev Jain, and Ramakrishnan Kannan. Identification and functional characterization of two novel mutations in kcnj10 and pi4kb in sesame syndrome without electrolyte imbalance. Human Genomics, Oct 2019. URL: https://doi.org/10.1186/s40246-019-0236-0, doi:10.1186/s40246-019-0236-0. This article has 10 citations and is from a peer-reviewed journal.

  3. (reichold2010kcnj10genemutations pages 1-2): Markus Reichold, Anselm A. Zdebik, Evelyn Lieberer, Markus Rapedius, Katharina Schmidt, Sascha Bandulik, Christina Sterner, Ines Tegtmeier, David Penton, Thomas Baukrowitz, Sally-Anne Hulton, Ralph Witzgall, Bruria Ben-Zeev, Alexander J. Howie, Robert Kleta, Detlef Bockenhauer, and Richard Warth. Kcnj10 gene mutations causing east syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function. Proceedings of the National Academy of Sciences, 107:14490-14495, Jul 2010. URL: https://doi.org/10.1073/pnas.1003072107, doi:10.1073/pnas.1003072107. This article has 256 citations and is from a highest quality peer-reviewed journal.

  4. (thimm2024untanglingtheuncertain pages 6-6): Chantelle Thimm and James Adjaye. Untangling the uncertain role of overactivation of the renin–angiotensin–aldosterone system with the aging process based on sodium wasting human models. International Journal of Molecular Sciences, 25:9332, Aug 2024. URL: https://doi.org/10.3390/ijms25179332, doi:10.3390/ijms25179332. This article has 6 citations.

  5. (roesch2021geneticdeterminantsof pages 9-10): Sebastian Roesch, Gerd Rasp, Antonio Sarikas, and Silvia Dossena. Genetic determinants of non-syndromic enlarged vestibular aqueduct: a review. Audiology Research, 11:423-442, Aug 2021. URL: https://doi.org/10.3390/audiolres11030040, doi:10.3390/audiolres11030040. This article has 52 citations.

  6. (reichold2010kcnj10genemutations pages 3-4): Markus Reichold, Anselm A. Zdebik, Evelyn Lieberer, Markus Rapedius, Katharina Schmidt, Sascha Bandulik, Christina Sterner, Ines Tegtmeier, David Penton, Thomas Baukrowitz, Sally-Anne Hulton, Ralph Witzgall, Bruria Ben-Zeev, Alexander J. Howie, Robert Kleta, Detlef Bockenhauer, and Richard Warth. Kcnj10 gene mutations causing east syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function. Proceedings of the National Academy of Sciences, 107:14490-14495, Jul 2010. URL: https://doi.org/10.1073/pnas.1003072107, doi:10.1073/pnas.1003072107. This article has 256 citations and is from a highest quality peer-reviewed journal.

  7. (fracaro2024roleofkir4.1 pages 12-14): Silvia Fracaro, Filippo Hellies, Gino Marioni, Davide Brotto, Sebastiano Franchella, Elisabetta Zanoletti, Giovanna Albertin, and Laura Astolfi. Role of kir4.1 channel in auditory function: impact on endocochlear potential and hearing loss. Applied Sciences, 14:4985, Jun 2024. URL: https://doi.org/10.3390/app14124985, doi:10.3390/app14124985. This article has 6 citations.

  8. (thompson2011alteredelectroretinogramsin pages 1-2): Dorothy A. Thompson, Sally Feather, Horia C. Stanescu, Bernard Freudenthal, Anselm A. Zdebik, Richard Warth, Milos Ognjanovic, Sally A. Hulton, Evangeline Wassmer, William van't Hoff, Isabelle Russell‐Eggitt, Angus Dobbie, Eamonn Sheridan, Robert Kleta, and Detlef Bockenhauer. Altered electroretinograms in patients with kcnj10 mutations and east syndrome. The Journal of Physiology, 589:1681-1689, Apr 2011. URL: https://doi.org/10.1113/jphysiol.2010.198531, doi:10.1113/jphysiol.2010.198531. This article has 90 citations.

  9. (reichold2010kcnj10genemutations pages 4-5): Markus Reichold, Anselm A. Zdebik, Evelyn Lieberer, Markus Rapedius, Katharina Schmidt, Sascha Bandulik, Christina Sterner, Ines Tegtmeier, David Penton, Thomas Baukrowitz, Sally-Anne Hulton, Ralph Witzgall, Bruria Ben-Zeev, Alexander J. Howie, Robert Kleta, Detlef Bockenhauer, and Richard Warth. Kcnj10 gene mutations causing east syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function. Proceedings of the National Academy of Sciences, 107:14490-14495, Jul 2010. URL: https://doi.org/10.1073/pnas.1003072107, doi:10.1073/pnas.1003072107. This article has 256 citations and is from a highest quality peer-reviewed journal.

  10. (gur2025bioinformaticanalysisof pages 2-4): Tamer Gür, Ömer Faruk Karasakal, and Mesut Karahan. Bioinformatic analysis of missense snps in the kcnj10 gene associated with neurological disorders. Egyptian Journal of Medical Human Genetics, Oct 2025. URL: https://doi.org/10.1186/s43042-025-00800-w, doi:10.1186/s43042-025-00800-w. This article has 0 citations and is from a peer-reviewed journal.

  11. (gondra2026typelocationand pages 1-2): Leire Gondra, Shivani Mora, Imran G Shaikh, Alejandro Garcia-Castaño, Franziska Schilling, Gema Ariceta, Leire García-Suarez, Patricia Tejera-Carreño, Gema Fernández-Juarez, Alfredo Santana Rodríguez, Jonai Pujol-Giménez, Marta García-Alonso, Sara Gómez-Conde, Ainhoa Camille Aranaga-Decori, Martin Koemhoff, Vijay Renigunta, Stefanie Weber, Leire Madariaga, and Aparna Renigunta. Type, location and zygosity of kcnj16 mutations may determine the clinical severity of hypokalemic tubulopathy and deafness (hktd). Unknown journal, Jan 2026. URL: https://doi.org/10.64898/2026.01.07.25343066, doi:10.64898/2026.01.07.25343066.

  12. (gondra2026typelocationand pages 8-9): Leire Gondra, Shivani Mora, Imran G Shaikh, Alejandro Garcia-Castaño, Franziska Schilling, Gema Ariceta, Leire García-Suarez, Patricia Tejera-Carreño, Gema Fernández-Juarez, Alfredo Santana Rodríguez, Jonai Pujol-Giménez, Marta García-Alonso, Sara Gómez-Conde, Ainhoa Camille Aranaga-Decori, Martin Koemhoff, Vijay Renigunta, Stefanie Weber, Leire Madariaga, and Aparna Renigunta. Type, location and zygosity of kcnj16 mutations may determine the clinical severity of hypokalemic tubulopathy and deafness (hktd). Unknown journal, Jan 2026. URL: https://doi.org/10.64898/2026.01.07.25343066, doi:10.64898/2026.01.07.25343066.

  13. (nadella2018novelkcnj10mutation pages 13-15): Ravi K Nadella, Anirudh Chellappa, Anand G Subramaniam, Ravi Prabhakar More, Srividya Shetty, Suriya Prakash, Nikhil Ratna, VP Vandana, Meera Purushottam, Jitender Saini, Biju Viswanath, PS Bindu, Madhu Nagappa, Bhupesh Mehta, Sanjeev Jain, and Ramakrishnan Kannan. Novel kcnj10 mutation identified in a sesame family compromise channel function and impairs drosophila locomotor behavior. bioRxiv, pages 506949, Dec 2018. URL: https://doi.org/10.1101/506949, doi:10.1101/506949. This article has 0 citations.

  14. (reichold2010kcnj10genemutations pages 2-3): Markus Reichold, Anselm A. Zdebik, Evelyn Lieberer, Markus Rapedius, Katharina Schmidt, Sascha Bandulik, Christina Sterner, Ines Tegtmeier, David Penton, Thomas Baukrowitz, Sally-Anne Hulton, Ralph Witzgall, Bruria Ben-Zeev, Alexander J. Howie, Robert Kleta, Detlef Bockenhauer, and Richard Warth. Kcnj10 gene mutations causing east syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function. Proceedings of the National Academy of Sciences, 107:14490-14495, Jul 2010. URL: https://doi.org/10.1073/pnas.1003072107, doi:10.1073/pnas.1003072107. This article has 256 citations and is from a highest quality peer-reviewed journal.

  15. (reichold2010kcnj10genemutations media 4e065939): Markus Reichold, Anselm A. Zdebik, Evelyn Lieberer, Markus Rapedius, Katharina Schmidt, Sascha Bandulik, Christina Sterner, Ines Tegtmeier, David Penton, Thomas Baukrowitz, Sally-Anne Hulton, Ralph Witzgall, Bruria Ben-Zeev, Alexander J. Howie, Robert Kleta, Detlef Bockenhauer, and Richard Warth. Kcnj10 gene mutations causing east syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function. Proceedings of the National Academy of Sciences, 107:14490-14495, Jul 2010. URL: https://doi.org/10.1073/pnas.1003072107, doi:10.1073/pnas.1003072107. This article has 256 citations and is from a highest quality peer-reviewed journal.

  16. (reichold2010kcnj10genemutations media 5b951dbe): Markus Reichold, Anselm A. Zdebik, Evelyn Lieberer, Markus Rapedius, Katharina Schmidt, Sascha Bandulik, Christina Sterner, Ines Tegtmeier, David Penton, Thomas Baukrowitz, Sally-Anne Hulton, Ralph Witzgall, Bruria Ben-Zeev, Alexander J. Howie, Robert Kleta, Detlef Bockenhauer, and Richard Warth. Kcnj10 gene mutations causing east syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function. Proceedings of the National Academy of Sciences, 107:14490-14495, Jul 2010. URL: https://doi.org/10.1073/pnas.1003072107, doi:10.1073/pnas.1003072107. This article has 256 citations and is from a highest quality peer-reviewed journal.

  17. (reichold2010kcnj10genemutations media 0b7ee06e): Markus Reichold, Anselm A. Zdebik, Evelyn Lieberer, Markus Rapedius, Katharina Schmidt, Sascha Bandulik, Christina Sterner, Ines Tegtmeier, David Penton, Thomas Baukrowitz, Sally-Anne Hulton, Ralph Witzgall, Bruria Ben-Zeev, Alexander J. Howie, Robert Kleta, Detlef Bockenhauer, and Richard Warth. Kcnj10 gene mutations causing east syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function. Proceedings of the National Academy of Sciences, 107:14490-14495, Jul 2010. URL: https://doi.org/10.1073/pnas.1003072107, doi:10.1073/pnas.1003072107. This article has 256 citations and is from a highest quality peer-reviewed journal.

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