Agenesis of the Corpus Callosum with Peripheral Neuropathy

Mendelian MONDO:0000902 Pathograph 24 Show in embeddings browser Inherited neurodegenerative disorder

Agenesis of the corpus callosum with peripheral neuropathy, also known as Andermann syndrome or HMSN/ACC, is an autosomal recessive neurodevelopmental and neurodegenerative disorder caused by biallelic pathogenic variants in SLC12A6, encoding the potassium-chloride cotransporter KCC3. KCC3 dysfunction impairs potassium-chloride cotransport and cellular ionic homeostasis, but the bridge from transporter dysfunction to axonopathy and variable callosal dysgenesis remains unresolved. Clinically, the disorder features severe infantile-onset progressive sensorimotor neuropathy with hypotonia, areflexia, amyotrophy, variable corpus callosum dysgenesis, developmental delay or intellectual disability, seizures, and progressive loss of ambulation.

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1
Mappings
1
Definitions
1
Inheritance
6
Pathophys.
20
Phenotypes
3
Hypotheses
3
Gaps
24
Pathograph
1
Genes
2
Variants
7
Medical Actions
4
Models
11
References
1
Deep Research
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Mappings

MONDO
MONDO:0000902 agenesis of the corpus callosum with peripheral neuropathy
skos:exactMatch Orphanet ORPHA:1496
Orphanet ORPHA:1496 lists MONDO:0000902 as an exact cross-reference for corpus callosum agenesis-neuronopathy syndrome.
📘

Definitions

1
Orphanet corpus callosum agenesis-neuronopathy syndrome definition
A rare autosomal recessive neurodegenerative disorder with severe infantile-onset progressive sensorimotor neuropathy, hypotonia, areflexia, amyotrophy, variable corpus callosum dysgenesis, developmental delay or intellectual disability, psychiatric manifestations, early wheelchair dependence, and reduced survival.
OTHER
Show evidence (2 references)
ORPHA:1496 SUPPORT Other
"severe progressive sensorimotor neuropathy beginning in infancy with resulting hypotonia, areflexia, amyotrophy"
Orphanet defines the disorder by early progressive sensorimotor neuropathy and neuromuscular signs.
PMID:20301546 SUPPORT Other
"a neurodevelopmental and neurodegenerative"
GeneReviews supports the combined neurodevelopmental and neurodegenerative framing.
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
The disorder is inherited in an autosomal recessive pattern.
Autosomal recessive inheritance
Show evidence (2 references)
ORPHA:1496 SUPPORT Other
"Autosomal recessive"
Orphanet records autosomal recessive inheritance.
PMID:12368912 SUPPORT Human Clinical
"transmitted in an autosomal recessive fashion and is found at a high frequency"
The SLC12A6 discovery study reports autosomal recessive inheritance.
◈

Mechanistic Hypotheses

3
Canonical SLC12A6 Loss-of-Function and Axonopathy Model
canonical_slc12a6_loss_axonopathy_model CANONICAL
Evidence balance 2 support
Biallelic SLC12A6 variants abolish or impair KCC3 function. Human neuropathology and knockout-model physiology support KCC3 deficiency as the upstream lesion for peripheral nerve dysfunction and a central/peripheral axonopathy, although the molecular bridge from transporter loss to axonal degeneration remains incompletely defined.
Pathograph links
SLC12A6 KCC3 loss of function -> Impaired KCC3-mediated ion transport and ionic homeostasis DIRECT KCC3 loss directly reduces potassium-chloride transport and disrupts cellular ion homeostasis.
SLC12A6 KCC3 loss of function -> Peripheral nerve impulse-propagation failure DIRECT KCC3 deficiency reduces compound action-potential measures and nerve-conduction velocity in knockout mouse nerves.
SLC12A6 KCC3 loss of function -> Central and peripheral axonopathy INDIRECT UNKNOWN INTERMEDIATES Human pathology attributes the degenerative deficit to axonopathy caused ultimately by the KCC3 defect, with unknown intervening molecular steps. Intermediates: Molecular steps connecting KCC3 transport loss to axonal degeneration remain unresolved.
Peripheral nerve impulse-propagation failure -> Progressive sensorimotor neuropathy UNKNOWN Impaired impulse propagation is a mouse and ex vivo functional readout relevant to neuropathy, but a causal link to the human degenerative phenotype is not established.
Central and peripheral axonopathy -> Progressive sensorimotor neuropathy DIRECT The central and peripheral axonopathy manifests clinically as a progressive sensorimotor neuropathy.
Central and peripheral axonopathy -> Hypotonia INDIRECT KNOWN INTERMEDIATES Severe progressive sensorimotor neuropathy produces hypotonia. Intermediates: progressive sensorimotor neuropathy
Central and peripheral axonopathy -> Areflexia INDIRECT KNOWN INTERMEDIATES Severe progressive sensorimotor neuropathy produces loss of reflexes. Intermediates: progressive sensorimotor neuropathy
Central and peripheral axonopathy -> Skeletal muscle atrophy INDIRECT KNOWN INTERMEDIATES Progressive sensorimotor neuropathy downstream of axonopathy contributes to amyotrophy. Intermediates: progressive sensorimotor neuropathy
Show evidence (2 references)
PMID:12368912 SUPPORT Human Clinical
"Our findings identify mutations in SLC12A6 as the genetic lesion underlying ACCPN and suggest a critical role for SLC12A6 in the development and maintenance of the nervous system."
Patient mutation evidence establishes SLC12A6 as the causal disease gene.
PMID:27230413 SUPPORT Human Clinical
"We conclude that the neurodegenerative deficits in HMSN/ACC are primarily caused by an axonopathy superimposed upon abnormal development"
Human autopsy evidence supports axonopathy superimposed on abnormal development.
Emerging Motoneuron Electrical and Neuromuscular-Junction Model
emerging_motoneuron_nmj_model EMERGING
Evidence balance 1 support
Global and neuron-specific KCC3 loss in mice produces abnormal motoneuron electrical activity, Na+/K+-ATPase alpha-1 mislocalization, early neuromuscular-junction abnormalities, denervation, and muscle atrophy. This is a parallel model-supported branch, not yet a demonstrated human treatment mechanism.
Pathograph links
SLC12A6 KCC3 loss of function -> Activity-dependent motoneuron and neuromuscular-junction dysfunction DIRECT Neuron-specific KCC3 loss produces abnormal motoneuron activity and early NMJ abnormalities in mice.
Activity-dependent motoneuron and neuromuscular-junction dysfunction -> Skeletal muscle atrophy UNKNOWN Early NMJ abnormalities, denervation, and muscle atrophy co-occur downstream of neuron-specific KCC3 loss in mice; their direct causal ordering is unresolved.
Activity-dependent motoneuron and neuromuscular-junction dysfunction -> Progressive sensorimotor neuropathy UNKNOWN Abnormal motoneuron activity is proposed to contribute to the human neuropathy, but this link remains model-derived.
Show evidence (1 reference)
PMID:28647557 SUPPORT Model Organism
"neuron-specific KCC3 loss-of-function in mice leads to early neuromuscular junction (NMJ) abnormalities and muscular atrophy"
Mouse evidence supports a neuron-autonomous NMJ and muscle-atrophy branch.
Emerging Central Commissural Development Model
emerging_central_commissural_development_model EMERGING
Evidence balance 2 support
Human neuropathology establishes commissural and corticospinal-tract hypoplasia, but the developmental intermediates downstream of KCC3 loss and the reason corpus-callosum dysgenesis is variable remain unknown.
Pathograph links
SLC12A6 KCC3 loss of function -> Commissural and corticospinal developmental abnormalities INDIRECT UNKNOWN INTERMEDIATES KCC3 deficiency is associated with abnormal commissural and corticospinal development, but the intervening developmental mechanism is unknown. Intermediates: Developmental steps connecting KCC3 loss to tract dysgenesis remain unresolved.
Commissural and corticospinal developmental abnormalities -> Agenesis of corpus callosum DIRECT Absence or hypoplasia of the major telencephalic commissures includes the corpus-callosum dysgenesis phenotype.
Show evidence (2 references)
PMID:27230413 SUPPORT Human Clinical
"Hypoplasia or absence of the major telencephalic commissures and a hypoplasia of corticospinal tracts to half the normal size"
Human autopsy tissue establishes the central developmental lesions.
PMID:32765936 SUPPORT Human Clinical
"We confirm that ACC is not a mandatory feature"
A genetically confirmed case shows that callosal agenesis is not obligatory.
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Discussions and Knowledge Gaps

3
Which molecular intermediates connect loss of KCC3 transport to the central and peripheral axonopathy observed in human disease?
KNOWLEDGE GAP OPEN gap_kcc3_transport_to_human_axonopathy
Attached to
pathophysiology#SLC12A6 KCC3 loss of function pathophysiology#Central and peripheral axonopathy
Genetic, functional, model, and human-pathology evidence establish both endpoints, but not the intervening causal sequence.
Show evidence (1 reference)
PMID:29366908 SUPPORT Other
"we still do not understand how dysfunction of this cotransporter can lead to the pathophysiology of peripheral neuropathy."
The review explicitly identifies the transporter-to-neuropathy mechanism as unresolved.
To what extent do mouse impulse-propagation and motoneuron/NMJ mechanisms reproduce the human motor and sensory neuropathy?
HUMAN MODEL MISMATCH OPEN mismatch_mouse_kcc3_motor_unit_to_human_neuropathy
Attached to
pathophysiology#Peripheral nerve impulse-propagation failure pathophysiology#Activity-dependent motoneuron and neuromuscular-junction dysfunction
The strongest conduction and NMJ causal data are from mice, and both loss-of-function and gain-of-function mouse models can show peripheral-neuropathy-like phenotypes.
Show evidence (2 references)
PMID:29366908 SUPPORT Other
"recapitulated a peripheral neuropathy-like phenotype originating from a KCC3 gain-of-function (GOF)."
The review notes that opposite KCC3 perturbations can converge on a neuropathy-like mouse phenotype.
PMID:28647557 SUPPORT Model Organism
"here propose that abnormal motoneuron electrical activity contributes to the peripheral neuropathy observed in Andermann syndrome."
The authors frame translation from mouse motoneuron biology to human neuropathy as a proposal.
Why is corpus-callosum dysgenesis variable or absent in some people with biallelic pathogenic SLC12A6 variants?
KNOWLEDGE GAP OPEN gap_variable_corpus_callosum_dysgenesis
Attached to
pathophysiology#Commissural and corticospinal developmental abnormalities phenotypes#Agenesis of corpus callosum
Variable callosal anatomy affects disease naming, diagnostic interpretation, and the developmental mechanism assigned to KCC3 deficiency.
Show evidence (1 reference)
PMID:32765936 SUPPORT Human Clinical
"We confirm that ACC is not a mandatory feature"
A molecularly confirmed case demonstrates that callosal agenesis is not required.
⚙

Pathophysiology

6
SLC12A6 KCC3 loss of function
Biallelic pathogenic SLC12A6 variants cause the disorder. Assays of the 2436delG founder truncating variant and p.H371R missense variant show, respectively, a membrane-localized but nonfunctional protein and a mislocalized protein with impaired ion transport.
Canonical SLC12A6 Loss-of-Function and Axonopathy Model Emerging Central Commissural Development Model Emerging Motoneuron Electrical and Neuromuscular-Junction Model
SLC12A6 hgnc:10914 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SLC12A6 (hgnc:10914). hgnc:10914 is a gene from the HUGO Gene Nomenclature Committee.
potassium:chloride symporter activity GO:0015379 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased potassium:chloride symporter activity (GO:0015379). GO:0015379 is a molecular function from the Gene Ontology. ↓ DECREASED
Experimental models
Xenopus-oocyte KCC3 founder-variant transport assay OTHER Assays whether the founder truncating variant preserves KCC3 transport function.
Downstream
Impaired KCC3-mediated ion transport and ionic homeostasis KCC3 loss directly reduces potassium-chloride transport and disrupts cellular ion homeostasis. Canonical SLC12A6 Loss-of-Function and Axonopathy Model
Peripheral nerve impulse-propagation failure KCC3 deficiency reduces compound action-potential measures and nerve-conduction velocity in knockout mouse nerves. Canonical SLC12A6 Loss-of-Function and Axonopathy Model
Central and peripheral axonopathy Human pathology attributes the degenerative deficit to axonopathy caused ultimately by the KCC3 defect, with unknown intervening molecular steps. Canonical SLC12A6 Loss-of-Function and Axonopathy Model
Activity-dependent motoneuron and neuromuscular-junction dysfunction Neuron-specific KCC3 loss produces abnormal motoneuron activity and early NMJ abnormalities in mice. Emerging Motoneuron Electrical and Neuromuscular-Junction Model
Commissural and corticospinal developmental abnormalities KCC3 deficiency is associated with abnormal commissural and corticospinal development, but the intervening developmental mechanism is unknown. Emerging Central Commissural Development Model
Show evidence (2 references)
PMID:12368912 SUPPORT In Vitro
"the truncated mutant is appropriately glycosylated and expressed at the cellular membrane, where it is non-functional."
Heterologous expression demonstrates absent transport function for the founder truncating variant.
PMID:39988558 SUPPORT In Vitro
"type, the mutant protein was mislocalized to the cytoplasm, disrupting its ion transport function."
Patient-cell analysis supports mislocalization and impaired transport for a missense variant.
Impaired KCC3-mediated ion transport and ionic homeostasis
KCC3 normally mediates electroneutral potassium and chloride efflux in neurons. Proband-derived cells with the p.H371R missense variant showed mutant mislocalization, transport impairment, and potassium/chloride imbalance; abnormal cell volume was not measured in the cached abstract.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
potassium:chloride symporter activity GO:0015379 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased potassium:chloride symporter activity (GO:0015379). GO:0015379 is a molecular function from the Gene Ontology. ↓ DECREASED
Experimental models
p.H371R proband-cell functional assay OTHER Measures mutant localization, transport impairment, and potassium/chloride imbalance in the proband's cells.
Show evidence (2 references)
PMID:29366908 SUPPORT Other
"KCC3 is responsible for the efflux of K+ and Cl- in neurons to help maintain cell volume and intracellular chloride levels."
The review defines KCC3's normal ion-efflux and volume-homeostasis role but does not demonstrate abnormal cell volume in human disease.
PMID:39988558 SUPPORT In Vitro
"transport function. This mislocalization caused an imbalance in potassium and chloride ion levels in the proband's cells."
Patient-derived cells show ion imbalance downstream of mutant-protein mislocalization.
Peripheral nerve impulse-propagation failure
In peripheral nerves, pharmacologic KCC inhibition and genetic KCC3 deficiency reduce compound muscle action-potential amplitude and area; KCC3 knockout also slows nerve-conduction velocity.
Canonical SLC12A6 Loss-of-Function and Axonopathy Model
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology. Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology.
neuronal action potential GO:0019228 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal neuronal action potential (GO:0019228). GO:0019228 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Progressive sensorimotor neuropathy Impaired impulse propagation is a mouse and ex vivo functional readout relevant to neuropathy, but a causal link to the human degenerative phenotype is not established. Canonical SLC12A6 Loss-of-Function and Axonopathy Model
Show evidence (1 reference)
PMID:20549748 SUPPORT Model Organism
"This is the first study to demonstrate that the K(+)-Cl(-) cotransporter activity of KCC3 contributes to the propagation of action potentials along peripheral nerves."
Mouse and ex vivo physiology supports KCC3-dependent peripheral impulse propagation.
Central and peripheral axonopathy
Human autopsy tissue shows axonomas and axonal degeneration in the central and peripheral nervous systems. The authors interpret axonopathy superimposed on abnormal development as the principal neurodegenerative lesion.
Canonical SLC12A6 Loss-of-Function and Axonopathy Model
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Downstream
Progressive sensorimotor neuropathy The central and peripheral axonopathy manifests clinically as a progressive sensorimotor neuropathy. Canonical SLC12A6 Loss-of-Function and Axonopathy Model
Hypotonia Severe progressive sensorimotor neuropathy produces hypotonia. Canonical SLC12A6 Loss-of-Function and Axonopathy Model
Areflexia Severe progressive sensorimotor neuropathy produces loss of reflexes. Canonical SLC12A6 Loss-of-Function and Axonopathy Model
Skeletal muscle atrophy Progressive sensorimotor neuropathy downstream of axonopathy contributes to amyotrophy. Canonical SLC12A6 Loss-of-Function and Axonopathy Model
Show evidence (2 references)
PMID:27230413 SUPPORT Human Clinical
"Small tumor-like overgrowths of axons, termed axonomas, were found in the central and peripheral nervous system, indicating attempted axonal regeneration."
Human neuropathology directly documents central and peripheral axonal lesions.
PMID:27230413 SUPPORT Human Clinical
"We conclude that the neurodegenerative deficits in HMSN/ACC are primarily caused by an axonopathy superimposed upon abnormal development"
The autopsy series identifies axonopathy as the main degenerative process.
Activity-dependent motoneuron and neuromuscular-junction dysfunction
In global and neuron-specific KCC3-loss mice, abnormal motoneuron electrical activity and Na+/K+-ATPase alpha-1 mislocalization accompany early neuromuscular-junction abnormalities, denervation, and muscle atrophy. This branch is supported by model-organism evidence.
Emerging Motoneuron Electrical and Neuromuscular-Junction Model
motor neuron CL:0000100 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves motor neuron (CL:0000100). CL:0000100 is a cell type from the Cell Ontology.
modulation of chemical synaptic transmission GO:0050804 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal modulation of chemical synaptic transmission (GO:0050804). GO:0050804 is a biological process from the Gene Ontology. ⚠ ABNORMAL neuromuscular junction development GO:0007528 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal neuromuscular junction development (GO:0007528). GO:0007528 is a biological process from the Gene Ontology. ⚠ ABNORMAL
spinal cord UBERON:0002240 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in spinal cord (UBERON:0002240). UBERON:0002240 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Skeletal muscle atrophy Early NMJ abnormalities, denervation, and muscle atrophy co-occur downstream of neuron-specific KCC3 loss in mice; their direct causal ordering is unresolved. Emerging Motoneuron Electrical and Neuromuscular-Junction Model
Progressive sensorimotor neuropathy Abnormal motoneuron activity is proposed to contribute to the human neuropathy, but this link remains model-derived. Emerging Motoneuron Electrical and Neuromuscular-Junction Model
Show evidence (1 reference)
PMID:28647557 SUPPORT Model Organism
"KCC3 depletion does not modify chloride handling, but promotes an abnormal electrical activity among primary motoneurons and mislocalization of Na+/K+-ATPase α1 in spinal cord motoneurons."
Mouse motoneuron evidence supports the electrical-activity and ATPase-localization defect, independent of altered chloride handling.
Commissural and corticospinal developmental abnormalities
Human autopsy tissue shows hypoplasia or absence of major telencephalic commissures and marked corticospinal-tract hypoplasia, establishing a developmental central-nervous-system branch alongside axonopathy.
Emerging Central Commissural Development Model
axon development GO:0061564 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal axon development (GO:0061564). GO:0061564 is a biological process from the Gene Ontology. ⚠ ABNORMAL
corpus callosum UBERON:0002336 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in corpus callosum (UBERON:0002336). UBERON:0002336 is an anatomical location from the Uberon multi-species anatomy ontology. spinal cord UBERON:0002240 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in spinal cord (UBERON:0002240). UBERON:0002240 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Agenesis of corpus callosum Absence or hypoplasia of the major telencephalic commissures includes the corpus-callosum dysgenesis phenotype. Emerging Central Commissural Development Model
Show evidence (1 reference)
PMID:27230413 SUPPORT Human Clinical
"Hypoplasia or absence of the major telencephalic commissures and a hypoplasia of corticospinal tracts to half the normal size"
Human autopsy tissue directly supports commissural and corticospinal developmental abnormalities.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Agenesis of the Corpus Callosum with Peripheral Neuropathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

20
Eye 4
Nystagmus OCCASIONAL HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1496 SUPPORT Other
"HP:0000639 | Nystagmus | Occasional (29-5%)"
Orphanet classifies nystagmus as occasional.
Strabismus OCCASIONAL HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1496 SUPPORT Other
"HP:0000486 | Strabismus | Occasional (29-5%)"
Orphanet classifies strabismus as occasional.
Myopia OCCASIONAL HP:0000545 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopia (HP:0000545). HP:0000545 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1496 SUPPORT Other
"HP:0000545 | Myopia | Occasional (29-5%)"
Orphanet classifies myopia as occasional.
Abnormal retinal pigmentation OCCASIONAL HP:0007703 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of retinal pigmentation, annotated with Abnormal retinal pigmentation (HP:0007703). HP:0007703 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1496 SUPPORT Other
"HP:0007703 | Abnormality of retinal pigmentation | Occasional (29-5%)"
Orphanet classifies abnormal retinal pigmentation as occasional.
Head and Neck 2
Microcephaly VERY_FREQUENT HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1496 SUPPORT Other
"HP:0000252 | Microcephaly | Very frequent (99-80%)"
Orphanet classifies microcephaly as very frequent.
Craniosynostosis OCCASIONAL HP:0001363 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Craniosynostosis (HP:0001363). HP:0001363 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1496 SUPPORT Other
"HP:0001363 | Craniosynostosis | Occasional (29-5%)"
Orphanet classifies craniosynostosis as occasional.
Musculoskeletal 3
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252), qualified as congenital onset. HP:0001252 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (2 references)
PMID:12838516 SUPPORT Human Clinical
"amyotrophy, hypotonia, and cognitive impairment."
Clinical review lists hypotonia among core manifestations.
PMID:27230413 SUPPORT Human Clinical
"Patients are hypotonic and areflexic from birth, with abnormal facial features and"
Human clinical-pathologic evidence supports congenital hypotonia.
Skeletal muscle atrophy HP:0003202 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Amyotrophy, annotated with Skeletal muscle atrophy (HP:0003202). HP:0003202 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1496 SUPPORT Other
"resulting hypotonia, areflexia, amyotrophy"
Orphanet definition lists amyotrophy among resulting neuromuscular manifestations.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301546 SUPPORT Other
"severity, individuals with HMSN/ACC usually require corrective surgery for scoliosis."
GeneReviews supports scoliosis as a clinically significant manifestation requiring surveillance and sometimes corrective surgery.
Nervous System 8
Progressive sensorimotor neuropathy Peripheral neuropathy HP:0009830 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral neuropathy (HP:0009830), qualified as course progressive; infantile onset. HP:0009830 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE Onset: INFANTILE
Show evidence (3 references)
ORPHA:1496 SUPPORT Other
"severe progressive sensorimotor neuropathy beginning in infancy"
Orphanet directly supports infantile onset of the progressive sensorimotor neuropathy.
PMID:20301546 SUPPORT Other
"disorder, is characterized by severe progressive sensorimotor neuropathy with resulting hypotonia, areflexia, and amyotrophy"
GeneReviews identifies severe progressive sensorimotor neuropathy as a core clinical feature.
PMID:32765936 SUPPORT Human Clinical
"intellectual disability, and severe motor and sensory demyelinating peripheral neuropathy."
Case evidence supports severe sensorimotor peripheral neuropathy even without corpus callosum agenesis.
Agenesis of corpus callosum VERY_FREQUENT HP:0001274 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Agenesis of corpus callosum (HP:0001274). HP:0001274 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
ORPHA:1496 SUPPORT Other
"HP:0001274 | Agenesis of corpus callosum | Very frequent (99-80%)"
Orphanet classifies corpus callosum agenesis as very frequent.
PMID:20301546 SUPPORT Other
"dysgenesis of the corpus callosum."
GeneReviews supports variable corpus callosum dysgenesis.
PMID:32765936 SUPPORT Human Clinical
"We confirm that ACC is not a mandatory feature"
A genetically confirmed case demonstrates that corpus-callosum agenesis is not obligatory.
Global developmental delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1496 SUPPORT Other
"HP:0001263 | Global developmental delay | Very frequent (99-80%)"
Orphanet classifies global developmental delay as very frequent.
Intellectual disability VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:1496 SUPPORT Other
"HP:0001249 | Intellectual disability | Very frequent (99-80%)"
Orphanet classifies intellectual disability as very frequent.
PMID:20301546 SUPPORT Other
"Mild-to-severe intellectual disability"
GeneReviews supports variable intellectual disability.
Seizure VERY_FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1496 SUPPORT Other
"HP:0001250 | Seizure | Very frequent (99-80%)"
Orphanet classifies seizures as very frequent.
Psychotic episodes Psychosis HP:0000709 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Psychosis (HP:0000709). HP:0000709 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1496 SUPPORT Other
"psychiatric manifestations that include paranoid delusions, depression, hallucinations"
Orphanet lists psychotic and psychiatric manifestations among additional features.
Areflexia HP:0001284 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Areflexia (HP:0001284), qualified as congenital onset. HP:0001284 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (2 references)
PMID:12838516 SUPPORT Human Clinical
"characterized by a delay in developmental milestones, a severe sensory-motor polyneuropathy with areflexia, a variable degree of agenesis of the corpus"
Clinical review supports areflexia as part of the neuropathy phenotype.
PMID:27230413 SUPPORT Human Clinical
"Patients are hypotonic and areflexic from birth, with abnormal facial features and"
Human clinical-pathologic evidence supports congenital areflexia.
EEG abnormality VERY_FREQUENT HP:0002353 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is EEG abnormality (HP:0002353). HP:0002353 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1496 SUPPORT Other
"HP:0002353 | EEG abnormality | Very frequent (99-80%)"
Orphanet classifies EEG abnormality as very frequent.
Other 3
Turricephaly OCCASIONAL HP:0000262 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Turricephaly (HP:0000262). HP:0000262 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1496 SUPPORT Other
"HP:0000262 | Turricephaly | Occasional (29-5%)"
Orphanet classifies turricephaly as occasional.
Hemiplegia or hemiparesis VERY_FREQUENT Hemiplegia/hemiparesis HP:0004374 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemiplegia/hemiparesis (HP:0004374). HP:0004374 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1496 SUPPORT Other
"HP:0004374 | Hemiplegia/hemiparesis | Very frequent (99-80%)"
Orphanet classifies hemiplegia/hemiparesis as very frequent.
Aqueductal stenosis FREQUENT HP:0002410 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aqueductal stenosis (HP:0002410). HP:0002410 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1496 SUPPORT Other
"HP:0002410 | Aqueductal stenosis | Frequent (79-30%)"
Orphanet classifies aqueductal stenosis as frequent.
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Genetic Associations

1
SLC12A6 (Causal biallelic pathogenic variants)
Gene: SLC12A6 hgnc:10914 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SLC12A6 (hgnc:10914). hgnc:10914 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (4 references)
ORPHA:1496 SUPPORT Other
"SLC12A6 | solute carrier family 12 member 6 | hgnc:10914 | Disease-causing germline mutation(s) in"
Orphanet lists SLC12A6 as the disease-causing gene.
PMID:12368912 SUPPORT Human Clinical
"gating deficit, similar to the human disease. Our findings identify mutations in SLC12A6 as the genetic lesion underlying ACCPN and suggest a critical role for"
The original mapping and mutation study identifies SLC12A6 as causal.
PMID:16606917 SUPPORT Human Clinical
"CONCLUSIONS: Not only truncating but also missense mutations of the KCC3 gene are associated with Andermann syndrome. Different types of KCC3 mutations may"
Additional patient reports support both truncating and missense SLC12A6 variants.
+ 1 more reference
Variants (2)
2436delG (Thr813fsX813) founder truncating variant
The predominant French Canadian frameshift variant produces a truncated KCC3 protein that reaches the cell membrane but is nonfunctional in a Xenopus-oocyte heterologous-expression assay.
Show evidence (1 reference)
PMID:12368912 SUPPORT In Vitro
"the truncated mutant is appropriately glycosylated and expressed at the cellular membrane, where it is non-functional."
The functional assay shows that the founder truncating protein reaches the membrane but is nonfunctional.
Truncating and missense pathogenic SLC12A6 variants
Both truncating and missense variants are reported; the small clinical series suggests that variant class can modify the neurologic phenotype.
Show evidence (1 reference)
PMID:16606917 SUPPORT Human Clinical
"CONCLUSIONS: Not only truncating but also missense mutations of the KCC3 gene are associated with Andermann syndrome. Different types of KCC3 mutations may"
Patient evidence broadens the causal allelic spectrum beyond truncating variants.
🗃️

External Assertions

1
Orphanet corpus callosum agenesis-neuronopathy syndrome record
Orphanet structured disease record ORPHA:1496
Orphanet's ORPHA:1496 structured record provides the exact MONDO and OMIM cross-references, synonyms, definition, autosomal recessive inheritance, population-specific prevalence, SLC12A6 gene association, and HPO phenotype annotations used in this entry.
Show evidence (2 references)
ORPHA:1496 SUPPORT Other
"MONDO:0000902 | Exact"
Orphanet maps ORPHA:1496 to the MONDO identifier used by this entry.
ORPHA:1496 SUPPORT Other
"OMIM:218000 | Exact"
Orphanet lists OMIM:218000 as an exact external cross-reference.
💊

Medical Actions

7
Walking and mobility aids
Category: Therapeutic Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Canes, walkers, and other mobility aids are used as progressive neuropathy impairs ambulation.
Target Phenotypes: Peripheral neuropathy HP:0009830 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Peripheral neuropathy (HP:0009830). HP:0009830 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301546 SUPPORT Other
"Walking aids such as canes or walkers"
GeneReviews directly recommends walking aids for mobility support.
Orthoses and physiotherapy
Category: Therapeutic Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Upper- and lower-limb orthoses and physiotherapy are used as disease progresses to prevent contractures.
Show evidence (1 reference)
PMID:20301546 SUPPORT Other
"orthoses for upper and lower limbs and physiotherapy are needed to prevent contractures."
GeneReviews directly supports orthoses and physiotherapy for contracture prevention.
Developmental and educational intervention
Category: Therapeutic Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Early developmental and educational intervention addresses cognitive and developmental delays.
Target Phenotypes: Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology. Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301546 SUPPORT Other
"developmental/educational intervention addresses cognitive delays."
GeneReviews supports early developmental and educational intervention.
Corrective scoliosis surgery
Category: Therapeutic Action: Orthopedic Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Orthopedic Surgical Procedure (NCIT:C16186). NCIT:C16186 is a clinical intervention from the NCI Thesaurus. NCIT:C16186
Corrective orthopedic surgery may be required when scoliosis becomes severe.
Target Phenotypes: Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301546 SUPPORT Other
"severity, individuals with HMSN/ACC usually require corrective surgery for scoliosis."
GeneReviews supports severity-dependent corrective surgery for scoliosis.
Neuroleptic treatment of psychiatric manifestations
Category: Therapeutic Action: pharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Neuroleptic pharmacotherapy may be used for adolescent psychotic or other psychiatric manifestations.
Target Phenotypes: Psychosis HP:0000709 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Psychosis (HP:0000709). HP:0000709 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301546 SUPPORT Other
"Neuroleptics may be used to treat psychiatric manifestations, usually during adolescence."
GeneReviews supports neuroleptic treatment for adolescent psychiatric manifestations.
Adolescent scoliosis and psychiatric surveillance
Category: Monitoring Action: clinical assessmentNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is clinical assessment, annotated with Clinical Evaluation (NCIT:C124351). NCIT:C124351 is a clinical intervention from the NCI Thesaurus. Ontology label: Clinical Evaluation NCIT:C124351
Clinical surveillance focuses on scoliosis in the early teens and psychiatric manifestations in the late teens.
Show evidence (1 reference)
PMID:20301546 SUPPORT Other
"Surveillance: Monitor in the early teens for scoliosis and in the late teens for psychiatric manifestations."
GeneReviews provides age-specific scoliosis and psychiatric surveillance guidance.
Genetic counseling and family testing
Category: Counseling / Informational Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Counseling addresses autosomal-recessive recurrence risk, carrier testing for relatives, and prenatal or preimplantation testing once familial SLC12A6 variants are known.
Show evidence (2 references)
PMID:20301546 SUPPORT Other
"At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."
GeneReviews quantifies recurrence and carrier risks for siblings.
PMID:20301546 SUPPORT Other
"carrier testing for at-risk family members and prenatal and preimplantation genetic testing are possible."
GeneReviews supports carrier, prenatal, and preimplantation testing once familial variants are known.
🔬

Diagnosis

2
SLC12A6 molecular genetic testing
The diagnosis is established in a person with suggestive findings by identifying biallelic pathogenic SLC12A6 variants.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: Biallelic pathogenic SLC12A6 variants establish the molecular diagnosis.
Show evidence (1 reference)
PMID:20301546 SUPPORT Other
"suggestive findings and biallelic pathogenic variants in SLC12A6 identified by molecular genetic testing."
GeneReviews directly supports biallelic SLC12A6 testing as confirmatory.
Brain MRI
Brain MRI assesses complete or partial corpus-callosum dysgenesis and other structural abnormalities. A normal corpus callosum does not exclude SLC12A6-related disease.
MRI of the brain NCIT:C16809 NCI Thesaurus (NCIT)
Results: Corpus-callosum agenesis or dysgenesis is supportive but not obligatory.
Show evidence (2 references)
PMID:16606917 SUPPORT Human Clinical
"defects. The cerebral MRI reveals a variable degree of agenesis of the corpus callosum."
A patient series supports MRI characterization of variable callosal agenesis.
PMID:32765936 SUPPORT Human Clinical
"Brain magnetic resonance imaging showed intact corpus callosum."
A molecularly confirmed case establishes that intact callosal anatomy does not exclude the disease.
📈

Progression

3
Congenital and infantile neuromuscular onset
Age: Birth through infancy
Hypotonia and areflexia may be present from birth, and sensory impairment is evident in infancy.
Show evidence (2 references)
PMID:27230413 SUPPORT Human Clinical
"Patients are hypotonic and areflexic from birth, with abnormal facial features and"
Human clinical-pathologic evidence supports congenital hypotonia and areflexia.
PMID:20301546 SUPPORT Other
"Sensory modalities are moderately to severely affected beginning in infancy."
GeneReviews supports infantile sensory involvement.
Childhood and adolescent motor decline
Age: Childhood through adolescence
Walking is delayed, and the progressive neuropathy typically causes loss of ambulation and wheelchair dependence during adolescence.
Show evidence (2 references)
PMID:20301546 SUPPORT Other
"The average age of onset of walking is 3.8 years; the average age of loss of walking is 13.8 years; the"
GeneReviews quantifies delayed walking and adolescent loss of ambulation.
PMID:27230413 SUPPORT Human Clinical
"Progressive peripheral neuropathy eventually confines them to a wheelchair in the second decade of life"
Human clinical-pathologic evidence supports wheelchair dependence in the second decade.
Reduced adult survival
Age: Adulthood
Survival is shortened; GeneReviews reports an average age at death of 33 years, while an autopsy series describes death by the fourth decade.
Show evidence (2 references)
PMID:20301546 SUPPORT Other
"average age of death is 33 years."
GeneReviews reports reduced adult survival.
PMID:27230413 SUPPORT Human Clinical
"and death occurs by the fourth"
The human autopsy series supports death by the fourth decade.
📊

Prevalence

2
Saguenay-Lac-Saint-Jean region of Quebec
Point Prevalence 10.0–50.0 per 100,000 1–9 per 10,000
Orphanet records a high point-prevalence band in a specific population, reflecting the Quebec founder effect.
Show evidence (2 references)
ORPHA:1496 SUPPORT Other
"1-5 / 10 000 | Specific population | Point prevalence | PMID:20301546"
Orphanet records the specific-population point-prevalence band.
PMID:12838516 SUPPORT Human Clinical
"it has a high prevalence in the Saguenay-Lac-St-Jean region of the province of Quebec (Canada) predominantly because of a founder effect."
A clinical review supports the named Quebec region and founder-effect interpretation.
Worldwide
Point Prevalence ≤0.1 per 100,000 <1 in 1,000,000
Orphanet records the worldwide point-prevalence band as ultra-rare.
Show evidence (1 reference)
ORPHA:1496 SUPPORT Other
"<1 / 1 000 000 | Worldwide | Point prevalence | PMID:20301546"
Orphanet records the worldwide point-prevalence band.
🧫

Experimental Models

2
Xenopus-oocyte KCC3 founder-variant transport assay OTHER
Xenopus laevis oocytes heterologously expressing wild-type or 2436delG/Thr813fsX813 KCC3 test membrane localization, glycosylation, and transporter function.
wild-type KCC3 expression 2436delG (Thr813fsX813) KCC3 expression
Cell source
Xenopus laevis oocytes
Culture
Heterologous membrane-transporter expression assay
Publication
PMID:12368912
Pathograph links
SLC12A6 KCC3 loss of function Assays whether the founder truncating variant preserves KCC3 transport function.
Show evidence (1 reference)
PMID:12368912 SUPPORT In Vitro
"the truncated mutant is appropriately glycosylated and expressed at the cellular membrane, where it is non-functional."
The oocyte model directly measures nonfunction of membrane-localized mutant KCC3.
Findings
The founder truncating KCC3 protein reaches the membrane but is nonfunctional.
"the truncated mutant is appropriately glycosylated and expressed at the cellular membrane, where it is non-functional."
Show evidence (1 reference)
PMID:12368912 SUPPORT In Vitro
"the truncated mutant is appropriately glycosylated and expressed at the cellular membrane, where it is non-functional."
The assay finding is quoted directly from the functional study.
Show evidence (1 reference)
PMID:12368912 SUPPORT In Vitro
"the truncated mutant is appropriately glycosylated and expressed at the cellular membrane, where it is non-functional."
The heterologous assay establishes loss of function for the founder variant.
p.H371R proband-cell functional assay OTHER
Proband-derived cells carrying homozygous p.H371R SLC12A6 were compared with wild type for mutant-protein localization, ion-transport function, and potassium/chloride ion levels. The cached abstract does not identify the cell type.
homozygous SLC12A6 p.H371R wild-type comparator
Cell source
Proband-derived cells; cell type not identified in the cached abstract
Publication
PMID:39988558
Pathograph links
Impaired KCC3-mediated ion transport and ionic homeostasis Measures mutant localization, transport impairment, and potassium/chloride imbalance in the proband's cells.
Show evidence (1 reference)
PMID:39988558 SUPPORT In Vitro
"transport function. This mislocalization caused an imbalance in potassium and chloride ion levels in the proband's cells."
The proband-cell assay directly reports cellular ion imbalance downstream of mutant mislocalization.
Findings
p.H371R KCC3 mislocalizes to the cytoplasm and disrupts ion transport.
"type, the mutant protein was mislocalized to the cytoplasm, disrupting its ion transport function."
Show evidence (1 reference)
PMID:39988558 SUPPORT In Vitro
"type, the mutant protein was mislocalized to the cytoplasm, disrupting its ion transport function."
The finding is quoted directly from the proband-cell functional study.
Show evidence (1 reference)
PMID:39988558 SUPPORT In Vitro
"type, the mutant protein was mislocalized to the cytoplasm, disrupting its ion transport function."
The patient-cell assay supports mutant mislocalization and transport loss.
🐁

Animal Models

2
Global Slc12a6/Kcc3 targeted deletion mouse Genetically engineered mouse model
Global Kcc3-null mice model locomotor impairment, peripheral neuropathy, sensorimotor-gating deficits, reduced compound action potentials, and slowed peripheral nerve conduction.
locomotor deficit peripheral neuropathy sensorimotor gating deficit slowed peripheral nerve conduction
Species
mouse
Genotype
Global Slc12a6/Kcc3 targeted deletion
Genes
SLC12A6 hgnc:10914 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns SLC12A6 (hgnc:10914). hgnc:10914 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:12368912 SUPPORT Model Organism
"Mice generated with a targeted deletion of Slc12a6 have a locomotor deficit, peripheral neuropathy and a sensorimotor gating deficit, similar to the human disease."
The discovery study reports neurologic phenotypes in Slc12a6-targeted mice.
PMID:20549748 SUPPORT Model Organism
"and the nerve conduction velocity was slower in nerves from KCC3(-/-) mice than in nerves from wild-type mice"
Knockout-mouse physiology demonstrates slowed peripheral nerve conduction.
Global or neuron-specific Slc12a6/Kcc3 loss of function mouse Genetically engineered mouse model
Global and neuron-specific KCC3-loss mice model abnormal motoneuron electrical activity, Na+/K+-ATPase alpha-1 mislocalization, early NMJ abnormalities, denervation, and muscle atrophy.
neuromuscular junction abnormality skeletal muscle atrophy abnormal motoneuron electrical activity
Species
mouse
Genotype
Global or neuron-specific Slc12a6/Kcc3 loss of function
Genes
SLC12A6 hgnc:10914 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns SLC12A6 (hgnc:10914). hgnc:10914 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:28647557 SUPPORT Model Organism
"global or neuron-specific KCC3 loss-of-function in mice leads to early neuromuscular junction (NMJ) abnormalities and muscular atrophy"
Mouse genetics supports the motor-unit and NMJ model.
{ }

Source YAML

click to show 
name: Agenesis of the Corpus Callosum with Peripheral Neuropathy
category: Mendelian
creation_date: "2026-05-04T22:55:00Z"
synonyms:
- Andermann syndrome
- Charlevoix disease
- Corpus callosum agenesis-neuronopathy syndrome
- Hereditary motor and sensory neuropathy with agenesis of the corpus callosum
- HMSN/ACC
- ACCPN
description: >
  Agenesis of the corpus callosum with peripheral neuropathy, also known as
  Andermann syndrome or HMSN/ACC, is an autosomal recessive neurodevelopmental
  and neurodegenerative disorder caused by biallelic pathogenic variants in
  SLC12A6, encoding the potassium-chloride cotransporter KCC3. KCC3 dysfunction
  impairs potassium-chloride cotransport and cellular ionic homeostasis, but the
  bridge from transporter dysfunction to axonopathy and variable callosal
  dysgenesis remains unresolved. Clinically, the disorder features severe
  infantile-onset progressive sensorimotor neuropathy with hypotonia, areflexia,
  amyotrophy, variable corpus callosum dysgenesis, developmental delay or
  intellectual disability, seizures, and progressive loss of ambulation.
disease_term:
  preferred_term: Agenesis of the corpus callosum with peripheral neuropathy
  term:
    id: MONDO:0000902
    label: agenesis of the corpus callosum with peripheral neuropathy
parents:
- Inherited neurodegenerative disorder
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0000902
      label: agenesis of the corpus callosum with peripheral neuropathy
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:1496
    mapping_justification: >
      Orphanet ORPHA:1496 lists MONDO:0000902 as an exact cross-reference for
      corpus callosum agenesis-neuronopathy syndrome.
external_assertions:
- name: Orphanet corpus callosum agenesis-neuronopathy syndrome record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:1496
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=1496
  description: >
    Orphanet's ORPHA:1496 structured record provides the exact MONDO and OMIM
    cross-references, synonyms, definition, autosomal recessive inheritance,
    population-specific prevalence, SLC12A6 gene association, and HPO
    phenotype annotations used in this entry.
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0000902 | Exact"
    explanation: Orphanet maps ORPHA:1496 to the MONDO identifier used by this entry.
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:218000 | Exact"
    explanation: Orphanet lists OMIM:218000 as an exact external cross-reference.
definitions:
- name: Orphanet corpus callosum agenesis-neuronopathy syndrome definition
  definition_type: OTHER
  description: >
    A rare autosomal recessive neurodegenerative disorder with severe
    infantile-onset progressive sensorimotor neuropathy, hypotonia, areflexia,
    amyotrophy, variable corpus callosum dysgenesis, developmental delay or
    intellectual disability, psychiatric manifestations, early wheelchair
    dependence, and reduced survival.
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "severe progressive sensorimotor neuropathy beginning in infancy with resulting hypotonia, areflexia, amyotrophy"
    explanation: Orphanet defines the disorder by early progressive sensorimotor neuropathy and neuromuscular signs.
  - reference: PMID:20301546
    reference_title: "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "a neurodevelopmental and neurodegenerative"
    explanation: GeneReviews supports the combined neurodevelopmental and neurodegenerative framing.
inheritance:
- name: Autosomal recessive inheritance
  description: The disorder is inherited in an autosomal recessive pattern.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet records autosomal recessive inheritance.
  - reference: PMID:12368912
    reference_title: "The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "transmitted in an autosomal recessive fashion and is found at a high frequency"
    explanation: The SLC12A6 discovery study reports autosomal recessive inheritance.
prevalence:
- population: Saguenay-Lac-Saint-Jean region of Quebec
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_low: 10.0
  rate_high: 50.0
  notes: >
    Orphanet records a high point-prevalence band in a specific population,
    reflecting the Quebec founder effect.
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-5 / 10 000 | Specific population | Point prevalence | PMID:20301546"
    explanation: Orphanet records the specific-population point-prevalence band.
  - reference: PMID:12838516
    reference_title: "Hereditary motor and sensory neuropathy with agenesis of the corpus callosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      it has a high prevalence in the
      Saguenay-Lac-St-Jean region of the province of Quebec (Canada) predominantly
      because of a founder effect.
    explanation: A clinical review supports the named Quebec region and founder-effect interpretation.
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_high: 0.1
  notes: Orphanet records the worldwide point-prevalence band as ultra-rare.
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | PMID:20301546"
    explanation: Orphanet records the worldwide point-prevalence band.
progression:
- phase: Congenital and infantile neuromuscular onset
  age_range: Birth through infancy
  notes: >
    Hypotonia and areflexia may be present from birth, and sensory impairment is
    evident in infancy.
  evidence:
  - reference: PMID:27230413
    reference_title: "KCC3 axonopathy: neuropathological features in the central and peripheral nervous system."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients are hypotonic and areflexic from birth, with abnormal facial features and"
    explanation: Human clinical-pathologic evidence supports congenital hypotonia and areflexia.
  - reference: PMID:20301546
    reference_title: "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      Sensory modalities are
      moderately to severely affected beginning in infancy.
    explanation: GeneReviews supports infantile sensory involvement.
- phase: Childhood and adolescent motor decline
  age_range: Childhood through adolescence
  notes: >
    Walking is delayed, and the progressive neuropathy typically causes loss of
    ambulation and wheelchair dependence during adolescence.
  evidence:
  - reference: PMID:20301546
    reference_title: "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      The average age of onset
      of walking is 3.8 years; the average age of loss of walking is 13.8 years; the
    explanation: GeneReviews quantifies delayed walking and adolescent loss of ambulation.
  - reference: PMID:27230413
    reference_title: "KCC3 axonopathy: neuropathological features in the central and peripheral nervous system."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Progressive peripheral neuropathy eventually confines them to
      a wheelchair in the second decade of life
    explanation: Human clinical-pathologic evidence supports wheelchair dependence in the second decade.
- phase: Reduced adult survival
  age_range: Adulthood
  notes: >
    Survival is shortened; GeneReviews reports an average age at death of 33
    years, while an autopsy series describes death by the fourth decade.
  evidence:
  - reference: PMID:20301546
    reference_title: "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "average age of death is 33 years."
    explanation: GeneReviews reports reduced adult survival.
  - reference: PMID:27230413
    reference_title: "KCC3 axonopathy: neuropathological features in the central and peripheral nervous system."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and death occurs by the fourth"
    explanation: The human autopsy series supports death by the fourth decade.
genetic:
- name: SLC12A6
  association: Causal biallelic pathogenic variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: SLC12A6
    term:
      id: hgnc:10914
      label: SLC12A6
  notes: >
    SLC12A6 encodes the potassium-chloride cotransporter KCC3. Biallelic
    truncating and missense pathogenic variants cause classic and variable
    Andermann syndrome phenotypes, including cases with intact corpus callosum.
  variants:
  - name: 2436delG (Thr813fsX813) founder truncating variant
    description: >
      The predominant French Canadian frameshift variant produces a truncated
      KCC3 protein that reaches the cell membrane but is nonfunctional in a
      Xenopus-oocyte heterologous-expression assay.
    evidence:
    - reference: PMID:12368912
      reference_title: "The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: |-
        the truncated mutant is appropriately glycosylated and expressed at the cellular
        membrane, where it is non-functional.
      explanation: The functional assay shows that the founder truncating protein reaches the membrane but is nonfunctional.
  - name: Truncating and missense pathogenic SLC12A6 variants
    description: >
      Both truncating and missense variants are reported; the small clinical
      series suggests that variant class can modify the neurologic phenotype.
    evidence:
    - reference: PMID:16606917
      reference_title: "Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        CONCLUSIONS: Not only truncating but also missense mutations of the KCC3 gene
        are associated with Andermann syndrome. Different types of KCC3 mutations may
      explanation: Patient evidence broadens the causal allelic spectrum beyond truncating variants.
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLC12A6 | solute carrier family 12 member 6 | hgnc:10914 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists SLC12A6 as the disease-causing gene.
  - reference: PMID:12368912
    reference_title: "The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      gating deficit, similar to the human disease. Our findings identify mutations in
      SLC12A6 as the genetic lesion underlying ACCPN and suggest a critical role for
    explanation: The original mapping and mutation study identifies SLC12A6 as causal.
  - reference: PMID:16606917
    reference_title: "Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      CONCLUSIONS: Not only truncating but also missense mutations of the KCC3 gene
      are associated with Andermann syndrome. Different types of KCC3 mutations may
    explanation: Additional patient reports support both truncating and missense SLC12A6 variants.
  - reference: PMID:32765936
    reference_title: "A Novel Splice-Site Variant in SLC12A6 Causes Andermann Syndrome without Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain magnetic resonance imaging showed intact corpus callosum."
    explanation: A genetically confirmed case supports the note that callosal agenesis is not obligatory.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_slc12a6_loss_axonopathy_model
  hypothesis_label: Canonical SLC12A6 Loss-of-Function and Axonopathy Model
  status: CANONICAL
  description: >
    Biallelic SLC12A6 variants abolish or impair KCC3 function. Human
    neuropathology and knockout-model physiology support KCC3 deficiency as the
    upstream lesion for peripheral nerve dysfunction and a central/peripheral
    axonopathy, although the molecular bridge from transporter loss to axonal
    degeneration remains incompletely defined.
  evidence:
  - reference: PMID:12368912
    reference_title: "The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Our findings identify mutations in
      SLC12A6 as the genetic lesion underlying ACCPN and suggest a critical role for
      SLC12A6 in the development and maintenance of the nervous system.
    explanation: Patient mutation evidence establishes SLC12A6 as the causal disease gene.
  - reference: PMID:27230413
    reference_title: "KCC3 axonopathy: neuropathological features in the central and peripheral nervous system."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      We conclude that the
      neurodegenerative deficits in HMSN/ACC are primarily caused by an axonopathy
      superimposed upon abnormal development
    explanation: Human autopsy evidence supports axonopathy superimposed on abnormal development.
- hypothesis_group_id: emerging_motoneuron_nmj_model
  hypothesis_label: Emerging Motoneuron Electrical and Neuromuscular-Junction Model
  status: EMERGING
  description: >
    Global and neuron-specific KCC3 loss in mice produces abnormal motoneuron
    electrical activity, Na+/K+-ATPase alpha-1 mislocalization, early
    neuromuscular-junction abnormalities, denervation, and muscle atrophy. This is a
    parallel model-supported branch, not yet a demonstrated human treatment
    mechanism.
  evidence:
  - reference: PMID:28647557
    reference_title: "KCC3 loss-of-function contributes to Andermann syndrome by inducing activity-dependent neuromuscular junction defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: |-
      neuron-specific KCC3 loss-of-function in mice leads to early neuromuscular
      junction (NMJ) abnormalities and muscular atrophy
    explanation: Mouse evidence supports a neuron-autonomous NMJ and muscle-atrophy branch.
- hypothesis_group_id: emerging_central_commissural_development_model
  hypothesis_label: Emerging Central Commissural Development Model
  status: EMERGING
  description: >
    Human neuropathology establishes commissural and corticospinal-tract
    hypoplasia, but the developmental intermediates downstream of KCC3 loss and
    the reason corpus-callosum dysgenesis is variable remain unknown.
  evidence:
  - reference: PMID:27230413
    reference_title: "KCC3 axonopathy: neuropathological features in the central and peripheral nervous system."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Hypoplasia or absence of the major telencephalic commissures and a
      hypoplasia of corticospinal tracts to half the normal size
    explanation: Human autopsy tissue establishes the central developmental lesions.
  - reference: PMID:32765936
    reference_title: "A Novel Splice-Site Variant in SLC12A6 Causes Andermann Syndrome without Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We confirm that ACC is not a mandatory feature"
    explanation: A genetically confirmed case shows that callosal agenesis is not obligatory.

pathophysiology:
- name: SLC12A6 KCC3 loss of function
  description: >
    Biallelic pathogenic SLC12A6 variants cause the disorder. Assays of the
    2436delG founder truncating variant and p.H371R missense variant show,
    respectively, a membrane-localized but nonfunctional protein and a
    mislocalized protein with impaired ion transport.
  genes:
  - preferred_term: SLC12A6
    term:
      id: hgnc:10914
      label: SLC12A6
  molecular_functions:
  - preferred_term: potassium:chloride symporter activity
    term:
      id: GO:0015379
      label: potassium:chloride symporter activity
    modifier: DECREASED
  evidence:
  - reference: PMID:12368912
    reference_title: "The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      the truncated mutant is appropriately glycosylated and expressed at the cellular
      membrane, where it is non-functional.
    explanation: Heterologous expression demonstrates absent transport function for the founder truncating variant.
  - reference: PMID:39988558
    reference_title: "A Novel Missense Mutation in SLC12A6 Impairs Ion Transport Function of the Protein to Cause Agenesis of the Corpus Callosum With Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      type, the mutant protein was mislocalized to the cytoplasm, disrupting its ion
      transport function.
    explanation: Patient-cell analysis supports mislocalization and impaired transport for a missense variant.
  downstream:
  - target: Impaired KCC3-mediated ion transport and ionic homeostasis
    description: KCC3 loss directly reduces potassium-chloride transport and disrupts cellular ion homeostasis.
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_slc12a6_loss_axonopathy_model
    evidence:
    - reference: PMID:39988558
      reference_title: "A Novel Missense Mutation in SLC12A6 Impairs Ion Transport Function of the Protein to Cause Agenesis of the Corpus Callosum With Peripheral Neuropathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: |-
        type, the mutant protein was mislocalized to the cytoplasm, disrupting its ion
        transport function.
      explanation: Variant mislocalization directly impaired the transport function represented by the target node.
  - target: Peripheral nerve impulse-propagation failure
    description: KCC3 deficiency reduces compound action-potential measures and nerve-conduction velocity in knockout mouse nerves.
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_slc12a6_loss_axonopathy_model
    evidence:
    - reference: PMID:20549748
      reference_title: "Deficiency of electroneutral K+-Cl- cotransporter 3 causes a disruption in impulse propagation along peripheral nerves."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: |-
        and the nerve conduction velocity was slower in nerves from KCC3(-/-) mice than
        in nerves from wild-type mice
      explanation: Knockout-mouse nerve physiology directly links KCC3 deficiency to impaired impulse propagation.
  - target: Central and peripheral axonopathy
    description: Human pathology attributes the degenerative deficit to axonopathy caused ultimately by the KCC3 defect, with unknown intervening molecular steps.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Molecular steps connecting KCC3 transport loss to axonal degeneration remain unresolved.
    hypothesis_groups:
    - canonical_slc12a6_loss_axonopathy_model
    evidence:
    - reference: PMID:27230413
      reference_title: "KCC3 axonopathy: neuropathological features in the central and peripheral nervous system."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        affecting peripheral but also central
        nervous system axons, all ultimately because of a genetic defect in the axonal
        cotransporter KCC3.
      explanation: Human autopsy interpretation links the KCC3 defect to central and peripheral axonopathy while leaving intermediates unspecified.
  - target: Activity-dependent motoneuron and neuromuscular-junction dysfunction
    description: Neuron-specific KCC3 loss produces abnormal motoneuron activity and early NMJ abnormalities in mice.
    causal_link_type: DIRECT
    hypothesis_groups:
    - emerging_motoneuron_nmj_model
    evidence:
    - reference: PMID:28647557
      reference_title: "KCC3 loss-of-function contributes to Andermann syndrome by inducing activity-dependent neuromuscular junction defects."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: |-
        neuron-specific KCC3 loss-of-function in mice leads to early neuromuscular
        junction (NMJ) abnormalities and muscular atrophy
      explanation: Conditional mouse genetics directly supports a neuron-autonomous NMJ effect.
  - target: Commissural and corticospinal developmental abnormalities
    description: KCC3 deficiency is associated with abnormal commissural and corticospinal development, but the intervening developmental mechanism is unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Developmental steps connecting KCC3 loss to tract dysgenesis remain unresolved.
    hypothesis_groups:
    - emerging_central_commissural_development_model
    evidence:
    - reference: PMID:27230413
      reference_title: "KCC3 axonopathy: neuropathological features in the central and peripheral nervous system."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Hypoplasia or absence of the major telencephalic commissures and a
        hypoplasia of corticospinal tracts to half the normal size
      explanation: Human autopsy documents the developmental lesions, while the precise causal bridge from KCC3 loss remains unspecified.
- name: Impaired KCC3-mediated ion transport and ionic homeostasis
  description: >
    KCC3 normally mediates electroneutral potassium and chloride efflux in
    neurons. Proband-derived cells with the p.H371R missense variant showed
    mutant mislocalization, transport impairment, and potassium/chloride
    imbalance; abnormal cell volume was not measured in the cached abstract.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  molecular_functions:
  - preferred_term: potassium:chloride symporter activity
    term:
      id: GO:0015379
      label: potassium:chloride symporter activity
    modifier: DECREASED
  evidence:
  - reference: PMID:29366908
    reference_title: "A role for KCC3 in maintaining cell volume of peripheral nerve fibers."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      KCC3 is responsible for
      the efflux of K+ and Cl- in neurons to help maintain cell volume and
      intracellular chloride levels.
    explanation: The review defines KCC3's normal ion-efflux and volume-homeostasis role but does not demonstrate abnormal cell volume in human disease.
  - reference: PMID:39988558
    reference_title: "A Novel Missense Mutation in SLC12A6 Impairs Ion Transport Function of the Protein to Cause Agenesis of the Corpus Callosum With Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      transport function. This mislocalization caused an imbalance in potassium and
      chloride ion levels in the proband's cells.
    explanation: Patient-derived cells show ion imbalance downstream of mutant-protein mislocalization.
- name: Peripheral nerve impulse-propagation failure
  description: >
    In peripheral nerves, pharmacologic KCC inhibition and genetic KCC3
    deficiency reduce compound muscle action-potential amplitude and area; KCC3
    knockout also slows nerve-conduction velocity.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: neuronal action potential
    term:
      id: GO:0019228
      label: neuronal action potential
    modifier: ABNORMAL
  evidence:
  - reference: PMID:20549748
    reference_title: "Deficiency of electroneutral K+-Cl- cotransporter 3 causes a disruption in impulse propagation along peripheral nerves."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: |-
      This is the first study to
      demonstrate that the K(+)-Cl(-) cotransporter activity of KCC3 contributes to
      the propagation of action potentials along peripheral nerves.
    explanation: Mouse and ex vivo physiology supports KCC3-dependent peripheral impulse propagation.
  downstream:
  - target: Progressive sensorimotor neuropathy
    description: Impaired impulse propagation is a mouse and ex vivo functional readout relevant to neuropathy, but a causal link to the human degenerative phenotype is not established.
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - canonical_slc12a6_loss_axonopathy_model
    evidence:
    - reference: PMID:20549748
      reference_title: "Deficiency of electroneutral K+-Cl- cotransporter 3 causes a disruption in impulse propagation along peripheral nerves."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: |-
        Mutation in SLC12A6 gene
        encoding KCC3 results in an autosomal recessive disease, known as agenesis of
        the corpus callosum associated with peripheral neuropathy.
      explanation: The study places the conduction readout in the human disease context without establishing a causal progression to human neuropathy.
- name: Central and peripheral axonopathy
  description: >
    Human autopsy tissue shows axonomas and axonal degeneration in the central
    and peripheral nervous systems. The authors interpret axonopathy
    superimposed on abnormal development as the principal neurodegenerative
    lesion.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:27230413
    reference_title: "KCC3 axonopathy: neuropathological features in the central and peripheral nervous system."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Small tumor-like
      overgrowths of axons, termed axonomas, were found in the central and peripheral
      nervous system, indicating attempted axonal regeneration.
    explanation: Human neuropathology directly documents central and peripheral axonal lesions.
  - reference: PMID:27230413
    reference_title: "KCC3 axonopathy: neuropathological features in the central and peripheral nervous system."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      We conclude that the
      neurodegenerative deficits in HMSN/ACC are primarily caused by an axonopathy
      superimposed upon abnormal development
    explanation: The autopsy series identifies axonopathy as the main degenerative process.
  downstream:
  - target: Progressive sensorimotor neuropathy
    description: The central and peripheral axonopathy manifests clinically as a progressive sensorimotor neuropathy.
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_slc12a6_loss_axonopathy_model
    evidence:
    - reference: PMID:27230413
      reference_title: "KCC3 axonopathy: neuropathological features in the central and peripheral nervous system."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Progressive peripheral neuropathy eventually confines them to
        a wheelchair in the second decade of life
      explanation: Human clinical-pathologic evidence links progressive peripheral neuropathy to the documented axonopathy.
  - target: Hypotonia
    description: Severe progressive sensorimotor neuropathy produces hypotonia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - progressive sensorimotor neuropathy
    hypothesis_groups:
    - canonical_slc12a6_loss_axonopathy_model
    evidence:
    - reference: PMID:20301546
      reference_title: "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        disorder, is characterized by severe progressive sensorimotor neuropathy with
        resulting hypotonia, areflexia, and amyotrophy
      explanation: GeneReviews explicitly describes hypotonia as resulting from the progressive neuropathy.
  - target: Areflexia
    description: Severe progressive sensorimotor neuropathy produces loss of reflexes.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - progressive sensorimotor neuropathy
    hypothesis_groups:
    - canonical_slc12a6_loss_axonopathy_model
    evidence:
    - reference: PMID:20301546
      reference_title: "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        disorder, is characterized by severe progressive sensorimotor neuropathy with
        resulting hypotonia, areflexia, and amyotrophy
      explanation: GeneReviews explicitly describes areflexia as resulting from the progressive neuropathy.
  - target: Skeletal muscle atrophy
    description: Progressive sensorimotor neuropathy downstream of axonopathy contributes to amyotrophy.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - progressive sensorimotor neuropathy
    hypothesis_groups:
    - canonical_slc12a6_loss_axonopathy_model
    evidence:
    - reference: PMID:20301546
      reference_title: "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        disorder, is characterized by severe progressive sensorimotor neuropathy with
        resulting hypotonia, areflexia, and amyotrophy
      explanation: GeneReviews explicitly describes amyotrophy as resulting from the progressive neuropathy.
- name: Activity-dependent motoneuron and neuromuscular-junction dysfunction
  description: >
    In global and neuron-specific KCC3-loss mice, abnormal motoneuron electrical
    activity and Na+/K+-ATPase alpha-1 mislocalization accompany early
    neuromuscular-junction abnormalities, denervation, and muscle atrophy. This branch
    is supported by model-organism evidence.
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  locations:
  - preferred_term: spinal cord
    term:
      id: UBERON:0002240
      label: spinal cord
  biological_processes:
  - preferred_term: modulation of chemical synaptic transmission
    term:
      id: GO:0050804
      label: modulation of chemical synaptic transmission
    modifier: ABNORMAL
  - preferred_term: neuromuscular junction development
    term:
      id: GO:0007528
      label: neuromuscular junction development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:28647557
    reference_title: "KCC3 loss-of-function contributes to Andermann syndrome by inducing activity-dependent neuromuscular junction defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: |-
      KCC3 depletion does
      not modify chloride handling, but promotes an abnormal electrical activity among
      primary motoneurons and mislocalization of Na+/K+-ATPase α1 in spinal cord
      motoneurons.
    explanation: Mouse motoneuron evidence supports the electrical-activity and ATPase-localization defect, independent of altered chloride handling.
  downstream:
  - target: Skeletal muscle atrophy
    description: Early NMJ abnormalities, denervation, and muscle atrophy co-occur downstream of neuron-specific KCC3 loss in mice; their direct causal ordering is unresolved.
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - emerging_motoneuron_nmj_model
    evidence:
    - reference: PMID:28647557
      reference_title: "KCC3 loss-of-function contributes to Andermann syndrome by inducing activity-dependent neuromuscular junction defects."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: |-
        neuron-specific KCC3 loss-of-function in mice leads to early neuromuscular
        junction (NMJ) abnormalities and muscular atrophy
      explanation: Conditional mouse genetics shows NMJ abnormalities and muscle atrophy together downstream of neuron-specific KCC3 loss, without proving direct ordering.
  - target: Progressive sensorimotor neuropathy
    description: Abnormal motoneuron activity is proposed to contribute to the human neuropathy, but this link remains model-derived.
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - emerging_motoneuron_nmj_model
    evidence:
    - reference: PMID:28647557
      reference_title: "KCC3 loss-of-function contributes to Andermann syndrome by inducing activity-dependent neuromuscular junction defects."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: |-
        here propose that abnormal motoneuron electrical activity contributes to the
        peripheral neuropathy observed in Andermann syndrome.
      explanation: The authors explicitly frame this link as a proposal based on model-organism evidence.
- name: Commissural and corticospinal developmental abnormalities
  description: >
    Human autopsy tissue shows hypoplasia or absence of major telencephalic
    commissures and marked corticospinal-tract hypoplasia, establishing a
    developmental central-nervous-system branch alongside axonopathy.
  locations:
  - preferred_term: corpus callosum
    term:
      id: UBERON:0002336
      label: corpus callosum
  - preferred_term: spinal cord
    term:
      id: UBERON:0002240
      label: spinal cord
  biological_processes:
  - preferred_term: axon development
    term:
      id: GO:0061564
      label: axon development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:27230413
    reference_title: "KCC3 axonopathy: neuropathological features in the central and peripheral nervous system."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Hypoplasia or absence of the major telencephalic commissures and a
      hypoplasia of corticospinal tracts to half the normal size
    explanation: Human autopsy tissue directly supports commissural and corticospinal developmental abnormalities.
  downstream:
  - target: Agenesis of corpus callosum
    description: Absence or hypoplasia of the major telencephalic commissures includes the corpus-callosum dysgenesis phenotype.
    causal_link_type: DIRECT
    hypothesis_groups:
    - emerging_central_commissural_development_model
    evidence:
    - reference: PMID:27230413
      reference_title: "KCC3 axonopathy: neuropathological features in the central and peripheral nervous system."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Hypoplasia or absence of the major telencephalic commissures and a
        hypoplasia of corticospinal tracts to half the normal size
      explanation: Human pathology directly links commissural maldevelopment to the callosal-dysgenesis phenotype.
phenotypes:
- name: Progressive sensorimotor neuropathy
  description: >
    Severe motor and sensory peripheral neuropathy begins in infancy and
    progresses to major motor disability and loss of ambulation.
  diagnostic: true
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
    clinical_course: PROGRESSIVE
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "severe progressive sensorimotor neuropathy beginning in infancy"
    explanation: Orphanet directly supports infantile onset of the progressive sensorimotor neuropathy.
  - reference: PMID:20301546
    reference_title: "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      disorder, is characterized by severe progressive sensorimotor neuropathy with
      resulting hypotonia, areflexia, and amyotrophy
    explanation: GeneReviews identifies severe progressive sensorimotor neuropathy as a core clinical feature.
  - reference: PMID:32765936
    reference_title: "A Novel Splice-Site Variant in SLC12A6 Causes Andermann Syndrome without Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      intellectual disability, and severe motor and sensory demyelinating peripheral
      neuropathy.
    explanation: Case evidence supports severe sensorimotor peripheral neuropathy even without corpus callosum agenesis.
- name: Agenesis of corpus callosum
  description: >
    Complete or partial corpus-callosum agenesis/dysgenesis is a strong imaging
    feature but is variable and is not required for molecularly confirmed disease.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Agenesis of corpus callosum
    term:
      id: HP:0001274
      label: Agenesis of corpus callosum
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001274 | Agenesis of corpus callosum | Very frequent (99-80%)"
    explanation: Orphanet classifies corpus callosum agenesis as very frequent.
  - reference: PMID:20301546
    reference_title: "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "dysgenesis of the corpus callosum."
    explanation: GeneReviews supports variable corpus callosum dysgenesis.
  - reference: PMID:32765936
    reference_title: "A Novel Splice-Site Variant in SLC12A6 Causes Andermann Syndrome without Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We confirm that ACC is not a mandatory feature"
    explanation: A genetically confirmed case demonstrates that corpus-callosum agenesis is not obligatory.
- name: Global developmental delay
  description: Global developmental delay is a very frequent neurodevelopmental manifestation.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001263 | Global developmental delay | Very frequent (99-80%)"
    explanation: Orphanet classifies global developmental delay as very frequent.
- name: Intellectual disability
  description: Intellectual disability ranges from mild to severe.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001249 | Intellectual disability | Very frequent (99-80%)"
    explanation: Orphanet classifies intellectual disability as very frequent.
  - reference: PMID:20301546
    reference_title: "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Mild-to-severe intellectual disability"
    explanation: GeneReviews supports variable intellectual disability.
- name: Seizure
  description: Seizures are reported as a very frequent neurologic manifestation in Orphanet.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001250 | Seizure | Very frequent (99-80%)"
    explanation: Orphanet classifies seizures as very frequent.
- name: Psychotic episodes
  description: >
    Adolescent psychiatric manifestations include psychotic episodes, paranoid
    delusions, depression, and hallucinations.
  phenotype_term:
    preferred_term: Psychosis
    term:
      id: HP:0000709
      label: Psychosis
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "psychiatric manifestations that include paranoid delusions, depression, hallucinations"
    explanation: Orphanet lists psychotic and psychiatric manifestations among additional features.
- name: Hypotonia
  description: Hypotonia may be present from birth and accompanies the severe peripheral neuropathy.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:12838516
    reference_title: "Hereditary motor and sensory neuropathy with agenesis of the corpus callosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "amyotrophy, hypotonia, and cognitive impairment."
    explanation: Clinical review lists hypotonia among core manifestations.
  - reference: PMID:27230413
    reference_title: "KCC3 axonopathy: neuropathological features in the central and peripheral nervous system."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients are hypotonic and areflexic from birth, with abnormal facial features and"
    explanation: Human clinical-pathologic evidence supports congenital hypotonia.
- name: Areflexia
  description: Areflexia may be present from birth and reflects severe sensorimotor neuropathy.
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:12838516
    reference_title: "Hereditary motor and sensory neuropathy with agenesis of the corpus callosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      characterized by a delay in developmental milestones, a severe sensory-motor
      polyneuropathy with areflexia, a variable degree of agenesis of the corpus
    explanation: Clinical review supports areflexia as part of the neuropathy phenotype.
  - reference: PMID:27230413
    reference_title: "KCC3 axonopathy: neuropathological features in the central and peripheral nervous system."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients are hypotonic and areflexic from birth, with abnormal facial features and"
    explanation: Human clinical-pathologic evidence supports congenital areflexia.
- name: Skeletal muscle atrophy
  description: Amyotrophy develops as a neuromuscular consequence of progressive neuropathy.
  phenotype_term:
    preferred_term: Amyotrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "resulting hypotonia, areflexia, amyotrophy"
    explanation: Orphanet definition lists amyotrophy among resulting neuromuscular manifestations.
- name: Scoliosis
  description: Scoliosis can become sufficiently severe to require corrective surgery.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:20301546
    reference_title: "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      severity, individuals with HMSN/ACC usually require corrective surgery for
      scoliosis.
    explanation: GeneReviews supports scoliosis as a clinically significant manifestation requiring surveillance and sometimes corrective surgery.
- name: EEG abnormality
  description: EEG abnormality is a very frequent structured-database phenotype annotation.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: EEG abnormality
    term:
      id: HP:0002353
      label: EEG abnormality
  electrophysiology:
    electrophysiology_modality: EEG
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002353 | EEG abnormality | Very frequent (99-80%)"
    explanation: Orphanet classifies EEG abnormality as very frequent.
- name: Microcephaly
  description: Microcephaly is a very frequent structured-database phenotype annotation.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000252 | Microcephaly | Very frequent (99-80%)"
    explanation: Orphanet classifies microcephaly as very frequent.
- name: Turricephaly
  description: Turricephaly is an occasional structured-database phenotype annotation.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Turricephaly
    term:
      id: HP:0000262
      label: Turricephaly
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000262 | Turricephaly | Occasional (29-5%)"
    explanation: Orphanet classifies turricephaly as occasional.
- name: Hemiplegia or hemiparesis
  description: Hemiplegia or hemiparesis is a very frequent structured-database phenotype annotation.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hemiplegia/hemiparesis
    term:
      id: HP:0004374
      label: Hemiplegia/hemiparesis
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004374 | Hemiplegia/hemiparesis | Very frequent (99-80%)"
    explanation: Orphanet classifies hemiplegia/hemiparesis as very frequent.
- name: Aqueductal stenosis
  description: Aqueductal stenosis is a frequent structured-database phenotype annotation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Aqueductal stenosis
    term:
      id: HP:0002410
      label: Aqueductal stenosis
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002410 | Aqueductal stenosis | Frequent (79-30%)"
    explanation: Orphanet classifies aqueductal stenosis as frequent.
- name: Craniosynostosis
  description: Craniosynostosis is an occasional structured-database phenotype annotation.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Craniosynostosis
    term:
      id: HP:0001363
      label: Craniosynostosis
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001363 | Craniosynostosis | Occasional (29-5%)"
    explanation: Orphanet classifies craniosynostosis as occasional.
- name: Nystagmus
  description: Nystagmus is an occasional ocular manifestation.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000639 | Nystagmus | Occasional (29-5%)"
    explanation: Orphanet classifies nystagmus as occasional.
- name: Strabismus
  description: Strabismus is an occasional ocular manifestation.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000486 | Strabismus | Occasional (29-5%)"
    explanation: Orphanet classifies strabismus as occasional.
- name: Myopia
  description: Myopia is an occasional ocular manifestation.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000545 | Myopia | Occasional (29-5%)"
    explanation: Orphanet classifies myopia as occasional.
- name: Abnormal retinal pigmentation
  description: Abnormal retinal pigmentation is an occasional ocular manifestation.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Abnormality of retinal pigmentation
    term:
      id: HP:0007703
      label: Abnormal retinal pigmentation
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007703 | Abnormality of retinal pigmentation | Occasional (29-5%)"
    explanation: Orphanet classifies abnormal retinal pigmentation as occasional.
diagnosis:
- name: SLC12A6 molecular genetic testing
  description: >
    The diagnosis is established in a person with suggestive findings by
    identifying biallelic pathogenic SLC12A6 variants.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: Biallelic pathogenic SLC12A6 variants establish the molecular diagnosis.
  evidence:
  - reference: PMID:20301546
    reference_title: "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      suggestive findings and biallelic pathogenic variants in SLC12A6 identified by
      molecular genetic testing.
    explanation: GeneReviews directly supports biallelic SLC12A6 testing as confirmatory.
- name: Brain MRI
  description: >
    Brain MRI assesses complete or partial corpus-callosum dysgenesis and other
    structural abnormalities. A normal corpus callosum does not exclude
    SLC12A6-related disease.
  diagnosis_term:
    preferred_term: MRI of the brain
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  results: Corpus-callosum agenesis or dysgenesis is supportive but not obligatory.
  evidence:
  - reference: PMID:16606917
    reference_title: "Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      defects. The cerebral MRI reveals a variable degree of agenesis of the corpus
      callosum.
    explanation: A patient series supports MRI characterization of variable callosal agenesis.
  - reference: PMID:32765936
    reference_title: "A Novel Splice-Site Variant in SLC12A6 Causes Andermann Syndrome without Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain magnetic resonance imaging showed intact corpus callosum."
    explanation: A molecularly confirmed case establishes that intact callosal anatomy does not exclude the disease.

treatments:
- name: Walking and mobility aids
  description: >
    Canes, walkers, and other mobility aids are used as progressive neuropathy
    impairs ambulation.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:20301546
    reference_title: "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Walking aids such as canes or walkers"
    explanation: GeneReviews directly recommends walking aids for mobility support.
- name: Orthoses and physiotherapy
  therapeutic_modality: BEHAVIORAL
  description: >
    Upper- and lower-limb orthoses and physiotherapy are used as disease
    progresses to prevent contractures.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:20301546
    reference_title: "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      orthoses for upper and lower limbs and
      physiotherapy are needed to prevent contractures.
    explanation: GeneReviews directly supports orthoses and physiotherapy for contracture prevention.
- name: Developmental and educational intervention
  description: >
    Early developmental and educational intervention addresses cognitive and
    developmental delays.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  - preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:20301546
    reference_title: "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "developmental/educational intervention addresses cognitive delays."
    explanation: GeneReviews supports early developmental and educational intervention.
- name: Corrective scoliosis surgery
  description: >
    Corrective orthopedic surgery may be required when scoliosis becomes severe.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Orthopedic Surgical Procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  target_phenotypes:
  - preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:20301546
    reference_title: "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      severity, individuals with HMSN/ACC usually require corrective surgery for
      scoliosis.
    explanation: GeneReviews supports severity-dependent corrective surgery for scoliosis.
- name: Neuroleptic treatment of psychiatric manifestations
  description: >
    Neuroleptic pharmacotherapy may be used for adolescent psychotic or other
    psychiatric manifestations.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Psychosis
    term:
      id: HP:0000709
      label: Psychosis
  evidence:
  - reference: PMID:20301546
    reference_title: "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      Neuroleptics may be used to treat psychiatric manifestations, usually
      during adolescence.
    explanation: GeneReviews supports neuroleptic treatment for adolescent psychiatric manifestations.
- name: Adolescent scoliosis and psychiatric surveillance
  description: >
    Clinical surveillance focuses on scoliosis in the early teens and
    psychiatric manifestations in the late teens.
  action_category: MONITORING
  treatment_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:20301546
    reference_title: "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      Surveillance: Monitor in the early teens for scoliosis and
      in the late teens for psychiatric manifestations.
    explanation: GeneReviews provides age-specific scoliosis and psychiatric surveillance guidance.
- name: Genetic counseling and family testing
  description: >
    Counseling addresses autosomal-recessive recurrence risk, carrier testing
    for relatives, and prenatal or preimplantation testing once familial
    SLC12A6 variants are known.
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301546
    reference_title: "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      At
      conception, each sib of an affected individual has a 25% chance of being
      affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of
      being unaffected and not a carrier.
    explanation: GeneReviews quantifies recurrence and carrier risks for siblings.
  - reference: PMID:20301546
    reference_title: "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      carrier testing for at-risk family members and prenatal and
      preimplantation genetic testing are possible.
    explanation: GeneReviews supports carrier, prenatal, and preimplantation testing once familial variants are known.

animal_models:
- species: mouse
  genotype: Global Slc12a6/Kcc3 targeted deletion
  category: Genetically engineered mouse model
  genes:
  - preferred_term: SLC12A6
    term:
      id: hgnc:10914
      label: SLC12A6
  description: >
    Global Kcc3-null mice model locomotor impairment, peripheral neuropathy,
    sensorimotor-gating deficits, reduced compound action potentials, and slowed
    peripheral nerve conduction.
  associated_phenotypes:
  - locomotor deficit
  - peripheral neuropathy
  - sensorimotor gating deficit
  - slowed peripheral nerve conduction
  evidence:
  - reference: PMID:12368912
    reference_title: "The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: |-
      Mice generated with a targeted deletion of
      Slc12a6 have a locomotor deficit, peripheral neuropathy and a sensorimotor
      gating deficit, similar to the human disease.
    explanation: The discovery study reports neurologic phenotypes in Slc12a6-targeted mice.
  - reference: PMID:20549748
    reference_title: "Deficiency of electroneutral K+-Cl- cotransporter 3 causes a disruption in impulse propagation along peripheral nerves."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: |-
      and the nerve conduction velocity was slower in nerves from KCC3(-/-) mice than
      in nerves from wild-type mice
    explanation: Knockout-mouse physiology demonstrates slowed peripheral nerve conduction.
- species: mouse
  genotype: Global or neuron-specific Slc12a6/Kcc3 loss of function
  category: Genetically engineered mouse model
  genes:
  - preferred_term: SLC12A6
    term:
      id: hgnc:10914
      label: SLC12A6
  description: >
    Global and neuron-specific KCC3-loss mice model abnormal motoneuron
    electrical activity, Na+/K+-ATPase alpha-1 mislocalization, early NMJ
    abnormalities, denervation, and muscle atrophy.
  associated_phenotypes:
  - neuromuscular junction abnormality
  - skeletal muscle atrophy
  - abnormal motoneuron electrical activity
  evidence:
  - reference: PMID:28647557
    reference_title: "KCC3 loss-of-function contributes to Andermann syndrome by inducing activity-dependent neuromuscular junction defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: |-
      global or
      neuron-specific KCC3 loss-of-function in mice leads to early neuromuscular
      junction (NMJ) abnormalities and muscular atrophy
    explanation: Mouse genetics supports the motor-unit and NMJ model.

experimental_models:
- name: Xenopus-oocyte KCC3 founder-variant transport assay
  description: >
    Xenopus laevis oocytes heterologously expressing wild-type or
    2436delG/Thr813fsX813 KCC3 test membrane localization, glycosylation, and
    transporter function.
  experimental_model_type: OTHER
  conditions:
  - wild-type KCC3 expression
  - 2436delG (Thr813fsX813) KCC3 expression
  cell_source: Xenopus laevis oocytes
  culture_system: Heterologous membrane-transporter expression assay
  publication: PMID:12368912
  modeled_mechanisms:
  - target: SLC12A6 KCC3 loss of function
    description: Assays whether the founder truncating variant preserves KCC3 transport function.
    evidence:
    - reference: PMID:12368912
      reference_title: "The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: |-
        the truncated mutant is appropriately glycosylated and expressed at the cellular
        membrane, where it is non-functional.
      explanation: The oocyte model directly measures nonfunction of membrane-localized mutant KCC3.
  findings:
  - statement: The founder truncating KCC3 protein reaches the membrane but is nonfunctional.
    supporting_text: |-
      the truncated mutant is appropriately glycosylated and expressed at the cellular
      membrane, where it is non-functional.
    evidence:
    - reference: PMID:12368912
      reference_title: "The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: |-
        the truncated mutant is appropriately glycosylated and expressed at the cellular
        membrane, where it is non-functional.
      explanation: The assay finding is quoted directly from the functional study.
  evidence:
  - reference: PMID:12368912
    reference_title: "The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      the truncated mutant is appropriately glycosylated and expressed at the cellular
      membrane, where it is non-functional.
    explanation: The heterologous assay establishes loss of function for the founder variant.
- name: p.H371R proband-cell functional assay
  description: >
    Proband-derived cells carrying homozygous p.H371R SLC12A6 were compared with
    wild type for mutant-protein localization, ion-transport function, and
    potassium/chloride ion levels. The cached abstract does not
    identify the cell type.
  experimental_model_type: OTHER
  conditions:
  - homozygous SLC12A6 p.H371R
  - wild-type comparator
  cell_source: Proband-derived cells; cell type not identified in the cached abstract
  publication: PMID:39988558
  modeled_mechanisms:
  - target: Impaired KCC3-mediated ion transport and ionic homeostasis
    description: Measures mutant localization, transport impairment, and potassium/chloride imbalance in the proband's cells.
    evidence:
    - reference: PMID:39988558
      reference_title: "A Novel Missense Mutation in SLC12A6 Impairs Ion Transport Function of the Protein to Cause Agenesis of the Corpus Callosum With Peripheral Neuropathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: |-
        transport function. This mislocalization caused an imbalance in potassium and
        chloride ion levels in the proband's cells.
      explanation: The proband-cell assay directly reports cellular ion imbalance downstream of mutant mislocalization.
  findings:
  - statement: p.H371R KCC3 mislocalizes to the cytoplasm and disrupts ion transport.
    supporting_text: |-
      type, the mutant protein was mislocalized to the cytoplasm, disrupting its ion
      transport function.
    evidence:
    - reference: PMID:39988558
      reference_title: "A Novel Missense Mutation in SLC12A6 Impairs Ion Transport Function of the Protein to Cause Agenesis of the Corpus Callosum With Peripheral Neuropathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: |-
        type, the mutant protein was mislocalized to the cytoplasm, disrupting its ion
        transport function.
      explanation: The finding is quoted directly from the proband-cell functional study.
  evidence:
  - reference: PMID:39988558
    reference_title: "A Novel Missense Mutation in SLC12A6 Impairs Ion Transport Function of the Protein to Cause Agenesis of the Corpus Callosum With Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      type, the mutant protein was mislocalized to the cytoplasm, disrupting its ion
      transport function.
    explanation: The patient-cell assay supports mutant mislocalization and transport loss.

discussions:
- discussion_id: gap_kcc3_transport_to_human_axonopathy
  prompt: >
    Which molecular intermediates connect loss of KCC3 transport to the central
    and peripheral axonopathy observed in human disease?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - "pathophysiology#SLC12A6 KCC3 loss of function"
  - "pathophysiology#Central and peripheral axonopathy"
  rationale: >
    Genetic, functional, model, and human-pathology evidence establish both
    endpoints, but not the intervening causal sequence.
  evidence:
  - reference: PMID:29366908
    reference_title: "A role for KCC3 in maintaining cell volume of peripheral nerve fibers."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      we still do not understand how
      dysfunction of this cotransporter can lead to the pathophysiology of peripheral
      neuropathy.
    explanation: The review explicitly identifies the transporter-to-neuropathy mechanism as unresolved.
- discussion_id: mismatch_mouse_kcc3_motor_unit_to_human_neuropathy
  prompt: >
    To what extent do mouse impulse-propagation and motoneuron/NMJ mechanisms
    reproduce the human motor and sensory neuropathy?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - "pathophysiology#Peripheral nerve impulse-propagation failure"
  - "pathophysiology#Activity-dependent motoneuron and neuromuscular-junction dysfunction"
  rationale: >
    The strongest conduction and NMJ causal data are from mice, and both
    loss-of-function and gain-of-function mouse models can show
    peripheral-neuropathy-like phenotypes.
  evidence:
  - reference: PMID:29366908
    reference_title: "A role for KCC3 in maintaining cell volume of peripheral nerve fibers."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      recapitulated a peripheral neuropathy-like phenotype originating from a KCC3
      gain-of-function (GOF).
    explanation: The review notes that opposite KCC3 perturbations can converge on a neuropathy-like mouse phenotype.
  - reference: PMID:28647557
    reference_title: "KCC3 loss-of-function contributes to Andermann syndrome by inducing activity-dependent neuromuscular junction defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: |-
      here propose that abnormal motoneuron electrical activity contributes to the
      peripheral neuropathy observed in Andermann syndrome.
    explanation: The authors frame translation from mouse motoneuron biology to human neuropathy as a proposal.
- discussion_id: gap_variable_corpus_callosum_dysgenesis
  prompt: >
    Why is corpus-callosum dysgenesis variable or absent in some people with
    biallelic pathogenic SLC12A6 variants?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - "pathophysiology#Commissural and corticospinal developmental abnormalities"
  - "phenotypes#Agenesis of corpus callosum"
  rationale: >
    Variable callosal anatomy affects disease naming, diagnostic interpretation,
    and the developmental mechanism assigned to KCC3 deficiency.
  evidence:
  - reference: PMID:32765936
    reference_title: "A Novel Splice-Site Variant in SLC12A6 Causes Andermann Syndrome without Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We confirm that ACC is not a mandatory feature"
    explanation: A molecularly confirmed case demonstrates that callosal agenesis is not required.

references:
- reference: ORPHA:1496
  title: Corpus callosum agenesis-neuronopathy syndrome
  findings: []
- reference: PMID:12368912
  title: The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum.
  findings: []
- reference: PMID:12838516
  title: Hereditary motor and sensory neuropathy with agenesis of the corpus callosum.
  findings: []
- reference: PMID:16606917
  title: Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome.
  findings: []
- reference: PMID:20301546
  title: Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum.
  tags:
  - GeneReviews
  findings: []
- reference: PMID:20549748
  title: Deficiency of electroneutral K+-Cl- cotransporter 3 causes a disruption in impulse propagation along peripheral nerves.
  findings: []
- reference: PMID:27230413
  title: "KCC3 axonopathy: neuropathological features in the central and peripheral nervous system."
  findings: []
- reference: PMID:28647557
  title: KCC3 loss-of-function contributes to Andermann syndrome by inducing activity-dependent neuromuscular junction defects.
  findings: []
- reference: PMID:29366908
  title: A role for KCC3 in maintaining cell volume of peripheral nerve fibers.
  findings: []
- reference: PMID:32765936
  title: A Novel Splice-Site Variant in SLC12A6 Causes Andermann Syndrome without Agenesis of the Corpus Callosum.
  findings: []
- reference: PMID:39988558
  title: A Novel Missense Mutation in SLC12A6 Impairs Ion Transport Function of the Protein to Cause Agenesis of the Corpus Callosum With Peripheral Neuropathy.
  findings: []
📚

References & Deep Research

References

11
ORPHA:1496
Corpus callosum agenesis-neuronopathy syndrome
No top-level findings curated for this source.
PMID:12368912
The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum.
No top-level findings curated for this source.
PMID:12838516
Hereditary motor and sensory neuropathy with agenesis of the corpus callosum.
No top-level findings curated for this source.
PMID:16606917
Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome.
No top-level findings curated for this source.
PMID:20301546
Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum.
No top-level findings curated for this source.
PMID:20549748
Deficiency of electroneutral K+-Cl- cotransporter 3 causes a disruption in impulse propagation along peripheral nerves.
No top-level findings curated for this source.
PMID:27230413
KCC3 axonopathy: neuropathological features in the central and peripheral nervous system.
No top-level findings curated for this source.
PMID:28647557
KCC3 loss-of-function contributes to Andermann syndrome by inducing activity-dependent neuromuscular junction defects.
No top-level findings curated for this source.
PMID:29366908
A role for KCC3 in maintaining cell volume of peripheral nerve fibers.
No top-level findings curated for this source.
PMID:32765936
A Novel Splice-Site Variant in SLC12A6 Causes Andermann Syndrome without Agenesis of the Corpus Callosum.
No top-level findings curated for this source.
PMID:39988558
A Novel Missense Mutation in SLC12A6 Impairs Ion Transport Function of the Protein to Cause Agenesis of the Corpus Callosum With Peripheral Neuropathy.
No top-level findings curated for this source.

Deep Research

1
Agenesis of the Corpus Callosum with Peripheral Neuropathy Deep Research Fallback ▸

Agenesis of the Corpus Callosum with Peripheral Neuropathy Deep Research Fallback

Provider Attempts

  • 2026-05-05T06:00Z: timeout 900 just research-disorder falcon Agenesis_of_the_Corpus_Callosum_with_Peripheral_Neuropathy was terminated after approximately 12 minutes with no provider output or research artifact.
  • 2026-05-05T06:17Z: timeout 420 just research-disorder openai Agenesis_of_the_Corpus_Callosum_with_Peripheral_Neuropathy timed out with exit code 124 and produced no research artifact.

No provider-generated research artifact was available to integrate. Curation therefore proceeded from generated structured Orphanet evidence and fetched PubMed caches, without hand-editing any references_cache/*.md files.

Evidence Scope Used For Curation

  • ORPHA:1496 structured record for disease definition, MONDO and OMIM exact mappings, autosomal recessive inheritance, prevalence, SLC12A6 gene association, onset, and HPO phenotype frequencies.
  • PMID:12368912 for the original SLC12A6/KCC3 disease-gene discovery and functional evidence that the founder truncated KCC3 protein is membrane expressed but nonfunctional.
  • PMID:20301546 for GeneReviews clinical characteristics, SLC12A6 diagnostic testing, progression, supportive management, surveillance, genetic counseling, and reproductive testing.
  • PMID:12838516 and PMID:16606917 for clinical-review and patient-series evidence of early-onset sensorimotor neuropathy, corpus callosum dysgenesis, and truncating or missense KCC3 variant associations.
  • PMID:20549748, PMID:27230413, PMID:28647557, and PMID:29366908 for mechanism evidence linking KCC3 loss to disturbed neuronal ion or volume homeostasis, peripheral nerve conduction defects, axonopathy, and activity-dependent neuromuscular junction pathology.
  • PMID:32765936 and PMID:39988558 for recent human clinical and functional reports supporting variable corpus callosum involvement and SLC12A6 variant effects on ion transport or cellular localization.

Curation Conclusions

The accepted disease model is biallelic SLC12A6 loss of KCC3 potassium-chloride cotransporter function. KCC3 dysfunction disrupts neuronal potassium/chloride transport and cell-volume homeostasis, leading to peripheral axonopathy, nerve conduction failure, and neuromuscular junction pathology that manifest as progressive sensorimotor neuropathy, hypotonia, areflexia, and amyotrophy. Human clinical and structured Orphanet evidence support variable corpus callosum dysgenesis, developmental delay or intellectual disability, seizures, EEG abnormalities, and less frequent craniofacial, ocular, and CNS structural findings. Management is supportive, with molecular SLC12A6 testing, brain MRI, nerve electrophysiology, EEG when indicated, physiotherapy, orthoses, multidisciplinary developmental and psychiatric support, and genetic counseling.