Agenesis of the Corpus Callosum with Peripheral Neuropathy

Mendelian MONDO:0000902 Pathograph 13 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 neuronal volume/ion homeostasis, producing 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
5
Pathophys.
20
Phenotypes
13
Pathograph
1
Genes
3
Treatments
1
Deep Research
🔗

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.
⚙

Pathophysiology

5
SLC12A6 KCC3 loss of function
Biallelic SLC12A6 pathogenic variants impair or abolish KCC3 potassium-chloride cotransporter function. Functional assays of disease variants show nonfunctional membrane-expressed or mislocalized transporter, establishing loss of KCC3 activity as the upstream molecular lesion.
SLC12A6 link
potassium:chloride symporter activity link ↓ DECREASED
Downstream
Impaired neuronal potassium-chloride cotransport and cell-volume regulation Loss of KCC3 reduces neuronal K-Cl efflux and disturbs ion and volume homeostasis.
Corpus callosum and corticospinal tract developmental abnormalities KCC3 loss is linked to developmental commissural and corticospinal tract abnormalities.
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 supports loss of transporter function for a founder variant.
PMID:39988558 SUPPORT In Vitro
"type, the mutant protein was mislocalized to the cytoplasm, disrupting its ion transport function."
Functional analysis of a missense variant supports impaired KCC3 transport.
Impaired neuronal potassium-chloride cotransport and cell-volume regulation
KCC3 normally mediates electroneutral potassium and chloride efflux in neurons, contributing to cell volume and intracellular chloride homeostasis. Loss of this function disturbs ion homeostasis in neurons and peripheral nerve fibers.
neuron link
cell volume homeostasis link ⚠ ABNORMAL monoatomic ion transmembrane transport link ↓ DECREASED
potassium:chloride symporter activity link ↓ DECREASED
Downstream
Peripheral axonopathy and nerve conduction failure Ion and volume-homeostasis defects in peripheral nerve fibers contribute to axonal dysfunction.
Activity-dependent neuromuscular junction defects Altered motoneuron excitability contributes to presynaptic neuromuscular junction pathology.
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."
Review evidence states the neuronal transport and volume-homeostasis role of KCC3.
PMID:39988558 SUPPORT In Vitro
"transport function. This mislocalization caused an imbalance in potassium and chloride ion levels in the proband's cells."
Patient-cell functional analysis supports ion imbalance from SLC12A6 variant mislocalization.
Peripheral axonopathy and nerve conduction failure
KCC3 deficiency disrupts peripheral nerve conduction and produces a progressive central and peripheral axonopathy. Autopsy tissue shows developmental commissural abnormalities together with axonomas and axonal degeneration affecting peripheral and central axons.
neuron link Schwann cell link
neuronal action potential link ⚠ ABNORMAL
Downstream
Progressive sensorimotor neuropathy Peripheral axonopathy manifests clinically as severe progressive sensorimotor neuropathy.
Show evidence (2 references)
PMID:20549748 SUPPORT Model Organism
"and the nerve conduction velocity was slower in nerves from KCC3(-/-) mice than in nerves from wild-type mice"
Mouse peripheral nerve physiology supports KCC3-dependent nerve conduction.
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 neuropathology supports axonopathy as the main degenerative lesion.
Activity-dependent neuromuscular junction defects
KCC3 loss in neurons produces abnormal motoneuron electrical activity, presynaptic neurotransmission defects, neuromuscular junction abnormalities, denervation, and muscle atrophy in model systems, connecting KCC3 loss to progressive motor impairment.
motor neuron link
modulation of chemical synaptic transmission link ⚠ ABNORMAL
Downstream
Progressive sensorimotor neuropathy NMJ denervation and muscular atrophy worsen motor disability.
Show evidence (2 references)
PMID:28647557 SUPPORT Model Organism
"neuron-specific KCC3 loss-of-function in mice leads to early neuromuscular junction (NMJ) abnormalities and muscular atrophy"
Mouse data support a neuron-autonomous KCC3 contribution to NMJ pathology and muscle atrophy.
PMID:28647557 SUPPORT Model Organism
"here propose that abnormal motoneuron electrical activity contributes to the peripheral neuropathy observed in Andermann syndrome."
The authors connect abnormal motoneuron activity to the peripheral neuropathy.
Corpus callosum and corticospinal tract developmental abnormalities
The disorder includes variable corpus callosum dysgenesis and other central commissural/corticospinal developmental abnormalities. Human autopsy series report hypoplasia or absence of major telencephalic commissures and corticospinal tract hypoplasia.
Downstream
Agenesis of corpus callosum Major telencephalic commissure hypoplasia or absence manifests as corpus callosum dysgenesis.
Hemiplegia or hemiparesis Corticospinal tract hypoplasia contributes to pyramidal motor manifestations.
Intellectual disability Central developmental abnormalities contribute to neurodevelopmental impairment.
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 supports central developmental abnormalities.
⬡

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.
●

Phenotypes

20
Eye 4
Nystagmus OCCASIONAL Nystagmus (HP:0000639)
Show evidence (1 reference)
ORPHA:1496 SUPPORT Other
"HP:0000639 | Nystagmus | Occasional (29-5%)"
Orphanet classifies nystagmus as occasional.
Strabismus OCCASIONAL Strabismus (HP:0000486)
Show evidence (1 reference)
ORPHA:1496 SUPPORT Other
"HP:0000486 | Strabismus | Occasional (29-5%)"
Orphanet classifies strabismus as occasional.
Myopia OCCASIONAL Myopia (HP:0000545)
Show evidence (1 reference)
ORPHA:1496 SUPPORT Other
"HP:0000545 | Myopia | Occasional (29-5%)"
Orphanet classifies myopia as occasional.
Abnormal retinal pigmentation OCCASIONAL Abnormal retinal pigmentation (HP:0007703)
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 Microcephaly (HP:0000252)
Show evidence (1 reference)
ORPHA:1496 SUPPORT Other
"HP:0000252 | Microcephaly | Very frequent (99-80%)"
Orphanet classifies microcephaly as very frequent.
Craniosynostosis OCCASIONAL Craniosynostosis (HP:0001363)
Show evidence (1 reference)
ORPHA:1496 SUPPORT Other
"HP:0001363 | Craniosynostosis | Occasional (29-5%)"
Orphanet classifies craniosynostosis as occasional.
Musculoskeletal 3
Hypotonia Hypotonia (HP:0001252)
Show evidence (1 reference)
PMID:12838516 SUPPORT Human Clinical
"amyotrophy, hypotonia, and cognitive impairment."
Clinical review lists hypotonia among core manifestations.
Skeletal muscle atrophy Skeletal muscle atrophy (HP:0003202)
Show evidence (1 reference)
ORPHA:1496 SUPPORT Other
"resulting hypotonia, areflexia, amyotrophy"
Orphanet definition lists amyotrophy among resulting neuromuscular manifestations.
Scoliosis Scoliosis (HP:0002650)
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)
Course: PROGRESSIVE
Show evidence (2 references)
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 Agenesis of corpus callosum (HP:0001274)
Show evidence (2 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.
Global developmental delay VERY_FREQUENT Global developmental delay (HP:0001263)
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 Intellectual disability (HP:0001249)
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 Seizure (HP:0001250)
Show evidence (1 reference)
ORPHA:1496 SUPPORT Other
"HP:0001250 | Seizure | Very frequent (99-80%)"
Orphanet classifies seizures as very frequent.
Psychiatric manifestations Psychosis (HP:0000709)
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 Areflexia (HP:0001284)
Show evidence (1 reference)
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.
EEG abnormality VERY_FREQUENT EEG abnormality (HP:0002353)
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 Turricephaly (HP:0000262)
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)
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 Aqueductal stenosis (HP:0002410)
Show evidence (1 reference)
ORPHA:1496 SUPPORT Other
"HP:0002410 | Aqueductal stenosis | Frequent (79-30%)"
Orphanet classifies aqueductal stenosis as frequent.
🧬

Genetic Associations

1
SLC12A6 (Causal biallelic pathogenic variants)
Show evidence (3 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.
💊

Treatments

3
Multidisciplinary supportive care
Action: supportive care MAXO:0000950
Management is supportive and multidisciplinary, including walking aids, orthoses, rehabilitation, developmental and educational supports, scoliosis monitoring and treatment when needed, and psychiatric symptom management during adolescence.
Target Phenotypes: Peripheral neuropathy ↗ Intellectual disability ↗
Show evidence (2 references)
PMID:20301546 SUPPORT Other
"MANAGEMENT: Treatment of manifestations: Walking aids such as canes or walkers"
GeneReviews supports supportive mobility management.
PMID:20301546 SUPPORT Other
"developmental/educational intervention addresses cognitive delays."
GeneReviews supports educational and developmental supportive care.
Physiotherapy and orthoses
Action: physical therapy MAXO:0000011
Physiotherapy and upper- and lower-limb orthoses are used as disease progresses to maintain mobility and prevent contractures.
Target Phenotypes: Peripheral neuropathy ↗ Skeletal muscle atrophy ↗
Show evidence (1 reference)
PMID:20301546 SUPPORT Other
"physiotherapy are needed to prevent contractures."
GeneReviews supports physiotherapy and orthoses for contracture prevention.
Genetic counseling
Action: genetic counseling MAXO:0000079
Genetic counseling supports recurrence-risk assessment, carrier testing, and reproductive testing options once familial SLC12A6 variants are known.
Show evidence (1 reference)
PMID:20301546 SUPPORT Other
"preimplantation genetic testing are possible."
GeneReviews supports family testing and reproductive counseling.
{ }

Source YAML

click to show 
name: Agenesis of the Corpus Callosum with Peripheral Neuropathy
category: Mendelian
creation_date: "2026-05-04T22:55:00Z"
updated_date: "2026-05-05T06:50:00Z"
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 neuronal volume/ion homeostasis,
  producing 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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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
  percentage: 1-5 / 10 000
  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 (Orphanet structured-database record)"
    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.
- population: Worldwide
  percentage: <1 / 1 000 000
  notes: Orphanet records the worldwide point-prevalence band as ultra-rare.
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome (Orphanet structured-database record)"
    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: Infancy and childhood onset
  age_range: Infancy to childhood
  notes: >
    Sensory modalities are affected from infancy; walking is delayed on
    average, and progressive neuropathy leads to loss of walking in adolescence.
  evidence:
  - reference: PMID:20301546
    reference_title: "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "moderately to severely affected beginning in infancy."
    explanation: GeneReviews supports infantile onset of sensory neuropathy.
  - reference: PMID:20301546
    reference_title: "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "of walking is 3.8 years; the average age of loss of walking is 13.8 years;"
    explanation: GeneReviews summarizes delayed walking and adolescent loss of ambulation.
- phase: Reduced adult survival
  age_range: Adulthood
  notes: Patients often have shortened survival, with average death in early adulthood in GeneReviews.
  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 survival.
genetic:
- name: SLC12A6
  association: Causal biallelic pathogenic variants
  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.
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome (Orphanet structured-database record)"
    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.
pathophysiology:
- name: SLC12A6 KCC3 loss of function
  description: >
    Biallelic SLC12A6 pathogenic variants impair or abolish KCC3
    potassium-chloride cotransporter function. Functional assays of disease
    variants show nonfunctional membrane-expressed or mislocalized transporter,
    establishing loss of KCC3 activity as the upstream molecular lesion.
  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 supports loss of transporter function for a founder 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: Functional analysis of a missense variant supports impaired KCC3 transport.
  downstream:
  - target: Impaired neuronal potassium-chloride cotransport and cell-volume regulation
    description: Loss of KCC3 reduces neuronal K-Cl efflux and disturbs ion and volume homeostasis.
    causal_link_type: DIRECT
  - target: Corpus callosum and corticospinal tract developmental abnormalities
    description: KCC3 loss is linked to developmental commissural and corticospinal tract abnormalities.
    causal_link_type: DIRECT
- name: Impaired neuronal potassium-chloride cotransport and cell-volume regulation
  description: >
    KCC3 normally mediates electroneutral potassium and chloride efflux in
    neurons, contributing to cell volume and intracellular chloride homeostasis.
    Loss of this function disturbs ion homeostasis in neurons and peripheral
    nerve fibers.
  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
  biological_processes:
  - preferred_term: cell volume homeostasis
    term:
      id: GO:0006884
      label: cell volume homeostasis
    modifier: ABNORMAL
  - preferred_term: monoatomic ion transmembrane transport
    term:
      id: GO:0034220
      label: monoatomic ion transmembrane transport
    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: Review evidence states the neuronal transport and volume-homeostasis role of KCC3.
  - 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-cell functional analysis supports ion imbalance from SLC12A6 variant mislocalization.
  downstream:
  - target: Peripheral axonopathy and nerve conduction failure
    description: Ion and volume-homeostasis defects in peripheral nerve fibers contribute to axonal dysfunction.
    causal_link_type: DIRECT
  - target: Activity-dependent neuromuscular junction defects
    description: Altered motoneuron excitability contributes to presynaptic neuromuscular junction pathology.
    causal_link_type: DIRECT
- name: Peripheral axonopathy and nerve conduction failure
  description: >
    KCC3 deficiency disrupts peripheral nerve conduction and produces a
    progressive central and peripheral axonopathy. Autopsy tissue shows
    developmental commissural abnormalities together with axonomas and axonal
    degeneration affecting peripheral and central axons.
  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: |-
      and the nerve conduction velocity was slower in nerves from KCC3(-/-) mice than
      in nerves from wild-type mice
    explanation: Mouse peripheral nerve physiology supports KCC3-dependent nerve conduction.
  - 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 neuropathology supports axonopathy as the main degenerative lesion.
  downstream:
  - target: Progressive sensorimotor neuropathy
    description: Peripheral axonopathy manifests clinically as severe progressive sensorimotor neuropathy.
    causal_link_type: DIRECT
- name: Activity-dependent neuromuscular junction defects
  description: >
    KCC3 loss in neurons produces abnormal motoneuron electrical activity,
    presynaptic neurotransmission defects, neuromuscular junction abnormalities,
    denervation, and muscle atrophy in model systems, connecting KCC3 loss to
    progressive motor impairment.
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  biological_processes:
  - preferred_term: modulation of chemical synaptic transmission
    term:
      id: GO:0050804
      label: modulation of chemical synaptic transmission
    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: |-
      neuron-specific KCC3 loss-of-function in mice leads to early neuromuscular
      junction (NMJ) abnormalities and muscular atrophy
    explanation: Mouse data support a neuron-autonomous KCC3 contribution to NMJ pathology and muscle atrophy.
  - 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 connect abnormal motoneuron activity to the peripheral neuropathy.
  downstream:
  - target: Progressive sensorimotor neuropathy
    description: NMJ denervation and muscular atrophy worsen motor disability.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Corpus callosum and corticospinal tract developmental abnormalities
  description: >
    The disorder includes variable corpus callosum dysgenesis and other central
    commissural/corticospinal developmental abnormalities. Human autopsy series
    report hypoplasia or absence of major telencephalic commissures and
    corticospinal tract hypoplasia.
  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 supports central developmental abnormalities.
  downstream:
  - target: Agenesis of corpus callosum
    description: Major telencephalic commissure hypoplasia or absence manifests as corpus callosum dysgenesis.
    causal_link_type: DIRECT
  - target: Hemiplegia or hemiparesis
    description: Corticospinal tract hypoplasia contributes to pyramidal motor manifestations.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Intellectual disability
    description: Central developmental abnormalities contribute to neurodevelopmental impairment.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
phenotypes:
- name: Progressive sensorimotor neuropathy
  diagnostic: true
  phenotype_term:
    preferred_term: Progressive sensorimotor neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
    clinical_course: PROGRESSIVE
  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 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
  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 (Orphanet structured-database record)"
    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.
- name: Global developmental delay
  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 (Orphanet structured-database record)"
    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
  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 (Orphanet structured-database record)"
    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
  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 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001250 | Seizure | Very frequent (99-80%)"
    explanation: Orphanet classifies seizures as very frequent.
- name: Psychiatric manifestations
  phenotype_term:
    preferred_term: Psychosis
    term:
      id: HP:0000709
      label: Psychosis
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome (Orphanet structured-database record)"
    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
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  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.
- name: Areflexia
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
  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.
- name: Skeletal muscle atrophy
  phenotype_term:
    preferred_term: Amyotrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "resulting hypotonia, areflexia, amyotrophy"
    explanation: Orphanet definition lists amyotrophy among resulting neuromuscular manifestations.
- name: Scoliosis
  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
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: EEG abnormality
    term:
      id: HP:0002353
      label: EEG abnormality
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002353 | EEG abnormality | Very frequent (99-80%)"
    explanation: Orphanet classifies EEG abnormality as very frequent.
- name: Microcephaly
  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 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000252 | Microcephaly | Very frequent (99-80%)"
    explanation: Orphanet classifies microcephaly as very frequent.
- name: Turricephaly
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Turricephaly
    term:
      id: HP:0000262
      label: Turricephaly
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000262 | Turricephaly | Occasional (29-5%)"
    explanation: Orphanet classifies turricephaly as occasional.
- name: Hemiplegia or hemiparesis
  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 (Orphanet structured-database record)"
    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
  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 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002410 | Aqueductal stenosis | Frequent (79-30%)"
    explanation: Orphanet classifies aqueductal stenosis as frequent.
- name: Craniosynostosis
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Craniosynostosis
    term:
      id: HP:0001363
      label: Craniosynostosis
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001363 | Craniosynostosis | Occasional (29-5%)"
    explanation: Orphanet classifies craniosynostosis as occasional.
- name: Nystagmus
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000639 | Nystagmus | Occasional (29-5%)"
    explanation: Orphanet classifies nystagmus as occasional.
- name: Strabismus
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000486 | Strabismus | Occasional (29-5%)"
    explanation: Orphanet classifies strabismus as occasional.
- name: Myopia
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000545 | Myopia | Occasional (29-5%)"
    explanation: Orphanet classifies myopia as occasional.
- name: Abnormal retinal pigmentation
  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 (Orphanet structured-database record)"
    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: >
    Molecular genetic testing confirms the diagnosis by identifying biallelic
    pathogenic SLC12A6 variants in a proband with suggestive neurologic,
    neuroimaging, and electrophysiologic findings.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  results: Biallelic pathogenic SLC12A6 variants confirm the 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 supports SLC12A6 molecular testing as confirmatory.
- name: Brain MRI for corpus callosum dysgenesis
  description: >
    Brain MRI evaluates complete or partial agenesis/dysgenesis of the corpus
    callosum and associated central nervous system abnormalities, while absence
    of agenesis does not exclude SLC12A6-related disease.
  results: Corpus callosum agenesis or dysgenesis supports the diagnosis, but may be absent.
  evidence:
  - reference: PMID:12838516
    reference_title: "Hereditary motor and sensory neuropathy with agenesis of the corpus callosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      polyneuropathy with areflexia, a variable degree of agenesis of the corpus
      callosum, amyotrophy, hypotonia, and cognitive impairment.
    explanation: Clinical review supports MRI evaluation for corpus callosum abnormalities.
  - 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: The case report cautions that intact corpus callosum does not exclude Andermann syndrome.
- name: Nerve conduction and electromyography
  description: >
    Peripheral nerve electrophysiology supports the diagnosis by documenting
    severe motor and sensory neuropathy and nerve conduction abnormalities.
  results: Motor and sensory peripheral neuropathy on electrophysiologic testing.
  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: |-
      intellectual disability, and severe motor and sensory demyelinating peripheral
      neuropathy.
    explanation: Case evidence supports peripheral nerve testing to document neuropathy.
- name: Electroencephalography
  description: EEG may document epileptiform or other abnormalities in patients with seizures.
  diagnosis_term:
    preferred_term: electroencephalography
    term:
      id: MAXO:0000932
      label: electroencephalography
  results: EEG abnormalities support seizure characterization and surveillance.
  evidence:
  - reference: ORPHA:1496
    reference_title: "Corpus callosum agenesis-neuronopathy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002353 | EEG abnormality | Very frequent (99-80%)"
    explanation: Orphanet's frequent EEG abnormality annotation supports EEG as relevant diagnostic assessment.
treatments:
- name: Multidisciplinary supportive care
  description: >
    Management is supportive and multidisciplinary, including walking aids,
    orthoses, rehabilitation, developmental and educational supports,
    scoliosis monitoring and treatment when needed, and psychiatric symptom
    management during adolescence.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  - 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: "MANAGEMENT: Treatment of manifestations: Walking aids such as canes or walkers"
    explanation: GeneReviews supports supportive mobility management.
  - 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 educational and developmental supportive care.
- name: Physiotherapy and orthoses
  description: >
    Physiotherapy and upper- and lower-limb orthoses are used as disease
    progresses to maintain mobility and prevent contractures.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  target_phenotypes:
  - preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  - preferred_term: Skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  evidence:
  - reference: PMID:20301546
    reference_title: "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "physiotherapy are needed to prevent contractures."
    explanation: GeneReviews supports physiotherapy and orthoses for contracture prevention.
- name: Genetic counseling
  description: >
    Genetic counseling supports recurrence-risk assessment, carrier testing,
    and reproductive testing options once familial SLC12A6 variants are known.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      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: "preimplantation genetic testing are possible."
    explanation: GeneReviews supports family testing and reproductive counseling.
📚

References & Deep Research

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.