Congenital Hypomyelinating Neuropathy

👪

Inheritance

2

Autosomal dominant HP:0000006

CHN is inherited as an autosomal dominant or an autosomal recessive trait depending on the gene and variant. The MPZ and EGR2 zinc-finger forms are typically dominant, and many are de novo.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:15184631 SUPPORT Human Clinical

"Congenital hypomyelinating neuropathy (CHN; MIM# 605253) is a severe neuropathy with early infancy onset inherited as an autosomal dominant or recessive trait."

States both inheritance modes for CHN as a genetically heterogeneous entity.

Autosomal recessive HP:0000007

The CNTNAP1 paranodal form and the EGR2 NAB-domain form are recessive.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:15184631 SUPPORT Human Clinical

"Congenital hypomyelinating neuropathy (CHN; MIM# 605253) is a severe neuropathy with early infancy onset inherited as an autosomal dominant or recessive trait."

Establishes that recessive inheritance also occurs in this genetically heterogeneous disorder.

◆

Subtypes

3

CHN1 (EGR2-related, Charcot-Marie-Tooth disease type 4E) MONDO:0011527

The EGR2/KROX20 form, catalogued in MONDO as Charcot-Marie-Tooth disease type 4E. EGR2 is the transcription factor that drives the Schwann cell myelination program, so its loss disables myelination at the level of the transcriptional switch rather than of a single structural protein. Zinc-finger domain variants act dominantly and their residual DNA-binding capacity correlates inversely with disease severity; a recessive variant in the NAB co-repressor binding domain acts by increasing transcriptional activity instead.

CHN2 (MPZ-related) MONDO:0020765

The MPZ form. Myelin protein zero is the principal structural adhesion protein of compact peripheral myelin; CHN-causing variants disrupt its folding and trafficking so that it fails to reach the cell surface. The same gene produces a phenotypic range from adult-onset CMT1B to neonatal CHN depending on the variant.

CHN3 (CNTNAP1-related, paranodal) MONDO:0020766

The CNTNAP1 form, mechanistically distinct from the compact-myelin arm: contactin-associated protein 1 builds the axo-glial septate-like junctions of the paranode, so the lesion is a failure to organize the axonal domains that make saltatory conduction possible rather than a failure to make compact myelin. It carries a high neonatal mortality and can present as a floppy neonate mimicking congenital myasthenic syndrome.

⚙

Pathophysiology

5

Myelination Gene Lesion in Developing Schwann Cells

A variant in a gene the Schwann cell requires to build compact myelin — MPZ (the principal compact-myelin adhesion protein), EGR2/KROX20 (the transcription factor driving the myelination program), PMP22, or MTMR2 — disables myelination during the perinatal window when peripheral nerve is normally myelinated. Because the lesion strikes before rather than after myelin is laid down, the resulting nerve is hypomyelinated from the outset rather than demyelinated, which is the defining difference between CHN and the later-onset demyelinating neuropathies caused by variants in the same genes.

myelinating Schwann cell CL:0000218

myelination in peripheral nervous system GO:0022011 ↓ DECREASED

Downstream

Myelin Protein Mistrafficking and Loss of Surface Adhesion Structural-protein variants prevent the protein reaching the myelin membrane.

Failure of Peripheral Nerve Myelination Loss of the transcriptional myelination program blocks myelination directly, without an intervening trafficking defect.

Show evidence (2 references)

PMID:15184631 SUPPORT Human Clinical

"Several mutations in the MTMR2, PMP22, EGR2, and MPZ genes have been found in patients with CHN."

Enumerates the causative myelination genes that constitute this trigger node.

PMID:10369870 SUPPORT In Vitro

"Mutations in the human EGR2 gene have recently been associated with the inherited peripheral neuropathies Charcot-Marie-Tooth type 1, Dejerine-Sottas syndrome and congenital hypomyelinating neuropathy."

Establishes the EGR2 arm of the trigger and places CHN at the severe end of a single gene's phenotypic range.

Myelin Protein Mistrafficking and Loss of Surface Adhesion

CHN-causing MPZ variants are predicted to destabilize the protein's fold, and the mutant protein fails to reach the plasma membrane, accumulating instead in the cytosol with reduced adhesive properties. Because myelin protein zero compacts myelin lamellae by homophilic adhesion across the extracellular face, a protein that never reaches the surface cannot perform that function, whatever else is wrong with it. Evidence scope: the localization was measured in transfected cells, not in Schwann cells, and the destabilization is a modeling prediction rather than a measurement. The mislocalization is specifically *cytosolic*, which is not the same as the ER and Golgi retention documented for other myelin-gene variants — so this node evidences the mistrafficking arm of the module node it conforms to, and NOT the proteostatic-stress/unfolded-protein-response arm. A curator should not read ER stress into this entry without evidence for it in CHN.

myelinating Schwann cell CL:0000218

protein localization to plasma membrane GO:0072659 ↓ DECREASED

Downstream

Failure of Peripheral Nerve Myelination

Show evidence (2 references)

PMID:22176150 SUPPORT In Vitro

"Subcellular location studies were performed and revealed that the mutant protein loses its correct location on the cell membrane surface and is mainly expressed in the cytosol, reducing its adhesive properties."

Direct demonstration of the mistrafficking mechanism and its functional consequence for myelin adhesion.

PMID:22176150 SUPPORT Computational

"In silico analyses and molecular modeling predicted that the replacement of a serine by a phenylalanine is a non-tolerated change and may affect the folding and the stability of the protein."

Supplies the structural rationale for the trafficking defect. Evidence source is COMPUTATIONAL because this is a modeling prediction, not a measurement.

Failure of Peripheral Nerve Myelination

Peripheral nerve fibers remain non-myelinated or only thinly myelinated. The histological signature on sural nerve biopsy is diagnostic and distinguishes CHN from acquired and later-onset inherited demyelinating neuropathy: poorly myelinated and unmyelinated axons surrounded by basal-lamina onion bulbs, with an absence of myelin breakdown products, because the myelin was never made rather than destroyed. The onion bulbs here reflect abortive Schwann cell ensheathment attempts rather than the repeated demyelination-remyelination cycles that produce them in CMT1.

myelinating Schwann cell CL:0000218

myelin assembly GO:0032288 ↓ DECREASED

myelin sheath GO:0043209

sural nerve UBERON:0015488

Downstream

Severe Nerve Conduction Slowing

Onion bulb formation

Show evidence (2 references)

PMID:15184631 SUPPORT Human Clinical

"Sural nerve biopsy shows a characteristic picture of nonmyelinated and poorly myelinated axons with basal lamina onion bulbs and lack of myelin breakdown products."

Establishes the defining histopathology of this node, including the absence of breakdown products that marks hypomyelination rather than demyelination.

PMID:22176150 SUPPORT Human Clinical

"sural nerve biopsy revealed non-myelinated and poorly myelinated axons, with no typical onion bulbs"

Confirms the hypomyelination while recording that onion bulbs are not invariable, which is why they are curated as a feature of this node rather than as a requirement.

Severe Nerve Conduction Slowing

Motor nerve conduction velocities are severely slowed, the electrophysiological correlate of near-absent myelin. Clinical accounts describe the slowing as severe; the cited sources do not give a numeric threshold separating CHN from early-onset CMT1, so none is asserted here.

transmission of nerve impulse GO:0019226 ↓ DECREASED

Animal models

Cntnap1 C324R and R765C knock-in mice Mouse recapitulates Both knock-in lines show reduced nerve conduction and progressive motor dysfunction, matching the human CHN3 electrophysiological phenotype.

Downstream

Neonatal Neuromuscular Failure

Decreased motor nerve conduction velocity

Show evidence (1 reference)

PMID:22176150 SUPPORT Human Clinical

"Congenital hypomyelinating neuropathy (CHN) is a severe inherited neuropathy with neonatal or early infancy onset, reduced nerve conduction velocity, and pathological evidence of hypomyelination."

Establishes reduced conduction velocity as a defining feature of the disorder alongside the histological hypomyelination.

Neonatal Neuromuscular Failure

The clinical terminus: a floppy neonate with profound hypotonia and weakness, progressing in the severe forms to cranial nerve dysfunction, bulbar and respiratory failure. Unlike the later-onset demyelinating neuropathies, where disability accrues over decades through secondary axonal loss, disability in CHN is present from birth and is driven by the failure of conduction itself.

Downstream

Neonatal hypotonia

Respiratory insufficiency

Facial palsy

Show evidence (2 references)

PMID:22176150 SUPPORT Human Clinical

"We describe a case of CHN that presented with neonatal hypotonia and a progressive downhill clinical course, developing cranial nerve dysfunction, and respiratory failure."

Documents the neonatal presentation and its progression to cranial and respiratory involvement.

PMID:35058287 SUPPORT Human Clinical

"We report a neonate with an atypical presentation in the form of global hypotonia, facial diparesis and partial response to neostigmine challenge test."

Documents the floppy-neonate presentation in the CNTNAP1 form, including the facial involvement and the neuromuscular-junction mimicry that complicates diagnosis.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

5

Head and Neck 1

Facial palsy HP:0010628

Show evidence (1 reference)

PMID:35058287 SUPPORT Human Clinical

"global hypotonia, facial diparesis and partial response to neostigmine challenge test"

Documents facial diparesis and the neuromuscular-junction mimicry it creates.

Musculoskeletal 1

Neonatal hypotonia HP:0001319

Show evidence (2 references)

PMID:22176150 SUPPORT Human Clinical

"We describe a case of CHN that presented with neonatal hypotonia and a progressive downhill clinical course"

Documents neonatal hypotonia as the presenting feature.

PMID:35058287 SUPPORT Human Clinical

"We report a neonate with an atypical presentation in the form of global hypotonia, facial diparesis and partial response to neostigmine challenge test."

Independently documents global hypotonia at neonatal presentation in a different causative gene.

Respiratory 1

Respiratory insufficiency HP:0002093

Show evidence (2 references)

PMID:22176150 SUPPORT Human Clinical

"developing cranial nerve dysfunction, and respiratory failure"

Documents respiratory failure in the clinical course of CHN.

PMID:35058287 SUPPORT Human Clinical

"The baby was given supportive care and she succumbed secondary to complications of prolonged ventilation."

Documents the fatal outcome from ventilatory dependence in the CNTNAP1 form.

Other 2

Decreased motor nerve conduction velocity OBLIGATE HP:0003431

Show evidence (1 reference)

PMID:22176150 SUPPORT Human Clinical

"Congenital hypomyelinating neuropathy (CHN) is a severe inherited neuropathy with neonatal or early infancy onset, reduced nerve conduction velocity, and pathological evidence of hypomyelination."

Reduced conduction velocity is stated as part of the definition of CHN, supporting an OBLIGATE band.

Onion bulb formation HP:0003383

Show evidence (2 references)

PMID:15184631 SUPPORT Human Clinical

"Sural nerve biopsy shows a characteristic picture of nonmyelinated and poorly myelinated axons with basal lamina onion bulbs and lack of myelin breakdown products."

Documents basal-lamina onion bulbs as a characteristic biopsy feature.

PMID:22176150 SUPPORT Human Clinical

"sural nerve biopsy revealed non-myelinated and poorly myelinated axons, with no typical onion bulbs"

A genetically confirmed case lacking typical onion bulbs, which is why no frequency band is asserted for this feature.

🧬

Genetic Associations

5

MPZ (Variants in MPZ, encoding myelin protein zero, cause CHN2. The same gene produces a phenotypic range from adult-onset CMT1B to neonatal CHN; the CHN variants are those that most severely disrupt folding, stability and trafficking of the protein.)

Gene: MPZ hgnc:7225 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:15184631 SUPPORT Human Clinical

"The authors describe the clinical and morphologic features of a patient with CHN and the identification of a novel Thr124Lys mutation in the MPZ gene."

Reports a causative MPZ variant in a biopsy-confirmed CHN patient.

PMID:22176150 SUPPORT Human Clinical

"This case illustrates the clinical heterogeneity that exists in neuropathies associated with MPZ mutations"

Establishes the phenotypic breadth of MPZ variants, of which CHN is the severe extreme.

EGR2 (Variants in EGR2/KROX20, the transcription factor controlling the Schwann cell myelination program, cause CHN1 (catalogued as CMT4E). Residual DNA-binding capacity of zinc-finger variants correlates directly with disease severity across the CMT1 / Dejerine-Sottas / CHN spectrum.)

Gene: EGR2 hgnc:3239 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:10369870 SUPPORT In Vitro

"The zinc finger mutations affect DNA binding and the amount of residual binding directly correlates with disease severity."

Supplies the genotype-phenotype mechanism placing CHN at the severe end of the EGR2 allelic series.

PMP22 (PMP22 variants are among the causes of CHN. As with MPZ, the same gene produces a wide severity range — the common CMT1A duplication and the HNPP deletion sit at the mild end of the same dosage axis — and the CHN-causing alleles are at the severe extreme.)

Gene: PMP22 hgnc:9118 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:15184631 SUPPORT Human Clinical

"Several mutations in the MTMR2, PMP22, EGR2, and MPZ genes have been found in patients with CHN."

Lists PMP22 among the genes in which mutations have been found in CHN patients.

MTMR2 (MTMR2 variants are among the causes of CHN. MTMR2 encodes a myotubularin-family phosphoinositide phosphatase and is better known as the CMT4B1 gene; the lesion is Schwann cell membrane trafficking rather than a compact-myelin structural protein, so this arm reaches the shared myelination-failure node by a different route than MPZ or EGR2.)

Gene: MTMR2 hgnc:7450 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:15184631 SUPPORT Human Clinical

"Several mutations in the MTMR2, PMP22, EGR2, and MPZ genes have been found in patients with CHN."

Lists MTMR2 among the genes in which mutations have been found in CHN patients.

CNTNAP1 (Biallelic CNTNAP1 variants cause CHN3. The mechanism is paranodal rather than compact-myelin: the mutant protein is depleted from the paranode, axo-glial junctions fail to form, and myelin loops evert.)

Gene: CNTNAP1 hgnc:8011 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:37862170 SUPPORT Human Clinical

"Human CNTNAP1 mutations are linked to hypomyelinating neuropathy-3, which causes severe neurological deficits."

Establishes CNTNAP1 as the CHN3 gene.

PMID:37862170 SUPPORT Model Organism

"The paranodal ultrastructure shows everted myelin loops and the absence of axo-glial junctions."

Documents the paranodal mechanism that distinguishes CHN3 from the compact-myelin forms. Evidence source is MODEL_ORGANISM because the ultrastructural finding is from knock-in mice.

💊

Medical Actions

1

Supportive and respiratory care

Action: Supportive Care NCIT:C15747

No disease-modifying therapy exists. Management is supportive: ventilatory support, feeding support, and physical therapy. Outcomes in the severe forms are poor, with death commonly resulting from complications of prolonged ventilation.

Show evidence (1 reference)

PMID:35058287 SUPPORT Human Clinical

"The baby was given supportive care and she succumbed secondary to complications of prolonged ventilation."

Documents supportive care as the available management and its limits.

🔬

Diagnosis

3

Nerve conduction studies

Motor nerve conduction velocities are severely slowed, which is the first objective step in separating CHN from the non-neuropathic causes of neonatal hypotonia. Separating it from early-onset CMT1 rests on the biopsy picture and the age of onset rather than on a cited velocity cut-off.

Show evidence (1 reference)

PMID:22176150 SUPPORT Human Clinical

"The nerve conduction velocities were severely slowed and sural nerve biopsy revealed non-myelinated and poorly myelinated axons"

Pairs the electrophysiological and histological diagnostic findings.

Sural nerve biopsy

Biopsy shows non-myelinated and poorly myelinated axons with basal-lamina onion bulbs and — the discriminating feature — no myelin breakdown products, indicating that myelin was never formed rather than lost.

Show evidence (1 reference)

PMID:15184631 SUPPORT Human Clinical

"Sural nerve biopsy shows a characteristic picture of nonmyelinated and poorly myelinated axons with basal lamina onion bulbs and lack of myelin breakdown products."

States the diagnostic biopsy picture, including the negative finding that distinguishes hypomyelination from demyelination.

Molecular genetic testing

Exome or targeted panel sequencing establishes the causative gene. Because the neonatal phenotype is non-specific, the diagnosis is frequently reached by sequencing first and reverse-phenotyping afterwards.

Show evidence (1 reference)

PMID:35058287 SUPPORT Human Clinical

"Detection of a pathogenic variant in CNTNAP1 gene by clinical exome sequencing and subsequent reverse phenotyping confirmed CHN as the aetiology for this floppy neonate"

Documents the sequencing-first, reverse-phenotyping diagnostic route used in practice.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Congenital Hypomyelinating Neuropathy:

Congenital Myasthenic Syndrome

Overlapping Features Both present as a floppy neonate with weakness and facial involvement, and the partial response to a neostigmine challenge seen in some CHN3 infants can reinforce the wrong diagnosis. Nerve conduction studies separate them: CHN shows severely slowed conduction, which a neuromuscular-junction disorder does not.

Show evidence (1 reference)

PMID:35058287 SUPPORT Human Clinical

"There was no clinical improvement on initiation of anticholinesterase drug for suspected congenital myasthenia and hence stopped."

Documents the misdiagnosis and its resolution in a real case.

Charcot-Marie-Tooth Disease Type 1

Overlapping Features The same genes (MPZ, EGR2, PMP22) cause both. CHN is distinguished by onset in the neonatal or early infantile period, far slower conduction velocities, and biopsy showing hypomyelination without myelin breakdown products, rather than the de- and remyelination of CMT1.

Show evidence (1 reference)

PMID:10369870 SUPPORT In Vitro

"Mutations in the human EGR2 gene have recently been associated with the inherited peripheral neuropathies Charcot-Marie-Tooth type 1, Dejerine-Sottas syndrome and congenital hypomyelinating neuropathy."

Establishes that these three entities form one allelic spectrum, which is why the distinction rests on severity and timing rather than on gene identity.

🐁

Animal Models

1

Cntnap1 C324R and R765C knock-in mice

Knock-in mice carrying the mouse equivalents of two human CHN3 variants. They reproduce reduced nerve conduction and progressive motor dysfunction, and the paranodal ultrastructural lesion; postnatal transgenic re-expression of Cntnap1 rescues the phenotype, which is the proof-of-concept for gene therapy in this form.

Species

Mouse

Genotype

Cntnap1 C324R and Cntnap1 R765C knock-in, modelling human CNTNAP1 C323R and R764C

Publication

PMID:37862170

Pathograph links

Severe Nerve Conduction Slowing recapitulates fidelity: high Both knock-in lines show reduced nerve conduction and progressive motor dysfunction, matching the human CHN3 electrophysiological phenotype.

Limitations: Mice model the CNTNAP1 paranodal form only; they say nothing about the compact-myelin (MPZ, EGR2, PMP22) arm of this disorder, and the human variants were transposed to the orthologous mouse residues rather than introduced verbatim.

Readouts

Nerve conduction velocity

Direction: DECREASED

Interpretation: Electrophysiological correlate of the paranodal junction failure.

Show evidence (1 reference)

PMID:37862170 SUPPORT Model Organism

"Both Cntnap1 mutants show weight loss, reduced nerve conduction, and progressive motor dysfunction."

Reports the conduction measurement behind this readout.

Motor function after postnatal Cntnap1 re-expression

Direction: RESTORED

Interpretation: The conduction and motor phenotype is reversible by restoring the protein postnatally, indicating the deficit is not fixed at birth in this model.

Show evidence (1 reference)

PMID:37862170 SUPPORT Model Organism

"Postnatal transgenic expression of Cntnap1 in the mutant backgrounds rescues the phenotypes and restores the organization of axonal domains with improved motor function."

Reports the rescue experiment behind this readout.

Show evidence (1 reference)

PMID:37862170 SUPPORT Model Organism

"To understand the human neuropathology and to model human CNTNAP1C323R and CNTNAP1R764C mutations, we generated Cntnap1C324R and Cntnap1R765C mouse mutants, respectively."

Establishes that these lines were built specifically to model the human CHN3 variants, supporting their use as informative for this node.

{ }

Source YAML

click to show

name: Congenital Hypomyelinating Neuropathy
creation_date: "2026-08-22T00:00:00Z"
description: >-
  Congenital hypomyelinating neuropathy (CHN) is the most severe end of the
  hereditary demyelinating neuropathy spectrum: a neuropathy of neonatal or
  early-infantile onset in which peripheral nerves are never adequately
  myelinated in the first place, rather than losing myelin they once had. Infants
  present as floppy neonates with profound hypotonia, areflexia, feeding and
  respiratory difficulty, and sometimes arthrogryposis from intrauterine
  akinesia. Motor nerve conduction velocities are extremely slow — typically far
  below the CMT1 range — and sural nerve biopsy shows non-myelinated and poorly
  myelinated axons with basal-lamina onion bulbs and, diagnostically, an absence
  of myelin breakdown products, because there was little myelin to break down.
  CHN is genetically heterogeneous and inherited as an autosomal dominant or
  recessive trait; causative variants have been found in MPZ, EGR2, PMP22, MTMR2
  and, in the paranodal form, CNTNAP1. Mechanistically it is the developmental
  extreme of the same Schwann cell myelination failure that produces
  Charcot-Marie-Tooth disease type 1 and Dejerine-Sottas syndrome, and the
  severity gradient across these three entities tracks the severity of the
  underlying molecular lesion rather than distinguishing separate mechanisms.
category: Mendelian
parents:
- Peripheral Neuropathy
- hereditary disease
disease_term:
  preferred_term: neuropathy, congenital hypomyelinating
  term:
    id: MONDO:0033352
    label: neuropathy, congenital hypomelinating
has_subtypes:
- name: CHN1
  display_name: CHN1 (EGR2-related, Charcot-Marie-Tooth disease type 4E)
  description: >-
    The EGR2/KROX20 form, catalogued in MONDO as Charcot-Marie-Tooth disease type
    4E. EGR2 is the transcription factor that drives the Schwann cell myelination
    program, so its loss disables myelination at the level of the transcriptional
    switch rather than of a single structural protein. Zinc-finger domain
    variants act dominantly and their residual DNA-binding capacity correlates
    inversely with disease severity; a recessive variant in the NAB co-repressor
    binding domain acts by increasing transcriptional activity instead.
  subtype_term:
    preferred_term: Charcot-Marie-Tooth disease type 4E
    term:
      id: MONDO:0011527
      label: Charcot-Marie-Tooth disease type 4E
- name: CHN2
  display_name: CHN2 (MPZ-related)
  description: >-
    The MPZ form. Myelin protein zero is the principal structural adhesion
    protein of compact peripheral myelin; CHN-causing variants disrupt its
    folding and trafficking so that it fails to reach the cell surface. The same
    gene produces a phenotypic range from adult-onset CMT1B to neonatal CHN
    depending on the variant.
  subtype_term:
    preferred_term: neuropathy, congenital hypomyelinating, 2
    term:
      id: MONDO:0020765
      label: neuropathy, congenital hypomyelinating, 2
- name: CHN3
  display_name: CHN3 (CNTNAP1-related, paranodal)
  description: >-
    The CNTNAP1 form, mechanistically distinct from the compact-myelin arm:
    contactin-associated protein 1 builds the axo-glial septate-like junctions of
    the paranode, so the lesion is a failure to organize the axonal domains that
    make saltatory conduction possible rather than a failure to make compact
    myelin. It carries a high neonatal mortality and can present as a floppy
    neonate mimicking congenital myasthenic syndrome.
  subtype_term:
    preferred_term: neuropathy, congenital hypomyelinating, 3
    term:
      id: MONDO:0020766
      label: neuropathy, congenital hypomyelinating, 3
inheritance:
- name: Autosomal dominant
  description: >-
    CHN is inherited as an autosomal dominant or an autosomal recessive trait
    depending on the gene and variant. The MPZ and EGR2 zinc-finger forms are
    typically dominant, and many are de novo.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:15184631
    reference_title: "A novel MPZ gene mutation in congenital neuropathy with hypomyelination."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital hypomyelinating neuropathy (CHN; MIM# 605253) is a severe
      neuropathy with early infancy onset inherited as an autosomal dominant or
      recessive trait.
    explanation: >-
      States both inheritance modes for CHN as a genetically heterogeneous
      entity.
- name: Autosomal recessive
  description: >-
    The CNTNAP1 paranodal form and the EGR2 NAB-domain form are recessive.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:15184631
    reference_title: "A novel MPZ gene mutation in congenital neuropathy with hypomyelination."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital hypomyelinating neuropathy (CHN; MIM# 605253) is a severe
      neuropathy with early infancy onset inherited as an autosomal dominant or
      recessive trait.
    explanation: >-
      Establishes that recessive inheritance also occurs in this genetically
      heterogeneous disorder.
pathophysiology:
- name: Myelination Gene Lesion in Developing Schwann Cells
  description: >-
    A variant in a gene the Schwann cell requires to build compact myelin — MPZ
    (the principal compact-myelin adhesion protein), EGR2/KROX20 (the
    transcription factor driving the myelination program), PMP22, or MTMR2 —
    disables myelination during the perinatal window when peripheral nerve is
    normally myelinated. Because the lesion strikes before rather than after
    myelin is laid down, the resulting nerve is hypomyelinated from the outset
    rather than demyelinated, which is the defining difference between CHN and
    the later-onset demyelinating neuropathies caused by variants in the same
    genes.
  role: trigger
  biological_scale: MOLECULAR
  conforms_to: "schwann_cell_myelin_maintenance#Myelin Gene Dosage or Structural Lesion in Schwann Cells"
  cell_types:
  - preferred_term: myelinating Schwann cell
    term:
      id: CL:0000218
      label: myelinating Schwann cell
  biological_processes:
  - preferred_term: myelination in peripheral nervous system
    term:
      id: GO:0022011
      label: myelination in peripheral nervous system
    modifier: DECREASED
  evidence:
  - reference: PMID:15184631
    reference_title: "A novel MPZ gene mutation in congenital neuropathy with hypomyelination."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Several mutations in the MTMR2, PMP22, EGR2, and MPZ genes have been found
      in patients with CHN.
    explanation: >-
      Enumerates the causative myelination genes that constitute this trigger
      node.
  - reference: PMID:10369870
    reference_title: "Functional consequences of mutations in the early growth response 2 gene (EGR2) correlate with severity of human myelinopathies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mutations in the human EGR2 gene have recently been associated with the
      inherited peripheral neuropathies Charcot-Marie-Tooth type 1,
      Dejerine-Sottas syndrome and congenital hypomyelinating neuropathy.
    explanation: >-
      Establishes the EGR2 arm of the trigger and places CHN at the severe end of
      a single gene's phenotypic range.
  downstream:
  - target: Myelin Protein Mistrafficking and Loss of Surface Adhesion
    description: >-
      Structural-protein variants prevent the protein reaching the myelin
      membrane.
  - target: Failure of Peripheral Nerve Myelination
    description: >-
      Loss of the transcriptional myelination program blocks myelination
      directly, without an intervening trafficking defect.

- name: Myelin Protein Mistrafficking and Loss of Surface Adhesion
  description: >-
    CHN-causing MPZ variants are predicted to destabilize the protein's fold, and
    the mutant protein fails to reach the plasma membrane, accumulating instead
    in the cytosol with reduced adhesive properties. Because myelin protein zero
    compacts myelin lamellae by homophilic adhesion across the extracellular
    face, a protein that never reaches the surface cannot perform that function,
    whatever else is wrong with it.

    Evidence scope: the localization was measured in transfected cells, not in
    Schwann cells, and the destabilization is a modeling prediction rather than a
    measurement. The mislocalization is specifically *cytosolic*, which is not
    the same as the ER and Golgi retention documented for other myelin-gene
    variants — so this node evidences the mistrafficking arm of the module node
    it conforms to, and NOT the proteostatic-stress/unfolded-protein-response
    arm. A curator should not read ER stress into this entry without evidence
    for it in CHN.
  role: amplifier
  biological_scale: CELLULAR
  conforms_to: "schwann_cell_myelin_maintenance#Schwann Cell Proteostatic Stress and Myelin Protein Mistrafficking"
  cell_types:
  - preferred_term: myelinating Schwann cell
    term:
      id: CL:0000218
      label: myelinating Schwann cell
  biological_processes:
  - preferred_term: protein localization to plasma membrane
    term:
      id: GO:0072659
      label: protein localization to plasma membrane
    modifier: DECREASED
  evidence:
  - reference: PMID:22176150
    reference_title: "Congenital hypomyelinating neuropathy due to a novel MPZ mutation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Subcellular location studies were performed and revealed that the mutant
      protein loses its correct location on the cell membrane surface and is
      mainly expressed in the cytosol, reducing its adhesive properties.
    explanation: >-
      Direct demonstration of the mistrafficking mechanism and its functional
      consequence for myelin adhesion.
  - reference: PMID:22176150
    reference_title: "Congenital hypomyelinating neuropathy due to a novel MPZ mutation."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      In silico analyses and molecular modeling predicted that the replacement of
      a serine by a phenylalanine is a non-tolerated change and may affect the
      folding and the stability of the protein.
    explanation: >-
      Supplies the structural rationale for the trafficking defect. Evidence
      source is COMPUTATIONAL because this is a modeling prediction, not a
      measurement.
  downstream:
  - target: Failure of Peripheral Nerve Myelination

- name: Failure of Peripheral Nerve Myelination
  description: >-
    Peripheral nerve fibers remain non-myelinated or only thinly myelinated. The
    histological signature on sural nerve biopsy is diagnostic and distinguishes
    CHN from acquired and later-onset inherited demyelinating neuropathy: poorly
    myelinated and unmyelinated axons surrounded by basal-lamina onion bulbs,
    with an absence of myelin breakdown products, because the myelin was never
    made rather than destroyed. The onion bulbs here reflect abortive Schwann
    cell ensheathment attempts rather than the repeated demyelination-remyelination
    cycles that produce them in CMT1.
  role: central_effector
  biological_scale: TISSUE
  conforms_to: "schwann_cell_myelin_maintenance#Dysmyelination and Segmental Demyelination of Peripheral Nerve"
  cell_types:
  - preferred_term: myelinating Schwann cell
    term:
      id: CL:0000218
      label: myelinating Schwann cell
  biological_processes:
  - preferred_term: myelin assembly
    term:
      id: GO:0032288
      label: myelin assembly
    modifier: DECREASED
  cellular_components:
  - preferred_term: myelin sheath
    term:
      id: GO:0043209
      label: myelin sheath
    modifier: ABNORMAL
  locations:
  - preferred_term: sural nerve
    term:
      id: UBERON:0015488
      label: sural nerve
  evidence:
  - reference: PMID:15184631
    reference_title: "A novel MPZ gene mutation in congenital neuropathy with hypomyelination."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sural nerve biopsy shows a characteristic picture of nonmyelinated and
      poorly myelinated axons with basal lamina onion bulbs and lack of myelin
      breakdown products.
    explanation: >-
      Establishes the defining histopathology of this node, including the absence
      of breakdown products that marks hypomyelination rather than
      demyelination.
  - reference: PMID:22176150
    reference_title: "Congenital hypomyelinating neuropathy due to a novel MPZ mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      sural nerve biopsy revealed non-myelinated and poorly myelinated axons,
      with no typical onion bulbs
    explanation: >-
      Confirms the hypomyelination while recording that onion bulbs are not
      invariable, which is why they are curated as a feature of this node rather
      than as a requirement.
  downstream:
  - target: Severe Nerve Conduction Slowing
  - target: Onion bulb formation

- name: Severe Nerve Conduction Slowing
  description: >-
    Motor nerve conduction velocities are severely slowed, the electrophysiological
    correlate of near-absent myelin. Clinical accounts describe the slowing as
    severe; the cited sources do not give a numeric threshold separating CHN from
    early-onset CMT1, so none is asserted here.
  role: effector
  biological_scale: TISSUE
  conforms_to: "schwann_cell_myelin_maintenance#Nerve Conduction Slowing and Conduction Block"
  biological_processes:
  - preferred_term: transmission of nerve impulse
    term:
      id: GO:0019226
      label: transmission of nerve impulse
    modifier: DECREASED
  evidence:
  - reference: PMID:22176150
    reference_title: "Congenital hypomyelinating neuropathy due to a novel MPZ mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital hypomyelinating neuropathy (CHN) is a severe inherited
      neuropathy with neonatal or early infancy onset, reduced nerve conduction
      velocity, and pathological evidence of hypomyelination.
    explanation: >-
      Establishes reduced conduction velocity as a defining feature of the
      disorder alongside the histological hypomyelination.
  downstream:
  - target: Neonatal Neuromuscular Failure
  - target: Decreased motor nerve conduction velocity

- name: Neonatal Neuromuscular Failure
  description: >-
    The clinical terminus: a floppy neonate with profound hypotonia and weakness,
    progressing in the severe forms to cranial nerve dysfunction, bulbar and
    respiratory failure. Unlike the later-onset demyelinating
    neuropathies, where disability accrues over decades through secondary axonal
    loss, disability in CHN is present from birth and is driven by the failure of
    conduction itself.
  role: consequence
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:22176150
    reference_title: "Congenital hypomyelinating neuropathy due to a novel MPZ mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a case of CHN that presented with neonatal hypotonia and a
      progressive downhill clinical course, developing cranial nerve dysfunction,
      and respiratory failure.
    explanation: >-
      Documents the neonatal presentation and its progression to cranial and
      respiratory involvement.
  - reference: PMID:35058287
    reference_title: "Diagnosis of a floppy neonate with misleading clues: unraveled as congenital hypomyelinating neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a neonate with an atypical presentation in the form of global
      hypotonia, facial diparesis and partial response to neostigmine challenge
      test.
    explanation: >-
      Documents the floppy-neonate presentation in the CNTNAP1 form, including
      the facial involvement and the neuromuscular-junction mimicry that
      complicates diagnosis.
  downstream:
  - target: Neonatal hypotonia
  - target: Respiratory insufficiency
  - target: Facial palsy

phenotypes:
- name: Neonatal hypotonia
  category: Clinical
  description: >-
    Profound generalized hypotonia from birth or the first weeks of life; the
    presentation is that of a floppy neonate.
  phenotype_term:
    preferred_term: Neonatal hypotonia
    term:
      id: HP:0001319
      label: Neonatal hypotonia
  evidence:
  - reference: PMID:22176150
    reference_title: "Congenital hypomyelinating neuropathy due to a novel MPZ mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a case of CHN that presented with neonatal hypotonia and a
      progressive downhill clinical course
    explanation: >-
      Documents neonatal hypotonia as the presenting feature.
  - reference: PMID:35058287
    reference_title: "Diagnosis of a floppy neonate with misleading clues: unraveled as congenital hypomyelinating neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a neonate with an atypical presentation in the form of global
      hypotonia, facial diparesis and partial response to neostigmine challenge
      test.
    explanation: >-
      Independently documents global hypotonia at neonatal presentation in a
      different causative gene.
- name: Decreased motor nerve conduction velocity
  category: Physiological
  frequency: OBLIGATE
  description: >-
    Severely slowed motor nerve conduction velocity, the electrophysiological
    hallmark and part of the operational definition of the disorder.
  phenotype_term:
    preferred_term: Decreased motor nerve conduction velocity
    term:
      id: HP:0003431
      label: Decreased motor nerve conduction velocity
  evidence:
  - reference: PMID:22176150
    reference_title: "Congenital hypomyelinating neuropathy due to a novel MPZ mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital hypomyelinating neuropathy (CHN) is a severe inherited
      neuropathy with neonatal or early infancy onset, reduced nerve conduction
      velocity, and pathological evidence of hypomyelination.
    explanation: >-
      Reduced conduction velocity is stated as part of the definition of CHN,
      supporting an OBLIGATE band.
- name: Onion bulb formation
  category: Histological
  description: >-
    Basal-lamina onion bulbs on sural nerve biopsy, reflecting abortive Schwann
    cell ensheathment. They are characteristic but not invariable — some
    genetically confirmed cases show hypomyelination without typical onion bulbs.
  phenotype_term:
    preferred_term: Onion bulb formation
    term:
      id: HP:0003383
      label: Onion bulb formation
  evidence:
  - reference: PMID:15184631
    reference_title: "A novel MPZ gene mutation in congenital neuropathy with hypomyelination."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sural nerve biopsy shows a characteristic picture of nonmyelinated and
      poorly myelinated axons with basal lamina onion bulbs and lack of myelin
      breakdown products.
    explanation: >-
      Documents basal-lamina onion bulbs as a characteristic biopsy feature.
  - reference: PMID:22176150
    reference_title: "Congenital hypomyelinating neuropathy due to a novel MPZ mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      sural nerve biopsy revealed non-myelinated and poorly myelinated axons,
      with no typical onion bulbs
    explanation: >-
      A genetically confirmed case lacking typical onion bulbs, which is why no
      frequency band is asserted for this feature.
- name: Respiratory insufficiency
  category: Clinical
  description: >-
    Respiratory failure from phrenic and intercostal nerve involvement, a major
    determinant of the high mortality of the severe forms; prolonged ventilation
    and its complications are a common cause of death.
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:22176150
    reference_title: "Congenital hypomyelinating neuropathy due to a novel MPZ mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      developing cranial nerve dysfunction, and respiratory failure
    explanation: >-
      Documents respiratory failure in the clinical course of CHN.
  - reference: PMID:35058287
    reference_title: "Diagnosis of a floppy neonate with misleading clues: unraveled as congenital hypomyelinating neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The baby was given supportive care and she succumbed secondary to
      complications of prolonged ventilation.
    explanation: >-
      Documents the fatal outcome from ventilatory dependence in the CNTNAP1
      form.
- name: Facial palsy
  category: Clinical
  description: >-
    Facial diparesis from cranial nerve involvement, which in the CNTNAP1 form
    can be prominent enough to prompt a neostigmine challenge and a working
    diagnosis of congenital myasthenic syndrome.
  phenotype_term:
    preferred_term: Facial palsy
    term:
      id: HP:0010628
      label: Facial palsy
  evidence:
  - reference: PMID:35058287
    reference_title: "Diagnosis of a floppy neonate with misleading clues: unraveled as congenital hypomyelinating neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      global hypotonia, facial diparesis and partial response to neostigmine
      challenge test
    explanation: >-
      Documents facial diparesis and the neuromuscular-junction mimicry it
      creates.

genetic:
- name: MPZ
  gene_term:
    preferred_term: MPZ
    term:
      id: hgnc:7225
      label: MPZ
  relationship_type: CAUSATIVE
  association: >-
    Variants in MPZ, encoding myelin protein zero, cause CHN2. The same gene
    produces a phenotypic range from adult-onset CMT1B to neonatal CHN; the CHN
    variants are those that most severely disrupt folding, stability and
    trafficking of the protein.
  evidence:
  - reference: PMID:15184631
    reference_title: "A novel MPZ gene mutation in congenital neuropathy with hypomyelination."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The authors describe the clinical and morphologic features of a patient
      with CHN and the identification of a novel Thr124Lys mutation in the MPZ
      gene.
    explanation: >-
      Reports a causative MPZ variant in a biopsy-confirmed CHN patient.
  - reference: PMID:22176150
    reference_title: "Congenital hypomyelinating neuropathy due to a novel MPZ mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This case illustrates the clinical heterogeneity that exists in
      neuropathies associated with MPZ mutations
    explanation: >-
      Establishes the phenotypic breadth of MPZ variants, of which CHN is the
      severe extreme.
- name: EGR2
  gene_term:
    preferred_term: EGR2
    term:
      id: hgnc:3239
      label: EGR2
  relationship_type: CAUSATIVE
  association: >-
    Variants in EGR2/KROX20, the transcription factor controlling the Schwann
    cell myelination program, cause CHN1 (catalogued as CMT4E). Residual
    DNA-binding capacity of zinc-finger variants correlates directly with disease
    severity across the CMT1 / Dejerine-Sottas / CHN spectrum.
  evidence:
  - reference: PMID:10369870
    reference_title: "Functional consequences of mutations in the early growth response 2 gene (EGR2) correlate with severity of human myelinopathies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The zinc finger mutations affect DNA binding and the amount of residual
      binding directly correlates with disease severity.
    explanation: >-
      Supplies the genotype-phenotype mechanism placing CHN at the severe end of
      the EGR2 allelic series.
- name: PMP22
  gene_term:
    preferred_term: PMP22
    term:
      id: hgnc:9118
      label: PMP22
  relationship_type: CAUSATIVE
  association: >-
    PMP22 variants are among the causes of CHN. As with MPZ, the same gene
    produces a wide severity range — the common CMT1A duplication and the HNPP
    deletion sit at the mild end of the same dosage axis — and the CHN-causing
    alleles are at the severe extreme.
  evidence:
  - reference: PMID:15184631
    reference_title: "A novel MPZ gene mutation in congenital neuropathy with hypomyelination."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Several mutations in the MTMR2, PMP22, EGR2, and MPZ genes have been found
      in patients with CHN.
    explanation: >-
      Lists PMP22 among the genes in which mutations have been found in CHN
      patients.
- name: MTMR2
  gene_term:
    preferred_term: MTMR2
    term:
      id: hgnc:7450
      label: MTMR2
  relationship_type: CAUSATIVE
  association: >-
    MTMR2 variants are among the causes of CHN. MTMR2 encodes a
    myotubularin-family phosphoinositide phosphatase and is better known as the
    CMT4B1 gene; the lesion is Schwann cell membrane trafficking rather than a
    compact-myelin structural protein, so this arm reaches the shared
    myelination-failure node by a different route than MPZ or EGR2.
  evidence:
  - reference: PMID:15184631
    reference_title: "A novel MPZ gene mutation in congenital neuropathy with hypomyelination."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Several mutations in the MTMR2, PMP22, EGR2, and MPZ genes have been found
      in patients with CHN.
    explanation: >-
      Lists MTMR2 among the genes in which mutations have been found in CHN
      patients.
- name: CNTNAP1
  gene_term:
    preferred_term: CNTNAP1
    term:
      id: hgnc:8011
      label: CNTNAP1
  relationship_type: CAUSATIVE
  association: >-
    Biallelic CNTNAP1 variants cause CHN3. The mechanism is paranodal rather than
    compact-myelin: the mutant protein is depleted from the paranode, axo-glial
    junctions fail to form, and myelin loops evert.
  evidence:
  - reference: PMID:37862170
    reference_title: "Mouse models of human CNTNAP1-associated congenital hypomyelinating neuropathy and genetic restoration of murine neurological deficits."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Human CNTNAP1 mutations are linked to hypomyelinating neuropathy-3, which
      causes severe neurological deficits.
    explanation: >-
      Establishes CNTNAP1 as the CHN3 gene.
  - reference: PMID:37862170
    reference_title: "Mouse models of human CNTNAP1-associated congenital hypomyelinating neuropathy and genetic restoration of murine neurological deficits."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The paranodal ultrastructure shows everted myelin loops and the absence of
      axo-glial junctions.
    explanation: >-
      Documents the paranodal mechanism that distinguishes CHN3 from the
      compact-myelin forms. Evidence source is MODEL_ORGANISM because the
      ultrastructural finding is from knock-in mice.

diagnosis:
- name: Nerve conduction studies
  description: >-
    Motor nerve conduction velocities are severely slowed, which is the first
    objective step in separating CHN from the non-neuropathic causes of neonatal
    hypotonia. Separating it from early-onset CMT1 rests on the biopsy picture
    and the age of onset rather than on a cited velocity cut-off.
  evidence:
  - reference: PMID:22176150
    reference_title: "Congenital hypomyelinating neuropathy due to a novel MPZ mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The nerve conduction velocities were severely slowed and sural nerve biopsy
      revealed non-myelinated and poorly myelinated axons
    explanation: >-
      Pairs the electrophysiological and histological diagnostic findings.
- name: Sural nerve biopsy
  description: >-
    Biopsy shows non-myelinated and poorly myelinated axons with basal-lamina
    onion bulbs and — the discriminating feature — no myelin breakdown products,
    indicating that myelin was never formed rather than lost.
  evidence:
  - reference: PMID:15184631
    reference_title: "A novel MPZ gene mutation in congenital neuropathy with hypomyelination."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sural nerve biopsy shows a characteristic picture of nonmyelinated and
      poorly myelinated axons with basal lamina onion bulbs and lack of myelin
      breakdown products.
    explanation: >-
      States the diagnostic biopsy picture, including the negative finding that
      distinguishes hypomyelination from demyelination.
- name: Molecular genetic testing
  description: >-
    Exome or targeted panel sequencing establishes the causative gene. Because
    the neonatal phenotype is non-specific, the diagnosis is frequently reached
    by sequencing first and reverse-phenotyping afterwards.
  evidence:
  - reference: PMID:35058287
    reference_title: "Diagnosis of a floppy neonate with misleading clues: unraveled as congenital hypomyelinating neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Detection of a pathogenic variant in CNTNAP1 gene by clinical exome
      sequencing and subsequent reverse phenotyping confirmed CHN as the
      aetiology for this floppy neonate
    explanation: >-
      Documents the sequencing-first, reverse-phenotyping diagnostic route used
      in practice.

treatments:
- name: Supportive and respiratory care
  description: >-
    No disease-modifying therapy exists. Management is supportive: ventilatory
    support, feeding support, and physical therapy. Outcomes in the severe forms
    are poor, with death commonly resulting from complications of prolonged
    ventilation.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:35058287
    reference_title: "Diagnosis of a floppy neonate with misleading clues: unraveled as congenital hypomyelinating neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The baby was given supportive care and she succumbed secondary to
      complications of prolonged ventilation.
    explanation: >-
      Documents supportive care as the available management and its limits.

animal_models:
- name: Cntnap1 C324R and R765C knock-in mice
  species: Mouse
  genotype: Cntnap1 C324R and Cntnap1 R765C knock-in, modelling human CNTNAP1 C323R and R764C
  publication: PMID:37862170
  description: >-
    Knock-in mice carrying the mouse equivalents of two human CHN3 variants.
    They reproduce reduced nerve conduction and progressive motor dysfunction,
    and the paranodal ultrastructural lesion; postnatal transgenic re-expression
    of Cntnap1 rescues the phenotype, which is the proof-of-concept for gene
    therapy in this form.
  modeled_mechanisms:
  - target: Severe Nerve Conduction Slowing
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Both knock-in lines show reduced nerve conduction and progressive motor
      dysfunction, matching the human CHN3 electrophysiological phenotype.
    limitations: >-
      Mice model the CNTNAP1 paranodal form only; they say nothing about the
      compact-myelin (MPZ, EGR2, PMP22) arm of this disorder, and the human
      variants were transposed to the orthologous mouse residues rather than
      introduced verbatim.
    readouts:
    - name: Nerve conduction velocity
      target: Severe Nerve Conduction Slowing
      direction: DECREASED
      interpretation: >-
        Electrophysiological correlate of the paranodal junction failure.
      evidence:
      - reference: PMID:37862170
        reference_title: "Mouse models of human CNTNAP1-associated congenital hypomyelinating neuropathy and genetic restoration of murine neurological deficits."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Both Cntnap1 mutants show weight loss, reduced nerve conduction, and
          progressive motor dysfunction.
        explanation: >-
          Reports the conduction measurement behind this readout.
    - name: Motor function after postnatal Cntnap1 re-expression
      target: Severe Nerve Conduction Slowing
      direction: RESTORED
      interpretation: >-
        The conduction and motor phenotype is reversible by restoring the
        protein postnatally, indicating the deficit is not fixed at birth in this
        model.
      evidence:
      - reference: PMID:37862170
        reference_title: "Mouse models of human CNTNAP1-associated congenital hypomyelinating neuropathy and genetic restoration of murine neurological deficits."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Postnatal transgenic expression of Cntnap1 in the mutant backgrounds
          rescues the phenotypes and restores the organization of axonal domains
          with improved motor function.
        explanation: >-
          Reports the rescue experiment behind this readout.
    evidence:
    - reference: PMID:37862170
      reference_title: "Mouse models of human CNTNAP1-associated congenital hypomyelinating neuropathy and genetic restoration of murine neurological deficits."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        To understand the human neuropathology and to model human CNTNAP1C323R
        and CNTNAP1R764C mutations, we generated Cntnap1C324R and Cntnap1R765C
        mouse mutants, respectively.
      explanation: >-
        Establishes that these lines were built specifically to model the human
        CHN3 variants, supporting their use as informative for this node.

differential_diagnoses:
- name: Congenital Myasthenic Syndrome
  description: >-
    Both present as a floppy neonate with weakness and facial involvement, and
    the partial response to a neostigmine challenge seen in some CHN3 infants can
    reinforce the wrong diagnosis. Nerve conduction studies separate them: CHN
    shows severely slowed conduction, which a neuromuscular-junction disorder
    does not.
  evidence:
  - reference: PMID:35058287
    reference_title: "Diagnosis of a floppy neonate with misleading clues: unraveled as congenital hypomyelinating neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was no clinical improvement on initiation of anticholinesterase drug
      for suspected congenital myasthenia and hence stopped.
    explanation: >-
      Documents the misdiagnosis and its resolution in a real case.
- name: Charcot-Marie-Tooth Disease Type 1
  description: >-
    The same genes (MPZ, EGR2, PMP22) cause both. CHN is distinguished by onset
    in the neonatal or early infantile period, far slower conduction velocities,
    and biopsy showing hypomyelination without myelin breakdown products, rather
    than the de- and remyelination of CMT1.
  evidence:
  - reference: PMID:10369870
    reference_title: "Functional consequences of mutations in the early growth response 2 gene (EGR2) correlate with severity of human myelinopathies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mutations in the human EGR2 gene have recently been associated with the
      inherited peripheral neuropathies Charcot-Marie-Tooth type 1,
      Dejerine-Sottas syndrome and congenital hypomyelinating neuropathy.
    explanation: >-
      Establishes that these three entities form one allelic spectrum, which is
      why the distinction rests on severity and timing rather than on gene
      identity.

notes: >-
  GeneReviews: no chapter exists for congenital hypomyelinating neuropathy. A
  PubMed check of `congenital hypomyelinating neuropathy[TI] GeneReviews[TI]`,
  `CNTNAP1 AND GeneReviews[Book]` and `Dejerine-Sottas AND GeneReviews[Book]`
  returns nothing; the CMT1, CMT2 and CMT4 chapters are all marked RETIRED, and
  `Hypomyelination and Congenital Cataract` (PMID:20301737) is a different,
  central-nervous-system disease. The nearest live chapter, the
  Charcot-Marie-Tooth Hereditary Neuropathy Overview (PMID:20301532), is neither
  CHN-specific nor structured into the four minable sections, so it is not cited
  here. This entry is therefore built from primary literature by design, not by
  omission.

  No frequency bands are asserted for the clinical phenotypes. The available
  cited sources are two single-case reports and a series description; neither
  supports a quantitative band, and the frequency SOP says to omit rather than
  to estimate. The one exception is the conduction-velocity phenotype, which is
  OBLIGATE because reduced conduction velocity is part of the cited definition
  of the disorder rather than an observed proportion.

  The primary disease term MONDO:0033352 carries the label "neuropathy,
  congenital hypomelinating" — the misspelling is upstream in MONDO and is
  reproduced verbatim in `term.label` because term labels must match the
  ontology exactly; `preferred_term` carries the corrected spelling.

  MONDO catalogues the EGR2 form as Charcot-Marie-Tooth disease type 4E rather
  than as CHN1, so that is the term bound to the CHN1 subtype. This is an
  ontology-level naming choice, not a claim that the EGR2 form is a CMT4
  recessive demyelinating neuropathy.

  CHN3 (CNTNAP1) is grouped here because MONDO places it under the same parent
  and because it shares the clinical presentation, but its mechanism is
  paranodal axo-glial junction failure rather than compact-myelin failure. Its
  pathophysiology is therefore represented only through the shared conduction
  and clinical nodes; it is deliberately NOT asserted to conform to the
  compact-myelin trigger and mistrafficking nodes, which describe the MPZ/EGR2
  arm.

Congenital Hypomyelinating Neuropathy

Ask OpenScientist

OpenScientist Report

Inheritance

Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Differential Diagnoses

Animal Models

Source YAML