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Charcot-Marie-Tooth disease type 4E(CHN1)

MedGen UID:
Concept ID:
Disease or Syndrome
Synonyms: Charcot-Marie-Tooth Neuropathy Type 4E; CHN1; CMT 4E; Congenital hypomyelinating neuropathy 1, autosomal recessive; Congenital Hypomyelination; Hypomyelination, severe congenital
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
Concept ID:
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Gene (location): EGR2 (10q21.3)
Monarch Initiative: MONDO:0011527
OMIM®: 605253
Orphanet: ORPHA99951


Congenital hypomyelinating neuropathy (CHN) is characterized clinically by onset of hypotonia at birth, areflexia, distal muscle weakness, and very slow nerve conduction velocities (often less than 10 m/s). Warner et al. (1997, 1998) noted that pathologic findings on sural nerve biopsies show hypomyelination of most or all fibers. Based on these findings, CHN is considered to be a result of congenital impairment in myelin formation. There has been some controversy and difficulty in differentiating congenital hypomyelination from Dejerine-Sottas syndrome (DSS; 145900) because there is considerable overlap in clinical presentation. Based on pathologic findings of sural nerve biopsies (the absence of active myelin breakdown and the paucity of the onion bulbs in CHN and the presence of demyelination/remyelination and an abundance of well-organized onion bulbs in DSS; see Balestrini et al., 1991), CHN is considered to result from a congenital impairment in myelin formation, whereas DSS is thought to be due to aberrant demyelination and subsequent remyelination of the peripheral nerve. There is also variation in the prognosis of patients diagnosed with CHN. In patients with CHN, Harati and Butler (1985) showed correlation of morbidity and mortality with the presence/absence of onion bulbs: patients with few onion bulbs died in early infancy, usually because of difficulty in swallowing and respiration after birth. Patients with atypical onion bulbs survived but were affected with severe motor and sensory impairment. These differences in outcome may represent genetic heterogeneity such that mutations in essential early myelin gene(s) cause a severe phenotype, whereas mutations in other, possibly later acting gene(s), such as MPZ, lead to a less severe outcome. Genetic Heterogeneity of Congenital Hypomyelinating Neuropathy See also CHN2 (618184), caused by mutation in the MPZ gene (159440) on chromosome 1q23; and CHN3 (618186), caused by mutation in the CNTNAP1 gene (602346) on chromosome 17q21. [from OMIM]

Clinical features

From HPO
Upper limb muscle weakness
MedGen UID:
Concept ID:
Weakness of the muscles of the arms.
Peripheral neuropathy
MedGen UID:
Concept ID:
Disease or Syndrome
Peripheral neuropathy is a general term for any disorder of the peripheral nervous system. The main clinical features used to classify peripheral neuropathy are distribution, type (mainly demyelinating versus mainly axonal), duration, and course.
MedGen UID:
Concept ID:
Absence of neurologic reflexes such as the knee-jerk reaction.
Onion bulb formation
MedGen UID:
Concept ID:
Repeated episodes of segmental demyelination and remyelination lead to the accumulation of supernumerary Schwann cells around axons, which is referred to as onion bulb formation. This finding affects peripheral nerves.
Motor delay
MedGen UID:
Concept ID:
A type of Developmental delay characterized by a delay in acquiring motor skills.
Abnormal cranial nerve morphology
MedGen UID:
Concept ID:
Anatomical Abnormality
Structural abnormality affecting one or more of the cranial nerves, which emerge directly from the brain stem.
Decreased motor nerve conduction velocity
MedGen UID:
Concept ID:
A type of decreased nerve conduction velocity that affects the motor neuron.
Peripheral hypomyelination
MedGen UID:
Concept ID:
Reduced amount of myelin in the nervous system resulting from defective myelinogenesis in the peripheral nervous system.
Distal muscle weakness
MedGen UID:
Concept ID:
Reduced strength of the musculature of the distal extremities.
Distal amyotrophy
MedGen UID:
Concept ID:
Disease or Syndrome
Muscular atrophy affecting muscles in the distal portions of the extremities.
Neonatal hypotonia
MedGen UID:
Concept ID:
Disease or Syndrome
Muscular hypotonia (abnormally low muscle tone) manifesting in the neonatal period.
Respiratory insufficiency
MedGen UID:
Concept ID:
Pathologic Function
Impairment of gas exchange within the lungs secondary to a disease process, neoplasm, or trauma, possibly resulting in hypoxia, hypercarbia, or both, but not requiring intubation or mechanical ventilation. Patients are normally managed with pharmaceutical therapy, supplemental oxygen, or both.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  

Recent clinical studies


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Clinical prediction guides

Jouaud M, Gonnaud PM, Richard L, Latour P, Ollagnon-Roman E, Sturtz F, Mathis S, Magy L, Vallat JM
Neuromuscul Disord 2016 Apr-May;26(4-5):316-21. Epub 2016 Apr 5 doi: 10.1016/j.nmd.2016.01.004. PMID: 27067623
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Cell Stem Cell 2013 Feb 7;12(2):252-64. doi: 10.1016/j.stem.2012.12.002. PMID: 23395447Free PMC Article
Funalot B, Topilko P, Arroyo MA, Sefiani A, Hedley-Whyte ET, Yoldi ME, Richard L, Touraille E, Laurichesse M, Khalifa E, Chauzeix J, Ouedraogo A, Cros D, Magdelaine C, Sturtz FG, Urtizberea JA, Charnay P, Bragado FG, Vallat JM
Ann Neurol 2012 May;71(5):719-23. doi: 10.1002/ana.23527. PMID: 22522483
Sevilla T, Lupo V, Sivera R, Marco-Marín C, Martínez-Rubio D, Rivas E, Hernández A, Palau F, Espinós C
J Peripher Nerv Syst 2011 Dec;16(4):347-52. doi: 10.1111/j.1529-8027.2011.00369.x. PMID: 22176150

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