Charcot-Marie-Tooth Disease Type 4

Mendelian MONDO:0018995 Pathograph 22 Show in embeddings browser Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease type 4 (CMT4) is the autosomal-recessive compartment of Charcot-Marie-Tooth disease. It is the recessive counterpart of the dominant demyelinating (CMT1) and axonal (CMT2) compartments: the primary lesion is again in the myelinating Schwann cell (most CMT4 subtypes are demyelinating, with slowed nerve conduction and, in several forms, redundant myelin outfoldings or onion-bulb formation on nerve biopsy), but inheritance is autosomal recessive and the clinical course is generally earlier in onset and more severe than in the dominant forms. CMT4 is genetically heterogeneous, with each subtype defined by biallelic loss of a distinct Schwann-cell or neuronal gene: GDAP1 (CMT4A, mitochondrial dynamics), MTMR2 (CMT4B1) and SBF2 / MTMR13 (CMT4B2) in the myotubularin phosphoinositide-phosphatase family, SBF1 / MTMR5 (CMT4B3) completing that family, SH3TC2 (CMT4C, the most common CMT4 subtype and a cause of early-onset scoliosis), NDRG1 (CMT4D / HMSN-Lom), EGR2 (CMT4E, a myelination transcription factor), PRX / periaxin (CMT4F), HK1 (CMT4G / HMSN-Russe), FGD4 / frabin (CMT4H, a Cdc42 exchange factor), FIG4 (CMT4J), and SURF1 (CMT4K, a cytochrome c oxidase assembly factor rather than a myelin or membrane-traffic protein). Several of these genes also cause dominant disease - GDAP1 axonal CMT2K, EGR2 dominant demyelinating CMT - so a gene appearing in both the CMT4 roster and a dominant compartment is expected rather than a contradiction. Whatever the upstream gene, the subtypes converge on the same terminal node as the other CMT compartments — demyelination with secondary, length-dependent axonal degeneration — producing the shared clinical phenotype of distal weakness, wasting, sensory loss, foot deformity, and depressed reflexes.

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Inheritance
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Pathophys.
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Phenotypes
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Pathograph
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Genes
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Medical Actions
12
Subtypes
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Differentials
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References
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Inheritance

1
Autosomal Recessive HP:0000007
By definition, the CMT4 subtypes are inherited in an autosomal recessive manner: affected individuals carry biallelic (homozygous or compound heterozygous) pathogenic variants, most commonly in consanguineous families. Recessive CMT is generally earlier in onset and clinically more severe than the dominant CMT1/CMT2 forms.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:10831399 SUPPORT Human Clinical
"Autosomal recessive peripheral neuropathies are relatively rare but are clinically more severe than autosomal dominant forms of CMT"
Documents autosomal recessive inheritance and the more severe course characteristic of CMT4.
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Subtypes

12
CMT4A (GDAP1-related) MONDO:0008961
GDAP1 hgnc:15968 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in GDAP1 (hgnc:15968). hgnc:15968 is a gene from the HUGO Gene Nomenclature Committee.
Caused by biallelic mutations in GDAP1, which regulates mitochondrial fission and the mitochondrial network. CMT4A can present with axonal or demyelinating (or mixed) pathology and is often associated with vocal cord paresis. The same gene also causes dominant/recessive axonal CMT2K.
Show evidence (1 reference)
PMID:11743580 SUPPORT Human Clinical
"These results establish the molecular etiology of CMT4A (MIM 214400) and suggest that it may be associated with both axonal and demyelinating phenotypes."
Establishes GDAP1 mutations as the molecular cause of CMT4A, with both axonal and demyelinating phenotypes.
CMT4B1 (MTMR2-related) MONDO:0011066
MTMR2 hgnc:7450 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in MTMR2 (hgnc:7450). hgnc:7450 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive demyelinating neuropathy with characteristic focally folded (outfolded) myelin, caused by biallelic mutations in MTMR2 encoding myotubularin-related protein-2, a phosphoinositide (dual-specificity) phosphatase.
Show evidence (1 reference)
PMID:10802647 SUPPORT Human Clinical
"we identified in unrelated CMT4B patients mutations occurring in the gene MTMR2, encoding myotubularin-related protein-2, a dual specificity phosphatase (DSP)."
Establishes MTMR2 mutations as the cause of demyelinating CMT4B (CMT4B1) with myelin outfoldings.
CMT4B2 (SBF2 / MTMR13-related) MONDO:0011475
SBF2 hgnc:2135 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SBF2 (hgnc:2135). hgnc:2135 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive demyelinating neuropathy with myelin outfoldings, in some families associated with early-onset glaucoma, caused by biallelic mutations in SBF2 (MTMR13), a catalytically inactive "pseudophosphatase" member of the myotubularin family.
Show evidence (1 reference)
PMID:12687498 SUPPORT Human Clinical
"a demyelinating CMT, mainly characterized by the presence of myelin outfoldings on nerve biopsies, cosegregated as an autosomal recessive trait with early-onset glaucoma."
Establishes SBF2 / MTMR13 mutations as the cause of demyelinating CMT4B2 with myelin outfoldings and early-onset glaucoma.
CMT4C (SH3TC2-related) MONDO:0011113
SH3TC2 hgnc:29427 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SH3TC2 (hgnc:29427). hgnc:29427 is a gene from the HUGO Gene Nomenclature Committee.
Childhood-onset demyelinating CMT associated with early-onset scoliosis and a distinct Schwann-cell pathology, caused by biallelic mutations in SH3TC2 (originally KIAA1985). CMT4C is the most frequently encountered CMT4 subtype. It also carries a dedicated entry, Charcot-Marie-Tooth Disease Type 4C, which owns the SH3TC2 variant spectrum and allele frequencies; this row and the genetic record below stay at the level the compartment needs.
Show evidence (1 reference)
PMID:14574644 SUPPORT Human Clinical
"Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary motor and sensory neuropathy associated with an early-onset scoliosis and a distinct Schwann cell pathology."
Establishes CMT4C as a childhood-onset demyelinating neuropathy with early-onset scoliosis caused by SH3TC2 (KIAA1985) mutations.
CMT4D / HMSN-Lom (NDRG1-related) MONDO:0011085
NDRG1 hgnc:7679 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in NDRG1 (hgnc:7679). hgnc:7679 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive demyelinating neuropathy (hereditary motor and sensory neuropathy-Lom, HMSNL) with Schwann-cell dysfunction and early axonal involvement, originally described in Roma communities with a founder NDRG1 mutation. It also carries a dedicated entry, Charcot-Marie-Tooth Disease Type 4D, which owns the NDRG1 variant spectrum, the founder-haplotype work and the non-Romani cases; this row and the genetic record below stay at the level the compartment needs.
Show evidence (1 reference)
PMID:10831399 SUPPORT Human Clinical
"identified the founder HMSNL mutation: a premature-termination codon at position 148 of the N-myc downstream-regulated gene 1 (NDRG1)."
Establishes a founder NDRG1 truncating mutation as the cause of HMSN-Lom (CMT4D).
CMT4F (PRX / periaxin-related) MONDO:0013959
PRX hgnc:13797 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in PRX (hgnc:13797). hgnc:13797 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive demyelinating CMT (Dejerine-Sottas-like at the severe end) caused by biallelic mutations in PRX encoding periaxin, a protein of myelinating Schwann cells required for myelin sheath stability.
Show evidence (1 reference)
PMID:11157804 SUPPORT Human Clinical
"a locus responsible for a demyelinating form of ARCMT disease, named CMT4F, has been mapped on 19q13 in a large consanguineous Lebanese family."
Establishes CMT4F as a demyelinating autosomal recessive CMT, subsequently attributed to a PRX (periaxin) nonsense mutation.
CMT4J (FIG4-related) MONDO:0012640
FIG4 hgnc:16873 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in FIG4 (hgnc:16873). hgnc:16873 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive CMT caused by biallelic mutations in FIG4, a phosphatidylinositol-3,5-bisphosphate [PtdIns(3,5)P2] 5-phosphatase that regulates membrane trafficking in the endosome-lysosome axis.
Show evidence (1 reference)
PMID:17572665 SUPPORT Human Clinical
"We identified pathogenic mutations of human FIG4 (KIAA0274) on chromosome 6q21 in four unrelated patients with hereditary motor and sensory neuropathy. This novel form of autosomal recessive Charcot-Marie-Tooth disorder is designated CMT4J."
Establishes biallelic FIG4 mutations as the cause of CMT4J in four unrelated patients.
CMT4B3 (SBF1 / MTMR5-related) MONDO:0014117
SBF1 hgnc:10542 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SBF1 (hgnc:10542). hgnc:10542 is a gene from the HUGO Gene Nomenclature Committee.
The third myotubularin-family CMT4B subtype, caused by biallelic SBF1 variants. This row exists to keep the compartment roster complete and MONDO-anchored; the gene-level curation, evidence and ClinGen assertion for SBF1 live in the dedicated entry Charcot-Marie-Tooth Disease Type 4B3, which names this entry as its parent, and are deliberately not duplicated here.
Show evidence (1 reference)
PMID:20301641 SUPPORT Other
"Detection of biallelic pathogenic variants in one of the following 11 genes establishes the diagnosis: GDAP1 (CMT4A), MTMR2 (CMT4B1), SBF2 (CMT4B2), SBF1 (CMT4B3), SH3TC2 (CMT4C), NDRG1 (CMT4D), EGR2 (CMT4E), PRX (CMT4F), HK1 (CMT4G), FGD4 (CMT4H), and FIG4 (CMT4J)."
The GeneReviews CMT4 gene-to-subtype roster, which assigns SBF1 to CMT4B3.
CMT4E (EGR2-related; congenital hypomyelinating neuropathy) MONDO:0011527
EGR2 hgnc:3239 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in EGR2 (hgnc:3239). hgnc:3239 is a gene from the HUGO Gene Nomenclature Committee.
The transcription-factor subtype. EGR2 encodes a zinc-finger transcription factor whose stable expression is tied to the onset of peripheral myelination, and the recessive EGR2 disease presents as congenital hypomyelinating neuropathy. EGR2 is one of the CMT4 genes that also causes dominant disease: the report that found a recessive EGR2 mutation in congenital hypomyelinating neuropathy found two dominant missense mutations in the same study, one in a Charcot-Marie-Tooth type 1 family, so EGR2 spans the dominant and recessive demyelinating compartments rather than belonging to one.
Show evidence (2 references)
PMID:9537424 SUPPORT Human Clinical
"we have identified one recessive and two dominant missense mutations in EGR2 (within regions encoding conserved functional domains) in patients with congenital hypomyelinating neuropathy (CHN) and a family with Charcot-Marie-Tooth type 1 (CMT1)"
Establishes EGR2 as a hereditary myelinopathy gene with both a recessive allele - the CMT4E side - and dominant alleles, as this description states.
PMID:20301641 SUPPORT Other
"Detection of biallelic pathogenic variants in one of the following 11 genes establishes the diagnosis: GDAP1 (CMT4A), MTMR2 (CMT4B1), SBF2 (CMT4B2), SBF1 (CMT4B3), SH3TC2 (CMT4C), NDRG1 (CMT4D), EGR2 (CMT4E), PRX (CMT4F), HK1 (CMT4G), FGD4 (CMT4H), and FIG4 (CMT4J)."
The GeneReviews CMT4 roster, which assigns EGR2 to CMT4E and confirms that biallelic EGR2 variants are diagnostic within this compartment.
CMT4G / HMSN-Russe (HK1-related) MONDO:0011534
HK1 hgnc:4922 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in HK1 (hgnc:4922). hgnc:4922 is a gene from the HUGO Gene Nomenclature Committee.
Hereditary motor and sensory neuropathy-Russe, a severe autosomal recessive neuropathy first identified in the Roma population and caused by a founder variant in an alternative untranslated exon of HK1. It is one of three autosomal recessive CMT subtypes with mutations private to that population, alongside CMT4C and CMT4D. Unlike every other subtype in this entry, the functional consequence of the CMT4G variant is unresolved: hexokinase activity and peripheral-nerve immunohistochemistry did not differ between patients and controls.
Show evidence (3 references)
PMID:19536174 SUPPORT Human Clinical
"We identified two sequence variants in complete linkage disequilibrium, a G>C in a novel alternative untranslated exon (AltT2) and a G>A in the adjacent intron, segregating with the disease in affected families and present in the heterozygote state in only 5/790 population controls."
The genetic evidence locating the HMSNR variant in an alternative untranslated HK1 exon, with its frequency in population controls.
PMID:19536174 SUPPORT Human Clinical
"Hexokinase activity measurement and immunohistochemistry of the peripheral nerve showed no difference between patients and controls. The mutational mechanism and functional effects remain unknown"
Source for this description's statement that the functional consequence is unresolved, and the reason no upstream mechanism node is curated for HK1.
PMID:23996628 SUPPORT Human Clinical
"There are three subtypes of autosomal recessive CMT with mutations private to the Roma population: CMT4C, CMT4D and CMT4G."
Source for the founder-population statement in this description, naming the three subtypes concerned.
CMT4H (FGD4 / frabin-related) MONDO:0012250
FGD4 hgnc:19125 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in FGD4 (hgnc:19125). hgnc:19125 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive demyelinating CMT caused by biallelic FGD4 mutations. FGD4 encodes frabin, a GDP/GTP nucleotide exchange factor specific to the Rho-family GTPase Cdc42, which places the CMT4H lesion in Schwann-cell actin cytoskeletal regulation rather than in myelin structure or membrane trafficking. It was the first Rho GEF implicated in CMT.
Show evidence (2 references)
PMID:17564959 SUPPORT Human Clinical
"The CMT4H subtype is an autosomal recessive demyelinating form of CMT that was recently mapped to a 15.8-Mb region at chromosome 12p11.21-q13.11, in two consanguineous families of Mediterranean origin, by homozygosity mapping. We report here the identification of mutations in FGD4, encoding FGD4..."
Establishes FGD4 as the CMT4H gene and characterizes the subtype as autosomal recessive and demyelinating.
PMID:17564959 SUPPORT Human Clinical
"To our knowledge, this is the first report of mutations in a Rho GEF protein being involved in CMT."
Source for the statement that FGD4 was the first Rho GEF implicated in CMT.
CMT4K (SURF1-related) MONDO:0014733
SURF1 hgnc:11474 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SURF1 (hgnc:11474). hgnc:11474 is a gene from the HUGO Gene Nomenclature Committee.
Demyelinating CMT4 caused by biallelic SURF1 variants: a cytochrome c oxidase assembly defect rather than a Schwann-cell myelin-maintenance defect. It is not among the eleven genes the GeneReviews CMT4 chapter lists, and its mechanism and course set it apart from the rest of the compartment - the differential_diagnoses entry below carries the distinguishing features. Gene-level curation lives in the dedicated entry Charcot-Marie-Tooth Disease Type 4K and is not duplicated here.
Show evidence (1 reference)
PMID:24027061 SUPPORT Human Clinical
"We found SURF1 mutations in 5% of families (2/41) presenting with CMT4."
Establishes SURF1 as a cause of CMT4 and quantifies its share of an otherwise unsolved CMT4 cohort.
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Pathophysiology

8
GDAP1 Mitochondrial Dynamics Defect
Biallelic GDAP1 mutations (CMT4A) disrupt regulation of the mitochondrial network. GDAP1 promotes mitochondrial fission, and its loss impairs mitochondrial dynamics in Schwann cells and neurons, producing a neuropathy that can be axonal, demyelinating, or mixed and is frequently accompanied by vocal cord paresis.
Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology. Motor neuron CL:0000100 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Motor neuron (CL:0000100). CL:0000100 is a cell type from the Cell Ontology.
GDAP1 hgnc:15968 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GDAP1 (hgnc:15968). hgnc:15968 is a gene from the HUGO Gene Nomenclature Committee.
Mitochondrial fission GO:0000266 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Mitochondrial fission (GO:0000266). GO:0000266 is a biological process from the Gene Ontology.
Downstream
Demyelination and Secondary Axonal Loss GDAP1-driven mitochondrial dysfunction impairs Schwann-cell and axonal homeostasis, converging on demyelination with secondary axonal loss.
Show evidence (1 reference)
PMID:11743580 SUPPORT Human Clinical
"These results establish the molecular etiology of CMT4A (MIM 214400) and suggest that it may be associated with both axonal and demyelinating phenotypes."
Establishes GDAP1 as the CMT4A gene with both axonal and demyelinating phenotypes.
Myotubularin Phosphoinositide Dysregulation and Myelin Outfolding
Biallelic loss of the myotubularin-family phosphoinositide phosphatases MTMR2 (CMT4B1) and SBF2 / MTMR13 (CMT4B2) dysregulates Schwann-cell membrane phosphoinositide turnover. The resulting membrane-trafficking defect produces the redundant, focally folded (outfolded) myelin that is the histological hallmark of CMT4B, and a demyelinating neuropathy.
Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology.
MTMR2 hgnc:7450 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MTMR2 (hgnc:7450). hgnc:7450 is a gene from the HUGO Gene Nomenclature Committee. SBF2 hgnc:2135 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SBF2 (hgnc:2135). hgnc:2135 is a gene from the HUGO Gene Nomenclature Committee.
Phosphatidylinositol dephosphorylation GO:0046856 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Phosphatidylinositol dephosphorylation (GO:0046856). GO:0046856 is a biological process from the Gene Ontology.
Downstream
Demyelination and Secondary Axonal Loss Dysregulated Schwann-cell phosphoinositide metabolism produces myelin outfoldings and demyelination with secondary axonal loss.
Show evidence (2 references)
PMID:10802647 SUPPORT Human Clinical
"A gene mutated in Charcot-Marie-Tooth disease type 4B (CMT4B), an autosomal recessive demyelinating neuropathy with myelin outfoldings, has been mapped on chromosome 11q22."
Establishes CMT4B as an autosomal recessive demyelinating neuropathy with myelin outfoldings; MTMR2 (CMT4B1) is the causal phosphoinositide phosphatase.
PMID:12687498 SUPPORT Human Clinical
"we identified two different nonsense mutations in the myotubularin-related 13 gene, MTMR13."
Establishes SBF2 / MTMR13 loss as the CMT4B2 lesion in the same myotubularin outfolding mechanism.
SH3TC2 Endosomal Recycling Defect in Schwann Cells
Biallelic SH3TC2 (KIAA1985) mutations (CMT4C) disrupt an endosomal-recycling function required for normal Schwann-cell myelination, producing a childhood-onset demyelinating neuropathy with a distinct Schwann-cell pathology and prominent early-onset scoliosis.
Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology.
SH3TC2 hgnc:29427 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SH3TC2 (hgnc:29427). hgnc:29427 is a gene from the HUGO Gene Nomenclature Committee.
Endocytic recycling GO:0032456 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Endocytic recycling (GO:0032456). GO:0032456 is a biological process from the Gene Ontology.
Downstream
Demyelination and Secondary Axonal Loss Impaired SH3TC2-dependent Schwann-cell membrane trafficking produces demyelination with secondary axonal loss.
Show evidence (1 reference)
PMID:14574644 SUPPORT Human Clinical
"We subsequently identified mutations in an uncharacterized transcript, KIAA1985, in 12 families with autosomal recessive neuropathy."
Establishes SH3TC2 (KIAA1985) as the CMT4C gene across 12 autosomal recessive neuropathy families.
Impaired Axon-Glia Interaction
Biallelic loss of Schwann-cell genes NDRG1 (CMT4D / HMSN-Lom) and PRX / periaxin (CMT4F) disrupts myelinating Schwann-cell function and the axon-glia interaction required to maintain the myelin sheath. NDRG1 loss produces Schwann-cell dysfunction with early axonal involvement, and periaxin loss destabilizes the myelin sheath, in both cases yielding a demyelinating neuropathy.
Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology. Sensory neuron of peripheral nervous system CL:0000101 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sensory neuron of peripheral nervous system, annotated with sensory neuron (CL:0000101). CL:0000101 is a cell type from the Cell Ontology.
NDRG1 hgnc:7679 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NDRG1 (hgnc:7679). hgnc:7679 is a gene from the HUGO Gene Nomenclature Committee. PRX hgnc:13797 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PRX (hgnc:13797). hgnc:13797 is a gene from the HUGO Gene Nomenclature Committee.
Myelination in the peripheral nervous system GO:0022011 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Myelination in the peripheral nervous system, annotated with myelination in peripheral nervous system (GO:0022011). GO:0022011 is a biological process from the Gene Ontology.
Downstream
Demyelination and Secondary Axonal Loss Loss of NDRG1- and periaxin-dependent Schwann-cell function impairs myelin maintenance and axon-glia interaction, producing demyelination with secondary axonal loss.
Show evidence (2 references)
PMID:10831399 SUPPORT Human Clinical
"HMSNL shows features of Schwann-cell dysfunction and a concomitant early axonal involvement, suggesting that impaired axon-glia interactions play a major role in its pathogenesis."
Establishes impaired axon-glia interaction from Schwann-cell NDRG1 loss as the CMT4D (HMSN-Lom) mechanism.
PMID:11157804 SUPPORT Model Organism
"L- and S-periaxin are proteins of myelinating Schwann cells and homozygous periaxin-null mice display extensive demyelination of myelinated fibers in the peripheral nervous system"
Periaxin-null mice show extensive PNS demyelination, supporting periaxin's role in Schwann-cell myelin maintenance in CMT4F.
EGR2-Dependent Schwann Cell Differentiation Block
The CMT4E route. EGR2 is a transcription factor whose stable expression is specifically associated with the onset of peripheral myelination, and Egr2 null mice show a block of Schwann-cell differentiation at an early stage. Recessive EGR2 missense mutation in humans produces congenital hypomyelinating neuropathy, a hypomyelinating rather than a demyelinating presentation. Note that the mouse evidence is from a null allele while the human CMT4E allele is missense, so the severity of the differentiation block in patients is an extrapolation, and this node records the program as abnormal rather than abolished.
Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology.
EGR2 hgnc:3239 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves EGR2 (hgnc:3239). hgnc:3239 is a gene from the HUGO Gene Nomenclature Committee.
Schwann cell differentiation GO:0014037 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Schwann cell differentiation (GO:0014037). GO:0014037 is a biological process from the Gene Ontology.
DNA-binding transcription factor activity GO:0003700 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal DNA-binding transcription factor activity (GO:0003700). GO:0003700 is a molecular function from the Gene Ontology.
Downstream
Demyelination and Secondary Axonal Loss A block in Schwann-cell differentiation leaves the axon without a competent myelinating partner, reaching the compartment's shared terminal node by hypomyelination rather than by demyelination of formed myelin.
Show evidence (2 references)
PMID:9537424 SUPPORT Model Organism
"Egr2(-/-) mice display disrupted hindbrain segmentation and development, and a block of Schwann-cell differentiation at an early stage."
The differentiation block this node asserts, measured in the null mouse.
PMID:9537424 SUPPORT BACKGROUND Model Organism
"Stable expression of Egr2 is specifically associated with the onset of myelination in the peripheral nervous system (PNS)."
Establishes the normal timing of Egr2 expression that makes a differentiation block the expected consequence of its loss. The sentence is the study's framing of prior work rather than its own result, hence quote_role BACKGROUND; the expression data it restates are rodent, which is what evidence_source grades.
Frabin Cdc42 Exchange Factor Defect
The CMT4H route. FGD4 encodes frabin, a GDP/GTP nucleotide exchange factor specific to Cdc42, a Rho-family GTPase. Truncated FRABIN mutants expressed in rat primary motoneurons and rat Schwann cells induce significantly fewer microspikes than wild-type protein, placing the lesion in Cdc42-dependent actin remodelling in the myelinating cell rather than in myelin protein structure or in membrane trafficking.
Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology. Motor neuron CL:0000100 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Motor neuron (CL:0000100). CL:0000100 is a cell type from the Cell Ontology.
FGD4 hgnc:19125 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FGD4 (hgnc:19125). hgnc:19125 is a gene from the HUGO Gene Nomenclature Committee.
actin cytoskeleton organization GO:0030036 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal actin cytoskeleton organization (GO:0030036). GO:0030036 is a biological process from the Gene Ontology.
guanyl-nucleotide exchange factor activity GO:0005085 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal guanyl-nucleotide exchange factor activity (GO:0005085). GO:0005085 is a molecular function from the Gene Ontology.
Downstream
Demyelination and Secondary Axonal Loss CMT4H is a demyelinating neuropathy, and the reported functional defect is reduced Cdc42-dependent actin protrusion in Schwann cells and motoneurons. The steps between that cytoskeletal defect and demyelination are not established in the reporting study.
Show evidence (2 references)
PMID:17564959 SUPPORT In Vitro
"expression of truncated FRABIN mutants in rat primary motoneurons and rat Schwann cells induced significantly fewer microspikes than expression of wild-type FRABIN"
The functional measurement this node asserts, in the two cultured cell types bound here.
PMID:17564959 SUPPORT Human Clinical
"FRABIN is a GDP/GTP nucleotide exchange factor (GEF), specific to Cdc42, a member of the Rho family of small guanosine triphosphate (GTP)-binding proteins (Rho GTPases)."
Identifies the molecular function bound on this node and its Cdc42 specificity.
Endosome-Lysosome Trafficking Defect
The CMT4J route, and the reason FIG4 was previously the one CMT4 gene in this entry that reached no mechanism node. FIG4 is a phosphatidylinositol-3,5-bisphosphate 5-phosphatase. Fibroblasts from the Fig4 mutant pale tremor mouse carry an abnormal concentration of PtdIns(3,5)P2 and a cytoplasm filled with large LAMP-2-immunoreactive vacuoles, which the authors read as dysfunction of the late endosome-lysosome axis. FIG4 is a second phosphoinositide lesion in this compartment, alongside the myotubularin lesion of CMT4B1 and CMT4B2, but the pathology reported for it is vacuolar rather than the myelin outfolding that characterizes CMT4B.
FIG4 hgnc:16873 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FIG4 (hgnc:16873). hgnc:16873 is a gene from the HUGO Gene Nomenclature Committee.
phosphatidylinositol dephosphorylation GO:0046856 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal phosphatidylinositol dephosphorylation (GO:0046856). GO:0046856 is a biological process from the Gene Ontology. lysosome organization GO:0007040 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal lysosome organization (GO:0007040). GO:0007040 is a biological process from the Gene Ontology.
phosphatidylinositol-3,5-bisphosphate 5-phosphatase activity GO:0043813 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal phosphatidylinositol-3,5-bisphosphate 5-phosphatase activity (GO:0043813). GO:0043813 is a molecular function from the Gene Ontology.
Downstream
Demyelination and Secondary Axonal Loss The Fig4 mutant mouse sciatic nerve shows reduced numbers of large-diameter myelinated axons with slowed conduction and reduced compound muscle action potential amplitude, the model correlate of this entry's terminal node. The steps from endolysosomal dysfunction to that nerve pathology are not established.
Show evidence (2 references)
PMID:17572665 SUPPORT Model Organism
"The cytoplasm of fibroblasts from pale tremor mice is filled with large vacuoles that are immunoreactive for LAMP-2 (lysosomal-associated membrane protein 2), consistent with dysfunction of the late endosome-lysosome axis."
The endolysosomal phenotype this node asserts, and the basis for the lysosome-organization binding.
PMID:17572665 SUPPORT Model Organism
"The abnormal concentration of PtdIns(3,5)P2 in cultured fibroblasts from pale tremor mice demonstrates the conserved biochemical function of mammalian Fig4."
The phosphoinositide measurement behind the dephosphorylation binding, and the reason the modifier is ABNORMAL rather than directional.
Demyelination and Secondary Axonal Loss
The shared terminal node of the autosomal-recessive CMT4 compartment. The diverse Schwann-cell and neuronal lesions (GDAP1 mitochondrial dysfunction, myotubularin phosphoinositide dysregulation, SH3TC2 trafficking defect, NDRG1 and periaxin loss, the EGR2 differentiation block, the frabin actin-remodelling defect, and the FIG4 endolysosomal defect) converge on demyelination — often with redundant myelin outfoldings or onion-bulb formation — and, over time, length-dependent secondary axonal degeneration. It is this secondary axonal loss, affecting the longest motor and sensory fibers first, that produces the progressive distal clinical deficit shared across all CMT compartments, typically with earlier onset and greater severity in the recessive forms. HK1 (CMT4G) is deliberately not linked to this or any other node: the CMT4G founder variant's functional effect is explicitly unresolved, so what is established for that subtype is an early-onset demyelinating neuropathy, not a mechanism through which the gene acts.
Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology. Sensory neuron of peripheral nervous system CL:0000101 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sensory neuron of peripheral nervous system, annotated with sensory neuron (CL:0000101). CL:0000101 is a cell type from the Cell Ontology.
Myelination in the peripheral nervous system GO:0022011 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Myelination in the peripheral nervous system, annotated with myelination in peripheral nervous system (GO:0022011). GO:0022011 is a biological process from the Gene Ontology.
Downstream
Distal Muscle Weakness
Distal Sensory Loss
Pes Cavus
Decreased Tendon Reflexes
Scoliosis
Show evidence (3 references)
PMID:10831399 SUPPORT Human Clinical
"Autosomal recessive peripheral neuropathies are relatively rare but are clinically more severe than autosomal dominant forms of CMT"
Supports the earlier-onset, more-severe clinical course that distinguishes the recessive CMT4 compartment from dominant CMT.
PMID:23996628 SUPPORT Human Clinical
"We report on the molecular examination of four families of Roma origin in Slovakia with early-onset demyelinating neuropathy and autosomal recessive inheritance."
Supports including the CMT4G families in this shared demyelinating outcome: the established CMT4G finding is early-onset demyelinating neuropathy. HK1 is deliberately not linked to this node, because no mechanism is established for the gene to act through.
PMID:20301641 SUPPORT Other
"Charcot-Marie-Tooth neuropathy type 4 (CMT4) is a group of progressive motor and sensory axonal and demyelinating neuropathies that are distinguished from other forms of CMT by autosomal recessive inheritance."
Supports treating demyelination with secondary axonal involvement as the shared terminal state of the whole recessive compartment.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Charcot-Marie-Tooth Disease Type 4 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

6
Limbs 1
Pes Cavus HP:0001761 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pes cavus (HP:0001761). HP:0001761 is a phenotype from the Human Phenotype Ontology.
Musculoskeletal 2
Distal Muscle Weakness HP:0002460 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal muscle weakness (HP:0002460), qualified as course progressive. HP:0002460 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:11157804 SUPPORT Human Clinical
"Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies characterized by chronic distal weakness with progressive muscular atrophy and sensory loss in the distal extremities."
Supports progressive distal weakness and muscular atrophy as the core CMT phenotype shared by the recessive CMT4 forms.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:14574644 SUPPORT Human Clinical
"Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary motor and sensory neuropathy associated with an early-onset scoliosis and a distinct Schwann cell pathology."
Establishes early-onset scoliosis as a characteristic CMT4C phenotype.
Nervous System 3
Distal Sensory Loss Distal sensory impairment HP:0002936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal sensory impairment (HP:0002936). HP:0002936 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11157804 SUPPORT Human Clinical
"characterized by chronic distal weakness with progressive muscular atrophy and sensory loss in the distal extremities."
Supports distal sensory loss as part of the shared CMT sensorimotor phenotype.
Decreased Tendon Reflexes Hyporeflexia HP:0001265 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyporeflexia (HP:0001265). HP:0001265 is a phenotype from the Human Phenotype Ontology.
Onion Bulb Formation HP:0003383 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Onion bulb formation (HP:0003383). HP:0003383 is a phenotype from the Human Phenotype Ontology.
🧬

Genetic Associations

10
GDAP1 (Causal)
Gene: GDAP1 hgnc:15968 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GDAP1 (hgnc:15968). hgnc:15968 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:11743580 SUPPORT Human Clinical
"These results establish the molecular etiology of CMT4A (MIM 214400) and suggest that it may be associated with both axonal and demyelinating phenotypes."
Establishes GDAP1 as the CMT4A gene.
MTMR2 (Causal)
Gene: MTMR2 hgnc:7450 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MTMR2 (hgnc:7450). hgnc:7450 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:10802647 SUPPORT Human Clinical
"we identified in unrelated CMT4B patients mutations occurring in the gene MTMR2, encoding myotubularin-related protein-2, a dual specificity phosphatase (DSP)."
Establishes MTMR2 as the CMT4B1 gene.
SBF2 (Causal)
Gene: SBF2 hgnc:2135 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SBF2 (hgnc:2135). hgnc:2135 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:12687498 SUPPORT Human Clinical
"we identified two different nonsense mutations in the myotubularin-related 13 gene, MTMR13."
Establishes SBF2 / MTMR13 as the CMT4B2 gene.
SH3TC2 (Causal)
Gene: SH3TC2 hgnc:29427 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SH3TC2 (hgnc:29427). hgnc:29427 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:14574644 SUPPORT Human Clinical
"We subsequently identified mutations in an uncharacterized transcript, KIAA1985, in 12 families with autosomal recessive neuropathy."
Establishes SH3TC2 (KIAA1985) as the CMT4C gene.
NDRG1 (Causal)
Gene: NDRG1 hgnc:7679 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NDRG1 (hgnc:7679). hgnc:7679 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:10831399 SUPPORT Human Clinical
"identified the founder HMSNL mutation: a premature-termination codon at position 148 of the N-myc downstream-regulated gene 1 (NDRG1)."
Establishes NDRG1 as the CMT4D (HMSN-Lom) gene.
PRX (Causal)
Gene: PRX hgnc:13797 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PRX (hgnc:13797). hgnc:13797 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:11157804 SUPPORT Human Clinical
"we identified a nonsense R196X mutation in the Lebanese family which cosegregated with CMT."
Establishes a PRX (periaxin) nonsense mutation cosegregating with CMT4F.
FIG4 (Causal)
Gene: FIG4 hgnc:16873 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FIG4 (hgnc:16873). hgnc:16873 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:17572665 SUPPORT Human Clinical
"We identified pathogenic mutations of human FIG4 (KIAA0274) on chromosome 6q21 in four unrelated patients with hereditary motor and sensory neuropathy. This novel form of autosomal recessive Charcot-Marie-Tooth disorder is designated CMT4J."
Establishes FIG4 as the CMT4J gene in four unrelated patients.
EGR2 (Causal)
Gene: EGR2 hgnc:3239 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is EGR2 (hgnc:3239). hgnc:3239 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:9537424 SUPPORT Human Clinical
"we have identified one recessive and two dominant missense mutations in EGR2 (within regions encoding conserved functional domains) in patients with congenital hypomyelinating neuropathy (CHN) and a family with Charcot-Marie-Tooth type 1 (CMT1)"
Establishes EGR2 as causal for hereditary myelinopathy in both recessive and dominant form, which is why this record says the gene is shared.
HK1 (Causal)
Gene: HK1 hgnc:4922 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is HK1 (hgnc:4922). hgnc:4922 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:19536174 SUPPORT Human Clinical
"Sequence conservation of the AltT2 exon in 16 species with invariable preservation of the G allele at the mutated site, strongly favour the exonic change as the pathogenic mutation."
The conservation argument the authors use to nominate the exonic variant as pathogenic, which is the strength of the causal claim available here.
PMID:23996628 SUPPORT Human Clinical
"We detected mutation p.R148X (g.631C>T) in the NDRG1 (NM_006096.3) gene in two families and mutation g.9712G>C in the HK1 (NM_033498) gene in the other two families. These mutations cause CMT4D and CMT4G, respectively."
Independent replication of the HK1 founder variant in CMT4G families, in a cohort separate from the original HMSNR mapping study.
FGD4 (Causal)
Gene: FGD4 hgnc:19125 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FGD4 (hgnc:19125). hgnc:19125 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:17564959 SUPPORT Human Clinical
"We report here the identification of mutations in FGD4, encoding FGD4 or FRABIN (FGD1-related F-actin binding protein), in both families."
Establishes FGD4 as the CMT4H gene in the two mapped consanguineous families.
PMID:17564959 SUPPORT In Vitro
"expression of truncated FRABIN mutants in rat primary motoneurons and rat Schwann cells induced significantly fewer microspikes than expression of wild-type FRABIN"
The cell-culture measurement behind this record's mechanistic statement, and the evidence for the FGD4 pathophysiology node.
💊

Medical Actions

4
Physical and Occupational Therapy
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Mainstay of supportive care to maintain mobility and function.
Orthotic Bracing
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Ankle-foot orthoses to compensate for foot drop and improve gait.
Scoliosis Management
Action: orthopedic surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is orthopedic surgical procedure (NCIT:C16186). NCIT:C16186 is a clinical intervention from the NCI Thesaurus. Ontology label: Orthopedic Surgical Procedure NCIT:C16186
Bracing and, when required, corrective spinal surgery for the early-onset scoliosis that is prominent in CMT4C.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counseling for affected individuals and families, with attention to the recessive inheritance pattern, recurrence risk in consanguineous unions, and carrier testing.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Charcot-Marie-Tooth Disease Type 4:

Charcot-Marie-Tooth Disease Type 4K
Overlapping Features CMT4K (MONDO:0014733, SURF1-related) is a cytochrome c oxidase assembly defect rather than a Schwann-cell myelin-maintenance defect, and is distinguished clinically by lactic acidosis and by putaminal and periaqueductal lesions developing years after the neuropathy — features no other CMT4 subtype shows. It is listed in the has_subtypes roster above, because it is a hierarchical MONDO descendant of this entry's own term, and is kept here as well for those distinguishing features. Four subtypes of this compartment carry dedicated dismech entries - CMT4B3, CMT4C, CMT4D and CMT4K.
Distinguishing Features
  • Lactic acidosis
  • Putaminal and periaqueductal brain MRI lesions
  • Cerebellar ataxia developing years after the polyneuropathy
Show evidence (1 reference)
PMID:24027061 SUPPORT Human Clinical
"We found SURF1 mutations in 5% of families (2/41) presenting with CMT4."
Establishes SURF1 as a cause of CMT4 and quantifies its share of otherwise unsolved CMT4.
{ }

Source YAML

click to show 
name: Charcot-Marie-Tooth Disease Type 4
creation_date: "2026-07-31T00:00:00Z"
category: Mendelian
description: >-
  Charcot-Marie-Tooth disease type 4 (CMT4) is the autosomal-recessive
  compartment of Charcot-Marie-Tooth disease. It is the recessive counterpart of
  the dominant demyelinating (CMT1) and axonal (CMT2) compartments: the primary
  lesion is again in the myelinating Schwann cell (most CMT4 subtypes are
  demyelinating, with slowed nerve conduction and, in several forms, redundant
  myelin outfoldings or onion-bulb formation on nerve biopsy), but inheritance is
  autosomal recessive and the clinical course is generally earlier in onset and
  more severe than in the dominant forms. CMT4 is genetically heterogeneous, with
  each subtype defined by biallelic loss of a distinct Schwann-cell or
  neuronal gene: GDAP1 (CMT4A, mitochondrial dynamics), MTMR2 (CMT4B1) and SBF2 /
  MTMR13 (CMT4B2) in the myotubularin phosphoinositide-phosphatase family,
  SBF1 / MTMR5 (CMT4B3) completing that family, SH3TC2 (CMT4C, the most common
  CMT4 subtype and a cause of early-onset
  scoliosis), NDRG1 (CMT4D / HMSN-Lom), EGR2 (CMT4E, a myelination transcription
  factor), PRX / periaxin (CMT4F), HK1 (CMT4G / HMSN-Russe), FGD4 / frabin
  (CMT4H, a Cdc42 exchange factor), FIG4 (CMT4J), and SURF1 (CMT4K, a
  cytochrome c oxidase assembly factor rather than a myelin or membrane-traffic
  protein). Several of these genes also cause
  dominant disease - GDAP1 axonal CMT2K, EGR2 dominant demyelinating CMT - so a
  gene appearing in both the CMT4 roster and a dominant compartment is expected
  rather than a contradiction.
  Whatever the upstream gene, the subtypes converge on the same terminal node as
  the other CMT compartments — demyelination with secondary, length-dependent
  axonal degeneration — producing the shared clinical phenotype of distal
  weakness, wasting, sensory loss, foot deformity, and depressed reflexes.
disease_term:
  preferred_term: Autosomal recessive Charcot-Marie-Tooth disease (CMT4)
  term:
    id: MONDO:0018995
    label: Charcot-Marie-Tooth disease type 4
parents:
- Charcot-Marie-Tooth disease
has_subtypes:
- name: CMT4A
  display_name: CMT4A (GDAP1-related)
  subtype_term:
    preferred_term: Charcot-Marie-Tooth disease type 4A
    term:
      id: MONDO:0008961
      label: Charcot-Marie-Tooth disease type 4A
  genes:
  - preferred_term: GDAP1
    term:
      id: hgnc:15968
      label: GDAP1
  description: >-
    Caused by biallelic mutations in GDAP1, which regulates mitochondrial
    fission and the mitochondrial network. CMT4A can present with axonal or
    demyelinating (or mixed) pathology and is often associated with vocal cord
    paresis. The same gene also causes dominant/recessive axonal CMT2K.
  evidence:
  - reference: PMID:11743580
    reference_title: "The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results establish the molecular etiology of CMT4A (MIM 214400) and suggest that it may be associated with both axonal and demyelinating phenotypes."
    explanation: Establishes GDAP1 mutations as the molecular cause of CMT4A, with both axonal and demyelinating phenotypes.
- name: CMT4B1
  display_name: CMT4B1 (MTMR2-related)
  subtype_term:
    preferred_term: Charcot-Marie-Tooth disease type 4B1
    term:
      id: MONDO:0011066
      label: Charcot-Marie-Tooth disease type 4B1
  genes:
  - preferred_term: MTMR2
    term:
      id: hgnc:7450
      label: MTMR2
  description: >-
    Autosomal recessive demyelinating neuropathy with characteristic focally
    folded (outfolded) myelin, caused by biallelic mutations in MTMR2 encoding
    myotubularin-related protein-2, a phosphoinositide (dual-specificity)
    phosphatase.
  evidence:
  - reference: PMID:10802647
    reference_title: "Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified in unrelated CMT4B patients mutations occurring in the gene MTMR2, encoding myotubularin-related protein-2, a dual specificity phosphatase (DSP)."
    explanation: Establishes MTMR2 mutations as the cause of demyelinating CMT4B (CMT4B1) with myelin outfoldings.
- name: CMT4B2
  display_name: CMT4B2 (SBF2 / MTMR13-related)
  subtype_term:
    preferred_term: Charcot-Marie-Tooth disease type 4B2
    term:
      id: MONDO:0011475
      label: Charcot-Marie-Tooth disease type 4B2
  genes:
  - preferred_term: SBF2
    term:
      id: hgnc:2135
      label: SBF2
  description: >-
    Autosomal recessive demyelinating neuropathy with myelin outfoldings, in
    some families associated with early-onset glaucoma, caused by biallelic
    mutations in SBF2 (MTMR13), a catalytically inactive "pseudophosphatase"
    member of the myotubularin family.
  evidence:
  - reference: PMID:12687498
    reference_title: "Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a demyelinating CMT, mainly characterized by the presence of myelin outfoldings on nerve biopsies, cosegregated as an autosomal recessive trait with early-onset glaucoma."
    explanation: Establishes SBF2 / MTMR13 mutations as the cause of demyelinating CMT4B2 with myelin outfoldings and early-onset glaucoma.
- name: CMT4C
  display_name: CMT4C (SH3TC2-related)
  subtype_term:
    preferred_term: Charcot-Marie-Tooth disease type 4C
    term:
      id: MONDO:0011113
      label: Charcot-Marie-Tooth disease type 4C
  genes:
  - preferred_term: SH3TC2
    term:
      id: hgnc:29427
      label: SH3TC2
  description: >-
    Childhood-onset demyelinating CMT associated with early-onset scoliosis and
    a distinct Schwann-cell pathology, caused by biallelic mutations in SH3TC2
    (originally KIAA1985). CMT4C is the most frequently encountered CMT4 subtype.
    It also carries a dedicated entry, Charcot-Marie-Tooth Disease Type 4C, which
    owns the SH3TC2 variant spectrum and allele frequencies; this row and the
    genetic record below stay at the level the compartment needs.
  evidence:
  - reference: PMID:14574644
    reference_title: "Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary motor and sensory neuropathy associated with an early-onset scoliosis and a distinct Schwann cell pathology."
    explanation: Establishes CMT4C as a childhood-onset demyelinating neuropathy with early-onset scoliosis caused by SH3TC2 (KIAA1985) mutations.
- name: CMT4D
  display_name: CMT4D / HMSN-Lom (NDRG1-related)
  subtype_term:
    preferred_term: Charcot-Marie-Tooth disease type 4D
    term:
      id: MONDO:0011085
      label: Charcot-Marie-Tooth disease type 4D
  genes:
  - preferred_term: NDRG1
    term:
      id: hgnc:7679
      label: NDRG1
  description: >-
    Autosomal recessive demyelinating neuropathy (hereditary motor and sensory
    neuropathy-Lom, HMSNL) with Schwann-cell dysfunction and early axonal
    involvement, originally described in Roma communities with a founder NDRG1
    mutation. It also carries a dedicated entry, Charcot-Marie-Tooth Disease Type
    4D, which owns the NDRG1 variant spectrum, the founder-haplotype work and the
    non-Romani cases; this row and the genetic record below stay at the level the
    compartment needs.
  evidence:
  - reference: PMID:10831399
    reference_title: "N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified the founder HMSNL mutation: a premature-termination codon at position 148 of the N-myc downstream-regulated gene 1 (NDRG1)."
    explanation: Establishes a founder NDRG1 truncating mutation as the cause of HMSN-Lom (CMT4D).
- name: CMT4F
  display_name: CMT4F (PRX / periaxin-related)
  subtype_term:
    preferred_term: Charcot-Marie-Tooth disease type 4F
    term:
      id: MONDO:0013959
      label: Charcot-Marie-Tooth disease type 4F
  genes:
  - preferred_term: PRX
    term:
      id: hgnc:13797
      label: PRX
  description: >-
    Autosomal recessive demyelinating CMT (Dejerine-Sottas-like at the severe
    end) caused by biallelic mutations in PRX encoding periaxin, a protein of
    myelinating Schwann cells required for myelin sheath stability.
  evidence:
  - reference: PMID:11157804
    reference_title: "A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a locus responsible for a demyelinating form of ARCMT disease, named CMT4F, has been mapped on 19q13 in a large consanguineous Lebanese family."
    explanation: Establishes CMT4F as a demyelinating autosomal recessive CMT, subsequently attributed to a PRX (periaxin) nonsense mutation.
- name: CMT4J
  display_name: CMT4J (FIG4-related)
  subtype_term:
    preferred_term: Charcot-Marie-Tooth disease type 4J
    term:
      id: MONDO:0012640
      label: Charcot-Marie-Tooth disease type 4J
  genes:
  - preferred_term: FIG4
    term:
      id: hgnc:16873
      label: FIG4
  description: >-
    Autosomal recessive CMT caused by biallelic mutations in FIG4, a
    phosphatidylinositol-3,5-bisphosphate [PtdIns(3,5)P2] 5-phosphatase that
    regulates membrane trafficking in the endosome-lysosome axis.
  evidence:
  - reference: PMID:17572665
    reference_title: "Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified pathogenic mutations of human FIG4 (KIAA0274) on chromosome 6q21 in four unrelated patients with hereditary motor and sensory neuropathy. This novel form of autosomal recessive Charcot-Marie-Tooth disorder is designated CMT4J."
    explanation: Establishes biallelic FIG4 mutations as the cause of CMT4J in four unrelated patients.
- name: CMT4B3
  display_name: CMT4B3 (SBF1 / MTMR5-related)
  subtype_term:
    preferred_term: Charcot-Marie-Tooth disease type 4B3
    term:
      id: MONDO:0014117
      label: Charcot-Marie-Tooth disease type 4B3
  genes:
  - preferred_term: SBF1
    term:
      id: hgnc:10542
      label: SBF1
  description: >-
    The third myotubularin-family CMT4B subtype, caused by biallelic SBF1
    variants. This row exists to keep the compartment roster complete and
    MONDO-anchored; the gene-level curation, evidence and ClinGen assertion for
    SBF1 live in the dedicated entry Charcot-Marie-Tooth Disease Type 4B3, which
    names this entry as its parent, and are deliberately not duplicated here.
  evidence:
  - reference: PMID:20301641
    reference_title: "Charcot-Marie-Tooth Neuropathy Type 4 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Detection of biallelic pathogenic variants in one of the following 11 genes establishes the diagnosis: GDAP1 (CMT4A), MTMR2 (CMT4B1), SBF2 (CMT4B2), SBF1 (CMT4B3), SH3TC2 (CMT4C), NDRG1 (CMT4D), EGR2 (CMT4E), PRX (CMT4F), HK1 (CMT4G), FGD4 (CMT4H), and FIG4 (CMT4J)."
    explanation: >-
      The GeneReviews CMT4 gene-to-subtype roster, which assigns SBF1 to CMT4B3.
- name: CMT4E
  display_name: CMT4E (EGR2-related; congenital hypomyelinating neuropathy)
  subtype_term:
    preferred_term: Charcot-Marie-Tooth disease type 4E
    term:
      id: MONDO:0011527
      label: Charcot-Marie-Tooth disease type 4E
  genes:
  - preferred_term: EGR2
    term:
      id: hgnc:3239
      label: EGR2
  description: >-
    The transcription-factor subtype. EGR2 encodes a zinc-finger transcription
    factor whose stable expression is tied to the onset of peripheral
    myelination, and the recessive EGR2 disease presents as congenital
    hypomyelinating neuropathy. EGR2 is one of the CMT4 genes that also causes
    dominant disease: the report that found a recessive EGR2 mutation in
    congenital hypomyelinating neuropathy found two dominant missense mutations
    in the same study, one in a Charcot-Marie-Tooth type 1 family, so EGR2 spans
    the dominant and recessive demyelinating compartments rather than belonging
    to one.
  evidence:
  - reference: PMID:9537424
    reference_title: "Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we have identified one recessive and two dominant missense mutations in EGR2 (within regions encoding conserved functional domains) in patients with congenital hypomyelinating neuropathy (CHN) and a family with Charcot-Marie-Tooth type 1 (CMT1)"
    explanation: >-
      Establishes EGR2 as a hereditary myelinopathy gene with both a recessive
      allele - the CMT4E side - and dominant alleles, as this description states.
  - reference: PMID:20301641
    reference_title: "Charcot-Marie-Tooth Neuropathy Type 4 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Detection of biallelic pathogenic variants in one of the following 11 genes establishes the diagnosis: GDAP1 (CMT4A), MTMR2 (CMT4B1), SBF2 (CMT4B2), SBF1 (CMT4B3), SH3TC2 (CMT4C), NDRG1 (CMT4D), EGR2 (CMT4E), PRX (CMT4F), HK1 (CMT4G), FGD4 (CMT4H), and FIG4 (CMT4J)."
    explanation: >-
      The GeneReviews CMT4 roster, which assigns EGR2 to CMT4E and confirms that
      biallelic EGR2 variants are diagnostic within this compartment.
- name: CMT4G
  display_name: CMT4G / HMSN-Russe (HK1-related)
  subtype_term:
    preferred_term: Charcot-Marie-Tooth disease type 4G
    term:
      id: MONDO:0011534
      label: Charcot-Marie-Tooth disease type 4G
  genes:
  - preferred_term: HK1
    term:
      id: hgnc:4922
      label: HK1
  description: >-
    Hereditary motor and sensory neuropathy-Russe, a severe autosomal recessive
    neuropathy first identified in the Roma population and caused by a founder
    variant in an alternative untranslated exon of HK1. It is one of three
    autosomal recessive CMT subtypes with mutations private to that population,
    alongside CMT4C and CMT4D. Unlike every other subtype in this entry, the
    functional consequence of the CMT4G variant is unresolved: hexokinase
    activity and peripheral-nerve immunohistochemistry did not differ between
    patients and controls.
  evidence:
  - reference: PMID:19536174
    reference_title: "A mutation in an alternative untranslated exon of hexokinase 1 associated with hereditary motor and sensory neuropathy -- Russe (HMSNR)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified two sequence variants in complete linkage disequilibrium, a G>C in a novel alternative untranslated exon (AltT2) and a G>A in the adjacent intron, segregating with the disease in affected families and present in the heterozygote state in only 5/790 population controls."
    explanation: >-
      The genetic evidence locating the HMSNR variant in an alternative
      untranslated HK1 exon, with its frequency in population controls.
  - reference: PMID:19536174
    reference_title: "A mutation in an alternative untranslated exon of hexokinase 1 associated with hereditary motor and sensory neuropathy -- Russe (HMSNR)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hexokinase activity measurement and immunohistochemistry of the peripheral nerve showed no difference between patients and controls. The mutational mechanism and functional effects remain unknown"
    explanation: >-
      Source for this description's statement that the functional consequence is
      unresolved, and the reason no upstream mechanism node is curated for HK1.
  - reference: PMID:23996628
    reference_title: "Founder mutations in NDRG1 and HK1 genes are common causes of inherited neuropathies among Roma/Gypsies in Slovakia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There are three subtypes of autosomal recessive CMT with mutations private to the Roma population: CMT4C, CMT4D and CMT4G."
    explanation: >-
      Source for the founder-population statement in this description, naming
      the three subtypes concerned.
- name: CMT4H
  display_name: CMT4H (FGD4 / frabin-related)
  subtype_term:
    preferred_term: Charcot-Marie-Tooth disease type 4H
    term:
      id: MONDO:0012250
      label: Charcot-Marie-Tooth disease type 4H
  genes:
  - preferred_term: FGD4
    term:
      id: hgnc:19125
      label: FGD4
  description: >-
    Autosomal recessive demyelinating CMT caused by biallelic FGD4 mutations.
    FGD4 encodes frabin, a GDP/GTP nucleotide exchange factor specific to the
    Rho-family GTPase Cdc42, which places the CMT4H lesion in Schwann-cell actin
    cytoskeletal regulation rather than in myelin structure or membrane
    trafficking. It was the first Rho GEF implicated in CMT.
  evidence:
  - reference: PMID:17564959
    reference_title: "Mutations in FGD4 encoding the Rho GDP/GTP exchange factor FRABIN cause autosomal recessive Charcot-Marie-Tooth type 4H."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The CMT4H subtype is an autosomal recessive demyelinating form of CMT that was recently mapped to a 15.8-Mb region at chromosome 12p11.21-q13.11, in two consanguineous families of Mediterranean origin, by homozygosity mapping. We report here the identification of mutations in FGD4, encoding FGD4 or FRABIN (FGD1-related F-actin binding protein), in both families."
    explanation: >-
      Establishes FGD4 as the CMT4H gene and characterizes the subtype as
      autosomal recessive and demyelinating.
  - reference: PMID:17564959
    reference_title: "Mutations in FGD4 encoding the Rho GDP/GTP exchange factor FRABIN cause autosomal recessive Charcot-Marie-Tooth type 4H."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To our knowledge, this is the first report of mutations in a Rho GEF protein being involved in CMT."
    explanation: >-
      Source for the statement that FGD4 was the first Rho GEF implicated in CMT.
- name: CMT4K
  display_name: CMT4K (SURF1-related)
  subtype_term:
    preferred_term: Charcot-Marie-Tooth disease type 4K
    term:
      id: MONDO:0014733
      label: Charcot-Marie-Tooth disease type 4K
  genes:
  - preferred_term: SURF1
    term:
      id: hgnc:11474
      label: SURF1
  description: >-
    Demyelinating CMT4 caused by biallelic SURF1 variants: a cytochrome c
    oxidase assembly defect rather than a Schwann-cell myelin-maintenance defect.
    It is not among the eleven genes the GeneReviews CMT4 chapter lists, and its
    mechanism and course set it apart from the rest of the compartment - the
    differential_diagnoses entry below carries the distinguishing features.
    Gene-level curation lives in the dedicated entry Charcot-Marie-Tooth Disease
    Type 4K and is not duplicated here.
  evidence:
  - reference: PMID:24027061
    reference_title: "SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found SURF1 mutations in 5% of families (2/41) presenting with CMT4."
    explanation: >-
      Establishes SURF1 as a cause of CMT4 and quantifies its share of an
      otherwise unsolved CMT4 cohort.
pathophysiology:
- name: GDAP1 Mitochondrial Dynamics Defect
  description: >-
    Biallelic GDAP1 mutations (CMT4A) disrupt regulation of the mitochondrial
    network. GDAP1 promotes mitochondrial fission, and its loss impairs
    mitochondrial dynamics in Schwann cells and neurons, producing a neuropathy
    that can be axonal, demyelinating, or mixed and is frequently accompanied by
    vocal cord paresis.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  - preferred_term: Motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  biological_processes:
  - preferred_term: Mitochondrial fission
    term:
      id: GO:0000266
      label: mitochondrial fission
    modifier: ABNORMAL
  genes:
  - preferred_term: GDAP1
    term:
      id: hgnc:15968
      label: GDAP1
  downstream:
  - target: Demyelination and Secondary Axonal Loss
    description: >-
      GDAP1-driven mitochondrial dysfunction impairs Schwann-cell and axonal
      homeostasis, converging on demyelination with secondary axonal loss.
  evidence:
  - reference: PMID:11743580
    reference_title: "The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results establish the molecular etiology of CMT4A (MIM 214400) and suggest that it may be associated with both axonal and demyelinating phenotypes."
    explanation: Establishes GDAP1 as the CMT4A gene with both axonal and demyelinating phenotypes.
- name: Myotubularin Phosphoinositide Dysregulation and Myelin Outfolding
  conforms_to: "schwann_cell_myelin_maintenance#Myelin Gene Dosage or Structural Lesion in Schwann Cells"
  description: >-
    Biallelic loss of the myotubularin-family phosphoinositide phosphatases MTMR2
    (CMT4B1) and SBF2 / MTMR13 (CMT4B2) dysregulates Schwann-cell membrane
    phosphoinositide turnover. The resulting membrane-trafficking defect produces
    the redundant, focally folded (outfolded) myelin that is the histological
    hallmark of CMT4B, and a demyelinating neuropathy.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: Phosphatidylinositol dephosphorylation
    term:
      id: GO:0046856
      label: phosphatidylinositol dephosphorylation
    modifier: ABNORMAL
  genes:
  - preferred_term: MTMR2
    term:
      id: hgnc:7450
      label: MTMR2
  - preferred_term: SBF2
    term:
      id: hgnc:2135
      label: SBF2
  downstream:
  - target: Demyelination and Secondary Axonal Loss
    description: >-
      Dysregulated Schwann-cell phosphoinositide metabolism produces myelin
      outfoldings and demyelination with secondary axonal loss.
  evidence:
  - reference: PMID:10802647
    reference_title: "Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A gene mutated in Charcot-Marie-Tooth disease type 4B (CMT4B), an autosomal recessive demyelinating neuropathy with myelin outfoldings, has been mapped on chromosome 11q22."
    explanation: Establishes CMT4B as an autosomal recessive demyelinating neuropathy with myelin outfoldings; MTMR2 (CMT4B1) is the causal phosphoinositide phosphatase.
  - reference: PMID:12687498
    reference_title: "Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified two different nonsense mutations in the myotubularin-related 13 gene, MTMR13."
    explanation: Establishes SBF2 / MTMR13 loss as the CMT4B2 lesion in the same myotubularin outfolding mechanism.
- name: SH3TC2 Endosomal Recycling Defect in Schwann Cells
  conforms_to: "schwann_cell_myelin_maintenance#Myelin Gene Dosage or Structural Lesion in Schwann Cells"
  description: >-
    Biallelic SH3TC2 (KIAA1985) mutations (CMT4C) disrupt an endosomal-recycling
    function required for normal Schwann-cell myelination, producing a
    childhood-onset demyelinating neuropathy with a distinct Schwann-cell
    pathology and prominent early-onset scoliosis.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: Endocytic recycling
    term:
      id: GO:0032456
      label: endocytic recycling
    modifier: ABNORMAL
  genes:
  - preferred_term: SH3TC2
    term:
      id: hgnc:29427
      label: SH3TC2
  downstream:
  - target: Demyelination and Secondary Axonal Loss
    description: >-
      Impaired SH3TC2-dependent Schwann-cell membrane trafficking produces
      demyelination with secondary axonal loss.
  evidence:
  - reference: PMID:14574644
    reference_title: "Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We subsequently identified mutations in an uncharacterized transcript, KIAA1985, in 12 families with autosomal recessive neuropathy."
    explanation: Establishes SH3TC2 (KIAA1985) as the CMT4C gene across 12 autosomal recessive neuropathy families.
- name: Impaired Axon-Glia Interaction
  conforms_to: "schwann_cell_myelin_maintenance#Myelin Gene Dosage or Structural Lesion in Schwann Cells"
  description: >-
    Biallelic loss of Schwann-cell genes NDRG1 (CMT4D / HMSN-Lom) and PRX /
    periaxin (CMT4F) disrupts myelinating Schwann-cell function and the
    axon-glia interaction required to maintain the myelin sheath. NDRG1 loss
    produces Schwann-cell dysfunction with early axonal involvement, and
    periaxin loss destabilizes the myelin sheath, in both cases yielding a
    demyelinating neuropathy.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  - preferred_term: Sensory neuron of peripheral nervous system
    term:
      id: CL:0000101
      label: sensory neuron
  biological_processes:
  - preferred_term: Myelination in the peripheral nervous system
    term:
      id: GO:0022011
      label: myelination in peripheral nervous system
    modifier: DECREASED
  genes:
  - preferred_term: NDRG1
    term:
      id: hgnc:7679
      label: NDRG1
  - preferred_term: PRX
    term:
      id: hgnc:13797
      label: PRX
  downstream:
  - target: Demyelination and Secondary Axonal Loss
    description: >-
      Loss of NDRG1- and periaxin-dependent Schwann-cell function impairs
      myelin maintenance and axon-glia interaction, producing demyelination
      with secondary axonal loss.
  evidence:
  - reference: PMID:10831399
    reference_title: "N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HMSNL shows features of Schwann-cell dysfunction and a concomitant early axonal involvement, suggesting that impaired axon-glia interactions play a major role in its pathogenesis."
    explanation: Establishes impaired axon-glia interaction from Schwann-cell NDRG1 loss as the CMT4D (HMSN-Lom) mechanism.
  - reference: PMID:11157804
    reference_title: "A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "L- and S-periaxin are proteins of myelinating Schwann cells and homozygous periaxin-null mice display extensive demyelination of myelinated fibers in the peripheral nervous system"
    explanation: Periaxin-null mice show extensive PNS demyelination, supporting periaxin's role in Schwann-cell myelin maintenance in CMT4F.
- name: EGR2-Dependent Schwann Cell Differentiation Block
  conforms_to: "schwann_cell_myelin_maintenance#Myelin Gene Dosage or Structural Lesion in Schwann Cells"
  description: >-
    The CMT4E route. EGR2 is a transcription factor whose stable expression is
    specifically associated with the onset of peripheral myelination, and Egr2
    null mice show a block of Schwann-cell differentiation at an early stage.
    Recessive EGR2 missense mutation in humans produces congenital
    hypomyelinating neuropathy, a hypomyelinating rather than a demyelinating
    presentation. Note that the mouse evidence is from a null allele while the
    human CMT4E allele is missense, so the severity of the differentiation block
    in patients is an extrapolation, and this node records the program as
    abnormal rather than abolished.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  molecular_functions:
  - preferred_term: DNA-binding transcription factor activity
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    modifier: ABNORMAL
  biological_processes:
  - preferred_term: Schwann cell differentiation
    term:
      id: GO:0014037
      label: Schwann cell differentiation
    modifier: ABNORMAL
  genes:
  - preferred_term: EGR2
    term:
      id: hgnc:3239
      label: EGR2
  downstream:
  - target: Demyelination and Secondary Axonal Loss
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Failure of the Schwann-cell differentiation step that precedes myelin gene expression.
    description: >-
      A block in Schwann-cell differentiation leaves the axon without a competent
      myelinating partner, reaching the compartment's shared terminal node by
      hypomyelination rather than by demyelination of formed myelin.
    evidence:
    - reference: PMID:9537424
      reference_title: "Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we have identified one recessive and two dominant missense mutations in EGR2 (within regions encoding conserved functional domains) in patients with congenital hypomyelinating neuropathy (CHN) and a family with Charcot-Marie-Tooth type 1 (CMT1)"
      explanation: >-
        The study's own finding rather than its premise: EGR2 missense mutations
        in patients whose disease is hypomyelinating neuropathy, which is the
        clinical form this edge's differentiation block produces.
  evidence:
  - reference: PMID:9537424
    reference_title: "Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Egr2(-/-) mice display disrupted hindbrain segmentation and development, and a block of Schwann-cell differentiation at an early stage."
    explanation: >-
      The differentiation block this node asserts, measured in the null mouse.
  - reference: PMID:9537424
    reference_title: "Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "Stable expression of Egr2 is specifically associated with the onset of myelination in the peripheral nervous system (PNS)."
    explanation: >-
      Establishes the normal timing of Egr2 expression that makes a
      differentiation block the expected consequence of its loss. The sentence is
      the study's framing of prior work rather than its own result, hence
      quote_role BACKGROUND; the expression data it restates are rodent, which is
      what evidence_source grades.
- name: Frabin Cdc42 Exchange Factor Defect
  conforms_to: "schwann_cell_myelin_maintenance#Myelin Gene Dosage or Structural Lesion in Schwann Cells"
  description: >-
    The CMT4H route. FGD4 encodes frabin, a GDP/GTP nucleotide exchange factor
    specific to Cdc42, a Rho-family GTPase. Truncated FRABIN mutants expressed in
    rat primary motoneurons and rat Schwann cells induce significantly fewer
    microspikes than wild-type protein, placing the lesion in Cdc42-dependent
    actin remodelling in the myelinating cell rather than in myelin protein
    structure or in membrane trafficking.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  - preferred_term: Motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  molecular_functions:
  - preferred_term: guanyl-nucleotide exchange factor activity
    term:
      id: GO:0005085
      label: guanyl-nucleotide exchange factor activity
    modifier: ABNORMAL
  biological_processes:
  - preferred_term: actin cytoskeleton organization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
    modifier: ABNORMAL
  genes:
  - preferred_term: FGD4
    term:
      id: hgnc:19125
      label: FGD4
  downstream:
  - target: Demyelination and Secondary Axonal Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      CMT4H is a demyelinating neuropathy, and the reported functional defect is
      reduced Cdc42-dependent actin protrusion in Schwann cells and motoneurons.
      The steps between that cytoskeletal defect and demyelination are not
      established in the reporting study.
    evidence:
    - reference: PMID:17564959
      reference_title: "Mutations in FGD4 encoding the Rho GDP/GTP exchange factor FRABIN cause autosomal recessive Charcot-Marie-Tooth type 4H."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The CMT4H subtype is an autosomal recessive demyelinating form of CMT that was recently mapped to a 15.8-Mb region at chromosome 12p11.21-q13.11, in two consanguineous families of Mediterranean origin, by homozygosity mapping."
      explanation: >-
        Establishes that the FGD4 subtype is demyelinating, which is what this
        edge asserts.
  evidence:
  - reference: PMID:17564959
    reference_title: "Mutations in FGD4 encoding the Rho GDP/GTP exchange factor FRABIN cause autosomal recessive Charcot-Marie-Tooth type 4H."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "expression of truncated FRABIN mutants in rat primary motoneurons and rat Schwann cells induced significantly fewer microspikes than expression of wild-type FRABIN"
    explanation: >-
      The functional measurement this node asserts, in the two cultured cell
      types bound here.
  - reference: PMID:17564959
    reference_title: "Mutations in FGD4 encoding the Rho GDP/GTP exchange factor FRABIN cause autosomal recessive Charcot-Marie-Tooth type 4H."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FRABIN is a GDP/GTP nucleotide exchange factor (GEF), specific to Cdc42, a member of the Rho family of small guanosine triphosphate (GTP)-binding proteins (Rho GTPases)."
    explanation: >-
      Identifies the molecular function bound on this node and its Cdc42
      specificity.
- name: Endosome-Lysosome Trafficking Defect
  description: >-
    The CMT4J route, and the reason FIG4 was previously the one CMT4 gene in this
    entry that reached no mechanism node. FIG4 is a
    phosphatidylinositol-3,5-bisphosphate 5-phosphatase. Fibroblasts from the
    Fig4 mutant pale tremor mouse carry an abnormal concentration of
    PtdIns(3,5)P2 and a cytoplasm filled with large LAMP-2-immunoreactive
    vacuoles, which the authors read as dysfunction of the late
    endosome-lysosome axis. FIG4 is a second phosphoinositide lesion in this
    compartment, alongside the myotubularin lesion of CMT4B1 and CMT4B2, but the
    pathology reported for it is vacuolar rather than the myelin outfolding that
    characterizes CMT4B.
  biological_scale: CELLULAR
  molecular_functions:
  - preferred_term: phosphatidylinositol-3,5-bisphosphate 5-phosphatase activity
    term:
      id: GO:0043813
      label: phosphatidylinositol-3,5-bisphosphate 5-phosphatase activity
    modifier: ABNORMAL
  biological_processes:
  - preferred_term: phosphatidylinositol dephosphorylation
    term:
      id: GO:0046856
      label: phosphatidylinositol dephosphorylation
    modifier: ABNORMAL
  - preferred_term: lysosome organization
    term:
      id: GO:0007040
      label: lysosome organization
    modifier: ABNORMAL
  genes:
  - preferred_term: FIG4
    term:
      id: hgnc:16873
      label: FIG4
  downstream:
  - target: Demyelination and Secondary Axonal Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The Fig4 mutant mouse sciatic nerve shows reduced numbers of
      large-diameter myelinated axons with slowed conduction and reduced compound
      muscle action potential amplitude, the model correlate of this entry's
      terminal node. The steps from endolysosomal dysfunction to that nerve
      pathology are not established.
    evidence:
    - reference: PMID:17572665
      reference_title: "Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The sciatic nerve exhibits reduced numbers of large-diameter myelinated axons, slowed nerve conduction velocity and reduced amplitude of compound muscle action potentials."
      explanation: >-
        The peripheral-nerve phenotype of the Fig4 mutant mouse, which is the
        model evidence for this edge.
  evidence:
  - reference: PMID:17572665
    reference_title: "Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The cytoplasm of fibroblasts from pale tremor mice is filled with large vacuoles that are immunoreactive for LAMP-2 (lysosomal-associated membrane protein 2), consistent with dysfunction of the late endosome-lysosome axis."
    explanation: >-
      The endolysosomal phenotype this node asserts, and the basis for the
      lysosome-organization binding.
  - reference: PMID:17572665
    reference_title: "Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The abnormal concentration of PtdIns(3,5)P2 in cultured fibroblasts from pale tremor mice demonstrates the conserved biochemical function of mammalian Fig4."
    explanation: >-
      The phosphoinositide measurement behind the dephosphorylation binding, and
      the reason the modifier is ABNORMAL rather than directional.
- name: Demyelination and Secondary Axonal Loss
  conforms_to: "peripheral_axonal_degeneration#Distal Axonal Degeneration and Demyelination"
  description: >-
    The shared terminal node of the autosomal-recessive CMT4 compartment. The
    diverse Schwann-cell and neuronal lesions (GDAP1 mitochondrial dysfunction,
    myotubularin phosphoinositide dysregulation, SH3TC2 trafficking defect,
    NDRG1 and periaxin loss, the EGR2 differentiation block, the frabin
    actin-remodelling defect, and the FIG4 endolysosomal defect) converge on
    demyelination — often with redundant
    myelin outfoldings or onion-bulb formation — and, over time, length-dependent
    secondary axonal degeneration. It is this secondary axonal loss, affecting
    the longest motor and sensory fibers first, that produces the progressive
    distal clinical deficit shared across all CMT compartments, typically with
    earlier onset and greater severity in the recessive forms. HK1 (CMT4G) is
    deliberately not linked to this or any other node: the CMT4G founder
    variant's functional effect is explicitly unresolved, so what is established
    for that subtype is an early-onset demyelinating neuropathy, not a
    mechanism through which the gene acts.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  - preferred_term: Sensory neuron of peripheral nervous system
    term:
      id: CL:0000101
      label: sensory neuron
  biological_processes:
  - preferred_term: Myelination in the peripheral nervous system
    term:
      id: GO:0022011
      label: myelination in peripheral nervous system
    modifier: DECREASED
  downstream:
  - target: Distal Muscle Weakness
  - target: Distal Sensory Loss
  - target: Pes Cavus
  - target: Decreased Tendon Reflexes
  - target: Scoliosis
  evidence:
  - reference: PMID:10831399
    reference_title: "N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive peripheral neuropathies are relatively rare but are clinically more severe than autosomal dominant forms of CMT"
    explanation: Supports the earlier-onset, more-severe clinical course that distinguishes the recessive CMT4 compartment from dominant CMT.
  - reference: PMID:23996628
    reference_title: "Founder mutations in NDRG1 and HK1 genes are common causes of inherited neuropathies among Roma/Gypsies in Slovakia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on the molecular examination of four families of Roma origin in Slovakia with early-onset demyelinating neuropathy and autosomal recessive inheritance."
    explanation: >-
      Supports including the CMT4G families in this shared demyelinating
      outcome: the established CMT4G finding is early-onset demyelinating
      neuropathy. HK1 is deliberately not linked to this node, because no
      mechanism is established for the gene to act through.
  - reference: PMID:20301641
    reference_title: "Charcot-Marie-Tooth Neuropathy Type 4 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Charcot-Marie-Tooth neuropathy type 4 (CMT4) is a group of progressive motor and sensory axonal and demyelinating neuropathies that are distinguished from other forms of CMT by autosomal recessive inheritance."
    explanation: >-
      Supports treating demyelination with secondary axonal involvement as the
      shared terminal state of the whole recessive compartment.
phenotypes:
- category: Neurologic
  name: Distal Muscle Weakness
  diagnostic: true
  phenotype_term:
    preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:11157804
    reference_title: "A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies characterized by chronic distal weakness with progressive muscular atrophy and sensory loss in the distal extremities."
    explanation: Supports progressive distal weakness and muscular atrophy as the core CMT phenotype shared by the recessive CMT4 forms.
- category: Neurologic
  name: Distal Sensory Loss
  phenotype_term:
    preferred_term: Distal sensory impairment
    term:
      id: HP:0002936
      label: Distal sensory impairment
  evidence:
  - reference: PMID:11157804
    reference_title: "A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by chronic distal weakness with progressive muscular atrophy and sensory loss in the distal extremities."
    explanation: Supports distal sensory loss as part of the shared CMT sensorimotor phenotype.
- category: Musculoskeletal
  name: Pes Cavus
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
- category: Neurologic
  name: Decreased Tendon Reflexes
  phenotype_term:
    preferred_term: Hyporeflexia
    term:
      id: HP:0001265
      label: Hyporeflexia
- category: Musculoskeletal
  name: Scoliosis
  subtype: CMT4C
  description: >-
    Early-onset scoliosis is a distinctive and prominent feature of CMT4C
    (SH3TC2), often bringing affected children to attention.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:14574644
    reference_title: "Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary motor and sensory neuropathy associated with an early-onset scoliosis and a distinct Schwann cell pathology."
    explanation: Establishes early-onset scoliosis as a characteristic CMT4C phenotype.
- category: Neurologic
  name: Onion Bulb Formation
  description: >-
    Concentric Schwann-cell processes around demyelinated and remyelinated
    axons, together with redundant myelin outfoldings in the CMT4B subtypes,
    are the biopsy hallmarks of the demyelinating CMT4 forms.
  phenotype_term:
    preferred_term: Onion bulb formation
    term:
      id: HP:0003383
      label: Onion bulb formation
genetic:
- name: GDAP1
  gene_term:
    preferred_term: GDAP1
    term:
      id: hgnc:15968
      label: GDAP1
  association: Causal
  subtype: CMT4A
  notes: >-
    Regulates mitochondrial fission; biallelic mutations cause CMT4A (axonal,
    demyelinating, or mixed, often with vocal cord paresis). The same gene also
    causes axonal CMT2K.
  evidence:
  - reference: PMID:11743580
    reference_title: "The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results establish the molecular etiology of CMT4A (MIM 214400) and suggest that it may be associated with both axonal and demyelinating phenotypes."
    explanation: Establishes GDAP1 as the CMT4A gene.
- name: MTMR2
  gene_term:
    preferred_term: MTMR2
    term:
      id: hgnc:7450
      label: MTMR2
  association: Causal
  subtype: CMT4B1
  notes: >-
    Myotubularin-related protein-2, a phosphoinositide phosphatase; biallelic
    mutations cause demyelinating CMT4B1 with myelin outfoldings.
  evidence:
  - reference: PMID:10802647
    reference_title: "Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified in unrelated CMT4B patients mutations occurring in the gene MTMR2, encoding myotubularin-related protein-2, a dual specificity phosphatase (DSP)."
    explanation: Establishes MTMR2 as the CMT4B1 gene.
- name: SBF2
  gene_term:
    preferred_term: SBF2
    term:
      id: hgnc:2135
      label: SBF2
  association: Causal
  subtype: CMT4B2
  notes: >-
    SBF2 (MTMR13), a catalytically inactive pseudophosphatase of the myotubularin
    family; biallelic mutations cause demyelinating CMT4B2 with myelin
    outfoldings, sometimes with early-onset glaucoma.
  evidence:
  - reference: PMID:12687498
    reference_title: "Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified two different nonsense mutations in the myotubularin-related 13 gene, MTMR13."
    explanation: Establishes SBF2 / MTMR13 as the CMT4B2 gene.
- name: SH3TC2
  gene_term:
    preferred_term: SH3TC2
    term:
      id: hgnc:29427
      label: SH3TC2
  association: Causal
  subtype: CMT4C
  notes: >-
    Encodes an SH3/TPR-domain protein (originally KIAA1985) required for
    Schwann-cell myelination; biallelic mutations cause CMT4C, the most common
    CMT4 subtype, with early-onset scoliosis.
  evidence:
  - reference: PMID:14574644
    reference_title: "Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We subsequently identified mutations in an uncharacterized transcript, KIAA1985, in 12 families with autosomal recessive neuropathy."
    explanation: Establishes SH3TC2 (KIAA1985) as the CMT4C gene.
- name: NDRG1
  gene_term:
    preferred_term: NDRG1
    term:
      id: hgnc:7679
      label: NDRG1
  association: Causal
  subtype: CMT4D
  notes: >-
    N-myc downstream-regulated gene 1; a founder truncating mutation causes
    CMT4D / HMSN-Lom with Schwann-cell dysfunction and early axonal involvement.
  evidence:
  - reference: PMID:10831399
    reference_title: "N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified the founder HMSNL mutation: a premature-termination codon at position 148 of the N-myc downstream-regulated gene 1 (NDRG1)."
    explanation: Establishes NDRG1 as the CMT4D (HMSN-Lom) gene.
- name: PRX
  gene_term:
    preferred_term: PRX
    term:
      id: hgnc:13797
      label: PRX
  association: Causal
  subtype: CMT4F
  notes: >-
    Periaxin, a protein of myelinating Schwann cells required for myelin-sheath
    stability; biallelic mutations cause demyelinating CMT4F (Dejerine-Sottas-like
    at the severe end).
  evidence:
  - reference: PMID:11157804
    reference_title: "A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a nonsense R196X mutation in the Lebanese family which cosegregated with CMT."
    explanation: Establishes a PRX (periaxin) nonsense mutation cosegregating with CMT4F.
- name: FIG4
  gene_term:
    preferred_term: FIG4
    term:
      id: hgnc:16873
      label: FIG4
  association: Causal
  subtype: CMT4J
  notes: >-
    A PtdIns(3,5)P2 5-phosphatase regulating endosome-lysosome membrane
    trafficking; biallelic mutations cause CMT4J.
  evidence:
  - reference: PMID:17572665
    reference_title: "Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified pathogenic mutations of human FIG4 (KIAA0274) on chromosome 6q21 in four unrelated patients with hereditary motor and sensory neuropathy. This novel form of autosomal recessive Charcot-Marie-Tooth disorder is designated CMT4J."
    explanation: Establishes FIG4 as the CMT4J gene in four unrelated patients.
- name: EGR2
  gene_term:
    preferred_term: EGR2
    term:
      id: hgnc:3239
      label: EGR2
  association: Causal
  relationship_type: CAUSATIVE
  subtype: CMT4E
  notes: >-
    A Cys2His2 zinc-finger transcription factor, formerly symbolized KROX20,
    whose stable expression is specifically associated with the onset of
    peripheral myelination. The recessive EGR2 allele causes congenital
    hypomyelinating neuropathy, which is the CMT4E subtype; dominant EGR2
    missense alleles cause demyelinating dominant disease, so this gene is
    shared with the CMT1 compartment and is not exclusive to CMT4.
  evidence:
  - reference: PMID:9537424
    reference_title: "Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we have identified one recessive and two dominant missense mutations in EGR2 (within regions encoding conserved functional domains) in patients with congenital hypomyelinating neuropathy (CHN) and a family with Charcot-Marie-Tooth type 1 (CMT1)"
    explanation: >-
      Establishes EGR2 as causal for hereditary myelinopathy in both recessive
      and dominant form, which is why this record says the gene is shared.
- name: HK1
  gene_term:
    preferred_term: HK1
    term:
      id: hgnc:4922
      label: HK1
  association: Causal
  relationship_type: CAUSATIVE
  subtype: CMT4G
  notes: >-
    Hexokinase 1. The HMSN-Russe founder variant lies in an alternative
    untranslated exon rather than in coding sequence, and the reporting study
    measured no difference in hexokinase activity or peripheral-nerve
    immunostaining between patients and controls, leaving the mechanism open.
    This record therefore asserts causation without asserting a mechanism, and
    HK1 is deliberately not linked to any pathophysiology node.
  evidence:
  - reference: PMID:19536174
    reference_title: "A mutation in an alternative untranslated exon of hexokinase 1 associated with hereditary motor and sensory neuropathy -- Russe (HMSNR)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequence conservation of the AltT2 exon in 16 species with invariable preservation of the G allele at the mutated site, strongly favour the exonic change as the pathogenic mutation."
    explanation: >-
      The conservation argument the authors use to nominate the exonic variant as
      pathogenic, which is the strength of the causal claim available here.
  - reference: PMID:23996628
    reference_title: "Founder mutations in NDRG1 and HK1 genes are common causes of inherited neuropathies among Roma/Gypsies in Slovakia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We detected mutation p.R148X (g.631C>T) in the NDRG1 (NM_006096.3) gene in two families and mutation g.9712G>C in the HK1 (NM_033498) gene in the other two families. These mutations cause CMT4D and CMT4G, respectively."
    explanation: >-
      Independent replication of the HK1 founder variant in CMT4G families, in a
      cohort separate from the original HMSNR mapping study.
- name: FGD4
  gene_term:
    preferred_term: FGD4
    term:
      id: hgnc:19125
      label: FGD4
  association: Causal
  relationship_type: CAUSATIVE
  subtype: CMT4H
  notes: >-
    Encodes frabin, a GDP/GTP nucleotide exchange factor specific to Cdc42.
    Truncated FRABIN mutants expressed in rat primary motoneurons and rat
    Schwann cells induce significantly fewer microspikes than wild-type, which is
    the functional evidence for the actin-cytoskeletal lesion in CMT4H.
  evidence:
  - reference: PMID:17564959
    reference_title: "Mutations in FGD4 encoding the Rho GDP/GTP exchange factor FRABIN cause autosomal recessive Charcot-Marie-Tooth type 4H."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report here the identification of mutations in FGD4, encoding FGD4 or FRABIN (FGD1-related F-actin binding protein), in both families."
    explanation: >-
      Establishes FGD4 as the CMT4H gene in the two mapped consanguineous
      families.
  - reference: PMID:17564959
    reference_title: "Mutations in FGD4 encoding the Rho GDP/GTP exchange factor FRABIN cause autosomal recessive Charcot-Marie-Tooth type 4H."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "expression of truncated FRABIN mutants in rat primary motoneurons and rat Schwann cells induced significantly fewer microspikes than expression of wild-type FRABIN"
    explanation: >-
      The cell-culture measurement behind this record's mechanistic statement,
      and the evidence for the FGD4 pathophysiology node.
inheritance:
- name: Autosomal Recessive
  description: >-
    By definition, the CMT4 subtypes are inherited in an autosomal recessive
    manner: affected individuals carry biallelic (homozygous or compound
    heterozygous) pathogenic variants, most commonly in consanguineous families.
    Recessive CMT is generally earlier in onset and clinically more severe than
    the dominant CMT1/CMT2 forms.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:10831399
    reference_title: "N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive peripheral neuropathies are relatively rare but are clinically more severe than autosomal dominant forms of CMT"
    explanation: Documents autosomal recessive inheritance and the more severe course characteristic of CMT4.
treatments:
- name: Physical and Occupational Therapy
  description: Mainstay of supportive care to maintain mobility and function.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
- name: Orthotic Bracing
  description: Ankle-foot orthoses to compensate for foot drop and improve gait.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Scoliosis Management
  description: >-
    Bracing and, when required, corrective spinal surgery for the early-onset
    scoliosis that is prominent in CMT4C.
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
- name: Genetic Counseling
  description: >-
    Counseling for affected individuals and families, with attention to the
    recessive inheritance pattern, recurrence risk in consanguineous unions, and
    carrier testing.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
differential_diagnoses:
- name: Charcot-Marie-Tooth Disease Type 4K
  description: >-
    CMT4K (MONDO:0014733, SURF1-related) is a cytochrome c oxidase assembly
    defect rather than a Schwann-cell myelin-maintenance defect, and is
    distinguished clinically by lactic acidosis and by putaminal and
    periaqueductal lesions developing years after the neuropathy — features no
    other CMT4 subtype shows. It is listed in the has_subtypes roster above,
    because it is a hierarchical MONDO descendant of this entry's own term, and
    is kept here as well for those distinguishing features. Four subtypes of this
    compartment carry dedicated dismech entries - CMT4B3, CMT4C, CMT4D and CMT4K.
  distinguishing_features:
  - Lactic acidosis
  - Putaminal and periaqueductal brain MRI lesions
  - Cerebellar ataxia developing years after the polyneuropathy
  evidence:
  - reference: PMID:24027061
    reference_title: "SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found SURF1 mutations in 5% of families (2/41) presenting with CMT4."
    explanation: >-
      Establishes SURF1 as a cause of CMT4 and quantifies its share of
      otherwise unsolved CMT4.
references:
- reference: PMID:20301641
  title: "Charcot-Marie-Tooth Neuropathy Type 4 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:20301532
  title: "Charcot-Marie-Tooth Hereditary Neuropathy Overview."
  tags:
  - GeneReviews
  findings: []
datasets: []
📚

References & Deep Research

References

2
PMID:20301641
Charcot-Marie-Tooth Neuropathy Type 4 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
No top-level findings curated for this source.
PMID:20301532
Charcot-Marie-Tooth Hereditary Neuropathy Overview.
No top-level findings curated for this source.