Intermediate Charcot-Marie-Tooth Disease

Mendelian MONDO:0018778 Pathograph 19 Show in embeddings browser Charcot-Marie-Tooth disease

Intermediate Charcot-Marie-Tooth disease (intermediate CMT / CMTi) is the compartment of Charcot-Marie-Tooth disease that sits electrophysiologically and pathologically between the demyelinating (CMT1) and axonal (CMT2) compartments. It is defined by upper-limb motor nerve conduction velocities in an intermediate range (classically ~25–45 m/s, overlapping the CMT1 and CMT2 cut-offs) and by nerve pathology that combines features of both demyelination and axonal degeneration — sometimes varying between affected members of a single family. Intermediate CMT is not a trivial category: in a 1,515-patient specialist cohort it comprised 13.5% of all CMT presentations (205 patients), the third largest group in that cohort after CMT1 (41.0%) and CMT2 (19.4%). It occurs in dominant-intermediate (DI-CMT) and recessive-intermediate (RI-CMT) forms. The dominant-intermediate subtypes include DI-CMTB (DNM2 / dynamin-2, a membrane-remodelling large GTPase), DI-CMTC (YARS1 / tyrosyl-tRNA synthetase), DI-CMTD (MPZ / myelin protein zero), DI-CMTE (INF2 / inverted formin 2, with focal segmental glomerulosclerosis), DI-CMTF (GNB4 / G-protein beta-4) and DI-CMTG (NEFL / neurofilament light chain); the recessive-intermediate subtypes are RI-CMTA (GDAP1), RI-CMTB (KARS1 / lysyl-tRNA synthetase, so the aminoacyl-tRNA-synthetase mechanism recurs recessively), RI-CMTC (PLEKHG5) and RI-CMTD (COX6A1, which is simultaneously a mitochondrial complex IV disorder). Several intermediate-CMT genes are pleiotropic — DNM2, for example, also causes centronuclear myopathy — and MPZ, NEFL and GDAP1 each carry allelic series that cross the compartment boundary, producing demyelinating or axonal CMT with other alleles. Whatever the gene, the subtypes converge on the shared CMT terminal node — combined demyelination and length-dependent axonal degeneration — producing the uniform clinical picture of distal weakness, wasting, sensory loss, foot deformity, and depressed reflexes.

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2
Inheritance
7
Pathophys.
5
Phenotypes
19
Pathograph
7
Genes
3
Medical Actions
10
Subtypes
3
References
👪

Inheritance

2
Autosomal Dominant HP:0000006
The dominant-intermediate CMT subtypes — DI-CMTB (DNM2), DI-CMTC (YARS1), DI-CMTD (MPZ), DI-CMTE (INF2), DI-CMTF (GNB4) and DI-CMTG (NEFL) — are inherited in an autosomal dominant manner.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:15731758 SUPPORT Human Clinical
"Different chromosomal loci have been linked with three autosomal dominant, 'intermediate' types of CMT: DI-CMTA, DI-CMTB and DI-CMTC."
Documents autosomal dominant inheritance of the dominant-intermediate CMT subtypes.
Autosomal Recessive HP:0000007
The recessive-intermediate CMT (RI-CMT) subtypes — RI-CMTA (GDAP1), RI-CMTB (KARS1), RI-CMTC (PLEKHG5) and RI-CMTD (COX6A1) — are inherited in an autosomal recessive manner, requiring biallelic (compound-heterozygous or homozygous) loss-of-function variants.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:20920668 SUPPORT Human Clinical
"we describe three variants (p.Leu133His, p.Tyr173SerfsX7, and p.Ile302Met) in the lysyl-tRNA synthetase (KARS) gene in two patients from this cohort."
Documents compound-heterozygous (autosomal recessive) inheritance for RI-CMTB.
PMID:12566285 SUPPORT Human Clinical
"Homozygosity for a single base pair insertion in exon 3 (c.349_350insT) was observed in affected children from a Turkish inbred pedigree."
Documents homozygous (autosomal recessive) inheritance for RI-CMTA.
PMID:23777631 SUPPORT Human Clinical
"Molecular investigation of the genes from this region allowed identification of two homozygous mutations in PLEKHG5 that produce premature stop codons and are predicted to result in functional null alleles."
Documents homozygous (autosomal recessive) inheritance for RI-CMTC.
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Subtypes

10
DI-CMTB (DNM2 / dynamin-2) MONDO:0011674
DNM2 hgnc:2974 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in DNM2 (hgnc:2974). hgnc:2974 is a gene from the HUGO Gene Nomenclature Committee.
Dominant-intermediate CMT type B, caused by mutations in DNM2 encoding dynamin-2, a large GTPase of the cellular membrane fission-fusion apparatus. DNM2 is pleiotropic — other DNM2 mutations cause centronuclear myopathy. Subtype-level clinical and management detail is curated in the dedicated entry Charcot-Marie-Tooth Disease Dominant Intermediate B; this row records the subtype's membership of the intermediate compartment and its gene.
Show evidence (1 reference)
PMID:15731758 SUPPORT Human Clinical
"we identified unique mutations in dynamin 2 (DNM2) in all families. DNM2 belongs to the family of large GTPases and is part of the cellular fusion-fission apparatus."
Establishes DNM2 mutations as the cause of dominant-intermediate CMT (DI-CMTB).
DI-CMTC (YARS1 / tyrosyl-tRNA synthetase) MONDO:0012012
YARS1 hgnc:12840 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in YARS1 (hgnc:12840). hgnc:12840 is a gene from the HUGO Gene Nomenclature Committee.
Dominant-intermediate CMT type C, caused by mutations in YARS1 (YARS) encoding tyrosyl-tRNA synthetase — the first aminoacyl-tRNA synthetase linked to CMT, mislocalizing to axonal termini and partially losing aminoacylation activity.
Show evidence (1 reference)
PMID:16429158 SUPPORT Human Clinical
"we identify two heterozygous missense mutations (G41R and E196K) and one de novo deletion (153-156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three unrelated families affected with DI-CMTC."
Establishes YARS1 (YARS) mutations as the cause of dominant-intermediate CMT (DI-CMTC).
DI-CMTD (MPZ / myelin protein zero) MONDO:0011909
MPZ hgnc:7225 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in MPZ (hgnc:7225). hgnc:7225 is a gene from the HUGO Gene Nomenclature Committee.
Dominant-intermediate CMT type D, caused by heterozygous mutations in MPZ encoding myelin protein zero, the major structural glycoprotein of compact peripheral-nerve myelin. MPZ is one of several genes in this compartment whose allelic series crosses the CMT compartment boundaries: different MPZ alleles produce demyelinating, axonal or intermediate neuropathy, so the demyelinating form (CMT1B) is curated on the Charcot-Marie-Tooth Disease Type 1 entry and the axonal forms (CMT2I/CMT2J) on Charcot-Marie-Tooth Disease Type 2, while this row holds only the intermediate presentation.
Show evidence (2 references)
PMID:22704856 SUPPORT BACKGROUND Human Clinical
"Myelin protein zero is a key structural component of compact myelin, and over 100 mutations in this protein have been reported, which can give rise to neuropathies with either axonal, demyelinating, or intermediate features encompassing a wide range of severity."
States that MPZ alleles can produce axonal, demyelinating or intermediate neuropathy, which is why the intermediate presentation is a distinct subtype row here rather than being folded into CMT1B.
PMID:22704856 SUPPORT Human Clinical
"Electrophysiological studies revealed mild features of demyelination with median conduction velocity in the intermediate range."
The electrophysiological observation that places this MPZ kindred in the intermediate conduction-velocity compartment.
DI-CMTE (INF2 / inverted formin 2) MONDO:0013758
INF2 hgnc:23791 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in INF2 (hgnc:23791). hgnc:23791 is a gene from the HUGO Gene Nomenclature Committee.
Dominant-intermediate CMT type E, caused by mutations in INF2 encoding inverted formin 2, and distinguished from the other intermediate subtypes by co-occurring focal segmental glomerulosclerosis. The mechanism, renal phenotype and management are curated in the dedicated entry Charcot-Marie-Tooth Disease Dominant Intermediate E; this row records the subtype's membership of the intermediate compartment and its gene.
Show evidence (2 references)
PMID:25326399 SUPPORT REVIEW SYNTHESIS Other
"GJB1 is currently considered to be associated with X-linked DI-CMT, and MPZ, INF2, DNM2, YARS, GNB4, NEFL, and MFN2 are associated with autosomal DI-CMT."
A review of the intermediate CMT compartment that names INF2 among the genes associated with autosomal dominant-intermediate CMT.
PMID:22187985 SUPPORT Human Clinical
"INF2 mutations appear to cause many cases of FSGS-associated Charcot-Marie-Tooth neuropathy, showing that INF2 is involved in a disease affecting both the kidney glomerulus and the peripheral nervous system."
Source for the co-occurring focal segmental glomerulosclerosis that distinguishes this subtype from the other intermediate forms.
DI-CMTF (GNB4 / G-protein beta-4) MONDO:0014074
GNB4 hgnc:20731 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in GNB4 (hgnc:20731). hgnc:20731 is a gene from the HUGO Gene Nomenclature Committee.
Dominant-intermediate CMT type F, caused by mutations in GNB4 encoding the G-protein beta-4 subunit, implicating G-protein-coupled receptor signaling in peripheral-nerve function.
Show evidence (1 reference)
PMID:23434117 SUPPORT Human Clinical
"revealed heterozygous mutation c.158G>A (p.Gly53Asp) in GNB4, encoding guanine-nucleotide-binding protein subunit beta-4"
Establishes GNB4 mutations as the cause of dominant-intermediate CMT (DI-CMTF).
DI-CMTG (NEFL / neurofilament light chain) MONDO:0036484
NEFL hgnc:7739 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in NEFL (hgnc:7739). hgnc:7739 is a gene from the HUGO Gene Nomenclature Committee.
Dominant-intermediate CMT type G, caused by mutations in NEFL encoding neurofilament light chain. NEFL is another gene whose alleles cross the compartment boundary: the axonal presentation is curated as CMT2E on Charcot-Marie-Tooth Disease Type 2, the demyelinating CMT1F presentation is the CMT1F subtype row of Charcot-Marie-Tooth Disease Type 1, which binds MONDO:0011902, and the intermediate form has its own dedicated entry, Charcot-Marie-Tooth Disease Dominant Intermediate G, which holds the mechanism and allele detail.
Show evidence (1 reference)
PMID:25326399 SUPPORT REVIEW SYNTHESIS Other
"GJB1 is currently considered to be associated with X-linked DI-CMT, and MPZ, INF2, DNM2, YARS, GNB4, NEFL, and MFN2 are associated with autosomal DI-CMT."
A review of the intermediate CMT compartment that names NEFL among the genes associated with autosomal dominant-intermediate CMT.
RI-CMTA (GDAP1 / ganglioside-induced differentiation-associated protein 1) MONDO:0012014
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.
Recessive-intermediate CMT type A, caused by biallelic GDAP1 mutations. GDAP1 alleles produce demyelinating, axonal and intermediate neuropathy in different families, so the demyelinating recessive form (CMT4A) is curated on Charcot-Marie-Tooth Disease Type 4 and the axonal form (CMT2K) on Charcot-Marie-Tooth Disease Type 2, while this row holds the intermediate presentation.
Show evidence (1 reference)
PMID:12566285 SUPPORT Human Clinical
"Nerve conduction velocities were between 25 and 35 m/s and peripheral nerve pathology showed axonal as well as demyelinating changes. These findings fitted the definition of intermediate type CMT and further support the view that GDAP1 is vital for both, axonal integrity and Schwann cell properties."
Establishes biallelic GDAP1 mutations as a cause of intermediate-type CMT, with both the conduction-velocity range and the mixed nerve pathology that define the compartment.
RI-CMTB (KARS1 / lysyl-tRNA synthetase) MONDO:0013338
KARS1 hgnc:6215 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in KARS1 (hgnc:6215). hgnc:6215 is a gene from the HUGO Gene Nomenclature Committee.
Recessive-intermediate CMT type B, caused by biallelic loss-of-function mutations in KARS1 (KARS) encoding lysyl-tRNA synthetase — a second aminoacyl-tRNA synthetase implicated in CMT, here acting recessively.
Show evidence (1 reference)
PMID:20920668 SUPPORT Human Clinical
"we describe three variants (p.Leu133His, p.Tyr173SerfsX7, and p.Ile302Met) in the lysyl-tRNA synthetase (KARS) gene in two patients from this cohort."
Establishes compound-heterozygous KARS1 (KARS) loss-of-function variants as a cause of recessive-intermediate CMT (RI-CMTB).
RI-CMTC (PLEKHG5 / pleckstrin-homology and RhoGEF domain containing G5) MONDO:0014154
PLEKHG5 hgnc:29105 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in PLEKHG5 (hgnc:29105). hgnc:29105 is a gene from the HUGO Gene Nomenclature Committee.
Recessive-intermediate CMT type C, caused by biallelic PLEKHG5 null alleles. PLEKHG5 is expressed in both neurons and glia of the peripheral nervous system, and different PLEKHG5 genotypes produce either this intermediate neuropathy or a severe childhood-onset lower motor neuron disease.
Show evidence (2 references)
PMID:23777631 SUPPORT Human Clinical
"Molecular investigation of the genes from this region allowed identification of two homozygous mutations in PLEKHG5 that produce premature stop codons and are predicted to result in functional null alleles."
Establishes biallelic PLEKHG5 null alleles as the cause of recessive-intermediate CMT in two consanguineous families with an intermediate-CMT phenotype.
PMID:23777631 SUPPORT Human Clinical
"Together, these observations indicate that different mutations in PLEKHG5 lead to clinically diverse outcomes (intermediate CMT or LMND) affecting the function of neurons and glial cells."
Supports the allelic heterogeneity recorded in this row: PLEKHG5 genotype determines whether the phenotype is intermediate CMT or lower motor neuron disease.
RI-CMTD (COX6A1 / cytochrome c oxidase subunit 6A1) MONDO:0014467
COX6A1 hgnc:2277 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in COX6A1 (hgnc:2277). hgnc:2277 is a gene from the HUGO Gene Nomenclature Committee.
Recessive-intermediate CMT type D, caused by a splice-element deletion in COX6A1, a subunit of mitochondrial respiratory complex IV. It is the one intermediate-CMT subtype that is simultaneously a mitochondrial oxidative phosphorylation disorder, and the respiratory-chain mechanism and its metabolic consequences are curated in the dedicated entry Charcot-Marie-Tooth Disease Recessive Intermediate D.
Show evidence (2 references)
PMID:25152455 SUPPORT Human Clinical
"Those data indicated that COX6A1 mutation causes the autosomal-recessive axonal or mixed CMT."
Establishes COX6A1 as the cause of a recessive CMT that includes the mixed (intermediate) electrophysiological presentation.
PMID:25152455 SUPPORT Human Clinical
"revealed a disease-specific 5 bp deletion (c.247-10_247-6delCACTC) in a splicing element (pyrimidine tract) of intron 2 adjacent to the third exon of cytochrome c oxidase subunit VIa polypeptide 1 (COX6A1), which is a component of mitochondrial respiratory complex IV (cytochrome c oxidase [COX])"
Identifies the splice-element deletion and places COX6A1 in mitochondrial respiratory complex IV, which is why this subtype is also a mitochondrial oxidative phosphorylation disorder.
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Pathophysiology

7
DNM2 Membrane Remodeling Defect
Mutations in DNM2 (DI-CMTB) impair dynamin-2, a large GTPase of the membrane fission-fusion machinery that mediates membrane scission during endocytosis and vesicle trafficking. Disrupted DNM2-dependent membrane remodeling in Schwann cells and neurons produces a mixed demyelinating-and-axonal (intermediate) 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. 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.
DNM2 hgnc:2974 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DNM2 (hgnc:2974). hgnc:2974 is a gene from the HUGO Gene Nomenclature Committee.
Endocytosis GO:0006897 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Endocytosis (GO:0006897). GO:0006897 is a biological process from the Gene Ontology.
Downstream
Combined Demyelinating and Axonal Degeneration DNM2-dependent membrane-trafficking failure impairs both Schwann-cell and axonal homeostasis, converging on the mixed intermediate lesion.
Show evidence (1 reference)
PMID:15731758 SUPPORT Human Clinical
"we identified unique mutations in dynamin 2 (DNM2) in all families. DNM2 belongs to the family of large GTPases and is part of the cellular fusion-fission apparatus."
Establishes DNM2 (a membrane fission-fusion GTPase) as the DI-CMTB gene.
Aminoacyl-tRNA Synthetase Dysfunction
Mutations in the aminoacyl-tRNA synthetases YARS1 (tyrosyl-tRNA synthetase, DI-CMTC) and KARS1 (lysyl-tRNA synthetase, RI-CMTB) partially impair tRNA-charging (aminoacylation) activity and, for YARS1, mislocalize the enzyme within the axon. Aminoacyl-tRNA synthetase impairment is a recurrent CMT mechanism, predominantly producing axonal pathology, and here yields the intermediate phenotype.
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. Sensory neuron CL:0000101 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sensory neuron (CL:0000101). CL:0000101 is a cell type from the Cell Ontology.
YARS1 hgnc:12840 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves YARS1 (hgnc:12840). hgnc:12840 is a gene from the HUGO Gene Nomenclature Committee. KARS1 hgnc:6215 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KARS1 (hgnc:6215). hgnc:6215 is a gene from the HUGO Gene Nomenclature Committee.
tRNA aminoacylation for protein translation GO:0006418 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased tRNA aminoacylation for protein translation (GO:0006418). GO:0006418 is a biological process from the Gene Ontology.
Downstream
Combined Demyelinating and Axonal Degeneration Impaired tRNA aminoacylation compromises protein synthesis in long peripheral neurons, converging on the intermediate demyelinating-and-axonal lesion.
Show evidence (2 references)
PMID:16429158 SUPPORT In Vitro
"Biochemical experiments and genetic complementation in yeast show partial loss of aminoacylation activity of the mutant proteins"
Demonstrates partial loss of aminoacylation activity for DI-CMTC YARS1 mutants.
PMID:20920668 SUPPORT Human Clinical
"Mutations in three genes encoding aminoacyl-tRNA synthetases (ARSs) have been implicated in CMT disease primarily associated with an axonal pathology."
Establishes aminoacyl-tRNA synthetase dysfunction (including KARS1) as a recurrent CMT mechanism.
GNB4 G-Protein Signaling Defect
Mutations in GNB4 (DI-CMTF) disrupt the G-protein beta-4 subunit, which is expressed in axons and Schwann cells of peripheral nerve, implicating G-protein-coupled receptor signaling in the maintenance of peripheral-nerve function.
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.
GNB4 hgnc:20731 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GNB4 (hgnc:20731). hgnc:20731 is a gene from the HUGO Gene Nomenclature Committee.
G protein-coupled receptor signaling pathway GO:0007186 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal G protein-coupled receptor signaling pathway (GO:0007186). GO:0007186 is a biological process from the Gene Ontology.
Downstream
Combined Demyelinating and Axonal Degeneration Disrupted Gβ4-related GPCR signaling in peripheral nerve converges on the mixed intermediate lesion.
Show evidence (1 reference)
PMID:23434117 SUPPORT Human Clinical
"revealed heterozygous mutation c.158G>A (p.Gly53Asp) in GNB4, encoding guanine-nucleotide-binding protein subunit beta-4"
Establishes GNB4 (G-protein beta-4) as the DI-CMTF gene.
MPZ Compact-Myelin Structural Defect
Heterozygous MPZ mutations (DI-CMTD) disrupt myelin protein zero, the major structural glycoprotein of compact peripheral-nerve myelin made by Schwann cells. Different MPZ alleles shift the balance between demyelinating and axonal pathology; the intermediate presentation shows mild demyelinating features with conduction velocities in the intermediate range.
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.
MPZ hgnc:7225 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MPZ (hgnc:7225). hgnc:7225 is a gene from the HUGO Gene Nomenclature Committee.
Myelination in the peripheral nervous system GO:0022011 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal 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
Combined Demyelinating and Axonal Degeneration Loss of myelin protein zero from compact myelin degrades the myelin sheath and, through MPZ's allele-dependent axonal effects, converges on the mixed intermediate lesion.
Show evidence (2 references)
PMID:22704856 SUPPORT BACKGROUND Human Clinical
"Myelin protein zero is a key structural component of compact myelin, and over 100 mutations in this protein have been reported, which can give rise to neuropathies with either axonal, demyelinating, or intermediate features encompassing a wide range of severity."
Establishes MPZ as a structural component of compact myelin and states that its mutations can produce intermediate as well as demyelinating and axonal neuropathy, which is the claim this node makes.
PMID:22704856 SUPPORT Human Clinical
"Electrophysiological studies revealed mild features of demyelination with median conduction velocity in the intermediate range."
The abnormal-myelination observation in an MPZ kindred whose conduction velocities sit in the intermediate range.
GDAP1 Loss of Axonal and Schwann-Cell Integrity
Biallelic GDAP1 loss-of-function alleles (RI-CMTA) compromise peripheral nerve on both sides of the axon-glia partnership: nerve pathology in intermediate-type GDAP1 families shows axonal degeneration together with demyelinating change, which is why GDAP1 alleles can present as axonal, demyelinating or intermediate 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. peripheral nerve axon-bearing neuron CL:2000032 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves peripheral nerve axon-bearing neuron, annotated with peripheral nervous system neuron (CL:2000032). CL:2000032 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.
Downstream
Combined Demyelinating and Axonal Degeneration Because GDAP1 loss impairs axonal integrity and Schwann-cell properties at the same time, the resulting nerve pathology is mixed rather than predominantly demyelinating or predominantly axonal.
Show evidence (2 references)
PMID:12566285 SUPPORT Human Clinical
"Nerve conduction velocities were between 25 and 35 m/s and peripheral nerve pathology showed axonal as well as demyelinating changes. These findings fitted the definition of intermediate type CMT and further support the view that GDAP1 is vital for both, axonal integrity and Schwann cell properties."
States both halves of this node's claim: GDAP1 is required for axonal integrity and for Schwann-cell properties, and its loss produces mixed nerve pathology in the intermediate conduction-velocity range.
PMID:12566285 SUPPORT Human Clinical
"Neurophysiology and nerve pathology were heterogeneous in these cases: a subset of GDAP1 mutations was associated with peripheral nerve demyelination, whereas others resulted in axonal degeneration."
Records the allele-dependent split between demyelinating and axonal GDAP1 pathology that the intermediate presentation sits between.
PLEKHG5 Deficiency in Peripheral Nerve Neurons and Glia
Biallelic PLEKHG5 null alleles (RI-CMTC) remove a protein expressed in both the neurons and the glial cells of the peripheral nervous system. Plekhg5 knockout mice reproduce the reduced nerve conduction velocities seen in affected individuals, and the same gene produces a severe childhood-onset lower motor neuron disease with other genotypes.
peripheral nervous system neuron CL:2000032 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves peripheral nervous system neuron (CL:2000032). CL:2000032 is a cell type from the Cell Ontology. peripheral nervous system glial cell CL:0000125 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves peripheral nervous system glial cell, annotated with glial cell (CL:0000125). CL:0000125 is a cell type from the Cell Ontology.
PLEKHG5 hgnc:29105 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PLEKHG5 (hgnc:29105). hgnc:29105 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Combined Demyelinating and Axonal Degeneration Loss of PLEKHG5 from both the neuronal and the glial compartment of peripheral nerve converges on the mixed intermediate lesion, measured as reduced nerve conduction velocity in patients and in knockout mice.
Show evidence (2 references)
PMID:23777631 SUPPORT Model Organism
"Analysis of Plekhg5 in the mouse revealed that this gene is expressed in neurons and glial cells of the peripheral nervous system, and that knockout mice display reduced nerve conduction velocities that are comparable with those of affected individuals from both families."
Supports both cell types bound on this node and the reduced conduction velocity that is the compartment-defining readout, in a mouse null model whose values match the affected families.
PMID:23777631 SUPPORT Human Clinical
"Following the analysis of two consanguineous families affected by a medium to late-onset recessive form of intermediate CMT, we identified overlapping regions of homozygosity on chromosome 1p36 with a combined maximum LOD score of 5.4."
The human genetic observation that places PLEKHG5 in the intermediate CMT compartment.
Combined Demyelinating and Axonal Degeneration
The shared terminal node of the intermediate CMT compartment. The diverse upstream lesions (DNM2 membrane-remodelling failure, aminoacyl-tRNA synthetase dysfunction, GNB4 signaling defect, MPZ compact-myelin structural failure, GDAP1 loss of axonal and Schwann-cell integrity, and PLEKHG5 deficiency in peripheral nerve neurons and glia) converge on peripheral nerve pathology that combines demyelination and length-dependent axonal degeneration — the combination that produces the intermediate nerve conduction velocities defining this compartment and the progressive distal deficit shared with the CMT1 and CMT2 compartments.
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 CL:0000101 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sensory neuron (CL:0000101). CL:0000101 is a cell type from the Cell Ontology.
Myelination in the peripheral nervous system GO:0022011 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal 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
Decreased Nerve Conduction Velocity
Show evidence (1 reference)
PMID:16429158 SUPPORT Human Clinical
"Charcot-Marie-Tooth (CMT) neuropathies are common disorders of the peripheral nervous system caused by demyelination or axonal degeneration, or a combination of both features."
Supports the combined demyelinating-and-axonal pathology that underlies the intermediate CMT compartment.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Intermediate Charcot-Marie-Tooth Disease 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

5
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 1
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:20920668 SUPPORT Human Clinical
"Charcot-Marie-Tooth (CMT) disease comprises a genetically and clinically heterogeneous group of peripheral nerve disorders characterized by impaired distal motor and sensory function."
Supports impaired distal motor function as a core CMT phenotype shared by the intermediate forms.
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:20920668 SUPPORT Human Clinical
"Charcot-Marie-Tooth (CMT) disease comprises a genetically and clinically heterogeneous group of peripheral nerve disorders characterized by impaired distal motor and sensory function."
Supports impaired distal sensory function as a core CMT phenotype shared by the intermediate forms.
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.
Decreased Nerve Conduction Velocity HP:0000762 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased nerve conduction velocity (HP:0000762). HP:0000762 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15731758 SUPPORT Human Clinical
"Different chromosomal loci have been linked with three autosomal dominant, 'intermediate' types of CMT: DI-CMTA, DI-CMTB and DI-CMTC."
Establishes the 'intermediate' electrophysiologic category of CMT that this entry models.
🧬

Genetic Associations

7
DNM2 (Causal)
Gene: DNM2 hgnc:2974 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DNM2 (hgnc:2974). hgnc:2974 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:15731758 SUPPORT Human Clinical
"we identified unique mutations in dynamin 2 (DNM2) in all families. DNM2 belongs to the family of large GTPases and is part of the cellular fusion-fission apparatus."
Establishes DNM2 as the DI-CMTB gene.
YARS1 (Causal)
Gene: YARS1 hgnc:12840 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is YARS1 (hgnc:12840). hgnc:12840 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:16429158 SUPPORT Human Clinical
"we identify two heterozygous missense mutations (G41R and E196K) and one de novo deletion (153-156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three unrelated families affected with DI-CMTC."
Establishes YARS1 as the DI-CMTC gene.
GNB4 (Causal)
Gene: GNB4 hgnc:20731 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GNB4 (hgnc:20731). hgnc:20731 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:23434117 SUPPORT Human Clinical
"we previously mapped a dominant intermediate CMT to chromosomal region 3q28-q29."
Establishes the dominant-intermediate CMT locus (3q28-q29) subsequently attributed to GNB4 (DI-CMTF).
KARS1 (Causal)
Gene: KARS1 hgnc:6215 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KARS1 (hgnc:6215). hgnc:6215 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:20920668 SUPPORT Human Clinical
"we describe three variants (p.Leu133His, p.Tyr173SerfsX7, and p.Ile302Met) in the lysyl-tRNA synthetase (KARS) gene in two patients from this cohort."
Establishes KARS1 as the RI-CMTB gene.
MPZ (Causal)
Gene: MPZ hgnc:7225 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MPZ (hgnc:7225). hgnc:7225 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:22704856 SUPPORT Human Clinical
"There was an autosomal-dominant pattern of inheritance, and genetic testing revealed a novel heterozygous Trp101X mutation in exon 3 coding for a portion of the extracellular domain of myelin protein zero."
A heterozygous MPZ allele segregating dominantly in a kindred whose conduction velocities were in the intermediate range.
PMID:22704856 SUPPORT BACKGROUND Human Clinical
"Myelin protein zero is a key structural component of compact myelin, and over 100 mutations in this protein have been reported, which can give rise to neuropathies with either axonal, demyelinating, or intermediate features encompassing a wide range of severity."
Supports both the protein's role and the allele-dependent spread across the demyelinating, axonal and intermediate compartments recorded in the notes.
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. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:12566285 SUPPORT Human Clinical
"Homozygosity for a single base pair insertion in exon 3 (c.349_350insT) was observed in affected children from a Turkish inbred pedigree."
A homozygous frameshift GDAP1 allele in a consanguineous pedigree, establishing recessive inheritance for this subtype.
PMID:12566285 SUPPORT Human Clinical
"Nerve conduction velocities were between 25 and 35 m/s and peripheral nerve pathology showed axonal as well as demyelinating changes. These findings fitted the definition of intermediate type CMT and further support the view that GDAP1 is vital for both, axonal integrity and Schwann cell properties."
Places these GDAP1 families in the intermediate compartment and states the dual axonal and Schwann-cell requirement this entry wires as a pathophysiology node.
PLEKHG5 (Causal)
Gene: PLEKHG5 hgnc:29105 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PLEKHG5 (hgnc:29105). hgnc:29105 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:23777631 SUPPORT Human Clinical
"Molecular investigation of the genes from this region allowed identification of two homozygous mutations in PLEKHG5 that produce premature stop codons and are predicted to result in functional null alleles."
Establishes biallelic PLEKHG5 null alleles as the cause of this recessive intermediate subtype.
PMID:23777631 SUPPORT Human Clinical
"Interestingly, a homozygous PLEKHG5 missense mutation was previously reported in a recessive form of severe childhood onset lower motor neuron disease (LMND) leading to loss of the ability to walk and need for respiratory assistance."
Source for the pleiotropy recorded in the notes: a different PLEKHG5 genotype produces lower motor neuron disease rather than intermediate CMT.
💊

Medical Actions

3
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.
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, addressing the mixed dominant and recessive inheritance across intermediate-CMT subtypes.
🔬

Diagnosis

1
Intermediate Nerve Conduction Velocities
The defining diagnostic feature of intermediate CMT is upper-limb motor nerve conduction velocities in an intermediate range that overlaps the CMT1 (<38 m/s) and CMT2 (>38 m/s) cut-offs, with nerve biopsy showing both demyelinating and axonal features. Intermediate CMT is a substantial fraction of all CMT: it comprised 13.5% of a large single-centre specialist cohort.
Distinguishes the intermediate compartment from demyelinating CMT1 and axonal CMT2.
Show evidence (1 reference)
DOI:10.1093/brain/awae064 SUPPORT Human Clinical
"205 intermediate CMT (CMTi, 13.5%)"
Intermediate CMT comprised 13.5% (205/1515) of a specialist CMT cohort, quantifying the size of this compartment.
{ }

Source YAML

click to show 
name: Intermediate Charcot-Marie-Tooth Disease
creation_date: "2026-07-31T00:00:00Z"
category: Mendelian
description: >-
  Intermediate Charcot-Marie-Tooth disease (intermediate CMT / CMTi) is the
  compartment of Charcot-Marie-Tooth disease that sits electrophysiologically and
  pathologically between the demyelinating (CMT1) and axonal (CMT2) compartments.
  It is defined by upper-limb motor nerve conduction velocities in an intermediate
  range (classically ~25–45 m/s, overlapping the CMT1 and CMT2 cut-offs) and by
  nerve pathology that combines features of both demyelination and axonal
  degeneration — sometimes varying between affected members of a single family.
  Intermediate CMT is not a trivial category: in a 1,515-patient specialist
  cohort it comprised 13.5% of all CMT presentations (205 patients), the third
  largest group in that cohort after CMT1 (41.0%) and CMT2 (19.4%). It occurs in dominant-intermediate (DI-CMT) and
  recessive-intermediate (RI-CMT) forms. The dominant-intermediate subtypes
  include DI-CMTB (DNM2 / dynamin-2, a membrane-remodelling large GTPase),
  DI-CMTC (YARS1 / tyrosyl-tRNA synthetase), DI-CMTD (MPZ / myelin protein
  zero), DI-CMTE (INF2 / inverted formin 2, with focal segmental
  glomerulosclerosis), DI-CMTF (GNB4 / G-protein beta-4) and DI-CMTG (NEFL /
  neurofilament light chain); the recessive-intermediate subtypes are RI-CMTA
  (GDAP1), RI-CMTB (KARS1 / lysyl-tRNA synthetase, so the
  aminoacyl-tRNA-synthetase mechanism recurs recessively), RI-CMTC (PLEKHG5)
  and RI-CMTD (COX6A1, which is simultaneously a mitochondrial complex IV
  disorder). Several intermediate-CMT genes are pleiotropic — DNM2, for example,
  also causes centronuclear myopathy — and MPZ, NEFL and GDAP1 each carry
  allelic series that cross the compartment boundary, producing demyelinating or
  axonal CMT with other alleles. Whatever the gene, the subtypes converge on the shared CMT
  terminal node — combined demyelination and length-dependent axonal
  degeneration — producing the uniform clinical picture of distal weakness,
  wasting, sensory loss, foot deformity, and depressed reflexes.
disease_term:
  preferred_term: Intermediate Charcot-Marie-Tooth disease (CMTi)
  term:
    id: MONDO:0018778
    label: intermediate Charcot-Marie-Tooth disease
parents:
- Charcot-Marie-Tooth disease
notes: >-
  Scope and placement of the intermediate-CMT series. This entry is the
  intermediate compartment of CMT, the sibling of Charcot-Marie-Tooth Disease
  Type 1 (demyelinating), Type 2 (axonal) and Type 4 (recessive demyelinating).
  Its `has_subtypes` rows inventory the ten numbered dominant-intermediate and
  recessive-intermediate subtypes MONDO files under `MONDO:0018778`, each bound to
  its MONDO term. Four of them — DI-CMTB,
  DI-CMTE, DI-CMTG and RI-CMTD — also have dedicated Disease entries in this KB
  that hold their mechanism, allele and management detail; the rows here record
  compartment membership and the causal gene, and each row's description names
  the entry that owns the rest.

  Two MONDO descendants of `MONDO:0018778` are deliberately not subtype rows.
  `MONDO:0011675` is labelled "Charcot-Marie-Tooth Disease, axonal, type 2GG",
  carries GBF1 as its causal gene, and is described by its own MedGen record
  (MEDGEN:1794143) as an autosomal dominant axonal neuropathy with
  electrophysiology consistent with an axonal process — so it belongs to the
  axonal compartment, and it reaches this branch only through an `is_a` edge to
  `MONDO:0019548 autosomal dominant intermediate Charcot-Marie-Tooth disease`.
  That edge sits alongside CMTDIA and "Charcot-Marie-Tooth disease, dominant
  intermediate A" synonyms which the same term still carries, even though a
  separate term now bears that label; both look like residue of the earlier
  naming of OMIM:606483 rather than a claim about the disease. CMT2GG has an open
  stub (`stubs/Charcot-Marie-Tooth_Disease_Axonal_Type_2GG.yaml`) and is left
  there for the axonal compartment to curate. `MONDO:0957273`, xrefed to
  OMIM:620378 and MEDGEN:376235, is the term whose primary label is
  "Charcot-Marie-Tooth disease, dominant intermediate A"; MONDO records no causal
  gene for it and its MedGen description states that one family has been
  reported, so there is no gene-defined subtype here to curate.

  MPZ, NEFL and GDAP1 each cause CMT in more than one compartment. The
  demyelinating MPZ form (CMT1B) is curated on Charcot-Marie-Tooth Disease
  Type 1, the axonal MPZ forms (CMT2I/CMT2J) and the axonal NEFL form (CMT2E) on
  Charcot-Marie-Tooth Disease Type 2, the demyelinating recessive GDAP1 form
  (CMT4A) on Charcot-Marie-Tooth Disease Type 4 and the axonal GDAP1 form (CMT2K)
  on Charcot-Marie-Tooth Disease Type 2. Only the intermediate presentations are
  curated here, and the `genetic:` records say so. DNM2 probably belongs on that
  list too — `MONDO:0016431 autosomal dominant Charcot-Marie-Tooth disease
  type 2M` has both DI-CMTB and CMT2 as MONDO parents — but MONDO puts no causal
  gene on that term, so the cross-compartment claim for DNM2 rests on the gene
  symbol's history rather than on an ontology edge, and no entry or stub here
  binds it.
has_subtypes:
- name: DI-CMTB
  display_name: DI-CMTB (DNM2 / dynamin-2)
  subtype_term:
    preferred_term: DI-CMTB
    term:
      id: MONDO:0011674
      label: Charcot-Marie-Tooth disease dominant intermediate B
  description: >-
    Dominant-intermediate CMT type B, caused by mutations in DNM2 encoding
    dynamin-2, a large GTPase of the cellular membrane fission-fusion apparatus.
    DNM2 is pleiotropic — other DNM2 mutations cause centronuclear myopathy.
    Subtype-level clinical and management detail is curated in the dedicated
    entry Charcot-Marie-Tooth Disease Dominant Intermediate B; this row records
    the subtype's membership of the intermediate compartment and its gene.
  genes:
  - preferred_term: DNM2
    term:
      id: hgnc:2974
      label: DNM2
  evidence:
  - reference: PMID:15731758
    reference_title: "Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified unique mutations in dynamin 2 (DNM2) in all families. DNM2 belongs to the family of large GTPases and is part of the cellular fusion-fission apparatus."
    explanation: Establishes DNM2 mutations as the cause of dominant-intermediate CMT (DI-CMTB).
- name: DI-CMTC
  display_name: DI-CMTC (YARS1 / tyrosyl-tRNA synthetase)
  subtype_term:
    preferred_term: DI-CMTC
    term:
      id: MONDO:0012012
      label: Charcot-Marie-Tooth disease dominant intermediate C
  description: >-
    Dominant-intermediate CMT type C, caused by mutations in YARS1 (YARS)
    encoding tyrosyl-tRNA synthetase — the first aminoacyl-tRNA synthetase linked
    to CMT, mislocalizing to axonal termini and partially losing aminoacylation
    activity.
  genes:
  - preferred_term: YARS1
    term:
      id: hgnc:12840
      label: YARS1
  evidence:
  - reference: PMID:16429158
    reference_title: "Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identify two heterozygous missense mutations (G41R and E196K) and one de novo deletion (153-156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three unrelated families affected with DI-CMTC."
    explanation: Establishes YARS1 (YARS) mutations as the cause of dominant-intermediate CMT (DI-CMTC).
- name: DI-CMTD
  display_name: DI-CMTD (MPZ / myelin protein zero)
  subtype_term:
    preferred_term: DI-CMTD
    term:
      id: MONDO:0011909
      label: Charcot-Marie-Tooth disease dominant intermediate D
  description: >-
    Dominant-intermediate CMT type D, caused by heterozygous mutations in MPZ
    encoding myelin protein zero, the major structural glycoprotein of compact
    peripheral-nerve myelin. MPZ is one of several genes in this compartment whose
    allelic series crosses the CMT compartment boundaries: different MPZ alleles
    produce
    demyelinating, axonal or intermediate neuropathy, so the demyelinating form
    (CMT1B) is curated on the Charcot-Marie-Tooth Disease Type 1 entry and the
    axonal forms (CMT2I/CMT2J) on Charcot-Marie-Tooth Disease Type 2, while this
    row holds only the intermediate presentation.
  genes:
  - preferred_term: MPZ
    term:
      id: hgnc:7225
      label: MPZ
  evidence:
  - reference: PMID:22704856
    reference_title: "Intermediate Charcot-Marie-Tooth disease due to a novel Trp101Stop myelin protein zero mutation associated with debilitating neuropathic pain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Myelin protein zero is a key structural component of compact myelin, and over 100 mutations in this protein have been reported, which can give rise to neuropathies with either axonal, demyelinating, or intermediate features encompassing a wide range of severity."
    explanation: >-
      States that MPZ alleles can produce axonal, demyelinating or intermediate
      neuropathy, which is why the intermediate presentation is a distinct
      subtype row here rather than being folded into CMT1B.
  - reference: PMID:22704856
    reference_title: "Intermediate Charcot-Marie-Tooth disease due to a novel Trp101Stop myelin protein zero mutation associated with debilitating neuropathic pain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electrophysiological studies revealed mild features of demyelination with median conduction velocity in the intermediate range."
    explanation: >-
      The electrophysiological observation that places this MPZ kindred in the
      intermediate conduction-velocity compartment.
- name: DI-CMTE
  display_name: DI-CMTE (INF2 / inverted formin 2)
  subtype_term:
    preferred_term: DI-CMTE
    term:
      id: MONDO:0013758
      label: Charcot-Marie-Tooth disease dominant intermediate E
  description: >-
    Dominant-intermediate CMT type E, caused by mutations in INF2 encoding
    inverted formin 2, and distinguished from the other intermediate subtypes by
    co-occurring focal segmental glomerulosclerosis. The mechanism, renal
    phenotype and management are curated in the dedicated entry
    Charcot-Marie-Tooth Disease Dominant Intermediate E; this row records the
    subtype's membership of the intermediate compartment and its gene.
  genes:
  - preferred_term: INF2
    term:
      id: hgnc:23791
      label: INF2
  evidence:
  - reference: PMID:25326399
    reference_title: Intermediate Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "GJB1 is currently considered to be associated with X-linked DI-CMT, and MPZ, INF2, DNM2, YARS, GNB4, NEFL, and MFN2 are associated with autosomal DI-CMT."
    explanation: >-
      A review of the intermediate CMT compartment that names INF2 among the
      genes associated with autosomal dominant-intermediate CMT.
  - reference: PMID:22187985
    reference_title: INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "INF2 mutations appear to cause many cases of FSGS-associated Charcot-Marie-Tooth neuropathy, showing that INF2 is involved in a disease affecting both the kidney glomerulus and the peripheral nervous system."
    explanation: >-
      Source for the co-occurring focal segmental glomerulosclerosis that
      distinguishes this subtype from the other intermediate forms.
- name: DI-CMTF
  display_name: DI-CMTF (GNB4 / G-protein beta-4)
  subtype_term:
    preferred_term: DI-CMTF
    term:
      id: MONDO:0014074
      label: Charcot-Marie-Tooth disease dominant intermediate F
  description: >-
    Dominant-intermediate CMT type F, caused by mutations in GNB4 encoding the
    G-protein beta-4 subunit, implicating G-protein-coupled receptor signaling in
    peripheral-nerve function.
  genes:
  - preferred_term: GNB4
    term:
      id: hgnc:20731
      label: GNB4
  evidence:
  - reference: PMID:23434117
    reference_title: "Exome sequencing identifies GNB4 mutations as a cause of dominant intermediate Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "revealed heterozygous mutation c.158G>A (p.Gly53Asp) in GNB4, encoding guanine-nucleotide-binding protein subunit beta-4"
    explanation: Establishes GNB4 mutations as the cause of dominant-intermediate CMT (DI-CMTF).
- name: DI-CMTG
  display_name: DI-CMTG (NEFL / neurofilament light chain)
  subtype_term:
    preferred_term: DI-CMTG
    term:
      id: MONDO:0036484
      label: Charcot-Marie-Tooth disease, dominant intermediate G
  description: >-
    Dominant-intermediate CMT type G, caused by mutations in NEFL encoding
    neurofilament light chain. NEFL is another gene whose alleles cross the
    compartment boundary: the axonal presentation is curated as CMT2E on
    Charcot-Marie-Tooth Disease Type 2, the demyelinating CMT1F presentation is
    the CMT1F subtype row of Charcot-Marie-Tooth Disease Type 1, which binds
    MONDO:0011902, and the intermediate form has its own dedicated entry,
    Charcot-Marie-Tooth Disease Dominant Intermediate G, which holds the
    mechanism and allele detail.
  genes:
  - preferred_term: NEFL
    term:
      id: hgnc:7739
      label: NEFL
  evidence:
  - reference: PMID:25326399
    reference_title: Intermediate Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "GJB1 is currently considered to be associated with X-linked DI-CMT, and MPZ, INF2, DNM2, YARS, GNB4, NEFL, and MFN2 are associated with autosomal DI-CMT."
    explanation: >-
      A review of the intermediate CMT compartment that names NEFL among the
      genes associated with autosomal dominant-intermediate CMT.
- name: RI-CMTA
  display_name: RI-CMTA (GDAP1 / ganglioside-induced differentiation-associated protein 1)
  subtype_term:
    preferred_term: RI-CMTA
    term:
      id: MONDO:0012014
      label: Charcot-Marie-Tooth disease recessive intermediate A
  description: >-
    Recessive-intermediate CMT type A, caused by biallelic GDAP1 mutations.
    GDAP1 alleles produce demyelinating, axonal and intermediate neuropathy in
    different families, so the demyelinating recessive form (CMT4A) is curated on
    Charcot-Marie-Tooth Disease Type 4 and the axonal form (CMT2K) on
    Charcot-Marie-Tooth Disease Type 2, while this row holds the intermediate
    presentation.
  genes:
  - preferred_term: GDAP1
    term:
      id: hgnc:15968
      label: GDAP1
  evidence:
  - reference: PMID:12566285
    reference_title: "Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nerve conduction velocities were between 25 and 35 m/s and peripheral nerve pathology showed axonal as well as demyelinating changes. These findings fitted the definition of intermediate type CMT and further support the view that GDAP1 is vital for both, axonal integrity and Schwann cell properties."
    explanation: >-
      Establishes biallelic GDAP1 mutations as a cause of intermediate-type CMT,
      with both the conduction-velocity range and the mixed nerve pathology that
      define the compartment.
- name: RI-CMTB
  display_name: RI-CMTB (KARS1 / lysyl-tRNA synthetase)
  subtype_term:
    preferred_term: RI-CMTB
    term:
      id: MONDO:0013338
      label: Charcot-Marie-Tooth disease recessive intermediate B
  description: >-
    Recessive-intermediate CMT type B, caused by biallelic loss-of-function
    mutations in KARS1 (KARS) encoding lysyl-tRNA synthetase — a second
    aminoacyl-tRNA synthetase implicated in CMT, here acting recessively.
  genes:
  - preferred_term: KARS1
    term:
      id: hgnc:6215
      label: KARS1
  evidence:
  - reference: PMID:20920668
    reference_title: "Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we describe three variants (p.Leu133His, p.Tyr173SerfsX7, and p.Ile302Met) in the lysyl-tRNA synthetase (KARS) gene in two patients from this cohort."
    explanation: Establishes compound-heterozygous KARS1 (KARS) loss-of-function variants as a cause of recessive-intermediate CMT (RI-CMTB).
- name: RI-CMTC
  display_name: RI-CMTC (PLEKHG5 / pleckstrin-homology and RhoGEF domain containing G5)
  subtype_term:
    preferred_term: RI-CMTC
    term:
      id: MONDO:0014154
      label: Charcot-Marie-Tooth disease recessive intermediate C
  description: >-
    Recessive-intermediate CMT type C, caused by biallelic PLEKHG5 null alleles.
    PLEKHG5 is expressed in both neurons and glia of the peripheral nervous
    system, and different PLEKHG5 genotypes produce either this intermediate
    neuropathy or a severe childhood-onset lower motor neuron disease.
  genes:
  - preferred_term: PLEKHG5
    term:
      id: hgnc:29105
      label: PLEKHG5
  evidence:
  - reference: PMID:23777631
    reference_title: PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular investigation of the genes from this region allowed identification of two homozygous mutations in PLEKHG5 that produce premature stop codons and are predicted to result in functional null alleles."
    explanation: >-
      Establishes biallelic PLEKHG5 null alleles as the cause of
      recessive-intermediate CMT in two consanguineous families with an
      intermediate-CMT phenotype.
  - reference: PMID:23777631
    reference_title: PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Together, these observations indicate that different mutations in PLEKHG5 lead to clinically diverse outcomes (intermediate CMT or LMND) affecting the function of neurons and glial cells."
    explanation: >-
      Supports the allelic heterogeneity recorded in this row: PLEKHG5 genotype
      determines whether the phenotype is intermediate CMT or lower motor neuron
      disease.
- name: RI-CMTD
  display_name: RI-CMTD (COX6A1 / cytochrome c oxidase subunit 6A1)
  subtype_term:
    preferred_term: RI-CMTD
    term:
      id: MONDO:0014467
      label: Charcot-Marie-Tooth disease recessive intermediate D
  description: >-
    Recessive-intermediate CMT type D, caused by a splice-element deletion in
    COX6A1, a subunit of mitochondrial respiratory complex IV. It is the one
    intermediate-CMT subtype that is simultaneously a mitochondrial oxidative
    phosphorylation disorder, and the respiratory-chain mechanism and its
    metabolic consequences are curated in the dedicated entry
    Charcot-Marie-Tooth Disease Recessive Intermediate D.
  genes:
  - preferred_term: COX6A1
    term:
      id: hgnc:2277
      label: COX6A1
  evidence:
  - reference: PMID:25152455
    reference_title: A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Those data indicated that COX6A1 mutation causes the autosomal-recessive axonal or mixed CMT."
    explanation: >-
      Establishes COX6A1 as the cause of a recessive CMT that includes the mixed
      (intermediate) electrophysiological presentation.
  - reference: PMID:25152455
    reference_title: A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "revealed a disease-specific 5 bp deletion (c.247-10_247-6delCACTC) in a splicing element (pyrimidine tract) of intron 2 adjacent to the third exon of cytochrome c oxidase subunit VIa polypeptide 1 (COX6A1), which is a component of mitochondrial respiratory complex IV (cytochrome c oxidase [COX])"
    explanation: >-
      Identifies the splice-element deletion and places COX6A1 in mitochondrial
      respiratory complex IV, which is why this subtype is also a mitochondrial
      oxidative phosphorylation disorder.
pathophysiology:
- name: DNM2 Membrane Remodeling Defect
  description: >-
    Mutations in DNM2 (DI-CMTB) impair dynamin-2, a large GTPase of the membrane
    fission-fusion machinery that mediates membrane scission during endocytosis
    and vesicle trafficking. Disrupted DNM2-dependent membrane remodeling in
    Schwann cells and neurons produces a mixed demyelinating-and-axonal
    (intermediate) neuropathy.
  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: Endocytosis
    term:
      id: GO:0006897
      label: endocytosis
    modifier: ABNORMAL
  genes:
  - preferred_term: DNM2
    term:
      id: hgnc:2974
      label: DNM2
  downstream:
  - target: Combined Demyelinating and Axonal Degeneration
    description: >-
      DNM2-dependent membrane-trafficking failure impairs both Schwann-cell and
      axonal homeostasis, converging on the mixed intermediate lesion.
  evidence:
  - reference: PMID:15731758
    reference_title: "Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified unique mutations in dynamin 2 (DNM2) in all families. DNM2 belongs to the family of large GTPases and is part of the cellular fusion-fission apparatus."
    explanation: Establishes DNM2 (a membrane fission-fusion GTPase) as the DI-CMTB gene.
- name: Aminoacyl-tRNA Synthetase Dysfunction
  description: >-
    Mutations in the aminoacyl-tRNA synthetases YARS1 (tyrosyl-tRNA synthetase,
    DI-CMTC) and KARS1 (lysyl-tRNA synthetase, RI-CMTB) partially impair
    tRNA-charging (aminoacylation) activity and, for YARS1, mislocalize the
    enzyme within the axon. Aminoacyl-tRNA synthetase impairment is a recurrent
    CMT mechanism, predominantly producing axonal pathology, and here yields the
    intermediate phenotype.
  cell_types:
  - preferred_term: Motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  - preferred_term: Sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  biological_processes:
  - preferred_term: tRNA aminoacylation for protein translation
    term:
      id: GO:0006418
      label: tRNA aminoacylation for protein translation
    modifier: DECREASED
  genes:
  - preferred_term: YARS1
    term:
      id: hgnc:12840
      label: YARS1
  - preferred_term: KARS1
    term:
      id: hgnc:6215
      label: KARS1
  downstream:
  - target: Combined Demyelinating and Axonal Degeneration
    description: >-
      Impaired tRNA aminoacylation compromises protein synthesis in long
      peripheral neurons, converging on the intermediate demyelinating-and-axonal
      lesion.
  evidence:
  - reference: PMID:16429158
    reference_title: "Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Biochemical experiments and genetic complementation in yeast show partial loss of aminoacylation activity of the mutant proteins"
    explanation: Demonstrates partial loss of aminoacylation activity for DI-CMTC YARS1 mutants.
  - reference: PMID:20920668
    reference_title: "Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in three genes encoding aminoacyl-tRNA synthetases (ARSs) have been implicated in CMT disease primarily associated with an axonal pathology."
    explanation: Establishes aminoacyl-tRNA synthetase dysfunction (including KARS1) as a recurrent CMT mechanism.
- name: GNB4 G-Protein Signaling Defect
  description: >-
    Mutations in GNB4 (DI-CMTF) disrupt the G-protein beta-4 subunit, which is
    expressed in axons and Schwann cells of peripheral nerve, implicating
    G-protein-coupled receptor signaling in the maintenance of peripheral-nerve
    function.
  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: G protein-coupled receptor signaling pathway
    term:
      id: GO:0007186
      label: G protein-coupled receptor signaling pathway
    modifier: ABNORMAL
  genes:
  - preferred_term: GNB4
    term:
      id: hgnc:20731
      label: GNB4
  downstream:
  - target: Combined Demyelinating and Axonal Degeneration
    description: >-
      Disrupted Gβ4-related GPCR signaling in peripheral nerve converges on the
      mixed intermediate lesion.
  evidence:
  - reference: PMID:23434117
    reference_title: "Exome sequencing identifies GNB4 mutations as a cause of dominant intermediate Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "revealed heterozygous mutation c.158G>A (p.Gly53Asp) in GNB4, encoding guanine-nucleotide-binding protein subunit beta-4"
    explanation: Establishes GNB4 (G-protein beta-4) as the DI-CMTF gene.
- name: MPZ Compact-Myelin Structural Defect
  biological_scale: CELLULAR
  description: >-
    Heterozygous MPZ mutations (DI-CMTD) disrupt myelin protein zero, the major
    structural glycoprotein of compact peripheral-nerve myelin made by Schwann
    cells. Different MPZ alleles shift the balance between demyelinating and
    axonal pathology; the intermediate presentation shows mild demyelinating
    features with conduction velocities in the intermediate range.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: Myelination in the peripheral nervous system
    term:
      id: GO:0022011
      label: myelination in peripheral nervous system
    modifier: ABNORMAL
  genes:
  - preferred_term: MPZ
    term:
      id: hgnc:7225
      label: MPZ
  downstream:
  - target: Combined Demyelinating and Axonal Degeneration
    description: >-
      Loss of myelin protein zero from compact myelin degrades the myelin sheath
      and, through MPZ's allele-dependent axonal effects, converges on the mixed
      intermediate lesion.
  evidence:
  - reference: PMID:22704856
    reference_title: "Intermediate Charcot-Marie-Tooth disease due to a novel Trp101Stop myelin protein zero mutation associated with debilitating neuropathic pain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Myelin protein zero is a key structural component of compact myelin, and over 100 mutations in this protein have been reported, which can give rise to neuropathies with either axonal, demyelinating, or intermediate features encompassing a wide range of severity."
    explanation: >-
      Establishes MPZ as a structural component of compact myelin and states that
      its mutations can produce intermediate as well as demyelinating and axonal
      neuropathy, which is the claim this node makes.
  - reference: PMID:22704856
    reference_title: "Intermediate Charcot-Marie-Tooth disease due to a novel Trp101Stop myelin protein zero mutation associated with debilitating neuropathic pain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electrophysiological studies revealed mild features of demyelination with median conduction velocity in the intermediate range."
    explanation: >-
      The abnormal-myelination observation in an MPZ kindred whose conduction
      velocities sit in the intermediate range.
- name: GDAP1 Loss of Axonal and Schwann-Cell Integrity
  biological_scale: CELLULAR
  description: >-
    Biallelic GDAP1 loss-of-function alleles (RI-CMTA) compromise peripheral
    nerve on both sides of the axon-glia partnership: nerve pathology in
    intermediate-type GDAP1 families shows axonal degeneration together with
    demyelinating change, which is why GDAP1 alleles can present as axonal,
    demyelinating or intermediate neuropathy.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  - preferred_term: peripheral nerve axon-bearing neuron
    term:
      id: CL:2000032
      label: peripheral nervous system neuron
  genes:
  - preferred_term: GDAP1
    term:
      id: hgnc:15968
      label: GDAP1
  downstream:
  - target: Combined Demyelinating and Axonal Degeneration
    description: >-
      Because GDAP1 loss impairs axonal integrity and Schwann-cell properties at
      the same time, the resulting nerve pathology is mixed rather than
      predominantly demyelinating or predominantly axonal.
  evidence:
  - reference: PMID:12566285
    reference_title: "Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nerve conduction velocities were between 25 and 35 m/s and peripheral nerve pathology showed axonal as well as demyelinating changes. These findings fitted the definition of intermediate type CMT and further support the view that GDAP1 is vital for both, axonal integrity and Schwann cell properties."
    explanation: >-
      States both halves of this node's claim: GDAP1 is required for axonal
      integrity and for Schwann-cell properties, and its loss produces mixed
      nerve pathology in the intermediate conduction-velocity range.
  - reference: PMID:12566285
    reference_title: "Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurophysiology and nerve pathology were heterogeneous in these cases: a subset of GDAP1 mutations was associated with peripheral nerve demyelination, whereas others resulted in axonal degeneration."
    explanation: >-
      Records the allele-dependent split between demyelinating and axonal GDAP1
      pathology that the intermediate presentation sits between.
- name: PLEKHG5 Deficiency in Peripheral Nerve Neurons and Glia
  biological_scale: CELLULAR
  description: >-
    Biallelic PLEKHG5 null alleles (RI-CMTC) remove a protein expressed in both
    the neurons and the glial cells of the peripheral nervous system. Plekhg5
    knockout mice reproduce the reduced nerve conduction velocities seen in
    affected individuals, and the same gene produces a severe childhood-onset
    lower motor neuron disease with other genotypes.
  cell_types:
  - preferred_term: peripheral nervous system neuron
    term:
      id: CL:2000032
      label: peripheral nervous system neuron
  - preferred_term: peripheral nervous system glial cell
    term:
      id: CL:0000125
      label: glial cell
  notes: >-
    The glial binding stays at the root CL:0000125 glial cell because CL has no
    peripheral-nervous-system glia class. Searched ols:cl on 2026-09-26:
    `l^peripheral nervous system` returns exactly one term, CL:2000032 peripheral
    nervous system neuron, and no glial counterpart; `peripheral nervous system
    glial cell` and `satellite glial cell` both return nothing, against a working
    control (`Schwann cell` returns six terms). `l^satellite` returns CL:0000516
    perineuronal satellite cell, which is a real PNS glial type but is not what
    this node claims - the cited sentence reports Plekhg5 expression in peripheral
    glia generally, not in ganglionic satellite glia, so binding it would assert a
    specificity the source does not support. Schwann cell is deliberately not used
    either: it is bound on the GDAP1 node, where the source names Schwann-cell
    properties directly.
  genes:
  - preferred_term: PLEKHG5
    term:
      id: hgnc:29105
      label: PLEKHG5
  downstream:
  - target: Combined Demyelinating and Axonal Degeneration
    description: >-
      Loss of PLEKHG5 from both the neuronal and the glial compartment of
      peripheral nerve converges on the mixed intermediate lesion, measured as
      reduced nerve conduction velocity in patients and in knockout mice.
  evidence:
  - reference: PMID:23777631
    reference_title: PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Analysis of Plekhg5 in the mouse revealed that this gene is expressed in neurons and glial cells of the peripheral nervous system, and that knockout mice display reduced nerve conduction velocities that are comparable with those of affected individuals from both families."
    explanation: >-
      Supports both cell types bound on this node and the reduced conduction
      velocity that is the compartment-defining readout, in a mouse null model
      whose values match the affected families.
  - reference: PMID:23777631
    reference_title: PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following the analysis of two consanguineous families affected by a medium to late-onset recessive form of intermediate CMT, we identified overlapping regions of homozygosity on chromosome 1p36 with a combined maximum LOD score of 5.4."
    explanation: >-
      The human genetic observation that places PLEKHG5 in the intermediate CMT
      compartment.
- name: Combined Demyelinating and Axonal Degeneration
  conforms_to: "peripheral_axonal_degeneration#Distal Axonal Degeneration and Demyelination"
  description: >-
    The shared terminal node of the intermediate CMT compartment. The diverse
    upstream lesions (DNM2 membrane-remodelling failure, aminoacyl-tRNA
    synthetase dysfunction, GNB4 signaling defect, MPZ compact-myelin structural
    failure, GDAP1 loss of axonal and Schwann-cell integrity, and PLEKHG5
    deficiency in peripheral nerve neurons and glia) converge on peripheral nerve
    pathology that combines demyelination and length-dependent axonal
    degeneration — the combination that produces the intermediate nerve
    conduction velocities defining this compartment and the progressive distal
    deficit shared with the CMT1 and CMT2 compartments.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  - preferred_term: Sensory neuron
    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: ABNORMAL
  downstream:
  - target: Distal Muscle Weakness
  - target: Distal Sensory Loss
  - target: Pes Cavus
  - target: Decreased Tendon Reflexes
  - target: Decreased Nerve Conduction Velocity
  evidence:
  - reference: PMID:16429158
    reference_title: "Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Charcot-Marie-Tooth (CMT) neuropathies are common disorders of the peripheral nervous system caused by demyelination or axonal degeneration, or a combination of both features."
    explanation: Supports the combined demyelinating-and-axonal pathology that underlies the intermediate CMT 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:20920668
    reference_title: "Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Charcot-Marie-Tooth (CMT) disease comprises a genetically and clinically heterogeneous group of peripheral nerve disorders characterized by impaired distal motor and sensory function."
    explanation: Supports impaired distal motor function as a core CMT phenotype shared by the intermediate 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:20920668
    reference_title: "Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Charcot-Marie-Tooth (CMT) disease comprises a genetically and clinically heterogeneous group of peripheral nerve disorders characterized by impaired distal motor and sensory function."
    explanation: Supports impaired distal sensory function as a core CMT phenotype shared by the intermediate forms.
- 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: Neurophysiologic
  name: Decreased Nerve Conduction Velocity
  description: >-
    Motor nerve conduction velocities fall in an intermediate range (classically
    ~25–45 m/s) that overlaps the demyelinating CMT1 (<38 m/s) and axonal CMT2
    (>38 m/s) cut-offs, reflecting the combined demyelinating-and-axonal
    pathology that defines this compartment.
  phenotype_term:
    preferred_term: Decreased nerve conduction velocity
    term:
      id: HP:0000762
      label: Decreased nerve conduction velocity
  evidence:
  - reference: PMID:15731758
    reference_title: "Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Different chromosomal loci have been linked with three autosomal dominant, 'intermediate' types of CMT: DI-CMTA, DI-CMTB and DI-CMTC."
    explanation: Establishes the 'intermediate' electrophysiologic category of CMT that this entry models.
genetic:
- name: DNM2
  gene_term:
    preferred_term: DNM2
    term:
      id: hgnc:2974
      label: DNM2
  association: Causal
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: DI-CMTB
  notes: >-
    Dynamin-2, a large GTPase of the membrane fission-fusion apparatus; dominant
    mutations cause DI-CMTB. The gene is pleiotropic (also centronuclear myopathy).
  evidence:
  - reference: PMID:15731758
    reference_title: "Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified unique mutations in dynamin 2 (DNM2) in all families. DNM2 belongs to the family of large GTPases and is part of the cellular fusion-fission apparatus."
    explanation: Establishes DNM2 as the DI-CMTB gene.
- name: YARS1
  gene_term:
    preferred_term: YARS1
    term:
      id: hgnc:12840
      label: YARS1
  association: Causal
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: DI-CMTC
  notes: >-
    Tyrosyl-tRNA synthetase; dominant mutations cause DI-CMTC (the first
    aminoacyl-tRNA synthetase linked to CMT).
  evidence:
  - reference: PMID:16429158
    reference_title: "Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identify two heterozygous missense mutations (G41R and E196K) and one de novo deletion (153-156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three unrelated families affected with DI-CMTC."
    explanation: Establishes YARS1 as the DI-CMTC gene.
- name: GNB4
  gene_term:
    preferred_term: GNB4
    term:
      id: hgnc:20731
      label: GNB4
  association: Causal
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: DI-CMTF
  notes: >-
    G-protein beta-4 subunit expressed in axons and Schwann cells; dominant
    mutations cause DI-CMTF, implicating GPCR signaling in peripheral nerve.
  evidence:
  - reference: PMID:23434117
    reference_title: "Exome sequencing identifies GNB4 mutations as a cause of dominant intermediate Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we previously mapped a dominant intermediate CMT to chromosomal region 3q28-q29."
    explanation: Establishes the dominant-intermediate CMT locus (3q28-q29) subsequently attributed to GNB4 (DI-CMTF).
- name: KARS1
  gene_term:
    preferred_term: KARS1
    term:
      id: hgnc:6215
      label: KARS1
  association: Causal
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: RI-CMTB
  notes: >-
    Lysyl-tRNA synthetase; biallelic loss-of-function variants cause
    recessive-intermediate CMT (RI-CMTB), a second ARS implicated in CMT.
  evidence:
  - reference: PMID:20920668
    reference_title: "Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we describe three variants (p.Leu133His, p.Tyr173SerfsX7, and p.Ile302Met) in the lysyl-tRNA synthetase (KARS) gene in two patients from this cohort."
    explanation: Establishes KARS1 as the RI-CMTB gene.
- name: MPZ
  gene_term:
    preferred_term: MPZ
    term:
      id: hgnc:7225
      label: MPZ
  association: Causal
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: DI-CMTD
  notes: >-
    Myelin protein zero, the major structural glycoprotein of compact
    peripheral-nerve myelin. Heterozygous MPZ alleles cause DI-CMTD. MPZ is the
    clearest cross-compartment allelic series in CMT — the demyelinating form is
    curated as CMT1B on the Charcot-Marie-Tooth Disease Type 1 entry and the
    axonal forms as CMT2I/CMT2J on Charcot-Marie-Tooth Disease Type 2 — so this
    record covers only the intermediate presentation.
  evidence:
  - reference: PMID:22704856
    reference_title: "Intermediate Charcot-Marie-Tooth disease due to a novel Trp101Stop myelin protein zero mutation associated with debilitating neuropathic pain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was an autosomal-dominant pattern of inheritance, and genetic testing revealed a novel heterozygous Trp101X mutation in exon 3 coding for a portion of the extracellular domain of myelin protein zero."
    explanation: >-
      A heterozygous MPZ allele segregating dominantly in a kindred whose
      conduction velocities were in the intermediate range.
  - reference: PMID:22704856
    reference_title: "Intermediate Charcot-Marie-Tooth disease due to a novel Trp101Stop myelin protein zero mutation associated with debilitating neuropathic pain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Myelin protein zero is a key structural component of compact myelin, and over 100 mutations in this protein have been reported, which can give rise to neuropathies with either axonal, demyelinating, or intermediate features encompassing a wide range of severity."
    explanation: >-
      Supports both the protein's role and the allele-dependent spread across the
      demyelinating, axonal and intermediate compartments recorded in the notes.
- name: GDAP1
  gene_term:
    preferred_term: GDAP1
    term:
      id: hgnc:15968
      label: GDAP1
  association: Causal
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: RI-CMTA
  notes: >-
    Ganglioside-induced differentiation-associated protein 1. Biallelic
    loss-of-function alleles cause RI-CMTA. As with MPZ, the GDAP1 allelic series
    crosses compartments: the demyelinating recessive form is curated as CMT4A on
    Charcot-Marie-Tooth Disease Type 4 and the axonal form as CMT2K on
    Charcot-Marie-Tooth Disease Type 2, so this record covers only the
    intermediate presentation.
  evidence:
  - reference: PMID:12566285
    reference_title: "Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygosity for a single base pair insertion in exon 3 (c.349_350insT) was observed in affected children from a Turkish inbred pedigree."
    explanation: >-
      A homozygous frameshift GDAP1 allele in a consanguineous pedigree,
      establishing recessive inheritance for this subtype.
  - reference: PMID:12566285
    reference_title: "Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nerve conduction velocities were between 25 and 35 m/s and peripheral nerve pathology showed axonal as well as demyelinating changes. These findings fitted the definition of intermediate type CMT and further support the view that GDAP1 is vital for both, axonal integrity and Schwann cell properties."
    explanation: >-
      Places these GDAP1 families in the intermediate compartment and states the
      dual axonal and Schwann-cell requirement this entry wires as a
      pathophysiology node.
- name: PLEKHG5
  gene_term:
    preferred_term: PLEKHG5
    term:
      id: hgnc:29105
      label: PLEKHG5
  association: Causal
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: RI-CMTC
  notes: >-
    Pleckstrin homology and RhoGEF domain containing G5. Biallelic null alleles
    cause RI-CMTC. PLEKHG5 is pleiotropic within the motor-neuron and neuropathy
    space: a homozygous missense allele was reported in a severe childhood-onset
    recessive lower motor neuron disease, which this KB curates as the HMNR4
    subtype row on Distal Hereditary Motor Neuronopathy Autosomal Recessive
    rather than here.
  evidence:
  - reference: PMID:23777631
    reference_title: PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular investigation of the genes from this region allowed identification of two homozygous mutations in PLEKHG5 that produce premature stop codons and are predicted to result in functional null alleles."
    explanation: >-
      Establishes biallelic PLEKHG5 null alleles as the cause of this recessive
      intermediate subtype.
  - reference: PMID:23777631
    reference_title: PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, a homozygous PLEKHG5 missense mutation was previously reported in a recessive form of severe childhood onset lower motor neuron disease (LMND) leading to loss of the ability to walk and need for respiratory assistance."
    explanation: >-
      Source for the pleiotropy recorded in the notes: a different PLEKHG5
      genotype produces lower motor neuron disease rather than intermediate CMT.
inheritance:
- name: Autosomal Dominant
  description: >-
    The dominant-intermediate CMT subtypes — DI-CMTB (DNM2), DI-CMTC (YARS1),
    DI-CMTD (MPZ), DI-CMTE (INF2), DI-CMTF (GNB4) and DI-CMTG (NEFL) — are
    inherited in an autosomal dominant manner.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:15731758
    reference_title: "Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Different chromosomal loci have been linked with three autosomal dominant, 'intermediate' types of CMT: DI-CMTA, DI-CMTB and DI-CMTC."
    explanation: Documents autosomal dominant inheritance of the dominant-intermediate CMT subtypes.
- name: Autosomal Recessive
  description: >-
    The recessive-intermediate CMT (RI-CMT) subtypes — RI-CMTA (GDAP1), RI-CMTB
    (KARS1), RI-CMTC (PLEKHG5) and RI-CMTD (COX6A1) — are inherited in an
    autosomal recessive manner, requiring biallelic (compound-heterozygous or
    homozygous) loss-of-function variants.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20920668
    reference_title: "Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we describe three variants (p.Leu133His, p.Tyr173SerfsX7, and p.Ile302Met) in the lysyl-tRNA synthetase (KARS) gene in two patients from this cohort."
    explanation: Documents compound-heterozygous (autosomal recessive) inheritance for RI-CMTB.
  - reference: PMID:12566285
    reference_title: "Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygosity for a single base pair insertion in exon 3 (c.349_350insT) was observed in affected children from a Turkish inbred pedigree."
    explanation: Documents homozygous (autosomal recessive) inheritance for RI-CMTA.
  - reference: PMID:23777631
    reference_title: PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular investigation of the genes from this region allowed identification of two homozygous mutations in PLEKHG5 that produce premature stop codons and are predicted to result in functional null alleles."
    explanation: Documents homozygous (autosomal recessive) inheritance for RI-CMTC.
diagnosis:
- name: Intermediate Nerve Conduction Velocities
  description: >-
    The defining diagnostic feature of intermediate CMT is upper-limb motor nerve
    conduction velocities in an intermediate range that overlaps the CMT1 (<38
    m/s) and CMT2 (>38 m/s) cut-offs, with nerve biopsy showing both
    demyelinating and axonal features. Intermediate CMT is a substantial fraction
    of all CMT: it comprised 13.5% of a large single-centre specialist cohort.
  notes: Distinguishes the intermediate compartment from demyelinating CMT1 and axonal CMT2.
  evidence:
  - reference: DOI:10.1093/brain/awae064
    reference_title: "Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "205 intermediate CMT (CMTi, 13.5%)"
    explanation: Intermediate CMT comprised 13.5% (205/1515) of a specialist CMT cohort, quantifying the size of this compartment.
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: Genetic Counseling
  description: >-
    Counseling for affected individuals and families, addressing the mixed
    dominant and recessive inheritance across intermediate-CMT subtypes.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
references:
- reference: PMID:20301532
  title: "Charcot-Marie-Tooth Hereditary Neuropathy Overview."
  tags:
  - GeneReviews
  findings: []
- reference: DOI:10.1093/brain/awae064
  title: "Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease"
  findings: []
- reference: PMID:25326399
  title: Intermediate Charcot-Marie-Tooth disease.
  findings: []
datasets: []
📚

References & Deep Research

References

3
PMID:20301532
Charcot-Marie-Tooth Hereditary Neuropathy Overview.
No top-level findings curated for this source.
DOI:10.1093/brain/awae064
Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease
No top-level findings curated for this source.
PMID:25326399
Intermediate Charcot-Marie-Tooth disease.
No top-level findings curated for this source.