Charcot-Marie-Tooth Disease Type 4

Mendelian MONDO:0018995 Pathograph 16 Show in embeddings browser Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease type 4 (CMT4) is the autosomal-recessive compartment of Charcot-Marie-Tooth disease. It is the recessive counterpart of the dominant demyelinating (CMT1) and axonal (CMT2) compartments: the primary lesion is again in the myelinating Schwann cell (most CMT4 subtypes are demyelinating, with slowed nerve conduction and, in several forms, redundant myelin outfoldings or onion-bulb formation on nerve biopsy), but inheritance is autosomal recessive and the clinical course is generally earlier in onset and more severe than in the dominant forms. CMT4 is genetically heterogeneous, with each subtype defined by biallelic loss of a distinct Schwann-cell or neuronal gene: GDAP1 (CMT4A, mitochondrial dynamics), MTMR2 (CMT4B1) and SBF2 / MTMR13 (CMT4B2) in the myotubularin phosphoinositide-phosphatase family, SH3TC2 (CMT4C, the most common CMT4 subtype and a cause of early-onset scoliosis), NDRG1 (CMT4D / HMSN-Lom), PRX / periaxin (CMT4F), and FIG4 (CMT4J). Whatever the upstream gene, the subtypes converge on the same terminal node as the other CMT compartments — demyelination with secondary, length-dependent axonal degeneration — producing the shared clinical phenotype of distal weakness, wasting, sensory loss, foot deformity, and depressed reflexes.

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1
Inheritance
5
Pathophys.
6
Phenotypes
16
Pathograph
7
Genes
4
Medical Actions
7
Subtypes
1
Differentials
1
References
👪

Inheritance

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

Subtypes

7
CMT4A (GDAP1-related)
Caused by biallelic mutations in GDAP1, which regulates mitochondrial fission and the mitochondrial network. CMT4A can present with axonal or demyelinating (or mixed) pathology and is often associated with vocal cord paresis. The same gene also causes dominant/recessive axonal CMT2K.
Show evidence (1 reference)
PMID:11743580 SUPPORT Human Clinical
"These results establish the molecular etiology of CMT4A (MIM 214400) and suggest that it may be associated with both axonal and demyelinating phenotypes."
Establishes GDAP1 mutations as the molecular cause of CMT4A, with both axonal and demyelinating phenotypes.
CMT4B1 (MTMR2-related)
Autosomal recessive demyelinating neuropathy with characteristic focally folded (outfolded) myelin, caused by biallelic mutations in MTMR2 encoding myotubularin-related protein-2, a phosphoinositide (dual-specificity) phosphatase.
Show evidence (1 reference)
PMID:10802647 SUPPORT Human Clinical
"we identified in unrelated CMT4B patients mutations occurring in the gene MTMR2, encoding myotubularin-related protein-2, a dual specificity phosphatase (DSP)."
Establishes MTMR2 mutations as the cause of demyelinating CMT4B (CMT4B1) with myelin outfoldings.
CMT4B2 (SBF2 / MTMR13-related)
Autosomal recessive demyelinating neuropathy with myelin outfoldings, in some families associated with early-onset glaucoma, caused by biallelic mutations in SBF2 (MTMR13), a catalytically inactive "pseudophosphatase" member of the myotubularin family.
Show evidence (1 reference)
PMID:12687498 SUPPORT Human Clinical
"a demyelinating CMT, mainly characterized by the presence of myelin outfoldings on nerve biopsies, cosegregated as an autosomal recessive trait with early-onset glaucoma."
Establishes SBF2 / MTMR13 mutations as the cause of demyelinating CMT4B2 with myelin outfoldings and early-onset glaucoma.
CMT4C (SH3TC2-related)
Childhood-onset demyelinating CMT associated with early-onset scoliosis and a distinct Schwann-cell pathology, caused by biallelic mutations in SH3TC2 (originally KIAA1985). CMT4C is the most frequently encountered CMT4 subtype.
Show evidence (1 reference)
PMID:14574644 SUPPORT Human Clinical
"Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary motor and sensory neuropathy associated with an early-onset scoliosis and a distinct Schwann cell pathology."
Establishes CMT4C as a childhood-onset demyelinating neuropathy with early-onset scoliosis caused by SH3TC2 (KIAA1985) mutations.
CMT4D / HMSN-Lom (NDRG1-related)
Autosomal recessive demyelinating neuropathy (hereditary motor and sensory neuropathy-Lom, HMSNL) with Schwann-cell dysfunction and early axonal involvement, originally described in Roma communities with a founder NDRG1 mutation.
Show evidence (1 reference)
PMID:10831399 SUPPORT Human Clinical
"identified the founder HMSNL mutation: a premature-termination codon at position 148 of the N-myc downstream-regulated gene 1 (NDRG1)."
Establishes a founder NDRG1 truncating mutation as the cause of HMSN-Lom (CMT4D).
CMT4F (PRX / periaxin-related)
Autosomal recessive demyelinating CMT (Dejerine-Sottas-like at the severe end) caused by biallelic mutations in PRX encoding periaxin, a protein of myelinating Schwann cells required for myelin sheath stability.
Show evidence (1 reference)
PMID:11157804 SUPPORT Human Clinical
"a locus responsible for a demyelinating form of ARCMT disease, named CMT4F, has been mapped on 19q13 in a large consanguineous Lebanese family."
Establishes CMT4F as a demyelinating autosomal recessive CMT, subsequently attributed to a PRX (periaxin) nonsense mutation.
CMT4J (FIG4-related)
Autosomal recessive CMT caused by biallelic mutations in FIG4, a phosphatidylinositol-3,5-bisphosphate [PtdIns(3,5)P2] 5-phosphatase that regulates membrane trafficking in the endosome-lysosome axis.
Show evidence (1 reference)
PMID:17572665 SUPPORT Human Clinical
"We identified pathogenic mutations of human FIG4 (KIAA0274) on chromosome 6q21 in four unrelated patients with hereditary motor and sensory neuropathy. This novel form of autosomal recessive Charcot-Marie-Tooth disorder is designated CMT4J."
Establishes biallelic FIG4 mutations as the cause of CMT4J in four unrelated patients.
⚙

Pathophysiology

5
GDAP1 Mitochondrial Dynamics Defect
Biallelic GDAP1 mutations (CMT4A) disrupt regulation of the mitochondrial network. GDAP1 promotes mitochondrial fission, and its loss impairs mitochondrial dynamics in Schwann cells and neurons, producing a neuropathy that can be axonal, demyelinating, or mixed and is frequently accompanied by vocal cord paresis.
Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology. Motor neuron CL:0000100 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Motor neuron (CL:0000100). CL:0000100 is a cell type from the Cell Ontology.
GDAP1 hgnc:15968 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GDAP1 (hgnc:15968). hgnc:15968 is a gene from the HUGO Gene Nomenclature Committee.
Mitochondrial fission GO:0000266 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Mitochondrial fission (GO:0000266). GO:0000266 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Demyelination and Secondary Axonal Loss GDAP1-driven mitochondrial dysfunction impairs Schwann-cell and axonal homeostasis, converging on demyelination with secondary axonal loss.
Show evidence (1 reference)
PMID:11743580 SUPPORT Human Clinical
"These results establish the molecular etiology of CMT4A (MIM 214400) and suggest that it may be associated with both axonal and demyelinating phenotypes."
Establishes GDAP1 as the CMT4A gene with both axonal and demyelinating phenotypes.
Myotubularin Phosphoinositide Dysregulation and Myelin Outfolding
Biallelic loss of the myotubularin-family phosphoinositide phosphatases MTMR2 (CMT4B1) and SBF2 / MTMR13 (CMT4B2) dysregulates Schwann-cell membrane phosphoinositide turnover. The resulting membrane-trafficking defect produces the redundant, focally folded (outfolded) myelin that is the histological hallmark of CMT4B, and a demyelinating neuropathy.
Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology.
MTMR2 hgnc:7450 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MTMR2 (hgnc:7450). hgnc:7450 is a gene from the HUGO Gene Nomenclature Committee. SBF2 hgnc:2135 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SBF2 (hgnc:2135). hgnc:2135 is a gene from the HUGO Gene Nomenclature Committee.
Phosphatidylinositol dephosphorylation GO:0046856 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Phosphatidylinositol dephosphorylation (GO:0046856). GO:0046856 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Demyelination and Secondary Axonal Loss Dysregulated Schwann-cell phosphoinositide metabolism produces myelin outfoldings and demyelination with secondary axonal loss.
Show evidence (2 references)
PMID:10802647 SUPPORT Human Clinical
"A gene mutated in Charcot-Marie-Tooth disease type 4B (CMT4B), an autosomal recessive demyelinating neuropathy with myelin outfoldings, has been mapped on chromosome 11q22."
Establishes CMT4B as an autosomal recessive demyelinating neuropathy with myelin outfoldings; MTMR2 (CMT4B1) is the causal phosphoinositide phosphatase.
PMID:12687498 SUPPORT Human Clinical
"we identified two different nonsense mutations in the myotubularin-related 13 gene, MTMR13."
Establishes SBF2 / MTMR13 loss as the CMT4B2 lesion in the same myotubularin outfolding mechanism.
SH3TC2 Endosomal Recycling Defect in Schwann Cells
Biallelic SH3TC2 (KIAA1985) mutations (CMT4C) disrupt an endosomal-recycling function required for normal Schwann-cell myelination, producing a childhood-onset demyelinating neuropathy with a distinct Schwann-cell pathology and prominent early-onset scoliosis.
Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology.
SH3TC2 hgnc:29427 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SH3TC2 (hgnc:29427). hgnc:29427 is a gene from the HUGO Gene Nomenclature Committee.
Endocytic recycling GO:0032456 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Endocytic recycling (GO:0032456). GO:0032456 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Demyelination and Secondary Axonal Loss Impaired SH3TC2-dependent Schwann-cell membrane trafficking produces demyelination with secondary axonal loss.
Show evidence (1 reference)
PMID:14574644 SUPPORT Human Clinical
"We subsequently identified mutations in an uncharacterized transcript, KIAA1985, in 12 families with autosomal recessive neuropathy."
Establishes SH3TC2 (KIAA1985) as the CMT4C gene across 12 autosomal recessive neuropathy families.
Impaired Axon-Glia Interaction
Biallelic loss of Schwann-cell genes NDRG1 (CMT4D / HMSN-Lom) and PRX / periaxin (CMT4F) disrupts myelinating Schwann-cell function and the axon-glia interaction required to maintain the myelin sheath. NDRG1 loss produces Schwann-cell dysfunction with early axonal involvement, and periaxin loss destabilizes the myelin sheath, in both cases yielding a demyelinating neuropathy.
Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology. Sensory neuron of peripheral nervous system CL:0000101 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sensory neuron of peripheral nervous system, annotated with sensory neuron (CL:0000101). CL:0000101 is a cell type from the Cell Ontology.
NDRG1 hgnc:7679 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NDRG1 (hgnc:7679). hgnc:7679 is a gene from the HUGO Gene Nomenclature Committee. PRX hgnc:13797 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PRX (hgnc:13797). hgnc:13797 is a gene from the HUGO Gene Nomenclature Committee.
Myelination in the peripheral nervous system GO:0022011 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Myelination in the peripheral nervous system, annotated with myelination in peripheral nervous system (GO:0022011). GO:0022011 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Demyelination and Secondary Axonal Loss Loss of NDRG1- and periaxin-dependent Schwann-cell function impairs myelin maintenance and axon-glia interaction, producing demyelination with secondary axonal loss.
Show evidence (2 references)
PMID:10831399 SUPPORT Human Clinical
"HMSNL shows features of Schwann-cell dysfunction and a concomitant early axonal involvement, suggesting that impaired axon-glia interactions play a major role in its pathogenesis."
Establishes impaired axon-glia interaction from Schwann-cell NDRG1 loss as the CMT4D (HMSN-Lom) mechanism.
PMID:11157804 SUPPORT Model Organism
"L- and S-periaxin are proteins of myelinating Schwann cells and homozygous periaxin-null mice display extensive demyelination of myelinated fibers in the peripheral nervous system"
Periaxin-null mice show extensive PNS demyelination, supporting periaxin's role in Schwann-cell myelin maintenance in CMT4F.
Demyelination and Secondary Axonal Loss
The shared terminal node of the autosomal-recessive CMT4 compartment. The diverse Schwann-cell and neuronal lesions (GDAP1 mitochondrial dysfunction, myotubularin phosphoinositide dysregulation, SH3TC2 trafficking defect, NDRG1 and periaxin loss) converge on demyelination — often with redundant myelin outfoldings or onion-bulb formation — and, over time, length-dependent secondary axonal degeneration. It is this secondary axonal loss, affecting the longest motor and sensory fibers first, that produces the progressive distal clinical deficit shared across all CMT compartments, typically with earlier onset and greater severity in the recessive forms.
Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology. Sensory neuron of peripheral nervous system CL:0000101 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sensory neuron of peripheral nervous system, annotated with sensory neuron (CL:0000101). CL:0000101 is a cell type from the Cell Ontology.
Myelination in the peripheral nervous system GO:0022011 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Myelination in the peripheral nervous system, annotated with myelination in peripheral nervous system (GO:0022011). GO:0022011 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Distal Muscle Weakness
Distal Sensory Loss
Pes Cavus
Decreased Tendon Reflexes
Scoliosis
Show evidence (1 reference)
PMID:10831399 SUPPORT Human Clinical
"Autosomal recessive peripheral neuropathies are relatively rare but are clinically more severe than autosomal dominant forms of CMT"
Supports the earlier-onset, more-severe clinical course that distinguishes the recessive CMT4 compartment from dominant CMT.
⬡

Pathograph

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

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

Genetic Associations

7
GDAP1 (Causal)
Gene: GDAP1 hgnc:15968 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GDAP1 (hgnc:15968). hgnc:15968 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:11743580 SUPPORT Human Clinical
"These results establish the molecular etiology of CMT4A (MIM 214400) and suggest that it may be associated with both axonal and demyelinating phenotypes."
Establishes GDAP1 as the CMT4A gene.
MTMR2 (Causal)
Gene: MTMR2 hgnc:7450 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MTMR2 (hgnc:7450). hgnc:7450 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:10802647 SUPPORT Human Clinical
"we identified in unrelated CMT4B patients mutations occurring in the gene MTMR2, encoding myotubularin-related protein-2, a dual specificity phosphatase (DSP)."
Establishes MTMR2 as the CMT4B1 gene.
SBF2 (Causal)
Gene: SBF2 hgnc:2135 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SBF2 (hgnc:2135). hgnc:2135 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:12687498 SUPPORT Human Clinical
"we identified two different nonsense mutations in the myotubularin-related 13 gene, MTMR13."
Establishes SBF2 / MTMR13 as the CMT4B2 gene.
SH3TC2 (Causal)
Gene: SH3TC2 hgnc:29427 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SH3TC2 (hgnc:29427). hgnc:29427 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:14574644 SUPPORT Human Clinical
"We subsequently identified mutations in an uncharacterized transcript, KIAA1985, in 12 families with autosomal recessive neuropathy."
Establishes SH3TC2 (KIAA1985) as the CMT4C gene.
NDRG1 (Causal)
Gene: NDRG1 hgnc:7679 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NDRG1 (hgnc:7679). hgnc:7679 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:10831399 SUPPORT Human Clinical
"identified the founder HMSNL mutation: a premature-termination codon at position 148 of the N-myc downstream-regulated gene 1 (NDRG1)."
Establishes NDRG1 as the CMT4D (HMSN-Lom) gene.
PRX (Causal)
Gene: PRX hgnc:13797 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PRX (hgnc:13797). hgnc:13797 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:11157804 SUPPORT Human Clinical
"we identified a nonsense R196X mutation in the Lebanese family which cosegregated with CMT."
Establishes a PRX (periaxin) nonsense mutation cosegregating with CMT4F.
FIG4 (Causal)
Gene: FIG4 hgnc:16873 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FIG4 (hgnc:16873). hgnc:16873 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:17572665 SUPPORT Human Clinical
"We identified pathogenic mutations of human FIG4 (KIAA0274) on chromosome 6q21 in four unrelated patients with hereditary motor and sensory neuropathy. This novel form of autosomal recessive Charcot-Marie-Tooth disorder is designated CMT4J."
Establishes FIG4 as the CMT4J gene in four unrelated patients.
💊

Medical Actions

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

Differential Diagnoses

1

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

Charcot-Marie-Tooth Disease Type 4K
Overlapping Features CMT4K (MONDO:0014733, SURF1-related) is the one CMT4 subtype curated as its own dismech entry rather than in the has_subtypes list above. It is a cytochrome c oxidase assembly defect rather than a Schwann-cell myelin-maintenance defect, and is distinguished clinically by lactic acidosis and by putaminal and periaqueductal lesions developing years after the neuropathy — features no other CMT4 subtype shows.
Distinguishing Features
  • Lactic acidosis
  • Putaminal and periaqueductal brain MRI lesions
  • Cerebellar ataxia developing years after the polyneuropathy
Show evidence (1 reference)
PMID:24027061 SUPPORT Human Clinical
"We found SURF1 mutations in 5% of families (2/41) presenting with CMT4."
Establishes SURF1 as a cause of CMT4 that this entry's has_subtypes list does not cover, and quantifies its share of otherwise unsolved CMT4.
{ }

Source YAML

click to show 
name: Charcot-Marie-Tooth Disease Type 4
creation_date: "2026-07-31T00:00:00Z"
category: Mendelian
description: >-
  Charcot-Marie-Tooth disease type 4 (CMT4) is the autosomal-recessive
  compartment of Charcot-Marie-Tooth disease. It is the recessive counterpart of
  the dominant demyelinating (CMT1) and axonal (CMT2) compartments: the primary
  lesion is again in the myelinating Schwann cell (most CMT4 subtypes are
  demyelinating, with slowed nerve conduction and, in several forms, redundant
  myelin outfoldings or onion-bulb formation on nerve biopsy), but inheritance is
  autosomal recessive and the clinical course is generally earlier in onset and
  more severe than in the dominant forms. CMT4 is genetically heterogeneous, with
  each subtype defined by biallelic loss of a distinct Schwann-cell or
  neuronal gene: GDAP1 (CMT4A, mitochondrial dynamics), MTMR2 (CMT4B1) and SBF2 /
  MTMR13 (CMT4B2) in the myotubularin phosphoinositide-phosphatase family,
  SH3TC2 (CMT4C, the most common CMT4 subtype and a cause of early-onset
  scoliosis), NDRG1 (CMT4D / HMSN-Lom), PRX / periaxin (CMT4F), and FIG4 (CMT4J).
  Whatever the upstream gene, the subtypes converge on the same terminal node as
  the other CMT compartments — demyelination with secondary, length-dependent
  axonal degeneration — producing the shared clinical phenotype of distal
  weakness, wasting, sensory loss, foot deformity, and depressed reflexes.
disease_term:
  preferred_term: Autosomal recessive Charcot-Marie-Tooth disease (CMT4)
  term:
    id: MONDO:0018995
    label: Charcot-Marie-Tooth disease type 4
parents:
- Charcot-Marie-Tooth disease
has_subtypes:
- name: CMT4A
  display_name: CMT4A (GDAP1-related)
  description: >-
    Caused by biallelic mutations in GDAP1, which regulates mitochondrial
    fission and the mitochondrial network. CMT4A can present with axonal or
    demyelinating (or mixed) pathology and is often associated with vocal cord
    paresis. The same gene also causes dominant/recessive axonal CMT2K.
  evidence:
  - reference: PMID:11743580
    reference_title: "The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results establish the molecular etiology of CMT4A (MIM 214400) and suggest that it may be associated with both axonal and demyelinating phenotypes."
    explanation: Establishes GDAP1 mutations as the molecular cause of CMT4A, with both axonal and demyelinating phenotypes.
- name: CMT4B1
  display_name: CMT4B1 (MTMR2-related)
  description: >-
    Autosomal recessive demyelinating neuropathy with characteristic focally
    folded (outfolded) myelin, caused by biallelic mutations in MTMR2 encoding
    myotubularin-related protein-2, a phosphoinositide (dual-specificity)
    phosphatase.
  evidence:
  - reference: PMID:10802647
    reference_title: "Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified in unrelated CMT4B patients mutations occurring in the gene MTMR2, encoding myotubularin-related protein-2, a dual specificity phosphatase (DSP)."
    explanation: Establishes MTMR2 mutations as the cause of demyelinating CMT4B (CMT4B1) with myelin outfoldings.
- name: CMT4B2
  display_name: CMT4B2 (SBF2 / MTMR13-related)
  description: >-
    Autosomal recessive demyelinating neuropathy with myelin outfoldings, in
    some families associated with early-onset glaucoma, caused by biallelic
    mutations in SBF2 (MTMR13), a catalytically inactive "pseudophosphatase"
    member of the myotubularin family.
  evidence:
  - reference: PMID:12687498
    reference_title: "Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a demyelinating CMT, mainly characterized by the presence of myelin outfoldings on nerve biopsies, cosegregated as an autosomal recessive trait with early-onset glaucoma."
    explanation: Establishes SBF2 / MTMR13 mutations as the cause of demyelinating CMT4B2 with myelin outfoldings and early-onset glaucoma.
- name: CMT4C
  display_name: CMT4C (SH3TC2-related)
  description: >-
    Childhood-onset demyelinating CMT associated with early-onset scoliosis and
    a distinct Schwann-cell pathology, caused by biallelic mutations in SH3TC2
    (originally KIAA1985). CMT4C is the most frequently encountered CMT4 subtype.
  evidence:
  - reference: PMID:14574644
    reference_title: "Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary motor and sensory neuropathy associated with an early-onset scoliosis and a distinct Schwann cell pathology."
    explanation: Establishes CMT4C as a childhood-onset demyelinating neuropathy with early-onset scoliosis caused by SH3TC2 (KIAA1985) mutations.
- name: CMT4D
  display_name: CMT4D / HMSN-Lom (NDRG1-related)
  description: >-
    Autosomal recessive demyelinating neuropathy (hereditary motor and sensory
    neuropathy-Lom, HMSNL) with Schwann-cell dysfunction and early axonal
    involvement, originally described in Roma communities with a founder NDRG1
    mutation.
  evidence:
  - reference: PMID:10831399
    reference_title: "N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified the founder HMSNL mutation: a premature-termination codon at position 148 of the N-myc downstream-regulated gene 1 (NDRG1)."
    explanation: Establishes a founder NDRG1 truncating mutation as the cause of HMSN-Lom (CMT4D).
- name: CMT4F
  display_name: CMT4F (PRX / periaxin-related)
  description: >-
    Autosomal recessive demyelinating CMT (Dejerine-Sottas-like at the severe
    end) caused by biallelic mutations in PRX encoding periaxin, a protein of
    myelinating Schwann cells required for myelin sheath stability.
  evidence:
  - reference: PMID:11157804
    reference_title: "A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a locus responsible for a demyelinating form of ARCMT disease, named CMT4F, has been mapped on 19q13 in a large consanguineous Lebanese family."
    explanation: Establishes CMT4F as a demyelinating autosomal recessive CMT, subsequently attributed to a PRX (periaxin) nonsense mutation.
- name: CMT4J
  display_name: CMT4J (FIG4-related)
  description: >-
    Autosomal recessive CMT caused by biallelic mutations in FIG4, a
    phosphatidylinositol-3,5-bisphosphate [PtdIns(3,5)P2] 5-phosphatase that
    regulates membrane trafficking in the endosome-lysosome axis.
  evidence:
  - reference: PMID:17572665
    reference_title: "Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified pathogenic mutations of human FIG4 (KIAA0274) on chromosome 6q21 in four unrelated patients with hereditary motor and sensory neuropathy. This novel form of autosomal recessive Charcot-Marie-Tooth disorder is designated CMT4J."
    explanation: Establishes biallelic FIG4 mutations as the cause of CMT4J in four unrelated patients.
pathophysiology:
- name: GDAP1 Mitochondrial Dynamics Defect
  description: >-
    Biallelic GDAP1 mutations (CMT4A) disrupt regulation of the mitochondrial
    network. GDAP1 promotes mitochondrial fission, and its loss impairs
    mitochondrial dynamics in Schwann cells and neurons, producing a neuropathy
    that can be axonal, demyelinating, or mixed and is frequently accompanied by
    vocal cord paresis.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  - preferred_term: Motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  biological_processes:
  - preferred_term: Mitochondrial fission
    term:
      id: GO:0000266
      label: mitochondrial fission
    modifier: ABNORMAL
  genes:
  - preferred_term: GDAP1
    term:
      id: hgnc:15968
      label: GDAP1
  downstream:
  - target: Demyelination and Secondary Axonal Loss
    description: >-
      GDAP1-driven mitochondrial dysfunction impairs Schwann-cell and axonal
      homeostasis, converging on demyelination with secondary axonal loss.
  evidence:
  - reference: PMID:11743580
    reference_title: "The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results establish the molecular etiology of CMT4A (MIM 214400) and suggest that it may be associated with both axonal and demyelinating phenotypes."
    explanation: Establishes GDAP1 as the CMT4A gene with both axonal and demyelinating phenotypes.
- name: Myotubularin Phosphoinositide Dysregulation and Myelin Outfolding
  conforms_to: "schwann_cell_myelin_maintenance#Myelin Gene Dosage or Structural Lesion in Schwann Cells"
  description: >-
    Biallelic loss of the myotubularin-family phosphoinositide phosphatases MTMR2
    (CMT4B1) and SBF2 / MTMR13 (CMT4B2) dysregulates Schwann-cell membrane
    phosphoinositide turnover. The resulting membrane-trafficking defect produces
    the redundant, focally folded (outfolded) myelin that is the histological
    hallmark of CMT4B, and a demyelinating neuropathy.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: Phosphatidylinositol dephosphorylation
    term:
      id: GO:0046856
      label: phosphatidylinositol dephosphorylation
    modifier: ABNORMAL
  genes:
  - preferred_term: MTMR2
    term:
      id: hgnc:7450
      label: MTMR2
  - preferred_term: SBF2
    term:
      id: hgnc:2135
      label: SBF2
  downstream:
  - target: Demyelination and Secondary Axonal Loss
    description: >-
      Dysregulated Schwann-cell phosphoinositide metabolism produces myelin
      outfoldings and demyelination with secondary axonal loss.
  evidence:
  - reference: PMID:10802647
    reference_title: "Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A gene mutated in Charcot-Marie-Tooth disease type 4B (CMT4B), an autosomal recessive demyelinating neuropathy with myelin outfoldings, has been mapped on chromosome 11q22."
    explanation: Establishes CMT4B as an autosomal recessive demyelinating neuropathy with myelin outfoldings; MTMR2 (CMT4B1) is the causal phosphoinositide phosphatase.
  - reference: PMID:12687498
    reference_title: "Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified two different nonsense mutations in the myotubularin-related 13 gene, MTMR13."
    explanation: Establishes SBF2 / MTMR13 loss as the CMT4B2 lesion in the same myotubularin outfolding mechanism.
- name: SH3TC2 Endosomal Recycling Defect in Schwann Cells
  conforms_to: "schwann_cell_myelin_maintenance#Myelin Gene Dosage or Structural Lesion in Schwann Cells"
  description: >-
    Biallelic SH3TC2 (KIAA1985) mutations (CMT4C) disrupt an endosomal-recycling
    function required for normal Schwann-cell myelination, producing a
    childhood-onset demyelinating neuropathy with a distinct Schwann-cell
    pathology and prominent early-onset scoliosis.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: Endocytic recycling
    term:
      id: GO:0032456
      label: endocytic recycling
    modifier: ABNORMAL
  genes:
  - preferred_term: SH3TC2
    term:
      id: hgnc:29427
      label: SH3TC2
  downstream:
  - target: Demyelination and Secondary Axonal Loss
    description: >-
      Impaired SH3TC2-dependent Schwann-cell membrane trafficking produces
      demyelination with secondary axonal loss.
  evidence:
  - reference: PMID:14574644
    reference_title: "Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We subsequently identified mutations in an uncharacterized transcript, KIAA1985, in 12 families with autosomal recessive neuropathy."
    explanation: Establishes SH3TC2 (KIAA1985) as the CMT4C gene across 12 autosomal recessive neuropathy families.
- name: Impaired Axon-Glia Interaction
  conforms_to: "schwann_cell_myelin_maintenance#Myelin Gene Dosage or Structural Lesion in Schwann Cells"
  description: >-
    Biallelic loss of Schwann-cell genes NDRG1 (CMT4D / HMSN-Lom) and PRX /
    periaxin (CMT4F) disrupts myelinating Schwann-cell function and the
    axon-glia interaction required to maintain the myelin sheath. NDRG1 loss
    produces Schwann-cell dysfunction with early axonal involvement, and
    periaxin loss destabilizes the myelin sheath, in both cases yielding a
    demyelinating neuropathy.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  - preferred_term: Sensory neuron of peripheral nervous system
    term:
      id: CL:0000101
      label: sensory neuron
  biological_processes:
  - preferred_term: Myelination in the peripheral nervous system
    term:
      id: GO:0022011
      label: myelination in peripheral nervous system
    modifier: DECREASED
  genes:
  - preferred_term: NDRG1
    term:
      id: hgnc:7679
      label: NDRG1
  - preferred_term: PRX
    term:
      id: hgnc:13797
      label: PRX
  downstream:
  - target: Demyelination and Secondary Axonal Loss
    description: >-
      Loss of NDRG1- and periaxin-dependent Schwann-cell function impairs
      myelin maintenance and axon-glia interaction, producing demyelination
      with secondary axonal loss.
  evidence:
  - reference: PMID:10831399
    reference_title: "N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HMSNL shows features of Schwann-cell dysfunction and a concomitant early axonal involvement, suggesting that impaired axon-glia interactions play a major role in its pathogenesis."
    explanation: Establishes impaired axon-glia interaction from Schwann-cell NDRG1 loss as the CMT4D (HMSN-Lom) mechanism.
  - reference: PMID:11157804
    reference_title: "A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "L- and S-periaxin are proteins of myelinating Schwann cells and homozygous periaxin-null mice display extensive demyelination of myelinated fibers in the peripheral nervous system"
    explanation: Periaxin-null mice show extensive PNS demyelination, supporting periaxin's role in Schwann-cell myelin maintenance in CMT4F.
- name: Demyelination and Secondary Axonal Loss
  conforms_to: "peripheral_axonal_degeneration#Distal Axonal Degeneration and Demyelination"
  description: >-
    The shared terminal node of the autosomal-recessive CMT4 compartment. The
    diverse Schwann-cell and neuronal lesions (GDAP1 mitochondrial dysfunction,
    myotubularin phosphoinositide dysregulation, SH3TC2 trafficking defect,
    NDRG1 and periaxin loss) converge on demyelination — often with redundant
    myelin outfoldings or onion-bulb formation — and, over time, length-dependent
    secondary axonal degeneration. It is this secondary axonal loss, affecting
    the longest motor and sensory fibers first, that produces the progressive
    distal clinical deficit shared across all CMT compartments, typically with
    earlier onset and greater severity in the recessive forms.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  - preferred_term: Sensory neuron of peripheral nervous system
    term:
      id: CL:0000101
      label: sensory neuron
  biological_processes:
  - preferred_term: Myelination in the peripheral nervous system
    term:
      id: GO:0022011
      label: myelination in peripheral nervous system
    modifier: DECREASED
  downstream:
  - target: Distal Muscle Weakness
  - target: Distal Sensory Loss
  - target: Pes Cavus
  - target: Decreased Tendon Reflexes
  - target: Scoliosis
  evidence:
  - reference: PMID:10831399
    reference_title: "N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive peripheral neuropathies are relatively rare but are clinically more severe than autosomal dominant forms of CMT"
    explanation: Supports the earlier-onset, more-severe clinical course that distinguishes the recessive CMT4 compartment from dominant CMT.
phenotypes:
- category: Neurologic
  name: Distal Muscle Weakness
  diagnostic: true
  phenotype_term:
    preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:11157804
    reference_title: "A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies characterized by chronic distal weakness with progressive muscular atrophy and sensory loss in the distal extremities."
    explanation: Supports progressive distal weakness and muscular atrophy as the core CMT phenotype shared by the recessive CMT4 forms.
- category: Neurologic
  name: Distal Sensory Loss
  phenotype_term:
    preferred_term: Distal sensory impairment
    term:
      id: HP:0002936
      label: Distal sensory impairment
  evidence:
  - reference: PMID:11157804
    reference_title: "A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by chronic distal weakness with progressive muscular atrophy and sensory loss in the distal extremities."
    explanation: Supports distal sensory loss as part of the shared CMT sensorimotor phenotype.
- category: Musculoskeletal
  name: Pes Cavus
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
- category: Neurologic
  name: Decreased Tendon Reflexes
  phenotype_term:
    preferred_term: Hyporeflexia
    term:
      id: HP:0001265
      label: Hyporeflexia
- category: Musculoskeletal
  name: Scoliosis
  subtype: CMT4C
  description: >-
    Early-onset scoliosis is a distinctive and prominent feature of CMT4C
    (SH3TC2), often bringing affected children to attention.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:14574644
    reference_title: "Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary motor and sensory neuropathy associated with an early-onset scoliosis and a distinct Schwann cell pathology."
    explanation: Establishes early-onset scoliosis as a characteristic CMT4C phenotype.
- category: Neurologic
  name: Onion Bulb Formation
  description: >-
    Concentric Schwann-cell processes around demyelinated and remyelinated
    axons, together with redundant myelin outfoldings in the CMT4B subtypes,
    are the biopsy hallmarks of the demyelinating CMT4 forms.
  phenotype_term:
    preferred_term: Onion bulb formation
    term:
      id: HP:0003383
      label: Onion bulb formation
genetic:
- name: GDAP1
  gene_term:
    preferred_term: GDAP1
    term:
      id: hgnc:15968
      label: GDAP1
  association: Causal
  subtype: CMT4A
  notes: >-
    Regulates mitochondrial fission; biallelic mutations cause CMT4A (axonal,
    demyelinating, or mixed, often with vocal cord paresis). The same gene also
    causes axonal CMT2K.
  evidence:
  - reference: PMID:11743580
    reference_title: "The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results establish the molecular etiology of CMT4A (MIM 214400) and suggest that it may be associated with both axonal and demyelinating phenotypes."
    explanation: Establishes GDAP1 as the CMT4A gene.
- name: MTMR2
  gene_term:
    preferred_term: MTMR2
    term:
      id: hgnc:7450
      label: MTMR2
  association: Causal
  subtype: CMT4B1
  notes: >-
    Myotubularin-related protein-2, a phosphoinositide phosphatase; biallelic
    mutations cause demyelinating CMT4B1 with myelin outfoldings.
  evidence:
  - reference: PMID:10802647
    reference_title: "Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified in unrelated CMT4B patients mutations occurring in the gene MTMR2, encoding myotubularin-related protein-2, a dual specificity phosphatase (DSP)."
    explanation: Establishes MTMR2 as the CMT4B1 gene.
- name: SBF2
  gene_term:
    preferred_term: SBF2
    term:
      id: hgnc:2135
      label: SBF2
  association: Causal
  subtype: CMT4B2
  notes: >-
    SBF2 (MTMR13), a catalytically inactive pseudophosphatase of the myotubularin
    family; biallelic mutations cause demyelinating CMT4B2 with myelin
    outfoldings, sometimes with early-onset glaucoma.
  evidence:
  - reference: PMID:12687498
    reference_title: "Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified two different nonsense mutations in the myotubularin-related 13 gene, MTMR13."
    explanation: Establishes SBF2 / MTMR13 as the CMT4B2 gene.
- name: SH3TC2
  gene_term:
    preferred_term: SH3TC2
    term:
      id: hgnc:29427
      label: SH3TC2
  association: Causal
  subtype: CMT4C
  notes: >-
    Encodes an SH3/TPR-domain protein (originally KIAA1985) required for
    Schwann-cell myelination; biallelic mutations cause CMT4C, the most common
    CMT4 subtype, with early-onset scoliosis.
  evidence:
  - reference: PMID:14574644
    reference_title: "Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We subsequently identified mutations in an uncharacterized transcript, KIAA1985, in 12 families with autosomal recessive neuropathy."
    explanation: Establishes SH3TC2 (KIAA1985) as the CMT4C gene.
- name: NDRG1
  gene_term:
    preferred_term: NDRG1
    term:
      id: hgnc:7679
      label: NDRG1
  association: Causal
  subtype: CMT4D
  notes: >-
    N-myc downstream-regulated gene 1; a founder truncating mutation causes
    CMT4D / HMSN-Lom with Schwann-cell dysfunction and early axonal involvement.
  evidence:
  - reference: PMID:10831399
    reference_title: "N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified the founder HMSNL mutation: a premature-termination codon at position 148 of the N-myc downstream-regulated gene 1 (NDRG1)."
    explanation: Establishes NDRG1 as the CMT4D (HMSN-Lom) gene.
- name: PRX
  gene_term:
    preferred_term: PRX
    term:
      id: hgnc:13797
      label: PRX
  association: Causal
  subtype: CMT4F
  notes: >-
    Periaxin, a protein of myelinating Schwann cells required for myelin-sheath
    stability; biallelic mutations cause demyelinating CMT4F (Dejerine-Sottas-like
    at the severe end).
  evidence:
  - reference: PMID:11157804
    reference_title: "A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a nonsense R196X mutation in the Lebanese family which cosegregated with CMT."
    explanation: Establishes a PRX (periaxin) nonsense mutation cosegregating with CMT4F.
- name: FIG4
  gene_term:
    preferred_term: FIG4
    term:
      id: hgnc:16873
      label: FIG4
  association: Causal
  subtype: CMT4J
  notes: >-
    A PtdIns(3,5)P2 5-phosphatase regulating endosome-lysosome membrane
    trafficking; biallelic mutations cause CMT4J.
  evidence:
  - reference: PMID:17572665
    reference_title: "Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified pathogenic mutations of human FIG4 (KIAA0274) on chromosome 6q21 in four unrelated patients with hereditary motor and sensory neuropathy. This novel form of autosomal recessive Charcot-Marie-Tooth disorder is designated CMT4J."
    explanation: Establishes FIG4 as the CMT4J gene in four unrelated patients.
inheritance:
- name: Autosomal Recessive
  description: >-
    By definition, the CMT4 subtypes are inherited in an autosomal recessive
    manner: affected individuals carry biallelic (homozygous or compound
    heterozygous) pathogenic variants, most commonly in consanguineous families.
    Recessive CMT is generally earlier in onset and clinically more severe than
    the dominant CMT1/CMT2 forms.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:10831399
    reference_title: "N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive peripheral neuropathies are relatively rare but are clinically more severe than autosomal dominant forms of CMT"
    explanation: Documents autosomal recessive inheritance and the more severe course characteristic of CMT4.
treatments:
- name: Physical and Occupational Therapy
  description: Mainstay of supportive care to maintain mobility and function.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
- name: Orthotic Bracing
  description: Ankle-foot orthoses to compensate for foot drop and improve gait.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Scoliosis Management
  description: >-
    Bracing and, when required, corrective spinal surgery for the early-onset
    scoliosis that is prominent in CMT4C.
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
- name: Genetic Counseling
  description: >-
    Counseling for affected individuals and families, with attention to the
    recessive inheritance pattern, recurrence risk in consanguineous unions, and
    carrier testing.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
differential_diagnoses:
- name: Charcot-Marie-Tooth Disease Type 4K
  description: >-
    CMT4K (MONDO:0014733, SURF1-related) is the one CMT4 subtype curated as its
    own dismech entry rather than in the has_subtypes list above. It is a
    cytochrome c oxidase assembly defect rather than a Schwann-cell
    myelin-maintenance defect, and is distinguished clinically by lactic
    acidosis and by putaminal and periaqueductal lesions developing years after
    the neuropathy — features no other CMT4 subtype shows.
  distinguishing_features:
  - Lactic acidosis
  - Putaminal and periaqueductal brain MRI lesions
  - Cerebellar ataxia developing years after the polyneuropathy
  evidence:
  - reference: PMID:24027061
    reference_title: "SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found SURF1 mutations in 5% of families (2/41) presenting with CMT4."
    explanation: >-
      Establishes SURF1 as a cause of CMT4 that this entry's has_subtypes list
      does not cover, and quantifies its share of otherwise unsolved CMT4.
references:
- reference: PMID:20301532
  title: "Charcot-Marie-Tooth Hereditary Neuropathy Overview."
  tags:
  - GeneReviews
  findings: []
datasets: []
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References & Deep Research

References

1
PMID:20301532
Charcot-Marie-Tooth Hereditary Neuropathy Overview.
No top-level findings curated for this source.