Charcot-Marie-Tooth Disease Dominant Intermediate G

Mendelian MONDO:0036484 Pathograph 24 Show in embeddings browser Intermediate Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease dominant intermediate G (CMTDIG) is the intermediate-conduction presentation of autosomal dominant NEFL-related neuropathy: heterozygous missense variants in the neurofilament light polypeptide gene produce upper-limb motor conduction velocities in the intermediate band (roughly 25-45 m/s) that fit neither the demyelinating (CMT1F) nor the axonal (CMT2E) category. The mechanism explains why. NEFL variants disrupt neurofilament co-assembly and cause the protein to misdistribute and aggregate in neuronal cell bodies and proximal axons, so neurofilaments never reach the distal axon. Because neurofilaments are the space-filling structures that drive radial axonal growth, the axon fails to expand to normal calibre — and conduction velocity depends on calibre as well as on myelin. Slowed conduction therefore arises without a primary myelin lesion, which is exactly what an intermediate electrophysiological picture looks like. Two further features recur in reported CMTDIG families and set the entity apart from the ordinary length-dependent CMT picture: central nervous system involvement, from abnormal evoked potentials and blink reflexes through to cerebellar ataxia with cerebellar atrophy; and early onset, with delayed motor milestones in the more severe pedigrees.

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1
Inheritance
7
Pathophys.
14
Phenotypes
3
Gaps
24
Pathograph
1
Genes
2
Medical Actions
3
Differentials
2
Models
1
References
1
Deep Research
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Inheritance

1
Autosomal Dominant HP:0000006
Heterozygous NEFL missense variants, transmitted dominantly. De novo variants are common: eight of 17 NEFL families in a Korean national series were de novo, three of them in the CMTDIG subgroup, so a negative family history does not argue against the diagnosis.
Autosomal dominant inheritance
Show evidence (2 references)
CGGV:assertion_57ec533a-b1cb-4d1d-b12a-61ee6ac6ab07-2023-01-10T170000.000Z SUPPORT DIRECT Other
"NEFL | HGNC:7739 | Charcot-Marie-Tooth disease | MONDO:0015626 | AD | Definitive"
ClinGen classifies autosomal dominant NEFL-related CMT as a definitive gene-disease relationship.
PMID:35044100 SUPPORT DIRECT Human Clinical
"Eight de novo cases (FC549 in CMT1F; FC441, FC838, and FC984 in CMTDIG; and FC21, FC264, FC497, and FC930 in CMT2E) were identified at a rate of 0.47 based on a trio-family analysis"
Quantifies the de novo rate and names three CMTDIG families among the de novo cases.
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Discussions and Knowledge Gaps

3
Is CMTDIG a distinct disease, or an electrophysiological presentation of one autosomal dominant NEFL neuropathy that also presents as CMT1F and CMT2E?
KNOWLEDGE GAP cmtdig_is_a_presentation_not_an_entity
Attached to
disease#Charcot-Marie-Tooth Disease Dominant Intermediate G pathophysiology#Intermediate-Range Nerve Conduction Slowing
Two independent authorities say the latter. A dedicated review of the NEFL clinical literature found no correlation between variant, protein domain and disease classification, found six variants each reported under more than one label, and concluded that all NEFL-related CMT is axonal in nature. ClinGen curates one autosomal dominant NEFL-CMT gene-disease relationship and does not recognize CMT1F, CMT2E or CMTDIG as separate entities. Against that, MONDO and OMIM both carry CMTDIG as its own concept, the label is in active clinical use — applied to 29% of kindreds in a pooled literature analysis and 64.9% of patients in a Korean national cohort — and one cohort reports a leg MRI compartment pattern that differs between the three groups. This entry is curated as a Disease because the concept is real, uncurated and in use, and because the mechanism by which conduction becomes intermediate is worth stating explicitly. It should not be read as an assertion that CMTDIG is mechanistically distinct from CMT2E; the entry says the opposite. A curator who preferred to fold this into the NEFL subtype of Charcot-Marie-Tooth Disease Type 2 would be acting on the same evidence, and this discussion exists so that decision can be made from the record rather than made again from scratch.
What is the substrate of the central nervous system involvement in dominant-intermediate NEFL neuropathy?
KNOWLEDGE GAP cmtdig_central_nervous_system_substrate
Attached to
pathophysiology#Central Nervous System Involvement
The defining pedigree has abnormal multimodal evoked potentials, an abnormal blink reflex and a spastic gait; a second pedigree has cerebellar ataxia with cerebellar atrophy. The Nefl N98S mouse shows neurofilament aggregation in cerebellum, cortex and pons, which is a plausible substrate, but no human neuropathology has been reported and no imaging or electrophysiological series has quantified central involvement in this group. The edge into the central node is therefore typed as having unknown intermediates.
Does any animal model reproduce intermediate-range conduction slowing, the feature that defines this entity?
HUMAN MODEL MISMATCH cmtdig_no_model_of_the_defining_feature
Attached to
animal_models#Nefl N98S knock-in mouse animal_models#Nefl E397K knock-in mouse
Both available knock-in mice carry variants reported in dominant-intermediate pedigrees — N98S, and the murine equivalent of the CMTDIG-defining E396K — and both are characterized and published by their authors as models of CMT2E. The E397K longitudinal electrophysiology reports distal latency, CMAP amplitude and negative area, which is an axonal pattern; conduction velocity is not among the reported measures. So the models reproduce the neurofilament and calibre mechanism well and say nothing about the electrophysiological threshold that gives the entity its name. This is consistent with the view that the intermediate label reflects human presentation variability rather than a separate mechanism, but it has not been tested.
Proposed experiments
Conduction velocity phenotyping of the Nefl E397K knock-in mouse
cmtdig_e397k_conduction_velocity
Measure motor nerve conduction velocity longitudinally in Nefl(+/E397K) mice against wild-type littermates, and relate it to axon calibre distribution and myelin morphometry in the same nerves.
Would support
pathophysiology#Failure of Radial Axonal Growth
Would refute
pathophysiology#Failure of Radial Axonal Growth
Supporting outcome
  • Conduction velocity falls in proportion to the loss of large-calibre axons while myelin thickness relative to a matched axon is preserved, confirming that reduced calibre alone produces the slowing.
Refuting outcome
  • Conduction velocity is preserved despite reduced axon calibre, or falls only where myelin is abnormal, which would mean the calibre mechanism does not explain the human intermediate velocities.
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Pathophysiology

7
Heterozygous NEFL Missense Variant
A single missense allele of NEFL, encoding neurofilament light polypeptide. Variants span the head, rod and tail domains, with recurrent hotspots at Pro8, Pro22 and Asn98; p.Glu396Lys, which lies just outside the rod domain and disrupts the heptad repeat that defines the coiled coil, is the variant reported in the pedigree on which the CMTDIG designation rests. ClinGen characterizes the pathogenic mechanism as a gain of function arising from misdistribution and aggregation of the protein — that is, the mutant subunit poisons the co-assembled network rather than simply being absent, which is consistent with the observation that heterozygous carriers of NEFL null alleles are unaffected.
Genetic context NEFL hgnc:7739 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns NEFL (hgnc:7739). hgnc:7739 is a gene from the HUGO Gene Nomenclature Committee. zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
Downstream
Neurofilament Network Disruption and NFL Aggregation The mutant subunit co-assembles into the neurofilament network and disrupts it.
Show evidence (3 references)
CGGV:assertion_57ec533a-b1cb-4d1d-b12a-61ee6ac6ab07-2023-01-10T170000.000Z SUPPORT DIRECT Other
"The mechanism of pathogenicity appears to be a gain-of-function due to misdistribution and aggregate formations of NFL."
ClinGen's mechanism statement, which is the basis for the functional_impact_category set on this node.
PMID:25877835 SUPPORT DIRECT Human Clinical
"The purpose of the study was to describe a pedigree with NEFL E396K mutation associated with a novel dominant intermediate Charcot-Marie-Tooth disease (DI-CMT) phenotype."
The pedigree that established the CMTDIG designation and its causal variant.
PMID:33993654 SUPPORT DIRECT Human Clinical
"Where the inheritance pattern of the mutations is known, it is always autosomal dominant for the in-frame deletion and missense mutations and autosomal recessive for the nonsense mutations located in the rod domain."
Separates the dominant missense alleles relevant to CMTDIG from the recessive null alleles, which cause a different disease.
Neurofilament Network Disruption and NFL Aggregation
Every CMTDIG-associated variant tested in vitro disrupts the neurofilament network and causes NFL to aggregate. In the Nefl N98S knock-in mouse the aggregates are visible as inclusions in the cell bodies and proximal axons of spinal cord neurons.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
neurofilament cytoskeleton organization GO:0060052 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated neurofilament cytoskeleton organization (GO:0060052). GO:0060052 is a biological process from the Gene Ontology. ↕ DYSREGULATED
neurofilament GO:0005883 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves neurofilament (GO:0005883). GO:0005883 is a cellular component from the Gene Ontology.
Animal models
Nefl N98S knock-in mouse Mouse recapitulates Neurofilament inclusions appear in neuronal cell bodies and proximal axons, matching the misdistribution-and-aggregation mechanism ClinGen describes for the human disease.
Downstream
Failure of Neurofilament Delivery to Distal Axons Neurofilaments trapped in aggregates in the cell body and proximal axon do not travel down the axon.
Central Nervous System Involvement NEFL is expressed in central as well as peripheral neurons, and the mouse shows aggregation in cerebellum, cortex and pons; the steps between that and the human central findings have not been established.
Show evidence (2 references)
CGGV:assertion_57ec533a-b1cb-4d1d-b12a-61ee6ac6ab07-2023-01-10T170000.000Z SUPPORT INDIRECT Other
"In-vitro functional studies for all described variants depict disruptions in NF network and aggregation of NFL."
ClinGen's summary of the in vitro functional evidence across all curated dominant NEFL variants. Graded OTHER, not IN_VITRO: evidence_source classifies the cited publication, and a ClinGen curation record is a curation record throughout, whatever kind of study it is summarizing. INDIRECT for the same reason -- it reports somebody else's experiments.
PMID:25552649 SUPPORT DIRECT Model Organism
"Immunohistochemical analysis revealed multiple inclusions in the cell bodies and proximal axons of spinal cord neurons, disorganized processes in the cerebellum and abnormal processes in the cerebral cortex and pons."
Shows the aggregation in vivo, and shows it in central as well as peripheral neurons.
Failure of Neurofilament Delivery to Distal Axons
Neurofilaments are assembled in the cell body and delivered along the axon by microtubule-based transport. In the Nefl N98S mouse the sciatic nerve shows fewer neurofilaments, more microtubules, and smaller axons — the axonal content of the cytoskeleton is changed, not just its organization.
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.
neurofilament bundle assembly GO:0033693 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neurofilament bundle assembly (GO:0033693). GO:0033693 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Nefl N98S knock-in mouse Mouse recapitulates Sciatic nerve ultrastructure shows the axon depleted of neurofilaments and reduced in diameter, which is the step this entry places between the aggregation and the slowed conduction.
Downstream
Failure of Radial Axonal Growth Without axonal neurofilaments the axon cannot expand and maintain its diameter.
Show evidence (1 reference)
PMID:25552649 SUPPORT DIRECT Model Organism
"Electron microscopic analysis of sciatic nerves showed a reduction in the number of neurofilaments, an increase in the number of microtubules and a decrease in the axonal diameters."
Direct ultrastructural measurement of neurofilament loss from the peripheral axon and the accompanying loss of calibre.
Failure of Radial Axonal Growth
Neurofilaments are the structures responsible for radial growth of axons during development and for maintaining axonal diameter afterwards. Losing them from the axon leaves a thin axon. This is the step that makes CMTDIG intermediate rather than axonal or demyelinating, and it has been measured directly in the mouse carrying the CMTDIG variant, where sciatic axon area and diameter are reduced from postnatal day 21 onward.
radial growth and maintenance of axon diameter GO:0031133 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased radial growth and maintenance of axon diameter, annotated with regulation of axon diameter (GO:0031133). GO:0031133 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Nefl E397K knock-in mouse Mouse recapitulates Sciatic axon area and diameter are significantly reduced from postnatal day 21 and worsen through twelve months, matching the failure of radial growth this entry places upstream of the conduction abnormality.
Downstream
Intermediate-Range Nerve Conduction Slowing Conduction velocity scales with axonal calibre, so a thin axon conducts slowly even with an intact myelin sheath.
Length-Dependent Sensorimotor Axonal Degeneration An axon that cannot build or maintain its cytoskeleton eventually degenerates, longest fibres first.
Show evidence (2 references)
PMID:28501821 SUPPORT INDIRECT Human Clinical
"Neurofilaments are neuron-specific intermediate filaments essential for the radial growth of axons during development and the maintenance of the axonal diameter."
Establishes the normal function whose loss this node describes. Graded INDIRECT because it states the physiology rather than measuring the defect in CMTDIG patients.
PMID:40635134 SUPPORT DIRECT Model Organism
"A significant reduction in the sciatic nerve axon area, diameter, and G-ratio was also present as early as P21."
Measures reduced axonal calibre in a mouse carrying the murine equivalent of the CMTDIG variant p.Glu396Lys. Note the g-ratio falls together with axon diameter, meaning the axon shrank relative to its sheath; this is not a demyelination finding.
Intermediate-Range Nerve Conduction Slowing
Upper-limb motor conduction velocities fall in the intermediate band of roughly 25-45 m/s, in proximal as well as distal nerve segments, and this is what the CMTDIG label denotes. The important interpretive point is that a slow velocity is conventionally read as demyelination, but velocity also depends on axonal calibre — so a widespread reduction in calibre produces the same reading with normal myelin. NEFL is a neuronal protein and is not expressed in myelinating cells at all.
Animal models
Nefl E397K knock-in mouse Mouse fails to recapitulate The human pedigree carrying this variant is defined by uniform slowing of conduction velocity into the intermediate range. The mouse carrying the equivalent variant is reported with an axonal electrophysiological signature — distal latency and CMAP amplitude and negative area — and its authors classify it as CMT2E. The one feature that makes CMTDIG a named entity is therefore not what this model reproduces.
Downstream
Intermediate-Range Motor Nerve Conduction Slowing The measured electrophysiological abnormality.
Show evidence (3 references)
PMID:25877835 SUPPORT DIRECT Human Clinical
"Electrophysiology showed uniform nerve conduction slowing in the intermediate range, both in distal and proximal nerve segments."
The electrophysiological finding that defines this entity, in the defining pedigree.
PMID:28501821 SUPPORT DIRECT Human Clinical
"although intermediate forms of CMT with MNCV of 25-45 m/s are also recognised"
Gives the conduction velocity band that defines the intermediate category.
PMID:33993654 SUPPORT DIRECT Human Clinical
"However, it is important to note that axonal conduction velocity is also influenced by other factors including axonal caliber (Waxman 1980). Thus, a widespread reduction in axonal caliber could also result in a reduction in NCV."
States the interpretive argument that links the calibre node to the conduction node without invoking demyelination.
Length-Dependent Sensorimotor Axonal Degeneration
The clinical neuropathy: distal-predominant weakness, wasting and sensory loss with foot deformity, which in the more severely affected reported families ascends to involve pelvic musculature and produces a waddling gait. Sural nerve biopsies in NEFL-related CMT show preferential loss of large myelinated fibres.
Downstream
Onion Bulb Formation Repeated de- and remyelination around a failing axon produces onion bulbs without a primary myelin defect.
Claw Hand Deformity Intrinsic hand muscle weakness with preserved long flexors produces the clawed posture.
Areflexia Loss of the afferent limb of the tendon reflex.
Delayed Ability to Walk In the early-onset pedigree the neuropathy is present before walking is acquired, so it delays the milestone rather than degrading a skill already gained. The mildly affected child had hypotonia and areflexia at 5 years, which is why this edge comes from the peripheral node rather than from the central one.
Distal Muscle Weakness Distal motor involvement.
Distal Sensory Impairment Distal sensory involvement.
Pes Cavus Foot deformity from imbalanced weakness of intrinsic and extrinsic foot muscles.
Proximal Muscle Weakness Ascending involvement of pelvic musculature in the more advanced reported patients.
Show evidence (3 references)
PMID:25877835 SUPPORT DIRECT Human Clinical
"Their clinical picture was characterized by pes cavus, sensorimotor neuropathy and spastic gait. Both older patients showed ascending leg weakness to involve pelvic musculature."
The clinical syndrome in the defining CMTDIG pedigree.
PMID:28501821 SUPPORT INDIRECT Human Clinical
"Although the reduced velocities may well be mainly explained by preferential loss of large-myelinated fibres confirmed in 21 sural nerve biopsies"
The nerve-biopsy correlate. Graded INDIRECT because the 21 biopsies come from NEFL-related CMT as a whole rather than from CMTDIG patients specifically.
PMID:12566280 SUPPORT DIRECT Human Clinical
"We report the first nerve biopsy of a CMT patient with a de novo missense mutation in NEFL, and found an axonal pathology with axonal regeneration clusters and onion bulb formations."
Onion bulbs, the histological hallmark of demyelination and remyelination, appear in a nerve whose primary pathology is axonal and whose causal gene is not expressed by Schwann cells at all. This is the histological form of the entry's central claim: the myelin-range findings in NEFL neuropathy are secondary to the axon, not a primary Schwann-cell lesion.
Central Nervous System Involvement
CMTDIG is not confined to the peripheral nerve. In the defining pedigree, multimodal evoked potentials and blink reflex studies showed central sensorimotor pathway dysfunction, and the patients had a spastic gait. In a second dominant-intermediate pedigree the proband had cerebellar ataxia, nystagmus and dysarthria with cerebellar atrophy on MRI, and had been misdiagnosed as sporadic early-onset cerebellar ataxia. The route from NEFL aggregation to these findings is not established, which is why the edge into this node is typed as having unknown intermediates.
Downstream
Ataxia Cerebellar ataxia in the reported severe phenotype.
Cerebellar Atrophy The structural correlate on MRI.
Dysarthria Part of the cerebellar syndrome in the same patient as the ataxia, not a bulbar consequence of the peripheral neuropathy.
Nystagmus Gaze-evoked nystagmus, recorded alongside the ataxia and dysarthria.
Spastic Gait Corticospinal involvement in the defining pedigree.
Show evidence (2 references)
PMID:25877835 SUPPORT DIRECT Human Clinical
"Multimodal evoked potential and blink reflex studies revealed abnormalities indicative of central sensorimotor pathway dysfunction."
Electrophysiological evidence of central involvement in the defining CMTDIG pedigree.
PMID:26645395 SUPPORT DIRECT Human Clinical
"In the proband, cranial magnetic resonance imaging (MRI) showed cerebellar atrophy, electromyography disclosed active denervation in tibialis anterior, and MRI of lower-limb musculature demonstrated widespread and distally accentuated muscle fatty atrophy"
Imaging evidence of cerebellar involvement in a second dominant-intermediate NEFL pedigree.
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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 Charcot-Marie-Tooth Disease Dominant Intermediate G 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

14
Eye 1
Nystagmus HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26645395 SUPPORT DIRECT Human Clinical
"gait and kinetic cerebellar ataxia, nystagmus and dysarthria, she being wheelchair bound"
Nystagmus recorded in the same patient.
Limbs 2
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.
Show evidence (1 reference)
PMID:25877835 SUPPORT DIRECT Human Clinical
"Their clinical picture was characterized by pes cavus, sensorimotor neuropathy and spastic gait."
Pes cavus in all four patients of the defining pedigree.
Claw Hand Deformity HP:0034337 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Claw hand deformity (HP:0034337). HP:0034337 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26645395 SUPPORT DIRECT Human Clinical
"severe phenotype consisting of sensorimotor neuropathy, pes cavus, clawing hands, gait and kinetic cerebellar ataxia"
Clawed hands recorded in the dominant-intermediate proband.
Musculoskeletal 3
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:25877835 SUPPORT DIRECT Human Clinical
"CMT neuropathy score ranged from 14 to 26 (moderate to severe disease)."
Quantifies severity in the four patients of the defining pedigree. No frequency band is set because the published CMTDIG series are too small to support one.
Proximal Muscle Weakness HP:0003701 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proximal muscle weakness (HP:0003701). HP:0003701 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25877835 SUPPORT DIRECT Human Clinical
"In both patients exhibiting waddling gait, there was atrophy of pelvic muscles mainly involving gluteus medius, gluteus minimus and piriformis."
Imaging confirmation of proximal muscle involvement in two of four patients.
Spastic Gait HP:0002064 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spastic gait (HP:0002064). HP:0002064 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25877835 SUPPORT DIRECT Human Clinical
"Their clinical picture was characterized by pes cavus, sensorimotor neuropathy and spastic gait."
Spastic gait recorded in the defining pedigree.
Nervous System 8
Intermediate-Range Motor Nerve Conduction Slowing OBLIGATE Decreased motor nerve conduction velocity HP:0003431 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intermediate-range motor nerve conduction slowing, annotated with Decreased motor nerve conduction velocity (HP:0003431). HP:0003431 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25877835 SUPPORT DIRECT Human Clinical
"Electrophysiology showed uniform nerve conduction slowing in the intermediate range, both in distal and proximal nerve segments."
The defining electrophysiological finding.
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:35044100 SUPPORT INDIRECT Human Clinical
"In all subtypes, sensory electrophysiological data indicate more prominent impairment than those for motor function."
Graded INDIRECT because the statement is made across all three NEFL subgroups rather than for CMTDIG alone, though it explicitly includes it.
Ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar ataxia, annotated with Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26645395 SUPPORT DIRECT Human Clinical
"The proband, evaluated at age 31, showed delayed motor milestones that, as of the second decade, evolved into severe phenotype consisting of sensorimotor neuropathy, pes cavus, clawing hands, gait and kinetic cerebellar ataxia, nystagmus and dysarthria, she being wheelchair bound."
Cerebellar ataxia in a dominant-intermediate NEFL patient.
PMID:35044100 SUPPORT INDIRECT Human Clinical
"Signs of ataxia were found in 26 patients (70.3%)."
A frequency for NEFL-related CMT as a whole, not for CMTDIG. Curated as context and deliberately not used to set a frequency band.
Cerebellar Atrophy HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar atrophy (HP:0001272). HP:0001272 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26645395 SUPPORT DIRECT Human Clinical
"In the proband, cranial magnetic resonance imaging (MRI) showed cerebellar atrophy"
Imaging finding in the one patient in whom it was sought.
Delayed Ability to Walk HP:0031936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed ability to walk (HP:0031936), qualified as infantile onset. HP:0031936 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (1 reference)
PMID:26645395 SUPPORT DIRECT Human Clinical
"Her son showed a mild phenotype characterized by delayed motor milestones, and lower-limb hypotonia and areflexia."
Delayed milestones in the mildly affected second family member.
Dysarthria HP:0001260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysarthria (HP:0001260). HP:0001260 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26645395 SUPPORT DIRECT Human Clinical
"gait and kinetic cerebellar ataxia, nystagmus and dysarthria, she being wheelchair bound"
Dysarthria recorded in the same patient as the ataxia.
Onion Bulb Formation HP:0003383 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Onion bulb formation on nerve biopsy, annotated with Onion bulb formation (HP:0003383). HP:0003383 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:12566280 SUPPORT DIRECT Human Clinical
"and found an axonal pathology with axonal regeneration clusters and onion bulb formations"
The nerve biopsy finding. No frequency band is set from this single biopsy.
PMID:28501821 SUPPORT INDIRECT Human Clinical
"additional features suggestive of demyelination and remyelination (onion bulbs and/or thin myelin sheaths) were observed in 67% of them"
A frequency across NEFL-related CMT biopsies generally, not CMTDIG specifically, so it is not used to set a band.
Areflexia HP:0001284 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lower-limb areflexia, annotated with Areflexia (HP:0001284). HP:0001284 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26645395 SUPPORT DIRECT Human Clinical
"Her son showed a mild phenotype characterized by delayed motor milestones, and lower-limb hypotonia and areflexia."
Areflexia in the mildly affected second family member.
🧬

Genetic Associations

1
NEFL (Heterozygous Missense Variants)
Gene: NEFL hgnc:7739 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NEFL (hgnc:7739). hgnc:7739 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
CGGV:assertion_57ec533a-b1cb-4d1d-b12a-61ee6ac6ab07-2023-01-10T170000.000Z SUPPORT DIRECT Other
"Based on the literature we differentiate between autosomal dominant NEFL CMT (MONDO:0015626), autosomal recessive NEFL CMT (MONDO:0018993)."
ClinGen's own statement of how it partitions NEFL disease — by inheritance, not by electrophysiological subtype.
PMID:33993654 SUPPORT DIRECT Human Clinical
"Individuals who are heterozygous for the null allele are asymptomatic, indicating that there is no haploinsufficiency."
Establishes that the dominant disease is not a dosage effect, which is why the causal node is a missense allele rather than loss of the gene.
PMID:35044100 SUPPORT DIRECT Human Clinical
"Notably, the p.E396K mutation was found in both CMT1F and CMTDIG patients."
The CMTDIG-defining variant does not map exclusively to the CMTDIG label, which is the central caveat this entry records.
💊

Medical Actions

2
Multidisciplinary Symptomatic Management
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
Platform: Behavioral / lifestyle
No disease-modifying therapy exists for NEFL-related CMT. Management is the generic CMT package of rehabilitation, orthotics and orthopaedic care. No treatment study specific to CMTDIG was found.
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. Ontology label: Genetic Counseling NCIT:C15240
Autosomal dominant transmission with a 50% recurrence risk to offspring, but a high de novo rate — roughly half of NEFL families in one national series — so an isolated case does not exclude the diagnosis and parental testing is informative.
Show evidence (1 reference)
PMID:35044100 SUPPORT DIRECT Human Clinical
"Eight de novo cases (FC549 in CMT1F; FC441, FC838, and FC984 in CMTDIG; and FC21, FC264, FC497, and FC930 in CMT2E) were identified at a rate of 0.47 based on a trio-family analysis"
The de novo rate that genetic counselling has to communicate.
🔬

Diagnosis

1
Nerve conduction studies with NEFL sequencing
Median or ulnar motor conduction velocity in the 25-45 m/s band in a patient with dominant or de novo sensorimotor neuropathy, confirmed by a heterozygous NEFL missense variant. Because the intermediate range is a threshold rather than a disease boundary, the same patient can be reclassified as CMT1F or CMT2E on a different study, and NEFL should be tested whichever band the velocity falls in.
Show evidence (1 reference)
PMID:35044100 SUPPORT DIRECT Human Clinical
"the intermediate CMT subtype, which has median MNCVs of 25-45 m/s"
The conduction-velocity criterion by which the diagnosis is assigned.
🩻

Imaging Findings

1
Posterior-compartment-predominant lower-limb muscle fat infiltration
In a Korean series that stratified leg MRI by electrophysiological subgroup, fat infiltration in the CMTDIG group predominated in the posterior compartment, whereas CMT2E patients showed anterior and anterolateral involvement and CMT1F patients were affected evenly. This is the only reported observation that separates the three NEFL presentations by something other than conduction velocity, and it rests on one cohort.
Show evidence (1 reference)
PMID:35044100 SUPPORT DIRECT Human Clinical
"All compartments were evenly affected in CMT1F patients. The anterior and anterolateral compartments were affected in CMT2E, and the posterior compartment was affected in CMTDIG."
The compartment pattern reported for the CMTDIG subgroup.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
No population prevalence has been published for CMTDIG, and none can be derived, because the label is applied on an electrophysiological threshold rather than to a fixed set of variants. What is published is the size of the parent set and the share within it: NEFL accounts for under 1% of CMT in large cohorts, and within NEFL-related CMT the intermediate classification was applied to 29% of 58 kindreds in a pooled literature analysis and to 64.9% of patients in a Korean national series. Those two shares are not reconcilable with each other, which is itself informative about how stable the category is.
Show evidence (3 references)
PMID:28501821 SUPPORT INDIRECT Human Clinical
"it is a rare form of inherited neuropathy, accounting for less than 1% of all CMT cases in large cohorts"
Bounds the size of the parent set, NEFL-related CMT. Graded INDIRECT because it is a figure for the gene, not for the CMTDIG presentation.
PMID:28501821 SUPPORT DIRECT Human Clinical
"intermediate CMT or neuropathy with axonal and demyelinating features in 17 kindreds (29%)"
The share of NEFL-related CMT kindreds classified as intermediate in a pooled literature analysis.
PMID:35044100 SUPPORT DIRECT Human Clinical
"Neurophysiologically, NEFL-related CMT was classified as demyelinating, axonal, and intermediate neuropathy in 24.3%, 10.8%, and 64.9% of cases, respectively."
A very different share in a single national cohort, quoted alongside the 29% figure rather than averaged with it.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Charcot-Marie-Tooth Disease Dominant Intermediate G:

Hereditary Cerebellar Ataxia
Overlapping Features The N98S proband was worked up as sporadic early-onset cerebellar ataxia with peripheral neuropathy, and screened negative for SCA and autosomal recessive ataxia genes, before NEFL was found. A CMTDIG patient presenting with ataxia can therefore be missed for years.
Show evidence (1 reference)
PMID:26645395 SUPPORT DIRECT Human Clinical
"By then, a working diagnosis of sporadic early onset cerebellar ataxia with peripheral neuropathy was established. Screening of mutations associated with SCA and autosomal recessive cerebellar ataxias was negative."
Documents the misdiagnosis actually occurring.
Other Intermediate CMT Subtypes
Overlapping Features DI-CMTB (DNM2), DI-CMTC (YARS1), DI-CMTF (GNB4) and RI-CMTB (KARS1) are curated as has_subtypes entries on Intermediate Charcot-Marie-Tooth Disease. Unlike those, CMTDIG's gene also produces demyelinating and axonal presentations, so the intermediate label is less stable here than in the others.
🐁

Animal Models

2
Nefl N98S knock-in mouse
Knock-in of the N98S hotspot variant at the endogenous mouse Nefl locus. N98S is one of the variants reported in a dominant-intermediate pedigree, and this model is the clearest demonstration that the peripheral axon loses its neurofilaments and its calibre.
Species
Mouse
Genotype
Nefl(N98S/+)
Publication
PMID:25552649
Pathograph links
Neurofilament Network Disruption and NFL Aggregation recapitulates fidelity: high Neurofilament inclusions appear in neuronal cell bodies and proximal axons, matching the misdistribution-and-aggregation mechanism ClinGen describes for the human disease.
Limitations: The authors classify the model as CMT2E, not as dominant-intermediate CMT. N98S causes both presentations in humans, so the model is informative for the shared mechanism but cannot be read as a model of the intermediate conduction phenotype specifically.
Readouts
Neurofilament inclusions in neuronal cell bodies and proximal axons
Direction: INCREASED
Interpretation: Aggregated neurofilament protein accumulating where it is assembled rather than where it is needed.
Show evidence (1 reference)
PMID:25552649 SUPPORT DIRECT Model Organism
"Immunohistochemical analysis revealed multiple inclusions in the cell bodies and proximal axons of spinal cord neurons, disorganized processes in the cerebellum and abnormal processes in the cerebral cortex and pons."
Reports the inclusion measurement.
Show evidence (1 reference)
PMID:25552649 SUPPORT DIRECT Model Organism
"The Nefl(N98S/+) mice provide an excellent model to study the pathogenesis of CMT2E and should prove useful for testing potential therapies."
The authors' assessment of the model, quoted in their own terms including the CMT2E label they use.
Failure of Neurofilament Delivery to Distal Axons recapitulates fidelity: high Sciatic nerve ultrastructure shows the axon depleted of neurofilaments and reduced in diameter, which is the step this entry places between the aggregation and the slowed conduction.
Limitations: Measured in the sciatic nerve of a mouse; no equivalent ultrastructural quantification exists from a CMTDIG patient nerve.
Readouts
Sciatic nerve neurofilament number and axonal diameter
Direction: DECREASED
Interpretation: Fewer neurofilaments and thinner axons, with microtubule number rising as the filaments are lost.
Show evidence (1 reference)
PMID:25552649 SUPPORT DIRECT Model Organism
"Electron microscopic analysis of sciatic nerves showed a reduction in the number of neurofilaments, an increase in the number of microtubules and a decrease in the axonal diameters."
Reports the ultrastructural measurements.
Show evidence (1 reference)
PMID:25552649 SUPPORT DIRECT Model Organism
"Nefl(N98S/+) mice had a noticeable tremor, and most animals showed a hindlimb clasping phenotype."
Establishes that the heterozygous knock-in is symptomatic, which is what makes its nerve pathology informative rather than incidental.
Nefl E397K knock-in mouse
Knock-in of the murine equivalent of human p.Glu396Lys, the variant of the pedigree that defines CMTDIG. It shows early and progressive axonal pathology, and it is the model that most directly tests whether the CMTDIG allele produces an intermediate phenotype.
Species
Mouse
Genotype
Nefl(+/E397K)
Publication
PMID:40635134
Pathograph links
Failure of Radial Axonal Growth recapitulates fidelity: moderate Sciatic axon area and diameter are significantly reduced from postnatal day 21 and worsen through twelve months, matching the failure of radial growth this entry places upstream of the conduction abnormality.
Limitations: The g-ratio falls together with the axon diameter, so the finding is a shrunken axon rather than a thinned sheath, and cannot be read as demyelination. More importantly, the authors characterize the model as CMT2E and report an axonal electrophysiological phenotype dominated by reduced CMAP amplitude, not the intermediate-range velocity slowing that the human carriers of this variant show.
Readouts
Sciatic nerve axon area, diameter and g-ratio
Direction: DECREASED
Interpretation: The axon fails to reach normal calibre, the structural claim of this node.
Show evidence (1 reference)
PMID:40635134 SUPPORT DIRECT Model Organism
"A significant reduction in the sciatic nerve axon area, diameter, and G-ratio was also present as early as P21."
Reports the axonal morphometry.
Show evidence (1 reference)
PMID:40635134 SUPPORT DIRECT Model Organism
"Collectively, these results demonstrate an early and robust in vivo electrophysiological phenotype and axonal pathology, making Nefl+/E397K and NeflE397K/E397K mice ideal for the evaluation of therapeutic approaches."
The authors' assessment of the model, in their own framing as an axonal neuropathy model.
Intermediate-Range Nerve Conduction Slowing fails to recapitulate fidelity: low The human pedigree carrying this variant is defined by uniform slowing of conduction velocity into the intermediate range. The mouse carrying the equivalent variant is reported with an axonal electrophysiological signature — distal latency and CMAP amplitude and negative area — and its authors classify it as CMT2E. The one feature that makes CMTDIG a named entity is therefore not what this model reproduces.
Limitations: The reported longitudinal electrophysiology is distal latency, CMAP amplitude and negative area; conduction velocity is not among the measures quoted, so this is an absence of the defining read-out rather than a measured normal velocity. It is recorded as a failure to recapitulate because the authors' own classification of the model is axonal, but a velocity measurement could change that reading.
Readouts
Longitudinal motor electrophysiology
Interpretation: The reported abnormalities are amplitude and latency measures, which is an axonal pattern; no direction is given for conduction velocity because it is not among the measures reported.
Show evidence (1 reference)
PMID:40635134 NO_EVIDENCE DIRECT Model Organism
"A longitudinal electrophysiology study demonstrated significant in vivo functional abnormalities as early as P21 in distal latency, compound muscle action potential (CMAP) amplitude and negative area."
Lists the electrophysiological measures reported. Conduction velocity, the measure that defines the intermediate category, is not among them, so this item records the absence of the relevant experiment rather than a negative result.
Show evidence (1 reference)
PMID:40635134 SUPPORT DIRECT Model Organism
"Mutations in the neurofilament light chain (NEFL) gene result in a specific form of CMT2 disease, CMT2E."
The authors frame the model as CMT2E throughout, which is the basis for recording that it does not reproduce the intermediate presentation.
{ }

Source YAML

click to show 
name: Charcot-Marie-Tooth Disease Dominant Intermediate G
creation_date: "2026-09-01T00:00:00Z"
category: Mendelian
description: >-
  Charcot-Marie-Tooth disease dominant intermediate G (CMTDIG) is the
  intermediate-conduction presentation of autosomal dominant NEFL-related
  neuropathy: heterozygous missense variants in the neurofilament light
  polypeptide gene produce upper-limb motor conduction velocities in the
  intermediate band (roughly 25-45 m/s) that fit neither the demyelinating
  (CMT1F) nor the axonal (CMT2E) category. The mechanism explains why. NEFL
  variants disrupt neurofilament co-assembly and cause the protein to
  misdistribute and aggregate in neuronal cell bodies and proximal axons, so
  neurofilaments never reach the distal axon. Because neurofilaments are the
  space-filling structures that drive radial axonal growth, the axon fails to
  expand to normal calibre — and conduction velocity depends on calibre as well
  as on myelin. Slowed conduction therefore arises without a primary myelin
  lesion, which is exactly what an intermediate electrophysiological picture
  looks like. Two further features recur in reported CMTDIG families and set the
  entity apart from the ordinary length-dependent CMT picture: central nervous
  system involvement, from abnormal evoked potentials and blink reflexes through
  to cerebellar ataxia with cerebellar atrophy; and early onset, with delayed
  motor milestones in the more severe pedigrees.
disease_term:
  preferred_term: Charcot-Marie-Tooth disease, dominant intermediate G
  term:
    id: MONDO:0036484
    label: Charcot-Marie-Tooth disease, dominant intermediate G
synonyms:
- CMTDIG
- DI-CMTG
- Charcot-Marie-Tooth disease dominant intermediate G
- autosomal dominant intermediate Charcot-Marie-Tooth disease type G
parents:
- Intermediate Charcot-Marie-Tooth Disease
references:
- reference: PMID:20301532
  title: Charcot-Marie-Tooth Hereditary Neuropathy Overview.
  tags:
  - GeneReviews
  findings: []
inheritance:
- name: Autosomal Dominant
  description: >-
    Heterozygous NEFL missense variants, transmitted dominantly. De novo
    variants are common: eight of 17 NEFL families in a Korean national series
    were de novo, three of them in the CMTDIG subgroup, so a negative family
    history does not argue against the diagnosis.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: CGGV:assertion_57ec533a-b1cb-4d1d-b12a-61ee6ac6ab07-2023-01-10T170000.000Z
    reference_title: "NEFL / Charcot-Marie-Tooth disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: "NEFL | HGNC:7739 | Charcot-Marie-Tooth disease | MONDO:0015626 | AD | Definitive"
    explanation: >-
      ClinGen classifies autosomal dominant NEFL-related CMT as a definitive
      gene-disease relationship.
  - reference: PMID:35044100
    reference_title: Phenotypic heterogeneity in patients with NEFL-related Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Eight de novo cases (FC549 in CMT1F; FC441, FC838, and FC984 in CMTDIG;
      and FC21, FC264, FC497, and FC930 in CMT2E) were identified at a rate of
      0.47 based on a trio-family analysis
    explanation: >-
      Quantifies the de novo rate and names three CMTDIG families among the de
      novo cases.
pathophysiology:
- name: Heterozygous NEFL Missense Variant
  biological_scale: MOLECULAR
  description: >-
    A single missense allele of NEFL, encoding neurofilament light polypeptide.
    Variants span the head, rod and tail domains, with recurrent hotspots at
    Pro8, Pro22 and Asn98; p.Glu396Lys, which lies just outside the rod domain
    and disrupts the heptad repeat that defines the coiled coil, is the variant
    reported in the pedigree on which the CMTDIG designation rests. ClinGen
    characterizes the pathogenic mechanism as a gain of function arising from
    misdistribution and aggregation of the protein — that is, the mutant subunit
    poisons the co-assembled network rather than simply being absent, which is
    consistent with the observation that heterozygous carriers of NEFL null
    alleles are unaffected.
  genetic_context:
    gene:
      preferred_term: NEFL
      term:
        id: hgnc:7739
        label: NEFL
    zygosity: HETEROZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
  evidence:
  - reference: CGGV:assertion_57ec533a-b1cb-4d1d-b12a-61ee6ac6ab07-2023-01-10T170000.000Z
    reference_title: "NEFL / Charcot-Marie-Tooth disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: >-
      The mechanism of pathogenicity appears to be a gain-of-function due to
      misdistribution and aggregate formations of NFL.
    explanation: >-
      ClinGen's mechanism statement, which is the basis for the
      functional_impact_category set on this node.
  - reference: PMID:25877835
    reference_title: NEFL E396K mutation is associated with a novel dominant intermediate Charcot-Marie-Tooth disease phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The purpose of the study was to describe a pedigree with NEFL E396K
      mutation associated with a novel dominant intermediate Charcot-Marie-Tooth
      disease (DI-CMT) phenotype.
    explanation: >-
      The pedigree that established the CMTDIG designation and its causal
      variant.
  - reference: PMID:33993654
    reference_title: A review and analysis of the clinical literature on Charcot-Marie-Tooth disease caused by mutations in neurofilament protein L.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Where the inheritance pattern of the mutations is known, it is always
      autosomal dominant for the in-frame deletion and missense mutations and
      autosomal recessive for the nonsense mutations located in the rod domain.
    explanation: >-
      Separates the dominant missense alleles relevant to CMTDIG from the
      recessive null alleles, which cause a different disease.
  downstream:
  - target: Neurofilament Network Disruption and NFL Aggregation
    causal_link_type: DIRECT
    description: >-
      The mutant subunit co-assembles into the neurofilament network and
      disrupts it.
- name: Neurofilament Network Disruption and NFL Aggregation
  biological_scale: CELLULAR
  description: >-
    Every CMTDIG-associated variant tested in vitro disrupts the neurofilament
    network and causes NFL to aggregate. In the Nefl N98S knock-in mouse the
    aggregates are visible as inclusions in the cell bodies and proximal axons of
    spinal cord neurons.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: neurofilament cytoskeleton organization
    term:
      id: GO:0060052
      label: neurofilament cytoskeleton organization
    modifier: DYSREGULATED
  cellular_components:
  - preferred_term: neurofilament
    term:
      id: GO:0005883
      label: neurofilament
  evidence:
  - reference: CGGV:assertion_57ec533a-b1cb-4d1d-b12a-61ee6ac6ab07-2023-01-10T170000.000Z
    reference_title: "NEFL / Charcot-Marie-Tooth disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: >-
      In-vitro functional studies for all described variants depict disruptions
      in NF network and aggregation of NFL.
    explanation: >-
      ClinGen's summary of the in vitro functional evidence across all curated
      dominant NEFL variants. Graded OTHER, not IN_VITRO: evidence_source
      classifies the cited publication, and a ClinGen curation record is a
      curation record throughout, whatever kind of study it is summarizing.
      INDIRECT for the same reason -- it reports somebody else's experiments.
  - reference: PMID:25552649
    reference_title: Neurofilament light polypeptide gene N98S mutation in mice leads to neurofilament network abnormalities and a Charcot-Marie-Tooth Type 2E phenotype.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Immunohistochemical analysis revealed multiple inclusions in the cell
      bodies and proximal axons of spinal cord neurons, disorganized processes
      in the cerebellum and abnormal processes in the cerebral cortex and pons.
    explanation: >-
      Shows the aggregation in vivo, and shows it in central as well as
      peripheral neurons.
  downstream:
  - target: Failure of Neurofilament Delivery to Distal Axons
    causal_link_type: DIRECT
    description: >-
      Neurofilaments trapped in aggregates in the cell body and proximal axon do
      not travel down the axon.
  - target: Central Nervous System Involvement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      NEFL is expressed in central as well as peripheral neurons, and the mouse
      shows aggregation in cerebellum, cortex and pons; the steps between that
      and the human central findings have not been established.
- name: Failure of Neurofilament Delivery to Distal Axons
  biological_scale: CELLULAR
  description: >-
    Neurofilaments are assembled in the cell body and delivered along the axon by
    microtubule-based transport. In the Nefl N98S mouse the sciatic nerve shows
    fewer neurofilaments, more microtubules, and smaller axons — the axonal
    content of the cytoskeleton is changed, not just its organization.
  cell_types:
  - preferred_term: peripheral nervous system neuron
    term:
      id: CL:2000032
      label: peripheral nervous system neuron
  biological_processes:
  - preferred_term: neurofilament bundle assembly
    term:
      id: GO:0033693
      label: neurofilament bundle assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:25552649
    reference_title: Neurofilament light polypeptide gene N98S mutation in mice leads to neurofilament network abnormalities and a Charcot-Marie-Tooth Type 2E phenotype.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Electron microscopic analysis of sciatic nerves showed a reduction in the
      number of neurofilaments, an increase in the number of microtubules and a
      decrease in the axonal diameters.
    explanation: >-
      Direct ultrastructural measurement of neurofilament loss from the
      peripheral axon and the accompanying loss of calibre.
  downstream:
  - target: Failure of Radial Axonal Growth
    causal_link_type: DIRECT
    description: >-
      Without axonal neurofilaments the axon cannot expand and maintain its
      diameter.
- name: Failure of Radial Axonal Growth
  biological_scale: TISSUE
  description: >-
    Neurofilaments are the structures responsible for radial growth of axons
    during development and for maintaining axonal diameter afterwards. Losing
    them from the axon leaves a thin axon. This is the step that makes CMTDIG
    intermediate rather than axonal or demyelinating, and it has been measured
    directly in the mouse carrying the CMTDIG variant, where sciatic axon area
    and diameter are reduced from postnatal day 21 onward.
  biological_processes:
  - preferred_term: radial growth and maintenance of axon diameter
    term:
      id: GO:0031133
      label: regulation of axon diameter
    modifier: DECREASED
  evidence:
  - reference: PMID:28501821
    reference_title: Genetic and clinical characteristics of NEFL-related Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Neurofilaments are neuron-specific intermediate filaments essential for
      the radial growth of axons during development and the maintenance of the
      axonal diameter.
    explanation: >-
      Establishes the normal function whose loss this node describes. Graded
      INDIRECT because it states the physiology rather than measuring the defect
      in CMTDIG patients.
  - reference: PMID:40635134
    reference_title: Novel neurofilament light (Nefl) E397K mouse models of Charcot-Marie-tooth type 2E (CMT2E) present early and chronic axonal neuropathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      A significant reduction in the sciatic nerve axon area, diameter, and
      G-ratio was also present as early as P21.
    explanation: >-
      Measures reduced axonal calibre in a mouse carrying the murine equivalent
      of the CMTDIG variant p.Glu396Lys. Note the g-ratio falls together with
      axon diameter, meaning the axon shrank relative to its sheath; this is not
      a demyelination finding.
  downstream:
  - target: Intermediate-Range Nerve Conduction Slowing
    causal_link_type: DIRECT
    description: >-
      Conduction velocity scales with axonal calibre, so a thin axon conducts
      slowly even with an intact myelin sheath.
  - target: Length-Dependent Sensorimotor Axonal Degeneration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      An axon that cannot build or maintain its cytoskeleton eventually
      degenerates, longest fibres first.
- name: Intermediate-Range Nerve Conduction Slowing
  biological_scale: TISSUE
  description: >-
    Upper-limb motor conduction velocities fall in the intermediate band of
    roughly 25-45 m/s, in proximal as well as distal nerve segments, and this is
    what the CMTDIG label denotes. The important interpretive point is that a
    slow velocity is conventionally read as demyelination, but velocity also
    depends on axonal calibre — so a widespread reduction in calibre produces
    the same reading with normal myelin. NEFL is a neuronal protein and is not
    expressed in myelinating cells at all.
  evidence:
  - reference: PMID:25877835
    reference_title: NEFL E396K mutation is associated with a novel dominant intermediate Charcot-Marie-Tooth disease phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Electrophysiology showed uniform nerve conduction slowing in the
      intermediate range, both in distal and proximal nerve segments.
    explanation: >-
      The electrophysiological finding that defines this entity, in the
      defining pedigree.
  - reference: PMID:28501821
    reference_title: Genetic and clinical characteristics of NEFL-related Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      although intermediate forms of CMT with MNCV of 25-45 m/s are also
      recognised
    explanation: >-
      Gives the conduction velocity band that defines the intermediate category.
  - reference: PMID:33993654
    reference_title: A review and analysis of the clinical literature on Charcot-Marie-Tooth disease caused by mutations in neurofilament protein L.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      However, it is important to note that axonal conduction velocity is also
      influenced by other factors including axonal caliber (Waxman 1980). Thus,
      a widespread reduction in axonal caliber could also result in a reduction
      in NCV.
    explanation: >-
      States the interpretive argument that links the calibre node to the
      conduction node without invoking demyelination.
  downstream:
  - target: Intermediate-Range Motor Nerve Conduction Slowing
    causal_link_type: DIRECT
    description: The measured electrophysiological abnormality.
- name: Length-Dependent Sensorimotor Axonal Degeneration
  biological_scale: ORGANISM
  conforms_to: "peripheral_axonal_degeneration#Distal Axonal Degeneration and Demyelination"
  description: >-
    The clinical neuropathy: distal-predominant weakness, wasting and sensory
    loss with foot deformity, which in the more severely affected reported
    families ascends to involve pelvic musculature and produces a waddling gait.
    Sural nerve biopsies in NEFL-related CMT show preferential loss of large
    myelinated fibres.
  evidence:
  - reference: PMID:25877835
    reference_title: NEFL E396K mutation is associated with a novel dominant intermediate Charcot-Marie-Tooth disease phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Their clinical picture was characterized by pes cavus, sensorimotor
      neuropathy and spastic gait. Both older patients showed ascending leg
      weakness to involve pelvic musculature.
    explanation: >-
      The clinical syndrome in the defining CMTDIG pedigree.
  - reference: PMID:28501821
    reference_title: Genetic and clinical characteristics of NEFL-related Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Although the reduced velocities may well be mainly explained by
      preferential loss of large-myelinated fibres confirmed in 21 sural nerve
      biopsies
    explanation: >-
      The nerve-biopsy correlate. Graded INDIRECT because the 21 biopsies come
      from NEFL-related CMT as a whole rather than from CMTDIG patients
      specifically.
  - reference: PMID:12566280
    reference_title: Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      We report the first nerve biopsy of a CMT patient with a de novo missense
      mutation in NEFL, and found an axonal pathology with axonal regeneration
      clusters and onion bulb formations.
    explanation: >-
      Onion bulbs, the histological hallmark of demyelination and remyelination,
      appear in a nerve whose primary pathology is axonal and whose causal gene
      is not expressed by Schwann cells at all. This is the histological form of
      the entry's central claim: the myelin-range findings in NEFL neuropathy are
      secondary to the axon, not a primary Schwann-cell lesion.
  downstream:
  - target: Onion Bulb Formation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Repeated de- and remyelination around a failing axon produces onion bulbs
      without a primary myelin defect.
  - target: Claw Hand Deformity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Intrinsic hand muscle weakness with preserved long flexors produces the
      clawed posture.
  - target: Areflexia
    causal_link_type: DIRECT
    description: Loss of the afferent limb of the tendon reflex.
  - target: Delayed Ability to Walk
    causal_link_type: DIRECT
    description: >-
      In the early-onset pedigree the neuropathy is present before walking is
      acquired, so it delays the milestone rather than degrading a skill already
      gained. The mildly affected child had hypotonia and areflexia at 5 years,
      which is why this edge comes from the peripheral node rather than from the
      central one.
  - target: Distal Muscle Weakness
    causal_link_type: DIRECT
    description: Distal motor involvement.
  - target: Distal Sensory Impairment
    causal_link_type: DIRECT
    description: Distal sensory involvement.
  - target: Pes Cavus
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Foot deformity from imbalanced weakness of intrinsic and extrinsic foot
      muscles.
  - target: Proximal Muscle Weakness
    causal_link_type: DIRECT
    description: >-
      Ascending involvement of pelvic musculature in the more advanced reported
      patients.
- name: Central Nervous System Involvement
  biological_scale: ORGANISM
  description: >-
    CMTDIG is not confined to the peripheral nerve. In the defining pedigree,
    multimodal evoked potentials and blink reflex studies showed central
    sensorimotor pathway dysfunction, and the patients had a spastic gait. In a
    second dominant-intermediate pedigree the proband had cerebellar ataxia,
    nystagmus and dysarthria with cerebellar atrophy on MRI, and had been
    misdiagnosed as sporadic early-onset cerebellar ataxia. The route from NEFL
    aggregation to these findings is not established, which is why the edge into
    this node is typed as having unknown intermediates.
  evidence:
  - reference: PMID:25877835
    reference_title: NEFL E396K mutation is associated with a novel dominant intermediate Charcot-Marie-Tooth disease phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Multimodal evoked potential and blink reflex studies revealed
      abnormalities indicative of central sensorimotor pathway dysfunction.
    explanation: >-
      Electrophysiological evidence of central involvement in the defining
      CMTDIG pedigree.
  - reference: PMID:26645395
    reference_title: "NEFL N98S mutation: another cause of dominant intermediate Charcot-Marie-Tooth disease with heterogeneous early-onset phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      In the proband, cranial magnetic resonance imaging (MRI) showed cerebellar
      atrophy, electromyography disclosed active denervation in tibialis
      anterior, and MRI of lower-limb musculature demonstrated widespread and
      distally accentuated muscle fatty atrophy
    explanation: >-
      Imaging evidence of cerebellar involvement in a second
      dominant-intermediate NEFL pedigree.
  downstream:
  - target: Ataxia
    causal_link_type: DIRECT
    description: Cerebellar ataxia in the reported severe phenotype.
  - target: Cerebellar Atrophy
    causal_link_type: DIRECT
    description: The structural correlate on MRI.
  - target: Dysarthria
    causal_link_type: DIRECT
    description: >-
      Part of the cerebellar syndrome in the same patient as the ataxia, not a
      bulbar consequence of the peripheral neuropathy.
  - target: Nystagmus
    causal_link_type: DIRECT
    description: >-
      Gaze-evoked nystagmus, recorded alongside the ataxia and dysarthria.
  - target: Spastic Gait
    causal_link_type: DIRECT
    description: Corticospinal involvement in the defining pedigree.
phenotypes:
- category: Neurological
  name: Intermediate-Range Motor Nerve Conduction Slowing
  description: >-
    Upper-limb motor conduction velocity in the intermediate band of roughly
    25-45 m/s, in proximal as well as distal segments. This is the criterion by
    which the CMTDIG label is applied, so it is obligate by definition rather
    than by observation.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Intermediate-range motor nerve conduction slowing
    term:
      id: HP:0003431
      label: Decreased motor nerve conduction velocity
  evidence:
  - reference: PMID:25877835
    reference_title: NEFL E396K mutation is associated with a novel dominant intermediate Charcot-Marie-Tooth disease phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Electrophysiology showed uniform nerve conduction slowing in the
      intermediate range, both in distal and proximal nerve segments.
    explanation: >-
      The defining electrophysiological finding.
- category: Neurological
  name: Distal Muscle Weakness
  description: >-
    Distal-predominant weakness and wasting, the core CMT phenotype. In the
    defining pedigree the CMT neuropathy score ranged from 14 to 26, which the
    authors describe as moderate to severe.
  phenotype_term:
    preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:25877835
    reference_title: NEFL E396K mutation is associated with a novel dominant intermediate Charcot-Marie-Tooth disease phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      CMT neuropathy score ranged from 14 to 26 (moderate to severe disease).
    explanation: >-
      Quantifies severity in the four patients of the defining pedigree. No
      frequency band is set because the published CMTDIG series are too small
      to support one.
- category: Neurological
  name: Distal Sensory Impairment
  description: >-
    Sensory loss accompanying the motor deficit. In the pooled NEFL literature
    sensory electrophysiological abnormalities are more prominent than motor
    ones.
  phenotype_term:
    preferred_term: Distal sensory impairment
    term:
      id: HP:0002936
      label: Distal sensory impairment
  evidence:
  - reference: PMID:35044100
    reference_title: Phenotypic heterogeneity in patients with NEFL-related Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      In all subtypes, sensory electrophysiological data indicate more prominent
      impairment than those for motor function.
    explanation: >-
      Graded INDIRECT because the statement is made across all three NEFL
      subgroups rather than for CMTDIG alone, though it explicitly includes it.
- category: Musculoskeletal
  name: Pes Cavus
  description: Foot deformity, present in both reported dominant-intermediate pedigrees.
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  evidence:
  - reference: PMID:25877835
    reference_title: NEFL E396K mutation is associated with a novel dominant intermediate Charcot-Marie-Tooth disease phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Their clinical picture was characterized by pes cavus, sensorimotor
      neuropathy and spastic gait.
    explanation: >-
      Pes cavus in all four patients of the defining pedigree.
- category: Neurological
  name: Proximal Muscle Weakness
  description: >-
    Ascending weakness reaching pelvic musculature in the two older patients of
    the defining pedigree, with a waddling gait and imaging-confirmed atrophy of
    gluteus medius, gluteus minimus and piriformis. Proximal involvement is
    unusual in a length-dependent neuropathy.
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  evidence:
  - reference: PMID:25877835
    reference_title: NEFL E396K mutation is associated with a novel dominant intermediate Charcot-Marie-Tooth disease phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      In both patients exhibiting waddling gait, there was atrophy of pelvic
      muscles mainly involving gluteus medius, gluteus minimus and piriformis.
    explanation: >-
      Imaging confirmation of proximal muscle involvement in two of four
      patients.
- category: Neurological
  name: Spastic Gait
  description: >-
    Spastic gait in the defining pedigree, alongside evoked-potential evidence of
    central sensorimotor pathway dysfunction. A pyramidal sign in a patient
    labelled as having a peripheral neuropathy.
  phenotype_term:
    preferred_term: Spastic gait
    term:
      id: HP:0002064
      label: Spastic gait
  evidence:
  - reference: PMID:25877835
    reference_title: NEFL E396K mutation is associated with a novel dominant intermediate Charcot-Marie-Tooth disease phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Their clinical picture was characterized by pes cavus, sensorimotor
      neuropathy and spastic gait.
    explanation: >-
      Spastic gait recorded in the defining pedigree.
- category: Neurological
  name: Ataxia
  description: >-
    Gait and kinetic cerebellar ataxia in the proband of the N98S
    dominant-intermediate pedigree, severe enough that she was worked up for
    hereditary ataxia before the NEFL diagnosis. Ataxia is also common across
    NEFL-related CMT as a whole, reported in 26 of 37 Korean patients (70.3%);
    that figure spans all three electrophysiological subgroups, so it is not used
    to band this phenotype.
  phenotype_term:
    preferred_term: Cerebellar ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:26645395
    reference_title: "NEFL N98S mutation: another cause of dominant intermediate Charcot-Marie-Tooth disease with heterogeneous early-onset phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The proband, evaluated at age 31, showed delayed motor milestones that, as
      of the second decade, evolved into severe phenotype consisting of
      sensorimotor neuropathy, pes cavus, clawing hands, gait and kinetic
      cerebellar ataxia, nystagmus and dysarthria, she being wheelchair bound.
    explanation: >-
      Cerebellar ataxia in a dominant-intermediate NEFL patient.
  - reference: PMID:35044100
    reference_title: Phenotypic heterogeneity in patients with NEFL-related Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Signs of ataxia were found in 26 patients (70.3%).
    explanation: >-
      A frequency for NEFL-related CMT as a whole, not for CMTDIG. Curated as
      context and deliberately not used to set a frequency band.
- category: Neurological
  name: Cerebellar Atrophy
  description: >-
    Cerebellar atrophy on cranial MRI in the N98S proband, the structural
    correlate of the ataxia.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:26645395
    reference_title: "NEFL N98S mutation: another cause of dominant intermediate Charcot-Marie-Tooth disease with heterogeneous early-onset phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      In the proband, cranial magnetic resonance imaging (MRI) showed cerebellar
      atrophy
    explanation: >-
      Imaging finding in the one patient in whom it was sought.
- category: Neurological
  name: Delayed Ability to Walk
  description: >-
    Delayed motor milestones in both members of the N98S dominant-intermediate
    pedigree, including the mildly affected 5-year-old son. Across NEFL-related
    CMT, onset at or before age 3 occurred in 13.5% of the Korean series.
  phenotype_term:
    preferred_term: Delayed ability to walk
    term:
      id: HP:0031936
      label: Delayed ability to walk
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:26645395
    reference_title: "NEFL N98S mutation: another cause of dominant intermediate Charcot-Marie-Tooth disease with heterogeneous early-onset phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Her son showed a mild phenotype characterized by delayed motor milestones,
      and lower-limb hypotonia and areflexia.
    explanation: >-
      Delayed milestones in the mildly affected second family member.
- category: Neurological
  name: Dysarthria
  description: >-
    Dysarthria in the N98S proband, part of the cerebellar syndrome rather than
    of the peripheral neuropathy.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:26645395
    reference_title: "NEFL N98S mutation: another cause of dominant intermediate Charcot-Marie-Tooth disease with heterogeneous early-onset phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      gait and kinetic cerebellar ataxia, nystagmus and dysarthria, she being
      wheelchair bound
    explanation: >-
      Dysarthria recorded in the same patient as the ataxia.
- category: Neurological
  name: Nystagmus
  description: Nystagmus in the N98S proband, again a central sign.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:26645395
    reference_title: "NEFL N98S mutation: another cause of dominant intermediate Charcot-Marie-Tooth disease with heterogeneous early-onset phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      gait and kinetic cerebellar ataxia, nystagmus and dysarthria, she being
      wheelchair bound
    explanation: >-
      Nystagmus recorded in the same patient.
- category: Neurological
  name: Onion Bulb Formation
  description: >-
    Onion bulbs on sural nerve biopsy in a patient with a de novo NEFL missense
    variant, alongside axonal pathology and regeneration clusters. Across
    NEFL-related CMT, onion bulbs or thin myelin sheaths were present in 67% of
    21 biopsies. Because NEFL is not expressed in Schwann cells, these are read
    as secondary to axonal disease rather than as primary demyelination.
  phenotype_term:
    preferred_term: Onion bulb formation on nerve biopsy
    term:
      id: HP:0003383
      label: Onion bulb formation
  evidence:
  - reference: PMID:12566280
    reference_title: Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      and found an axonal pathology with axonal regeneration clusters and onion
      bulb formations
    explanation: >-
      The nerve biopsy finding. No frequency band is set from this single
      biopsy.
  - reference: PMID:28501821
    reference_title: Genetic and clinical characteristics of NEFL-related Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      additional features suggestive of demyelination and remyelination (onion
      bulbs and/or thin myelin sheaths) were observed in 67% of them
    explanation: >-
      A frequency across NEFL-related CMT biopsies generally, not CMTDIG
      specifically, so it is not used to set a band.
- category: Musculoskeletal
  name: Claw Hand Deformity
  description: >-
    Clawing of the hands in the N98S dominant-intermediate proband, from
    intrinsic hand muscle wasting.
  phenotype_term:
    preferred_term: Claw hand deformity
    term:
      id: HP:0034337
      label: Claw hand deformity
  evidence:
  - reference: PMID:26645395
    reference_title: "NEFL N98S mutation: another cause of dominant intermediate Charcot-Marie-Tooth disease with heterogeneous early-onset phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      severe phenotype consisting of sensorimotor neuropathy, pes cavus, clawing
      hands, gait and kinetic cerebellar ataxia
    explanation: >-
      Clawed hands recorded in the dominant-intermediate proband.
- category: Neurological
  name: Areflexia
  description: >-
    Absent tendon reflexes, recorded in the lower limbs of the mildly affected
    child of the N98S pedigree — present before the weakness became disabling.
  phenotype_term:
    preferred_term: Lower-limb areflexia
    term:
      id: HP:0001284
      label: Areflexia
  evidence:
  - reference: PMID:26645395
    reference_title: "NEFL N98S mutation: another cause of dominant intermediate Charcot-Marie-Tooth disease with heterogeneous early-onset phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Her son showed a mild phenotype characterized by delayed motor milestones,
      and lower-limb hypotonia and areflexia.
    explanation: >-
      Areflexia in the mildly affected second family member.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population prevalence has been published for CMTDIG, and none can be
    derived, because the label is applied on an electrophysiological threshold
    rather than to a fixed set of variants. What is published is the size of the
    parent set and the share within it: NEFL accounts for under 1% of CMT in
    large cohorts, and within NEFL-related CMT the intermediate classification
    was applied to 29% of 58 kindreds in a pooled literature analysis and to
    64.9% of patients in a Korean national series. Those two shares are not
    reconcilable with each other, which is itself informative about how stable
    the category is.
  evidence:
  - reference: PMID:28501821
    reference_title: Genetic and clinical characteristics of NEFL-related Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      it is a rare form of inherited neuropathy, accounting for less than 1% of
      all CMT cases in large cohorts
    explanation: >-
      Bounds the size of the parent set, NEFL-related CMT. Graded INDIRECT
      because it is a figure for the gene, not for the CMTDIG presentation.
  - reference: PMID:28501821
    reference_title: Genetic and clinical characteristics of NEFL-related Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      intermediate CMT or neuropathy with axonal and demyelinating features in
      17 kindreds (29%)
    explanation: >-
      The share of NEFL-related CMT kindreds classified as intermediate in a
      pooled literature analysis.
  - reference: PMID:35044100
    reference_title: Phenotypic heterogeneity in patients with NEFL-related Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Neurophysiologically, NEFL-related CMT was classified as demyelinating,
      axonal, and intermediate neuropathy in 24.3%, 10.8%, and 64.9% of cases,
      respectively.
    explanation: >-
      A very different share in a single national cohort, quoted alongside the
      29% figure rather than averaged with it.
genetic:
- name: NEFL
  gene_term:
    preferred_term: NEFL
    term:
      id: hgnc:7739
      label: NEFL
  relationship_type: CAUSATIVE
  association: Heterozygous Missense Variants
  notes: >-
    ClinGen curates two separate NEFL gene-disease relationships and this entry
    sits under the dominant one: autosomal dominant NEFL CMT (MONDO:0015626,
    Definitive) and autosomal recessive NEFL CMT (MONDO:0018993, Definitive) are
    curated apart, and ClinGen does not recognize CMT1F, CMT2E and CMTDIG as
    separate gene-disease entities. Heterozygous carriers of NEFL null alleles
    are unaffected, so the dominant disease is not caused by haploinsufficiency.
    p.Glu396Lys is the variant of the pedigree the CMTDIG designation comes from;
    the same variant has also been reported in patients classified CMT1F.
  evidence:
  - reference: CGGV:assertion_57ec533a-b1cb-4d1d-b12a-61ee6ac6ab07-2023-01-10T170000.000Z
    reference_title: "NEFL / Charcot-Marie-Tooth disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: >-
      Based on the literature we differentiate between autosomal dominant NEFL
      CMT (MONDO:0015626), autosomal recessive NEFL CMT (MONDO:0018993).
    explanation: >-
      ClinGen's own statement of how it partitions NEFL disease — by inheritance,
      not by electrophysiological subtype.
  - reference: PMID:33993654
    reference_title: A review and analysis of the clinical literature on Charcot-Marie-Tooth disease caused by mutations in neurofilament protein L.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Individuals who are heterozygous for the null allele are asymptomatic,
      indicating that there is no haploinsufficiency.
    explanation: >-
      Establishes that the dominant disease is not a dosage effect, which is why
      the causal node is a missense allele rather than loss of the gene.
  - reference: PMID:35044100
    reference_title: Phenotypic heterogeneity in patients with NEFL-related Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Notably, the p.E396K mutation was found in both CMT1F and CMTDIG patients.
    explanation: >-
      The CMTDIG-defining variant does not map exclusively to the CMTDIG label,
      which is the central caveat this entry records.
diagnosis:
- name: Nerve conduction studies with NEFL sequencing
  description: >-
    Median or ulnar motor conduction velocity in the 25-45 m/s band in a patient
    with dominant or de novo sensorimotor neuropathy, confirmed by a heterozygous
    NEFL missense variant. Because the intermediate range is a threshold rather
    than a disease boundary, the same patient can be reclassified as CMT1F or
    CMT2E on a different study, and NEFL should be tested whichever band the
    velocity falls in.
  evidence:
  - reference: PMID:35044100
    reference_title: Phenotypic heterogeneity in patients with NEFL-related Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      the intermediate CMT subtype, which has median MNCVs of 25-45 m/s
    explanation: >-
      The conduction-velocity criterion by which the diagnosis is assigned.
imaging_findings:
- name: Posterior-compartment-predominant lower-limb muscle fat infiltration
  description: >-
    In a Korean series that stratified leg MRI by electrophysiological subgroup,
    fat infiltration in the CMTDIG group predominated in the posterior
    compartment, whereas CMT2E patients showed anterior and anterolateral
    involvement and CMT1F patients were affected evenly. This is the only
    reported observation that separates the three NEFL presentations by
    something other than conduction velocity, and it rests on one cohort.
  evidence:
  - reference: PMID:35044100
    reference_title: Phenotypic heterogeneity in patients with NEFL-related Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      All compartments were evenly affected in CMT1F patients. The anterior and
      anterolateral compartments were affected in CMT2E, and the posterior
      compartment was affected in CMTDIG.
    explanation: >-
      The compartment pattern reported for the CMTDIG subgroup.
animal_models:
- name: Nefl N98S knock-in mouse
  species: Mouse
  genotype: Nefl(N98S/+)
  description: >-
    Knock-in of the N98S hotspot variant at the endogenous mouse Nefl locus. N98S
    is one of the variants reported in a dominant-intermediate pedigree, and this
    model is the clearest demonstration that the peripheral axon loses its
    neurofilaments and its calibre.
  publication: PMID:25552649
  modeled_mechanisms:
  - target: Neurofilament Network Disruption and NFL Aggregation
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Neurofilament inclusions appear in neuronal cell bodies and proximal axons,
      matching the misdistribution-and-aggregation mechanism ClinGen describes
      for the human disease.
    limitations: >-
      The authors classify the model as CMT2E, not as dominant-intermediate CMT.
      N98S causes both presentations in humans, so the model is informative for
      the shared mechanism but cannot be read as a model of the intermediate
      conduction phenotype specifically.
    readouts:
    - name: Neurofilament inclusions in neuronal cell bodies and proximal axons
      target: Neurofilament Network Disruption and NFL Aggregation
      direction: INCREASED
      interpretation: >-
        Aggregated neurofilament protein accumulating where it is assembled
        rather than where it is needed.
      evidence:
      - reference: PMID:25552649
        reference_title: Neurofilament light polypeptide gene N98S mutation in mice leads to neurofilament network abnormalities and a Charcot-Marie-Tooth Type 2E phenotype.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        directness: DIRECT
        snippet: >-
          Immunohistochemical analysis revealed multiple inclusions in the cell
          bodies and proximal axons of spinal cord neurons, disorganized
          processes in the cerebellum and abnormal processes in the cerebral
          cortex and pons.
        explanation: Reports the inclusion measurement.
    evidence:
    - reference: PMID:25552649
      reference_title: Neurofilament light polypeptide gene N98S mutation in mice leads to neurofilament network abnormalities and a Charcot-Marie-Tooth Type 2E phenotype.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        The Nefl(N98S/+) mice provide an excellent model to study the
        pathogenesis of CMT2E and should prove useful for testing potential
        therapies.
      explanation: >-
        The authors' assessment of the model, quoted in their own terms
        including the CMT2E label they use.
  - target: Failure of Neurofilament Delivery to Distal Axons
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Sciatic nerve ultrastructure shows the axon depleted of neurofilaments and
      reduced in diameter, which is the step this entry places between the
      aggregation and the slowed conduction.
    limitations: >-
      Measured in the sciatic nerve of a mouse; no equivalent ultrastructural
      quantification exists from a CMTDIG patient nerve.
    readouts:
    - name: Sciatic nerve neurofilament number and axonal diameter
      target: Failure of Neurofilament Delivery to Distal Axons
      direction: DECREASED
      interpretation: >-
        Fewer neurofilaments and thinner axons, with microtubule number rising
        as the filaments are lost.
      evidence:
      - reference: PMID:25552649
        reference_title: Neurofilament light polypeptide gene N98S mutation in mice leads to neurofilament network abnormalities and a Charcot-Marie-Tooth Type 2E phenotype.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        directness: DIRECT
        snippet: >-
          Electron microscopic analysis of sciatic nerves showed a reduction in
          the number of neurofilaments, an increase in the number of
          microtubules and a decrease in the axonal diameters.
        explanation: Reports the ultrastructural measurements.
    evidence:
    - reference: PMID:25552649
      reference_title: Neurofilament light polypeptide gene N98S mutation in mice leads to neurofilament network abnormalities and a Charcot-Marie-Tooth Type 2E phenotype.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Nefl(N98S/+) mice had a noticeable tremor, and most animals showed a
        hindlimb clasping phenotype.
      explanation: >-
        Establishes that the heterozygous knock-in is symptomatic, which is what
        makes its nerve pathology informative rather than incidental.
- name: Nefl E397K knock-in mouse
  species: Mouse
  genotype: Nefl(+/E397K)
  description: >-
    Knock-in of the murine equivalent of human p.Glu396Lys, the variant of the
    pedigree that defines CMTDIG. It shows early and progressive axonal
    pathology, and it is the model that most directly tests whether the CMTDIG
    allele produces an intermediate phenotype.
  publication: PMID:40635134
  modeled_mechanisms:
  - target: Failure of Radial Axonal Growth
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Sciatic axon area and diameter are significantly reduced from postnatal
      day 21 and worsen through twelve months, matching the failure of radial
      growth this entry places upstream of the conduction abnormality.
    limitations: >-
      The g-ratio falls together with the axon diameter, so the finding is a
      shrunken axon rather than a thinned sheath, and cannot be read as
      demyelination. More importantly, the authors characterize the model as
      CMT2E and report an axonal electrophysiological phenotype dominated by
      reduced CMAP amplitude, not the intermediate-range velocity slowing that
      the human carriers of this variant show.
    readouts:
    - name: Sciatic nerve axon area, diameter and g-ratio
      target: Failure of Radial Axonal Growth
      direction: DECREASED
      interpretation: >-
        The axon fails to reach normal calibre, the structural claim of this
        node.
      evidence:
      - reference: PMID:40635134
        reference_title: Novel neurofilament light (Nefl) E397K mouse models of Charcot-Marie-tooth type 2E (CMT2E) present early and chronic axonal neuropathy.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        directness: DIRECT
        snippet: >-
          A significant reduction in the sciatic nerve axon area, diameter, and
          G-ratio was also present as early as P21.
        explanation: Reports the axonal morphometry.
    evidence:
    - reference: PMID:40635134
      reference_title: Novel neurofilament light (Nefl) E397K mouse models of Charcot-Marie-tooth type 2E (CMT2E) present early and chronic axonal neuropathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Collectively, these results demonstrate an early and robust in vivo
        electrophysiological phenotype and axonal pathology, making
        Nefl+/E397K and NeflE397K/E397K mice ideal for the evaluation of
        therapeutic approaches.
      explanation: >-
        The authors' assessment of the model, in their own framing as an axonal
        neuropathy model.
  - target: Intermediate-Range Nerve Conduction Slowing
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The human pedigree carrying this variant is defined by uniform slowing of
      conduction velocity into the intermediate range. The mouse carrying the
      equivalent variant is reported with an axonal electrophysiological
      signature — distal latency and CMAP amplitude and negative area — and its
      authors classify it as CMT2E. The one feature that makes CMTDIG a named
      entity is therefore not what this model reproduces.
    limitations: >-
      The reported longitudinal electrophysiology is distal latency, CMAP
      amplitude and negative area; conduction velocity is not among the measures
      quoted, so this is an absence of the defining read-out rather than a
      measured normal velocity. It is recorded as a failure to recapitulate
      because the authors' own classification of the model is axonal, but a
      velocity measurement could change that reading.
    readouts:
    - name: Longitudinal motor electrophysiology
      target: Intermediate-Range Nerve Conduction Slowing
      interpretation: >-
        The reported abnormalities are amplitude and latency measures, which is
        an axonal pattern; no direction is given for conduction velocity because
        it is not among the measures reported.
      evidence:
      - reference: PMID:40635134
        reference_title: Novel neurofilament light (Nefl) E397K mouse models of Charcot-Marie-tooth type 2E (CMT2E) present early and chronic axonal neuropathy.
        supports: NO_EVIDENCE
        evidence_source: MODEL_ORGANISM
        directness: DIRECT
        snippet: >-
          A longitudinal electrophysiology study demonstrated significant in
          vivo functional abnormalities as early as P21 in distal latency,
          compound muscle action potential (CMAP) amplitude and negative area.
        explanation: >-
          Lists the electrophysiological measures reported. Conduction velocity,
          the measure that defines the intermediate category, is not among them,
          so this item records the absence of the relevant experiment rather
          than a negative result.
    evidence:
    - reference: PMID:40635134
      reference_title: Novel neurofilament light (Nefl) E397K mouse models of Charcot-Marie-tooth type 2E (CMT2E) present early and chronic axonal neuropathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Mutations in the neurofilament light chain (NEFL) gene result in a
        specific form of CMT2 disease, CMT2E.
      explanation: >-
        The authors frame the model as CMT2E throughout, which is the basis for
        recording that it does not reproduce the intermediate presentation.
treatments:
- name: Multidisciplinary Symptomatic Management
  description: >-
    No disease-modifying therapy exists for NEFL-related CMT. Management is the
    generic CMT package of rehabilitation, orthotics and orthopaedic care. No
    treatment study specific to CMTDIG was found.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Genetic Counseling
  description: >-
    Autosomal dominant transmission with a 50% recurrence risk to offspring, but
    a high de novo rate — roughly half of NEFL families in one national series —
    so an isolated case does not exclude the diagnosis and parental testing is
    informative.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:35044100
    reference_title: Phenotypic heterogeneity in patients with NEFL-related Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Eight de novo cases (FC549 in CMT1F; FC441, FC838, and FC984 in CMTDIG;
      and FC21, FC264, FC497, and FC930 in CMT2E) were identified at a rate of
      0.47 based on a trio-family analysis
    explanation: >-
      The de novo rate that genetic counselling has to communicate.
differential_diagnoses:
- name: NEFL-Related CMT2E and CMT1F
  description: >-
    The nearest differentials are the other two electrophysiological
    presentations of the same gene, and the boundary is a conduction-velocity
    threshold rather than a biological one. The same variant, including the
    CMTDIG-defining p.Glu396Lys, has been reported in patients classified CMT1F.
    dismech curates NEFL-related CMT2E as a subtype of Charcot-Marie-Tooth
    Disease Type 2.
  evidence:
  - reference: PMID:33993654
    reference_title: A review and analysis of the clinical literature on Charcot-Marie-Tooth disease caused by mutations in neurofilament protein L.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      In fact, different individuals with the same mutation can be classified as
      having axonal, demyelinating, or dominant intermediate forms of the
      disease.
    explanation: >-
      States the overlap that makes these differentials inseparable on genotype.
- name: Hereditary Cerebellar Ataxia
  description: >-
    The N98S proband was worked up as sporadic early-onset cerebellar ataxia with
    peripheral neuropathy, and screened negative for SCA and autosomal recessive
    ataxia genes, before NEFL was found. A CMTDIG patient presenting with ataxia
    can therefore be missed for years.
  evidence:
  - reference: PMID:26645395
    reference_title: "NEFL N98S mutation: another cause of dominant intermediate Charcot-Marie-Tooth disease with heterogeneous early-onset phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      By then, a working diagnosis of sporadic early onset cerebellar ataxia with
      peripheral neuropathy was established. Screening of mutations associated
      with SCA and autosomal recessive cerebellar ataxias was negative.
    explanation: >-
      Documents the misdiagnosis actually occurring.
- name: Other Intermediate CMT Subtypes
  description: >-
    DI-CMTB (DNM2), DI-CMTC (YARS1), DI-CMTF (GNB4) and RI-CMTB (KARS1) are
    curated as has_subtypes entries on Intermediate Charcot-Marie-Tooth Disease.
    Unlike those, CMTDIG's gene also produces demyelinating and axonal
    presentations, so the intermediate label is less stable here than in the
    others.
discussions:
- discussion_id: cmtdig_is_a_presentation_not_an_entity
  kind: KNOWLEDGE_GAP
  attaches_to:
  - disease#Charcot-Marie-Tooth Disease Dominant Intermediate G
  - pathophysiology#Intermediate-Range Nerve Conduction Slowing
  prompt: >-
    Is CMTDIG a distinct disease, or an electrophysiological presentation of one
    autosomal dominant NEFL neuropathy that also presents as CMT1F and CMT2E?
  rationale: >-
    Two independent authorities say the latter. A dedicated review of the NEFL
    clinical literature found no correlation between variant, protein domain and
    disease classification, found six variants each reported under more than one
    label, and concluded that all NEFL-related CMT is axonal in nature. ClinGen
    curates one autosomal dominant NEFL-CMT gene-disease relationship and does
    not recognize CMT1F, CMT2E or CMTDIG as separate entities. Against that,
    MONDO and OMIM both carry CMTDIG as its own concept, the label is in active
    clinical use — applied to 29% of kindreds in a pooled literature analysis and
    64.9% of patients in a Korean national cohort — and one cohort reports a leg
    MRI compartment pattern that differs between the three groups.

    This entry is curated as a Disease because the concept is real, uncurated and
    in use, and because the mechanism by which conduction becomes intermediate is
    worth stating explicitly. It should not be read as an assertion that CMTDIG
    is mechanistically distinct from CMT2E; the entry says the opposite. A
    curator who preferred to fold this into the NEFL subtype of
    Charcot-Marie-Tooth Disease Type 2 would be acting on the same evidence, and
    this discussion exists so that decision can be made from the record rather
    than made again from scratch.
- discussion_id: cmtdig_central_nervous_system_substrate
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Central Nervous System Involvement
  prompt: >-
    What is the substrate of the central nervous system involvement in
    dominant-intermediate NEFL neuropathy?
  rationale: >-
    The defining pedigree has abnormal multimodal evoked potentials, an abnormal
    blink reflex and a spastic gait; a second pedigree has cerebellar ataxia with
    cerebellar atrophy. The Nefl N98S mouse shows neurofilament aggregation in
    cerebellum, cortex and pons, which is a plausible substrate, but no human
    neuropathology has been reported and no imaging or electrophysiological
    series has quantified central involvement in this group. The edge into the
    central node is therefore typed as having unknown intermediates.
- discussion_id: cmtdig_no_model_of_the_defining_feature
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - animal_models#Nefl N98S knock-in mouse
  - animal_models#Nefl E397K knock-in mouse
  prompt: >-
    Does any animal model reproduce intermediate-range conduction slowing, the
    feature that defines this entity?
  rationale: >-
    Both available knock-in mice carry variants reported in
    dominant-intermediate pedigrees — N98S, and the murine equivalent of the
    CMTDIG-defining E396K — and both are characterized and published by their
    authors as models of CMT2E. The E397K longitudinal electrophysiology reports
    distal latency, CMAP amplitude and negative area, which is an axonal pattern;
    conduction velocity is not among the reported measures. So the models
    reproduce the neurofilament and calibre mechanism well and say nothing about
    the electrophysiological threshold that gives the entity its name. This is
    consistent with the view that the intermediate label reflects human
    presentation variability rather than a separate mechanism, but it has not
    been tested.
  proposed_experiments:
  - experiment_id: cmtdig_e397k_conduction_velocity
    name: Conduction velocity phenotyping of the Nefl E397K knock-in mouse
    description: >-
      Measure motor nerve conduction velocity longitudinally in Nefl(+/E397K)
      mice against wild-type littermates, and relate it to axon calibre
      distribution and myelin morphometry in the same nerves.
    would_support:
    - pathophysiology#Failure of Radial Axonal Growth
    supporting_outcome:
    - >-
      Conduction velocity falls in proportion to the loss of large-calibre axons
      while myelin thickness relative to a matched axon is preserved, confirming
      that reduced calibre alone produces the slowing.
    would_refute:
    - pathophysiology#Failure of Radial Axonal Growth
    refuting_outcome:
    - >-
      Conduction velocity is preserved despite reduced axon calibre, or falls
      only where myelin is abnormal, which would mean the calibre mechanism does
      not explain the human intermediate velocities.
notes: >-
  Entry type. Curated as a standalone Disease. MONDO:0036484 and OMIM 617882 both
  carry CMTDIG as a concept, no dismech entry binds it, and dismech's
  Intermediate Charcot-Marie-Tooth Disease entry lists DI-CMTB, DI-CMTC, DI-CMTF
  and RI-CMTB but not this one, so the intermediate compartment has a real gap
  here. The countervailing evidence — that the label is a presentation category
  within one dominant NEFL disease — is substantial and is recorded as a
  discussion rather than buried, together with the alternative disposition. No
  existing entry was modified; in particular the NEFL coverage on
  Charcot-Marie-Tooth Disease Type 2 (CMT2E subtype, NEFL genetic record,
  neurofilament assembly node, NEFL-targeting ASO treatment) is real and was left
  alone.

  Named entity confusion. NEFL is the hard case in this batch and gene-frequency
  preflight (PASS, 81 mentions) establishes nothing, because almost all of the
  literature it would pass is about something else. Three separate off-target
  bodies were excluded by hand:

  1. Serum neurofilament light as a biomarker. This is one of the most-measured
  proteins in neurology and dismech itself cites it that way in Frontotemporal
  Dementia. Not one biomarker paper is cited here. The one place NfL appears in
  this entry's sources is as a treatment-response measure in a mouse, and it is
  not curated.

  2. The other NEFL diseases. CMT1F and CMT2E are the same gene and frequently
  the same variant. Every clinical citation here was checked to be about a
  patient or cohort classified as dominant intermediate, or is explicitly labelled
  in its explanation as a NEFL-wide figure being used for context — the 70.3%
  ataxia frequency, the 21 sural biopsies and the under-1%-of-CMT figure are all
  marked that way and none of them sets a frequency band. Autosomal recessive
  NEFL CMT is a different ClinGen entity and is excluded.

  3. Giant axonal neuropathy. dismech's Giant_Axonal_Neuropathy_1 entry involves
  neurofilament biology but is caused by GAN, not NEFL. No source from it is used.

  Frequency bands. Only one phenotype carries a band, and it is OBLIGATE by
  definition rather than by observation: intermediate-range conduction slowing is
  the criterion for applying the label. Every other phenotype rests on two
  pedigrees totalling six patients, which is too few to band, so `frequency` is
  left absent and the description says what was actually observed in how many
  people. The 70.3% ataxia figure is curated but explicitly not used as a band,
  because it is a NEFL-wide figure spanning all three subgroups.

  The animal models are labelled CMT2E by their own authors. Both are curated
  anyway, because both carry variants reported in dominant-intermediate pedigrees
  and both measure the neurofilament and calibre steps this entry depends on. The
  mismatch is recorded structurally with a FAILS_TO_RECAPITULATE link and a
  HUMAN_MODEL_MISMATCH discussion rather than smoothed over. The
  FAILS_TO_RECAPITULATE readout carries `supports: NO_EVIDENCE`, not `REFUTE`:
  conduction velocity is absent from the reported measures, so this is a missing
  experiment, not a measured normal result.

  Tooling. `just clingen-refresh` exits non-zero on a drifted sha256 against the
  2026-08-13 pin, but it downloads gene_validity.csv before failing, and
  `just clingen-rebuild --id ...` then works against the file on disk. That is how
  the ClinGen record cited here was produced. The manifest was not repinned.

  Non-cell-autonomous myelin findings. Onion bulbs are curated as a phenotype and
  as a downstream consequence of the axonal node, not as evidence of primary
  demyelination. NEFL is a neuronal protein that Schwann cells do not express, so
  any myelin-range finding in this disease has to be secondary to the axon. This
  is the same argument as the calibre explanation of intermediate conduction,
  seen histologically instead of electrophysiologically.

  Not curated. No prevalence rate — none exists and none can be derived from a
  threshold-defined category, so the record is CASES_IN_LITERATURE with
  ULTRA_RARE and the two irreconcilable within-NEFL shares in its notes. No
  biochemical block. No datasets block. No treatments beyond supportive care and
  counselling: an NEFL-targeting antisense oligonucleotide and CRISPR haplotype
  editing are in preclinical development for dominant NEFL neuropathy, and
  dismech already carries the ASO on Charcot-Marie-Tooth Disease Type 2, but
  neither has been reported in a CMTDIG-classified patient and neither is curated
  here.
📚

References & Deep Research

References

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

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 34 citations 2026-09-01T10:16:19.842593

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Charcot-Marie-Tooth disease dominant intermediate G (CMTDIG), caused by heterozygous NEFL variants
  • MONDO ID: MONDO:0036484 (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Charcot-Marie-Tooth disease dominant intermediate G (CMTDIG), caused by heterozygous NEFL variants covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Charcot–Marie–Tooth disease, dominant intermediate G (CMTDIG)

Executive summary and evidence scope

CMTDIG is an ultrarare, autosomal-dominant hereditary sensorimotor neuropathy caused by a heterozygous pathogenic variant in NEFL, which encodes neurofilament light chain (NF-L). Its defining “intermediate” physiology lies between conventionally demyelinating and axonal CMT. Importantly, NEFL disease is a continuous allelic spectrum: reports may label patients CMTDIG/dominant-intermediate CMT G, CMT1F, or CMT2E according to nerve-conduction findings rather than a sharp biological boundary. MONDO:0036484 is directly associated with NEFL in aggregated disease-target evidence. (OpenTargets Search: Charcot-Marie-Tooth disease dominant intermediate G-NEFL, medina2024customizedantisenseoligonucleotidebased pages 1-2, marina2024novelgeneticand pages 1-3)

The strongest CMTDIG-like primary evidence is a multigenerational family with heterozygous NEFL c.1189G>A, p.Glu397Lys (E397K), intermediate-to-demyelinating conduction velocities, axonal loss, and secondary demyelinating pathology. Most recent mechanistic work instead uses the severe p.Asn98Ser (N98S) CMT2E model; those findings are biologically relevant to dominant NEFL neuropathy but are not automatically variant-specific evidence for p.Glu397Lys. (zuchner2004thenovelneurofilament pages 1-2, zuchner2004thenovelneurofilament pages 6-7, marina2024novelgeneticand pages 1-3)

Domain Best-supported finding Evidence type/sample Key quantitative detail Confidence/limitation
Disease identity CMTDIG is the dominant-intermediate NEFL-associated CMT entity and overlaps clinically/genetically with NEFL-related CMT1F and CMT2E classifications rather than forming a sharply isolated syndrome Disease-target aggregation plus review/cohort synthesis MONDO:0036484 linked to NEFL; review notes NEFL variants cause demyelinating, axonal, and intermediate CMT forms; NF-related CMT accounts for ~1% of diagnosed CMT cases (OpenTargets Search: Charcot-Marie-Tooth disease dominant intermediate G-NEFL, marina2024novelgeneticand pages 1-3) Moderate confidence; nomenclature is stable but human reports often classify the same NEFL families as CMT1F, CMT2E, or intermediate depending on conduction/pathology
Foundational human family Heterozygous NEFL p.Glu397Lys was reported in a multigenerational family with autosomal dominant, clinically heterogeneous neuropathy in the intermediate/demyelinating range Human clinical family study; 3 generations, 6 mutation carriers/affected relatives described (zuchner2004thenovelneurofilament pages 1-2, zuchner2004thenovelneurofilament pages 6-7) Variant absent in 65 controls; by 2004, 11 NEFL mutations affecting 8 amino acids had been reported, ~2% of 323 CMT cases screened (zuchner2004thenovelneurofilament pages 1-2, zuchner2004thenovelneurofilament pages 7-10) High confidence for this family; low generalizability because subtype-specific literature is sparse and older
2024 variant landscape Modern literature synthesis reports a broader NEFL disease spectrum with mostly heterozygous missense variants acting through gain-of-function mechanisms; somatic mosaicism can also be pathogenic 2024 retrospective case study + literature review 34 distinct CMT-causing NEFL variants in 174 reported patients; first reported pathogenic somatic NEFL mosaicism at 15% for p.Pro8Ser father (marina2024novelgeneticand pages 1-3, marina2024novelgeneticand pages 18-19) High confidence for counts at publication date; counts will change as new cases accumulate
Core phenotypes / natural history NEFL-related CMT commonly causes distal-predominant sensorimotor neuropathy with foot deformity and variable onset/severity; severe alleles can produce early-onset multisystem neuromuscular phenotypes Human family studies p.Glu397Lys family: onset ranged from age 4 to 82 years, with two clinically/electrophysiologically healthy carriers at age 21; severe family with NEFL nonsense variant had 4 affected members, infantile hypotonia, contractures, scoliosis, wheelchair dependence, and one death at 35 years likely from respiratory insufficiency (zuchner2004thenovelneurofilament pages 6-7, agrawal2014expandingthephenotype pages 3-4, agrawal2014expandingthephenotype pages 4-5) High confidence for variable expressivity and age-dependent/incomplete penetrance; phenotype frequencies across CMTDIG specifically are unavailable
Electrophysiology and pathology Dominant-intermediate labeling is supported by slowed motor conduction plus mixed axonal-demyelinating nerve pathology Human electrophysiology and sural nerve biopsy Motor NCVs in reported NEFL family ranged 27–43 m/s; peroneal NCV 25–27 m/s in some subjects; myelin area 12–16% versus ~23% normal; onion bulbs, loss of large myelinated fibers, atrophic axons, regenerated clusters (zuchner2004thenovelneurofilament pages 1-2, zuchner2004thenovelneurofilament pages 6-7, zuchner2004thenovelneurofilament pages 7-10) High confidence in family-level evidence; pathology is based on very small numbers and may not represent all NEFL variants
Mechanism / pathophysiology Pathogenic NEFL variants disrupt neurofilament assembly/organization, axonal caliber, intracellular transport, and likely axon-Schwann-cell interactions; some effects are modulated by post-translational regulation such as O-GlcNAcylation Cell biology, review synthesis, and inference from human pathology Neurofilament assembly defect and organelle transport disruption highlighted in 2024 review; 2023 O-GlcNAc study identified 5 NF-L O-GlcNAc sites and showed mutant NF-L can resist O-GlcNAc effects on assembly; severe NCV slowing may reflect axon/axonal-caliber loss and secondary demyelination (marina2024novelgeneticand pages 1-3, medina2024molecularphenotypicanalysisa pages 30-35) Moderate confidence; aggregation/assembly defects are demonstrated in models, while the precise causal link to each human phenotype remains partly inferred
Model organisms and human cellular models N98S is the best-developed experimental NEFL model, reproducing inclusion pathology and axonal structural abnormalities; patient iPSC-derived motor neurons recapitulate disease-relevant biomarkers Knock-in mouse and patient-derived iPSC motor neuron models NeflN98S/+ mice showed tremor, hindlimb clasping, inclusions in spinal neurons, abnormalities by postnatal day 7, fewer neurofilaments, more microtubules, and reduced axonal diameters; P8R mice were behaviorally similar to wild type (feliciano2021allelespecificgeneediting pages 1-3, marina2024novelgeneticand pages 1-3) High confidence for N98S model validity; model findings may not extrapolate to all NEFL variants or specifically to p.Glu397Lys/CMTDIG
Experimental therapy Allele-preferential ASO therapy is the most advanced NEFL-targeted approach currently gathered, with biomarker rescue in a preclinical human model 2024 preclinical therapeutic study in patient iPSC-derived motor neurons ASO produced ~20% reduction of mutant p.N98S allele expression and ~38% reduction of total NEFL transcript, with decreased supernatant NF-L and peripherin biomarkers (medina2024customizedantisenseoligonucleotidebased pages 11-12) Moderate confidence; strong proof-of-concept but not yet human clinical efficacy or safety data for NEFL/CMTDIG
Diagnostics Diagnosis currently depends on clinical neuropathy assessment plus molecular testing, with WGS improving but not replacing phenotype-driven workflows Specialist-center cohort and hereditary neuropathy testing studies In a 1515-patient inherited neuropathy center cohort, intermediate CMT accounted for 205/1515 (13.5%) and had 81.0% genetic diagnosis; overall diagnostic rate 76.9%, WGS diagnostic uplift 3.5%, true 100KGP WGS rate 19.7% (46/233) (marina2024novelgeneticand pages 1-3) Moderate confidence for general CMT diagnostics; no CMTDIG-specific diagnostic algorithm validated beyond identifying heterozygous NEFL variants via panels/WES/WGS
Treatment gap / current care No disease-modifying therapy specific to NEFL-related CMTDIG was identified; present real-world management is supportive, while NEFL-targeted precision therapy remains preclinical Evidence gap plus broader CMT practice context Clinical trial searches retrieved broader CMT studies but no NEFL/CMTDIG-specific interventional trial; customized ASO remains preclinical proof-of-concept (medina2024customizedantisenseoligonucleotidebased pages 11-12) High confidence for current treatment gap; limitation is absence of subtype-specific management trials and sparse published QoL/outcome data

Table: This table summarizes the strongest currently gathered evidence for NEFL-related dominant-intermediate Charcot-Marie-Tooth disease and overlapping NEFL neuropathies. It is calibrated to separate well-supported family/model findings from areas where evidence remains sparse or indirect.

1. Disease information

Definition and classification

CMTDIG is a chronic, usually slowly progressive, inherited peripheral neuropathy characterized by length-dependent distal weakness and wasting, foot deformity, depressed reflexes, and variable sensory loss. “Intermediate” generally denotes motor nerve-conduction velocities (MNCVs) between classic demyelinating and axonal ranges; NEFL families may cross those thresholds within the same pedigree. In the p.Glu397Lys family, lower-limb MNCVs ranged approximately 27–43 m/s, and some peroneal values were 25–27 m/s. Biopsy nevertheless showed both chronic axonopathy and demyelination/remyelination. (zuchner2004thenovelneurofilament pages 1-2, zuchner2004thenovelneurofilament pages 6-7, zuchner2004thenovelneurofilament pages 7-10)

Identifiers and synonyms

  • MONDO: MONDO:0036484, Charcot-Marie-Tooth disease, dominant intermediate G.
  • EFO: EFO:0010267, autosomal dominant intermediate Charcot-Marie-Tooth disease type G. (OpenTargets Search: Charcot-Marie-Tooth disease dominant intermediate G-NEFL)
  • Common names: CMTDIG; dominant-intermediate CMT type G; DI-CMTG; DICMTG; autosomal dominant intermediate CMT type G; NEFL-related dominant-intermediate neuropathy.
  • Overlapping labels: NEFL-related CMT2E and CMT1F. These should be retained as related entities rather than treated as exact synonyms in every patient.
  • OMIM: NEFL-related classifications are commonly represented within the NEFL/CMT2E–CMT1F allelic spectrum; an exact CMTDIG OMIM number was not securely verified in the retrieved evidence and should not be populated without direct OMIM confirmation.
  • ICD-10-CM: no subtype-specific code; typically G60.0, hereditary motor and sensory neuropathy.
  • ICD-11: hereditary motor and sensory neuropathy/CMT category; no independently validated CMTDIG leaf code found.
  • MeSH: Charcot-Marie-Tooth Disease; no NEFL/CMTDIG-specific MeSH descriptor found.

The evidence is aggregated disease-level literature and family/cohort research, not individual EHR data. OpenTargets aggregates five evidence records connecting MONDO:0036484 to NEFL. (OpenTargets Search: Charcot-Marie-Tooth disease dominant intermediate G-NEFL)

2. Etiology

Causal factor

The cause is a germline heterozygous pathogenic NEFL variant, most often missense. Dominant variants generally act through toxic gain-of-function and/or dominant interference with neurofilament assembly, rather than simple haploinsufficiency. Heterozygous loss-of-function carriers can be neurologically normal, whereas biallelic loss-of-function causes an earlier recessive phenotype. (medina2024molecularphenotypicanalysis pages 13-17, feliciano2021allelespecificgeneediting pages 1-3, marina2024novelgeneticand pages 1-3)

The canonical CMTDIG-like p.Glu397Lys variant alters a highly conserved LLEGEE motif near the end of the coiled-coil rod domain. It segregated across three generations and was absent from 65 controls. (zuchner2004thenovelneurofilament pages 6-7, zuchner2004thenovelneurofilament pages 7-10)

Risk factors

  • Genetic: an affected parent or a de novo pathogenic NEFL allele; variant position and biochemical effect influence onset. Head-domain variants tend to present earlier, although this is not an absolute rule. (marina2024novelgeneticand pages 1-3, marina2024novelgeneticand pages 18-19)
  • Family history: strongly informative under autosomal-dominant inheritance, but a negative history does not exclude de novo variation, age-dependent penetrance, or mosaicism.
  • Somatic mosaicism: a 2024 report identified 15% mosaic p.Pro8Ser in a mildly affected father, establishing that low-level mosaic NEFL variation can be clinically relevant. (marina2024novelgeneticand pages 1-3, marina2024novelgeneticand pages 18-19)
  • Trauma: experimental work suggests nerve injury can aggravate an NEFL neuropathy phenotype, but this is not established as a population-level cause or risk estimate.

No reproducible susceptibility loci, modifier genes, sex-specific risk, infectious causes, or environmental causes have been established for CMTDIG.

Protective factors and gene–environment interaction

No validated protective allele, diet, drug, or exposure has been demonstrated. Avoidance of neurotoxic medications, excessive alcohol, repetitive nerve compression, and preventable trauma is clinically prudent for inherited neuropathy, but is tertiary risk reduction—not prevention of the genetic disease. The nutrient-sensitive O-GlcNAc regulation of NF-L is a plausible molecular interface with cellular metabolism, but no human diet–NEFL interaction has been shown.

3. Phenotypes

Frequency estimates below are qualitative because no sufficiently large CMTDIG-specific natural-history cohort exists.

  • Distal lower-limb weakness and wasting — core sign, usually symmetric and progressive; HP:0009053 (distal lower-limb muscle weakness), HP:0003693 (distal amyotrophy).
  • Foot drop and gait impairment — common; can begin in childhood; HP:0003376, HP:0001288.
  • Pes cavus/other foot deformity — frequent presenting manifestation; in one carrier it was apparent by age four; HP:0001761, HP:0001839.
  • Distal sensory loss or sensory ataxia — variable and sometimes mild; one p.Glu397Lys subject presented prominently with sensory ataxia; HP:0000763, HP:0002066.
  • Hyporeflexia/areflexia — expected in length-dependent neuropathy; HP:0001265, HP:0001284.
  • Reduced motor NCV — intermediate or occasionally demyelinating range; HP:0003431. Sensory responses may be relatively preserved. (zuchner2004thenovelneurofilament pages 6-7)
  • Hearing impairment/deafness — reported in the p.Glu397Lys family, including an 82-year-old with deafness and only minor neuropathy; frequency unknown; HP:0000365. (zuchner2004thenovelneurofilament pages 6-7, zuchner2004thenovelneurofilament pages 1-2)
  • Contractures, scoliosis, facial weakness, ptosis, shoulder weakness, respiratory impairment — documented in a severe heterozygous NEFL nonsense-variant family, not established as typical CMTDIG features; suggested terms include HP:0001371, HP:0002650, HP:0002058, HP:0000508, and HP:0002093. Four relatives had infantile hypotonia, delayed milestones, progressive contractures and scoliosis; wheelchair dependence ranged from adolescence to the mid-50s, and one died at 35, probably from respiratory insufficiency. (agrawal2014expandingthephenotype pages 3-4, agrawal2014expandingthephenotype pages 4-5)
  • Muscle pathology: usually secondary denervation, but primary muscle vulnerability is possible. A 2024 p.Phe104Val case had weakness, myalgia, cramps, Z-band changes and mini-cores; proteomics implicated cytoskeletal proteins. (marina2024novelgeneticand pages 1-3)

No behavioral or psychiatric phenotype is characteristic. Quality-of-life data specific to CMTDIG are unavailable. Functionally, foot drop, balance impairment, hand weakness in later disease, contractures, and fatigue can impair walking, falls risk, employment, self-care, and participation.

4. Genetic and molecular information

  • Gene: NEFL, neurofilament light chain; approved human protein-coding gene, chromosome 8p21 region; Ensembl target ENSG00000277586 in the retrieved aggregation. (OpenTargets Search: Charcot-Marie-Tooth disease dominant intermediate G-NEFL)
  • Inheritance/origin: usually autosomal-dominant germline; de novo and somatic-mosaic cases are possible.
  • Variant spectrum: by April 2024, 34 CMT-causing NEFL variants in 174 reported patients had been compiled. Variants produce demyelinating, axonal, and intermediate phenotypes. (marina2024novelgeneticand pages 1-3)
  • Important dominant variants: p.Glu397Lys for the intermediate phenotype; p.Asn98Ser, p.Pro8Arg/Ser/Leu, p.Pro22Ser/Thr, and others across head and rod domains. More than 30 pathogenic variants have been reported in modern CMT2E summaries. (medina2024customizedantisenseoligonucleotidebased pages 1-2, marina2024novelgeneticand pages 1-3, medina2024molecularphenotypicanalysisa pages 30-35)
  • Classes: predominantly missense; rare nonsense/truncating alleles and recessive loss-of-function are reported. Variant interpretation must therefore consider inheritance and mechanism rather than assuming every NEFL loss-of-function allele causes dominant disease.
  • Population frequency: pathogenic dominant alleles are expected to be absent or extremely rare in population databases. Exact current gnomAD allele counts were not available from the retrieved documents and should be queried variant-by-variant using the correct transcript/build.
  • Classification: clinical laboratories should apply ACMG/AMP criteria using segregation, de novo status, population rarity, domain/hotspot evidence, phenotype, functional data, and ClinVar assertions. Variant-specific classification may differ; an NEFL VUS alone is not diagnostic.
  • Mechanism: dominant toxic gain-of-function/dominant interference; simple haploinsufficiency is unlikely for many dominant missense disorders. (medina2024customizedantisenseoligonucleotidebased pages 11-12, feliciano2021allelespecificgeneediting pages 1-3)
  • Modifiers/epigenetics/chromosomal abnormalities: no validated modifier gene, disease-specific methylation signature, recurrent copy-number lesion, translocation, or inversion is established.

5. Environmental information

CMTDIG is not caused by toxin, lifestyle, radiation, pollution, or infection. Environmental exposures may change functional reserve or aggravate symptoms but do not replace the Mendelian cause. No CMTDIG-specific data quantify effects of smoking, diet, alcohol, exercise, occupation, or infection. Exercise should be individualized to maintain strength and conditioning without overuse injury. There is no zoonotic or infectious transmission.

6. Mechanism and pathophysiology

Ordered causal chain

  1. A heterozygous pathogenic NEFL variant leads to altered NF-L structure, stoichiometry, or post-translational regulation.
  2. Altered NF-L leads to defective neurofilament coiled-coil assembly, network organization, and—in many model systems—abnormal accumulation or aggregation.
  3. Neurofilament disorganization results in disturbed axonal cytoskeletal architecture, organelle transport, and radial axonal growth.
  4. Reduced axonal caliber and axonal dysfunction lead to impaired impulse conduction and length-dependent degeneration of long motor and sensory axons.
  5. Axonal degeneration results in denervation, distal muscle atrophy, weakness, foot deformity, sensory loss, and reduced reflexes.
  6. Inferred branch: disturbed axon–Schwann-cell signaling leads to secondary demyelination/remyelination, onion bulbs, and conduction velocities in the intermediate or demyelinating range.
  7. Variant-dependent branch: severe alleles may lead to broader neuronal, muscular, auditory, or respiratory involvement.

Molecular and cellular detail

NF-L monomers form coiled-coil dimers, nonpolar tetramers, unit-length filaments, and mature neurofilaments. Neurofilaments provide axonal mechanical stability, regulate radial growth and caliber, interact with microtubules, and help organize organelles and synaptic function. Relevant processes include GO:0005882 intermediate filament, GO:0045109 intermediate filament organization, GO:0031175 neuron projection development, GO:0008088 axonal transport, and GO:0007411 axon guidance. (medina2024customizedantisenseoligonucleotidebased pages 1-2, medina2024molecularphenotypicanalysisa pages 30-35)

Phosphorylation at NF-L head-domain residues—including Ser2, Ser55, Ser57 and Ser66—regulates severing, annealing and transport; some Pro22 substitutions abolish normal head-domain phosphorylation. (medina2024molecularphenotypicanalysisa pages 30-35)

A major 2023 development showed that NF-L is modified at five O-GlcNAc sites. O-GlcNAcylation regulated neurofilament assembly and NF-L interactions with itself and α-internexin, and was required for normal organelle trafficking in primary neurons. Several CMT-causing mutants had abnormal O-GlcNAc levels or resisted O-GlcNAc-dependent assembly effects. The authors’ key abstract conclusion was: “aberrant NF O-GlcNAcylation may contribute to CMT and other neurodegenerative disorders.” This is mechanistically compelling but not yet a patient biomarker or treatment target. Huynh et al., Nature Communications 2023, DOI: 10.1038/s41467-023-42227-0.

Human nerve pathology shows loss of large myelinated fibers, axonal atrophy, regeneration clusters, and onion bulbs. Myelin area in studied p.Glu397Lys biopsies was approximately 12–16%, versus about 23% normal. These observations support primary axonopathy with secondary myelin injury rather than a purely Schwann-cell-autonomous disorder. (zuchner2004thenovelneurofilament pages 6-7, zuchner2004thenovelneurofilament pages 7-10)

Cells: motor neuron (CL:0000100), sensory neuron (CL:0000101), peripheral-neuron axon, Schwann cell (CL:0002573), and secondarily skeletal muscle fiber (CL:0000188). No convincing NEFL-specific immune, apoptotic, metabolic, lipidomic, single-cell, spatial-transcriptomic, or epigenomic disease program has been validated in humans.

7. Anatomical structures affected

  • Primary system: peripheral nervous system; long motor and sensory nerves (UBERON:0000010 nervous system, UBERON:0000381 peripheral nervous system).
  • Principal sites: distal lower-limb nerves and muscles first; later distal upper limbs in some patients. Involvement is usually bilateral and approximately symmetric.
  • Axonal compartments: axoplasm and neurofilament cytoskeleton; GO:0030424 axon, GO:0043209 myelin sheath, GO:0005882 intermediate filament.
  • Secondary tissues: Schwann-cell/myelin units and denervated skeletal muscle (UBERON:0001630 muscle organ).
  • Model-dependent CNS sites: spinal cord, cerebellum, cortex and pons show abnormalities in N98S mice, but clinically important CNS disease is not established as a universal CMTDIG feature.

8. Temporal development

Onset is typically insidious and may occur from early childhood through adulthood. The p.Glu397Lys pedigree ranged from foot deformity at age 4 to very mild neuropathy/deafness at age 82; two carriers were clinically and electrophysiologically normal at 21. This demonstrates age-dependent or incomplete penetrance and marked intrafamilial variability. (zuchner2004thenovelneurofilament pages 6-7, zuchner2004thenovelneurofilament pages 1-2, zuchner2004thenovelneurofilament pages 7-10)

The usual course is chronic, lifelong and slowly progressive, without spontaneous remission. Early disease often consists of pes cavus, ankle weakness or foot drop; intermediate disease adds distal wasting, gait impairment and sensory loss; advanced cases may require orthoses, walking aids, orthopedic procedures, or a wheelchair. These are pragmatic clinical phases, not validated CMTDIG staging criteria. No critical therapeutic window has been established in humans, although experimental ASO investigators argue that treatment before major axonal loss should offer the greatest benefit. (medina2024customizedantisenseoligonucleotidebased pages 11-12)

9. Inheritance and population

  • Inheritance: autosomal dominant for CMTDIG; each child of a heterozygous germline carrier has a theoretical 50% transmission risk.
  • Penetrance: incomplete and/or age-dependent in at least some families.
  • Expressivity: highly variable, even within one pedigree.
  • Anticipation: not demonstrated.
  • Mosaicism: documented; low-level parental mosaicism can alter recurrence counseling. (marina2024novelgeneticand pages 1-3, marina2024novelgeneticand pages 18-19)
  • Founder effects/consanguinity: none established for dominant CMTDIG. Consanguinity is not a causal factor, although it matters for recessive NEFL disease.
  • Sex ratio: no established sex bias; autosomal inheritance predicts both sexes can be affected.
  • Geography/ethnicity: cases occur across populations; no reliable high-prevalence region is known.

CMT overall is often estimated at approximately 1 in 2,500, but that figure must not be assigned to CMTDIG. Neurofilament-related CMT is estimated at roughly 1% of diagnosed CMT, and CMTDIG itself is only a subset. No valid CMTDIG-specific incidence or prevalence per 100,000 is available. (medina2024customizedantisenseoligonucleotidebased pages 1-2, medina2024molecularphenotypicanalysisa pages 30-35)

10. Diagnostics

Clinical and electrophysiological assessment

Diagnosis begins with a three-generation pedigree; neurologic examination for distal weakness/atrophy, pes cavus, sensory loss and reflex reduction; and nerve-conduction studies/EMG. Intermediate or discordant axonal–demyelinating findings should not exclude NEFL testing. The p.Glu397Lys study explicitly recommended considering NEFL beyond purely axonal CMT. (zuchner2004thenovelneurofilament pages 10-10, zuchner2004thenovelneurofilament pages 7-10)

Nerve or muscle biopsy is not routinely required after a molecular diagnosis. If performed for atypical disease, nerve pathology can show large-fiber loss, axonal atrophy, regenerative clusters and onion bulbs; muscle can show neurogenic atrophy and, rarely, nemaline rods or mini-cores. Serum creatine kinase may be normal even in severe NEFL neuromuscular disease. (agrawal2014expandingthephenotype pages 3-4, agrawal2014expandingthephenotype pages 4-5, agrawal2014expandingthephenotype pages 1-2)

Genetic testing algorithm

  1. Confirm a hereditary neuropathy phenotype and conduction category.
  2. Exclude common PMP22 duplication/deletion when clinically indicated.
  3. Use a comprehensive inherited-neuropathy NGS panel that includes NEFL and major CMT genes.
  4. If negative, proceed to trio WES or preferably WGS with copy-number, structural-variant, repeat, mitochondrial and noncoding analysis as appropriate.
  5. Confirm a candidate variant by an orthogonal method, establish phase/segregation, and test parental blood for mosaicism when a variant appears de novo.
  6. Interpret under ACMG/AMP criteria and correlate the variant’s mechanism with phenotype.

In a 2024 specialist-center series of 1,515 CMT-related patients, 205 (13.5%) had intermediate CMT; 81.0% (166/205) received a genetic diagnosis. Overall yield was 76.9%, while WGS added a 3.5% diagnostic uplift; the true 100,000 Genomes Project WGS yield was 19.7% (46/233) after accounting for diagnoses made elsewhere. These figures concern all CMT, not NEFL alone. Record et al., Brain 2024, DOI: 10.1093/brain/awae064.

CMA, karyotyping and FISH have low yield for a typical single-gene phenotype unless a larger chromosomal lesion is suspected. Repeat-expansion and mitochondrial testing are differential-diagnosis tools, not direct NEFL assays. RNA-seq, proteomics and metabolomics remain research adjuncts.

Differential diagnosis

Consider PMP22-related CMT1A/HNPP, GJB1-CMTX1, MPZ neuropathy, MFN2-CMT2A, other intermediate CMT genes, hereditary transthyretin amyloidosis, distal hereditary motor neuropathy, hereditary sensory neuropathy, hereditary spastic paraplegia, CIDP, toxic/metabolic neuropathy, Friedreich ataxia, and motor-neuron disease. Uniform familial slowing favors inherited CMT; conduction block, marked temporal dispersion, acute/subacute progression, systemic features or monoclonal protein should prompt evaluation for acquired neuropathy.

Asymptomatic relatives should receive pre-test genetic counseling. Predictive/cascade testing is appropriate only after a familial pathogenic/likely pathogenic variant is established; CMTDIG is not included in routine newborn screening.

11. Outcome and prognosis

Most dominant NEFL neuropathies are chronic and disabling rather than acutely lethal. There are no CMTDIG-specific 5- or 10-year survival estimates, mortality rates, or validated prognostic calculators. Life expectancy is likely near normal in mildly to moderately affected individuals, but this cannot be generalized to severe NEFL alleles. A severe four-person family included probable respiratory death at 35; that outlier should not be represented as typical CMTDIG prognosis. (agrawal2014expandingthephenotype pages 3-4)

Long-term morbidity includes gait limitation, falls, foot deformity, distal hand dysfunction, pain/cramps, contractures, scoliosis, fatigue and dependence on assistive devices. Axonal loss is generally irreversible; rehabilitation can preserve function and prevent secondary complications but does not restore lost axons. Prognosis is influenced by the specific allele, age at onset, baseline axonal loss, respiratory involvement, contractures and rate of progression. No validated molecular prognostic biomarker exists. Circulating or culture-supernatant NF-L and peripherin are promising pharmacodynamic markers, but in NEFL disease an NF-L assay may reflect both protein expression and injury, complicating interpretation. (medina2024customizedantisenseoligonucleotidebased pages 11-12)

12. Treatment

Current clinical management

There is no approved disease-modifying treatment specific to NEFL/CMTDIG. Management is multidisciplinary and individualized:

  • physical therapy, stretching, balance and low-impact aerobic conditioning (NCIt: Physical Therapy);
  • occupational therapy and hand-function adaptations (NCIt: Occupational Therapy);
  • ankle–foot orthoses, custom footwear, canes/walkers/wheelchairs (NCIt: Orthopedic Device);
  • podiatry and orthopedic correction of rigid cavovarus deformity or contracture when conservative treatment fails (NCIt: Orthopedic Surgery);
  • symptomatic treatment of neuropathic pain and cramps, with attention to sedation, cardiac risk and weakness;
  • respiratory/sleep assessment for severe early-onset disease, scoliosis, morning headaches or sleep-disordered breathing;
  • hearing evaluation where clinically indicated;
  • avoidance, where alternatives exist, of medications with substantial peripheral-neurotoxicity.

No NEFL-specific pharmacogenomic guidance or response rate is available.

2023–2024 experimental developments

The leading precision strategy is suppression of the toxic mutant transcript while retaining sufficient wild-type NF-L. In 2024, Medina et al. used p.N98S patient-derived iPSC motor neurons and an RNase-H1-compatible allele-preferential ASO. Treatment reduced mutant expression by about 20%, total NEFL transcript by 38%, and decreased extracellular NF-L and peripherin injury markers. The abstract describes this as “the first clinically viable genetic therapeutic for CMT2E,” but “clinically viable” means a preclinical development strategy—not demonstrated human efficacy. Brain, published July 2024, DOI: 10.1093/brain/awae225. (medina2024customizedantisenseoligonucleotidebased pages 11-12, medina2024customizedantisenseoligonucleotidebased pages 1-2)

Allele-specific gene editing has also rescued pathology in a human N98S model, supporting toxic-allele inactivation. Both approaches remain variant-dependent and face delivery, off-target, durability and wild-type dosage constraints. (feliciano2021allelespecificgeneediting pages 1-3)

No retrieved ClinicalTrials.gov study specifically tested an NEFL-targeted therapy in CMTDIG. Broader CMT trials cannot be assumed effective in this genotype. Cell therapy, immunotherapy and nonspecific anti-inflammatory therapy have no established CMTDIG role.

13. Prevention

Primary prevention by lifestyle or vaccination is impossible because the initiating lesion is genetic. Reproductive options after molecular confirmation include genetic counseling, prenatal diagnosis, and IVF with preimplantation genetic testing for monogenic disease. Counseling should cover 50% transmission risk, variable expressivity, age-dependent penetrance, de novo disease, and possible parental mosaicism.

Secondary prevention consists of cascade testing, early neurologic/orthopedic assessment, and timely orthoses or rehabilitation before fixed deformity. Tertiary prevention includes fall reduction, stretching to prevent contractures, skin and foot care for sensory loss, weight and cardiometabolic management, monitoring for respiratory/hearing complications when indicated, and avoidance of avoidable neurotoxic exposure. There is no population screening or prophylactic medication.

14. Other species and natural disease

No well-established naturally occurring veterinary counterpart specifically equivalent to human heterozygous NEFL-CMTDIG was identified. The disorder is not infectious or zoonotic and cannot be transmitted between species. Relevant orthologues include mouse Nefl in Mus musculus (NCBI Taxonomy 10090) and homologues in rat, zebrafish and other vertebrates. Neurofilament structure and axonal-caliber functions are evolutionarily conserved, which supports comparative modeling, but engineered model disease should not be coded as naturally occurring veterinary CMT without species-specific evidence.

15. Model organisms and experimental systems

Mouse

The best-characterized model is heterozygous Nefl N98S knock-in mouse. It develops tremor and hindlimb clasping, neuronal inclusions in cell bodies/proximal axons, disorganized cerebellar processes, cortical and pontine abnormalities, and sciatic nerves with fewer neurofilaments, more microtubules and smaller axonal diameters. Abnormal processes were evident by postnatal day 7. In contrast, P8R heterozygous and homozygous mice were behaviorally indistinguishable from wild type, illustrating strong variant- and species-dependent effects. Adebola et al., Human Molecular Genetics 2015, DOI: 10.1093/hmg/ddu736.

A p.Glu397Lys-proximal mouse mutation, Leu394Pro, did not reproduce human demyelination, possibly because lifespan or species biology was insufficient for secondary myelin pathology. (zuchner2004thenovelneurofilament pages 10-10)

Cellular and human models

Transfected-cell systems demonstrate mutant-dependent filament-network abnormalities and aggregation, but overexpression can distort stoichiometry. Patient iPSC-derived motor neurons are more disease-relevant and reproduce N98S NF-L accumulation and axonal-injury biomarkers; they supported both allele-specific editing and ASO rescue. The main limitation is that cultured neurons do not fully reproduce decades-long axon–Schwann-cell interaction, biomechanics, immune context, or distal nerve length. (medina2024customizedantisenseoligonucleotidebased pages 11-12, feliciano2021allelespecificgeneediting pages 1-3)

Primary-neuron studies of O-GlcNAcylation and proposed future muscle organoids can dissect assembly, organelle transport and direct muscle vulnerability. No validated CMTDIG organoid, single-cell atlas, spatial-transcriptomic model, or high-throughput CRISPR modifier screen was identified. (marina2024novelgeneticand pages 1-3, marina2024novelgeneticand pages 18-19)

Evidence-calibrated conclusions

  1. High confidence: CMTDIG is a heterozygous NEFL neuropathy with dominant inheritance, marked variable expressivity, and mixed axonal/demyelinating physiology and pathology.
  2. High confidence: p.Glu397Lys family evidence supports the intermediate designation through MNCVs, large-fiber axonal loss, onion bulbs and secondary myelin abnormalities. (zuchner2004thenovelneurofilament pages 1-2, zuchner2004thenovelneurofilament pages 6-7)
  3. Moderate-to-high confidence: dominant variants perturb NF-L assembly, axonal caliber and intracellular transport; the contribution of aggregation and O-GlcNAc dysregulation varies by allele.
  4. High confidence: current care is supportive; no NEFL/CMTDIG-targeted therapy has demonstrated clinical efficacy.
  5. Promising but preclinical: allele-preferential ASO and gene editing can reduce N98S-associated pathology in human cellular models. (medina2024customizedantisenseoligonucleotidebased pages 11-12, feliciano2021allelespecificgeneediting pages 1-3)
  6. Major knowledge gaps: CMTDIG-specific prevalence, incidence, penetrance by age, phenotype frequencies, longitudinal progression, quality-of-life statistics, circulating biomarker validation, genotype-specific treatment response, and human trial data remain unavailable.

Key primary/recent sources

  • Züchner S, et al. “The novel neurofilament light (NEFL) mutation Glu397Lys…” Neuromuscular Disorders. February 2004;14:147–157. PMID: 14733962. DOI: 10.1016/j.nmd.2003.10.003. (zuchner2004thenovelneurofilament pages 1-2)
  • Della Marina A, et al. “Novel Genetic and Biochemical Insights into the Spectrum of NEFL-Associated Phenotypes.” Journal of Neuromuscular Diseases. April 2024;11:625–645. DOI: 10.3233/JND-230230. (marina2024novelgeneticand pages 1-3)
  • Huynh DT, et al. “O-GlcNAcylation regulates neurofilament-light assembly and function and is perturbed by Charcot-Marie-Tooth disease mutations.” Nature Communications. 2023;14. DOI: 10.1038/s41467-023-42227-0.
  • Medina J, et al. “Customized antisense oligonucleotide-based therapy for neurofilament-associated Charcot-Marie-Tooth disease.” Brain. July 2024;147:4227–4239. DOI: 10.1093/brain/awae225. (medina2024customizedantisenseoligonucleotidebased pages 11-12)
  • Adebola AA, et al. “Neurofilament light polypeptide gene N98S mutation in mice…” Human Molecular Genetics. April 2015;24:2163–2174. DOI: 10.1093/hmg/ddu736.
  • Agrawal PB, et al. “Expanding the phenotype associated with the NEFL mutation…” JAMA Neurology. November 2014;71:1413–1420. DOI: 10.1001/jamaneurol.2014.1432. (agrawal2014expandingthephenotype pages 3-4, agrawal2014expandingthephenotype pages 1-2)

References

  1. (OpenTargets Search: Charcot-Marie-Tooth disease dominant intermediate G-NEFL): Open Targets Query (Charcot-Marie-Tooth disease dominant intermediate G-NEFL, 2 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  2. (medina2024customizedantisenseoligonucleotidebased pages 1-2): Jessica Medina, Adriana Rebelo, Matt C Danzi, Elizabeth H Jacobs, Isaac R L Xu, Kathleen P Ahrens, Sitong Chen, Jacquelyn Raposo, Christopher Yanick, Stephan Zuchner, and Mario A Saporta. Customized antisense oligonucleotide-based therapy for neurofilament-associated charcot-marie-tooth disease. Brain : a journal of neurology, 147:4227-4239, Jul 2024. URL: https://doi.org/10.1093/brain/awae225, doi:10.1093/brain/awae225. This article has 9 citations.

  3. (marina2024novelgeneticand pages 1-3): Adela Della Marina, Andreas Hentschel, Artur Czech, Ulrike Schara-Schmidt, Corinna Preusse, Andreas Laner, Angela Abicht, Tobias Ruck, Joachim Weis, Catherine Choueiri, Hanns Lochmüller, Heike Kölbel, and Andreas Roos. Novel genetic and biochemical insights into the spectrum of nefl-associated phenotypes. Journal of Neuromuscular Diseases, 11:625-645, Apr 2024. URL: https://doi.org/10.3233/jnd-230230, doi:10.3233/jnd-230230. This article has 12 citations and is from a peer-reviewed journal.

  4. (zuchner2004thenovelneurofilament pages 1-2): Stephan Züchner, Matthias Vorgerd, Eckhart Sindern, and J.Michael Schröder. The novel neurofilament light (nefl) mutation glu397lys is associated with a clinically and morphologically heterogeneous type of charcot-marie-tooth neuropathy. Neuromuscular Disorders, 14:147-157, Feb 2004. URL: https://doi.org/10.1016/j.nmd.2003.10.003, doi:10.1016/j.nmd.2003.10.003. This article has 120 citations and is from a peer-reviewed journal.

  5. (zuchner2004thenovelneurofilament pages 6-7): Stephan Züchner, Matthias Vorgerd, Eckhart Sindern, and J.Michael Schröder. The novel neurofilament light (nefl) mutation glu397lys is associated with a clinically and morphologically heterogeneous type of charcot-marie-tooth neuropathy. Neuromuscular Disorders, 14:147-157, Feb 2004. URL: https://doi.org/10.1016/j.nmd.2003.10.003, doi:10.1016/j.nmd.2003.10.003. This article has 120 citations and is from a peer-reviewed journal.

  6. (zuchner2004thenovelneurofilament pages 7-10): Stephan Züchner, Matthias Vorgerd, Eckhart Sindern, and J.Michael Schröder. The novel neurofilament light (nefl) mutation glu397lys is associated with a clinically and morphologically heterogeneous type of charcot-marie-tooth neuropathy. Neuromuscular Disorders, 14:147-157, Feb 2004. URL: https://doi.org/10.1016/j.nmd.2003.10.003, doi:10.1016/j.nmd.2003.10.003. This article has 120 citations and is from a peer-reviewed journal.

  7. (marina2024novelgeneticand pages 18-19): Adela Della Marina, Andreas Hentschel, Artur Czech, Ulrike Schara-Schmidt, Corinna Preusse, Andreas Laner, Angela Abicht, Tobias Ruck, Joachim Weis, Catherine Choueiri, Hanns Lochmüller, Heike Kölbel, and Andreas Roos. Novel genetic and biochemical insights into the spectrum of nefl-associated phenotypes. Journal of Neuromuscular Diseases, 11:625-645, Apr 2024. URL: https://doi.org/10.3233/jnd-230230, doi:10.3233/jnd-230230. This article has 12 citations and is from a peer-reviewed journal.

  8. (agrawal2014expandingthephenotype pages 3-4): Pankaj B. Agrawal, Mugdha Joshi, Nicholas S. Marinakis, Klaus Schmitz-Abe, Pedro D. S. C. Ciarlini, Jane C. Sargent, Kyriacos Markianos, Umberto De Girolami, David A. Chad, and Alan H. Beggs. Expanding the phenotype associated with the nefl mutation: neuromuscular disease in a family with overlapping myopathic and neurogenic findings. JAMA neurology, 71 11:1413-20, Nov 2014. URL: https://doi.org/10.1001/jamaneurol.2014.1432, doi:10.1001/jamaneurol.2014.1432. This article has 46 citations and is from a highest quality peer-reviewed journal.

  9. (agrawal2014expandingthephenotype pages 4-5): Pankaj B. Agrawal, Mugdha Joshi, Nicholas S. Marinakis, Klaus Schmitz-Abe, Pedro D. S. C. Ciarlini, Jane C. Sargent, Kyriacos Markianos, Umberto De Girolami, David A. Chad, and Alan H. Beggs. Expanding the phenotype associated with the nefl mutation: neuromuscular disease in a family with overlapping myopathic and neurogenic findings. JAMA neurology, 71 11:1413-20, Nov 2014. URL: https://doi.org/10.1001/jamaneurol.2014.1432, doi:10.1001/jamaneurol.2014.1432. This article has 46 citations and is from a highest quality peer-reviewed journal.

  10. (medina2024molecularphenotypicanalysisa pages 30-35): J Medina. Molecular phenotypic analysis following antisense oligonucleotide treatment in a pre-clinical charcot-marie-tooth disease model. Unknown journal, 2024.

  11. (feliciano2021allelespecificgeneediting pages 1-3): CM Feliciano, K Wu, and HL Watry. Allele-specific gene editing rescues pathology in a human model of charcot-marie. Unknown journal, 2021.

  12. (medina2024customizedantisenseoligonucleotidebased pages 11-12): Jessica Medina, Adriana Rebelo, Matt C Danzi, Elizabeth H Jacobs, Isaac R L Xu, Kathleen P Ahrens, Sitong Chen, Jacquelyn Raposo, Christopher Yanick, Stephan Zuchner, and Mario A Saporta. Customized antisense oligonucleotide-based therapy for neurofilament-associated charcot-marie-tooth disease. Brain : a journal of neurology, 147:4227-4239, Jul 2024. URL: https://doi.org/10.1093/brain/awae225, doi:10.1093/brain/awae225. This article has 9 citations.

  13. (medina2024molecularphenotypicanalysis pages 13-17): J Medina. Molecular phenotypic analysis following antisense oligonucleotide treatment in a pre-clinical charcot-marie-tooth disease model. Unknown journal, 2024.

  14. (zuchner2004thenovelneurofilament pages 10-10): Stephan Züchner, Matthias Vorgerd, Eckhart Sindern, and J.Michael Schröder. The novel neurofilament light (nefl) mutation glu397lys is associated with a clinically and morphologically heterogeneous type of charcot-marie-tooth neuropathy. Neuromuscular Disorders, 14:147-157, Feb 2004. URL: https://doi.org/10.1016/j.nmd.2003.10.003, doi:10.1016/j.nmd.2003.10.003. This article has 120 citations and is from a peer-reviewed journal.

  15. (agrawal2014expandingthephenotype pages 1-2): Pankaj B. Agrawal, Mugdha Joshi, Nicholas S. Marinakis, Klaus Schmitz-Abe, Pedro D. S. C. Ciarlini, Jane C. Sargent, Kyriacos Markianos, Umberto De Girolami, David A. Chad, and Alan H. Beggs. Expanding the phenotype associated with the nefl mutation: neuromuscular disease in a family with overlapping myopathic and neurogenic findings. JAMA neurology, 71 11:1413-20, Nov 2014. URL: https://doi.org/10.1001/jamaneurol.2014.1432, doi:10.1001/jamaneurol.2014.1432. This article has 46 citations and is from a highest quality peer-reviewed journal.

Artifacts

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These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0036484 (8 mentions) - the report calls it "if available", "MONDO"; MONDO calls it Charcot-Marie-Tooth disease, dominant intermediate G

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  • MONDO:0036484 - called "if available", "MONDO"