Charcot-Marie-Tooth Disease Axonal Type 2S

Genetic MONDO:0014511 Pathograph 25 Show in embeddings browser MONDO:0018993

Charcot-Marie-Tooth disease axonal type 2S (CMT2S; OMIM #616155) is an autosomal recessive, slowly progressive, length-dependent axonal sensorimotor neuropathy caused by biallelic variants in IGHMBP2, which encodes immunoglobulin mu-binding protein 2, a ubiquitously expressed UPF1-like ATP-dependent DNA/RNA helicase implicated in ribosome biogenesis and translation. It is the milder allelic counterpart of spinal muscular atrophy with respiratory distress type 1 (SMARD1): variants that retain residual IGHMBP2 abundance and biochemical activity spare the diaphragm and phrenic motor neurons and produce CMT2S, whereas those that abolish activity cause infantile diaphragmatic paralysis and death. Onset is usually in infancy or early childhood (mean about 3.8 years) with distal weakness, delayed milestones, foot deformity, gait disturbance and foot drop, progressing to distal amyotrophy with mild sensory and occasional autonomic involvement; electrophysiology shows reduced motor and sensory amplitudes with preserved conduction velocities. Respiratory function is normally preserved, but late diaphragmatic weakness and acute Guillain-Barre-like presentations are reported, so respiratory surveillance is advised. About two-thirds of reported variants are missense changes clustering in the helicase and ATPase domains and a third are truncating. Dedicated knock-in mouse models reproduce progressive motor and sensory axonal degeneration, and neuromuscular junction denervation correlates with residual IGHMBP2 activity. Care is supportive and rehabilitative; an intrathecal AAV9-IGHMBP2 gene therapy trial enrolling both SMARD1 and CMT2S (NCT05152823) and a personalised splice-correcting antisense oligonucleotide are in development.

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1
Inheritance
4
Pathophys.
10
Phenotypes
1
Gaps
25
Pathograph
1
Genes
2
Variants
6
Medical Actions
2
Differentials
1
Trials
3
Models
1
References
1
Deep Research
🏷

Classifications

Harrison's Part
NEUROLOGIC GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal recessive HP:0000007
Autosomal recessive; heterozygous carriers are unaffected. Expressivity spans the SMARD1-CMT2S continuum, including within families sharing the same genotype.
Autosomal recessive inheritance Penetrance: COMPLETE Expressivity: VARIABLE
Show evidence (2 references)
PMID:35660062 SUPPORT Human Clinical
"Autosomal recessive Charcot-Marie-Tooth disease Type 2S (AR-CMT2S) caused by IGHMBP2 mutation was first reported in 2014, and an increasing number of cases have been reported in the past eight years."
States the inheritance pattern.
PMID:27450922 SUPPORT Human Clinical
"Biallelic mutations in IGHMBP2 cause spinal muscular atrophy with respiratory distress type 1 (SMARD1) or Charcot-Marie-Tooth type 2S (CMT2S)."
Biallelic requirement and allelic relationship to SMARD1.
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Discussions and Knowledge Gaps

1
Which IGHMBP2-dependent RNA process (pre-rRNA processing, tRNA metabolism, translation, mRNA export) is rate-limiting in long peripheral axons, and why does partial loss spare respiratory motor neurons while abolished activity does not?
KNOWLEDGE GAP OPEN cmt2s_rna_process_gap
Attached to
pathophysiology#Disturbed Ribosome Biogenesis and Translation
IGHMBP2 has several proposed roles in gene expression and the field has not determined which, when dysregulated, causes neurodegeneration; the residual-activity threshold that separates CMT2S from SMARD1 is established at the biochemical level but its cellular basis in neuron subtypes is not.
Show evidence (1 reference)
PMID:39119929 SUPPORT Other
"More than 20 years after the link between IGHMBP2 and SMARD1 was revealed, and 10 years after the discovery of the association between IGHMBP2 and CMT2S, the pathogenic mechanism of these diseases is still not well defined."
Review statement of the mechanistic gap.
⚙

Pathophysiology

4
Biallelic Hypomorphic IGHMBP2 Variants
CMT2S alleles reduce, but do not abolish, IGHMBP2 abundance and its ATP-dependent DNA/RNA helicase activity. Association with the activator ABT1 stimulates IGHMBP2 ATPase and helicase activity, and CMT2S variants such as p.His924Tyr retain ABT1 association and substantial activity, whereas SMARD1 variants such as p.Asp565Asn lose it; in compound heterozygotes the summed activity of the two mutant proteins predicts severity. This residual-activity threshold is the disorder-specific insult to peripheral neurons.
DNA/RNA helicase activity GO:0003678 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased DNA/RNA helicase activity, annotated with DNA helicase activity (GO:0003678). GO:0003678 is a molecular function from the Gene Ontology. ↓ DECREASED RNA helicase activity GO:0003724 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased RNA helicase activity (GO:0003724). GO:0003724 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Disturbed Ribosome Biogenesis and Translation
Show evidence (3 references)
PMID:38403020 SUPPORT In Vitro
"For the first time, we demonstrate a correlation between the altered IGHMBP2 biochemical activity associated with the D565N and H924Y mutations and disease severity and pathology in patients and our Ighmbp2 mouse models."
Residual activity determines severity along the SMARD1-CMT2S continuum.
PMID:38403020 SUPPORT In Vitro
"In the context of the compound heterozygous patient, we demonstrate that the total biochemical activity associated with IGHMBP2-D565N and IGHMBP2-H924Y proteins is improved over IGHMBP2-D565N alone."
Summed activity of two alleles explains compound heterozygous phenotypes.
PMID:39119929 SUPPORT Other
"The discovery that IGHMBP2 functions as an RNA/DNA helicase was an important step, but it did not reveal the pathogenic mechanism."
Review framing of the helicase function and the open mechanism question.
Disturbed Ribosome Biogenesis and Translation
IGHMBP2, with ABT1, binds the 47S pre-rRNA 5' external transcribed spacer and U3 snoRNA, implicating it in pre-rRNA processing; it is also associated with tRNA and translation machinery. Loss of activity is proposed to impair ribosome biogenesis and translation, with a low-grade integrated stress response in knockout cells, but which of IGHMBP2's RNA-metabolic roles drives neuronal pathology is unresolved.
rRNA processing GO:0006364 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated rRNA processing (GO:0006364). GO:0006364 is a biological process from the Gene Ontology. ↕ DYSREGULATED translation GO:0006412 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased translation (GO:0006412). GO:0006412 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Motor and Sensory Axonal Degeneration
Show evidence (4 references)
PMID:36480289 SUPPORT In Vitro
"We provide a mechanism proposing that ABT1 decreases disease pathology in FVB-Ighmbp2nmd/nmd mutants by optimizing IGHMBP2 biochemical activity (ATPase and helicase activity). Our studies provide insight into SMARD1 pathogenesis, suggesting that ABT1 modifies IGHMBP2 activity as a means to..."
Proposes pre-rRNA processing as the affected pathway.
PMID:39119929 SUPPORT Other
"IGHMBP2 appears to be a multifunctional factor involved in several cellular processes that regulate gene expression. It is difficult to determine which processes, when dysregulated, lead to pathology."
Records the unresolved link between RNA functions and pathology.
PMID:38803225 SUPPORT In Vitro
"we found that IGHMBP2 deletion modestly reduces global translation"
Direct measurement of reduced global translation in IGHMBP2-knockout cells, supporting the DECREASED translation modifier.
+ 1 more reference
Motor and Sensory Axonal Degeneration
Long peripheral motor and sensory axons degenerate progressively, producing an axonal neuropathy with reduced amplitudes and largely preserved conduction velocities; CMT2S knock-in mice show progressive motor and sensory axonal degeneration in femoral nerves with motor deficits and mechanical allodynia. In contrast to SMARD1, spinal alpha-motor neurons supplying the diaphragm are relatively spared.
motor neuron CL:0000100 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves motor neuron (CL:0000100). CL:0000100 is a cell type from the Cell Ontology. sensory neuron CL:0000101 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves sensory neuron (CL:0000101). CL:0000101 is a cell type from the Cell Ontology.
Animal models
Ighmbp2 E365del and Y918C knock-in mice Mouse recapitulates Progressive femoral motor and sensory axonal degeneration with motor and sensory behavioural deficits.
Downstream
Neuromuscular Junction Denervation and Distal Muscle Atrophy
Peripheral axonal neuropathy
Sensory neuropathy
Abnormal autonomic nervous system physiology
Show evidence (2 references)
PMID:36413117 SUPPORT Model Organism
"Phenotypic characterization of the homozygous models found progressive peripheral motor and sensory axonal degeneration."
Direct demonstration of axonal degeneration in CMT2S models.
PMID:25568292 SUPPORT Human Clinical
"All patients had a predominantly axonal sensorimotor neuropathy with subsequent muscle atrophy, but without obvious sensory symptoms."
Human electrophysiological and clinical correlate.
Neuromuscular Junction Denervation and Distal Muscle Atrophy
Loss of motor axons denervates neuromuscular junctions, causing neurogenic distal muscle atrophy, weakness, foot deformity and gait impairment. In compound heterozygous Ighmbp2 D564N/H922Y mice NMJ denervation and reduced fibre area are marked, whereas the CMT2S-like H922Y homozygote shows minimal NMJ changes even at six months; patient-derived neuromuscular co-cultures show high fatigue and chaotic tetanus that are rescued by restoring IGHMBP2.
neuromuscular junction development GO:0007528 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal neuromuscular junction development (GO:0007528). GO:0007528 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Experimental models
Patient fibroblast and neuromuscular junction co-culture model PRIMARY CELL CULTURE NMJ fatigue and chaotic tetanus in patient-derived cells, rescued by ASO-mediated IGHMBP2 restoration.
Animal models
Ighmbp2 H922Y and D564N/H922Y mice Mouse partially recapitulates NMJ denervation is marked in the compound heterozygote but minimal in the CMT2S-like homozygote.
Downstream
Distal muscle weakness
Distal amyotrophy
Foot dorsiflexor weakness
Pes cavus
Gait disturbance
Motor delay
Diaphragmatic weakness
Show evidence (3 references)
PMID:39461706 SUPPORT Model Organism
"There was decreased limb skeletal muscle fiber area and increased neuromuscular junction (NMJ) denervation in Ighmbp2D564N/H922Y mice."
NMJ denervation and muscle atrophy in the compound heterozygous model.
PMID:39461706 SUPPORT Model Organism
"Consistent with CMT2S, Ighmbp2H922Y/H922Y mice did not have altered lifespans nor respiratory pathology."
The CMT2S-like allele spares respiration and lifespan.
PMID:40060931 SUPPORT In Vitro
"Neuromuscular junction analyses revealed high fatigue and chaotic tetanus formulation in untreated patient cells. We demonstrate rescue of NMJ function following ASO treatment, captured by a reduction in fatigue and chaotic tetanus responses."
Patient-derived NMJ dysfunction and its rescue by IGHMBP2 restoration.
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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 Axonal Type 2S 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

10
Limbs 2
Foot dorsiflexor weakness FREQUENT HP:0009027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Foot drop, annotated with Foot dorsiflexor weakness (HP:0009027). HP:0009027 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35660062 SUPPORT Human Clinical
"The initial symptoms included muscle weakness (15, 33.3%), delayed milestones (9, 20%), feet deformity (8, 17.8%), gait disturbance (8, 17.8%), feet drop (7, 15.6%), frequent falls (3, 6.7%), hypotonia (2, 4.4%) and thenar atrophy (1, 2.2%)."
Foot drop as an initial symptom. The frequency band is inferred from the share presenting with this feature, which is a lower bound on its lifetime frequency.
Pes cavus FREQUENT HP:0001761 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Foot deformity (pes cavus), annotated with Pes cavus (HP:0001761). HP:0001761 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30409445 SUPPORT Human Clinical
"A 9 month old boy presented with bilateral feet deformities and axonal neuropathy."
Foot deformity as the presenting feature.
PMID:35660062 SUPPORT Human Clinical
"The initial symptoms included muscle weakness (15, 33.3%), delayed milestones (9, 20%), feet deformity (8, 17.8%), gait disturbance (8, 17.8%), feet drop (7, 15.6%), frequent falls (3, 6.7%), hypotonia (2, 4.4%) and thenar atrophy (1, 2.2%)."
Frequency of foot deformity at onset. The frequency band is inferred from the share presenting with this feature, which is a lower bound on its lifetime frequency.
Musculoskeletal 3
Distal muscle weakness VERY_FREQUENT HP:0002460 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal muscle weakness (HP:0002460). HP:0002460 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35660062 SUPPORT Human Clinical
"The initial symptoms included muscle weakness (15, 33.3%), delayed milestones (9, 20%), feet deformity (8, 17.8%), gait disturbance (8, 17.8%), feet drop (7, 15.6%), frequent falls (3, 6.7%), hypotonia (2, 4.4%) and thenar atrophy (1, 2.2%)."
Initial symptom frequencies across 45 patients. The frequency band is inferred from the share presenting with this feature, which is a lower bound on its lifetime frequency.
Distal amyotrophy VERY_FREQUENT HP:0003693 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal amyotrophy (HP:0003693). HP:0003693 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25568292 SUPPORT Human Clinical
"All patients had a predominantly axonal sensorimotor neuropathy with subsequent muscle atrophy, but without obvious sensory symptoms."
Muscle atrophy secondary to the neuropathy.
Diaphragmatic weakness VERY_RARE HP:0009113 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Late-onset diaphragmatic weakness, annotated with Diaphragmatic weakness (HP:0009113). HP:0009113 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30409445 SUPPORT Human Clinical
"At 9 years, he developed diaphragmatic weakness, following which he was established on non-invasive ventilation."
Documented late diaphragmatic involvement.
Nervous System 5
Peripheral axonal neuropathy OBLIGATE HP:0003477 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Axonal sensorimotor polyneuropathy, annotated with Peripheral axonal neuropathy (HP:0003477). HP:0003477 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25568292 SUPPORT Human Clinical
"All patients had a predominantly axonal sensorimotor neuropathy with subsequent muscle atrophy, but without obvious sensory symptoms."
Defining neuropathy phenotype.
PMID:28202949 SUPPORT Human Clinical
"Three patients presented with childhood-onset axonal predominant sensorimotor polyneuropathies, whereas the other case was diagnosed with SMARD1"
Independent cohort confirming the axonal sensorimotor phenotype.
Motor delay OCCASIONAL HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed motor milestones, annotated with Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35660062 SUPPORT Human Clinical
"The initial symptoms included muscle weakness (15, 33.3%), delayed milestones (9, 20%), feet deformity (8, 17.8%), gait disturbance (8, 17.8%), feet drop (7, 15.6%), frequent falls (3, 6.7%), hypotonia (2, 4.4%) and thenar atrophy (1, 2.2%)."
Frequency of delayed milestones as the initial symptom.
Gait disturbance FREQUENT HP:0001288 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gait disturbance (HP:0001288). HP:0001288 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35660062 SUPPORT Human Clinical
"The initial symptoms included muscle weakness (15, 33.3%), delayed milestones (9, 20%), feet deformity (8, 17.8%), gait disturbance (8, 17.8%), feet drop (7, 15.6%), frequent falls (3, 6.7%), hypotonia (2, 4.4%) and thenar atrophy (1, 2.2%)."
Gait-related initial symptoms. The frequency band is inferred from the share presenting with this feature, which is a lower bound on its lifetime frequency.
Sensory neuropathy FREQUENT HP:0000763 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensory axonal involvement, annotated with Sensory neuropathy (HP:0000763). HP:0000763 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25568292 SUPPORT Human Clinical
"All patients had a predominantly axonal sensorimotor neuropathy with subsequent muscle atrophy, but without obvious sensory symptoms."
Sensorimotor involvement with subclinical sensory symptoms.
Abnormal autonomic nervous system physiology OCCASIONAL HP:0012332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autonomic neuropathy, annotated with Abnormal autonomic nervous system physiology (HP:0012332). HP:0012332 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25568292 SUPPORT Human Clinical
"Two patients had signs of autonomic neuropathy."
Autonomic involvement in the original series.
🧬

Genetic Associations

1
IGHMBP2
Gene: IGHMBP2 hgnc:5542 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is IGHMBP2 (hgnc:5542). hgnc:5542 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (5 references)
PMID:25439726 SUPPORT Human Clinical
"Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations."
The paper that established IGHMBP2 as the CMT2S gene, in 11 recessive families.
PMID:25439726 SUPPORT Human Clinical
"Mutations in CMT2 were predicted to be less aggressive as compared to those in SMARD1, and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences are..."
Residual protein level as the basis of the CMT2S-versus-SMARD1 distinction.
PMID:25568292 SUPPORT Human Clinical
"We report on 5 patients with neuropathy from 3 families who carried truncating mutations in IGHMBP2. Contrary to the "classic" phenotype, they did not manifest with respiratory distress, but with progressive sensorimotor neuropathy."
Establishes IGHMBP2 as a cause of axonal neuropathy without respiratory distress.
+ 2 more references
Variants (2)
c.2770C>T (p.His924Tyr) Pathogenic
missense
CMT2S-associated missense variant in the C-terminal region; alters IGHMBP2 activity to a lesser extent than the SMARD1 variant p.Asp565Asn while maintaining association with ABT1, and the equivalent H922Y knock-in mouse has a normal lifespan without respiratory pathology, modelling the CMT2S end of the spectrum.
Show evidence (2 references)
PMID:38403020 SUPPORT In Vitro
"The IGHMBP2-D565N mutation has been identified in SMARD1 patients, while the IGHMBP2-H924Y mutation has been identified in CMT2S patients."
Assigns the variant to the CMT2S phenotype.
PMID:38403020 SUPPORT In Vitro
"The H924Y mutation alters IGHMBP2 activity to a lesser extent while maintaining association with ABT1."
Biochemical basis for the milder phenotype.
c.1156T>C (p.Trp386Arg) / c.2747G>A (p.Cys916Tyr) Pathogenic
missense
Compound heterozygous missense variants in a boy with CMT2S who developed diaphragmatic weakness at 9 years.
Show evidence (1 reference)
PMID:30409445 SUPPORT Human Clinical
"Genetic testing revealed two heterozygous variants in the IGHMBP2 gene: c.1156 T > C p.(Trp386Arg) in exon 8 and c.2747G > A p.(Cys916Tyr) in exon 14, that were inherited from his father and mother respectively."
Reports the variants and their segregation.
💊

Medical Actions

6
Physiotherapy, orthoses and rehabilitation
Action: Physical therapy and rehabilitationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Physical therapy and rehabilitation, annotated with Physical Therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Platform: Behavioral / lifestyle
Care is supportive and extrapolated from general CMT practice: individualised physiotherapy, occupational therapy, ankle-foot orthoses and mobility aids, pain management, and orthopaedic correction of fixed foot deformity or scoliosis after specialist assessment.
Target Phenotypes: Distal muscle weakness HP:0002460 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Distal muscle weakness (HP:0002460). HP:0002460 is a phenotype from the Human Phenotype Ontology.
Respiratory surveillance and non-invasive ventilation
Action: Non-invasive ventilationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Non-invasive ventilation, annotated with Non-Invasive Mechanical Ventilation (NCIT:C171457). NCIT:C171457 is a clinical intervention from the NCI Thesaurus. Ontology label: Non-Invasive Mechanical Ventilation NCIT:C171457
Platform: Device
Lifelong respiratory surveillance is advised because diaphragmatic weakness can appear years after onset; non-invasive ventilation is instituted when it does.
Target Phenotypes: Diaphragmatic weakness HP:0009113 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Diaphragmatic weakness (HP:0009113). HP:0009113 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30409445 SUPPORT Human Clinical
"At 9 years, he developed diaphragmatic weakness, following which he was established on non-invasive ventilation. Our case emphasizes the importance of life long respiratory surveillance for patients with CMT2S and expands the phenotype of this condition."
Basis for surveillance and ventilatory support.
Intrathecal AAV9-IGHMBP2 gene therapy (investigational)
Action: Gene therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Gene therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. Ontology label: Gene Therapy NCIT:C15238
Platform: Gene therapy
Single intrathecal AAV9-IGHMBP2 delivery is in a phase I/IIa trial enrolling genetically confirmed SMARD1 or CMT2S (NCT05152823). In the SMARD1 mouse, optimised AAV9-IGHMBP2 vectors rescued survival, motor function, motor neurons and neuromuscular junctions and resolved spinal cord inflammatory changes, with a truncated MeCP2 (P546) promoter giving superior long-term efficacy and safety.
Mechanism Target:
Biallelic Hypomorphic IGHMBP2 Variants — Restores IGHMBP2 expression in motor neurons irrespective of genotype.
Show evidence (2 references)
PMID:41486111 SUPPORT Model Organism
"Corroborating previous findings, both constructs effectively rescued the pathological phenotype, significantly improving survival, body weight, and motor function while preserving motor neurons and neuromuscular junctions."
Preclinical efficacy in the IGHMBP2-deficient mouse.
clinicaltrials:NCT05152823 SUPPORT Human Clinical
"Open-label, single intrathecal injection study of a AAV9 vector carrying the IGHMBP2 gene for IGHMBP2-related diseases."
Registered trial covering IGHMBP2-related diseases including CMT2S.
Personalised splice-correcting antisense oligonucleotide (preclinical)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Platform: Antisense oligonucleotide Splice modulation (exon skipping)
RNA target: IGHMBP2 hgnc:5542 HUGO Gene Nomenclature Committee (hgnc) Relation: this treatment base-pairs with the transcript of this gene This treatment base-pairs with the transcript of IGHMBP2 (hgnc:5542). hgnc:5542 is a gene from the HUGO Gene Nomenclature Committee. IGHMBP2 pre-mRNA deep intronic cryptic splice acceptor
For a compound heterozygous patient with a deep intronic cryptic-splice variant, a 19-mer antisense oligonucleotide blocking the cryptic acceptor restored wild-type transcript, raised IGHMBP2 protein by over 50% in fibroblasts, rescued neuromuscular junction function in vitro and was well tolerated intrathecally in rats; an N-of-1 strategy applicable only to that variant class.
Mechanism Target:
Biallelic Hypomorphic IGHMBP2 Variants — Blocks a variant-created cryptic splice site so that normally spliced, stable IGHMBP2 transcript is restored.
Show evidence (1 reference)
PMID:40060931 SUPPORT In Vitro
"ASO treatment of patient fibroblasts significantly increased the ratio of restored wild-type transcript to cryptic exon-containing transcript and resulted in over a 50% increase in IGHMBP2 protein levels."
Molecular rescue in patient cells.
ABT1 augmentation (preclinical)
Action: Gene therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Gene therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. Ontology label: Gene Therapy NCIT:C15238
Platform: Gene therapy
Intracerebroventricular scAAV9-Abt1 reduced disease pathology, extended lifespan and decreased neuromuscular junction denervation in the SMARD1-nmd mouse by stimulating the ATPase and helicase activity of residual IGHMBP2; a modifier-based strategy potentially suited to hypomorphic CMT2S alleles.
Mechanism Target:
Biallelic Hypomorphic IGHMBP2 Variants — Increases the activity of residual mutant IGHMBP2 through its activator ABT1.
Show evidence (1 reference)
PMID:36480289 SUPPORT Model Organism
"Intracerebroventricular injection of scAAV9-Abt1 decreases FVB-Ighmbp2nmd/nmd disease pathology, significantly increases lifespan, and substantially decreases neuromuscular junction denervation."
Preclinical proof of the modifier approach.
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 recessive counselling with a 25% recurrence risk; the SMARD1-CMT2S continuum within a sibship should be explained.
Show evidence (1 reference)
PMID:27450922 SUPPORT Human Clinical
"The clinical presentation in Patients 1 and 3 were consistent with SMARD1, whereas Patients 2 and 4 were in agreement with CMT2S."
Illustrates the intrafamilial phenotypic range relevant to counselling.
🔬

Diagnosis

3
Molecular genetic testing for biallelic IGHMBP2 variants
IGHMBP2 screening is recommended for early-onset, sporadic or autosomal recessive axonal CMT2, and should not be withheld in the absence of respiratory symptoms.
Show evidence (2 references)
PMID:28065684 SUPPORT Human Clinical
"In conclusion, mutation screening of IGHMBP2 should be especially considered in AR-CMT2 and sporadic CMT2 patients."
Testing recommendation.
PMID:25568292 SUPPORT Human Clinical
"Mutations in IGHMBP2 should be considered in the molecular genetic workup of patients with hereditary sensorimotor neuropathies, even in the absence of respiratory symptoms."
Extends testing to patients without respiratory involvement.
Nerve conduction studies
Reduced motor and sensory amplitudes with relatively preserved conduction velocities confirm an axonal sensorimotor neuropathy.
Show evidence (1 reference)
PMID:28202949 SUPPORT Human Clinical
"Three patients presented with childhood-onset axonal predominant sensorimotor polyneuropathies"
Electrophysiological classification.
Recognition of acute Guillain-Barre-like presentations
Acute motor and sensory axonal neuropathy with cauda equina enhancement and raised CSF protein has been reported as the presentation of CMT2S, so genetic testing should be considered when an apparent immune neuropathy has an atypical course.
Show evidence (1 reference)
PMID:41468720 SUPPORT Human Clinical
"Case 3 and 4, two siblings, presented with a Guillain-Barré syndrome-like phenotype, cauda equina enhancement on spinal neuroimaging, elevated cerebrospinal fluid protein, and electromyography revealing acute motor and sensory axonal neuropathy."
Atypical presentation relevant to diagnosis.
📈

Progression

2
Infantile or childhood onset
Onset ranges from the first months of life to 20 years (mean 3.8 years), with about half presenting before age two with weakness, delayed milestones, foot deformity, gait disturbance or foot drop; the course is slowly progressive with distal-to-proximal spread and preserved respiratory function in most patients.
Show evidence (2 references)
PMID:35660062 SUPPORT Human Clinical
"The age at onset ranged from 0.11 years to 20 years (mean±SD: 3.76±3.93 years) and the infantile (0-2 years) onset group accounted for the most patients (51.1%)."
Age-of-onset distribution across reported patients.
PMID:25568292 SUPPORT Human Clinical
"Only one patient required nocturnal mask ventilation, while 4 others maintained normal respiratory function by the age of 14, 18, 22, and 37 years. Three patients were still able to walk independently."
Long-term respiratory and ambulatory course.
Late respiratory involvement (rare)
Diaphragmatic weakness can emerge years after onset in patients with an otherwise typical CMT2S course, requiring non-invasive ventilation; lifelong respiratory surveillance is recommended.
Show evidence (1 reference)
PMID:30409445 SUPPORT Human Clinical
"At 9 years, he developed diaphragmatic weakness, following which he was established on non-invasive ventilation. Our case emphasizes the importance of life long respiratory surveillance for patients with CMT2S and expands the phenotype of this condition."
Documents late diaphragmatic weakness in CMT2S.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Forty-five patients from 34 families with 47 distinct variants reported between 2014 and 2022. IGHMBP2 was the most frequent cause of autosomal recessive CMT2 in a Chinese cohort of 178 CMT2 families and accounted for about 1.6% of axonal CMT in a Japanese series.
Show evidence (3 references)
PMID:35660062 SUPPORT Human Clinical
"From 2014 to 2022, 34 AR-CMT2S families, including 45 patients and 47 different mutations, were reported."
Literature case count.
PMID:28202949 SUPPORT Human Clinical
"We present the original report of CMT type 2S in Japan, and illustrate that recessive IGHMBP2 variants account for ~1.6% of axonal CMT in our cohort."
Share of axonal CMT attributable to IGHMBP2 in a diagnostic cohort.
PMID:28065684 SUPPORT Human Clinical
"We found four families with autosomal recessive IGHMBP2 mutations, and the frequency of IGHMBP2 mutations is 6.5% in CMT2 without dominant inheritance."
Frequency among non-dominant CMT2.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Charcot-Marie-Tooth Disease Axonal Type 2S:

Spinal muscular atrophy with respiratory distress type 1
Overlapping Features The severe allelic disorder: infantile axonal neuropathy with diaphragmatic paralysis and death usually before one year. Distinguished by early respiratory failure and abolished IGHMBP2 activity; the same genotype can produce either phenotype within a family.
Distinguishing Features
  • Infantile diaphragmatic paralysis and respiratory distress
  • Low birth weight, weak cry, reduced spontaneous movement
  • Alleles with abolished IGHMBP2 ATPase/helicase activity
Show evidence (1 reference)
PMID:28202949 SUPPORT Human Clinical
"the other case was diagnosed with SMARD1, manifesting as low birth weight, weak cry, reduced spontaneous movement and developed respiratory distress 4 months after birth"
Contrasting SMARD1 presentation in the same cohort.
Guillain-Barre syndrome
Overlapping Features Acute-onset CMT2S with CSF protein elevation and root enhancement can mimic an immune axonal neuropathy.
Distinguishing Features
  • Family history or preceding chronic deficits
  • Biallelic IGHMBP2 variants
Show evidence (1 reference)
PMID:41468720 SUPPORT Human Clinical
"Thus, the list of overlapping genetic and acquired neuropathies now also includes IGHMBP2-related CMT2S."
Recognised mimic.
🔬

Clinical Trials

1
NCT05152823 PHASE_I ENROLLING_BY_INVITATION
Phase I/IIa open-label, single-group study of one intrathecal dose of an AAV9 vector carrying IGHMBP2 in genetically confirmed SMARD1 or CMT2S.
Show evidence (1 reference)
clinicaltrials:NCT05152823 SUPPORT Human Clinical
"Open-label, single intrathecal injection study of a AAV9 vector carrying the IGHMBP2 gene for IGHMBP2-related diseases."
Trial registration summary.
🧫

Experimental Models

1
Patient fibroblast and neuromuscular junction co-culture model PRIMARY_CELL_CULTURE
Fibroblasts from a compound heterozygous CMT2S patient with a deep intronic cryptic-splice variant, and a derived neuromuscular junction functional assay, used to test a personalised splice-correcting antisense oligonucleotide.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:40060931
Pathograph links
Neuromuscular Junction Denervation and Distal Muscle Atrophy partially recapitulates fidelity: moderate observes: cellular NMJ fatigue and chaotic tetanus in patient-derived cells, rescued by ASO-mediated IGHMBP2 restoration.
Limitations: An in vitro NMJ functional assay from one patient genotype; it does not model axonal length dependence or the in vivo denervation process.
Show evidence (1 reference)
PMID:40060931 SUPPORT In Vitro
"Neuromuscular junction analyses revealed high fatigue and chaotic tetanus formulation in untreated patient cells."
Reports the NMJ phenotype in the patient-derived system.
🐁

Animal Models

2
Ighmbp2 E365del and Y918C knock-in mice
The first CMT2S mouse models, generated by CRISPR-Cas9; both show progressive peripheral motor and sensory axonal degeneration with motor deficits and normal survival, E365del mice develop mechanical allodynia, and femoral nerve axon loss reduces conduction velocity in Y918C but not E365del mice.
Species
Mouse
Genotype
Ighmbp2 p.Glu365del homozygous; Ighmbp2 p.Tyr918Cys (human CMT2S allele) homozygous
Publication
PMID:36413117
Pathograph links
Motor and Sensory Axonal Degeneration recapitulates fidelity: high observes: tissue Progressive femoral motor and sensory axonal degeneration with motor and sensory behavioural deficits.
Limitations: Engineered alleles with a short murine lifespan; foot deformity and the human disability trajectory are not reproduced, and conduction-velocity effects differ between alleles.
Readouts
Femoral motor and sensory axon counts
Direction: DECREASED
Interpretation: Structural readout of the axonal degeneration node.
Show evidence (1 reference)
PMID:36413117 SUPPORT Model Organism
"Analysis of femoral motor and sensory nerves identified axonal degeneration, which does not impact nerve conduction velocities in E365del mice, but it does so in the Y918C model."
Reports the nerve histology readout.
Show evidence (1 reference)
PMID:36413117 SUPPORT Model Organism
"Based on these results, the E365del mutant mouse, and the human allele knock-in, Y918C, represent mouse models with the hallmark phenotypes of CMT2S, which will be critical for understanding the pathogenic mechanisms of IGHMBP2."
Authors' assessment of model relevance.
Ighmbp2 H922Y and D564N/H922Y mice
Patient-mutation models spanning the continuum: H922Y homozygotes have normal lifespan and no respiratory pathology with minimal NMJ change, whereas D564N/H922Y compound heterozygotes show early motor deficits, reduced fibre area, NMJ denervation and a bimodal lifespan predicted by early respiratory pathology, with severity tracking IGHMBP2 biochemical activity.
Species
Mouse
Genotype
Ighmbp2 p.His922Tyr homozygous (CMT2S allele); Ighmbp2 p.Asp564Asn/p.His922Tyr compound heterozygous
Publication
PMID:39461706
Pathograph links
Neuromuscular Junction Denervation and Distal Muscle Atrophy partially recapitulates fidelity: moderate observes: tissue NMJ denervation is marked in the compound heterozygote but minimal in the CMT2S-like homozygote.
Limitations: The pure CMT2S allele produces little NMJ pathology by six months, so the distal denervation of human CMT2S is best represented by the compound heterozygote, which carries a SMARD1 allele.
Readouts
Neuromuscular junction innervation
Direction: DECREASED
Interpretation: Denervation in D564N/H922Y mice; minimal change in H922Y homozygotes.
Show evidence (1 reference)
PMID:39461706 SUPPORT Model Organism
"Interestingly, Ighmbp2H922Y/H922Y limb muscle fibers demonstrated an increase in muscle fiber area followed by a reduction while changes in NMJ innervation were minimal even at P180."
Reports the NMJ readout in the CMT2S-like model.
Show evidence (1 reference)
PMID:39461706 SUPPORT Model Organism
"Significant to our understanding of IGHMBP2 function, we demonstrate that there is a direct correlation between disease pathogenesis associated with these IGHMBP2 patient mutations and IGHMBP2 biochemical activity."
Establishes the activity-severity correlation the models are used for.
{ }

Source YAML

click to show 
name: Charcot-Marie-Tooth Disease Axonal Type 2S
category: Genetic
creation_date: "2026-09-05T16:30:00Z"
synonyms:
- CMT2S
- AR-CMT2S
- Autosomal recessive axonal Charcot-Marie-Tooth disease type 2S
- IGHMBP2-related axonal neuropathy
- Charcot-Marie-Tooth neuropathy type 2S
description: >
  Charcot-Marie-Tooth disease axonal type 2S (CMT2S; OMIM #616155) is an autosomal recessive,
  slowly progressive, length-dependent axonal sensorimotor neuropathy caused by biallelic
  variants in IGHMBP2, which encodes immunoglobulin mu-binding protein 2, a ubiquitously
  expressed UPF1-like ATP-dependent DNA/RNA helicase implicated in ribosome biogenesis and
  translation. It is the milder allelic counterpart of spinal muscular atrophy with respiratory
  distress type 1 (SMARD1): variants that retain residual IGHMBP2 abundance and biochemical
  activity spare the diaphragm and phrenic motor neurons and produce CMT2S, whereas those that
  abolish activity cause infantile diaphragmatic paralysis and death. Onset is usually in
  infancy or early childhood (mean about 3.8 years) with distal weakness, delayed milestones,
  foot deformity, gait disturbance and foot drop, progressing to distal amyotrophy with mild
  sensory and occasional autonomic involvement; electrophysiology shows reduced motor and
  sensory amplitudes with preserved conduction velocities. Respiratory function is normally
  preserved, but late diaphragmatic weakness and acute Guillain-Barre-like presentations are
  reported, so respiratory surveillance is advised. About two-thirds of reported variants are
  missense changes clustering in the helicase and ATPase domains and a third are truncating.
  Dedicated knock-in mouse models reproduce progressive motor and sensory axonal degeneration,
  and neuromuscular junction denervation correlates with residual IGHMBP2 activity. Care is
  supportive and rehabilitative; an intrathecal AAV9-IGHMBP2 gene therapy trial enrolling both
  SMARD1 and CMT2S (NCT05152823) and a personalised splice-correcting antisense
  oligonucleotide are in development.
disease_term:
  preferred_term: Charcot-Marie-Tooth disease axonal type 2S
  term:
    id: MONDO:0014511
    label: Charcot-Marie-Tooth disease axonal type 2S
parents:
- MONDO:0018993
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Forty-five patients from 34 families with 47 distinct variants reported between 2014 and
    2022. IGHMBP2 was the most frequent cause of autosomal recessive CMT2 in a Chinese cohort
    of 178 CMT2 families and accounted for about 1.6% of axonal CMT in a Japanese series.
  evidence:
  - reference: PMID:35660062
    reference_title: "Clinical and genetic features of Charcot-Marie-Tooth disease patients with IGHMBP2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "From 2014 to 2022, 34 AR-CMT2S families, including 45 patients and 47 different mutations, were reported."
    explanation: Literature case count.
  - reference: PMID:28202949
    reference_title: "Clinical diversity caused by novel IGHMBP2 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present the original report of CMT type 2S in Japan, and illustrate that recessive IGHMBP2 variants account for ~1.6% of axonal CMT in our cohort."
    explanation: Share of axonal CMT attributable to IGHMBP2 in a diagnostic cohort.
  - reference: PMID:28065684
    reference_title: "IGHMBP2-related clinical and genetic features in a cohort of Chinese Charcot-Marie-Tooth disease type 2 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found four families with autosomal recessive IGHMBP2 mutations, and the frequency of IGHMBP2 mutations is 6.5% in CMT2 without dominant inheritance."
    explanation: Frequency among non-dominant CMT2.
progression:
- phase: Infantile or childhood onset
  notes: >-
    Onset ranges from the first months of life to 20 years (mean 3.8 years), with about half
    presenting before age two with weakness, delayed milestones, foot deformity, gait
    disturbance or foot drop; the course is slowly progressive with distal-to-proximal
    spread and preserved respiratory function in most patients.
  evidence:
  - reference: PMID:35660062
    reference_title: "Clinical and genetic features of Charcot-Marie-Tooth disease patients with IGHMBP2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The age at onset ranged from 0.11 years to 20 years (mean±SD: 3.76±3.93 years) and the infantile (0-2 years) onset group accounted for the most patients (51.1%)."
    explanation: Age-of-onset distribution across reported patients.
  - reference: PMID:25568292
    reference_title: "Recessive truncating IGHMBP2 mutations presenting as axonal sensorimotor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only one patient required nocturnal mask ventilation, while 4 others maintained normal respiratory function by the age of 14, 18, 22, and 37 years. Three patients were still able to walk independently."
    explanation: Long-term respiratory and ambulatory course.
- phase: Late respiratory involvement (rare)
  notes: >-
    Diaphragmatic weakness can emerge years after onset in patients with an otherwise typical
    CMT2S course, requiring non-invasive ventilation; lifelong respiratory surveillance is
    recommended.
  evidence:
  - reference: PMID:30409445
    reference_title: "Charcot Marie Tooth disease type 2S with late onset diaphragmatic weakness: An atypical case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 9 years, he developed diaphragmatic weakness, following which he was established on non-invasive ventilation. Our case emphasizes the importance of life long respiratory surveillance for patients with CMT2S and expands the phenotype of this condition."
    explanation: Documents late diaphragmatic weakness in CMT2S.
genetic:
- name: IGHMBP2
  gene_term:
    preferred_term: IGHMBP2
    term:
      id: hgnc:5542
      label: IGHMBP2
  relationship_type: CAUSATIVE
  notes: >
    Biallelic IGHMBP2 (11q13.3) variants cause CMT2S; the same gene causes SMARD1, and
    compound heterozygotes for one severe and one milder allele can present with either
    phenotype, even within a sibship. Two-thirds of reported CMT2S variants are missense changes
    clustering in the helicase and ATPase domains and one-third are presumed loss-of-function
    (nonsense, frameshift, splice) alleles; missense changes near the RNA-binding channel or the
    nucleotide-binding pocket may be associated with more severe outcomes. Residual protein
    level and biochemical (ATPase/helicase) activity correlate with the SMARD1-versus-CMT2S
    outcome. Deep intronic variants activating cryptic splice sites are a recognised class.
  variants:
  - name: c.2770C>T (p.His924Tyr)
    description: >
      CMT2S-associated missense variant in the C-terminal region; alters IGHMBP2 activity to a
      lesser extent than the SMARD1 variant p.Asp565Asn while maintaining association with
      ABT1, and the equivalent H922Y knock-in mouse has a normal lifespan without respiratory
      pathology, modelling the CMT2S end of the spectrum.
    type: missense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:38403020
      reference_title: "The contribution and therapeutic implications of IGHMBP2 mutations on IGHMBP2 biochemical activity and ABT1 association."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The IGHMBP2-D565N mutation has been identified in SMARD1 patients, while the IGHMBP2-H924Y mutation has been identified in CMT2S patients."
      explanation: Assigns the variant to the CMT2S phenotype.
    - reference: PMID:38403020
      reference_title: "The contribution and therapeutic implications of IGHMBP2 mutations on IGHMBP2 biochemical activity and ABT1 association."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The H924Y mutation alters IGHMBP2 activity to a lesser extent while maintaining association with ABT1."
      explanation: Biochemical basis for the milder phenotype.
  - name: c.1156T>C (p.Trp386Arg) / c.2747G>A (p.Cys916Tyr)
    description: Compound heterozygous missense variants in a boy with CMT2S who developed diaphragmatic weakness at 9 years.
    type: missense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:30409445
      reference_title: "Charcot Marie Tooth disease type 2S with late onset diaphragmatic weakness: An atypical case."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Genetic testing revealed two heterozygous variants in the IGHMBP2 gene: c.1156 T > C p.(Trp386Arg) in exon 8 and c.2747G > A p.(Cys916Tyr) in exon 14, that were inherited from his father and mother respectively."
      explanation: Reports the variants and their segregation.
  evidence:
  - reference: PMID:25439726
    reference_title: "Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations."
    explanation: The paper that established IGHMBP2 as the CMT2S gene, in 11 recessive families.
  - reference: PMID:25439726
    reference_title: "Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in CMT2 were predicted to be less aggressive as compared to those in SMARD1, and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences are related to the IGHMBP2 protein levels."
    explanation: Residual protein level as the basis of the CMT2S-versus-SMARD1 distinction.
  - reference: PMID:25568292
    reference_title: "Recessive truncating IGHMBP2 mutations presenting as axonal sensorimotor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on 5 patients with neuropathy from 3 families who carried truncating mutations in IGHMBP2. Contrary to the \"classic\" phenotype, they did not manifest with respiratory distress, but with progressive sensorimotor neuropathy."
    explanation: Establishes IGHMBP2 as a cause of axonal neuropathy without respiratory distress.
  - reference: PMID:35660062
    reference_title: "Clinical and genetic features of Charcot-Marie-Tooth disease patients with IGHMBP2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One third of identified mutations represented presumed loss-of-function variants (nonsense, frameshift and splicing), while two-thirds were missense changes which clustered in the helicase and ATPase domains."
    explanation: Variant spectrum.
  - reference: PMID:27450922
    reference_title: "Clinical and molecular characteristics in three families with biallelic mutations in IGHMBP2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, clinical phenotypes differed markedly as the elder with sensorimotor axonal neuropathy had still unaffected respiratory function at 4.5 years, whereas the younger presented as infantile spinal muscular atrophy and died from relentless respiratory failure at 11 months."
    explanation: Intrafamilial SMARD1/CMT2S discordance with identical genotype.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  penetrance: COMPLETE
  expressivity: VARIABLE
  description: >
    Autosomal recessive; heterozygous carriers are unaffected. Expressivity spans the
    SMARD1-CMT2S continuum, including within families sharing the same genotype.
  evidence:
  - reference: PMID:35660062
    reference_title: "Clinical and genetic features of Charcot-Marie-Tooth disease patients with IGHMBP2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive Charcot-Marie-Tooth disease Type 2S (AR-CMT2S) caused by IGHMBP2 mutation was first reported in 2014, and an increasing number of cases have been reported in the past eight years."
    explanation: States the inheritance pattern.
  - reference: PMID:27450922
    reference_title: "Clinical and molecular characteristics in three families with biallelic mutations in IGHMBP2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biallelic mutations in IGHMBP2 cause spinal muscular atrophy with respiratory distress type 1 (SMARD1) or Charcot-Marie-Tooth type 2S (CMT2S)."
    explanation: Biallelic requirement and allelic relationship to SMARD1.
pathophysiology:
- name: Biallelic Hypomorphic IGHMBP2 Variants
  description: >
    CMT2S alleles reduce, but do not abolish, IGHMBP2 abundance and its ATP-dependent
    DNA/RNA helicase activity. Association with the activator ABT1 stimulates IGHMBP2 ATPase
    and helicase activity, and CMT2S variants such as p.His924Tyr retain ABT1 association and
    substantial activity, whereas SMARD1 variants such as p.Asp565Asn lose it; in compound
    heterozygotes the summed activity of the two mutant proteins predicts severity. This
    residual-activity threshold is the disorder-specific insult to peripheral neurons.
  biological_scale: MOLECULAR
  conforms_to: "peripheral_axonal_degeneration#Insult to Peripheral Neurons and Schwann Cells"
  molecular_functions:
  - preferred_term: DNA/RNA helicase activity
    term:
      id: GO:0003678
      label: DNA helicase activity
    modifier: DECREASED
  - preferred_term: RNA helicase activity
    term:
      id: GO:0003724
      label: RNA helicase activity
    modifier: DECREASED
  downstream:
  - target: Disturbed Ribosome Biogenesis and Translation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36480289
      reference_title: "ABT1 modifies SMARD1 pathology via interactions with IGHMBP2 and stimulation of ATPase and helicase activity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The IGHMBP2/ABT1 complex interacts with the 47S pre-rRNA 5' external transcribed spacer and U3 small nucleolar RNA (snoRNA), suggesting that the IGHMBP2/ABT1 complex is important for pre-rRNA processing."
      explanation: Links helicase function to pre-rRNA processing.
  evidence:
  - reference: PMID:38403020
    reference_title: "The contribution and therapeutic implications of IGHMBP2 mutations on IGHMBP2 biochemical activity and ABT1 association."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "For the first time, we demonstrate a correlation between the altered IGHMBP2 biochemical activity associated with the D565N and H924Y mutations and disease severity and pathology in patients and our Ighmbp2 mouse models."
    explanation: Residual activity determines severity along the SMARD1-CMT2S continuum.
  - reference: PMID:38403020
    reference_title: "The contribution and therapeutic implications of IGHMBP2 mutations on IGHMBP2 biochemical activity and ABT1 association."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In the context of the compound heterozygous patient, we demonstrate that the total biochemical activity associated with IGHMBP2-D565N and IGHMBP2-H924Y proteins is improved over IGHMBP2-D565N alone."
    explanation: Summed activity of two alleles explains compound heterozygous phenotypes.
  - reference: PMID:39119929
    reference_title: "The molecular mechanisms that underlie IGHMBP2-related diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The discovery that IGHMBP2 functions as an RNA/DNA helicase was an important step, but it did not reveal the pathogenic mechanism."
    explanation: Review framing of the helicase function and the open mechanism question.
- name: Disturbed Ribosome Biogenesis and Translation
  description: >
    IGHMBP2, with ABT1, binds the 47S pre-rRNA 5' external transcribed spacer and U3 snoRNA,
    implicating it in pre-rRNA processing; it is also associated with tRNA and translation
    machinery. Loss of activity is proposed to impair ribosome biogenesis and translation,
    with a low-grade integrated stress response in knockout cells, but which of IGHMBP2's
    RNA-metabolic roles drives neuronal pathology is unresolved.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: rRNA processing
    term:
      id: GO:0006364
      label: rRNA processing
    modifier: DYSREGULATED
  - preferred_term: translation
    term:
      id: GO:0006412
      label: translation
    modifier: DECREASED
  downstream:
  - target: Motor and Sensory Axonal Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:36480289
    reference_title: "ABT1 modifies SMARD1 pathology via interactions with IGHMBP2 and stimulation of ATPase and helicase activity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We provide a mechanism proposing that ABT1 decreases disease pathology in FVB-Ighmbp2nmd/nmd mutants by optimizing IGHMBP2 biochemical activity (ATPase and helicase activity). Our studies provide insight into SMARD1 pathogenesis, suggesting that ABT1 modifies IGHMBP2 activity as a means to regulate pre-rRNA processing."
    explanation: Proposes pre-rRNA processing as the affected pathway.
  - reference: PMID:39119929
    reference_title: "The molecular mechanisms that underlie IGHMBP2-related diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "IGHMBP2 appears to be a multifunctional factor involved in several cellular processes that regulate gene expression. It is difficult to determine which processes, when dysregulated, lead to pathology."
    explanation: Records the unresolved link between RNA functions and pathology.
  - reference: PMID:38803225
    reference_title: "IGHMBP2 deletion suppresses translation and activates the integrated stress response."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we found that IGHMBP2 deletion modestly reduces global translation"
    explanation: Direct measurement of reduced global translation in IGHMBP2-knockout cells, supporting the DECREASED translation modifier.
  - reference: PMID:38803225
    reference_title: "IGHMBP2 deletion suppresses translation and activates the integrated stress response."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We generated ATF4 reporter cell lines and found IGHMBP2 knockout cells demonstrate basal, chronic ISR activation."
    explanation: Source for the low-grade integrated stress response in knockout cells.
- name: Motor and Sensory Axonal Degeneration
  description: >
    Long peripheral motor and sensory axons degenerate progressively, producing an axonal
    neuropathy with reduced amplitudes and largely preserved conduction velocities; CMT2S
    knock-in mice show progressive motor and sensory axonal degeneration in femoral nerves with
    motor deficits and mechanical allodynia. In contrast to SMARD1, spinal alpha-motor neurons
    supplying the diaphragm are relatively spared.
  biological_scale: TISSUE
  conforms_to: "peripheral_axonal_degeneration#Distal Axonal Degeneration and Demyelination"
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  - preferred_term: sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  downstream:
  - target: Neuromuscular Junction Denervation and Distal Muscle Atrophy
    causal_link_type: DIRECT
  - target: Peripheral axonal neuropathy
    causal_link_type: DIRECT
  - target: Sensory neuropathy
    causal_link_type: DIRECT
  - target: Abnormal autonomic nervous system physiology
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:36413117
    reference_title: "Clinically relevant mouse models of Charcot-Marie-Tooth type 2S."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Phenotypic characterization of the homozygous models found progressive peripheral motor and sensory axonal degeneration."
    explanation: Direct demonstration of axonal degeneration in CMT2S models.
  - reference: PMID:25568292
    reference_title: "Recessive truncating IGHMBP2 mutations presenting as axonal sensorimotor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had a predominantly axonal sensorimotor neuropathy with subsequent muscle atrophy, but without obvious sensory symptoms."
    explanation: Human electrophysiological and clinical correlate.
- name: Neuromuscular Junction Denervation and Distal Muscle Atrophy
  description: >
    Loss of motor axons denervates neuromuscular junctions, causing neurogenic distal muscle
    atrophy, weakness, foot deformity and gait impairment. In compound heterozygous
    Ighmbp2 D564N/H922Y mice NMJ denervation and reduced fibre area are marked, whereas the
    CMT2S-like H922Y homozygote shows minimal NMJ changes even at six months; patient-derived
    neuromuscular co-cultures show high fatigue and chaotic tetanus that are rescued by
    restoring IGHMBP2.
  biological_scale: TISSUE
  conforms_to: "peripheral_axonal_degeneration#Length-Dependent Nerve Fiber Dysfunction"
  biological_processes:
  - preferred_term: neuromuscular junction development
    term:
      id: GO:0007528
      label: neuromuscular junction development
    modifier: ABNORMAL
  downstream:
  - target: Distal muscle weakness
    causal_link_type: DIRECT
  - target: Distal amyotrophy
    causal_link_type: DIRECT
  - target: Foot dorsiflexor weakness
    causal_link_type: DIRECT
  - target: Pes cavus
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Gait disturbance
    causal_link_type: DIRECT
  - target: Motor delay
    causal_link_type: DIRECT
  - target: Diaphragmatic weakness
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:39461706
    reference_title: "Ighmbp2 mutations and disease pathology: Defining differences that differentiate SMARD1 and CMT2S."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "There was decreased limb skeletal muscle fiber area and increased neuromuscular junction (NMJ) denervation in Ighmbp2D564N/H922Y mice."
    explanation: NMJ denervation and muscle atrophy in the compound heterozygous model.
  - reference: PMID:39461706
    reference_title: "Ighmbp2 mutations and disease pathology: Defining differences that differentiate SMARD1 and CMT2S."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Consistent with CMT2S, Ighmbp2H922Y/H922Y mice did not have altered lifespans nor respiratory pathology."
    explanation: The CMT2S-like allele spares respiration and lifespan.
  - reference: PMID:40060931
    reference_title: "Potential ASO-based personalized treatment for Charcot-Marie-Tooth disease type 2S."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Neuromuscular junction analyses revealed high fatigue and chaotic tetanus formulation in untreated patient cells. We demonstrate rescue of NMJ function following ASO treatment, captured by a reduction in fatigue and chaotic tetanus responses."
    explanation: Patient-derived NMJ dysfunction and its rescue by IGHMBP2 restoration.
phenotypes:
- name: Peripheral axonal neuropathy
  category: Neurological
  frequency: OBLIGATE
  description: >
    Predominantly axonal sensorimotor polyneuropathy with reduced compound muscle and sensory
    action potential amplitudes and relatively preserved conduction velocities.
  phenotype_term:
    preferred_term: Axonal sensorimotor polyneuropathy
    term:
      id: HP:0003477
      label: Peripheral axonal neuropathy
  evidence:
  - reference: PMID:25568292
    reference_title: "Recessive truncating IGHMBP2 mutations presenting as axonal sensorimotor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had a predominantly axonal sensorimotor neuropathy with subsequent muscle atrophy, but without obvious sensory symptoms."
    explanation: Defining neuropathy phenotype.
  - reference: PMID:28202949
    reference_title: "Clinical diversity caused by novel IGHMBP2 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients presented with childhood-onset axonal predominant sensorimotor polyneuropathies, whereas the other case was diagnosed with SMARD1"
    explanation: Independent cohort confirming the axonal sensorimotor phenotype.
- name: Distal muscle weakness
  category: Neurological
  frequency: VERY_FREQUENT
  description: Muscle weakness, usually of the lower limbs first, is the commonest initial symptom and spreads proximally over time.
  phenotype_term:
    preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
  evidence:
  - reference: PMID:35660062
    reference_title: "Clinical and genetic features of Charcot-Marie-Tooth disease patients with IGHMBP2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The initial symptoms included muscle weakness (15, 33.3%), delayed milestones (9, 20%), feet deformity (8, 17.8%), gait disturbance (8, 17.8%), feet drop (7, 15.6%), frequent falls (3, 6.7%), hypotonia (2, 4.4%) and thenar atrophy (1, 2.2%)."
    explanation: Initial symptom frequencies across 45 patients. The frequency band is inferred from the share presenting with this feature, which is a lower bound on its lifetime frequency.
- name: Distal amyotrophy
  category: Neurological
  frequency: VERY_FREQUENT
  description: Neurogenic atrophy of distal limb muscles follows the axonal loss.
  phenotype_term:
    preferred_term: Distal amyotrophy
    term:
      id: HP:0003693
      label: Distal amyotrophy
  evidence:
  - reference: PMID:25568292
    reference_title: "Recessive truncating IGHMBP2 mutations presenting as axonal sensorimotor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had a predominantly axonal sensorimotor neuropathy with subsequent muscle atrophy, but without obvious sensory symptoms."
    explanation: Muscle atrophy secondary to the neuropathy.
- name: Motor delay
  category: Neurological
  frequency: OCCASIONAL
  description: Delayed motor milestones are the presenting feature in a fifth of patients with infantile onset.
  phenotype_term:
    preferred_term: Delayed motor milestones
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:35660062
    reference_title: "Clinical and genetic features of Charcot-Marie-Tooth disease patients with IGHMBP2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The initial symptoms included muscle weakness (15, 33.3%), delayed milestones (9, 20%), feet deformity (8, 17.8%), gait disturbance (8, 17.8%), feet drop (7, 15.6%), frequent falls (3, 6.7%), hypotonia (2, 4.4%) and thenar atrophy (1, 2.2%)."
    explanation: Frequency of delayed milestones as the initial symptom.
- name: Gait disturbance
  category: Neurological
  frequency: FREQUENT
  description: Gait disturbance, frequent falls and steppage gait from distal weakness and foot drop.
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  evidence:
  - reference: PMID:35660062
    reference_title: "Clinical and genetic features of Charcot-Marie-Tooth disease patients with IGHMBP2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The initial symptoms included muscle weakness (15, 33.3%), delayed milestones (9, 20%), feet deformity (8, 17.8%), gait disturbance (8, 17.8%), feet drop (7, 15.6%), frequent falls (3, 6.7%), hypotonia (2, 4.4%) and thenar atrophy (1, 2.2%)."
    explanation: Gait-related initial symptoms. The frequency band is inferred from the share presenting with this feature, which is a lower bound on its lifetime frequency.
- name: Foot dorsiflexor weakness
  category: Neurological
  frequency: FREQUENT
  description: Foot drop from weakness of the anterior compartment muscles.
  phenotype_term:
    preferred_term: Foot drop
    term:
      id: HP:0009027
      label: Foot dorsiflexor weakness
  evidence:
  - reference: PMID:35660062
    reference_title: "Clinical and genetic features of Charcot-Marie-Tooth disease patients with IGHMBP2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The initial symptoms included muscle weakness (15, 33.3%), delayed milestones (9, 20%), feet deformity (8, 17.8%), gait disturbance (8, 17.8%), feet drop (7, 15.6%), frequent falls (3, 6.7%), hypotonia (2, 4.4%) and thenar atrophy (1, 2.2%)."
    explanation: Foot drop as an initial symptom. The frequency band is inferred from the share presenting with this feature, which is a lower bound on its lifetime frequency.
- name: Pes cavus
  category: Musculoskeletal
  frequency: FREQUENT
  description: Foot deformities (cavus, cavovarus) arise from chronic muscle imbalance and can be the presenting sign in infancy.
  phenotype_term:
    preferred_term: Foot deformity (pes cavus)
    term:
      id: HP:0001761
      label: Pes cavus
  evidence:
  - reference: PMID:30409445
    reference_title: "Charcot Marie Tooth disease type 2S with late onset diaphragmatic weakness: An atypical case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 9 month old boy presented with bilateral feet deformities and axonal neuropathy."
    explanation: Foot deformity as the presenting feature.
  - reference: PMID:35660062
    reference_title: "Clinical and genetic features of Charcot-Marie-Tooth disease patients with IGHMBP2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The initial symptoms included muscle weakness (15, 33.3%), delayed milestones (9, 20%), feet deformity (8, 17.8%), gait disturbance (8, 17.8%), feet drop (7, 15.6%), frequent falls (3, 6.7%), hypotonia (2, 4.4%) and thenar atrophy (1, 2.2%)."
    explanation: Frequency of foot deformity at onset. The frequency band is inferred from the share presenting with this feature, which is a lower bound on its lifetime frequency.
- name: Sensory neuropathy
  category: Neurological
  frequency: FREQUENT
  description: Sensory axons are involved electrophysiologically, though sensory symptoms are often mild or absent.
  phenotype_term:
    preferred_term: Sensory axonal involvement
    term:
      id: HP:0000763
      label: Sensory neuropathy
  evidence:
  - reference: PMID:25568292
    reference_title: "Recessive truncating IGHMBP2 mutations presenting as axonal sensorimotor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had a predominantly axonal sensorimotor neuropathy with subsequent muscle atrophy, but without obvious sensory symptoms."
    explanation: Sensorimotor involvement with subclinical sensory symptoms.
- name: Abnormal autonomic nervous system physiology
  category: Neurological
  frequency: OCCASIONAL
  description: Signs of autonomic neuropathy in a minority of patients.
  phenotype_term:
    preferred_term: Autonomic neuropathy
    term:
      id: HP:0012332
      label: Abnormal autonomic nervous system physiology
  evidence:
  - reference: PMID:25568292
    reference_title: "Recessive truncating IGHMBP2 mutations presenting as axonal sensorimotor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients had signs of autonomic neuropathy."
    explanation: Autonomic involvement in the original series.
- name: Diaphragmatic weakness
  category: Respiratory
  frequency: VERY_RARE
  description: Late-onset diaphragmatic weakness requiring non-invasive ventilation is reported in otherwise typical CMT2S; infantile diaphragmatic paralysis defines SMARD1 instead.
  phenotype_term:
    preferred_term: Late-onset diaphragmatic weakness
    term:
      id: HP:0009113
      label: Diaphragmatic weakness
  evidence:
  - reference: PMID:30409445
    reference_title: "Charcot Marie Tooth disease type 2S with late onset diaphragmatic weakness: An atypical case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 9 years, he developed diaphragmatic weakness, following which he was established on non-invasive ventilation."
    explanation: Documented late diaphragmatic involvement.
treatments:
- name: Physiotherapy, orthoses and rehabilitation
  description: >
    Care is supportive and extrapolated from general CMT practice: individualised physiotherapy,
    occupational therapy, ankle-foot orthoses and mobility aids, pain management, and orthopaedic
    correction of fixed foot deformity or scoliosis after specialist assessment.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical therapy and rehabilitation
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
- name: Respiratory surveillance and non-invasive ventilation
  description: >
    Lifelong respiratory surveillance is advised because diaphragmatic weakness can appear
    years after onset; non-invasive ventilation is instituted when it does.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Non-invasive ventilation
    term:
      id: NCIT:C171457
      label: Non-Invasive Mechanical Ventilation
  target_phenotypes:
  - preferred_term: Diaphragmatic weakness
    term:
      id: HP:0009113
      label: Diaphragmatic weakness
  evidence:
  - reference: PMID:30409445
    reference_title: "Charcot Marie Tooth disease type 2S with late onset diaphragmatic weakness: An atypical case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 9 years, he developed diaphragmatic weakness, following which he was established on non-invasive ventilation. Our case emphasizes the importance of life long respiratory surveillance for patients with CMT2S and expands the phenotype of this condition."
    explanation: Basis for surveillance and ventilatory support.
- name: Intrathecal AAV9-IGHMBP2 gene therapy (investigational)
  description: >
    Single intrathecal AAV9-IGHMBP2 delivery is in a phase I/IIa trial enrolling genetically
    confirmed SMARD1 or CMT2S (NCT05152823). In the SMARD1 mouse, optimised AAV9-IGHMBP2
    vectors rescued survival, motor function, motor neurons and neuromuscular junctions and
    resolved spinal cord inflammatory changes, with a truncated MeCP2 (P546) promoter giving
    superior long-term efficacy and safety.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: Gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Biallelic Hypomorphic IGHMBP2 Variants
    description: Restores IGHMBP2 expression in motor neurons irrespective of genotype.
  evidence:
  - reference: PMID:41486111
    reference_title: "AAV9 gene therapy optimization for SMARD1/CMT2S: safety and long-term efficacy comparison of two vectors in a SMARD1 preclinical model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Corroborating previous findings, both constructs effectively rescued the pathological phenotype, significantly improving survival, body weight, and motor function while preserving motor neurons and neuromuscular junctions."
    explanation: Preclinical efficacy in the IGHMBP2-deficient mouse.
  - reference: clinicaltrials:NCT05152823
    reference_title: "Phase I/IIa Intrathecal Gene Delivery Clinical Trial for IGHMBP2-Related Diseases"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Open-label, single intrathecal injection study of a AAV9 vector carrying the IGHMBP2 gene for IGHMBP2-related diseases."
    explanation: Registered trial covering IGHMBP2-related diseases including CMT2S.
- name: Personalised splice-correcting antisense oligonucleotide (preclinical)
  description: >
    For a compound heterozygous patient with a deep intronic cryptic-splice variant, a 19-mer
    antisense oligonucleotide blocking the cryptic acceptor restored wild-type transcript,
    raised IGHMBP2 protein by over 50% in fibroblasts, rescued neuromuscular junction function
    in vitro and was well tolerated intrathecally in rats; an N-of-1 strategy applicable only
    to that variant class.
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  aso_details:
    aso_mechanism: SPLICE_MODULATION_EXON_SKIPPING
    target_gene:
      preferred_term: IGHMBP2
      term:
        id: hgnc:5542
        label: IGHMBP2
    target_transcript: IGHMBP2 pre-mRNA deep intronic cryptic splice acceptor
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Biallelic Hypomorphic IGHMBP2 Variants
    description: Blocks a variant-created cryptic splice site so that normally spliced, stable IGHMBP2 transcript is restored.
  evidence:
  - reference: PMID:40060931
    reference_title: "Potential ASO-based personalized treatment for Charcot-Marie-Tooth disease type 2S."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ASO treatment of patient fibroblasts significantly increased the ratio of restored wild-type transcript to cryptic exon-containing transcript and resulted in over a 50% increase in IGHMBP2 protein levels."
    explanation: Molecular rescue in patient cells.
- name: ABT1 augmentation (preclinical)
  description: >
    Intracerebroventricular scAAV9-Abt1 reduced disease pathology, extended lifespan and
    decreased neuromuscular junction denervation in the SMARD1-nmd mouse by stimulating the
    ATPase and helicase activity of residual IGHMBP2; a modifier-based strategy potentially
    suited to hypomorphic CMT2S alleles.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: Gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Biallelic Hypomorphic IGHMBP2 Variants
    description: Increases the activity of residual mutant IGHMBP2 through its activator ABT1.
  evidence:
  - reference: PMID:36480289
    reference_title: "ABT1 modifies SMARD1 pathology via interactions with IGHMBP2 and stimulation of ATPase and helicase activity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Intracerebroventricular injection of scAAV9-Abt1 decreases FVB-Ighmbp2nmd/nmd disease pathology, significantly increases lifespan, and substantially decreases neuromuscular junction denervation."
    explanation: Preclinical proof of the modifier approach.
- name: Genetic counseling
  description: Autosomal recessive counselling with a 25% recurrence risk; the SMARD1-CMT2S continuum within a sibship should be explained.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:27450922
    reference_title: "Clinical and molecular characteristics in three families with biallelic mutations in IGHMBP2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical presentation in Patients 1 and 3 were consistent with SMARD1, whereas Patients 2 and 4 were in agreement with CMT2S."
    explanation: Illustrates the intrafamilial phenotypic range relevant to counselling.
clinical_trials:
- name: NCT05152823
  phase: PHASE_I
  status: ENROLLING_BY_INVITATION
  description: >
    Phase I/IIa open-label, single-group study of one intrathecal dose of an AAV9 vector
    carrying IGHMBP2 in genetically confirmed SMARD1 or CMT2S.
  evidence:
  - reference: clinicaltrials:NCT05152823
    reference_title: "Phase I/IIa Intrathecal Gene Delivery Clinical Trial for IGHMBP2-Related Diseases"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Open-label, single intrathecal injection study of a AAV9 vector carrying the IGHMBP2 gene for IGHMBP2-related diseases."
    explanation: Trial registration summary.
diagnosis:
- name: Molecular genetic testing for biallelic IGHMBP2 variants
  description: >
    IGHMBP2 screening is recommended for early-onset, sporadic or autosomal recessive axonal
    CMT2, and should not be withheld in the absence of respiratory symptoms.
  evidence:
  - reference: PMID:28065684
    reference_title: "IGHMBP2-related clinical and genetic features in a cohort of Chinese Charcot-Marie-Tooth disease type 2 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, mutation screening of IGHMBP2 should be especially considered in AR-CMT2 and sporadic CMT2 patients."
    explanation: Testing recommendation.
  - reference: PMID:25568292
    reference_title: "Recessive truncating IGHMBP2 mutations presenting as axonal sensorimotor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in IGHMBP2 should be considered in the molecular genetic workup of patients with hereditary sensorimotor neuropathies, even in the absence of respiratory symptoms."
    explanation: Extends testing to patients without respiratory involvement.
- name: Nerve conduction studies
  description: Reduced motor and sensory amplitudes with relatively preserved conduction velocities confirm an axonal sensorimotor neuropathy.
  evidence:
  - reference: PMID:28202949
    reference_title: "Clinical diversity caused by novel IGHMBP2 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients presented with childhood-onset axonal predominant sensorimotor polyneuropathies"
    explanation: Electrophysiological classification.
- name: Recognition of acute Guillain-Barre-like presentations
  description: >
    Acute motor and sensory axonal neuropathy with cauda equina enhancement and raised CSF
    protein has been reported as the presentation of CMT2S, so genetic testing should be
    considered when an apparent immune neuropathy has an atypical course.
  evidence:
  - reference: PMID:41468720
    reference_title: "Phenotypic continuum in IGHMBP2-related disorders: a portfolio of cases from typical to Guillain-Barré syndrome-like presentation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Case 3 and 4, two siblings, presented with a Guillain-Barré syndrome-like phenotype, cauda equina enhancement on spinal neuroimaging, elevated cerebrospinal fluid protein, and electromyography revealing acute motor and sensory axonal neuropathy."
    explanation: Atypical presentation relevant to diagnosis.
differential_diagnoses:
- name: Spinal muscular atrophy with respiratory distress type 1
  description: >
    The severe allelic disorder: infantile axonal neuropathy with diaphragmatic paralysis and
    death usually before one year. Distinguished by early respiratory failure and abolished
    IGHMBP2 activity; the same genotype can produce either phenotype within a family.
  distinguishing_features:
  - Infantile diaphragmatic paralysis and respiratory distress
  - Low birth weight, weak cry, reduced spontaneous movement
  - Alleles with abolished IGHMBP2 ATPase/helicase activity
  evidence:
  - reference: PMID:28202949
    reference_title: "Clinical diversity caused by novel IGHMBP2 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the other case was diagnosed with SMARD1, manifesting as low birth weight, weak cry, reduced spontaneous movement and developed respiratory distress 4 months after birth"
    explanation: Contrasting SMARD1 presentation in the same cohort.
- name: Guillain-Barre syndrome
  description: Acute-onset CMT2S with CSF protein elevation and root enhancement can mimic an immune axonal neuropathy.
  distinguishing_features:
  - Family history or preceding chronic deficits
  - Biallelic IGHMBP2 variants
  evidence:
  - reference: PMID:41468720
    reference_title: "Phenotypic continuum in IGHMBP2-related disorders: a portfolio of cases from typical to Guillain-Barré syndrome-like presentation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus, the list of overlapping genetic and acquired neuropathies now also includes IGHMBP2-related CMT2S."
    explanation: Recognised mimic.
animal_models:
- name: Ighmbp2 E365del and Y918C knock-in mice
  species: Mouse
  genotype: Ighmbp2 p.Glu365del homozygous; Ighmbp2 p.Tyr918Cys (human CMT2S allele) homozygous
  publication: PMID:36413117
  description: >
    The first CMT2S mouse models, generated by CRISPR-Cas9; both show progressive peripheral
    motor and sensory axonal degeneration with motor deficits and normal survival, E365del mice
    develop mechanical allodynia, and femoral nerve axon loss reduces conduction velocity in
    Y918C but not E365del mice.
  modeled_mechanisms:
  - target: Motor and Sensory Axonal Degeneration
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: Progressive femoral motor and sensory axonal degeneration with motor and sensory behavioural deficits.
    limitations: >-
      Engineered alleles with a short murine lifespan; foot deformity and the human disability
      trajectory are not reproduced, and conduction-velocity effects differ between alleles.
    readouts:
    - name: Femoral motor and sensory axon counts
      target: Motor and Sensory Axonal Degeneration
      direction: DECREASED
      interpretation: Structural readout of the axonal degeneration node.
      evidence:
      - reference: PMID:36413117
        reference_title: "Clinically relevant mouse models of Charcot-Marie-Tooth type 2S."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Analysis of femoral motor and sensory nerves identified axonal degeneration, which does not impact nerve conduction velocities in E365del mice, but it does so in the Y918C model."
        explanation: Reports the nerve histology readout.
    evidence:
    - reference: PMID:36413117
      reference_title: "Clinically relevant mouse models of Charcot-Marie-Tooth type 2S."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Based on these results, the E365del mutant mouse, and the human allele knock-in, Y918C, represent mouse models with the hallmark phenotypes of CMT2S, which will be critical for understanding the pathogenic mechanisms of IGHMBP2."
      explanation: Authors' assessment of model relevance.
- name: Ighmbp2 H922Y and D564N/H922Y mice
  species: Mouse
  genotype: Ighmbp2 p.His922Tyr homozygous (CMT2S allele); Ighmbp2 p.Asp564Asn/p.His922Tyr compound heterozygous
  publication: PMID:39461706
  description: >
    Patient-mutation models spanning the continuum: H922Y homozygotes have normal lifespan
    and no respiratory pathology with minimal NMJ change, whereas D564N/H922Y compound
    heterozygotes show early motor deficits, reduced fibre area, NMJ denervation and a
    bimodal lifespan predicted by early respiratory pathology, with severity tracking
    IGHMBP2 biochemical activity.
  modeled_mechanisms:
  - target: Neuromuscular Junction Denervation and Distal Muscle Atrophy
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: NMJ denervation is marked in the compound heterozygote but minimal in the CMT2S-like homozygote.
    limitations: >-
      The pure CMT2S allele produces little NMJ pathology by six months, so the distal
      denervation of human CMT2S is best represented by the compound heterozygote, which
      carries a SMARD1 allele.
    readouts:
    - name: Neuromuscular junction innervation
      target: Neuromuscular Junction Denervation and Distal Muscle Atrophy
      direction: DECREASED
      interpretation: Denervation in D564N/H922Y mice; minimal change in H922Y homozygotes.
      evidence:
      - reference: PMID:39461706
        reference_title: "Ighmbp2 mutations and disease pathology: Defining differences that differentiate SMARD1 and CMT2S."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Interestingly, Ighmbp2H922Y/H922Y limb muscle fibers demonstrated an increase in muscle fiber area followed by a reduction while changes in NMJ innervation were minimal even at P180."
        explanation: Reports the NMJ readout in the CMT2S-like model.
    evidence:
    - reference: PMID:39461706
      reference_title: "Ighmbp2 mutations and disease pathology: Defining differences that differentiate SMARD1 and CMT2S."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Significant to our understanding of IGHMBP2 function, we demonstrate that there is a direct correlation between disease pathogenesis associated with these IGHMBP2 patient mutations and IGHMBP2 biochemical activity."
      explanation: Establishes the activity-severity correlation the models are used for.
experimental_models:
- name: Patient fibroblast and neuromuscular junction co-culture model
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >
    Fibroblasts from a compound heterozygous CMT2S patient with a deep intronic cryptic-splice
    variant, and a derived neuromuscular junction functional assay, used to test a
    personalised splice-correcting antisense oligonucleotide.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:40060931
  modeled_mechanisms:
  - target: Neuromuscular Junction Denervation and Distal Muscle Atrophy
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: NMJ fatigue and chaotic tetanus in patient-derived cells, rescued by ASO-mediated IGHMBP2 restoration.
    limitations: >-
      An in vitro NMJ functional assay from one patient genotype; it does not model axonal
      length dependence or the in vivo denervation process.
    evidence:
    - reference: PMID:40060931
      reference_title: "Potential ASO-based personalized treatment for Charcot-Marie-Tooth disease type 2S."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Neuromuscular junction analyses revealed high fatigue and chaotic tetanus formulation in untreated patient cells."
      explanation: Reports the NMJ phenotype in the patient-derived system.
discussions:
- discussion_id: cmt2s_rna_process_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Disturbed Ribosome Biogenesis and Translation
  prompt: >
    Which IGHMBP2-dependent RNA process (pre-rRNA processing, tRNA metabolism, translation,
    mRNA export) is rate-limiting in long peripheral axons, and why does partial loss spare
    respiratory motor neurons while abolished activity does not?
  rationale: >
    IGHMBP2 has several proposed roles in gene expression and the field has not determined
    which, when dysregulated, causes neurodegeneration; the residual-activity threshold that
    separates CMT2S from SMARD1 is established at the biochemical level but its cellular basis
    in neuron subtypes is not.
  evidence:
  - reference: PMID:39119929
    reference_title: "The molecular mechanisms that underlie IGHMBP2-related diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "More than 20 years after the link between IGHMBP2 and SMARD1 was revealed, and 10 years after the discovery of the association between IGHMBP2 and CMT2S, the pathogenic mechanism of these diseases is still not well defined."
    explanation: Review statement of the mechanistic gap.
references:
- reference: PMID:20301532
  title: "Charcot-Marie-Tooth Hereditary Neuropathy Overview."
  tags:
  - GeneReviews
notes: >
  Curated as a separate Disease entry from the allelic Spinal_Muscular_Atrophy_with_Respiratory_Distress_Type_1
  (stub entry_type decision: DISEASE), distinguished by residual-activity genotype-phenotype
  correlation, preserved respiration and a chronic axonal-neuropathy course. Conforms to the
  peripheral_axonal_degeneration module. Sources: the 2014-2017 cohort papers (PMID:25568292,
  PMID:27450922, PMID:28202949, PMID:28065684), the 2022 systematic cohort (PMID:35660062),
  the CMT2S mouse models (PMID:36413117, PMID:39461706), biochemical genotype-phenotype work
  (PMID:38403020, PMID:36480289), the 2024 mechanism review (PMID:39119929), therapeutic
  development (PMID:40060931, PMID:41486111, NCT05152823) and atypical presentations
  (PMID:30409445, PMID:41468720). Deep research: Edison/falcon report
  research/Charcot-Marie-Tooth_Disease_Axonal_Type_2S-deep-research-falcon.md (10/10 references
  verified, 36/38 terms verified, preflight-dr PASS); its phenotype table and mechanism chain
  were cross-checked. The report's suggested GO term for axon maintenance (GO:0023055) is
  obsolete and was not used. There is no CMT2S-specific GeneReviews chapter; the
  Charcot-Marie-Tooth Hereditary Neuropathy Overview is tagged. Scoliosis and areflexia are
  described in reviews but had no quotable abstract-level evidence and are omitted.
📚

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.

Evaluations and curation notes (2)

Record notes

Curated as a separate Disease entry from the allelic Spinal_Muscular_Atrophy_with_Respiratory_Distress_Type_1 (stub entry_type decision: DISEASE), distinguished by residual-activity genotype-phenotype correlation, preserved respiration and a chronic axonal-neuropathy course. Conforms to the peripheral_axonal_degeneration module. Sources: the 2014-2017 cohort papers (PMID:25568292, PMID:27450922, PMID:28202949, PMID:28065684), the 2022 systematic cohort (PMID:35660062), the CMT2S mouse models (PMID:36413117, PMID:39461706), biochemical genotype-phenotype work (PMID:38403020, PMID:36480289), the 2024 mechanism review (PMID:39119929), therapeutic development (PMID:40060931, PMID:41486111, NCT05152823) and atypical presentations (PMID:30409445, PMID:41468720). Deep research: Edison/falcon report research/Charcot-Marie-Tooth_Disease_Axonal_Type_2S-deep-research-falcon.md (10/10 references verified, 36/38 terms verified, preflight-dr PASS); its phenotype table and mechanism chain were cross-checked. The report's suggested GO term for axon maintenance (GO:0023055) is obsolete and was not used. There is no CMT2S-specific GeneReviews chapter; the Charcot-Marie-Tooth Hereditary Neuropathy Overview is tagged. Scoliosis and areflexia are described in reviews but had no quotable abstract-level evidence and are omitted.

Create: Charcot-Marie-Tooth_Disease_Axonal_Type_2S (IGHMBP2, MONDO:0014511) · 2026-09-06T02:36:57Z · View source

Created CMT2S as a Disease entry separate from the allelic SMARD1 entry (stub entry_type decision: DISEASE), conforming to the peripheral_axonal_degeneration module at the insult, distal-degeneration and length-dependent-dysfunction nodes. Sources: PMID:25568292, PMID:27450922, PMID:28202949, PMID:28065684, PMID:35660062 (cohorts and variant spectrum), PMID:36413117 and PMID:39461706 (CMT2S mouse models), PMID:38403020 and PMID:36480289 (residual-activity genotype-phenotype correlation and ABT1), PMID:39119929 (mechanism review), PMID:40060931 (personalised ASO), PMID:41486111 (AAV9 gene therapy), clinicaltrials:NCT05152823 (intrathecal AAV9-IGHMBP2 trial, fetched and cached), PMID:30409445 and PMID:41468720 (atypical presentations). GeneReviews: no CMT2S-specific chapter; the CMT Hereditary Neuropathy Overview (PMID:20301532) is tagged. Deep research: Edison/falcon report research/Charcot-Marie-Tooth_Disease_Axonal_Type_2S-deep-research-falcon.md (10/10 references verified, 36/38 terms verified, preflight-dr PASS); the report's suggested GO:0023055 (axon maintenance) is obsolete and was not used. Scoliosis and areflexia were not curated for lack of quotable abstract evidence. Validation: just validate pass, just validate-terms pass, count-verified-snippets 56/56, check-causal-targets and check-entity-refs clean.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 30 citations 2026-09-05T19:11:11.047429

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 Axonal Type 2S
  • MONDO ID: MONDO:0014511 (if available)
  • Category: Genetic

Research Objectives

Please provide a comprehensive research report on Charcot-Marie-Tooth Disease Axonal Type 2S 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, Axonal Type 2S (CMT2S)

Executive summary

Charcot–Marie–Tooth disease type 2S (CMT2S) is an ultra-rare, autosomal-recessive, hereditary motor-and-sensory axonal neuropathy caused by biallelic pathogenic variants in IGHMBP2. It usually begins in childhood with length-dependent distal weakness and wasting, sensory loss, areflexia, gait impairment, and foot deformity, and then progresses slowly proximally. Severe early diaphragmatic paralysis favors the allelic disorder spinal muscular atrophy with respiratory distress type 1 (SMARD1), but the two conditions form an overlapping IGHMBP2-related spectrum rather than an absolute binary. The foundational CMT2S association is Cottenie et al., American Journal of Human Genetics, published 6 November 2014, PMID 25439726, DOI 10.1016/j.ajhg.2014.10.002. (tian2023exploringtherelationship pages 1-2, NCT05152823 chunk 1)

The strongest recent advances are: dedicated CMT2S knock-in/deletion mouse models in 2023; systematic genotype–phenotype synthesis in 2023; new human IGHMBP2 cases in 2024; RNA-seq/Ribo-seq evidence in 2024 linking IGHMBP2 loss to translational suppression and chronic integrated-stress-response activation; and an ongoing phase I/IIa intrathecal AAV9–IGHMBP2 trial, NCT05152823. No disease-modifying treatment has yet been established as clinically effective. (tran2024anovelighmbp2 pages 5-6, tian2023exploringtherelationship pages 1-2, NCT05152823 chunk 1, park2024ighmbp2deletionsuppresses pages 1-2, martin2023clinicallyrelevantmouse pages 1-2)

The following evidence map distinguishes CMT2S-specific findings from evidence extrapolated from broader CMT or SMARD1.

Domain Best-supported finding Evidence type Key quantitative detail Source/year/DOI or PMID
Disease identity Charcot–Marie–Tooth disease axonal type 2S (CMT2S) is a rare hereditary motor-and-sensory axonal neuropathy; identifiers include OMIM 616155 and MONDO:0014511. Aggregated disease-level resource plus human genetics Open Targets associates MONDO:0014511 with one causal target, IGHMBP2. Open Targets/MONDO; Cottenie et al., 2014, PMID: 25439726, DOI: 10.1016/j.ajhg.2014.10.002 (OpenTargets Search: Charcot-Marie-Tooth disease type 2S-IGHMBP2, NCT05152823 chunk 1)
Etiology and inheritance CMT2S is caused by biallelic germline pathogenic variants in IGHMBP2 and follows autosomal-recessive inheritance; heterozygous carriers are generally unaffected. CMT2S-specific human genetics, supported by mouse segregation Vietnamese patients were homozygous or compound heterozygous; heterozygous E365del mice lacked the homozygous phenotype. Tran et al., 2024, DOI: 10.3389/fped.2024.1165492; Martin et al., 2023, DOI: 10.1093/hmg/ddac283 (tran2024anovelighmbp2 pages 5-6, martin2023clinicallyrelevantmouse pages 2-4)
Allelic spectrum Missense, nonsense/truncating, splice-altering, frameshift, and small-deletion variants are reported. CMT2S and SMARD1 form an allelic spectrum, and identical genotypes can yield different phenotypes; complete loss of function is more strongly associated with SMARD1. Human cases plus systematic review The 2023 review included 52 articles, identified 6 hotspot variants, and found that two truncating variants in trans were associated with SMARD1. Tian et al., 2023, DOI: 10.3389/fnins.2023.1252075 (tian2023exploringtherelationship pages 8-9, tian2023exploringtherelationship pages 1-2)
Core phenotype Typical CMT2S involves juvenile/early-onset, slowly progressive, length-dependent distal weakness and wasting, distal sensory loss, gait impairment, and reduced or absent tendon reflexes; weakness may spread proximally. Respiratory failure is usually absent, unlike SMARD1, although rare later diaphragmatic weakness has been reported. CMT2S-specific human clinical evidence Reported onset is commonly after age 1 year and often before age 10 years; frequencies cannot be estimated reliably from the small published cohorts. Tran et al., 2024, DOI: 10.3389/fped.2024.1165492; Tian et al., 2023, DOI: 10.3389/fnins.2023.1252075 (tran2024anovelighmbp2 pages 5-6, tian2023exploringtherelationship pages 8-9, tian2023exploringtherelationship pages 1-2)
Electrophysiology CMT2S is primarily an axonal neuropathy: motor and sensory response amplitudes are reduced, while conduction velocities are relatively preserved or normal unless axon loss is advanced. CMT2S-specific human evidence and concordant mouse evidence The E365del mouse had progressive axon loss without altered conduction velocity; Y918C mice also developed motor-and-sensory axonal degeneration but showed conduction-velocity effects. Tran et al., 2024, DOI: 10.3389/fped.2024.1165492; Martin et al., 2023, DOI: 10.1093/hmg/ddac283 (tran2024anovelighmbp2 pages 5-6, martin2023clinicallyrelevantmouse pages 1-2)
Epidemiology CMT2S is ultra-rare; no robust population-based incidence or prevalence study is available. The often-cited general CMT prevalence of approximately 1 in 2,500 must not be assigned to CMT2S. Review estimate; limited subtype-specific evidence Estimated CMT2S prevalence: <1 per 1,000,000 worldwide. Smieszek et al., 2025, DOI: 10.1016/j.omtn.2025.102479 (smieszek2025potentialasobasedpersonalized pages 1-2)
2023 disease models CRISPR-generated homozygous Ighmbp2 p.Glu365del and human-allele knock-in p.Tyr918Cys mice are the first dedicated CMT2S mouse models; both reproduce progressive motor-and-sensory axonal degeneration and motor deficits. CMT2S-specific mouse models E365del mice showed about 50% sensory-axon loss and 31% motor-axon loss by 20 weeks; motor deficits appeared by 6 weeks and mechanical allodynia by 12 weeks, without reduced survival. Martin et al., 2023, DOI: 10.1093/hmg/ddac283 (martin2023clinicallyrelevantmouse pages 1-2, martin2023clinicallyrelevantmouse pages 2-4)
2024 molecular mechanism IGHMBP2 is a cytoplasmic SF1 DNA/RNA helicase associated with ribosomes, pre-rRNA-processing factors, elongation factors, and tRNA species. Experimental deletion reduces global translation and chronically activates the integrated stress response, including ATF4 upregulation; relevance to patient neurons remains inferential. Human K562-cell CRISPR knockout; not direct CMT2S tissue evidence Full deletion slowed proliferation, modestly suppressed translation, altered the transcriptome/translatome, and produced reversible basal ISR activation; a 122-gene ATF4 target set did not reach significant enrichment. Park et al., published 21 May 2024, DOI: 10.26508/lsa.202302554 (park2024ighmbp2deletionsuppresses pages 1-2, park2024ighmbp2deletionsuppresses pages 8-9)
Current management No approved disease-modifying therapy is established for CMT2S. Current care is extrapolated mainly from broader CMT practice: individualized physical and occupational therapy, stretching and moderate exercise, ankle–foot orthoses, mobility aids, pain management, and orthopedic correction of fixed deformity. Broader-CMT clinical evidence; not CMT2S-specific A 2024 real-practice study of 37 mixed-CMT patients found short-term improvement after 3 weeks of intensive rehabilitation, but benefits were lost by 12 months; an AFO meta-analysis included 15 studies, with pooled effects not statistically significant. Ferraro et al., 2024, DOI: 10.1007/s10072-023-06998-0; Kim et al., 2024, DOI: 10.1002/jfa2.70003
Clinical gene therapy NCT05152823 is evaluating a single intrathecal dose of an AAV9 vector carrying human IGHMBP2 in genetically confirmed IGHMBP2-related disease, including CMT2S. It is experimental and has no posted efficacy result in the cited record. CMT2S/SMARD1 human interventional trial Open-label, single-group phase I/IIa study; estimated 10 participants, ages 2 months–14 years; primary safety follow-up 3 years; status verified September 2025: enrolling by invitation. ClinicalTrials.gov, first posted 10 December 2021, NCT05152823 (NCT05152823 chunk 1)
Translational qualification AAV9-IGHMBP2 rescue in SMARD1 mice and patient-derived IGHMBP2-disorder neurons supports gene-replacement plausibility, but SMARD1-model efficacy cannot be treated as demonstrated CMT2S clinical benefit. SMARD1 mouse and mixed SMARD1/CMT2S in-vitro extrapolation Patient-derived induced neurons showed shortened neurites and variable improvement after IGHMBP2 restoration; clinical benefit and durability remain unknown. Sierra-Delgado et al., 2023, DOI: 10.3390/biology12060867; NCT05152823 (NCT05152823 chunk 2, NCT05152823 chunk 1)

Table: Compact evidence map distinguishing disease-specific human and mouse findings from broader CMT care evidence and SMARD1-based mechanistic extrapolation. It highlights the strongest quantitative findings and the current experimental status of IGHMBP2 gene therapy.

1. Disease information

Definition and identifiers

CMT2S is a genetic peripheral neuropathy characterized pathologically and electrophysiologically by degeneration/loss of motor and sensory axons rather than primary demyelination. Open Targets maps MONDO:0014511 (“Charcot-Marie-Tooth disease axonal type 2S”) to the single established target IGHMBP2 (Ensembl ENSG00000132740), supported by the foundational human-genetics publication PMID 25439726. (OpenTargets Search: Charcot-Marie-Tooth disease type 2S-IGHMBP2)

  • MONDO: MONDO:0014511.
  • OMIM disease: 616155.
  • OMIM gene: IGHMBP2, 600502.
  • Gene: IGHMBP2, immunoglobulin mu DNA-binding protein 2; historical protein name SIP1.
  • Common names: Charcot–Marie–Tooth disease type 2S; CMT2S; Charcot–Marie–Tooth disease, axonal, type 2S; autosomal-recessive CMT2S; IGHMBP2-related axonal neuropathy; hereditary motor and sensory neuropathy due to IGHMBP2.
  • Orphanet: A CMT2S-specific ORPHA number was not verified in the retrieved evidence; it should not be inferred from SMARD1’s ORPHA:98920.
  • ICD-10-CM: No subtype-specific code was verified; CMT is generally represented under G60.0, hereditary motor and sensory neuropathy.
  • ICD-11/MeSH: No CMT2S-specific identifier was verified. The trial’s indexed MeSH concept concerns the related SMARD1 phenotype, not CMT2S specifically. (NCT05152823 chunk 1)

The report synthesizes aggregated disease resources, published case series/families, experimental models, and a trial registry. It is not derived from an individual EHR. Because cohorts are very small, most phenotype frequencies cannot be generalized reliably.

2. Etiology

Causal and genetic risk factors

The necessary causal factor is normally two pathogenic germline IGHMBP2 alleles, either homozygous or compound heterozygous. The 2024 Vietnamese study evaluated eight patients with IGHMBP2-related disease: three were homozygous and five compound heterozygous, while parents were carriers. Reported variants included c.1235+3A>G, c.1334A>C (p.His445Pro), c.1574T>C (p.Leu525Pro), c.1813C>T (p.Arg605Ter), and c.2362C>T (p.Arg788Ter). (tran2024anovelighmbp2 pages 5-6)

Consanguinity increases the probability that both parents carry the same rare allele but is not mechanistically required. Family history may be absent because of recessive inheritance. Heterozygous carriers are generally asymptomatic; concordantly, heterozygous E365del mice did not show the homozygous neuropathy phenotype. (martin2023clinicallyrelevantmouse pages 2-4)

Modifiers, protective factors, and gene–environment interaction

Residual IGHMBP2 abundance/function appears important: partial loss is more often compatible with CMT2S, whereas profound or complete loss—particularly two truncating alleles in trans—is strongly associated with SMARD1. A 2023 systematic review searched through 1 April 2023, included 52 articles, found six hotspot variants, and reported that truncating variants in trans were all associated with SMARD1. This is a probabilistic relationship, not a deterministic rule. (tian2023exploringtherelationship pages 1-2)

Identical variants can nevertheless yield markedly different outcomes. In the 2024 Vietnamese series, individuals with c.1235+3A>G/c.1334A>C had either fatal infantile SMARD1 or CMT2S without respiratory distress, supporting modifier genes, expression differences, or other unidentified factors. (tran2024anovelighmbp2 pages 5-6)

ABT1 and linked tRNA-Tyr genes modify disease severity in mice, but no clinically validated human modifier or protective allele is established. No reproducible environmental risk or protective factor, infection, diet, smoking effect, toxin, occupational exposure, or formal gene–environment interaction has been demonstrated for CMT2S. Avoidance of neurotoxic exposures is prudent clinical practice but does not prevent the inherited molecular lesion. (park2024ighmbp2deletionsuppresses pages 1-2, park2024ighmbp2deletionsuppresses pages 8-9)

3. Phenotypes

The core phenotype is chronic, length-dependent motor-and-sensory neuropathy. Onset has often been reported after age one and before age ten, although both earlier and later presentations occur. Severity varies from ambulant childhood disease to severe disability; reliable percentages are unavailable. (tran2024anovelighmbp2 pages 5-6, tian2023exploringtherelationship pages 1-2)

Phenotype Characteristics and suggested HPO annotation
Distal limb weakness Usually lower limbs first; slowly progressive, potentially spreading proximally. HP:0002460, Distal muscle weakness; HP:0009055, Generalized distal muscle weakness.
Distal muscle atrophy Feet/lower legs and later hands; neurogenic. HP:0008944, Distal amyotrophy.
Sensory loss Length-dependent distal loss, potentially spreading proximally. HP:0000763, Sensory neuropathy; HP:0002936, Distal sensory impairment.
Reduced/absent reflexes Common clinical sign. HP:0001284, Areflexia; HP:0001315, Reduced tendon reflexes.
Gait disorder/foot drop Tripping, falls, steppage gait, impaired running or stair climbing. HP:0001288, Gait disturbance; HP:0003376, Steppage gait; HP:0009536, Foot drop.
Foot deformity Pes cavus/cavovarus and contracture may emerge with chronic muscle imbalance. HP:0001761, Pes cavus; HP:0008110, Equinovarus deformity.
Scoliosis Variable and sometimes severe. HP:0002650, Scoliosis.
Axonal neuropathy Low compound muscle and sensory action-potential amplitudes with relatively preserved conduction velocity. HP:0003477, Peripheral axonal neuropathy.
Respiratory involvement Usually absent in classic CMT2S; severe infantile diaphragmatic paralysis points to SMARD1. Rare late diaphragmatic weakness means respiratory surveillance should be symptom-driven. HP:0002791, Hypoventilation and HP:0009113, Diaphragmatic paralysis only when documented.

The disease impairs walking, balance, endurance, hand function, schooling/work, independence, and social participation; falls, fatigue, pain, and orthotic or mobility-aid needs can reduce quality of life. No CMT2S-specific EQ-5D, SF-36, PROMIS, or phenotype-frequency dataset was found. A detailed 2025 patient report illustrates severity but not population frequency: foot inversion began at approximately three months, weakness became proximal, and by 11 years the patient had recurrent falls and impaired ambulation. (smieszek2025potentialasobasedpersonalized pages 1-2)

Behavioral or primary psychiatric changes are not defining. Intellectual disability should prompt consideration of an expanded phenotype, a second diagnosis, or another neuropathy gene rather than automatic assignment to CMT2S.

4. Genetic and molecular information

Gene and protein

IGHMBP2 lies on chromosome 11q13 and contains 15 exons. It encodes a 993-amino-acid, ubiquitously expressed superfamily-1 ATP-dependent DNA/RNA helicase that unwinds GC-rich duplex RNA in the 5′→3′ direction. It contains ATPase/helicase and zinc-finger-related functional regions and associates predominantly with cytoplasmic translation machinery. (tran2024anovelighmbp2 pages 5-6, tian2023exploringtherelationship pages 1-2, park2024ighmbp2deletionsuppresses pages 1-2, martin2023clinicallyrelevantmouse pages 1-2)

Suggested annotations include GO:0004386 helicase activity, GO:0003723 RNA binding, GO:0005524 ATP binding, GO:0034061 DNA helicase activity, GO:0006412 translation, and GO:0008380 RNA splicing. Exact HGNC numeric ID was not verified in the retrieved evidence and should be sourced directly from HGNC before database loading.

Pathogenic variants

Missense, nonsense, frameshift, splice-site, small in-frame deletion, and larger disruptive variants have been reported. The foundational paper’s title provides the exact abstract-level statement: “Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2.” (tian2023exploringtherelationship pages 8-9, NCT05152823 chunk 1)

Variants are germline, not somatic. The predominant mechanism is loss or reduction of protein function through altered helicase activity, protein instability, abnormal splicing, frameshift, or nonsense-mediated decay. A deep intronic/cryptic splice variant can create an aberrant acceptor, disrupt the reading frame, and trigger nonsense-mediated decay. (smieszek2025potentialasobasedpersonalized pages 1-2)

Variant-level ACMG classification and gnomAD/TOPMed frequencies must be checked individually using the precise transcript and genome build. Ultra-rarity and segregation support pathogenicity but do not alone establish it. No recurrent chromosomal aneuploidy, translocation, inversion, or copy-number mechanism is established as characteristic. No disease-specific epigenetic signature is validated.

5. Environmental information

CMT2S is a monogenic inherited disease. No infectious agent, radiation exposure, pollutant, diet, alcohol use, smoking pattern, or occupational exposure is known to cause it. Environmental and lifestyle variables may alter function or complications—exercise conditioning, falls, obesity, orthopedic strain, and exposure to neurotoxic medicines—but are not established causes. No quantitative CMT2S-specific exposure study was found.

6. Mechanism and pathophysiology

Ordered causal chain

  1. Biallelic pathogenic IGHMBP2 variants lead to reduced abundance or function of ATP-dependent IGHMBP2 helicase.
  2. Reduced IGHMBP2 function leads to disturbed RNA metabolism, including translation-associated, pre-rRNA/tRNA-related, mRNA-processing, and potentially THO-complex-dependent mRNA-export functions; the relative contribution of each pathway in human CMT2S remains incompletely resolved. (park2024ighmbp2deletionsuppresses pages 1-2, park2024ighmbp2deletionsuppresses pages 8-9)
  3. Translation/RNA-homeostasis disturbance leads to modest global translational suppression and chronic ATF4-associated integrated stress response in IGHMBP2-knockout human cells; extrapolation to patient peripheral neurons is currently inferred. (park2024ighmbp2deletionsuppresses pages 1-2)
  4. Chronic neuronal RNA/proteostasis stress is inferred to lead to impaired axonal maintenance and local protein synthesis, especially in long peripheral motor and sensory neurons.
  5. Impaired axonal maintenance leads to progressive length-dependent motor- and sensory-axon degeneration; dedicated mouse models directly demonstrate this step. (martin2023clinicallyrelevantmouse pages 1-2, martin2023clinicallyrelevantmouse pages 2-4)
  6. Motor-axon and neuromuscular-junction loss leads to denervation, distal muscle wasting, weakness, foot imbalance/deformity, and gait impairment.
  7. Sensory-axon loss leads to distal sensory impairment and altered nociception; E365del mice also show mechanical allodynia. (martin2023clinicallyrelevantmouse pages 2-4)
  8. Branch—when residual IGHMBP2 function is extremely low, the lesion more often leads to spinal α-motor-neuron loss and diaphragmatic paralysis/SMARD1 rather than classic CMT2S; genotype alone does not perfectly determine this branch. (tran2024anovelighmbp2 pages 5-6, tian2023exploringtherelationship pages 1-2)

Cellular and molecular detail

The 2024 human K562 CRISPR study used polysome profiling, nascent-protein synthesis, RNA-seq, Ribo-seq, and ATF4 reporters. Full deletion slowed proliferation, modestly reduced global translation, changed the transcriptome/translatome, and produced basal chronic ISR activation. Its exact abstract statement is: “IGHMBP2 knockout cells demonstrate basal, chronic ISR activation.” The response was low-grade and reversible; CHOP induction was not detected, suggesting a pro-survival rather than overtly apoptotic program. A 122-gene ATF4 set did not reach significant enrichment, emphasizing that effect sizes were modest. (park2024ighmbp2deletionsuppresses pages 1-2, park2024ighmbp2deletionsuppresses pages 8-9)

Suggested processes/cells:

  • GO: translation (GO:0006412), response to endoplasmic-reticulum stress (GO:0034976), integrated stress response, axon maintenance (GO:0023055), axon degeneration (GO:0030516), neuromuscular-junction development (GO:0007528), peripheral nervous system development (GO:0007422).
  • CL: motor neuron (CL:0000100), sensory neuron (CL:0000101), alpha motor neuron where available, skeletal muscle cell/myocyte (CL:0000187), Schwann cell (CL:0002573). Axons—not Schwann-cell myelin—are the primary lesion in CMT2S.

No validated CMT2S-specific metabolomic, lipidomic, methylomic, spatial-transcriptomic, or single-cell patient-tissue signature was found. RNA-seq/Ribo-seq evidence currently comes from engineered cells rather than affected human nerves. (park2024ighmbp2deletionsuppresses pages 1-2)

7. Anatomical structures affected

The principal system is the peripheral nervous system, especially long motor and sensory axons to distal limbs, with secondary denervation of skeletal muscle and neuromuscular junctions. The process is generally bilateral and approximately symmetric, though severity may differ between sides.

Suggested locations are peripheral nerve (UBERON:0000010), spinal nerve, lower-limb peripheral nerve, upper-limb peripheral nerve, skeletal muscle (UBERON:0001134), neuromuscular junction, foot, lower leg, and hand. Relevant subcellular compartments include cytoplasm (GO:0005737), ribosome (GO:0005840), axon (GO:0030424), and presynaptic/neuromuscular-junction compartments. The diaphragm is usually spared in classic CMT2S but can be involved in the broader IGHMBP2 spectrum.

8. Temporal development

Onset is usually insidious and pediatric/juvenile, commonly after infancy and often before ten years. Early manifestations include delayed or abnormal walking, foot inversion/deformity, tripping, falls, distal weakness, and absent reflexes. Disease is chronic and generally slowly progressive, with distal-to-proximal spread and possible later hand involvement. (tran2024anovelighmbp2 pages 5-6, tian2023exploringtherelationship pages 1-2)

There are no validated disease stages. A practical clinical framework is: early gait/foot weakness; intermediate established distal weakness, sensory loss, and deformity; and advanced proximal spread, hand involvement, scoliosis, and need for mobility assistance. Remission is not expected. The critical therapeutic window is likely before irreversible axon and motor-unit loss, but this remains inferred rather than proven in humans.

9. Inheritance and population

Inheritance is autosomal recessive. For two confirmed heterozygous parents, each pregnancy has a 25% probability of an affected child, 50% of a heterozygous carrier, and 25% of an unaffected non-carrier, assuming conventional Mendelian segregation.

Penetrance for appropriately classified biallelic pathogenic variants appears high, but phenotype and age of onset are variable. Expressivity spans CMT2S, intermediate presentations, and SMARD1. Anticipation is not established. Germline mosaicism has not been quantified. Founder effects may occur in individual consanguineous families, but no globally dominant founder allele or reliable carrier frequency is known.

A later review estimates CMT2S prevalence at <1 per 1,000,000 worldwide; no population-based incidence estimate exists. General CMT prevalence—often quoted around 1:2,500—must not be applied to this ultra-rare subtype. Both sexes are affected. Reports span European, Asian, Middle Eastern, and other ancestries, without a demonstrated sex or ethnic predominance. (smieszek2025potentialasobasedpersonalized pages 1-2, martin2023clinicallyrelevantmouse pages 1-2)

10. Diagnostics

Clinical and electrophysiologic evaluation

Diagnosis begins with history, three-generation pedigree, neurologic examination, foot/spine assessment, functional measures, and nerve-conduction studies/EMG. The characteristic electrophysiology is reduced motor and sensory response amplitudes with relatively normal or mildly reduced conduction velocity, supporting axonal rather than primary demyelinating disease. (tran2024anovelighmbp2 pages 5-6, martin2023clinicallyrelevantmouse pages 1-2)

EMG may show chronic neurogenic denervation/reinnervation. Imaging is not diagnostic but may assess spine/foot deformity or alternative causes. Nerve or muscle biopsy is usually unnecessary after molecular confirmation and would be expected to show axonal loss and neurogenic muscle change rather than a unique CMT2S marker.

Genetic testing strategy

  1. Use a comprehensive inherited-neuropathy/CMT panel that includes IGHMBP2, or exome/genome sequencing where phenotype is atypical or panel testing is negative.
  2. Confirm two variants, phase them in trans through parental testing, and classify them under ACMG/AMP criteria.
  3. Use deletion/duplication analysis if sequencing detects only one allele.
  4. Use RNA studies when a synonymous, intronic, or suspected splice variant remains unresolved; WGS can identify deep intronic or structural variants missed by WES.
  5. Test relatives for cascade screening only after the familial variants are established.

WES identified biallelic variants in the Vietnamese cohort, while prior WGS identified a cryptic splice-site CMT phenotype, demonstrating complementary utility. (tran2024anovelighmbp2 pages 5-6, tian2023exploringtherelationship pages 8-9)

CMA, karyotyping, FISH, mitochondrial-DNA analysis, and repeat-expansion testing are not first-line for a molecularly typical CMT2S case, but may be appropriate if the broader phenotype suggests another diagnosis.

Differential diagnosis

Important alternatives include other axonal CMT2 forms, hereditary motor neuropathy, hereditary sensory neuropathy, 5q SMA, SMARD1, distal SMA, Friedreich ataxia, hereditary spastic paraplegia, metabolic neuropathy, and acquired inflammatory/toxic neuropathy. Early respiratory failure or diaphragm paralysis strongly favors SMARD1; prominent demyelinating slowing favors CMT1; acquired rapid progression, conduction block, or inflammatory markers warrant evaluation for CIDP/GBS.

There is no newborn biochemical screen or validated circulating biomarker. Prenatal and preimplantation testing are technically possible when familial variants are known.

11. Outcome and prognosis

Classic CMT2S is generally less acutely life-threatening than SMARD1, and respiratory failure is usually absent. Nevertheless, progressive weakness can cause substantial lifelong disability, falls, loss of independent ambulation, scoliosis, contractures, chronic pain, fatigue, and reduced participation. No reliable CMT2S-specific survival curve, mortality rate, five- or ten-year survival statistic, or validated prognostic biomarker exists. (tian2023exploringtherelationship pages 1-2)

Residual IGHMBP2 function, variant combination, age at onset, rate of motor decline, scoliosis, and respiratory involvement are plausible prognostic factors, but genotype–phenotype prediction remains imprecise. Rare later diaphragmatic weakness justifies pulmonary assessment when orthopnea, weak cough, sleep-disordered breathing, or declining vital capacity occurs. (tian2023exploringtherelationship pages 8-9)

12. Treatment

Current clinical management

There is no established curative or approved CMT2S-specific pharmacotherapy. Care is multidisciplinary and mainly extrapolated from broader CMT practice:

  • individualized physiotherapy with stretching, balance, aerobic conditioning, and non-excessive strengthening;
  • occupational therapy and energy-conservation/adaptive strategies;
  • custom ankle–foot orthoses, footwear, canes, walkers, or wheelchairs;
  • treatment of neuropathic or musculoskeletal pain;
  • surveillance and management of contractures, cavovarus feet, scoliosis, falls, and respiratory symptoms;
  • orthopedic tendon transfer, osteotomy, fusion, or scoliosis surgery for function-limiting fixed deformity after specialist assessment.

Suggested NCIt intervention concepts include Physical Therapy, Occupational Therapy, Orthotic Device, Pain Management, Orthopedic Surgery, Genetic Counseling, and Gene Therapy; NCIt identifiers should be verified against the current release before ingestion.

Broader-CMT real-world evidence remains modest. A 2024 retrospective study included 37 mild/moderate CMT patients—28 demyelinating, eight axonal, one mixed—and used 2–4 hours/day, five days/week for three weeks. Outcomes improved immediately but gains were lost by 12 months, so the results are not CMT2S-specific or evidence of disease modification. A 2024 AFO review included 15 studies; pooled gait effects were small-to-moderate but statistically non-significant because of small, heterogeneous samples, supporting individualized fitting rather than a universal device.

Experimental gene therapy

ClinicalTrials.gov NCT05152823, “Phase I/IIa Intrathecal Gene Delivery Clinical Trial for IGHMBP2-Related Diseases,” is an open-label, single-group study of one intrathecal dose of AAV9 carrying IGHMBP2. It includes genetically confirmed SMARD1 or CMT2S, requires two pathogenic variants, enrolls ages two months to 14 years, and has an estimated sample of ten. The primary endpoint is unacceptable grade III-or-higher treatment-related toxicity over three years; functional endpoints include GRO, 100-m timed testing, and RULM according to age/ambulatory status. The study began 4 November 2021; the record was verified September 2025 as enrolling by invitation, with estimated primary completion July 2028. No efficacy result was posted in the retrieved record. (NCT05152823 chunk 1)

Patient-derived induced neurons exhibit shortened neurites and variable improvement after AAV9-mediated IGHMBP2 restoration, supporting biological plausibility but not clinical efficacy. A later splice-correction ASO study reported >50% protein increase and improved in-vitro NMJ behavior for one personalized variant; this is mutation-specific preclinical evidence, not a general CMT2S treatment. (smieszek2025potentialasobasedpersonalized pages 1-2)

No established CMT2S pharmacogenomic guidance, cell therapy, immunotherapy, or combination regimen exists.

13. Prevention

Primary prevention by lifestyle change or vaccination is not possible because the initiating lesion is inherited. Reproductive prevention options after identification of familial variants include genetic counseling, partner/carrier testing, prenatal diagnosis, and preimplantation genetic testing. Cascade testing permits earlier recognition of biallelic relatives and clarifies carrier status.

Secondary prevention consists of early molecular diagnosis and early rehabilitation/orthotic management before fixed deformity and severe axon loss. Tertiary prevention includes fall prevention, stretching to reduce contractures, appropriate footwear/AFOs, weight and activity management, spine/foot surveillance, and symptom-triggered pulmonary assessment. There is no population newborn-screening program, vaccine, environmental-control program, or prophylactic medication specific to CMT2S.

14. Other species and natural disease

The relevant experimental ortholog is mouse Ighmbp2 in Mus musculus (NCBI Taxon 10090). The human taxon is Homo sapiens (9606). No well-established naturally occurring veterinary disease specifically equivalent to human CMT2S was identified in the retrieved literature; therefore no breed/VBO annotation or zoonotic transmission applies. CMT2S is not infectious and has no zoonotic potential.

Cross-species conservation is strong enough that engineered mouse alleles reproduce motor-and-sensory axon degeneration, but species differences in lifespan, axon length, dosage, and respiratory biology limit direct clinical translation.

15. Model organisms and experimental systems

Dedicated CMT2S mouse models

Martin et al. generated homozygous CRISPR Ighmbp2 c.1093_1095del, p.Glu365del (E365del) mice and a human-allele knock-in p.Tyr918Cys (Y918C) model. The abstract states that these models showed “progressive peripheral motor and sensory axonal degeneration.” Both had motor deficits; E365del mice developed mechanical allodynia. (martin2023clinicallyrelevantmouse pages 1-2)

E365del mice developed hindquarter paresis/wasting at two to three months, rotarod deficits by six weeks, and allodynia by 12 weeks. At 20 weeks they had about 50% fewer femoral sensory axons—404±50 versus 794±96—and approximately 31% fewer motor axons—342.3±47 versus 496±28.3. Conduction velocity remained preserved, matching an axonal phenotype, and survival did not differ from wild type. Heterozygotes were phenotypically normal. (martin2023clinicallyrelevantmouse pages 2-4)

Strengths include recessive inheritance, progressive motor/sensory deficits, axon loss, and CMT2S-relevant electrophysiology. Limitations include engineered alleles, short murine lifespan, incomplete reproduction of human deformity/disability, and inter-model differences—Y918C affected conduction velocity more than E365del.

Cellular models

Patient fibroblasts, iPSCs, induced motor neurons, and engineered human K562/HeLa cells are useful for variant interpretation, RNA processing, translation, ISR biology, and therapeutic testing. However, K562 cells are not peripheral neurons, and mixed SMARD1/CMT2S patient-neuron studies cannot fully resolve subtype-specific mechanisms. (smieszek2025potentialasobasedpersonalized pages 1-2, park2024ighmbp2deletionsuppresses pages 1-2, park2024ighmbp2deletionsuppresses pages 8-9)

Evidence limitations and expert interpretation

CMT2S evidence is dominated by small families, referral cohorts, and model systems. Consequently, prevalence, penetrance, phenotype frequencies, survival, and treatment-response rates remain uncertain. The most defensible current interpretation is that IGHMBP2 disease is a continuum governed partly by residual protein function but substantially modified by yet-unresolved biological factors. The discovery that the same genotype can cause fatal SMARD1 in one child and non-respiratory CMT2S in another makes phenotype prediction from sequence alone unsafe. (tran2024anovelighmbp2 pages 5-6)

The 2024 translational/ISR study is mechanistically important but does not prove that ATF4 activation is the principal lesion in patient axons. Conversely, the dedicated CMT2S mice provide direct evidence that biallelic Ighmbp2 dysfunction is sufficient for progressive motor-and-sensory axon loss. The phase I/IIa AAV9 trial is the leading real-world disease-modifying implementation, but it remains experimental and presently supplies a safety framework rather than proof of benefit. (NCT05152823 chunk 1, park2024ighmbp2deletionsuppresses pages 1-2, martin2023clinicallyrelevantmouse pages 1-2)

Key primary and recent sources

  1. Cottenie E, et al. “Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2.” Am J Hum Genet. Published 6 November 2014;95:590–601. PMID 25439726. DOI: 10.1016/j.ajhg.2014.10.002. (NCT05152823 chunk 1)
  2. Martin PB, et al. “Clinically relevant mouse models of Charcot–Marie–Tooth type 2S.” Human Molecular Genetics. 2023;32:1276–1288; online 22 November 2022. DOI: 10.1093/hmg/ddac283. (martin2023clinicallyrelevantmouse pages 1-2, martin2023clinicallyrelevantmouse pages 2-4)
  3. Tian Y, et al. “Exploring the relationship between IGHMBP2 gene mutations and SMARD1 and CMT2S: a systematic review.” Front Neurosci. Published 17 November 2023. DOI: 10.3389/fnins.2023.1252075. (tian2023exploringtherelationship pages 1-2)
  4. Tran VK, et al. “A novel IGHMBP2 variant and clinical diversity in Vietnamese SMARD1 and CMT2S patients.” Front Pediatr. February 2024. DOI: 10.3389/fped.2024.1165492. Exact abstract conclusion: “The presence of three patients with the same genotype but distinct clinical outcomes suggested the interaction of variants and other factors including relating modified genes.” (tran2024anovelighmbp2 pages 5-6)
  5. Park J, et al. “IGHMBP2 deletion suppresses translation and activates the integrated stress response.” Life Sci Alliance. Published online 21 May 2024. DOI: 10.26508/lsa.202302554. (park2024ighmbp2deletionsuppresses pages 1-2, park2024ighmbp2deletionsuppresses pages 8-9)
  6. ClinicalTrials.gov. “Gene Therapy for IGHMBP2-Related Diseases.” First posted 10 December 2021. NCT05152823. (NCT05152823 chunk 1)

References

  1. (tian2023exploringtherelationship pages 1-2): Yuan Tian, Jinfang Xing, Ying Shi, and Enwu Yuan. Exploring the relationship between ighmbp2 gene mutations and spinal muscular atrophy with respiratory distress type 1 and charcot-marie-tooth disease type 2s: a systematic review. Frontiers in Neuroscience, Nov 2023. URL: https://doi.org/10.3389/fnins.2023.1252075, doi:10.3389/fnins.2023.1252075. This article has 15 citations and is from a peer-reviewed journal.

  2. (NCT05152823 chunk 1): Megan Waldrop. Gene Therapy for IGHMBP2-Related Diseases. Megan Waldrop. 2021. ClinicalTrials.gov Identifier: NCT05152823

  3. (tran2024anovelighmbp2 pages 5-6): Van Khanh Tran, My Ha Cao, Thi Thanh Hai Nguyen, Phuong Thi Le, Hai Anh Tran, Dung Chi Vu, Ha Thu Nguyen, Mai Thi Phương Nguyen, The-Hung Bui, Thanh Binh Nguyen, Thanh Van Ta, and Thinh Huy Tran. A novel ighmbp2 variant and clinical diversity in vietnamese smard1 and cmt2s patients. Frontiers in Pediatrics, Feb 2024. URL: https://doi.org/10.3389/fped.2024.1165492, doi:10.3389/fped.2024.1165492. This article has 7 citations.

  4. (park2024ighmbp2deletionsuppresses pages 1-2): Jesslyn Park, Hetvee Desai, José M Liboy-Lugo, Sohyun Gu, Ziad Jowhar, Albert Xu, and Stephen N Floor. Ighmbp2 deletion suppresses translation and activates the integrated stress response. May 2024. URL: https://doi.org/10.26508/lsa.202302554, doi:10.26508/lsa.202302554. This article has 10 citations and is from a peer-reviewed journal.

  5. (martin2023clinicallyrelevantmouse pages 1-2): Paige B Martin, Sarah E Holbrook, Amy N Hicks, Timothy J Hines, Laurent P Bogdanik, Robert W Burgess, and Gregory A Cox. Clinically relevant mouse models of charcot-marie-tooth type 2s. Human molecular genetics, 32:1276-1288, Nov 2023. URL: https://doi.org/10.1093/hmg/ddac283, doi:10.1093/hmg/ddac283. This article has 17 citations and is from a domain leading peer-reviewed journal.

  6. (OpenTargets Search: Charcot-Marie-Tooth disease type 2S-IGHMBP2): Open Targets Query (Charcot-Marie-Tooth disease type 2S-IGHMBP2, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  7. (martin2023clinicallyrelevantmouse pages 2-4): Paige B Martin, Sarah E Holbrook, Amy N Hicks, Timothy J Hines, Laurent P Bogdanik, Robert W Burgess, and Gregory A Cox. Clinically relevant mouse models of charcot-marie-tooth type 2s. Human molecular genetics, 32:1276-1288, Nov 2023. URL: https://doi.org/10.1093/hmg/ddac283, doi:10.1093/hmg/ddac283. This article has 17 citations and is from a domain leading peer-reviewed journal.

  8. (tian2023exploringtherelationship pages 8-9): Yuan Tian, Jinfang Xing, Ying Shi, and Enwu Yuan. Exploring the relationship between ighmbp2 gene mutations and spinal muscular atrophy with respiratory distress type 1 and charcot-marie-tooth disease type 2s: a systematic review. Frontiers in Neuroscience, Nov 2023. URL: https://doi.org/10.3389/fnins.2023.1252075, doi:10.3389/fnins.2023.1252075. This article has 15 citations and is from a peer-reviewed journal.

  9. (smieszek2025potentialasobasedpersonalized pages 1-2): Sandra Smieszek, Bartlomiej Przychodzen, Christina Tyner, Caroline Johnson, Haimeng Bai, Jennifer M. Kwon, D. Walker Hagan, Caitlyn Niccum, Rocky Brighton, Kenneth Hawkins, Romy Aiken, Ahmad Nawaz, Xiufang Guo, James Hickman, Christos M. Polymeropoulos, Gunther Birznieks, and Mihael H. Polymeropoulos. Potential aso-based personalized treatment for charcot-marie-tooth disease type 2s. Molecular Therapy Nucleic Acids, 36:102479, Mar 2025. URL: https://doi.org/10.1016/j.omtn.2025.102479, doi:10.1016/j.omtn.2025.102479. This article has 8 citations and is from a peer-reviewed journal.

  10. (park2024ighmbp2deletionsuppresses pages 8-9): Jesslyn Park, Hetvee Desai, José M Liboy-Lugo, Sohyun Gu, Ziad Jowhar, Albert Xu, and Stephen N Floor. Ighmbp2 deletion suppresses translation and activates the integrated stress response. May 2024. URL: https://doi.org/10.26508/lsa.202302554, doi:10.26508/lsa.202302554. This article has 10 citations and is from a peer-reviewed journal.

  11. (NCT05152823 chunk 2): Megan Waldrop. Gene Therapy for IGHMBP2-Related Diseases. Megan Waldrop. 2021. ClinicalTrials.gov Identifier: NCT05152823

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 10
Resolved 10
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 10
On topic 6
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 38
Resolved 36
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 1
Terms whose name was checked 2
Terms named correctly 0
Terms named as a different term 1
Terms whose name is worth a second look 1

Terms the report names something else

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:0014511 (5 mentions) - the report calls it "if available"; MONDO calls it Charcot-Marie-Tooth disease axonal type 2S

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0023055 (obsolete signal initiation by peptide hormone) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0006412 (2 mentions) - the report calls it "GO: translation"; GO calls it translation**

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.