| 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](https://doi.org/10.1016/j.ajhg.2014.10.002) (pqac-00000000, pqac-00000009) |
| 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](https://doi.org/10.3389/fped.2024.1165492); Martin et al., 2023, DOI: [10.1093/hmg/ddac283](https://doi.org/10.1093/hmg/ddac283) (pqac-00000002, pqac-00000013) |
| 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](https://doi.org/10.3389/fnins.2023.1252075) (pqac-00000003, pqac-00000004) |
| 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](https://doi.org/10.3389/fped.2024.1165492); Tian et al., 2023, DOI: [10.3389/fnins.2023.1252075](https://doi.org/10.3389/fnins.2023.1252075) (pqac-00000002, pqac-00000003, pqac-00000004) |
| 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](https://doi.org/10.3389/fped.2024.1165492); Martin et al., 2023, DOI: [10.1093/hmg/ddac283](https://doi.org/10.1093/hmg/ddac283) (pqac-00000002, pqac-00000012) |
| 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](https://doi.org/10.1016/j.omtn.2025.102479) (pqac-00000001) |
| 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](https://doi.org/10.1093/hmg/ddac283) (pqac-00000012, pqac-00000013) |
| 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](https://doi.org/10.26508/lsa.202302554) (pqac-00000010, pqac-00000011) |
| 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](https://doi.org/10.1007/s10072-023-06998-0); Kim et al., 2024, DOI: [10.1002/jfa2.70003](https://doi.org/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](https://clinicaltrials.gov/study/NCT05152823) (pqac-00000009) |
| 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](https://doi.org/10.3390/biology12060867); NCT05152823 (pqac-00000007, pqac-00000009) |


*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.*