SLC25A46-Related Hereditary Motor and Sensory Neuropathy (CMT6B / HMSN6B): Research Report

Target: MONDO:0014671 · OMIM:616505 · causal gene SLC25A46 (solute carrier family 25 member 46; chromosome 5q22.1)

Scope and verification. This report was assembled from web searches. Some citations were confirmed against PubMed or PMC records during the search; others are given from prior knowledge, with their PMIDs marked [verify]. Text in quotation marks comes from search-result excerpts of the cited papers, not from a fetched abstract. Re-check every quote with just fetch-reference and just count-verified-snippets before using it as a dismech snippet. Treat every CURIE below as a lead, per the repository's term contract: look each one up before binding it.

1. Disease information

Overview. CMT6B (HMSN6B) is an autosomal recessive neurodegenerative disorder caused by biallelic loss-of-function variants in SLC25A46. The core phenotype combines: - early-onset optic atrophy; and - axonal sensorimotor peripheral neuropathy (CMT2-like).

Many patients also have cerebellar ataxia and cerebellar atrophy. Abrams et al. (2015) reported the gene after whole-exome sequencing of patients with optic atrophy and CMT2 identified four families with recessive SLC25A46 mutations. They described it as an "optic atrophy spectrum disorder" that overlaps clinically with OPA1- and MFN2-related disease (Abrams et al., Nat Genet 2015;47:926–932, PMID:26168012 — confirmed).

The disorder sits on a severity spectrum: - Mildest: isolated or mild optic atrophy with survival into adulthood. - Classic: optic atrophy plus axonal neuropathy (HMSN6B). - Intermediate: progressive myoclonic ataxia with optic atrophy and neuropathy (Charlesworth et al., Mov Disord 2016;31:1249–1251, doi:10.1002/mds.26716). - Ataxia-predominant: autosomal recessive cerebellar ataxia without optic atrophy (Hammer et al., Neurodegener Dis 2017;17:208–212, doi:10.1159/000464445). - Severe: Leigh syndrome (Janer et al., EMBO Mol Med 2016, PMID:27390132 — confirmed). - Most severe: lethal congenital pontocerebellar hypoplasia (Wan et al., Brain 2016;139:2877, PMID:27543974 — confirmed).

Identifiers

Synonyms. CMT6B; Charcot-Marie-Tooth disease type 6B; HMSN6B; neuropathy, hereditary motor and sensory, type VIB; SLC25A46 hereditary motor and sensory neuropathy type 6.

Source of the information. All of it comes from aggregated case reports and small family series. There are no EHR-derived cohorts. A natural-history study is registered: NCT04594590, "Natural History Study of SLC25A46 Mutation-related Mitochondriopathy."

Naming note for curation. MONDO:0014671 and OMIM:616505 refer to the HMSN6B phenotype. The Leigh syndrome and pontocerebellar hypoplasia presentations are best treated as allelic severity strata. They can be modeled as has_subtypes or recorded in the notes, but they should not be described as a separate gene's disease.

2. Etiology

• Causal factor. The cause is genetic: biallelic (homozygous or compound heterozygous) germline variants in SLC25A46. No environmental cause has been described.
• Genetic risk factors. Consanguinity raises risk, since many reported families are consanguineous, including the North African and Middle Eastern families. No susceptibility loci or modifier genes are established.
• Allelic severity correlation. Disease severity correlates inversely with how stable the mutant protein is. Wan et al. (2016) reported that "missense mutations causing lethal congenital pontocerebellar hypoplasia markedly destabilize the protein," and that variants associated with isolated optic atrophy do not cause instability. Abrams et al. (2018, Hum Mutat, PMID:30178502 — confirmed) proposed two pathogenic routes:
• protein destabilization; and
• altered molecular interactions, seen with p.R257Q and p.G249D in a domain not tied to transport function.
• Protective factors and gene–environment interactions. None reported.

3. Phenotypes

Quality of life. Combined visual and motor disability is substantial: legal blindness in advanced optic atrophy, gait impairment, and use of orthotics or wheelchairs in later disease. No validated QoL instrument data have been published for this disease.

Two caveats on the HPO suggestions: - Bind HP:0007108 only where a source documents demyelination. The published electrophysiology is predominantly axonal. - HP:0001337 is "Tremor". It is not a Leigh syndrome term, which is why it carries a question mark in the table. Look up the correct term for Leigh-like lesions before binding anything.

4. Genetic and molecular information

• Gene. SLC25A46, at 5q22.1. It encodes an atypical member of the mitochondrial carrier family (SLC25) that sits in the outer mitochondrial membrane (OMM). It is a distant homolog of yeast Ugo1. Abrams et al. (2015) put it this way: "SLC25A46, like Ugo1, is a modified carrier protein that has been recruited to the outer mitochondrial membrane and interacts with the inner membrane remodeling protein mitofilin (Fcj1)."
• Variant classes reported. Missense variants dominate, including:
• p.T142I, p.R257Q, p.E335D, p.G249D;
• p.L341P (the PCH-associated variant in Wan et al. 2016) [verify];
• p.Trp160Ser, in North African ataxia families.

The other reported classes are frameshift and nonsense variants, a splice-site variant, and exonic deletions (an exonic deletion in a PCH family; Wan et al. 2016). Novel compound-heterozygous variants were found on exome reanalysis in a Leigh-syndrome infant (J Pers Med 2021, PMC8703603). - Classification. Most published variants are listed in ClinVar as Pathogenic or Likely pathogenic. ClinGen gene–disease validity: not found during this search. Check just list-gene-validity and the CGGV records before recording a tier, and do not assign one. - Population frequency. Pathogenic alleles are very rare in gnomAD. There are no common founder alleles, apart from possible local recurrence in North African families. - Origin. Germline. - Functional consequence. Loss of function, in two forms: - many variants destabilize the protein, which is then rapidly removed by the ubiquitin–proteasome system (Steffen et al., Mol Biol Cell 2017, PMID:28057766 [verify]); - milder variants disrupt the SLC25A46–MIC60 complex.

No dominant-negative effect has been reported. - Modifier genes, epigenetics, chromosomal abnormalities. None reported.

5. Environmental information

There are no known environmental, lifestyle or infectious contributors. Not applicable.

6. Mechanism and pathophysiology

Causal chain

1. Biallelic SLC25A46 loss-of-function variants lead to absent, unstable or interaction-defective SLC25A46 protein in the outer mitochondrial membrane.
2. Destabilizing missense variants are degraded by the ubiquitin–proteasome system (Steffen 2017 [verify]; Wan 2016; Janer 2016).
3. Loss of SLC25A46 results in an imbalance of fission and fusion towards MFN1/2-mediated mitochondrial hyperfusion, giving elongated, hyperconnected networks.
4. Shown in patient fibroblasts, knockout cells and zebrafish (Abrams 2015; Janer 2016).
5. SLC25A46 interacts with MFN2 and OPA1. A 2023 Life Science Alliance study in knockout fibroblasts (testing p.T142I, p.R257Q and p.E335D) localized SLC25A46 to discrete foci involved in fission and fusion.
6. A 2024 C. elegans preprint argues instead for a role in promoting fusion through FZO-1. That preprint is not peer-reviewed.
7. Branch A, cristae and membrane lipids. Loss of the SLC25A46–MIC60 (MICOS) interaction leads to abnormal cristae architecture and altered mitochondrial phospholipid composition. Janer et al. (2016) report that SLC25A46 functions upstream of MICOS and is required for cristae maintenance, with changes in ER morphology suggesting a defect at ER–mitochondria contact sites.
8. Branch B, organelle distribution. Enlarged, hyperfused mitochondria lead to impaired axonal transport and abnormal distribution in long axons. This was shown in Slc25a46-knockout mouse neurons (Li et al., Hum Mol Genet 2017;26:3776, PMID:28934388 [verify]).
9. Defective cristae and impaired mitophagy or quality control lead to reduced oxidative phosphorylation. Reported findings include:
10. impaired respiration;
11. reduced respiratory-chain complex activities and a raised lactate:pyruvate ratio in some patient fibroblasts;
12. premature senescence (Janer 2016).

The link between step 4 and the energy deficit is inferred from cell and mouse data. 6. A bioenergetic and trafficking deficit in neurons with long axons and high energy demand results in degeneration of: - retinal ganglion cells and optic nerve axons, causing optic atrophy; - peripheral motor and sensory axons, causing axonal neuropathy; - cerebellar Purkinje cells, causing ataxia and cerebellar atrophy.

All three are shown in knockout mice (Li 2017; Terzenidou et al., PLoS Genet 2017, PMC5380310, PMID:28376086 [verify]). 7. In the most destabilizing genotypes, near-complete loss during brain development leads to pontocerebellar hypoplasia and neonatal death (Wan 2016) or to Leigh syndrome (Janer 2016). The genotype–severity relationship is graded.

Suggested GO, CL and UBERON terms

GO biological processes (look up each one): - GO:0000266 mitochondrial fission - GO:0008053 mitochondrial fusion - GO:0042407 cristae formation - GO:0047497 mitochondrion transport along microtubule - GO:0000423 mitophagy - GO:0006119 oxidative phosphorylation - GO:0007005 mitochondrion organization

GO cellular components: - GO:0005741 mitochondrial outer membrane - GO:0061617 MICOS complex

CL cell types: - CL:0000740 retinal ganglion cell - CL:0000121 Purkinje cell - CL:0000100 motor neuron - CL:0000101 sensory neuron - CL:0000057 fibroblast (patient-derived cell model only)

UBERON anatomy: - UBERON:0000941 cranial nerve II (optic nerve) - UBERON:0001021 nerve (peripheral nerve) - UBERON:0002037 cerebellum - UBERON:0000988 pons

Molecular profiling. No transcriptomic, proteomic, metabolomic or single-cell datasets specific to this disease were found. Lipidomic changes in mitochondria were reported by Janer et al. (2016).

7. Anatomical structures affected

• Primary: the optic nerve and retinal ganglion cells, and peripheral nerves (length-dependent axonal involvement).
• Variable: the cerebellum (Purkinje cells, atrophy) and, in severe forms, the pons, brainstem and basal ganglia.
• Secondary: distal limb musculature (neurogenic atrophy) and the feet (pes cavus).
• Subcellular: the mitochondrial outer membrane, inner-membrane cristae through MICOS, and ER–mitochondria contacts.
• Laterality: bilateral and symmetric.

8. Temporal development

• Onset.
• Classic HMSN6B begins in childhood (often in the first decade) with visual loss and/or gait difficulty.
• Ataxia-predominant forms begin in childhood or adolescence.
• PCH forms are congenital or neonatal.
• Course. Chronic and slowly progressive. There is no remission.
• Duration. Lifelong. The severe forms are lethal in infancy.
• Critical period. In severe genotypes, CNS development (prenatal and neonatal) is the vulnerable window. Natural-history data are being collected under NCT04594590.

9. Inheritance and population

10. Diagnostics

• Electrophysiology. Nerve conduction studies show reduced or absent sensory and motor amplitudes with relatively preserved conduction velocities, i.e. an axonal pattern. EMG shows chronic denervation.
• Ophthalmology. Fundoscopy shows optic disc pallor. OCT shows thinning of the retinal nerve fiber layer. Visual evoked potentials are abnormal.
• Imaging. Brain MRI may show cerebellar atrophy, pontocerebellar hypoplasia in severe cases, or Leigh-type lesions.
• Laboratory. Lactate and the lactate:pyruvate ratio are raised in some patients. Respiratory-chain enzymology in fibroblasts or muscle may show combined deficiency.
• Pathology. Nerve biopsy (where performed) shows axonal loss. In fibroblasts, hyperfused mitochondrial networks support functional confirmation.
• Genetic testing. Exome or genome sequencing, or a CMT/hereditary optic neuropathy panel that includes SLC25A46. Deletion/duplication analysis is needed because exonic deletions have been reported. Confirm biallelic phase by parental testing.
• Differential diagnosis. MFN2-related CMT2A with optic atrophy (CMT6A), OPA1 "plus" disease, Friedreich ataxia, other mitochondrial disorders (POLG, NDUFS), Behr syndrome (OPA1, OPA3), and other forms of pontocerebellar hypoplasia (TSEN, EXOSC3).
• Clinical criteria and screening. There are no formal criteria and no newborn screening. Cascade carrier testing and prenatal or preimplantation diagnosis are available once the familial variants are known.

11. Outcome and prognosis

• Classic HMSN6B: survival into adulthood with progressive visual and motor disability.
• PCH and Leigh forms: death in the neonatal period or infancy (Wan 2016; Janer 2016; J Pers Med 2021).
• Prognostic factor: protein stability of the variant, i.e. destabilizing variants carry a worse outcome (Wan 2016; Abrams 2018).
• Data gaps: no survival statistics or QoL data are available.

12. Treatment

There is no disease-modifying therapy. Management is supportive:

Mitochondrial "cocktails" (coenzyme Q10, riboflavin) have been used empirically, but there is no evidence of benefit. Idebenone, approved for LHON in Europe, has not been studied in this disease. No interventional trials were found; NCT04594590 is an observational natural-history study.

13. Prevention

There is no primary prevention. The available measures are: - genetic counseling, with 25% recurrence risk for carrier parents; - carrier testing of relatives; - prenatal or preimplantation genetic diagnosis; - tertiary care for the feet, falls and vision.

14. Other species and natural disease

• No naturally occurring animal disease is recorded in OMIA (to be confirmed).
• Orthologs:
• mouse Slc25a46;
• zebrafish slc25a46;
• C. elegans slc-25A46;
• yeast UGO1, which is a distant functional analog rather than a strict ortholog.
• The protein's role in mitochondrial dynamics is conserved from yeast (Ugo1 links Fzo1 and Mgm1 in fusion) to vertebrates.

15. Model organisms

Limitations of these models: - The mouse models are more severe than classic human HMSN6B and resemble the PCH end of the spectrum. - No knock-in mice carrying the milder human missense variants have been reported. - No iPSC-derived motor neuron or RGC model was identified.

Key references

Confirmed during this search 1. Abrams AJ et al. Nat Genet 2015;47:926–32. PMID:26168012 2. Janer A et al. EMBO Mol Med 2016;8:1019–38. PMID:27390132 3. Wan J et al. Brain 2016;139:2877–90. PMID:27543974 4. Abrams AJ et al. Hum Mutat 2018. PMID:30178502

PMID still to verify 5. Li Z et al. Hum Mol Genet 2017;26:3776. PMID:28934388 [verify] 6. Terzenidou ME et al. PLoS Genet 2017;13:e1006656. PMID:28376086 [verify] 7. Steffen J et al. Mol Biol Cell 2017. PMID:28057766 [verify] 8. Charlesworth G et al. Mov Disord 2016;31:1249. PMID [verify] 9. Hammer MB et al. Neurodegener Dis 2017;17:208. PMID [verify] 10. Kodal LS et al. Front Neurol 2022. doi:10.3389/fneur.2022.1066040 11. Life Science Alliance 2023;6(6):e202301914. PMID [verify] 12. NCT04594590 (ClinicalTrials.gov)

Sources

• Nature Genetics – Abrams 2015
• Weill Cornell VIVO – PMID 26168012
• Janer 2016 (PMC5009808)
• SGD reference 27390132
• PubMed 27543974 – Wan 2016
• Brain – Wan 2016
• Abrams 2018 (PMC6240357)
• HMG – Loss of SLC25A46 in mice
• eScholarship – mouse paper
• PLoS Genet – Terzenidou 2017
• Reanalysis – Leigh syndrome (PMC8703603)
• UCL Discovery – Charlesworth 2016
• Bordeaux Neurocampus – Hammer 2017
• Frontiers in Neurology – Kodal 2022
• Life Science Alliance 2023
• bioRxiv 2024 – C. elegans
• IntechOpen review chapter
• ClinicalTrials.gov NCT04594590
• WikiPathways WP5521
• GeneCards SLC25A46

Reference Validation

Checked with linkml-reference-validator 0.5.1.

All extracted references resolved successfully.

Term Validation

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

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:0014671 (3 mentions) - the report calls it "MONDO"; MONDO calls it neuropathy, hereditary motor and sensory, type 6B

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:

• HP:0000007 (1 mention) - the report calls it "Autosomal recessive"; HP calls it Autosomal recessive inheritance, and lists "Autosomal recessive" among its other names

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: OMIM, ORPHA.