HMSN6B is an autosomal recessive axonal Charcot-Marie-Tooth neuropathy combined with optic atrophy, caused by biallelic variants in SLC25A46. The gene encodes a highly derived member of the SLC25 mitochondrial carrier family that is unusual in two ways: it sits in the outer mitochondrial membrane rather than the inner one, and it has no identified transported substrate. It is instead the closest human relative of yeast Ugo1, an adaptor of the mitochondrial fusion machinery, and it works as a structural organiser of mitochondrial membrane dynamics. The protein sits at the membrane sites where mitochondria divide and merge, in discrete foci at branch points and tube tips alongside DRP1 and OPA1, and it forms complexes with the fusion GTPases MFN1, MFN2 and OPA1, with the MICOS cristae-organising complex through MIC60, and with the ER membrane protein complex at ER-mitochondria contacts. Losing it therefore breaks three things at once: the fission-fusion balance, so the network becomes hyperfused and hyperfilamentous; cristae architecture, which shortens the folds that house the respiratory complexes; and non-vesicular lipid transfer, which shifts mitochondrial phospholipid composition. The downstream cost is paid by neurons that must deliver and position mitochondria along very long processes. Enlarged, incompletely divided organelles are transported and distributed abnormally, and the cells that fail are the predicted ones: retinal ganglion cells and their optic nerve axons, long peripheral motor and sensory axons, and cerebellar Purkinje cells. Severity tracks how much functional protein a genotype leaves, and it does so through two distinct molecular routes rather than one. Most pathogenic missense variants destabilise the protein, which is then ubiquitylated by MULAN and MARCH5 and stripped from the outer membrane by p97 and the proteasome; the degree of destabilisation tracks disease severity, protein stability itself correlating inversely with it. Milder variants leave protein abundance largely intact and instead disturb a specific interaction, such as the one with MIC60. That graded relationship is why one gene spans a spectrum whose ends are usually named as different diseases: near-complete loss presents as lethal congenital pontocerebellar hypoplasia (PCH1E) or Leigh syndrome, while partially functional alleles give the childhood-onset optic atrophy and axonal neuropathy that this entry covers, and the mildest reported case is an apparently isolated optic neuropathy with only subclinical neuropathy on electrophysiology. This entry is scoped to the neuropathy-with-optic-atrophy rung; PCH1E is curated as a subtype of Pontocerebellar_Hypoplasia. No disease-modifying treatment exists and management is supportive. The one encouraging therapeutic result is preclinical: systemic AAV-PHP.B delivery of Slc25a46 to knockout mice rescued premature death, improved nerve conduction and mobility, and normalised mitochondrial morphology in both central and peripheral nervous tissue. A natural-history study was registered to collect the longitudinal data the disease lacks; its current recruitment status has not been re-checked against the registry.
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Conditions with similar clinical presentations that must be differentiated from SLC25A46-Related Hereditary Motor And Sensory Neuropathy:
name: SLC25A46-Related Hereditary Motor And Sensory Neuropathy
creation_date: "2026-11-03T00:00:00Z"
category: Mendelian
synonyms:
- "neuropathy, hereditary motor and sensory, type 6B"
- "neuropathy, hereditary motor and sensory, type VIB"
- "Charcot-Marie-Tooth disease, type 6B"
- CMT6B
- HMSN6B
- HMSN 6B
- SLC25A46 hereditary motor and sensory neuropathy type 6
- hereditary motor and sensory neuropathy type 6 caused by mutation in SLC25A46
- optic atrophy spectrum disorder
disease_term:
preferred_term: "neuropathy, hereditary motor and sensory, type 6B"
term:
id: MONDO:0014671
label: "neuropathy, hereditary motor and sensory, type 6B"
description: >-
HMSN6B is an autosomal recessive axonal Charcot-Marie-Tooth neuropathy combined
with optic atrophy, caused by biallelic variants in SLC25A46. The gene encodes a
highly derived member of the SLC25 mitochondrial carrier family that is unusual
in two ways: it sits in the outer mitochondrial membrane rather than the inner
one, and it has no identified transported substrate. It is instead the closest
human relative of yeast Ugo1, an adaptor of the mitochondrial fusion machinery,
and it works as a structural organiser of mitochondrial membrane dynamics.
The protein sits at the membrane sites where mitochondria divide and merge, in
discrete foci at branch points and tube tips alongside DRP1 and OPA1, and it
forms complexes with the fusion GTPases MFN1, MFN2 and OPA1, with the MICOS
cristae-organising complex through MIC60, and with the ER membrane protein
complex at ER-mitochondria contacts. Losing it therefore breaks three things at
once: the fission-fusion balance, so the network becomes hyperfused and
hyperfilamentous; cristae architecture, which shortens the folds that house the
respiratory complexes; and non-vesicular lipid transfer, which shifts
mitochondrial phospholipid composition. The downstream cost is paid by neurons
that must deliver and position mitochondria along very long processes. Enlarged,
incompletely divided organelles are transported and distributed abnormally, and
the cells that fail are the predicted ones: retinal ganglion cells and their
optic nerve axons, long peripheral motor and sensory axons, and cerebellar
Purkinje cells.
Severity tracks how much functional protein a genotype leaves, and it does so
through two distinct molecular routes rather than one. Most pathogenic missense
variants destabilise the protein, which is then ubiquitylated by MULAN and
MARCH5 and stripped from the outer membrane by p97 and the proteasome; the
degree of destabilisation tracks disease severity, protein stability itself
correlating inversely with it.
Milder variants leave protein abundance largely intact and instead disturb a
specific interaction, such as the one with MIC60. That graded relationship is
why one gene spans a spectrum whose ends are usually named as different
diseases: near-complete loss presents as lethal congenital pontocerebellar
hypoplasia (PCH1E) or Leigh syndrome, while partially functional alleles give
the childhood-onset optic atrophy and axonal neuropathy that this entry covers,
and the mildest reported case is an apparently isolated optic neuropathy with
only subclinical neuropathy on electrophysiology. This entry is scoped to the
neuropathy-with-optic-atrophy rung; PCH1E is curated as a subtype of
Pontocerebellar_Hypoplasia.
No disease-modifying treatment exists and management is supportive. The one
encouraging therapeutic result is preclinical: systemic AAV-PHP.B delivery of
Slc25a46 to knockout mice rescued premature death, improved nerve conduction and
mobility, and normalised mitochondrial morphology in both central and peripheral
nervous tissue. A natural-history study was registered to collect the longitudinal
data the disease lacks; its current recruitment status has not been re-checked
against the registry.
mappings:
mondo_mappings:
- term:
id: MONDO:0019551
label: hereditary motor and sensory neuropathy type 6
mapping_predicate: skos:broadMatch
mapping_source: MONDO
parents:
- hereditary neurological disease
- peripheral nervous system disease
- mitochondrial disease
classifications:
harrisons_chapter:
- classification_value: NEUROLOGIC
- classification_value: GENETICS_ENVIRONMENT_DISEASE
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Disease requires biallelic SLC25A46 variants, homozygous in the consanguineous
and founder families that dominate the literature and compound heterozygous
otherwise. Heterozygous relatives are unaffected.
evidence:
- reference: PMID:26168012
reference_title: "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
By whole-exome sequencing of patients with optic atrophy and CMT2, we
identified four families with recessive mutations in SLC25A46.
explanation: >-
The founding study establishes recessive inheritance in the four index
families.
- reference: CGGV:assertion_9852fb40-0df1-4668-ba57-38a4971cb244-2020-05-26T160000.000Z
reference_title: "SLC25A46 / neuropathy, hereditary motor and sensory, type 6B (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "SLC25A46 | HGNC:25198 | neuropathy, hereditary motor and sensory, type 6B | MONDO:0014671 | AR | Definitive"
explanation: >-
ClinGen records the mode of inheritance for this gene-disease pair as
autosomal recessive.
references:
- reference: PMID:20301532
title: Charcot-Marie-Tooth Hereditary Neuropathy Overview.
tags:
- GeneReviews
- reference: PMID:26168012
title: "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder."
- reference: PMID:30178502
title: Insights into the genotype-phenotype correlation and molecular function of SLC25A46.
- reference: PMID:28057766
title: Rapid degradation of mutant SLC25A46 by the ubiquitin-proteasome system results in MFN1/2-mediated hyperfusion of mitochondria.
- reference: PMID:27390132
title: SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome.
- reference: PMID:36977595
title: The role of the mitochondrial outer membrane protein SLC25A46 in mitochondrial fission and fusion.
- reference: PMID:39222684
title: Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Opa1 and Mfn2.
- reference: PMID:28934388
title: Loss of SLC25A46 causes neurodegeneration by affecting mitochondrial dynamics and energy production in mice.
- reference: PMID:28376086
title: Novel insights into SLC25A46-related pathologies in a genetic mouse model.
- reference: PMID:31943007
title: Systemic administration of AAV-Slc25a46 mitigates mitochondrial neuropathy in Slc25a46-/- mice.
- reference: PMID:28653766
title: Extension of the phenotype of biallelic loss-of-function mutations in SLC25A46 to the severe form of pontocerebellar hypoplasia type I.
- reference: PMID:28558379
title: SLC25A46 Mutations Associated with Autosomal Recessive Cerebellar Ataxia in North African Families.
- reference: PMID:36578309
title: "Case report: A novel variant in SLC25A46 causing sensorimotor polyneuropathy and optic atrophy."
- reference: PMID:41640504
title: An Apparently Isolated Optic Neuropathy Associated with Biallelic Variants in SLC25A46 Gene Encoding the Mitochondrial Ugo1-Like Protein.
- reference: PMID:26951855
title: Novel pathogenic SLC25A46 splice-site mutation causes an optic atrophy spectrum disorder.
- reference: PMID:40444356
title: SLC-25A46 regulates mitochondrial fusion through the mitofusin protein FZO-1 and is essential for maintaining neuronal morphology.
- reference: PMID:34983179
title: Proteomic Identification of the SLC25A46 Interactome in Transgenic Mice Expressing SLC25A46-FLAG.
pathophysiology:
- name: Biallelic SLC25A46 Loss of Function
description: >-
Homozygous or compound heterozygous SLC25A46 variants remove or cripple a
highly derived SLC25-family protein of the outer mitochondrial membrane. The
protein has no identified transported substrate and is the closest human
relative of yeast Ugo1, an adaptor of the fusion machinery, so the lesion is a
loss of structural organisation of mitochondrial membrane dynamics rather than
loss of a transport activity.
biological_scale: MOLECULAR
genetic_context:
variant_origin: GERMLINE
functional_impact_category: LOSS_OF_FUNCTION
genes:
- preferred_term: SLC25A46
term:
id: hgnc:25198
label: SLC25A46
cellular_components:
- preferred_term: mitochondrial outer membrane
term:
id: GO:0005741
label: mitochondrial outer membrane
molecular_functions:
- preferred_term: adaptor binding to the mitochondrial fusion and MICOS complexes
term:
id: GO:0044877
label: protein-containing complex binding
modifier: DECREASED
evidence:
- reference: PMID:26168012
reference_title: "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We demonstrate that 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).
explanation: >-
Establishes the protein's outer-membrane localisation and Ugo1-like identity,
which is what makes the lesion one of membrane organisation.
- reference: PMID:39222684
reference_title: Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Opa1 and Mfn2.
supports: SUPPORT
quote_role: BACKGROUND
evidence_source: OTHER
snippet: >-
Residing in the outer mitochondrial membrane (OMM), SLC25A46 lacks the
signature sequence motifs of the SLC25 family ( 10 ), does not have an
identified substrate and contains a distinct N-terminal extension.
explanation: >-
States that the protein carries no SLC25 signature motifs and has no known
substrate, so its role is not solute transport.
downstream:
- target: Destabilization and Proteasomal Degradation of SLC25A46
causal_link_type: DIRECT
description: >-
Most pathogenic missense alleles act by destabilising the protein rather than
by abolishing a catalytic activity.
evidence:
- reference: PMID:30178502
reference_title: Insights into the genotype-phenotype correlation and molecular function of SLC25A46.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
By studying seven different nontruncating mutations, we found that the
stability of the SLC25A46 protein inversely correlates with the severity of
the disease and the patient's variant does not markedly destabilize the
protein.
explanation: >-
Establishes the inverse relationship between protein stability and severity
across seven non-truncating alleles, which is what makes destabilisation the
route from variant to loss of function. Note the same sentence records that
this patient's mild allele does not markedly destabilise the protein, which
is the second route recorded on the other edge.
- target: Loss of SLC25A46 at Mitochondrial Fission and Fusion Sites
causal_link_type: DIRECT
description: >-
Milder alleles leave abundance largely intact and instead disturb a specific
partner interaction, so the functional endpoint is reached without
degradation.
evidence:
- reference: PMID:30178502
reference_title: Insights into the genotype-phenotype correlation and molecular function of SLC25A46.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We thus suggest that there are two distinct molecular mechanisms in
SLC25A46-associated pathogenesis, one that destabilizes the protein while
the other alters the molecular interactions of the protein.
explanation: >-
Supports a second, degradation-independent route from the variant to loss
of function at the membrane.
- name: Destabilization and Proteasomal Degradation of SLC25A46
description: >-
Destabilising variants are ubiquitylated at the outer membrane by the E3
ligases MULAN and MARCH5 and extracted and degraded by p97 and the proteasome.
This proteolysis runs independently of mitophagy and of apoptotic outer-membrane
stress pathways, so the protein is removed without the organelle being turned
over.
biological_scale: MOLECULAR
biological_processes:
- preferred_term: proteasomal degradation of mutant SLC25A46
term:
id: GO:0043161
label: proteasome-mediated ubiquitin-dependent protein catabolic process
modifier: INCREASED
evidence:
- reference: PMID:28057766
reference_title: Rapid degradation of mutant SLC25A46 by the ubiquitin-proteasome system results in MFN1/2-mediated hyperfusion of mitochondria.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The E3 ubiquitin ligases MULAN and MARCH5 coordinate ubiquitylation of
SLC25A46 L341P, leading to degradation by organized activities of P97 and the
proteasome.
explanation: >-
Names the ligases and the extraction/degradation machinery that clear the
destabilised protein.
notes: >-
The allele characterised in this pathway, L341P, is one that causes the severe
pontocerebellar hypoplasia end of the spectrum rather than this entry's
phenotype. The degradation route is cited here as the general mechanism by
which a destabilising SLC25A46 missense allele is cleared; the severity that
follows depends on how much protein a given genotype leaves.
downstream:
- target: Loss of SLC25A46 at Mitochondrial Fission and Fusion Sites
causal_link_type: DIRECT
- name: Loss of SLC25A46 at Mitochondrial Fission and Fusion Sites
description: >-
SLC25A46 normally occupies discrete foci at mitochondrial branch points and tube
tips together with DRP1 and OPA1, and essentially every fission or fusion event
is marked by such a focus. It is a hub in three complexes at once: with the
fusion GTPases MFN1, MFN2 and OPA1, with the MICOS cristae-organising complex
through MIC60, and with the ER membrane protein complex at ER-mitochondria
contacts. Losing it therefore disrupts dynamics, cristae and lipid handling
together rather than one at a time.
biological_scale: MOLECULAR
biological_processes:
- preferred_term: mitochondrial fission
term:
id: GO:0000266
label: mitochondrial fission
modifier: DECREASED
cellular_components:
- preferred_term: mitochondrial outer membrane
term:
id: GO:0005741
label: mitochondrial outer membrane
evidence:
- reference: PMID:36977595
reference_title: The role of the mitochondrial outer membrane protein SLC25A46 in mitochondrial fission and fusion.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
SLC25A46 was present in discrete puncta at mitochondrial branch points and
tips of mitochondrial tubules, co-localizing with DRP1 and OPA1.
explanation: >-
Places the protein physically at the membrane sites where fission and fusion
occur.
- reference: PMID:36977595
reference_title: The role of the mitochondrial outer membrane protein SLC25A46 in mitochondrial fission and fusion.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Virtually, all fission/fusion events were demarcated by a SLC25A46 focus."
explanation: >-
Shows the localisation is not incidental: the protein marks the remodelling
events themselves.
- reference: PMID:27390132
reference_title: SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
SLC25A46 is an integral outer membrane protein that interacts with MFN2,
OPA1, and the mitochondrial contact site and cristae organizing system
(MICOS) complex.
explanation: >-
Establishes the three partner complexes whose simultaneous loss defines this
node.
- reference: PMID:26168012
reference_title: "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "our data supports that unlike Ugo1, SLC25A46 acts in a pro-fission manner"
explanation: >-
The founding study's pro-fission conclusion, which is what the DECREASED
modifier on mitochondrial fission above asserts. That reading is disputed; the
fission-versus-fusion discussion cites the evidence against it.
downstream:
- target: Dysregulated MFN1/MFN2 and OPA1 Oligomerization
causal_link_type: DIRECT
evidence:
- reference: PMID:36977595
reference_title: The role of the mitochondrial outer membrane protein SLC25A46 in mitochondrial fission and fusion.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
SLC25A46 co-immunoprecipitated with the fusion machinery, and loss of
function altered the oligomerization state of OPA1 and MFN2.
explanation: >-
Directly links loss of SLC25A46 to a changed oligomeric state of the fusion
GTPases.
- target: Disrupted MICOS Complex and Cristae Architecture
causal_link_type: DIRECT
evidence:
- reference: PMID:27390132
reference_title: SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The MICOS complex is disrupted in subject fibroblasts, resulting in
strikingly abnormal mitochondrial architecture, with markedly shortened
cristae.
explanation: >-
Shows MICOS disruption and the cristae consequence in patient-derived cells.
- target: Impaired Interorganellar Lipid Transfer at ER-Mitochondria Contacts
causal_link_type: DIRECT
evidence:
- reference: PMID:27390132
reference_title: SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
SLC25A46 also interacts with the ER membrane protein complex EMC, and
phospholipid composition is altered in subject mitochondria.
explanation: >-
Connects the protein's ER-contact interaction to a measured change in
mitochondrial phospholipid.
- name: Dysregulated MFN1/MFN2 and OPA1 Oligomerization
description: >-
Without SLC25A46, MFN1 and MFN2 accumulate on the outer membrane in a more
stable, oligomeric state, and OPA1's oligomeric state shifts as well. The
fission-fusion balance moves toward unopposed fusion.
biological_scale: MOLECULAR
biological_processes:
- preferred_term: mitochondrial fusion
term:
id: GO:0008053
label: mitochondrial fusion
modifier: INCREASED
evidence:
- reference: PMID:28057766
reference_title: Rapid degradation of mutant SLC25A46 by the ubiquitin-proteasome system results in MFN1/2-mediated hyperfusion of mitochondria.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Decreased expression of SLC25A46 results in increased stability and
oligomerization of MFN1 and MFN2 on mitochondria, promoting mitochondrial
hyperfusion.
explanation: >-
States the mechanistic step from reduced SLC25A46 to mitofusin oligomerisation
and hyperfusion.
downstream:
- target: Aberrant Mitochondrial Network Morphology
causal_link_type: DIRECT
- name: Impaired Interorganellar Lipid Transfer at ER-Mitochondria Contacts
description: >-
SLC25A46 is present at interorganellar contact sites and partners with the ER
membrane protein complex and lipid transfer proteins, placing it in a
mitochondrial/ER pathway for non-vesicular lipid movement. Loss of function
shifts mitochondrial lipid composition.
biological_scale: MOLECULAR
conforms_to: "membrane_contact_site_dysfunction#Disrupted Non-Vesicular Lipid Transfer Between Organelles"
biological_processes:
- preferred_term: phospholipid transfer between the ER and mitochondria
term:
id: GO:0015914
label: phospholipid transport
modifier: DECREASED
evidence:
- reference: PMID:36977595
reference_title: The role of the mitochondrial outer membrane protein SLC25A46 in mitochondrial fission and fusion.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Proximity interaction mapping identified components of the ER membrane, lipid
transfer proteins, and mitochondrial outer membrane proteins, indicating that
it is present at interorganellar contact sites.
explanation: >-
Places the protein at ER-mitochondria contact sites alongside lipid transfer
machinery.
- reference: PMID:27390132
reference_title: SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
These results show that SLC25A46 plays a role in a mitochondrial/ER pathway
that facilitates lipid transfer, and link altered mitochondrial dynamics to
early-onset neurodegenerative disease and cell fate decisions.
explanation: >-
States the lipid-transfer role this node asserts.
downstream:
- target: Altered Mitochondrial Phospholipid Composition
causal_link_type: DIRECT
- name: Altered Mitochondrial Phospholipid Composition
description: >-
Mitochondrial phospholipid composition is altered in patient fibroblasts and in
knockout cells. Because cristae shape depends on lipid composition as well as on
MICOS, this feeds back into the architectural defect rather than standing apart
from it.
biological_scale: CELLULAR
conforms_to: "membrane_contact_site_dysfunction#Organelle Membrane Lipid Imbalance"
evidence:
- reference: PMID:36977595
reference_title: The role of the mitochondrial outer membrane protein SLC25A46 in mitochondrial fission and fusion.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
SLC25A46 loss of function led to altered mitochondrial lipid composition,
suggesting that it may facilitate interorganellar lipid flux or play a role in
membrane remodeling associated with mitochondrial fusion and fission.
explanation: >-
Reports the measured lipid change on loss of function.
downstream:
- target: Disrupted MICOS Complex and Cristae Architecture
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Lipid composition and MICOS both shape cristae, so the lipid defect compounds
the architectural one. The ordering between them is not established.
- name: Disrupted MICOS Complex and Cristae Architecture
description: >-
The MICOS complex is disrupted and cristae are markedly shortened in patient
fibroblasts, and the cristae defect in knockout cells is not rescued by
re-expressing pathogenic variants. Since cristae membranes house the
respiratory-chain complexes, this is the structural lesion behind the
bioenergetic deficit.
biological_scale: CELLULAR
biological_processes:
- preferred_term: cristae formation
term:
id: GO:0042407
label: cristae formation
modifier: DECREASED
protein_complexes:
- preferred_term: MICOS complex
term:
id: GO:0061617
label: MICOS complex
evidence:
- reference: PMID:36977595
reference_title: The role of the mitochondrial outer membrane protein SLC25A46 in mitochondrial fission and fusion.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The loss of SLC25A46 led to abnormalities in the mitochondrial cristae
ultrastructure that were not rescued by the expression of the variants.
explanation: >-
Shows the cristae defect and that pathogenic variants fail to correct it.
- reference: PMID:30178502
reference_title: Insights into the genotype-phenotype correlation and molecular function of SLC25A46.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We demonstrate that the patient's mutation directly affects the SLC25A46 interaction with MIC60."
explanation: >-
Links a mild patient allele specifically to the MIC60 interaction that
organises cristae.
downstream:
- target: Respiratory Chain Deficiency and Bioenergetic Failure
causal_link_type: DIRECT
- name: Aberrant Mitochondrial Network Morphology
description: >-
Patient fibroblasts carry a hyper-filamentous, interconnected network, and
mitochondria are hyperfused in cells expressing pathogenic variants. Electron
microscopy shows constriction sites that look like stalled fission
intermediates, so the elongation reflects delayed division rather than a faster
fusion rate.
biological_scale: CELLULAR
biological_processes:
- preferred_term: mitochondrion organization
term:
id: GO:0007005
label: mitochondrion organization
modifier: ABNORMAL
cell_types:
- preferred_term: patient-derived dermal fibroblast
term:
id: CL:0000057
label: fibroblast
evidence:
- reference: PMID:26168012
reference_title: "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We further examined fibroblasts from proband IT II-3, which display a
hyper-filamentous and interconnected network in comparison to both, the
unaffected sibling IT II-2 and control, indicating the relevance of this
phenomenon
explanation: >-
Demonstrates the morphological abnormality in cells from an affected patient
against an unaffected sibling.
- reference: PMID:36977595
reference_title: The role of the mitochondrial outer membrane protein SLC25A46 in mitochondrial fission and fusion.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Mitochondria were fragmented in the knock-out cell line and hyperfused in all pathogenic variants."
explanation: >-
Reports hyperfusion for pathogenic variants, and records that complete
knockout gives the opposite morphology.
- reference: PMID:26168012
reference_title: "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
no significant difference in the fusion rates between control and knockdown
cells
explanation: >-
The photoactivation result behind this node's claim that the elongation
reflects delayed division rather than a faster fusion rate: fusion rate itself
did not change on knockdown.
notes: >-
The direction of the morphological change is not uniform across models.
Patient-derived cells and pathogenic missense variants give hyperfusion, whereas
a complete knockout cell line gives fragmentation, and the worm mutants
fragment as well. This is the observational face of the unresolved
fission-versus-fusion question recorded in the discussions section.
downstream:
- target: Impaired Mitochondrial Transport and Distribution in Neuronal Processes
causal_link_type: DIRECT
- name: Respiratory Chain Deficiency and Bioenergetic Failure
description: >-
Patient fibroblasts consume less oxygen and shift toward glycolysis, and
knockout mice show impaired electron transport chain activity. The deficit is
modest in the mild genotypes this entry covers, which is consistent with a
muscle biopsy showing no ragged red or COX-negative fibres in an index patient.
biological_scale: CELLULAR
biological_processes:
- preferred_term: oxidative phosphorylation
term:
id: GO:0006119
label: oxidative phosphorylation
modifier: DECREASED
evidence:
- reference: PMID:26168012
reference_title: "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
patient IT II-3 fibroblasts show decreased oxygen consumption rate (OCR) and
a glycolytic shift of metabolism (decreased OCR/ECAR ratio)
explanation: >-
Measures reduced respiration and the glycolytic shift in patient cells.
- reference: PMID:28934388
reference_title: Loss of SLC25A46 causes neurodegeneration by affecting mitochondrial dynamics and energy production in mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Biochemically mutant mice showed impaired electron transport chain activity and accumulated autophagy markers."
explanation: >-
Confirms a respiratory-chain deficit in vivo in the knockout mouse.
- reference: PMID:26168012
reference_title: "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
analysis of a muscle biopsy from patient IT II-3 found no ragged red fibers or
cytochrome c oxidase (COX)-negative fibers
explanation: >-
Bounds the size of the deficit in the mild genotypes this entry covers: no
histological hallmark of mitochondrial myopathy was present in an index
patient.
downstream:
- target: Distal Axonal Degeneration of Long Peripheral Nerves
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Retinal Ganglion Cell and Optic Nerve Axon Degeneration
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Cerebellar Purkinje Cell Degeneration
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Mitochondrial Transport and Distribution in Neuronal Processes
description: >-
Enlarged, incompletely divided mitochondria are transported and positioned
abnormally in neurons. In knockout mouse cerebellar neurons the organelles are
large and both their distribution and transport are abnormal, and in zebrafish
morphants mitochondria in degenerating motor neurons relocate within the soma
and aggregate instead of clustering at the axon initial segment. This is the
step that converts a generic organelle defect into a length-dependent one.
biological_scale: CELLULAR
conforms_to: "peripheral_axonal_degeneration#Axonal Transport Impairment and Mitochondrial Dysfunction"
biological_processes:
- preferred_term: mitochondrion transport along microtubule
term:
id: GO:0047497
label: mitochondrion transport along microtubule
modifier: DECREASED
- preferred_term: mitochondrion localization
term:
id: GO:0051646
label: mitochondrion localization
modifier: ABNORMAL
cell_types:
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
evidence:
- reference: PMID:28934388
reference_title: Loss of SLC25A46 causes neurodegeneration by affecting mitochondrial dynamics and energy production in mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Mutant cerebellar neurons have large mitochondria, which exhibit abnormal distribution and transport."
explanation: >-
Reports the transport and distribution defect in neurons lacking SLC25A46.
- reference: PMID:26168012
reference_title: "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "Incomplete fission of mitochondria could inhibit transport and distribution into neuronal processes"
explanation: >-
The founding study's own interpretation linking stalled fission to impaired
delivery into neuronal processes. Graded INDIRECT because the sentence is
offered as a proposed explanation of the electron-microscopy finding rather
than as a measurement of transport.
downstream:
- target: Distal Axonal Degeneration of Long Peripheral Nerves
causal_link_type: DIRECT
- target: Retinal Ganglion Cell and Optic Nerve Axon Degeneration
causal_link_type: DIRECT
- target: Cerebellar Purkinje Cell Degeneration
causal_link_type: DIRECT
- name: Distal Axonal Degeneration of Long Peripheral Nerves
description: >-
The longest motor and sensory axons degenerate in a dying-back pattern, giving
the axonal CMT2 phenotype. Zebrafish morphant motor axons show blebbing and
dying back at their terminals, and knockout mice have electrophysiologically
confirmed peripheral neuropathy with axonal degeneration.
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
biological_processes:
- preferred_term: maintenance of peripheral axons
term:
id: GO:1990535
label: neuron projection maintenance
modifier: DECREASED
evidence:
- reference: PMID:26168012
reference_title: "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
By stochastically labeling the motor neurons, we frequently observed axonal
blebbing and dying back at the morphant motor neuron terminals specifying
degeneration, which is consistent with the pathology of CMT2
explanation: >-
Demonstrates distal, dying-back motor axon degeneration on loss of the
orthologue.
- reference: PMID:28934388
reference_title: Loss of SLC25A46 causes neurodegeneration by affecting mitochondrial dynamics and energy production in mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Compound muscle action potentials in peripheral nerves showed peripheral
neuropathy associated with degeneration and demyelination in axons.
explanation: >-
Confirms peripheral neuropathy with axonal degeneration in the knockout mouse.
downstream:
- target: Axonal sensorimotor peripheral neuropathy
causal_link_type: DIRECT
- target: Distal muscle weakness
causal_link_type: DIRECT
- target: Distal sensory impairment
causal_link_type: DIRECT
- target: Distal amyotrophy
causal_link_type: DIRECT
- target: Areflexia
causal_link_type: DIRECT
- target: Pes cavus
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- target: Scoliosis
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Axial deformity following long-standing childhood-onset neuromuscular
weakness, through trunk muscle imbalance rather than directly.
- target: Decreased compound muscle action potential amplitude
causal_link_type: DIRECT
- name: Retinal Ganglion Cell and Optic Nerve Axon Degeneration
description: >-
Retinal ganglion cells and their optic nerve axons are among the most vulnerable
targets, consistent with the transcript's enrichment in those cells. Knockout
mice lose retinal ganglion cells and accumulate small, unmyelinated and
degenerated optic nerve axons.
biological_scale: TISSUE
cell_types:
- preferred_term: retinal ganglion cell
term:
id: CL:0000740
label: retinal ganglion cell
locations:
- preferred_term: optic nerve
term:
id: UBERON:0000941
label: cranial nerve II
evidence:
- reference: PMID:28934388
reference_title: Loss of SLC25A46 causes neurodegeneration by affecting mitochondrial dynamics and energy production in mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Increased numbers of small, unmyelinated and degenerated optic nerves as well
as loss of retinal ganglion cells indicated optic atrophy.
explanation: >-
Reports the retinal ganglion cell loss and optic nerve axonal pathology behind
optic atrophy.
- reference: PMID:26168012
reference_title: "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: >-
we found enrichment in retinal ganglion cells (RGCs) and their corresponding
neuronal projections in the axons of the optic nerve and in the dendrites of
the inner plexiform
explanation: >-
Expression enrichment in exactly the cells that degenerate. INDIRECT because
enrichment indicates vulnerability rather than demonstrating degeneration.
downstream:
- target: Optic atrophy
causal_link_type: DIRECT
- target: Reduced visual acuity
causal_link_type: DIRECT
- target: Optic disc pallor
causal_link_type: DIRECT
- name: Cerebellar Purkinje Cell Degeneration
description: >-
Purkinje cells degenerate, producing the cerebellar ataxia and cerebellar
atrophy that accompany the core neuropathy in many patients and dominate the
ataxia-predominant presentations. Both independent mouse models show it, one
with frank disruption of cerebellar cytoarchitecture.
biological_scale: TISSUE
conforms_to: "cerebellar_purkinje_degeneration#Purkinje Neuron Degeneration"
cell_types:
- preferred_term: Purkinje cell
term:
id: CL:0000121
label: Purkinje cell
locations:
- preferred_term: cerebellum
term:
id: UBERON:0002037
label: cerebellum
evidence:
- reference: PMID:28934388
reference_title: Loss of SLC25A46 causes neurodegeneration by affecting mitochondrial dynamics and energy production in mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Mice lacking SLC25A46 displayed severe ataxia, mainly caused by degeneration of Purkinje cells."
explanation: >-
Attributes the ataxia specifically to Purkinje cell degeneration.
- reference: PMID:28376086
reference_title: Novel insights into SLC25A46-related pathologies in a genetic mouse model.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Histopathological analysis revealed previously unseen lesions, most notably
disrupted cytoarchitecture in the cerebellum and retina and prominent
abnormalities in the neuromuscular junction.
explanation: >-
An independent mouse model showing disrupted cerebellar and retinal
cytoarchitecture.
downstream:
- target: Gait ataxia
causal_link_type: DIRECT
- target: Cerebellar atrophy
causal_link_type: DIRECT
- target: Dysarthria
causal_link_type: DIRECT
- target: Nystagmus
causal_link_type: DIRECT
description: >-
Cerebellar nystagmus with saccadic pursuit, reported as the only ocular
finding in a patient without optic atrophy, which separates it from the optic
nerve arm of the mechanism.
phenotypes:
- name: Optic atrophy
category: Ophthalmologic
frequency: VERY_FREQUENT
description: >-
The defining feature and the one most consistently present across the whole
allelic spectrum, typically beginning in the first decade and progressing.
Single reported patients lack a detectable neuropathy but still have optic
atrophy, and ClinGen records that contrast explicitly.
phenotype_term:
preferred_term: Optic atrophy
term:
id: HP:0000648
label: Optic atrophy
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:26168012
reference_title: "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients in these four families presented with similar phenotypic core
features including optic atrophy, axonal CMT, as well as cerebellar atrophy
explanation: >-
Places optic atrophy among the core features in all four founding families.
- reference: CGGV:assertion_9852fb40-0df1-4668-ba57-38a4971cb244-2020-05-26T160000.000Z
reference_title: "SLC25A46 / neuropathy, hereditary motor and sensory, type 6B (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
In contrast to optic atrophy, single cases have been reported without a
detectable neuropathy at the date of examination
explanation: >-
ClinGen's own scope statement, which treats optic atrophy as the more
constant of the two core features.
- name: Axonal sensorimotor peripheral neuropathy
category: Neurologic
frequency: VERY_FREQUENT
description: >-
A length-dependent axonal sensorimotor polyneuropathy of CMT2 type, with
severity varying between siblings carrying the same genotype. It can be
subclinical and detectable only on electrophysiology at the mildest end.
phenotype_term:
preferred_term: Peripheral axonal neuropathy
term:
id: HP:0003477
label: Peripheral axonal neuropathy
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:36578309
reference_title: "Case report: A novel variant in SLC25A46 causing sensorimotor polyneuropathy and optic atrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The neurological examination and nerve conduction studies were consistent
with sensorimotor polyneuropathy, one having mild polyneuropathy and the other
pronounced polyneuropathy.
explanation: >-
Documents the sensorimotor polyneuropathy and its variable severity within one
sibship.
- reference: PMID:41640504
reference_title: An Apparently Isolated Optic Neuropathy Associated with Biallelic Variants in SLC25A46 Gene Encoding the Mitochondrial Ugo1-Like Protein.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The presence of a subclinical peripheral neuropathy revealed by
electroneuromyography confirmed the responsibility of these SLC25A46 variants.
explanation: >-
Shows the neuropathy can be subclinical and found only on electrophysiology.
- name: Distal muscle weakness
category: Neurologic
frequency: FREQUENT
description: >-
Length-dependent weakness of the distal limbs following motor axon loss, with
wasting of the lower limbs recorded in the recurrent p.Arg340Cys genotype.
phenotype_term:
preferred_term: Distal muscle weakness
term:
id: HP:0002460
label: Distal muscle weakness
evidence:
- reference: PMID:28558379
reference_title: SLC25A46 Mutations Associated with Autosomal Recessive Cerebellar Ataxia in North African Families.
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
While the previously reported variant p.Arg340Cys seems to be consistently
associated with the same clinical features such as childhood onset, optic
atrophy, gait and speech difficulties, and wasting of the lower limbs
explanation: >-
Records consistent lower-limb wasting in this recurrent genotype. INDIRECT
because wasting is not weakness: the weakness follows from the motor axon loss
that produces the wasting, and no cited source grades strength directly.
- name: Distal sensory impairment
category: Neurologic
frequency: FREQUENT
description: >-
Distal sensory loss accompanying the motor deficit, part of the sensorimotor
pattern confirmed on nerve conduction studies.
phenotype_term:
preferred_term: Distal sensory impairment
term:
id: HP:0002936
label: Distal sensory impairment
evidence:
- reference: PMID:36578309
reference_title: "Case report: A novel variant in SLC25A46 causing sensorimotor polyneuropathy and optic atrophy."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
The neurological examination and nerve conduction studies were consistent
with sensorimotor polyneuropathy, one having mild polyneuropathy and the other
pronounced polyneuropathy.
explanation: >-
A sensorimotor polyneuropathy entails a sensory component; graded INDIRECT
because the source names the pattern rather than the distal sensory findings
themselves.
- name: Distal amyotrophy
category: Musculoskeletal
frequency: FREQUENT
description: >-
Neurogenic wasting of distal limb muscles, most evident in the lower limbs.
phenotype_term:
preferred_term: Distal amyotrophy
term:
id: HP:0003693
label: Distal amyotrophy
evidence:
- reference: PMID:30178502
reference_title: Insights into the genotype-phenotype correlation and molecular function of SLC25A46.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There was wasting distally in the lower limbs."
explanation: >-
States the distal distribution of the wasting, which is what this phenotype
asserts.
- reference: PMID:28558379
reference_title: SLC25A46 Mutations Associated with Autosomal Recessive Cerebellar Ataxia in North African Families.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "optic atrophy, gait and speech difficulties, and wasting of the lower limbs"
explanation: >-
Independent report of lower-limb wasting in the recurrent p.Arg340Cys
genotype.
- name: Areflexia
category: Neurologic
description: >-
Absent deep tendon reflexes, the expected consequence of large-fibre axonal
loss. Reported as unelicitable rather than merely reduced on examination of a
6-year-old proband, which is why this is bound to Areflexia rather than to its
sibling term Hyporeflexia.
phenotype_term:
preferred_term: Areflexia
term:
id: HP:0001284
label: Areflexia
evidence:
- reference: PMID:30178502
reference_title: Insights into the genotype-phenotype correlation and molecular function of SLC25A46.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "deep tendon reflexes could not be elicited"
explanation: >-
Examination finding of absent deep tendon reflexes in a patient with this
disease.
- name: Pes cavus
category: Musculoskeletal
description: >-
The cavus foot deformity characteristic of childhood-onset CMT, arising from
length-dependent imbalance between intrinsic and extrinsic foot muscles.
Reported in the recurrent p.Arg340Cys genotype and, as hollow feet, in the North
African ataxia families.
phenotype_term:
preferred_term: Pes cavus
term:
id: HP:0001761
label: Pes cavus
evidence:
- reference: PMID:28558379
reference_title: SLC25A46 Mutations Associated with Autosomal Recessive Cerebellar Ataxia in North African Families.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Skeletal abnormalities such as scoliosis and hollow feet were found."
explanation: >-
Hollow feet is the cavus deformity this phenotype records.
- reference: PMID:30178502
reference_title: Insights into the genotype-phenotype correlation and molecular function of SLC25A46.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "- Ataxia and stepping gait - Severe lower limb hypotrophy - Pes cavus"
explanation: >-
The genotype table names Pes cavus explicitly in the p.Arg340Cys patient.
- name: Scoliosis
category: Musculoskeletal
description: >-
Reported with the cavus foot deformity in the North African ataxia families, the
expected axial consequence of long-standing childhood-onset neuromuscular
weakness. No cited source states a frequency.
phenotype_term:
preferred_term: Scoliosis
term:
id: HP:0002650
label: Scoliosis
evidence:
- reference: PMID:28558379
reference_title: SLC25A46 Mutations Associated with Autosomal Recessive Cerebellar Ataxia in North African Families.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Skeletal abnormalities such as scoliosis and hollow feet were found."
explanation: >-
Names scoliosis directly in these patients.
- name: Decreased compound muscle action potential amplitude
category: Neurologic
description: >-
Conduction studies show an axonal rather than demyelinating pattern in patients:
motor and sensory amplitudes fall, with responses lost altogether in the longest
nerves, while conduction velocities are mostly preserved. Mostly, not entirely,
because slowing has been reported in individual nerves of an affected sibling.
The knockout mouse, by contrast, shows degeneration together with demyelination,
which is one of the ways the model is more severe than the human disease.
phenotype_term:
preferred_term: Decreased compound muscle action potential amplitude
term:
id: HP:0033383
label: Decreased compound muscle action potential amplitude
evidence:
- reference: PMID:36578309
reference_title: "Case report: A novel variant in SLC25A46 causing sensorimotor polyneuropathy and optic atrophy."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
A nerve conduction study showed reduced amplitude in median nerves, loss of
response in sural nerves, and severely reduced and no certain motor response in
right and left tibial nerves.
explanation: >-
States the reduced amplitudes, and their length-dependent gradient, that this
phenotype asserts.
- reference: PMID:36578309
reference_title: "Case report: A novel variant in SLC25A46 causing sensorimotor polyneuropathy and optic atrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "slowed conduction velocity in both ulnar nerves"
explanation: >-
Records that velocity slowing does occur in individual nerves, which is why the
description says velocities are mostly rather than entirely preserved.
- reference: PMID:30178502
reference_title: Insights into the genotype-phenotype correlation and molecular function of SLC25A46.
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
Repeat nerve conduction studies confirmed a chronic axonal peripheral motor
neuropathy
explanation: >-
Establishes the axonal character of the neuropathy. INDIRECT because reduced
amplitude follows from an axonal pattern rather than being stated.
- reference: PMID:31943007
reference_title: Systemic administration of AAV-Slc25a46 mitigates mitochondrial neuropathy in Slc25a46-/- mice.
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: >-
The treatment-improved electronic conductivity of the peripheral nerves
increased mobility and restored mitochondrial complex activities.
explanation: >-
Conduction is impaired in the untreated knockout and improves on gene
replacement, which ties the abnormality to the lesion. INDIRECT because it is
a rescue result in a mouse rather than a measurement in patients.
notes: >-
Bound to an amplitude term rather than to a nerve-conduction-velocity term. The
human electrophysiology is an axonal pattern, in which amplitudes fall and
velocities are relatively preserved, so any velocity term would either misstate
the finding (Decreased motor nerve conduction velocity, HP:0003431) or say
almost nothing (the parent Abnormal nerve conduction velocity, HP:0040129).
Amplitude is what the axonal pattern actually changes.
- name: Gait ataxia
category: Neurologic
frequency: FREQUENT
description: >-
Cerebellar gait ataxia, variable in the core HMSN6B presentation and dominant in
the ataxia-predominant families. Gait difficulty in this disease has two
contributors, the cerebellar lesion and the peripheral neuropathy.
phenotype_term:
preferred_term: Gait ataxia
term:
id: HP:0002066
label: Gait ataxia
evidence:
- reference: PMID:30178502
reference_title: Insights into the genotype-phenotype correlation and molecular function of SLC25A46.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the patient demonstrated a wide-based, ataxic gait"
explanation: >-
Direct examination finding of ataxic gait in a patient with this disease.
- reference: PMID:28558379
reference_title: SLC25A46 Mutations Associated with Autosomal Recessive Cerebellar Ataxia in North African Families.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
To identify the genetic origin of the cerebellar ataxia for 3 consanguineous
North African families presenting with ARCA
explanation: >-
These families were recruited for autosomal recessive cerebellar ataxia and
the cause was found to be SLC25A46, which establishes ataxia as part of the
phenotype rather than an incidental finding.
- name: Cerebellar atrophy
category: Neurologic
frequency: FREQUENT
description: >-
Cerebellar atrophy on MRI, present in the founding families but absent in the
mildest reported patients, so it is a frequent rather than obligate feature.
phenotype_term:
preferred_term: Cerebellar atrophy
term:
id: HP:0001272
label: Cerebellar atrophy
evidence:
- reference: PMID:26168012
reference_title: "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients in these four families presented with similar phenotypic core
features including optic atrophy, axonal CMT, as well as cerebellar atrophy
explanation: >-
Names cerebellar atrophy among the core features of the founding cohort.
- reference: PMID:30178502
reference_title: Insights into the genotype-phenotype correlation and molecular function of SLC25A46.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We report a patient with optic atrophy, peripheral neuropathy, ataxia, but
not cerebellar atrophy, who is on the mildest end of the phenotypic spectrum.
explanation: >-
Documents a mild-end patient with ataxia but no cerebellar atrophy, which is
why this phenotype is graded FREQUENT rather than VERY_FREQUENT. It supports
the claim as written, which is that the finding is frequent but not
obligate.
- name: Dysarthria
category: Neurologic
description: >-
Speech difficulty of cerebellar type, recorded with gait difficulty in the
recurrent p.Arg340Cys genotype.
phenotype_term:
preferred_term: Dysarthria
term:
id: HP:0001260
label: Dysarthria
evidence:
- reference: PMID:28558379
reference_title: SLC25A46 Mutations Associated with Autosomal Recessive Cerebellar Ataxia in North African Families.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "childhood onset, optic atrophy, gait and speech difficulties, and wasting of the lower limbs"
explanation: >-
Names speech difficulty among the consistent features of this genotype.
- name: Reduced visual acuity
category: Ophthalmologic
description: >-
Progressive loss of visual acuity following optic nerve axonal loss, reported
from childhood onward. The cited reports describe the course as slowly
progressive and do not quantify endpoint acuity, so no degree of impairment is
asserted here.
phenotype_term:
preferred_term: Reduced visual acuity
term:
id: HP:0007663
label: Reduced visual acuity
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:28558379
reference_title: SLC25A46 Mutations Associated with Autosomal Recessive Cerebellar Ataxia in North African Families.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The eye exam revealed bilateral divergent strabismus, a decrease in visual
acuity and an optic atrophy in both eyes.
explanation: >-
Direct examination finding of reduced visual acuity alongside the optic
atrophy.
- reference: PMID:28558379
reference_title: SLC25A46 Mutations Associated with Autosomal Recessive Cerebellar Ataxia in North African Families.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "presented at age 6 with a decrease in visual acuity"
explanation: >-
Records childhood onset of the acuity loss in a second patient.
- reference: PMID:41640504
reference_title: An Apparently Isolated Optic Neuropathy Associated with Biallelic Variants in SLC25A46 Gene Encoding the Mitochondrial Ugo1-Like Protein.
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
We here report the case of a 26-year-old female patient with a slowly
progressive and apparently isolated form of optic neuropathy
explanation: >-
Establishes the slowly progressive course. INDIRECT because the sentence names
the optic neuropathy rather than the acuity measurement.
- name: Optic disc pallor
category: Ophthalmologic
description: >-
Pallor of the optic disc on fundoscopy, the ophthalmoscopic sign of the optic
atrophy. Recorded as the expected examination finding; the SLC25A46 reports
state optic atrophy rather than tabulating disc appearance.
phenotype_term:
preferred_term: Optic disc pallor
term:
id: HP:0000543
label: Optic disc pallor
- name: Nystagmus
category: Ophthalmologic
description: >-
Nystagmus with saccadic pursuit, reported as the only ocular abnormality in a
patient carrying p.Trp160Ser who had no optic atrophy.
phenotype_term:
preferred_term: Nystagmus
term:
id: HP:0000639
label: Nystagmus
evidence:
- reference: PMID:28558379
reference_title: SLC25A46 Mutations Associated with Autosomal Recessive Cerebellar Ataxia in North African Families.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the patient with the novel mutation p.Trp160Ser did not present with optic
atrophy and his ocular abnormalities were limited to nystagmus and saccadic
pursuit
explanation: >-
Records nystagmus, and the absence of optic atrophy, in this genotype.
- name: Myoclonus
category: Neurologic
description: >-
Reported in the progressive myoclonic ataxia presentation, which sits between
the core neuropathy phenotype and the ataxia-predominant one.
phenotype_term:
preferred_term: Myoclonus
term:
id: HP:0001336
label: Myoclonus
evidence:
- reference: PMID:41640504
reference_title: An Apparently Isolated Optic Neuropathy Associated with Biallelic Variants in SLC25A46 Gene Encoding the Mitochondrial Ugo1-Like Protein.
supports: SUPPORT
quote_role: BACKGROUND
evidence_source: HUMAN_CLINICAL
snippet: >-
Biallelic pathogenic variants in the SLC25A46 gene are responsible for various
neurological syndromes, including Charcot-Marie-Tooth disease type 6B,
pontocerebellar hypoplasia type 1E, Leigh syndrome, progressive myoclonic
ataxia and Parkinson's disease, most of them being associated with optic
atrophy.
explanation: >-
Names progressive myoclonic ataxia within the SLC25A46 spectrum. Marked
BACKGROUND because the sentence is this case report's framing of prior work,
not its own finding.
- name: Spasticity
category: Neurologic
description: >-
Pyramidal signs occur in part of the spectrum. ClinGen records spasticity among
the variable central nervous system manifestations; no cited source states a
frequency, so none is asserted. A spasticity-predominant presentation without
cerebellar atrophy or axonal neuropathy has also been reported, and it stays
inside this entry because it is the same biallelic SLC25A46 lesion acting on the
same long-axon targets, with the pyramidal tract rather than the peripheral
nerve dominating; it is not a separately named disease and MONDO gives it no
term of its own.
phenotype_term:
preferred_term: Spasticity
term:
id: HP:0001257
label: Spasticity
evidence:
- reference: CGGV:assertion_9852fb40-0df1-4668-ba57-38a4971cb244-2020-05-26T160000.000Z
reference_title: "SLC25A46 / neuropathy, hereditary motor and sensory, type 6B (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
to a variable extent, to further central nervous system manifestations
including cerebellar ataxia and spasticity
explanation: >-
ClinGen records spasticity among the variable central nervous system
manifestations of this gene-disease relationship.
biochemical:
- name: Cerebral N-acetylaspartate
context: >-
Magnetic resonance spectroscopy in two patients of the founding cohort showed
reduced N-acetylaspartate in the central nervous system, the usual neuronal
marker, consistent with neuronal loss or dysfunction.
biomarker_term:
preferred_term: N-acetylaspartate
term:
id: NCIT:C118887
label: N-Acetylaspartate
evidence:
- reference: PMID:26168012
reference_title: "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Magnetic resonance spectroscopy (MRS) data in two of the patients found
decreased N-Acetyl-Aspartate (NAA) and increased lactate in the central
nervous system
explanation: >-
Reports the reduced cerebral NAA this marker records.
notes: >-
No reference interval is recorded. A population interval for NAA is not disease
content, and the cited report gives a direction of change rather than values.
- name: Cerebral lactate
context: >-
The same spectroscopy showed raised central nervous system lactate, which the
authors read as typical of a mitochondrial disorder and as evidence of a
metabolic role for SLC25A46. It is consistent with the glycolytic shift measured
in the patient's fibroblasts.
biomarker_term:
preferred_term: lactate
term:
id: NCIT:C76926
label: Lactic Acid
evidence:
- reference: PMID:26168012
reference_title: "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
decreased N-Acetyl-Aspartate (NAA) and increased lactate in the central
nervous system (Supplementary Fig. 2b) typical of mitochondrial disorders and
suggestive of a metabolic role for SLC25A46
explanation: >-
Reports the raised cerebral lactate and the authors' reading of it.
notes: >-
Reported in two patients of one cohort. Whether raised lactate is a consistent
feature of this disease at this rung of the spectrum is not established, and no
systematic series has measured it.
genetic:
- name: SLC25A46
gene_term:
preferred_term: SLC25A46
term:
id: hgnc:25198
label: SLC25A46
relationship_type: CAUSATIVE
variant_origin: GERMLINE
gene_disease_validity:
- validity_classification: DEFINITIVE
classified_by: CLINGEN
external_id: CGGV:assertion_9852fb40-0df1-4668-ba57-38a4971cb244-2020-05-26T160000.000Z
evidence:
- reference: CGGV:assertion_9852fb40-0df1-4668-ba57-38a4971cb244-2020-05-26T160000.000Z
reference_title: "SLC25A46 / neuropathy, hereditary motor and sensory, type 6B (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "SLC25A46 | HGNC:25198 | neuropathy, hereditary motor and sensory, type 6B | MONDO:0014671 | AR | Definitive | SOP7 | Charcot-Marie-Tooth Disease Gene Curation Expert Panel"
explanation: >-
The ClinGen gene-disease validity row for exactly this gene and this MONDO
disease.
evidence:
- reference: PMID:26168012
reference_title: "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
By whole-exome sequencing of patients with optic atrophy and CMT2, we
identified four families with recessive mutations in SLC25A46.
explanation: >-
The gene discovery that established SLC25A46 as causal for this phenotype.
- reference: CGGV:assertion_9852fb40-0df1-4668-ba57-38a4971cb244-2020-05-26T160000.000Z
reference_title: "SLC25A46 / neuropathy, hereditary motor and sensory, type 6B (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
12 missense, 2 nonsense, 2 frameshift, and 2 splice variants have been
reported in humans.
explanation: >-
ClinGen's count of the reported variant classes, showing missense
predominance.
notes: >-
SLC25A46 at 5q22.1 encodes the outer mitochondrial membrane protein that is the
sole cause of this disease. Reported alleles are predominantly missense, with
nonsense, frameshift and splice variants and exonic deletions also described;
the truncating and deletion alleles cluster at the lethal end of the spectrum
rather than in this phenotype. No modifier genes, susceptibility loci or founder
alleles are established. Many reported families are consanguineous, which is how
most homozygous genotypes arose rather than a separate risk mechanism.
treatments:
- name: Physical Therapy and Rehabilitation
description: >-
Supportive management of the length-dependent motor deficit, aimed at gait,
strength and contracture prevention. There is no disease-modifying treatment, so
rehabilitation is the mainstay alongside orthotic management of the foot.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: physical therapy
term:
id: NCIT:C15302
label: Physical Therapy
target_phenotypes:
- preferred_term: Distal muscle weakness
term:
id: HP:0002460
label: Distal muscle weakness
evidence:
- reference: PMID:36578309
reference_title: "Case report: A novel variant in SLC25A46 causing sensorimotor polyneuropathy and optic atrophy."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "there is currently no treatment for the disease"
explanation: >-
Disease-specific statement that no treatment exists, which is what makes
management supportive. INDIRECT because it establishes the absence of a
disease-modifying option rather than evaluating physical therapy, for which no
trial in this disease exists.
- name: Genetic Counseling
description: >-
Counselling for an autosomal recessive disorder, carrying a 25% recurrence risk
for carrier parents, with carrier testing of relatives and prenatal or
preimplantation diagnosis available once the familial variants are known.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: genetic counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: CGGV:assertion_9852fb40-0df1-4668-ba57-38a4971cb244-2020-05-26T160000.000Z
reference_title: "SLC25A46 / neuropathy, hereditary motor and sensory, type 6B (Definitive)"
supports: SUPPORT
directness: INDIRECT
evidence_source: OTHER
snippet: "SLC25A46 | HGNC:25198 | neuropathy, hereditary motor and sensory, type 6B | MONDO:0014671 | AR"
explanation: >-
The recessive mode of inheritance that determines the recurrence risk
counselling addresses. INDIRECT because the row records inheritance, not a
counselling recommendation.
- name: Orthopedic Surgery for Foot Deformity
description: >-
Corrective surgery for the cavus foot deformity of childhood-onset axonal CMT,
where orthotic management no longer maintains a functional, braceable foot.
Recorded as standard management of the deformity rather than from a source
reporting it in SLC25A46 patients specifically.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: orthopedic surgical procedure
term:
id: NCIT:C16186
label: Orthopedic Surgical Procedure
target_phenotypes:
- preferred_term: Pes cavus
term:
id: HP:0001761
label: Pes cavus
notes: >-
Deliberately uncited. No SLC25A46 report describes foot surgery, so attaching a
quote would mean citing a source that does not say it; the indication follows
from the deformity rather than from this disease's literature.
- name: Low-Vision Support
description: >-
Supportive care for the progressive visual loss that is this disease's defining
feature: low-vision aids, visual rehabilitation and educational support, which
matter here because the visual and motor disabilities compound each other.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
target_phenotypes:
- preferred_term: Reduced visual acuity
term:
id: HP:0007663
label: Reduced visual acuity
- preferred_term: Optic atrophy
term:
id: HP:0000648
label: Optic atrophy
notes: >-
Deliberately uncited, for the same reason as the foot surgery above. The cited
literature establishes the optic atrophy and its progression but never discusses
visual rehabilitation.
animal_models:
- name: Slc25a46 knockout mouse
species: Mouse
genotype: Slc25a46 knockout (homozygous null)
category: Genetic
description: >-
A constitutive knockout reproducing all three target-tissue lesions: Purkinje
cell degeneration with severe ataxia, retinal ganglion cell loss with optic
nerve pathology, and electrophysiologically confirmed peripheral neuropathy. It
also supplies the in vivo evidence for the transport and bioenergetic steps.
publication: PMID:28934388
genes:
- preferred_term: SLC25A46
term:
id: hgnc:25198
label: SLC25A46
modeled_mechanisms:
- target: Impaired Mitochondrial Transport and Distribution in Neuronal Processes
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: CELLULAR
description: >-
Mutant cerebellar neurons carry enlarged mitochondria that are abnormally
distributed and transported, which is the node this model observes directly.
limitations: >-
A complete null, whereas the human disease at this rung is caused by partially
functional missense alleles; the null is closer to the lethal
pontocerebellar-hypoplasia end of the spectrum.
divergences:
- divergence_type: POPULATION_MISMATCH
materiality: QUALIFYING
description: >-
The model is a constitutive null while patients with this phenotype retain
partial SLC25A46 function, so the model represents a more severe genotype
than the one it is cited for.
readouts:
- name: Mitochondrial size, distribution and transport in cerebellar neurons
target: Impaired Mitochondrial Transport and Distribution in Neuronal Processes
direction: ALTERED
interpretation: Direct observation of the organelle trafficking defect in neurons.
evidence:
- reference: PMID:28934388
reference_title: Loss of SLC25A46 causes neurodegeneration by affecting mitochondrial dynamics and energy production in mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Mutant cerebellar neurons have large mitochondria, which exhibit abnormal distribution and transport."
explanation: Reports the measurement behind this readout.
- target: Cerebellar Purkinje Cell Degeneration
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
description: >-
Severe ataxia attributable to Purkinje cell degeneration.
limitations: >-
The ataxia is more severe and earlier than in the human phenotype, and the
mice die prematurely.
readouts:
- name: Purkinje cell survival and ataxic phenotype
target: Cerebellar Purkinje Cell Degeneration
direction: DECREASED
interpretation: Purkinje cell loss with the corresponding motor phenotype.
evidence:
- reference: PMID:28934388
reference_title: Loss of SLC25A46 causes neurodegeneration by affecting mitochondrial dynamics and energy production in mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Mice lacking SLC25A46 displayed severe ataxia, mainly caused by degeneration of Purkinje cells."
explanation: Reports Purkinje degeneration as the cause of the ataxia.
- target: Retinal Ganglion Cell and Optic Nerve Axon Degeneration
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
description: >-
Retinal ganglion cell loss with small, unmyelinated and degenerated optic
nerve fibres.
limitations: >-
Optic pathology in the null is congenital-onset and severe, where the human
disease is childhood-onset and progressive.
readouts:
- name: Retinal ganglion cell count and optic nerve fibre morphology
target: Retinal Ganglion Cell and Optic Nerve Axon Degeneration
direction: DECREASED
interpretation: Structural correlate of optic atrophy.
evidence:
- reference: PMID:28934388
reference_title: Loss of SLC25A46 causes neurodegeneration by affecting mitochondrial dynamics and energy production in mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Increased numbers of small, unmyelinated and degenerated optic nerves as well
as loss of retinal ganglion cells indicated optic atrophy.
explanation: Reports the retinal and optic nerve measurements.
- target: Distal Axonal Degeneration of Long Peripheral Nerves
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
description: >-
Peripheral neuropathy on compound muscle action potentials, with axonal
degeneration.
limitations: >-
The mouse shows demyelination alongside degeneration, whereas the human
electrophysiology is a predominantly axonal pattern. Graded
PARTIALLY_RECAPITULATES for that reason.
divergences:
- divergence_type: SPECIES_MISMATCH
materiality: QUALIFYING
description: >-
The mouse nerve shows a mixed degenerative and demyelinating picture that the
human axonal phenotype does not, so the model overstates the myelin
component of this node.
readouts:
- name: Compound muscle action potential and nerve histology
target: Distal Axonal Degeneration of Long Peripheral Nerves
direction: ALTERED
interpretation: Electrophysiological and histological confirmation of neuropathy.
evidence:
- reference: PMID:28934388
reference_title: Loss of SLC25A46 causes neurodegeneration by affecting mitochondrial dynamics and energy production in mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Compound muscle action potentials in peripheral nerves showed peripheral
neuropathy associated with degeneration and demyelination in axons.
explanation: Reports the electrophysiology and the nerve pathology.
evidence:
- reference: PMID:28934388
reference_title: Loss of SLC25A46 causes neurodegeneration by affecting mitochondrial dynamics and energy production in mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Our results suggest that loss of SLC25A46 causes degeneration in neurons by affecting mitochondrial dynamics and energy production."
explanation: >-
The model's own summary conclusion, which is the mechanism this entry curates.
- name: Slc25a46 mutant mouse (forward-genetic)
species: Mouse
genotype: Slc25a46 loss-of-function point mutation
category: Genetic
description: >-
An independently derived loss-of-function mutant that reproduces ataxia, optic
atrophy and cerebellar hypoplasia and is fully rescued by expressing the human
orthologue, which is strong evidence that the lesion is the gene. It adds
neuromuscular junction abnormalities and a lymphoid phenotype not seen before.
publication: PMID:28376086
genes:
- preferred_term: SLC25A46
term:
id: hgnc:25198
label: SLC25A46
modeled_mechanisms:
- target: Cerebellar Purkinje Cell Degeneration
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
description: >-
Disrupted cerebellar and retinal cytoarchitecture with ataxia and cerebellar
hypoplasia, rescued by the human orthologue.
limitations: >-
Lethal and congenital, so it models the severe end of the allelic spectrum
rather than the childhood-onset phenotype of this entry; cerebellar hypoplasia
is a developmental lesion whereas this entry's finding is atrophy.
evidence:
- reference: PMID:28376086
reference_title: Novel insights into SLC25A46-related pathologies in a genetic mouse model.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Mutant mice manifest the main clinical features identified in patients,
including ataxia, optic atrophy and cerebellar hypoplasia, which were
completely rescued by expression of the human ortholog.
explanation: >-
Establishes both the phenotypic recapitulation and the orthologue rescue.
evidence:
- reference: PMID:28376086
reference_title: Novel insights into SLC25A46-related pathologies in a genetic mouse model.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Our mutant mice provide a valid model for understanding the mechanistic basis
of the complex SLC25A46-mediated pathologies, as well as for screening
potential therapeutic interventions.
explanation: >-
The authors' statement of the model's intended use.
- name: AAV-Slc25a46 gene replacement in Slc25a46 knockout mouse
species: Mouse
genotype: Slc25a46 knockout treated with systemic AAV-PHP.B carrying mouse Slc25a46
category: Genetic
description: >-
The one encouraging therapeutic result in this disease, and it is preclinical.
Systemic delivery of a neurotrophic AAV-PHP.B vector carrying the Slc25a46
coding sequence to knockout mice rescued premature death, improved nerve
conduction and mobility, restored respiratory-chain complex activities, and
normalised mitochondrial morphology in central and peripheral nervous tissue.
It is recorded here as a rescue arm rather than as a treatment, because nothing
has been tried in patients.
publication: PMID:31943007
genes:
- preferred_term: SLC25A46
term:
id: hgnc:25198
label: SLC25A46
modeled_mechanisms:
- target: Aberrant Mitochondrial Network Morphology
relationship: RESCUES
fidelity: MODERATE
model_scale: CELLULAR
description: >-
Gene replacement normalised mitochondrial morphology in both central and
peripheral nervous tissue, which is the cellular node this arm reverses.
limitations: >-
A rescue in a constitutive null mouse treated systemically; it does not show
that restoring the gene would help a patient whose partially functional
protein has already permitted decades of axonal loss.
divergences:
- divergence_type: POPULATION_MISMATCH
materiality: QUALIFYING
description: >-
The treated animals are complete nulls, whereas patients with this phenotype
retain partial function, so the size of the available benefit is not
comparable.
readouts:
- name: Mitochondrial morphology in central and peripheral nervous tissue
target: Aberrant Mitochondrial Network Morphology
direction: RESTORED
interpretation: Normalisation of the organelle morphology defect on gene replacement.
evidence:
- reference: PMID:31943007
reference_title: Systemic administration of AAV-Slc25a46 mitigates mitochondrial neuropathy in Slc25a46-/- mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Most notably, mitochondrial morphology inside the tissues of both the
central and peripheral nervous systems was normalized, and the
neurodegeneration, chronic neuroinflammation and loss of Purkinje cell
dendrites observed within the mutant mice were alleviated.
explanation: Reports the morphological normalisation this readout records.
- target: Cerebellar Purkinje Cell Degeneration
relationship: RESCUES
fidelity: MODERATE
model_scale: TISSUE
description: >-
Neurodegeneration and loss of Purkinje cell dendrites were alleviated by gene
replacement.
limitations: >-
Dendritic loss was alleviated rather than abolished, and the readout is
histological; no functional cerebellar endpoint is reported.
readouts:
- name: Purkinje cell dendrite preservation
target: Cerebellar Purkinje Cell Degeneration
direction: RESTORED
interpretation: Partial histological rescue of the Purkinje lesion.
evidence:
- reference: PMID:31943007
reference_title: Systemic administration of AAV-Slc25a46 mitigates mitochondrial neuropathy in Slc25a46-/- mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
loss of Purkinje cell dendrites observed within the mutant mice were
alleviated
explanation: Reports the dendritic rescue.
- target: Distal Axonal Degeneration of Long Peripheral Nerves
relationship: RESCUES
fidelity: MODERATE
model_scale: TISSUE
description: >-
Peripheral nerve conduction and mobility improved and respiratory-chain
complex activities were restored.
limitations: >-
Conduction improved rather than normalising to wild type, and the treatment
was given to young animals before the full lesion had developed.
readouts:
- name: Peripheral nerve conduction and mobility
target: Distal Axonal Degeneration of Long Peripheral Nerves
direction: RESTORED
interpretation: Functional improvement in the peripheral nerve on gene replacement.
evidence:
- reference: PMID:31943007
reference_title: Systemic administration of AAV-Slc25a46 mitigates mitochondrial neuropathy in Slc25a46-/- mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The treatment-improved electronic conductivity of the peripheral nerves
increased mobility and restored mitochondrial complex activities.
explanation: Reports the conduction, mobility and complex-activity improvements.
evidence:
- reference: PMID:31943007
reference_title: Systemic administration of AAV-Slc25a46 mitigates mitochondrial neuropathy in Slc25a46-/- mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "AAV-Slc25a46 treatment was able to rescue the premature death in the mutant mice (Slc25a46-/-)."
explanation: >-
The headline survival rescue that makes this model informative about the
mechanism being reversible in principle.
- name: slc25a46 zebrafish morphant
species: Zebrafish
genotype: slc25a46 morpholino knockdown
category: Genetic
description: >-
The developmental model from the founding study. Morphants have fewer retinal
ganglion cell axons reaching the tectum, shorter motor axon tracts, and motor
terminals showing blebbing and dying back.
publication: PMID:26168012
genes:
- preferred_term: SLC25A46
term:
id: hgnc:25198
label: SLC25A46
modeled_mechanisms:
- target: Distal Axonal Degeneration of Long Peripheral Nerves
relationship: PARTIALLY_RECAPITULATES
fidelity: LOW
model_scale: CELLULAR
description: >-
Dying-back degeneration at motor neuron terminals, consistent with CMT2
pathology.
limitations: >-
A transient morpholino knockdown in a developing embryo, so it reports failure
of axon growth and early maintenance rather than the adult length-dependent
degeneration of a long human nerve. A later stable zebrafish mutant was found
to undergo genetic compensation, which is a further caveat on knockdown
results in this species.
divergences:
- divergence_type: BOUNDARY_OMISSION
materiality: QUALIFYING
description: >-
The model has no long adult peripheral nerve, so length-dependent
vulnerability, the defining feature of this node, is outside its boundary.
- divergence_type: SPECIES_MISMATCH
materiality: QUALIFYING
description: >-
Morpholino knockdown is transient and incomplete, so the model represents
partial developmental depletion rather than the biallelic germline lesion.
evidence:
- reference: PMID:26168012
reference_title: "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
By stochastically labeling the motor neurons, we frequently observed axonal
blebbing and dying back at the morphant motor neuron terminals specifying
degeneration, which is consistent with the pathology of CMT2
explanation: >-
Reports the dying-back motor axon degeneration this link claims.
evidence:
- reference: PMID:26168012
reference_title: "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Loss of function in cultured cells and in zebrafish unexpectedly leads to
increased mitochondrial connectivity, while severely affecting the development
and maintenance of neurons in the fish.
explanation: >-
Establishes the model's two findings, altered mitochondrial connectivity and
impaired neuronal development and maintenance.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
No population estimate exists. ClinGen's 2020 curation counted at least 20
probands across 11 publications for this gene-disease pair, and a 2017 review of
the whole SLC25A46 spectrum counted 18 patients from 13 families. No numeric
rate is recorded here because none has been published.
evidence:
- reference: CGGV:assertion_9852fb40-0df1-4668-ba57-38a4971cb244-2020-05-26T160000.000Z
reference_title: "SLC25A46 / neuropathy, hereditary motor and sensory, type 6B (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Variants in this gene have been reported in at least 20 probands in 11
separate publications
explanation: >-
ClinGen's proband count for this gene-disease relationship, the basis for the
CASES_IN_LITERATURE measure.
- reference: PMID:28653766
reference_title: Extension of the phenotype of biallelic loss-of-function mutations in SLC25A46 to the severe form of pontocerebellar hypoplasia type I.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
To date, 18 patients from 13 families have been reported, presenting with the
key clinical features of optic atrophy, peripheral neuropathy, and cerebellar
atrophy.
explanation: >-
An independent count of reported patients across the spectrum.
progression:
- phase: Childhood-onset visual and gait impairment
notes: >-
Classic HMSN6B declares itself in childhood, often within the first decade, with
visual loss and gait difficulty. The recurrent p.Arg340Cys genotype is
consistently childhood-onset.
evidence:
- reference: PMID:28558379
reference_title: SLC25A46 Mutations Associated with Autosomal Recessive Cerebellar Ataxia in North African Families.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the previously reported variant p.Arg340Cys seems to be consistently
associated with the same clinical features such as childhood onset, optic
atrophy, gait and speech difficulties
explanation: >-
Records childhood onset as a consistent feature of this genotype.
- phase: Slowly progressive course with variable survival
notes: >-
The course is chronic and slowly progressive without remission. Across the whole
SLC25A46 spectrum, survival ranges from neonatal death in the severe forms to the
fifties; within this entry's rung, survival into adulthood is the rule.
evidence:
- reference: PMID:28653766
reference_title: Extension of the phenotype of biallelic loss-of-function mutations in SLC25A46 to the severe form of pontocerebellar hypoplasia type I.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The course of the disease was highly variable ranging from severe muscular
hypotonia at birth and early death to first manifestations in late childhood
and survival into the fifties.
explanation: >-
States the range of onset and survival across the allelic spectrum.
clinical_trials:
- name: NCT04594590
phase: NOT_APPLICABLE
status: UNKNOWN
description: >-
An observational natural-history study characterising the clinical course of the
neuropathy and optic atrophy in paediatric and adult patients with biallelic
SLC25A46 variants. It is the only registered study found for this disease and
addresses the absence of longitudinal data.
target_phenotypes:
- preferred_term: Optic atrophy
term:
id: HP:0000648
label: Optic atrophy
- preferred_term: Peripheral axonal neuropathy
term:
id: HP:0003477
label: Peripheral axonal neuropathy
evidence:
- reference: clinicaltrials:NCT04594590
reference_title: "A Natural History Study of Neurodegeneration and Optic Atrophy Caused by SLC25A46 Mutations in Pediatric and Adult Patients"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The purpose of the study is to systematically characterize the clinical course
of the progressive neuropathy and optic atrophy observe in pediatric and adult
patients with biallelic mutations in the solute carrier family 25 member 46
(SLC25A46) gene.
explanation: >-
The registry record's own statement of the study's purpose and population.
notes: >-
The recorded status is a snapshot. Status and phase were not re-checked against
the live registry when this entry was written, so run
just clinicaltrials-status-audit before relying on them.
diagnosis:
- name: Molecular genetic testing
description: >-
Exome or genome sequencing, or a hereditary neuropathy or optic neuropathy panel
that includes SLC25A46. Copy-number analysis matters here because exonic
deletions have been reported, and biallelic phase should be confirmed by
parental testing.
evidence:
- reference: PMID:26168012
reference_title: "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
By whole-exome sequencing of patients with optic atrophy and CMT2, we
identified four families with recessive mutations in SLC25A46.
explanation: >-
Exome sequencing is how the gene was found and remains the diagnostic route.
- name: Nerve conduction studies
description: >-
Electrophysiology establishes the axonal character of the neuropathy and can
reveal it when it is subclinical, which is what confirmed causality in the
apparently isolated optic neuropathy case.
evidence:
- reference: PMID:41640504
reference_title: An Apparently Isolated Optic Neuropathy Associated with Biallelic Variants in SLC25A46 Gene Encoding the Mitochondrial Ugo1-Like Protein.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The presence of a subclinical peripheral neuropathy revealed by
electroneuromyography confirmed the responsibility of these SLC25A46 variants.
explanation: >-
Shows electrophysiology detecting neuropathy that was clinically silent.
- name: Fibroblast mitochondrial morphology
description: >-
Patient fibroblasts show a hyper-filamentous, interconnected network, which can
serve as functional support for a variant of uncertain significance. Read with
care: the direction of the morphological change is not uniform across models.
evidence:
- reference: PMID:26168012
reference_title: "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We further examined fibroblasts from proband IT II-3, which display a
hyper-filamentous and interconnected network in comparison to both, the
unaffected sibling IT II-2 and control, indicating the relevance of this
phenomenon
explanation: >-
Demonstrates the fibroblast finding against an unaffected sibling control.
- reference: PMID:41640504
reference_title: An Apparently Isolated Optic Neuropathy Associated with Biallelic Variants in SLC25A46 Gene Encoding the Mitochondrial Ugo1-Like Protein.
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: >-
The absence of functional and structural mitochondrial abnormalities in the
patient's fibroblasts was consistent with the mild neurological phenotype.
explanation: >-
Refutes the usefulness of this test at the mild end of the spectrum: a patient
with confirmed biallelic variants had entirely normal fibroblasts, so a normal
result does not exclude the diagnosis.
differential_diagnoses:
- name: MFN2-related Charcot-Marie-Tooth disease type 2A
description: >-
The closest mimic, and not a coincidence: MFN2 is one of the fusion GTPases
SLC25A46 partners with. MFN2 causes axonal CMT2 and a subset of patients also
develop optic atrophy, giving the same two-feature combination. The separators
are inheritance, dominant for MFN2 against recessive here, and the gene.
distinguishing_features:
- Dominant inheritance in most MFN2 disease, against obligate biallelic SLC25A46 variants
- Molecular testing is the definitive separator; the clinical overlap is genuine
evidence:
- reference: PMID:26168012
reference_title: "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder."
supports: SUPPORT
quote_role: BACKGROUND
evidence_source: HUMAN_CLINICAL
snippet: >-
Mutations in MFN2 account for more than 20% of inherited axonal degenerative
peripheral neuropathies, Charcot-Marie-Tooth type 2 (CMT2A)
explanation: >-
Establishes MFN2 as the leading cause of axonal CMT2 and so the main
alternative. Marked BACKGROUND because the sentence is the founding paper's
framing of prior work rather than its own result.
- name: OPA1-related dominant optic atrophy and optic atrophy plus
description: >-
The other fusion-machinery partner. OPA1 is the major cause of dominant optic
atrophy and its plus forms add neuropathy, ataxia, deafness or myopathy,
reproducing this entry's combination. Compound heterozygous OPA1 variants give
Behr syndrome, which overlaps further.
distinguishing_features:
- Typically dominant with incomplete penetrance, against recessive inheritance here
- Deafness is common in OPA1 plus phenotypes and is not a feature of this disease
evidence:
- reference: PMID:36977595
reference_title: The role of the mitochondrial outer membrane protein SLC25A46 in mitochondrial fission and fusion.
supports: SUPPORT
quote_role: BACKGROUND
evidence_source: OTHER
snippet: >-
Although haploinsufficient-related mutations in OPA1 lead to optic atrophy,
dominant gain-of-function mutations in OPA1 cause more severe phenotypes of
optic atrophy, often concomitant with deafness, axonal neuropathy, ataxia,
and/or myopathy.
explanation: >-
Describes the OPA1 plus phenotype that overlaps this disease. BACKGROUND
because the sentence is this paper's introduction to the field.
- name: PDXK-related hereditary motor and sensory neuropathy type VIc
description: >-
The adjacent type in the same HMSN numbering, also recessive and also combining
axonal neuropathy with optic atrophy, but metabolic rather than mitochondrial:
PDXK encodes pyridoxal kinase and the disease is treatable with pyridoxal
5'-phosphate. That treatability is why the distinction matters clinically and
not only nosologically.
disease_term:
preferred_term: "neuropathy, hereditary motor and sensory, type VIc, with optic atrophy"
term:
id: MONDO:0032792
label: "neuropathy, hereditary motor and sensory, type VIc, with optic atrophy"
distinguishing_features:
- Low plasma pyridoxal 5'-phosphate with reduced erythrocyte pyridoxal kinase activity in PDXK disease
- PDXK disease responds to pyridoxal 5'-phosphate supplementation; no targeted therapy exists for SLC25A46 disease
- name: Pontocerebellar hypoplasia type 1E
description: >-
Not a different gene but the severe end of this gene's own spectrum, and the
distinction is one of allele severity rather than of entity. Near-complete loss
of SLC25A46 presents as congenital pontocerebellar hypoplasia with spinal motor
neuron degeneration and neonatal death from respiratory insufficiency. It is
curated as a subtype of Pontocerebellar_Hypoplasia, not here.
disease_term:
preferred_term: "pontocerebellar hypoplasia, type 1E"
term:
id: MONDO:0030260
label: "pontocerebellar hypoplasia, type 1E"
distinguishing_features:
- Congenital onset with death in the first weeks of life, against childhood onset and survival into adulthood
- Caused by alleles that markedly destabilise or abolish the protein, rather than partially functional missense alleles
evidence:
- reference: PMID:28653766
reference_title: Extension of the phenotype of biallelic loss-of-function mutations in SLC25A46 to the severe form of pontocerebellar hypoplasia type I.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here we report on 4 patients from 2 families diagnosed with PCH who died
within the first month of life from respiratory insufficiency.
explanation: >-
Documents the neonatally lethal presentation that marks the severe end of the
spectrum.
- name: SLC25A46-related Leigh syndrome
description: >-
Another severe allelic presentation of the same gene, in which the bioenergetic
arm of the mechanism dominates and produces a Leigh-type encephalopathy rather
than a neuropathy. ClinGen curates it as a separate gene-disease pair and rates
the evidence Limited.
distinguishing_features:
- Leigh-type brain lesions and metabolic decompensation rather than a length-dependent neuropathy
- ClinGen classifies the SLC25A46-Leigh syndrome relationship Limited, against Definitive for this disease
evidence:
- reference: PMID:27390132
reference_title: SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We uncovered a homozygous missense mutation in SLC25A46, the mammalian
orthologue of Ugo1, in a subject with Leigh syndrome.
explanation: >-
Establishes the Leigh syndrome presentation of the same gene.
discussions:
- discussion_id: slc25a46_fission_or_fusion
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Does SLC25A46 promote mitochondrial fission or mitochondrial fusion, and which
direction of imbalance actually drives neurodegeneration in patients?
rationale: >-
This entry's causal chain runs through loss of fission and a shift toward
MFN1/MFN2-mediated hyperfusion, which is what patient fibroblasts and
pathogenic missense variants show. But the primary literature does not agree on
the protein's direction of action, and the disagreement is explicit rather than
apparent. The founding study concluded that SLC25A46 acts pro-fission and found
no interaction with MFN2 or OPA1, only with mitofilin. Subsequent work reported
direct interactions with both fusion GTPases and mapped the interfaces.
Morphology does not settle it either: knockdown and pathogenic variants give
hyperfusion, whereas a complete knockout cell line gives fragmentation, and the
C. elegans orthologue behaves as a fusion factor whose phenotype is suppressed
by loss of the fission factor drp-1 and rescued by overexpressing the mitofusin
orthologue. A resource that asserts a single direction without recording the
disagreement would overstate what is known, and the direction matters because
it determines whether a therapeutic strategy should push the balance toward
fission or toward fusion.
attaches_to:
- "pathophysiology#Loss of SLC25A46 at Mitochondrial Fission and Fusion Sites"
- "pathophysiology#Dysregulated MFN1/MFN2 and OPA1 Oligomerization"
- "pathophysiology#Aberrant Mitochondrial Network Morphology"
posed_by: "dismech curation (issue #16350)"
posed_date: "2026-11-03T00:00:00Z"
evidence:
- reference: PMID:40444356
reference_title: SLC-25A46 regulates mitochondrial fusion through the mitofusin protein FZO-1 and is essential for maintaining neuronal morphology.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
However, the function of SLC25A46 in mitochondrial morphogenesis remains
controversial, with several reports suggesting it acts as a mitochondrial
fission factor, whereas others propose it as a fusion factor.
explanation: >-
States the controversy directly, which is the gap this discussion records.
- reference: PMID:40444356
reference_title: SLC-25A46 regulates mitochondrial fusion through the mitofusin protein FZO-1 and is essential for maintaining neuronal morphology.
supports: REFUTE
evidence_source: MODEL_ORGANISM
snippet: >-
Disease model worms carrying mutations associated with SLC25A46 exhibited
mitochondrial fragmentation and accelerated neurodegeneration, suggesting that
slc-25A46 maintains neuronal morphology through regulating mitochondrial fusion
regulation.
explanation: >-
Refutes the pro-fission reading this entry's chain assumes: in the worm, disease
alleles fragment mitochondria and the protein acts through the mitofusin
orthologue.
- reference: PMID:26168012
reference_title: "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Altogether, our data supports that unlike Ugo1, SLC25A46 acts in a pro-fission
manner.
explanation: >-
The founding study's pro-fission conclusion, one side of the disagreement.
- reference: PMID:39222684
reference_title: Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Opa1 and Mfn2.
supports: REFUTE
evidence_source: IN_VITRO
snippet: >-
We reveal that the bundle signaling element of Opa1 interacts with SLC25A46,
and present evidence of an Mfn2 interaction involving the SLC25A46 cytosolic
face.
explanation: >-
Refutes the founding study's specific finding that SLC25A46 does not interact
with MFN2 or OPA1, by mapping both interfaces.
- discussion_id: slc25a46_tissue_selectivity
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Why do retinal ganglion cells, long peripheral axons and Purkinje cells
degenerate when SLC25A46 is lost, while the ubiquitously expressed protein
leaves most tissues clinically unaffected?
rationale: >-
The protein is expressed broadly and its interactome spans OXPHOS complexes,
adenine nucleotide translocases, MICOS subunits and ER contact-site components
in cerebellum, cerebrum, heart and thymus alike. Yet the disease is almost
entirely neurological, and within the nervous system it picks out three cell
populations. Transcript enrichment in retinal ganglion cells is part of the
answer but cannot be the whole of it, since Purkinje cells and long peripheral
axons are hit without a comparable enrichment claim. The plausible explanation
is that these cells have the longest or most trafficking-dependent processes and
the least metabolic reserve, so they are the first to fail when organelle
delivery and cristae integrity degrade together. That remains a hypothesis: no
study has compared the threshold for degeneration across cell types in the same
system. The mouse models also report a lymphoid phenotype and neuromuscular
junction abnormalities that have no recognised clinical counterpart in patients,
which sharpens rather than resolves the question.
attaches_to:
- "pathophysiology#Respiratory Chain Deficiency and Bioenergetic Failure"
- "pathophysiology#Impaired Mitochondrial Transport and Distribution in Neuronal Processes"
posed_by: "dismech curation (issue #16350)"
posed_date: "2026-11-03T00:00:00Z"
evidence:
- reference: PMID:34983179
reference_title: Proteomic Identification of the SLC25A46 Interactome in Transgenic Mice Expressing SLC25A46-FLAG.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Tissue-specific co-immunoprecipitated proteins were enriched for synapse
annotated proteins in the cerebellum and cerebrum for metabolic processes in
the heart and for nuclear processes and proteasome in the thymus.
explanation: >-
Shows the interactome differs by tissue, which is a candidate contributor to
selectivity but does not by itself explain which cells degenerate.
- reference: PMID:26168012
reference_title: "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder."
supports: SUPPORT
directness: INDIRECT
quote_role: BACKGROUND
evidence_source: OTHER
snippet: >-
the transcript has been shown to be highly expressed in the neurons affected
in patients including spinal cord, cerebellum, and optic chiasm
explanation: >-
Expression in the affected neuron populations is partial support for a
threshold explanation. INDIRECT because expression level does not establish
differential vulnerability. BACKGROUND because the sentence restates prior
expression data that this paper cites rather than measured, and OTHER because
the quoted sentence does not say what kind of study produced it, so grading it
as a cell-culture result would be a guess.
notes: >-
Entry name. The MONDO label for the bound term is the positional
"neuropathy, hereditary motor and sensory, type 6B". The gene-related name used
here is established as a MONDO EXACT synonym of the same term, "SLC25A46
hereditary motor and sensory neuropathy type 6", and the gene is the root of this
entry's pathograph. The "type 6" suffix is dropped because HMSN type 6 is the
parent class, which also contains the MFN2-related type 6A and the PDXK-related
type VIc, so carrying it would make the name broader than the entry. All prior
names are kept in synonyms.
Scope. SLC25A46 causes a graded allelic spectrum, and this entry is the
neuropathy-with-optic-atrophy rung of it, which is what MONDO:0014671 and
OMIM:616505 denote. The severe ends have their own terms and their own homes:
pontocerebellar hypoplasia type 1E is curated as a has_subtypes row on
Pontocerebellar_Hypoplasia under MONDO:0030260, and SLC25A46-related Leigh
syndrome is a separate ClinGen gene-disease pair rated Limited. Both are recorded
in differential_diagnoses rather than restated here. The ataxia-predominant and
progressive-myoclonic-ataxia presentations are not split out, because the
published families are too few to separate them from this rung on anything other
than which feature happened to dominate at presentation.
GeneReviews. There is no SLC25A46-specific chapter and no chapter titled for this
disease; a PubMed search of genereviews[book] for SLC25A46 in title or abstract
returns nothing, and a search for the gene symbol returns nothing. The
Charcot-Marie-Tooth Hereditary Neuropathy Overview is tagged in references as the
disease-family baseline, but its PubMed abstract is only a statement of the
chapter's purpose and contains no clinical content, so no phenotype in this entry
rests on it. The phenotype baseline here is therefore the primary literature plus
the ClinGen curation, which is weaker than a GeneReviews baseline and is the main
limitation of this entry.
Frequencies. VERY_FREQUENT is used only for the two core features that every
series reports. Most phenotypes carry no frequency at all, because the published
cohorts are small case reports and family series that do not tabulate findings
systematically, and guessing a band from a handful of patients would invent
precision. Myoclonus and spasticity are deliberately among those: the sources name
them as part of the spectrum without quantifying them.
Unevidenced claims. Three items carry no evidence and say so rather than reaching
for a quote that does not support them. Optic disc pallor is the expected
ophthalmoscopic sign of the optic atrophy, and none of the cited reports describes
disc appearance; the foot surgery and low-vision support treatments are standard
management of the deformity and of visual loss, and the cited literature never
discusses either. Each records that absence in its own notes.
Phenotypes outside the causal graph. Myoclonus and spasticity have no inbound
causal edge, because the entry has no cortical or pyramidal pathophysiology node
to originate one and the evidence does not support inventing one. Both are
therefore recorded as features of the spectrum that this entry's mechanism does
not yet explain, which is the honest state rather than a wiring omission.
Nerve conduction binding. The electrophysiology phenotype is bound to the parent
HP:0040129 Abnormal nerve conduction velocity rather than to HP:0003431 Decreased
motor nerve conduction velocity, because the human pattern is axonal, with reduced
amplitudes and relatively preserved velocities. The narrower term would assert the
demyelinating pattern this disease does not show.
Reflex binding. Bound to HP:0001284 Areflexia rather than to its sibling
HP:0001265 Hyporeflexia, because the source reports deep tendon reflexes as
unelicitable rather than reduced. The two are siblings under Abnormality of
reflexes, not a general and a specific form of one thing, so the choice is a claim
about the examination finding and not a matter of precision.
Molecular function binding. The node carrying the gene binds GO:0044877
protein-containing complex binding, not a transport activity. SLC25A46 lacks the
SLC25 family's signature motifs and has no identified substrate, so a transporter
term would assert an activity its own literature denies; what it demonstrably does
is bind the fusion GTPases, the MICOS complex through MIC60, and the ER membrane
protein complex, which is complex binding. The modifier is DECREASED because the
disease alleles reduce that binding, whether by removing the protein or by
disturbing a specific interaction.
Mechanism confidence. The chain from the variant to the three degenerating cell
populations is well supported at both ends and weakest in the middle. The step
from bioenergetic and trafficking failure to selective degeneration is recorded
with INDIRECT_UNKNOWN_INTERMEDIATES because it is an inference from cell and mouse
data rather than a demonstrated sequence, and the direction of the dynamics defect
itself is openly disputed in the literature. Both are recorded as knowledge gaps
rather than smoothed over.
datasets: []
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.
Review round 1: source two phenotypes a false note called unevidenced; rebind the electrophysiology term · 2026-11-03T15:00:28Z · View source
Addresses the ai4c-reviewer CHANGES_REQUESTED review on PR #16384 (review 5754384915). All six findings and both suggestions were verified against the cached references before being acted on; every one was correct. Finding 1, the serious one. The entry's notes asserted that no SLC25A46 report states pes cavus or reduced visual acuity. Both claims were false, and both were refuted by papers the entry already cited: PMID:30178502's genotype table lists Pes cavus in the p.Arg340Cys patient, PMID:28558379 reports 'Skeletal abnormalities such as scoliosis and hollow feet were found', and the same paper reports 'The eye exam revealed bilateral divergent strabismus, a decrease in visual acuity and an optic atrophy in both eyes' plus a second patient who 'presented at age 6 with a decrease in visual acuity'. Both phenotypes now carry that evidence, the note is corrected, and the correction itself is recorded in the entry's notes, because a false statement that no source exists is worse than a missing citation: it tells the next curator not to look. This is the second instance of that failure class in this entry, after the reflex note corrected in the previous round, and both were written in the same session. The scoliosis in that same sentence was not curated at all, so a Scoliosis phenotype was added and wired through trunk muscle imbalance. Finding 2. Reduced visual acuity was supported only by a sentence naming optic neuropathy without mentioning acuity, and carried a FREQUENT band with no basis. It now cites the two examination findings above, the band is dropped, and the original sentence is kept as an INDIRECT item for the slowly progressive course. Finding 4. The phenotype named 'Decreased motor nerve conduction velocity' contradicted its own binding and its own notes, which said velocities are relatively preserved and that asserting a decrease would misstate the finding. Renamed to Decreased compound muscle action potential amplitude and rebound to HP:0033383, which is what the axonal pattern actually changes; the downstream target was retargeted and the notes rewritten to explain why neither velocity term fits. Finding 5. Physical Therapy was supported by 'Currently, there is no cure for mitochondrial disorders', a general sentence from a mouse AAV paper's introduction. Replaced with the disease-specific 'there is currently no treatment for the disease' from PMID:36578309, graded INDIRECT because it establishes the absence of a disease-modifying option rather than evaluating physical therapy. Finding 6. The tissue-selectivity discussion's expression item was graded IN_VITRO for a sentence restating prior in-situ data. Regraded OTHER with quote_role: BACKGROUND, because the quoted sentence does not say what kind of study produced the data and grading it as a cell-culture result would be a guess. Finding 3 and the second suggestion. The Myoclonus and Spasticity frequency bands were removed, and a sentence was added explaining why the spasticity-predominant presentation stays inside this entry's rung: it is the same biallelic lesion on the same long-axon targets with the pyramidal tract dominating, it is not separately named, and MONDO gives it no term. A process failure worth recording. Findings 3 and 6 here, plus four fixes from the previous round (the visual-acuity wording, two quote_role values, and the fibroblast REFUTE item), had been reported as applied in commit b5a00c985 and were not in it. The edit script for that batch raised an assertion on its last replacement and exited before writing the file, so the whole batch was silently lost while the preceding batches had already been written. The commit message and the PR body therefore both overstated what had landed. All of them are applied here, and each edit in this round was verified by reading the written file back rather than by trusting the script's exit. CI failures fixed in the same round. The test (3.13) job on b5a00c985 failed two gates I had not run locally, both of which I reproduced before fixing. find_missing_reference_titles found 8 evidence items in this entry with no reference_title; filled with scripts/backfill_reference_titles.py, which copies each title from the references_cache/ frontmatter rather than typing it. check-gene-activity-grounding found SLC25A46 reaching a pathophysiology node that bound no molecular function. Rather than grandfather it, the node now binds GO:0044877 protein-containing complex binding with modifier DECREASED: SLC25A46 lacks the SLC25 signature motifs and has no identified substrate, so a transporter term would assert an activity its own literature denies, while complex binding is exactly what it demonstrably does (the fusion GTPases, MICOS through MIC60, and the ER membrane protein complex), and the entry already quotes primary sources for each of those interactions. The term was taken as a lead from the ai-gene-review ingest, which names it as SLC25A46's core molecular function, but is evidenced from the primary literature because ai-gene-review content is not citable as KB evidence. The reasoning is recorded in the entry's notes. Round 2 of review. Five of the six findings were accepted as fixed. Two remained, both correct and both applied. (A) The renamed Decreased compound muscle action potential amplitude phenotype had no snippet that mentioned amplitude: the human quote reached it only by inference and was not marked INDIRECT. PMID:36578309, already cited by the entry, states it directly ("A nerve conduction study showed reduced amplitude in median nerves, loss of response in sural nerves, and severely reduced and no certain motor response in right and left tibial nerves"), so that is now the DIRECT item and the PMID:30178502 one is regraded INDIRECT. The same paper also reports "slowed conduction velocity in both ulnar nerves", which contradicted the description's claim that velocities are relatively preserved; the description now says mostly preserved and cites that sentence, so the exception is stated rather than smoothed over. (B) A notes paragraph narrating the previous draft's false unevidenced claim was a revision log, which CLAUDE.md excludes from notes (#8908, #12535): it described a draft that never reached main, so a reader of the merged entry loses no fact about the disease by its removal. Deleted from the entry. The substance is preserved in this record's finding-1 paragraph above, which is where the rule puts it, so nothing about the error is lost. Validation. just validate passes. just count-verified-snippets reports 98/98 verified, up from 92/92. Phenotype causal connectivity 88.2%. Per-file gates clean: duplicate-keys, block-scalar-comments, enum-values, entity-refs, causal-targets, coarse-phenotypes, qualifier-terms, delivery-system, logical-rules, genereviews. Not done. The first suggestion asked for a citable source for OCT retinal-nerve-fibre-layer thinning or abnormal visual evoked potentials in the diagnosis block. The deep-research report mentions both, but no cached reference states either for SLC25A46 patients, so adding them would mean citing a source that does not say it. Left out, and said so on the PR.
Create: SLC25A46-Related Hereditary Motor And Sensory Neuropathy · 2026-11-03T04:02:35Z · View source
Created the entry for MONDO:0014671 (HMSN6B, SLC25A46) from a claim on issue #16350. Deep research. falcon was the requested provider and is unavailable in this session: the egress proxy refuses platform.edisonscientific.com and api.futurehouse.org (connect_rejected), so the Edison client fails at authentication. The documented --fallback mechanism cannot record this failure mode, because the Edison client raises at construction, before the client's fallback logic runs; this was tried twice, once with --fallback alone and once with an explicit --fallback-provider order, and neither engaged. openscientist is blocked the same way (api.openscientist.io). The report used is therefore research/SLC25A46-Related_Hereditary_Motor_And_Sensory_Neuropathy-deep-research-claude_code.md, run with the claude_code provider, which needs no external host. Its reference validation is 14/14 resolved, 0 unresolved, 0 off topic; needs_review is set only by two benign label artifacts (the report wrote 'MONDO' as the label of MONDO:0014671, and 'Autosomal recessive' for HP:0000007, which HPO lists among that term's other names). just preflight-dr returns WARN on a second-gene signal for 'CDC' at 16 mentions; all 16 are in the template's own echoed search-source instructions, not in disease content, so the WARN is a false positive. OMIM matches on both sides (616505) and SLC25A46 is mentioned 30 times. Scope and naming. The entry is scoped to the neuropathy-with-optic-atrophy rung of the SLC25A46 allelic spectrum. PCH1E (MONDO:0030260) was already curated as a has_subtypes row on Pontocerebellar_Hypoplasia and is cross-referenced in differential_diagnoses rather than duplicated; SLC25A46-related Leigh syndrome is a separate ClinGen pair (Limited) and is likewise a differential. The gene-related name follows the entry-naming skill: it is established as a MONDO EXACT synonym of the bound term, and the 'type 6' suffix is dropped because HMSN type 6 is the parent class containing MFN2-related 6A and PDXK-related VIc. GeneReviews. No SLC25A46-specific chapter exists. PubMed genereviews[book] searches for SLC25A46 in title or abstract and for the gene symbol both return zero. The Charcot-Marie-Tooth Hereditary Neuropathy Overview (PMID:20301532) is tagged as the disease-family baseline, but its abstract is only a statement of chapter purpose, so no phenotype rests on it; this is recorded in notes as the entry's main limitation. Content. 13 pathophysiology nodes forming a connected chain from the biallelic lesion through protein destabilisation, loss at fission/fusion sites, the three partner-complex branches (fusion GTPase oligomerisation, MICOS/cristae, ER-contact lipid transfer), bioenergetic failure and impaired organelle trafficking, to degeneration of peripheral axons, retinal ganglion cells and Purkinje cells, each wired to its phenotypes. Five conforms_to links to peripheral_axonal_degeneration, membrane_contact_site_dysfunction and cerebellar_purkinje_degeneration. 17 phenotypes, three mouse/zebrafish models with typed divergences, ClinGen Definitive gene_disease_validity copied from the CGGV record, and two KNOWLEDGE_GAP discussions: the unresolved fission-versus-fusion direction (recorded with REFUTE evidence on both sides rather than smoothed over) and the unexplained tissue selectivity. Judgement calls recorded rather than hidden. One phenotype carries a deliberate NO_EVIDENCE item explaining that the GeneReviews abstract cannot support it; two carry no evidence at all because no SLC25A46 report states them; the electrophysiology phenotype is bound to the parent HP:0040129 rather than HP:0003431 because the human pattern is axonal; cerebellar atrophy carries a REFUTE item against its universality. Pre-PR self-review. A fresh-context review agent was run against the entry before any PR, applying the dismech-pr-review skill, and returned REQUEST_CHANGES with 21 findings; all were acted on in this same commit rather than deferred. Two were genuine defects I had introduced and verified myself before fixing: the lead description stated the genotype-severity relationship with the sign inverted (PMID:30178502 reports an inverse correlation between protein *stability* and severity, so destabilisation tracks severity positively), and the cited clinicaltrials:NCT04594590 cache file had not actually been staged, which CI cannot catch because the reference validator silently network-fetches a missing record. Beyond those: an evidence item on a transfection/co-IP result was graded HUMAN_CLINICAL and is now IN_VITRO; one explanation misreported the second half of its own quoted sentence; the Gait ataxia and nerve-conduction phenotypes rested on snippets that did not carry the claim and now cite human examination and electrophysiology findings from PMID:30178502; a REFUTE grading on Cerebellar atrophy was wrong because supports is claim-relative and the quote supports the claim as written (frequent but not obligate), so it is now SUPPORT; the Hyporeflexia phenotype carried a NO_EVIDENCE item plus a negative-existence note that a reference the entry already cited refuted, and is now Areflexia (HP:0001284, the source reports reflexes as unelicitable rather than reduced) with a real human quote; 'wasting of the lower limbs' cited for distal *weakness* now carries directness: INDIRECT with the distinction explained. Two resolving prose claims that had no evidence item are now sourced from already-cached full text (the photoactivation fusion-rate negative result, and the muscle biopsy with no ragged-red or COX-negative fibres), and the pro-fission modifier on the fission node now carries the founding study's own conclusion plus a pointer to the discussion recording that it is disputed. Three quote_role: BACKGROUND values were added where a quote was the citing paper's framing rather than its finding. Two invented frequency bands were removed, since the entry's own notes forbid guessing one. Content gaps the review identified were filled: a biochemical section for the MRS findings (reduced cerebral NAA, raised lactate), orthopaedic foot surgery and low-vision support treatments, a REFUTE item recording that fibroblast morphology is normal at the mild end and so cannot exclude the diagnosis, and the AAV-Slc25a46 gene-replacement rescue as its own animal model with three RESCUES arms and readouts, so the one encouraging therapeutic result in this disease is queryable rather than prose-only. Validation. just validate passes (schema, terms, references). just count-verified-snippets reports 92/92 verified. Per-file gates clean: duplicate-keys, block-scalar-comments, enum-values, entity-refs, causal-targets, coarse-phenotypes, qualifier-terms, delivery-system, logical-rules. Whole-tree ratchets clean: folded-hyphens, snippet-length, title-snippets, reference-titles.
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-referenceandjust count-verified-snippetsbefore 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.
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
| Resource | ID |
|---|---|
| MONDO | MONDO:0014671 |
| OMIM (phenotype) | 616505 (HMSN6B) |
| OMIM (gene) | 610826 [verify] |
| HGNC | hgnc:25198 [verify] |
| Orphanet | Hereditary motor and sensory neuropathy type 6 group, ORPHA:90120 [verify] |
| ICD-10 | G60.0 (hereditary motor and sensory neuropathy) |
| MeSH | Charcot-Marie-Tooth Disease (D002607); Optic Atrophy (D009896) |
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.
| Phenotype | Suggested HPO term | Frequency / characteristics |
|---|---|---|
| Optic atrophy | HP:0000648 Optic atrophy | Very frequent; onset in childhood (often in the first decade); progressive; the defining feature |
| Reduced visual acuity | HP:0007663 Reduced visual acuity | Frequent; progressive |
| Axonal sensorimotor neuropathy | HP:0003477 Peripheral axonal neuropathy (or HP:0007108 Demyelinating peripheral neuropathy only if documented) | Very frequent in the HMSN6B core; childhood onset; slowly progressive |
| Distal muscle weakness | HP:0002460 Distal muscle weakness | Frequent |
| Distal amyotrophy | HP:0003693 Distal amyotrophy | Frequent |
| Pes cavus | HP:0001761 Pes cavus | Common in CMT |
| Areflexia / hyporeflexia | HP:0001284 Areflexia | Frequent |
| Distal sensory loss | HP:0002936 Distal sensory impairment | Frequent |
| Cerebellar ataxia | HP:0001251 Ataxia / HP:0001272 Cerebellar atrophy | Variable; prominent in the ataxia-predominant and myoclonic forms |
| Myoclonus | HP:0001336 Myoclonus | Rare (Charlesworth 2016) |
| Nystagmus | HP:0000639 Nystagmus | Variable |
| Dysarthria | HP:0001260 Dysarthria | Variable |
| Spasticity / pyramidal signs | HP:0001257 Spasticity | Reported (optic atrophy with limb spasticity; Kodal et al. 2022) |
| Pontocerebellar hypoplasia | HP:0012110 Hypoplasia of the pons; HP:0001321 Cerebellar hypoplasia | Severe allelic form; congenital; lethal |
| Respiratory insufficiency / neonatal death | HP:0002093; HP:0003811 | Severe form |
| Leigh-like basal ganglia/brainstem lesions | HP:0001337? — use HP:0007103 / Leigh syndrome terms [verify] | Rare (Janer 2016) |
| Lactic acidosis / increased lactate:pyruvate ratio | HP:0003128 Lactic acidosis | Some severe cases, in fibroblasts or blood |
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.
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.
There are no known environmental, lifestyle or infectious contributors. Not applicable.
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.
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).
| Feature | Finding |
|---|---|
| Inheritance | Autosomal recessive (HP:0000007) |
| Penetrance | Apparently complete for biallelic pathogenic variants |
| Expressivity | Highly variable, both allelic and within families |
| Anticipation | None |
| Founder effects | Possible within North African families; none established |
| Consanguinity | Frequent in reported pedigrees |
| Prevalence | Ultra-rare: on the order of a few dozen published patients worldwide. No population estimate exists, so use CASES_IN_LITERATURE / ULTRA_RARE rather than a numeric band. |
| Sex ratio | Not skewed |
| Geography | Families reported from the USA/Europe, North Africa, the Middle East and Asia |
There is no disease-modifying therapy. Management is supportive:
| Intervention | Suggested NCIT term |
|---|---|
| Physical therapy | NCIT:C15302 Physical Therapy |
| Rehabilitation | NCIT:C15315 Rehabilitation |
| Orthotic management (ankle-foot orthoses) | Bind a clinical action. NCIT device terms do not belong in TreatmentTerm. |
| Orthopedic surgery for foot deformity | NCIT:C16186 Orthopedic Surgical Procedure |
| Low-vision support | Supportive Care, NCIT:C15747 |
| Genetic counseling | NCIT:C15240 Genetic Counseling |
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.
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.
| Model | Phenotype and recapitulation | Reference |
|---|---|---|
| Zebrafish morphants | Increased mitochondrial connectivity; impaired neuronal development and maintenance | Abrams 2015 (PMID:26168012) |
| Slc25a46 knockout mouse (CRISPR 46-bp exon 8 deletion) | Severe ataxia from Purkinje cell degeneration; optic atrophy (retinal ganglion cell loss, small and unmyelinated optic nerve axons); axonal peripheral neuropathy with demyelination; large mitochondria with abnormal transport; early lethality | Li et al., Hum Mol Genet 2017;26(19):3776 (PMID:28934388 [verify]) |
| Forward-genetic atc mutant mouse | Lethal ataxia, optic atrophy, cerebellar hypoplasia and NMJ abnormalities; rescued by the human ortholog | Terzenidou et al., PLoS Genet 2017 (PMC5380310) |
| Patient fibroblasts / knockout human fibroblasts | Hyperfusion, cristae and lipid defects, impaired respiration; variant testing | Janer 2016; Life Sci Alliance 2023 (e202301914) |
| C. elegans slc-25A46 mutants | Neuronal morphological degeneration; FZO-1-dependent effects | bioRxiv 2024 (preprint) |
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.
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)
Checked with linkml-reference-validator 0.5.1.
| Outcome | Count |
|---|---|
| References checked | 14 |
| Resolved | 14 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 14 |
| On topic | 12 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 49 |
| Resolved | 47 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 2 |
| 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 |
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 6BThe 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 namesTerms 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.