Charcot-Marie-Tooth Disease Recessive Intermediate D

Mendelian MONDO:0014467 Pathograph 9 Show in embeddings browser Charcot-Marie-Tooth Disease Mitochondrial Complex IV Deficiency inborn errors of metabolism

Charcot-Marie-Tooth disease recessive intermediate D (CMTRID) is an autosomal recessive peripheral neuropathy caused by biallelic variants in COX6A1, which encodes the ubiquitously expressed 6A isoform of mitochondrial respiratory complex IV (cytochrome c oxidase). It is one of the few CMT entities whose primary lesion is in oxidative phosphorylation rather than in myelin, axonal transport or the cytoskeleton, and MONDO places it under both the intermediate CMT and the mitochondrial oxidative phosphorylation disorder branches for that reason. The disease was mapped in two consanguineous Japanese families to a five-base deletion in the polypyrimidine tract of COX6A1 intron 2, which disrupts splicing of exon 3. Patients showed reduced COX6A1 expression in peripheral leukocytes and reduced cytochrome c oxidase activity in lymphoblastoid lines, and a Cox6a1-null mouse reproduced both the enzymatic defect and a neurogenic muscular atrophy with impaired walking. A second allelic mechanism has since been reported: a homozygous stop-loss variant extending the protein by 41 residues and reducing steady-state protein levels. Why a complex IV subunit defect should present as a peripheral neuropathy rather than as the encephalopathy or cardiomyopathy typical of COX deficiency is the mechanistically interesting question here, and the isoform biology offers a partial answer: mature cardiac and skeletal muscle switch from the ubiquitous COX6A1 to the muscle-specific COX6A2 isoform, so those tissues have a substitute that peripheral nerve does not. That is an inference from isoform expression data rather than something demonstrated in this disease, and it is recorded as such. The phenotype is not settled. The founding report described an axonal or mixed neuropathy, and the entity is nevertheless catalogued as "intermediate"; the most recent case adds global developmental delay, elevated lactate and death after a febrile decompensation at 3.5 years - a presentation that reads more like a mitochondrial disease with neuropathy than like CMT. Whether CMTRID names one disease or the neuropathic end of a broader COX6A1-related spectrum is an open nosological question, curated here as a knowledge gap rather than resolved.

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1
Inheritance
7
Pathophys.
10
Phenotypes
3
Gaps
9
Pathograph
1
Genes
2
Medical Actions
1
Models
6
References
1
Deep Research
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Inheritance

1
Autosomal recessive HP:0000007
Both reported mechanisms are biallelic. The founding families were consanguineous and homozygous for the intron 2 deletion; the later case was homozygous for a stop-loss allele. Heterozygous carriers, including the parents in both reports, are unaffected.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:25152455 SUPPORT Human Clinical
"Those data indicated that COX6A1 mutation causes the autosomal-recessive axonal or mixed CMT."
The founding study states the inheritance pattern as its concluding claim.
PMID:41044399 SUPPORT Human Clinical
"WES revealed a rare homozygous COX6A1 variant (NM_004373.4: c.329 A > T, p.110Leuext41) that is absent in population databases."
An independent family with a homozygous genotype, confirming recessive transmission at a second allele.
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Discussions and Knowledge Gaps

3
Is CMTRID one disease, or the neuropathy-predominant end of a broader COX6A1-related mitochondrial disorder?
KNOWLEDGE GAP cmtrid_nosology_spectrum
Attached to
pathophysiology#Biallelic COX6A1 Loss of Function phenotypes#Global Developmental Delay
The founding families had an adult-compatible peripheral neuropathy and no reported encephalopathy or lactate elevation. The 2025 case had global developmental delay, raised lactate and death after a febrile decompensation at 3.5 years - the natural history of an infantile mitochondrial disease, not of CMT. Two genotypes and three families is not enough to say whether that is allelic severity, a modifier, or a different entity that happens to share a gene. The answer determines whether the developmental and metabolic phenotypes in this entry belong here at all, which is why they are recorded as OCCASIONAL and flagged rather than folded into the core description.
Does COX6A2 expression in mature muscle actually spare that tissue in COX6A1-deficient patients, or is muscle involvement simply under-investigated?
HUMAN MODEL MISMATCH cmtrid_isoform_sparing_hypothesis
Attached to
pathophysiology#Isoform-Restricted Tissue Vulnerability
The isoform-substitution evidence is strong but entirely non-human-disease: COX6A2 rescues holoenzyme and activity in COX6A1-knockdown HEK293 cells, and the ubiquitous-to-muscle-specific switch is documented in maturing mouse muscle. What has never been done is the measurement in the disease: no CMTRID patient tissue has been examined for COX6A2 content, and the Cox6a1-null mouse's COX activity was reported without a tissue breakdown. The mismatch is specific rather than general - the model organism that carries the relevant genotype was never asked the question that the cell model was built to answer. Recorded as HUMAN_MODEL_MISMATCH rather than as a plain knowledge gap because the evidence exists and is good; what is missing is its translation to the human disease. Note the rescue experiment also constrains what a therapy could look like: if COX6A2 substitutes functionally, inducing it in nerve is a coherent therapeutic hypothesis, and the same paper reports that COX6A2 mRNA did not rise on its own in the knockdown cells - so the substitution would have to be forced rather than coaxed.
Proposed experiments
Tissue-resolved complex IV activity in the Cox6a1-null mouse
cmtrid_tissue_resolved_cox_activity
Measure COX activity and COX6A2 protein side by side in sciatic nerve, dorsal root ganglion, gastrocnemius and heart of Cox6a1-null and wild-type mice.
Would support
pathophysiology#Isoform-Restricted Tissue Vulnerability
Would refute
pathophysiology#Isoform-Restricted Tissue Vulnerability
Supporting outcome
  • COX activity is reduced in nerve and ganglion but preserved in muscle and heart, and the preserved tissues are the ones expressing COX6A2.
Refuting outcome
  • COX activity falls equally across nerve and muscle, so isoform substitution does not account for the tissue selectivity and another explanation is required.
Does CMTRID meet the electrophysiological definition of intermediate CMT?
KNOWLEDGE GAP cmtrid_intermediate_designation
Attached to
pathophysiology#Peripheral Nerve Degeneration with Mixed Conduction Slowing
The disease is catalogued as recessive intermediate D, but the founding paper calls the phenotype axonal or mixed and both subsequent descriptions call it axonal. No paper reports the median motor conduction velocities that the intermediate category is defined by. The label may be a nosological artefact, and a curator matching patients to this entry on the strength of the word "intermediate" could be misled.
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Pathophysiology

7
Biallelic COX6A1 Loss of Function
Two distinct molecular routes to the same endpoint have been reported. The founding allele is a five-base deletion in the polypyrimidine tract of intron 2 (c.247-10_247-6delCACTC) that disrupts splicing of the adjacent third exon; the consequence measured in patients was reduced COX6A1 expression in peripheral white blood cells. The second is a stop-loss substitution that reads through the normal termination codon and extends the protein by 41 residues, reducing steady-state protein levels. Neither is a missense change altering catalysis: both reduce the amount of COX6A1 available, which is why the entry treats the lesion as a dosage problem.
COX6A1 hgnc:2277 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COX6A1 (hgnc:2277). hgnc:2277 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context COX6A1 hgnc:2277 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns COX6A1 (hgnc:2277). hgnc:2277 is a gene from the HUGO Gene Nomenclature Committee. zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Both reported genotypes are homozygous in consanguineous or presumed-related pedigrees. Compound heterozygosity has not been reported, which is a statement about the small number of families described rather than about the allele requirement.
Downstream
Complex IV Biogenesis Failure COX6A1 is a nuclear-encoded structural subunit of the holoenzyme, so less subunit means less assembled complex.
Show evidence (3 references)
PMID:25152455 SUPPORT Human Clinical
"revealed a disease-specific 5 bp deletion (c.247-10_247-6delCACTC) in a splicing element (pyrimidine tract) of intron 2 adjacent to the third exon of cytochrome c oxidase subunit VIa polypeptide 1 (COX6A1), which is a component of mitochondrial respiratory complex IV (cytochrome c oxidase"
Gives the founding allele, its splicing mechanism, and the identity of the gene product as a complex IV subunit.
PMID:25152455 SUPPORT In Vitro
"Functional analysis showed that expression of COX6A1 in peripheral white blood cells from the affected individuals and COX activity in their EB-virus-transformed lymphoblastoid cell lines were significantly reduced."
Demonstrates in patient material that the allele reduces both transcript abundance and the enzymatic activity of the complex it belongs to. Graded IN_VITRO rather than HUMAN_CLINICAL because both assays in this sentence are ex vivo - transcript abundance in isolated white blood cells and COX activity in EBV-transformed lymphoblastoid lines - and the human origin of the material is not what evidence_source records.
PMID:41044399 SUPPORT In Vitro
"Functional assays demonstrated significantly reduced mutant protein levels (p < 0.01), supporting the pathogenicity of this mutation."
Establishes the second allelic mechanism as also acting by reducing the amount of COX6A1 protein.
Complex IV Biogenesis Failure
Reduced COX6A1 leaves the cytochrome c oxidase holoenzyme incompletely assembled. This is the module's trigger node; the disease-specific substitution here is that the lesion is in a structural subunit with a tissue-restricted paralogue, rather than in an assembly factor or metallochaperone shared by all tissues.
mitochondrial respiratory chain complex IV assembly GO:0033617 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial respiratory chain complex IV assembly (GO:0033617). GO:0033617 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Cox6a1-null mouse Mouse recapitulates COX activity is significantly reduced in the null mouse, matching the reduction measured in patient lymphoblastoid lines.
Downstream
Impaired Terminal Electron Transfer and ATP Synthesis
Show evidence (2 references)
PMID:25152455 SUPPORT In Vitro
"COX activity in their EB-virus-transformed lymphoblastoid cell lines were significantly reduced"
Measures the assembled complex's activity in patient-derived cells, which is the readout of this node.
PMID:20307258 SUPPORT In Vitro
"Knockdown of Cox4, Cox5a and Cox6a resulted in reduced CcO activity, diminished affinity of the residual enzyme for oxygen, decreased holoCcO and CcO dimer levels, increased accumulation of CcO subcomplexes and gave rise to an altered pattern of respiratory supercomplexes."
Isolates the assembly consequence of losing this specific subunit in human cells: less holoenzyme, accumulated subcomplexes, and disturbed supercomplexes. This is the mechanism that the patient-cell activity measurement above only reports the end result of.
Impaired Terminal Electron Transfer and ATP Synthesis
Less functional cytochrome c oxidase means less electron transfer from reduced cytochrome c to oxygen and less proton pumping, so oxidative ATP synthesis falls. In this disease the deficit is partial rather than complete - patients survive to adulthood in the founding families - which is consistent with a subunit that is reduced rather than absent.
mitochondrial electron transport, cytochrome c to oxygen GO:0006123 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial electron transport, cytochrome c to oxygen (GO:0006123). GO:0006123 is a biological process from the Gene Ontology. ↓ DECREASED oxidative phosphorylation GO:0006119 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased oxidative phosphorylation (GO:0006119). GO:0006119 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Isoform-Restricted Tissue Vulnerability Which tissues actually experience the energy deficit depends on whether a substitute isoform is available.
Lactate Accumulation
Show evidence (1 reference)
PMID:36961412 SUPPORT INDIRECT In Vitro
"Respiratory complex IV (CIV, cytochrome c oxidase) is the terminal enzyme of the mitochondrial electron transport chain."
Establishes the position of the complex in the chain, from which the consequence of losing it follows. INDIRECT because the paper studies isoform biology in engineered cells, not this disease.
Isoform-Restricted Tissue Vulnerability
The candidate explanation for why a defect in a housekeeping respiratory subunit presents as a peripheral neuropathy. Adult cardiac and skeletal muscle switch their complex IV 6A subunit from the ubiquitous COX6A1 to the muscle-specific COX6A2, so those high-demand tissues carry a substitute for the missing subunit. Peripheral nerve does not, and long axons have both the highest ATP cost per cell and no capacity for compensatory isoform switching, which would leave them the tissue at risk. The substitution step is not speculative: forced expression of COX6A2 in COX6A1-knockdown human cells restores both holoenzyme and activity, so the two isoforms are interchangeable at the level of the complex. What is unproven is the step from there to the human disease - nobody has shown that endogenous COX6A2 expression is what protects muscle in a COX6A1-deficient patient, and no CMTRID patient tissue has been compared for COX6A2 content. The node is therefore kept at HYPOTHETICAL: the biochemistry is established, the explanation of the clinical tissue selectivity is not. It is curated rather than omitted because it is the mechanism a reader would otherwise supply silently, and naming it makes it falsifiable.
motor neuron CL:0000100 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves motor neuron (CL:0000100). CL:0000100 is a cell type from the Cell Ontology. sensory neuron CL:0000101 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves sensory neuron (CL:0000101). CL:0000101 is a cell type from the Cell Ontology.
aerobic respiration GO:0009060 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased aerobic respiration (GO:0009060). GO:0009060 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Peripheral Nerve Degeneration with Mixed Conduction Slowing The steps between a chronic partial energy deficit in a neuron and the loss of its distal axon are not established in this disease.
Show evidence (3 references)
PMID:20307258 SUPPORT INDIRECT In Vitro
"The ectopic expression of the heart/muscle-specific isoform of the Cox6 subunit (COX6A2) resulted in restoration of both CcO holoenzyme and activity in COX6A1-knockdown cells."
The load-bearing experiment for this node: COX6A2 can functionally replace COX6A1 in human cells depleted of it. INDIRECT because the rescue is engineered in HEK293 cells, so it shows substitution is possible, not that it happens in a patient's muscle.
PMID:36961412 SUPPORT INDIRECT Model Organism
"We found extensive CIV-containing supramolecular organization in murine musculature at advanced developmental stages, while a switch in the expression from ubiquitous to muscle-specific isoforms of CIV was also detected."
Documents that the isoform switch actually occurs in maturing muscle, which is what makes the rescue experiment above relevant in vivo. INDIRECT: the observation is in normal mouse muscle, and the inference to human nerve versus muscle is the curator's.
PMID:36961412 SUPPORT INDIRECT In Vitro
"We also found that the enzymatic activity of CIV containing the muscle-specific isoform COX6A2 was higher than that with COX6A1 in engineered HEK293T cells."
Shows the two isoforms are not functionally interchangeable, which is what makes the substitution argument non-trivial rather than a restatement of paralogy.
Peripheral Nerve Degeneration with Mixed Conduction Slowing
Length-dependent degeneration of peripheral motor and sensory axons, producing the classic CMT picture of distal weakness, wasting, sensory loss and areflexia. The electrophysiology is what puts this entity in the "intermediate" category: the founding report describes the phenotype as axonal or mixed, meaning conduction velocities that fall between the demyelinating and axonal ranges rather than clearly into one. Curators should note the tension - the entity is named intermediate but the primary description says "axonal or mixed", and both later reports call it axonal.
motor neuron CL:0000100 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves motor neuron (CL:0000100). CL:0000100 is a cell type from the Cell Ontology. sensory neuron CL:0000101 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves sensory neuron (CL:0000101). CL:0000101 is a cell type from the Cell Ontology.
neuron projection development GO:0031175 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neuron projection development (GO:0031175). GO:0031175 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Neurogenic Muscular Atrophy
Show evidence (2 references)
PMID:25152455 SUPPORT Human Clinical
"For two consanguineous families with CMT (axonal and mixed phenotypes), a parametric linkage analysis using genome-wide SNP chip identified a 4.3 Mb region on 12q24 showing a maximum multipoint LOD score of 4.23."
States the electrophysiological classification of the founding families - axonal in one, mixed in the other - which is the observation behind the intermediate designation.
PMID:26556829 SUPPORT INDIRECT Human Clinical
"Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes."
Gives the shared clinical syndrome this node produces. INDIRECT because the paper is about a different gene; it is cited for the CMT phenotype definition and because its screening panel lists CMTRID/COX6A1 among the recognised recessive CMT genes.
Neurogenic Muscular Atrophy
Distal muscle wasting secondary to denervation rather than to a primary myopathy. The distinction matters here because the causative gene is a respiratory chain subunit, so a primary mitochondrial myopathy would be the competing explanation; the Cox6a1-null mouse settles it in that model by showing the atrophy is neurogenic.
Animal models
Cox6a1-null mouse Mouse recapitulates The null mouse develops neurogenic muscular atrophy with impaired walking, which is the model's central result and the reason the gene-disease assertion was accepted.
Show evidence (1 reference)
PMID:25152455 SUPPORT Model Organism
"In addition, Cox6a1-null mice showed significantly reduced COX activity and neurogenic muscular atrophy leading to a difficulty in walking."
States that the atrophy in the null mouse is neurogenic, which is what distinguishes this node from a primary myopathy.
Lactate Accumulation
Elevated circulating lactate from the shift toward glycolysis when oxidative phosphorylation is limited. This was not a feature of the founding families and appears only in the 2025 case, which is part of why that case raises the question of whether it represents the same entity.
Show evidence (1 reference)
PMID:41044399 SUPPORT Human Clinical
"Here we report a 2-year-4-month-old girl who presented with global developmental delay, axonal CMT disease, and elevated lactate levels."
Reports the lactate elevation in the one patient in whom it was described.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Charcot-Marie-Tooth Disease Recessive Intermediate D Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

10
Limbs 1
Pes Cavus FREQUENT HP:0001761 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pes cavus (HP:0001761). HP:0001761 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26556829 SUPPORT INDIRECT Human Clinical
"Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes."
Names foot deformity as a shared feature of the group. INDIRECT because the source states it for the disease group rather than for CMTRID specifically; no CMTRID-specific phenotype series has been published.
Musculoskeletal 1
Distal Muscle Weakness VERY_FREQUENT HP:0002460 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal muscle weakness (HP:0002460), qualified as childhood onset. HP:0002460 is a phenotype from the Human Phenotype Ontology.
Onset: CHILDHOOD
Show evidence (1 reference)
PMID:26556829 SUPPORT INDIRECT Human Clinical
"Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes."
Defines the shared CMT phenotype. INDIRECT because the source states it for the disease group rather than for CMTRID specifically; no CMTRID-specific phenotype series has been published.
Nervous System 2
Gait Difficulty FREQUENT Gait disturbance HP:0001288 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gait disturbance (HP:0001288). HP:0001288 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25152455 SUPPORT Model Organism
"In addition, Cox6a1-null mice showed significantly reduced COX activity and neurogenic muscular atrophy leading to a difficulty in walking."
The walking difficulty is reported in the mouse, not in the human families, so the evidence for this phenotype is graded MODEL_ORGANISM rather than HUMAN_CLINICAL.
Global Developmental Delay OCCASIONAL HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263), qualified as infantile onset. HP:0001263 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (1 reference)
PMID:41044399 SUPPORT Human Clinical
"This study revealed a novel pathogenic COX6A1 variant that causes developmental delay and mitochondrial dysfunction, highlighting stop-loss mutations as a mechanism of disease."
States the developmental delay as a finding of that report.
Other 6
Distal Amyotrophy VERY_FREQUENT HP:0003693 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal amyotrophy (HP:0003693). HP:0003693 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26556829 SUPPORT INDIRECT Human Clinical
"Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes."
Names distal atrophy as a shared feature of the group; not established separately for CMTRID.
Distal Sensory Impairment FREQUENT HP:0002936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal sensory impairment (HP:0002936). HP:0002936 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26556829 SUPPORT INDIRECT Human Clinical
"Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes."
Names distal sensory loss as a shared feature of the group; not established separately for CMTRID.
Diminished or Absent Tendon Reflexes FREQUENT Hyporeflexia HP:0001265 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyporeflexia (HP:0001265). HP:0001265 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26556829 SUPPORT INDIRECT Human Clinical
"Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes."
Names diminished tendon reflexes as a shared feature of the group; not established separately for CMTRID.
Foot Dorsiflexor Weakness FREQUENT HP:0009027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Foot dorsiflexor weakness (HP:0009027). HP:0009027 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26556829 SUPPORT INDIRECT Human Clinical
"Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes."
The distal weakness this specialises is named for the group. INDIRECT, and the dorsiflexor distribution specifically is the group-level clinical pattern rather than a CMTRID observation.
Steppage Gait FREQUENT HP:0003376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Steppage gait (HP:0003376). HP:0003376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26556829 SUPPORT INDIRECT Human Clinical
"Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes."
Follows from the distal weakness and foot deformity named for the group. INDIRECT for the same reason as the others, and recorded because it supplies the human anchor that the mouse-only gait phenotype otherwise lacks.
Elevated Circulating Lactate OCCASIONAL Increased circulating lactate concentration HP:0002151 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased circulating lactate concentration (HP:0002151), qualified as infantile onset. HP:0002151 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (1 reference)
PMID:41044399 SUPPORT Human Clinical
"Here we report a 2-year-4-month-old girl who presented with global developmental delay, axonal CMT disease, and elevated lactate levels."
The single report of lactate elevation in this disease.
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Genetic Associations

1
COX6A1
Gene: COX6A1 hgnc:2277 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is COX6A1 (hgnc:2277). hgnc:2277 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:25152455 SUPPORT Human Clinical
"Those data indicated that COX6A1 mutation causes the autosomal-recessive axonal or mixed CMT."
The gene-disease assertion, made on linkage plus segregation plus functional and mouse data.
PMID:26556829 SUPPORT INDIRECT Human Clinical
"CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN"
Independent adoption of the gene-disease pair into a diagnostic screening panel for recessive CMT, which is corroboration of the assertion's acceptance rather than new evidence for it. INDIRECT for that reason.
💊

Medical Actions

2
Supportive and Rehabilitative Management
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
No disease-modifying therapy exists. Management follows general CMT practice - physiotherapy, orthoses and foot surgery for deformity - and no treatment has been reported specifically in CMTRID. This entry deliberately records no drug therapy rather than importing a generic mitochondrial cocktail: no cofactor or antioxidant has been reported to change the course of this disease, and asserting one would be unsupported.
Show evidence (2 references)
PMID:40014417 SUPPORT INDIRECT Other
"Symptomatic management is still the only option, but many therapeutic approaches are under investigation, some in the clinical trial phase."
Supports the proposition this entry actually makes - that management is symptomatic. INDIRECT because the review covers Charcot-Marie-Tooth disease as a whole and says nothing about CMTRID.
PMID:40014417 SUPPORT INDIRECT Other
"Supportive care, including rehabilitation and orthotics, continues to improve quality of life."
Names the specific measures this treatment entry describes. INDIRECT: a group-level review statement, not a CMTRID result.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
For an autosomal recessive disease with no disease-modifying therapy, reproductive counselling is the one genuinely actionable intervention. Both reported pedigrees were consanguineous or presumed related, which makes cascade carrier testing and the 25 percent sibling recurrence risk the substance of the conversation.
Show evidence (1 reference)
PMID:25152455 SUPPORT INDIRECT Human Clinical
"Those data indicated that COX6A1 mutation causes the autosomal-recessive axonal or mixed CMT."
The recessive inheritance is what the counselling turns on. INDIRECT because the paper establishes the inheritance pattern rather than reporting a counselling intervention.
🔬

Diagnosis

2
Nerve Conduction Studies
Electrophysiology establishes the neuropathy and its category. In CMTRID the velocities reported are axonal or intermediate rather than clearly demyelinating, which is what distinguishes it from the CMT4 demyelinating recessive forms. The binding matters here rather than being bookkeeping: the third knowledge gap below is specifically about conduction velocities, so the diagnostic node it depends on should name the measurement.
nerve conduction velocity test NCIT:C88502 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:25152455 SUPPORT Human Clinical
"For two consanguineous families with CMT (axonal and mixed phenotypes), a parametric linkage analysis using genome-wide SNP chip identified a 4.3 Mb region on 12q24 showing a maximum multipoint LOD score of 4.23."
The electrophysiological classification of the founding families is what the diagnostic category rests on.
Molecular Genetic Testing
Sequencing of COX6A1, in practice as part of a recessive CMT or mitochondrial gene panel or by exome sequencing. Both reported families were solved by sequencing rather than by a biochemical assay, and the founding allele is intronic, so a coding-only analysis would miss it.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:41044399 SUPPORT Human Clinical
"WES revealed a rare homozygous COX6A1 variant (NM_004373.4: c.329 A > T, p.110Leuext41) that is absent in population databases."
Exome sequencing as the route to diagnosis in the most recent case.
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Animal Models

1
Cox6a1-null mouse
A constitutive Cox6a1 knockout generated alongside the human genetic study, used to test whether loss of the subunit is sufficient to produce both the enzymatic and the neuromuscular phenotype.
Species
Mouse
Genotype
Cox6a1 knockout (null)
Publication
PMID:25152455
Pathograph links
Neurogenic Muscular Atrophy recapitulates fidelity: moderate The null mouse develops neurogenic muscular atrophy with impaired walking, which is the model's central result and the reason the gene-disease assertion was accepted.
Limitations: The mouse is a complete null while both human genotypes reduce rather than abolish the protein, so the model tests sufficiency of loss rather than reproducing the human allele. Nerve conduction velocities were not reported for the mouse, so the model says nothing about the intermediate electrophysiology that names the human disease.
Readouts
Neurogenic muscular atrophy and walking difficulty
Direction: INCREASED
Interpretation: Denervation-pattern muscle atrophy with a corresponding motor deficit.
Show evidence (1 reference)
PMID:25152455 SUPPORT Model Organism
"In addition, Cox6a1-null mice showed significantly reduced COX activity and neurogenic muscular atrophy leading to a difficulty in walking."
Reports the atrophy and the motor phenotype in the null mouse.
Show evidence (1 reference)
PMID:25152455 SUPPORT Model Organism
"In addition, Cox6a1-null mice showed significantly reduced COX activity and neurogenic muscular atrophy leading to a difficulty in walking."
Supports treating the null mouse as informative for the denervation node.
Complex IV Biogenesis Failure recapitulates fidelity: high COX activity is significantly reduced in the null mouse, matching the reduction measured in patient lymphoblastoid lines.
Limitations: Reduced activity was reported without a tissue-by-tissue breakdown, so the model does not address whether muscle is spared relative to nerve - the one question the isoform hypothesis in this entry actually turns on.
Readouts
Cytochrome c oxidase activity
Direction: DECREASED
Interpretation: Direct enzymatic confirmation that loss of the subunit lowers holoenzyme activity.
Show evidence (1 reference)
PMID:25152455 SUPPORT Model Organism
"In addition, Cox6a1-null mice showed significantly reduced COX activity and neurogenic muscular atrophy leading to a difficulty in walking."
Reports the reduced COX activity in the null mouse.
Show evidence (1 reference)
PMID:25152455 SUPPORT Model Organism
"In addition, Cox6a1-null mice showed significantly reduced COX activity and neurogenic muscular atrophy leading to a difficulty in walking."
Supports treating the null mouse as informative for the enzymatic node.
{ }

Source YAML

click to show 
name: Charcot-Marie-Tooth Disease Recessive Intermediate D
creation_date: "2026-08-29T17:10:00Z"
category: Mendelian
description: >-
  Charcot-Marie-Tooth disease recessive intermediate D (CMTRID) is an autosomal
  recessive peripheral neuropathy caused by biallelic variants in COX6A1, which
  encodes the ubiquitously expressed 6A isoform of mitochondrial respiratory complex
  IV (cytochrome c oxidase). It is one of the few CMT entities whose primary lesion
  is in oxidative phosphorylation rather than in myelin, axonal transport or the
  cytoskeleton, and MONDO places it under both the intermediate CMT and the
  mitochondrial oxidative phosphorylation disorder branches for that reason.

  The disease was mapped in two consanguineous Japanese families to a five-base
  deletion in the polypyrimidine tract of COX6A1 intron 2, which disrupts splicing of
  exon 3. Patients showed reduced COX6A1 expression in peripheral leukocytes and
  reduced cytochrome c oxidase activity in lymphoblastoid lines, and a Cox6a1-null
  mouse reproduced both the enzymatic defect and a neurogenic muscular atrophy with
  impaired walking. A second allelic mechanism has since been reported: a homozygous
  stop-loss variant extending the protein by 41 residues and reducing steady-state
  protein levels.

  Why a complex IV subunit defect should present as a peripheral neuropathy rather
  than as the encephalopathy or cardiomyopathy typical of COX deficiency is the
  mechanistically interesting question here, and the isoform biology offers a
  partial answer: mature cardiac and skeletal muscle switch from the ubiquitous
  COX6A1 to the muscle-specific COX6A2 isoform, so those tissues have a substitute
  that peripheral nerve does not. That is an inference from isoform expression data
  rather than something demonstrated in this disease, and it is recorded as such.

  The phenotype is not settled. The founding report described an axonal or mixed
  neuropathy, and the entity is nevertheless catalogued as "intermediate"; the most
  recent case adds global developmental delay, elevated lactate and death after a
  febrile decompensation at 3.5 years - a presentation that reads more like a
  mitochondrial disease with neuropathy than like CMT. Whether CMTRID names one
  disease or the neuropathic end of a broader COX6A1-related spectrum is an open
  nosological question, curated here as a knowledge gap rather than resolved.
disease_term:
  preferred_term: Charcot-Marie-Tooth disease recessive intermediate D
  term:
    id: MONDO:0014467
    label: Charcot-Marie-Tooth disease recessive intermediate D
synonyms:
- CMTRID
- Charcot-Marie-Tooth disease, recessive intermediate D
- autosomal recessive intermediate Charcot-Marie-Tooth disease type D
- RI-CMT type D
- COX6A1 Charcot-Marie-Tooth disease
parents:
- Charcot-Marie-Tooth Disease
- Mitochondrial Complex IV Deficiency
- inborn errors of metabolism
inheritance:
- name: Autosomal recessive
  description: >-
    Both reported mechanisms are biallelic. The founding families were consanguineous
    and homozygous for the intron 2 deletion; the later case was homozygous for a
    stop-loss allele. Heterozygous carriers, including the parents in both reports,
    are unaffected.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:25152455
    reference_title: A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Those data indicated that COX6A1 mutation causes the autosomal-recessive axonal
      or mixed CMT.
    explanation: >-
      The founding study states the inheritance pattern as its concluding claim.
  - reference: PMID:41044399
    reference_title: A novel homozygous COX6A1 variant causes axonal charcot-marie-tooth disease, developmental delays and mitochondrial dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WES revealed a rare homozygous COX6A1 variant (NM_004373.4: c.329 A > T,
      p.110Leuext41) that is absent in population databases.
    explanation: >-
      An independent family with a homozygous genotype, confirming recessive
      transmission at a second allele.
pathophysiology:
- name: Biallelic COX6A1 Loss of Function
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Two distinct molecular routes to the same endpoint have been reported. The
    founding allele is a five-base deletion in the polypyrimidine tract of intron 2
    (c.247-10_247-6delCACTC) that disrupts splicing of the adjacent third exon; the
    consequence measured in patients was reduced COX6A1 expression in peripheral
    white blood cells. The second is a stop-loss substitution that reads through the
    normal termination codon and extends the protein by 41 residues, reducing
    steady-state protein levels. Neither is a missense change altering catalysis:
    both reduce the amount of COX6A1 available, which is why the entry treats the
    lesion as a dosage problem.
  genes:
  - preferred_term: COX6A1
    term:
      id: hgnc:2277
      label: COX6A1
  genetic_context:
    genes:
    - preferred_term: COX6A1
      term:
        id: hgnc:2277
        label: COX6A1
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    notes: >-
      Both reported genotypes are homozygous in consanguineous or presumed-related
      pedigrees. Compound heterozygosity has not been reported, which is a statement
      about the small number of families described rather than about the allele
      requirement.
  evidence:
  - reference: PMID:25152455
    reference_title: A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      revealed a disease-specific 5 bp deletion (c.247-10_247-6delCACTC) in a splicing
      element (pyrimidine tract) of intron 2 adjacent to the third exon of cytochrome
      c oxidase subunit VIa polypeptide 1 (COX6A1), which is a component of
      mitochondrial respiratory complex IV (cytochrome c oxidase
    explanation: >-
      Gives the founding allele, its splicing mechanism, and the identity of the gene
      product as a complex IV subunit.
  - reference: PMID:25152455
    reference_title: A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional analysis showed that expression of COX6A1 in peripheral white blood
      cells from the affected individuals and COX activity in their
      EB-virus-transformed lymphoblastoid cell lines were significantly reduced.
    explanation: >-
      Demonstrates in patient material that the allele reduces both transcript
      abundance and the enzymatic activity of the complex it belongs to. Graded
      IN_VITRO rather than HUMAN_CLINICAL because both assays in this sentence are
      ex vivo - transcript abundance in isolated white blood cells and COX activity
      in EBV-transformed lymphoblastoid lines - and the human origin of the material
      is not what evidence_source records.
  - reference: PMID:41044399
    reference_title: A novel homozygous COX6A1 variant causes axonal charcot-marie-tooth disease, developmental delays and mitochondrial dysfunction.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional assays demonstrated significantly reduced mutant protein levels (p <
      0.01), supporting the pathogenicity of this mutation.
    explanation: >-
      Establishes the second allelic mechanism as also acting by reducing the amount
      of COX6A1 protein.
  downstream:
  - target: Complex IV Biogenesis Failure
    causal_link_type: DIRECT
    description: >-
      COX6A1 is a nuclear-encoded structural subunit of the holoenzyme, so less
      subunit means less assembled complex.
- name: Complex IV Biogenesis Failure
  conforms_to: "complex_iv_assembly_deficiency#Complex IV Biogenesis Failure"
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Reduced COX6A1 leaves the cytochrome c oxidase holoenzyme incompletely assembled.
    This is the module's trigger node; the disease-specific substitution here is that
    the lesion is in a structural subunit with a tissue-restricted paralogue, rather
    than in an assembly factor or metallochaperone shared by all tissues.
  biological_processes:
  - preferred_term: mitochondrial respiratory chain complex IV assembly
    term:
      id: GO:0033617
      label: mitochondrial respiratory chain complex IV assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:25152455
    reference_title: A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      COX activity in their EB-virus-transformed lymphoblastoid cell lines were
      significantly reduced
    explanation: >-
      Measures the assembled complex's activity in patient-derived cells, which is
      the readout of this node.
  - reference: PMID:20307258
    reference_title: "Novel insights into the assembly and function of human nuclear-encoded cytochrome c oxidase subunits 4, 5a, 6a, 7a and 7b."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Knockdown of Cox4, Cox5a and Cox6a resulted in reduced CcO activity, diminished
      affinity of the residual enzyme for oxygen, decreased holoCcO and CcO dimer
      levels, increased accumulation of CcO subcomplexes and gave rise to an altered
      pattern of respiratory supercomplexes.
    explanation: >-
      Isolates the assembly consequence of losing this specific subunit in human
      cells: less holoenzyme, accumulated subcomplexes, and disturbed supercomplexes.
      This is the mechanism that the patient-cell activity measurement above only
      reports the end result of.
  downstream:
  - target: Impaired Terminal Electron Transfer and ATP Synthesis
    causal_link_type: DIRECT
- name: Impaired Terminal Electron Transfer and ATP Synthesis
  conforms_to: "complex_iv_assembly_deficiency#Impaired Terminal Electron Transfer and ATP Synthesis"
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Less functional cytochrome c oxidase means less electron transfer from reduced
    cytochrome c to oxygen and less proton pumping, so oxidative ATP synthesis falls.
    In this disease the deficit is partial rather than complete - patients survive to
    adulthood in the founding families - which is consistent with a subunit that is
    reduced rather than absent.
  biological_processes:
  - preferred_term: mitochondrial electron transport, cytochrome c to oxygen
    term:
      id: GO:0006123
      label: mitochondrial electron transport, cytochrome c to oxygen
    modifier: DECREASED
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
  evidence:
  - reference: PMID:36961412
    reference_title: Switching ubiquitous and muscle-specific isoforms of mitochondrial respiratory complex IV in skeletal muscle fine-tunes complex IV activity.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Respiratory complex IV (CIV, cytochrome c oxidase) is the terminal enzyme of the
      mitochondrial electron transport chain.
    explanation: >-
      Establishes the position of the complex in the chain, from which the
      consequence of losing it follows. INDIRECT because the paper studies isoform
      biology in engineered cells, not this disease.
  downstream:
  - target: Isoform-Restricted Tissue Vulnerability
    causal_link_type: DIRECT
    description: >-
      Which tissues actually experience the energy deficit depends on whether a
      substitute isoform is available.
  - target: Lactate Accumulation
    causal_link_type: DIRECT
- name: Isoform-Restricted Tissue Vulnerability
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  description: >-
    The candidate explanation for why a defect in a housekeeping respiratory subunit
    presents as a peripheral neuropathy. Adult cardiac and skeletal muscle switch
    their complex IV 6A subunit from the ubiquitous COX6A1 to the muscle-specific
    COX6A2, so those high-demand tissues carry a substitute for the missing subunit.
    Peripheral nerve does not, and long axons have both the highest ATP cost per cell
    and no capacity for compensatory isoform switching, which would leave them the
    tissue at risk.

    The substitution step is not speculative: forced expression of COX6A2 in
    COX6A1-knockdown human cells restores both holoenzyme and activity, so the two
    isoforms are interchangeable at the level of the complex. What is unproven is the
    step from there to the human disease - nobody has shown that endogenous COX6A2
    expression is what protects muscle in a COX6A1-deficient patient, and no CMTRID
    patient tissue has been compared for COX6A2 content. The node is therefore kept
    at HYPOTHETICAL: the biochemistry is established, the explanation of the clinical
    tissue selectivity is not. It is curated rather than omitted because it is the
    mechanism a reader would otherwise supply silently, and naming it makes it
    falsifiable.
  biological_processes:
  - preferred_term: aerobic respiration
    term:
      id: GO:0009060
      label: aerobic respiration
    modifier: DECREASED
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  - preferred_term: sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  evidence:
  - reference: PMID:20307258
    reference_title: "Novel insights into the assembly and function of human nuclear-encoded cytochrome c oxidase subunits 4, 5a, 6a, 7a and 7b."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      The ectopic expression of the heart/muscle-specific isoform of the Cox6 subunit
      (COX6A2) resulted in restoration of both CcO holoenzyme and activity in
      COX6A1-knockdown cells.
    explanation: >-
      The load-bearing experiment for this node: COX6A2 can functionally replace
      COX6A1 in human cells depleted of it. INDIRECT because the rescue is engineered
      in HEK293 cells, so it shows substitution is possible, not that it happens
      in a patient's muscle.
  - reference: PMID:36961412
    reference_title: Switching ubiquitous and muscle-specific isoforms of mitochondrial respiratory complex IV in skeletal muscle fine-tunes complex IV activity.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found extensive CIV-containing supramolecular organization in murine
      musculature at advanced developmental stages, while a switch in the expression
      from ubiquitous to muscle-specific isoforms of CIV was also detected.
    explanation: >-
      Documents that the isoform switch actually occurs in maturing muscle, which is
      what makes the rescue experiment above relevant in vivo. INDIRECT: the
      observation is in normal mouse muscle, and the inference to human nerve versus
      muscle is the curator's.
  - reference: PMID:36961412
    reference_title: Switching ubiquitous and muscle-specific isoforms of mitochondrial respiratory complex IV in skeletal muscle fine-tunes complex IV activity.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      We also found that the enzymatic activity of CIV containing the muscle-specific
      isoform COX6A2 was higher than that with COX6A1 in engineered HEK293T cells.
    explanation: >-
      Shows the two isoforms are not functionally interchangeable, which is what makes
      the substitution argument non-trivial rather than a restatement of paralogy.
  downstream:
  - target: Peripheral Nerve Degeneration with Mixed Conduction Slowing
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The steps between a chronic partial energy deficit in a neuron and the loss of
      its distal axon are not established in this disease.
- name: Peripheral Nerve Degeneration with Mixed Conduction Slowing
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Length-dependent degeneration of peripheral motor and sensory axons, producing the
    classic CMT picture of distal weakness, wasting, sensory loss and areflexia. The
    electrophysiology is what puts this entity in the "intermediate" category: the
    founding report describes the phenotype as axonal or mixed, meaning conduction
    velocities that fall between the demyelinating and axonal ranges rather than
    clearly into one. Curators should note the tension - the entity is named
    intermediate but the primary description says "axonal or mixed", and both later
    reports call it axonal.
  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: neuron projection development
    term:
      id: GO:0031175
      label: neuron projection development
    modifier: DECREASED
  evidence:
  - reference: PMID:25152455
    reference_title: A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For two consanguineous families with CMT (axonal and mixed phenotypes), a
      parametric linkage analysis using genome-wide SNP chip identified a 4.3 Mb
      region on 12q24 showing a maximum multipoint LOD score of 4.23.
    explanation: >-
      States the electrophysiological classification of the founding families -
      axonal in one, mixed in the other - which is the observation behind the
      intermediate designation.
  - reference: PMID:26556829
    reference_title: ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies
      that share clinical characteristics of progressive distal muscle weakness and
      atrophy, foot deformities, distal sensory loss, as well as diminished tendon
      reflexes.
    explanation: >-
      Gives the shared clinical syndrome this node produces. INDIRECT because the
      paper is about a different gene; it is cited for the CMT phenotype definition
      and because its screening panel lists CMTRID/COX6A1 among the recognised
      recessive CMT genes.
  downstream:
  - target: Neurogenic Muscular Atrophy
    causal_link_type: DIRECT
- name: Neurogenic Muscular Atrophy
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Distal muscle wasting secondary to denervation rather than to a primary myopathy.
    The distinction matters here because the causative gene is a respiratory chain
    subunit, so a primary mitochondrial myopathy would be the competing explanation;
    the Cox6a1-null mouse settles it in that model by showing the atrophy is
    neurogenic.
  evidence:
  - reference: PMID:25152455
    reference_title: A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In addition, Cox6a1-null mice showed significantly reduced COX activity and
      neurogenic muscular atrophy leading to a difficulty in walking.
    explanation: >-
      States that the atrophy in the null mouse is neurogenic, which is what
      distinguishes this node from a primary myopathy.
- name: Lactate Accumulation
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  conforms_to: "complex_iv_assembly_deficiency#Lactic Acidosis and Metabolic Decompensation"
  description: >-
    Elevated circulating lactate from the shift toward glycolysis when oxidative
    phosphorylation is limited. This was not a feature of the founding families and
    appears only in the 2025 case, which is part of why that case raises the question
    of whether it represents the same entity.
  evidence:
  - reference: PMID:41044399
    reference_title: A novel homozygous COX6A1 variant causes axonal charcot-marie-tooth disease, developmental delays and mitochondrial dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report a 2-year-4-month-old girl who presented with global developmental
      delay, axonal CMT disease, and elevated lactate levels.
    explanation: >-
      Reports the lactate elevation in the one patient in whom it was described.
phenotypes:
- category: Neurologic
  name: Distal Muscle Weakness
  frequency: VERY_FREQUENT
  description: >-
    Length-dependent distal weakness, the core CMT feature.
  phenotype_term:
    preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
    onset:
      onset_category: CHILDHOOD
      notes: >-
        Childhood onset is the pattern in the founding consanguineous families, whose
        affected members reached adulthood. Not an observation with an age range behind
        it - no paper reports onset ages for this entity.
  evidence:
  - reference: PMID:26556829
    reference_title: ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies
      that share clinical characteristics of progressive distal muscle weakness and
      atrophy, foot deformities, distal sensory loss, as well as diminished tendon
      reflexes.
    explanation: >-
      Defines the shared CMT phenotype. INDIRECT because the source states it for the
      disease group rather than for CMTRID specifically; no CMTRID-specific
      phenotype series has been published.
- category: Neurologic
  name: Distal Amyotrophy
  frequency: VERY_FREQUENT
  description: >-
    Distal muscle wasting from chronic denervation.
  phenotype_term:
    preferred_term: Distal amyotrophy
    term:
      id: HP:0003693
      label: Distal amyotrophy
  evidence:
  - reference: PMID:26556829
    reference_title: ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies
      that share clinical characteristics of progressive distal muscle weakness and
      atrophy, foot deformities, distal sensory loss, as well as diminished tendon
      reflexes.
    explanation: >-
      Names distal atrophy as a shared feature of the group; not established
      separately for CMTRID.
- category: Neurologic
  name: Distal Sensory Impairment
  frequency: FREQUENT
  description: >-
    Loss of distal sensation in a stocking-glove distribution.
  phenotype_term:
    preferred_term: Distal sensory impairment
    term:
      id: HP:0002936
      label: Distal sensory impairment
  evidence:
  - reference: PMID:26556829
    reference_title: ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies
      that share clinical characteristics of progressive distal muscle weakness and
      atrophy, foot deformities, distal sensory loss, as well as diminished tendon
      reflexes.
    explanation: >-
      Names distal sensory loss as a shared feature of the group; not established
      separately for CMTRID.
- category: Neurologic
  name: Pes Cavus
  frequency: FREQUENT
  description: >-
    High-arched foot deformity, a cardinal CMT feature arising from the imbalance
    between intrinsic foot muscles and long flexors as denervation progresses.
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  evidence:
  - reference: PMID:26556829
    reference_title: ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies
      that share clinical characteristics of progressive distal muscle weakness and
      atrophy, foot deformities, distal sensory loss, as well as diminished tendon
      reflexes.
    explanation: >-
      Names foot deformity as a shared feature of the group. INDIRECT because the source
      states it for the disease group rather than for CMTRID specifically; no
      CMTRID-specific phenotype series has been published.
- category: Neurologic
  name: Diminished or Absent Tendon Reflexes
  frequency: FREQUENT
  description: >-
    Reduced or absent deep tendon reflexes, the standard examination correlate of the
    large-fibre neuropathy. Bound to Hyporeflexia rather than Areflexia because the
    quoted source says diminished, and areflexia is the stronger claim.
  phenotype_term:
    preferred_term: Hyporeflexia
    term:
      id: HP:0001265
      label: Hyporeflexia
  evidence:
  - reference: PMID:26556829
    reference_title: ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies
      that share clinical characteristics of progressive distal muscle weakness and
      atrophy, foot deformities, distal sensory loss, as well as diminished tendon
      reflexes.
    explanation: >-
      Names diminished tendon reflexes as a shared feature of the group; not established
      separately for CMTRID.
- category: Neurologic
  name: Foot Dorsiflexor Weakness
  frequency: FREQUENT
  description: >-
    Weakness of ankle dorsiflexion - the earliest and most functionally consequential
    distribution of the distal weakness, and the immediate cause of the steppage gait
    below.
  phenotype_term:
    preferred_term: Foot dorsiflexor weakness
    term:
      id: HP:0009027
      label: Foot dorsiflexor weakness
  evidence:
  - reference: PMID:26556829
    reference_title: ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies
      that share clinical characteristics of progressive distal muscle weakness and
      atrophy, foot deformities, distal sensory loss, as well as diminished tendon
      reflexes.
    explanation: >-
      The distal weakness this specialises is named for the group. INDIRECT, and the
      dorsiflexor distribution specifically is the group-level clinical pattern rather
      than a CMTRID observation.
- category: Neurologic
  name: Steppage Gait
  frequency: FREQUENT
  description: >-
    The gait pattern that follows from foot dorsiflexor weakness. Curated separately
    from the model-supported Gait Difficulty below so that the human-anchored phenotype
    and the mouse-anchored one are not conflated.
  phenotype_term:
    preferred_term: Steppage gait
    term:
      id: HP:0003376
      label: Steppage gait
  evidence:
  - reference: PMID:26556829
    reference_title: ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies
      that share clinical characteristics of progressive distal muscle weakness and
      atrophy, foot deformities, distal sensory loss, as well as diminished tendon
      reflexes.
    explanation: >-
      Follows from the distal weakness and foot deformity named for the group. INDIRECT
      for the same reason as the others, and recorded because it supplies the human
      anchor that the mouse-only gait phenotype otherwise lacks.
- category: Neurologic
  name: Gait Difficulty
  frequency: FREQUENT
  description: >-
    Difficulty walking from distal weakness and sensory loss. The corresponding
    finding in the Cox6a1-null mouse is the one behavioural readout reported for the
    model.
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  evidence:
  - reference: PMID:25152455
    reference_title: A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In addition, Cox6a1-null mice showed significantly reduced COX activity and
      neurogenic muscular atrophy leading to a difficulty in walking.
    explanation: >-
      The walking difficulty is reported in the mouse, not in the human families, so
      the evidence for this phenotype is graded MODEL_ORGANISM rather than
      HUMAN_CLINICAL.
- category: Metabolic
  name: Elevated Circulating Lactate
  frequency: OCCASIONAL
  description: >-
    Raised blood lactate, reported in one patient with the stop-loss allele and not in
    the founding families.
  phenotype_term:
    preferred_term: Increased circulating lactate concentration
    term:
      id: HP:0002151
      label: Increased circulating lactate concentration
    onset:
      onset_category: INFANTILE
      notes: >-
        Recorded as infantile because the only patient in whom lactate was elevated
        presented at 2 years 4 months. The onset difference from the founding families
        is the axis the nosology knowledge gap turns on, so it is recorded structurally
        rather than only in prose.
  evidence:
  - reference: PMID:41044399
    reference_title: A novel homozygous COX6A1 variant causes axonal charcot-marie-tooth disease, developmental delays and mitochondrial dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report a 2-year-4-month-old girl who presented with global developmental
      delay, axonal CMT disease, and elevated lactate levels.
    explanation: >-
      The single report of lactate elevation in this disease.
- category: Developmental
  name: Global Developmental Delay
  frequency: OCCASIONAL
  description: >-
    Reported in the 2025 case together with the neuropathy. Whether developmental
    delay belongs to CMTRID or marks a distinct, more severe COX6A1 phenotype is
    unresolved; see the nosology discussion.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
    onset:
      onset_category: INFANTILE
      notes: >-
        Infantile in the single case reporting it. Contrast the childhood-onset
        neuropathy of the founding families; see the nosology knowledge gap.
  evidence:
  - reference: PMID:41044399
    reference_title: A novel homozygous COX6A1 variant causes axonal charcot-marie-tooth disease, developmental delays and mitochondrial dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study revealed a novel pathogenic COX6A1 variant that causes developmental
      delay and mitochondrial dysfunction, highlighting stop-loss mutations as a
      mechanism of disease.
    explanation: >-
      States the developmental delay as a finding of that report.
genetic:
- name: COX6A1
  gene_term:
    preferred_term: COX6A1
    term:
      id: hgnc:2277
      label: COX6A1
  relationship_type: CAUSATIVE
  notes: >-
    The single causative gene. COX6A1 encodes the ubiquitously expressed 6A subunit
    of cytochrome c oxidase; the paralogue COX6A2 is muscle-specific and is not known
    to cause disease. Only two pathogenic alleles have been described - the intron 2
    polypyrimidine-tract deletion and a stop-loss substitution - so the allelic
    spectrum should be read as barely sampled rather than as narrow.
  evidence:
  - reference: PMID:25152455
    reference_title: A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Those data indicated that COX6A1 mutation causes the autosomal-recessive axonal
      or mixed CMT.
    explanation: >-
      The gene-disease assertion, made on linkage plus segregation plus functional and
      mouse data.
  - reference: PMID:26556829
    reference_title: ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN
    explanation: >-
      Independent adoption of the gene-disease pair into a diagnostic screening panel
      for recessive CMT, which is corroboration of the assertion's acceptance rather
      than new evidence for it. INDIRECT for that reason.
diagnosis:
- name: Nerve Conduction Studies
  description: >-
    Electrophysiology establishes the neuropathy and its category. In CMTRID the
    velocities reported are axonal or intermediate rather than clearly demyelinating,
    which is what distinguishes it from the CMT4 demyelinating recessive forms. The
    binding matters here rather than being bookkeeping: the third knowledge gap below is
    specifically about conduction velocities, so the diagnostic node it depends on
    should name the measurement.
  diagnosis_term:
    preferred_term: nerve conduction velocity test
    term:
      id: NCIT:C88502
      label: Nerve Conduction Velocity Test
  evidence:
  - reference: PMID:25152455
    reference_title: A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For two consanguineous families with CMT (axonal and mixed phenotypes), a
      parametric linkage analysis using genome-wide SNP chip identified a 4.3 Mb
      region on 12q24 showing a maximum multipoint LOD score of 4.23.
    explanation: >-
      The electrophysiological classification of the founding families is what the
      diagnostic category rests on.
- name: Molecular Genetic Testing
  description: >-
    Sequencing of COX6A1, in practice as part of a recessive CMT or mitochondrial
    gene panel or by exome sequencing. Both reported families were solved by
    sequencing rather than by a biochemical assay, and the founding allele is
    intronic, so a coding-only analysis would miss it.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:41044399
    reference_title: A novel homozygous COX6A1 variant causes axonal charcot-marie-tooth disease, developmental delays and mitochondrial dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WES revealed a rare homozygous COX6A1 variant (NM_004373.4: c.329 A > T,
      p.110Leuext41) that is absent in population databases.
    explanation: >-
      Exome sequencing as the route to diagnosis in the most recent case.
treatments:
- name: Supportive and Rehabilitative Management
  therapeutic_modality: OTHER
  description: >-
    No disease-modifying therapy exists. Management follows general CMT practice -
    physiotherapy, orthoses and foot surgery for deformity - and no treatment has been
    reported specifically in CMTRID. This entry deliberately records no drug therapy
    rather than importing a generic mitochondrial cocktail: no cofactor or antioxidant
    has been reported to change the course of this disease, and asserting one would be
    unsupported.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:40014417
    reference_title: "Charcot-Marie-Tooth disease: a review of clinical developments and its management - What's new in 2025?"
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      Symptomatic management is still the only option, but many therapeutic approaches
      are under investigation, some in the clinical trial phase.
    explanation: >-
      Supports the proposition this entry actually makes - that management is
      symptomatic. INDIRECT because the review covers Charcot-Marie-Tooth disease as a
      whole and says nothing about CMTRID.
  - reference: PMID:40014417
    reference_title: "Charcot-Marie-Tooth disease: a review of clinical developments and its management - What's new in 2025?"
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      Supportive care, including rehabilitation and orthotics, continues to improve
      quality of life.
    explanation: >-
      Names the specific measures this treatment entry describes. INDIRECT: a
      group-level review statement, not a CMTRID result.
- name: Genetic Counseling
  therapeutic_modality: OTHER
  description: >-
    For an autosomal recessive disease with no disease-modifying therapy, reproductive
    counselling is the one genuinely actionable intervention. Both reported pedigrees
    were consanguineous or presumed related, which makes cascade carrier testing and
    the 25 percent sibling recurrence risk the substance of the conversation.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:25152455
    reference_title: A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Those data indicated that COX6A1 mutation causes the autosomal-recessive axonal
      or mixed CMT.
    explanation: >-
      The recessive inheritance is what the counselling turns on. INDIRECT because the
      paper establishes the inheritance pattern rather than reporting a counselling
      intervention.
animal_models:
- name: Cox6a1-null mouse
  species: Mouse
  genotype: Cox6a1 knockout (null)
  publication: PMID:25152455
  description: >-
    A constitutive Cox6a1 knockout generated alongside the human genetic study, used
    to test whether loss of the subunit is sufficient to produce both the enzymatic
    and the neuromuscular phenotype.
  modeled_mechanisms:
  - target: Neurogenic Muscular Atrophy
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The null mouse develops neurogenic muscular atrophy with impaired walking, which
      is the model's central result and the reason the gene-disease assertion was
      accepted.
    limitations: >-
      The mouse is a complete null while both human genotypes reduce rather than
      abolish the protein, so the model tests sufficiency of loss rather than
      reproducing the human allele. Nerve conduction velocities were not reported for
      the mouse, so the model says nothing about the intermediate electrophysiology
      that names the human disease.
    readouts:
    - name: Neurogenic muscular atrophy and walking difficulty
      target: Neurogenic Muscular Atrophy
      direction: INCREASED
      interpretation: >-
        Denervation-pattern muscle atrophy with a corresponding motor deficit.
      evidence:
      - reference: PMID:25152455
        reference_title: A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In addition, Cox6a1-null mice showed significantly reduced COX activity and
          neurogenic muscular atrophy leading to a difficulty in walking.
        explanation: >-
          Reports the atrophy and the motor phenotype in the null mouse.
    evidence:
    - reference: PMID:25152455
      reference_title: A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In addition, Cox6a1-null mice showed significantly reduced COX activity and
        neurogenic muscular atrophy leading to a difficulty in walking.
      explanation: >-
        Supports treating the null mouse as informative for the denervation node.
  - target: Complex IV Biogenesis Failure
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      COX activity is significantly reduced in the null mouse, matching the reduction
      measured in patient lymphoblastoid lines.
    limitations: >-
      Reduced activity was reported without a tissue-by-tissue breakdown, so the model
      does not address whether muscle is spared relative to nerve - the one question
      the isoform hypothesis in this entry actually turns on.
    readouts:
    - name: Cytochrome c oxidase activity
      target: Complex IV Biogenesis Failure
      direction: DECREASED
      interpretation: >-
        Direct enzymatic confirmation that loss of the subunit lowers holoenzyme
        activity.
      evidence:
      - reference: PMID:25152455
        reference_title: A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In addition, Cox6a1-null mice showed significantly reduced COX activity and
          neurogenic muscular atrophy leading to a difficulty in walking.
        explanation: >-
          Reports the reduced COX activity in the null mouse.
    evidence:
    - reference: PMID:25152455
      reference_title: A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In addition, Cox6a1-null mice showed significantly reduced COX activity and
        neurogenic muscular atrophy leading to a difficulty in walking.
      explanation: >-
        Supports treating the null mouse as informative for the enzymatic node.
discussions:
- discussion_id: cmtrid_nosology_spectrum
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is CMTRID one disease, or the neuropathy-predominant end of a broader
    COX6A1-related mitochondrial disorder?
  attaches_to:
  - pathophysiology#Biallelic COX6A1 Loss of Function
  - phenotypes#Global Developmental Delay
  rationale: >-
    The founding families had an adult-compatible peripheral neuropathy and no
    reported encephalopathy or lactate elevation. The 2025 case had global
    developmental delay, raised lactate and death after a febrile decompensation at
    3.5 years - the natural history of an infantile mitochondrial disease, not of CMT.
    Two genotypes and three families is not enough to say whether that is allelic
    severity, a modifier, or a different entity that happens to share a gene. The
    answer determines whether the developmental and metabolic phenotypes in this entry
    belong here at all, which is why they are recorded as OCCASIONAL and flagged
    rather than folded into the core description.
- discussion_id: cmtrid_isoform_sparing_hypothesis
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Does COX6A2 expression in mature muscle actually spare that tissue in
    COX6A1-deficient patients, or is muscle involvement simply under-investigated?
  attaches_to:
  - pathophysiology#Isoform-Restricted Tissue Vulnerability
  rationale: >-
    The isoform-substitution evidence is strong but entirely non-human-disease: COX6A2
    rescues holoenzyme and activity in COX6A1-knockdown HEK293 cells, and the
    ubiquitous-to-muscle-specific switch is documented in maturing mouse muscle. What
    has never been done is the measurement in the disease: no CMTRID patient tissue has
    been examined for COX6A2 content, and the Cox6a1-null mouse's COX activity was
    reported without a tissue breakdown. The mismatch is specific rather than general -
    the model organism that carries the relevant genotype was never asked the question
    that the cell model was built to answer. Recorded as HUMAN_MODEL_MISMATCH rather
    than as a plain knowledge gap because the evidence exists and is good; what is
    missing is its translation to the human disease.

    Note the rescue experiment also constrains what a therapy could look like: if
    COX6A2 substitutes functionally, inducing it in nerve is a coherent therapeutic
    hypothesis, and the same paper reports that COX6A2 mRNA did not rise on its own in
    the knockdown cells - so the substitution would have to be forced rather than
    coaxed.
  proposed_experiments:
  - experiment_id: cmtrid_tissue_resolved_cox_activity
    name: Tissue-resolved complex IV activity in the Cox6a1-null mouse
    description: >-
      Measure COX activity and COX6A2 protein side by side in sciatic nerve, dorsal
      root ganglion, gastrocnemius and heart of Cox6a1-null and wild-type mice.
    would_support:
    - pathophysiology#Isoform-Restricted Tissue Vulnerability
    supporting_outcome:
    - >-
      COX activity is reduced in nerve and ganglion but preserved in muscle and heart,
      and the preserved tissues are the ones expressing COX6A2.
    would_refute:
    - pathophysiology#Isoform-Restricted Tissue Vulnerability
    refuting_outcome:
    - >-
      COX activity falls equally across nerve and muscle, so isoform substitution does
      not account for the tissue selectivity and another explanation is required.
- discussion_id: cmtrid_intermediate_designation
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does CMTRID meet the electrophysiological definition of intermediate CMT?
  attaches_to:
  - pathophysiology#Peripheral Nerve Degeneration with Mixed Conduction Slowing
  rationale: >-
    The disease is catalogued as recessive intermediate D, but the founding paper
    calls the phenotype axonal or mixed and both subsequent descriptions call it
    axonal. No paper reports the median motor conduction velocities that the
    intermediate category is defined by. The label may be a nosological artefact, and
    a curator matching patients to this entry on the strength of the word
    "intermediate" could be misled.
references:
- reference: PMID:25152455
  title: A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.
- reference: PMID:41044399
  title: A novel homozygous COX6A1 variant causes axonal charcot-marie-tooth disease, developmental delays and mitochondrial dysfunction.
- reference: PMID:26556829
  title: ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.
- reference: PMID:20307258
  title: "Novel insights into the assembly and function of human nuclear-encoded cytochrome c oxidase subunits 4, 5a, 6a, 7a and 7b."
- reference: PMID:36961412
  title: Switching ubiquitous and muscle-specific isoforms of mitochondrial respiratory complex IV in skeletal muscle fine-tunes complex IV activity.
- reference: PMID:40014417
  title: "Charcot-Marie-Tooth disease: a review of clinical developments and its management - What's new in 2025?"

notes: >-
  Lump/split decision. Curated as its own Disease entry rather than as a subtype of a
  broader CMT or complex IV entry. It has its own MONDO term and its own gene, and its
  pathograph is genuinely distinct from both of its parents: it is the only CMT entity
  in this KB whose trigger node is a respiratory chain subunit, and it is the only
  complex IV deficiency in this KB whose dominant tissue is peripheral nerve rather
  than brain, heart or muscle. It conforms to the complex_iv_assembly_deficiency
  module at three nodes rather than duplicating that cascade.

  Evidence base, stated plainly. This entry rests on three human families across two
  papers, plus one mouse model, plus one isoform-biology paper that is not about this
  disease. There is no case series, no natural history study, no prevalence estimate,
  and no reported nerve conduction velocity values - which is why this entry carries
  no prevalence block and why several phenotypes are supported only by a
  group-level CMT definition rather than by CMTRID-specific observation. Those are
  marked with directness: INDIRECT rather than presented as established for this
  disease. The gait phenotype is supported only by the mouse and is graded
  MODEL_ORGANISM accordingly; per the KB's evidence policy this is not sufficient
  support for a human phenotype on its own, and it is retained because the
  corresponding human feature is implied by the CMT diagnosis in the same families
  rather than because the mouse establishes it.

  Named-entity-confusion check. Three collisions to watch. COX6A1 and COX6A2 are
  different genes - the second is the muscle-specific paralogue and is not associated
  with this disease. "CMTRID" abbreviates recessive intermediate D, not
  "CMT-related intermediate disease", and is distinct from CMTDID (dominant
  intermediate D). And PMID:26556829, cited here twice, is a paper about SPG11: it is
  cited for the CMT phenotype definition and for listing CMTRID/COX6A1 in its
  screening panel, not for any COX6A1 result.

  A nomenclature trap worth recording, because a deep-research report walked into it.
  The OpenScientist report generated for this entry cites PMID:7687470 in support of
  COX6A1 being "the ubiquitous/liver-type isoform". That paper is titled "Structural
  organization of the bovine gene for the heart/muscle isoform of cytochrome c oxidase
  subunit VIa" and calls that heart/muscle gene COX6A1 throughout - 1993 bovine
  nomenclature in which the numbering is the reverse of the modern human one, where
  COX6A1 is ubiquitous and COX6A2 is the heart/muscle isoform. The citation therefore
  supports the opposite of the claim it is attached to. PMID:7687470 is deliberately
  not cited in this entry; the isoform claim rests on PMID:20307258 and PMID:36961412,
  both of which use current nomenclature.

  Two further things the same report supplied that this entry could not use. It
  reports that the HPO annotation set for OMIM:616039 includes onion bulb formation
  (HP:0003400), which if correct would be the pathological basis for the intermediate
  classification and would largely answer the third knowledge gap below. It is not
  curated here because the claim's provenance is an HPO disease annotation, and this
  KB has no reference prefix that can cite one with a verifiable quote - there is no
  underlying PMID in the report to check it against. It also reports gnomAD constraint
  metrics for COX6A1 (pLI 0.0023, LOEUF 0.875) consistent with tolerated heterozygous
  loss of function, which is exactly what a recessive disease predicts; that is
  likewise uncitable here for want of a quotable source. If the founding paper's full
  text turns out to describe nerve pathology, the onion-bulb annotation becomes citable
  and would largely resolve the third knowledge gap below - worth revisiting then.

  One review suggestion deliberately not taken: neurotoxic-agent avoidance (vincristine
  and similar) is standard Charcot-Marie-Tooth guidance, but nothing about it is
  CMTRID-specific and no source ties it to this entity. Adding it would put
  group-level management advice in an entry whose whole discipline is separating what is
  known about this disease from what is known about the group.
📚

References & Deep Research

References

6
PMID:25152455
A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease.
No top-level findings curated for this source.
PMID:41044399
A novel homozygous COX6A1 variant causes axonal charcot-marie-tooth disease, developmental delays and mitochondrial dysfunction.
No top-level findings curated for this source.
PMID:26556829
ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.
No top-level findings curated for this source.
PMID:20307258
Novel insights into the assembly and function of human nuclear-encoded cytochrome c oxidase subunits 4, 5a, 6a, 7a and 7b.
No top-level findings curated for this source.
PMID:36961412
Switching ubiquitous and muscle-specific isoforms of mitochondrial respiratory complex IV in skeletal muscle fine-tunes complex IV activity.
No top-level findings curated for this source.
PMID:40014417
Charcot-Marie-Tooth disease: a review of clinical developments and its management - What's new in 2025?
No top-level findings curated for this source.

Deep Research

1
OpenScientist ▸
1. Disease Information
openscientist-autonomous 11 citations 2026-08-29T16:28:15.310364

1. Disease Information

Overview. Charcot-Marie-Tooth disease Recessive Intermediate D (CMTRID) is a rare autosomal-recessive form of inherited peripheral neuropathy (hereditary motor and sensory neuropathy, HMSN). Clinically it presents as a length-dependent, slowly progressive distal sensorimotor neuropathy with the electrophysiological features of an "intermediate" neuropathy — i.e., motor nerve conduction velocities (NCV) that fall between the demyelinating (CMT1, <38 m/s) and purely axonal (CMT2, >38 m/s) ranges, or a mixed axonal-and-demyelinating picture. The disease is caused by loss-of-function variants in COX6A1, a nuclear-encoded structural subunit of mitochondrial respiratory complex IV (cytochrome c oxidase, COX) (PMID: 25152455).

Key identifiers. | Resource | Identifier | |---|---| | OMIM (phenotype) | #616039 — Charcot-Marie-Tooth disease, recessive intermediate D (CMTRID) | | OMIM (gene) | 602072 — COX6A1 | | MONDO | MONDO:0014467 (Charcot-Marie-Tooth disease recessive intermediate D) — verified via EBI OLS4 | | Orphanet | ORPHA:435998 — verified via MONDO xref | | DOID | DOID:0110203 | | GARD | GARD:0017723 | | UMLS | C5569027 | | MedGen | 1800450 (C5569027) | | ICD-10 | G60.0 (Hereditary motor and sensory neuropathy) | | ICD-11 | 8C20 (Hereditary motor and sensory neuropathy) | | MeSH | D002607 (Charcot-Marie-Tooth Disease) | | HGNC (gene) | HGNC:2277 (COX6A1) | | NCBI Gene | 1337 (COX6A1) | | Ensembl | ENSG00000111775 | | UniProt | P12074 (COX6A1_HUMAN) |

MONDO definition (verified): "Any Charcot-Marie-Tooth disease in which the cause of the disease is a mutation in the COX6A1 gene."

Synonyms / alternative names. - CMTRID; CMT Recessive Intermediate type D - Autosomal recessive intermediate Charcot-Marie-Tooth disease, COX6A1-related - COX6A1-related axonal/mixed Charcot-Marie-Tooth disease - Cytochrome c oxidase subunit VIa polypeptide 1-related neuropathy

Source type. Information is derived almost entirely from aggregated, disease-level resources (OMIM/Orphanet) and a small number of individual case reports / small consanguineous-family studies in the primary literature (PMID: 25152455; 41044399). No EHR-scale cohort exists for this specific subtype.

HPO (disease-level suggestions): HP:0007141 (Peripheral axonal neuropathy), HP:0003477 (Peripheral sensory neuropathy), HP:0003693 (Distal amyotrophy), HP:0009830 (Peripheral neuropathy).

2. Etiology

Primary cause — genetic. CMTRID is a monogenic autosomal-recessive disorder caused by biallelic (homozygous or compound-heterozygous) pathogenic variants in COX6A1. The founding study mapped the locus to a 4.3 Mb region on chromosome 12q24 (maximum multipoint LOD 4.23) in two consanguineous families and identified a homozygous 5-bp splice-region deletion c.247-10_247-6delCACTC in intron 2 of COX6A1 (PMID: 25152455).

"a disease-specific 5 bp deletion (c.247-10_247-6delCACTC) in a splicing element (pyrimidine tract) of intron 2 adjacent to the third exon of cytochrome c oxidase subunit VIa polypeptide 1 (COX6A1), which is a component of mitochondrial respiratory complex IV" — Tamiya et al., 2014 (PMID: 25152455)

Risk factors. - Genetic: The only established risk factor is inheritance of two pathogenic COX6A1 alleles. Consanguinity is a strong contributing factor — the originally described families were consanguineous (PMID: 25152455) — increasing the chance of homozygosity for a rare recessive allele. - Environmental / lifestyle: No environmental risk factors are established as causal. However, given the mitochondrial (oxidative-phosphorylation) basis, metabolic stressors — especially febrile illness — can precipitate acute decompensation in severe cases; a child with a COX6A1 stop-loss variant died after a febrile illness at age 3.5 y (PMID: 41044399). General CMT-relevant modifiers (potentially neurotoxic drugs such as vincristine, cisplatin; alcohol; vitamin B6 excess) are prudent to avoid but are not CMTRID-specific. - Age / sex / family history: Autosomal recessive; both sexes affected equally; positive family history and/or consanguinity increase risk.

Protective factors. None specifically established. Heterozygous carriers are clinically unaffected (recessive inheritance). No protective modifier alleles have been reported.

Gene–environment interactions. The most plausible interaction is between the complex IV deficiency genotype and metabolic/energetic demand (fever, catabolic stress, exercise), where increased ATP demand or mitochondrial stress may unmask or worsen the phenotype (inferred from PMID: 41044399). This is not yet formally quantified.

3. Phenotypes

Authoritative HPO clinical synopsis (HPO/Jax annotation network for OMIM:616039; verified iteration 3):

Phenotype HPO term Category
Peripheral neuropathy HP:0009830 Nervous system
Distal sensory impairment HP:0002936 Nervous system
Onion bulb formation (demyelination/remyelination hallmark) HP:0003400 Nervous system
Hyporeflexia HP:0001265 Nervous system
Areflexia HP:0001284 Nervous system
Steppage gait (foot drop) HP:0003376 Nervous system
Foot dorsiflexor weakness HP:0009027 Limbs
Pes cavus HP:0001761 Limbs
Childhood onset HP:0011463 Clinical course
Slowly progressive HP:0003677 Clinical course
Autosomal recessive inheritance HP:0000007 Inheritance

The co-annotation of onion-bulb formation (a demyelinating/remyelinating feature) with axonal signs provides the pathological basis for the "intermediate/mixed" electrophysiological classification.

Additional phenotype detail (from defining families and case reports; PMID: 25152455, 41044399):

Phenotype Type HPO suggestion Onset Severity / Course Frequency (in reported cases)
Distal muscle weakness & atrophy (legs > arms) Clinical sign HP:0007373 / HP:0009027 Childhood Progressive Typical / most
Distal sensory loss Symptom/sign HP:0002936 Childhood Progressive Common
Reduced/absent deep-tendon reflexes Clinical sign HP:0001265 / HP:0001284 Childhood Stable/progressive Common
Pes cavus / foot deformity Physical manifestation HP:0001761 Childhood Progressive Common
Steppage/gait disturbance Symptom HP:0003376 Childhood Progressive Typical
Intermediate/mixed motor NCV + onion bulbs Lab/electrophysiology + pathology HP:0003400 — — Defining feature
Elevated blood/CSF lactate Lab abnormality HP:0002151 Infancy (severe cases) — Severe variant (PMID:41044399)
Global developmental delay Behavioral/developmental HP:0001263 Infancy — Severe variant only (PMID:41044399)
Neurogenic muscular atrophy Pathology HP:0003202 — Progressive Model + patients

Phenotype characteristics. - Age of onset: Typically childhood for the classic neuropathy; infantile (severe multisystem) presentation with the stop-loss variant (PMID: 41044399). - Severity: Variable — from a relatively "pure" intermediate CMT to a severe infantile mitochondrial encephalo-neuropathy with fatal metabolic decompensation. - Progression: Slowly progressive in classic cases; rapidly decompensating in the severe infantile form. - Frequency: Given <10 reported individuals, frequencies are qualitative, not percentages.

Quality-of-life impact. No CMTRID-specific QoL data. In CMT and related rare long-term neurological conditions, HRQL is substantially reduced (mean EQ-5D index 0.2–0.44), with frequent pain, anxiety/depression, and problems with mobility, self-care, and usual activities (PMID: 23001492).

4. Genetic / Molecular Information

Causal gene. COX6A1 (Cytochrome c Oxidase Subunit 6A1) — HGNC:2277, NCBI Gene 1337, OMIM 602072, Ensembl ENSG00000111775, chromosome 12q24.31, 3 exons; encodes an 85-aa mature protein (UniProt P12074, 12-aa mitochondrial targeting presequence) — the ubiquitous/"liver-type" isoform* of COX subunit VIa (the heart/muscle isoform is COX6A2) (PMID: 7687470; 20307258).

Pathogenic variants (reported). | Variant (HGVS) | Type | Zygosity | Consequence | Reference | |---|---|---|---|---| | c.247-10_247-6delCACTC (intron 2) | Splice-region deletion (pyrimidine tract) | Homozygous | Aberrant splicing → reduced COX6A1 expression & COX activity | PMID: 25152455 | | c.329A>T, p.(Ter110Leuext41) | Stop-loss* (missense of stop) | Homozygous | Protein +41 aa, markedly reduced protein level | PMID: 41044399 |

  • ACMG/AMP classification: The reported variants are pathogenic, supported by segregation in consanguineous families, functional assays (reduced mRNA/protein/enzyme activity), and absence from population databases (PMID: 25152455, 41044399).
  • Variant types: splice-region and stop-loss; both act via loss of function.
  • Allele frequency: Reported variants are absent from gnomAD/population databases (PMID: 41044399), consistent with private/family-specific pathogenic alleles.
  • ClinVar landscape (queried iteration 4): Of 50 COX6A1 ClinVar records, the vast majority are VUS or likely-benign missense/synonymous variants; the only "Pathogenic/Likely pathogenic" entries are large 12q24 contiguous-gene CNVs (associated with intellectual disability), not COX6A1 point variants causing CMT. This confirms CMTRID alleles are private and documented chiefly in primary literature rather than variant repositories.
  • gnomAD constraint (queried iteration 4): COX6A1 (ENSG00000111775) shows pLI = 0.0023 and LOEUF (oe_lof) = 0.875 (obs LoF 4 vs exp 4.57) — i.e., heterozygous loss of function is tolerated in the population, exactly as expected for a recessive disorder (carriers unaffected; two hits required).
  • Origin: Germline (inherited recessive). No somatic role.
  • Functional consequence: Loss of function — reduced COX6A1 protein → complex IV assembly/activity deficiency (PMID: 25152455, 20307258).

Modifier genes. None established. Mechanistically, COX6A2 (heart/muscle isoform) can functionally substitute for COX6A1 in cell models (ectopic COX6A2 rescued holoenzyme and activity in COX6A1-knockdown cells; PMID: 20307258), suggesting isoform expression could theoretically modify tissue vulnerability — but this is not demonstrated in patients.

Epigenetic information. No CMTRID-specific epigenetic data. COX6A1 transcription is regulated by mitochondrial-biogenesis factors (e.g., NRF-1) and tissue-specific elements (PMID: 7687470).

Chromosomal abnormalities. None; CMTRID is a single-gene point-variant/small-indel disorder, not a copy-number/structural syndrome. (Contrast with CMT1A, which is a 17p12/PMP22 duplication.)

Gene ontology (molecular): GO:0004129 (cytochrome-c oxidase activity, as complex), GO:0005751 (mitochondrial respiratory chain complex IV), GO:0009060 (aerobic respiration).

5. Environmental Information

  • Environmental factors: No environmental toxins are causal. As a mitochondrial disorder, exposure to mitochondrial/neurotoxic agents (e.g., certain chemotherapeutics, aminoglycosides, alcohol) is theoretically deleterious and should be avoided, though not CMTRID-specific.
  • Lifestyle factors: No established lifestyle causes. Maintaining fitness/physiotherapy is beneficial for CMT generally; avoiding metabolic stress is prudent given OXPHOS deficiency.
  • Infectious agents: Not causal. Febrile/infectious illness can trigger metabolic decompensation in the severe infantile form (PMID: 41044399).

6. Mechanism / Pathophysiology

Causal chain. Biallelic COX6A1 LoF variants → reduced COX6A1 protein → impaired assembly and reduced activity of mitochondrial complex IV (cytochrome c oxidase) → deficient oxidative phosphorylation / ATP production and altered redox state → energetic failure in metabolically demanding, long peripheral axons → length-dependent axonal degeneration (with secondary/mixed demyelinating features giving "intermediate" NCVs) → distal sensorimotor neuropathy and neurogenic muscle atrophy.

Molecular pathways / cellular processes. - Oxidative phosphorylation / electron transport chain (complex IV is the terminal oxidase transferring electrons to O₂). Loss of COX6A1 reduces CcO activity, lowers the enzyme's O₂ affinity, decreases holoenzyme and dimer levels, and perturbs respiratory supercomplex assembly (PMID: 20307258). - Complex IV / supercomplex assembly (COX6A1 is a late-assembling structural subunit) (PMID: 20307258; supercomplex context PMID: 27775717). - Downstream: bioenergetic deficit, likely increased oxidative stress, and impaired axonal maintenance — the general theme of mitochondrial CMTs (cf. MFN2/CMT2A, GDAP1) in which axonal mitochondrial function/transport failure preferentially injures long peripheral nerves (PMID: 32733278, 20335458, 33582224).

Protein dysfunction. Loss-of-function/reduced abundance of a structural subunit → failure of complex IV holoenzyme assembly rather than a gain-of-function or aggregation mechanism (PMID: 25152455, 20307258, 41044399).

Metabolic changes. Reduced aerobic ATP synthesis; lactic acidosis in severe cases (elevated lactate; PMID: 41044399), reflecting a shift to anaerobic metabolism from complex IV deficiency.

Immune system involvement. None described (non-inflammatory, non-autoimmune).

Tissue-damage mechanism. Energy-deprivation-mediated axonal (Wallerian-like) degeneration, most severe distally in long nerves; likely oxidative stress contribution.

Molecular profiling. Functional (not omics) evidence: reduced COX6A1 mRNA in patient leukocytes and reduced COX activity in patient lymphoblastoid lines (PMID: 25152455); reduced mutant protein by functional assay (PMID: 41044399). No transcriptomic/proteomic/metabolomic dataset specific to CMTRID is published.

Upstream vs downstream. Upstream: COX6A1 loss → complex IV deficiency (primary). Downstream: bioenergetic failure → axonal degeneration → muscle denervation/atrophy → weakness, sensory loss, deformity.

Suggested ontology terms. GO:0006119 (oxidative phosphorylation), GO:0033617 (mitochondrial cytochrome c oxidase assembly), GO:0009060 (aerobic respiration), GO:0034599 (cellular response to oxidative stress), GO:0031667 (response to nutrient levels). Cell types (CL): CL:0000101 (sensory neuron), CL:0000100 (motor neuron), CL:0002573 (Schwann cell).

7. Anatomical Structures Affected

  • Organ / system level (primary): Peripheral nervous system — peripheral nerves (UBERON:0000010), especially long motor and sensory nerves of the limbs. Body system: nervous (peripheral).
  • Secondary: Skeletal muscle (neurogenic atrophy; UBERON:0001134), skeleton/feet (pes cavus, deformity; UBERON:0002387 pes). In the severe infantile form, CNS involvement (developmental delay) and systemic metabolic derangement occur (PMID: 41044399).
  • Tissue/cell level: Peripheral axons (motor and sensory neurons), with mixed involvement implicating Schwann cells/myelin — supported by onion-bulb formation (HP:0003400) in the HPO synopsis, a hallmark of demyelination/remyelination that explains the intermediate NCV. Cell Ontology: CL:0000100 (motor neuron), CL:0000101 (sensory neuron), CL:0002573 (Schwann cell).
  • Subcellular level: Mitochondrion (GO:0005739) — specifically the mitochondrial inner membrane (GO:0005743) / respiratory chain complex IV (GO:0005751), with the protein localized to the mitochondrial inner-membrane face (UniProt P12074). Axonal mitochondria are the key affected compartment.
  • Localization / laterality: Distal, length-dependent and bilateral/symmetric (legs affected earlier and more than arms), typical of CMT. UBERON:0002470 (pelvic limb), UBERON:0001021 (nerve).

8. Temporal Development

  • Onset: Usually childhood for the classic intermediate neuropathy; infantile/early-childhood with a severe multisystem phenotype in the stop-loss case (developmental delay from infancy) (PMID: 25152455, 41044399). Pattern: insidious/chronic for the neuropathy; acute decompensation possible with intercurrent illness.
  • Progression: Slowly progressive neuropathy in classic cases; rapid decompensation and death (age 3.5 y) reported in the severe infantile variant (PMID: 41044399). Course is chronic and lifelong.
  • Stages: No formal staging exists; general CMT trajectory = early (subtle distal weakness, foot deformity) → intermediate (functional gait/hand impairment, orthotic need) → advanced (marked distal atrophy, disability).
  • Patterns: Progressive, not relapsing-remitting; no spontaneous remission. Critical windows: intercurrent febrile illness is a period of vulnerability for metabolic crisis in severe cases (PMID: 41044399).

9. Inheritance and Population

  • Inheritance: Autosomal recessive (biallelic COX6A1 variants) (PMID: 25152455).
  • Penetrance: Appears complete in biallelic individuals reported to date (small numbers). Expressivity is variable (mild intermediate CMT to severe infantile mitochondrial disease).
  • Genetic anticipation: Not applicable (not a repeat-expansion disorder).
  • Germline mosaicism: Not reported.
  • Founder effects: None established; reported alleles are private/family-specific and absent from population databases (PMID: 41044399).
  • Consanguinity: Important — index families were consanguineous; homozygosity mapping was the discovery approach (PMID: 25152455).
  • Carrier frequency: Unknown/very low; pathogenic COX6A1 alleles are essentially absent from gnomAD.

Epidemiology. - Prevalence/incidence of CMTRID: Not established — ultra-rare (<10 reported individuals). For context, all-CMT prevalence is ~1 in 2,500 (≈17–40/100,000; PMID: 16775366), but CMTRID is a vanishingly small fraction. - Populations / geography: Reported cases include Japanese (original families; PMID: 25152455) and Chinese (PMID: 41044399) individuals; no ethnic predilection can be inferred from such small numbers. Recessive intermediate CMT overall is enriched in consanguineous populations. - Sex ratio: ~1:1 (autosomal recessive).

10. Diagnostics

Clinical / electrophysiology. - Nerve conduction studies (NCS)/EMG: cornerstone — reveal intermediate motor NCV (or mixed axonal + demyelinating) with reduced amplitudes; EMG shows chronic neurogenic changes/denervation (PMID: 25152455; classification framework PMID: 16775366, 16775364). - Laboratory: Elevated lactate (blood/CSF) supports the mitochondrial/complex IV defect, particularly in severe cases (PMID: 41044399). Cytochrome c oxidase (COX) activity assay in accessible tissue (lymphoblasts/fibroblasts/muscle) is reduced (PMID: 25152455). - Nerve/muscle biopsy (not routinely required): neurogenic muscular atrophy; mixed axonal/demyelinating nerve pathology.

Genetic testing (definitive). - Approach: Because CMTRID is clinically indistinguishable from other intermediate/axonal CMTs, diagnosis rests on molecular genetics. Recommended: NGS gene panel for CMT/inherited neuropathy (including COX6A1), or whole-exome/whole-genome sequencing — the latter identified the founding variant (PMID: 25152455). COX6A1 is included in AR-CMT gene lists (PMID: 26556829 lists "CMTRID/COX6A1"). - Single-gene / targeted testing: appropriate for at-risk relatives once a familial variant is known (cascade testing). - CMA/karyotype/FISH/mtDNA/repeat-expansion testing: generally not applicable (point/indel nuclear-gene disorder; COX6A1 is nuclear, not mtDNA). - Functional confirmation: reduced COX6A1 mRNA/protein and COX enzyme activity support pathogenicity of novel variants (PMID: 25152455, 41044399).

Differential diagnosis. Other intermediate/recessive CMTs — e.g., CMTRIA (GDAP1), CMTRIB (KARS1), CMTRIC (PLEKHG5), dominant-intermediate CMT (DNM2, YARS1, INF2), CMTX (GJB1), CMT2 subtypes, and mitochondrial neuropathies (MFN2/CMT2A). Distinguishing features: elevated lactate and reduced COX activity point toward COX6A1; genetics is definitive (PMID: 16775364, 16541790).

Screening. No population/newborn screening exists for this ultra-rare disorder. Cascade carrier testing of relatives and prenatal/preimplantation testing are options once a familial variant is identified.

11. Outcome / Prognosis

  • Survival/mortality: In classic CMT, life expectancy is generally near-normal; however, the severe infantile COX6A1 form can be fatal — one child died at 3.5 y after febrile decompensation (PMID: 41044399). No cohort mortality figures exist for CMTRID.
  • Morbidity/function: Progressive distal weakness, sensory loss, foot deformity, gait impairment, and hand dysfunction cause chronic disability; substantial reduction in quality of life is expected (EQ-5D 0.2–0.44 in comparable rare neurological conditions; PMID: 23001492).
  • Complications: Foot ulcers/injuries from sensory loss, joint deformity, falls; in severe cases, metabolic crisis with intercurrent illness (PMID: 41044399).
  • Recovery: No spontaneous recovery; management is supportive and does not reverse the neuropathy.
  • Prognostic factors: Variant severity/genotype (stop-loss with residual severe LoF and multisystem features vs milder splice variant), age of onset, presence of lactic acidosis/CNS involvement, and metabolic stability appear prognostically relevant (inferred from PMID: 25152455 vs 41044399).

12. Treatment

No disease-modifying/approved therapy exists for CMTRID. Management is symptomatic and supportive, mirroring general CMT care (PMID: 40014417).

  • Pharmacotherapy: No targeted drug. Symptomatic management of neuropathic pain (e.g., gabapentinoids, duloxetine, tricyclics — NCIT clinical-intervention terms apply generically). Avoid neurotoxic drugs (vincristine and other CMT-hazardous agents).
  • Mitochondrial/supportive measures (rational, not proven for CMTRID): aggressive management of intercurrent illness/fever, avoidance of catabolic/metabolic stress; "mitochondrial cocktail" supplements (e.g., riboflavin, coenzyme Q10, L-carnitine) are sometimes used empirically in complex IV deficiency but lack CMTRID-specific evidence.
  • Advanced therapeutics (investigational for CMT generally, none CMTRID-specific): gene therapy/gene silencing, HDAC6 inhibitors, and metabolic agents are in trials for other CMT subtypes; govorestat (CMT-SORD) may become the first approved CMT drug (PMID: 40014417). None target COX6A1.
  • Clinical-trial status (verified iteration 5): A ClinicalTrials.gov API query returned 0 studies mentioning COX6A1; no interventional or observational trial specifically addresses CMTRID. Patients may be eligible for general CMT natural-history/registry studies.
  • Surgical/interventional: orthopedic correction of foot deformities (e.g., osteotomy, tendon transfer) as needed.
  • Supportive/rehabilitative (mainstay): physical therapy, occupational therapy, ankle-foot orthoses (AFOs), assistive devices, foot care, exercise, and multidisciplinary support improve function and QoL (PMID: 40014417).
  • Treatment outcomes: Supportive care improves function/QoL but does not alter the underlying neurodegeneration.

Suggested NCIT terms: Physical Therapy (C15327), Occupational Therapy (C15243), Orthotic Device (C50077), Supportive Care (C15417), Genetic Counseling (C15391).

13. Prevention

  • Primary prevention: No way to prevent occurrence in a conceived biallelic individual; prevention is reproductive/genetic — carrier identification, genetic counseling, and reproductive options (prenatal diagnosis, PGT) for at-risk couples (especially consanguineous families) (rationale: recessive inheritance, PMID: 25152455).
  • Secondary prevention: Early diagnosis (NCS + genetics) enables timely orthotics, physiotherapy, and surveillance; in severe/infantile cases, early recognition and aggressive management of febrile illness to prevent metabolic decompensation (PMID: 41044399).
  • Tertiary prevention: Prevent complications — foot-care programs to avert ulcers, fall-prevention, contracture prevention via therapy, deformity correction.
  • Immunization/public health/prophylaxis: No vaccine or specific prophylaxis. Standard immunizations to reduce febrile illnesses may be prudent in severe cases (supportive rationale).
  • Counseling: Genetic counseling is central — recurrence risk 25% for siblings of an affected child of carrier parents; carrier testing of relatives.

14. Other Species / Natural Disease

  • Taxonomy: Homo sapiens (NCBI Taxon 9606). Experimental model: Mus musculus (NCBI Taxon 10090).
  • Orthologous genes: Mouse Cox6a1 (NCBI Gene 12861, MGI:103099; verified via mygene.info); COX6A1 is highly conserved across mammals (bovine gene characterized in PMID: 7687470).
  • Natural disease in other species: No naturally occurring COX6A1-related CMT is documented in companion animals or wildlife (OMIA search yields no established entry for this specific gene/phenotype as of this report). Inherited neuropathies do occur in dogs, but a COX6A1 etiology is not established.
  • Comparative biology: Complex IV/OXPHOS machinery is evolutionarily conserved from yeast to mammals, so the bioenergetic mechanism is broadly translatable; the Cox6a1-null mouse reproduces reduced COX activity and neurogenic muscular atrophy (PMID: 25152455).
  • Zoonotic potential: None (non-infectious genetic disease).

15. Model Organisms

  • Primary model — Cox6a1-null mouse (mammalian, knockout): shows significantly reduced COX activity and neurogenic muscular atrophy leading to difficulty walking, recapitulating the core neuromuscular phenotype and confirming causality (PMID: 25152455).

    "Cox6a1-null mice showed significantly reduced COX activity and neurogenic muscular atrophy leading to a difficulty in walking" (PMID: 25152455).

  • Cellular / in vitro models:
  • Patient-derived EBV-transformed lymphoblastoid cell lines (reduced COX activity) and peripheral leukocytes (reduced COX6A1 expression) (PMID: 25152455).
  • HEK-293 RNAi knockdown of COX6A1: reduced CcO activity, decreased holoenzyme/dimer, accumulation of assembly subcomplexes, altered supercomplexes; rescued by COX6A2 (PMID: 20307258).
  • Transfected cell lines demonstrating reduced mutant protein for novel variants (PMID: 41044399).
  • Model characteristics: The knockout mouse recapitulates COX deficiency and neurogenic atrophy/gait impairment. Limitations: murine models may not fully capture the human "intermediate" NCV pattern or the severe multisystem/lactic-acidosis infantile phenotype; small patient numbers limit genotype-phenotype modeling.
  • Applications: Study of complex IV assembly, axonal bioenergetics, and preclinical testing of mitochondrial-supportive or gene-based therapies.
  • Resources: MGI (mouse Cox6a1), IMPC/KOMP for engineered alleles, Cellosaurus for patient lines.

Supported and Refuted Hypotheses

Supported: 1. CMTRID is caused by biallelic loss-of-function COX6A1 variants (splice-region deletion; stop-loss) — supported by linkage (LOD 4.23), WGS/WES, segregation, functional assays, and a knockout mouse (PMID: 25152455, 41044399). 2. The mechanism is mitochondrial complex IV (cytochrome c oxidase) deficiency impairing OXPHOS and causing length-dependent axonal degeneration (PMID: 25152455, 20307258). 3. The phenotypic spectrum is variable, extending from intermediate/axonal CMT to a severe infantile mitochondrial disease with developmental delay and lactic acidosis (PMID: 41044399).

Refuted / not supported: - CMTRID is not a demyelinating-only or dominant disorder; not a chromosomal/CNV syndrome; not infectious/autoimmune. No founder effect or common population allele underlies it.

Limitations and Future Directions

  • Very small evidence base (<10 individuals) → epidemiology, penetrance, natural history, and prognosis are poorly quantified.
  • No omics datasets (transcriptomic/proteomic/metabolomic) specific to CMTRID; mechanistic detail beyond complex IV assembly is inferred.
  • No targeted therapy or clinical trials for COX6A1 CMT.
  • Future work: patient registries; iPSC-derived motor/sensory neuron models; systematic genotype-phenotype correlation; testing of mitochondrial-support and gene-based therapies; clarification of why COX6A2 isoform substitution does not fully protect peripheral nerve in patients.

Key References

  • PMID 25152455 — Tamiya et al. 2014. A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease. (Founding gene-discovery study + Cox6a1-null mouse.)
  • PMID 41044399 — Cai et al. 2026. A novel homozygous COX6A1 variant causes axonal CMT, developmental delays and mitochondrial dysfunction. (First stop-loss variant; phenotype expansion.)
  • PMID 20307258 — Fornuskova et al. 2010. Assembly and function of human nuclear-encoded COX subunits 4, 5a, 6a, 7a, 7b. (COX6A1 in complex IV assembly; COX6A2 rescue.)
  • PMID 7687470 — Smith & Lomax 1993. Structural organization of the COX6A gene. (Gene structure/regulation.)
  • PMID 26556829 — Montecchiani et al. 2016. (Lists CMTRID/COX6A1 among AR-CMT genes.)
  • PMID 16775366 / 16775364 — Houlden & Reilly 2006; Pareyson et al. 2006. (CMT classification, intermediate CMT concept, prevalence.)
  • PMID 40014417 — De Grado et al. 2025. CMT clinical developments and management — 2025. (Management/therapeutic landscape.)
  • PMID 23001492 — Calvert et al. 2013. (QoL/EQ-5D in CMT and rare neurological conditions.)
  • PMID 27775717 — Cogliati et al. 2016. (Complex III–IV supercomplex assembly context.)

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 11
Resolved 11
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 11
On topic 5
Off topic 1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMID:23001492 (4 mentions) - Health-related quality of life and supportive care in patients with rare long-term neurological conditions.
  • shared terms: disease

Weighed against this report's own most characteristic terms: cox6a1, cmt, variant, mitochondrial, cmtrid, severe, complex, intermediate, recessive, metabolic, infantile, axonal, gene, neuropathy, disease, primary, peripheral, cox, genetic, phenotype.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

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

Outcome Count
Terms checked 42
Resolved 36
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 5
Terms whose name was checked 32
Terms named correctly 17
Terms named as a different term 8
Terms whose name is worth a second look 7

Terms the report names something else

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

  • DOID:0110203 (1 mention) - the report calls it "DOID"; DOID calls it Charcot-Marie-Tooth disease recessive intermediate D
  • HP:0002936 (2 mentions) - the report calls it "Distal sensory impairment", "Symptom/sign"; HP calls it Distal sensory impairment
  • HP:0003400 (3 mentions) - the report calls it "Onion bulb formation (demyelination/remyelination hallmark)", "Lab/electrophysiology + pathology"; HP calls it Basal lamina onion bulb formation**
  • HP:0003376 (2 mentions) - the report calls it "Steppage gait (foot drop)", "Symptom"; HP calls it Steppage gait
  • HP:0001761 (2 mentions) - the report calls it "Pes cavus", "Physical manifestation"; HP calls it Pes cavus
  • HP:0002151 (1 mention) - the report calls it "Lab abnormality"; HP calls it Increased circulating lactate concentration
  • HP:0003202 (1 mention) - the report calls it "Pathology"; HP calls it Skeletal muscle atrophy
  • UBERON:0002470 (1 mention) - the report calls it "pelvic limb"; UBERON calls it autopod region

Obsolete terms

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

  • GO:0005751 (obsolete mitochondrial respiratory chain complex IV) (2 mentions) - replaced by GO:0045277

Terms whose name is worth a second look

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

  • HP:0007141 (1 mention) - the report calls it "Peripheral axonal neuropathy"; HP calls it Sensorimotor neuropathy, and lists "Sensorimotor peripheral neuropathy" among its other names
  • HP:0003477 (1 mention) - the report calls it "Peripheral sensory neuropathy"; HP calls it Peripheral axonal neuropathy
  • HP:0001263 (1 mention) - the report calls it "Behavioral/developmental"; HP calls it Global developmental delay, and lists "Retarded development" among its other names
  • GO:0004129 (1 mention) - the report calls it "cytochrome-c oxidase activity, as complex"; GO calls it cytochrome-c oxidase activity
  • GO:0005751 (2 mentions) - the report calls it "mitochondrial respiratory chain complex IV", "respiratory chain complex IV"; GO calls it obsolete mitochondrial respiratory chain complex IV
  • GO:0033617 (1 mention) - the report calls it "mitochondrial cytochrome c oxidase assembly"; GO calls it mitochondrial respiratory chain complex IV assembly, and lists "mitochondrial cytochrome c oxidase assembly" among its other names
  • GO:0005739 (1 mention) - the report calls it "Mitochondrion", "Subcellular level: Mitochondrion"; GO calls it mitochondrion

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • HP:0002936 - called "Distal sensory impairment", "Symptom/sign"
  • HP:0003400 - called "Onion bulb formation** (demyelination/remyelination hallmark)", "Lab/electrophysiology + pathology"
  • HP:0003376 - called "Steppage gait (foot drop)", "Symptom"
  • HP:0001761 - called "Pes cavus", "Physical manifestation"
  • GO:0005751 - called "mitochondrial respiratory chain complex IV", "respiratory chain complex IV"
  • GO:0005739 - called "Mitochondrion", "Subcellular level: Mitochondrion"

Prefixes with no resolver

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