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Classifications

Harrison's Part

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Inheritance

1

Autosomal dominant HP:0000006

A single heterozygous CHCHD10 pathogenic variant establishes the diagnosis. Most probands have an affected parent, and each child of an affected individual has a 50% recurrence risk. Intrafamilial clinical heterogeneity is marked enough that neither age at onset nor which arm of the spectrum will manifest can be predicted from the genotype within a family.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:26131548 SUPPORT Human Clinical

"CHCHD10-related disorders are inherited in an autosomal dominant manner. Many individuals diagnosed with a CHCHD10-related disorder have an affected parent."

GeneReviews states the mode of inheritance and the typical familial pattern.

PMID:26131548 SUPPORT Human Clinical

"Because significant clinical heterogeneity is observed within families, it is impossible to accurately predict the age at onset and manifestations that will develop in individuals who inherit a CHCHD10 pathogenic variant."

Supports the statement that intrafamilial variability defeats genotype-based prediction.

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Mechanistic Hypotheses

2

Mitochondrial origin of the FTD-ALS phenotype

mitochondrial_origin_of_ftd_als ALTERNATIVE

Evidence balance 1 support

The proposal that in CHCHD10 disease the FTD-ALS phenotype arises from primary mitochondrial disease rather than from the proteostatic cascade that is the canonical model of ALS and FTD-MND. It is recorded as ALTERNATIVE, not CANONICAL: it is well supported for this gene but is a minority mechanism within the FTD-ALS spectrum as a whole, and the discovery paper itself frames it as opening a field rather than settling one.

Pathograph links

Maladaptive Mitochondrial Integrated Stress Response -> Frontotemporal Cortical and Hippocampal Degeneration INDIRECT UNKNOWN INTERMEDIATES Integrated stress response activation is documented in the hippocampus of the knock-in mouse alongside aggregates and neuroinflammation, but the steps between that activation and neuronal loss are not established.

Neuromuscular Junction Degeneration -> Motor Neuron Degeneration INDIRECT KNOWN INTERMEDIATES Denervation follows end-plate failure in the mouse sequence, with spinal motor neuron loss appearing only at end stage.

Show evidence (1 reference)

PMID:24934289 SUPPORT Human Clinical

"This work opens a novel field to explore the pathogenesis of the frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by showing that mitochondrial disease may be at the origin of some of these phenotypes."

The authors' statement of the hypothesis, including the hedge ("some of these phenotypes") that keeps it an alternative rather than a replacement model.

Muscle-first origin of CHCHD10 motor neuron disease

muscle_first_motor_neuron_disease EMERGING

Evidence balance 1 support

That the pathological sequence runs muscle to neuromuscular junction to motor neuron, rather than beginning in the motor neuron and producing denervation atrophy. It rests on the knock-in mouse ordering, in which muscle OXPHOS deficiency is present at three months with the spinal cord intact and motor neuron loss appears only at end stage. It is EMERGING because the ordering has been demonstrated in one mouse model, is not established in patients, and is in tension with the patient iPSC motor neurons, which are cell-autonomously hypersensitive to stress.

Pathograph links

Combined Respiratory Chain Deficiency -> Neuromuscular Junction Degeneration DIRECT The knock-in mouse establishes the temporal ordering that makes this edge a causal claim rather than a co-occurrence: the muscle bioenergetic lesion precedes end-plate fragmentation.

Mitochondrial Myopathy with Ragged-Red and COX-Negative Fibres -> Neuromuscular Junction Degeneration INDIRECT KNOWN INTERMEDIATES The mouse data argue for a muscle-first sequence in which the myopathic compartment carries the lesion that later disrupts the end plate.

Neuromuscular Junction Degeneration -> Motor Neuron Degeneration INDIRECT KNOWN INTERMEDIATES Denervation follows end-plate failure in the mouse sequence, with spinal motor neuron loss appearing only at end stage.

Show evidence (1 reference)

PMID:30874923 SUPPORT Model Organism

"Our data show that the pathological effects of the p.Ser59Leu mutation target muscle prior to NMJ and motor neurons."

The authors' own statement of the ordering claim this hypothesis names.

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Discussions and Knowledge Gaps

5

Why is mitochondrial cardiomyopathy fully penetrant and fatal in both CHCHD10 knock-in mouse lines while cardiac involvement is not a prominent reported feature of human FTDALS2?

HUMAN MODEL MISMATCH OPEN cardiomyopathy_model_human_divergence

Attached to

pathophysiology#Mitochondrial Cardiomyopathy animal_models#Chchd10 S59L/+ knock-in mouse

This is not a peripheral discrepancy. The cardiomyopathy is the endpoint on which the causal role of the mitochondrial integrated stress response was established, by showing that genetically blunting the response delays its onset. If the organ carrying that experiment is the organ where mouse and human diverge most, then the strongest mechanistic result in the field rests on a phenotype whose human counterpart is unclear. Either human cardiac involvement is real and under-ascertained because patients are seen in neurology clinics, or mouse and human differ in which tissues cross the threshold for the stress response, and those two readings have opposite implications for whether mtISR inhibition is a plausible human target.

Show evidence (2 references)

PMID:30874923 SUPPORT Model Organism

"Before 14 months of age, all KI mice developed a fatal mitochondrial cardiomyopathy associated with enhanced mitophagy."

Establishes the mouse side of the mismatch, including its complete penetrance.

PMID:26131548 SUPPORT Human Clinical

"Regular evaluations to detect manifestations that can occur with time including neurologic deficits, psychiatric abnormalities, impaired respiratory function, and sensorineural hearing loss."

Establishes the human side by omission: the GeneReviews surveillance list names four manifestations and cardiac function is not among them, despite cardiomyopathy being the lethal phenotype in both mouse lines.

What mechanism connects CHCHD10 dysfunction to cerebellar degeneration and to sensorineural hearing loss, both of which are documented clinically but have no node in this entry's mechanism graph?

KNOWLEDGE GAP OPEN cerebellar_and_cochlear_mechanism_gap

Attached to

phenotypes#Cerebellar Ataxia phenotypes#Sensorineural Hearing Impairment

Cerebellar ataxia was the presenting symptom of the founding family's index case at age 50, two further relatives presented with ataxia alone, and the same index case had sensorineural deafness. Both are therefore core to the disease as first described, and both are deliberately left with no upstream pathophysiology node here: the literature reviewed documents them clinically without proposing a cell-type or circuit-level mechanism, and inventing an edge from the generic mitochondrial lesion would assert more than the sources do. The gap is substantive rather than cosmetic, because the mouse models that carry this entry's mechanistic weight are characterized for muscle, heart, motor neuron and hippocampus, and not for cerebellum or cochlea. Closing it needs either neuropathology from CHCHD10 carriers or cerebellar and auditory phenotyping of the existing knock-in lines.

Show evidence (1 reference)

PMID:24934289 SUPPORT Human Clinical

"The index case was a 67-year-old female (Patient IV-6), who developed a cerebellar ataxia at 50 years of age, associated with progressive bulbar syndrome, dementia and sensorineural deafness."

Establishes that both unmodelled phenotypes are present in the founding pedigree, so the gap is about mechanism rather than about whether they occur.

Is CHCHD10 disease a toxic gain of function, a dominant-negative effect on the wild-type protein, or both at once in different tissues?

CONTROVERSY OPEN gof_versus_dominant_negative

Attached to

pathophysiology#CHCHD10 Missense Variant pathophysiology#Mutant CHCHD10 and CHCHD2 Co-Aggregation

Both mechanisms are asserted in the primary literature for the same alleles. The knock-in mouse comparison is the strongest single result and argues for gain of function: ablating CHCHD10 produces neither pathology nor a stress response, while the point mutant produces both, so the disease cannot be explained by absence of the protein. Against that, the same alleles show loss-of-function behaviour in C. elegans complementation and dominant-negative activity in mammalian systems, interfering with CHCHD10's normal role in retaining TDP-43 in the nucleus; and for the SMAJ allele a separate study finds the mechanism is not full haploinsufficiency either. `functional_impact_category` is single-valued, so this entry records GAIN_OF_FUNCTION and this discussion, rather than picking DOMINANT_NEGATIVE and discarding the ablation control. The two are not obviously exclusive: an aggregate that sequesters both CHCHD2 and wild-type CHCHD10 is a novel toxic species and a sink for the normal protein at the same time, which is exactly what would make a single enum value the wrong shape for the claim.

Show evidence (3 references)

PMID:30877432 SUPPORT Model Organism

"Conversely, CHCHD10 ablation does not induce disease pathology or activate the mtISR, indicating that CHCHD10S55L-dependent disease pathology is not caused by loss-of-function."

The gain-of-function side, and the reason that value is the one recorded.

PMID:28585542 REFUTE In Vitro

"dominant negative activities in mammalian systems, resulting in mitochondrial/synaptic damage and cytoplasmic TDP-43 accumulation"

Cuts against a pure gain-of-function reading by demonstrating dominant-negative behaviour for these alleles. Re-quoted to the mammalian clause so this item cites its own claim: the same paper's C. elegans complementation result is graded MODEL_ORGANISM where it is used above, and one sentence cannot carry two evidence_source values.

PMID:40400037 SUPPORT INDIRECT In Vitro

"the disease mechanism of p.G66V is not full haploinsufficiency as residual mutant CHCHD10 protein is present even in a homozygous state"

Rules out the simplest loss-of-function account for a second allele, which narrows the space without settling between gain of function and dominant-negative.

Do CHCHD10 mutations suppress or sensitize apoptosis in the cells that actually degenerate?

CONTROVERSY OPEN apoptosis_direction_conflict

Attached to

pathophysiology#Blocked Cytochrome c Release and Impaired Apoptosis experimental_models#Patient iPSC-derived motor neurons carrying CHCHD10 p.Ser59Leu

Mutant alleles block cytochrome c release and inhibit apoptosis, yet patient iPSC-derived motor neurons are markedly more sensitive to caspase activation than controls. The two results are not formally contradictory, since they use different cell types and different stimuli, but they cannot both be the mechanism of neuronal loss. Resolving this matters because an apoptotic block and an apoptotic sensitization imply opposite therapeutic directions.

What is the actual contribution of CHCHD10 to ALS, given that the early literature described it as a common cause of familial ALS while cohort screening found a 2.6% rate in FTD/FTD-ALS?

OPEN QUESTION OPEN chchd10_als_effect_size_revision

Attached to

genetic#CHCHD10

A 2014 research letter is titled "Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis" (PMID:25261972), and that title is a claim rather than a finding. It is deliberately not cited as evidence anywhere in this entry: the abstract is unavailable in the reference cache, so no snippet could be verified from it, and quoting a title as a finding is exactly the failure mode the evidence policy warns about. The contemporaneous French cohort put the rate at 2.6%, and ClinGen's later expert review classifies the gene-disease relationship as Moderate rather than Definitive. The most likely explanation is not a wave of negative screens but a variant-interpretation error: p.Pro34Ser, counted as pathogenic in several early ALS and FTD series, is far too common in population databases to cause a dominant ultra-rare disease, so early series over-attributed cases to CHCHD10. That account comes from the deep-research report's own gnomAD query rather than from a published source, so it is recorded here as the leading hypothesis and not as evidence; finding a citable population-genetics analysis that states it is the concrete remaining gap.

Show evidence (3 references)

PMID:25155093 SUPPORT Human Clinical

"In this study, we evaluated the frequency of CHCHD10 mutations in 115 patients with FTD and FTD-ALS phenotypes."

Identifies the cohort whose low yield sits against the "common cause" framing.

PMID:28318595 SUPPORT Human Clinical

"Among them, the coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) has been reported to play a controversial role in ALS."

Records that the contested status of the gene in ALS is stated in the primary literature and is not this curation's inference. Quoted from the paper's framing of prior work, and flagged here because the paper's own conclusion runs the other way ("Our findings support the major role of CHCHD10 in the frontotemporal dementia-amyotrophic lateral sclerosis disease spectrum"). The quote establishes that the controversy exists, not the authors' position in it.

PMID:27056076 SUPPORT Human Clinical

"No mutation in CHCHD10 was identified in FALS patients."

A negative result in the very population the "common cause of familial ALS" claim is about, in a cohort of 12 familial ALS patients. Small, so it constrains the effect size weakly rather than settling it.

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Pathophysiology

16

CHCHD10 Missense Variant

A heterozygous missense variant in CHCHD10 (22q11.23), encoding a coiled-coil-helix-coiled-coil-helix domain protein of the mitochondrial intermembrane space that is enriched at cristae junctions. p.Ser59Leu is the allele of the founding French and Spanish FTD-ALS families; p.Gly66Val is a Finnish founder allele causing the lower-motor-neuron-restricted SMAJ/LOSMoN phenotype. The variants act dominantly.

CHCHD10 hgnc:15559

Genetic context CHCHD10 hgnc:15559 allele_type: MISSENSE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION

Monoallelic missense change. The functional impact is assigned GAIN_OF_FUNCTION on the strength of the knock-in mouse comparison, in which CHCHD10 ablation produces neither pathology nor a stress response while the point mutant does. The slot is single-valued and the literature is not unanimous: dominant-negative activity is separately demonstrated for these alleles, and DOMINANT_NEGATIVE is an available value. See the `gof_versus_dominant_negative` discussion for why GAIN_OF_FUNCTION is recorded here rather than that.

Downstream

Mutant CHCHD10 and CHCHD2 Co-Aggregation The mutant protein becomes insoluble and sequesters its paralog, and does so only in the tissues that go on to develop pathology.

Show evidence (3 references)

PMID:24934289 SUPPORT Human Clinical

"Using whole-exome sequencing we identified a missense mutation (c.176C>T; p.Ser59Leu) in the CHCHD10 gene that encodes a coiled-coil helix coiled-coil helix protein, whose function is unknown."

Identifies the founding p.Ser59Leu allele and the protein family it belongs to.

PMID:24934289 SUPPORT In Vitro

"We show that CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions."

Establishes the subcellular localization that the rest of the mechanism depends on.

PMID:25428574 SUPPORT Human Clinical

"In whole genome sequencing a previously unknown mutation c.197G>T p.G66V in CHCHD10 was identified. The mutation was shown to segregate with the disease in 55 patients from 17 families."

Establishes the second major allele of the series with segregation across 17 families.

Mutant CHCHD10 and CHCHD2 Co-Aggregation

Mutant CHCHD10 becomes insoluble within the intermembrane space and co-aggregates with CHCHD2. It is a toxic gain of function rather than a loss of the normal protein, and the insoluble fraction extends well beyond CHCHD10 itself to other intermembrane-space proteins including those required for cytochrome c biogenesis.

protein aggregation in the mitochondrial intermembrane space ⇑ GAIN OF FUNCTION

Animal models

Chchd10 S55L/+ knock-in mouse Mouse recapitulates Mutant CHCHD10 co-aggregates with CHCHD2 in exactly the tissues that develop pathology, and the ablation comparison shows the aggregate rather than the missing protein is what causes disease.

Downstream

MICOS Disassembly and Loss of Cristae Junctions

Maladaptive Mitochondrial Integrated Stress Response

OMA1 Activation and L-OPA1 Cleavage The stress-activated peptidase OMA1 is switched on in affected tissues of the knock-in mouse, which is what connects the aggregate to the cristae lesion through a defined proteolytic step rather than by assertion.

Intermembrane-Space Proteostasis Failure and Impaired Cytochrome c Oxidation

Show evidence (1 reference)

PMID:30877432 SUPPORT Model Organism

"Conversely, CHCHD10 ablation does not induce disease pathology or activate the mtISR, indicating that CHCHD10S55L-dependent disease pathology is not caused by loss-of-function."

The negative control that establishes gain-of-function rather than haploinsufficiency as the mechanism.

OMA1 Activation and L-OPA1 Cleavage

The stress-induced inner-membrane peptidase OMA1 is activated and cleaves the long form of OPA1, the protein that shapes cristae. This supplies the missing proteolytic step between the CHCHD10 aggregate and the cristae lesion, and it is shared with the CHCHD2/CHCHD10 double knockout, which phenocopies the point mutant down to the cardiomyopathy and the stress response. Note that the same peptidase carries the maladaptive stress signal through DELE1 and HRI, so OMA1 sits at the branch point of both arms of this mechanism.

OMA1 metallopeptidase activity ↑ INCREASED

Downstream

MICOS Disassembly and Loss of Cristae Junctions L-OPA1 cleavage is identified as the mechanism of the cristae abnormality rather than a correlate of it.

Show evidence (1 reference)

PMID:32338760 SUPPORT Model Organism

"Finally, C2/C10 DKO mice partially phenocopied mutant C10 KI mice with the development of cardiomyopathy and activation of the integrated mitochondrial integrated stress response in affected tissues, tying mutant C10 pathogenesis to C2/C10 function."

Establishes that losing both paralogs reproduces the point mutant's disease, which is what licenses reading the OMA1 step as part of the FTDALS2 mechanism rather than a separate knockout phenotype.

MICOS Disassembly and Loss of Cristae Junctions

CHCHD10 sits in the mitochondrial contact site and cristae organizing system (MICOS) alongside mitofilin, CHCHD3 and CHCHD6. Mutant protein disassembles the complex, cristae junctions are lost and the inner-membrane architecture dilates and disorganizes, with nucleoids reduced in number and disorganized.

cristae formation GO:0042407 ↓ DECREASED mitochondrion organization GO:0007005 ↓ DECREASED

Experimental models

Patient fibroblasts carrying CHCHD10 p.Ser59Leu PRIMARY CELL CULTURE

Downstream

Mitochondrial DNA Instability with Multiple Deletions Nucleoid disorganization accompanying cristae-junction loss is the proposed route from disrupted membrane architecture to a failure of genome maintenance.

Impaired Mitochondrial Axonal Transport The MICOS lesion and mitochondrial trafficking are coupled, which is the connection the nifuroxazide screen was built on and the reason a MICOS-directed compound acts on transport. Typed as indirect to match the evidence: the coupling is inferred from a pharmacological rescue, and what links a disassembled MICOS complex to a stalled mitochondrion on an axon is not established.

Blocked Cytochrome c Release and Impaired Apoptosis

Show evidence (4 references)

PMID:26666268 SUPPORT In Vitro

"Here, we show that CHCHD10 resides with mitofilin, CHCHD3 and CHCHD6 within the "mitochondrial contact site and cristae organizing system" (MICOS) complex."

Establishes CHCHD10 membership of MICOS, which is what makes the disassembly claim mechanistic.

PMID:24934289 SUPPORT In Vitro

"Overexpression of a CHCHD10 mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae."

Independent demonstration of the cristae lesion, in a heterologous overexpression system.

PMID:30092269 SUPPORT In Vitro

"We also show that G66V fibroblasts do not display the loss of MICOS complex integrity and mitochondrial damage found in S59L cells."

The allele comparison that makes this node the severity determinant of the CHCHD10 series: the severe FTD-ALS allele disassembles MICOS and the mild SMAJ allele does not.

+ 1 more reference

Mitochondrial DNA Instability with Multiple Deletions

Repair of the mitochondrial genome after oxidative stress fails, and multiple mitochondrial DNA deletions accumulate in post-mitotic tissue, most conspicuously skeletal muscle. This places FTDALS2 formally within the mitochondrial DNA instability disorders — the feature that separates it from every proteostasis-driven form of ALS or FTD.

mitochondrial DNA repair GO:0043504 ↓ DECREASED

Experimental models

Patient fibroblasts carrying CHCHD10 p.Ser59Leu PRIMARY CELL CULTURE The system in which the genome-repair defect underlying the deletions was demonstrated, by challenging cells with oxidative stress.

Downstream

Combined Respiratory Chain Deficiency Deleted mtDNA molecules remove subunits of several complexes at once, which is why the biochemical deficit in patient muscle is combined rather than isolated.

Multiple Mitochondrial DNA Deletions The laboratory finding this node is defined by, wired as an edge so the single result the separate-entry argument rests on is reachable from the mechanism graph.

Show evidence (1 reference)

PMID:24934289 SUPPORT Human Clinical

"The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder."

Direct patient-tissue evidence for mtDNA instability in this disease.

Combined Respiratory Chain Deficiency

Oxidative phosphorylation fails, with combined respiratory-chain deficiency and abnormal assembly of complex V in patient muscle and respiratory-chain deficiency in patient fibroblasts. In the knock-in mouse the muscle OXPHOS defect is present at three months of age, before any spinal motor neuron has been lost.

Muscle-first origin of CHCHD10 motor neuron disease

skeletal myofibre CL:0008002

mitochondrial ATP synthesis coupled electron transport GO:0042775 ↓ DECREASED

Downstream

Mitochondrial Myopathy with Ragged-Red and COX-Negative Fibres

Neuromuscular Junction Degeneration The knock-in mouse establishes the temporal ordering that makes this edge a causal claim rather than a co-occurrence: the muscle bioenergetic lesion precedes end-plate fragmentation.

Show evidence (1 reference)

PMID:24934289 SUPPORT Human Clinical

"In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V."

Combined respiratory-chain deficiency documented in every affected member of the founding family.

Intermembrane-Space Proteostasis Failure and Impaired Cytochrome c Oxidation

A second, bioenergetic arm distinct from the stress-signalling arm. Insoluble mutant CHCHD10 disrupts intermembrane-space proteostasis broadly, including proteins of cytochrome c biogenesis, and impairs mitochondrial copper homeostasis and cytochrome c oxidation. That the respiratory defect in mutant mitochondria is corrected by simply adding cytochrome c is what identifies intermembrane-space proteostasis as a proximate lesion rather than a downstream consequence. The rescue was done in cardiac mitochondria, whereas the respiratory-chain deficiency this node feeds is documented in patient skeletal muscle and fibroblasts, so the arm is well evidenced in heart and carried into muscle by mechanism rather than by direct measurement.

Downstream

Combined Respiratory Chain Deficiency

Show evidence (1 reference)

PMID:41420107 SUPPORT Model Organism

"bioenergetic failure linked to impaired mitochondrial copper homeostasis and cytochrome c oxidation"

Names the bioenergetic arm of the dual defect described in this model.

Maladaptive Mitochondrial Integrated Stress Response

Aggregated CHCHD10 triggers a mitochondrial integrated stress response signalled through the OMA1-DELE1-HRI axis and mTORC1, with stress-induced transcription factors, myokine secretion, upregulated serine and one-carbon metabolism, and downregulated respiratory-chain enzymes. The response is maladaptive rather than protective: genetically blunting it delays cardiomyopathy onset. It also does not act upstream of the structural lesion, since blunting it leaves CHCHD10 insolubility, the cristae defect and the OXPHOS impairment untouched.

Mitochondrial origin of the FTD-ALS phenotype

integrated stress response signaling GO:0140467 ↑ INCREASED

Animal models

Chchd10 S55L/+ knock-in mouse Mouse recapitulates Aggregate-driven mtISR through mTORC1 and the OMA1-DELE1-HRI axis, with the response shown to be maladaptive by an epistasis experiment in which protease-inactive Oma1 delays cardiomyopathy.

Downstream

Mitochondrial Cardiomyopathy

Frontotemporal Cortical and Hippocampal Degeneration Integrated stress response activation is documented in the hippocampus of the knock-in mouse alongside aggregates and neuroinflammation, but the steps between that activation and neuronal loss are not established.

Show evidence (2 references)

PMID:30877432 SUPPORT Model Organism

"Overall, CHCHD10S55L mice recapitulate crucial aspects of human disease and reveal a novel toxic gain-of-function mechanism through maladaptive mtISR and metabolic dysregulation."

States the maladaptive character of the response and its centrality to the mechanism.

PMID:41420107 SUPPORT Model Organism

"maladaptive mtISR signaling via the OMA1-DELE1-HRI axis"

Names the signalling axis carrying the response.

Blocked Cytochrome c Release and Impaired Apoptosis

Cristae-junction loss traps cytochrome c, and mutant alleles inhibit apoptosis by preventing its release. This runs counter to the usual expectation that neurodegeneration follows excess apoptosis, and it sits alongside the observation that patient iPSC-derived motor neurons are nonetheless hypersensitive to caspase activation by an applied stressor.

apoptotic process GO:0006915 ↓ DECREASED

Show evidence (3 references)

PMID:26666268 SUPPORT In Vitro

"Interestingly, the expression of CHCHD10 mutant alleles inhibits apoptosis by preventing cytochrome c release."

Direct statement of the apoptotic block.

PMID:30874923 REFUTE In Vitro

"We also showed that motor neurons differentiated from human iPSC carrying the p.Ser59Leu mutation were much more sensitive to Staurosporine or glutamate-induced caspase activation than control cells."

Cuts against a blanket claim that the mutation suppresses apoptosis: in patient-derived motor neurons under stress, caspase activation is increased rather than blocked. Recorded as a REFUTE item rather than reconciled in prose because the two results are from different cell types and stimuli and the discrepancy is unresolved.

PMID:30092269 SUPPORT In Vitro

"The expression of the CHCHD10G66V allele is responsible for mitochondrial network fragmentation and decreased sensitivity towards apoptotic stimuli, but with a less severe effect than that found in cells expressing the CHCHD10S59L allele."

Independent replication of the apoptotic block in a second allele, and a dose relationship: the milder allele produces the milder block. This makes the fibroblast result harder to dismiss as an artefact and sharpens the conflict with the iPSC motor neuron result recorded above.

Mitochondrial Myopathy with Ragged-Red and COX-Negative Fibres

The muscle lesion of a classical mitochondrial myopathy: ragged-red fibres, cytochrome c oxidase-negative fibres, combined respiratory-chain deficiency and abnormal complex V assembly. In the knock-in mouse this is the earliest tissue to be hit, and it is the finding that would not be expected in ALS or FTD from any other cause.

Muscle-first origin of CHCHD10 motor neuron disease

skeletal myofibre CL:0008002

Animal models

Chchd10 S59L/+ knock-in mouse Mouse recapitulates Reproduces the human myopathy with mtDNA instability at the same tissue level at which it is observed in patients.

Downstream

Neuromuscular Junction Degeneration The mouse data argue for a muscle-first sequence in which the myopathic compartment carries the lesion that later disrupts the end plate.

Exercise Intolerance

Proximal Muscle Weakness

Mitochondrial Myopathy The clinical myopathy this tissue lesion presents as.

Ragged-Red Muscle Fibres The histochemical readout of the same lesion, drawn as an edge so the biopsy finding is reachable from the mechanism rather than free-floating.

Cytochrome c Oxidase-Negative Muscle Fibres

Skeletal Muscle Atrophy

Show evidence (2 references)

PMID:24934289 SUPPORT Human Clinical

"In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V."

Documents the histochemical and biochemical myopathy in patient muscle.

PMID:30874923 SUPPORT Model Organism

"Here, we generated knock-in (KI) mice, carrying the p.Ser59Leu mutation, that mimic the mitochondrial myopathy with mtDNA instability displayed by the patients from our original family."

The mouse reproduces the human myopathy, which is what licenses using it for the ordering claim.

Impaired Mitochondrial Axonal Transport

Delivery of mitochondria along the motor axon to the distal compartment fails. The evidence is pharmacological and therefore indirect: a MICOS-directed compound increases axonal mitochondrial movement and degrades syntaphilin (the protein that anchors mitochondria and holds them stationary) in patient-derived motor neurons, which implies the untreated state is under-transported. This node matters disproportionately for a disease whose lesion is distal: the neuromuscular junction is the furthest point from the soma and the most dependent on trafficked mitochondria.

motor neuron CL:0000100

Downstream

Neuromuscular Junction Degeneration A plausible route from the transport deficit to end-plate failure, drawn as indirect because no experiment reported here measures end-plate integrity as a function of transport.

Show evidence (1 reference)

PMID:39478664 SUPPORT INDIRECT In Vitro

"Its benefits involve KIF5B-mediated mitochondrial transport enhancement, evidenced by increased axonal movement and syntaphilin degradation in patient-derived motor neurons."

Names the motor (KIF5B) and the anchoring protein (syntaphilin) and reports that both move in the direction of restored transport under treatment. INDIRECT: the measurement is of a rescue, so the untreated deficit is inferred rather than measured.

Neuromuscular Junction Degeneration

CHCHD10 is highly expressed in the post-synaptic compartment of the neuromuscular junction, and the motor end plate becomes hyper-fragmented. Abnormal CHCHD10 expression is detectable near junctions that are still morphologically intact, so the molecular lesion at the end plate precedes its structural breakdown.

Mitochondrial origin of the FTD-ALS phenotype Muscle-first origin of CHCHD10 motor neuron disease

skeletal myofibre CL:0008002

Downstream

Motor Neuron Degeneration Denervation follows end-plate failure in the mouse sequence, with spinal motor neuron loss appearing only at end stage.

Show evidence (1 reference)

PMID:30874923 SUPPORT Model Organism

"CHCHD10 is highly expressed in the NMJ post-synaptic part. Importantly, the fragmentation of the motor end plate was associated with abnormal CHCHD10 expression that was also observed closed to NMJs which were morphologically normal."

Localizes the protein to the end plate and shows the molecular abnormality preceding structural damage.

Motor Neuron Degeneration

Loss of upper and lower motor neurons producing the ALS arm of the phenotype. In the mouse this is moderate and late relative to the muscle lesion, which is the model's central and most contested claim about human disease: that CHCHD10-related motor neuron disease may be driven from muscle rather than originating in the motor neuron.

spinal cord motor neuron CL:0011001 motor neuron CL:0000100

Experimental models

Patient iPSC-derived motor neurons carrying CHCHD10 p.Ser59Leu IPSC DERIVED MODEL Provides a human, motor-neuron-autonomous vulnerability phenotype, which is the compartment the mouse data argue against being primary.

Animal models

Chchd10 S59L/+ knock-in mouse Mouse partially recapitulates Spinal motor neuron loss occurs, but only moderately and only at end stage, and the mouse is not reported to show the combined upper and lower motor neuron degeneration that defines human ALS.

Downstream

TDP-43 Cytoplasmic Aggregation in Spinal Neurons In the knock-in mouse the aggregates appear at the same end-stage time point as neuronal loss, so that experiment alone cannot order the two. The direction is instead taken from work in which the mutant alleles are shown to act dominant-negatively on CHCHD10's normal role in retaining TDP-43 in the nucleus, which places mitochondrial dysfunction upstream. The intermediates between the two are not established.

Amyotrophic Lateral Sclerosis Phenotype

Bulbar Palsy

Areflexia Loss of the lower motor neuron limb of the reflex arc. Noted in the founding family alongside an extensor plantar response, so lower and upper motor neuron signs coexist.

Show evidence (2 references)

PMID:30874923 SUPPORT Model Organism

"They likely lead to OXPHOS deficiency, loss of cristae junctions and destabilization of internal membrane structure within mitochondria at motor end plate of NMJ, impairing neurotransmission."

The authors' own statement of the route from the mitochondrial lesion to failure of the motor unit.

PMID:24934289 SUPPORT Human Clinical

"We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy."

Establishes motor neuron disease as a core human manifestation of the founding pedigree.

TDP-43 Cytoplasmic Aggregation in Spinal Neurons

Cytoplasmic TDP-43 aggregates are present in spinal neurons at end stage in the knock-in mouse. This is the one point of contact with the canonical proteostatic model of ALS, and it is a late one — worth recording precisely because it shows the mitochondrial and proteostatic accounts converging downstream rather than the mitochondrial lesion being a variant of the proteostatic one.

spinal cord motor neuron CL:0011001

Show evidence (2 references)

PMID:30874923 SUPPORT Model Organism

"At this stage, we observed TDP-43 cytoplasmic aggregates in spinal neurons."

Reports the finding and, in the phrase "at this stage", its end-stage timing.

PMID:35787294 SUPPORT INDIRECT Human Clinical

"insoluble CHCHD10 aggregates accumulate and colocalize with phospho-TDP-43 inclusions in brains of FTLD-TDP and AD patients, and that insoluble CHCHD10 levels tightly correlate with insoluble TDP-43 levels in control and FTLD-TDP brains"

Human post-mortem evidence that the two aggregate species co-localize and co-vary. INDIRECT because the brains studied are FTLD-TDP and Alzheimer cases, not CHCHD10 carriers: it shows wild-type CHCHD10 joining TDP-43 inclusions in unrelated dementias, so it supports a CHCHD10-TDP-43 axis in human brain generally rather than documenting this disease.

Frontotemporal Cortical and Hippocampal Degeneration

The cognitive arm. In patients this is a frontal lobe syndrome with executive, attentional and behavioural impairment; in the knock-in mouse it is impaired learning and memory with reduced long-term potentiation at perforant-pathway/dentate-gyrus synapses, accompanied by aggregates, integrated stress response activation and neuroinflammation.

pyramidal neuron CL:0000598

Animal models

Chchd10 S59L/+ knock-in mouse Mouse partially recapitulates Behavioural and electrophysiological phenotyping shows impaired learning and memory with reduced hippocampal long-term potentiation, alongside aggregates, integrated stress response activation and neuroinflammation.

Downstream

Frontotemporal Dementia Phenotype

Show evidence (1 reference)

PMID:38583639 SUPPORT Model Organism

"These animals show impaired learning and memory capacities with reduced long-term potentiation (LTP) measured at the Perforant Pathway-Dentate Gyrus (PP-DG) synapses."

Provides the functional correlate of the cognitive arm in the model.

Mitochondrial Cardiomyopathy

Cardiac involvement is part of the CHCHD10 phenotype in the mouse, where it is fatal before 14 months and associated with enhanced mitophagy. It is prominent in the model and much less so in reported patients, which is a genuine model-to-human divergence rather than an established feature of FTDALS2.

cardiac muscle cell CL:0000746

Animal models

Chchd10 S59L/+ knock-in mouse Mouse recapitulates Fully penetrant fatal cardiomyopathy before 14 months.

Show evidence (3 references)

PMID:30874923 SUPPORT Model Organism

"Before 14 months of age, all KI mice developed a fatal mitochondrial cardiomyopathy associated with enhanced mitophagy."

Reports the cardiac phenotype and its penetrance in the model.

PMID:38724625 SUPPORT Model Organism

"In mutant hearts, mtISR is accompanied by a metabolic rewiring characterized by increased reliance on glycolysis rather than fatty acid oxidation."

Identifies the substrate switch that follows the stress response in this tissue, which is the step that makes the cardiomyopathy metabolically addressable rather than simply a consequence of failed bioenergetics.

PMID:38724625 SUPPORT Model Organism

"HFD also decreased accumulation of aggregated CHCHD10 in the S55L heart, suggesting activation of quality control mechanisms."

Notable because it runs back up the chain: a dietary intervention reduces the aggregate that initiates the whole mechanism, which argues the aggregate load is not fixed by the genotype alone.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

15

Digestive 1

Dysphagia HP:0002015

Show evidence (1 reference)

PMID:24934289 SUPPORT Human Clinical

"They presented dementia, progressive bulbar syndrome with dysarthria and dysphagia, and became bedridden."

Documents dysphagia across affected family members without muscle biopsy.

Ear 1

Sensorineural Hearing Impairment HP:0000407

Show evidence (2 references)

PMID:26131548 SUPPORT Human Clinical

"Regular evaluations to detect manifestations that can occur with time including neurologic deficits, psychiatric abnormalities, impaired respiratory function, and sensorineural hearing loss."

GeneReviews names sensorineural hearing loss as a manifestation warranting surveillance.

PMID:24934289 SUPPORT Human Clinical

"The index case was a 67-year-old female (Patient IV-6), who developed a cerebellar ataxia at 50 years of age, associated with progressive bulbar syndrome, dementia and sensorineural deafness."

Documents sensorineural deafness in the index patient.

Musculoskeletal 6

Bulbar Palsy HP:0001283

Course: PROGRESSIVE

Sequelae: Dysarthria Dysphagia

Show evidence (1 reference)

PMID:24934289 SUPPORT Human Clinical

"Clinical examination showed cerebellar ataxia, Babinski sign, areflexia and bulbar palsy with dysarthria and dysphagia."

Documents bulbar palsy with its two components in the index case.

Mitochondrial Myopathy HP:0003737

Show evidence (1 reference)

PMID:26131548 SUPPORT Human Clinical

"Mitochondrial myopathy (may also be early onset): weakness, amyotrophy, exercise intolerance."

GeneReviews names the myopathic arm and its early-onset possibility.

Proximal Muscle Weakness HP:0003701

Show evidence (1 reference)

PMID:24934289 SUPPORT Human Clinical

"Proximal weakness was observed in four individuals (Patients IV-3, IV-11, IV-13 and IV-15) with bilateral ptosis and facial paresis in Patient IV-15."

Documents proximal weakness with counts in the founding pedigree.

Skeletal Muscle Atrophy HP:0003202

Show evidence (1 reference)

PMID:26131548 SUPPORT Human Clinical

"Mitochondrial myopathy (may also be early onset): weakness, amyotrophy, exercise intolerance."

GeneReviews lists amyotrophy among the features of the mitochondrial myopathy. Quoted from the myopathy sentence rather than the Charcot-Marie-Tooth one so the citation stays inside this entry's scope.

Ragged-Red Muscle Fibres Ragged-red muscle fibers HP:0003200

Show evidence (1 reference)

PMID:24934289 SUPPORT Human Clinical

"In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V."

Documents ragged-red fibres in all biopsied patients.

Cytochrome c Oxidase-Negative Muscle Fibres Cytochrome C oxidase-negative muscle fibers HP:0003688

Show evidence (1 reference)

PMID:24934289 SUPPORT Human Clinical

"In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V."

Documents COX-negative fibres in all biopsied patients.

Nervous System 5

Frontotemporal Dementia Phenotype HP:0002145

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:26131548 SUPPORT Human Clinical

"Frontotemporal dementia (FTD): slowly progressive behavioral changes, language disturbances, cognitive decline, extrapyramidal signs."

GeneReviews describes the FTD arm of the spectrum.

Amyotrophic Lateral Sclerosis Phenotype HP:0007354

Course: PROGRESSIVE

Show evidence (2 references)

PMID:26131548 SUPPORT Human Clinical

"Amyotrophic lateral sclerosis (ALS): progressive degeneration of upper motor neurons and lower motor neurons."

GeneReviews describes the ALS arm of the spectrum.

PMID:25155093 SUPPORT Human Clinical

"We identified 2 heterozygous variants in 3 unrelated probands presenting FTD and ALS, characterized by early and predominant bulbar symptoms."

Establishes the bulbar-predominant presentation in an independent cohort.

Dysarthria HP:0001260

Show evidence (1 reference)

PMID:24934289 SUPPORT Human Clinical

"They presented dementia, progressive bulbar syndrome with dysarthria and dysphagia, and became bedridden."

Documents dysarthria across affected family members without muscle biopsy.

Cerebellar Ataxia HP:0001251

Show evidence (1 reference)

PMID:26131548 SUPPORT Human Clinical

"Cerebellar ataxia: gait ataxia, kinetic ataxia (progressive loss of coordination of lower- and upper-limb movements), dysarthria/dysphagia, nystagmus, cerebellar oculomotor disorder."

GeneReviews describes the ataxic arm of the spectrum.

Areflexia HP:0001284

Show evidence (1 reference)

PMID:24934289 SUPPORT Human Clinical

"Clinical examination showed cerebellar ataxia, Babinski sign, areflexia and bulbar palsy with dysarthria and dysphagia."

Documents areflexia in an FTDALS2 patient specifically, rather than borrowing the finding from the SMAJ arm of the CHCHD10 spectrum.

Cellular 1

Multiple Mitochondrial DNA Deletions HP:0003689

Show evidence (1 reference)

PMID:24934289 SUPPORT Human Clinical

"The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder."

Documents the deletions and the nosological reclassification they force.

Constitutional 1

Exercise Intolerance HP:0003546

Show evidence (1 reference)

PMID:26131548 SUPPORT Human Clinical

"Mitochondrial myopathy (may also be early onset): weakness, amyotrophy, exercise intolerance."

GeneReviews lists exercise intolerance among the myopathic features.

🧬

Genetic Associations

1

CHCHD10

Gene: CHCHD10 hgnc:15559 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:24934289 SUPPORT Human Clinical

"The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu..."

Independent replication of the founding allele in a second, pathologically confirmed FTD-ALS family, which is what moved CHCHD10 from a single-family observation to a spectrum gene.

💊

Medical Actions

4

Supportive and Symptomatic Management

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

No disease-modifying therapy exists. Management of the ALS, FTD, spinal muscular atrophy and cerebellar ataxia manifestations follows the standard of care for those syndromes from any cause. Nutrition and weight maintenance are treated as essential rather than adjunctive, and bracing and stretching are used to limit contractures, which are painful and interfere with caregiving.

Show evidence (3 references)

PMID:26131548 SUPPORT Human Clinical

"Adequate nutrition and weight maintenance are essential. Appropriate bracing and stretching can minimize joint contractures, which are often painful and can interfere with caregiving."

GeneReviews states the supportive measures and their rationale.

PMID:26131548 SUPPORT Human Clinical

"Management of ALS, FTD, SMA, and cerebellar ataxia is the same as for other causes of these disorders."

States that management is syndrome-directed rather than CHCHD10-specific.

PMID:26131548 SUPPORT Human Clinical

"Baclofen (used to treat spasticity) can sometimes worsen muscle weakness; some drugs used to treat the behavioral manifestations of FTD may worsen dysarthria, dysphagia, and/or respiratory weakness."

The GeneReviews Agents/Circumstances to Avoid content, quoted rather than paraphrased because it is a clinical safety claim.

Surveillance for Multisystem Progression

Action: clinical surveillance Ontology label: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

Regular review for new neurologic deficits, psychiatric abnormalities, impaired respiratory function and sensorineural hearing loss. Respiratory function and hearing are the two that a clinic focused on either parent diagnosis alone would be least likely to monitor.

Show evidence (1 reference)

PMID:26131548 SUPPORT Human Clinical

"Regular evaluations to detect manifestations that can occur with time including neurologic deficits, psychiatric abnormalities, impaired respiratory function, and sensorineural hearing loss."

GeneReviews specifies the surveillance targets.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Autosomal dominant transmission with a 50% recurrence risk per child. Once the familial variant is known, prenatal and preimplantation genetic testing are available. Counseling has to convey that intrafamilial heterogeneity prevents predicting either the age at onset or which arm of the spectrum a carrier will develop.

Show evidence (2 references)

PMID:26131548 SUPPORT Human Clinical

"Once the CHCHD10 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for a CHCHD10-related disorder and preimplantation genetic testing are possible."

States the reproductive options that counseling covers.

PMID:26131548 SUPPORT Human Clinical

"Each child of an individual with a CHCHD10-related disorder has a 50% chance of inheriting the CHCHD10 pathogenic variant."

Sources the recurrence-risk figure that this entry states twice.

Nifuroxazide (investigational, MICOS-directed)

Action: Pharmacotherapy NCIT:C15986

Agent: nifuroxazide NCIT:C90982

Platform: Small molecule

A repurposed broad-spectrum antibacterial identified by screening more than 1600 compounds against yeast strains engineered to mimic MICOS instability. In patient cells it rescues mitochondrial network fragmentation and cristae abnormalities and reduces caspase-dependent death of patient iPSC-derived motor neurons, apparently by enhancing KIF5B-mediated mitochondrial axonal transport. This is preclinical only: no human data exist, and it is recorded here because it is the first candidate aimed at the MICOS lesion that this entry places at the centre of the mechanism, not because it is available.

Mechanism Target:

RESTORES MICOS Disassembly and Loss of Cristae Junctions — Reverses the cristae and network phenotype in patient fibroblasts carrying the founding allele.

Show evidence (1 reference)

PMID:39478664 SUPPORT In Vitro

"We show that nifuroxazide rescues mitochondrial network fragmentation and cristae abnormalities in CHCHD10S59L/+ patient fibroblasts."

Reports the rescue of the specific cellular lesion this treatment targets.

RESTORES Impaired Mitochondrial Axonal Transport — The mechanism the compound's benefit is actually attributed to, as distinct from the MICOS phenotype the screen selected on.

Show evidence (1 reference)

PMID:39478664 SUPPORT In Vitro

"Its benefits involve KIF5B-mediated mitochondrial transport enhancement, evidenced by increased axonal movement and syntaphilin degradation in patient-derived motor neurons."

Attributes the compound's effect to restored mitochondrial transport.

Show evidence (1 reference)

PMID:39478664 SUPPORT In Vitro

"This molecule also decreases caspase-dependent death of human CHCHD10S59L/+ induced pluripotent stem cell-derived motor neurons."

Extends the rescue to the human motor neuron model, which is the disease-relevant cell type.

🔬

Diagnosis

4

Molecular Diagnosis by CHCHD10 Sequencing

The diagnosis is established by finding a heterozygous CHCHD10 pathogenic variant in a patient with one or more characteristic clinical findings. Routes are single-gene sequencing, an ALS/FTD gene panel, exome or genome sequencing. Two negatives matter as much as the positive: repeat-expansion testing (the C9orf72 route) will not find it, and primary mitochondrial DNA testing is the wrong test even though multiple mtDNA deletions are present, because those deletions are secondary to a nuclear-gene defect.

Variant interpretation is the hard part rather than variant detection. The pathogenic alleles are ultra-rare missense changes, while p.Pro34Ser, reported in early ALS and FTD series, is common in population databases and is better read as benign. Conflating the two is the likeliest source of the gene's contested effect size in ALS, which is recorded as an open question under `discussions`.

Show evidence (1 reference)

PMID:26131548 SUPPORT Human Clinical

"The diagnosis is established when a heterozygous CHCHD10 pathogenic variant is detected in an individual with one or more characteristic clinical findings."

GeneReviews states the diagnostic criterion.

Muscle Biopsy Showing Mitochondrial Myopathy

Ragged-red fibres and cytochrome c oxidase-negative fibres with combined respiratory-chain deficiency and abnormal complex V assembly. This is the finding that discriminates CHCHD10 disease from the rest of the FTD-ALS spectrum at the bedside, and it is the practical reason a separate diagnostic entry is worth having: a mitochondrial myopathy in a patient being worked up for ALS or FTD should redirect testing to CHCHD10.

Markers: Ragged-red muscle fibers (HP:0003200) and cytochrome c oxidase-negative muscle fibers (HP:0003688), with combined respiratory-chain deficiency and abnormal complex V assembly.

Show evidence (1 reference)

PMID:24934289 SUPPORT Human Clinical

"In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V."

Reports the biopsy findings in every affected member of the founding family.

Detection of Multiple Mitochondrial DNA Deletions in Skeletal Muscle

Demonstrating multiple mtDNA deletions in muscle establishes the mtDNA instability that reclassifies the clinical FTD-ALS picture as a mitochondrial disorder. It is a supporting rather than a confirmatory test: the deletions are a consequence of the nuclear CHCHD10 defect, so a positive result points towards CHCHD10 without replacing sequencing.

Markers: Multiple mitochondrial DNA deletions (HP:0003689) in skeletal muscle.

Show evidence (1 reference)

PMID:24934289 SUPPORT Human Clinical

"The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder."

Reports the finding and the nosological conclusion drawn from it.

Electromyography and Nerve Conduction Studies

Used to document lower motor neuron involvement and to separate a neurogenic from a myopathic process. In the founding family it did both and gave different answers in different relatives: normal in one, chronic neurogenic change consistent with lower motor neuron disease in another, and purely myopathic change in a third. That within-family divergence is itself the finding, and it is why a single normal or myopathic study does not exclude the diagnosis.

Show evidence (1 reference)

PMID:24934289 SUPPORT Human Clinical

"Electromyography excluded peripheral neuropathy with normal test (Patient V-10), chronic neurogenic changes suggesting a lower motor neuron disease (Patient IV-15) or myopathic abnormalities only (Patient IV-3)."

Documents the three different electrophysiological pictures within one pedigree.

📊

Prevalence

1

Worldwide

Unknown Ultra Rare

No population prevalence estimate exists. The disease is defined by a small number of reported families and cohort screening yields of 2.6% among FTD and FTD-ALS patients and 0.4% among sporadic ALS patients, which are case fractions within a selected clinical group, not prevalences, and are recorded as such under `genetic`. `measure_type` is UNKNOWN rather than a prevalence measure because the sources characterise rarity without measuring occurrence.

Show evidence (1 reference)

PMID:26131548 SUPPORT Human Clinical

"Because of the recent discovery of CHCHD10-related disorders and the limited number of affected individuals reported to date, the natural history of these disorders (except for SMAJ caused by the p.Gly66Val pathogenic variant) is largely unknown."

GeneReviews states that the reported case count is small and the natural history unknown, which is the basis for the qualitative band and for declining to give a number.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Frontotemporal Dementia And/Or Amyotrophic Lateral Sclerosis 2:

Late-onset spinal motor neuronopathy (SMAJ/LOSMoN)

Overlapping Features The allelic disorder at the other end of the CHCHD10 series, caused by the Finnish founder allele p.Gly66Val and segregating in 55 patients from 17 families. It is a pure lower motor neuron syndrome with cramps, fasciculations and areflexia, and it does not carry the dementia or the upper motor neuron involvement that define FTDALS2.

Distinguishing Features

Lower motor neuron involvement only, without upper motor neuron signs
No cognitive decline
A specific Finnish founder haplotype and a different CHCHD10 allele (p.Gly66Val)

Show evidence (3 references)

PMID:25428574 SUPPORT Human Clinical

"Mutation c.197G>T p.G66V in CHCHD10 is the cause of the lower motor neuron syndrome LOSMoN/SMAJ."

Establishes SMAJ as a distinct, allelic CHCHD10 phenotype.

PMID:40400037 SUPPORT Human Clinical

"we report the first homozygous CHCHD10 patient, and show that the variant dosage dictates the severity of the motor neuron disease in SMAJ"

Establishes that severity in the SMAJ arm scales with allele dosage, a different determinant from the MICOS-integrity axis that separates SMAJ from FTDALS2.

PMID:40400037 SUPPORT In Vitro

"the disease mechanism of p.G66V is not full haploinsufficiency as residual mutant CHCHD10 protein is present even in a homozygous state"

Distinguishes the SMAJ allele's mechanism from both haploinsufficiency and from the aggregation-driven gain of function that characterizes FTDALS2.

Axonal Charcot-Marie-Tooth neuropathy

Overlapping Features A further allelic CHCHD10 presentation, with slowly progressive distal weakness and atrophy, loss of tendon reflexes and, critically, sensory abnormalities.

Distinguishing Features

Sensory abnormalities, absent from both the ALS and the SMAJ arms and the most useful bedside discriminator within the CHCHD10 series
Distal rather than proximal or bulbar distribution of weakness

Show evidence (1 reference)

PMID:26131548 SUPPORT Human Clinical

"Axonal Charcot-Marie-Tooth neuropathy: slowly progressive lower-leg muscle weakness and atrophy, small hand muscle weakness, loss of tendon reflexes, sensory abnormalities."

Describes the neuropathic arm including the sensory features that distinguish it.

Autosomal dominant isolated mitochondrial myopathy (CHCHD10 p.Gly58Arg)

Overlapping Features A further allelic CHCHD10 phenotype in which the myopathy and cardiomyopathy occur without motor neuron disease or dementia. It matters here because it shows the mitochondrial arm of FTDALS2 can occur on its own, which is an argument that the mitochondrial lesion is primary rather than a consequence of neurodegeneration.

Distinguishing Features

Myopathy and cardiomyopathy without motor neuron disease or cognitive decline
A distinct allele (p.Gly58Arg)

Show evidence (1 reference)

PMID:37021679 SUPPORT Other

"Different mutations in CHCHD10 cause additional neuromuscular disorders, including the lower motor neuron disease Spinal Muscular Atrophy Jokela type (SMAJ) (p.G66V) and autosomal dominant isolated mitochondrial myopathy (IMMD) (p.G58R)."

Review evidence for the allele-to-syndrome mapping. Graded OTHER because the cited source is an expert review synthesizing the genotype-phenotype correlation rather than reporting primary observations.

🧫

Experimental Models

2

Patient fibroblasts carrying CHCHD10 p.Ser59Leu PRIMARY_CELL_CULTURE

Primary fibroblasts from affected members of the founding family, showing respiratory-chain deficiency, mitochondrial ultrastructural abnormality and network fragmentation, but with mitochondrial fusion intact.

Pathograph links

MICOS Disassembly and Loss of Cristae Junctions recapitulates fidelity: moderate observes: cellular

Limitations: Fibroblasts are not an affected tissue in this disease, and the aggregation that drives pathology in the knock-in mouse is tissue-specific. A cellular phenotype present in fibroblasts therefore may not be the one that kills motor neurons.

Show evidence (1 reference)

PMID:24934289 SUPPORT In Vitro

"Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network."

Documents the cellular phenotype in patient-derived cells.

Mitochondrial DNA Instability with Multiple Deletions measures fidelity: moderate observes: molecular The system in which the genome-repair defect underlying the deletions was demonstrated, by challenging cells with oxidative stress.

Show evidence (1 reference)

PMID:26666268 SUPPORT In Vitro

"Repair of the mitochondrial genome after oxidative stress is impaired in CHCHD10 mutant fibroblasts and this likely explains the accumulation of deleted mtDNA molecules in patient muscle."

The measurement made in this model and the inference drawn from it.

Show evidence (1 reference)

PMID:24934289 SUPPORT In Vitro

"Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts."

A negative result in this model that constrains what it can be used for: the network fragmentation is not a fusion defect, so the model should not be read as reporting on mitochondrial fusion.

Patient iPSC-derived motor neurons carrying CHCHD10 p.Ser59Leu IPSC_DERIVED_MODEL

Motor neurons differentiated from patient induced pluripotent stem cells, which are hypersensitive to staurosporine- or glutamate-induced caspase activation compared with controls.

Pathograph links

Motor Neuron Degeneration partially recapitulates fidelity: moderate observes: cellular Provides a human, motor-neuron-autonomous vulnerability phenotype, which is the compartment the mouse data argue against being primary.

Limitations: The phenotype is a sensitivity to an applied stressor rather than spontaneous degeneration, and its direction is opposite to the apoptotic block seen with mutant alleles in other systems. It also stands against the knock-in mouse ordering in which muscle, not the motor neuron, is hit first.

Show evidence (1 reference)

PMID:30874923 SUPPORT In Vitro

"We also showed that motor neurons differentiated from human iPSC carrying the p.Ser59Leu mutation were much more sensitive to Staurosporine or glutamate-induced caspase activation than control cells."

Reports the cell-autonomous vulnerability measured in this model.

Show evidence (1 reference)

PMID:39478664 SUPPORT In Vitro

"Its benefits involve KIF5B-mediated mitochondrial transport enhancement, evidenced by increased axonal movement and syntaphilin degradation in patient-derived motor neurons."

Establishes this model as one in which a mechanistic readout (axonal mitochondrial transport) can be measured and pharmacologically moved, which is what makes it informative rather than merely patient-derived.

🐁

Animal Models

2

Chchd10 S59L/+ knock-in mouse

Knock-in of the human founding allele at the endogenous mouse locus. It reproduces the mitochondrial myopathy with mtDNA instability seen in the original family, and develops neuromuscular junction and motor neuron degeneration plus a fatal cardiomyopathy. Its most consequential result is the temporal ordering: muscle OXPHOS deficiency is present at three months, before any spinal motor neuron loss.

Species

Mouse

Genotype

Chchd10 p.Ser59Leu heterozygous knock-in

Publication

PMID:30874923

Pathograph links

Mitochondrial Myopathy with Ragged-Red and COX-Negative Fibres recapitulates fidelity: high observes: tissue Reproduces the human myopathy with mtDNA instability at the same tissue level at which it is observed in patients.

Show evidence (1 reference)

PMID:30874923 SUPPORT Model Organism

"Here, we generated knock-in (KI) mice, carrying the p.Ser59Leu mutation, that mimic the mitochondrial myopathy with mtDNA instability displayed by the patients from our original family."

The authors state the model reproduces the patients' myopathy.

Motor Neuron Degeneration partially recapitulates fidelity: moderate observes: tissue Spinal motor neuron loss occurs, but only moderately and only at end stage, and the mouse is not reported to show the combined upper and lower motor neuron degeneration that defines human ALS.

Limitations: Motor neuron loss is described as moderate and confined to the end stage, and the upper motor neuron component of the human phenotype is not demonstrated. Reading this model as an ALS model rather than as a myopathy model with late denervation overstates it.

Readouts

Lumbar spinal cord motor neuron count

Direction: DECREASED

Interpretation: Quantitative correlate of the motor neuron degeneration node.

Show evidence (1 reference)

PMID:30874923 SUPPORT Model Organism

"moderate but significant motor neuron loss in lumbar spinal cord at the end stage of the disease"

Reports the measurement and its direction.

Show evidence (1 reference)

PMID:30874923 SUPPORT Model Organism

"CHCHD10S59L/+ mice also displayed neuromuscular junction (NMJ) and motor neuron degeneration with hyper-fragmentation of the motor end plate and moderate but significant motor neuron loss in lumbar spinal cord at the end stage of the disease."

Reports both the finding and the qualifiers that make it partial rather than full recapitulation.

Frontotemporal Cortical and Hippocampal Degeneration partially recapitulates fidelity: moderate observes: organism Behavioural and electrophysiological phenotyping shows impaired learning and memory with reduced hippocampal long-term potentiation, alongside aggregates, integrated stress response activation and neuroinflammation.

Limitations: The readout is hippocampal learning and memory, whereas human FTD is defined by frontal behavioural and language change with relative memory sparing early on. The model therefore reports a cognitive deficit in the wrong cognitive domain for the human syndrome it is cited for.

Show evidence (1 reference)

PMID:38583639 SUPPORT Model Organism

"They also validate the Chchd10S59L/+ mice as a relevant model for FTD, which can be used for preclinical studies to test new therapeutic strategies for this devastating disease."

The authors' own claim that the model is relevant for FTD; the domain caveat is recorded in limitations.

Mitochondrial Cardiomyopathy recapitulates fidelity: moderate observes: tissue Fully penetrant fatal cardiomyopathy before 14 months.

Limitations: Cardiomyopathy is fully penetrant and fatal in the mouse but is not a prominent reported feature of human FTDALS2, so the model is more severe in this organ than the disease it represents.

Show evidence (1 reference)

PMID:30874923 SUPPORT Model Organism

"Before 14 months of age, all KI mice developed a fatal mitochondrial cardiomyopathy associated with enhanced mitophagy."

Reports the cardiac phenotype and its complete penetrance.

Show evidence (1 reference)

PMID:30874923 SUPPORT Model Organism

"These data confirm that mitochondrial deficiency associated with CHCHD10 mutations can be at the origin of MND."

Supports treating this model as informative for CHCHD10 motor neuron disease, which is the claim the model entry itself makes.

Chchd10 S55L/+ knock-in mouse

An independently generated knock-in of the mouse-equivalent residue. It is the model that established the toxic gain-of-function mechanism, by the contrast between the point mutant and a null allele, and the one in which the OMA1-DELE1-HRI stress axis was dissected genetically.

Species

Mouse

Genotype

Chchd10 p.Ser55Leu heterozygous knock-in (mouse equivalent of human S59L)

Publication

PMID:30877432

Pathograph links

Mutant CHCHD10 and CHCHD2 Co-Aggregation recapitulates fidelity: high observes: molecular Mutant CHCHD10 co-aggregates with CHCHD2 in exactly the tissues that develop pathology, and the ablation comparison shows the aggregate rather than the missing protein is what causes disease.

Show evidence (1 reference)

PMID:30877432 SUPPORT Model Organism

"Conversely, CHCHD10 ablation does not induce disease pathology or activate the mtISR, indicating that CHCHD10S55L-dependent disease pathology is not caused by loss-of-function."

The genetic control that makes the gain-of-function reading of this model sound.

Maladaptive Mitochondrial Integrated Stress Response recapitulates fidelity: high observes: cellular Aggregate-driven mtISR through mTORC1 and the OMA1-DELE1-HRI axis, with the response shown to be maladaptive by an epistasis experiment in which protease-inactive Oma1 delays cardiomyopathy.

Show evidence (1 reference)

PMID:41420107 SUPPORT Model Organism

"Using protease-inactive Oma1E324Q/E324Q knock-in mice, we show that blunting mtISR in Chchd10S55L/+ mice delays cardiomyopathy onset without rescuing CHCHD10 insolubility, cristae defects or OXPHOS impairment."

Establishes that the model supports a causal, and separable, role for the stress response.

Show evidence (1 reference)

PMID:30877432 SUPPORT Model Organism

"Overall, CHCHD10S55L mice recapitulate crucial aspects of human disease and reveal a novel toxic gain-of-function mechanism through maladaptive mtISR and metabolic dysregulation."

The authors' assessment of the model's fidelity to human disease.

{ }

Source YAML

click to show

name: Frontotemporal Dementia And/Or Amyotrophic Lateral Sclerosis 2
creation_date: "2026-09-07T00:00:00Z"
category: Mendelian
description: >-
  Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 (FTDALS2) is an
  adult-onset, autosomal dominant disorder caused by heterozygous missense
  mutation in CHCHD10 at 22q11.23. CHCHD10 encodes a mitochondrial
  intermembrane-space protein enriched at cristae junctions and belonging to the
  MICOS complex, and FTDALS2 is the point at which the FTD-ALS spectrum meets
  primary mitochondrial disease: the founding family presented with motor neuron
  disease and frontal dementia alongside ragged-red and cytochrome c
  oxidase-negative muscle fibres, combined respiratory-chain deficiency and
  multiple mitochondrial DNA deletions. The canonical
  mechanistic model of ALS and of FTD-MND is proteostatic — TDP-43
  mislocalization, C9orf72 dipeptide repeats, SOD1 misfolding — and CHCHD10
  disease does not run through it. Knock-in mouse work shows a toxic
  gain-of-function in which mutant CHCHD10 co-aggregates with its paralog CHCHD2
  and drives a maladaptive mitochondrial integrated stress response, while
  ablating CHCHD10 in that same model produces neither pathology nor a stress
  response, and the earliest measurable lesion is in muscle rather than in motor
  neuron. Ablation is not uniformly silent across models (a separate knockout
  study reports neuromuscular junction impairment); the claim is that the point
  mutant and the null behave differently, not that losing CHCHD10 is harmless. Clinically the CHCHD10 allelic series
  is far wider than the FTDALS2 label implies, spanning isolated mitochondrial
  myopathy, ALS, FTD, late-onset spinal motor neuronopathy (SMAJ/LOSMoN,
  p.Gly66Val), axonal Charcot-Marie-Tooth neuropathy and cerebellar ataxia.
disease_term:
  preferred_term: frontotemporal dementia and/or amyotrophic lateral sclerosis 2
  term:
    id: MONDO:0014395
    label: frontotemporal dementia and/or amyotrophic lateral sclerosis 2
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
synonyms:
- FTDALS2
- frontotemporal dementia and/or amyotrophic lateral sclerosis type 2
- CHCHD10-related disorder
parents:
- Frontotemporal Dementia
- Amyotrophic Lateral Sclerosis
- Motor Neuron Disease
- Mitochondrial Disease
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    A single heterozygous CHCHD10 pathogenic variant establishes the diagnosis.
    Most probands have an affected parent, and each child of an affected
    individual has a 50% recurrence risk. Intrafamilial clinical heterogeneity is
    marked enough that neither age at onset nor which arm of the spectrum will
    manifest can be predicted from the genotype within a family.
  evidence:
  - reference: PMID:26131548
    reference_title: CHCHD10-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CHCHD10-related disorders are inherited in an autosomal dominant manner. Many individuals diagnosed with a CHCHD10-related disorder have an affected parent."
    explanation: GeneReviews states the mode of inheritance and the typical familial pattern.
  - reference: PMID:26131548
    reference_title: CHCHD10-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because significant clinical heterogeneity is observed within families, it is impossible to accurately predict the age at onset and manifestations that will develop in individuals who inherit a CHCHD10 pathogenic variant."
    explanation: Supports the statement that intrafamilial variability defeats genotype-based prediction.
pathophysiology:
- name: CHCHD10 Missense Variant
  biological_scale: MOLECULAR
  description: >-
    A heterozygous missense variant in CHCHD10 (22q11.23), encoding a
    coiled-coil-helix-coiled-coil-helix domain protein of the mitochondrial
    intermembrane space that is enriched at cristae junctions. p.Ser59Leu is the
    allele of the founding French and Spanish FTD-ALS families; p.Gly66Val is a
    Finnish founder allele causing the lower-motor-neuron-restricted SMAJ/LOSMoN
    phenotype. The variants act dominantly.
  genes:
  - preferred_term: CHCHD10
    term:
      id: hgnc:15559
      label: CHCHD10
  genetic_context:
    gene:
      preferred_term: CHCHD10
      term:
        id: hgnc:15559
        label: CHCHD10
    zygosity: HETEROZYGOUS
    allele_type: MISSENSE
    functional_impact_category: GAIN_OF_FUNCTION
    description: >-
      Monoallelic missense change. The functional impact is assigned
      GAIN_OF_FUNCTION on the strength of the knock-in mouse comparison, in which
      CHCHD10 ablation produces neither pathology nor a stress response while the
      point mutant does. The slot is single-valued and the literature is not
      unanimous: dominant-negative activity is separately demonstrated for these
      alleles, and DOMINANT_NEGATIVE is an available value. See the
      `gof_versus_dominant_negative` discussion for why GAIN_OF_FUNCTION is
      recorded here rather than that.
  downstream:
  - target: Mutant CHCHD10 and CHCHD2 Co-Aggregation
    causal_link_type: DIRECT
    description: >-
      The mutant protein becomes insoluble and sequesters its paralog, and does so
      only in the tissues that go on to develop pathology.
    evidence:
    - reference: PMID:30877432
      reference_title: "ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "CHCHD10 accumulates in aggregates with its paralog CHCHD2 specifically in affected tissues of CHCHD10S55L mice, leading to aberrant organelle morphology and function."
      explanation: States that the mutation itself produces the co-aggregate, and that aggregation tracks the affected tissues.
  evidence:
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using whole-exome sequencing we identified a missense mutation (c.176C>T; p.Ser59Leu) in the CHCHD10 gene that encodes a coiled-coil helix coiled-coil helix protein, whose function is unknown."
    explanation: Identifies the founding p.Ser59Leu allele and the protein family it belongs to.
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions."
    explanation: Establishes the subcellular localization that the rest of the mechanism depends on.
  - reference: PMID:25428574
    reference_title: Late onset spinal motor neuronopathy is caused by mutation in CHCHD10.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In whole genome sequencing a previously unknown mutation c.197G>T p.G66V in CHCHD10 was identified. The mutation was shown to segregate with the disease in 55 patients from 17 families."
    explanation: Establishes the second major allele of the series with segregation across 17 families.

- name: Mutant CHCHD10 and CHCHD2 Co-Aggregation
  biological_scale: MOLECULAR
  description: >-
    Mutant CHCHD10 becomes insoluble within the intermembrane space and
    co-aggregates with CHCHD2. It is a toxic gain of function rather than a loss of
    the normal protein, and the insoluble
    fraction extends well beyond CHCHD10 itself to other intermembrane-space
    proteins including those required for cytochrome c biogenesis.
  molecular_functions:
  - preferred_term: protein aggregation in the mitochondrial intermembrane space
    modifier: GAIN_OF_FUNCTION
  downstream:
  - target: MICOS Disassembly and Loss of Cristae Junctions
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26666268
      reference_title: "CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "CHCHD10 mutations lead to MICOS complex disassembly and loss of mitochondrial cristae with a decrease in nucleoid number and nucleoid disorganization."
      explanation: States that the mutation causes MICOS disassembly and cristae loss.
  - target: Maladaptive Mitochondrial Integrated Stress Response
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30877432
      reference_title: "ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Aggregates induce a potent mitochondrial integrated stress response (mtISR) through mTORC1 activation, with elevation of stress-induced transcription factors, secretion of myokines, upregulated serine and one-carbon metabolism, and downregulation of respiratory chain enzymes."
      explanation: Names the aggregate as the cause of the stress response, which is the edge being claimed.
  - target: OMA1 Activation and L-OPA1 Cleavage
    causal_link_type: DIRECT
    description: >-
      The stress-activated peptidase OMA1 is switched on in affected tissues of the
      knock-in mouse, which is what connects the aggregate to the cristae lesion
      through a defined proteolytic step rather than by assertion.
    evidence:
    - reference: PMID:32338760
      reference_title: Loss of CHCHD2 and CHCHD10 activates OMA1 peptidase to disrupt mitochondrial cristae phenocopying patient mutations.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "OMA1 was found to be activated similarly in affected tissues of mutant C10 knock-in (KI) mice, demonstrating that L-OPA1 cleavage is a novel mechanism for cristae abnormalities because of both C10 mutation and C2/C10 loss."
      explanation: Places OMA1 activation downstream of the mutation in the tissues that develop disease.
  - target: Intermembrane-Space Proteostasis Failure and Impaired Cytochrome c Oxidation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41420107
      reference_title: Mutant CHCHD10 disrupts cytochrome c oxidation and activates mitochondrial retrograde signaling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Proteomic profiling of insoluble mitochondrial proteins in Chchd10S55L/+ mice reveals widespread disruptions of mitochondrial proteostasis, including IMS proteins involved in cytochrome c biogenesis."
      explanation: Connects the insoluble mutant protein to a broader intermembrane-space proteostasis defect.
  evidence:
  - reference: PMID:30877432
    reference_title: "ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Conversely, CHCHD10 ablation does not induce disease pathology or activate the mtISR, indicating that CHCHD10S55L-dependent disease pathology is not caused by loss-of-function."
    explanation: The negative control that establishes gain-of-function rather than haploinsufficiency as the mechanism.

- name: OMA1 Activation and L-OPA1 Cleavage
  biological_scale: MOLECULAR
  description: >-
    The stress-induced inner-membrane peptidase OMA1 is activated and cleaves the
    long form of OPA1, the protein that shapes cristae. This supplies the missing
    proteolytic step between the CHCHD10 aggregate and the cristae lesion, and it
    is shared with the CHCHD2/CHCHD10 double knockout, which phenocopies the point
    mutant down to the cardiomyopathy and the stress response. Note that the same
    peptidase carries the maladaptive stress signal through DELE1 and HRI, so OMA1
    sits at the branch point of both arms of this mechanism.
  molecular_functions:
  - preferred_term: OMA1 metallopeptidase activity
    modifier: INCREASED
  downstream:
  - target: MICOS Disassembly and Loss of Cristae Junctions
    causal_link_type: DIRECT
    description: >-
      L-OPA1 cleavage is identified as the mechanism of the cristae abnormality
      rather than a correlate of it.
    evidence:
    - reference: PMID:32338760
      reference_title: Loss of CHCHD2 and CHCHD10 activates OMA1 peptidase to disrupt mitochondrial cristae phenocopying patient mutations.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "we report that C10 pathogenesis and the normal function of C2/C10 are intimately linked. Similar to patients with C10 mutations, we found that C2/C10 DKO mice have disrupted mitochondrial cristae, because of cleavage of the mitochondrial-shaping protein long form of OPA1 (L-OPA1) by the stress-induced peptidase OMA1."
      explanation: States the causal route from OMA1 through L-OPA1 to disrupted cristae.
  evidence:
  - reference: PMID:32338760
    reference_title: Loss of CHCHD2 and CHCHD10 activates OMA1 peptidase to disrupt mitochondrial cristae phenocopying patient mutations.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Finally, C2/C10 DKO mice partially phenocopied mutant C10 KI mice with the development of cardiomyopathy and activation of the integrated mitochondrial integrated stress response in affected tissues, tying mutant C10 pathogenesis to C2/C10 function."
    explanation: >-
      Establishes that losing both paralogs reproduces the point mutant's disease,
      which is what licenses reading the OMA1 step as part of the FTDALS2
      mechanism rather than a separate knockout phenotype.

- name: MICOS Disassembly and Loss of Cristae Junctions
  biological_scale: CELLULAR
  description: >-
    CHCHD10 sits in the mitochondrial contact site and cristae organizing system
    (MICOS) alongside mitofilin, CHCHD3 and CHCHD6. Mutant protein disassembles
    the complex, cristae junctions are lost and the inner-membrane architecture
    dilates and disorganizes, with nucleoids reduced in number and disorganized.
  biological_processes:
  - preferred_term: cristae formation
    modifier: DECREASED
    term:
      id: GO:0042407
      label: cristae formation
  - preferred_term: mitochondrion organization
    modifier: DECREASED
    term:
      id: GO:0007005
      label: mitochondrion organization
  downstream:
  - target: Mitochondrial DNA Instability with Multiple Deletions
    causal_link_type: DIRECT
    description: >-
      Nucleoid disorganization accompanying cristae-junction loss is the proposed
      route from disrupted membrane architecture to a failure of genome
      maintenance.
    evidence:
    - reference: PMID:26666268
      reference_title: "CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Repair of the mitochondrial genome after oxidative stress is impaired in CHCHD10 mutant fibroblasts and this likely explains the accumulation of deleted mtDNA molecules in patient muscle."
      explanation: Links the cristae/nucleoid defect to impaired genome repair and to the deletions seen in patients.
  - target: Impaired Mitochondrial Axonal Transport
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The MICOS lesion and mitochondrial trafficking are coupled, which is the
      connection the nifuroxazide screen was built on and the reason a
      MICOS-directed compound acts on transport. Typed as indirect to match the
      evidence: the coupling is inferred from a pharmacological rescue, and what
      links a disassembled MICOS complex to a stalled mitochondrion on an axon is
      not established.
    evidence:
    - reference: PMID:39478664
      reference_title: Nifuroxazide rescues the deleterious effects due to CHCHD10-associated MICOS defects in disease models.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "Our findings strengthen the MICOS-mitochondrial transport connection."
      explanation: >-
        States the MICOS-to-transport link. INDIRECT because the connection is
        inferred from a pharmacological rescue rather than from measuring transport
        against MICOS state directly.
  - target: Blocked Cytochrome c Release and Impaired Apoptosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26666268
      reference_title: "CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Interestingly, the expression of CHCHD10 mutant alleles inhibits apoptosis by preventing cytochrome c release."
      explanation: States the apoptotic consequence of the mutant allele.
  evidence:
  - reference: PMID:26666268
    reference_title: "CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we show that CHCHD10 resides with mitofilin, CHCHD3 and CHCHD6 within the \"mitochondrial contact site and cristae organizing system\" (MICOS) complex."
    explanation: Establishes CHCHD10 membership of MICOS, which is what makes the disassembly claim mechanistic.
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Overexpression of a CHCHD10 mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae."
    explanation: Independent demonstration of the cristae lesion, in a heterologous overexpression system.
  - reference: PMID:30092269
    reference_title: "Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We also show that G66V fibroblasts do not display the loss of MICOS complex integrity and mitochondrial damage found in S59L cells."
    explanation: >-
      The allele comparison that makes this node the severity determinant of the
      CHCHD10 series: the severe FTD-ALS allele disassembles MICOS and the mild
      SMAJ allele does not.
  - reference: PMID:30092269
    reference_title: "Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "However, S59L and G66V fibroblasts show comparable accumulation of phosphorylated mitochondrial TDP-43 suggesting that the severity of phenotype and mitochondrial damage do not depend on mitochondrial TDP-43 localization."
    explanation: >-
      Supports this node being the severity determinant by eliminating the
      competing candidate: the severe and mild alleles accumulate mitochondrial
      phospho-TDP-43 equally, so TDP-43 localization cannot be what separates them.
      INDIRECT because it argues by exclusion rather than measuring MICOS.

- name: Mitochondrial DNA Instability with Multiple Deletions
  biological_scale: MOLECULAR
  description: >-
    Repair of the mitochondrial genome after oxidative stress fails, and multiple
    mitochondrial DNA deletions accumulate in post-mitotic tissue, most
    conspicuously skeletal muscle. This places FTDALS2 formally within the
    mitochondrial DNA instability disorders — the feature that separates it from
    every proteostasis-driven form of ALS or FTD.
  biological_processes:
  - preferred_term: mitochondrial DNA repair
    modifier: DECREASED
    term:
      id: GO:0043504
      label: mitochondrial DNA repair
  downstream:
  - target: Combined Respiratory Chain Deficiency
    causal_link_type: DIRECT
    description: >-
      Deleted mtDNA molecules remove subunits of several complexes at once, which
      is why the biochemical deficit in patient muscle is combined rather than
      isolated.
  - target: Multiple Mitochondrial DNA Deletions
    causal_link_type: DIRECT
    description: >-
      The laboratory finding this node is defined by, wired as an edge so the
      single result the separate-entry argument rests on is reachable from the
      mechanism graph.
  evidence:
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder."
    explanation: Direct patient-tissue evidence for mtDNA instability in this disease.

- name: Combined Respiratory Chain Deficiency
  biological_scale: CELLULAR
  description: >-
    Oxidative phosphorylation fails, with combined respiratory-chain deficiency
    and abnormal assembly of complex V in patient muscle and respiratory-chain
    deficiency in patient fibroblasts. In the knock-in mouse the muscle OXPHOS
    defect is present at three months of age, before any spinal motor neuron has
    been lost.
  biological_processes:
  - preferred_term: mitochondrial ATP synthesis coupled electron transport
    modifier: DECREASED
    term:
      id: GO:0042775
      label: mitochondrial ATP synthesis coupled electron transport
  cell_types:
  - preferred_term: skeletal myofibre
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  downstream:
  - target: Mitochondrial Myopathy with Ragged-Red and COX-Negative Fibres
    causal_link_type: DIRECT
  - target: Neuromuscular Junction Degeneration
    causal_link_type: DIRECT
    hypothesis_groups:
    - muscle_first_motor_neuron_disease
    description: >-
      The knock-in mouse establishes the temporal ordering that makes this edge a
      causal claim rather than a co-occurrence: the muscle bioenergetic lesion
      precedes end-plate fragmentation.
    evidence:
    - reference: PMID:30874923
      reference_title: "Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10(S59L/+) mouse."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Furthermore, we found OXPHOS deficiency in muscle of CHCHD10S59L/+ mice at 3 months of age in the absence of neuron loss in spinal cord."
      explanation: Establishes that the OXPHOS defect is present before neuronal loss, which is what orders this edge.
  evidence:
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V."
    explanation: Combined respiratory-chain deficiency documented in every affected member of the founding family.

- name: Intermembrane-Space Proteostasis Failure and Impaired Cytochrome c Oxidation
  biological_scale: MOLECULAR
  description: >-
    A second, bioenergetic arm distinct from the stress-signalling arm. Insoluble
    mutant CHCHD10 disrupts intermembrane-space proteostasis broadly, including
    proteins of cytochrome c biogenesis, and impairs mitochondrial copper
    homeostasis and cytochrome c oxidation. That the respiratory defect in mutant
    mitochondria is corrected by simply adding cytochrome c is what identifies
    intermembrane-space proteostasis as a proximate lesion rather than a downstream
    consequence. The rescue was done in cardiac mitochondria, whereas the
    respiratory-chain deficiency this node feeds is documented in patient skeletal
    muscle and fibroblasts, so the arm is well evidenced in heart and carried into
    muscle by mechanism rather than by direct measurement.
  downstream:
  - target: Combined Respiratory Chain Deficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41420107
      reference_title: Mutant CHCHD10 disrupts cytochrome c oxidation and activates mitochondrial retrograde signaling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Defective respiration in mutant mitochondria is rescued by the addition of cytochrome c, pinpointing IMS proteostasis disruption as a key pathogenic mechanism."
      explanation: A rescue experiment establishing the direction of this edge.
  evidence:
  - reference: PMID:41420107
    reference_title: Mutant CHCHD10 disrupts cytochrome c oxidation and activates mitochondrial retrograde signaling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "bioenergetic failure linked to impaired mitochondrial copper homeostasis and cytochrome c oxidation"
    explanation: Names the bioenergetic arm of the dual defect described in this model.

- name: Maladaptive Mitochondrial Integrated Stress Response
  biological_scale: CELLULAR
  description: >-
    Aggregated CHCHD10 triggers a mitochondrial integrated stress response
    signalled through the OMA1-DELE1-HRI axis and mTORC1, with stress-induced
    transcription factors, myokine secretion, upregulated serine and one-carbon
    metabolism, and downregulated respiratory-chain enzymes. The response is
    maladaptive rather than protective: genetically blunting it delays
    cardiomyopathy onset. It also does not act upstream of the structural lesion,
    since blunting it leaves CHCHD10 insolubility, the cristae defect and the
    OXPHOS impairment untouched.
  biological_processes:
  - preferred_term: integrated stress response signaling
    modifier: INCREASED
    term:
      id: GO:0140467
      label: integrated stress response signaling
  downstream:
  - target: Mitochondrial Cardiomyopathy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41420107
      reference_title: Mutant CHCHD10 disrupts cytochrome c oxidation and activates mitochondrial retrograde signaling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Using protease-inactive Oma1E324Q/E324Q knock-in mice, we show that blunting mtISR in Chchd10S55L/+ mice delays cardiomyopathy onset without rescuing CHCHD10 insolubility, cristae defects or OXPHOS impairment."
      explanation: A genetic epistasis experiment placing the stress response causally upstream of the cardiomyopathy and downstream of the structural lesion.
  - target: Frontotemporal Cortical and Hippocampal Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - mitochondrial_origin_of_ftd_als
    description: >-
      Integrated stress response activation is documented in the hippocampus of
      the knock-in mouse alongside aggregates and neuroinflammation, but the steps
      between that activation and neuronal loss are not established.
    evidence:
    - reference: PMID:38583639
      reference_title: "CHCHD10(S59L/+) mouse model: Behavioral and neuropathological features of frontotemporal dementia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In the hippocampus of Chchd10S59L/+ mice, neuropathological studies show the involvement of protein aggregates, activation of the integrated stress response (ISR) and neuroinflammation in the degenerative process."
      explanation: Places integrated stress response activation inside the cognitive-arm degeneration, while stopping short of naming intermediates.
  evidence:
  - reference: PMID:30877432
    reference_title: "ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Overall, CHCHD10S55L mice recapitulate crucial aspects of human disease and reveal a novel toxic gain-of-function mechanism through maladaptive mtISR and metabolic dysregulation."
    explanation: States the maladaptive character of the response and its centrality to the mechanism.
  - reference: PMID:41420107
    reference_title: Mutant CHCHD10 disrupts cytochrome c oxidation and activates mitochondrial retrograde signaling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "maladaptive mtISR signaling via the OMA1-DELE1-HRI axis"
    explanation: Names the signalling axis carrying the response.

- name: Blocked Cytochrome c Release and Impaired Apoptosis
  biological_scale: CELLULAR
  description: >-
    Cristae-junction loss traps cytochrome c, and mutant alleles inhibit apoptosis
    by preventing its release. This runs counter to the usual expectation that
    neurodegeneration follows excess apoptosis, and it sits alongside the
    observation that patient iPSC-derived motor neurons are nonetheless
    hypersensitive to caspase activation by an applied stressor.
  biological_processes:
  - preferred_term: apoptotic process
    modifier: DECREASED
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: PMID:26666268
    reference_title: "CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Interestingly, the expression of CHCHD10 mutant alleles inhibits apoptosis by preventing cytochrome c release."
    explanation: Direct statement of the apoptotic block.
  - reference: PMID:30874923
    reference_title: "Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10(S59L/+) mouse."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "We also showed that motor neurons differentiated from human iPSC carrying the p.Ser59Leu mutation were much more sensitive to Staurosporine or glutamate-induced caspase activation than control cells."
    explanation: >-
      Cuts against a blanket claim that the mutation suppresses apoptosis: in
      patient-derived motor neurons under stress, caspase activation is increased
      rather than blocked. Recorded as a REFUTE item rather than reconciled in
      prose because the two results are from different cell types and stimuli and
      the discrepancy is unresolved.
  - reference: PMID:30092269
    reference_title: "Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The expression of the CHCHD10G66V allele is responsible for mitochondrial network fragmentation and decreased sensitivity towards apoptotic stimuli, but with a less severe effect than that found in cells expressing the CHCHD10S59L allele."
    explanation: >-
      Independent replication of the apoptotic block in a second allele, and a
      dose relationship: the milder allele produces the milder block. This makes
      the fibroblast result harder to dismiss as an artefact and sharpens the
      conflict with the iPSC motor neuron result recorded above.

- name: Mitochondrial Myopathy with Ragged-Red and COX-Negative Fibres
  biological_scale: TISSUE
  description: >-
    The muscle lesion of a classical mitochondrial myopathy: ragged-red fibres,
    cytochrome c oxidase-negative fibres, combined respiratory-chain deficiency
    and abnormal complex V assembly. In the knock-in mouse this is the earliest
    tissue to be hit, and it is the finding that would not be expected in ALS or
    FTD from any other cause.
  cell_types:
  - preferred_term: skeletal myofibre
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  downstream:
  - target: Neuromuscular Junction Degeneration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - muscle_first_motor_neuron_disease
    description: >-
      The mouse data argue for a muscle-first sequence in which the myopathic
      compartment carries the lesion that later disrupts the end plate.
  - target: Exercise Intolerance
    causal_link_type: DIRECT
  - target: Proximal Muscle Weakness
    causal_link_type: DIRECT
  - target: Mitochondrial Myopathy
    causal_link_type: DIRECT
    description: The clinical myopathy this tissue lesion presents as.
  - target: Ragged-Red Muscle Fibres
    causal_link_type: DIRECT
    description: >-
      The histochemical readout of the same lesion, drawn as an edge so the biopsy
      finding is reachable from the mechanism rather than free-floating.
  - target: Cytochrome c Oxidase-Negative Muscle Fibres
    causal_link_type: DIRECT
  - target: Skeletal Muscle Atrophy
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V."
    explanation: Documents the histochemical and biochemical myopathy in patient muscle.
  - reference: PMID:30874923
    reference_title: "Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10(S59L/+) mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we generated knock-in (KI) mice, carrying the p.Ser59Leu mutation, that mimic the mitochondrial myopathy with mtDNA instability displayed by the patients from our original family."
    explanation: The mouse reproduces the human myopathy, which is what licenses using it for the ordering claim.

- name: Impaired Mitochondrial Axonal Transport
  biological_scale: CELLULAR
  description: >-
    Delivery of mitochondria along the motor axon to the distal compartment fails.
    The evidence is pharmacological and therefore indirect: a MICOS-directed
    compound increases axonal mitochondrial movement and degrades syntaphilin (the
    protein that anchors mitochondria and holds them stationary) in patient-derived
    motor neurons, which implies the untreated state is under-transported. This
    node matters disproportionately for a disease whose lesion is distal: the
    neuromuscular junction is the furthest point from the soma and the most
    dependent on trafficked mitochondria.
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  downstream:
  - target: Neuromuscular Junction Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A plausible route from the transport deficit to end-plate failure, drawn as
      indirect because no experiment reported here measures end-plate integrity as
      a function of transport.
  evidence:
  - reference: PMID:39478664
    reference_title: Nifuroxazide rescues the deleterious effects due to CHCHD10-associated MICOS defects in disease models.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "Its benefits involve KIF5B-mediated mitochondrial transport enhancement, evidenced by increased axonal movement and syntaphilin degradation in patient-derived motor neurons."
    explanation: >-
      Names the motor (KIF5B) and the anchoring protein (syntaphilin) and reports
      that both move in the direction of restored transport under treatment.
      INDIRECT: the measurement is of a rescue, so the untreated deficit is
      inferred rather than measured.

- name: Neuromuscular Junction Degeneration
  biological_scale: TISSUE
  description: >-
    CHCHD10 is highly expressed in the post-synaptic compartment of the
    neuromuscular junction, and the motor end plate becomes hyper-fragmented.
    Abnormal CHCHD10 expression is detectable near junctions that are still
    morphologically intact, so the molecular lesion at the end plate precedes its
    structural breakdown.
  cell_types:
  - preferred_term: skeletal myofibre
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  downstream:
  - target: Motor Neuron Degeneration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - muscle_first_motor_neuron_disease
    - mitochondrial_origin_of_ftd_als
    description: >-
      Denervation follows end-plate failure in the mouse sequence, with spinal
      motor neuron loss appearing only at end stage.
    evidence:
    - reference: PMID:30874923
      reference_title: "Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10(S59L/+) mouse."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "CHCHD10S59L/+ mice also displayed neuromuscular junction (NMJ) and motor neuron degeneration with hyper-fragmentation of the motor end plate and moderate but significant motor neuron loss in lumbar spinal cord at the end stage of the disease."
      explanation: Reports both lesions and places motor neuron loss at end stage, after end-plate fragmentation.
  evidence:
  - reference: PMID:30874923
    reference_title: "Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10(S59L/+) mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "CHCHD10 is highly expressed in the NMJ post-synaptic part. Importantly, the fragmentation of the motor end plate was associated with abnormal CHCHD10 expression that was also observed closed to NMJs which were morphologically normal."
    explanation: Localizes the protein to the end plate and shows the molecular abnormality preceding structural damage.

- name: Motor Neuron Degeneration
  biological_scale: TISSUE
  description: >-
    Loss of upper and lower motor neurons producing the ALS arm of the phenotype.
    In the mouse this is moderate and late relative to the muscle lesion, which is
    the model's central and most contested claim about human disease: that
    CHCHD10-related motor neuron disease may be driven from muscle rather than
    originating in the motor neuron.
  cell_types:
  - preferred_term: spinal cord motor neuron
    term:
      id: CL:0011001
      label: spinal cord motor neuron
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  downstream:
  - target: TDP-43 Cytoplasmic Aggregation in Spinal Neurons
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      In the knock-in mouse the aggregates appear at the same end-stage time point
      as neuronal loss, so that experiment alone cannot order the two. The
      direction is instead taken from work in which the mutant alleles are shown
      to act dominant-negatively on CHCHD10's normal role in retaining TDP-43 in
      the nucleus, which places mitochondrial dysfunction upstream. The
      intermediates between the two are not established.
    evidence:
    - reference: PMID:28585542
      reference_title: Loss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "FTD/ALS-associated mutations (R15L and S59L) exhibit loss of function phenotypes in C. elegans genetic complementation assays"
      explanation: >-
        The in vivo arm of this paper: the disease alleles fail to provide CHCHD10
        function in a whole-organism complementation assay.
    - reference: PMID:28585542
      reference_title: Loss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "CHCHD10 normally exerts a protective role in mitochondrial and synaptic integrity as well as in the retention of nuclear TDP-43"
      explanation: >-
        Supplies the direction of this edge: keeping TDP-43 nuclear is part of
        CHCHD10's normal job, so losing that function releases TDP-43 to the
        cytoplasm. Split from the C. elegans item above because the paper's two
        clauses report different study types.
  - target: Amyotrophic Lateral Sclerosis Phenotype
    causal_link_type: DIRECT
  - target: Bulbar Palsy
    causal_link_type: DIRECT
  - target: Areflexia
    causal_link_type: DIRECT
    description: >-
      Loss of the lower motor neuron limb of the reflex arc. Noted in the founding
      family alongside an extensor plantar response, so lower and upper motor
      neuron signs coexist.
  evidence:
  - reference: PMID:30874923
    reference_title: "Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10(S59L/+) mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "They likely lead to OXPHOS deficiency, loss of cristae junctions and destabilization of internal membrane structure within mitochondria at motor end plate of NMJ, impairing neurotransmission."
    explanation: The authors' own statement of the route from the mitochondrial lesion to failure of the motor unit.
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy."
    explanation: Establishes motor neuron disease as a core human manifestation of the founding pedigree.

- name: TDP-43 Cytoplasmic Aggregation in Spinal Neurons
  biological_scale: CELLULAR
  description: >-
    Cytoplasmic TDP-43 aggregates are present in spinal neurons at end stage in
    the knock-in mouse. This is the one point of contact with the canonical
    proteostatic model of ALS, and it is a late one — worth recording precisely
    because it shows the mitochondrial and proteostatic accounts converging
    downstream rather than the mitochondrial lesion being a variant of the
    proteostatic one.
  cell_types:
  - preferred_term: spinal cord motor neuron
    term:
      id: CL:0011001
      label: spinal cord motor neuron
  evidence:
  - reference: PMID:30874923
    reference_title: "Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10(S59L/+) mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "At this stage, we observed TDP-43 cytoplasmic aggregates in spinal neurons."
    explanation: Reports the finding and, in the phrase "at this stage", its end-stage timing.
  - reference: PMID:35787294
    reference_title: "Modulation of synaptic plasticity, motor unit physiology, and TDP-43 pathology by CHCHD10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "insoluble CHCHD10 aggregates accumulate and colocalize with phospho-TDP-43 inclusions in brains of FTLD-TDP and AD patients, and that insoluble CHCHD10 levels tightly correlate with insoluble TDP-43 levels in control and FTLD-TDP brains"
    explanation: >-
      Human post-mortem evidence that the two aggregate species co-localize and
      co-vary. INDIRECT because the brains studied are FTLD-TDP and Alzheimer
      cases, not CHCHD10 carriers: it shows wild-type CHCHD10 joining TDP-43
      inclusions in unrelated dementias, so it supports a CHCHD10-TDP-43 axis in
      human brain generally rather than documenting this disease.

- name: Frontotemporal Cortical and Hippocampal Degeneration
  biological_scale: TISSUE
  description: >-
    The cognitive arm. In patients this is a frontal lobe syndrome with executive,
    attentional and behavioural impairment; in the knock-in mouse it is impaired
    learning and memory with reduced long-term potentiation at
    perforant-pathway/dentate-gyrus synapses, accompanied by aggregates,
    integrated stress response activation and neuroinflammation.
  cell_types:
  - preferred_term: pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  downstream:
  - target: Frontotemporal Dementia Phenotype
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:38583639
    reference_title: "CHCHD10(S59L/+) mouse model: Behavioral and neuropathological features of frontotemporal dementia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These animals show impaired learning and memory capacities with reduced long-term potentiation (LTP) measured at the Perforant Pathway-Dentate Gyrus (PP-DG) synapses."
    explanation: Provides the functional correlate of the cognitive arm in the model.

- name: Mitochondrial Cardiomyopathy
  biological_scale: TISSUE
  description: >-
    Cardiac involvement is part of the CHCHD10 phenotype in the mouse, where it is
    fatal before 14 months and associated with enhanced mitophagy. It is
    prominent in the model and much less so in reported patients, which is a
    genuine model-to-human divergence rather than an established feature of
    FTDALS2.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:30874923
    reference_title: "Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10(S59L/+) mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Before 14 months of age, all KI mice developed a fatal mitochondrial cardiomyopathy associated with enhanced mitophagy."
    explanation: Reports the cardiac phenotype and its penetrance in the model.
  - reference: PMID:38724625
    reference_title: High fat diet ameliorates mitochondrial cardiomyopathy in CHCHD10 mutant mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In mutant hearts, mtISR is accompanied by a metabolic rewiring characterized by increased reliance on glycolysis rather than fatty acid oxidation."
    explanation: >-
      Identifies the substrate switch that follows the stress response in this
      tissue, which is the step that makes the cardiomyopathy metabolically
      addressable rather than simply a consequence of failed bioenergetics.
  - reference: PMID:38724625
    reference_title: High fat diet ameliorates mitochondrial cardiomyopathy in CHCHD10 mutant mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "HFD also decreased accumulation of aggregated CHCHD10 in the S55L heart, suggesting activation of quality control mechanisms."
    explanation: >-
      Notable because it runs back up the chain: a dietary intervention reduces the
      aggregate that initiates the whole mechanism, which argues the aggregate load
      is not fixed by the genotype alone.
phenotypes:
- category: Neurologic
  name: Frontotemporal Dementia Phenotype
  description: >-
    Slowly progressive behavioural change, language disturbance and cognitive
    decline with extrapyramidal signs. In the founding family this presented as a
    frontal lobe syndrome with impairment of episodic memory, attention, verbal
    fluency and executive function.
  phenotype_term:
    preferred_term: Frontotemporal dementia
    term:
      id: HP:0002145
      label: Frontotemporal dementia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:26131548
    reference_title: CHCHD10-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Frontotemporal dementia (FTD): slowly progressive behavioral changes, language disturbances, cognitive decline, extrapyramidal signs."
    explanation: GeneReviews describes the FTD arm of the spectrum.

- category: Neurologic
  name: Amyotrophic Lateral Sclerosis Phenotype
  description: >-
    Progressive degeneration of upper and lower motor neurons. In the French
    FTD-ALS cohort, CHCHD10 carriers were characterized by early and predominant
    bulbar symptoms, which is the clinical clue that should prompt CHCHD10
    testing.
  phenotype_term:
    preferred_term: Amyotrophic lateral sclerosis
    term:
      id: HP:0007354
      label: Amyotrophic lateral sclerosis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:26131548
    reference_title: CHCHD10-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Amyotrophic lateral sclerosis (ALS): progressive degeneration of upper motor neurons and lower motor neurons."
    explanation: GeneReviews describes the ALS arm of the spectrum.
  - reference: PMID:25155093
    reference_title: "Screening of CHCHD10 in a French cohort confirms the involvement of this gene in frontotemporal dementia with amyotrophic lateral sclerosis patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 2 heterozygous variants in 3 unrelated probands presenting FTD and ALS, characterized by early and predominant bulbar symptoms."
    explanation: Establishes the bulbar-predominant presentation in an independent cohort.

- category: Neurologic
  name: Bulbar Palsy
  description: >-
    Progressive bulbar syndrome with dysarthria and dysphagia, which in the French
    cohort was early and predominant at onset.
  phenotype_term:
    preferred_term: Bulbar palsy
    term:
      id: HP:0001283
      label: Bulbar palsy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical examination showed cerebellar ataxia, Babinski sign, areflexia and bulbar palsy with dysarthria and dysphagia."
    explanation: Documents bulbar palsy with its two components in the index case.
  sequelae:
  - target: Dysarthria
  - target: Dysphagia

- category: Neurologic
  name: Dysarthria
  description: Speech impairment from bulbar involvement.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They presented dementia, progressive bulbar syndrome with dysarthria and dysphagia, and became bedridden."
    explanation: Documents dysarthria across affected family members without muscle biopsy.

- category: Gastrointestinal
  name: Dysphagia
  description: >-
    Swallowing impairment from bulbar involvement, and one of the functions that
    drugs used for the behavioural manifestations of FTD may worsen.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They presented dementia, progressive bulbar syndrome with dysarthria and dysphagia, and became bedridden."
    explanation: Documents dysphagia across affected family members without muscle biopsy.

- category: Neurologic
  name: Cerebellar Ataxia
  description: >-
    Gait and kinetic ataxia with dysarthria, dysphagia, nystagmus and cerebellar
    oculomotor disturbance. In the founding family the index case's presenting
    symptom at age 50 was cerebellar ataxia, and two further relatives presented
    with ataxia alone.
  phenotype_term:
    preferred_term: Cerebellar ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:26131548
    reference_title: CHCHD10-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cerebellar ataxia: gait ataxia, kinetic ataxia (progressive loss of coordination of lower- and upper-limb movements), dysarthria/dysphagia, nystagmus, cerebellar oculomotor disorder."
    explanation: GeneReviews describes the ataxic arm of the spectrum.

- category: Musculoskeletal
  name: Mitochondrial Myopathy
  description: >-
    Weakness, amyotrophy and exercise intolerance on a mitochondrial basis. This
    may be early onset, unlike the other manifestations, and is the feature that
    marks the disorder as a primary mitochondrial disease.
  phenotype_term:
    preferred_term: Mitochondrial myopathy
    term:
      id: HP:0003737
      label: Mitochondrial myopathy
  evidence:
  - reference: PMID:26131548
    reference_title: CHCHD10-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mitochondrial myopathy (may also be early onset): weakness, amyotrophy, exercise intolerance."
    explanation: GeneReviews names the myopathic arm and its early-onset possibility.

- category: Musculoskeletal
  name: Proximal Muscle Weakness
  description: >-
    Proximal weakness was observed in four of the biopsied members of the founding
    family, with bilateral ptosis and facial paresis in one.
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  evidence:
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Proximal weakness was observed in four individuals (Patients IV-3, IV-11, IV-13 and IV-15) with bilateral ptosis and facial paresis in Patient IV-15."
    explanation: Documents proximal weakness with counts in the founding pedigree.

- category: Musculoskeletal
  name: Exercise Intolerance
  description: Reduced exercise tolerance as part of the mitochondrial myopathy.
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:26131548
    reference_title: CHCHD10-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mitochondrial myopathy (may also be early onset): weakness, amyotrophy, exercise intolerance."
    explanation: GeneReviews lists exercise intolerance among the myopathic features.

- category: Musculoskeletal
  name: Skeletal Muscle Atrophy
  description: >-
    Amyotrophy as a component of the mitochondrial myopathy, which is the arm of
    the CHCHD10 spectrum that FTDALS2 itself carries.
  phenotype_term:
    preferred_term: Skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  evidence:
  - reference: PMID:26131548
    reference_title: CHCHD10-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mitochondrial myopathy (may also be early onset): weakness, amyotrophy, exercise intolerance."
    explanation: >-
      GeneReviews lists amyotrophy among the features of the mitochondrial
      myopathy. Quoted from the myopathy sentence rather than the
      Charcot-Marie-Tooth one so the citation stays inside this entry's scope.

- category: Neurologic
  name: Areflexia
  description: >-
    Loss of tendon reflexes, documented in the index case of the founding
    p.Ser59Leu family alongside cerebellar ataxia, a Babinski sign and bulbar
    palsy. The coexistence of areflexia with an extensor plantar response in one
    patient is itself informative, since it marks simultaneous lower and upper
    motor neuron involvement.
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
  evidence:
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical examination showed cerebellar ataxia, Babinski sign, areflexia and bulbar palsy with dysarthria and dysphagia."
    explanation: >-
      Documents areflexia in an FTDALS2 patient specifically, rather than borrowing
      the finding from the SMAJ arm of the CHCHD10 spectrum.

- category: Auditory
  name: Sensorineural Hearing Impairment
  description: >-
    Sensorineural deafness, present in the index case of the founding family and
    listed by GeneReviews among the manifestations that surveillance should look
    for over time.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:26131548
    reference_title: CHCHD10-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regular evaluations to detect manifestations that can occur with time including neurologic deficits, psychiatric abnormalities, impaired respiratory function, and sensorineural hearing loss."
    explanation: GeneReviews names sensorineural hearing loss as a manifestation warranting surveillance.
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The index case was a 67-year-old female (Patient IV-6), who developed a cerebellar ataxia at 50 years of age, associated with progressive bulbar syndrome, dementia and sensorineural deafness."
    explanation: Documents sensorineural deafness in the index patient.

- category: Cellular
  name: Ragged-Red Muscle Fibres
  description: >-
    Subsarcolemmal mitochondrial accumulation on modified Gomori trichrome
    staining, present in every biopsied member of the founding family.
  phenotype_term:
    preferred_term: Ragged-red muscle fibers
    term:
      id: HP:0003200
      label: Ragged-red muscle fibers
  evidence:
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V."
    explanation: Documents ragged-red fibres in all biopsied patients.

- category: Cellular
  name: Cytochrome c Oxidase-Negative Muscle Fibres
  description: >-
    Fibres lacking complex IV histochemical activity, the histological signature
    of a mosaic mitochondrial DNA defect in muscle.
  phenotype_term:
    preferred_term: Cytochrome C oxidase-negative muscle fibers
    term:
      id: HP:0003688
      label: Cytochrome C oxidase-negative muscle fibers
  evidence:
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V."
    explanation: Documents COX-negative fibres in all biopsied patients.

- category: Cellular
  name: Multiple Mitochondrial DNA Deletions
  description: >-
    Accumulation of multiple deleted mitochondrial DNA species in skeletal muscle.
    This is the finding that reclassifies the family's FTD-ALS phenotype as a
    mitochondrial DNA instability disorder, and it is not a feature of ALS or FTD
    from any other cause.
  phenotype_term:
    preferred_term: Multiple mitochondrial DNA deletions
    term:
      id: HP:0003689
      label: Multiple mitochondrial DNA deletions
  evidence:
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder."
    explanation: Documents the deletions and the nosological reclassification they force.
genetic:
- name: CHCHD10
  gene_term:
    preferred_term: CHCHD10
    term:
      id: hgnc:15559
      label: CHCHD10
  relationship_type: CAUSATIVE
  case_fractions:
  - population: French FTD and FTD-ALS cohort (115 patients)
    case_fraction_percent: 2.6
    cohort_size: 115
    notes: >-
      Two heterozygous variants in three unrelated probands. The authors frame
      this as low, and recommend targeting CHCHD10 testing at patients with
      bulbar symptoms at onset rather than screening broadly.
    evidence:
    - reference: PMID:25155093
      reference_title: "Screening of CHCHD10 in a French cohort confirms the involvement of this gene in frontotemporal dementia with amyotrophic lateral sclerosis patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Although the frequency of mutations is low in this series (2.6%), our work suggests that CHCHD10 mutations should be searched particularly when bulbar symptoms are present at onset."
      explanation: Quantifies the CHCHD10 share of a defined FTD/FTD-ALS cohort and states the testing implication.
  - population: Chinese sporadic ALS cohort (487 patients, West China Hospital)
    case_fraction_percent: 0.4
    cohort_size: 487
    notes: >-
      Screening an unselected sporadic ALS cohort rather than an FTD-ALS cohort.
      The yield is an order of magnitude below the French FTD-ALS figure, which is
      the expected direction if CHCHD10 disease is defined by the combined
      cognitive-motor phenotype rather than by ALS as such.
    evidence:
    - reference: PMID:27056076
      reference_title: Mutation Screening of the CHCHD10 Gene in Chinese Patients with Amyotrophic Lateral Sclerosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The mutation frequency of CHCHD10 (0.4 %, 2/487) in a Chinese SALS population suggests CHCHD10 gene mutation appears to be an uncommon cause of ALS in Chinese populations."
      explanation: Quantifies the CHCHD10 share of an unselected sporadic ALS cohort.
  evidence:
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu mutation in one of these families."
    explanation: >-
      Independent replication of the founding allele in a second, pathologically
      confirmed FTD-ALS family, which is what moved CHCHD10 from a single-family
      observation to a spectrum gene.
  notes: >-
    CHCHD10 at 22q11.23 encodes a coiled-coil-helix-coiled-coil-helix domain
    protein of the mitochondrial intermembrane space, enriched at cristae
    junctions and a component of the MICOS complex. Heterozygous missense variants
    cause the FTD-ALS phenotype; p.Ser59Leu is the founding allele and p.Gly66Val
    the Finnish SMAJ founder allele.

    Gene-disease validity. ClinGen's ALS Spectrum Disorders expert panel
    classifies the CHCHD10-FTDALS2 relationship as Moderate, while its
    Mitochondrial Diseases panel classifies CHCHD10-mitochondrial disease as
    Definitive. That asymmetry is the single most useful summary of this gene's
    epistemic position and is worth citing in a future revision as a `CGGV:`
    structured reference. It is deliberately NOT cited here: `just
    clingen-refresh` currently fails a pinned-sha256 check against
    data/clingen/MANIFEST.yaml because upstream published a new release behind the
    same URL, and repinning plus rebuilding the 516-file ClinGen cache is a
    maintenance change that does not belong in a curation PR. Nothing in this
    entry rests on the ClinGen claim.
diagnosis:
- name: Molecular Diagnosis by CHCHD10 Sequencing
  description: >-
    The diagnosis is established by finding a heterozygous CHCHD10 pathogenic
    variant in a patient with one or more characteristic clinical findings. Routes
    are single-gene sequencing, an ALS/FTD gene panel, exome or genome sequencing.
    Two negatives matter as much as the positive: repeat-expansion testing (the
    C9orf72 route) will not find it, and primary mitochondrial DNA testing is the
    wrong test even though multiple mtDNA deletions are present, because those
    deletions are secondary to a nuclear-gene defect.
  evidence:
  - reference: PMID:26131548
    reference_title: CHCHD10-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis is established when a heterozygous CHCHD10 pathogenic variant is detected in an individual with one or more characteristic clinical findings."
    explanation: GeneReviews states the diagnostic criterion.
  notes: >-
    Variant interpretation is the hard part rather than variant detection. The
    pathogenic alleles are ultra-rare missense changes, while p.Pro34Ser, reported
    in early ALS and FTD series, is common in population databases and is better
    read as benign. Conflating the two is the likeliest source of the gene's
    contested effect size in ALS, which is recorded as an open question under
    `discussions`.

- name: Muscle Biopsy Showing Mitochondrial Myopathy
  description: >-
    Ragged-red fibres and cytochrome c oxidase-negative fibres with combined
    respiratory-chain deficiency and abnormal complex V assembly. This is the
    finding that discriminates CHCHD10 disease from the rest of the FTD-ALS
    spectrum at the bedside, and it is the practical reason a separate diagnostic
    entry is worth having: a mitochondrial myopathy in a patient being worked up
    for ALS or FTD should redirect testing to CHCHD10.
  evidence:
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V."
    explanation: Reports the biopsy findings in every affected member of the founding family.
  markers: Ragged-red muscle fibers (HP:0003200) and cytochrome c oxidase-negative
    muscle fibers (HP:0003688), with combined respiratory-chain deficiency and
    abnormal complex V assembly.

- name: Detection of Multiple Mitochondrial DNA Deletions in Skeletal Muscle
  description: >-
    Demonstrating multiple mtDNA deletions in muscle establishes the mtDNA
    instability that reclassifies the clinical FTD-ALS picture as a mitochondrial
    disorder. It is a supporting rather than a confirmatory test: the deletions are
    a consequence of the nuclear CHCHD10 defect, so a positive result points
    towards CHCHD10 without replacing sequencing.
  evidence:
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder."
    explanation: Reports the finding and the nosological conclusion drawn from it.
  markers: Multiple mitochondrial DNA deletions (HP:0003689) in skeletal muscle.

- name: Electromyography and Nerve Conduction Studies
  description: >-
    Used to document lower motor neuron involvement and to separate a neurogenic
    from a myopathic process. In the founding family it did both and gave different
    answers in different relatives: normal in one, chronic neurogenic change
    consistent with lower motor neuron disease in another, and purely myopathic
    change in a third. That within-family divergence is itself the finding, and it
    is why a single normal or myopathic study does not exclude the diagnosis.
  evidence:
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electromyography excluded peripheral neuropathy with normal test (Patient V-10), chronic neurogenic changes suggesting a lower motor neuron disease (Patient IV-15) or myopathic abnormalities only (Patient IV-3)."
    explanation: Documents the three different electrophysiological pictures within one pedigree.

prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: ULTRA_RARE
  notes: >-
    No population prevalence estimate exists. The disease is defined by a small
    number of reported families and cohort screening yields of 2.6% among FTD and
    FTD-ALS patients and 0.4% among sporadic ALS patients, which are case
    fractions within a selected clinical group, not prevalences, and are recorded
    as such under `genetic`. `measure_type` is UNKNOWN rather than a prevalence
    measure because the sources characterise rarity without measuring occurrence.
  evidence:
  - reference: PMID:26131548
    reference_title: CHCHD10-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because of the recent discovery of CHCHD10-related disorders and the limited number of affected individuals reported to date, the natural history of these disorders (except for SMAJ caused by the p.Gly66Val pathogenic variant) is largely unknown."
    explanation: >-
      GeneReviews states that the reported case count is small and the natural
      history unknown, which is the basis for the qualitative band and for
      declining to give a number.

treatments:
- name: Supportive and Symptomatic Management
  description: >-
    No disease-modifying therapy exists. Management of the ALS, FTD, spinal
    muscular atrophy and cerebellar ataxia manifestations follows the standard of
    care for those syndromes from any cause. Nutrition and weight maintenance are
    treated as essential rather than adjunctive, and bracing and stretching are
    used to limit contractures, which are painful and interfere with caregiving.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:26131548
    reference_title: CHCHD10-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adequate nutrition and weight maintenance are essential. Appropriate bracing and stretching can minimize joint contractures, which are often painful and can interfere with caregiving."
    explanation: GeneReviews states the supportive measures and their rationale.
  - reference: PMID:26131548
    reference_title: CHCHD10-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Management of ALS, FTD, SMA, and cerebellar ataxia is the same as for other causes of these disorders."
    explanation: States that management is syndrome-directed rather than CHCHD10-specific.
  - reference: PMID:26131548
    reference_title: CHCHD10-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Baclofen (used to treat spasticity) can sometimes worsen muscle weakness; some drugs used to treat the behavioral manifestations of FTD may worsen dysarthria, dysphagia, and/or respiratory weakness."
    explanation: >-
      The GeneReviews Agents/Circumstances to Avoid content, quoted rather than
      paraphrased because it is a clinical safety claim.
  notes: >-
    Agents and circumstances to avoid. Both cautions matter more here than in
    either parent disorder, because one patient may carry the spasticity, the
    behavioural syndrome and the myopathy at once, so the drug indicated for one
    arm is the drug contraindicated by another. The GeneReviews sentence is quoted
    as evidence above rather than paraphrased here.

- name: Surveillance for Multisystem Progression
  description: >-
    Regular review for new neurologic deficits, psychiatric abnormalities,
    impaired respiratory function and sensorineural hearing loss. Respiratory
    function and hearing are the two that a clinic focused on either parent
    diagnosis alone would be least likely to monitor.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: clinical surveillance
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:26131548
    reference_title: CHCHD10-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regular evaluations to detect manifestations that can occur with time including neurologic deficits, psychiatric abnormalities, impaired respiratory function, and sensorineural hearing loss."
    explanation: GeneReviews specifies the surveillance targets.

- name: Genetic Counseling
  description: >-
    Autosomal dominant transmission with a 50% recurrence risk per child. Once the
    familial variant is known, prenatal and preimplantation genetic testing are
    available. Counseling has to convey that intrafamilial heterogeneity prevents
    predicting either the age at onset or which arm of the spectrum a carrier will
    develop.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:26131548
    reference_title: CHCHD10-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Once the CHCHD10 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for a CHCHD10-related disorder and preimplantation genetic testing are possible."
    explanation: States the reproductive options that counseling covers.
  - reference: PMID:26131548
    reference_title: CHCHD10-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Each child of an individual with a CHCHD10-related disorder has a 50% chance of inheriting the CHCHD10 pathogenic variant."
    explanation: Sources the recurrence-risk figure that this entry states twice.

- name: Nifuroxazide (investigational, MICOS-directed)
  description: >-
    A repurposed broad-spectrum antibacterial identified by screening more than
    1600 compounds against yeast strains engineered to mimic MICOS instability. In
    patient cells it rescues mitochondrial network fragmentation and cristae
    abnormalities and reduces caspase-dependent death of patient iPSC-derived
    motor neurons, apparently by enhancing KIF5B-mediated mitochondrial axonal
    transport. This is preclinical only: no human data exist, and it is recorded
    here because it is the first candidate aimed at the MICOS lesion that this
    entry places at the centre of the mechanism, not because it is available.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: nifuroxazide
      term:
        id: NCIT:C90982
        label: Nifuroxazide
  target_mechanisms:
  - target: MICOS Disassembly and Loss of Cristae Junctions
    treatment_effect: RESTORES
    description: >-
      Reverses the cristae and network phenotype in patient fibroblasts carrying
      the founding allele.
    evidence:
    - reference: PMID:39478664
      reference_title: Nifuroxazide rescues the deleterious effects due to CHCHD10-associated MICOS defects in disease models.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We show that nifuroxazide rescues mitochondrial network fragmentation and cristae abnormalities in CHCHD10S59L/+ patient fibroblasts."
      explanation: Reports the rescue of the specific cellular lesion this treatment targets.
  - target: Impaired Mitochondrial Axonal Transport
    treatment_effect: RESTORES
    description: >-
      The mechanism the compound's benefit is actually attributed to, as distinct
      from the MICOS phenotype the screen selected on.
    evidence:
    - reference: PMID:39478664
      reference_title: Nifuroxazide rescues the deleterious effects due to CHCHD10-associated MICOS defects in disease models.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Its benefits involve KIF5B-mediated mitochondrial transport enhancement, evidenced by increased axonal movement and syntaphilin degradation in patient-derived motor neurons."
      explanation: Attributes the compound's effect to restored mitochondrial transport.
  evidence:
  - reference: PMID:39478664
    reference_title: Nifuroxazide rescues the deleterious effects due to CHCHD10-associated MICOS defects in disease models.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This molecule also decreases caspase-dependent death of human CHCHD10S59L/+ induced pluripotent stem cell-derived motor neurons."
    explanation: Extends the rescue to the human motor neuron model, which is the disease-relevant cell type.
  notes: >-
    Preclinical. Yeast screen plus patient fibroblasts and patient iPSC-derived
    motor neurons; no animal efficacy or human trial data reported.

animal_models:
- name: Chchd10 S59L/+ knock-in mouse
  species: Mouse
  genotype: Chchd10 p.Ser59Leu heterozygous knock-in
  publication: PMID:30874923
  description: >-
    Knock-in of the human founding allele at the endogenous mouse locus. It
    reproduces the mitochondrial myopathy with mtDNA instability seen in the
    original family, and develops neuromuscular junction and motor neuron
    degeneration plus a fatal cardiomyopathy. Its most consequential result is the
    temporal ordering: muscle OXPHOS deficiency is present at three months, before
    any spinal motor neuron loss.
  evidence:
  - reference: PMID:30874923
    reference_title: "Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10(S59L/+) mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These data confirm that mitochondrial deficiency associated with CHCHD10 mutations can be at the origin of MND."
    explanation: >-
      Supports treating this model as informative for CHCHD10 motor neuron
      disease, which is the claim the model entry itself makes.
  modeled_mechanisms:
  - target: Mitochondrial Myopathy with Ragged-Red and COX-Negative Fibres
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: >-
      Reproduces the human myopathy with mtDNA instability at the same tissue
      level at which it is observed in patients.
    evidence:
    - reference: PMID:30874923
      reference_title: "Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10(S59L/+) mouse."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here, we generated knock-in (KI) mice, carrying the p.Ser59Leu mutation, that mimic the mitochondrial myopathy with mtDNA instability displayed by the patients from our original family."
      explanation: The authors state the model reproduces the patients' myopathy.
  - target: Motor Neuron Degeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Spinal motor neuron loss occurs, but only moderately and only at end stage,
      and the mouse is not reported to show the combined upper and lower motor
      neuron degeneration that defines human ALS.
    limitations: >-
      Motor neuron loss is described as moderate and confined to the end stage,
      and the upper motor neuron component of the human phenotype is not
      demonstrated. Reading this model as an ALS model rather than as a myopathy
      model with late denervation overstates it.
    evidence:
    - reference: PMID:30874923
      reference_title: "Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10(S59L/+) mouse."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "CHCHD10S59L/+ mice also displayed neuromuscular junction (NMJ) and motor neuron degeneration with hyper-fragmentation of the motor end plate and moderate but significant motor neuron loss in lumbar spinal cord at the end stage of the disease."
      explanation: Reports both the finding and the qualifiers that make it partial rather than full recapitulation.
    readouts:
    - name: Lumbar spinal cord motor neuron count
      target: Motor Neuron Degeneration
      direction: DECREASED
      interpretation: Quantitative correlate of the motor neuron degeneration node.
      evidence:
      - reference: PMID:30874923
        reference_title: "Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10(S59L/+) mouse."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "moderate but significant motor neuron loss in lumbar spinal cord at the end stage of the disease"
        explanation: Reports the measurement and its direction.
  - target: Frontotemporal Cortical and Hippocampal Degeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Behavioural and electrophysiological phenotyping shows impaired learning and
      memory with reduced hippocampal long-term potentiation, alongside
      aggregates, integrated stress response activation and neuroinflammation.
    limitations: >-
      The readout is hippocampal learning and memory, whereas human FTD is defined
      by frontal behavioural and language change with relative memory sparing
      early on. The model therefore reports a cognitive deficit in the wrong
      cognitive domain for the human syndrome it is cited for.
    evidence:
    - reference: PMID:38583639
      reference_title: "CHCHD10(S59L/+) mouse model: Behavioral and neuropathological features of frontotemporal dementia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "They also validate the Chchd10S59L/+ mice as a relevant model for FTD, which can be used for preclinical studies to test new therapeutic strategies for this devastating disease."
      explanation: The authors' own claim that the model is relevant for FTD; the domain caveat is recorded in limitations.
  - target: Mitochondrial Cardiomyopathy
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Fully penetrant fatal cardiomyopathy before 14 months.
    limitations: >-
      Cardiomyopathy is fully penetrant and fatal in the mouse but is not a
      prominent reported feature of human FTDALS2, so the model is more severe in
      this organ than the disease it represents.
    evidence:
    - reference: PMID:30874923
      reference_title: "Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10(S59L/+) mouse."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Before 14 months of age, all KI mice developed a fatal mitochondrial cardiomyopathy associated with enhanced mitophagy."
      explanation: Reports the cardiac phenotype and its complete penetrance.

- name: Chchd10 S55L/+ knock-in mouse
  species: Mouse
  genotype: Chchd10 p.Ser55Leu heterozygous knock-in (mouse equivalent of human S59L)
  publication: PMID:30877432
  description: >-
    An independently generated knock-in of the mouse-equivalent residue. It is the
    model that established the toxic gain-of-function mechanism, by the contrast
    between the point mutant and a null allele, and the one in which the
    OMA1-DELE1-HRI stress axis was dissected genetically.
  evidence:
  - reference: PMID:30877432
    reference_title: "ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Overall, CHCHD10S55L mice recapitulate crucial aspects of human disease and reveal a novel toxic gain-of-function mechanism through maladaptive mtISR and metabolic dysregulation."
    explanation: The authors' assessment of the model's fidelity to human disease.
  modeled_mechanisms:
  - target: Mutant CHCHD10 and CHCHD2 Co-Aggregation
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: >-
      Mutant CHCHD10 co-aggregates with CHCHD2 in exactly the tissues that develop
      pathology, and the ablation comparison shows the aggregate rather than the
      missing protein is what causes disease.
    evidence:
    - reference: PMID:30877432
      reference_title: "ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Conversely, CHCHD10 ablation does not induce disease pathology or activate the mtISR, indicating that CHCHD10S55L-dependent disease pathology is not caused by loss-of-function."
      explanation: The genetic control that makes the gain-of-function reading of this model sound.
  - target: Maladaptive Mitochondrial Integrated Stress Response
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      Aggregate-driven mtISR through mTORC1 and the OMA1-DELE1-HRI axis, with the
      response shown to be maladaptive by an epistasis experiment in which
      protease-inactive Oma1 delays cardiomyopathy.
    evidence:
    - reference: PMID:41420107
      reference_title: Mutant CHCHD10 disrupts cytochrome c oxidation and activates mitochondrial retrograde signaling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Using protease-inactive Oma1E324Q/E324Q knock-in mice, we show that blunting mtISR in Chchd10S55L/+ mice delays cardiomyopathy onset without rescuing CHCHD10 insolubility, cristae defects or OXPHOS impairment."
      explanation: Establishes that the model supports a causal, and separable, role for the stress response.

experimental_models:
- name: Patient fibroblasts carrying CHCHD10 p.Ser59Leu
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Primary fibroblasts from affected members of the founding family, showing
    respiratory-chain deficiency, mitochondrial ultrastructural abnormality and
    network fragmentation, but with mitochondrial fusion intact.
  evidence:
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts."
    explanation: >-
      A negative result in this model that constrains what it can be used for:
      the network fragmentation is not a fusion defect, so the model should not be
      read as reporting on mitochondrial fusion.
  modeled_mechanisms:
  - target: MICOS Disassembly and Loss of Cristae Junctions
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    limitations: >-
      Fibroblasts are not an affected tissue in this disease, and the aggregation
      that drives pathology in the knock-in mouse is tissue-specific. A cellular
      phenotype present in fibroblasts therefore may not be the one that kills
      motor neurons.
    evidence:
    - reference: PMID:24934289
      reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network."
      explanation: Documents the cellular phenotype in patient-derived cells.
  - target: Mitochondrial DNA Instability with Multiple Deletions
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      The system in which the genome-repair defect underlying the deletions was
      demonstrated, by challenging cells with oxidative stress.
    evidence:
    - reference: PMID:26666268
      reference_title: "CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Repair of the mitochondrial genome after oxidative stress is impaired in CHCHD10 mutant fibroblasts and this likely explains the accumulation of deleted mtDNA molecules in patient muscle."
      explanation: The measurement made in this model and the inference drawn from it.

- name: Patient iPSC-derived motor neurons carrying CHCHD10 p.Ser59Leu
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    Motor neurons differentiated from patient induced pluripotent stem cells,
    which are hypersensitive to staurosporine- or glutamate-induced caspase
    activation compared with controls.
  evidence:
  - reference: PMID:39478664
    reference_title: Nifuroxazide rescues the deleterious effects due to CHCHD10-associated MICOS defects in disease models.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Its benefits involve KIF5B-mediated mitochondrial transport enhancement, evidenced by increased axonal movement and syntaphilin degradation in patient-derived motor neurons."
    explanation: >-
      Establishes this model as one in which a mechanistic readout (axonal
      mitochondrial transport) can be measured and pharmacologically moved, which
      is what makes it informative rather than merely patient-derived.
  modeled_mechanisms:
  - target: Motor Neuron Degeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Provides a human, motor-neuron-autonomous vulnerability phenotype, which is
      the compartment the mouse data argue against being primary.
    limitations: >-
      The phenotype is a sensitivity to an applied stressor rather than
      spontaneous degeneration, and its direction is opposite to the apoptotic
      block seen with mutant alleles in other systems. It also stands against the
      knock-in mouse ordering in which muscle, not the motor neuron, is hit first.
    evidence:
    - reference: PMID:30874923
      reference_title: "Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10(S59L/+) mouse."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We also showed that motor neurons differentiated from human iPSC carrying the p.Ser59Leu mutation were much more sensitive to Staurosporine or glutamate-induced caspase activation than control cells."
      explanation: Reports the cell-autonomous vulnerability measured in this model.
mechanistic_hypotheses:
- hypothesis_group_id: mitochondrial_origin_of_ftd_als
  hypothesis_label: Mitochondrial origin of the FTD-ALS phenotype
  status: ALTERNATIVE
  description: >-
    The proposal that in CHCHD10 disease the FTD-ALS phenotype arises from primary
    mitochondrial disease rather than from the proteostatic cascade that is the
    canonical model of ALS and FTD-MND. It is recorded as ALTERNATIVE, not
    CANONICAL: it is well supported for this gene but is a minority mechanism
    within the FTD-ALS spectrum as a whole, and the discovery paper itself frames
    it as opening a field rather than settling one.
  evidence:
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This work opens a novel field to explore the pathogenesis of the frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by showing that mitochondrial disease may be at the origin of some of these phenotypes."
    explanation: >-
      The authors' statement of the hypothesis, including the hedge ("some of
      these phenotypes") that keeps it an alternative rather than a replacement
      model.

- hypothesis_group_id: muscle_first_motor_neuron_disease
  hypothesis_label: Muscle-first origin of CHCHD10 motor neuron disease
  status: EMERGING
  description: >-
    That the pathological sequence runs muscle to neuromuscular junction to motor
    neuron, rather than beginning in the motor neuron and producing denervation
    atrophy. It rests on the knock-in mouse ordering, in which muscle OXPHOS
    deficiency is present at three months with the spinal cord intact and motor
    neuron loss appears only at end stage. It is EMERGING because the ordering has
    been demonstrated in one mouse model, is not established in patients, and is
    in tension with the patient iPSC motor neurons, which are cell-autonomously
    hypersensitive to stress.
  evidence:
  - reference: PMID:30874923
    reference_title: "Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10(S59L/+) mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our data show that the pathological effects of the p.Ser59Leu mutation target muscle prior to NMJ and motor neurons."
    explanation: The authors' own statement of the ordering claim this hypothesis names.

discussions:
- discussion_id: cardiomyopathy_model_human_divergence
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why is mitochondrial cardiomyopathy fully penetrant and fatal in both CHCHD10
    knock-in mouse lines while cardiac involvement is not a prominent reported
    feature of human FTDALS2?
  attaches_to:
  - pathophysiology#Mitochondrial Cardiomyopathy
  - animal_models#Chchd10 S59L/+ knock-in mouse
  rationale: >-
    This is not a peripheral discrepancy. The cardiomyopathy is the endpoint on
    which the causal role of the mitochondrial integrated stress response was
    established, by showing that genetically blunting the response delays its
    onset. If the organ carrying that experiment is the organ where mouse and
    human diverge most, then the strongest mechanistic result in the field rests
    on a phenotype whose human counterpart is unclear. Either human cardiac
    involvement is real and under-ascertained because patients are seen in
    neurology clinics, or mouse and human differ in which tissues cross the
    threshold for the stress response, and those two readings have opposite
    implications for whether mtISR inhibition is a plausible human target.
  evidence:
  - reference: PMID:30874923
    reference_title: "Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10(S59L/+) mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Before 14 months of age, all KI mice developed a fatal mitochondrial cardiomyopathy associated with enhanced mitophagy."
    explanation: Establishes the mouse side of the mismatch, including its complete penetrance.
  - reference: PMID:26131548
    reference_title: CHCHD10-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regular evaluations to detect manifestations that can occur with time including neurologic deficits, psychiatric abnormalities, impaired respiratory function, and sensorineural hearing loss."
    explanation: >-
      Establishes the human side by omission: the GeneReviews surveillance list
      names four manifestations and cardiac function is not among them, despite
      cardiomyopathy being the lethal phenotype in both mouse lines.

- discussion_id: cerebellar_and_cochlear_mechanism_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What mechanism connects CHCHD10 dysfunction to cerebellar degeneration and to
    sensorineural hearing loss, both of which are documented clinically but have no
    node in this entry's mechanism graph?
  attaches_to:
  - phenotypes#Cerebellar Ataxia
  - phenotypes#Sensorineural Hearing Impairment
  rationale: >-
    Cerebellar ataxia was the presenting symptom of the founding family's index
    case at age 50, two further relatives presented with ataxia alone, and the same
    index case had sensorineural deafness. Both are therefore core to the disease as
    first described, and both are deliberately left with no upstream pathophysiology
    node here: the literature reviewed documents them clinically without proposing a
    cell-type or circuit-level mechanism, and inventing an edge from the generic
    mitochondrial lesion would assert more than the sources do. The gap is
    substantive rather than cosmetic, because the mouse models that carry this
    entry's mechanistic weight are characterized for muscle, heart, motor neuron and
    hippocampus, and not for cerebellum or cochlea. Closing it needs either
    neuropathology from CHCHD10 carriers or cerebellar and auditory phenotyping of
    the existing knock-in lines.
  evidence:
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The index case was a 67-year-old female (Patient IV-6), who developed a cerebellar ataxia at 50 years of age, associated with progressive bulbar syndrome, dementia and sensorineural deafness."
    explanation: Establishes that both unmodelled phenotypes are present in the founding pedigree, so the gap is about mechanism rather than about whether they occur.

- discussion_id: gof_versus_dominant_negative
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Is CHCHD10 disease a toxic gain of function, a dominant-negative effect on the
    wild-type protein, or both at once in different tissues?
  attaches_to:
  - pathophysiology#CHCHD10 Missense Variant
  - pathophysiology#Mutant CHCHD10 and CHCHD2 Co-Aggregation
  rationale: >-
    Both mechanisms are asserted in the primary literature for the same alleles.
    The knock-in mouse comparison is the strongest single result and argues for
    gain of function: ablating CHCHD10 produces neither pathology nor a stress
    response, while the point mutant produces both, so the disease cannot be
    explained by absence of the protein. Against that, the same alleles show
    loss-of-function behaviour in C. elegans complementation and dominant-negative
    activity in mammalian systems, interfering with CHCHD10's normal role in
    retaining TDP-43 in the nucleus; and for the SMAJ allele a separate study finds
    the mechanism is not full haploinsufficiency either. `functional_impact_category`
    is single-valued, so this entry records GAIN_OF_FUNCTION and this discussion,
    rather than picking DOMINANT_NEGATIVE and discarding the ablation control. The
    two are not obviously exclusive: an aggregate that sequesters both CHCHD2 and
    wild-type CHCHD10 is a novel toxic species and a sink for the normal protein at
    the same time, which is exactly what would make a single enum value the wrong
    shape for the claim.
  evidence:
  - reference: PMID:30877432
    reference_title: "ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Conversely, CHCHD10 ablation does not induce disease pathology or activate the mtISR, indicating that CHCHD10S55L-dependent disease pathology is not caused by loss-of-function."
    explanation: The gain-of-function side, and the reason that value is the one recorded.
  - reference: PMID:28585542
    reference_title: Loss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "dominant negative activities in mammalian systems, resulting in mitochondrial/synaptic damage and cytoplasmic TDP-43 accumulation"
    explanation: >-
      Cuts against a pure gain-of-function reading by demonstrating dominant-negative
      behaviour for these alleles. Re-quoted to the mammalian clause so this item
      cites its own claim: the same paper's C. elegans complementation result is
      graded MODEL_ORGANISM where it is used above, and one sentence cannot carry
      two evidence_source values.
  - reference: PMID:40400037
    reference_title: Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "the disease mechanism of p.G66V is not full haploinsufficiency as residual mutant CHCHD10 protein is present even in a homozygous state"
    explanation: >-
      Rules out the simplest loss-of-function account for a second allele, which
      narrows the space without settling between gain of function and
      dominant-negative.

- discussion_id: apoptosis_direction_conflict
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Do CHCHD10 mutations suppress or sensitize apoptosis in the cells that
    actually degenerate?
  attaches_to:
  - pathophysiology#Blocked Cytochrome c Release and Impaired Apoptosis
  - experimental_models#Patient iPSC-derived motor neurons carrying CHCHD10 p.Ser59Leu
  rationale: >-
    Mutant alleles block cytochrome c release and inhibit apoptosis, yet patient
    iPSC-derived motor neurons are markedly more sensitive to caspase activation
    than controls. The two results are not formally contradictory, since they use
    different cell types and different stimuli, but they cannot both be the
    mechanism of neuronal loss. Resolving this matters because an apoptotic block
    and an apoptotic sensitization imply opposite therapeutic directions.

- discussion_id: chchd10_als_effect_size_revision
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    What is the actual contribution of CHCHD10 to ALS, given that the early
    literature described it as a common cause of familial ALS while cohort
    screening found a 2.6% rate in FTD/FTD-ALS?
  attaches_to:
  - genetic#CHCHD10
  rationale: >-
    A 2014 research letter is titled "Mutations in the CHCHD10 gene are a common
    cause of familial amyotrophic lateral sclerosis" (PMID:25261972), and that
    title is a claim rather than a finding. It is deliberately not cited as
    evidence anywhere in this entry: the abstract is unavailable in the reference
    cache, so no snippet could be verified from it, and quoting a title as a
    finding is exactly the failure mode the evidence policy warns about. The
    contemporaneous French cohort put the rate at 2.6%, and ClinGen's later expert
    review classifies the gene-disease relationship as Moderate rather than
    Definitive. The most likely explanation is not a wave of negative screens but a
    variant-interpretation error: p.Pro34Ser, counted as pathogenic in several
    early ALS and FTD series, is far too common in population databases to cause a
    dominant ultra-rare disease, so early series over-attributed cases to CHCHD10.
    That account comes from the deep-research report's own gnomAD query rather than
    from a published source, so it is recorded here as the leading hypothesis and
    not as evidence; finding a citable population-genetics analysis that states it
    is the concrete remaining gap.
  evidence:
  - reference: PMID:25155093
    reference_title: "Screening of CHCHD10 in a French cohort confirms the involvement of this gene in frontotemporal dementia with amyotrophic lateral sclerosis patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, we evaluated the frequency of CHCHD10 mutations in 115 patients with FTD and FTD-ALS phenotypes."
    explanation: Identifies the cohort whose low yield sits against the "common cause" framing.
  - reference: PMID:28318595
    reference_title: CHCHD10 mutations in patients with amyotrophic lateral sclerosis in Mainland China.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among them, the coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) has been reported to play a controversial role in ALS."
    explanation: >-
      Records that the contested status of the gene in ALS is stated in the primary
      literature and is not this curation's inference. Quoted from the paper's
      framing of prior work, and flagged here because the paper's own conclusion
      runs the other way ("Our findings support the major role of CHCHD10 in the
      frontotemporal dementia-amyotrophic lateral sclerosis disease spectrum"). The
      quote establishes that the controversy exists, not the authors' position in
      it.
  - reference: PMID:27056076
    reference_title: Mutation Screening of the CHCHD10 Gene in Chinese Patients with Amyotrophic Lateral Sclerosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No mutation in CHCHD10 was identified in FALS patients."
    explanation: >-
      A negative result in the very population the "common cause of familial ALS"
      claim is about, in a cohort of 12 familial ALS patients. Small, so it
      constrains the effect size weakly rather than settling it.
differential_diagnoses:
- name: Late-onset spinal motor neuronopathy (SMAJ/LOSMoN)
  description: >-
    The allelic disorder at the other end of the CHCHD10 series, caused by the
    Finnish founder allele p.Gly66Val and segregating in 55 patients from 17
    families. It is a pure lower motor neuron syndrome with cramps,
    fasciculations and areflexia, and it does not carry the dementia or the upper
    motor neuron involvement that define FTDALS2.
  distinguishing_features:
  - Lower motor neuron involvement only, without upper motor neuron signs
  - No cognitive decline
  - A specific Finnish founder haplotype and a different CHCHD10 allele (p.Gly66Val)
  evidence:
  - reference: PMID:25428574
    reference_title: Late onset spinal motor neuronopathy is caused by mutation in CHCHD10.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation c.197G>T p.G66V in CHCHD10 is the cause of the lower motor neuron syndrome LOSMoN/SMAJ."
    explanation: Establishes SMAJ as a distinct, allelic CHCHD10 phenotype.
  - reference: PMID:40400037
    reference_title: Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report the first homozygous CHCHD10 patient, and show that the variant dosage dictates the severity of the motor neuron disease in SMAJ"
    explanation: >-
      Establishes that severity in the SMAJ arm scales with allele dosage, a
      different determinant from the MICOS-integrity axis that separates SMAJ from
      FTDALS2.
  - reference: PMID:40400037
    reference_title: Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the disease mechanism of p.G66V is not full haploinsufficiency as residual mutant CHCHD10 protein is present even in a homozygous state"
    explanation: >-
      Distinguishes the SMAJ allele's mechanism from both haploinsufficiency and
      from the aggregation-driven gain of function that characterizes FTDALS2.

- name: Axonal Charcot-Marie-Tooth neuropathy
  description: >-
    A further allelic CHCHD10 presentation, with slowly progressive distal
    weakness and atrophy, loss of tendon reflexes and, critically, sensory
    abnormalities.
  distinguishing_features:
  - >-
    Sensory abnormalities, absent from both the ALS and the SMAJ arms and the most
    useful bedside discriminator within the CHCHD10 series
  - Distal rather than proximal or bulbar distribution of weakness
  evidence:
  - reference: PMID:26131548
    reference_title: CHCHD10-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Axonal Charcot-Marie-Tooth neuropathy: slowly progressive lower-leg muscle weakness and atrophy, small hand muscle weakness, loss of tendon reflexes, sensory abnormalities."
    explanation: Describes the neuropathic arm including the sensory features that distinguish it.

- name: Autosomal dominant isolated mitochondrial myopathy (CHCHD10 p.Gly58Arg)
  description: >-
    A further allelic CHCHD10 phenotype in which the myopathy and cardiomyopathy
    occur without motor neuron disease or dementia. It matters here because it
    shows the mitochondrial arm of FTDALS2 can occur on its own, which is an
    argument that the mitochondrial lesion is primary rather than a consequence of
    neurodegeneration.
  distinguishing_features:
  - Myopathy and cardiomyopathy without motor neuron disease or cognitive decline
  - A distinct allele (p.Gly58Arg)
  evidence:
  - reference: PMID:37021679
    reference_title: "CHCHD2 and CHCHD10-related neurodegeneration: molecular pathogenesis and the path to precision therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Different mutations in CHCHD10 cause additional neuromuscular disorders, including the lower motor neuron disease Spinal Muscular Atrophy Jokela type (SMAJ) (p.G66V) and autosomal dominant isolated mitochondrial myopathy (IMMD) (p.G58R)."
    explanation: >-
      Review evidence for the allele-to-syndrome mapping. Graded OTHER because the
      cited source is an expert review synthesizing the genotype-phenotype
      correlation rather than reporting primary observations.

- name: C9orf72-related frontotemporal dementia with motor neuron disease
  description: >-
    The dominant genetic cause of FTD-MND and the diagnosis a CHCHD10 patient will
    usually be worked up for first. Both present as combined dementia and motor
    neuron disease, but the mechanisms are unrelated.
  distinguishing_features:
  - >-
    A mitochondrial signature on muscle biopsy (ragged-red or cytochrome c
    oxidase-negative fibres, combined respiratory-chain deficiency, multiple
    mitochondrial DNA deletions) is rare in the FTD-ALS spectrum generally, so
    finding it carries high diagnostic weight for CHCHD10 over C9orf72. Stated as
    the positive predictive direction rather than as a negative claim about
    C9orf72 disease, which is not sourced here.
  - >-
    A hexanucleotide repeat expansion rather than a missense variant, so a repeat
    expansion assay is needed and exome sequencing will miss it
  evidence:
  - reference: PMID:24934289
    reference_title: "A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mitochondrial DNA instability disorders are responsible for a large clinical spectrum, among which amyotrophic lateral sclerosis-like symptoms and frontotemporal dementia are extremely rare."
    explanation: >-
      Supports the discriminator indirectly, by establishing that a mitochondrial
      DNA instability picture is a rare accompaniment of ALS/FTD and so carries
      high diagnostic weight when present.
    directness: INDIRECT

references:
- reference: PMID:26131548
  title: CHCHD10-Related Disorders.
  tags:
  - GeneReviews
notes: >-
  Why this is a separate entry. Issue #8946 filed this MONDO term for curation and
  was closed as `not_planned`/`wontfix`, on the reasoning that the priority
  dashboard recommends LUMP_INTO_PARENT for numbered series members and that
  MONDO:0014395 could be handled as a `has_subtypes` term or a
  `mappings.mondo_mappings` row on a parent entry. The closing comment invited a
  standalone entry on the condition that it "state explicitly what it adds beyond
  the parent". This entry is that argument, and the addition is mechanistic
  rather than nosological.

  The parent entries model FTD-ALS proteostatically. Amyotrophic_Lateral_Sclerosis
  carries a CANONICAL hypothesis of motor neuron proteostatic failure built on
  TDP-43, C9orf72 dipeptide repeats, SOD1 and FUS; Frontotemporal_Dementia
  describes its FTD-MND subtype as almost exclusively C9orf72. The ALS parent's
  canonical model does name mitochondrial dysfunction among its drivers, so the
  claim here is not that mitochondria are absent from it. It is that they occupy
  the opposite position: in the parent model mitochondrial dysfunction is one of
  several convergent contributors to proteostatic failure, whereas in CHCHD10
  disease it is the initiating lesion and the proteostatic changes are downstream.
  The specific chain — MICOS disassembly, cristae-junction collapse, mitochondrial
  DNA instability, OMA1-mediated L-OPA1 cleavage, a maladaptive integrated stress
  response — appears in neither parent, and neither parent's mechanism predicts a
  mitochondrial myopathy on muscle biopsy. Folding the term into a parent as a mapping
  row would record the identifier and discard all of that. Three specific things
  would have no home on either parent: the muscle-first ordering, in which the
  OXPHOS defect precedes motor neuron loss and so inverts the parent's causal
  direction; the allele-severity axis, in which MICOS integrity rather than TDP-43
  localization separates severe from mild disease; and the drug cautions, which
  arise from one patient carrying spasticity, a behavioural syndrome and a
  myopathy at once.

  Scope. The entry is anchored on MONDO:0014395 and curates the FTDALS2 arm. The
  other arms of the CHCHD10 allelic series (SMAJ/LOSMoN p.Gly66Val, axonal CMT2,
  isolated mitochondrial myopathy p.Gly58Arg) are recorded as differential
  diagnoses rather than as `has_subtypes`, because they are separate diseases with
  their own OMIM entries and not subdivisions of FTDALS2. If the KB later wants a
  single record spanning the series, "CHCHD10-related disorder" would be the
  honest unit and this entry would become part of it.

  Provenance. Deep research was requested from falcon, which failed with HTTP 402
  (account out of credits) and fell back to openscientist via
  `just dr_fallback='--fallback'`; the run recorded `fell_back: true`,
  `requested_provider: falcon` and the provider attempts in the report frontmatter.
  The report validated 21/21 references with a 0.0 confabulation rate, and
  `just preflight-dr ... MONDO:0014395` PASSED (CHCHD10 mentioned 82 times, report
  OMIM 615911 matching MONDO's). Its `needs_review: true` flag is driven by term
  validation, not references: one obsolete term (HP:0002355) and two identifiers
  the report "names" with frequency-table cell values rather than labels
  (HP:0001638, HP:0009830). None of the three is bound in this entry. The
  GeneReviews chapter (PMID:26131548) was used as the phenotype baseline per the
  curation SOP. `phenotypes` carries the arms of its Clinical Characteristics list
  that belong to FTDALS2 itself — mitochondrial myopathy, ALS, FTD and cerebellar
  ataxia — and deliberately omits the features GeneReviews attributes to the other
  allelic disorders, since those are curated as differential diagnoses under the
  scope rule above. Concretely, cramps, fasciculations and distal weakness with
  sensory signs are cited by GeneReviews to the SMAJ and Charcot-Marie-Tooth arms,
  so listing them here would have meant quoting a sentence about one disease to
  support a claim about another. Areflexia and amyotrophy are retained because each
  has a source inside scope: the founding pedigree's examination findings, and the
  mitochondrial myopathy sentence respectively. The psychiatric abnormalities named
  only in the surveillance sentence are too unspecific to bind to an HP term.
  Cerebellar ataxia and sensorineural hearing loss are curated as phenotypes but
  have no pathophysiology node, which is recorded as an explicit knowledge gap
  rather than papered over with an invented edge.

  No datasets, and why. `just discover-datasets` returned 12 candidates, all
  tagged DIRECT and all rejected. Every one was matched by relaxing this entry's
  name to the generic string "Frontotemporal Dementia Amyotrophic Lateral
  Sclerosis", and none of the 12 mentions CHCHD10: seven are C9orf72
  hexanucleotide-repeat series from a single paper, three are TDP-43 or FUS
  studies, one is an E. coli phase-transition experiment, and one is a generic
  human ALS upper-motor-neuron transcriptome. That last one is not the
  C9orf72/TDP-43 mechanism this entry is defined against; it was rejected for the
  simpler reason that it is not CHCHD10-specific. This is the Named Entity
  Confusion case the
  dataset SOP warns about, and it is sharper than usual here because C9orf72 is
  precisely the gene this entry's mechanism is defined against, so a C9orf72
  transcriptome attached to this record would assert the opposite of what the
  entry argues. `datasets` is therefore empty by decision, not by omission.

  Treatments deliberately not modelled. Riluzole and edaravone are not curated
  here. Both are standard of care for ALS from any cause, and GeneReviews states
  that management of the ALS, FTD, SMA and cerebellar arms is the same as for other
  causes of those syndromes, so neither is CHCHD10-specific; the available sources
  for them are also generic ALS reviews rather than anything about this gene. A
  reader expecting them should read their absence as scoping, not as an oversight.

  Why the surveillance treatment reuses the supportive-care binding. Both
  treatments bind NCIT:C15747 (Supportive Care), which makes them
  indistinguishable by term. This is not an oversight: `TreatmentTerm` is rooted at
  NCIT:C25218 (Clinical Intervention or Procedure), and neither NCIT:C15719
  (Surveillance) nor NCIT:C53607 (Patient Monitoring) is reachable from it, so
  binding either would fail the dynamic enum. NCIT:C15302 and NCIT:C15747 were
  checked as controls and do reach that root. The specificity therefore lives in
  `name` and `preferred_term`. Recorded here so the next curator does not repeat
  the lookup.

  Identifiers. OMIM:615911 anchors this entry's identity alongside the MONDO term
  and is named here rather than in `mappings`, because `DiseaseMappings` carries
  slots for ICD-10-CM, ICD-11, MONDO and NCIT only, with no OMIM slot to put it in.

  What is deliberately not cited. PMID:25261972, titled "Mutations in the CHCHD10
  gene are a common cause of familial amyotrophic lateral sclerosis", is not used
  as evidence anywhere. Its abstract is unavailable (the publisher returned 403 to
  the full-text fetch and PubMed carries no abstract for the research letter), so
  no snippet could be verified, and its title is a claim rather than a finding.
  ClinGen's Moderate classification for the CHCHD10-FTDALS2 relationship is
  likewise described in the `genetic` notes but not cited: `just clingen-refresh`
  currently fails a pinned-sha256 check because upstream published a new release
  behind the same URL, and repinning plus rebuilding the ClinGen cache is a
  maintenance change that does not belong in a curation PR.

📚

References & Deep Research

References

1

PMID:26131548

CHCHD10-Related Disorders.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

Why this is a separate entry. Issue #8946 filed this MONDO term for curation and was closed as `not_planned`/`wontfix`, on the reasoning that the priority dashboard recommends LUMP_INTO_PARENT for numbered series members and that MONDO:0014395 could be handled as a `has_subtypes` term or a `mappings.mondo_mappings` row on a parent entry. The closing comment invited a standalone entry on the condition that it "state explicitly what it adds beyond the parent". This entry is that argument, and the addition is mechanistic rather than nosological. The parent entries model FTD-ALS proteostatically. Amyotrophic_Lateral_Sclerosis carries a CANONICAL hypothesis of motor neuron proteostatic failure built on TDP-43, C9orf72 dipeptide repeats, SOD1 and FUS; Frontotemporal_Dementia describes its FTD-MND subtype as almost exclusively C9orf72. The ALS parent's canonical model does name mitochondrial dysfunction among its drivers, so the claim here is not that mitochondria are absent from it. It is that they occupy the opposite position: in the parent model mitochondrial dysfunction is one of several convergent contributors to proteostatic failure, whereas in CHCHD10 disease it is the initiating lesion and the proteostatic changes are downstream. The specific chain — MICOS disassembly, cristae-junction collapse, mitochondrial DNA instability, OMA1-mediated L-OPA1 cleavage, a maladaptive integrated stress response — appears in neither parent, and neither parent's mechanism predicts a mitochondrial myopathy on muscle biopsy. Folding the term into a parent as a mapping row would record the identifier and discard all of that. Three specific things would have no home on either parent: the muscle-first ordering, in which the OXPHOS defect precedes motor neuron loss and so inverts the parent's causal direction; the allele-severity axis, in which MICOS integrity rather than TDP-43 localization separates severe from mild disease; and the drug cautions, which arise from one patient carrying spasticity, a behavioural syndrome and a myopathy at once. Scope. The entry is anchored on MONDO:0014395 and curates the FTDALS2 arm. The other arms of the CHCHD10 allelic series (SMAJ/LOSMoN p.Gly66Val, axonal CMT2, isolated mitochondrial myopathy p.Gly58Arg) are recorded as differential diagnoses rather than as `has_subtypes`, because they are separate diseases with their own OMIM entries and not subdivisions of FTDALS2. If the KB later wants a single record spanning the series, "CHCHD10-related disorder" would be the honest unit and this entry would become part of it. Provenance. Deep research was requested from falcon, which failed with HTTP 402 (account out of credits) and fell back to openscientist via `just dr_fallback='--fallback'`; the run recorded `fell_back: true`, `requested_provider: falcon` and the provider attempts in the report frontmatter. The report validated 21/21 references with a 0.0 confabulation rate, and `just preflight-dr ... MONDO:0014395` PASSED (CHCHD10 mentioned 82 times, report OMIM 615911 matching MONDO's). Its `needs_review: true` flag is driven by term validation, not references: one obsolete term (HP:0002355) and two identifiers the report "names" with frequency-table cell values rather than labels (HP:0001638, HP:0009830). None of the three is bound in this entry. The GeneReviews chapter (PMID:26131548) was used as the phenotype baseline per the curation SOP. `phenotypes` carries the arms of its Clinical Characteristics list that belong to FTDALS2 itself — mitochondrial myopathy, ALS, FTD and cerebellar ataxia — and deliberately omits the features GeneReviews attributes to the other allelic disorders, since those are curated as differential diagnoses under the scope rule above. Concretely, cramps, fasciculations and distal weakness with sensory signs are cited by GeneReviews to the SMAJ and Charcot-Marie-Tooth arms, so listing them here would have meant quoting a sentence about one disease to support a claim about another. Areflexia and amyotrophy are retained because each has a source inside scope: the founding pedigree's examination findings, and the mitochondrial myopathy sentence respectively. The psychiatric abnormalities named only in the surveillance sentence are too unspecific to bind to an HP term. Cerebellar ataxia and sensorineural hearing loss are curated as phenotypes but have no pathophysiology node, which is recorded as an explicit knowledge gap rather than papered over with an invented edge. No datasets, and why. `just discover-datasets` returned 12 candidates, all tagged DIRECT and all rejected. Every one was matched by relaxing this entry's name to the generic string "Frontotemporal Dementia Amyotrophic Lateral Sclerosis", and none of the 12 mentions CHCHD10: seven are C9orf72 hexanucleotide-repeat series from a single paper, three are TDP-43 or FUS studies, one is an E. coli phase-transition experiment, and one is a generic human ALS upper-motor-neuron transcriptome. That last one is not the C9orf72/TDP-43 mechanism this entry is defined against; it was rejected for the simpler reason that it is not CHCHD10-specific. This is the Named Entity Confusion case the dataset SOP warns about, and it is sharper than usual here because C9orf72 is precisely the gene this entry's mechanism is defined against, so a C9orf72 transcriptome attached to this record would assert the opposite of what the entry argues. `datasets` is therefore empty by decision, not by omission. Treatments deliberately not modelled. Riluzole and edaravone are not curated here. Both are standard of care for ALS from any cause, and GeneReviews states that management of the ALS, FTD, SMA and cerebellar arms is the same as for other causes of those syndromes, so neither is CHCHD10-specific; the available sources for them are also generic ALS reviews rather than anything about this gene. A reader expecting them should read their absence as scoping, not as an oversight. Why the surveillance treatment reuses the supportive-care binding. Both treatments bind NCIT:C15747 (Supportive Care), which makes them indistinguishable by term. This is not an oversight: `TreatmentTerm` is rooted at NCIT:C25218 (Clinical Intervention or Procedure), and neither NCIT:C15719 (Surveillance) nor NCIT:C53607 (Patient Monitoring) is reachable from it, so binding either would fail the dynamic enum. NCIT:C15302 and NCIT:C15747 were checked as controls and do reach that root. The specificity therefore lives in `name` and `preferred_term`. Recorded here so the next curator does not repeat the lookup. Identifiers. OMIM:615911 anchors this entry's identity alongside the MONDO term and is named here rather than in `mappings`, because `DiseaseMappings` carries slots for ICD-10-CM, ICD-11, MONDO and NCIT only, with no OMIM slot to put it in. What is deliberately not cited. PMID:25261972, titled "Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis", is not used as evidence anywhere. Its abstract is unavailable (the publisher returned 403 to the full-text fetch and PubMed carries no abstract for the research letter), so no snippet could be verified, and its title is a claim rather than a finding. ClinGen's Moderate classification for the CHCHD10-FTDALS2 relationship is likewise described in the `genetic` notes but not cited: `just clingen-refresh` currently fails a pinned-sha256 check because upstream published a new release behind the same URL, and repinning plus rebuilding the ClinGen cache is a maintenance change that does not belong in a curation PR.

Create: Frontotemporal Dementia And/Or Amyotrophic Lateral Sclerosis 2 (CHCHD10) · 2026-09-07T11:08:42Z · View source

Created kb/disorders/Frontotemporal_Dementia_And_Or_Amyotrophic_Lateral_Sclerosis_2.yaml for MONDO:0014395 (FTDALS2, causal gene CHCHD10, OMIM:615911). Lump/split decision. Issue #8946 filed this term and closed it as not_planned/wontfix on a LUMP_INTO_PARENT recommendation, inviting a standalone entry only if it states what it adds beyond the parent. A standalone entry was created and that argument is written into the entry's notes: block. The substance is that both parent entries model FTD-ALS proteostatically (Amyotrophic_Lateral_Sclerosis carries a CANONICAL "Motor Neuron Proteostatic Failure Model"; Frontotemporal_Dementia describes its FTD-MND subtype as almost exclusively C9orf72-linked, both verified against the current files), whereas CHCHD10 disease runs through MICOS disassembly, cristae-junction loss, mtDNA instability, OMA1-mediated L-OPA1 cleavage and a maladaptive mitochondrial integrated stress response, with a mitochondrial myopathy on muscle biopsy that neither parent's mechanism predicts. Three things specifically would have no home on a mapping row: the muscle-first ordering, the MICOS-integrity severity axis, and the GeneReviews drug cautions. The other arms of the CHCHD10 allelic series (SMAJ p.Gly66Val, axonal CMT2, isolated mitochondrial myopathy p.Gly58Arg) were deliberately recorded as differential_diagnoses rather than has_subtypes, since they are separate diseases with their own OMIM entries. Deep research. falcon was the requested provider and failed with HTTP 402 (Edison account out of credits). Rather than substituting a provider by hand, the run was re-issued through the recorded fallback path (just dr_fallback='--fallback' research-disorder falcon ...), which produced research/Frontotemporal_Dementia_And_Or_Amyotrophic_Lateral_Sclerosis_2-deep-research-openscientist.md carrying fell_back: true, requested_provider: falcon and both provider_attempts in its frontmatter. The report validated 21/21 references with confabulation_rate 0.0. Its needs_review: true flag is driven entirely by term validation, not references: one obsolete term (HP:0002355) and two identifiers the report "names" with frequency-table cell values rather than labels (HP:0001638 named "Spectrum-dependent", HP:0009830 named "Allele-dependent"). None of those three is bound in this entry. just preflight-dr <report> MONDO:0014395 PASSED (CHCHD10 mentioned 82 times; report OMIM 615911 matches MONDO's), so no Named Entity Confusion. GeneReviews baseline. PMID:26131548 (CHCHD10-Related Disorders) was found, fetched, cached, and tagged GeneReviews in the top-level references: block. Every arm of its Clinical Characteristics list is represented in phenotypes (mitochondrial myopathy, ALS, FTD, SMAJ features, axonal CMT features, cerebellar ataxia) except the "psychiatric abnormalities" named only in the surveillance sentence, which is too unspecific to bind to an HP term; that omission is stated in the entry notes. The Agents/Circumstances to Avoid content (baclofen worsening weakness; FTD behavioural drugs worsening dysarthria, dysphagia and respiratory weakness) is carried in the supportive-care treatment's notes. Evidence. 20 PMIDs, 101/101 snippets verified against the local cache. Sources are a mix of the founding clinical report (PMID:24934289), cohort screens (PMID:25155093, PMID:27056076, PMID:28318595), mechanism papers (PMID:26666268, PMID:32338760, PMID:28585542, PMID:30092269, PMID:41420107), knock-in mouse work (PMID:30877432, PMID:30874923, PMID:38583639, PMID:38724625) and human post-mortem neuropathology (PMID:35787294). Two supports: REFUTE items were recorded rather than smoothed over in prose: patient iPSC motor neurons are hypersensitive to caspase activation while mutant alleles block cytochrome c release in fibroblasts, and mitochondrial phospho-TDP-43 accumulates equally in the severe S59L and mild G66V alleles, which argues against TDP-43 localization being the severity determinant. Both are also carried as discussions. Deliberately not cited. PMID:25261972 ("Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis") is referenced only in a discussion rationale as prose, never as an evidence item: the publisher returned 403 to the full-text fetch and PubMed carries no abstract for the research letter, so no snippet could be verified, and its title is a claim rather than a finding. ClinGen's Moderate classification for CHCHD10-FTDALS2 (versus Definitive for CHCHD10-mitochondrial disease) is described in the genetic notes but not cited as a CGGV: reference, because just clingen-refresh currently fails a pinned-sha256 check against data/clingen/MANIFEST.yaml after an upstream release behind the same URL, and repinning plus rebuilding the 516-file ClinGen cache is a maintenance change that does not belong in a curation PR. Nothing in the entry rests on the ClinGen claim. Datasets. Empty by decision. just discover-datasets returned 12 candidates, all tagged DIRECT, and none mentions CHCHD10: seven are C9orf72 hexanucleotide-repeat studies, three are TDP-43/FUS studies, one is an E. coli phase-transition experiment. All were matched by relaxing this entry's name to the generic string "Frontotemporal Dementia Amyotrophic Lateral Sclerosis". This is the Named Entity Confusion case the dataset SOP describes, and it is sharper than usual because C9orf72 is the gene this entry's mechanism is defined against. Validation. just validate-disorders passed (schema, terms, 101/101 reference snippets). just check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values and check-qualifier-terms all OK on the file; check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading and check-environmental-evidence all OK whole-KB with no new baseline entries. linkml-data-qc reports 91.7% global / 92.0% weighted compliance. Uncited reference caches fetched during the session were pruned and snippet verification was re-run afterwards on the pruned tree. The stub stubs/Frontotemporal_Dementia_And_Or_Amyotrophic_Lateral_Sclerosis_2.yaml was deleted and just check-stubs reports no errors. The full pytest suite (6160 checks) passes. It caught one defect the validators did not: check_upward_extrapolating_links_are_caveated flagged the S55L mouse's integrated-stress-response link as an uncaveated MOLECULAR-model to CELLULAR-target extrapolation. Fixed by correcting model_scale to CELLULAR rather than adding a caveat, because MOLECULAR was simply the wrong tag: the model observes a cellular-scale programme (stress-induced transcription factors, myokine secretion, one-carbon metabolism, respiratory-chain enzyme downregulation), not a single molecular species. Pre-PR adversarial review. A red-team pass over the finished entry (per the dismech-pr-review skill) returned seven blocking findings, all fixed before commit. (1) No diagnosis: section existed, so the GeneReviews DIAGNOSIS/TESTING content was unmined; four diagnosis records were added covering the molecular route, the muscle biopsy, mtDNA-deletion detection and EMG/NCS, including the negatives that repeat-expansion and primary mtDNA testing are the wrong tests. (2) A supports: REFUTE item on the TDP-43 node refuted a severity claim that lives on the MICOS node, not a claim that node made; it was moved to the MICOS node and regraded SUPPORT with directness: INDIRECT. (3) A PMID:28585542 item graded IN_VITRO quoted a sentence naming C. elegans complementation assays; it was split into a MODEL_ORGANISM item and an IN_VITRO item, each quoting its own clause. (4) A PMID:35787294 explanation claimed human FTDALS2 evidence, but that paper's brains are FTLD-TDP and Alzheimer cases, not CHCHD10 carriers; the explanation was rewritten and directness: INDIRECT added. (5) A scope contradiction: notes: said the other CHCHD10 allelic arms are differential diagnoses while phenotypes: curated their features, each cited to a GeneReviews sentence explicitly about a different disease. Fasciculations, Muscle Cramps and Distal Muscle Weakness were removed; Areflexia was re-evidenced from the founding pedigree's examination findings and Skeletal Muscle Atrophy from the mitochondrial-myopathy sentence, both inside scope. (6) Unevidenced negative claims about C9orf72 disease in a differential's distinguishing_features were rewritten as the positive predictive direction the cited quote actually supports. (7) Both mechanistic_hypotheses were declared but no downstream edge opted into either, so the contested muscle-first ordering was asserted in the pathograph indistinguishably from settled edges; hypothesis_groups tags were added to the four relevant edges. Major findings also fixed: CL:0002372 (myotube, the immature precursor) was the wrong cell type for adult patient muscle fibre claims and was replaced with CL:0008002 skeletal muscle fiber in three places; orphaned phenotype nodes were wired into the graph, including Multiple Mitochondrial DNA Deletions, which the separate-entry argument rests on and which was hanging off the graph entirely; the description's claim that CHCHD10 ablation "produces no disease at all" was softened, since PMID:40400037 notes a knockout study reporting neuromuscular junction impairment; the PMID:28318595 "controversial role" quote is from that paper's framing of prior work while its own conclusion runs the other way, which the explanation now says; and the notes' dataset enumeration accounted for 11 of 12 rejected candidates and mischaracterised the twelfth, now corrected. Two findings were not actionable and are recorded rather than silently dropped. The reviewer asked for OMIM:615911 in mappings:, but DiseaseMappings has slots for ICD-10-CM, ICD-11, MONDO and NCIT only, with no OMIM slot; this is noted in the entry. The reviewer also judged the notes' claim that CHCHD10 disease "does not run through" the parent's proteostatic model to be overstated, since that model does list mitochondrial dysfunction among its drivers. Verified and correct: the argument was rewritten to the accurate and stronger form, that mitochondrial dysfunction occupies the opposite position in the two models (one of several convergent contributors in the parent, the initiating lesion here). Cerebellar ataxia and sensorineural hearing loss are curated as phenotypes with no upstream pathophysiology node. Rather than invent an edge from the generic mitochondrial lesion, this is recorded as an explicit KNOWLEDGE_GAP discussion: both were presenting features of the founding pedigree, and the knock-in mice that carry this entry's mechanistic weight are phenotyped for muscle, heart, motor neuron and hippocampus but not cerebellum or cochlea. Final state: 106/106 snippets verified, 20 PMIDs, 1987 lines, 91.5% global / 91.8% weighted compliance, all offline gates and 6160 pytest checks green. Review round on PR #11339. The automated reviewer approved with no blocking findings and five optional suggestions; four were taken and bundled into one push, since every push to this repo dismisses the standing approval. Added an Impaired Mitochondrial Axonal Transport pathophysiology node between the MICOS lesion and neuromuscular junction degeneration — the evidence (PMID:39478664, KIF5B-mediated transport and syntaphilin degradation) was already in the file but only inside a treatment description, so the nifuroxazide treatment now targets the mechanism its benefit is actually attributed to rather than only the MICOS phenotype the screen selected on. Both new evidence items are graded directness: INDIRECT because the transport deficit is inferred from a pharmacological rescue rather than measured. Bound NCIT:C90982 Nifuroxazide as therapeutic_agent (CHEBI has no nifuroxazide term). Recorded in notes why riluzole and edaravone are out of scope. Added the PR and issue links here. One suggestion was not actionable and is recorded rather than silently dropped: the reviewer asked whether a monitoring-specific NCIT term could separate the surveillance treatment from general supportive care. Neither NCIT:C15719 (Surveillance) nor NCIT:C53607 (Patient Monitoring) is reachable from NCIT:C25218, the TreatmentTerm root, so binding either would fail the dynamic enum; NCIT:C15747 stands. Method checked against NCIT:C15302 and NCIT:C15747, both of which do reach C25218. While applying these, the edit introduced a duplicate `evidence` key inside the nifuroxazide target_mechanisms block — the dismech#8623 failure mode. Caught by just validate before pushing, and fixed by restoring each target's own evidence rather than dropping a block. Second review round. The re-review approved the current head and raised three further optional suggestions, all taken in one push. (1) The new MICOS to axonal-transport edge was typed causal_link_type: DIRECT while its only evidence carried directness: INDIRECT — an edge stronger than its own evidence, and inconsistent with the sibling TDP-43 edge. Retyped INDIRECT_UNKNOWN_INTERMEDIATES. (2) functional_impact_category: GAIN_OF_FUNCTION sat alongside dominant-negative and loss-of-function language elsewhere in the file. The value is kept, because the knock-in ablation control is the strongest single result and switching to DOMINANT_NEGATIVE would discard it, but a gof_versus_dominant_negative CONTROVERSY discussion now records the tension with evidence on both sides, and the genetic_context description points at it. The two mechanisms may not even be exclusive: an aggregate that sequesters both CHCHD2 and wild-type CHCHD10 is a novel toxic species and a sink for the normal protein at once, which is what makes a single-valued enum the wrong shape here. (3) The NCIT:C25218 reachability finding was recorded only in this history file, where the next curator would not meet it; it is now also in the entry's notes. Writing that discussion tripped check-snippet-grading: the new evidence item quoted a sentence beginning with the same C. elegans clause already graded MODEL_ORGANISM in pathophysiology, but graded it IN_VITRO. The gate was right — evidence_source classifies the cited study and cannot change because the quote moved. Fixed by re-quoting the discussion item to the mammalian dominant-negative clause, which is the claim it actually needed, rather than by regrading either item. Final: 112/112 snippets verified, all gates and 6160 pytest checks green.

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Frontotemporal Dementia And/Or Amyotrophic Lateral Sclerosis 2 (FTDALS2): Comprehensive Disease Characteristics Report

openscientist-autonomous 21 citations 2026-09-07T10:48:31.411994

Frontotemporal Dementia And/Or Amyotrophic Lateral Sclerosis 2 (FTDALS2): Comprehensive Disease Characteristics Report

Disease: Frontotemporal Dementia And/Or Amyotrophic Lateral Sclerosis 2 (FTDALS2) MONDO ID: MONDO:0014395 · OMIM: #615911 · Causal gene: CHCHD10 (HGNC:15559) Category: Mendelian (autosomal dominant)

Summary

Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis 2 (FTDALS2; OMIM #615911, MONDO:0014395) is a rare, adult/late-onset, autosomal dominant neurodegenerative disorder caused by heterozygous gain-of-function missense mutations in CHCHD10, a gene encoding a small mitochondrial intermembrane-space protein. It was defined by the discovery of the founding p.Ser59Leu (c.176C>T) mutation in a large French family exhibiting a strikingly multisystem "mitochondrial" phenotype that combined motor neuron disease, frontotemporal-dementia–like cognitive decline, cerebellar ataxia, and mitochondrial myopathy with ragged-red/COX-negative fibres and multiple mitochondrial DNA (mtDNA) deletions [PMID: 24934289]. FTDALS2 sits within a broader CHCHD10 spectrum that spans classical ALS, FTD-ALS, isolated mitochondrial myopathy/cardiomyopathy, late-onset spinal motor neuronopathy (SMAJ, Spinal Muscular Atrophy Jokela type), and Charcot-Marie-Tooth disease type 2, with a strong allele-specific genotype–phenotype correlation [PMID: 37021679; PMID: 25428574].

Mechanistically, mutant CHCHD10 misfolds and aggregates, disassembles the MICOS (mitochondrial contact site and cristae organizing system) complex, collapses cristae junctions, and destabilizes the mitochondrial genome — explaining the accumulation of deleted mtDNA in patient muscle [PMID: 26666268]. Downstream, mutant protein activates the OMA1 peptidase, which cleaves the long form of the fusion protein OPA1 (L-OPA1), triggers the mitochondrial integrated stress response (mtISR), impairs mitochondrial axonal transport, and drives cytoplasmic accumulation of TDP-43, the pathological hallmark shared with sporadic ALS/FTLD-TDP [PMID: 32338760; PMID: 30877432; PMID: 28585542]. The mechanism is best described as a toxic gain-of-function / dominant-negative, not simple haploinsufficiency; the degree of MICOS disruption tracks clinical severity [PMID: 30092269].

CHCHD10 mutations are an ultra-rare cause of ALS/FTD (~0.4% of cohorts), and careful population-genetics work is essential to separate genuinely pathogenic ultra-rare alleles (p.Ser59Leu, p.Arg15Leu) from historically-reported benign polymorphisms such as p.Pro34Ser (gnomAD allele frequency ~0.4%, far too common to be causal) [PMID: 27056076; PMID: 28318595]. There is no disease-specific therapy; management follows ALS/FTD symptomatic standards (riluzole, edaravone, multidisciplinary supportive care) [PMID: 42113599; PMID: 42666355]. Experimental precision strategies targeting the MICOS/mitochondrial-transport axis (e.g., nifuroxazide), the integrated stress response, and metabolic/creatine buffering are under active investigation in yeast, knock-in mouse, and patient iPSC-derived motor neuron models [PMID: 39478664; PMID: 40400037].

Key Findings

Finding 1 — CHCHD10 is the causal gene (autosomal dominant)

FTDALS2 is caused by heterozygous mutations in CHCHD10 (coiled-coil-helix-coiled-coil-helix domain containing 10, chromosome 22q11.23, HGNC:15559), encoding a mitochondrial intermembrane-space protein. The founding p.Ser59Leu mutation was identified in a large French family with mitochondrial myopathy associated with motor neuron disease: "We reported patients, carrying the p.Ser59Leu heterozygous mutation in CHCHD10, from a large family with a mitochondrial myopathy associated with motor neuron disease (MND)" [PMID: 30874923]. The allelic spectrum was subsequently extended across ALS, FTD-ALS, and milder syndromes; for example, a distinct milder allele defines a lower motor neuron syndrome: "Mutation c.197G>T p.G66V in CHCHD10 is the cause of the lower motor neuron syndrome LOSMoN/SMAJ" [PMID: 25428574]. Inheritance is autosomal dominant.

Finding 2 — Core lesion: MICOS disassembly, cristae collapse, mtDNA instability

CHCHD10 resides within the MICOS complex together with mitofilin (MIC60), CHCHD3, and CHCHD6. Mutant CHCHD10 disassembles MICOS and collapses cristae junctions: "CHCHD10 resides with mitofilin, CHCHD3 and CHCHD6 within the 'mitochondrial contact site and cristae organizing system' (MICOS) complex. CHCHD10 mutations lead to MICOS complex disassembly and loss of mitochondrial cristae with a decrease in nucleoid number and nucleoid disorganization" [PMID: 26666268]. This links directly to mtDNA instability: "Repair of the mitochondrial genome after oxidative stress is impaired in CHCHD10 mutant fibroblasts and this likely explains the accumulation of deleted mtDNA molecules in patient muscle" [PMID: 26666268]. Importantly, the degree of MICOS disruption correlates with disease severity: "Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseases" [PMID: 30092269].

Finding 3 — Toxic gain-of-function → OMA1/OPA1 cleavage → mtISR → cytoplasmic TDP-43

The pathogenic mechanism is a tissue-specific toxic gain-of-function with dominant-negative activity, not haploinsufficiency. A knock-in mouse bearing the mouse-equivalent S59L (S55L) mutation was generated "to investigate the pathogenic mechanisms of CHCHD10 … harboring the mouse-equivalent of a disease-associated human S59L mutation, S55L in the endogenous mouse gene," demonstrating a tissue-specific toxic gain-of-function and mitochondrial stress response [PMID: 30877432]. The downstream cristae-shaping mechanism is OMA1-mediated: "C2/C10 DKO mice have disrupted mitochondrial cristae, because of cleavage of the mitochondrial-shaping protein long form of OPA1 (L-OPA1) by the stress-induced peptidase OMA1," and these mice "partially phenocopied mutant C10 KI mice with the development of cardiomyopathy and activation of the integrated mitochondrial integrated stress response in affected tissues" [PMID: 32338760]. The link to TDP-43 pathology is direct: "FTD/ALS-associated mutations (R15L and S59L) exhibit loss of function phenotypes in C. elegans genetic complementation assays and dominant negative activities in mammalian systems, resulting in mitochondrial/synaptic damage and cytoplasmic TDP-43 accumulation" [PMID: 28585542]. Insoluble CHCHD10 co-aggregates with phospho-TDP-43 and correlates with insoluble TDP-43 in FTLD-TDP brains [PMID: 35787294].

Finding 4 — Multisystem late-onset clinical phenotype

In the founding p.Ser59Leu (c.176C>T) family, "We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy" [PMID: 24934289]. Muscle biopsy findings were characteristically mitochondrial: "In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V," and "The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder" [PMID: 24934289]. Patient fibroblasts showed respiratory chain deficiency, mitochondrial ultrastructural alterations, and fragmentation of the mitochondrial network; overexpression of mutant CHCHD10 in HeLa cells caused loss, disorganization, and dilatation of cristae.

Finding 5 — Rarity, severity gradient, and pathology staging

CHCHD10 mutations are a rare cause of ALS/FTD-ALS. Screening of 499 Chinese ALS patients found "The mutation frequency of CHCHD10 (0.4 %, 2/487) in a Chinese SALS population" [PMID: 27056076], and some variants have a "controversial role in ALS" [PMID: 28318595]. Variant-dependent severity is well established: p.Ser59Leu causes severe FTD-ALS with mtDNA instability, whereas the SMAJ phenotype is mild — "patients presenting with SMAJ phenotype have neither mitochondrial myopathy nor mtDNA instability" [PMID: 30092269; PMID: 25428574]. In knock-in mice, "Mitochondrial defect in muscle precedes neuromuscular junction degeneration and motor neuron death in CHCHD10" [PMID: 30874923], establishing a muscle → NMJ → motor neuron staging.

Finding 6 — Population genetics separates pathogenic from benign variants

A direct gnomAD v4 query (CHCHD10, ENSG00000250479, chr22:23,765,834–23,767,972, GRCh38) confirmed that pathogenic FTD-ALS alleles are ultra-rare: p.Ser59Leu allele frequency (AF) = 6.9×10⁻⁷ (1 of 1,446,818 exome alleles); p.Arg15Leu AF = 0 (0 of 949,590); p.Ala35Asp AF = 6.1×10⁻⁶; the Finnish SMAJ founder p.Gly66Val AF = 2.1×10⁻⁶ (3 alleles). By stark contrast, p.Pro34Ser, reported in early ALS/FTD studies, has AF = 0.0043 (5,542 exome alleles; ~0.23% in genomes) — far above any plausible disease-allele frequency, indicating it is a benign/likely-benign common polymorphism (ACMG BA1/BS1). This population evidence explains the literature's caution that CHCHD10 has "a controversial role in ALS" [PMID: 28318595] — the controversy largely reflects benign common variants being conflated with true ultra-rare pathogenic alleles.

Finding 7 — Strong allele-specific genotype–phenotype correlation

Distinct CHCHD10 alleles map to distinct clinical syndromes: "dominant mutations in the mitochondrial protein CHCHD10 (p.R15L and p.S59L) and its paralog CHCHD2 (p.T61I) were shown to cause familial amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), respectively" [PMID: 37021679]. Further: "Different mutations in CHCHD10 cause additional neuromuscular disorders, including the lower motor neuron disease Spinal Muscular Atrophy Jokela type (SMAJ) (p.G66V) and autosomal dominant isolated mitochondrial myopathy (IMMD) (p.G58R)" [PMID: 37021679]. The unifying mechanism is toxic misfolding: "mitochondrial dysfunction may drive ALS and PD pathogenesis by a gain of function mechanism, driven by protein misfolding of CHCHD2 and CHCHD10 into toxic species" [PMID: 37021679]. CHCHD10 is an intrinsically disordered/low-complexity protein that heterodimerizes with its paralog CHCHD2 [PMID: 35791387; PMID: 36158221].

Finding 8 — No disease-specific therapy; emerging precision strategies

No approved CHCHD10-specific therapy exists; management follows ALS/FTD symptomatic standards (riluzole — modest survival benefit; edaravone — narrow eligibility; multidisciplinary care) [PMID: 42113599; PMID: 42666355]. Experimental precision approaches are emerging. A yeast-based repurposing screen identified nifuroxazide: "nifuroxazide rescues mitochondrial network fragmentation and cristae abnormalities in CHCHD10^S59L/+ patient fibroblasts. This molecule also decreases caspase-dependent death of human CHCHD10^S59L/+ induced pluripotent stem cell-derived motor neurons," and "Its benefits involve KIF5B-mediated mitochondrial transport enhancement, evidenced by increased axonal movement and syntaphilin degradation in patient-derived motor neurons" [PMID: 39478664]. Metabolic dysregulation is a downstream feature and potential biomarker/target: "CHCHD10 p.G66V dysregulates energy metabolism, leading to altered redox balance and energy buffering by creatine metabolism," and "we report the first homozygous CHCHD10 patient, and show that the variant dosage dictates the severity of the motor neuron disease in SMAJ" [PMID: 40400037].

Report by Section

1. Disease Information

FTDALS2 is a Mendelian, autosomal dominant, adult/late-onset neurodegenerative disorder within the ALS–FTD spectrum, caused by CHCHD10 mutations and distinguished by prominent mitochondrial features (myopathy with ragged-red/COX-negative fibres, mtDNA instability) alongside motor neuron disease, FTD-like cognitive decline, and cerebellar ataxia [PMID: 24934289].

Key identifiers: OMIM #615911; MONDO:0014395; gene CHCHD10 (HGNC:15559; NCBI Gene 400916; Ensembl ENSG00000250479); chromosome 22q11.23. ICD-10 mapping is via G31.0 (frontotemporal dementia) and G12.21 (ALS); ICD-11 in the 8B60/8B00 range. MeSH: Frontotemporal Dementia; Amyotrophic Lateral Sclerosis.
Synonyms / alternative names: FTDALS2; "FTD-ALS type 2"; part of the "CHCHD10 spectrum" / "CHCHD10-related disease"; historically described as "mitochondrial myopathy with motor neuron disease." Related spectrum entities include SMAJ (Jokela-type spinal muscular atrophy), isolated mitochondrial myopathy (IMMD), and CMT2.
Data source type: Information is derived from aggregated disease-level resources (OMIM, Orphanet, ClinVar, gnomAD) and primary literature (family pedigrees, cohort screens, model organisms), not from EHR-level individual patient records.

2. Etiology

Causal factors: Genetic. Heterozygous gain-of-function missense mutations in CHCHD10 [PMID: 24934289; PMID: 37021679]. No infectious or purely environmental cause.
Genetic risk factors: The causal variants are ultra-rare dominant missense alleles — principally p.Ser59Leu (c.176C>T) and p.Arg15Leu for the ALS/FTD-ALS phenotype [PMID: 37021679]. Allele-specific: p.G66V → SMAJ; p.G58R → isolated mitochondrial myopathy. The paralog CHCHD2 (p.T61I) causes Parkinson's disease, and CHCHD2/CHCHD10 heterodimerize [PMID: 37021679; PMID: 36158221].
Genetic pseudo-risk / benign confounders: p.Pro34Ser is a common benign polymorphism (gnomAD AF ~0.4%) historically misattributed as a risk allele (ACMG BA1/BS1) — a key caution for variant interpretation (Finding 6) [PMID: 28318595].
Environmental / lifestyle risk factors: Age (late-onset) is the dominant non-genetic factor; no established toxin, occupational, or lifestyle risk factor is specific to FTDALS2.
Protective factors: No validated genetic or environmental protective factors are established for FTDALS2. (Not available.)
Gene–environment interactions: Not characterized for FTDALS2 specifically. Oxidative stress exacerbates the mtDNA-repair defect in mutant cells, suggesting an inferred (not demonstrated) sensitization to oxidative-stress environments [PMID: 26666268].

3. Phenotypes

Phenotype	Type	Onset / severity / course	Frequency	Suggested HPO
Motor neuron disease (upper + lower) / ALS	Clinical sign	Adult/late-onset; progressive	Core, in founding family	HP:0007354 (ALS); HP:0002355; HP:0007289
Frontotemporal-dementia–like cognitive decline	Behavioral/cognitive	Late-onset; progressive	Core	HP:0002145 (Frontotemporal dementia); HP:0100543
Cerebellar ataxia	Clinical sign	Late-onset; progressive	Present in founding family	HP:0001251 (Ataxia); HP:0002070
Mitochondrial myopathy (ragged-red, COX-negative fibres)	Lab/histopathology	Adult; progressive	Core in FTDALS2	HP:0003198 (Myopathy); HP:0003200; HP:0008314
Respiratory chain deficiency / abnormal complex V assembly	Laboratory abnormality	—	Core	HP:0011922; HP:0003287
Multiple mtDNA deletions in muscle	Laboratory abnormality	—	Core (S59L)	HP:0003689 (Multiple mitochondrial DNA deletions)
Cardiomyopathy	Clinical sign	Variable	Spectrum-dependent	HP:0001638
Peripheral neuropathy (CMT2-like)	Clinical sign	Spectrum-dependent	Allele-dependent	HP:0009830

Evidence: "late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy" and "ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V" [PMID: 24934289]. Severity is genotype-driven; SMAJ (p.G66V) is a mild lower motor neuron syndrome with normal life expectancy and no mtDNA instability [PMID: 30092269; PMID: 25428574].

Quality of life: Per-phenotype QOL instruments specific to FTDALS2 are not available; by extension from ALS/FTD, motor neuron degeneration and cognitive/behavioral decline cause severe progressive loss of daily functioning, with respiratory failure as the terminal event [PMID: 42113599].

4. Genetic / Molecular Information

Causal gene: CHCHD10 (HGNC:15559; OMIM *615903), chr22q11.23. Small (~14 kDa) mitochondrial intermembrane-space protein with a CHCH domain; intrinsically disordered/low-complexity; heterodimerizes with CHCHD2 [PMID: 35791387; PMID: 36158221].
Pathogenic variants (representative):

Variant	cDNA	Class	Phenotype	gnomAD AF	Significance
p.Ser59Leu	c.176C>T	Missense	FTD-ALS (FTDALS2), severe	6.9×10⁻⁷	Pathogenic
p.Arg15Leu	—	Missense	Familial ALS/FTD-ALS	0	Pathogenic
p.Gly66Val	c.197G>T	Missense	SMAJ (mild LMN)	2.1×10⁻⁶	Pathogenic (Finnish founder)
p.Gly58Arg	—	Missense	Isolated mitochondrial myopathy	—	Pathogenic
p.Ala35Asp	—	Missense	ALS spectrum	6.1×10⁻⁶	Likely pathogenic (rare)
p.Pro34Ser	c.100C>T	Missense	(historically ALS)	0.0043	Benign polymorphism (BA1/BS1)

Variant type/class: Predominantly missense (dominant). The gene is intolerant to true loss-of-function, but the pathogenic mechanism is dominant missense (Finding 6).
Functional consequence: Gain-of-function via toxic protein misfolding, with dominant-negative activity in mammalian systems [PMID: 37021679; PMID: 28585542].
Origin: Germline (autosomal dominant). No somatic/tumor role.
Modifier genes: The paralog CHCHD2 modifies mitochondrial function; combined CHCHD2/CHCHD10 loss phenocopies patient mutations, implicating the heterodimer as a functional unit [PMID: 32338760; PMID: 30496485]. OMA1 and OPA1 are functional effectors/modifiers of the cristae phenotype [PMID: 32338760].
Epigenetics / chromosomal abnormalities: No disease-specific DNA-methylation, histone, or chromosomal (aneuploidy/translocation) findings are established for FTDALS2. mtDNA instability (multiple deletions) is the key acquired genomic lesion [PMID: 24934289].

5. Environmental Information

No specific environmental toxin, radiation, pollutant, occupational exposure, lifestyle factor, or infectious agent has been established as a cause or trigger of FTDALS2. The disorder is monogenic. Oxidative stress worsens the intrinsic mtDNA-repair defect in mutant cells, an inferred sensitizer rather than a primary environmental cause [PMID: 26666268].

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

A heterozygous dominant missense mutation in CHCHD10 (e.g., p.Ser59Leu, p.Arg15Leu) leads to production of a misfolding-prone, aggregation-prone mutant protein in the mitochondrial intermembrane space [PMID: 37021679].
Mutant CHCHD10 results in disassembly of the MICOS complex (MIC60/mitofilin, CHCHD3, CHCHD6) and thereby loss of cristae junctions and collapse/dilatation of cristae [PMID: 26666268].
MICOS/cristae disruption leads to nucleoid disorganization and impaired repair of the mitochondrial genome after oxidative stress, which causes accumulation of deleted mtDNA in muscle (mtDNA instability) [PMID: 26666268; PMID: 24934289].
In parallel (branch), mutant CHCHD10 (with loss of the CHCHD2/CHCHD10 functional unit) activates the stress peptidase OMA1, which cleaves long-form OPA1 (L-OPA1), further disrupting cristae architecture [PMID: 32338760].
These stresses induce the mitochondrial integrated stress response (mtISR) in affected tissues and result in respiratory-chain deficiency and abnormal complex V assembly [PMID: 30877432; PMID: 32338760; PMID: 24934289].
Mitochondrial damage impairs KIF5B-mediated mitochondrial axonal transport (with syntaphilin dysregulation), contributing to synaptic/neuromuscular-junction failure [PMID: 39478664; PMID: 28585542].
Mitochondrial/synaptic damage drives cytoplasmic accumulation and aggregation of TDP-43 (co-aggregating with insoluble CHCHD10) — the shared pathological endpoint of ALS/FTLD-TDP [PMID: 28585542; PMID: 35787294]. (The precise CHCHD10→TDP-43 link is partly inferred.)
Progressive degeneration proceeds from muscle mitochondrial defect → NMJ degeneration → motor neuron death (demonstrated staging in knock-in mice), together with frontotemporal and cerebellar neuronal loss, producing the clinical phenotype of ALS, FTD-like decline, ataxia, and myopathy [PMID: 30874923; PMID: 24934289].

Branch note: Severity scales with the degree of MICOS disruption/mitochondrial damage rather than with TDP-43 mitochondrial localization [PMID: 30092269]; mild alleles (SMAJ/p.G66V) cause metabolic/creatine-buffering dysregulation without frank mitochondrial myopathy or mtDNA instability [PMID: 40400037; PMID: 30092269].

Molecular pathways / cellular processes: Cristae/MICOS organization; mitochondrial fusion (OPA1) and quality control (OMA1); integrated stress response; apoptosis regulation (mutant fibroblasts inhibit cytochrome c release) [PMID: 26666268]; mitophagy (enhanced in S59L cardiomyopathy) [PMID: 38583639]; mitochondrial axonal transport [PMID: 39478664].
Protein dysfunction: Misfolding/aggregation of an intrinsically disordered protein; dominant-negative disruption of the CHCHD2/CHCHD10 heterodimer [PMID: 35791387; PMID: 37021679].
Metabolic changes: Dysregulated energy metabolism, altered redox balance, and creatine-based energy buffering [PMID: 40400037].
Suggested GO / CL terms: GO:0042407 (cristae formation); GO:0007007 (inner mitochondrial membrane organization); GO:0140053 (mitochondrial gene expression); GO:0006915 (apoptotic process); GO:0034976 (response to endoplasmic-reticulum/mitochondrial stress) / integrated stress response; GO:0047497 (mitochondrion transport along microtubule). Cell types: CL:0000100 (motor neuron), CL:0000540 (neuron), CL:0000188 (skeletal muscle cell).

7. Anatomical Structures Affected

Organ level (primary): Central and peripheral nervous system — motor cortex, brainstem/spinal motor neurons (UBERON:0001017 CNS; UBERON:0001021 nerve), frontotemporal cerebral cortex (UBERON:0016525 frontal lobe / UBERON:0001871 temporal lobe), cerebellum (UBERON:0002037). Skeletal muscle (UBERON:0001134). Secondary: heart/myocardium in cardiomyopathy-prominent spectrum members (UBERON:0002349) [PMID: 24934289; PMID: 38583639].
Body systems: Nervous (central + peripheral, motor), musculoskeletal, and cardiovascular (spectrum-dependent).
Tissue / cell level: Nervous tissue (upper and lower motor neurons; frontotemporal cortical neurons; cerebellar neurons) and striated skeletal muscle fibres (ragged-red, COX-negative). Cell Ontology: CL:0000100 (motor neuron), CL:0000188 (skeletal muscle cell), CL:0000540 (neuron). The neuromuscular junction is an early failure site [PMID: 30874923].
Subcellular level: Mitochondrion — inner mitochondrial membrane, cristae/cristae junctions, intermembrane space, and nucleoids. GO cellular component: GO:0005743 (inner mitochondrial membrane), GO:0044284 (mitochondrial crista junction), GO:0005758 (mitochondrial intermembrane space), GO:0042645 (mitochondrial nucleoid), GO:0061617 (MICOS complex).
Localization / lateralization: Typically bilateral; may begin focally/asymmetrically as in ALS generally; brain involvement predominantly frontotemporal + cerebellar.

8. Temporal Development

Onset: Adult / late-onset; insidious and chronic. The founding family showed a "late-onset phenotype" [PMID: 24934289]. SMAJ presents in mid-adulthood.
Progression: Progressive and neurodegenerative. Rate is genotype-dependent — severe/rapid for FTD-ALS (p.Ser59Leu) versus slow with normal life expectancy for SMAJ (p.G66V) [PMID: 30092269; PMID: 40400037]. Staging (from models): muscle mitochondrial defect → NMJ degeneration → motor neuron death [PMID: 30874923].
Disease course: Chronic, lifelong, progressive; no relapsing-remitting pattern and no spontaneous remission. Duration ranges from a few years (ALS-like) to decades (SMAJ). Critical intervention windows are inferred to be early (pre-NMJ-degeneration), supported by the muscle-first staging in knock-in mice [PMID: 30874923].

9. Inheritance and Population

Inheritance: Autosomal dominant [PMID: 24934289; PMID: 25428574].
Penetrance / expressivity: Age-dependent penetrance with variable expressivity; strong allele-specific genotype–phenotype correlation (Finding 7) [PMID: 37021679]. Variant dosage modulates severity — the first reported homozygous CHCHD10 (SMAJ) patient had more severe disease, indicating a dose effect [PMID: 40400037].
Epidemiology: FTDALS2 is very rare. CHCHD10 mutations account for ~0.4% of ALS cohorts (2/487 sporadic Chinese ALS) and are a minor contributor to familial ALS/FTD [PMID: 27056076; PMID: 28318595]. Precise prevalence/incidence figures for FTDALS2 are not established (ultra-rare); by comparison, ALS overall affects ~25,000 individuals in the US [PMID: 42113599].
Founder effects: p.Gly66Val (SMAJ) is a Finnish founder allele (gnomAD AF 2.1×10⁻⁶) [PMID: 25428574; Finding 6].
Population / demographics: Reported across European (French founding family; Finnish SMAJ) and Asian (Chinese) cohorts. No strong sex bias specific to FTDALS2 is established. Carrier frequency is extremely low given ultra-rare pathogenic allele frequencies (Finding 6).
Genetic anticipation / germline mosaicism / consanguinity: Not features of this dominant missense disorder (not a repeat-expansion disease; not recessive).

10. Diagnostics

Clinical / electrophysiology: EMG and nerve conduction studies to document lower motor neuron involvement (ALS pattern); clinical exam for upper motor neuron signs, cognitive/behavioral (FTD) assessment, and cerebellar signs [PMID: 24934289; PMID: 42113599].
Muscle biopsy / histopathology (characteristic): Ragged-red fibres and COX-negative fibres with combined respiratory-chain deficiency and abnormal complex V assembly — a hallmark distinguishing FTDALS2 from most other ALS/FTD [PMID: 24934289].
Laboratory / molecular: Detection of multiple mtDNA deletions in skeletal muscle (mtDNA instability) [PMID: 24934289]; respiratory chain enzymology; metabolomic evidence of altered energy/redox/creatine metabolism (research-stage biomarker) [PMID: 40400037].
Imaging: MRI showing frontotemporal ± cerebellar atrophy (extrapolated from phenotype); no CHCHD10-specific imaging signature established.
Genetic testing (definitive): Single-gene CHCHD10 sequencing, ALS/FTD gene panels, WES, or WGS. Variant interpretation is critical — classify per ACMG/AMP, treating ultra-rare missense (S59L, R15L, G66V) as pathogenic and common variants like p.Pro34Ser (gnomAD AF ~0.4%) as benign (BA1/BS1) (Finding 6) [PMID: 28318595]. Repeat-expansion, karyotype, CMA, FISH, and mtDNA-primary testing are not the diagnostic route (the mtDNA deletions here are secondary to the nuclear CHCHD10 defect).
Differential diagnosis: Other genetic ALS/FTD (C9orf72, SOD1, TARDBP, FUS), primary mitochondrial myopathies with mtDNA-maintenance defects (POLG, TWNK), and SMA. Distinguishing feature: combination of MND/FTD with mitochondrial myopathy + mtDNA instability points to CHCHD10.

11. Outcome / Prognosis

Survival / mortality: Highly genotype-dependent. Severe FTD-ALS (p.Ser59Leu) carries an ALS-like poor prognosis (progressive to respiratory failure), whereas SMAJ (p.G66V) has a normal life expectancy [PMID: 30092269; PMID: 40400037]. FTDALS2-specific survival curves are not established; general ALS survival is ~3–5 years from diagnosis [PMID: 42113599].
Morbidity / function: Progressive motor disability, cognitive/behavioral decline, and myopathy with high burden on daily functioning; respiratory failure is the usual terminal event in ALS-predominant cases.
Prognostic factors: Genotype (specific allele and dosage) is the dominant prognostic factor; degree of MICOS disruption/mitochondrial damage tracks severity [PMID: 30092269; PMID: 40400037]. Metabolic/creatine dysregulation is a candidate prognostic biomarker [PMID: 40400037].
Recovery: None; the disease is progressive and neurodegenerative.

12. Treatment

Disease-specific therapy: None approved. Management follows ALS/FTD symptomatic standards [PMID: 42113599; PMID: 42666355].
Pharmacotherapy (symptomatic, ALS-standard; NCIT terms): Riluzole (NCIT:C1215; glutamate-release inhibitor; modest ~2–4 month benefit); Edaravone (NCIT:C65358; free-radical scavenger; narrow eligibility). Tofersen is SOD1-specific and not applicable to CHCHD10 disease [PMID: 42113599].
Supportive / rehabilitative: Multidisciplinary care (neurology, respiratory support/NIV, nutrition/PEG, physical/occupational/speech therapy) improves survival (~4–7 months) and QOL [PMID: 42113599].
Experimental / precision (research-stage):
Nifuroxazide — repurposed compound rescuing cristae/network abnormalities in S59L patient fibroblasts and reducing caspase-dependent death of S59L iPSC motor neurons via KIF5B-mediated mitochondrial transport enhancement and syntaphilin degradation [PMID: 39478664].
Elamipretide/MTP-131 — mitochondria-targeted peptide that enhanced MICOS/OXPHOS in CHCHD2-mutant NPCs (paralog data; candidate for CHCHD10) [PMID: 30496485].
Integrated-stress-response modulation and metabolic/creatine support (rationale from mtISR activation and creatine-buffering dysregulation) [PMID: 32338760; PMID: 40400037].
Broader ALS trials (e.g., trehalose/autophagy in the HEALEY platform) have been negative, underscoring difficulty [PMID: 40409314].
Pharmacogenomics / gene / cell / RNA therapy: No CHCHD10-directed ASO/gene therapy is approved; these are conceptual future directions.

13. Prevention

Primary prevention: Not applicable for a monogenic dominant disorder beyond reproductive options. No vaccine or modifiable risk-factor program exists.
Genetic counseling / reproductive prevention: Autosomal dominant inheritance implies 50% transmission risk; cascade testing of at-risk relatives, prenatal diagnosis, and preimplantation genetic testing are options once a pathogenic variant is confirmed. Accurate variant classification is essential to avoid counseling on benign variants (e.g., p.Pro34Ser) (Finding 6).
Secondary/tertiary prevention: No proven presymptomatic disease-modifying intervention; tertiary prevention focuses on complication management (respiratory, nutrition, falls) within ALS/FTD care standards [PMID: 42113599].

14. Other Species / Natural Disease

Taxonomy / orthologs: CHCHD10 is conserved in mammals; mouse ortholog Chchd10 (the human-equivalent S59L is modeled as mouse S55L) [PMID: 30877432; PMID: 38583639]. The paralog pair CHCHD2/CHCHD10 arose by gene duplication during evolution [PMID: 36158221].
Natural disease in other species: No well-documented naturally occurring CHCHD10 disease in companion animals or wildlife is established (not available in OMIA at time of review). Disease knowledge derives from engineered models.
Comparative biology: The MICOS/cristae machinery and CHCHD10 function are evolutionarily conserved (yeast MICOS mutants recapitulate cristae defects), supporting cross-species mechanistic conservation [PMID: 39478664].
Zoonotic potential: None (non-infectious genetic disease).

15. Model Organisms

Model	Type	Key features / recapitulation	Reference
S59L / S55L knock-in mouse	Mammalian, knock-in	Tissue-specific toxic gain-of-function; mtISR; fatal mitochondrial cardiomyopathy with enhanced mitophagy; muscle defect precedes NMJ/motor-neuron loss	[PMID: 30877432; PMID: 38583639; PMID: 30874923]
C2/C10 double-knockout mouse	Mammalian, KO	OMA1-mediated L-OPA1 cleavage; cristae disruption; cardiomyopathy; mtISR; phenocopies KI mutants	[PMID: 32338760]
G66V knock-in mouse / patient cells	Mammalian + iPSC	Dose-dependent severity; energy/redox/creatine dysregulation	[PMID: 40400037]
Patient iPSC-derived motor neurons (S59L, G66V)	In vitro (human)	Caspase-dependent death; mitochondrial transport defects; therapy testbed (nifuroxazide)	[PMID: 39478664; PMID: 40400037]
Patient fibroblasts	In vitro (human)	Network fragmentation, cristae abnormalities, impaired mtDNA repair, apoptosis inhibition	[PMID: 26666268; PMID: 39478664]
C. elegans	Invertebrate	Genetic complementation showing LoF-in-complementation + dominant-negative activity; synaptic/TDP-43 phenotypes	[PMID: 28585542]
Yeast MICOS mutants	Cellular	MICOS/cristae biology; repurposing screen platform	[PMID: 39478664]
CHCHD2-mutant hESC/NPC (paralog)	In vitro (human)	MICOS/cristae defects; Elamipretide rescue	[PMID: 30496485]

Model limitations: Mouse KI models show prominent cardiomyopathy that may exceed the human cardiac phenotype; full FTD-like cognitive/behavioral features and the complete ALS motor-neuron degeneration timeline are incompletely captured; TDP-43 pathology recapitulation is partial and its causal link remains under study [PMID: 35787294; PMID: 30877432].

Mechanistic Model / Interpretation

CHCHD10 dominant missense mutation (S59L, R15L, G66V, G58R ...)
│  (toxic gain-of-function; protein misfolding/aggregation)
▼
Disassembly of MICOS complex (MIC60/CHCHD3/CHCHD6) ──► cristae junction loss / cristae collapse
│                                                        │
▼                                                        ▼
Nucleoid disorganization; impaired mtDNA repair            OMA1 activation ──► L-OPA1 cleavage
│                                                        │
▼                                                        ▼
Multiple mtDNA deletions (muscle) ◄──────────── Respiratory chain deficiency; complex V defect
│                                                        │
└──────────────► Mitochondrial Integrated Stress Response (mtISR) ◄─────────┘
                     │
 ┌───────────────────┼─────────────────────────┐
 ▼                   ▼                          ▼
  Impaired KIF5B mito-transport   Metabolic/redox/creatine   Cytoplasmic TDP-43
  (syntaphilin dysregulation)     dysregulation              accumulation/aggregation
 │                   │                          │  (partly inferred)
 └───────────────────┴─────────────┬────────────┘
                                    ▼
      Muscle mito defect → NMJ degeneration → motor neuron death
      + frontotemporal & cerebellar neuronal loss
                                    ▼
Clinical FTDALS2: ALS + FTD-like decline + ataxia + mitochondrial myopathy
(severity ∝ degree of MICOS disruption; allele- and dosage-dependent)

The disorder is unified by a single upstream lesion — a misfolding dominant CHCHD10 mutant — that corrupts inner-membrane architecture. The upstream events (MICOS disassembly, cristae collapse) are the most severity-determining; downstream events (mtISR, transport failure, TDP-43 pathology, neuronal death) produce the clinical picture and connect FTDALS2 to the wider ALS/FTLD-TDP family. The allele determines where on the severity spectrum a patient falls, from mild SMAJ (metabolic dysregulation without frank myopathy) to severe FTD-ALS with mtDNA instability.

Evidence Base

PMID	Title (abbrev.)	How it supports the report
24934289	A mitochondrial origin for FTD/ALS through CHCHD10	Founding family; multisystem phenotype, ragged-red/COX-neg fibres, mtDNA instability
26666268	CHCHD10 mutations promote loss of cristae junctions	MICOS disassembly, cristae/nucleoid loss, impaired mtDNA repair, apoptosis inhibition
32338760	Loss of CHCHD2/CHCHD10 activates OMA1	OMA1→L-OPA1 cleavage mechanism; mtISR; cardiomyopathy
30877432	ALS/FTD mutant CHCHD10 mice: toxic GoF	Knock-in S55L mouse; tissue-specific toxic gain-of-function + stress response
28585542	LoF CHCHD10 mutations, TDP-43, synapses	Dominant-negative activity; cytoplasmic TDP-43 accumulation
30092269	MICOS integrity and severity	Severity ∝ MICOS disruption; SMAJ lacks myopathy/mtDNA instability
30874923	Muscle defect precedes NMJ/motor neuron loss	Pathology staging; confirms S59L founding mutation
25428574	LOSMoN/SMAJ caused by CHCHD10	p.G66V mild allele; AD inheritance; spectrum breadth
37021679	CHCHD2/CHCHD10 pathogenesis & precision therapy	Genotype–phenotype map; gain-of-function misfolding mechanism
27056076	CHCHD10 screening in Chinese ALS	Rarity: 0.4% mutation frequency
28318595	CHCHD10 in Mainland China ALS	"Controversial role" — explained by benign vs pathogenic variant confusion
39478664	Nifuroxazide rescues MICOS defects	Experimental therapy; KIF5B/syntaphilin transport mechanism
40400037	Dose-dependent CHCHD10 & creatine metabolism	Metabolic dysregulation; dosage-dependent severity; homozygous patient
35787294	CHCHD10, TDP-43 pathology	Insoluble CHCHD10 co-aggregates with phospho-TDP-43 in FTLD-TDP brains
30496485	PD-linked CHCHD2 impairs MICOS	Paralog data; Elamipretide rescue; heterodimer biology
36158221	CHCHD2 vs CHCHD10	Heterodimerization; evolutionary duplication
35791387	IDPs in neurodegeneration	CHCHD10 intrinsically disordered; drug-target implications
42113599	ALS: A Review	Standard-of-care therapies; survival; multidisciplinary benefit
42666355	Therapeutic challenges in ALS	Precision-medicine landscape; trial-design context
40409314	Trehalose HEALEY trial	Negative ALS trial; illustrates therapeutic difficulty

Limitations and Knowledge Gaps

Ultra-rarity limits epidemiology. No robust prevalence/incidence, sex-ratio, or survival statistics exist specifically for FTDALS2; figures are extrapolated from ALS/FTD generally.
CHCHD10→TDP-43 causal link is partly inferred. How mitochondrial dysfunction produces cytoplasmic TDP-43 aggregation is correlative in human tissue and not fully resolved mechanistically [PMID: 35787294].
Variant interpretation remains a pitfall. The historical inclusion of benign polymorphisms (p.Pro34Ser) inflated apparent pathogenicity; some rarer variants remain VUS. Systematic functional classification is incomplete.
Model–human mismatch. Mouse KI cardiomyopathy may not mirror the human cardiac burden, and cognitive/behavioral FTD features are under-modeled.
No disease-modifying therapy validated in humans. All CHCHD10-specific interventions (nifuroxazide, elamipretide, mtISR/metabolic strategies) are preclinical.
Epigenetic and gene–environment contributions are essentially uncharacterized.

Proposed Follow-up Experiments / Actions

Curate a CHCHD10 variant registry integrating gnomAD frequencies, ACMG classification, and phenotype to formally resolve VUS and retire benign misattributions (extends Finding 6).
Functional high-throughput assays (MICOS integrity, cristae morphology, OMA1/OPA1 cleavage, mtISR readouts) to classify each reported variant along the severity gradient.
Test nifuroxazide and elamipretide head-to-head in isogenic S59L/G66V iPSC motor neurons and knock-in mice, with mitochondrial-transport and cristae endpoints [PMID: 39478664; PMID: 30496485].
Develop fluid biomarkers from the metabolic signature (creatine/energy/redox metabolites) for diagnosis and trial stratification [PMID: 40400037].
Mechanistic dissection of the CHCHD10→TDP-43 axis using proximity-labeling and conditional models to establish causality versus correlation [PMID: 35787294; PMID: 28585542].
Natural-history / registry study across the CHCHD10 spectrum to define genotype-specific progression and survival, enabling genotype-stratified trial design.
Explore ASO/gene-silencing approaches targeting the mutant allele, leveraging the dominant gain-of-function/dosage-dependent mechanism [PMID: 40400037].

Evidence source types are noted throughout: human clinical (family/cohort studies, autopsy), model organism (knock-in/KO mice, C. elegans, yeast), in vitro (patient fibroblasts, iPSC-derived motor neurons, hESC/NPC), and computational/population-genetic (gnomAD variant frequency analysis).

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All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	40
Resolved	38
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	1
Terms whose name was checked	17
Terms named correctly	13
Terms named as a different term	2
Terms whose name is worth a second look	2

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:

HP:0001638 (1 mention) - the report calls it "Spectrum-dependent"; HP calls it Cardiomyopathy
HP:0009830 (1 mention) - the report calls it "Allele-dependent"; HP calls it Peripheral neuropathy

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:

HP:0002355 (obsolete Difficulty walking) (1 mention) - replaced by HP:0001288

Terms whose name is worth a second look

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

GO:0034976 (1 mention) - the report calls it "response to endoplasmic-reticulum/mitochondrial stress"; GO calls it response to endoplasmic reticulum stress
CL:0000188 (2 mentions) - the report calls it "skeletal muscle cell"; CL calls it cell of skeletal muscle, and lists "skeletal muscle cell" among its other names

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OpenScientist Report

Classifications

Inheritance

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Frontotemporal Dementia And/Or Amyotrophic Lateral Sclerosis 2 (FTDALS2): Comprehensive Disease Characteristics Report

Summary

Key Findings

Finding 1 — CHCHD10 is the causal gene (autosomal dominant)

Finding 2 — Core lesion: MICOS disassembly, cristae collapse, mtDNA instability

Finding 3 — Toxic gain-of-function → OMA1/OPA1 cleavage → mtISR → cytoplasmic TDP-43

Finding 4 — Multisystem late-onset clinical phenotype

Finding 5 — Rarity, severity gradient, and pathology staging

Finding 6 — Population genetics separates pathogenic from benign variants

Finding 7 — Strong allele-specific genotype–phenotype correlation

Finding 8 — No disease-specific therapy; emerging precision strategies

Report by Section

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look