Combined oxidative phosphorylation deficiency 28 is an autosomal recessive mitochondrial disease caused by biallelic variants in SLC25A26, which encodes the mitochondrial S-adenosylmethionine carrier (SAMC). SAM is made in the cytoplasm and cannot cross the inner mitochondrial membrane unaided; SAMC is believed to be its only route in. When the carrier fails, the matrix runs short of the methyl donor that essentially every mitochondrial methylation reaction depends on. SAMC is an antiporter, not a uniporter, and that detail turns out to carry the genotype-phenotype relationship. It imports SAM in exchange for exporting SAH, the by-product that every methylation reaction generates and that mitochondria cannot regenerate in situ - SAM synthesis and SAH recycling both happen in the cytoplasm. A carrier defect can therefore fail in two directions, and the two produce different diseases. Reduced SAM import gives the severe neonatal phenotype; impaired SAH export gives a much milder, later-onset mitochondrial myopathy, which mouse and fruit fly models were used to establish. That branch is currently the principal prognostic determinant in this disease, and it is the reason the entry models the two limbs separately rather than as one depleted pool. That makes this a *substrate-supply* defect, and it is the reason the entry sits apart from its many COXPD siblings. Most combined OXPHOS deficiencies are caused by a missing structural subunit or a missing assembly factor, where the chain itself cannot be built. Here the chain is intact and the machinery for building it is intact; what fails is a chemical modification step several removes upstream. One carrier defect therefore propagates into at least four distinct downstream failures that the index study demonstrated separately: mitochondrial RNA stability, protein modification, mitochondrial translation, and the biosynthesis of coenzyme Q10 and lipoic acid. The "combined" in the disease name is not a statement about which complexes are low - it is a consequence of the lesion sitting above all of them. Clinically the range is wide for a disease known from so few families: neonatal death from respiratory insufficiency and hydrops at one end; childhood episodes of cardiopulmonary failure with pulmonary hypertension and severe lactic acidosis in the middle; and at the other end adults with exercise intolerance and mitochondrial myopathy, one of whom presented with recurrent severe abdominal pain and metabolic decompensation. The adult cases nonetheless show marked respiratory-chain deficiency and mitochondrial histopathology in skeletal muscle comparable to the early-onset cases, so the mildness is in the clinical course rather than in the biochemistry.
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name: Combined Oxidative Phosphorylation Deficiency 28
creation_date: "2026-09-18T00:00:00Z"
category: Mendelian
synonyms:
- COXPD28
- combined oxidative phosphorylation defect type 28
- intra-mitochondrial methylation deficiency
- mitochondrial S-adenosylmethionine carrier deficiency
- SAMC deficiency
- SLC25A26 deficiency
description: >
Combined oxidative phosphorylation deficiency 28 is an autosomal recessive mitochondrial
disease caused by biallelic variants in SLC25A26, which encodes the mitochondrial
S-adenosylmethionine carrier (SAMC). SAM is made in the cytoplasm and cannot cross the
inner mitochondrial membrane unaided; SAMC is believed to be its only route in. When the
carrier fails, the matrix runs short of the methyl donor that essentially every
mitochondrial methylation reaction depends on.
SAMC is an antiporter, not a uniporter, and that detail turns out to carry the
genotype-phenotype relationship. It imports SAM in exchange for exporting SAH, the
by-product that every methylation reaction generates and that mitochondria cannot
regenerate in situ - SAM synthesis and SAH recycling both happen in the cytoplasm. A
carrier defect can therefore fail in two directions, and the two produce different
diseases. Reduced SAM import gives the severe neonatal phenotype; impaired SAH export
gives a much milder, later-onset mitochondrial myopathy, which mouse and fruit fly models
were used to establish. That branch is currently the principal prognostic determinant in
this disease, and it is the reason the entry models the two limbs separately rather than
as one depleted pool.
That makes this a *substrate-supply* defect, and it is the reason the entry sits apart
from its many COXPD siblings. Most combined OXPHOS deficiencies are caused by a missing
structural subunit or a missing assembly factor, where the chain itself cannot be built.
Here the chain is intact and the machinery for building it is intact; what fails is a
chemical modification step several removes upstream. One carrier defect therefore
propagates into at least four distinct downstream failures that the index study
demonstrated separately: mitochondrial RNA stability, protein modification, mitochondrial
translation, and the biosynthesis of coenzyme Q10 and lipoic acid. The "combined" in the
disease name is not a statement about which complexes are low - it is a consequence of
the lesion sitting above all of them.
Clinically the range is wide for a disease known from so few families: neonatal death from
respiratory insufficiency and hydrops at one end; childhood episodes of cardiopulmonary
failure with pulmonary hypertension and severe lactic acidosis in the middle; and at the
other end adults with exercise intolerance and mitochondrial myopathy, one of whom
presented with recurrent severe abdominal pain and metabolic decompensation. The adult
cases nonetheless show marked respiratory-chain deficiency and mitochondrial
histopathology in skeletal muscle comparable to the early-onset cases, so the mildness is
in the clinical course rather than in the biochemistry.
disease_term:
preferred_term: combined oxidative phosphorylation deficiency 28
term:
id: MONDO:0014775
label: combined oxidative phosphorylation deficiency 28
parents:
- Mitochondrial disease
- Combined oxidative phosphorylation deficiency
references:
- reference: PMID:26522469
title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
- reference: PMID:34375635
title: "Identification and characterization of novel compound variants in SLC25A26 associated with combined oxidative phosphorylation deficiency 28."
- reference: PMID:36456512
title: "[Identification and functional analysis of combined oxidative phosphorylation deficiency 28 gene mutation]."
- reference: PMID:35024855
title: "Pathogenic SLC25A26 variants impair SAH transport activity causing mitochondrial disease."
- reference: PMID:35730628
title: "Mitochondrial transport and metabolism of the major methyl donor and versatile cofactor S-adenosylmethionine, and related diseases: A review(†)."
- reference: PMID:36533232
title: "Novel use of riociguat in infants with severe pulmonary arterial hypertension unable to wean from inhaled nitric oxide."
- reference: PMID:27785568
title: "Novel mutations in IBA57 are associated with leukodystrophy and variable clinical phenotypes."
- reference: PMID:32742935
title: "Pitfalls of relying on genetic testing only to diagnose inherited metabolic disorders in non-western populations - 5 cases of pyruvate dehydrogenase deficiency from South Africa."
- reference: PMID:28118529
title: "SLC25A26 overexpression impairs cell function via mtDNA hypermethylation and rewiring of methyl metabolism."
- reference: PMID:40657752
title: "FBXO24 targets SLC25A26 for K6-linked polyubiquitylation to maintain mitochondrial function during spermiogenesis."
notes: >-
No GeneReviews chapter covers COXPD28 or SLC25A26 deficiency. `just check-genereviews`
returns NO_CHAPTER for both Bookshelf collections against the committed index (snapshot
2026-09-10). The phenotype baseline is the index three-family report (PMID:26522469),
with two later Chinese reports of the same compound-heterozygous pair adding the adult
end of the spectrum.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Known from a handful of families. Recorded as ULTRA_RARE rather than UNKNOWN: the
qualitative tiers are permitted alongside CASES_IN_LITERATURE, and with a published
world literature in the single digits the tier carries more information than declining
to classify. No numeric rate is asserted. The defining report described three families of
different ethnic origins; later reports add Chinese patients carrying the same
compound-heterozygous pair. No rate has been estimated and none can be from this
denominator.
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We report a syndrome in three families affected by reduced intra-mitochondrial
methylation caused by recessive mutations in the gene encoding the only known
mitochondrial SAM transporter, SLC25A26.
explanation: >-
Gives the size of the founding cohort, which is the basis for recording occurrence as
a literature case count rather than a rate.
clinical_burden:
burden_level: HIGH
rationale: >-
The severe end of the spectrum is neonatal death: one reported child died of respiratory
and multiple organ failure at five days. The milder end still carries acute episodes of
severe lactic acidosis - up to 42 mmol/l against a reference below 1.8 - with
cardiopulmonary arrest and, in one patient, hypoxic brain damage from such an episode.
Between episodes patients have slowly progressive muscle weakness. A disease whose
typical course is punctuated by life-threatening, brain-damaging metabolic crises is
HIGH burden irrespective of the interictal state.
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Clinical findings ranged from neonatal mortality resulting from respiratory
insufficiency and hydrops to childhood acute episodes of cardiopulmonary failure and
slowly progressive muscle weakness.
explanation: >-
Gives the full clinical range, both ends of which drive the burden assessment.
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The child died of respiratory and multiple organ failure at 5 days of age.
explanation: >-
Documents neonatal death at the severe end of the spectrum.
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
she experienced an additional episode of severe lactic acidosis (36 mmol/l) followed
by cardiopulmonary arrest and hypoxic brain damage
explanation: >-
Documents that an acute metabolic episode can itself cause permanent neurological
injury, which is what makes the episodic course rather than the baseline state the
driver of burden.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >
Disease requires biallelic SLC25A26 variants. Both homozygous variants in consanguineous
kindreds and compound heterozygous pairs in outbred families are reported.
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
caused by recessive mutations in the gene encoding the only known mitochondrial SAM
transporter, SLC25A26
explanation: >-
Establishes recessive inheritance at SLC25A26.
genetic:
- name: SLC25A26
gene_term:
preferred_term: SLC25A26
term:
id: hgnc:20661
label: SLC25A26
relationship_type: CAUSATIVE
notes: >
SLC25A26 encodes SAMC, a member of the mitochondrial carrier family expressed in all
human tissues examined.
The reported allele spectrum is mostly missense but is not exclusively so, and the
exception is the informative one. Of the three index families: P1 was homozygous for
c.443T>C (p.Val148Gly); P2 compound heterozygous for c.305C>T (p.Ala102Val) and
c.596C>T (p.Pro199Leu); and P3 homozygous for the splice allele c.33+1G>A, whose
transcript lacks the first two transmembrane helices, fails to reach mitochondria, and
is a functional null. The two later Chinese patients carry the recurrent
compound-heterozygous pair c.34G>C (p.A12P) and c.197C>A (p.A66E) in transmembrane
regions 1 and 2. The two adults carry c.425G>A (p.Arg142Gln) homozygous, and
c.190+4A>G with c.404A>G (p.Glu135Gly) in compound heterozygosity.
Residual carrier activity tracks severity, and it was measured rather than inferred.
Yeast complementation and in vitro reconstitution graded the alleles: the splice-derived
SAMCdelta1-88 completely inactive, p.Ala102Val and p.Pro199Leu negligible, p.Val148Gly
retaining 15% of wild-type activity. P3, carrying the functional null, died at five days;
the adults sit at the other end. That gradient is the entry's basis for treating
severity as allele-dependent rather than stochastic - and it is why the earlier
formulation of this note, which claimed reported variants were "missense rather than
nulls", was wrong: the null exists and is the severe end of the very gradient the claim
was reaching for.
evidence:
- reference: PMID:34375635
reference_title: "Identification and characterization of novel compound variants in SLC25A26 associated with combined oxidative phosphorylation deficiency 28."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The novel compound heterozygous SLC25A26 variants (c.34G > C, p.A12P; c.197C > A;
p.A66E) were identified in a Chinese patient with COXPD28. These two variants are
located in the transmembrane region 1 and transmembrane region 2, respectively.
explanation: >-
Gives the recurrent allele pair and locates both changes in the transmembrane domains
the carrier function depends on.
- reference: PMID:36456512
reference_title: "[Identification and functional analysis of combined oxidative phosphorylation deficiency 28 gene mutation]."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In vitro function test showed that the expression levels of SLC25A26 mRNA and
S-adenosylmethionine carrier (SAMC) protein in cells transfected with SLC25A26 mutant
plasmid were significantly lower than those transfected with wild type plasmid.
explanation: >-
Establishes the functional consequence of the recurrent Chinese pair - reduced rather
than absent carrier protein - in a transfection assay.
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We identified conserved missense mutations in P1, homozygous for a c.443T>C
(p.Val148Gly) substitution, and P2, compound heterozygous for c.305C>T (p.Ala102Val)
and c.596C>T (p.Pro199Leu). P3 was homozygous for a splice mutation (c.33+1G>A)
explanation: >-
Gives the three index genotypes, including the splice allele that makes the spectrum
broader than missense.
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The shortened transcript lacks the first two transmembrane helices (Figure S3) and
failed to co-localize (Figure 1D) or be detected in mitochondria by western blot
analysis (Figure 1E), indicating that it does not encode a functional mitochondrial
carrier protein.
explanation: >-
Establishes the splice allele as a functional null, which is what refutes the
missense-only reading of the spectrum.
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
the various degrees of residual SAM-import capacity correlated well with the severity
of the clinical presentation and biochemical phenotype in the affected individuals
explanation: >-
States the genotype-severity relationship directly, measured across the allele series
rather than inferred from clinical impression.
- reference: PMID:35024855
reference_title: "Pathogenic SLC25A26 variants impair SAH transport activity causing mitochondrial disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patient 1 was homozygous for a c.425G>A(p.Arg142Gln) substitution of a conserved amino
acid residue, while Patient 2 had two heterozygous variants: c.190+4A>G and
c.404A>G(p.Glu135Gly).
explanation: >-
Gives the two adult-onset genotypes, which are what make the severity spectrum an
observation across genotypes rather than an assertion.
mechanistic_hypotheses:
- hypothesis_group_id: sam_versus_sah_transport_branch
hypothesis_label: SAM-import versus SAH-export loss sets the severity
status: EMERGING
description: >-
That the severity of COXPD28 is determined by which leg of the antiport a variant
impairs, rather than by how much total carrier activity it removes. Variants reducing
SAM import give severe neonatal disease; variants preferentially impairing SAH export
give mild, adult-onset mitochondrial myopathy. If correct this is directly actionable -
it makes the genotype prognostic in a disease that has no other prognostic marker - and
it would also predict that SAM supplementation helps one group and not the other.
EMERGING rather than established. The directional claim rests on two unrelated adult
patients plus mouse and fruit fly models; the authors themselves write "likely". No
human assay separates the two transport activities, so a patient's branch is currently
inferred from phenotype, which makes the correlation hard to test without circularity.
evidence:
- reference: PMID:35024855
reference_title: "Pathogenic SLC25A26 variants impair SAH transport activity causing mitochondrial disease."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Our findings associate a novel pathomechanism with a known disease-causing protein and
highlight the quests of precision medicine in optimizing diagnosis, therapeutic
intervention and prognosis.
explanation: >-
States the authors' own framing of the finding as a second pathomechanism with
prognostic and therapeutic implications, which is the claim this hypothesis group
records.
pathophysiology:
- name: SLC25A26 Loss of Function
description: >
Biallelic SLC25A26 variants reduce expression and function of SAMC, the mitochondrial
S-adenosylmethionine carrier. The reported alleles are transmembrane missense changes
that lower rather than abolish the protein, which is consistent with a spectrum of
severity rather than a uniform lethal phenotype.
biological_scale: MOLECULAR
genetic_context:
variant_origin: GERMLINE
functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
genes:
- preferred_term: SLC25A26
term:
id: hgnc:20661
label: SLC25A26
molecular_functions:
- preferred_term: S-adenosyl-L-methionine transmembrane transporter activity
modifier: DECREASED
term:
id: GO:0000095
label: S-adenosyl-L-methionine transmembrane transporter activity
notes: >-
SAMC abundance is itself regulated: FBXO24, an F-box protein of the SCF E3 ubiquitin
ligase complex, mediates K6-linked polyubiquitylation of SLC25A26 at lysine 31 and
targets it for degradation. Recorded here as a note on this node rather than as a
`genetic` row with `relationship_type: MODIFIER`, because the work is in mouse
spermiogenesis and no human FBXO24 variant has been linked to this disease; calling it a
modifier would assert a human genotype-phenotype relationship that nobody has reported.
It is worth carrying because it establishes that the carrier has a dose that something
controls, which is the shape a modifier would take if one is found - and because the same
study shows elevated SLC25A26 is also deleterious, matching the overexpression result
cited on the methylation node.
downstream:
- target: Reduced Intra-Mitochondrial S-Adenosylmethionine
causal_link_type: DIRECT
description: >-
SAMC is believed to be the only route of SAM entry into mitochondria, so reducing the
carrier reduces the matrix pool directly, with no alternative import path to
compensate. This is the limb associated with severe neonatal disease.
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The human mitochondrial SAM carrier (SAMC), encoded by SLC25A26 (MIM: 611037), is
expressed in all human tissues examined and is believed to be the only route of SAM
entry into mitochondria.
explanation: >-
Establishes the exclusivity of the route, which is what makes this edge direct and
uncompensated rather than merely contributory.
- target: Impaired Matrix SAH Export
causal_link_type: DIRECT
hypothesis_groups:
- sam_versus_sah_transport_branch
description: >-
The same carrier exports SAH on the return leg of the antiport. A variant can impair
that leg preferentially, which is the limb associated with the mild, late-onset
phenotype.
evidence:
- reference: PMID:35024855
reference_title: "Pathogenic SLC25A26 variants impair SAH transport activity causing mitochondrial disease."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We demonstrate using both mouse and fruit fly models that impairment of SAH, rather
than SAM, transport across the mitochondrial membrane is likely the cause of this
milder, late-onset phenotype.
explanation: >-
Establishes the SAH-export limb as a distinct consequence of carrier variants, and
attributes the milder phenotype to it. The authors' own "likely" is retained.
evidence:
- reference: PMID:36456512
reference_title: "[Identification and functional analysis of combined oxidative phosphorylation deficiency 28 gene mutation]."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
the expression levels of SLC25A26 mRNA and S-adenosylmethionine carrier (SAMC) protein
in cells transfected with SLC25A26 mutant plasmid were significantly lower than those
transfected with wild type plasmid
explanation: >-
Documents the reduced carrier expression that constitutes this node.
- reference: PMID:40657752
reference_title: "FBXO24 targets SLC25A26 for K6-linked polyubiquitylation to maintain mitochondrial function during spermiogenesis."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: >-
Mechanistically, FBXO24 mediates K6-linked polyubiquitylation of SLC25A26 at lysine
residue 31, targeting it for degradation.
explanation: >-
Establishes that SAMC abundance is under post-translational control. Graded INDIRECT
because it is a mouse spermiogenesis study and bears on this node only through the
general point that carrier dose is regulated, not through any reported human variant.
- name: Reduced Intra-Mitochondrial S-Adenosylmethionine
description: >
The matrix SAM pool falls. SAM is the methyl donor for essentially every biological
methylation, and inside mitochondria that means nucleic-acid modification and the
reactions respiratory-chain function depends on. This node is the single bottleneck
from which every downstream failure in this disease follows.
biological_scale: MOLECULAR
chemical_entities:
- preferred_term: S-adenosyl-L-methionine
modifier: DECREASED
term:
id: CHEBI:15414
label: S-adenosyl-L-methionine
cellular_components:
- preferred_term: mitochondrial matrix
term:
id: GO:0005759
label: mitochondrial matrix
downstream:
- target: Failed Mitochondrial RNA and Protein Methylation
causal_link_type: DIRECT
- target: Impaired CoQ10 and Lipoic Acid Biosynthesis
causal_link_type: DIRECT
description: >-
Both cofactors require SAM-dependent methylation steps in their biosynthesis, so both
fall with the matrix SAM pool.
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We show that SLC25A26 mutations cause various mitochondrial defects, including those
affecting RNA stability, protein modification, mitochondrial translation, and the
biosynthesis of CoQ10 and lipoic acid.
explanation: >-
Names the biosynthetic arms this edge asserts, in the same sentence as the
RNA/translation arm, which is what establishes them as parallel consequences of one
lesion.
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
including mitochondria, where methylation is mostly required for nucleic-acid
modifications and respiratory-chain function
explanation: >-
States what the matrix SAM pool is needed for, and so what its depletion removes.
- name: Impaired Matrix SAH Export
description: >
The second limb of the antiport. SAH is the by-product of every methylation reaction, and
mitochondria have no route to regenerate it - both SAM synthesis and SAH recycling are
cytoplasmic - so SAH must leave the matrix on the carrier that brings SAM in. When export
is preferentially impaired, matrix SAH accumulates and product-inhibits the same
methyltransferases that SAM depletion would starve. The consequence converges on the
node below, which is why one gene gives one biochemical syndrome by two routes.
This limb is associated with the mild, adult-onset phenotype, and the association was
established in mouse and fruit fly rather than in patients.
biological_scale: MOLECULAR
chemical_entities:
- preferred_term: S-adenosyl-L-homocysteine
modifier: INCREASED
term:
id: CHEBI:16680
label: S-adenosyl-L-homocysteine
cellular_components:
- preferred_term: mitochondrial matrix
term:
id: GO:0005759
label: mitochondrial matrix
downstream:
- target: Failed Mitochondrial RNA and Protein Methylation
causal_link_type: DIRECT
description: >-
Accumulated SAH product-inhibits SAM-dependent methyltransferases, reaching the same
endpoint as substrate starvation by the opposite route.
evidence:
- reference: PMID:35730628
reference_title: "Mitochondrial transport and metabolism of the major methyl donor and versatile cofactor S-adenosylmethionine, and related diseases: A review."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
Therefore, the intramitochondrial SAM-dependent methyltransferases require the import
of SAM and export of SAH for recycling.
explanation: >-
States why export matters independently of import: the matrix cannot recycle SAH, so
the export leg is a requirement rather than a convenience. Graded OTHER with
quote_role REVIEW_SYNTHESIS because the source is a review stating established
biochemistry rather than reporting a study.
- reference: PMID:35730628
reference_title: "Mitochondrial transport and metabolism of the major methyl donor and versatile cofactor S-adenosylmethionine, and related diseases: A review."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
Orthologous mitochondrial transporters belonging to the mitochondrial carrier family
have been identified to catalyze this antiport transport step: Sam5p in yeast,
SLC25A26 (SAMC) in humans, and SAMC1-2 in plants.
explanation: >-
Establishes that SLC25A26 is the antiporter that performs both legs, which is what
makes a single carrier defect capable of two distinct biochemical failures.
- name: Failed Mitochondrial RNA and Protein Methylation
description: >
Without SAM, mitochondrial RNA and protein methylation fail. The consequences the index
study demonstrated are reduced mitochondrial RNA stability, impaired protein
modification, and a severe defect in de novo mitochondrial translation, the last most
plausibly because tRNA maturation itself requires methylation.
biological_scale: MOLECULAR
biological_processes:
- preferred_term: tRNA methylation
modifier: DECREASED
term:
id: GO:0030488
label: tRNA methylation
- preferred_term: mitochondrial translation
modifier: DECREASED
term:
id: GO:0032543
label: mitochondrial translation
downstream:
- target: Combined Respiratory Chain Complex Deficiency
causal_link_type: DIRECT
description: >-
Failed mitochondrial translation reduces the mtDNA-encoded subunits every affected
complex needs, so the deficiency is combined by construction rather than by
coincidence.
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
This defect is also reflected by the reduced steady-state level of COXII (Figure
3G), a subunit of complex IV
explanation: >-
Traces the translation defect to the loss of a specific mtDNA-encoded complex IV
subunit, which is the mechanism by which this edge operates.
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
de novo mitochondrial translation25 was severely affected in P3 fibroblasts (Figure
3F), possibly because methylation is required for tRNA maturation
explanation: >-
Documents the translation defect in patient fibroblasts and the authors' proposed
mechanism, stated with their own hedge intact.
- reference: PMID:28118529
reference_title: "SLC25A26 overexpression impairs cell function via mtDNA hypermethylation and rewiring of methyl metabolism."
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
snippet: >-
overexpression of SLC25A26 in CaSki cells increases mitochondrial SAM availability and
promotes hypermethylation of mitochondrial DNA, leading to decreased expression of key
respiratory complex subunits
explanation: >-
Corroborates the SAM-to-respiratory-subunit link from the opposite direction: raising
matrix SAM also lowers respiratory subunit expression. Graded INDIRECT because it is a
gain-of-carrier experiment in a cancer cell line, not the disease state - but a
mechanism that breaks when the dose is moved either way is better supported than one
tested in one direction only.
- name: Impaired CoQ10 and Lipoic Acid Biosynthesis
description: >
Coenzyme Q10 and lipoic acid both require SAM-dependent methylation for their synthesis.
Their loss is a second, independent route from the same bottleneck to the same clinical
picture: CoQ10 is the electron carrier between complexes I/II and III, and lipoic acid
is the cofactor of pyruvate dehydrogenase, whose failure produces lactate directly.
biological_scale: MOLECULAR
biological_processes:
- preferred_term: ubiquinone biosynthetic process
modifier: DECREASED
term:
id: GO:0006744
label: ubiquinone biosynthetic process
- preferred_term: lipoate biosynthetic process
modifier: DECREASED
term:
id: GO:0009107
label: lipoate biosynthetic process
chemical_entities:
- preferred_term: coenzyme Q10
modifier: DECREASED
term:
id: CHEBI:46245
label: coenzyme Q10
downstream:
- target: Combined Respiratory Chain Complex Deficiency
causal_link_type: DIRECT
- target: Lactic acidosis
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Lipoic acid deficiency impairs pyruvate dehydrogenase, diverting pyruvate to lactate
independently of the respiratory chain defect.
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
and the biosynthesis of CoQ10 and lipoic acid
explanation: >-
Names the two biosynthetic pathways this node asserts are impaired.
- name: Combined Respiratory Chain Complex Deficiency
description: >
Measured respiratory-chain activity is reduced across more than one complex. In the
neonatal patient, fibroblast complex IV activity was decreased; in the surviving
patient's skeletal muscle, multiple complexes were affected. The pattern is consistent
with the upstream lesion: every complex containing mtDNA-encoded subunits is exposed to
the translation defect, and every complex downstream of CoQ10 is exposed to the
cofactor defect.
biological_scale: CELLULAR
biological_processes:
- preferred_term: mitochondrial respiratory chain complex assembly
modifier: DECREASED
term:
id: GO:0033108
label: mitochondrial respiratory chain complex assembly
downstream:
- target: Lactic acidosis
causal_link_type: DIRECT
- target: Muscle weakness
causal_link_type: DIRECT
- target: Decreased activity of mitochondrial complex IV
causal_link_type: DIRECT
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Measurement of respiratory-chain activity in fibroblasts demonstrated decreased complex
IV activity.
explanation: >-
Documents the measured respiratory-chain deficiency in patient cells.
- name: Acute Metabolic Decompensation
description: >
The clinical hallmark is not steady-state dysfunction but episodic crisis: acute
circulatory collapse with pulmonary hypertension and severe lactic acidosis, requiring
extracorporeal membrane oxygenation in one patient and causing cardiopulmonary arrest
with hypoxic brain damage in another. What precipitates an episode is not established.
biological_scale: ORGANISM
downstream:
- target: Pulmonary arterial hypertension
causal_link_type: DIRECT
- target: Lactic acidosis
causal_link_type: DIRECT
- target: Respiratory failure
causal_link_type: DIRECT
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
presented at 4 weeks with acute circulatory collapse and pulmonary hypertension,
requiring extra-corporeal membrane oxygenation for 5 days
explanation: >-
Documents the acute decompensation syndrome and its severity in the index patient.
phenotypes:
- category: Metabolic
name: Lactic acidosis
description: >
Severe, episodic lactic acidosis is the defining laboratory abnormality, reaching 42
mmol/l against a reference below 1.8 in one neonate and 36 mmol/l in a later episode in
another patient. Pyruvate is elevated alongside it.
phenotype_term:
preferred_term: Lactic acidosis
term:
id: HP:0003128
label: Lactic acidosis
frequency: VERY_FREQUENT
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
developed severe lactic acidosis up to 42 mmol/l (reference: <1.8), an elevated
pyruvate level (0.65 mmol/l; reference: <0.1), and respiratory failure 11 hr after
birth
explanation: >-
Gives the magnitude of the lactate elevation against its reference interval, and the
accompanying pyruvate rise.
- category: Cardiovascular
name: Pulmonary arterial hypertension
description: >
Pulmonary hypertension accompanies the acute decompensations and is recurrent - one
patient had a second episode at three and a half years that also resolved.
phenotype_term:
preferred_term: Pulmonary arterial hypertension
term:
id: HP:0002092
label: Pulmonary arterial hypertension
frequency: FREQUENT
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
At 3.5 years, he had a second episode of pulmonary hypertension, which also normalized.
explanation: >-
Documents pulmonary hypertension and its recurrent, reversible character.
- category: Musculoskeletal
name: Muscle weakness
description: >
Slowly progressive muscle weakness is the interictal phenotype at the milder end of the
spectrum, against a background of reduced respiratory-chain complex levels in skeletal
muscle.
phenotype_term:
preferred_term: Muscle weakness
term:
id: HP:0001324
label: Muscle weakness
clinical_course: PROGRESSIVE
frequency: FREQUENT
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
childhood acute episodes of cardiopulmonary failure and slowly progressive muscle
weakness
explanation: >-
Documents progressive muscle weakness as the interictal feature of the milder
phenotype.
- category: Respiratory
name: Respiratory failure
description: >
Respiratory insufficiency is the proximate cause of death at the severe end, and
mechanical ventilation was required within hours of birth in one neonate.
phenotype_term:
preferred_term: Respiratory failure
term:
id: HP:0002878
label: Respiratory failure
frequency: FREQUENT
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Clinical findings ranged from neonatal mortality resulting from respiratory
insufficiency and hydrops
explanation: >-
Documents respiratory insufficiency as the mode of death at the severe end.
- category: Laboratory
name: Decreased activity of mitochondrial complex IV
description: >
Reduced complex IV activity was measured in patient fibroblasts, with reduced COXII
steady-state level as the molecular correlate.
phenotype_term:
preferred_term: Decreased activity of mitochondrial complex IV
term:
id: HP:0008347
label: Decreased activity of mitochondrial complex IV
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Measurement of respiratory-chain activity in fibroblasts demonstrated decreased complex
IV activity.
explanation: >-
Documents the complex IV deficiency directly in patient-derived cells.
- category: Prenatal
name: Hydrops fetalis
description: >
Non-immune hydrops at the severe end of the spectrum, part of the neonatal presentation
that ends in death from respiratory insufficiency. It is quoted in this entry's clinical
range evidence and is modeled here so the phenotype is queryable rather than only
narrated.
phenotype_term:
preferred_term: Hydrops fetalis
term:
id: HP:0001789
label: Hydrops fetalis
frequency: OCCASIONAL
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Clinical findings ranged from neonatal mortality resulting from respiratory
insufficiency and hydrops
explanation: >-
Documents hydrops as part of the severe neonatal presentation.
- category: Neurological
name: Hypotonia
description: >
Reduced muscle tone in P3, the severe neonatal case, contributing with bradycardia and
respiratory insufficiency to a poor Apgar score and immediate need for high-frequency
oscillatory ventilation. P3 died at five days.
phenotype_term:
preferred_term: Hypotonia
term:
id: HP:0001252
label: Hypotonia
frequency: OCCASIONAL
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
but presented with a poor Apgar score (3-5-6) due to bradycardia, hypotonia, and
respiratory insufficiency, necessitating assisted ventilation with high-frequency
oscillation
explanation: >-
Names hypotonia directly, in P3's neonatal presentation, alongside the bradycardia and
respiratory insufficiency that share the sentence.
- category: Cardiovascular
name: Bradycardia
description: >
Slow heart rate in P3, the severe neonatal case, named as one of the three causes of a
poor Apgar score alongside hypotonia and respiratory insufficiency.
phenotype_term:
preferred_term: Bradycardia
term:
id: HP:0001662
label: Bradycardia
frequency: OCCASIONAL
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
but presented with a poor Apgar score (3-5-6) due to bradycardia, hypotonia, and
respiratory insufficiency, necessitating assisted ventilation with high-frequency
oscillation
explanation: >-
Names bradycardia directly as a cause of P3's poor Apgar score. The same sentence
carries hypotonia and respiratory insufficiency, which is why all three now cite it.
- category: Neurological
name: Global developmental delay
description: >
Developmental delay in survivors. In one patient, gross development was normal to two
years and then declined after a metabolic crisis with cardiopulmonary arrest and hypoxic
brain damage - so at least some of the delay in this disease is acquired at a crisis
rather than continuous from birth.
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
frequency: OCCASIONAL
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The child improved, and gross development was normal until 2 years of age, when she
experienced an additional episode of severe lactic acidosis (36 mmol/l) followed by
cardiopulmonary arrest and hypoxic brain damage.
explanation: >-
Documents the developmental trajectory and locates the inflection at a metabolic
crisis, which is what distinguishes acquired from congenital delay here.
- category: Musculoskeletal
name: Exercise intolerance
description: >
Exercise intolerance with mitochondrial myopathy is the presenting picture of the adult
phenotype. Despite the mild clinical course, skeletal muscle in these patients shows
marked respiratory-chain deficiency and mitochondrial histopathology comparable to that
of the early-onset cases.
phenotype_term:
preferred_term: Exercise intolerance
term:
id: HP:0003546
label: Exercise intolerance
frequency: OCCASIONAL
evidence:
- reference: PMID:35024855
reference_title: "Pathogenic SLC25A26 variants impair SAH transport activity causing mitochondrial disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Both patients had exercise intolerance and mitochondrial myopathy associated with
biallelic variants in SLC25A26, which led to marked respiratory chain deficiencies and
mitochondrial histopathological abnormalities in skeletal muscle that are comparable
to those previously described in early-onset cases.
explanation: >-
Documents the adult phenotype and, importantly, that its muscle biochemistry matches
the severe cases - so the mildness is clinical, not biochemical.
- category: Gastrointestinal
name: Recurrent abdominal pain with metabolic decompensation
description: >
One of the two reported adults presented with recurrent episodes of severe abdominal
pain accompanied by metabolic decompensation with lactic acidosis. The episodic pattern
is the same as in the childhood form; only the organ system announcing it differs.
frequency: VERY_RARE
evidence:
- reference: PMID:35024855
reference_title: "Pathogenic SLC25A26 variants impair SAH transport activity causing mitochondrial disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
one of whom presented with recurrent episodes of severe abdominal pain and metabolic
decompensation with lactic acidosis
explanation: >-
Documents this presentation in one of the two reported adult patients; recorded as
VERY_RARE because it is one patient of the whole reported literature.
experimental_models:
- name: Saccharomyces cerevisiae SAM5-null complementation assay
experimental_model_type: OTHER
organism:
preferred_term: Saccharomyces cerevisiae
term:
id: NCBITaxon:4932
label: Saccharomyces cerevisiae
publication: PMID:26522469
description: >
A yeast strain lacking the SAMC ortholog SAM5 cannot grow on non-fermentable carbon
sources. Expressing each human patient allele in that strain asks whether the allele can
do the job, and grades how well. This is the functional proof that the human protein is
the SAM carrier and that the patient alleles impair it, and it produced
the residual-activity gradient the entry's genotype-severity reading rests on.
Filed under experimental_models rather than animal_models: yeast is not an animal, and
ExperimentalModel is where non-animal systems belong. experimental_model_type is OTHER
because a complementation assay in a null strain is not an organoid, cell line, chip or
primary culture.
modeled_mechanisms:
- target: SLC25A26 Loss of Function
relationship: MEASURES
fidelity: HIGH
model_scale: MOLECULAR
description: >-
The assay measures the transport competence of each human allele directly, which is
precisely what this node asserts is impaired.
limitations: >-
Growth rescue in yeast reports carrier function in a yeast membrane and says nothing
about the human tissue distribution of the consequence, nor about which downstream
methylation reactions fail first. It also cannot address the SAM-versus-SAH branch,
since the readout is growth rather than directional flux.
readouts:
- name: Growth on non-fermentable carbon sources after complementation
target: SLC25A26 Loss of Function
direction: DECREASED
interpretation: >-
Failure to restore growth indicates the allele cannot perform the carrier function.
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
the growth phenotype of SAM5Δ cells on non-fermentable carbon sources could not be
restored by complementation of the knockout strain with the p.Ala102Val,
p.Pro199Leu, or SAMCΔ1–88 variant. Only the p.Val148Gly altered SAMC partially
rescued the growth de
explanation: >-
Reports the readout allele by allele, including the partial rescue that separates
p.Val148Gly from the rest.
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We confirmed pathogenicity by complementation studies in an S. cerevisiae SAMC-null
strain (SAM5Δ)
explanation: >-
States what the assay was used for - confirming pathogenicity - which is the claim
this link makes.
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
SAMCΔ1–88 was completely inactive, whereas p.Ala102Val and p.Pro199Leu variants
exhibited negligible activity, and p.Val148Gly strongly inhibited SAMC activity (15% of
wild-type SAMC).
explanation: >-
Gives the quantified residual-activity gradient across the allele series, which is what
makes this model informative beyond a binary pathogenic call.
animal_models:
- name: SAH-transport-impaired mouse and fruit fly models
species: Mouse and Drosophila melanogaster
genotype: Slc25a26 variants impairing SAH rather than SAM transport
publication: PMID:35024855
description: >
Two model organisms used together to separate the two legs of the antiport, which no
human assay currently does. They are what establishes that SAH-export impairment rather
than SAM-import loss underlies the mild late-onset phenotype.
modeled_mechanisms:
- target: Impaired Matrix SAH Export
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: MOLECULAR
description: >-
The models demonstrate the transport-direction defect itself, which is the node, rather
than the clinical phenotype it is invoked to explain.
limitations: >-
The models establish the transport biochemistry; the link from that to the mild human
phenotype is an inference the authors hedge as "likely". The human arm of the argument
is two unrelated patients. A fruit fly has no skeletal muscle phenotype comparable to
human mitochondrial myopathy, so the clinical end of the claim is not modelled at all.
divergences:
- divergence_type: BOUNDARY_OMISSION
materiality: QUALIFYING
description: >-
The models observe transport activity; the claim they are cited for is a
whole-organism severity difference. Everything in between - which tissues tolerate
SAH accumulation, and why skeletal muscle in particular - lies outside the model
boundary and is not observed. Typed BOUNDARY_OMISSION rather than
SCALE_EXTRAPOLATION because the model_scale and the target node are both MOLECULAR,
so there is no scale gap for that value to describe; the missing biology is
intervening, not higher.
- divergence_type: SPECIES_MISMATCH
materiality: QUALIFYING
description: >-
Mouse and Drosophila carriers stand in for a human mitochondrial myopathy. The fly in
particular has no skeletal muscle phenotype comparable to the human one, so the
clinical end of the severity claim has no counterpart in that organism at all.
evidence:
- reference: PMID:35024855
reference_title: "Pathogenic SLC25A26 variants impair SAH transport activity causing mitochondrial disease."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We demonstrate using both mouse and fruit fly models that impairment of SAH, rather
than SAM, transport across the mitochondrial membrane is likely the cause of this
milder, late-onset phenotype.
explanation: >-
States what the two models jointly demonstrate and the strength the authors claim for
it.
evidence:
- reference: PMID:35024855
reference_title: "Pathogenic SLC25A26 variants impair SAH transport activity causing mitochondrial disease."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The SLC25A26 gene encodes a mitochondrial inner membrane carrier that transports
S-adenosylmethionine (SAM) into the mitochondrial matrix in exchange for
S-adenosylhomocysteine (SAH).
explanation: >-
Establishes the antiport mechanism the models were built to interrogate, and so why
they are informative for this node.
diagnosis:
- name: Whole-exome plus mitochondrial genome sequencing
description: >
Diagnosis is genetic. The biochemical picture - severe lactic acidosis with a combined
respiratory-chain defect - places a patient in a large differential and does not
identify the gene, so the reported route is whole-exome sequencing alongside
mitochondrial genome sequencing, the latter to exclude a primary mtDNA cause of the same
biochemistry.
evidence:
- reference: PMID:34375635
reference_title: "Identification and characterization of novel compound variants in SLC25A26 associated with combined oxidative phosphorylation deficiency 28."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Whole-exome and mitochondrial genome sequencing was applied for the genetic analysis,
together with bioinformatic analysis of predicted consequences of the identified
variant.
explanation: >-
Describes the diagnostic route used to reach this disease, including the parallel mtDNA
sequencing that rules out the alternative cause of the same biochemistry.
- name: Differential against the lipoic-acid and PDH-complex disorders
description: >
The impaired lipoic acid biosynthesis in this disease puts it in the same biochemical
neighbourhood as the multiple mitochondrial dysfunction syndromes (NFU1, BOLA3, ISCA2,
IBA57), which share lactic acidosis, combined respiratory-chain defects, and impairment
of the lipoic-acid-dependent dehydrogenases. That overlap is the diagnostically useful
fact: it is why SLC25A26 sits on pyruvate-dehydrogenase-complex deficiency gene panels
rather than being reached by targeted testing, and why a patient with low PDHC activity
and no PDHA1 variant should have this gene covered.
evidence:
- reference: PMID:27785568
reference_title: "Novel mutations in IBA57 are associated with leukodystrophy and variable clinical phenotypes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
characterized by lactic acidosis, hyperglycinemia, multiple defects of the respiratory
chain complexes, and impairment of four lipoic acid-dependent enzymes
explanation: >-
Defines the biochemical signature of the differential class that this disease overlaps
through its lipoic-acid arm.
- reference: PMID:32742935
reference_title: "Pitfalls of relying on genetic testing only to diagnose inherited metabolic disorders in non-western populations - 5 cases of pyruvate dehydrogenase deficiency from South Africa."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Included in the panel were: PDHA1, PDHB, DLAT, DLD, PDHX, BOLA3, GLRX5, IBA57, LIAS,
LIPT1, LIPT2, NFU1, PDP1, PDP2, SLC19A2, SLC19A3, SLC25A19, SLC25A26, TPK1 and FBXL4.
explanation: >-
Shows SLC25A26 on a diagnostic PDH-complex deficiency panel, which is the practical
consequence of the biochemical overlap: this disease is reached through that
differential rather than around it.
treatments:
- name: Riociguat for Refractory Pulmonary Hypertension
description: >
Riociguat, an oral soluble guanylate cyclase stimulator, was used as rescue therapy in a
four-month-old with compound heterozygous SLC25A26 mutation and near-systemic pulmonary
hypertension, after conventional combination PAH therapy had failed. It allowed
successful weaning off inhaled nitric oxide over one week.
Two caveats are load-bearing. This is a single patient in a two-case series, and the
other case had an unrelated genotype (TBX4), so nothing here is specific to SLC25A26
beyond the fact that this patient had it. And riociguat acts on the pulmonary vasculature,
not on the carrier defect - it treats the most dangerous complication of the disease
without touching its cause.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: riociguat
term:
id: CHEBI:76018
label: riociguat
target_mechanisms:
- target: Pulmonary arterial hypertension
description: >-
Stimulating soluble guanylate cyclase lowers pulmonary vascular resistance. It acts on
the vascular consequence, downstream of everything this disease's pathograph models.
evidence:
- reference: PMID:36533232
reference_title: "Novel use of riociguat in infants with severe pulmonary arterial hypertension unable to wean from inhaled nitric oxide."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Case 2 is a 4-month-old term male with compound heterozygous SLC25A26 mutation and
severe pulmonary hypertension. Initial cardiac catheterization showed PVRi 28.2 WU*m2.
explanation: >-
Establishes that the treated patient carried this disease's genotype, which is what
makes the case relevant to this entry rather than to pulmonary hypertension generally.
- reference: PMID:36533232
reference_title: "Novel use of riociguat in infants with severe pulmonary arterial hypertension unable to wean from inhaled nitric oxide."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
After a 24-h sildenafil washout, he was initiated and uptitrated on riociguat with
concomitant, successful wean of nitric oxide over one week that was well tolerated.
explanation: >-
Documents the response to riociguat in this patient, including the sildenafil washout
the switch required.
- name: Conventional Combination PAH Therapy
description: >
Sildenafil, bosentan and intravenous treprostinil are the standard escalation for
paediatric pulmonary arterial hypertension, and in the one reported SLC25A26 patient
they failed: pulmonary pressures stayed near systemic and repeated attempts to wean
inhaled nitric oxide provoked tachypnoea, hypoxaemia and worsening echocardiographic
hypertension. The failure is the clinically useful part of the record, and it is why
this treatment is curated alongside the rescue therapy rather than omitted.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: sildenafil
term:
id: CHEBI:9139
label: sildenafil
- preferred_term: bosentan
term:
id: CHEBI:51450
label: bosentan
- preferred_term: treprostinil
term:
id: CHEBI:50861
label: treprostinil
target_mechanisms:
- target: Pulmonary arterial hypertension
description: >-
Standard pulmonary vasodilator combination, targeting the same vascular consequence.
evidence:
- reference: PMID:36533232
reference_title: "Novel use of riociguat in infants with severe pulmonary arterial hypertension unable to wean from inhaled nitric oxide."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: >-
After uptitration of sildenafil, bosentan, and IV treprostinil, serial echocardiograms
continued to demonstrate near-systemic pulmonary hypertension.
explanation: >-
Refutes the expectation that conventional combination therapy controls the pulmonary
hypertension in this disease. Recorded as REFUTE against that efficacy claim, which is
why the treatment is curated with its failure attached.
- reference: PMID:36533232
reference_title: "Novel use of riociguat in infants with severe pulmonary arterial hypertension unable to wean from inhaled nitric oxide."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: >-
He failed multiple attempts to wean off typical doses of iNO (10-20 ppm) over the
following weeks with tachypnea, hypoxemia, and worsening pulmonary hypertension on
echocardiogram despite continued aggressive combination targeted therapy.
explanation: >-
Documents the specific mode of failure - inability to wean nitric oxide - which is
what the rescue therapy was introduced to solve.
- name: Dichloroacetate for Acute Lactic Acidosis
description: >
Sodium dichloroacetate was given during acute decompensations and is recorded as having
had good effect in one patient and as part of the successful early management of another.
It activates pyruvate dehydrogenase, which is mechanistically apt here for a reason
specific to this disease: lipoic acid, the PDH cofactor, is itself depleted by the
upstream SAM defect. The evidence is individual case description, not a trial.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: dichloroacetate
term:
id: CHEBI:28240
label: dichloroacetate
target_mechanisms:
- target: Lactic acidosis
description: >-
Stimulating pyruvate dehydrogenase diverts pyruvate away from lactate, addressing the
acidosis rather than the carrier defect.
evidence:
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Sodium dichloroacetic acid had good effect, and the boy slowly normalized.
explanation: >-
Documents the clinical response to dichloroacetate in an acute episode. A single
patient's response, recorded as such.
- reference: PMID:26522469
reference_title: "Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
prompting mechanical ventilation and dichloroacetic acid treatment. The child improved,
and gross development was normal until 2 years of age
explanation: >-
Documents dichloroacetate use in a second patient's acute presentation and the interval
of normal development that followed.
discussions:
- discussion_id: coxpd28_sam_supplementation_untested
kind: KNOWLEDGE_GAP
prompt: >-
Can the matrix SAM pool be replenished pharmacologically - by SAM, methionine or
betaine supplementation - when the sole carrier is defective?
attaches_to:
- pathophysiology#Reduced Intra-Mitochondrial S-Adenosylmethionine
rationale: >-
The bottleneck in this disease is a single transported metabolite, which is the shape of
problem that sometimes yields to substrate supplementation. But the lesion is in the
transporter, not in supply: raising cytosolic SAM does not obviously raise matrix SAM
when the only route in is the thing that is broken. Whether the residual carrier
function that the missense alleles leave behind is enough to exploit a raised cytosolic
gradient is exactly the question, and it is untested. No treatment directed at the
mechanism is reported in any of the three publications; management is supportive, with
dichloroacetate for the acidosis. Recorded because the reasoning that makes
supplementation attractive is also the reasoning that might make it useless, and the
entry should not leave a reader to infer either.
The SAM/SAH branch point sharpens the question rather than answering it. If a patient's
defect is on the SAH-export leg, matrix SAH accumulation is the problem and adding SAM
could plausibly make it worse, not better. So "try SAM" is not even a single proposal:
it is two opposite proposals depending on which limb the genotype sits on, and nothing
currently assays that in a patient.
- discussion_id: coxpd28_decompensation_trigger
kind: KNOWLEDGE_GAP
prompt: >-
What precipitates an acute decompensation in COXPD28, and can episodes be prevented?
attaches_to:
- pathophysiology#Acute Metabolic Decompensation
rationale: >-
The episodes carry the mortality and the permanent neurological injury in this disease -
one patient's hypoxic brain damage followed a crisis, not the baseline disease - yet no
trigger is identified in any report. Patients have intervals of normal development
between crises. If the episodes were predictable, the burden would be a different
problem; as it stands, the pathograph has a node whose timing nothing explains.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Review round 1: address all six blocking findings on PR #12163 · 2026-09-18T18:34:08Z · View source
Single bundled push addressing every blocking finding and every suggestion from the ai4c-reviewer CHANGES_REQUESTED review, since main has dismiss_stale_reviews and a second push costs a full re-review cycle. The reviewer's central criticism was right: the entry consumed only about half its own deep-research artifact, and six of eleven committed reference caches were uncited. Reference caches were committed because the deep-research validation run fetched them; citing only some of them meant committing evidence the entry did not use. Blocking finding 2 was a factual error in my text, not an omission. The genetic notes asserted that reported variants are 'missense changes in the transmembrane regions rather than nulls'. PMID:26522469, which the entry cites for that sentence, reports P3 as homozygous for the splice allele c.33+1G>A whose transcript fails to reach mitochondria and 'does not encode a functional mitochondrial carrier protein'. That is a functional null. The genotype-severity story the note was reaching for is real and is now stated accurately, with the measured residual-activity gradient from yeast complementation and in vitro reconstitution (SAMCdelta1-88 completely inactive, p.Ala102Val and p.Pro199Leu negligible, p.Val148Gly 15% of wild-type) and the paper's own statement that residual SAM-import capacity correlated with clinical severity. Addressed: riociguat plus the failed conventional PAH combination (the failure cited as REFUTE against the efficacy claim, since that is the clinically load-bearing part); the four unmodeled phenotypes; a diagnosis section covering WES plus mitochondrial genome sequencing and the lipoic-acid/PDH-complex differential; the full four-genotype variant spectrum including the adult-onset alleles; the yeast SAM5-null complementation model; prevalence_class raised to ULTRA_RARE; FBXO24 and the overexpression corroboration; and the PMID:35730628 title corrected to match the cache byte for byte. Two departures from the review, both explained in the PR reply. The yeast assay is filed under experimental_models with experimental_model_type OTHER rather than animal_models, because yeast is not an animal and ExperimentalModel is where non-animal systems belong. FBXO24 is a note on the pathophysiology node rather than a genetic row with relationship_type MODIFIER, because the work is mouse spermiogenesis and no human FBXO24 variant has been linked to this disease; MODIFIER would assert a human genotype-phenotype relationship nobody has reported. All four NCIT drug CURIEs supplied in the review are wrong and were not used. NCIT:C82724 is MIR29B1 Pre-miRNA, not Riociguat; NCIT:C29277 is Nevirapine, not Sildenafil; NCIT:C47529 is Ezetimibe, not Bosentan; NCIT:C61885 is Pentobarbital, not Treprostinil. Each was checked against OLS before use, per the ontology-term contract, and CHEBI terms were used instead (riociguat CHEBI:76018, sildenafil CHEBI:9139, bosentan CHEBI:51450, treprostinil CHEBI:50861), consistent with this repo's preference for CHEBI on specific small molecules. I also fabricated four reference_title strings in this round, writing them from what the papers are about rather than copying the cache frontmatter. check-reference-titles caught all four before commit. Recorded because it is the second instance of writing-from-memory in this curation session and the titles read entirely plausibly. Validation after the round: just validate passes with 50/50 snippets verified; validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values and check-qualifier-terms all pass.
Create: Combined_Oxidative_Phosphorylation_Deficiency_28 · 2026-09-18T18:14:12Z · View source
De novo curation of COXPD28 / SLC25A26 deficiency (MONDO:0014775) from an openscientist deep-research report plus independent PubMed work. Deep research: just research-disorder openscientist; report committed at research/Combined_Oxidative_Phosphorylation_Deficiency_28-deep-research-openscientist.md. Frontmatter: reference_validation 11/11 verified, confabulation_rate 0.0. quotes_valid 22 of 23, with one quote flagged unsupported against PMID:26522469; that is an ellipsis artifact, not a fabrication - the report elided 'in three families' with a Unicode ellipsis and exact-substring matching correctly failed, and the validator printed the closest source text, which matches. The entry quotes the full unelided sentence. term_validation reports 2 mislabelled terms, both the same table-column parsing artifact seen in the CLIPPERS report: the report's identifier table has the ontology name in the column the parser read as the label, so MONDO:0014775 is 'reported as' MONDO. The report materially changed the entry and the change was a correction, not an addition. My first pass modelled SAMC as a SAM importer and the disease as a single depleted-pool bottleneck. SAMC is an antiporter: it imports SAM in exchange for exporting SAH, and PMID:35024855 shows in mouse and fruit fly that preferential impairment of the SAH-export leg underlies a mild adult-onset mitochondrial myopathy, distinct from the severe neonatal disease that SAM-import loss causes. That added a second molecular node (Impaired Matrix SAH Export), an EMERGING mechanistic_hypotheses group for the branch, an animal_models block with a SCALE_EXTRAPOLATION divergence, two adult phenotypes, and a rewritten description. It also changed the answer to the SAM-supplementation discussion: if a patient sits on the SAH-export limb, adding SAM could plausibly worsen matrix SAH accumulation, so 'try SAM' is two opposite proposals rather than one. Evidence grading notes. The two PMID:35730628 items are OTHER with quote_role REVIEW_SYNTHESIS: the source is a review stating established biochemistry rather than reporting a study. The PMID:36456512 transfection result is IN_VITRO. The branch-point claim is MODEL_ORGANISM throughout and the authors' own 'likely' is preserved in both the snippet and the hypothesis description. Validation: just validate passes with 31/31 snippets verified; validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values and check-qualifier-terms all pass. One duplicate evidence key was introduced during editing and caught by the validator before commit. GeneReviews: NO_CHAPTER for both collections.
Disease: Combined Oxidative Phosphorylation Deficiency 28 MONDO ID: MONDO:0014775 | OMIM: #616794 | Orphanet: ORPHA:466784 | Category: Mendelian (autosomal recessive mitochondrial disease) Causal gene: SLC25A26 (HGNC:20661; NCBI Gene 115286; OMIM *611037; locus 3p14.1)
Combined Oxidative Phosphorylation Deficiency 28 (COXPD28) is an ultra-rare, autosomal recessive, multisystem mitochondrial disease caused by biallelic loss-of-function mutations in SLC25A26, the gene that encodes SAMC, the only known mitochondrial carrier for S-adenosyl-L-methionine (SAM). SAMC imports cytosolic SAM into the mitochondrial matrix in antiport for S-adenosyl-L-homocysteine (SAH). Because virtually all mitochondrial methylation reactions depend on matrix SAM, loss of this transporter produces a global deficit of intramitochondrial methylation, which cripples multiple downstream processes — mitochondrial (mt) rRNA/tRNA methylation and mitoribosome assembly, mitochondrial translation of oxidative-phosphorylation (OXPHOS) subunits, and biosynthesis of the cofactors lipoic acid and coenzyme Q10 (CoQ10). The convergent result is a combined deficiency of respiratory-chain complexes I, II, and IV, reduced ATP synthesis, and lactic acidosis.
Clinically, COXPD28 spans a striking severity spectrum. The severe end presents in the neonatal period with fetal hydrops, hypotonia, bradycardia, respiratory insufficiency, and death; an intermediate childhood form causes acute, episodic cardiopulmonary failure with severe lactic acidosis; and a milder adult form manifests as slowly progressive mitochondrial myopathy with exercise intolerance and, in some, recurrent abdominal pain with metabolic decompensation. Elegant model-organism work has shown that this severity gradient tracks a mechanistic branch point: severe neonatal disease is driven by loss of SAM import, whereas the milder late-onset disease reflects impaired SAH export across the inner mitochondrial membrane. Pulmonary arterial hypertension (PAH) is a recurrent and prognostically important complication.
Fewer than approximately ten patients have been reported worldwide since the disorder was first defined in 2015. There is no disease-specific cure; management is supportive, centered on treating metabolic crises and lactic acidosis, mitochondrial cofactor supplementation, and PAH-directed therapy — with one reported case of severe SLC25A26-associated PAH responding to the soluble guanylate cyclase (sGC) stimulator riociguat. Diagnosis relies on whole-exome/genome sequencing plus a supporting mitochondrial biochemical workup; the disorder is not detectable by standard newborn screening. This report synthesizes 13 confirmed findings drawn from 17 reviewed papers into a comprehensive disease-knowledge-base entry.
Overview. COXPD28 is a rare inborn error of mitochondrial energy metabolism defined by reduced intramitochondrial methylation. It was first delineated by Kishita et al. (2015) in three families, who described "a syndrome … affected by reduced intra-mitochondrial methylation caused by recessive mutations in the gene encoding the only known mitochondrial SAM transporter, SLC25A26" (PMID: 26522469). Orphanet defines it as a rare mitochondrial disease with a variable phenotype ranging from fetal hydrops with postnatal hypotonia, bradycardia, and respiratory failure causing neonatal death, to infantile-onset episodes of acute cardiopulmonary failure with severe lactic acidosis and slowly progressive muscle weakness.
Key identifiers (Finding F013).
| Resource | Identifier |
|---|---|
| MONDO | MONDO:0014775 |
| OMIM | #616794 (Phenotypic Series PS609060) |
| Orphanet | ORPHA:466784 |
| Disease Ontology | DOID:0111470 |
| MedGen/UMLS | C5569081 |
| ICD-10 (via Orphanet) | E88.8 |
| MeSH | D028361 (mitochondrial diseases) |
| Gene | SLC25A26 — HGNC:20661; NCBI Gene 115286; OMIM *611037; locus 3p14.1 |
Synonyms / alternative names: COXPD28; Combined oxidative phosphorylation deficiency 28; Intramitochondrial methylation deficiency; "Neonatal severe cardiopulmonary failure due to mitochondrial methylation defect"; SLC25A26 deficiency.
Source of information. The evidence base is derived almost entirely from aggregated disease-level and case/pedigree-level resources (OMIM, Orphanet, individual case reports and small family series), not large EHR cohorts, reflecting the ultra-rare nature of the condition.
Primary cause — genetic (Finding F001). COXPD28 is caused by recessive (biallelic) loss-of-function mutations in SLC25A26. SLC25A26 encodes the only known mitochondrial S-adenosylmethionine transporter (SAMC), which imports cytosolic SAM into mitochondria in antiport for SAH. As Kishita et al. state, the syndrome is "caused by recessive mutations in the gene encoding the only known mitochondrial SAM transporter, SLC25A26" (PMID: 26522469). A comprehensive review confirms the transporter's identity and mechanism: "Orthologous mitochondrial transporters belonging to the mitochondrial carrier family have been identified to catalyze this antiport transport step: Sam5p in yeast, SLC25A26 (SAMC) in humans, and SAMC1-2 in plants" (PMID: 35730628).
Genetic risk factors. The disease is monogenic and fully penetrant with biallelic pathogenic genotypes; there are no established polygenic susceptibility loci or GWAS signals for the disease itself. Consanguinity is a risk factor for homozygous cases (e.g., a consanguineous Moroccan family with a homozygous splice variant; Finding F010).
Environmental risk factors. None are established as causal. As with other mitochondrial OXPHOS disorders, intercurrent metabolic stressors (infection, fasting, fever, surgery, catabolic states) plausibly precipitate the episodic acute cardiopulmonary/metabolic decompensations characteristic of the disease, though this is inferred from general mitochondrial-disease physiology rather than demonstrated specifically for COXPD28.
Protective factors. No genetic or environmental protective factors have been described.
Gene–environment interactions. Not formally characterized. The plausible interaction is metabolic-demand-dependent: energy-demanding tissues under stress unmask the OXPHOS deficit. This remains a knowledge gap.
COXPD28 is a multisystem disorder with a broad, severity-dependent phenotype (Findings F002, F008). Key manifestations, with suggested HPO terms:
| Phenotype | Type | Onset / severity | HPO suggestion |
|---|---|---|---|
| Fetal hydrops | Physical manifestation | Prenatal/neonatal; severe | HP:0001789 (Hydrops fetalis) |
| Neonatal respiratory insufficiency/failure | Clinical sign | Neonatal; severe/lethal | HP:0002098 (Respiratory insufficiency) |
| Episodic cardiopulmonary failure | Clinical sign | Infancy/childhood; episodic, severe | HP:0001635 (Congestive heart failure) |
| Pulmonary arterial hypertension | Clinical sign | Infancy; severe | HP:0002092 (Pulmonary arterial hypertension) |
| Hypotonia | Clinical sign | Neonatal/infantile | HP:0001252 (Hypotonia) |
| Slowly progressive muscle weakness / mitochondrial myopathy | Physical manifestation | Childhood–adult; progressive | HP:0003198 (Myopathy); HP:0003324 (Generalized muscle weakness) |
| Exercise intolerance | Symptom | Adult; mild–moderate | HP:0003546 (Exercise intolerance) |
| Recurrent abdominal pain / metabolic decompensation | Symptom | Adult; episodic | HP:0002027 (Abdominal pain) |
| Lactic acidosis / hyperlactatemia | Laboratory abnormality | Any age; variable | HP:0003128 (Lactic acidosis); HP:0002151 (Increased serum lactate) |
| Developmental delay | Behavioral/developmental | Infancy/childhood | HP:0001263 (Global developmental delay) |
| Bradycardia | Clinical sign | Neonatal | HP:0001662 (Bradycardia) |
Age of onset and severity spectrum. Kishita et al. capture the range: "Clinical findings ranged from neonatal mortality resulting from respiratory insufficiency and hydrops to childhood acute episodes of cardiopulmonary failure and slowly progressive muscle weakness" (PMID: 26522469). Adults present with exercise intolerance and mitochondrial myopathy, "one of whom presented with recurrent episodes of severe abdominal pain and metabolic decompensation with lactic acidosis" (PMID: 35024855). Severe pulmonary hypertension is documented: "Case 2 is a 4-month-old term male with compound heterozygous SLC25A26 mutation and severe pulmonary hypertension" (PMID: 36533232).
Progression. Episodic/fluctuating in the acute crises; slowly progressive in the myopathic form; rapidly fatal in severe neonatal presentations.
Frequency among affected individuals. Given <10 reported patients, frequencies are qualitative. Cardiorespiratory involvement and lactic acidosis are recurrent; PAH and myopathy are each documented in multiple cases.
Quality-of-life impact. Severe forms are lethal in infancy. Survivors face chronic exercise limitation, recurrent metabolic crises, and PAH-related functional impairment (one case reached WHO functional class II after treatment; Finding F009). Disease-specific QoL instruments (EQ-5D, SF-36) have not been applied in this ultra-rare cohort.
Causal gene (Findings F001, F004). SLC25A26 (HGNC:20661; NCBI Gene 115286; OMIM *611037; locus 3p14.1; reference transcript NM_173471.3). It is the sole mitochondrial SAM carrier.
Pathogenic variant spectrum (Finding F004). All reported variants are recessive and loss-of-function; missense variants cluster in highly conserved transmembrane domains, and functional assays (yeast complementation, in vitro transport) show decreased SAM/SAH transport.
| Patient / study | Genotype (NM_173471.3) | Protein | Type | Origin |
|---|---|---|---|---|
| Kishita 2015 — Japanese girl | c.305C>T + c.596C>T | p.Ala102Val / p.Pro199Leu | Compound het missense | Germline |
| Kishita 2015 — Moroccan girl (consanguineous) | c.33+1G>A (homozygous) | Splice donor | Homozygous splice | Germline |
| Wang/Ji 2021 — Chinese (4th case worldwide) | c.34G>C + c.197C>A | p.Ala12Pro / p.Ala66Glu (TMR1/TMR2) | Compound het missense | Germline |
| Rosenberger 2022 — adults | c.404A>G | p.Glu135Gly | Biallelic missense | Germline |
Ji 2021 reports: "The novel compound heterozygous SLC25A26 variants (c.34G > C, p.A12P; c.197C > A; p.A66E) were identified in a Chinese patient with COXPD28" (PMID: 34375635). Rosenberger 2022 confirms adult biallelic disease: "Both patients had exercise intolerance and mitochondrial myopathy associated with biallelic variants in SLC25A26" (PMID: 35024855).
Variant classification: Reported variants are pathogenic/likely pathogenic (ACMG criteria supported by functional data). Allele frequencies are extremely low/absent in gnomAD (consistent with ultra-rare recessive disease). Origin: germline; no somatic disease role. Functional consequence: loss of function (reduced transport activity).
Modifier genes. None formally established. FBXO24 is a physiological regulator of SLC25A26 abundance — it "mediates K6-linked polyubiquitylation of SLC25A26 at lysine residue 31, targeting it for degradation" (PMID: 40657752) — making it a candidate dosage modifier, though not demonstrated as a disease modifier in patients.
Epigenetic information. SLC25A26 dosage controls mitochondrial DNA methylation: overexpression "promotes hypermethylation of mitochondrial DNA, leading to decreased expression of key respiratory complex subunits" (PMID: 28118529). In COXPD28 (loss of function), the opposite — mitochondrial hypomethylation of rRNA/proteins — is the operative defect.
Chromosomal abnormalities. None; COXPD28 is a single-gene disorder without large structural rearrangements.
SLC25A26 LoF (biallelic)
│
▼
↓ SAMC antiport at inner mito membrane
│
┌────┴─────────────────────────┐
▼ (severe/neonatal) ▼ (mild/adult)
↓ matrix SAM import ↑ matrix SAH (failed export)
└────┬─────────────────────────┘
▼
impaired SAM-dependent mito methyltransferases
│
┌────┼───────────────────────────┐
▼ ▼ ▼
mt-rRNA/tRNA mitoribosome ↓ lipoic acid
hypomethylation assembly ↓ & CoQ10 synthesis
│ │ │
└────────────┴─────────────────┘
▼
↓ mito translation of OXPHOS subunits
▼
combined complex I/II/IV deficiency, ↓ ATP
▼
heart • lung vasculature • muscle • brain failure
▼
lactic acidosis, cardiorespiratory failure, PAH, myopathy
Molecular pathways & metabolic changes (Findings F003, F006, F012). SAM is the universal methyl donor: "SAM is synthesized by methionine adenosyltransferase from methionine and ATP in the cytoplasm and subsequently distributed throughout the different cellular compartments, including mitochondria, where methylation is mostly required for nucleic-acid modifications and respiratory-chain function" (PMID: 26522469). Within mitochondria, SAM supports "the maturation and assembly of mitochondrial tRNAs, ribosomes and protein complexes; and the biosynthesis of cofactors, such as ubiquinone, lipoate, and molybdopterin" (PMID: 35730628).
Biochemical abnormalities (Finding F006). Kishita et al. showed the defect enumerated as "those affecting RNA stability, protein modification, mitochondrial translation, and the biosynthesis of CoQ10 and lipoic acid" (PMID: 26522469). Patient tissues had variably decreased complex I, II, and IV activities, decreased ATP synthesis, and reduced methylation of ribosomal transcripts/proteins, with differences between patients and between tissues (skeletal muscle vs fibroblasts). Rosenberger 2022 found "marked respiratory chain deficiencies and mitochondrial histopathological abnormalities in skeletal muscle that are comparable to those previously described in early-onset cases" (PMID: 35024855).
Protein dysfunction. Missense variants map to conserved transmembrane regions of the six-transmembrane mitochondrial carrier fold, reducing transport (loss of function); the splice variant disrupts normal transcript processing.
Cellular processes. Bioenergetic insufficiency and stress-response activation (UPRmt). Notably, the lipoic-acid biosynthesis defect places COXPD28 mechanistically adjacent to the "multiple mitochondrial dysfunction" lipoic-acid disorders (NFU1, BOLA3, IBA57, LIPT1), which share combined respiratory-chain defects and impairment of lipoic-acid-dependent 2-ketoacid dehydrogenases (PMID: 27785568; PMID: 24256811).
Upstream vs downstream. Upstream: SLC25A26 transport loss and SAM/SAH imbalance. Central: failed mitochondrial methylation. Downstream: OXPHOS complex assembly/translation failure, cofactor deficiency, ATP shortfall, tissue crises, UPRmt.
Suggested ontology terms. GO biological processes: GO:0032259 (methylation), GO:0070125 (mitochondrial translational elongation), GO:0006744 (ubiquinone biosynthetic process), GO:0009107 (lipoate biosynthetic process), GO:0042775 (mitochondrial ATP synthesis coupled electron transport). GO molecular function: GO:0000095 (SAM transmembrane transporter activity). CL cell types: CL:0000746 (cardiac muscle cell), CL:0000187 (muscle cell/myocyte), CL:0000359 (vascular associated smooth muscle cell — pulmonary vasculature).
Organ level (Findings F002, F008). - Primary: heart (myocardium), lungs/pulmonary vasculature, skeletal muscle, brain. - Body systems: cardiovascular, respiratory, musculoskeletal, nervous, and metabolic. - Secondary involvement: systemic effects of lactic acidosis and cardiopulmonary failure; gastrointestinal (recurrent abdominal pain in adult form).
Tissue/cell level. Striated (cardiac and skeletal) muscle shows mitochondrial histopathological abnormalities; pulmonary arterial smooth muscle/endothelium is implicated in PAH.
Subcellular level. The mitochondrion — specifically the inner mitochondrial membrane (carrier location) and matrix (methylation, translation, cofactor synthesis) — is the central compartment. GO cellular component terms: GO:0005743 (mitochondrial inner membrane), GO:0005759 (mitochondrial matrix), GO:0005739 (mitochondrion).
Localization (UBERON). UBERON:0000948 (heart), UBERON:0002048 (lung), UBERON:0002012 (pulmonary artery), UBERON:0001134 (skeletal muscle tissue), UBERON:0000955 (brain). Involvement is systemic/bilateral where paired organs are affected.
Onset (Findings F002, F005, F008). Bimodal by mechanism: - Severe/neonatal: congenital/prenatal (fetal hydrops) to neonatal, acute, often lethal. - Childhood: episodic acute cardiopulmonary failure. - Mild/adult: insidious, slowly progressive myopathy.
Progression. The disease course is either rapidly fatal (neonatal), episodic/relapsing with acute crises (childhood), or slowly progressive/chronic (adult myopathy). Rosenberger et al. describe the milder end as a "milder, late-onset phenotype" contrasted with "a severe neonatal onset caused by decreased SAM transport activity" (PMID: 35024855).
Patterns. No spontaneous remission; treatment can stabilize complications (e.g., PAH improving to WHO class II). Critical period: the neonatal/infantile window is the point of greatest vulnerability and the key opportunity for supportive intervention.
Epidemiology (Finding F010). COXPD28 is ultra-rare, with fewer than ~10 reported patients worldwide. No formal prevalence or incidence figures exist; Orphanet lists it among ultra-rare mitochondrial diseases.
Inheritance. Autosomal recessive (OMIM #616794): "We report a syndrome in three families affected by reduced intra-mitochondrial methylation caused by recessive mutations" (PMID: 26522469). Both homozygous (consanguineous) and compound heterozygous genotypes are reported.
Penetrance / expressivity. Penetrance appears complete for biallelic loss-of-function genotypes; expressivity is highly variable, correlating with the SAM- vs SAH-transport mechanism (Finding F005).
Genetic anticipation: not applicable (not a repeat-expansion disorder). Germline mosaicism: not reported. Founder effects: none established. Consanguinity: contributes to homozygous cases (Moroccan family). Carrier frequency: not established; expected very low given rarity.
Demographics. Cases reported across diverse populations (Japanese, Moroccan, Chinese, and others). Sex ratio: both sexes affected; no strong sex bias documented. Age distribution: bimodal (neonatal/infantile and adult). Ji 2021 undertook their study to "identify and characterize pathogenic variants of SLC25A26 in a Chinese pedigree, provide a basis for clinical diagnosis and genetic counseling" (PMID: 34375635).
Diagnostic approach (Finding F011). Diagnosis rests on next-generation sequencing (whole-exome sequencing, with mitochondrial genome sequencing to exclude mtDNA causes) combined with homozygosity mapping in consanguineous families, supported by a mitochondrial biochemical/functional workup. Ji 2021: "Whole-exome and mitochondrial genome sequencing was applied for the genetic analysis, together with bioinformatic analysis of predicted consequences of the identified variant" (PMID: 34375635).
Laboratory tests / biomarkers. Elevated blood and CSF lactate; respiratory-chain enzyme assays (complex I/II/IV) in skeletal muscle and fibroblasts; reduced ATP synthesis; reduced CoQ10 and lipoic acid. No specific circulating protein biomarker exists.
Biopsy / pathology. Muscle histopathology shows mitochondrial abnormalities — "marked respiratory chain deficiencies and mitochondrial histopathological abnormalities in skeletal muscle" (PMID: 35024855).
Functional confirmation of variants. Yeast (Sam5Δ) complementation and mouse embryonic fibroblast (MEF) transport/flux assays confirm pathogenicity (Finding F007).
Genetic testing modalities. WES and WGS are the primary tools; targeted mitochondrial-disease gene panels including SLC25A26; single-gene testing for cascade testing of relatives. Mitochondrial DNA testing is used to exclude mtDNA disease. CMA, karyotyping, FISH, and repeat-expansion testing are not informative.
Imaging / electrophysiology. Echocardiography and cardiac catheterization document PAH (e.g., PVRi 28.2 WU·m²; Finding F009); ECG may show bradycardia.
Differential diagnosis. Other combined OXPHOS deficiencies and lipoic-acid biosynthesis disorders (NFU1, BOLA3, ISCA2, IBA57, LIPT1, LIAS) — which share lactic acidosis, combined respiratory-chain defects, and lipoic-acid-dependent enzyme impairment (PMID: 27785568; PMID: 24256811) — as well as mtDNA-encoded OXPHOS disorders and pyruvate dehydrogenase deficiency (PMID: 32742935). Genetic testing distinguishes COXPD28.
Screening. COXPD28 is not detectable by standard newborn screening; ascertainment is via clinical presentation followed by genetic diagnosis. Cascade carrier testing is appropriate once a proband is identified.
Survival and mortality (Findings F002, F008). Prognosis is severity-dependent. The neonatal form carries high mortality from respiratory insufficiency and hydrops. Childhood and adult forms are chronic; adults survive into adulthood with myopathy and episodic decompensations.
Morbidity and function. Chronic exercise intolerance, muscle weakness, recurrent metabolic crises, and PAH-related functional limitation dominate the morbidity profile.
Complications. Pulmonary arterial hypertension, cardiopulmonary failure/arrest, severe lactic acidosis, and metabolic decompensation are the major complications.
Recovery potential. No cure; complications can be stabilized. In the reported PAH case, riociguat therapy achieved WHO functional class II at 21 months (Finding F009).
Prognostic factors. The mechanistic branch (SAM- vs SAH-transport loss) is the principal prognostic determinant: SAM-import loss → severe neonatal disease; SAH-export impairment → milder late-onset disease (PMID: 35024855). Presence and severity of PAH and frequency of metabolic crises are additional determinants. No validated molecular prognostic biomarker beyond genotype exists.
Overall strategy (Finding F009). There is no disease-specific cure; management is supportive: treatment of acute metabolic crises and lactic acidosis, mitochondrial cofactor/vitamin cocktails (e.g., CoQ10 supplementation is biologically rational given impaired CoQ10 synthesis), nutritional support, and organ-directed therapy.
PAH-directed therapy. A landmark management observation: a 4-month-old with compound heterozygous SLC25A26 mutation and severe PAH (PVRi 28.2 WU·m²) failed to wean from inhaled nitric oxide despite sildenafil, bosentan, and IV treprostinil, but after a sildenafil washout was successfully transitioned to riociguat, a soluble guanylate cyclase (sGC) stimulator, weaned off iNO, and reached WHO functional class II at 21 months (PMID: 36533232). The paper notes: "Riociguat, an oral soluble guanylate cyclase stimulator, has been approved for use in adults with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension" (PMID: 36533232). NCIT suggestions: Riociguat (NCIT:C82724); Sildenafil (NCIT:C29277); Bosentan (NCIT:C47529); Treprostinil (NCIT:C61885); Coenzyme Q10 (NCIT:C1042).
Advanced therapeutics. No gene, cell, RNA-based, or targeted therapies exist for COXPD28. Gene replacement of SLC25A26 is a theoretical future avenue.
Surgical / rehabilitative. Supportive intensive care for cardiopulmonary crises; physical/occupational therapy for myopathy.
Treatment outcomes / adverse events. Data are anecdotal given rarity; the riociguat case is the best-documented response.
Personalized medicine. Genotype (SAM- vs SAH-transport defect) may guide prognostic counseling and anticipatory management, though genotype-specific therapies do not yet exist.
Model systems (Finding F007).
| Model | System | Key finding | Reference |
|---|---|---|---|
| Yeast Sam5Δ | S. cerevisiae | Complementation assays demonstrated loss of function of patient missense variants | PMID: 26522469 |
| Mouse | M. musculus | Showed SAH-transport impairment drives the milder phenotype | PMID: 35024855 |
| Fruit fly | D. melanogaster | Corroborated SAH- vs SAM-transport mechanistic branch | PMID: 35024855 |
| C. elegans (sams-1 silencing) | Nematode | Mitochondrial SAM deficiency induces UPRmt and extends lifespan | PMID: 38361361 |
| Fbxo24-knockout mouse | M. musculus | Reveals SLC25A26 dosage control of mitochondrial function/ATP in spermiogenesis | PMID: 40657752 |
Rosenberger et al. state: "We demonstrate using both mouse and fruit fly models that impairment of SAH, rather than SAM, transport across the mitochondrial membrane is likely the cause of this milder, late-onset phenotype" (PMID: 35024855). The C. elegans work reports: "Mitochondrial S-adenosylmethionine deficiency induces mitochondrial unfolded protein response and extends lifespan in Caenorhabditis elegans" (PMID: 38361361).
Phenotype recapitulation. Yeast faithfully reports transport loss for variant validation; mouse and fly recapitulate the SAM/SAH mechanistic dichotomy; C. elegans models the mitochondrial stress response. Limitations: no single model fully reproduces the human multisystem cardiopulmonary phenotype (especially PAH); invertebrate models cannot model complex human cardiovascular pathology.
Applications. Variant pathogenicity classification, dissection of the SAM- vs SAH-transport mechanism, and study of downstream mitochondrial stress signaling (UPRmt).
| ID | Finding | Primary evidence (PMID) |
|---|---|---|
| F001 | COXPD28 is caused by recessive SLC25A26 mutations disrupting the mitochondrial SAM carrier | 26522469; 35730628 |
| F002 | Clinical spectrum from lethal neonatal cardiopulmonary failure to slowly progressive myopathy | 26522469; 36533232 |
| F003 | SAMC loss causes mt-RNA stability, translation, protein-modification, and CoQ10/lipoic-acid defects | 26522469; 35730628 |
| F004 | Variant spectrum: conserved transmembrane missense + splice, all loss-of-function | 34375635; 35024855 |
| F005 | SAH-transport impairment underlies the milder adult phenotype (genotype–mechanism correlation) | 35024855 |
| F006 | Biochemical signature: combined complex I/II/IV deficiency, ↓ATP, ↓lipoic acid/CoQ10, mitoribosomal hypomethylation | 35024855; 26522469 |
| F007 | Yeast, fly, mouse, and C. elegans models recapitulate aspects of COXPD28 | 38361361; 35024855 |
| F008 | Phenotype: episodic decompensation, cardiorespiratory failure, PAH, myopathy, developmental delay, lactic acidosis | 26522469; 35024855 |
| F009 | Treatment supportive; PAH responded to riociguat | 36533232 |
| F010 | Ultra-rare autosomal recessive (<10 cases); consanguinity/compound het | 34375635; 26522469 |
| F011 | Diagnosis via exome/genome sequencing + mitochondrial biochemistry; not newborn-screenable | 34375635; 35024855 |
| F012 | Full causal chain: LoF → SAM/SAH imbalance → failed mito methylation → combined OXPHOS failure → tissue crisis | 26522469; 35730628 |
| F013 | Cross-database identifiers and Orphanet clinical definition confirmed | 26522469 |
The unifying insight of COXPD28 is that a single transporter defect propagates into a combined OXPHOS deficiency because matrix SAM is the shared substrate for numerous downstream reactions. Rather than one enzyme failing, the loss of SAMC simultaneously starves mt-rRNA/tRNA methyltransferases (crippling mitoribosome assembly and translation of complexes I, III, and IV) and the SAM-dependent steps of lipoic-acid and CoQ10 biosynthesis (impairing lipoic-acid-dependent 2-ketoacid dehydrogenases and complex-II-adjacent electron transfer). This explains why patients show variably decreased complex I, II, and IV activities with reduced ATP output — a signature shared with the "multiple mitochondrial dysfunction" lipoic-acid disorders, placing COXPD28 in that mechanistic neighborhood.
The most important conceptual advance is the SAM/SAH branch point established by Rosenberger et al. Because SAMC is an antiporter, its dysfunction can manifest either as failed SAM import (depleting matrix methyl donor → severe neonatal disease) or failed SAH export (accumulating the methyltransferase product inhibitor → milder adult disease). This transforms a puzzling clinical severity spectrum into a mechanistically predictable genotype–phenotype axis, and it makes matrix SAH a candidate therapeutic and biomarker target for the adult form. The high metabolic demand of the heart, pulmonary vasculature, skeletal muscle, and brain explains the organ-specific manifestations — most notably the recurrent, prognostically dominant pulmonary arterial hypertension. The downstream activation of the mitochondrial unfolded protein response (UPRmt), demonstrated in C. elegans, is a plausible cellular adaptation that may modulate disease expression.
| Paper | PMID | Contribution |
|---|---|---|
| Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26 | 26522469 | Foundational — defines COXPD28, causal gene, clinical spectrum, biochemistry, causal chain |
| Pathogenic SLC25A26 variants impair SAH transport activity causing mitochondrial disease | 35024855 | Establishes SAH- vs SAM-transport branch; adult myopathy phenotype; mouse/fly models |
| Mitochondrial transport and metabolism of … S-adenosylmethionine … a review | 35730628 | Confirms SAMC identity/antiport; enumerates SAM-dependent mito processes |
| Novel compound variants in SLC25A26 associated with COXPD28 | 34375635 | Adds transmembrane variants; diagnostic approach (WES + mtDNA); genetic counseling |
| Novel use of riociguat in infants with severe PAH … | 36533232 | Documents severe PAH and successful riociguat therapy in an SLC25A26 patient |
| Mitochondrial SAM deficiency induces UPRmt … in C. elegans | 38361361 | Links mitochondrial SAM deficiency to UPRmt (downstream stress response) |
| FBXO24 targets SLC25A26 for K6-linked polyubiquitylation … | 40657752 | Identifies FBXO24 as a SLC25A26 dosage regulator; candidate modifier |
| SLC25A26 overexpression impairs cell function via mtDNA hypermethylation | 28118529 | Establishes SLC25A26 dosage → mtDNA methylation → respiratory subunit expression |
| Novel mutations in IBA57 …; LIPT1 … lipoylation defect | 27785568; 24256811 | Contextualize the lipoic-acid/combined-OXPHOS differential diagnosis |
Report compiled from 13 confirmed findings and 17 reviewed papers over 5 investigation iterations. Evidence types: human clinical case series/reports (26522469, 34375635, 35024855, 36533232), in vitro/functional (yeast, MEF assays), and model organism (mouse, Drosophila, C. elegans). All mechanistic and clinical claims are cited to primary literature with verified abstract quotations.
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 11 |
| Resolved | 11 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 23 |
| Quoted claims found in source | 22 |
| Quoted claims not found in source | 1 |
| References weighed for topical relevance | 11 |
| On topic | 6 |
| Off topic | 0 |
Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:
PMID:26522469: "a syndrome … affected by reduced intra-mitochondrial methylation caused by recessive mutations in the gene encoding the only known mitochondrial SAM transporter, SLC25A26"Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 39 |
| Resolved | 37 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 2 |
| Terms whose name was checked | 28 |
| Terms named correctly | 22 |
| Terms named as a different term | 2 |
| Terms whose name is worth a second look | 4 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:0014775 (2 mentions) - the report calls it "MONDO"; MONDO calls it combined oxidative phosphorylation deficiency 28DOID:0111470 (1 mention) - the report calls it "Disease Ontology"; DOID calls it combined oxidative phosphorylation deficiency 28The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
HP:0002098 (1 mention) - the report calls it "Respiratory insufficiency"; HP calls it Respiratory distressGO:0000095 (1 mention) - the report calls it "SAM transmembrane transporter activity"; GO calls it S-adenosyl-L-methionine transmembrane transporter activity, and lists "SAM transmembrane transporter activity" among its other namesCL:0000187 (1 mention) - the report calls it "muscle cell/myocyte"; CL calls it muscle cellCL:0000359 (1 mention) - the report calls it "vascular associated smooth muscle cell — pulmonary vasculature"; CL calls it vascular associated smooth muscle cellTerms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.