Cardiomyopathy-Hypotonia-Lactic Acidosis Syndrome
Cardiomyopathy-hypotonia-lactic acidosis syndrome (mitochondrial phosphate carrier deficiency, SLC25A3 deficiency) is a rare autosomal recessive mitochondrial disorder. SLC25A3 encodes the inner-membrane carrier for inorganic phosphate and copper. Phosphate import supports mitochondrial ATP synthesis; copper transport supports respiratory-complex assembly and mitochondrial organization in experimental systems. Variants affecting alternatively spliced exon 3A preferentially disrupt the isoform enriched in heart and skeletal muscle, whereas variants in shared coding regions can also affect fibroblasts. Reported presentations include neonatal hypertrophic cardiomyopathy, hypotonia and lactic acidosis, but cardiomyopathy without lactic acidosis or clinical skeletal myopathy also occurs. Outcomes range from infantile death to survival after heart transplantation or into adulthood with residual myopathy. The relative contributions of phosphate transport, copper handling and mitochondrial dynamics to patient disease remain incompletely resolved.
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Classifications
Harrison's Part
Mechanistic Nosology
ICIMD (Inherited Metabolic Disorders)
Inheritance
1
Autosomal recessive
HP:0000007
Affected individuals have reported homozygous or compound heterozygous SLC25A3 variants. Segregation in the original family and parental phasing of the shared-exon variants support recessive inheritance; functional consequences must still be assessed separately for each allele.
Show evidence (2 references)
"Mitochondrial phosphate carrier (PiC) deficiency, caused by pathogenic variants in the SLC25A3 gene, is a rare autosomal recessive disorder primarily presenting with early-onset hypertrophic cardiomyopathy (HCMP), muscular hypotonia, and respiratory failure."
States explicitly that SLC25A3-related PiC deficiency is autosomal recessive.
"We identified a homozygous mutation--c.215G-->A (p.Gly72Glu)--in the alternatively spliced exon 3A of this enzyme in two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life."
Homozygosity in two affected siblings of unaffected parents is consistent with autosomal recessive inheritance.
Discussions and Knowledge Gaps
2How much do copper transport, phosphate supply and mitochondrial organization each contribute to human SLC25A3 disease across alleles and tissues?
Attached to
Direct transport and copper-selective rescue establish a copper-dependent carrier function in models, and human G72E has been tested in engineered fibroblasts. Patient studies, however, use different tissues and assays: some report normal respiratory-chain activity, while the founding paper gives COX 81 U/g against a 90–281 reference range in one sibling, later highlighted by Boulet et al. as a possible mild deficiency. Increased COX histochemical staining in another patient is not the same measurement. These observations limit a uniform clinical COX-deficiency claim without refuting carrier copper transport. Residual isoforms, allele, developmental timing and assay conditions require matched investigation.
Proposed experiments
Isoform-resolved copper transport and COX metalation assay
exp_slc25a3_isoform_copper_cox
Compare isogenic human cardiomyocytes carrying G72E, the recurrent splice variant, shared-exon variants and corrected controls. Measure isoform abundance, phosphate flux, matrix copper, COX assembly and activity under matched conditions. Copper-selective rescue would help separate substrate effects; translation to clinical tissues requires direct validation.
Model systems
Human iPSC-derived cardiomyocyte
Human isogenic cardiomyocytes with patient alleles and corrected controls to extend existing engineered mouse-cell evidence.
Show evidence (3 references)
"In SLC25A3, the L175A mutation separates Cu and phosphate transport by fully restoring COX activity and mitochondrial Cu levels without rescuing phosphate transport."
Engineered separation-of-function construct establishes the copper-dependent COX effect in cells.
"the data presented suggest that loss of SLC25A3 in muscle results in a mild, isolated COX deficiency"
Boulet et al. reinterpret a quantitative value from the founding clinical report; this is not a new patient assay.
"In a muscle biopsy normal activity of respiratory chain enzymes was found; however the amount of the mitochondrial phosphate carrier was decreased."
Normal enzyme activity in this muscle biopsy illustrates assay/tissue heterogeneity; it does not refute the molecular transport function.
What determines whether an individual with biallelic SLC25A3 variants dies in the first year of life or survives into adulthood with non-progressive hypertrophic cardiomyopathy?
Published outcomes include infantile death, stable childhood or adult survival, and survival after transplantation. The recurrent splice allele itself occurs with both early death and longer survival. Residual transcript/protein, isoform compensation, modifiers and supportive treatment are plausible contributors but are not resolved by these small reports; a genotype alone should not be treated as prognostic.
Show evidence (1 reference)
"This case supports the expansion of the clinical spectrum of mitochondrial PiC deficiency by presenting a patient with a later-onset phenotype compared to previously reported cases."
Documents that the phenotypic spectrum is still expanding and is not yet explained.
Pathophysiology
17SLC25A3 Exon 3A G72E Variant
Homozygous c.215G>A in the muscle-enriched exon 3A changes Gly72 to glutamate in isoform A (NM_005888 in the original report). Normal mutually exclusive exon selection determines the affected tissue context; splicing itself is not the initiating lesion.
Homozygous exon-3A G72E allele
Downstream
G72E fails yeast respiratory complementation.
Show evidence (3 references)
"We identified a homozygous mutation--c.215G-->A (p.Gly72Glu)--in the alternatively spliced exon 3A of this enzyme in two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life."
Reports the homozygous exon 3A missense allele in the index family.
"The enzyme defect was confirmed by complementation analysis in yeast."
Yeast complementation provides functional confirmation of pathogenicity.
"Finally, atomic absorption spectrometry of isolated mitochondria showed that Slc25a3 (G72E) could not replenish mitochondrial copper levels in Drp1Slc25a3-KO MEFs (Fig. 7L)."
Patient-allele functional test in engineered mouse embryonic fibroblasts, not patient muscle.
SLC25A3 Exon 3A Splice-Acceptor Variant
The homozygous intronic c.158-9A>G variant creates an alternative splice acceptor immediately before exon 3A. This is an isoform-specific RNA-processing lesion, distinct from the coding G72E allele.
Homozygous c.158-9A>G in isoform-A nomenclature
Downstream
The new acceptor alters exon-3A splicing.
Show evidence (1 reference)
"We identified a homozygous mutation c.158-9A>G located in the 5'-intron next to exon 3A specific for heart and skeletal muscle. This creates a novel splice site resulting in a more than 95% decrease of the wild type allele."
Reports the variant and quantifies its effect on wild-type exon 3A transcript levels.
Aberrant Exon 3A Splicing
The recurrent acceptor variant produces abnormal exon-3A RNA with intronic sequence inclusion and a marked reduction of normal transcript. The resulting frameshift/early termination is predicted; muscle immunodetection independently shows reduced carrier protein.
Downstream
Loss of normal exon-3A transcript is associated with reduced carrier protein; translation and turnover were not resolved separately.
Show evidence (2 references)
"We identified a homozygous mutation c.158-9A>G located in the 5'-intron next to exon 3A specific for heart and skeletal muscle. This creates a novel splice site resulting in a more than 95% decrease of the wild type allele."
Reports the variant and quantifies its effect on wild-type exon 3A transcript levels.
"This variant creates a novel splice site in intron 2 that leads to the inclusion of eight nucleotides on the 5′ side of exon 3A, predicted to result in a frame shift and early termination in the first quarter of the protein"
Separates the reported RNA alteration from the predicted downstream protein truncation.
Reduced Carrier Protein Abundance
Reduced SLC25A3 protein was observed in muscle from the splice-variant family and in fibroblasts carrying the shared-exon compound genotype. Normal RNA in the latter supports a post-transcriptional effect without establishing a particular degradation pathway.
Experimental models
Patient-derived shared-exon variant fibroblasts
Reduced carrier abundance despite unchanged RNA.
Downstream
Reduced abundance lowers available carrier capacity.
Show evidence (3 references)
"In a muscle biopsy normal activity of respiratory chain enzymes was found; however the amount of the mitochondrial phosphate carrier was decreased."
Shows reduced carrier protein with normal respiratory-chain enzyme activities in this patient muscle biopsy; this assay does not exclude every additional mitochondrial effect.
"PiC mRNA was unaffected by the mutations."
RNA abundance was unchanged in the compound-genotype fibroblasts.
"PiC protein abundance was substantially lower, and the cells were not phenotypically normal"
Patient-derived fibroblast protein and cellular phenotype.
Reduced Mitochondrial Phosphate Carrier Function
Disease-associated variants reduce carrier abundance and/or transport function. The affected substrates and tissue distribution depend on the allele, isoform, residual expression and assay. Phosphate and copper transport are separable carrier functions; loss of either should not be inferred solely from a generic mutation label.
Downstream
Loss of phosphate-carrier capacity reduces mitochondrial phosphate uptake.
Carrier depletion or human G72E expression reduces mitochondrial copper in cell models.
Patient fibroblast and HeLa experiments show reduced fusion without an established intervening pathway.
Carrier-deficient engineered cardiomyocytes show calcium dysregulation through incompletely defined metabolic intermediates.
Show evidence (3 references)
"We identified a homozygous mutation--c.215G-->A (p.Gly72Glu)--in the alternatively spliced exon 3A of this enzyme in two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life."
Identifies the causative exon 3A missense allele in the index family, establishing SLC25A3 loss of function as the primary lesion.
"In a muscle biopsy normal activity of respiratory chain enzymes was found; however the amount of the mitochondrial phosphate carrier was decreased."
Shows reduced carrier protein with normal respiratory-chain enzyme activities in this patient muscle biopsy; this assay does not exclude every additional mitochondrial effect.
"The enzyme defect was confirmed by complementation analysis in yeast."
Yeast complementation independently confirms that the patient allele is a loss-of-function carrier defect.
Reduced Mitochondrial Phosphate Import
Carrier deficiency reduces inorganic-phosphate import into mitochondria. Cardiac knockout mitochondria show reduced phosphate uptake; siRNA-treated HeLa cells show reduced mitochondrial phosphate levels that recover with TAT-mPiC. These model measurements do not establish uniform matrix phosphate depletion across all patient tissues.
Experimental models
Carrier-depleted HeLa cells with TAT-mPiC rescue
Mitochondrial phosphate content responds to depletion and replacement.
Animal models
Inducible cardiomyocyte-specific Slc25a3 deletion
Reduced phosphate uptake in isolated cardiac mitochondria.
Downstream
Insufficient phosphate delivery can limit ATP synthesis; substantial reserve capacity remains in some partially depleted cells.
Show evidence (2 references)
"Together, these results indicate that acute Slc25a3 deletion causes impaired mitochondrial Pi uptake that leads to reduced mitochondrial ATP synthesis."
Isolated cardiac mitochondria after inducible cardiomyocyte deletion.
"Mitochondrial inorganic phosphate levels were significantly decreased to 0.83 ± 0.09-fold upon mPiC knockdown."
Mitochondrial lysate measurement in siRNA-treated HeLa cells.
Reduced Mitochondrial ATP Synthesis
Reduced phosphate supply can constrain ATP synthase despite preserved respiratory-chain enzyme activities. This was demonstrated in muscle from the G72E family, whereas their fibroblasts retained ATP-synthesis capacity. In shared-exon patient fibroblasts, intact-cell respiration was impaired but maximal phosphorylating respiration after permeabilization was preserved, showing that substrate availability and depletion severity modify the defect.
Downstream
Reduced mitochondrial ATP-generating capacity imposes energetic stress even where bulk tissue ATP is maintained.
The cardiac knockout model increases glycolytic machinery as a compensatory response.
Show evidence (3 references)
"Functional investigation of intact mitochondria showed a deficiency of ATP synthesis in muscle but not in fibroblasts, which correlated with the tissue-specific expression of exon 3A in muscle versus exon 3B in fibroblasts."
Directly demonstrates a tissue-restricted ATP-synthesis defect in patient muscle mitochondria and links it to exon 3A expression.
"Variants in the SLC25A3 gene, which codes for the mitochondrial phosphate transporter (PiC), lead to a failure of inorganic phosphate (Pi) transport across the mitochondrial membrane, which is required in the final step of oxidative phosphorylation."
States that the transport failure specifically impairs the final (ATP synthase) step of oxidative phosphorylation.
"There were no differences between Ctrl and PiC mutant cells for either of the substrates or any of the conditions."
Maximal phosphorylating respiration was preserved in permeabilized shared-exon patient fibroblasts. This is counterevidence to reduced ATP-synthesis capacity in that assay and tissue context; it does not negate the positive muscle findings.
Cardiomyocyte and Skeletal Muscle Bioenergetic Stress
Reduced mitochondrial ATP-generating capacity stresses contractile cells. Whole-heart ATP content was nevertheless preserved in the conditional mouse knockout, so a uniformly depleted total ATP pool is not asserted. Engineered human iPSC-derived cardiomyocytes show impaired energy metabolism and diastolic dysfunction.
Downstream
Energetic stress is associated with hypertrophic remodeling; intervening growth signaling remains incompletely defined.
Skeletal-muscle dysfunction contributes to reduced tone.
Limited muscular bioenergetic reserve contributes to exertional symptoms.
Myopathy contributes to proximal weakness.
Mitochondrial dysfunction underlies the reported myopathy.
Muscle injury can increase circulating creatine kinase activity.
Show evidence (1 reference)
"These SLC25A3-KO or missense mutation hiPSC-CMs recapitulated the disease phenotype associated with myocardial hypertrophy, including diastolic dysfunction, Ca2+ homeostasis imbalance, and mitochondrial energy metabolism dysfunction."
CRISPR-engineered hiPSC-derived cardiomyocytes, not patient-derived lines, demonstrate metabolic and contractile dysfunction.
Compensatory Glycolytic Shift
Cardiac Slc25a3 deletion increases glucose-transporter and glycolytic-enzyme expression, supporting compensatory glycolytic ATP production. Glycolysis and lactate generation need not imply absence of oxygen. The degree of this response varies across models.
Downstream
Increased glycolytic flux and altered pyruvate handling can increase lactate output.
Show evidence (1 reference)
"These results suggest that glucose utilization through glycolysis is enhanced while mitochondrial metabolic flux is reduced as a direct mechanism of compensation for the reduction in mitochondrial ATP production."
Authors interpret the glucose-transporter and glycolytic-enzyme expression response in knockout hearts.
Increased Lactate Production
Carrier knockdown increases extracellular lactate in HeLa cells, and carrier replacement reduces it. Patient lactate elevation can persist despite clinical improvement but is absent in some affected individuals; elevated lactate does not invariably entail acidosis.
Downstream
Lactate-associated acid accumulation can exceed buffering and clearance; acid-base status must be assessed separately.
Increased lactate production can contribute to blood lactate elevation.
Show evidence (1 reference)
"lactate levels in si-mPiC-treated cells were significantly higher than in control untreated cells"
Cell-culture lactate response to carrier depletion.
Cardiomyocyte Hypertrophic Remodeling
Patients show hypertrophic cardiomyopathy with variable progression. Long-term cardiac Slc25a3 deletion in mice produces hypertrophy, dilation and reduced ventricular function, while engineered human cardiomyocytes reproduce cellular hypertrophy. The links from mitochondrial stress to growth signaling are not fully resolved.
Experimental models
Engineered SLC25A3 hiPSC-derived cardiomyocytes
Cellular hypertrophy is reproduced.
Animal models
Inducible cardiomyocyte-specific Slc25a3 deletion
Hypertrophy and ventricular dysfunction after sustained deletion.
Downstream
Myocardial hypertrophy manifests clinically as hypertrophic cardiomyopathy.
Severe remodeling can impair cardiac output.
Show evidence (2 references)
"deletion of the Slc25a3 gene from the heart long-term resulted in profound hypertrophy with ventricular dilation and depressed cardiac function, all features that reflect the cardiomyopathy observed in humans with mutations in SLC25A3"
Cardiac-specific Slc25a3 deletion in mice is sufficient to produce hypertrophy, ventricular remodeling, and contractile dysfunction, matching the human cardiomyopathy.
"mice lacking Slc25a3 in the heart serve as a novel model of metabolic, mitochondrial-driven cardiomyopathy"
Establishes the cardiac Slc25a3-null mouse as a metabolic, mitochondrially driven cardiomyopathy model for this disorder.
Reduced Mitochondrial Copper Delivery
SLC25A3 transports copper in reconstituted systems and supports the mitochondrial copper pool in cells. Depletion, deletion and human G72E expression can reduce mitochondrial copper. This carrier function is experimentally established, while the magnitude and clinical importance of copper deficiency in patient heart and muscle remain unresolved.
Experimental models
Carrier-depleted HeLa cells with TAT-mPiC rescue
Mitochondrial copper content responds to depletion and replacement.
Human G72E rescue assays in mouse fibroblasts
Mitochondrial copper measured in double-null cells expressing human G72E.
Slc25a3-depleted differentiated myotubes (preprint)
Copper-selective rescue tests the substrate requirement for myotube survival.
Downstream
Reduced copper availability impairs COX assembly/activity in carrier-deficient cells; copper-selective rescue separates this from phosphate transport.
Copper-selective carrier rescue restores cristae in engineered mouse fibroblasts; patient-tissue causality remains unproven.
Show evidence (2 references)
"Additionally, assays in Lactococcus lactis and in reconstituted liposomes directly demonstrated that SLC25A3 functions as a copper transporter."
Reconstituted-system assays demonstrate copper transport by SLC25A3 directly.
"Finally, atomic absorption spectrometry of isolated mitochondria showed that Slc25a3 (G72E) could not replenish mitochondrial copper levels in Drp1Slc25a3-KO MEFs (Fig. 7L)."
Patient-allele functional test in engineered mouse embryonic fibroblasts, not patient muscle.
Impaired Cytochrome c Oxidase Biogenesis
Carrier-deficient cell models show copper-responsive COX deficiency. The engineered mouse L175A carrier restores copper and COX without restoring phosphate transport. Patient enzyme results are variable and assay-specific; the model result does not imply that every affected muscle biopsy must show reduced COX staining.
Experimental models
Copper-selective rescue in Slc25a3-null fibroblasts
Separation-of-function rescue tests the copper requirement for COX.
Downstream
Reduced COX function could contribute to respiratory stress where this model-derived arm is engaged in vivo.
Show evidence (2 references)
"SLC25A3 knockdown or deletion consistently resulted in an isolated COX deficiency in these cells, and copper addition to the culture medium suppressed these biochemical defects."
Shows that loss of SLC25A3 in cultured cells produces a copper-remediable isolated cytochrome c oxidase deficiency.
"In SLC25A3, the L175A mutation separates Cu and phosphate transport by fully restoring COX activity and mitochondrial Cu levels without rescuing phosphate transport."
Engineered separation-of-function construct establishes the copper-dependent COX effect in cells.
Reduced Mitochondrial Fusion
Shared-exon patient fibroblasts and partially depleted HeLa cells have reduced mitochondrial fusion and network connectivity. This occurred without a shift in OPA1 forms, so it is not identified with the OPA1-processing response seen under Drp1-deficient stress in a separate model.
Experimental models
Patient-derived shared-exon variant fibroblasts
Live-cell measurements show reduced network connectivity and fusion.
Downstream
Reduced fusion may impair mitochondrial quality control; its contribution to patient symptoms is not quantified.
Show evidence (1 reference)
"Both mutant fibroblasts and HeLa cells with 60% PiC loss showed a less interconnected mitochondrial network and a mitochondrial fusion defect"
Reduced fusion in patient-derived fibroblasts and engineered HeLa cells.
Disordered Mitochondrial Cristae
Disrupted mitochondrial cristae are observed in Slc25a3-null mouse fibroblasts and conditional knockout hearts. Human G72E fails to restore cristae in null fibroblasts, whereas the copper-transporting L175A construct rescues them.
Experimental models
Human G72E rescue assays in mouse fibroblasts
Cristae and respiration measured in Slc25a3-null cells.
Downstream
Cristae disorganization may impair mitochondrial function; the causal relationship to ATP shortage is not fully separated.
Show evidence (2 references)
"In addition, we found that the G72E mutant failed to restore cristae morphology and mitochondrial respiration in Slc25a3-KO MEFs (Fig. 6D–G)."
Patient variant tested in an engineered null fibroblast background.
"examination of hearts from Slc25a3fl/fl-MCM mice by electron microscopy showed extensive sarcomeric disarray with fragmented and disrupted mitochondria, as well as mitochondrial hyperproliferation"
Cardiac knockout ultrastructure.
Cardiomyocyte Calcium Homeostasis Imbalance
CRISPR-engineered SLC25A3 knockout and missense hiPSC-derived cardiomyocytes show calcium-homeostasis imbalance with diastolic dysfunction. A contribution from accumulated glycolytic byproducts was proposed, rather than established as a universal direct mechanism.
Experimental models
Engineered SLC25A3 hiPSC-derived cardiomyocytes
Calcium homeostasis and diastolic dysfunction are measured.
Downstream
Calcium dysregulation accompanies hypertrophic dysfunction in the engineered cardiomyocyte model; its causal contribution remains provisional.
Show evidence (2 references)
"These SLC25A3-KO or missense mutation hiPSC-CMs recapitulated the disease phenotype associated with myocardial hypertrophy, including diastolic dysfunction, Ca2+ homeostasis imbalance, and mitochondrial energy metabolism dysfunction."
Engineered hiPSC-derived cardiomyocyte phenotype, not patient-derived tissue.
"Further studies suggested the potential link between the accumulation of glycolytic byproducts and Ca2+ homeostasis imbalance in SLC25A3-KO hiPSC-CMs."
Authors propose a link to glycolytic byproducts; the abstract does not establish the causal intermediate.
Histopathology
5
Type 1 fibre predominance on skeletal muscle biopsy
Skeletal muscle biopsy in a long-surviving SLC25A3 patient showed normal myofibre size with a predominance of type 1 (oxidative, slow-twitch) fibres.
Show evidence (1 reference)
"Muscle biopsy revealed normal muscle fiber size with a predominance of type 1 fibers."
Direct human histopathologic observation of fibre-type composition in SLC25A3 deficiency.
Mildly increased COX and SDH histochemical activity
A long-term survivor had mildly increased COX and SDH histochemical activity, interpreted as mitochondrial myopathy. Histochemical staining is not equivalent to a quantitative respiratory-chain enzyme assay and cannot by itself exclude copper-dependent effects in other tissues or genotypes.
Show evidence (1 reference)
"The histopathology showed a mild increase in cytochrome c oxidase (COX) and succinate dehydrogenase (SDH) activity, suggesting mitochondrial myopathy."
The adult biopsy finding is retained with its assay and single-patient context.
Lipid accumulation in skeletal muscle
The first index infant had lipid accumulation in both fiber types, prominent in type I fibers, without ragged red fibers.
Show evidence (1 reference)
"Histological examination showed lipid myopathy with lipid accumulation in both fiber types, prominent in type I fibers."
Full-text histology absent from the earlier abstract-only curation.
Abnormal mitochondrial ultrastructure
Electron microscopy showed atypical enlarged mitochondria and lipid droplets in an index sibling, while the compound-genotype patient had slight mitochondrial enlargement and abnormal cristae despite no clinical skeletal myopathy.
Show evidence (2 references)
"Electron microscopy revealed atypical and enlarged mitochondria, as well as an increased amount of lipid droplets"
Index sibling ultrastructure.
"electron microscopy demonstrated minimal enlargement in size of mitochondria with slightly abnormal cristae."
Compound-genotype skeletal muscle ultrastructure.
Myocardial disarray
An endomyocardial biopsy in the compound-genotype infant showed nonspecific cardiomyopathy with muscle disarray and no glycogen accumulation.
Show evidence (1 reference)
"Cardiac catheterization and endomyocardial muscle biopsy at three weeks of life revealed nonspecific findings of cardiomyopathy with muscle disarray; there was no evidence of glycogen accumulation."
Direct cardiac biopsy observation.
Pathograph
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Phenotypes
14Cardiovascular 2
Hypertrophic cardiomyopathy
HP:0001639
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
"We identified a homozygous mutation--c.215G-->A (p.Gly72Glu)--in the alternatively spliced exon 3A of this enzyme in two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life."
Hypertrophic cardiomyopathy in both siblings of the index family.
"In a family three children presented with severe neonatal lactic acidosis, hypertrophic cardiomyopathy and generalised muscular hypotonia."
Hypertrophic cardiomyopathy in all three affected children of a second family.
"At an age of 9 and 17years, respectively, they present with exercise intolerance, proximal muscle weakness, non-progressive hypertrophic cardiomyopathy and normal mental development."
Documents that the cardiomyopathy can be non-progressive in long-term survivors.
+ 1 more reference
Low-output congestive heart failure
HP:0009805
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Low-output congestive heart failure (HP:0009805). HP:0009805 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"At age 9 mo, the child died from intractable low-output hypertrophic heart failure."
Fatal low-output heart failure in an index sibling.
Integument 1
Cyanosis
HP:0000961
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Cyanosis (HP:0000961). HP:0000961 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"At age 12 h, the child presented with cyanosis and muscular hypotonia that necessitated intensive-care treatment."
Direct neonatal clinical observation.
Metabolism 4
Lactic acidosis
HP:0003128
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Lactic acidosis (HP:0003128). HP:0003128 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"We identified a homozygous mutation--c.215G-->A (p.Gly72Glu)--in the alternatively spliced exon 3A of this enzyme in two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life."
Lactic acidosis in both siblings of the index family.
"In a family three children presented with severe neonatal lactic acidosis, hypertrophic cardiomyopathy and generalised muscular hypotonia."
Severe neonatal lactic acidosis in all three affected children of a second family.
Elevated circulating creatine kinase activity
HP:0003236
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Elevated circulating creatine kinase activity (HP:0003236). HP:0003236 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"Here, described a patient with suspicion of infantile Pompe disease due to involvement of heart and muscle and high-level of plasma creatinine kinase but finally diagnosed mitochondrial phosphate-carrier deficiency."
Documents high plasma creatine kinase in a molecularly confirmed patient, and the resulting diagnostic confusion with infantile Pompe disease.
Increased circulating lactate concentration
HP:0002151
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Increased circulating lactate concentration (HP:0002151). HP:0002151 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"At the age of 32 years, the patient remained stable with HCMP and persistently high lactate levels."
Documents persistently elevated lactate in a long-term survivor.
"one of whom did not have skeletal myopathy nor elevated lactate."
Normal lactate in one molecularly investigated infant is counterevidence to an obligatory lactate elevation.
Elevated lactate:pyruvate ratio
HP:0032653
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Elevated lactate:pyruvate ratio (HP:0032653). HP:0032653 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"an increased lactate:pyruvate ratio of 62"
Index-family measurement.
"the lactate/pyruvate ratio was elevated at 53 (reference range 10–20)."
Ratio elevation in the compound-genotype patient despite normal lactate.
Musculoskeletal 3
Hypotonia
HP:0001252
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
"We identified a homozygous mutation--c.215G-->A (p.Gly72Glu)--in the alternatively spliced exon 3A of this enzyme in two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life."
Muscular hypotonia in both siblings of the index family.
"In a family three children presented with severe neonatal lactic acidosis, hypertrophic cardiomyopathy and generalised muscular hypotonia."
Generalised muscular hypotonia in all three affected children of a second family.
"Mitochondrial phosphate carrier (PiC) deficiency, caused by pathogenic variants in the SLC25A3 gene, is a rare autosomal recessive disorder primarily presenting with early-onset hypertrophic cardiomyopathy (HCMP), muscular hypotonia, and respiratory failure."
Lists muscular hypotonia among the primary presenting features in a 2026 literature review.
Proximal muscle weakness
HP:0003701
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Proximal muscle weakness (HP:0003701). HP:0003701 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"At an age of 9 and 17years, respectively, they present with exercise intolerance, proximal muscle weakness, non-progressive hypertrophic cardiomyopathy and normal mental development."
Proximal muscle weakness in the two long-surviving siblings.
Mitochondrial myopathy
HP:0003737
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Mitochondrial myopathy (HP:0003737). HP:0003737 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"The histopathology showed a mild increase in cytochrome c oxidase (COX) and succinate dehydrogenase (SDH) activity, suggesting mitochondrial myopathy."
Muscle histopathology in a molecularly confirmed patient was interpreted as mitochondrial myopathy.
"The literature described two affected sibships with variants in SLC25A3; all cases had skeletal myopathy and cardiomyopathy (OMIM 610773)."
Skeletal myopathy was present in every previously reported case.
Nervous System 1
Thin corpus callosum
HP:0033725
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Thin corpus callosum (HP:0033725). HP:0033725 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"MRI of the brain at 4 months of life showed prominence of the sulci, extra-axial spaces, and ventricles as well as thinning of the corpus callosum."
Single-case MRI observation, with uncertain etiologic specificity.
Respiratory 1
Respiratory failure
HP:0002878
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Respiratory failure (HP:0002878). HP:0002878 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"During her life, the child presented with severe muscular hypotonia and recurrent episodes of respiratory insufficiency that necessitated artificial ventilation."
Repeated ventilatory support in an index-family sibling.
Constitutional 1
Exercise intolerance
HP:0003546
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Exercise intolerance (HP:0003546). HP:0003546 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"At an age of 9 and 17years, respectively, they present with exercise intolerance, proximal muscle weakness, non-progressive hypertrophic cardiomyopathy and normal mental development."
Exercise intolerance in the two long-surviving siblings.
"The patient's neuromotor development was initially normal, but from 1.5 years of age, she exhibited fatigue and muscle weakness, particularly after walking."
Exertional fatigue beginning at 1.5 years in the patient later reported as an adult survivor.
Growth 1
Failure to thrive
HP:0001508
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"Severe muscular hypotonia and failure to thrive persisted. She had a poor weight gain despite high caloric intake."
Clinical growth failure in the first reported infant.
Genetic Associations
1
SLC25A3 biallelic pathogenic variants
Show evidence (3 references)
"We identified a homozygous mutation--c.215G-->A (p.Gly72Glu)--in the alternatively spliced exon 3A of this enzyme in two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life."
Reports the homozygous exon 3A missense allele in the index family.
"We identified a homozygous mutation c.158-9A>G located in the 5'-intron next to exon 3A specific for heart and skeletal muscle. This creates a novel splice site resulting in a more than 95% decrease of the wild type allele."
Reports the variant and quantifies its effect on wild-type exon 3A transcript levels.
"Patient 2 was found to be a compound heterozygote for two novel variants, c.599T>G (p.Leu200Trp) and c. 886_898delGGTAGCAGTGCTTinsCAGATAC (p.Gly296_Ser300delinsGlnIlePro)."
Reports the compound heterozygous genotype.
Variants (3)
SLC25A3 NM_005888:c.215G>A (p.Gly72Glu), exon 3A
Pathogenic
Homozygous missense allele affecting exon 3A of isoform A in the founding sisters; the original paper specifies NM_005888 without a version. The cDNA and protein numbering is isoform-dependent and should not be transferred to the exon-3B transcript. Yeast complementation demonstrates loss of carrier function; engineered mouse fibroblasts expressing human G72E also fail to restore mitochondrial copper and selected structural readouts.
Show evidence (3 references)
"We identified a homozygous mutation--c.215G-->A (p.Gly72Glu)--in the alternatively spliced exon 3A of this enzyme in two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life."
Reports the homozygous exon 3A missense allele in the index family.
"The enzyme defect was confirmed by complementation analysis in yeast."
Yeast complementation provides functional confirmation of pathogenicity.
"Finally, atomic absorption spectrometry of isolated mitochondria showed that Slc25a3 (G72E) could not replenish mitochondrial copper levels in Drp1Slc25a3-KO MEFs (Fig. 7L)."
Patient-allele functional test in engineered mouse embryonic fibroblasts, not patient muscle.
SLC25A3 c.158-9A>G (IVS2-9A>G), exon 3A splice acceptor region
Pathogenic
Recurrent homozygous intronic variant next to exon 3A, reported as c.158-9A>G in the isoform-A nomenclature. It creates an alternative acceptor with abnormal exon-3A RNA and markedly reduces normal transcript. Reported carriers of this homozygous allele include an infant who died and long-term survivors; the allele alone is not a reliable predictor of a mild course.
Functional effects
The novel acceptor introduces eight intronic nucleotides before exon 3A; the resulting reading-frame change and early termination are predicted in the 2015 report, which cites the original splice study.
Show evidence (4 references)
"We identified a homozygous mutation c.158-9A>G located in the 5'-intron next to exon 3A specific for heart and skeletal muscle. This creates a novel splice site resulting in a more than 95% decrease of the wild type allele."
Reports the variant and quantifies its effect on wild-type exon 3A transcript levels.
"Patient 1 had a homozygous splice site variant, c.158-9A>G, which has been previously reported in a Turkish family."
Documents recurrence of the allele in an unrelated patient.
"Genetic analysis identified a homozygous splicing variant in the SLC25A3 gene"
The adult report documents a homozygous splicing variant; the retrieved abstract does not itself give cDNA coordinates.
+ 1 more reference
SLC25A3 c.599T>G (p.Leu200Trp) and c.886_898delinsCAGATAC (p.Gly296_Ser300delinsGlnIlePro)
Compound heterozygous shared-exon variants reported in a patient with prenatal cardiomyopathy, normal lactate and no clinical skeletal myopathy. Initial structural modeling predicted both deleterious. Later yeast assays distinguished a loss-of-function GSSAS-to-QIP delins from L200W, which supported respiratory growth in that assay. Patient fibroblasts nevertheless had reduced carrier protein, altered growth and mitochondrial dynamics. These results do not independently prove L200W pathogenicity or establish that it is benign in every human context.
Show evidence (4 references)
"Patient 2 was found to be a compound heterozygote for two novel variants, c.599T>G (p.Leu200Trp) and c. 886_898delGGTAGCAGTGCTTinsCAGATAC (p.Gly296_Ser300delinsGlnIlePro)."
Reports the compound heterozygous genotype.
"Protein structure analysis indicated that both variants are likely to be pathogenic."
Original computational prediction, subsequently qualified by the allele-specific yeast assays.
"whereas the L200W variant is functionally neutral."
The yeast result is counterevidence to the original prediction that L200W is deleterious. It does not refute loss of function of the delins allele or establish clinical benignity in every human context.
+ 1 more reference
Medical Actions
7
Supportive and Heart-Failure Directed Care
Published management includes ventilation, diuretics, beta blockers and inotropes for respiratory or cardiac decompensation, and supportive metabolic care. These are case-based supportive measures; no disease-modifying efficacy is inferred from survival alone.
Show evidence (2 references)
"Medical treatment during the initial evaluation included courses of diuretics, beta blockers, and inotropes."
Reported heart-failure treatment in one infant.
"Artificial ventilation was necessary for a period of 3 mo."
Respiratory support in an index sibling.
Empirical Mitochondrial Supplements and Dietary Support
Empirical mitochondrial supplements and a fat-rich diet were associated with clinical improvement but persistent high lactate in an adult report. A separate infant received coenzyme Q, levocarnitine, riboflavin, thiamine, creatine and biotin while diagnostic testing was pending. These uncontrolled observations do not establish the efficacy of an individual supplement or diet.
Show evidence (2 references)
"The patient was treated with mitochondrial therapy, along with a fat-rich diet. Despite clinical improvement, lactate levels remained elevated."
Uncontrolled clinical improvement with persistent hyperlactatemia; no causal efficacy estimate.
"He was started on coenzyme Q, levocarnitine, riboflavin, thiamine, creatine, and biotin while his testing was pending."
The supplement regimen is reported, but a response to its individual components is not demonstrated.
Genetic Counseling
For two confirmed heterozygous parents of an autosomal recessive genotype, each pregnancy has a one-in-four Mendelian probability of inheriting both alleles. Counseling should distinguish this segregation calculation from allele-specific prognosis and the unresolved functional interpretation of some reported variants.
Show evidence (1 reference)
"The parents are heterozygous carriers."
Documented parental carrier state; the recurrence fraction is the Mendelian calculation, not an observed recurrence rate.
TAT-mPiC Protein Replacement (investigational, preclinical)
TAT-mPiC delivered recombinant isoform-A carrier into cultured cells and localized to the mitochondrial inner membrane. In siRNA-depleted HeLa cells it improved growth, oxygen consumption, ATP-related measures and mitochondrial phosphate/copper content while lowering extracellular lactate. This preclinical cell study did not test SLC25A3 patient cells or establish animal or human efficacy.
Show evidence (3 references)
"Treatment of mPiC-knockdown cells with TAT-mPiC fusion protein increased cell growth and improved bioenergetic capabilities, as measured by oxygen consumption rate (OCR), ATP production, and reduction in lactate secretion."
Demonstrates functional rescue of the bioenergetic defect in vitro.
"This study presents the first successful delivery of a mitochondrial transmembrane carrier using the TAT-fusion system, offering a potential early treatment strategy for newborns with mPiC deficiency."
The authors frame this explicitly as a potential, not established, treatment strategy.
"This study was conducted in vitro, however, in vivo testing in animal models is crucial to assess the systemic effects and potential therapeutic benefits of TAT-mPiC treatment in MPCD or other mitochondrial disorders."
Explicit study limitation.
Mitochondrial Transplantation (investigational, preclinical)
Mitochondrial transplantation was investigated in CRISPR-engineered SLC25A3 knockout or missense hiPSC-derived cardiomyocytes. The retrieved abstract frames this as an exploratory rescue strategy; it provides no clinical efficacy evidence.
Show evidence (1 reference)
"Finally, we explored the prospective therapeutic implications of mitochondrial transplantation in rescuing SLC25A3-related HCM."
The abstract documents exploration of mitochondrial transplantation, with limited intervention detail in the retrieved text.
Heart Transplantation
A compound-genotype infant with progressive cardiac failure underwent orthotopic heart transplantation at seven months. The postoperative course included respiratory and other complications; discharge home occurred at eleven months with close follow-up. This establishes feasibility in one case, not general candidacy or long-term outcome.
Show evidence (2 references)
"At 7 months of life, the patient underwent an orthotopic cardiac transplant."
Documented transplantation.
"He was able to be discharged home at 11 months of age and was doing well with close follow-up."
Early post-transplant outcome only.
Meclizine in a Cardiac Knockout Model (preprint, preclinical)
A 2025 bioRxiv preprint reports improved hypertrophy, systolic function and mitochondrial ultrastructure in cardiomyocyte-specific Slc25a3 knockout mice treated from the onset of deletion. Mitochondrial ATP production was not restored. MICOS-associated structural changes and improved NAD+/NADH balance were associated findings; their causal ordering remains unresolved. This does not establish efficacy or a dose for patients.
Show evidence (2 references)
"Chronic meclizine treatment in SLC25A3-deficient mice attenuated cardiac hypertrophy, improved systolic function, and restored mitochondrial ultrastructure."
Animal intervention result from a preprint, not a clinical treatment recommendation.
"meclizine treatment did not further increase ATP content of the Slc25a3fl/flxMCM hearts"
Benefit did not reflect increased bulk cardiac ATP.
Biochemical Markers
4
Blood lactate
(INCREASED)
Context: Elevated blood lactate is the principal biochemical marker. It is usually severe in the neonatal presentation and can persist for decades in long-term survivors despite clinical improvement on supportive metabolic therapy. It is not invariable - at least one molecularly confirmed patient with neonatal cardiomyopathy had normal lactate.
Show evidence (2 references)
"The patient was treated with mitochondrial therapy, along with a fat-rich diet. Despite clinical improvement, lactate levels remained elevated."
Documents persistent lactate elevation as a stable biochemical marker independent of clinical response.
"In a family three children presented with severe neonatal lactic acidosis, hypertrophic cardiomyopathy and generalised muscular hypotonia."
Severe neonatal lactate elevation in three affected siblings.
Plasma creatine kinase
(INCREASED)
Context: Raised plasma creatine kinase accompanies the striated-muscle involvement and is a source of diagnostic confusion with infantile-onset Pompe disease.
Show evidence (1 reference)
"Here, described a patient with suspicion of infantile Pompe disease due to involvement of heart and muscle and high-level of plasma creatinine kinase but finally diagnosed mitochondrial phosphate-carrier deficiency."
Documents raised plasma creatine kinase in a confirmed patient.
Mitochondrial ATP synthesis rate in skeletal muscle
(DECREASED)
Context: The founding G72E family had impaired muscle ATP synthesis but preserved fibroblast synthesis. A normal fibroblast assay cannot exclude muscle-selective disease; shared-exon patient fibroblasts can have other functional abnormalities.
Show evidence (1 reference)
"Functional investigation of intact mitochondria showed a deficiency of ATP synthesis in muscle but not in fibroblasts, which correlated with the tissue-specific expression of exon 3A in muscle versus exon 3B in fibroblasts."
Establishes the tissue-restricted ATP-synthesis defect as the functional biochemical signature.
Mitochondrial phosphate carrier protein in skeletal muscle
(DECREASED)
Context: Reduced carrier protein with normal respiratory-chain enzyme activity was reported in the splice-variant family. A normal routine enzyme panel therefore does not exclude carrier deficiency.
Show evidence (1 reference)
"In a muscle biopsy normal activity of respiratory chain enzymes was found; however the amount of the mitochondrial phosphate carrier was decreased."
Documents both the reduced carrier protein and the normal respiratory-chain enzyme activities in patient muscle.
Diagnosis
2
Molecular diagnosis by SLC25A3 sequencing
Molecular testing of SLC25A3 can establish a diagnosis in early-onset hypertrophic cardiomyopathy with or without lactic acidosis or skeletal myopathy. Normal respiratory-chain panels or fibroblast ATP-synthesis results do not exclude isoform-A disease; assay findings depend on genotype and tissue.
Show evidence (2 references)
"Sequencing of SLC25A3 should be considered in patients with isolated cardiomyopathy, even those without generalized skeletal myopathy or lactic acidosis."
Explicit diagnostic recommendation from the authors who expanded the phenotype.
"The characteristic clinical picture of a prominent early-onset hypertrophic cardiomyopathy and lactic acidosis may be an indication for analysis of the SLC25A3 gene."
Identifies the clinical trigger for SLC25A3 testing.
Functional assessment of intact muscle mitochondria
The founding study detected reduced ADP-stimulated respiration with preserved uncoupled respiration in fresh muscle mitochondria. Standard frozen-tissue respiratory-chain assays can miss the transport defect; this functional approach complements molecular testing.
Show evidence (2 references)
"Deficiency of the mitochondrial PiC cannot be identified by the analysis of the mitochondrial-energy metabolism in frozen tissue."
Diagnostic limitation described in the founding study.
"Functional investigation of intact mitochondria should be performed to detect disorders of ATP synthesis, including mitochondrial-PiC deficiency, and other mitochondrial transport defects."
Authors recommend intact-mitochondrial functional assessment.
Progression
3Prenatal or neonatal presentation
Hypertrophic cardiomyopathy can be detected prenatally. Neonatal hypotonia, respiratory decompensation and lactic acidosis characterize several reports, but the complete triad is not required.
Show evidence (2 references)
"In a family three children presented with severe neonatal lactic acidosis, hypertrophic cardiomyopathy and generalised muscular hypotonia."
Documents the neonatal onset of the full triad.
"Pregnancy was unremarkable except for hypertrophic cardiomyopathy noted on the second trimester ultrasound examination and confirmed by fetal echocardiogram."
Prenatal cardiac onset in patient 2.
Infantile-lethal course
Both siblings in the founding G72E family died in infancy, and one child in the recurrent splice-variant family also died. These case observations do not establish that infantile death is the usual outcome across all genotypes.
Show evidence (1 reference)
"two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life"
Both index-family siblings died within the first year of life.
Long-term survival with residual myopathy
Reported survivors include siblings with exercise intolerance, proximal weakness, stable hypertrophic cardiomyopathy and normal mental development, and an adult stable at age 32 despite persistent hyperlactatemia. These reports establish possible long-term survival, not its probability or a reliably mild splice-variant genotype.
Show evidence (2 references)
"At an age of 9 and 17years, respectively, they present with exercise intolerance, proximal muscle weakness, non-progressive hypertrophic cardiomyopathy and normal mental development."
Documents long-term survival with a stable myopathic and cardiac phenotype.
"At the age of 32 years, the patient remained stable with HCMP and persistently high lactate levels."
Documents a survivor stable at age 32; does not establish an exhaustive age maximum.
Prevalence
1Worldwide
The 2015 report summarized five previously reported patients in two sibships and added two patients. This historical series documents rarity, not a current global case count or population prevalence estimate.
Show evidence (1 reference)
"Of the five affected children in these families, three died within the first year of life from hypertrophic cardiomyopathy and lactic acidosis"
Historical published cases summarized in 2015; not a contemporary mortality rate or total census.
Differential Diagnoses
1Conditions with similar clinical presentations that must be differentiated from Cardiomyopathy-Hypotonia-Lactic Acidosis Syndrome:
Overlapping Features
Glycogen storage disease type II presents with the same combination of infantile hypertrophic cardiomyopathy, hypotonia, and raised creatine kinase, and has been the initial working diagnosis in at least one patient later shown to have mitochondrial phosphate-carrier deficiency. Acid alpha-glucosidase assay distinguishes the two.
Show evidence (2 references)
"Here, described a patient with suspicion of infantile Pompe disease due to involvement of heart and muscle and high-level of plasma creatinine kinase but finally diagnosed mitochondrial phosphate-carrier deficiency."
A published case in which infantile Pompe disease was the initial clinical suspicion.
"no evidence of Pompe disease with normal acid alpha-glucosidase activity levels."
Enzyme testing excluded Pompe disease in the compound-genotype infant.
Experimental Models
6
Engineered SLC25A3 hiPSC-derived cardiomyocytes
IPSC_DERIVED_MODEL
CRISPR-generated knockout and missense (reported c.C544T, c.A547G, c.C349T) models show hypertrophy, diastolic dysfunction, calcium imbalance and metabolic abnormalities; these are not patient-derived lines.
Cell source
CRISPR-engineered human induced pluripotent stem cells
Publication
Pathograph links
Cardiomyocyte Calcium Homeostasis Imbalance
Calcium homeostasis and diastolic dysfunction are measured.
Cardiomyocyte Hypertrophic Remodeling
Cellular hypertrophy is reproduced.
Show evidence (1 reference)
"These SLC25A3-KO or missense mutation hiPSC-CMs recapitulated the disease phenotype associated with myocardial hypertrophy, including diastolic dysfunction, Ca2+ homeostasis imbalance, and mitochondrial energy metabolism dysfunction."
CRISPR-engineered human cardiomyocytes reproduce selected metabolic and contractile features.
Carrier-depleted HeLa cells with TAT-mPiC rescue
CELL_LINE
siRNA against shared exons depletes both isoforms. Added TAT-mPiC improves carrier-dependent bioenergetic and transport readouts; delivery was also examined in other cell lines.
Cell source
HeLa cells
Publication
Pathograph links
Reduced Mitochondrial Phosphate Import
Mitochondrial phosphate content responds to depletion and replacement.
Reduced Mitochondrial Copper Delivery
Mitochondrial copper content responds to depletion and replacement.
Show evidence (1 reference)
"Treatment of mPiC-knockdown cells with TAT-mPiC fusion protein increased cell growth and improved bioenergetic capabilities, as measured by oxygen consumption rate (OCR), ATP production, and reduction in lactate secretion."
Demonstrates functional rescue of the bioenergetic defect in vitro.
Copper-selective rescue in Slc25a3-null fibroblasts
CELL_LINE
Engineered mouse fibroblasts expressing the L175A carrier regain mitochondrial copper and COX despite defective phosphate transport. The construct tests substrate specificity and is not a human disease allele.
Cell source
Engineered mouse embryonic fibroblasts
Publication
Pathograph links
Impaired Cytochrome c Oxidase Biogenesis
Separation-of-function rescue tests the copper requirement for COX.
Show evidence (1 reference)
"In SLC25A3, the L175A mutation separates Cu and phosphate transport by fully restoring COX activity and mitochondrial Cu levels without rescuing phosphate transport."
Engineered separation-of-function construct establishes the copper-dependent COX effect in cells.
Human G72E rescue assays in mouse fibroblasts
CELL_LINE
Slc25a3-null and Drp1/Slc25a3 double-null fibroblasts distinguish cristae/respiration defects from the flickering and OPA1-processing response to impaired fission. G72E fails selected rescue assays despite comparable expression.
Cell source
Engineered mouse embryonic fibroblasts
Publication
Pathograph links
Reduced Mitochondrial Copper Delivery
Mitochondrial copper measured in double-null cells expressing human G72E.
Disordered Mitochondrial Cristae
Cristae and respiration measured in Slc25a3-null cells.
The Drp1-deficient context links reduced copper-dependent membrane-potential flickering to OMA1-dependent OPA1 processing and mitochondrial morphology. This stress-specific pathway is distinct from the basal fusion defect without altered OPA1 processing reported in the 2016 patient fibroblasts.
Show evidence (1 reference)
"Finally, atomic absorption spectrometry of isolated mitochondria showed that Slc25a3 (G72E) could not replenish mitochondrial copper levels in Drp1Slc25a3-KO MEFs (Fig. 7L)."
Patient-allele functional test in engineered mouse embryonic fibroblasts, not patient muscle.
Slc25a3-depleted differentiated myotubes (preprint)
CELL_LINE
A June 2026 bioRxiv preprint reports reduced survival after knockdown in fully differentiated C2C12 and primary mouse myotubes. Either isoform, added copper, or a copper-selective isoform-A L176A construct rescues selected survival readouts. Differentiation and survival are distinct endpoints; patient benefit remains untested.
Cell source
C2C12 and primary mouse myotubes
Publication
Pathograph links
Reduced Mitochondrial Copper Delivery
Copper-selective rescue tests the substrate requirement for myotube survival.
Preprint; not peer reviewed at the retrieved version.
Show evidence (2 references)
"Knockdown of Slc25a3 in primary murine myotubes also led to cell death within 48 hours"
Preprint result in cultured mouse myotubes.
"survival of SLC25A3 deficient myotubes was restored by exogenous copper or expression of an SLC25A3 variant that transports copper but not phosphate."
Preprint rescue result; not evidence for clinical copper treatment.
Animal Models
1
Inducible cardiomyocyte-specific Slc25a3 deletion
Adult inducible deletion reduces mitochondrial phosphate uptake and ATP synthesis while preserving bulk cardiac ATP. Longer deletion produces hypertrophy, dilation, systolic dysfunction and disrupted ultrastructure. Acute MPTP desensitization and ischemia-reperfusion protection are distinct from the chronic cardiomyopathy.
Pathograph links
Reduced Mitochondrial Phosphate Import
Reduced phosphate uptake in isolated cardiac mitochondria.
Cardiomyocyte Hypertrophic Remodeling
Hypertrophy and ventricular dysfunction after sustained deletion.
Conditional adult total-gene deletion differs from congenital isoform-specific human alleles. PMID:40950028 tested concurrent meclizine treatment in this model; it is a preprint.
Show evidence (3 references)
"Loss of PiC protein did not prevent MPTP opening, suggesting it is not a direct pore-forming component of this complex."
Loss modulates rather than abolishes permeability transition.
"deletion of the Slc25a3 gene from the heart long-term resulted in profound hypertrophy with ventricular dilation and depressed cardiac function, all features that reflect the cardiomyopathy observed in humans with mutations in SLC25A3"
Cardiac-specific Slc25a3 deletion in mice is sufficient to produce hypertrophy, ventricular remodeling, and contractile dysfunction, matching the human cardiomyopathy.
"Notably, despite the impairment in mitochondrial ATP production, total cardiac tissue ATP levels were maintained"
Supports the model description of maintained bulk cardiac ATP despite reduced mitochondrial ATP-generating capacity; it is not supporting evidence for total ATP depletion.
Source YAML
click to showname: Cardiomyopathy-Hypotonia-Lactic Acidosis Syndrome
creation_date: "2026-07-31T00:00:00Z"
category: Mendelian
description: >-
Cardiomyopathy-hypotonia-lactic acidosis syndrome (mitochondrial phosphate carrier deficiency, SLC25A3
deficiency) is a rare autosomal recessive mitochondrial disorder. SLC25A3 encodes the inner-membrane
carrier for inorganic phosphate and copper. Phosphate import supports mitochondrial ATP synthesis; copper
transport supports respiratory-complex assembly and mitochondrial organization in experimental systems.
Variants affecting alternatively spliced exon 3A preferentially disrupt the isoform enriched in heart
and skeletal muscle, whereas variants in shared coding regions can also affect fibroblasts. Reported
presentations include neonatal hypertrophic cardiomyopathy, hypotonia and lactic acidosis, but cardiomyopathy
without lactic acidosis or clinical skeletal myopathy also occurs. Outcomes range from infantile death
to survival after heart transplantation or into adulthood with residual myopathy. The relative contributions
of phosphate transport, copper handling and mitochondrial dynamics to patient disease remain incompletely
resolved.
disease_term:
preferred_term: cardiomyopathy-hypotonia-lactic acidosis syndrome
term:
id: MONDO:0012557
label: cardiomyopathy-hypotonia-lactic acidosis syndrome
parents:
- Mitochondrial Disease
- Inborn Error of Metabolism
synonyms:
- mitochondrial phosphate carrier deficiency
- mitochondrial phosphate-carrier deficiency
- SLC25A3 deficiency
- mitochondrial phosphate transporter (PiC) deficiency
- hypertrophic cardiomyopathy with hypotonia and lactic acidosis syndrome
notes: >-
The GeneReviews baseline check found no matching chapter in the 2026-09-10 Bookshelf snapshot. Phenotype
frequency bands and a current worldwide patient count are omitted because the available reports do not
establish population frequencies or an exhaustive census. Prenatal, neonatal and later presentations
are a clinical spectrum, not separately established molecular subtypes. PMID:40505409 describes a Spanish-family
report, but neither the initial fetch nor a forced retry retrieved quotable text; its findings are not
inferred from the title. PMID:34052969 is a broader mitochondrial-ataxia cohort whose retrieved abstract
does not establish SLC25A3-specific ataxia. The meclizine study (PMID:40950028) and myotube-survival
study (PMID:42282837) are preprints; their findings are retained only as explicitly provisional model
evidence.
references:
- reference: PMID:17273968
title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
- reference: PMID:21763135
title: Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children.
- reference: PMID:24658400
title: Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy.
- reference: PMID:25681081
title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis."
- reference: PMID:27780865
title: "Natural and Induced Mitochondrial Phosphate Carrier Loss: DIFFERENTIAL DEPENDENCE OF MITOCHONDRIAL METABOLISM AND DYNAMICS AND CELL SURVIVAL ON THE EXTENT OF DEPLETION."
- reference: PMID:29237729
title: The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis.
- reference: PMID:33591272
title: Mitochondrial copper and phosphate transporter specificity was defined early in the evolution of eukaryotes.
- reference: PMID:38656665
title: Mitochondrial phosphate-carrier deficiency mimicking infantile-onset Pompe disease.
- reference: PMID:38986607
title: Slc25a3-dependent copper transport controls flickering-induced Opa1 processing for mitochondrial safeguard.
- reference: PMID:39671292
title: Mitochondrial transplantation rescues Ca(2+) homeostasis imbalance and myocardial hypertrophy in SLC25A3-related hypertrophic cardiomyopathy.
- reference: PMID:40362619
title: "Rescue of the First Mitochondrial Membrane Carrier, the mPiC, by TAT-Mediated Protein Replacement Treatment."
- reference: PMID:40944834
title: "Expanding the Clinical Spectrum of Mitochondrial Phosphate Carrier Deficiency: A Case Report With Literature Review."
- reference: PMID:40950028
title: Meclizine rescues cardiac function and mitochondrial ultrastructure by ATP- and glycolysis-independent mechanisms in a genetic model of mitochondrial energy dysfunction.
- reference: PMID:42282837
title: Copper transport to mitochondria by SLC25A3 contributes to skeletal myoblast differentiation and is required for survival of differentiated myotubes.
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4501241/?pdf=1
title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis - PMC"
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207081/
title: "Natural and Induced Mitochondrial Phosphate Carrier Loss: DIFFERENTIAL DEPENDENCE OF MITOCHONDRIAL METABOLISM AND DYNAMICS AND CELL SURVIVAL ON THE EXTENT OF DEPLETION - PMC"
classifications:
harrisons_chapter:
- classification_value: GENETICS_ENVIRONMENT_DISEASE
mechanistic_category:
- classification_value: mitochondrial disease
icimd_category:
- classification_value: mitochondrial_shuttles_and_carriers
notes: >-
SLC25A3 encodes the mitochondrial inorganic phosphate carrier, a member of
the SLC25 mitochondrial solute-carrier family, so the disorder belongs to
the ICIMD "disorders of mitochondrial shuttles and carriers" category
rather than to a respiratory-chain subunit or assembly-factor category.
inheritance:
- name: Autosomal recessive
description: >-
Affected individuals have reported homozygous or compound heterozygous SLC25A3 variants. Segregation
in the original family and parental phasing of the shared-exon variants support recessive inheritance;
functional consequences must still be assessed separately for each allele.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:40944834
reference_title: "Expanding the Clinical Spectrum of Mitochondrial Phosphate Carrier Deficiency: A Case Report With Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mitochondrial phosphate carrier (PiC) deficiency, caused by pathogenic variants in the SLC25A3 gene, is a rare autosomal recessive disorder primarily presenting with early-onset hypertrophic cardiomyopathy (HCMP), muscular hypotonia, and respiratory failure."
explanation: States explicitly that SLC25A3-related PiC deficiency is autosomal recessive.
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a homozygous mutation--c.215G-->A (p.Gly72Glu)--in the alternatively spliced exon 3A of this enzyme in two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life."
explanation: Homozygosity in two affected siblings of unaffected parents is consistent with autosomal recessive inheritance.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
The 2015 report summarized five previously reported patients in two sibships and added two patients.
This historical series documents rarity, not a current global case count or population prevalence
estimate.
evidence:
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4501241/?pdf=1
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis - PMC"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Of the five affected children in these families, three died within the first year of life from hypertrophic cardiomyopathy and lactic acidosis
explanation: >-
Historical published cases summarized in 2015; not a contemporary mortality rate or total census.
progression:
- phase: Prenatal or neonatal presentation
age_range: prenatal period to first weeks of life
notes: >-
Hypertrophic cardiomyopathy can be detected prenatally. Neonatal hypotonia, respiratory decompensation
and lactic acidosis characterize several reports, but the complete triad is not required.
evidence:
- reference: PMID:21763135
reference_title: "Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In a family three children presented with severe neonatal lactic acidosis, hypertrophic cardiomyopathy and generalised muscular hypotonia."
explanation: Documents the neonatal onset of the full triad.
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4501241/?pdf=1
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis - PMC"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Pregnancy was unremarkable except for hypertrophic cardiomyopathy noted on the second trimester ultrasound examination and confirmed by fetal echocardiogram.
explanation: >-
Prenatal cardiac onset in patient 2.
- phase: Infantile-lethal course
age_range: first year of life
notes: >-
Both siblings in the founding G72E family died in infancy, and one child in the recurrent splice-variant
family also died. These case observations do not establish that infantile death is the usual outcome
across all genotypes.
evidence:
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life"
explanation: Both index-family siblings died within the first year of life.
- phase: Long-term survival with residual myopathy
age_range: childhood to adulthood
notes: >-
Reported survivors include siblings with exercise intolerance, proximal weakness, stable hypertrophic
cardiomyopathy and normal mental development, and an adult stable at age 32 despite persistent hyperlactatemia.
These reports establish possible long-term survival, not its probability or a reliably mild splice-variant
genotype.
evidence:
- reference: PMID:21763135
reference_title: "Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At an age of 9 and 17years, respectively, they present with exercise intolerance, proximal muscle weakness, non-progressive hypertrophic cardiomyopathy and normal mental development."
explanation: Documents long-term survival with a stable myopathic and cardiac phenotype.
- reference: PMID:40944834
reference_title: "Expanding the Clinical Spectrum of Mitochondrial Phosphate Carrier Deficiency: A Case Report With Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At the age of 32 years, the patient remained stable with HCMP and persistently high lactate levels."
explanation: >-
Documents a survivor stable at age 32; does not establish an exhaustive age maximum.
pathophysiology:
- name: SLC25A3 Exon 3A G72E Variant
biological_scale: MOLECULAR
description: >-
Homozygous c.215G>A in the muscle-enriched exon 3A changes Gly72 to glutamate in isoform A (NM_005888
in the original report). Normal mutually exclusive exon selection determines the affected tissue context;
splicing itself is not the initiating lesion.
evidence:
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a homozygous mutation--c.215G-->A (p.Gly72Glu)--in the alternatively spliced exon 3A of this enzyme in two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life."
explanation: Reports the homozygous exon 3A missense allele in the index family.
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "The enzyme defect was confirmed by complementation analysis in yeast."
explanation: Yeast complementation provides functional confirmation of pathogenicity.
- reference: PMID:38986607
reference_title: Slc25a3-dependent copper transport controls flickering-induced Opa1 processing for mitochondrial safeguard.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Finally, atomic absorption spectrometry of isolated mitochondria showed that Slc25a3 (G72E) could not replenish mitochondrial copper levels in Drp1Slc25a3-KO MEFs (Fig. 7L).
explanation: >-
Patient-allele functional test in engineered mouse embryonic fibroblasts, not patient muscle.
gene:
preferred_term: SLC25A3
term:
id: hgnc:10989
label: SLC25A3
genetic_context:
gene:
preferred_term: SLC25A3
term:
id: hgnc:10989
label: SLC25A3
variant_type: single nucleotide variant
genomic_contexts:
- coding sequence
functional_impact_category: LOSS_OF_FUNCTION
description: Homozygous exon-3A G72E allele
downstream:
- target: Reduced Mitochondrial Phosphate Carrier Function
causal_link_type: DIRECT
description: >-
G72E fails yeast respiratory complementation.
- name: SLC25A3 Exon 3A Splice-Acceptor Variant
biological_scale: MOLECULAR
description: >-
The homozygous intronic c.158-9A>G variant creates an alternative splice acceptor immediately before
exon 3A. This is an isoform-specific RNA-processing lesion, distinct from the coding G72E allele.
evidence:
- reference: PMID:21763135
reference_title: "Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a homozygous mutation c.158-9A>G located in the 5'-intron next to exon 3A specific for heart and skeletal muscle. This creates a novel splice site resulting in a more than 95% decrease of the wild type allele."
explanation: Reports the variant and quantifies its effect on wild-type exon 3A transcript levels.
gene:
preferred_term: SLC25A3
term:
id: hgnc:10989
label: SLC25A3
genetic_context:
gene:
preferred_term: SLC25A3
term:
id: hgnc:10989
label: SLC25A3
variant_type: single nucleotide variant
genomic_contexts:
- intron
description: Homozygous c.158-9A>G in isoform-A nomenclature
downstream:
- target: Aberrant Exon 3A Splicing
causal_link_type: DIRECT
description: >-
The new acceptor alters exon-3A splicing.
- name: Aberrant Exon 3A Splicing
biological_scale: MOLECULAR
description: >-
The recurrent acceptor variant produces abnormal exon-3A RNA with intronic sequence inclusion and
a marked reduction of normal transcript. The resulting frameshift/early termination is predicted;
muscle immunodetection independently shows reduced carrier protein.
evidence:
- reference: PMID:21763135
reference_title: "Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a homozygous mutation c.158-9A>G located in the 5'-intron next to exon 3A specific for heart and skeletal muscle. This creates a novel splice site resulting in a more than 95% decrease of the wild type allele."
explanation: Reports the variant and quantifies its effect on wild-type exon 3A transcript levels.
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4501241/?pdf=1
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis - PMC"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: This variant creates a novel splice site in intron 2 that leads to the inclusion of eight nucleotides on the 5′ side of exon 3A, predicted to result in a frame shift and early termination in the first quarter of the protein
explanation: >-
Separates the reported RNA alteration from the predicted downstream protein truncation.
quote_role: BACKGROUND
biological_processes:
- preferred_term: alternative mRNA splicing, via spliceosome
term:
id: GO:0000380
label: alternative mRNA splicing, via spliceosome
modifier: ABNORMAL
downstream:
- target: Reduced Carrier Protein Abundance
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Loss of normal exon-3A transcript is associated with reduced carrier protein; translation and turnover
were not resolved separately.
- name: SLC25A3 Shared-Exon Compound Heterozygous Variants
biological_scale: MOLECULAR
description: >-
The shared-exon compound genotype comprises L200W and the GSSAS-to-QIP delins, inherited on opposite
parental alleles. Yeast assays identify loss of function for the delins, but not L200W under the conditions
tested. Both isoforms contain these shared regions; the patient fibroblasts are abnormal despite the
cardiac-predominant clinical presentation.
evidence:
- reference: PMID:25681081
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patient 2 was found to be a compound heterozygote for two novel variants, c.599T>G (p.Leu200Trp) and c. 886_898delGGTAGCAGTGCTTinsCAGATAC (p.Gly296_Ser300delinsGlnIlePro)."
explanation: Reports the compound heterozygous genotype.
- reference: PMID:25681081
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis."
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "Protein structure analysis indicated that both variants are likely to be pathogenic."
explanation: >-
Original computational prediction, subsequently qualified by the allele-specific yeast assays.
- reference: PMID:27780865
reference_title: "Natural and Induced Mitochondrial Phosphate Carrier Loss: DIFFERENTIAL DEPENDENCE OF MITOCHONDRIAL METABOLISM AND DYNAMICS AND CELL SURVIVAL ON THE EXTENT OF DEPLETION."
supports: REFUTE
evidence_source: MODEL_ORGANISM
snippet: whereas the L200W variant is functionally neutral.
explanation: >-
The yeast result is counterevidence to the original prediction that L200W is deleterious. It does not refute loss of function of the delins allele or establish clinical benignity in every human context.
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207081/
reference_title: "Natural and Induced Mitochondrial Phosphate Carrier Loss: DIFFERENTIAL DEPENDENCE OF MITOCHONDRIAL METABOLISM AND DYNAMICS AND CELL SURVIVAL ON THE EXTENT OF DEPLETION - PMC"
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: the GSSAS → QIP variant has relevance compatible with a loss of function.
explanation: >-
The delins, unlike L200W, impaired respiratory growth in the subsequent yeast experiment.
gene:
preferred_term: SLC25A3
term:
id: hgnc:10989
label: SLC25A3
genetic_context:
gene:
preferred_term: SLC25A3
term:
id: hgnc:10989
label: SLC25A3
description: Compound heterozygous L200W and p.Gly296_Ser300delinsGlnIlePro; allele-specific consequences differ
downstream:
- target: Reduced Carrier Protein Abundance
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Patient fibroblasts have reduced carrier protein despite unchanged RNA; the mechanism of protein
loss remains unresolved.
- target: Reduced Mitochondrial Phosphate Carrier Function
causal_link_type: DIRECT
description: >-
The delins fails respiratory growth complementation in yeast.
- name: Reduced Carrier Protein Abundance
biological_scale: MOLECULAR
description: >-
Reduced SLC25A3 protein was observed in muscle from the splice-variant family and in fibroblasts carrying
the shared-exon compound genotype. Normal RNA in the latter supports a post-transcriptional effect
without establishing a particular degradation pathway.
evidence:
- reference: PMID:21763135
reference_title: "Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In a muscle biopsy normal activity of respiratory chain enzymes was found; however the amount of the mitochondrial phosphate carrier was decreased."
explanation: >-
Shows reduced carrier protein with normal respiratory-chain enzyme activities in this patient muscle biopsy; this assay does not exclude every additional mitochondrial effect.
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207081/
reference_title: "Natural and Induced Mitochondrial Phosphate Carrier Loss: DIFFERENTIAL DEPENDENCE OF MITOCHONDRIAL METABOLISM AND DYNAMICS AND CELL SURVIVAL ON THE EXTENT OF DEPLETION - PMC"
supports: SUPPORT
evidence_source: IN_VITRO
snippet: PiC mRNA was unaffected by the mutations.
explanation: >-
RNA abundance was unchanged in the compound-genotype fibroblasts.
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207081/
reference_title: "Natural and Induced Mitochondrial Phosphate Carrier Loss: DIFFERENTIAL DEPENDENCE OF MITOCHONDRIAL METABOLISM AND DYNAMICS AND CELL SURVIVAL ON THE EXTENT OF DEPLETION - PMC"
supports: SUPPORT
evidence_source: IN_VITRO
snippet: PiC protein abundance was substantially lower, and the cells were not phenotypically normal
explanation: >-
Patient-derived fibroblast protein and cellular phenotype.
downstream:
- target: Reduced Mitochondrial Phosphate Carrier Function
causal_link_type: DIRECT
description: >-
Reduced abundance lowers available carrier capacity.
- name: Reduced Mitochondrial Phosphate Carrier Function
biological_scale: MOLECULAR
description: >-
Disease-associated variants reduce carrier abundance and/or transport function. The affected substrates
and tissue distribution depend on the allele, isoform, residual expression and assay. Phosphate and
copper transport are separable carrier functions; loss of either should not be inferred solely from
a generic mutation label.
mechanism_confidence: ESTABLISHED
gene:
preferred_term: SLC25A3
term:
id: hgnc:10989
label: SLC25A3
molecular_functions:
- preferred_term: phosphate transmembrane transporter activity
term:
id: GO:0005315
label: phosphate transmembrane transporter activity
modifier: DECREASED
cellular_components:
- preferred_term: mitochondrial inner membrane
term:
id: GO:0005743
label: mitochondrial inner membrane
cell_types:
- preferred_term: cardiac muscle cell
term:
id: CL:0000746
label: cardiac muscle cell
- preferred_term: skeletal muscle fiber
term:
id: CL:0008002
label: skeletal muscle fiber
evidence:
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a homozygous mutation--c.215G-->A (p.Gly72Glu)--in the alternatively spliced exon 3A of this enzyme in two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life."
explanation: Identifies the causative exon 3A missense allele in the index family, establishing SLC25A3 loss of function as the primary lesion.
- reference: PMID:21763135
reference_title: "Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In a muscle biopsy normal activity of respiratory chain enzymes was found; however the amount of the mitochondrial phosphate carrier was decreased."
explanation: >-
Shows reduced carrier protein with normal respiratory-chain enzyme activities in this patient muscle biopsy; this assay does not exclude every additional mitochondrial effect.
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "The enzyme defect was confirmed by complementation analysis in yeast."
explanation: Yeast complementation independently confirms that the patient allele is a loss-of-function carrier defect.
downstream:
- target: Reduced Mitochondrial Phosphate Import
causal_link_type: DIRECT
description: >-
Loss of phosphate-carrier capacity reduces mitochondrial phosphate uptake.
- target: Reduced Mitochondrial Copper Delivery
causal_link_type: DIRECT
description: >-
Carrier depletion or human G72E expression reduces mitochondrial copper in cell models.
- target: Reduced Mitochondrial Fusion
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Patient fibroblast and HeLa experiments show reduced fusion without an established intervening pathway.
- target: Cardiomyocyte Calcium Homeostasis Imbalance
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Carrier-deficient engineered cardiomyocytes show calcium dysregulation through incompletely defined
metabolic intermediates.
- name: Reduced Mitochondrial Phosphate Import
biological_scale: MOLECULAR
description: >-
Carrier deficiency reduces inorganic-phosphate import into mitochondria. Cardiac knockout mitochondria
show reduced phosphate uptake; siRNA-treated HeLa cells show reduced mitochondrial phosphate levels
that recover with TAT-mPiC. These model measurements do not establish uniform matrix phosphate depletion
across all patient tissues.
biological_processes:
- preferred_term: mitochondrial phosphate ion transmembrane transport
term:
id: GO:1990547
label: mitochondrial phosphate ion transmembrane transport
modifier: DECREASED
chemical_entities:
- preferred_term: phosphate ion
term:
id: CHEBI:35780
label: phosphate ion
modifier: DECREASED
evidence:
- reference: PMID:24658400
reference_title: Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Together, these results indicate that acute Slc25a3 deletion causes impaired mitochondrial Pi uptake that leads to reduced mitochondrial ATP synthesis.
explanation: >-
Isolated cardiac mitochondria after inducible cardiomyocyte deletion.
- reference: PMID:40362619
reference_title: "Rescue of the First Mitochondrial Membrane Carrier, the mPiC, by TAT-Mediated Protein Replacement Treatment."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Mitochondrial inorganic phosphate levels were significantly decreased to 0.83 ± 0.09-fold upon mPiC knockdown.
explanation: >-
Mitochondrial lysate measurement in siRNA-treated HeLa cells.
downstream:
- target: Reduced Mitochondrial ATP Synthesis
causal_link_type: DIRECT
description: >-
Insufficient phosphate delivery can limit ATP synthesis; substantial reserve capacity remains in
some partially depleted cells.
- name: Reduced Mitochondrial ATP Synthesis
biological_scale: MOLECULAR
description: >-
Reduced phosphate supply can constrain ATP synthase despite preserved respiratory-chain enzyme activities.
This was demonstrated in muscle from the G72E family, whereas their fibroblasts retained ATP-synthesis
capacity. In shared-exon patient fibroblasts, intact-cell respiration was impaired but maximal phosphorylating
respiration after permeabilization was preserved, showing that substrate availability and depletion
severity modify the defect.
mechanism_confidence: ESTABLISHED
biological_processes:
- preferred_term: proton motive force-driven mitochondrial ATP synthesis
term:
id: GO:0042776
label: proton motive force-driven mitochondrial ATP synthesis
modifier: DECREASED
- preferred_term: oxidative phosphorylation
term:
id: GO:0006119
label: oxidative phosphorylation
modifier: DECREASED
evidence:
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Functional investigation of intact mitochondria showed a deficiency of ATP synthesis in muscle but not in fibroblasts, which correlated with the tissue-specific expression of exon 3A in muscle versus exon 3B in fibroblasts."
explanation: Directly demonstrates a tissue-restricted ATP-synthesis defect in patient muscle mitochondria and links it to exon 3A expression.
- reference: PMID:25681081
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Variants in the SLC25A3 gene, which codes for the mitochondrial phosphate transporter (PiC), lead to a failure of inorganic phosphate (Pi) transport across the mitochondrial membrane, which is required in the final step of oxidative phosphorylation."
explanation: States that the transport failure specifically impairs the final (ATP synthase) step of oxidative phosphorylation.
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207081/
reference_title: "Natural and Induced Mitochondrial Phosphate Carrier Loss: DIFFERENTIAL DEPENDENCE OF MITOCHONDRIAL METABOLISM AND DYNAMICS AND CELL SURVIVAL ON THE EXTENT OF DEPLETION - PMC"
supports: REFUTE
evidence_source: IN_VITRO
snippet: There were no differences between Ctrl and PiC mutant cells for either of the substrates or any of the conditions.
explanation: >-
Maximal phosphorylating respiration was preserved in permeabilized shared-exon patient fibroblasts. This is counterevidence to reduced ATP-synthesis capacity in that assay and tissue context; it does not negate the positive muscle findings.
downstream:
- target: Cardiomyocyte and Skeletal Muscle Bioenergetic Stress
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Reduced mitochondrial ATP-generating capacity imposes energetic stress even where bulk tissue ATP
is maintained.
- target: Compensatory Glycolytic Shift
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The cardiac knockout model increases glycolytic machinery as a compensatory response.
- name: Cardiomyocyte and Skeletal Muscle Bioenergetic Stress
biological_scale: CELLULAR
conforms_to: cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult
description: >-
Reduced mitochondrial ATP-generating capacity stresses contractile cells. Whole-heart ATP content
was nevertheless preserved in the conditional mouse knockout, so a uniformly depleted total ATP pool
is not asserted. Engineered human iPSC-derived cardiomyocytes show impaired energy metabolism and
diastolic dysfunction.
cell_types:
- preferred_term: cardiac muscle cell
term:
id: CL:0000746
label: cardiac muscle cell
- preferred_term: skeletal muscle fiber
term:
id: CL:0008002
label: skeletal muscle fiber
evidence:
- reference: PMID:39671292
reference_title: "Mitochondrial transplantation rescues Ca(2+) homeostasis imbalance and myocardial hypertrophy in SLC25A3-related hypertrophic cardiomyopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "These SLC25A3-KO or missense mutation hiPSC-CMs recapitulated the disease phenotype associated with myocardial hypertrophy, including diastolic dysfunction, Ca2+ homeostasis imbalance, and mitochondrial energy metabolism dysfunction."
explanation: >-
CRISPR-engineered hiPSC-derived cardiomyocytes, not patient-derived lines, demonstrate metabolic
and contractile dysfunction.
downstream:
- target: Cardiomyocyte Hypertrophic Remodeling
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Energetic stress is associated with hypertrophic remodeling; intervening growth signaling remains
incompletely defined.
- target: Hypotonia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Skeletal-muscle dysfunction contributes to reduced tone.
- target: Exercise intolerance
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Limited muscular bioenergetic reserve contributes to exertional symptoms.
- target: Proximal muscle weakness
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Myopathy contributes to proximal weakness.
- target: Mitochondrial myopathy
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Mitochondrial dysfunction underlies the reported myopathy.
- target: Elevated circulating creatine kinase activity
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Muscle injury can increase circulating creatine kinase activity.
- name: Compensatory Glycolytic Shift
biological_scale: CELLULAR
description: >-
Cardiac Slc25a3 deletion increases glucose-transporter and glycolytic-enzyme expression, supporting
compensatory glycolytic ATP production. Glycolysis and lactate generation need not imply absence of
oxygen. The degree of this response varies across models.
biological_processes:
- preferred_term: glycolytic process
term:
id: GO:0006096
label: glycolytic process
modifier: INCREASED
evidence:
- reference: PMID:24658400
reference_title: Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: These results suggest that glucose utilization through glycolysis is enhanced while mitochondrial metabolic flux is reduced as a direct mechanism of compensation for the reduction in mitochondrial ATP production.
explanation: >-
Authors interpret the glucose-transporter and glycolytic-enzyme expression response in knockout
hearts.
downstream:
- target: Increased Lactate Production
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Increased glycolytic flux and altered pyruvate handling can increase lactate output.
- name: Increased Lactate Production
biological_scale: CELLULAR
description: >-
Carrier knockdown increases extracellular lactate in HeLa cells, and carrier replacement reduces it.
Patient lactate elevation can persist despite clinical improvement but is absent in some affected
individuals; elevated lactate does not invariably entail acidosis.
evidence:
- reference: PMID:40362619
reference_title: "Rescue of the First Mitochondrial Membrane Carrier, the mPiC, by TAT-Mediated Protein Replacement Treatment."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: lactate levels in si-mPiC-treated cells were significantly higher than in control untreated cells
explanation: >-
Cell-culture lactate response to carrier depletion.
chemical_entities:
- preferred_term: lactate
term:
id: CHEBI:24996
label: lactate
modifier: INCREASED
downstream:
- target: Lactic acidosis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Lactate-associated acid accumulation can exceed buffering and clearance; acid-base status must be
assessed separately.
- target: Increased circulating lactate concentration
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Increased lactate production can contribute to blood lactate elevation.
- name: Cardiomyocyte Hypertrophic Remodeling
biological_scale: TISSUE
conforms_to: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling
description: >-
Patients show hypertrophic cardiomyopathy with variable progression. Long-term cardiac Slc25a3 deletion
in mice produces hypertrophy, dilation and reduced ventricular function, while engineered human cardiomyocytes
reproduce cellular hypertrophy. The links from mitochondrial stress to growth signaling are not fully
resolved.
cell_types:
- preferred_term: cardiac muscle cell
term:
id: CL:0000746
label: cardiac muscle cell
locations:
- preferred_term: myocardium
term:
id: UBERON:0002349
label: myocardium
biological_processes:
- preferred_term: cardiac muscle hypertrophy
term:
id: GO:0003300
label: cardiac muscle hypertrophy
modifier: INCREASED
evidence:
- reference: PMID:24658400
reference_title: "Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "deletion of the Slc25a3 gene from the heart long-term resulted in profound hypertrophy with ventricular dilation and depressed cardiac function, all features that reflect the cardiomyopathy observed in humans with mutations in SLC25A3"
explanation: Cardiac-specific Slc25a3 deletion in mice is sufficient to produce hypertrophy, ventricular remodeling, and contractile dysfunction, matching the human cardiomyopathy.
- reference: PMID:24658400
reference_title: "Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "mice lacking Slc25a3 in the heart serve as a novel model of metabolic, mitochondrial-driven cardiomyopathy"
explanation: Establishes the cardiac Slc25a3-null mouse as a metabolic, mitochondrially driven cardiomyopathy model for this disorder.
downstream:
- target: Hypertrophic cardiomyopathy
causal_link_type: DIRECT
description: >-
Myocardial hypertrophy manifests clinically as hypertrophic cardiomyopathy.
- target: Low-output congestive heart failure
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Severe remodeling can impair cardiac output.
- name: Reduced Mitochondrial Copper Delivery
biological_scale: MOLECULAR
mechanism_confidence: PROVISIONAL
description: >-
SLC25A3 transports copper in reconstituted systems and supports the mitochondrial copper pool in cells.
Depletion, deletion and human G72E expression can reduce mitochondrial copper. This carrier function
is experimentally established, while the magnitude and clinical importance of copper deficiency in
patient heart and muscle remain unresolved.
biological_processes:
- preferred_term: copper ion transmembrane transport
term:
id: GO:0035434
label: copper ion transmembrane transport
modifier: DECREASED
chemical_entities:
- preferred_term: copper cation
term:
id: CHEBI:23378
label: copper cation
modifier: DECREASED
evidence:
- reference: PMID:29237729
reference_title: "The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Additionally, assays in Lactococcus lactis and in reconstituted liposomes directly demonstrated that SLC25A3 functions as a copper transporter."
explanation: Reconstituted-system assays demonstrate copper transport by SLC25A3 directly.
- reference: PMID:38986607
reference_title: Slc25a3-dependent copper transport controls flickering-induced Opa1 processing for mitochondrial safeguard.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Finally, atomic absorption spectrometry of isolated mitochondria showed that Slc25a3 (G72E) could not replenish mitochondrial copper levels in Drp1Slc25a3-KO MEFs (Fig. 7L).
explanation: >-
Patient-allele functional test in engineered mouse embryonic fibroblasts, not patient muscle.
downstream:
- target: Impaired Cytochrome c Oxidase Biogenesis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Reduced copper availability impairs COX assembly/activity in carrier-deficient cells; copper-selective
rescue separates this from phosphate transport.
- target: Disordered Mitochondrial Cristae
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Copper-selective carrier rescue restores cristae in engineered mouse fibroblasts; patient-tissue
causality remains unproven.
- name: Impaired Cytochrome c Oxidase Biogenesis
biological_scale: MOLECULAR
description: >-
Carrier-deficient cell models show copper-responsive COX deficiency. The engineered mouse L175A carrier
restores copper and COX without restoring phosphate transport. Patient enzyme results are variable
and assay-specific; the model result does not imply that every affected muscle biopsy must show reduced
COX staining.
evidence:
- reference: PMID:29237729
reference_title: "The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "SLC25A3 knockdown or deletion consistently resulted in an isolated COX deficiency in these cells, and copper addition to the culture medium suppressed these biochemical defects."
explanation: Shows that loss of SLC25A3 in cultured cells produces a copper-remediable isolated cytochrome c oxidase deficiency.
- reference: PMID:33591272
reference_title: Mitochondrial copper and phosphate transporter specificity was defined early in the evolution of eukaryotes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: In SLC25A3, the L175A mutation separates Cu and phosphate transport by fully restoring COX activity and mitochondrial Cu levels without rescuing phosphate transport.
explanation: >-
Engineered separation-of-function construct establishes the copper-dependent COX effect in cells.
mechanism_confidence: PROVISIONAL
biological_processes:
- preferred_term: respiratory chain complex IV assembly
term:
id: GO:0008535
label: respiratory chain complex IV assembly
modifier: DECREASED
downstream:
- target: Cardiomyocyte and Skeletal Muscle Bioenergetic Stress
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Reduced COX function could contribute to respiratory stress where this model-derived arm is engaged
in vivo.
- name: Reduced Mitochondrial Fusion
biological_scale: CELLULAR
description: >-
Shared-exon patient fibroblasts and partially depleted HeLa cells have reduced mitochondrial fusion
and network connectivity. This occurred without a shift in OPA1 forms, so it is not identified with
the OPA1-processing response seen under Drp1-deficient stress in a separate model.
evidence:
- reference: PMID:27780865
reference_title: "Natural and Induced Mitochondrial Phosphate Carrier Loss: DIFFERENTIAL DEPENDENCE OF MITOCHONDRIAL METABOLISM AND DYNAMICS AND CELL SURVIVAL ON THE EXTENT OF DEPLETION."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Both mutant fibroblasts and HeLa cells with 60% PiC loss showed a less interconnected mitochondrial network and a mitochondrial fusion defect
explanation: >-
Reduced fusion in patient-derived fibroblasts and engineered HeLa cells.
mechanism_confidence: PROVISIONAL
biological_processes:
- preferred_term: mitochondrial fusion
term:
id: GO:0008053
label: mitochondrial fusion
modifier: DECREASED
downstream:
- target: Cardiomyocyte and Skeletal Muscle Bioenergetic Stress
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Reduced fusion may impair mitochondrial quality control; its contribution to patient symptoms is
not quantified.
- name: Disordered Mitochondrial Cristae
biological_scale: CELLULAR
description: >-
Disrupted mitochondrial cristae are observed in Slc25a3-null mouse fibroblasts and conditional knockout
hearts. Human G72E fails to restore cristae in null fibroblasts, whereas the copper-transporting L175A
construct rescues them.
evidence:
- reference: PMID:38986607
reference_title: Slc25a3-dependent copper transport controls flickering-induced Opa1 processing for mitochondrial safeguard.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: In addition, we found that the G72E mutant failed to restore cristae morphology and mitochondrial respiration in Slc25a3-KO MEFs (Fig. 6D–G).
explanation: >-
Patient variant tested in an engineered null fibroblast background.
- reference: PMID:24658400
reference_title: Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: examination of hearts from Slc25a3fl/fl-MCM mice by electron microscopy showed extensive sarcomeric disarray with fragmented and disrupted mitochondria, as well as mitochondrial hyperproliferation
explanation: >-
Cardiac knockout ultrastructure.
mechanism_confidence: PROVISIONAL
downstream:
- target: Cardiomyocyte and Skeletal Muscle Bioenergetic Stress
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Cristae disorganization may impair mitochondrial function; the causal relationship to ATP shortage
is not fully separated.
cellular_components:
- preferred_term: mitochondrial crista
term:
id: GO:0030061
label: mitochondrial crista
modifier: ABNORMAL
- name: Cardiomyocyte Calcium Homeostasis Imbalance
biological_scale: CELLULAR
description: >-
CRISPR-engineered SLC25A3 knockout and missense hiPSC-derived cardiomyocytes show calcium-homeostasis
imbalance with diastolic dysfunction. A contribution from accumulated glycolytic byproducts was proposed,
rather than established as a universal direct mechanism.
evidence:
- reference: PMID:39671292
reference_title: "Mitochondrial transplantation rescues Ca(2+) homeostasis imbalance and myocardial hypertrophy in SLC25A3-related hypertrophic cardiomyopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "These SLC25A3-KO or missense mutation hiPSC-CMs recapitulated the disease phenotype associated with myocardial hypertrophy, including diastolic dysfunction, Ca2+ homeostasis imbalance, and mitochondrial energy metabolism dysfunction."
explanation: >-
Engineered hiPSC-derived cardiomyocyte phenotype, not patient-derived tissue.
- reference: PMID:39671292
reference_title: "Mitochondrial transplantation rescues Ca(2+) homeostasis imbalance and myocardial hypertrophy in SLC25A3-related hypertrophic cardiomyopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Further studies suggested the potential link between the accumulation of glycolytic byproducts and Ca2+ homeostasis imbalance in SLC25A3-KO hiPSC-CMs."
explanation: >-
Authors propose a link to glycolytic byproducts; the abstract does not establish the causal intermediate.
mechanism_confidence: PROVISIONAL
biological_processes:
- preferred_term: calcium ion homeostasis
term:
id: GO:0055074
label: calcium ion homeostasis
modifier: ABNORMAL
downstream:
- target: Cardiomyocyte Hypertrophic Remodeling
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Calcium dysregulation accompanies hypertrophic dysfunction in the engineered cardiomyocyte model;
its causal contribution remains provisional.
phenotypes:
- name: Hypertrophic cardiomyopathy
category: Cardiovascular
description: >-
Hypertrophic cardiomyopathy is prominent in the published cases and can begin prenatally or neonatally.
It can progress to low-output failure or remain stable in survivors; case-series consistency is not
proof of obligate penetrance.
phenotype_term:
preferred_term: Hypertrophic cardiomyopathy
term:
id: HP:0001639
label: Hypertrophic cardiomyopathy
evidence:
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a homozygous mutation--c.215G-->A (p.Gly72Glu)--in the alternatively spliced exon 3A of this enzyme in two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life."
explanation: Hypertrophic cardiomyopathy in both siblings of the index family.
- reference: PMID:21763135
reference_title: "Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In a family three children presented with severe neonatal lactic acidosis, hypertrophic cardiomyopathy and generalised muscular hypotonia."
explanation: Hypertrophic cardiomyopathy in all three affected children of a second family.
- reference: PMID:21763135
reference_title: "Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At an age of 9 and 17years, respectively, they present with exercise intolerance, proximal muscle weakness, non-progressive hypertrophic cardiomyopathy and normal mental development."
explanation: Documents that the cardiomyopathy can be non-progressive in long-term survivors.
- reference: PMID:25681081
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report here two new patients who had neonatal cardiomyopathy; one of whom did not have skeletal myopathy nor elevated lactate."
explanation: >-
Cardiomyopathy was present in these two cases, including one without clinical myopathy or raised
lactate; this does not prove universality.
- name: Hypotonia
category: Neurologic
description: >-
Generalised muscular hypotonia is part of the classical neonatal triad, with
hypertrophic cardiomyopathy and lactic acidosis. It is not universal - at least
one reported patient had isolated cardiomyopathy without skeletal muscle
involvement.
phenotype_term:
preferred_term: Hypotonia
term:
id: HP:0001252
label: Hypotonia
evidence:
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a homozygous mutation--c.215G-->A (p.Gly72Glu)--in the alternatively spliced exon 3A of this enzyme in two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life."
explanation: Muscular hypotonia in both siblings of the index family.
- reference: PMID:21763135
reference_title: "Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In a family three children presented with severe neonatal lactic acidosis, hypertrophic cardiomyopathy and generalised muscular hypotonia."
explanation: Generalised muscular hypotonia in all three affected children of a second family.
- reference: PMID:40944834
reference_title: "Expanding the Clinical Spectrum of Mitochondrial Phosphate Carrier Deficiency: A Case Report With Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mitochondrial phosphate carrier (PiC) deficiency, caused by pathogenic variants in the SLC25A3 gene, is a rare autosomal recessive disorder primarily presenting with early-onset hypertrophic cardiomyopathy (HCMP), muscular hypotonia, and respiratory failure."
explanation: Lists muscular hypotonia among the primary presenting features in a 2026 literature review.
- name: Lactic acidosis
category: Metabolic
description: >-
Severe neonatal lactic acidosis occurs in the classical presentation, but is not required: a patient
with severe cardiomyopathy repeatedly had normal lactate.
phenotype_term:
preferred_term: Lactic acidosis
term:
id: HP:0003128
label: Lactic acidosis
evidence:
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a homozygous mutation--c.215G-->A (p.Gly72Glu)--in the alternatively spliced exon 3A of this enzyme in two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life."
explanation: Lactic acidosis in both siblings of the index family.
- reference: PMID:21763135
reference_title: "Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In a family three children presented with severe neonatal lactic acidosis, hypertrophic cardiomyopathy and generalised muscular hypotonia."
explanation: Severe neonatal lactic acidosis in all three affected children of a second family.
- name: Exercise intolerance
category: Musculoskeletal
description: >-
Exercise intolerance was reported in childhood and adolescent survivors. In the patient followed to age 32, fatigue and muscle weakness after walking began in early childhood, at 1.5 years of age.
phenotype_term:
preferred_term: Exercise intolerance
term:
id: HP:0003546
label: Exercise intolerance
evidence:
- reference: PMID:21763135
reference_title: "Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At an age of 9 and 17years, respectively, they present with exercise intolerance, proximal muscle weakness, non-progressive hypertrophic cardiomyopathy and normal mental development."
explanation: Exercise intolerance in the two long-surviving siblings.
- reference: PMID:40944834
reference_title: "Expanding the Clinical Spectrum of Mitochondrial Phosphate Carrier Deficiency: A Case Report With Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient's neuromotor development was initially normal, but from 1.5 years of age, she exhibited fatigue and muscle weakness, particularly after walking."
explanation: >-
Exertional fatigue beginning at 1.5 years in the patient later reported as an adult survivor.
- name: Proximal muscle weakness
category: Musculoskeletal
description: >-
Proximal weakness reflects the myopathic arm of the disorder and is a
characteristic finding in patients who survive infancy.
phenotype_term:
preferred_term: Proximal muscle weakness
term:
id: HP:0003701
label: Proximal muscle weakness
evidence:
- reference: PMID:21763135
reference_title: "Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At an age of 9 and 17years, respectively, they present with exercise intolerance, proximal muscle weakness, non-progressive hypertrophic cardiomyopathy and normal mental development."
explanation: Proximal muscle weakness in the two long-surviving siblings.
- name: Mitochondrial myopathy
category: Musculoskeletal
description: >-
Skeletal myopathy accompanies the cardiomyopathy in most reported patients.
Muscle histopathology in a long-surviving adult showed a type 1 fibre
predominance with mildly increased cytochrome c oxidase and succinate
dehydrogenase staining, a mitochondrial-myopathy pattern.
phenotype_term:
preferred_term: Mitochondrial myopathy
term:
id: HP:0003737
label: Mitochondrial myopathy
evidence:
- reference: PMID:40944834
reference_title: "Expanding the Clinical Spectrum of Mitochondrial Phosphate Carrier Deficiency: A Case Report With Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The histopathology showed a mild increase in cytochrome c oxidase (COX) and succinate dehydrogenase (SDH) activity, suggesting mitochondrial myopathy."
explanation: Muscle histopathology in a molecularly confirmed patient was interpreted as mitochondrial myopathy.
- reference: PMID:25681081
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The literature described two affected sibships with variants in SLC25A3; all cases had skeletal myopathy and cardiomyopathy (OMIM 610773)."
explanation: Skeletal myopathy was present in every previously reported case.
- name: Respiratory failure
category: Respiratory
description: >-
Respiratory failure requiring prolonged or recurrent ventilation occurs in severe neonatal presentations.
Its relative cardiac, respiratory-muscle and other contributors were not resolved uniformly.
phenotype_term:
preferred_term: Respiratory failure
term:
id: HP:0002878
label: Respiratory failure
evidence:
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: During her life, the child presented with severe muscular hypotonia and recurrent episodes of respiratory insufficiency that necessitated artificial ventilation.
explanation: >-
Repeated ventilatory support in an index-family sibling.
- name: Elevated circulating creatine kinase activity
category: Laboratory
description: >-
High plasma creatine kinase reflects the skeletal- and cardiac-muscle
involvement and, together with the combined heart-and-muscle presentation, can
lead to an initial misdiagnosis of infantile-onset Pompe disease.
phenotype_term:
preferred_term: Elevated circulating creatine kinase activity
term:
id: HP:0003236
label: Elevated circulating creatine kinase activity
evidence:
- reference: PMID:38656665
reference_title: "Mitochondrial phosphate-carrier deficiency mimicking infantile-onset Pompe disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, described a patient with suspicion of infantile Pompe disease due to involvement of heart and muscle and high-level of plasma creatinine kinase but finally diagnosed mitochondrial phosphate-carrier deficiency."
explanation: Documents high plasma creatine kinase in a molecularly confirmed patient, and the resulting diagnostic confusion with infantile Pompe disease.
- name: Increased circulating lactate concentration
category: Laboratory
description: >-
Elevated blood lactate is a reported biochemical feature and can persist in clinically stable long-term survivors. It is not invariable: normal lactate was documented in a patient with severe cardiomyopathy.
phenotype_term:
preferred_term: Increased circulating lactate concentration
term:
id: HP:0002151
label: Increased circulating lactate concentration
evidence:
- reference: PMID:40944834
reference_title: "Expanding the Clinical Spectrum of Mitochondrial Phosphate Carrier Deficiency: A Case Report With Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At the age of 32 years, the patient remained stable with HCMP and persistently high lactate levels."
explanation: Documents persistently elevated lactate in a long-term survivor.
- reference: PMID:25681081
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "one of whom did not have skeletal myopathy nor elevated lactate."
explanation: >-
Normal lactate in one molecularly investigated infant is counterevidence to an obligatory lactate elevation.
- name: Failure to thrive
category: Growth
description: >-
Persistent poor weight gain despite high caloric intake was described in an index infant.
phenotype_term:
preferred_term: Failure to thrive
term:
id: HP:0001508
label: Failure to thrive
evidence:
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Severe muscular hypotonia and failure to thrive persisted. She had a poor weight gain despite high caloric intake.
explanation: >-
Clinical growth failure in the first reported infant.
- name: Cyanosis
category: Cardiovascular
description: >-
Cyanosis was an early neonatal sign in the first reported infant; its population frequency is unknown.
phenotype_term:
preferred_term: Cyanosis
term:
id: HP:0000961
label: Cyanosis
evidence:
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: At age 12 h, the child presented with cyanosis and muscular hypotonia that necessitated intensive-care treatment.
explanation: >-
Direct neonatal clinical observation.
- name: Low-output congestive heart failure
category: Cardiovascular
description: >-
Progressive hypertrophic cardiomyopathy caused low-output failure in the founding family.
phenotype_term:
preferred_term: Low-output congestive heart failure
term:
id: HP:0009805
label: Low-output congestive heart failure
evidence:
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: At age 9 mo, the child died from intractable low-output hypertrophic heart failure.
explanation: >-
Fatal low-output heart failure in an index sibling.
- name: Elevated lactate:pyruvate ratio
category: Laboratory
description: >-
An increased ratio was reported both with hyperlactatemia in the founding family and with normal lactate
but low pyruvate in the compound-genotype patient. Interpret the ratio alongside its component concentrations.
phenotype_term:
preferred_term: Elevated lactate:pyruvate ratio
term:
id: HP:0032653
label: Elevated lactate:pyruvate ratio
evidence:
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: an increased lactate:pyruvate ratio of 62
explanation: >-
Index-family measurement.
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4501241/?pdf=1
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis - PMC"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: the lactate/pyruvate ratio was elevated at 53 (reference range 10–20).
explanation: >-
Ratio elevation in the compound-genotype patient despite normal lactate.
- name: Thin corpus callosum
category: Neurologic
description: >-
MRI showed a thin corpus callosum in one severely affected infant before transplantation. The contribution
of SLC25A3 deficiency versus critical illness is unresolved; this is not asserted as a defining feature.
phenotype_term:
preferred_term: Thin corpus callosum
term:
id: HP:0033725
label: Thin corpus callosum
evidence:
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4501241/?pdf=1
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis - PMC"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: MRI of the brain at 4 months of life showed prominence of the sulci, extra-axial spaces, and ventricles as well as thinning of the corpus callosum.
explanation: >-
Single-case MRI observation, with uncertain etiologic specificity.
histopathology:
- name: Type 1 fibre predominance on skeletal muscle biopsy
description: >-
Skeletal muscle biopsy in a long-surviving SLC25A3 patient showed normal
myofibre size with a predominance of type 1 (oxidative, slow-twitch)
fibres.
context: Single long-term survivor biopsied in childhood; n=1.
evidence:
- reference: PMID:40944834
reference_title: "Expanding the Clinical Spectrum of Mitochondrial Phosphate Carrier Deficiency: A Case Report With Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Muscle biopsy revealed normal muscle fiber size with a predominance of type 1 fibers."
explanation: >-
Direct human histopathologic observation of fibre-type composition in
SLC25A3 deficiency.
- name: Mildly increased COX and SDH histochemical activity
description: >-
A long-term survivor had mildly increased COX and SDH histochemical activity, interpreted as mitochondrial
myopathy. Histochemical staining is not equivalent to a quantitative respiratory-chain enzyme assay
and cannot by itself exclude copper-dependent effects in other tissues or genotypes.
context: Single long-term survivor biopsied in childhood; n=1.
evidence:
- reference: PMID:40944834
reference_title: "Expanding the Clinical Spectrum of Mitochondrial Phosphate Carrier Deficiency: A Case Report With Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The histopathology showed a mild increase in cytochrome c oxidase (COX) and succinate dehydrogenase (SDH) activity, suggesting mitochondrial myopathy."
explanation: >-
The adult biopsy finding is retained with its assay and single-patient context.
- name: Lipid accumulation in skeletal muscle
description: >-
The first index infant had lipid accumulation in both fiber types, prominent in type I fibers, without
ragged red fibers.
context: Index-family skeletal muscle biopsy.
evidence:
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Histological examination showed lipid myopathy with lipid accumulation in both fiber types, prominent in type I fibers.
explanation: >-
Full-text histology absent from the earlier abstract-only curation.
- name: Abnormal mitochondrial ultrastructure
description: >-
Electron microscopy showed atypical enlarged mitochondria and lipid droplets in an index sibling,
while the compound-genotype patient had slight mitochondrial enlargement and abnormal cristae despite
no clinical skeletal myopathy.
context: Findings vary between individual muscle biopsies.
evidence:
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Electron microscopy revealed atypical and enlarged mitochondria, as well as an increased amount of lipid droplets
explanation: >-
Index sibling ultrastructure.
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4501241/?pdf=1
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis - PMC"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: electron microscopy demonstrated minimal enlargement in size of mitochondria with slightly abnormal cristae.
explanation: >-
Compound-genotype skeletal muscle ultrastructure.
- name: Myocardial disarray
description: >-
An endomyocardial biopsy in the compound-genotype infant showed nonspecific cardiomyopathy with muscle
disarray and no glycogen accumulation.
context: Single infant, biopsy at three weeks.
evidence:
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4501241/?pdf=1
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis - PMC"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Cardiac catheterization and endomyocardial muscle biopsy at three weeks of life revealed nonspecific findings of cardiomyopathy with muscle disarray; there was no evidence of glycogen accumulation.
explanation: >-
Direct cardiac biopsy observation.
biochemical:
- name: Blood lactate
presence: INCREASED
context: >-
Elevated blood lactate is the principal biochemical marker. It is usually
severe in the neonatal presentation and can persist for decades in long-term
survivors despite clinical improvement on supportive metabolic therapy. It is
not invariable - at least one molecularly confirmed patient with neonatal
cardiomyopathy had normal lactate.
evidence:
- reference: PMID:40944834
reference_title: "Expanding the Clinical Spectrum of Mitochondrial Phosphate Carrier Deficiency: A Case Report With Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient was treated with mitochondrial therapy, along with a fat-rich diet. Despite clinical improvement, lactate levels remained elevated."
explanation: Documents persistent lactate elevation as a stable biochemical marker independent of clinical response.
- reference: PMID:21763135
reference_title: "Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In a family three children presented with severe neonatal lactic acidosis, hypertrophic cardiomyopathy and generalised muscular hypotonia."
explanation: Severe neonatal lactate elevation in three affected siblings.
- name: Plasma creatine kinase
presence: INCREASED
context: >-
Raised plasma creatine kinase accompanies the striated-muscle involvement and
is a source of diagnostic confusion with infantile-onset Pompe disease.
evidence:
- reference: PMID:38656665
reference_title: "Mitochondrial phosphate-carrier deficiency mimicking infantile-onset Pompe disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, described a patient with suspicion of infantile Pompe disease due to involvement of heart and muscle and high-level of plasma creatinine kinase but finally diagnosed mitochondrial phosphate-carrier deficiency."
explanation: Documents raised plasma creatine kinase in a confirmed patient.
- name: Mitochondrial ATP synthesis rate in skeletal muscle
presence: DECREASED
context: >-
The founding G72E family had impaired muscle ATP synthesis but preserved fibroblast synthesis. A normal
fibroblast assay cannot exclude muscle-selective disease; shared-exon patient fibroblasts can have
other functional abnormalities.
evidence:
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Functional investigation of intact mitochondria showed a deficiency of ATP synthesis in muscle but not in fibroblasts, which correlated with the tissue-specific expression of exon 3A in muscle versus exon 3B in fibroblasts."
explanation: Establishes the tissue-restricted ATP-synthesis defect as the functional biochemical signature.
- name: Mitochondrial phosphate carrier protein in skeletal muscle
presence: DECREASED
context: >-
Reduced carrier protein with normal respiratory-chain enzyme activity was reported in the splice-variant
family. A normal routine enzyme panel therefore does not exclude carrier deficiency.
evidence:
- reference: PMID:21763135
reference_title: "Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In a muscle biopsy normal activity of respiratory chain enzymes was found; however the amount of the mitochondrial phosphate carrier was decreased."
explanation: Documents both the reduced carrier protein and the normal respiratory-chain enzyme activities in patient muscle.
genetic:
- name: SLC25A3 biallelic pathogenic variants
gene_term:
preferred_term: SLC25A3
term:
id: hgnc:10989
label: SLC25A3
features: >-
Reported alleles include exon-3A G72E, the recurrent intronic c.158-9A>G splice variant, and coding
variants in shared exons. Exon-3A effects depend on muscle-enriched isoform A; shared-exon alleles
can alter both isoforms and produce fibroblast abnormalities. Variant-specific functional evidence
and transcript choice are essential: the original in silico predictions for the compound genotype
were not fully reproduced by yeast assays.
evidence:
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a homozygous mutation--c.215G-->A (p.Gly72Glu)--in the alternatively spliced exon 3A of this enzyme in two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life."
explanation: Reports the homozygous exon 3A missense allele in the index family.
- reference: PMID:21763135
reference_title: "Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a homozygous mutation c.158-9A>G located in the 5'-intron next to exon 3A specific for heart and skeletal muscle. This creates a novel splice site resulting in a more than 95% decrease of the wild type allele."
explanation: Reports the variant and quantifies its effect on wild-type exon 3A transcript levels.
- reference: PMID:25681081
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patient 2 was found to be a compound heterozygote for two novel variants, c.599T>G (p.Leu200Trp) and c. 886_898delGGTAGCAGTGCTTinsCAGATAC (p.Gly296_Ser300delinsGlnIlePro)."
explanation: Reports the compound heterozygous genotype.
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:40944834
reference_title: "Expanding the Clinical Spectrum of Mitochondrial Phosphate Carrier Deficiency: A Case Report With Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mitochondrial phosphate carrier (PiC) deficiency, caused by pathogenic variants in the SLC25A3 gene, is a rare autosomal recessive disorder primarily presenting with early-onset hypertrophic cardiomyopathy (HCMP), muscular hypotonia, and respiratory failure."
explanation: States the autosomal recessive mode of inheritance for SLC25A3-related PiC deficiency.
variants:
- name: SLC25A3 NM_005888:c.215G>A (p.Gly72Glu), exon 3A
description: >-
Homozygous missense allele affecting exon 3A of isoform A in the founding sisters; the original
paper specifies NM_005888 without a version. The cDNA and protein numbering is isoform-dependent
and should not be transferred to the exon-3B transcript. Yeast complementation demonstrates loss
of carrier function; engineered mouse fibroblasts expressing human G72E also fail to restore mitochondrial
copper and selected structural readouts.
clinical_significance: PATHOGENIC
gene:
preferred_term: SLC25A3
term:
id: hgnc:10989
label: SLC25A3
evidence:
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a homozygous mutation--c.215G-->A (p.Gly72Glu)--in the alternatively spliced exon 3A of this enzyme in two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life."
explanation: Reports the homozygous exon 3A missense allele in the index family.
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "The enzyme defect was confirmed by complementation analysis in yeast."
explanation: Yeast complementation provides functional confirmation of pathogenicity.
- reference: PMID:38986607
reference_title: Slc25a3-dependent copper transport controls flickering-induced Opa1 processing for mitochondrial safeguard.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Finally, atomic absorption spectrometry of isolated mitochondria showed that Slc25a3 (G72E) could not replenish mitochondrial copper levels in Drp1Slc25a3-KO MEFs (Fig. 7L).
explanation: >-
Patient-allele functional test in engineered mouse embryonic fibroblasts, not patient muscle.
variant_type: single nucleotide variant
genomic_contexts:
- coding sequence
- name: SLC25A3 c.158-9A>G (IVS2-9A>G), exon 3A splice acceptor region
description: >-
Recurrent homozygous intronic variant next to exon 3A, reported as c.158-9A>G in the isoform-A nomenclature.
It creates an alternative acceptor with abnormal exon-3A RNA and markedly reduces normal transcript.
Reported carriers of this homozygous allele include an infant who died and long-term survivors;
the allele alone is not a reliable predictor of a mild course.
clinical_significance: PATHOGENIC
gene:
preferred_term: SLC25A3
term:
id: hgnc:10989
label: SLC25A3
evidence:
- reference: PMID:21763135
reference_title: "Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a homozygous mutation c.158-9A>G located in the 5'-intron next to exon 3A specific for heart and skeletal muscle. This creates a novel splice site resulting in a more than 95% decrease of the wild type allele."
explanation: Reports the variant and quantifies its effect on wild-type exon 3A transcript levels.
- reference: PMID:25681081
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patient 1 had a homozygous splice site variant, c.158-9A>G, which has been previously reported in a Turkish family."
explanation: Documents recurrence of the allele in an unrelated patient.
- reference: PMID:40944834
reference_title: "Expanding the Clinical Spectrum of Mitochondrial Phosphate Carrier Deficiency: A Case Report With Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Genetic analysis identified a homozygous splicing variant in the SLC25A3 gene"
explanation: >-
The adult report documents a homozygous splicing variant; the retrieved abstract does not itself
give cDNA coordinates.
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4501241/?pdf=1
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis - PMC"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: This variant creates a novel splice site in intron 2 that leads to the inclusion of eight nucleotides on the 5′ side of exon 3A, predicted to result in a frame shift and early termination in the first quarter of the protein
explanation: >-
Separates the reported RNA alteration from the predicted downstream protein truncation.
quote_role: BACKGROUND
variant_type: single nucleotide variant
genomic_contexts:
- intron
functional_effects:
- function: Aberrant splicing of the muscle-enriched isoform
description: >-
The novel acceptor introduces eight intronic nucleotides before exon 3A; the resulting reading-frame
change and early termination are predicted in the 2015 report, which cites the original splice
study.
- name: SLC25A3 c.599T>G (p.Leu200Trp) and c.886_898delinsCAGATAC (p.Gly296_Ser300delinsGlnIlePro)
description: >-
Compound heterozygous shared-exon variants reported in a patient with prenatal cardiomyopathy, normal
lactate and no clinical skeletal myopathy. Initial structural modeling predicted both deleterious.
Later yeast assays distinguished a loss-of-function GSSAS-to-QIP delins from L200W, which supported
respiratory growth in that assay. Patient fibroblasts nevertheless had reduced carrier protein,
altered growth and mitochondrial dynamics. These results do not independently prove L200W pathogenicity
or establish that it is benign in every human context.
gene:
preferred_term: SLC25A3
term:
id: hgnc:10989
label: SLC25A3
evidence:
- reference: PMID:25681081
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patient 2 was found to be a compound heterozygote for two novel variants, c.599T>G (p.Leu200Trp) and c. 886_898delGGTAGCAGTGCTTinsCAGATAC (p.Gly296_Ser300delinsGlnIlePro)."
explanation: Reports the compound heterozygous genotype.
- reference: PMID:25681081
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis."
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "Protein structure analysis indicated that both variants are likely to be pathogenic."
explanation: >-
Original computational prediction, subsequently qualified by the allele-specific yeast assays.
- reference: PMID:27780865
reference_title: "Natural and Induced Mitochondrial Phosphate Carrier Loss: DIFFERENTIAL DEPENDENCE OF MITOCHONDRIAL METABOLISM AND DYNAMICS AND CELL SURVIVAL ON THE EXTENT OF DEPLETION."
supports: REFUTE
evidence_source: MODEL_ORGANISM
snippet: whereas the L200W variant is functionally neutral.
explanation: >-
The yeast result is counterevidence to the original prediction that L200W is deleterious. It does not refute loss of function of the delins allele or establish clinical benignity in every human context.
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207081/
reference_title: "Natural and Induced Mitochondrial Phosphate Carrier Loss: DIFFERENTIAL DEPENDENCE OF MITOCHONDRIAL METABOLISM AND DYNAMICS AND CELL SURVIVAL ON THE EXTENT OF DEPLETION - PMC"
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: the GSSAS → QIP variant has relevance compatible with a loss of function.
explanation: >-
The delins, unlike L200W, impaired respiratory growth in the subsequent yeast experiment.
diagnosis:
- name: Molecular diagnosis by SLC25A3 sequencing
description: >-
Molecular testing of SLC25A3 can establish a diagnosis in early-onset hypertrophic cardiomyopathy
with or without lactic acidosis or skeletal myopathy. Normal respiratory-chain panels or fibroblast
ATP-synthesis results do not exclude isoform-A disease; assay findings depend on genotype and tissue.
evidence:
- reference: PMID:25681081
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Sequencing of SLC25A3 should be considered in patients with isolated cardiomyopathy, even those without generalized skeletal myopathy or lactic acidosis."
explanation: Explicit diagnostic recommendation from the authors who expanded the phenotype.
- reference: PMID:38656665
reference_title: "Mitochondrial phosphate-carrier deficiency mimicking infantile-onset Pompe disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The characteristic clinical picture of a prominent early-onset hypertrophic cardiomyopathy and lactic acidosis may be an indication for analysis of the SLC25A3 gene."
explanation: Identifies the clinical trigger for SLC25A3 testing.
- name: Functional assessment of intact muscle mitochondria
description: >-
The founding study detected reduced ADP-stimulated respiration with preserved uncoupled respiration
in fresh muscle mitochondria. Standard frozen-tissue respiratory-chain assays can miss the transport
defect; this functional approach complements molecular testing.
evidence:
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Deficiency of the mitochondrial PiC cannot be identified by the analysis of the mitochondrial-energy metabolism in frozen tissue.
explanation: >-
Diagnostic limitation described in the founding study.
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Functional investigation of intact mitochondria should be performed to detect disorders of ATP synthesis, including mitochondrial-PiC deficiency, and other mitochondrial transport defects.
explanation: >-
Authors recommend intact-mitochondrial functional assessment.
differential_diagnoses:
- name: Infantile-onset Pompe disease
description: >-
Glycogen storage disease type II presents with the same combination of
infantile hypertrophic cardiomyopathy, hypotonia, and raised creatine kinase,
and has been the initial working diagnosis in at least one patient later shown
to have mitochondrial phosphate-carrier deficiency. Acid alpha-glucosidase
assay distinguishes the two.
evidence:
- reference: PMID:38656665
reference_title: "Mitochondrial phosphate-carrier deficiency mimicking infantile-onset Pompe disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, described a patient with suspicion of infantile Pompe disease due to involvement of heart and muscle and high-level of plasma creatinine kinase but finally diagnosed mitochondrial phosphate-carrier deficiency."
explanation: A published case in which infantile Pompe disease was the initial clinical suspicion.
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4501241/?pdf=1
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis - PMC"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: no evidence of Pompe disease with normal acid alpha-glucosidase activity levels.
explanation: >-
Enzyme testing excluded Pompe disease in the compound-genotype infant.
disease_term:
preferred_term: glycogen storage disease II
term:
id: MONDO:0009290
label: glycogen storage disease II
treatments:
- name: Supportive and Heart-Failure Directed Care
description: >-
Published management includes ventilation, diuretics, beta blockers and inotropes for respiratory
or cardiac decompensation, and supportive metabolic care. These are case-based supportive measures;
no disease-modifying efficacy is inferred from survival alone.
therapeutic_modality: OTHER
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4501241/?pdf=1
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis - PMC"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Medical treatment during the initial evaluation included courses of diuretics, beta blockers, and inotropes.
explanation: >-
Reported heart-failure treatment in one infant.
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Artificial ventilation was necessary for a period of 3 mo.
explanation: >-
Respiratory support in an index sibling.
- name: Empirical Mitochondrial Supplements and Dietary Support
description: >-
Empirical mitochondrial supplements and a fat-rich diet were associated with clinical improvement
but persistent high lactate in an adult report. A separate infant received coenzyme Q, levocarnitine,
riboflavin, thiamine, creatine and biotin while diagnostic testing was pending. These uncontrolled
observations do not establish the efficacy of an individual supplement or diet.
therapeutic_modality: OTHER
context: >-
Case-based nutritional and supplement treatment; the adult abstract does not name the agents or document
a ketogenic or low-carbohydrate prescription.
treatment_term:
preferred_term: Dietary Intervention
term:
id: NCIT:C15447
label: Dietary Intervention
evidence:
- reference: PMID:40944834
reference_title: "Expanding the Clinical Spectrum of Mitochondrial Phosphate Carrier Deficiency: A Case Report With Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient was treated with mitochondrial therapy, along with a fat-rich diet. Despite clinical improvement, lactate levels remained elevated."
explanation: >-
Uncontrolled clinical improvement with persistent hyperlactatemia; no causal efficacy estimate.
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4501241/?pdf=1
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis - PMC"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: He was started on coenzyme Q, levocarnitine, riboflavin, thiamine, creatine, and biotin while his testing was pending.
explanation: >-
The supplement regimen is reported, but a response to its individual components is not demonstrated.
- name: Genetic Counseling
description: >-
For two confirmed heterozygous parents of an autosomal recessive genotype, each pregnancy has a one-in-four
Mendelian probability of inheriting both alleles. Counseling should distinguish this segregation calculation
from allele-specific prognosis and the unresolved functional interpretation of some reported variants.
therapeutic_modality: OTHER
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The parents are heterozygous carriers.
explanation: >-
Documented parental carrier state; the recurrence fraction is the Mendelian calculation, not an
observed recurrence rate.
- name: TAT-mPiC Protein Replacement (investigational, preclinical)
description: >-
TAT-mPiC delivered recombinant isoform-A carrier into cultured cells and localized to the mitochondrial
inner membrane. In siRNA-depleted HeLa cells it improved growth, oxygen consumption, ATP-related measures
and mitochondrial phosphate/copper content while lowering extracellular lactate. This preclinical
cell study did not test SLC25A3 patient cells or establish animal or human efficacy.
therapeutic_modality: PROTEIN_REPLACEMENT
context: >-
Preclinical HeLa siRNA model; delivery also examined in HEK293 and HepG2 cells.
treatment_term:
preferred_term: Protein Replacement Therapy
term:
id: NCIT:C16221
label: Protein Replacement Therapy
target_mechanisms:
- target: Reduced Mitochondrial Phosphate Carrier Function
treatment_effect: RESTORES
description: >-
Exogenous carrier protein delivered into mitochondria substitutes for the
deficient endogenous carrier, restoring matrix phosphate transport.
evidence:
- reference: PMID:40362619
reference_title: "Rescue of the First Mitochondrial Membrane Carrier, the mPiC, by TAT-Mediated Protein Replacement Treatment."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Treatment of mPiC-knockdown cells with TAT-mPiC fusion protein increased cell growth and improved bioenergetic capabilities, as measured by oxygen consumption rate (OCR), ATP production, and reduction in lactate secretion."
explanation: Demonstrates functional rescue of the bioenergetic defect in vitro.
- reference: PMID:40362619
reference_title: "Rescue of the First Mitochondrial Membrane Carrier, the mPiC, by TAT-Mediated Protein Replacement Treatment."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "This study presents the first successful delivery of a mitochondrial transmembrane carrier using the TAT-fusion system, offering a potential early treatment strategy for newborns with mPiC deficiency."
explanation: The authors frame this explicitly as a potential, not established, treatment strategy.
- reference: PMID:40362619
reference_title: "Rescue of the First Mitochondrial Membrane Carrier, the mPiC, by TAT-Mediated Protein Replacement Treatment."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: This study was conducted in vitro, however, in vivo testing in animal models is crucial to assess the systemic effects and potential therapeutic benefits of TAT-mPiC treatment in MPCD or other mitochondrial disorders.
explanation: >-
Explicit study limitation.
- name: Mitochondrial Transplantation (investigational, preclinical)
description: >-
Mitochondrial transplantation was investigated in CRISPR-engineered SLC25A3 knockout or missense hiPSC-derived
cardiomyocytes. The retrieved abstract frames this as an exploratory rescue strategy; it provides
no clinical efficacy evidence.
therapeutic_modality: OTHER
context: >-
Preclinical engineered hiPSC-derived cardiomyocytes; human treatment efficacy is not established.
treatment_term:
preferred_term: mitochondrial transplantation
target_mechanisms:
- target: Cardiomyocyte and Skeletal Muscle Bioenergetic Stress
treatment_effect: RESTORES
description: >-
Supplying functional mitochondria is intended to relieve the cardiomyocyte
bioenergetic deficit that drives the hypertrophic response.
evidence:
- reference: PMID:39671292
reference_title: "Mitochondrial transplantation rescues Ca(2+) homeostasis imbalance and myocardial hypertrophy in SLC25A3-related hypertrophic cardiomyopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Finally, we explored the prospective therapeutic implications of mitochondrial transplantation in rescuing SLC25A3-related HCM."
explanation: >-
The abstract documents exploration of mitochondrial transplantation, with limited intervention detail
in the retrieved text.
notes: >-
Needs an NCIT clinical-action term for transfer of isolated mitochondria. OLS4 searches on 2026-10-04 using ontology=ncit and rows=5: q='mitochondrial transplantation' returned only NCIT:C190625 CPS1 wt Allele; q='mitochondria transplantation' and q='organelle transplantation' returned no results. None describes this procedure, so the descriptor is unbound. Organelles rather than whole cells are transferred.
- name: Heart Transplantation
description: >-
A compound-genotype infant with progressive cardiac failure underwent orthotopic heart transplantation
at seven months. The postoperative course included respiratory and other complications; discharge
home occurred at eleven months with close follow-up. This establishes feasibility in one case, not
general candidacy or long-term outcome.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: Heart Transplantation
term:
id: NCIT:C15246
label: Heart Transplantation
evidence:
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4501241/?pdf=1
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis - PMC"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: At 7 months of life, the patient underwent an orthotopic cardiac transplant.
explanation: >-
Documented transplantation.
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC4501241/?pdf=1
reference_title: "Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis - PMC"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: He was able to be discharged home at 11 months of age and was doing well with close follow-up.
explanation: >-
Early post-transplant outcome only.
- name: Meclizine in a Cardiac Knockout Model (preprint, preclinical)
description: >-
A 2025 bioRxiv preprint reports improved hypertrophy, systolic function and mitochondrial ultrastructure
in cardiomyocyte-specific Slc25a3 knockout mice treated from the onset of deletion. Mitochondrial
ATP production was not restored. MICOS-associated structural changes and improved NAD+/NADH balance
were associated findings; their causal ordering remains unresolved. This does not establish efficacy
or a dose for patients.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: Meclizine
term:
id: CHEBI:6709
label: Meclizine
context: Unreviewed preprint; preventive/concurrent treatment in an inducible mouse model, not reversal of established human disease.
target_mechanisms:
- target: Disordered Mitochondrial Cristae
treatment_effect: RESTORES
description: Improved cristae ultrastructure in the treated mouse hearts.
evidence:
- reference: PMID:40950028
reference_title: Meclizine rescues cardiac function and mitochondrial ultrastructure by ATP- and glycolysis-independent mechanisms in a genetic model of mitochondrial energy dysfunction.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Chronic meclizine treatment in SLC25A3-deficient mice attenuated cardiac hypertrophy, improved systolic function, and restored mitochondrial ultrastructure.
explanation: >-
Animal intervention result from a preprint, not a clinical treatment recommendation.
- reference: PMID:40950028
reference_title: Meclizine rescues cardiac function and mitochondrial ultrastructure by ATP- and glycolysis-independent mechanisms in a genetic model of mitochondrial energy dysfunction.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: meclizine treatment did not further increase ATP content of the Slc25a3fl/flxMCM hearts
explanation: >-
Benefit did not reflect increased bulk cardiac ATP.
discussions:
- discussion_id: mismatch_copper_cox_arm_not_seen_in_patients
kind: HUMAN_MODEL_MISMATCH
status: OPEN
prompt: >-
How much do copper transport, phosphate supply and mitochondrial organization each contribute to human
SLC25A3 disease across alleles and tissues?
attaches_to:
- pathophysiology#Reduced Mitochondrial Copper Delivery
- pathophysiology#Impaired Cytochrome c Oxidase Biogenesis
- pathophysiology#Reduced Mitochondrial ATP Synthesis
rationale: >-
Direct transport and copper-selective rescue establish a copper-dependent carrier function in models,
and human G72E has been tested in engineered fibroblasts. Patient studies, however, use different
tissues and assays: some report normal respiratory-chain activity, while the founding paper gives
COX 81 U/g against a 90–281 reference range in one sibling, later highlighted by Boulet et al. as
a possible mild deficiency. Increased COX histochemical staining in another patient is not the same
measurement. These observations limit a uniform clinical COX-deficiency claim without refuting carrier
copper transport. Residual isoforms, allele, developmental timing and assay conditions require matched
investigation.
proposed_experiments:
- experiment_id: exp_slc25a3_isoform_copper_cox
name: Isoform-resolved copper transport and COX metalation assay
description: >-
Compare isogenic human cardiomyocytes carrying G72E, the recurrent splice variant, shared-exon variants
and corrected controls. Measure isoform abundance, phosphate flux, matrix copper, COX assembly and
activity under matched conditions. Copper-selective rescue would help separate substrate effects;
translation to clinical tissues requires direct validation.
experiment_type:
preferred_term: iPSC-derived cardiomyocyte perturbation assay
model_systems:
- name: Human iPSC-derived cardiomyocyte
description: >-
Human isogenic cardiomyocytes with patient alleles and corrected controls to extend existing engineered
mouse-cell evidence.
experimental_model_type: OTHER
evidence:
- reference: PMID:33591272
reference_title: Mitochondrial copper and phosphate transporter specificity was defined early in the evolution of eukaryotes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: In SLC25A3, the L175A mutation separates Cu and phosphate transport by fully restoring COX activity and mitochondrial Cu levels without rescuing phosphate transport.
explanation: >-
Engineered separation-of-function construct establishes the copper-dependent COX effect in cells.
- reference: PMID:29237729
reference_title: The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: the data presented suggest that loss of SLC25A3 in muscle results in a mild, isolated COX deficiency
explanation: >-
Boulet et al. reinterpret a quantitative value from the founding clinical report; this is not a
new patient assay.
quote_role: BACKGROUND
- reference: PMID:21763135
reference_title: "Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In a muscle biopsy normal activity of respiratory chain enzymes was found; however the amount of the mitochondrial phosphate carrier was decreased."
explanation: >-
Normal enzyme activity in this muscle biopsy illustrates assay/tissue heterogeneity; it does not
refute the molecular transport function.
- discussion_id: gap_genotype_phenotype_severity_spectrum
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
What determines whether an individual with biallelic SLC25A3 variants dies in
the first year of life or survives into adulthood with non-progressive
hypertrophic cardiomyopathy?
attaches_to:
- pathophysiology#Cardiomyocyte and Skeletal Muscle Bioenergetic Stress
rationale: >-
Published outcomes include infantile death, stable childhood or adult survival, and survival after
transplantation. The recurrent splice allele itself occurs with both early death and longer survival.
Residual transcript/protein, isoform compensation, modifiers and supportive treatment are plausible
contributors but are not resolved by these small reports; a genotype alone should not be treated as
prognostic.
evidence:
- reference: PMID:40944834
reference_title: "Expanding the Clinical Spectrum of Mitochondrial Phosphate Carrier Deficiency: A Case Report With Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This case supports the expansion of the clinical spectrum of mitochondrial PiC deficiency by presenting a patient with a later-onset phenotype compared to previously reported cases."
explanation: Documents that the phenotypic spectrum is still expanding and is not yet explained.
animal_models:
- name: Inducible cardiomyocyte-specific Slc25a3 deletion
species: Mus musculus
genotype: Slc25a3 floxed; alpha-MHC-MerCreMer
description: >-
Adult inducible deletion reduces mitochondrial phosphate uptake and ATP synthesis while preserving
bulk cardiac ATP. Longer deletion produces hypertrophy, dilation, systolic dysfunction and disrupted
ultrastructure. Acute MPTP desensitization and ischemia-reperfusion protection are distinct from the
chronic cardiomyopathy.
publication: PMID:24658400
modeled_mechanisms:
- target: Reduced Mitochondrial Phosphate Import
relationship: MEASURES
description: Reduced phosphate uptake in isolated cardiac mitochondria.
- target: Cardiomyocyte Hypertrophic Remodeling
relationship: RECAPITULATES
description: Hypertrophy and ventricular dysfunction after sustained deletion.
evidence:
- reference: PMID:24658400
reference_title: Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Loss of PiC protein did not prevent MPTP opening, suggesting it is not a direct pore-forming component of this complex.
explanation: >-
Loss modulates rather than abolishes permeability transition.
- reference: PMID:24658400
reference_title: "Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "deletion of the Slc25a3 gene from the heart long-term resulted in profound hypertrophy with ventricular dilation and depressed cardiac function, all features that reflect the cardiomyopathy observed in humans with mutations in SLC25A3"
explanation: Cardiac-specific Slc25a3 deletion in mice is sufficient to produce hypertrophy, ventricular remodeling, and contractile dysfunction, matching the human cardiomyopathy.
- reference: PMID:24658400
reference_title: Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Notably, despite the impairment in mitochondrial ATP production, total cardiac tissue ATP levels were maintained
explanation: >-
Supports the model description of maintained bulk cardiac ATP despite reduced mitochondrial ATP-generating capacity; it is not supporting evidence for total ATP depletion.
notes: >-
Conditional adult total-gene deletion differs from congenital isoform-specific human alleles. PMID:40950028
tested concurrent meclizine treatment in this model; it is a preprint.
experimental_models:
- name: Patient-derived shared-exon variant fibroblasts
experimental_model_type: PRIMARY_CELL_CULTURE
description: >-
Skin fibroblasts from the compound L200W/delins patient show reduced carrier protein, slower proliferation,
impaired intact-cell respiration and reduced mitochondrial fusion. Maximal phosphorylating respiration
in permeabilized cells remains preserved.
publication: PMID:27780865
modeled_mechanisms:
- target: Reduced Mitochondrial Fusion
relationship: MEASURES
description: >-
Live-cell measurements show reduced network connectivity and fusion.
- target: Reduced Carrier Protein Abundance
relationship: MEASURES
description: >-
Reduced carrier abundance despite unchanged RNA.
evidence:
- reference: PMID:27780865
reference_title: "Natural and Induced Mitochondrial Phosphate Carrier Loss: DIFFERENTIAL DEPENDENCE OF MITOCHONDRIAL METABOLISM AND DYNAMICS AND CELL SURVIVAL ON THE EXTENT OF DEPLETION."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: proliferation ceased when only mitochondrial substrate was provided.
explanation: >-
Substrate-challenge growth defect in the patient cells.
cell_source: Patient-derived skin fibroblasts
- name: Engineered SLC25A3 hiPSC-derived cardiomyocytes
experimental_model_type: IPSC_DERIVED_MODEL
description: >-
CRISPR-generated knockout and missense (reported c.C544T, c.A547G, c.C349T) models show hypertrophy,
diastolic dysfunction, calcium imbalance and metabolic abnormalities; these are not patient-derived
lines.
publication: PMID:39671292
modeled_mechanisms:
- target: Cardiomyocyte Calcium Homeostasis Imbalance
relationship: MEASURES
description: >-
Calcium homeostasis and diastolic dysfunction are measured.
- target: Cardiomyocyte Hypertrophic Remodeling
relationship: MEASURES
description: >-
Cellular hypertrophy is reproduced.
evidence:
- reference: PMID:39671292
reference_title: "Mitochondrial transplantation rescues Ca(2+) homeostasis imbalance and myocardial hypertrophy in SLC25A3-related hypertrophic cardiomyopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "These SLC25A3-KO or missense mutation hiPSC-CMs recapitulated the disease phenotype associated with myocardial hypertrophy, including diastolic dysfunction, Ca2+ homeostasis imbalance, and mitochondrial energy metabolism dysfunction."
explanation: >-
CRISPR-engineered human cardiomyocytes reproduce selected metabolic and contractile features.
cell_source: CRISPR-engineered human induced pluripotent stem cells
- name: Carrier-depleted HeLa cells with TAT-mPiC rescue
experimental_model_type: CELL_LINE
description: >-
siRNA against shared exons depletes both isoforms. Added TAT-mPiC improves carrier-dependent bioenergetic
and transport readouts; delivery was also examined in other cell lines.
publication: PMID:40362619
modeled_mechanisms:
- target: Reduced Mitochondrial Phosphate Import
relationship: MEASURES
description: >-
Mitochondrial phosphate content responds to depletion and replacement.
- target: Reduced Mitochondrial Copper Delivery
relationship: MEASURES
description: >-
Mitochondrial copper content responds to depletion and replacement.
evidence:
- reference: PMID:40362619
reference_title: "Rescue of the First Mitochondrial Membrane Carrier, the mPiC, by TAT-Mediated Protein Replacement Treatment."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Treatment of mPiC-knockdown cells with TAT-mPiC fusion protein increased cell growth and improved bioenergetic capabilities, as measured by oxygen consumption rate (OCR), ATP production, and reduction in lactate secretion."
explanation: Demonstrates functional rescue of the bioenergetic defect in vitro.
cell_source: HeLa cells
- name: Copper-selective rescue in Slc25a3-null fibroblasts
experimental_model_type: CELL_LINE
description: >-
Engineered mouse fibroblasts expressing the L175A carrier regain mitochondrial copper and COX despite
defective phosphate transport. The construct tests substrate specificity and is not a human disease
allele.
publication: PMID:33591272
modeled_mechanisms:
- target: Impaired Cytochrome c Oxidase Biogenesis
relationship: MEASURES
description: >-
Separation-of-function rescue tests the copper requirement for COX.
evidence:
- reference: PMID:33591272
reference_title: Mitochondrial copper and phosphate transporter specificity was defined early in the evolution of eukaryotes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: In SLC25A3, the L175A mutation separates Cu and phosphate transport by fully restoring COX activity and mitochondrial Cu levels without rescuing phosphate transport.
explanation: >-
Engineered separation-of-function construct establishes the copper-dependent COX effect in cells.
cell_source: Engineered mouse embryonic fibroblasts
- name: Human G72E rescue assays in mouse fibroblasts
experimental_model_type: CELL_LINE
description: >-
Slc25a3-null and Drp1/Slc25a3 double-null fibroblasts distinguish cristae/respiration defects from
the flickering and OPA1-processing response to impaired fission. G72E fails selected rescue assays
despite comparable expression.
publication: PMID:38986607
modeled_mechanisms:
- target: Reduced Mitochondrial Copper Delivery
relationship: MEASURES
description: >-
Mitochondrial copper measured in double-null cells expressing human G72E.
- target: Disordered Mitochondrial Cristae
relationship: MEASURES
description: >-
Cristae and respiration measured in Slc25a3-null cells.
evidence:
- reference: PMID:38986607
reference_title: Slc25a3-dependent copper transport controls flickering-induced Opa1 processing for mitochondrial safeguard.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Finally, atomic absorption spectrometry of isolated mitochondria showed that Slc25a3 (G72E) could not replenish mitochondrial copper levels in Drp1Slc25a3-KO MEFs (Fig. 7L).
explanation: >-
Patient-allele functional test in engineered mouse embryonic fibroblasts, not patient muscle.
cell_source: Engineered mouse embryonic fibroblasts
notes: >-
The Drp1-deficient context links reduced copper-dependent membrane-potential flickering to OMA1-dependent
OPA1 processing and mitochondrial morphology. This stress-specific pathway is distinct from the basal
fusion defect without altered OPA1 processing reported in the 2016 patient fibroblasts.
- name: Slc25a3-depleted differentiated myotubes (preprint)
experimental_model_type: CELL_LINE
description: >-
A June 2026 bioRxiv preprint reports reduced survival after knockdown in fully differentiated C2C12
and primary mouse myotubes. Either isoform, added copper, or a copper-selective isoform-A L176A construct
rescues selected survival readouts. Differentiation and survival are distinct endpoints; patient benefit
remains untested.
publication: PMID:42282837
modeled_mechanisms:
- target: Reduced Mitochondrial Copper Delivery
relationship: MEASURES
description: >-
Copper-selective rescue tests the substrate requirement for myotube survival.
evidence:
- reference: PMID:42282837
reference_title: Copper transport to mitochondria by SLC25A3 contributes to skeletal myoblast differentiation and is required for survival of differentiated myotubes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Knockdown of Slc25a3 in primary murine myotubes also led to cell death within 48 hours
explanation: >-
Preprint result in cultured mouse myotubes.
- reference: PMID:42282837
reference_title: Copper transport to mitochondria by SLC25A3 contributes to skeletal myoblast differentiation and is required for survival of differentiated myotubes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: survival of SLC25A3 deficient myotubes was restored by exogenous copper or expression of an SLC25A3 variant that transports copper but not phosphate.
explanation: >-
Preprint rescue result; not evidence for clinical copper treatment.
cell_source: C2C12 and primary mouse myotubes
notes: Preprint; not peer reviewed at the retrieved version.
References & Deep Research
References
16Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation.
No top-level findings curated for this source.
Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children.
No top-level findings curated for this source.
Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy.
No top-level findings curated for this source.
Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis.
No top-level findings curated for this source.
Natural and Induced Mitochondrial Phosphate Carrier Loss: DIFFERENTIAL DEPENDENCE OF MITOCHONDRIAL METABOLISM AND DYNAMICS AND CELL SURVIVAL ON THE EXTENT OF DEPLETION.
No top-level findings curated for this source.
The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis.
No top-level findings curated for this source.
Mitochondrial copper and phosphate transporter specificity was defined early in the evolution of eukaryotes.
No top-level findings curated for this source.
Mitochondrial phosphate-carrier deficiency mimicking infantile-onset Pompe disease.
No top-level findings curated for this source.
Slc25a3-dependent copper transport controls flickering-induced Opa1 processing for mitochondrial safeguard.
No top-level findings curated for this source.
Mitochondrial transplantation rescues Ca(2+) homeostasis imbalance and myocardial hypertrophy in SLC25A3-related hypertrophic cardiomyopathy.
No top-level findings curated for this source.
Rescue of the First Mitochondrial Membrane Carrier, the mPiC, by TAT-Mediated Protein Replacement Treatment.
No top-level findings curated for this source.
Expanding the Clinical Spectrum of Mitochondrial Phosphate Carrier Deficiency: A Case Report With Literature Review.
No top-level findings curated for this source.
Meclizine rescues cardiac function and mitochondrial ultrastructure by ATP- and glycolysis-independent mechanisms in a genetic model of mitochondrial energy dysfunction.
No top-level findings curated for this source.
Copper transport to mitochondria by SLC25A3 contributes to skeletal myoblast differentiation and is required for survival of differentiated myotubes.
No top-level findings curated for this source.
Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy/Skeletal Myopathy Phenotype With and Without Lactic Acidosis - PMC
No top-level findings curated for this source.
Natural and Induced Mitochondrial Phosphate Carrier Loss: DIFFERENTIAL DEPENDENCE OF MITOCHONDRIAL METABOLISM AND DYNAMICS AND CELL SURVIVAL ON THE EXTENT OF DEPLETION - PMC
No top-level findings curated for this source.
Deep Research
1Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Evaluations and curation notes (1)
Create: Cardiomyopathy-Hypotonia-Lactic Acidosis Syndrome (SLC25A3) · 2026-08-01T01:49:23Z · View source
REJECTED DEEP-RESEARCH REPORT (Named Entity Confusion). The Edison/Falcon run at research/Cardiomyopathy-Hypotonia-Lactic_Acidosis_Syndrome-deep-research-falcon.md is a confirmed NEC failure and was NOT used as a curation source. It contains zero mentions of SLC25A3 or "phosphate carrier" across 102KB and 57 mentions of MIPEP, and its executive summary maps the disease name to MIPEP-related combined oxidative phosphorylation deficiency 31 (COXPD31 / Eldomery-Sutton syndrome, OMIM 617228) rather than to SLC25A3 / MONDO:0012557 / OMIM 610773 / ORPHA:91130. Per the CLAUDE.md NEC rule the report was discarded entirely rather than cherry-picked; the report, its citations sidecar, and its artifacts directory are still committed as DR provenance. MIPEP/COXPD31-specific features (left ventricular noncompaction, cataracts, seizures, Wolff-Parkinson-White) were deliberately NOT curated into this entry. See tracking issue #7510. Target identity was verified independently with OAK against MONDO:0012557 (relationship RO:0004003 HGNC:10989 SLC25A3; xref OMIM:610773; xref Orphanet:91130; the definition names the exon 3A SLC25A3 mutation). The entry was then rebuilt from primary literature anchored on SLC25A3. Anchor papers (all fetched with just fetch-reference and read in full): PMID:17273968 Mayr 2007 AJHG - index report, two Turkish sisters, homozygous exon 3A c.215G>A p.Gly72Glu, yeast complementation, muscle-versus-fibroblast ATP-synthesis dissociation; PMID:21763135 Mayr 2011 - family with three affected children, homozygous c.158-9A>G, reduced carrier protein with NORMAL respiratory-chain enzyme activities; PMID:25681081 Bhoj 2015 - two new patients, phenotype expansion (isolated cardiomyopathy without myopathy or lactic acidosis), compound heterozygote; PMID:38656665 - infantile Pompe mimic; PMID:40944834 - 2026 case report plus literature review, 32-year-old survivor; PMID:24658400 Kwong 2014 - cardiac-specific Slc25a3-null mouse; PMID:29237729 Boulet 2018 - SLC25A3 as mitochondrial copper transporter required for COX biogenesis; PMID:39671292 Li 2024 - SLC25A3 hiPSC-cardiomyocyte disease model; PMID:40362619 Zabit 2025 - TAT-mPiC protein replacement; PMID:8980128 Dolce 1996 and PMID:9712911 Fiermonte 1998 - exon IIIA/IIIB isoform tissue distribution and transport kinetics. Curated content: 8 pathophysiology nodes forming a single connected chain (tissue-specific exon 3A/3B splicing -> carrier loss in heart/skeletal muscle -> reduced matrix inorganic phosphate -> ATP synthase substrate limitation and impaired oxidative phosphorylation -> striated-muscle energy deficit -> cardiomyocyte hypertrophy/ventricular remodeling, with a parallel compensatory-glycolysis/lactate branch and a PROVISIONAL copper/COX arm); 9 phenotypes with HPO terms; 4 biochemical markers; 1 genetic block with 3 SLC25A3 variants; 3 progression phases; 1 diagnosis and 1 differential-diagnosis entry; 5 treatments; and 2 discussions (a HUMAN_MODEL_MISMATCH on the copper/COX arm versus normal patient respiratory-chain enzymes, and a KNOWLEDGE_GAP on the unexplained genotype-phenotype severity spectrum). 73 evidence snippets, all exact substrings of cached abstracts. Module conformance: asserted against kb/modules/cardiomyopathy_maladaptive_remodeling.yaml at #Primary Cardiomyocyte Insult (the metabolic/bioenergetic cardiomyocyte insult) and #Ventricular Remodeling (supported directly by the cardiac Slc25a3-null mouse). The module's intervening neurohormonal-activation step is explicitly NOT asserted because no disease-specific evidence exists for it. Deliberate omissions and modeling decisions: no phenotype frequency bands are asserted anywhere - the published cohort (fewer than about a dozen molecularly confirmed patients) cannot support them. Prevalence uses measure_type CASES_IN_LITERATURE with prevalence_class ULTRA_RARE, never the deprecated percentage field. Death in infancy is curated under progression rather than phenotypes because HP:0001522 sits in the HPO Mortality/Aging branch, outside the PhenotypeTerm dynamic enum (matching the precedent in Isolated_Sulfite_Oxidase_Deficiency and MOPD Type I). No GeneReviews chapter exists (PubMed search "SLC25A3 GeneReviews" returned 0 hits on 2026-07-31), so the usual GeneReviews phenotype baseline was unavailable; this is documented in the entry notes. ORPHA:91130 was NOT cited: upstream Orphadata en_product1.xml has drifted from the sha256 pinned in data/orphadata/MANIFEST.yaml (54026799 vs 53331679 bytes), so just refresh-orphadata fails its checksum gate and the ORPHA cache file could not be built reproducibly against the pinned snapshot. PMID:40505409 (Spanish family, Med Clin Barc 2025) was fetched but has no abstract in PubMed, so it could not supply a verifiable snippet and is not cited. No reference_ranges were added for lactate because no citable interval could be sourced. No clinical trials exist for this disorder. Two treatments (TAT-mPiC protein replacement, mitochondrial transplantation) are labelled investigational/preclinical in name, description, and context so they cannot be mistaken for clinical options. Validation: just validate PASS (schema + terms + references); just validate-terms PASS; just validate-references PASS with 73/73 snippets verified against cached references; just compliance 89.0% global / 89.4% weighted; just validate-graphs shows no errors for this entry (pre-existing failures in other files only); pytest tests/test_data.py conformance and foreign-key subset 6841 passed. Treatment terms initially drafted with MAXO:0000088 and MAXO:0000079 were switched to NCIT:C15447 (Dietary Intervention) and NCIT:C15240 (Genetic Counseling) because the TreatmentActionTerm dynamic enum is reachable only from NCIT:C25218 and rejects MAXO ids, despite CLAUDE.md listing MAXO terms as usable there - worth flagging as a documentation/schema inconsistency.
Falcon
▸
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Disease Characteristics Research Template
Target Disease
- Disease Name: Cardiomyopathy-Hypotonia-Lactic Acidosis Syndrome
- MONDO ID: (if available)
- Category: Mendelian
Research Objectives
Please provide a comprehensive research report on Cardiomyopathy-Hypotonia-Lactic Acidosis Syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.
For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.
1. Disease Information
Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed
- What is the disease? Provide a concise overview.
- What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
- What are the common synonyms and alternative names?
- Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?
2. Etiology
- Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
- Risk Factors:
Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
- Genetic risk factors (causal variants, susceptibility loci, modifier genes)
- Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
- Protective Factors:
Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
- Genetic protective factors (protective variants, modifier alleles)
- Environmental protective factors (diet, lifestyle, exposures that reduce risk)
- Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?
Search first: CTD, PubMed, PheGenI, GxE databases
3. Phenotypes
Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC
For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities
For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype
4. Genetic/Molecular Information
- Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)
Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
- Pathogenic Variants:
- Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
- Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
- Variant type/class (missense, frameshift, nonsense, splice-site, structural)
- Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
- Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
- Functional consequences (loss of function, gain of function, dominant negative)
- Modifier Genes: Genes that modify disease severity or expression
- Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease
Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
- Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)
Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser
5. Environmental Information
- Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)
Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
- Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)
Search first: CDC databases, WHO, PubMed, NHANES
- Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)
Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON
6. Mechanism / Pathophysiology
- Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)
Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
- Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)
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- Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)
Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
- Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)
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- Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)
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- Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)
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- Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)
Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
- Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease
Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
- Molecular Profiling (if available):
- Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
- Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
- Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
- Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
- Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
- Advanced Technologies (if applicable):
- Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
- Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
- Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
- Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS
For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types
7. Anatomical Structures Affected
- Organ Level:
- Primary organs directly affected
- Secondary organ involvement (complications, secondary effects)
- Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)
Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
- Tissue and Cell Level:
- Specific tissue types affected (epithelial, connective, muscle, nervous)
- Specific cell populations targeted (with Cell Ontology terms)
Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
- Subcellular Level:
- Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)
Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
- Localization:
- Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
- Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases
8. Temporal Development
- Onset:
- Typical age of onset (congenital, pediatric, adult, geriatric)
- Onset pattern (acute, subacute, chronic, insidious)
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- Progression:
- Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
- Progression rate (rapid, slow, variable)
- Disease course pattern (episodic, relapsing-remitting, progressive, stable)
- Disease duration (self-limited, chronic lifelong)
Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
- Patterns:
- Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
- Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines
9. Inheritance and Population
- Epidemiology:
- Prevalence (cases per 100,000 at given time)
- Incidence (new cases per 100,000 per year)
Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
- For Genetic Etiology:
- Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
- Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
- Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
- Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
- Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
- Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
- Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
- Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
- Population Demographics:
- Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
- Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
- Geographic distribution of specific variants
- Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
- Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet
10. Diagnostics
- Clinical Tests:
- Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
- Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
- Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
- Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
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- Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
- Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
- Genetic Testing:
Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
- Overview of recommended genetic testing approach
- Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
- Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
- Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
- Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
- Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
- Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
- FISH > Search first: ClinVar, cytogenetics databases, PubMed
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- Omics-Based Diagnostics (if applicable):
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- Clinical Criteria:
- Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
- Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
- Screening:
- Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR
11. Outcome/Prognosis
- Survival and Mortality:
- Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
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- Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
- Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
- Morbidity and Function:
- Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
- Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
- Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
- Disease Course:
- Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
- Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
- Prediction:
- Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
- Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases
12. Treatment
- Pharmacotherapy:
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- Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
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- Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
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- Surgical and Interventional:
- Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
- Supportive and Rehabilitative:
- Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
- Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
- Experimental:
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- Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
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- Treatment Strategy:
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- Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
- Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases
For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.
13. Prevention
- Prevention Levels:
- Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
- Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
- Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
- Immunization: Vaccine strategies (if applicable)
Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
- Screening and Early Detection:
- Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
- Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
- Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
- Behavioral Interventions: Lifestyle modifications to reduce risk
Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
- Counseling: Genetic counseling (risk assessment, family planning guidance)
Search first: NSGC resources, ACMG guidelines, GeneReviews
- Public Health:
- Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
- Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
- Prophylaxis: Preventive medications or procedures
Search first: Clinical guidelines, FDA approvals, PubMed
14. Other Species / Natural Disease
- Taxonomy: Species affected (with NCBI Taxon identifiers)
Search first: NCBI Taxonomy
- Breed: Specific breeds affected (with VBO identifiers if applicable)
Search first: VBO (Vertebrate Breed Ontology)
- Gene: Orthologous genes in other species (with NCBI Gene IDs)
Search first: NCBI Gene
- Natural Disease:
- Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
- Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
- Comparative Biology:
- Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
- Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
- Transmission (if applicable):
- Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
- Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed
15. Model Organisms
- Model Types:
- Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
- Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
- Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
- Genetic Models:
- Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
- Model Characteristics:
- Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
- Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
- Applications:
- Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
- Resources:
- Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC
Citation Requirements
- Cite primary literature (PMID preferred) for all mechanistic and clinical claims
- Prioritize recent reviews and landmark papers
- Include direct quotes from abstracts where possible to support key statements
- Distinguish evidence source types: human clinical, model organism, in vitro, computational
Output Format
Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease
This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details
Cardiomyopathy–Hypotonia–Lactic Acidosis Syndrome
Executive summary
Cardiomyopathy–Hypotonia–Lactic Acidosis Syndrome is best mapped to MIPEP-related combined oxidative phosphorylation deficiency 31 (COXPD31), also called Eldomery–Sutton syndrome. It is an ultra-rare, autosomal-recessive mitochondrial proteostasis disorder caused by biallelic loss-of-function variants in MIPEP, which encodes mitochondrial intermediate peptidase (MIP). The defining presentation is neonatal or infantile cardiomyopathy—particularly left-ventricular noncompaction (LVNC), hypertrophic cardiomyopathy (HCM), or dilated cardiomyopathy (DCM)—with severe hypotonia, developmental impairment, seizures, and variably severe lactic acidosis. The original four-patient series reported death before age three years in three patients, indicating a frequently severe prognosis, although later reports suggest a broader neurological phenotype and occasional survival beyond infancy. (eldomery2016mipeprecessivevariants pages 9-11, eldomery2016mipeprecessivevariants pages 1-2, ruijmbeek2025biallelicvariantsin pages 34-35)
The central causal chain is:
biallelic MIPEP dysfunction → failed secondary cleavage of imported mitochondrial preproteins → unstable or incompletely matured respiratory-chain and matrix proteins → defective oxidative phosphorylation and mitochondrial proteostasis → ATP deficiency and lactate accumulation → injury of energy-dependent cardiomyocytes, skeletal muscle, and neurons. (eldomery2016mipeprecessivevariants pages 9-11, eldomery2016mipeprecessivevariants pages 1-2)
The following table summarizes the evidence base and its limitations.
| domain | established finding | quantitative/patient evidence | suggested ontology terms | evidence level/limitations |
|---|---|---|---|---|
| Identity / nosology | The target condition maps best to MIPEP-related combined oxidative phosphorylation deficiency 31 (COXPD31), also described clinically as cardiomyopathy-hypotonia-lactic acidosis syndrome and Eldomery-Sutton syndrome; OMIM 617228 for the disorder and MIPEP gene OMIM 602241. Disease-level knowledge is derived from aggregated case reports/reviews rather than EHR-scale datasets. | Landmark discovery study reported 4 unrelated probands with a shared syndromic presentation; later reviews consistently refer to this as COXPD31. (eldomery2016mipeprecessivevariants pages 1-2, palmer2021mitochondrialproteinimport pages 10-13, wachoskidark2022mitochondrialproteinhomeostasis pages 9-10) | MONDO/Orphanet/ICD/MeSH mappings: database verification needed; NCIT: mitochondrial disease/cardiomyopathy terms may be mappable but need verification | Primary human evidence plus expert reviews. Limitation: ultra-rare disorder with very small published cohort; nomenclature varies across papers. |
| Gene / inheritance | Cause is biallelic pathogenic variation in MIPEP encoding mitochondrial intermediate peptidase (MIP). Inheritance is autosomal recessive. | Discovery cohort: 4/4 had biallelic MIPEP variants (compound heterozygous, homozygous, or SNV+deletion). Reviews explicitly label COXPD31 as a severe autosomal recessive disorder. (eldomery2016mipeprecessivevariants pages 1-2, palmer2021mitochondrialproteinimport pages 10-13, eldomery2016mipeprecessivevariants pages 2-4) | HGNC: MIPEP; GO CC/BP suggestions: mitochondrial matrix, protein maturation, mitochondrial protein processing; MONDO inheritance term/HP inheritance term: database verification needed | Strong primary genetic evidence. Limitations: penetrance, carrier frequency, founder effects, and population prevalence not established. |
| Core phenotypes | Core syndrome includes left ventricular non-compaction (LVNC)/cardiomyopathy, severe hypotonia, developmental delay, seizures, cataracts, with lactic acidemia/acidosis in several patients and broader multisystem disease. | In discovery cohort, shared predominant features were LVNC, developmental delay, seizures, hypotonia; 3/4 had infantile/childhood death. Specific subsets included cataract (patient 2), microcephaly and basal ganglia MRI abnormalities (patient 3), congenital hyperinsulinism and severe neonatal lactic acidosis (patient 4), metabolic myopathy on biopsy (patients 1,2,4). (eldomery2016mipeprecessivevariants pages 1-2, eldomery2016mipeprecessivevariants pages 2-4, eldomery2016mipeprecessivevariants pages 6-7, eldomery2016mipeprecessivevariants pages 7-9, eldomery2016mipeprecessivevariants pages 4-6) | HPO suggestions needing verification: cardiomyopathy/LV noncompaction, hypotonia, developmental delay, seizures, cataract, lactic acidosis, failure to thrive, microcephaly, hypertrophic cardiomyopathy, dilated cardiomyopathy, facial dysmorphism | Primary human case evidence. Limitations: frequencies beyond the first 4 cases are unknown; phenotype appears broader than original syndrome label. |
| Discovery variants | Reported pathogenic discovery variants included missense, nonsense, and CNV alleles affecting MIPEP. | Patient 1: c.1745T>G p.L582R + c.212T>A p.L71Q; Patient 2: c.916C>T p.L306F + c.1804G>T p.E602*; Patient 3: c.1027A>G p.K343E homozygous; Patient 4: c.1534C>G p.H512D + maternal 1.4-Mb 13q12.12 deletion including MIPEP. ExAC frequencies reported for p.L306F 8.2×10^-6 and p.H512D 3.2×10^-5; other four variants were novel at publication. (eldomery2016mipeprecessivevariants pages 1-2, eldomery2016mipeprecessivevariants pages 6-7, eldomery2016mipeprecessivevariants pages 4-6, eldomery2016mipeprecessivevariants media 166e4a99) | Sequence Ontology suggestions: missense variant, stop gained, copy number loss; ClinVar/ACMG status: current database verification needed | Primary genetic evidence with segregation/confirmation. Limitation: current ClinVar classifications and modern population frequencies require live database check. |
| Cardiac phenotype | Cardiac disease is central and variable, including LVNC, dilated cardiomyopathy, hypertrophic cardiomyopathy, and conduction abnormalities. | Patient 1: LVNC + Wolff-Parkinson-White; Patient 2: LVNC with dilated cardiomyopathy; Patient 3: left ventricular hypertrophy without outflow obstruction; Patient 4: severe biventricular hypertrophic cardiomyopathy with non-compaction and heart failure. Reviews summarize LVNC, DCM, and HCM within the syndrome. (eldomery2016mipeprecessivevariants pages 4-6, eldomery2016mipeprecessivevariants pages 6-7, eldomery2016mipeprecessivevariants pages 7-9, wachoskidark2022mitochondrialproteinhomeostasis pages 9-10, palmer2021mitochondrialproteinimport pages 10-13) | UBERON: heart/left ventricle; HPO suggestions: LV noncompaction, hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmia, heart failure | Primary case evidence plus reviews. Limitation: no formal natural-history series defining cardiac progression. |
| Biochemical / pathology findings | Disease behaves as a mitochondrial proteostasis / OXPHOS disorder with metabolic acidosis, lactate elevation, abnormal ETC studies, and muscle/cardiac mitochondrial pathology. | Reported values/examples: patient 1 lactate 3.2 mmol/L with anion gap 25; patient 3 lactate 4.4 and 11.1 mmol/L at admissions; patient 4 lactate 8.9–10.4 mmol/L. Muscle/cardiac pathology showed lipid droplets, glycogen deposition, mitochondrial proliferation/pleomorphism, enlarged mitochondria with bloated vesicular cristae; mild reductions in multiple respiratory complexes reported in some tissues. (eldomery2016mipeprecessivevariants pages 4-6, eldomery2016mipeprecessivevariants pages 6-7, eldomery2016mipeprecessivevariants pages 7-9, eldomery2016mipeprecessivevariants pages 9-11) | CHEBI suggestions: lactate, pyruvate; HPO suggestions: lactic acidosis, increased serum alanine, mitochondrial myopathy, abnormal mitochondrial morphology | Primary human biochemical/pathology evidence. Limitation: ETC abnormalities were variable and not uniformly quantified across patients/tissues. |
| Mechanism / pathophysiology | MIPEP/MIP performs secondary cleavage of imported mitochondrial preproteins after MPP. Loss of function causes defective maturation/stability of a subset of matrix proteins, accumulation of processing intermediates, impaired respiratory-chain function, and bioenergetic failure in energy-demanding tissues. | Background: ~70% of mitochondrial preproteins are nuclear-encoded/imported; about 25% of preproteins require a second cleavage by MIP/Oct1 or XPNPEP3/Icp55. Yeast homolog experiments showed patient-corresponding mutants caused loss of localization (L83Q corresponding to human L71Q) or markedly reduced protease activity (L339F/K376E corresponding to human L306F/K343E), with accumulation of substrates including Sdh4, Rip1, Cox4, Mdh1, Mrp21, Prx1, Mdj1, and respiratory-growth defects. (eldomery2016mipeprecessivevariants pages 1-2, eldomery2016mipeprecessivevariants pages 9-11, eldomery2016mipeprecessivevariants pages 7-9, palmer2021mitochondrialproteinimport pages 10-13, kunova2022mitochondrialprocessingpeptidases—structure pages 13-15) | GO BP suggestions: protein targeting to mitochondrion, mitochondrial protein processing, oxidative phosphorylation, respiratory electron transport chain, mitochondrial protein stabilization; GO CC: mitochondrial matrix, inner mitochondrial membrane; CL suggestions: cardiomyocyte, skeletal muscle cell, neuron (verification needed) | Strong mechanistic evidence from functional modeling and established mitochondrial biology. Limitation: direct human cell multi-omics and tissue-specific mechanistic studies remain sparse. |
| Diagnosis | Best-supported diagnostic approach is genomic testing in the setting of infantile mitochondrial disease plus targeted biochemical/cardiac workup. | Discovery used whole-exome sequencing, Sanger confirmation, and array CGH for the deletion case. Reviews/guidelines for primary mitochondrial disease support WES/NGS as first-line or early testing, with adjunctive lactate/pyruvate, amino acids, urine organic acids, ECG/echocardiography, neuroimaging, and muscle biopsy where needed. (eldomery2016mipeprecessivevariants pages 1-2, eldomery2016mipeprecessivevariants pages 2-4, muraresku2018mitochondrialdiseaseadvances pages 2-4, muraresku2018mitochondrialdiseaseadvances pages 4-5, sue2022patientcarestandards pages 4-7) | NCIT/LOINC/HPO mappings for WES, echocardiogram, ECG, lactic acidosis, muscle biopsy: database verification needed | Primary disease-specific evidence for WES, broader expert-consensus extrapolation for surveillance/diagnostic workflow. Limitation: no MIPEP-specific diagnostic criteria published. |
| Treatment / management | No MIPEP-specific disease-modifying therapy has been established. Current care is supportive and complication-directed, extrapolated from primary mitochondrial disease standards and pediatric cardiology/epilepsy care. | Real-world interventions in the cohort included cataract surgery, ventilatory support, metabolic workup, transplant listing, and Berlin assist device in patient 2. Broader mitochondrial guidance supports avoiding fasting, optimizing nutrition/hydration, prompt treatment of intercurrent illness, annual or baseline cardiac surveillance, seizure management with standard antiseizure drugs (expert preference often levetiracetam/benzodiazepines), rehabilitation, and individualized supplement use only when gene-specific evidence exists. No relevant MIPEP/COXPD31 clinical trial was identified in the trial searches. (eldomery2016mipeprecessivevariants pages 6-7, eldomery2016mipeprecessivevariants pages 7-9, muraresku2018mitochondrialdiseaseadvances pages 4-5, sue2022patientcarestandards pages 26-28, mancuso2024managementofseizures pages 4-5, muraresku2018mitochondrialdiseaseadvances pages 2-4, sue2022patientcarestandards pages 4-7, enns2017pediatricmitochondrialdiseases pages 1-2) | NCIT suggestions needing verification: supportive care, physical therapy, occupational therapy, anticonvulsant therapy, cardiac assist device, heart transplantation evaluation | Disease-specific care evidence is weak; mainly expert-consensus extrapolation from broader mitochondrial disease. Limitation: no controlled treatment data and no MIPEP-targeted therapy/trial found. |
| Prognosis / outcomes | Prognosis appears severe, often infantile-onset and frequently fatal, driven largely by cardiomyopathy and multisystem decompensation. | In the original 4-patient cohort, 3/4 (75%) died within the first 3 years of life; one child was alive at 4.5 years with ongoing neurologic morbidity. Deaths occurred in infancy/early childhood, including patient 3 at 11 months, patient 4 at 19 days, and patient 2 at 2 years. (eldomery2016mipeprecessivevariants pages 9-11, eldomery2016mipeprecessivevariants pages 6-7, eldomery2016mipeprecessivevariants pages 7-9) | HPO suggestions: infantile onset, early death, global developmental delay, progressive neurologic deterioration | Primary outcome evidence but from a tiny cohort. Limitation: life expectancy, stage-specific survival, and prognostic biomarkers are not yet defined. |
| Epidemiology / population | The disease is ultra-rare; no disease-specific prevalence, incidence, sex ratio, or carrier frequency estimates were identified. | Published evidence located only a handful of cases/references; broader mitochondrial disease prevalence data do not allow reliable COXPD31-specific estimates. (eldomery2016mipeprecessivevariants pages 1-2, palmer2021mitochondrialproteinimport pages 10-13, sue2022patientcarestandards pages 4-7) | MONDO/Orphanet prevalence fields: database verification needed | Evidence gap. Important to state as unknown rather than infer from primary mitochondrial disease generally. |
| Environmental / protective factors | No validated environmental causes, infectious triggers, gene-environment interactions, or protective factors are known for COXPD31 specifically. Clinical stressors likely worsen decompensation, as in other mitochondrial diseases. | Broader mitochondrial standards note vulnerability during intercurrent illness and metabolic stress, but this is extrapolated and not MIPEP-specific. (muraresku2018mitochondrialdiseaseadvances pages 4-5, sue2022patientcarestandards pages 4-7) | HPO/ExO/ENVO mappings: database verification needed | Extrapolated expert opinion only; no disease-specific studies. |
| Model organism | Functional disease modeling has been demonstrated in Saccharomyces cerevisiae using Oct1, the MIPEP ortholog. | Yeast mutants corresponding to human variants showed absent mitochondrial localization (L83Q/human L71Q), reduced protease activity (L339F and K376E corresponding to human L306F and K343E), accumulation of non-processed substrates, and failure of respiratory growth at high temperature. (eldomery2016mipeprecessivevariants pages 1-2, eldomery2016mipeprecessivevariants pages 7-9, eldomery2016mipeprecessivevariants pages 9-11) | NCBI Taxon suggestion: S. cerevisiae (verification needed); GO: mitochondrial protein processing, respiratory growth | Direct functional evidence. Limitation: yeast does not model human organ-level phenotypes such as LVNC, seizures, or cataracts. |
Table: This table summarizes the strongest available evidence for MIPEP-related combined oxidative phosphorylation deficiency 31, including identity, inheritance, phenotypes, variants, mechanism, diagnosis, treatment, prognosis, and model systems. It emphasizes what is established from primary reports versus what still requires database verification or extrapolation from broader mitochondrial disease guidance.
1. Disease information
Definition and identifiers
- Preferred disease name: MIPEP-related combined oxidative phosphorylation deficiency 31.
- Common synonyms: COXPD31; combined oxidative phosphorylation deficiency type 31; Eldomery–Sutton syndrome; MIPEP-related mitochondrial disease; cardiomyopathy–hypotonia–lactic acidosis syndrome.
- OMIM disease: 617228.
- Causal-gene OMIM: MIPEP, 602241.
- MONDO: a definitive COXPD31-specific MONDO identifier could not be verified from the retrieved resources; this field should remain pending rather than be populated with a similarly named COXPD subtype.
- Orphanet: no disease-specific ORPHA identifier was verified.
- ICD-10/ICD-11 and MeSH: no syndrome-specific code was identified. In practice, coding would use broader mitochondrial-metabolism and cardiomyopathy categories.
The landmark primary report was Eldomery et al., Genome Medicine, published November 2016, DOI 10.1186/s13073-016-0360-6. Its abstract states: “Loss of MIP function results in a syndrome which consists of LVNC, DD, seizures, hypotonia, and cataracts.” (eldomery2016mipeprecessivevariants pages 1-2)
The evidence is principally aggregated disease-level information derived from a handful of published patients, not an EHR cohort, registry, or population study.
2. Etiology, risk, and protective factors
Causal factor
The established cause is germline biallelic pathogenic variation in MIPEP on chromosome 13q12.12. Reported alleles include missense, nonsense, and copy-number-loss variants. This is a primary nuclear-genome mitochondrial disease, not a maternally inherited mtDNA disorder. (eldomery2016mipeprecessivevariants pages 2-4, eldomery2016mipeprecessivevariants pages 1-2)
Risk factors
- Genetic: having two deleterious MIPEP alleles is the only established risk factor.
- Family history/consanguinity: consanguinity increases the probability that both parents carry the same rare allele; one discovery patient was born to first cousins and was homozygous for p.K343E. Other patients were compound heterozygotes from non-consanguineous families. (eldomery2016mipeprecessivevariants pages 2-4, eldomery2016mipeprecessivevariants pages 7-9)
- Environmental, infectious, lifestyle, occupational, age, or sex risks: none are established as causes.
- Metabolic stress: fasting, infection, fever, surgery, and poor intake may precipitate decompensation in mitochondrial disease generally, but this has not been quantified specifically for MIPEP deficiency. (muraresku2018mitochondrialdiseaseadvances pages 4-5, sue2022patientcarestandards pages 4-7)
No protective MIPEP alleles, modifier genes, epigenetic protective factors, diets, or environmental exposures have been demonstrated. Gene–environment interaction evidence is limited to the general mitochondrial principle that reduced bioenergetic reserve makes patients vulnerable during catabolic stress.
3. Phenotypic spectrum
Because denominators are tiny, frequencies below refer primarily to the four unrelated discovery patients and should not be treated as population estimates.
| Phenotype | Characterization and evidence | Suggested HPO term |
|---|---|---|
| Cardiomyopathy/LVNC | Core, early-onset feature. LVNC occurred across the discovery cohort; phenotypes included LVNC-DCM, ventricular hypertrophy/HCM, and severe biventricular HCM. | HP:0011663 Left ventricular noncompaction; HP:0001639 Hypertrophic cardiomyopathy; HP:0001644 Dilated cardiomyopathy |
| Hypotonia | Severe infantile hypotonia was shared across the original cohort; one child later developed hypertonia and dystonic posturing. | HP:0001252 Hypotonia |
| Developmental delay | Global delay was a predominant shared feature; some children never attained expected motor milestones. | HP:0001263 Global developmental delay |
| Seizures | Shared predominant feature; onset ranged from infancy to within the first hour after birth. | HP:0001250 Seizure |
| Lactic acidemia/acidosis | Variable and episodic or persistent. Reported lactates included 3.2, 4.4, 8.9–10.4, and 11.1 mmol/L against a stated reference interval of 0.7–2.1 mmol/L. | HP:0003128 Lactic acidosis |
| Failure to thrive/feeding difficulty | Poor feeding and failure to thrive often emerged in the first months. | HP:0008872 Feeding difficulties in infancy; HP:0001508 Failure to thrive |
| Microcephaly | Present or acquired in some patients, not universal. | HP:0000252 Microcephaly |
| Cataract | Congenital/early cataract occurred in a subset and in an affected sibling. | HP:0000518 Cataract |
| Arrhythmia/conduction abnormality | One patient had Wolff–Parkinson–White syndrome. | HP:0001678 Abnormal heart morphology/function; HP:0001716 WPW pattern |
| Respiratory failure | Neonatal respiratory depression or later respiratory decompensation occurred in severe cases. | HP:0002878 Respiratory failure |
| Metabolic myopathy | Muscle showed mitochondrial proliferation, pleomorphism, lipid droplets, glycogen accumulation, and enlarged mitochondria with abnormal cristae. | HP:0003198 Myopathy; HP:0003200 Ragged-red-type mitochondrial pathology, if histologically confirmed |
| Neuroimaging abnormalities | Reported findings included bilateral basal-ganglia signal abnormalities, white-matter changes, neuronal loss, and rhombencephalosynapsis in one neonate. | HP:0002134 Abnormal basal ganglia MRI signal; HP:0002187 Neurodegeneration |
| GI/hepatic abnormalities | Vomiting, constipation, eosinophilic esophagitis, microcolon, and transient aminotransferase elevation occurred variably. | Corresponding feature-specific HPO terms |
Patient-level evidence includes LVNC with WPW at 5.5 months in patient 1, LVNC-DCM requiring mechanical circulatory support in patient 2, recurrent metabolic acidosis with lactate up to 11.1 mmol/L in patient 3, and severe neonatal biventricular HCM with lactate 8.9–10.4 mmol/L in patient 4. (eldomery2016mipeprecessivevariants pages 6-7, eldomery2016mipeprecessivevariants pages 7-9, eldomery2016mipeprecessivevariants pages 4-6)
Quality-of-life instruments such as EQ-5D, SF-36, or PROMIS have not been reported. Clinically, profound hypotonia, developmental disability, feeding problems, epilepsy, respiratory dependence, and heart failure severely impair mobility, self-care, communication, and survival.
4. Genetic and molecular information
Gene and protein
- Gene: MIPEP, mitochondrial intermediate peptidase.
- Reference transcript used in the discovery report: NM_005932.
- Location: chromosome 13q12.12; 19 exons.
- Protein location/function: mitochondrial matrix peptidase that removes an additional N-terminal octapeptide from selected proteins after initial cleavage by mitochondrial processing peptidase. MIPEP is highly expressed in heart, brain, skeletal muscle, and pancreas. (eldomery2016mipeprecessivevariants pages 1-2)
Discovery variants
- c.1745T>G, p.Leu582Arg, with c.212T>A, p.Leu71Gln.
- c.916C>T, p.Leu306Phe, with c.1804G>T, p.Glu602Ter.
- c.1027A>G, p.Lys343Glu, homozygous.
- c.1534C>G, p.His512Asp, in trans with a maternally inherited approximately 1.4-Mb 13q12.12 deletion encompassing MIPEP. (eldomery2016mipeprecessivevariants pages 6-7, eldomery2016mipeprecessivevariants media 166e4a99)
At publication, p.Leu582Arg, p.Leu71Gln, p.Glu602Ter, and p.Lys343Glu were absent from the queried population resources. p.Leu306Phe and p.His512Asp had ExAC heterozygous frequencies of 8.2×10⁻⁶ and 3.2×10⁻⁵, respectively. These historical frequencies should be rechecked in current gnomAD before knowledge-base ingestion. (eldomery2016mipeprecessivevariants pages 4-6, eldomery2016mipeprecessivevariants media 166e4a99)
All established disease alleles are germline. No somatic role, dominant-negative mechanism, gain of function, repeat expansion, aneuploidy, or recurrent balanced rearrangement is established. The functional data support loss of function, including failed mitochondrial localization, absent protein, or reduced catalytic activity. No validated modifier gene or disease-specific epigenetic signature has been reported.
5. Environmental information
No toxin, radiation, pollution, occupational exposure, diet, alcohol, smoking, or infectious agent causes COXPD31. Catabolic illness, fasting, and dehydration are clinically relevant potential stressors rather than etiologic factors. Routine vaccination and prompt infection management are generally favored to reduce metabolic stress; no MIPEP-specific immunization strategy exists. (muraresku2018mitochondrialdiseaseadvances pages 4-5)
6. Mechanism and pathophysiology
Approximately 70% of nuclear-encoded mitochondrial preproteins carry N-terminal targeting presequences. Following import, mitochondrial processing peptidase removes most of the targeting sequence; about one quarter of preproteins undergo secondary processing by MIP/Oct1 or XPNPEP3/Icp55. This secondary cleavage exposes stabilizing N termini and prevents degradation under the mitochondrial N-end rule. (eldomery2016mipeprecessivevariants pages 9-11, eldomery2016mipeprecessivevariants pages 1-2)
In yeast, variants corresponding to human p.Leu71Gln caused loss of detectable mitochondrial Oct1, whereas variants corresponding to p.Leu306Phe and p.Lys343Glu markedly reduced protease activity. Processing intermediates accumulated for Sdh4, Rip1, Cox4, Mdh1, Mrp21, Prx1, and Mdj1. These proteins span complexes II–IV, the tricarboxylic-acid cycle, mitochondrial ribosome, antioxidant defense, and chaperone systems. Mutant yeast showed severe respiratory-growth defects, linking impaired substrate maturation directly to OXPHOS failure. (eldomery2016mipeprecessivevariants pages 9-11, eldomery2016mipeprecessivevariants pages 7-9)
Upstream mechanism: MIPEP loss and defective preprotein cleavage.
Intermediate effects: mitochondrial proteome instability, defective respiratory-chain maturation, impaired electron transport, ATP deficiency, altered redox balance, and probable proteostatic stress.
Downstream manifestations: lactate accumulation, cardiomyocyte contractile failure/remodeling, skeletal-muscle weakness, and neuronal dysfunction/seizures.
Suggested annotations include GO: mitochondrial protein processing; protein targeting to mitochondrion; oxidative phosphorylation; mitochondrial respiratory-chain complex assembly; cellular response to mitochondrial stress. Relevant cellular compartments are mitochondrial matrix and inner mitochondrial membrane. Suggested cell types are cardiomyocyte, skeletal muscle fiber, neuron, and lens epithelial cell. No disease-specific single-cell, spatial-transcriptomic, lipidomic, epigenomic, CRISPR-screen, or integrated multi-omics study was identified.
7. Anatomy affected
Primary organ involvement is cardiac, neurologic, and skeletal-muscular:
- Heart: ventricular myocardium, especially left ventricle; LVNC, hypertrophy, dilation, conduction disease, and heart failure.
- Brain: cortex, basal ganglia, white matter, and developmental hindbrain structures in individual cases.
- Skeletal muscle: mitochondrial and lipid/glycogen abnormalities.
- Eye: lens in cataract-associated cases.
- Secondary/variable: liver, gastrointestinal tract, lungs, and endocrine pancreas.
Suggested UBERON annotations include heart, myocardium, left ventricle, skeletal muscle tissue, brain, basal ganglion, cerebral white matter, lens, liver, and lung. Relevant GO cellular components are mitochondrial matrix, mitochondrial inner membrane, respiratory-chain complex, and mitochondrial ribosome. No consistent lateralization is known.
8. Temporal development
Onset is usually congenital, neonatal, or within the first year. Severe cases may present immediately after birth with respiratory depression, seizures, HCM, and persistent lactic acidosis; others present over several months with feeding failure, hypotonia, developmental delay, and cardiomyopathy. Progression is variable but can be rapid, with recurrent metabolic decompensation, worsening heart failure, and neurological deterioration. One original patient survived to 4.5 years, while three died at 19 days, 11 months, and 2 years. No validated disease stages, remission pattern, or intervention window has been defined. (eldomery2016mipeprecessivevariants pages 9-11, eldomery2016mipeprecessivevariants pages 6-7, eldomery2016mipeprecessivevariants pages 7-9)
9. Inheritance and population
Inheritance is autosomal recessive. For two carrier parents, the conventional per-pregnancy risks are 25% affected, 50% carrier, and 25% unaffected/non-carrier. Penetrance appears high for individuals with severe biallelic loss-of-function genotypes, but it cannot be quantified. Expressivity is variable, including cardiac-dominant, multisystem, and reportedly neurological presentations without cardiomyopathy. (palmer2021mitochondrialproteinimport pages 10-13, ruijmbeek2025biallelicvariantsin pages 34-35)
Prevalence, incidence, carrier frequency, sex ratio, founder alleles, anticipation, and germline-mosaicism rates are unknown. Cases have arisen in ancestrally diverse families, including European, Middle Eastern, and admixed American backgrounds; no population enrichment has been established. Consanguinity can increase recessive risk but is not required.
10. Diagnosis
Recommended approach
- Recognize the phenotype: infantile cardiomyopathy/LVNC plus hypotonia, developmental delay, seizures, or unexplained lactic acidosis.
- Immediate investigations: blood gas, lactate and pyruvate, glucose, electrolytes/anion gap, liver enzymes, CK, ammonia, plasma amino acids and acylcarnitines; urine organic acids and ketones.
- Cardiac evaluation: ECG, echocardiography, rhythm monitoring, and cardiac MRI when feasible. Baseline and at least annual cardiac review is recommended in broader mitochondrial-care standards, with shorter intervals for established cardiomyopathy. (muraresku2018mitochondrialdiseaseadvances pages 2-4, sue2022patientcarestandards pages 4-7)
- Neurological evaluation: EEG for seizures; brain MRI/MRS for developmental regression, movement disorder, or metabolic decompensation.
- Genetic testing: rapid trio WES or WGS with robust CNV calling is preferred in critically ill infants. A mitochondrial/cardiomyopathy panel must include MIPEP and detect deletions. Confirm candidate variants by Sanger sequencing, segregation analysis, and deletion-sensitive methods. The discovery cohort required both WES and array-CGH to detect all allele classes. (eldomery2016mipeprecessivevariants pages 2-4, eldomery2016mipeprecessivevariants pages 1-2)
- Functional testing if variants are uncertain: respiratory-chain enzymology, patient-cell protein processing/OXPHOS studies, or RNA analysis. Muscle biopsy is now adjunctive rather than obligatory but may show mitochondrial proliferation, lipid droplets, glycogen, and abnormal cristae.
CMA can detect a deletion encompassing MIPEP but will usually miss sequence variants; karyotyping and FISH are not first-line. mtDNA sequencing alone is insufficient because MIPEP is nuclear. Repeat-expansion testing is not relevant.
Differential diagnosis
Important alternatives include Sengers syndrome/AGK deficiency, MTO1-related disease, ACAD9 deficiency, SCO2-related disease, Barth syndrome/TAZ, mitochondrial translation defects, fatty-acid-oxidation disorders, pyruvate-dehydrogenase deficiency, Pompe disease, congenital disorders of glycosylation, and primary sarcomeric LVNC. Cataract plus HCM and lactic acidosis particularly raises AGK-related Sengers syndrome, whereas demonstrable biallelic MIPEP variants establish COXPD31. (palmer2021mitochondrialproteinimport pages 10-13)
There are no standardized clinical diagnostic criteria and no population newborn-screening assay. Cascade carrier testing, prenatal diagnosis, and preimplantation genetic testing become possible once familial alleles are known.
11. Outcome and prognosis
The original cohort’s 3/4 mortality by age three years is the best available quantitative disease-specific outcome, but it is vulnerable to ascertainment bias toward severe patients. Major causes of morbidity and mortality are cardiomyopathy/heart failure, arrhythmia, respiratory failure, seizures, and metabolic decompensation. No five- or ten-year survival estimate, validated prognostic score, or disease-specific quality-of-life dataset exists. (eldomery2016mipeprecessivevariants pages 9-11)
Likely adverse indicators include neonatal onset, severe or persistent hyperlactatemia, biventricular cardiomyopathy, respiratory dependence, and refractory seizures, but none has been validated in a MIPEP cohort.
12. Treatment and current applications
There is no approved or experimentally validated MIPEP replacement, gene therapy, RNA therapy, enzyme therapy, or small-molecule therapy. Searches found no relevant MIPEP/COXPD31 interventional clinical trial. Treatment is supportive and should be coordinated by mitochondrial medicine, metabolic genetics, cardiology, neurology, intensive care, nutrition, and rehabilitation teams.
- Cardiac: guideline-directed management of heart failure and arrhythmia; serial ECG/echocardiography; mechanical support or transplant evaluation in selected patients. One reported child received a Berlin ventricular-assist device while awaiting transplant. (eldomery2016mipeprecessivevariants pages 6-7)
- Seizures: standard antiseizure therapy under pediatric epilepsy expertise. The 2024 InterERN consensus recommends standard prescribing/monitoring and lactate surveillance when mitochondrial toxicity is uncertain; levetiracetam and benzodiazepines are commonly preferred in broader mitochondrial guidance. DOI 10.1111/ene.16275, published April 2024. (sue2022patientcarestandards pages 26-28, mancuso2024managementofseizures pages 4-5)
- Metabolic illness: avoid prolonged fasting; maintain calories and hydration; promptly treat fever, infection, vomiting, hypoglycemia, electrolyte abnormalities, and acidosis. (muraresku2018mitochondrialdiseaseadvances pages 4-5)
- Nutrition/rehabilitation: feeding assessment, enteral support when necessary, physical and occupational therapy, positioning/respiratory therapy, and developmental services.
- Cataract: ophthalmologic surveillance and surgery when indicated.
- Supplements: coenzyme Q10, riboflavin, thiamine, carnitine, antioxidants, or “mitochondrial cocktails” have no MIPEP-specific efficacy evidence. Gene-specific supplementation recommendations for other mitochondrial disorders must not be assumed to treat MIPEP deficiency. (sue2022patientcarestandards pages 26-28, enns2017pediatricmitochondrialdiseases pages 1-2)
- Ketogenic diet: evidence across mitochondrial diseases is sparse and includes metabolic-acidosis and rhabdomyolysis risks; it should only be considered for refractory epilepsy by an experienced metabolic/epilepsy team, not as routine MIPEP therapy.
NCIT intervention suggestions include Supportive Care, Anticonvulsant Therapy, Physical Therapy, Occupational Therapy, Mechanical Circulatory Support, Cataract Surgery, and Heart Transplantation, subject to terminology verification.
13. Prevention
Primary prevention through lifestyle modification is not possible. Effective genetic prevention options include carrier testing of parents and adult relatives, reproductive counseling, prenatal diagnosis, and preimplantation genetic testing for known familial variants. Secondary prevention consists of early molecular diagnosis, cardiac screening of affected siblings, and prompt seizure/metabolic management. Tertiary prevention includes avoiding fasting, maintaining immunizations, emergency illness planning, regular cardiac/rhythm surveillance, aspiration prevention, nutritional support, and rehabilitation. No vaccine or prophylactic medication specifically prevents COXPD31.
14. Other species and natural disease
No naturally occurring MIPEP-associated veterinary syndrome or zoonotic relevance was identified. The mechanism is evolutionarily conserved, but there is no evidence of cross-species transmission because this is a genetic, noninfectious disorder.
15. Model organisms
The principal validated model is Saccharomyces cerevisiae, in which Oct1 is the functional MIPEP ortholog. Patient-corresponding mutations reproduced failed mitochondrial localization, reduced proteolytic processing, accumulation of precursor intermediates, and impaired growth under respiration-dependent conditions. This provides strong variant-level functional evidence. Its limitation is that yeast cannot model LVNC, brain development, seizures, cataracts, or mammalian tissue-specific expression. (eldomery2016mipeprecessivevariants pages 9-11, eldomery2016mipeprecessivevariants pages 1-2, eldomery2016mipeprecessivevariants pages 7-9)
No disease-specific mouse, rat, zebrafish, Drosophila, patient-derived iPSC cardiomyocyte, or organoid model was identified in the literature retrieved through 2024. Developing MIPEP-deficient iPSC cardiomyocytes and neurons would be especially valuable for defining tissue specificity, genotype–phenotype relationships, biomarkers, and rescue by gene replacement.
Recent developments and evidence gaps
The most relevant 2023–2024 developments are not MIPEP-specific therapies but broader advances: wider use of rapid exome/genome sequencing for critically ill infants, improved genomic characterization of primary mitochondrial disease, and 2024 expert consensus for mitochondrial epilepsy management. A 2024 cohort reported a 37% diagnostic yield for clinical exome sequencing among suspected mitochondrial cases, illustrating the practical value of genomic-first diagnosis, although this statistic is not specific to MIPEP. DOI 10.1186/s13023-024-03437-x, published November 2024. The principal unmet needs remain a larger natural-history registry, current ClinVar/gnomAD curation, functional characterization in human cells, quantitative biomarkers, mammalian models, and MIPEP-directed therapeutic development. (mancuso2024managementofseizures pages 4-5, muraresku2018mitochondrialdiseaseadvances pages 2-4)
Overall, the causal gene and core biochemical mechanism are well supported, but nearly every epidemiologic, prognostic, and therapeutic conclusion remains constrained by the exceptionally small number of reported patients.
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