Cardiomyopathy-Hypotonia-Lactic Acidosis Syndrome
Cardiomyopathy-hypotonia-lactic acidosis syndrome (mitochondrial phosphate carrier deficiency, SLC25A3 deficiency) is an ultra-rare autosomal recessive mitochondrial disorder caused by biallelic pathogenic variants in SLC25A3, which encodes the mitochondrial inorganic phosphate carrier (PiC) of the inner mitochondrial membrane. PiC supplies the matrix inorganic phosphate consumed by ATP synthase, so loss of carrier function starves the terminal step of oxidative phosphorylation of substrate. SLC25A3 is transcribed as two mutually exclusive isoforms generated by alternative splicing of exon 3A or exon 3B; isoform A predominates in heart and skeletal muscle while isoform B is ubiquitous. Because most reported pathogenic alleles disrupt exon 3A or its splice acceptor, the bioenergetic defect is largely confined to high-energy-demand striated muscle, which explains the cardiac- and myopathy-predominant presentation and the sparing of fibroblasts. Affected individuals classically present at or shortly after birth with hypertrophic cardiomyopathy, generalised muscular hypotonia, and lactic acidosis, and many die within the first year of life; a minority survive into adolescence or adulthood with exercise intolerance, proximal muscle weakness, and non-progressive hypertrophic cardiomyopathy. Only a handful of families have been reported worldwide.
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Classifications
Harrison's Chapter
Mechanistic Nosology
Inheritance
1
Autosomal recessive
HP:0000007
Disease is caused by biallelic (homozygous or compound heterozygous) pathogenic variants in SLC25A3. Reported families include consanguineous and non-consanguineous pedigrees with homozygous exon 3A or exon 3A splice-region alleles, and one compound heterozygote.
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
2Does the copper-transport / cytochrome c oxidase arm of SLC25A3 function, demonstrated in knockdown cell lines and reconstituted systems, actually contribute to human cardiomyopathy-hypotonia-lactic acidosis syndrome, given that patient muscle biopsies show normal respiratory-chain enzyme activities?
Attached to
SLC25A3 has been shown directly, in Lactococcus lactis and reconstituted liposomes, to transport copper, and knockdown or deletion in murine and human cell lines produces an isolated cytochrome c oxidase deficiency that copper supplementation rescues. If that arm operated in patients, one would expect reduced COX activity in affected muscle. Instead, the patient muscle biopsy reported by Mayr et al. showed normal respiratory-chain enzyme activities with only the carrier protein reduced, and histopathology in a long-surviving adult showed mildly increased rather than decreased COX and SDH staining. The evidence therefore exists in a model system but its translational validity to human SLC25A3 disease is the open question, which is why this is recorded as HUMAN_MODEL_MISMATCH rather than a plain knowledge gap. Possible resolutions include isoform specificity (the copper work used total SLC25A3 loss, whereas most patient alleles ablate only isoform A), residual isoform B sufficing for copper delivery in patient muscle, or the copper function being dispensable in vivo.
Proposed experiments
Isoform-resolved copper transport and COX metalation assay
exp_slc25a3_isoform_copper_cox
In isogenic human iPSC-derived cardiomyocytes engineered to carry (a) an exon 3A-specific patient allele, (b) a total SLC25A3 knockout, and (c) the corrected genotype, quantify matrix copper, COX holoenzyme assembly and activity, and the response to copper supplementation. This directly tests whether the copper/COX arm is engaged by isoform-A-selective patient alleles or only by total carrier loss, reconciling the cell-line and patient-muscle observations.
Model systems
Human iPSC-derived cardiomyocyte
Cardiomyocytes differentiated from isogenic iPSC lines carrying exon-3A-selective versus total SLC25A3 loss, preserving the human isoform architecture that mouse and immortalised cell models do not reproduce.
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."
The model-system observation on one side of the mismatch.
"In a muscle biopsy normal activity of respiratory chain enzymes was found; however the amount of the mitochondrial phosphate carrier was decreased."
The human observation on the other side of the mismatch - normal respiratory-chain enzyme activity in patient muscle.
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?
The reported phenotypic range is extreme for a disorder with fewer than a dozen published patients: the index siblings died within the first year of life, whereas patients homozygous for the recurrent c.158-9A>G splice allele have survived to ages 9, 17, and 32 years with non-progressive hypertrophic cardiomyopathy and normal cognition, and one compound heterozygote had isolated cardiomyopathy with normal lactate and no myopathy. Whether the determinant is residual exon 3A transcript level, isoform-B compensation, modifier loci, or the standard of supportive care available at the time cannot be resolved from the published cases. The cohort is too small for a genotype-phenotype analysis, and no natural-history study exists.
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
8Tissue-Specific Exon 3A/3B Alternative Splicing of SLC25A3
The single SLC25A3 gene produces two mutually exclusive carrier isoforms by alternative splicing of exon 3A or exon 3B, which differ in 13 amino acids near the N-terminus. Isoform A (exon 3A) is the higher-affinity carrier expressed almost exclusively in heart, skeletal muscle, and diaphragm; isoform B (exon 3B) is ubiquitous. Because most reported pathogenic SLC25A3 alleles lie in exon 3A or its splice acceptor, the resulting carrier defect is restricted to striated muscle while other tissues retain functional isoform B. This splicing architecture is the mechanistic explanation for the cardiac-and-muscle-predominant phenotype and for the observation that patient fibroblasts, which use isoform B, have normal ATP synthesis.
Downstream
Pathogenic variants in exon 3A or its splice acceptor abolish or deplete the muscle-specific isoform A carrier while sparing ubiquitous isoform B.
Show evidence (4 references)
"Isoform A is highly expressed in heart and skeletal muscle. Isoform B is ubiquitously expressed in all tissues that were examined, although at different levels."
Northern blot analysis establishes the tissue-restricted expression of the exon IIIA isoform in heart and skeletal muscle. Evidence source is MODEL_ORGANISM because the measurements were made in bovine, not human, tissue.
"Western blot analysis demonstrated that isoform A is present in high amounts in heart, skeletal muscle, and diaphragm mitochondria, whereas isoform B is present in the mitochondria of all tissues examined."
Confirms the tissue-restricted distribution at the protein (not just transcript) level in bovine mitochondria.
"The transport affinities of isoform B for phosphate and arsenate were found to be 3-fold lower than those of isoform A."
Reconstituted-liposome kinetics show isoform A is the higher-affinity phosphate carrier, so loss of isoform A is not trivially compensated by residual isoform B in striated muscle.
+ 1 more reference
Loss of Mitochondrial Phosphate Carrier Function in Heart and Skeletal Muscle
Biallelic SLC25A3 variants reduce the amount and/or transport activity of the inorganic phosphate carrier in the inner mitochondrial membrane of cardiomyocytes and skeletal myofibres. The Turkish index family carried a homozygous missense allele in exon 3A (p.Gly72Glu); other families carry a homozygous splice-acceptor allele (c.158-9A>G) that creates a novel splice site and eliminates more than 95% of the wild-type exon 3A transcript, and one patient is a compound heterozygote for two novel coding alleles. Muscle biopsy in affected children shows reduced carrier protein.
Downstream
Fewer functional carriers reduce inorganic phosphate flux into the matrix.
The same carrier has been reported to contribute to mitochondrial copper delivery, so its loss reduces matrix copper availability in cell models. Whether this arm operates in patients is unresolved — patient respiratory-chain enzyme measurements are normal, and muscle histopathology shows increased rather than decreased COX activity. The target node is retained as PROVISIONAL and the contradiction is recorded in the HUMAN_MODEL_MISMATCH discussion.
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."
Demonstrates directly in patient muscle that the carrier protein is depleted while respiratory-chain enzyme activities are preserved, isolating the defect to the carrier itself.
"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 Matrix Inorganic Phosphate
The phosphate carrier is the principal route by which inorganic phosphate enters the mitochondrial matrix across the inner membrane, operating as a Pi/Pi antiporter and Pi/H+ symporter. When carrier capacity falls, matrix Pi concentration falls with it, depleting the pool available for matrix phosphorylation reactions.
Downstream
ATP synthase condenses matrix ADP with matrix Pi, so a fall in matrix Pi is a direct substrate limitation on the terminal step of oxidative phosphorylation.
Show evidence (3 references)
"The mitochondrial phosphate carrier SLC25A3 transports inorganic phosphate into the mitochondrial matrix, which is essential for the aerobic synthesis of adenosine triphosphate (ATP)."
States the carrier's function - matrix phosphate import - whose loss defines this node. Tagged OTHER rather than HUMAN_CLINICAL because the sentence is background biochemistry framing rather than a patient observation, matching how the analogous framing sentence from PMID:40362619 is tagged in this entry.
"mPiC imports inorganic phosphate (Pi) into the mitochondrial matrix for ATP production and other matrix phosphorylation reactions, as well as regulates mitochondrial Ca2+ uptake and buffering of matrix Ca2+."
Confirms that matrix Pi supply for ATP production depends on the carrier, and notes the carrier's additional role in matrix calcium handling.
"Most importantly, TAT-mPiC restored Pi and Cu delivery into the mitochondrial matrix."
Restoring the carrier restores matrix Pi delivery in knockdown cells, confirming the carrier is rate-limiting for this step.
Substrate Limitation of ATP Synthase and Impaired Oxidative Phosphorylation
Inorganic phosphate is a substrate of ATP synthase, so matrix Pi depletion limits proton-motive-force-driven ATP synthesis even when the respiratory chain complexes themselves are intact and normally assembled. This is the biochemical signature of the disorder: patient muscle mitochondria show deficient ATP synthesis while respiratory-chain enzyme activities are normal, and the defect is present in muscle but absent in fibroblasts, tracking the exon 3A/3B expression pattern.
Downstream
Reduced oxidative ATP output is felt first in the tissues with the highest and most sustained ATP demand.
When oxidative ATP supply falls short, ATP demand is met by anaerobic glycolysis, whose end product is lactate.
Show evidence (2 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.
Cardiomyocyte and Skeletal Muscle Energy Deficit
Heart and skeletal muscle have the highest and least interruptible ATP demand, and they are also the tissues that depend on the exon 3A carrier isoform. The combination makes them the target organs of the disease: cardiomyocytes and myofibres cannot sustain contractile work on a reduced oxidative ATP supply. This is the disease-specific instance of the "Primary Cardiomyocyte Insult" step of the conserved cardiomyopathy maladaptive-remodeling module, with a metabolic (bioenergetic) rather than sarcomeric insult. Human iPSC-derived cardiomyocytes carrying SLC25A3 knockout or missense alleles reproduce this state, showing mitochondrial energy-metabolism dysfunction together with diastolic dysfunction and calcium-handling imbalance.
Downstream
Sustained cardiomyocyte energy deficit drives a hypertrophic remodeling response; the intervening signalling steps have not been defined in SLC25A3 disease.
Skeletal-muscle energy failure contributes to generalised low muscle tone.
In longer-surviving patients the residual myopathy manifests as exertional fatigue.
Skeletal-muscle energy failure presents clinically as proximal-predominant weakness alongside the low tone.
Chronic myofibre bioenergetic failure produces the structural and histochemical myopathic changes seen on muscle biopsy.
Myofibre injury secondary to the energy deficit releases creatine kinase into the circulation.
Show evidence (2 references)
"The critical dependence on mitochondria as an energy source is especially evident in tissues with high-energy demands such as the heart, muscle; defects in the mitochondrial energy production machinery underlie a wide range of primary mitochondrial disorders that present with cardiac and muscle diseases."
Explains why heart and skeletal muscle are the target organs of a mitochondrial ATP-production defect such as phosphate-carrier deficiency.
"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."
Patient-genotype iPSC-derived cardiomyocytes show that SLC25A3 loss produces cardiomyocyte-autonomous energy-metabolism dysfunction and contractile (diastolic) impairment.
Compensatory Glycolysis and Lactate Accumulation
With oxidative ATP synthesis constrained, striated muscle shifts ATP production to anaerobic glycolysis, and the accumulating lactate spills into the circulation and produces the lactic acidosis that, together with hypertrophic cardiomyopathy, defines the classical neonatal presentation. Lactate elevation is often persistent and can remain high for decades in long-surviving patients even when they are clinically stable. Glycolytic byproduct accumulation has additionally been linked in SLC25A3-knockout cardiomyocytes to the calcium-handling imbalance that accompanies the hypertrophic phenotype.
Downstream
Circulating lactate accumulation produces metabolic (lactic) acidosis.
Glycolytic lactate output raises the measured blood lactate concentration, the laboratory correlate of the acidosis.
Show evidence (2 references)
"Further studies suggested the potential link between the accumulation of glycolytic byproducts and Ca2+ homeostasis imbalance in SLC25A3-KO hiPSC-CMs."
Shows glycolytic-byproduct accumulation in SLC25A3-null cardiomyocytes and links it mechanistically to calcium dysregulation.
"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."
Restoring carrier function lowers lactate secretion, confirming that lactate output is a direct consequence of the carrier deficit rather than an incidental finding.
Cardiomyocyte Hypertrophy and Ventricular Remodeling
The myocardial response to chronic bioenergetic insufficiency is hypertrophic remodeling. In patients this is seen as hypertrophic cardiomyopathy, usually already present in the neonatal period; in long-term survivors it can be non-progressive. Cardiac-specific deletion of Slc25a3 in mice reproduces the remodeling arm directly - profound hypertrophy with ventricular dilation and depressed cardiac function - establishing that carrier loss in cardiomyocytes is sufficient to cause the cardiomyopathy. This node is the disease-specific instance of the "Ventricular Remodeling" step of the conserved cardiomyopathy maladaptive-remodeling module. The module's intervening neurohormonal-activation step has not been studied in SLC25A3 deficiency and is deliberately not asserted here.
Downstream
Myocardial hypertrophic remodeling is the substrate of the clinical hypertrophic cardiomyopathy.
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.
Impaired Mitochondrial Copper Delivery and Cytochrome c Oxidase Biogenesis
Beyond phosphate, SLC25A3 has been shown in cell and reconstituted systems to transport copper into the mitochondrial matrix, supplying the labile copper pool required to metalate cytochrome c oxidase (complex IV). Knockdown or deletion of SLC25A3 in cultured cells causes an isolated COX deficiency that is rescued by copper supplementation, and restoring the carrier restores matrix copper delivery. Whether this second transport function contributes to the human disease is unresolved: patient muscle biopsies have shown normal respiratory-chain enzyme activities, so the copper/COX arm is recorded here as a provisional mechanism rather than an established component of the patient phenotype (see the HUMAN_MODEL_MISMATCH discussion).
Show evidence (3 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.
"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.
"In a muscle biopsy normal activity of respiratory chain enzymes was found; however the amount of the mitochondrial phosphate carrier was decreased."
Normal respiratory-chain enzyme activity in patient muscle argues against a clinically significant cytochrome c oxidase deficiency in vivo, which is why this mechanism is marked PROVISIONAL.
Histopathology
2
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
Histochemistry on the same biopsy showed a mild INCREASE in cytochrome c oxidase and succinate dehydrogenase activity, interpreted as mitochondrial myopathy. The direction matters: an increase, together with the normal respiratory-chain enzyme measurements reported by Mayr 2011, is a second independent human observation running against the cell-model copper/COX-deficiency arm. See the HUMAN_MODEL_MISMATCH discussion.
Show evidence (1 reference)
"The histopathology showed a mild increase in cytochrome c oxidase (COX) and succinate dehydrogenase (SDH) activity, suggesting mitochondrial myopathy."
Human muscle histochemistry showing increased rather than decreased COX activity, which is the observation that constrains the provisional copper/COX arm of the pathograph.
Pathograph
Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Phenotypes
9Cardiovascular 1
Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy
HP:0001639
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
Metabolism 2
Lactic acidosis
Lactic acidosis
HP:0003128
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."
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.
"We report here two new patients who had neonatal cardiomyopathy; one of whom did not have skeletal myopathy nor elevated lactate."
Marked PARTIAL because it documents an exception - a molecularly confirmed patient without elevated lactate - qualifying rather than supporting the universality of lactic acidosis.
Elevated circulating creatine kinase concentration
Elevated circulating creatine kinase concentration
HP:0003236
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.
Musculoskeletal 2
Hypotonia
Hypotonia
HP:0001252
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
Proximal muscle weakness
HP:0003701
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.
Respiratory 1
Respiratory failure
Respiratory failure
HP:0002878
Show evidence (1 reference)
"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 respiratory failure among the primary presenting features of PiC deficiency.
Constitutional 1
Exercise intolerance
Exercise intolerance
HP:0003546
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 after walking in the late-onset adult patient.
Other 2
Mitochondrial myopathy
Mitochondrial myopathy
HP:0003737
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.
Increased circulating lactate concentration
Increased circulating lactate concentration
HP:0002151
Show evidence (1 reference)
"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.
Genetic Associations
1
SLC25A3 biallelic pathogenic variants
Show evidence (2 references)
"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."
Establishes SLC25A3 as the disease gene and loss of phosphate transport as the molecular consequence of its pathogenic variants.
"This is the first report of patients with mitochondrial phosphate-carrier deficiency."
The gene-disease relationship was first established in the 2007 index report of the two Turkish sisters.
Medical Actions
5
Supportive and Heart-Failure Directed Care
No curative or disease-modifying therapy exists. Management is supportive and phenotype-directed: heart-failure management and cardiac surveillance for the hypertrophic cardiomyopathy, respiratory support, treatment of lactic acidosis and avoidance of catabolic stress, and nutritional support. Prognosis in the classical form remains poor, with most patients dying in the first year of life.
Show evidence (1 reference)
"Variants in SLC25A3 exist and lead to mPiC deficiency (MPCD), cause a rare autosomal recessive disease with no current cure; patients with MPCD usually die within the first year of life."
States explicitly that no cure exists and that the classical course is lethal in infancy, which is why care is supportive.
Mitochondrial Cofactor Therapy and Fat-Rich Diet
Empirical "mitochondrial cocktail" supplementation combined with a fat-rich (low-carbohydrate) diet was used in the longest-surviving reported patient and was associated with clinical improvement, although blood lactate remained elevated. This is a single-patient observation, not a trial result; there are no controlled efficacy data for any metabolic therapy in this disorder, and no specific agent can be recommended on the published evidence.
Show evidence (1 reference)
"The patient was treated with mitochondrial therapy, along with a fat-rich diet. Despite clinical improvement, lactate levels remained elevated."
Marked PARTIAL because this is an uncontrolled single-patient observation with an incomplete biochemical response.
Genetic Counseling
Autosomal recessive inheritance carries a 25% recurrence risk for siblings. Two of the reported pedigrees had multiple affected children, so counselling and discussion of prenatal or preimplantation testing are relevant once the familial variants are known.
Show evidence (1 reference)
"In a family three children presented with severe neonatal lactic acidosis, hypertrophic cardiomyopathy and generalised muscular hypotonia."
Three affected children in one sibship illustrates the recurrence risk that makes genetic counselling relevant.
TAT-mPiC Protein Replacement (investigational, preclinical)
A cell-penetrating TAT-fused recombinant phosphate carrier delivered to mPiC-knockdown cells localised correctly to the inner mitochondrial membrane and restored oxygen consumption, ATP production, matrix phosphate and copper delivery, and reduced lactate secretion. This is a preclinical cell-culture result only - there are no animal efficacy data and no human studies. It is recorded here as a mechanism-directed investigational strategy, not a clinical option.
Show evidence (2 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.
Mitochondrial Transplantation (investigational, preclinical)
Transfer of exogenous healthy mitochondria into SLC25A3-mutant human iPSC-derived cardiomyocytes was explored as a way to rescue the hypertrophic phenotype and calcium-handling imbalance. This is an exploratory in vitro finding in a disease-model cell system; no in vivo or clinical data exist.
Show evidence (1 reference)
"Finally, we explored the prospective therapeutic implications of mitochondrial transplantation in rescuing SLC25A3-related HCM."
Marked PARTIAL because the authors describe this as an exploratory, prospective therapeutic implication rather than a demonstrated therapy.
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 defining functional assay: ATP synthesis measured in intact mitochondria is deficient in patient skeletal muscle but normal in patient fibroblasts, mirroring the exon 3A (muscle) versus exon 3B (fibroblast) isoform-expression pattern. Fibroblast studies therefore cannot exclude the diagnosis.
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: Immunodetection of the carrier in muscle biopsy shows reduced protein amount in the presence of normal respiratory-chain enzyme activities. The normal respiratory-chain profile is diagnostically important: a standard respiratory-chain enzyme panel will not detect this disorder.
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.
Differential Diagnoses
1Conditions with similar clinical presentations that must be differentiated from Cardiomyopathy-Hypotonia-Lactic Acidosis Syndrome:
Infantile-onset Pompe disease
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 (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."
A published case in which infantile Pompe disease was the initial clinical suspicion.
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 an ultra-rare autosomal recessive
mitochondrial disorder caused by biallelic pathogenic variants in SLC25A3,
which encodes the mitochondrial inorganic phosphate carrier (PiC) of the inner
mitochondrial membrane. PiC supplies the matrix inorganic phosphate consumed by
ATP synthase, so loss of carrier function starves the terminal step of
oxidative phosphorylation of substrate. SLC25A3 is transcribed as two mutually
exclusive isoforms generated by alternative splicing of exon 3A or exon 3B;
isoform A predominates in heart and skeletal muscle while isoform B is
ubiquitous. Because most reported pathogenic alleles disrupt exon 3A or its
splice acceptor, the bioenergetic defect is largely confined to
high-energy-demand striated muscle, which explains the cardiac- and
myopathy-predominant presentation and the sparing of fibroblasts. Affected
individuals classically present at or shortly after birth with hypertrophic
cardiomyopathy, generalised muscular hypotonia, and lactic acidosis, and many
die within the first year of life; a minority survive into adolescence or
adulthood with exercise intolerance, proximal muscle weakness, and
non-progressive hypertrophic cardiomyopathy. Only a handful of families have
been reported worldwide.
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: >-
No GeneReviews chapter exists for SLC25A3 / mitochondrial phosphate carrier
deficiency - a PubMed search for "SLC25A3 GeneReviews" returned zero results on
2026-07-31 - so the usual GeneReviews phenotype baseline is unavailable and
this entry is anchored directly on the primary case reports and functional
literature. The disorder is ultra-rare: the index report described two Turkish
sisters, and fewer than about a dozen molecularly confirmed patients have been
described since. This entry is therefore deliberately restricted to claims that
can be quoted from a cached abstract. In particular, no frequency bands are
asserted for any phenotype because no cohort large enough to support them
exists. Death in infancy is curated under `progression` rather than as a
`phenotypes` entry because HP:0001522 (Death in infancy) sits in the HPO
Mortality/Aging branch, outside the Phenotypic abnormality subtree that the
PhenotypeTerm dynamic enum draws from.
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: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:38656665
title: "Mitochondrial phosphate-carrier deficiency mimicking infantile-onset Pompe disease."
- reference: PMID:40944834
title: "Expanding the Clinical Spectrum of Mitochondrial Phosphate Carrier Deficiency: A Case Report With Literature Review."
- reference: PMID:24658400
title: "Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy."
- reference: PMID:39671292
title: "Mitochondrial transplantation rescues Ca(2+) homeostasis imbalance and myocardial hypertrophy in SLC25A3-related hypertrophic cardiomyopathy."
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: >-
Disease is caused by biallelic (homozygous or compound heterozygous)
pathogenic variants in SLC25A3. Reported families include consanguineous and
non-consanguineous pedigrees with homozygous exon 3A or exon 3A splice-region
alleles, and one compound heterozygote.
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: >-
No population prevalence estimate exists. The disorder was first described in
2007 in two sisters from a non-consanguineous Turkish family; as of 2014-2015
the literature comprised only two affected sibships, to which a small number
of additional single-patient and single-family reports have since been added.
Fewer than about a dozen molecularly confirmed patients have been published,
so the only defensible occurrence statement is a literature case count in the
ultra-rare band.
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: "The literature described two affected sibships with variants in SLC25A3; all cases had skeletal myopathy and cardiomyopathy (OMIM 610773)."
explanation: Documents that the entire published literature at that time comprised two affected sibships, establishing the case-count basis for the ultra-rare classification.
- reference: PMID:40362619
reference_title: "Rescue of the First Mitochondrial Membrane Carrier, the mPiC, by TAT-Mediated Protein Replacement Treatment."
supports: SUPPORT
evidence_source: OTHER
snippet: "Variants in SLC25A3 exist and lead to mPiC deficiency (MPCD), cause a rare autosomal recessive disease with no current cure; patients with MPCD usually die within the first year of life."
explanation: Confirms the disorder is rare. Evidence source is OTHER because this statement is background framing in a methods paper rather than an epidemiological study.
progression:
- phase: Neonatal presentation
age_range: birth to first weeks of life
notes: >-
The classical presentation is at or shortly after birth with the triad of
hypertrophic cardiomyopathy, generalised muscular hypotonia, and severe lactic
acidosis. A minority of patients present later in infancy or childhood.
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.
- phase: Infantile-lethal course
age_range: first year of life
notes: >-
Death within the first year of life is the classical outcome and was the fate
of both index-family siblings. Note that the HPO term for this outcome,
HP:0001522 (Death in infancy), sits in the Mortality/Aging branch rather than
under Phenotypic abnormality, so it is curated here as natural history rather
than as a phenotype.
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.
- reference: PMID:40362619
reference_title: "Rescue of the First Mitochondrial Membrane Carrier, the mPiC, by TAT-Mediated Protein Replacement Treatment."
supports: SUPPORT
evidence_source: OTHER
snippet: "patients with MPCD usually die within the first year of life"
explanation: Confirms that infantile death is the usual course. Evidence source is OTHER because the statement is background framing in a methods paper.
- phase: Long-term survival with residual myopathy
age_range: childhood to adulthood
notes: >-
A minority of patients survive the neonatal period and stabilise, presenting
in later childhood or adulthood with exercise intolerance, proximal muscle
weakness, and non-progressive hypertrophic cardiomyopathy with normal
cognition. The longest-surviving reported patient was stable at age 32 years.
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 the oldest reported survivor, stable at 32 years.
pathophysiology:
- name: Tissue-Specific Exon 3A/3B Alternative Splicing of SLC25A3
biological_scale: MOLECULAR
description: >-
The single SLC25A3 gene produces two mutually exclusive carrier isoforms by
alternative splicing of exon 3A or exon 3B, which differ in 13 amino acids
near the N-terminus. Isoform A (exon 3A) is the higher-affinity carrier
expressed almost exclusively in heart, skeletal muscle, and diaphragm; isoform
B (exon 3B) is ubiquitous. Because most reported pathogenic SLC25A3 alleles
lie in exon 3A or its splice acceptor, the resulting carrier defect is
restricted to striated muscle while other tissues retain functional isoform B.
This splicing architecture is the mechanistic explanation for the
cardiac-and-muscle-predominant phenotype and for the observation that patient
fibroblasts, which use isoform B, have normal ATP synthesis.
mechanism_confidence: ESTABLISHED
gene:
preferred_term: SLC25A3
term:
id: hgnc:10989
label: SLC25A3
biological_processes:
- preferred_term: alternative mRNA splicing, via spliceosome
term:
id: GO:0000380
label: alternative mRNA splicing, via spliceosome
locations:
- preferred_term: heart
term:
id: UBERON:0000948
label: heart
- preferred_term: skeletal muscle tissue
term:
id: UBERON:0001134
label: skeletal muscle tissue
evidence:
- reference: PMID:8980128
reference_title: "Tissue-specific expression of the two isoforms of the mitochondrial phosphate carrier in bovine tissues."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Isoform A is highly expressed in heart and skeletal muscle. Isoform B is ubiquitously expressed in all tissues that were examined, although at different levels."
explanation: Northern blot analysis establishes the tissue-restricted expression of the exon IIIA isoform in heart and skeletal muscle. Evidence source is MODEL_ORGANISM because the measurements were made in bovine, not human, tissue.
- reference: PMID:9712911
reference_title: "Expression in Escherichia coli, functional characterization, and tissue distribution of isoforms A and B of the phosphate carrier from bovine mitochondria."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Western blot analysis demonstrated that isoform A is present in high amounts in heart, skeletal muscle, and diaphragm mitochondria, whereas isoform B is present in the mitochondria of all tissues examined."
explanation: Confirms the tissue-restricted distribution at the protein (not just transcript) level in bovine mitochondria.
- reference: PMID:9712911
reference_title: "Expression in Escherichia coli, functional characterization, and tissue distribution of isoforms A and B of the phosphate carrier from bovine mitochondria."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The transport affinities of isoform B for phosphate and arsenate were found to be 3-fold lower than those of isoform A."
explanation: Reconstituted-liposome kinetics show isoform A is the higher-affinity phosphate carrier, so loss of isoform A is not trivially compensated by residual isoform B in striated muscle.
- 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: "This protein is expressed in two tissue-specific isoforms generated by mutually exclusive alternative splicing of the SLC25A3 gene transcript."
explanation: States the mutually exclusive alternative-splicing architecture of human SLC25A3 in the context of patient disease.
downstream:
- target: Loss of Mitochondrial Phosphate Carrier Function in Heart and Skeletal Muscle
causal_link_type: DIRECT
description: >-
Pathogenic variants in exon 3A or its splice acceptor abolish or deplete the
muscle-specific isoform A carrier while sparing ubiquitous isoform B.
- name: Loss of Mitochondrial Phosphate Carrier Function in Heart and Skeletal Muscle
biological_scale: MOLECULAR
description: >-
Biallelic SLC25A3 variants reduce the amount and/or transport activity of the
inorganic phosphate carrier in the inner mitochondrial membrane of
cardiomyocytes and skeletal myofibres. The Turkish index family carried a
homozygous missense allele in exon 3A (p.Gly72Glu); other families carry a
homozygous splice-acceptor allele (c.158-9A>G) that creates a novel splice
site and eliminates more than 95% of the wild-type exon 3A transcript, and one
patient is a compound heterozygote for two novel coding alleles. Muscle biopsy
in affected children shows reduced carrier protein.
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: Demonstrates directly in patient muscle that the carrier protein is depleted while respiratory-chain enzyme activities are preserved, isolating the defect to the carrier itself.
- 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 Matrix Inorganic Phosphate
causal_link_type: DIRECT
description: Fewer functional carriers reduce inorganic phosphate flux into the matrix.
- target: Impaired Mitochondrial Copper Delivery and Cytochrome c Oxidase Biogenesis
causal_link_type: DIRECT
description: >-
The same carrier has been reported to contribute to mitochondrial copper
delivery, so its loss reduces matrix copper availability in cell models.
Whether this arm operates in patients is unresolved — patient
respiratory-chain enzyme measurements are normal, and muscle
histopathology shows increased rather than decreased COX activity. The
target node is retained as PROVISIONAL and the contradiction is recorded
in the HUMAN_MODEL_MISMATCH discussion.
- name: Reduced Mitochondrial Matrix Inorganic Phosphate
biological_scale: MOLECULAR
description: >-
The phosphate carrier is the principal route by which inorganic phosphate
enters the mitochondrial matrix across the inner membrane, operating as a
Pi/Pi antiporter and Pi/H+ symporter. When carrier capacity falls, matrix Pi
concentration falls with it, depleting the pool available for matrix
phosphorylation reactions.
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: inorganic phosphate
term:
id: CHEBI:43474
label: hydrogenphosphate
modifier: DECREASED
evidence:
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: OTHER
snippet: "The mitochondrial phosphate carrier SLC25A3 transports inorganic phosphate into the mitochondrial matrix, which is essential for the aerobic synthesis of adenosine triphosphate (ATP)."
explanation: >-
States the carrier's function - matrix phosphate import - whose loss
defines this node. Tagged OTHER rather than HUMAN_CLINICAL because the
sentence is background biochemistry framing rather than a patient
observation, matching how the analogous framing sentence from
PMID:40362619 is tagged in this entry.
- 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: "mPiC imports inorganic phosphate (Pi) into the mitochondrial matrix for ATP production and other matrix phosphorylation reactions, as well as regulates mitochondrial Ca2+ uptake and buffering of matrix Ca2+."
explanation: Confirms that matrix Pi supply for ATP production depends on the carrier, and notes the carrier's additional role in matrix calcium handling.
- 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: "Most importantly, TAT-mPiC restored Pi and Cu delivery into the mitochondrial matrix."
explanation: Restoring the carrier restores matrix Pi delivery in knockdown cells, confirming the carrier is rate-limiting for this step.
downstream:
- target: Substrate Limitation of ATP Synthase and Impaired Oxidative Phosphorylation
causal_link_type: DIRECT
description: >-
ATP synthase condenses matrix ADP with matrix Pi, so a fall in matrix Pi is
a direct substrate limitation on the terminal step of oxidative
phosphorylation.
- name: Substrate Limitation of ATP Synthase and Impaired Oxidative Phosphorylation
biological_scale: MOLECULAR
description: >-
Inorganic phosphate is a substrate of ATP synthase, so matrix Pi depletion
limits proton-motive-force-driven ATP synthesis even when the respiratory
chain complexes themselves are intact and normally assembled. This is the
biochemical signature of the disorder: patient muscle mitochondria show
deficient ATP synthesis while respiratory-chain enzyme activities are normal,
and the defect is present in muscle but absent in fibroblasts, tracking the
exon 3A/3B expression pattern.
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.
downstream:
- target: Cardiomyocyte and Skeletal Muscle Energy Deficit
causal_link_type: DIRECT
description: >-
Reduced oxidative ATP output is felt first in the tissues with the highest
and most sustained ATP demand.
- target: Compensatory Glycolysis and Lactate Accumulation
causal_link_type: DIRECT
description: >-
When oxidative ATP supply falls short, ATP demand is met by anaerobic
glycolysis, whose end product is lactate.
- name: Cardiomyocyte and Skeletal Muscle Energy Deficit
biological_scale: CELLULAR
conforms_to: cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult
description: >-
Heart and skeletal muscle have the highest and least interruptible ATP demand,
and they are also the tissues that depend on the exon 3A carrier isoform. The
combination makes them the target organs of the disease: cardiomyocytes and
myofibres cannot sustain contractile work on a reduced oxidative ATP supply.
This is the disease-specific instance of the "Primary Cardiomyocyte Insult"
step of the conserved cardiomyopathy maladaptive-remodeling module, with a
metabolic (bioenergetic) rather than sarcomeric insult. Human iPSC-derived
cardiomyocytes carrying SLC25A3 knockout or missense alleles reproduce this
state, showing mitochondrial energy-metabolism dysfunction together with
diastolic dysfunction and calcium-handling imbalance.
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
biological_processes:
- preferred_term: ATP metabolic process
term:
id: GO:0046034
label: ATP metabolic process
modifier: DECREASED
evidence:
- reference: PMID:38656665
reference_title: "Mitochondrial phosphate-carrier deficiency mimicking infantile-onset Pompe disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The critical dependence on mitochondria as an energy source is especially evident in tissues with high-energy demands such as the heart, muscle; defects in the mitochondrial energy production machinery underlie a wide range of primary mitochondrial disorders that present with cardiac and muscle diseases."
explanation: Explains why heart and skeletal muscle are the target organs of a mitochondrial ATP-production defect such as phosphate-carrier deficiency.
- 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: Patient-genotype iPSC-derived cardiomyocytes show that SLC25A3 loss produces cardiomyocyte-autonomous energy-metabolism dysfunction and contractile (diastolic) impairment.
downstream:
- target: Cardiomyocyte Hypertrophy and Ventricular Remodeling
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Sustained cardiomyocyte energy deficit drives a hypertrophic remodeling
response; the intervening signalling steps have not been defined in SLC25A3
disease.
- target: Hypotonia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Skeletal-muscle energy failure contributes to generalised low muscle tone.
- target: Exercise intolerance
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
In longer-surviving patients the residual myopathy manifests as exertional
fatigue.
- target: Proximal muscle weakness
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Skeletal-muscle energy failure presents clinically as proximal-predominant
weakness alongside the low tone.
- target: Mitochondrial myopathy
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Chronic myofibre bioenergetic failure produces the structural and
histochemical myopathic changes seen on muscle biopsy.
- target: Elevated circulating creatine kinase concentration
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Myofibre injury secondary to the energy deficit releases creatine kinase
into the circulation.
- name: Compensatory Glycolysis and Lactate Accumulation
biological_scale: ORGANISM
description: >-
With oxidative ATP synthesis constrained, striated muscle shifts ATP
production to anaerobic glycolysis, and the accumulating lactate spills into
the circulation and produces the lactic acidosis that, together with
hypertrophic cardiomyopathy, defines the classical neonatal presentation.
Lactate elevation is often persistent and can remain high for decades in
long-surviving patients even when they are clinically stable. Glycolytic
byproduct accumulation has additionally been linked in SLC25A3-knockout
cardiomyocytes to the calcium-handling imbalance that accompanies the
hypertrophic phenotype.
biological_processes:
- preferred_term: glycolytic process
term:
id: GO:0006096
label: glycolytic process
modifier: INCREASED
- preferred_term: lactate biosynthetic process
term:
id: GO:0019249
label: lactate biosynthetic process
modifier: INCREASED
chemical_entities:
- preferred_term: lactate
term:
id: CHEBI:24996
label: lactate
modifier: INCREASED
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: "Further studies suggested the potential link between the accumulation of glycolytic byproducts and Ca2+ homeostasis imbalance in SLC25A3-KO hiPSC-CMs."
explanation: Shows glycolytic-byproduct accumulation in SLC25A3-null cardiomyocytes and links it mechanistically to calcium dysregulation.
- 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: Restoring carrier function lowers lactate secretion, confirming that lactate output is a direct consequence of the carrier deficit rather than an incidental finding.
downstream:
- target: Lactic acidosis
causal_link_type: DIRECT
description: Circulating lactate accumulation produces metabolic (lactic) acidosis.
- target: Increased circulating lactate concentration
causal_link_type: DIRECT
description: >-
Glycolytic lactate output raises the measured blood lactate concentration,
the laboratory correlate of the acidosis.
- name: Cardiomyocyte Hypertrophy and Ventricular Remodeling
biological_scale: TISSUE
conforms_to: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling
description: >-
The myocardial response to chronic bioenergetic insufficiency is hypertrophic
remodeling. In patients this is seen as hypertrophic cardiomyopathy, usually
already present in the neonatal period; in long-term survivors it can be
non-progressive. Cardiac-specific deletion of Slc25a3 in mice reproduces the
remodeling arm directly - profound hypertrophy with ventricular dilation and
depressed cardiac function - establishing that carrier loss in cardiomyocytes
is sufficient to cause the cardiomyopathy. This node is the disease-specific
instance of the "Ventricular Remodeling" step of the conserved cardiomyopathy
maladaptive-remodeling module. The module's intervening
neurohormonal-activation step has not been studied in SLC25A3 deficiency and
is deliberately not asserted here.
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 hypertrophic remodeling is the substrate of the clinical hypertrophic cardiomyopathy.
- name: Impaired Mitochondrial Copper Delivery and Cytochrome c Oxidase Biogenesis
biological_scale: MOLECULAR
mechanism_confidence: PROVISIONAL
description: >-
Beyond phosphate, SLC25A3 has been shown in cell and reconstituted systems to
transport copper into the mitochondrial matrix, supplying the labile copper
pool required to metalate cytochrome c oxidase (complex IV). Knockdown or
deletion of SLC25A3 in cultured cells causes an isolated COX deficiency that
is rescued by copper supplementation, and restoring the carrier restores
matrix copper delivery. Whether this second transport function contributes to
the human disease is unresolved: patient muscle biopsies have shown normal
respiratory-chain enzyme activities, so the copper/COX arm is recorded here as
a provisional mechanism rather than an established component of the patient
phenotype (see the HUMAN_MODEL_MISMATCH discussion).
biological_processes:
- preferred_term: copper ion transmembrane transport
term:
id: GO:0035434
label: copper ion transmembrane transport
modifier: DECREASED
- preferred_term: respiratory chain complex IV assembly
term:
id: GO:0008535
label: respiratory chain complex IV assembly
modifier: DECREASED
chemical_entities:
- preferred_term: copper
term:
id: CHEBI:28694
label: copper atom
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: "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: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:21763135
reference_title: "Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children."
supports: REFUTE
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 respiratory-chain enzyme activity in patient muscle argues against a clinically significant cytochrome c oxidase deficiency in vivo, which is why this mechanism is marked PROVISIONAL.
phenotypes:
- name: Hypertrophic cardiomyopathy
category: Cardiovascular
description: >-
Hypertrophic cardiomyopathy is the most consistent feature of the disorder and
is typically present at or shortly after birth. It is the one finding shared
by every reported patient, including those without skeletal myopathy or lactic
acidosis. In long-term survivors it can be non-progressive.
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: Shows cardiomyopathy is the obligate feature, present even when myopathy and lactic acidosis are absent.
- 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 lactic acidosis is typically present from the neonatal period and
reflects the shift to anaerobic glycolysis in energy-starved striated muscle.
It is not obligatory: one reported patient with neonatal cardiomyopathy 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.
- 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: PARTIAL
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: Marked PARTIAL because it documents an exception - a molecularly confirmed patient without elevated lactate - qualifying rather than supporting the universality of lactic acidosis.
- name: Exercise intolerance
category: Musculoskeletal
description: >-
In patients who survive the neonatal period, exertional fatigue is a prominent
residual manifestation of the skeletal-muscle bioenergetic defect, reported
both in adolescents and in an adult surviving to age 32.
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 after walking in the late-onset adult patient.
- 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 is listed among the primary presenting features of the
early-onset form, consistent with severe respiratory-muscle involvement and
cardiac decompensation in the neonatal period.
phenotype_term:
preferred_term: Respiratory failure
term:
id: HP:0002878
label: Respiratory failure
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: Lists respiratory failure among the primary presenting features of PiC deficiency.
- name: Elevated circulating creatine kinase concentration
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 concentration
term:
id: HP:0003236
label: Elevated circulating creatine kinase concentration
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: >-
Persistently elevated blood lactate is the biochemical hallmark and can remain
high for decades in stable long-term survivors, even when treated and
clinically improved.
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.
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
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: >-
Histochemistry on the same biopsy showed a mild INCREASE in cytochrome c
oxidase and succinate dehydrogenase activity, interpreted as mitochondrial
myopathy. The direction matters: an increase, together with the normal
respiratory-chain enzyme measurements reported by Mayr 2011, is a second
independent human observation running against the cell-model
copper/COX-deficiency arm. See the HUMAN_MODEL_MISMATCH discussion.
context: Single long-term survivor biopsied in childhood; n=1.
evidence:
- reference: PMID:40944834
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: >-
Human muscle histochemistry showing increased rather than decreased COX
activity, which is the observation that constrains the provisional
copper/COX arm of the pathograph.
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 defining functional assay: ATP synthesis measured in intact mitochondria is
deficient in patient skeletal muscle but normal in patient fibroblasts,
mirroring the exon 3A (muscle) versus exon 3B (fibroblast) isoform-expression
pattern. Fibroblast studies therefore cannot exclude the diagnosis.
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: >-
Immunodetection of the carrier in muscle biopsy shows reduced protein amount in
the presence of normal respiratory-chain enzyme activities. The normal
respiratory-chain profile is diagnostically important: a standard
respiratory-chain enzyme panel will not detect this disorder.
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: >-
SLC25A3 encodes the mitochondrial inorganic phosphate carrier. Reported disease
alleles cluster on the muscle-specific exon 3A and its splice acceptor: a
homozygous exon 3A missense allele (c.215G>A, p.Gly72Glu) in the Turkish index
family, and a recurrent homozygous splice-region allele (c.158-9A>G) that
creates a novel splice site and removes over 95% of the wild-type exon 3A
transcript, found in a second family, in an unrelated patient, and in a
late-onset adult. One patient is a compound heterozygote for two novel coding
variants outside exon 3A. Because the ubiquitous exon 3B isoform is retained in
the exon 3A alleles, the biochemical defect is restricted to heart and skeletal
muscle.
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: "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: Establishes SLC25A3 as the disease gene and loss of phosphate transport as the molecular consequence of its pathogenic variants.
- reference: PMID:17273968
reference_title: "Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This is the first report of patients with mitochondrial phosphate-carrier deficiency."
explanation: The gene-disease relationship was first established in the 2007 index report of the two Turkish sisters.
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 c.215G>A (p.Gly72Glu), exon 3A
description: >-
The first reported SLC25A3 disease allele: a homozygous missense variant in
the muscle-specific exon 3A, identified in two sisters from a
non-consanguineous Turkish family who both died within the first year of
life. Pathogenicity was confirmed by yeast complementation.
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.
- name: SLC25A3 c.158-9A>G (IVS2-9A>G), exon 3A splice acceptor region
description: >-
A recurrent homozygous intronic variant immediately 5' of the muscle-specific
exon 3A. It creates a novel splice site and abolishes more than 95% of the
wild-type transcript. First reported in a family with three affected
children, subsequently found in an unrelated patient with neonatal
cardiomyopathy and in a woman who survived to age 32 with hypertrophic
cardiomyopathy and myopathy - making it the allele most clearly associated
with the milder, longer-surviving end of the phenotypic spectrum.
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: Documents the same c.158-9A>G splicing allele in the latest-onset patient reported to date.
- name: SLC25A3 c.599T>G (p.Leu200Trp) and c.886_898delinsCAGATAC (p.Gly296_Ser300delinsGlnIlePro)
description: >-
Two novel coding variants found in a compound heterozygous patient with
neonatal cardiomyopathy but no skeletal myopathy and no elevated lactate.
Protein structure analysis indicated both are likely pathogenic. These lie
outside exon 3A, so they affect both carrier isoforms; the patient
nonetheless presented with isolated cardiomyopathy.
clinical_significance: LIKELY_PATHOGENIC
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: In silico protein structure analysis is the basis for the likely-pathogenic classification; no functional assay was reported.
diagnosis:
- name: Molecular diagnosis by SLC25A3 sequencing
description: >-
Because the classical presentation - early-onset hypertrophic cardiomyopathy
with lactic acidosis - is shared with several other mitochondrial and metabolic
cardiomyopathies (and with infantile-onset Pompe disease), and because standard
respiratory-chain enzyme panels and fibroblast studies are normal in this
disorder, molecular sequencing of SLC25A3 is the practical diagnostic route.
Sequencing should be considered even in isolated cardiomyopathy without
myopathy or lactic acidosis.
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.
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.
treatments:
- name: Supportive and Heart-Failure Directed Care
description: >-
No curative or disease-modifying therapy exists. Management is supportive and
phenotype-directed: heart-failure management and cardiac surveillance for the
hypertrophic cardiomyopathy, respiratory support, treatment of lactic acidosis
and avoidance of catabolic stress, and nutritional support. Prognosis in the
classical form remains poor, with most patients dying in the first year of
life.
therapeutic_modality: OTHER
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
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: OTHER
snippet: "Variants in SLC25A3 exist and lead to mPiC deficiency (MPCD), cause a rare autosomal recessive disease with no current cure; patients with MPCD usually die within the first year of life."
explanation: States explicitly that no cure exists and that the classical course is lethal in infancy, which is why care is supportive.
- name: Mitochondrial Cofactor Therapy and Fat-Rich Diet
description: >-
Empirical "mitochondrial cocktail" supplementation combined with a fat-rich
(low-carbohydrate) diet was used in the longest-surviving reported patient and
was associated with clinical improvement, although blood lactate remained
elevated. This is a single-patient observation, not a trial result; there are
no controlled efficacy data for any metabolic therapy in this disorder, and no
specific agent can be recommended on the published evidence.
therapeutic_modality: BEHAVIORAL
context: >-
Single-case, uncontrolled observation in a 32-year-old with the c.158-9A>G
genotype. The dietary component is why the modality is tagged BEHAVIORAL; the
specific cofactor agents were not named in the source abstract, so no
therapeutic_agent is asserted.
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: PARTIAL
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: Marked PARTIAL because this is an uncontrolled single-patient observation with an incomplete biochemical response.
- name: Genetic Counseling
description: >-
Autosomal recessive inheritance carries a 25% recurrence risk for siblings. Two
of the reported pedigrees had multiple affected children, so counselling and
discussion of prenatal or preimplantation testing are relevant once the
familial variants are known.
therapeutic_modality: OTHER
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
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: Three affected children in one sibship illustrates the recurrence risk that makes genetic counselling relevant.
- name: TAT-mPiC Protein Replacement (investigational, preclinical)
description: >-
A cell-penetrating TAT-fused recombinant phosphate carrier delivered to
mPiC-knockdown cells localised correctly to the inner mitochondrial membrane
and restored oxygen consumption, ATP production, matrix phosphate and copper
delivery, and reduced lactate secretion. This is a preclinical cell-culture
result only - there are no animal efficacy data and no human studies. It is
recorded here as a mechanism-directed investigational strategy, not a clinical
option.
therapeutic_modality: PROTEIN_REPLACEMENT
context: >-
Preclinical, in vitro (mPiC-knockdown cell lines). No animal or human efficacy
data.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
target_mechanisms:
- target: Loss of Mitochondrial Phosphate Carrier Function in Heart and Skeletal Muscle
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.
- name: Mitochondrial Transplantation (investigational, preclinical)
description: >-
Transfer of exogenous healthy mitochondria into SLC25A3-mutant human
iPSC-derived cardiomyocytes was explored as a way to rescue the hypertrophic
phenotype and calcium-handling imbalance. This is an exploratory in vitro
finding in a disease-model cell system; no in vivo or clinical data exist.
therapeutic_modality: CELL_THERAPY
context: >-
Preclinical, in vitro (SLC25A3-mutant hiPSC-derived cardiomyocytes). No animal
or human efficacy data.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
target_mechanisms:
- target: Cardiomyocyte and Skeletal Muscle Energy Deficit
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: PARTIAL
evidence_source: IN_VITRO
snippet: "Finally, we explored the prospective therapeutic implications of mitochondrial transplantation in rescuing SLC25A3-related HCM."
explanation: Marked PARTIAL because the authors describe this as an exploratory, prospective therapeutic implication rather than a demonstrated therapy.
discussions:
- discussion_id: mismatch_copper_cox_arm_not_seen_in_patients
kind: HUMAN_MODEL_MISMATCH
status: OPEN
prompt: >-
Does the copper-transport / cytochrome c oxidase arm of SLC25A3 function,
demonstrated in knockdown cell lines and reconstituted systems, actually
contribute to human cardiomyopathy-hypotonia-lactic acidosis syndrome, given
that patient muscle biopsies show normal respiratory-chain enzyme activities?
attaches_to:
- pathophysiology#Impaired Mitochondrial Copper Delivery and Cytochrome c Oxidase Biogenesis
- pathophysiology#Loss of Mitochondrial Phosphate Carrier Function in Heart and Skeletal Muscle
rationale: >-
SLC25A3 has been shown directly, in Lactococcus lactis and reconstituted
liposomes, to transport copper, and knockdown or deletion in murine and human
cell lines produces an isolated cytochrome c oxidase deficiency that copper
supplementation rescues. If that arm operated in patients, one would expect
reduced COX activity in affected muscle. Instead, the patient muscle biopsy
reported by Mayr et al. showed normal respiratory-chain enzyme activities with
only the carrier protein reduced, and histopathology in a long-surviving adult
showed mildly increased rather than decreased COX and SDH staining. The
evidence therefore exists in a model system but its translational validity to
human SLC25A3 disease is the open question, which is why this is recorded as
HUMAN_MODEL_MISMATCH rather than a plain knowledge gap. Possible resolutions
include isoform specificity (the copper work used total SLC25A3 loss, whereas
most patient alleles ablate only isoform A), residual isoform B sufficing for
copper delivery in patient muscle, or the copper function being dispensable in
vivo.
proposed_experiments:
- experiment_id: exp_slc25a3_isoform_copper_cox
name: Isoform-resolved copper transport and COX metalation assay
description: >-
In isogenic human iPSC-derived cardiomyocytes engineered to carry (a) an exon
3A-specific patient allele, (b) a total SLC25A3 knockout, and (c) the
corrected genotype, quantify matrix copper, COX holoenzyme assembly and
activity, and the response to copper supplementation. This directly tests
whether the copper/COX arm is engaged by isoform-A-selective patient alleles
or only by total carrier loss, reconciling the cell-line and patient-muscle
observations.
experiment_type:
preferred_term: iPSC-derived cardiomyocyte perturbation assay
model_systems:
- name: Human iPSC-derived cardiomyocyte
description: >-
Cardiomyocytes differentiated from isogenic iPSC lines carrying
exon-3A-selective versus total SLC25A3 loss, preserving the human isoform
architecture that mouse and immortalised cell models do not reproduce.
experimental_model_type: OTHER
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: The model-system observation on one side of the mismatch.
- reference: PMID:21763135
reference_title: "Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children."
supports: REFUTE
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: The human observation on the other side of the mismatch - normal respiratory-chain enzyme activity in patient muscle.
- 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 Energy Deficit
rationale: >-
The reported phenotypic range is extreme for a disorder with fewer than a dozen
published patients: the index siblings died within the first year of life,
whereas patients homozygous for the recurrent c.158-9A>G splice allele have
survived to ages 9, 17, and 32 years with non-progressive hypertrophic
cardiomyopathy and normal cognition, and one compound heterozygote had isolated
cardiomyopathy with normal lactate and no myopathy. Whether the determinant is
residual exon 3A transcript level, isoform-B compensation, modifier loci, or
the standard of supportive care available at the time cannot be resolved from
the published cases. The cohort is too small for a genotype-phenotype analysis,
and no natural-history study exists.
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.
References & Deep Research
References
7Mitochondrial 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.
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.
Mitochondrial phosphate-carrier deficiency mimicking infantile-onset Pompe disease.
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.
Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy.
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.
Deep Research
1
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.)
Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
- 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)
Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
- Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)
Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
- Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)
Search first: PubMed, Gene Ontology, Reactome
- 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)
Search first: OMIM, Orphanet, HPO, PubMed
- 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
- Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
- 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
- Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
- Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
- Omics-Based Diagnostics (if applicable):
- RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
- Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
- Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
- Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
- Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
- 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
- Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
- 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:
- Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
- Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
- Advanced Therapeutics:
- Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
- Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
- RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
- Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
- Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
- 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:
- Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
- Treatment Outcomes:
- Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
- Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
- Treatment Strategy:
- Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
- 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:
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14. Other Species / Natural Disease
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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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