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Classifications

Harrison's Part

Mechanistic Nosology

ICIMD (Inherited Metabolic Disorders)

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Both 2018 families are biallelic and parental heterozygosity was confirmed by segregation in each. The Austrian patient is compound heterozygous for two missense alleles inherited one from each parent; the Tunisian patient is homozygous for a third missense allele with both parents heterozygous. MRPS2 is nuclear-encoded and autosomal, so despite the mitochondrial biochemistry this is a nuclear recessive disease with a 25 percent sibling recurrence risk and no maternal transmission.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Segregation analysis confirmed that both parents are heterozygous for one of these variants."

Biparental transmission of the two alleles in the compound heterozygous family, which is what distinguishes recessive inheritance from a de novo or dominant configuration.

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"in only one gene: MRPS2, which encodes a known mitochondrial protein. Segregation analysis confirmed that both parents are heterozygous for this variant."

The homozygous family, with carrier parents — the second independent recessive configuration.

PMID:34991560 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The proband had the homozygous mutation C. 412C>G(p.R138G). The parents of the proband were all heterozygous for this mutation"

A third independent recessive family, homozygous with carrier parents, in a non-consanguineous sibship where the brother is unaffected.

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Discussions and Knowledge Gaps

3

Why does a generalised mitochondrial translation defect produce hearing loss as its most consistent and earliest-recognised feature, when the cochlea is not where the biochemistry was measured?

KNOWLEDGE GAP OPEN copd36_cochlear_mechanism

Attached to

phenotypes#Sensorineural Hearing Loss pathophysiology#Combined Deficiency of OXPHOS Complexes I and IV

Hearing loss is the only feature present in all four published patients and the only one with an effective intervention, yet the entire mechanistic chain in this entry is measured in fibroblasts, liver and muscle. No cochlear tissue, no auditory-nerve measurement and no animal model of MRPS2 deficiency exists. The edge from the OXPHOS node to the hearing phenotype is therefore carried as INDIRECT_UNKNOWN_INTERMEDIATES, and is an argument from organ vulnerability across the mitoribosomal group rather than a finding about MRPS2. This matters beyond bookkeeping. Cochlear implantation works in these patients, which implies the lesion is at the hair cell or before the spiral ganglion rather than central — but that inference from a therapeutic response is the only evidence about the site of the lesion that this literature contains.

Does the position of a mitoribosomal protein in the assembly pathway predict how severe the resulting disease is?

OPEN QUESTION OPEN copd36_late_assembly_severity

Attached to

pathophysiology#Failure of Mitoribosomal Small Subunit Assembly

The founding authors propose that variants in subunits that join late produce milder disease than variants in subunits that join early, and offer MRPS2 as their case: the roughly 300 kDa early subassembly containing MRPS22 and MRPS16 is still present in patient cells, and these patients were alive at eleven where about a third of the mitoribosomal-disease series died before one year. Recorded as an open question rather than as mechanism because it is a hypothesis about the whole mitoribosomal group, testable across it, and the authors state plainly that the order of steps in mitoribosomal assembly is not known. A single mild entity is consistent with the hypothesis and does not establish it; the comparison that would is an assembly-order ranking against outcome across all the MRPS and MRPL disorders, which nobody has published.

Show evidence (1 reference)

PMID:29576219 SUPPORT INDIRECT PRIMARY RESULT Other

"Despite recent advances in elucidating the structure of the mammalian mitoribosome,3 the order of steps in the assembly process of the mitochondrial ribosome remains elusive."

The authors' own statement of the gap that keeps this a hypothesis — the assembly order the proposal depends on is not established.

Are the wrinkled skin of the first 2018 patient and the joint hypermobility of the 2024 patient two expressions of one connective-tissue involvement, or two unrelated findings in a series of four?

OPEN QUESTION OPEN copd36_connective_tissue

Attached to

phenotypes#Excessive Wrinkled Skin phenotypes#Joint Hypermobility

Each feature is reported once, in a different patient, by a different group, six years apart, and neither report mentions the other finding. The founding paper argues at length that wrinkled skin is the discriminating feature of the entity and compares it with the cutis laxa syndromes, which are themselves connective-tissue disorders with laxity at the joints. That makes the pairing suggestive. It is not more than suggestive, and the arrival of the 2022 patient sharpens rather than settles it. She has neither finding: her physical examination is reported as revealing no abnormal findings. So across four patients the skin feature is 1 of 4 and the joint feature is 1 of 4, in different individuals, with two patients having neither — which is what two unrelated occasional findings look like, and also what one variably expressed connective-tissue feature looks like. Four is not enough to tell those apart. There is no dermal or fibroblast matrix measurement in any patient — the fibroblasts in this literature were used for mitochondrial assays, not for collagen or elastin. Resolving it needs a fifth patient examined for both, or a matrix assay on the fibroblast lines that already exist.

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Pathophysiology

8

Biallelic MRPS2 Missense Variants

Mechanism confidence: Established

Four missense alleles are known across three genotyped families. The Austrian patient is compound heterozygous for c.328C>T, p.Arg110Cys and c.340G>A, p.Asp114Asn; the Tunisian patient is homozygous for c.413G>A, p.Arg138His; the Chinese patient is homozygous for c.412C>G, p.Arg138Gly. The 2018 alleles change residues conserved across species, were predicted damaging by at least two of three in-silico tools, and appear in gnomAD only as very rare heterozygotes. The fourth allele is the interesting one. c.412C>G and c.413G>A are adjacent nucleotides of the same codon, so two unrelated families — one Tunisian, one Chinese — independently carry substitutions of the same arginine, to histidine in one and to glycine in the other. Two independent hits at one residue in a series of three genotyped families is a stronger statement about which part of the protein matters than any single allele makes, and it is a statement no in-silico predictor supplied. Two things are worth keeping separate here. That the alleles are rare and conserved is a prediction; that they are pathogenic is a measurement, made by the lentiviral complementation experiment recorded further down this chain. This entry treats the second as the basis for the LOSS_OF_FUNCTION call, not the first. The positions of the residues within the assembled subunit also differ between the families, and the founding authors use that difference to explain a quantitative difference in the biochemistry: Arg110 and Asp114 face the 12S rRNA and contact several other proteins, while Arg138 sits near the surface of the small subunit, and 12S rRNA loss was correspondingly deeper in the compound heterozygote.

MRPS2 hgnc:14495

Genetic context MRPS2 hgnc:14495 allele_type: two missense variants in trans in one family, and a homozygous missense variant in the other variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Zygosity differs between the two founding families — compound heterozygous in one, homozygous in the other — so no single zygosity value describes the entity and the slot is left unset rather than asserting one family's configuration for both.

LOSS_OF_FUNCTION is supported by measurement rather than prediction: patient fibroblasts carry reduced steady-state MRPS2, and re-expressing wild-type MRPS2 restores mitochondrial translation and OXPHOS assembly in both patients' cells. No allele is a nonsense or frameshift variant, so this is a hypomorphic loss rather than a demonstrated null, which is consistent with the comparatively mild course.

Downstream

Destabilization of the MRPS2 Protein Each of the three missense substitutions reduces the steady-state amount of MRPS2 protein in patient fibroblasts, so the primary consequence of the allele is loss of the protein rather than a protein present but inactive.

Show evidence (3 references)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"This resulted in the identification of a single candidate gene, mitochondrial ribosomal protein S2 (MRPS2; GenBank: NM_016034.3), carrying two heterozygous sequence variants, c.328C>T (p.Arg110Cys) and c.340G>A (p.Asp114Asn)"

The two alleles of the compound heterozygous family, and the gene they are in.

PMID:29576219 SUPPORT INDIRECT PRIMARY RESULT Computational

"All identified variants affect highly conserved amino acids (Figure 2C) and were predicted to be pathogenic by at least two of the three in silico prediction programs that were used."

The conservation and prediction argument. Graded COMPUTATIONAL and INDIRECT because prediction is what it is: it makes the alleles candidates, and the complementation experiment below is what makes them causal.

PMID:34991560 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"A homozygous C.412C > G variant that could cause complex oxidative phosphorylation deficiency and had not been reported before was identified."

The fourth allele, which falls on the codon immediately adjacent to the 2018 homozygous allele — the recurrence at Arg138 this node describes. Note this family had no functional work: the variant was called on its novelty and the phenotype match, not on an assay.

Destabilization of the MRPS2 Protein

Mechanism confidence: Established

MRPS2 is one of roughly thirty nucleus-encoded proteins of the 28S small subunit of the mitochondrial ribosome. It spans all three domains of that subunit and contacts seven other small-subunit proteins, which is the structural argument the founding authors give for treating its role as scaffolding rather than catalytic. The bacterial orthologue bS2 has a translation-initiation function that depends on the Shine-Dalgarno sequence. Mitochondrial mRNAs have no Shine-Dalgarno sequence, so that function has most likely been lost, and what remains is structural. This matters for reading the phenotype: the defect downstream is a failure to build the subunit, not a failure to initiate on particular messages.

MRPS2 hgnc:14495

structural constituent of the mitoribosomal small subunit GO:0003735 ↓ DECREASED

mitochondrial small ribosomal subunit GO:0005763

Downstream

Failure of Mitoribosomal Small Subunit Assembly Losing MRPS2 prevents the 28S subunit from assembling. Complexome profiling shows fully assembled small subunits are hardly detectable in patient fibroblasts while large subunits are normal, so the defect is specific to the subunit MRPS2 belongs to.

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Other

"This extended range of interactors suggests that MRPS2 has adopted a primarily structural role, which is consistent with our findings that its loss is associated with impaired mt-SSU assembly."

The authors' structural reading of the protein's role. Graded OTHER because it is an inference from the published mitoribosome structure rather than an experiment in this paper, and DIRECT because the sentence asserts exactly the claim this node makes.

Failure of Mitoribosomal Small Subunit Assembly

Mechanism confidence: Established

The small subunit fails to form. Three measurements agree: the other small-subunit proteins MRPS5, MRPS18B and MRPS28 fall with MRPS2 while the large-subunit proteins MRPL37 and MRPL44 do not; the 12S rRNA that the small subunit is built around falls while 16S rRNA does not; and complexome profiling finds no fully assembled small subunit. The roughly 300 kDa early subassembly containing MRPS16, MRPS17, MRPS18B, MRPS22, MRPS26, MRPS27 and MRPS34 survives in patient cells, at reduced level. That observation is what places MRPS2 late in the assembly pathway, and it is the mechanistic basis for the severity hypothesis recorded in this entry's discussions.

patient-derived skin fibroblast CL:0000057

mitochondrial small ribosomal subunit assembly GO:0180026 ↓ DECREASED

mitochondrial small ribosomal subunit GO:0005763

Downstream

Loss of Mitochondrial 12S Ribosomal RNA Newly imported mitoribosomal proteins and nascent 12S rRNA are stable only once they have assembled together, so a subunit that cannot assemble loses its rRNA as well as its protein.

Inhibition of Mitochondrial Translation Without an assembled small subunit there is no functional monosome, so translation of the mtDNA-encoded messages stops.

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Similarly, the mt-SSU proteins MRPS5, MRPS18B, and MRPS28 were less abundant in subject fibroblasts. Amounts of the mt-LSU proteins MRPL37 and MRPL44 remained unchanged."

The co-depletion of small-subunit partners with large-subunit proteins spared, which is what makes this an assembly failure rather than a general loss of mitochondrial protein.

Loss of Mitochondrial 12S Ribosomal RNA

Mechanism confidence: Established

12S rRNA, the RNA core of the small subunit, is specifically reduced in patient fibroblasts while 16S rRNA — the large subunit's RNA — is not. The same pattern is seen in the MRPS22-mutant control line, so it is a general consequence of small-subunit protein loss rather than something particular to MRPS2. This node is drawn separately from the assembly failure because it is separately measured and because it is the quantity that differs between the two families: the compound heterozygote, whose substituted residues face the RNA, loses slightly more of it than the homozygote whose substituted residue sits at the subunit surface.

mitochondrial small ribosomal subunit GO:0005763

Downstream

Inhibition of Mitochondrial Translation The 12S rRNA is the catalytic and structural core of the small subunit; losing it removes the decoding capacity of the mitoribosome.

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Consistent with this, steady-state abundance of 12S rRNA, but not that of 16S rRNA, was specifically decreased in S1 and S2 fibroblasts"

The measurement, in both patients' cells, with the large-subunit rRNA as internal control.

Inhibition of Mitochondrial Translation

Mechanism confidence: Established

Pulse labelling of mitochondrial translation products with radiolabelled methionine and cysteine shows a profound and generalised defect in both patients' fibroblasts. Generalised is the operative word: it is not a subset of messages, which is what would be expected if MRPS2 retained the bacterial orthologue's message-selection function.

mitochondrial translation GO:0032543 ↓ DECREASED

Experimental models

MRPS2-complemented patient fibroblast lines PRIMARY CELL CULTURE Re-expressing wild-type MRPS2 partially restores mitochondrial translation in both patients' cells, and restores assembly of complexes I and IV.

Downstream

Combined Deficiency of OXPHOS Complexes I and IV The thirteen mtDNA-encoded polypeptides are all subunits of complexes I, III, IV and V, so a general translation failure starves those complexes of subunits while leaving complex II, which is entirely nucleus-encoded, intact.

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT In Vitro

"in vitro pulse labeling of mitochondrial translation products with radiolabeled methionine and cysteine revealed a profound and generalized translation defect of mtDNA-encoded polypeptides in both S1 and S2 fibroblasts"

The translation defect measured directly, and its generalised character.

Combined Deficiency of OXPHOS Complexes I and IV

Mechanism confidence: Established

In fibroblasts, complexes I and IV are reduced, complex III and the nucleus-encoded complex II are not, and complex V is present at normal amount but with subcomplexes that do not occur in control cells. In tissue the picture is broader: multiple complexes are deficient in liver and muscle in the first patient, and in liver and fibroblasts with an isolated complex IV deficiency in muscle in the second. That discrepancy between fibroblast and tissue, and between the two patients' muscle, is worth stating rather than smoothing over. It means a normal muscle respiratory-chain panel does not exclude the diagnosis, and it is the reason the entity is named for a combined deficiency even though any single biopsy may show something narrower. This is the convergence point of the entry. Every systemic feature below is downstream of this node.

patient-derived skin fibroblast CL:0000057

oxidative phosphorylation GO:0006119 ↓ DECREASED

Downstream

Anaerobic Redirection of Pyruvate and Accumulation of Krebs-Cycle Intermediates A respiratory chain that cannot reoxidise NADH forces pyruvate to lactate and backs up the Krebs cycle, which is the standard biochemical consequence and the one the patients' lactate and 2-oxoglutarate measurements report.

Failure of Fasting Metabolic Adaptation Gluconeogenesis and fatty-acid oxidation are the most ATP-demanding parts of the hepatic fasting response, so a hepatic OXPHOS deficit shows itself first as an inability to hold blood glucose through a fast.

Sensorineural Hearing Loss The cochlea is among the tissues most vulnerable to a respiratory-chain deficit, and sensorineural hearing loss is a recurring feature across mitoribosomal-protein disease. No cochlear measurement exists in any MRPS2 patient, so this edge is the general organ-vulnerability argument applied to this entity, not a finding about it.

Developmental Delay and Intellectual Disability Both 2018 patients have developmental delay with normal brain MRI, which is the pattern expected from a diffuse energetic deficit rather than from a structural malformation. The step from OXPHOS deficiency to the cognitive phenotype is not measured in this disease.

Exercise Intolerance and Myalgia Skeletal muscle in the second patient carries a complex IV deficiency, and his exertional myalgia and lower-limb weakness are the clinical expression expected from it. The attribution is clinical rather than measured.

Elevated Hepatic Transaminases Liver in both patients carries a multiple-complex deficiency, and the first patient's transaminases run three- to four-fold high. Hepatocyte injury from an energetic deficit is the usual reading, but no liver histology or mechanism study exists here.

Failure to Thrive Growth is the first thing an infant gives up when ATP supply is short, and failure to thrive is near-universal across the mitoribosomal-protein disorders. In this entity it is reported in one patient of four, so the edge asserts the general relationship rather than anything measured in MRPS2 disease.

Hypotonia Hypotonia is the commonest neuromuscular sign across the mitoribosomal-protein disorders and is present in both 2018 patients. Muscle in the second of them carries a complex IV deficiency, so a muscular contribution is measured; whether the tone abnormality is muscular, central, or both is not established in this disease.

Lower Limb Muscle Weakness The patient with lower-limb weakness is the one whose muscle biopsy carries an isolated complex IV deficiency, which is the respiratory-chain correlate. The attribution is clinical rather than measured in the weak muscle itself.

Show evidence (2 references)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Measurements of OXPHOS complex activities in liver, muscle, and fibroblasts showed a decrease in multiple enzyme complexes"

The combined deficiency in patient tissue rather than only in cultured cells.

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Measurements of OXPHOS complex activities showed a decrease in multiple complexes in liver and fibroblasts and a complex IV deficiency in muscle."

The second patient's tissue pattern, which differs from the first — the basis for this node's warning that a single tissue can look isolated rather than combined.

Anaerobic Redirection of Pyruvate and Accumulation of Krebs-Cycle Intermediates

Mechanism confidence: Established

A respiratory chain that cannot reoxidise NADH leaves pyruvate to be reduced to lactate and leaves the Krebs cycle backed up behind its NAD-dependent dehydrogenases. In these patients that shows as raised blood lactate, raised serum alanine — the transamination product of the pyruvate that accumulates with it — and increased urinary excretion of 2-oxoglutarate, with a trace of succinate. 2-oxoglutarate is the more informative of the two urinary findings, because its dehydrogenase is NAD-dependent and it is the intermediate the founding authors single out as part of the recognisable biochemical signature.

tricarboxylic acid cycle GO:0006099 ↓ DECREASED

Downstream

Lactic Acidaemia

Increased Urinary 2-Oxoglutarate

Hyperalaninaemia

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"elevated serum alanine (up to 850 μmol/L; reference values = 99–350 μmol/L), and increased excretion of Krebs cycle intermediates"

The alanine elevation and the Krebs-cycle intermediate excretion, with the laboratory's own reference interval, measured in the first patient.

Failure of Fasting Metabolic Adaptation

Mechanism confidence: Provisional

Both 2018 patients become hypoglycaemic on fasting, and in the second patient a formal fasting test reproduced it with a simultaneous rise in lactate to 5 mmol/L and increased 2-oxoglutarate excretion. The coupling of hypoglycaemia to hyperlactataemia within one provoked test is what identifies the defect as a failure of energy-dependent hepatic adaptation rather than, say, hyperinsulinism, where lactate would not rise. Graded PROVISIONAL rather than ESTABLISHED because no measurement of gluconeogenic flux or of hepatic ATP exists in any MRPS2 patient. What is established is the clinical coupling; the hepatocyte-level explanation is inferred from the liver OXPHOS deficiency measured in the same patients.

gluconeogenesis GO:0006094 ↓ DECREASED

Downstream

Fasting Hypoglycaemia

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"A clinical fasting test showed hypoglycemia with hyperlactatemia (5 mmol/L) and slightly increased excretion of 2-oxoglutarate"

The provoked test that couples the hypoglycaemia to the lactate rise, which is the observation this node rests on.

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Pathograph

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Phenotypes

21

Digestive 2

Cholelithiasis with Chronic Cholecystitis OCCASIONAL HP:0001081

1 of 4 published patients, and new to the phenotype in 2022. Whether it belongs to the disease at all is open: it is a single instance, no mechanism links MRPS2 to biliary physiology, and childhood gallstones have many causes including the haemolysis this patient was not reported to have. It is recorded because a feature that appears once in a series of four is exactly what a fifth report would confirm or dismiss, and it cannot be confirmed if nobody wrote it down.

Show evidence (1 reference)

PMID:34991560 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"When she was 4 years and 9 months old, she had gall bladder calculi due to chronic cholecystitis, which was accompanied by erosion and bile reflux, and was treated by laparoscopic cholecystectomy under general anesthesia."

The finding, its age, its stated cause and its treatment, in the one patient who has it.

Recurrent Vomiting with Poor Appetite OCCASIONAL HP:0002013

Temporal: RECURRENT

1 of 4 published patients. Recorded because it changes what the fasting-avoidance advice in this entry has to cover — a child who vomits and will not eat is fasting whether or not anyone intended a fast.

Sequelae: Fasting Hypoglycaemia

Show evidence (1 reference)

PMID:34991560 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The girl aged 6.5 years old was hospitalized because of recurrent vomiting for more than 2 years. She had poor appetite and hypoglycemia during hospitalization"

The presenting complaint, its duration, and its coincidence with the hypoglycaemia.

Ear 2

Sensorineural Hearing Loss VERY_FREQUENT Sensorineural hearing impairment HP:0000407

4 of 4 published patients. VERY_FREQUENT rather than OBLIGATE: universal in the series, but a denominator of four cannot carry an obligate claim. The general sensorineural term is bound rather than a congenital one, because in every patient the loss was recognised between two and four years and described as progressive in the first rather than present at birth.

Show evidence (3 references)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"At the age of 3 years, she had developed progressive sensorineural hearing loss, which required the use of a hearing aid and was corrected with bilateral cochlea implants. After this correction, both her speech and development improved markedly."

Onset, progression and the response to implantation in the first patient — the evidence behind both this phenotype and the cochlear-implantation treatment entry.

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Speech development was delayed as a result of severe sensorineural deafness at the age of 2 years, necessitating the use of a hearing aid."

The second patient's hearing loss, its severity and its age of recognition.

PMID:34991560 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"When she was 4 years old, she had sensorineural hearing loss and was treated by parallel cochlear implants."

The third patient's hearing loss, its age of recognition and its treatment — the second independent instance of cochlear implantation in this disease.

Low-Set Ears OCCASIONAL HP:0000369

1 of 4 published patients.

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"She had minor dysmorphic features, including low-set ears and slightly up-slanting palpebral fissures."

The dysmorphic features of the first patient, and the source for the palpebral-fissure phenotype below.

Eye 1

Intermittent Divergent Strabismus OCCASIONAL Exodeviation HP:0020049

1 of 4 published patients. Bound to the exodeviation term rather than to the general HP:0000486 Strabismus because the source specifies the direction, and the laterality and intermittency are carried in preferred_term.

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"She had an intermittent divergent strabismus of the left eye."

The finding with its direction, laterality and intermittency.

Genitourinary 1

Increased Urinary 2-Oxoglutarate FREQUENT Increased urine alpha-ketoglutarate concentration HP:0012402

2 of 4 published patients, both in the 2018 report; neither later report mentions organic acids, and the 2022 patient's urine gas chromatography is reported as normal. HPO names the compound alpha-ketoglutarate where the source names it 2-oxoglutarate; these are the same molecule, and preferred_term keeps the source's spelling.

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"2-oxoglutaric acid between 50–220 μmol/mmol creatinine; reference values = 0–50 μmol/mmol creatinine and trace elevation of succinic acid"

The measured excretion with its reference interval, and the accompanying succinate trace.

Head and Neck 2

Upslanted Palpebral Fissures OCCASIONAL HP:0000582

1 of 4 published patients.

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"including low-set ears and slightly up-slanting palpebral fissures"

The second of the two dysmorphic features reported in the first patient.

Microcephaly OCCASIONAL HP:0000252

1 of 4 published patients, and new to the phenotype as of 2024. Recorded because a feature a later report adds is exactly what a reader consulting an entry written from the founding paper would otherwise miss.

Show evidence (1 reference)

PMID:38029925 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"we describe a new MRPS2 homozygous subject who shows particular features which have not yet been reported: initial microcephaly, joint hypermobility and autistic features."

The three features the 2024 report adds, and the authors' own statement that they were not previously reported in MRPS2 disease.

Integument 1

Excessive Wrinkled Skin OCCASIONAL HP:0007392

1 of 4 published patients; the second 2018 patient is explicitly recorded as having no skin involvement, the 2022 patient's physical examination is reported as revealing no abnormal findings, and the 2024 abstract does not mention skin. So this is a variable feature with high diagnostic value when present and no negative predictive value when absent — which is worth stating because the founding paper's framing could be read as making it a requirement.

Show evidence (2 references)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Skin wrinkling, most pronounced on the abdomen and hands, was apparent from birth."

The distribution and congenital onset in the patient who has it.

PMID:29576219 SUPPORT INDIRECT BACKGROUND Human Clinical

"To date, dermatological symptoms in subjects with mutations in MRP genes have been limited to redundant skin of the neck, which was previously described in single subjects carrying either MRPS22 or MRPS16 mutations."

Why the finding is diagnostically informative — it is unusual within the mitoribosomal group. Graded BACKGROUND because the sentence summarises other groups' published patients, not a result of this study, and INDIRECT because it supports the significance of the finding rather than the finding itself.

Limbs 1

Lower Limb Muscle Weakness OCCASIONAL HP:0007340

1 of 4 published patients. Kept separate from Exercise Intolerance and Myalgia because weakness at rest and pain on exertion are different findings, and this patient has both.

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"a moderate intellectual disability, frequent headache episodes, and muscular weakness of the lower limbs"

The three features of the second patient at eleven years, including this one.

Metabolism 4

Fasting Hypoglycaemia FREQUENT Hypoglycemia HP:0001943

Temporal: RECURRENT

3 of 4 published patients — both 2018 patients and the 2022 patient. The 2024 abstract does not mention glucose. The 2022 patient's presentation differs in a way worth noting: her hypoglycaemia came with two years of recurrent vomiting and poor appetite rather than with a documented fast, so the trigger there is reduced intake rather than fasting duration.

Show evidence (2 references)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Medical history was marked by several acute episodes of hypoglycemia after an overnight or a 12-hr fasting since the age of 18 months, especially when these episodes coincided with illness and poor oral intake, which associated with lactic acidosis."

The fasting duration that provokes it, the age of onset, the illness trigger, and the coupling to lactic acidosis — everything the management advice rests on.

PMID:34991560 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Blood glucose was 1.2–2.5 mmol/L when she was hospitalized."

The measured glucose range in the third patient — the only numerical hypoglycaemia values published for this disease.

Lactic Acidaemia FREQUENT Increased circulating lactate concentration HP:0002151

3 of 4 published patients. Bound to the circulating-lactate term rather than HP:0003128 Lactic acidosis, even though the 2022 patient has a measured acidosis (pH 7.224, bicarbonate 4.3 mmol/L, base excess minus 24): the two 2018 patients have raised lactate without a reported pH, so the term that covers the whole series is the concentration one. The 2022 patient's acidosis is recorded in her evidence item rather than by changing the binding.

Show evidence (3 references)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"repetitive elevated lactate levels (>8 mmol/L; reference values < 2 mmol/L)"

The first patient's lactate with the laboratory's reference interval.

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Metabolic investigations showed repetitive mildly increased lactate levels in plasma (2.2–3.8 mmol/L; reference values < 2 mmol/L) and urine"

The second patient's much milder lactate, quoted because the range between the two patients is part of what a reader needs in order not to exclude the diagnosis on a mild value.

PMID:34991560 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"lactate: 8.9 mmol/L [reference value: 0.5–1.5 mmol/L]"

The third patient's lactate with her laboratory's reference interval, measured alongside a frank metabolic acidosis rather than a raised lactate alone.

Hyperalaninaemia OCCASIONAL Hyperalaninemia HP:0003348

1 of 4 published patients — reported for the first 2018 patient only. Amino-acid analysis is reported as normal by tandem mass spectrometry in the 2022 patient, which is a recorded negative rather than a silence.

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"elevated serum alanine (up to 850 μmol/L; reference values = 99–350 μmol/L)"

The measured alanine with its reference interval.

Elevated Hepatic Transaminases OCCASIONAL Elevated circulating hepatic transaminase concentration HP:0002910

1 of 4 published patients, and explicitly absent in the 2022 patient, whose liver enzymes are reported as normal. No patient in the series developed liver failure, which distinguishes this entity from the MRPS7 disorder where progressive hepatic failure was the cause of death.

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Biochemical evaluation revealed elevated liver enzymes (3- to 4-fold elevation in aspartate-amino transferase and alanine-amino transferase"

The magnitude and the two enzymes involved.

Musculoskeletal 2

Hypotonia FREQUENT HP:0001252

2 of 4 published patients. The evidence is a row of Table 1, where the first two data columns are this paper's own two subjects; the later reports do not mention tone, and the 2022 patient's muscle tension and tone are explicitly normal, so the denominator stays four.

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Hypotonia | + | + | NR | + | + | + | NR | NR | + | NR | + | + | NR"

The Table 1 row. The table's column order is given three rows above as "this article (S1) | this article (S2) | Menezes et al.16 | ...", so the two leading plus signs are this paper's own two MRPS2 patients rather than the comparison cohorts.

Joint Hypermobility OCCASIONAL HP:0001382

1 of 4 published patients. Connective-tissue laxity sits beside the wrinkled skin of the first 2018 patient, and whether the two are one feature of the entity or two coincidences in a series of four is recorded as a knowledge gap in this entry's discussions.

Show evidence (1 reference)

PMID:38029925 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"initial microcephaly, joint hypermobility and autistic features"

The feature as listed by the 2024 authors.

Nervous System 3

Developmental Delay and Intellectual Disability FREQUENT Global developmental delay HP:0001263

3 of 4 published patients — both 2018 patients and the 2022 patient, with the 2024 patient adding autistic features. The 2022 patient is the informative one for scope: her language was retarded while her motor development was normal, so the delay is not uniformly global across the series and this binding is the term that covers the 2018 patients rather than all four. Speech delay in every patient who has it was attributed by the reporting authors to the hearing loss and improved once that was corrected, which is why it is recorded under hearing loss rather than as a separate phenotype.

Show evidence (3 references)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Her last formal developmental assessment at the age of 5 years and 10 months showed an average developmental state of 2 years and 6 months of age."

The quantified delay in the first patient.

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"At the age of 11 years he had a normal physical appearance, with normal growth parameters, but a moderate intellectual disability, frequent headache episodes, and muscular weakness of the lower limbs."

The second patient's cognitive outcome at eleven, together with the headache and lower-limb weakness recorded elsewhere in this entry.

PMID:34991560 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"The girl was taciturn with language retardation. She could only say simple words and sentences, but her motor development was normal."

The third patient's developmental profile. Graded INDIRECT against a global-delay node because it reports a dissociation — language affected, motor spared — rather than the global delay this phenotype names.

Headache OCCASIONAL HP:0002315

Temporal: RECURRENT

1 of 4 published patients.

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"frequent headache episodes, and muscular weakness of the lower limbs"

The headache and the lower-limb weakness below, both from the second patient's assessment at eleven years.

Autistic Behaviour OCCASIONAL Autistic behavior HP:0000729

1 of 4 published patients.

Show evidence (1 reference)

PMID:38029925 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"who shows particular features which have not yet been reported: initial microcephaly, joint hypermobility and autistic features"

The feature as listed by the 2024 authors, with their own novelty claim attached.

Constitutional 1

Exercise Intolerance and Myalgia OCCASIONAL HP:0003546

1 of 4 published patients. The first patient's motor delay is recorded under developmental delay rather than here, since it was a delay in acquisition rather than exertional intolerance; the 2022 patient's muscle tension and tone are reported as normal.

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He suffered from exercise intolerance marked by myalgia after walking."

The exertional phenotype in the patient who has it.

Growth 1

Failure to Thrive OCCASIONAL HP:0001508

1 of 4 published patients; the second 2018 patient is explicitly recorded as growing normally and the 2022 patient's physical examination revealed no abnormal findings.

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"During the first year of life she developed a failure to thrive."

The growth phenotype and its timing in the first patient.

🧬

Genetic Associations

1

MRPS2

Gene: MRPS2 hgnc:14495 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Cumulatively, our complementation experiments confirm the pathogenicity of MRPS2 mutations."

The authors' own statement of what establishes causality here, and the reason this entry grades the gene-disease relationship on function rather than on prediction.

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Consistent with these observations, mitochondrial translation was partially restored in both subject cell lines complemented with wild-type MRPS2 (Figure 6B), as was the assembly of OXPHOS complexes I and IV (Figure 6C)."

The rescue itself, in both patients' cells. Note the restoration is partial rather than complete, which the entry states rather than rounding up.

💊

Medical Actions

3

Cochlear Implantation and Hearing Amplification

Action: cochlear device implantation Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

The first patient's progressive hearing loss was managed with a hearing aid and then with bilateral cochlear implants, after which her speech and general development improved markedly; the second patient's severe deafness was managed with a hearing aid, again with improvement in speech. In a disease with no disease-modifying therapy this is the intervention that changes the trajectory, and it is the reason hearing assessment belongs in the initial work-up rather than being deferred until speech delay is noticed.

Mechanism Target:

Sensorineural Hearing Loss — The implant bypasses the cochlear lesion rather than correcting it. It addresses the phenotype and leaves the OXPHOS deficiency that produced it untouched, which is why it is recorded against the phenotype and not against a pathophysiology node.

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"which required the use of a hearing aid and was corrected with bilateral cochlea implants. After this correction, both her speech and development improved markedly."

The intervention and the outcome in the first patient. Two patients is not a trial, and this entry claims no more than the two reported courses.

Avoidance of Prolonged Fasting

Action: dietary intervention Ontology label: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

The second patient's hypoglycaemic episodes followed overnight or twelve-hour fasts and were worse when illness reduced oral intake. No formal regimen has been published for this disease, so what is recorded here is the management implication of the reported trigger rather than a trialled intervention: fasts of that length are the exposure, and intercurrent illness is the risk period.

Mechanism Target:

Failure of Fasting Metabolic Adaptation — Removing the fast removes the demand the hepatic adaptation cannot meet. The underlying OXPHOS deficiency is unchanged.

Show evidence (1 reference)

PMID:29576219 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"several acute episodes of hypoglycemia after an overnight or a 12-hr fasting since the age of 18 months, especially when these episodes coincided with illness and poor oral intake"

The trigger, quoted as the basis for the avoidance advice. Graded INDIRECT because the source documents the provocation and not the benefit of avoiding it — no one has tested the intervention.

Carbohydrate Administration for Acute Hypoglycaemia

Action: Pharmacotherapy NCIT:C15986

Agent: glucose CHEBI:17234

Platform: Small molecule

The 2022 patient's hypoglycaemia and lactic acidosis both improved on sugary liquid with supportive treatment, and her appetite recovered as glucose normalised. It is the only treatment in this disease with a reported response, and the response includes the lactate — which is not obvious, since giving glucose to a patient who cannot oxidise pyruvate could reasonably be expected to raise it. It is also not a cure, and the entry does not present it as one: the same patient's hypoglycaemia recurred and she was admitted repeatedly.

Mechanism Target:

Fasting Hypoglycaemia — Exogenous carbohydrate substitutes for the hepatic glucose output the patient cannot generate. It corrects the consequence and leaves the OXPHOS deficiency producing it untouched, which is why the hypoglycaemia recurs.

Show evidence (2 references)

PMID:34991560 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Hypoglycemia and lactic acidosis improved after the administration of sugary liquid and supportive treatments."

The only treatment response reported in this disease, and the fact that the lactate improved with the glucose rather than worsening.

PMID:34991560 REFUTE DIRECT PRIMARY RESULT Human Clinical

"Her condition improved after the administration of sugary liquid and supportive treatments. However, her hypoglycemia was recurring."

Graded REFUTE against any reading of this as durable control. The same sentence that reports the response reports the recurrence, and a treatment section that quoted only the first clause would be selecting.

🔬

Diagnosis

3

Respiratory-chain enzymology in liver, muscle and fibroblasts

Measurement of OXPHOS complex activities is what identifies the biochemical class of the disease. It should be read with the tissue discrepancy in mind: the first patient showed multiple complex deficiencies in liver, muscle and fibroblasts, while the second showed multiple deficiencies in liver and fibroblasts but an isolated complex IV deficiency in muscle. A single muscle panel can therefore look like an isolated complex IV disorder in a patient who has a combined one.

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Measurements of OXPHOS complex activities showed a decrease in multiple complexes in liver and fibroblasts and a complex IV deficiency in muscle."

The tissue discrepancy this diagnostic caution rests on, in the patient who shows it.

Exome sequencing

Both 2018 diagnoses were made by exome sequencing, and in each the filtering converged on a single candidate gene. The 2024 patient was also identified by sequencing. There is no biochemical test specific to MRPS2; enzymology localises the defect to mitochondrial translation and sequencing names the gene.

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Exome sequencing was performed to identify pathogenic variants underlying the disease in both subjects"

The diagnostic route used in both founding cases.

Transferrin and apolipoprotein-CIII isoelectric focusing (ABSENT)

Glycosylation screening was normal in the first patient. This is recorded as a negative because the differential for an infant with wrinkled skin, developmental delay and raised transaminases includes the congenital disorders of glycosylation, and a normal screen is what removes them.

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Glycosylation screening (transferrin and apolipoprotein-CIII isoelectric focusing) was unremarkable."

The negative screen in the first patient.

📈

Progression

2

Infantile presentation

The first patient presented from birth with wrinkled skin and minor dysmorphism, then failure to thrive in the first year and psychomotor delay. The second presented later — recurrent hypoglycaemia from eighteen months, walking at twenty-two months — and was not investigated for hypoglycaemia until six years. The 2022 patient is the clearest case of the same delay: hearing loss at four, gallstones at four and nine months, two years of vomiting, and a genetic test only at six and a half, ordered because the cause of the hypoglycaemia was unknown. That gap between first symptom and investigation is the diagnostic delay this entity's stub was nominated for.

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Subject 2, a boy, presented with fasting hypoglycemia at the age of 6 years."

Age at presentation in the second patient, against an eighteen-month age of first hypoglycaemic episode recorded elsewhere in the same paragraph.

Survival into the second decade with treated hearing loss

Both 2018 patients were alive at eleven years at the time of report, with hearing corrected and speech recovered, and the 2022 patient was seven at last follow-up. No death is reported in this entity, and nobody developed the hepatic or renal failure that kills patients with some other mitoribosomal-protein defects. Against a series in which about a third of mitoribosomal-disease patients die before one year, this is the mild end of the group — and the reason this entity's prognosis should not be quoted from the mitoribosomal literature at large.

Show evidence (1 reference)

PMID:29576219 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Most subjects presented in the neonatal period, and about one-third of the subjects died before the age of 1 year."

The mortality of the mitoribosomal-protein group as a whole, which is the comparison that makes this entity's survival notable. Graded REVIEW_SYNTHESIS because it is the authors' tabulation of twenty-two previously published patients from other groups, and INDIRECT because it bears on this entity only by contrast.

📊

Prevalence

1

Worldwide

Cases In Literature <1 in 1,000,000

Four patients in four unrelated families: two in the 2018 report that defined the entity — one of Austrian and one of Tunisian origin — one Chinese patient in 2022, and one in 2024. No population estimate exists and none can be constructed: all were ascertained through diagnostic sequencing of an unexplained metabolic or mitochondrial phenotype, so the denominator is unknown by construction. prevalence_class is the numeric floor tier and rate_per_100000 is left unset, because no rate has ever been reported and computing one from four cases would be inventing a figure.

Show evidence (1 reference)

PMID:38029925 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Mutated mito-ribosomal protein S2 (MRPS2) was already described in only three subjects"

The size of the literature as counted by the most recent report — three prior subjects, which with the 2024 patient makes four. The third prior subject is the 2022 Chinese patient, which is the one the 2024 authors describe as having a less severe phenotype.

🧫

Experimental Models

1

MRPS2-complemented patient fibroblast lines PRIMARY_CELL_CULTURE

Skin fibroblasts from both 2018 patients, transduced with a lentivirus expressing either wild-type MRPS2 or GFP as a negative control. This is the model that establishes causality in this disease, and it is a rescue rather than a knockdown, so it tests the patients' own alleles rather than a constructed one.

Pathograph links

Inhibition of Mitochondrial Translation rescues fidelity: high observes: molecular Re-expressing wild-type MRPS2 partially restores mitochondrial translation in both patients' cells, and restores assembly of complexes I and IV.

Limitations: The restoration is partial rather than complete, and the readouts are steady-state abundance and pulse-labelled synthesis rather than respiratory flux or ATP output. A fibroblast is also not the cochlea, the liver or the brain, so the model speaks to the molecular step and not to any clinical feature.

Readouts

Pulse-labelled mitochondrial translation products

Direction: RESTORED

Interpretation: Synthesis of mtDNA-encoded polypeptides recovers when wild-type MRPS2 is supplied, which is what makes the translation defect attributable to the MRPS2 alleles.

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Pulse labeling of mitochondrial translation products demonstrates that the presence of wild-type MRPS2 partially restores mitochondrial translation in S1 and S2 fibroblasts."

The measurement, with the authors' own qualifier that the restoration is partial.

Show evidence (1 reference)

PMID:29576219 SUPPORT DIRECT PRIMARY RESULT In Vitro

"To demonstrate the disease-causing nature of MRPS2 mutations, we carried out functional complementation experiments by generating control, S1, and S2 cell lines stably expressing either green fluorescent protein (GFP) as a negative control or wild-type MRPS2"

The design of the model, including the GFP control arm that makes the rescue interpretable.

Overexpressing MRPS2 in control cells had no negative effect on translation or OXPHOS assembly, which is the dose control for the rescue arm and is worth knowing for anyone considering gene-replacement approaches in this pathway.

{ }

Source YAML

click to show

name: Combined Oxidative Phosphorylation Deficiency 36
category: Mendelian
creation_date: "2026-09-22T00:00:00Z"
synonyms:
- COXPD36
- combined oxidative phosphorylation deficiency type 36
- MRPS2 deficiency
- MRPS2-related mitochondrial disease
- mitochondrial ribosomal protein S2 deficiency
disease_term:
  preferred_term: combined oxidative phosphorylation deficiency 36
  term:
    id: MONDO:0054781
    label: combined oxidative phosphorylation deficiency 36
description: >-
  COXPD36 is the combined oxidative phosphorylation deficiency caused by biallelic variants in
  MRPS2, which encodes a structural protein of the small subunit of the mitochondrial ribosome.
  Four patients in four unrelated families have been published: two in the 2018 report that
  defined the entity, one in 2022 and one in 2024.

  The mechanism is a mitochondrial translation defect, and the chain from allele to biochemistry
  was worked out in full in the founding paper rather than inferred. Patient fibroblasts carry
  less MRPS2 protein; the other small-subunit proteins MRPS5, MRPS18B and MRPS28 fall with it
  while the large-subunit proteins do not; 12S rRNA falls while 16S rRNA does not; complexome
  profiling shows fully assembled small subunits are hardly detectable while large subunits are
  normal; pulse labelling shows a generalised failure to translate the mtDNA-encoded
  polypeptides; and blue-native PAGE shows reduced complexes I and IV with complex II, which is
  entirely nucleus-encoded, untouched. Re-expressing wild-type MRPS2 by lentivirus reverses the
  translation and assembly phenotypes. Each step of that sequence is a measurement in patient
  cells, which is unusual for an entity this small.

  Clinically the recognisable triad is sensorineural hearing loss, fasting hypoglycaemia and
  lactic acidaemia, with developmental delay. All four patients have the hearing loss, and three
  of the four have both hypoglycaemia and raised lactate. The founding authors argue the combination is
  specific enough to point at a mitoribosomal defect before sequencing, and add wrinkled skin as
  the discriminating extra feature — present in one of their two patients, and otherwise reported
  in mitoribosomal disease only as redundant neck skin with MRPS22 and MRPS16 variants.

  What sets COXPD36 apart from most of the numbered COXPD series is severity rather than
  mechanism. Roughly a third of patients with mitoribosomal-protein disease die before the age of
  one; both 2018 patients were alive at eleven, and the hearing loss responded to cochlear
  implantation and to hearing aids well enough that speech development recovered. The founding
  authors offer an explanation that is testable rather than decorative: MRPS2 joins the small
  subunit late, after the roughly 300 kDa core subassembly containing MRPS22 and MRPS16 has
  formed, and that subassembly is still present in patient cells. A late-assembling subunit is
  a less catastrophic thing to lose than an early one. That is a hypothesis about the whole
  series, not a fact about this entity, and it is recorded here as such.
parents:
- Combined Oxidative Phosphorylation Deficiency
- Mitochondrial Disease
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A Mendelian, mechanism-defined mitochondrial disorder, diagnosed and managed as an
      inherited disease rather than within a single organ-system Part.
  mechanistic_category:
  - classification_value: mitochondrial disease
  icimd_category:
  - classification_value: mitoribosome
    notes: >-
      MRPS2 is a structural protein of the mitoribosomal small subunit, so the lesion is in the
      mitochondrial translation apparatus rather than in a respiratory-chain subunit or an
      assembly factor. The combined rather than isolated complex deficiency follows from that
      placement.
references:
- reference: PMID:29576219
  title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
- reference: PMID:38029925
  title: "New description of an MRPS2 homozygous patient: Further features to help expend the phenotype."
- reference: PMID:34991560
  title: "Hypoglycemia with lactic acidosis caused by a new MRPS2 gene mutation in a Chinese girl: a case report."
- reference: PMID:34505344
  title: "Patient care standards for primary mitochondrial disease in Australia: an Australian adaptation of the Mitochondrial Medicine Society recommendations."
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Both 2018 families are biallelic and parental heterozygosity was confirmed by segregation in
    each. The Austrian patient is compound heterozygous for two missense alleles inherited one
    from each parent; the Tunisian patient is homozygous for a third missense allele with both
    parents heterozygous. MRPS2 is nuclear-encoded and autosomal, so despite the mitochondrial
    biochemistry this is a nuclear recessive disease with a 25 percent sibling recurrence risk
    and no maternal transmission.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Segregation analysis confirmed that both parents are heterozygous for one of these variants."
    explanation: >-
      Biparental transmission of the two alleles in the compound heterozygous family, which is
      what distinguishes recessive inheritance from a de novo or dominant configuration.
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "in only one gene: MRPS2, which encodes a known mitochondrial protein. Segregation analysis confirmed that both parents are heterozygous for this variant."
    explanation: >-
      The homozygous family, with carrier parents — the second independent recessive
      configuration.
  - reference: PMID:34991560
    reference_title: "Hypoglycemia with lactic acidosis caused by a new MRPS2 gene mutation in a Chinese girl: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The proband had the homozygous mutation C. 412C>G(p.R138G). The parents of the proband were all heterozygous for this mutation"
    explanation: >-
      A third independent recessive family, homozygous with carrier parents, in a
      non-consanguineous sibship where the brother is unaffected.
pathophysiology:
- name: Biallelic MRPS2 Missense Variants
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Four missense alleles are known across three genotyped families. The Austrian patient is
    compound heterozygous for c.328C>T, p.Arg110Cys and c.340G>A, p.Asp114Asn; the Tunisian
    patient is homozygous for c.413G>A, p.Arg138His; the Chinese patient is homozygous for
    c.412C>G, p.Arg138Gly. The 2018 alleles change residues conserved across species, were
    predicted damaging by at least two of three in-silico tools, and appear in gnomAD only as
    very rare heterozygotes.

    The fourth allele is the interesting one. c.412C>G and c.413G>A are adjacent nucleotides of
    the same codon, so two unrelated families — one Tunisian, one Chinese — independently carry
    substitutions of the same arginine, to histidine in one and to glycine in the other. Two
    independent hits at one residue in a series of three genotyped families is a stronger
    statement about which part of the protein matters than any single allele makes, and it is a
    statement no in-silico predictor supplied.

    Two things are worth keeping separate here. That the alleles are rare and conserved is a
    prediction; that they are pathogenic is a measurement, made by the lentiviral complementation
    experiment recorded further down this chain. This entry treats the second as the basis for
    the LOSS_OF_FUNCTION call, not the first.

    The positions of the residues within the assembled subunit also differ between the families,
    and the founding authors use that difference to explain a quantitative difference in the
    biochemistry: Arg110 and Asp114 face the 12S rRNA and contact several other proteins, while
    Arg138 sits near the surface of the small subunit, and 12S rRNA loss was correspondingly
    deeper in the compound heterozygote.
  genes:
  - preferred_term: MRPS2
    term:
      id: hgnc:14495
      label: MRPS2
  genetic_context:
    genes:
    - preferred_term: MRPS2
      term:
        id: hgnc:14495
        label: MRPS2
    allele_type: two missense variants in trans in one family, and a homozygous missense variant in the other
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Zygosity differs between the two founding families — compound heterozygous in one,
      homozygous in the other — so no single zygosity value describes the entity and the slot is
      left unset rather than asserting one family's configuration for both.
    notes: >-
      LOSS_OF_FUNCTION is supported by measurement rather than prediction: patient fibroblasts
      carry reduced steady-state MRPS2, and re-expressing wild-type MRPS2 restores mitochondrial
      translation and OXPHOS assembly in both patients' cells. No allele is a nonsense or
      frameshift variant, so this is a hypomorphic loss rather than a demonstrated null, which is
      consistent with the comparatively mild course.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "This resulted in the identification of a single candidate gene, mitochondrial ribosomal protein S2 (MRPS2; GenBank: NM_016034.3), carrying two heterozygous sequence variants, c.328C>T (p.Arg110Cys) and c.340G>A (p.Asp114Asn)"
    explanation: The two alleles of the compound heterozygous family, and the gene they are in.
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    quote_role: PRIMARY_RESULT
    snippet: "All identified variants affect highly conserved amino acids (Figure 2C) and were predicted to be pathogenic by at least two of the three in silico prediction programs that were used."
    explanation: >-
      The conservation and prediction argument. Graded COMPUTATIONAL and INDIRECT because
      prediction is what it is: it makes the alleles candidates, and the complementation
      experiment below is what makes them causal.
  - reference: PMID:34991560
    reference_title: "Hypoglycemia with lactic acidosis caused by a new MRPS2 gene mutation in a Chinese girl: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "A homozygous C.412C > G variant that could cause complex oxidative phosphorylation deficiency and had not been reported before was identified."
    explanation: >-
      The fourth allele, which falls on the codon immediately adjacent to the 2018 homozygous
      allele — the recurrence at Arg138 this node describes. Note this family had no functional
      work: the variant was called on its novelty and the phenotype match, not on an assay.
  downstream:
  - target: Destabilization of the MRPS2 Protein
    causal_link_type: DIRECT
    description: >-
      Each of the three missense substitutions reduces the steady-state amount of MRPS2 protein
      in patient fibroblasts, so the primary consequence of the allele is loss of the protein
      rather than a protein present but inactive.
    evidence:
    - reference: PMID:29576219
      reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "SDS-PAGE analysis of mitochondrial extracts (for methods, see Supplemental Data) from these fibroblasts showed decreased steady-state amounts of the protein MRPS2 in both S1 and S2 fibroblasts"
      explanation: >-
        Direct measurement that the variant protein is depleted, in cells from both families —
        which is the step that makes this a quantitative loss rather than an inferred one.
- name: Destabilization of the MRPS2 Protein
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    MRPS2 is one of roughly thirty nucleus-encoded proteins of the 28S small subunit of the
    mitochondrial ribosome. It spans all three domains of that subunit and contacts seven other
    small-subunit proteins, which is the structural argument the founding authors give for
    treating its role as scaffolding rather than catalytic.

    The bacterial orthologue bS2 has a translation-initiation function that depends on the
    Shine-Dalgarno sequence. Mitochondrial mRNAs have no Shine-Dalgarno sequence, so that
    function has most likely been lost, and what remains is structural. This matters for reading
    the phenotype: the defect downstream is a failure to build the subunit, not a failure to
    initiate on particular messages.
  genes:
  - preferred_term: MRPS2
    term:
      id: hgnc:14495
      label: MRPS2
  cellular_components:
  - preferred_term: mitochondrial small ribosomal subunit
    term:
      id: GO:0005763
      label: mitochondrial small ribosomal subunit
    modifier: DECREASED
  molecular_functions:
  - preferred_term: structural constituent of the mitoribosomal small subunit
    term:
      id: GO:0003735
      label: structural constituent of ribosome
    modifier: DECREASED
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    snippet: "This extended range of interactors suggests that MRPS2 has adopted a primarily structural role, which is consistent with our findings that its loss is associated with impaired mt-SSU assembly."
    explanation: >-
      The authors' structural reading of the protein's role. Graded OTHER because it is an
      inference from the published mitoribosome structure rather than an experiment in this
      paper, and DIRECT because the sentence asserts exactly the claim this node makes.
  downstream:
  - target: Failure of Mitoribosomal Small Subunit Assembly
    causal_link_type: DIRECT
    description: >-
      Losing MRPS2 prevents the 28S subunit from assembling. Complexome profiling shows fully
      assembled small subunits are hardly detectable in patient fibroblasts while large subunits
      are normal, so the defect is specific to the subunit MRPS2 belongs to.
    evidence:
    - reference: PMID:29576219
      reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "Fully assembled mt-SSU particles were hardly detectable in both S1 and S3 fibroblasts, whereas mt-LSU particles were assembled at a normal level"
      explanation: >-
        The assembly defect and its subunit specificity, measured by complexome profiling. Note
        S3 is the MRPS22-mutant positive control, not a third MRPS2 patient.
- name: Failure of Mitoribosomal Small Subunit Assembly
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The small subunit fails to form. Three measurements agree: the other small-subunit proteins
    MRPS5, MRPS18B and MRPS28 fall with MRPS2 while the large-subunit proteins MRPL37 and MRPL44
    do not; the 12S rRNA that the small subunit is built around falls while 16S rRNA does not;
    and complexome profiling finds no fully assembled small subunit.

    The roughly 300 kDa early subassembly containing MRPS16, MRPS17, MRPS18B, MRPS22, MRPS26,
    MRPS27 and MRPS34 survives in patient cells, at reduced level. That observation is what
    places MRPS2 late in the assembly pathway, and it is the mechanistic basis for the severity
    hypothesis recorded in this entry's discussions.
  cellular_components:
  - preferred_term: mitochondrial small ribosomal subunit
    term:
      id: GO:0005763
      label: mitochondrial small ribosomal subunit
    modifier: DECREASED
  biological_processes:
  - preferred_term: mitochondrial small ribosomal subunit assembly
    term:
      id: GO:0180026
      label: mitochondrial small ribosomal subunit assembly
    modifier: DECREASED
  cell_types:
  - preferred_term: patient-derived skin fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Similarly, the mt-SSU proteins MRPS5, MRPS18B, and MRPS28 were less abundant in subject fibroblasts. Amounts of the mt-LSU proteins MRPL37 and MRPL44 remained unchanged."
    explanation: >-
      The co-depletion of small-subunit partners with large-subunit proteins spared, which is
      what makes this an assembly failure rather than a general loss of mitochondrial protein.
  downstream:
  - target: Loss of Mitochondrial 12S Ribosomal RNA
    causal_link_type: DIRECT
    description: >-
      Newly imported mitoribosomal proteins and nascent 12S rRNA are stable only once they have
      assembled together, so a subunit that cannot assemble loses its rRNA as well as its
      protein.
    evidence:
    - reference: PMID:29576219
      reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "Stability of newly imported mitoribosomal proteins and nascent 12S rRNA depends on their coordinated assembly into ribonucleoprotein complexes."
      explanation: >-
        States the dependency this edge asserts — the rRNA loss is a consequence of the assembly
        failure and not a separate lesion.
  - target: Inhibition of Mitochondrial Translation
    causal_link_type: DIRECT
    description: >-
      Without an assembled small subunit there is no functional monosome, so translation of the
      mtDNA-encoded messages stops.
    evidence:
    - reference: PMID:29576219
      reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "Decreased mt-SSU assembly and the resulting lack of functional mitoribosomes invariably lead to an inhibition of mitochondrial translation and multiple OXPHOS deficiencies."
      explanation: The authors' statement of the step this edge draws, immediately before they measure it.
- name: Loss of Mitochondrial 12S Ribosomal RNA
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    12S rRNA, the RNA core of the small subunit, is specifically reduced in patient fibroblasts
    while 16S rRNA — the large subunit's RNA — is not. The same pattern is seen in the
    MRPS22-mutant control line, so it is a general consequence of small-subunit protein loss
    rather than something particular to MRPS2.

    This node is drawn separately from the assembly failure because it is separately measured
    and because it is the quantity that differs between the two families: the compound
    heterozygote, whose substituted residues face the RNA, loses slightly more of it than the
    homozygote whose substituted residue sits at the subunit surface.
  cellular_components:
  - preferred_term: mitochondrial small ribosomal subunit
    term:
      id: GO:0005763
      label: mitochondrial small ribosomal subunit
    modifier: DECREASED
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Consistent with this, steady-state abundance of 12S rRNA, but not that of 16S rRNA, was specifically decreased in S1 and S2 fibroblasts"
    explanation: The measurement, in both patients' cells, with the large-subunit rRNA as internal control.
  downstream:
  - target: Inhibition of Mitochondrial Translation
    causal_link_type: DIRECT
    description: >-
      The 12S rRNA is the catalytic and structural core of the small subunit; losing it removes
      the decoding capacity of the mitoribosome.
- name: Inhibition of Mitochondrial Translation
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Pulse labelling of mitochondrial translation products with radiolabelled methionine and
    cysteine shows a profound and generalised defect in both patients' fibroblasts. Generalised
    is the operative word: it is not a subset of messages, which is what would be expected if
    MRPS2 retained the bacterial orthologue's message-selection function.
  biological_processes:
  - preferred_term: mitochondrial translation
    term:
      id: GO:0032543
      label: mitochondrial translation
    modifier: DECREASED
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "in vitro pulse labeling of mitochondrial translation products with radiolabeled methionine and cysteine revealed a profound and generalized translation defect of mtDNA-encoded polypeptides in both S1 and S2 fibroblasts"
    explanation: The translation defect measured directly, and its generalised character.
  downstream:
  - target: Combined Deficiency of OXPHOS Complexes I and IV
    causal_link_type: DIRECT
    description: >-
      The thirteen mtDNA-encoded polypeptides are all subunits of complexes I, III, IV and V, so
      a general translation failure starves those complexes of subunits while leaving complex II,
      which is entirely nucleus-encoded, intact.
    evidence:
    - reference: PMID:29576219
      reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "In line with this impaired translation, BN-PAGE analysis of OXPHOS complex assembly revealed decreased amounts of fully assembled OXPHOS complexes I and IV but not of complex III and the exclusively nucleus-encoded complex II"
      explanation: >-
        The assembly consequence, with complex II as the internal control that makes the
        mtDNA-dependence of the defect visible.
- name: Combined Deficiency of OXPHOS Complexes I and IV
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    In fibroblasts, complexes I and IV are reduced, complex III and the nucleus-encoded complex
    II are not, and complex V is present at normal amount but with subcomplexes that do not occur
    in control cells. In tissue the picture is broader: multiple complexes are deficient in liver
    and muscle in the first patient, and in liver and fibroblasts with an isolated complex IV
    deficiency in muscle in the second.

    That discrepancy between fibroblast and tissue, and between the two patients' muscle, is
    worth stating rather than smoothing over. It means a normal muscle respiratory-chain panel
    does not exclude the diagnosis, and it is the reason the entity is named for a combined
    deficiency even though any single biopsy may show something narrower.

    This is the convergence point of the entry. Every systemic feature below is downstream of
    this node.
  biological_processes:
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
  cell_types:
  - preferred_term: patient-derived skin fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Measurements of OXPHOS complex activities in liver, muscle, and fibroblasts showed a decrease in multiple enzyme complexes"
    explanation: The combined deficiency in patient tissue rather than only in cultured cells.
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Measurements of OXPHOS complex activities showed a decrease in multiple complexes in liver and fibroblasts and a complex IV deficiency in muscle."
    explanation: >-
      The second patient's tissue pattern, which differs from the first — the basis for this
      node's warning that a single tissue can look isolated rather than combined.
  downstream:
  - target: Anaerobic Redirection of Pyruvate and Accumulation of Krebs-Cycle Intermediates
    causal_link_type: DIRECT
    description: >-
      A respiratory chain that cannot reoxidise NADH forces pyruvate to lactate and backs up the
      Krebs cycle, which is the standard biochemical consequence and the one the patients' lactate
      and 2-oxoglutarate measurements report.
  - target: Failure of Fasting Metabolic Adaptation
    causal_link_type: DIRECT
    description: >-
      Gluconeogenesis and fatty-acid oxidation are the most ATP-demanding parts of the hepatic
      fasting response, so a hepatic OXPHOS deficit shows itself first as an inability to hold
      blood glucose through a fast.
  - target: Sensorineural Hearing Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The cochlea is among the tissues most vulnerable to a respiratory-chain deficit, and
      sensorineural hearing loss is a recurring feature across mitoribosomal-protein disease. No
      cochlear measurement exists in any MRPS2 patient, so this edge is the general
      organ-vulnerability argument applied to this entity, not a finding about it.
  - target: Developmental Delay and Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Both 2018 patients have developmental delay with normal brain MRI, which is the pattern
      expected from a diffuse energetic deficit rather than from a structural malformation. The
      step from OXPHOS deficiency to the cognitive phenotype is not measured in this disease.
  - target: Exercise Intolerance and Myalgia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Skeletal muscle in the second patient carries a complex IV deficiency, and his exertional
      myalgia and lower-limb weakness are the clinical expression expected from it. The
      attribution is clinical rather than measured.
  - target: Elevated Hepatic Transaminases
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Liver in both patients carries a multiple-complex deficiency, and the first patient's
      transaminases run three- to four-fold high. Hepatocyte injury from an energetic deficit is
      the usual reading, but no liver histology or mechanism study exists here.
  - target: Failure to Thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Growth is the first thing an infant gives up when ATP supply is short, and failure to
      thrive is near-universal across the mitoribosomal-protein disorders. In this entity it is
      reported in one patient of four, so the edge asserts the general relationship rather than
      anything measured in MRPS2 disease.
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Hypotonia is the commonest neuromuscular sign across the mitoribosomal-protein disorders
      and is present in both 2018 patients. Muscle in the second of them carries a complex IV
      deficiency, so a muscular contribution is measured; whether the tone abnormality is
      muscular, central, or both is not established in this disease.
  - target: Lower Limb Muscle Weakness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The patient with lower-limb weakness is the one whose muscle biopsy carries an isolated
      complex IV deficiency, which is the respiratory-chain correlate. The attribution is
      clinical rather than measured in the weak muscle itself.
- name: Anaerobic Redirection of Pyruvate and Accumulation of Krebs-Cycle Intermediates
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    A respiratory chain that cannot reoxidise NADH leaves pyruvate to be reduced to lactate and
    leaves the Krebs cycle backed up behind its NAD-dependent dehydrogenases. In these patients
    that shows as raised blood lactate, raised serum alanine — the transamination product of the
    pyruvate that accumulates with it — and increased urinary excretion of 2-oxoglutarate, with
    a trace of succinate.

    2-oxoglutarate is the more informative of the two urinary findings, because its dehydrogenase
    is NAD-dependent and it is the intermediate the founding authors single out as part of the
    recognisable biochemical signature.
  biological_processes:
  - preferred_term: tricarboxylic acid cycle
    term:
      id: GO:0006099
      label: tricarboxylic acid cycle
    modifier: DECREASED
  chemical_entities:
  - preferred_term: lactate
    term:
      id: CHEBI:24996
      label: lactate
    modifier: INCREASED
  - preferred_term: 2-oxoglutarate
    term:
      id: CHEBI:30915
      label: 2-oxoglutaric acid
    modifier: INCREASED
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "elevated serum alanine (up to 850 μmol/L; reference values = 99–350 μmol/L), and increased excretion of Krebs cycle intermediates"
    explanation: >-
      The alanine elevation and the Krebs-cycle intermediate excretion, with the laboratory's own
      reference interval, measured in the first patient.
  downstream:
  - target: Lactic Acidaemia
    causal_link_type: DIRECT
  - target: Increased Urinary 2-Oxoglutarate
    causal_link_type: DIRECT
  - target: Hyperalaninaemia
    causal_link_type: DIRECT
- name: Failure of Fasting Metabolic Adaptation
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  description: >-
    Both 2018 patients become hypoglycaemic on fasting, and in the second patient a formal
    fasting test reproduced it with a simultaneous rise in lactate to 5 mmol/L and increased
    2-oxoglutarate excretion. The coupling of hypoglycaemia to hyperlactataemia within one
    provoked test is what identifies the defect as a failure of energy-dependent hepatic
    adaptation rather than, say, hyperinsulinism, where lactate would not rise.

    Graded PROVISIONAL rather than ESTABLISHED because no measurement of gluconeogenic flux or
    of hepatic ATP exists in any MRPS2 patient. What is established is the clinical coupling;
    the hepatocyte-level explanation is inferred from the liver OXPHOS deficiency measured in
    the same patients.
  biological_processes:
  - preferred_term: gluconeogenesis
    term:
      id: GO:0006094
      label: gluconeogenesis
    modifier: DECREASED
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "A clinical fasting test showed hypoglycemia with hyperlactatemia (5 mmol/L) and slightly increased excretion of 2-oxoglutarate"
    explanation: >-
      The provoked test that couples the hypoglycaemia to the lactate rise, which is the
      observation this node rests on.
  downstream:
  - target: Fasting Hypoglycaemia
    causal_link_type: DIRECT
phenotypes:
- name: Sensorineural Hearing Loss
  category: Nervous System
  description: >-
    Present in all four published patients and the feature with the most therapeutic consequence.
    In the first patient it was progressive, recognised at three years, and treated first with a
    hearing aid and then with bilateral cochlear implants; in the second it was severe and
    recognised at two years, and treated with a hearing aid; in the third it was recognised at
    four years and treated with bilateral cochlear implants. In all three of those, speech
    development improved markedly after correction — which is the single most actionable fact in
    this entry.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Progressive sensorineural hearing loss
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  notes: >-
    4 of 4 published patients. VERY_FREQUENT rather than OBLIGATE: universal in the series, but a
    denominator of four cannot carry an obligate claim. The general sensorineural term is bound
    rather than a congenital one, because in every patient the loss was recognised between two
    and four years and described as progressive in the first rather than present at birth.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "At the age of 3 years, she had developed progressive sensorineural hearing loss, which required the use of a hearing aid and was corrected with bilateral cochlea implants. After this correction, both her speech and development improved markedly."
    explanation: >-
      Onset, progression and the response to implantation in the first patient — the evidence
      behind both this phenotype and the cochlear-implantation treatment entry.
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Speech development was delayed as a result of severe sensorineural deafness at the age of 2 years, necessitating the use of a hearing aid."
    explanation: The second patient's hearing loss, its severity and its age of recognition.
  - reference: PMID:34991560
    reference_title: "Hypoglycemia with lactic acidosis caused by a new MRPS2 gene mutation in a Chinese girl: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "When she was 4 years old, she had sensorineural hearing loss and was treated by parallel cochlear implants."
    explanation: >-
      The third patient's hearing loss, its age of recognition and its treatment — the second
      independent instance of cochlear implantation in this disease.
- name: Fasting Hypoglycaemia
  category: Metabolism
  description: >-
    Episodic hypoglycaemia provoked by an overnight or twelve-hour fast, and in the second
    patient by intercurrent illness with poor oral intake. This is the feature that makes the
    disease dangerous between crises and the one that generates a management rule: avoid
    prolonged fasting, and treat illness as a risk period.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Fasting hypoglycaemia
    term:
      id: HP:0001943
      label: Hypoglycemia
    temporality: RECURRENT
  notes: >-
    3 of 4 published patients — both 2018 patients and the 2022 patient. The 2024 abstract does
    not mention glucose. The 2022 patient's presentation differs in a way worth noting: her
    hypoglycaemia came with two years of recurrent vomiting and poor appetite rather than with a
    documented fast, so the trigger there is reduced intake rather than fasting duration.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Medical history was marked by several acute episodes of hypoglycemia after an overnight or a 12-hr fasting since the age of 18 months, especially when these episodes coincided with illness and poor oral intake, which associated with lactic acidosis."
    explanation: >-
      The fasting duration that provokes it, the age of onset, the illness trigger, and the
      coupling to lactic acidosis — everything the management advice rests on.
  - reference: PMID:34991560
    reference_title: "Hypoglycemia with lactic acidosis caused by a new MRPS2 gene mutation in a Chinese girl: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Blood glucose was 1.2–2.5 mmol/L when she was hospitalized."
    explanation: >-
      The measured glucose range in the third patient — the only numerical hypoglycaemia values
      published for this disease.
- name: Lactic Acidaemia
  category: Metabolism
  description: >-
    Repeatedly raised blood lactate, severe in the first patient (above 8 mmol/L against a
    reference of under 2) and mild in the second (2.2 to 3.8 mmol/L), rising to 5 mmol/L under a
    provoked fast. Urinary lactate was also raised in the second patient.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Lactic acidaemia
    term:
      id: HP:0002151
      label: Increased circulating lactate concentration
  notes: >-
    3 of 4 published patients. Bound to the circulating-lactate term rather than HP:0003128
    Lactic acidosis, even though the 2022 patient has a measured acidosis (pH 7.224, bicarbonate
    4.3 mmol/L, base excess minus 24): the two 2018 patients have raised lactate without a
    reported pH, so the term that covers the whole series is the concentration one. The 2022
    patient's acidosis is recorded in her evidence item rather than by changing the binding.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "repetitive elevated lactate levels (>8 mmol/L; reference values < 2 mmol/L)"
    explanation: The first patient's lactate with the laboratory's reference interval.
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Metabolic investigations showed repetitive mildly increased lactate levels in plasma (2.2–3.8 mmol/L; reference values < 2 mmol/L) and urine"
    explanation: >-
      The second patient's much milder lactate, quoted because the range between the two patients
      is part of what a reader needs in order not to exclude the diagnosis on a mild value.
  - reference: PMID:34991560
    reference_title: "Hypoglycemia with lactic acidosis caused by a new MRPS2 gene mutation in a Chinese girl: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "lactate: 8.9 mmol/L [reference value: 0.5–1.5 mmol/L]"
    explanation: >-
      The third patient's lactate with her laboratory's reference interval, measured alongside a
      frank metabolic acidosis rather than a raised lactate alone.
- name: Increased Urinary 2-Oxoglutarate
  category: Metabolism
  description: >-
    Raised urinary excretion of 2-oxoglutarate in both 2018 patients, marked in the first
    (50 to 220 against a reference of 0 to 50 μmol/mmol creatinine) and slight in the second. The
    founding authors include it in the biochemical signature they say should prompt suspicion of
    a mitoribosomal defect.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: 2-oxoglutaric aciduria
    term:
      id: HP:0012402
      label: Increased urine alpha-ketoglutarate concentration
  notes: >-
    2 of 4 published patients, both in the 2018 report; neither later report mentions organic
    acids, and the 2022 patient's urine gas chromatography is reported as normal. HPO names the
    compound alpha-ketoglutarate where the source names it 2-oxoglutarate; these are the same
    molecule, and preferred_term keeps the source's spelling.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "2-oxoglutaric acid between 50–220 μmol/mmol creatinine; reference values = 0–50 μmol/mmol creatinine and trace elevation of succinic acid"
    explanation: The measured excretion with its reference interval, and the accompanying succinate trace.
- name: Hyperalaninaemia
  category: Metabolism
  description: >-
    Serum alanine up to 850 μmol/L against a reference of 99 to 350 in the first patient. Alanine
    rises with pyruvate through transamination, so it is a marker of the same block that raises
    lactate rather than an independent amino-acid disorder.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hyperalaninaemia
    term:
      id: HP:0003348
      label: Hyperalaninemia
  notes: >-
    1 of 4 published patients — reported for the first 2018 patient only. Amino-acid analysis is
    reported as normal by tandem mass spectrometry in the 2022 patient, which is a recorded
    negative rather than a silence.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "elevated serum alanine (up to 850 μmol/L; reference values = 99–350 μmol/L)"
    explanation: The measured alanine with its reference interval.
- name: Developmental Delay and Intellectual Disability
  category: Nervous System
  description: >-
    Psychomotor delay in the first patient, most pronounced in the motor domain, with a formal
    assessment at five years and ten months giving a developmental level of two years and six
    months; moderate intellectual disability in the second patient at eleven years. Brain MRI was
    normal in both, at three years and in adulthood respectively.

    The normal imaging matters. It separates this entity from the mitoribosomal disorders that
    present with structural brain abnormality or Leigh syndrome, and it is part of the argument
    that the neurological phenotype here is energetic rather than malformative.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  notes: >-
    3 of 4 published patients — both 2018 patients and the 2022 patient, with the 2024 patient
    adding autistic features. The 2022 patient is the informative one for scope: her language was
    retarded while her motor development was normal, so the delay is not uniformly global across
    the series and this binding is the term that covers the 2018 patients rather than all four.
    Speech delay in every patient who has it was attributed by the reporting authors to the
    hearing loss and improved once that was corrected, which is why it is recorded under hearing
    loss rather than as a separate phenotype.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Her last formal developmental assessment at the age of 5 years and 10 months showed an average developmental state of 2 years and 6 months of age."
    explanation: The quantified delay in the first patient.
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "At the age of 11 years he had a normal physical appearance, with normal growth parameters, but a moderate intellectual disability, frequent headache episodes, and muscular weakness of the lower limbs."
    explanation: >-
      The second patient's cognitive outcome at eleven, together with the headache and
      lower-limb weakness recorded elsewhere in this entry.
  - reference: PMID:34991560
    reference_title: "Hypoglycemia with lactic acidosis caused by a new MRPS2 gene mutation in a Chinese girl: a case report."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The girl was taciturn with language retardation. She could only say simple words and sentences, but her motor development was normal."
    explanation: >-
      The third patient's developmental profile. Graded INDIRECT against a global-delay node
      because it reports a dissociation — language affected, motor spared — rather than the
      global delay this phenotype names.
- name: Cholelithiasis with Chronic Cholecystitis
  category: Gastrointestinal
  description: >-
    Gallbladder calculi from chronic cholecystitis with erosion and bile reflux in the 2022
    patient, at four years and nine months, treated by laparoscopic cholecystectomy. Gallstones
    at that age are unusual enough to be worth recording even from a single case.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Gallbladder calculi with chronic cholecystitis
    term:
      id: HP:0001081
      label: Cholelithiasis
  notes: >-
    1 of 4 published patients, and new to the phenotype in 2022. Whether it belongs to the
    disease at all is open: it is a single instance, no mechanism links MRPS2 to biliary
    physiology, and childhood gallstones have many causes including the haemolysis this patient
    was not reported to have. It is recorded because a feature that appears once in a series of
    four is exactly what a fifth report would confirm or dismiss, and it cannot be confirmed if
    nobody wrote it down.
  evidence:
  - reference: PMID:34991560
    reference_title: "Hypoglycemia with lactic acidosis caused by a new MRPS2 gene mutation in a Chinese girl: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "When she was 4 years and 9 months old, she had gall bladder calculi due to chronic cholecystitis, which was accompanied by erosion and bile reflux, and was treated by laparoscopic cholecystectomy under general anesthesia."
    explanation: The finding, its age, its stated cause and its treatment, in the one patient who has it.
- name: Recurrent Vomiting with Poor Appetite
  category: Gastrointestinal
  description: >-
    More than two years of recurrent vomiting with poor appetite was the presenting complaint of
    the 2022 patient, and the reason she was admitted. It matters because it is how her
    hypoglycaemia was produced: reduced intake rather than a documented fast.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Recurrent vomiting
    term:
      id: HP:0002013
      label: Vomiting
    temporality: RECURRENT
  notes: >-
    1 of 4 published patients. Recorded because it changes what the fasting-avoidance advice in
    this entry has to cover — a child who vomits and will not eat is fasting whether or not
    anyone intended a fast.
  evidence:
  - reference: PMID:34991560
    reference_title: "Hypoglycemia with lactic acidosis caused by a new MRPS2 gene mutation in a Chinese girl: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The girl aged 6.5 years old was hospitalized because of recurrent vomiting for more than 2 years. She had poor appetite and hypoglycemia during hospitalization"
    explanation: The presenting complaint, its duration, and its coincidence with the hypoglycaemia.
  sequelae:
  - target: Fasting Hypoglycaemia
    description: >-
      Two years of vomiting and poor appetite is a sustained reduction in substrate intake, which
      in a patient who cannot sustain hepatic gluconeogenesis is the same exposure as a fast. In
      the 2022 patient the hypoglycaemia and the vomiting were recorded together and both
      resolved with glucose.
- name: Hypotonia
  category: Musculoskeletal
  description: >-
    Recorded as present in both 2018 patients in the founding paper's comparative table of
    mitoribosomal-protein disorders. It is not mentioned in either patient's narrative case
    description, which is why it was missed on a first pass through the prose and found in the
    table.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  notes: >-
    2 of 4 published patients. The evidence is a row of Table 1, where the first two data columns
    are this paper's own two subjects; the later reports do not mention tone, and the 2022
    patient's muscle tension and tone are explicitly normal, so the denominator stays four.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Hypotonia | + | + | NR | + | + | + | NR | NR | + | NR | + | + | NR"
    explanation: >-
      The Table 1 row. The table's column order is given three rows above as "this article (S1) |
      this article (S2) | Menezes et al.16 | ...", so the two leading plus signs are this paper's
      own two MRPS2 patients rather than the comparison cohorts.
- name: Low-Set Ears
  category: Craniofacial
  description: >-
    One of the minor dysmorphic features of the first 2018 patient. The second 2018 patient is
    recorded in Table 1 as having no dysmorphic features.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  notes: 1 of 4 published patients.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "She had minor dysmorphic features, including low-set ears and slightly up-slanting palpebral fissures."
    explanation: >-
      The dysmorphic features of the first patient, and the source for the palpebral-fissure
      phenotype below.
- name: Upslanted Palpebral Fissures
  category: Craniofacial
  description: Slightly up-slanting palpebral fissures in the first 2018 patient.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Slightly up-slanting palpebral fissures
    term:
      id: HP:0000582
      label: Upslanted palpebral fissure
  notes: 1 of 4 published patients.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "including low-set ears and slightly up-slanting palpebral fissures"
    explanation: The second of the two dysmorphic features reported in the first patient.
- name: Intermittent Divergent Strabismus
  category: Ophthalmologic
  description: Intermittent divergent strabismus of the left eye in the first 2018 patient.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Intermittent divergent strabismus of the left eye
    term:
      id: HP:0020049
      label: Exodeviation
  notes: >-
    1 of 4 published patients. Bound to the exodeviation term rather than to the general
    HP:0000486 Strabismus because the source specifies the direction, and the laterality and
    intermittency are carried in preferred_term.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "She had an intermittent divergent strabismus of the left eye."
    explanation: The finding with its direction, laterality and intermittency.
- name: Headache
  category: Nervous System
  description: Frequent headache episodes in the second 2018 patient at eleven years.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Frequent headache episodes
    term:
      id: HP:0002315
      label: Headache
    temporality: RECURRENT
  notes: 1 of 4 published patients.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "frequent headache episodes, and muscular weakness of the lower limbs"
    explanation: >-
      The headache and the lower-limb weakness below, both from the second patient's assessment
      at eleven years.
- name: Lower Limb Muscle Weakness
  category: Musculoskeletal
  description: >-
    Muscular weakness of the lower limbs in the second 2018 patient at eleven years, alongside
    the exertional myalgia recorded separately.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Muscular weakness of the lower limbs
    term:
      id: HP:0007340
      label: Lower limb muscle weakness
  notes: >-
    1 of 4 published patients. Kept separate from Exercise Intolerance and Myalgia because
    weakness at rest and pain on exertion are different findings, and this patient has both.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "a moderate intellectual disability, frequent headache episodes, and muscular weakness of the lower limbs"
    explanation: The three features of the second patient at eleven years, including this one.
- name: Excessive Wrinkled Skin
  category: Integumentary
  description: >-
    Skin wrinkling present from birth in the first patient, most pronounced on the abdomen and
    hands. The founding authors treat this as the discriminating feature of the phenotype: skin
    findings in mitoribosomal disease have otherwise been limited to redundant neck skin with
    MRPS22 and MRPS16 variants, and the combination of wrinkled skin with hearing impairment is
    what distinguishes this from the cutis laxa syndromes it otherwise resembles.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Wrinkled skin of the abdomen and hands, present from birth
    term:
      id: HP:0007392
      label: Excessive wrinkled skin
  notes: >-
    1 of 4 published patients; the second 2018 patient is explicitly recorded as having no skin
    involvement, the 2022 patient's physical examination is reported as revealing no abnormal
    findings, and the 2024 abstract does not mention skin. So this is a variable feature with
    high diagnostic value when present and no negative predictive value when absent — which is
    worth stating because the founding paper's framing could be read as making it a requirement.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Skin wrinkling, most pronounced on the abdomen and hands, was apparent from birth."
    explanation: The distribution and congenital onset in the patient who has it.
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "To date, dermatological symptoms in subjects with mutations in MRP genes have been limited to redundant skin of the neck, which was previously described in single subjects carrying either MRPS22 or MRPS16 mutations."
    explanation: >-
      Why the finding is diagnostically informative — it is unusual within the mitoribosomal
      group. Graded BACKGROUND because the sentence summarises other groups' published patients,
      not a result of this study, and INDIRECT because it supports the significance of the
      finding rather than the finding itself.
- name: Elevated Hepatic Transaminases
  category: Gastrointestinal
  description: >-
    Three- to four-fold elevation of aspartate and alanine aminotransferase in the first patient,
    alongside the multiple-complex OXPHOS deficiency measured in her liver biopsy. Creatine kinase
    was normal, which argues the transaminase rise is hepatic rather than muscular in origin.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Elevated aspartate and alanine aminotransferase
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  notes: >-
    1 of 4 published patients, and explicitly absent in the 2022 patient, whose liver enzymes are
    reported as normal. No patient in the series developed liver failure, which distinguishes
    this entity from the MRPS7 disorder where progressive hepatic failure was the cause of death.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Biochemical evaluation revealed elevated liver enzymes (3- to 4-fold elevation in aspartate-amino transferase and alanine-amino transferase"
    explanation: The magnitude and the two enzymes involved.
- name: Exercise Intolerance and Myalgia
  category: Musculoskeletal
  description: >-
    Exertional myalgia after walking, with lower-limb muscle weakness, in the second patient at
    eleven years. His muscle biopsy carried an isolated complex IV deficiency, which is the
    respiratory-chain correlate.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Exercise intolerance with myalgia after walking
    term:
      id: HP:0003546
      label: Exercise intolerance
  notes: >-
    1 of 4 published patients. The first patient's motor delay is recorded under developmental
    delay rather than here, since it was a delay in acquisition rather than exertional
    intolerance; the 2022 patient's muscle tension and tone are reported as normal.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "He suffered from exercise intolerance marked by myalgia after walking."
    explanation: The exertional phenotype in the patient who has it.
- name: Failure to Thrive
  category: Growth
  description: >-
    Failure to thrive during the first year of life in the first patient. The second patient had
    normal growth parameters at eleven years, so growth failure is not a constant of the entity.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Failure to thrive in the first year
    term:
      id: HP:0001508
      label: Failure to thrive
  notes: >-
    1 of 4 published patients; the second 2018 patient is explicitly recorded as growing normally
    and the 2022 patient's physical examination revealed no abnormal findings.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "During the first year of life she developed a failure to thrive."
    explanation: The growth phenotype and its timing in the first patient.
- name: Microcephaly
  category: Nervous System
  description: >-
    Reported as an initial feature in the 2024 patient and described by those authors as not
    previously reported in this disease. It is absent from both 2018 patients.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Initial microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  notes: >-
    1 of 4 published patients, and new to the phenotype as of 2024. Recorded because a feature a
    later report adds is exactly what a reader consulting an entry written from the founding
    paper would otherwise miss.
  evidence:
  - reference: PMID:38029925
    reference_title: "New description of an MRPS2 homozygous patient: Further features to help expend the phenotype."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "we describe a new MRPS2 homozygous subject who shows particular features which have not yet been reported: initial microcephaly, joint hypermobility and autistic features."
    explanation: >-
      The three features the 2024 report adds, and the authors' own statement that they were not
      previously reported in MRPS2 disease.
- name: Joint Hypermobility
  category: Musculoskeletal
  description: Reported in the 2024 patient and new to the phenotype at that point.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  notes: >-
    1 of 4 published patients. Connective-tissue laxity sits beside the wrinkled skin of the
    first 2018 patient, and whether the two are one feature of the entity or two coincidences in
    a series of four is recorded as a knowledge gap in this entry's discussions.
  evidence:
  - reference: PMID:38029925
    reference_title: "New description of an MRPS2 homozygous patient: Further features to help expend the phenotype."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "initial microcephaly, joint hypermobility and autistic features"
    explanation: The feature as listed by the 2024 authors.
- name: Autistic Behaviour
  category: Nervous System
  description: Autistic features reported in the 2024 patient and new to the phenotype at that point.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Autistic features
    term:
      id: HP:0000729
      label: Autistic behavior
  notes: 1 of 4 published patients.
  evidence:
  - reference: PMID:38029925
    reference_title: "New description of an MRPS2 homozygous patient: Further features to help expend the phenotype."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "who shows particular features which have not yet been reported: initial microcephaly, joint hypermobility and autistic features"
    explanation: The feature as listed by the 2024 authors, with their own novelty claim attached.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Four patients in four unrelated families: two in the 2018 report that defined the entity —
    one of Austrian and one of Tunisian origin — one Chinese patient in 2022, and one in 2024.
    No population estimate exists and none can be constructed: all were ascertained through
    diagnostic sequencing of an unexplained metabolic or mitochondrial phenotype, so the
    denominator is unknown by construction.

    prevalence_class is the numeric floor tier and rate_per_100000 is left unset, because no rate
    has ever been reported and computing one from four cases would be inventing a figure.
  evidence:
  - reference: PMID:38029925
    reference_title: "New description of an MRPS2 homozygous patient: Further features to help expend the phenotype."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Mutated mito-ribosomal protein S2 (MRPS2) was already described in only three subjects"
    explanation: >-
      The size of the literature as counted by the most recent report — three prior subjects,
      which with the 2024 patient makes four. The third prior subject is the 2022 Chinese
      patient, which is the one the 2024 authors describe as having a less severe phenotype.
progression:
- phase: Infantile presentation
  notes: >-
    The first patient presented from birth with wrinkled skin and minor dysmorphism, then failure
    to thrive in the first year and psychomotor delay. The second presented later — recurrent
    hypoglycaemia from eighteen months, walking at twenty-two months — and was not investigated
    for hypoglycaemia until six years. The 2022 patient is the clearest case of the same delay:
    hearing loss at four, gallstones at four and nine months, two years of vomiting, and a
    genetic test only at six and a half, ordered because the cause of the hypoglycaemia was
    unknown. That gap between first symptom and investigation is the diagnostic delay this
    entity's stub was nominated for.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Subject 2, a boy, presented with fasting hypoglycemia at the age of 6 years."
    explanation: >-
      Age at presentation in the second patient, against an eighteen-month age of first
      hypoglycaemic episode recorded elsewhere in the same paragraph.
- phase: Survival into the second decade with treated hearing loss
  notes: >-
    Both 2018 patients were alive at eleven years at the time of report, with hearing corrected
    and speech recovered, and the 2022 patient was seven at last follow-up. No death is reported
    in this entity, and nobody developed the hepatic or renal failure that kills patients with
    some other mitoribosomal-protein defects. Against a series in which about a third of
    mitoribosomal-disease patients die before one year, this is the mild end of the group — and
    the reason this entity's prognosis should not be quoted from the mitoribosomal literature at
    large.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Most subjects presented in the neonatal period, and about one-third of the subjects died before the age of 1 year."
    explanation: >-
      The mortality of the mitoribosomal-protein group as a whole, which is the comparison that
      makes this entity's survival notable. Graded REVIEW_SYNTHESIS because it is the authors'
      tabulation of twenty-two previously published patients from other groups, and INDIRECT
      because it bears on this entity only by contrast.
genetic:
- name: MRPS2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    The single causal gene. Four missense alleles in three genotyped families, two of them
    substitutions of the same arginine at codon 138 in unrelated populations. Causality rests on
    lentiviral complementation with wild-type MRPS2 in the two 2018 patients' fibroblasts rather
    than on segregation and prediction alone; the 2022 and 2024 alleles have no functional data
    and inherit their pathogenicity from the gene-disease relationship the 2018 work established.
  gene_term:
    preferred_term: MRPS2
    term:
      id: hgnc:14495
      label: MRPS2
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Cumulatively, our complementation experiments confirm the pathogenicity of MRPS2 mutations."
    explanation: >-
      The authors' own statement of what establishes causality here, and the reason this entry
      grades the gene-disease relationship on function rather than on prediction.
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Consistent with these observations, mitochondrial translation was partially restored in both subject cell lines complemented with wild-type MRPS2 (Figure 6B), as was the assembly of OXPHOS complexes I and IV (Figure 6C)."
    explanation: >-
      The rescue itself, in both patients' cells. Note the restoration is partial rather than
      complete, which the entry states rather than rounding up.
diagnosis:
- name: Respiratory-chain enzymology in liver, muscle and fibroblasts
  description: >-
    Measurement of OXPHOS complex activities is what identifies the biochemical class of the
    disease. It should be read with the tissue discrepancy in mind: the first patient showed
    multiple complex deficiencies in liver, muscle and fibroblasts, while the second showed
    multiple deficiencies in liver and fibroblasts but an isolated complex IV deficiency in
    muscle. A single muscle panel can therefore look like an isolated complex IV disorder in a
    patient who has a combined one.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Measurements of OXPHOS complex activities showed a decrease in multiple complexes in liver and fibroblasts and a complex IV deficiency in muscle."
    explanation: The tissue discrepancy this diagnostic caution rests on, in the patient who shows it.
- name: Exome sequencing
  description: >-
    Both 2018 diagnoses were made by exome sequencing, and in each the filtering converged on a
    single candidate gene. The 2024 patient was also identified by sequencing. There is no
    biochemical test specific to MRPS2; enzymology localises the defect to mitochondrial
    translation and sequencing names the gene.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Exome sequencing was performed to identify pathogenic variants underlying the disease in both subjects"
    explanation: The diagnostic route used in both founding cases.
- name: Transferrin and apolipoprotein-CIII isoelectric focusing
  presence: ABSENT
  description: >-
    Glycosylation screening was normal in the first patient. This is recorded as a negative
    because the differential for an infant with wrinkled skin, developmental delay and raised
    transaminases includes the congenital disorders of glycosylation, and a normal screen is what
    removes them.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Glycosylation screening (transferrin and apolipoprotein-CIII isoelectric focusing) was unremarkable."
    explanation: The negative screen in the first patient.
experimental_models:
- name: MRPS2-complemented patient fibroblast lines
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Skin fibroblasts from both 2018 patients, transduced with a lentivirus expressing either
    wild-type MRPS2 or GFP as a negative control. This is the model that establishes causality in
    this disease, and it is a rescue rather than a knockdown, so it tests the patients' own
    alleles rather than a constructed one.
  modeled_mechanisms:
  - target: Inhibition of Mitochondrial Translation
    relationship: RESCUES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: >-
      Re-expressing wild-type MRPS2 partially restores mitochondrial translation in both
      patients' cells, and restores assembly of complexes I and IV.
    limitations: >-
      The restoration is partial rather than complete, and the readouts are steady-state
      abundance and pulse-labelled synthesis rather than respiratory flux or ATP output. A
      fibroblast is also not the cochlea, the liver or the brain, so the model speaks to the
      molecular step and not to any clinical feature.
    readouts:
    - name: Pulse-labelled mitochondrial translation products
      target: Inhibition of Mitochondrial Translation
      direction: RESTORED
      interpretation: >-
        Synthesis of mtDNA-encoded polypeptides recovers when wild-type MRPS2 is supplied, which
        is what makes the translation defect attributable to the MRPS2 alleles.
      evidence:
      - reference: PMID:29576219
        reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
        supports: SUPPORT
        directness: DIRECT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: "Pulse labeling of mitochondrial translation products demonstrates that the presence of wild-type MRPS2 partially restores mitochondrial translation in S1 and S2 fibroblasts."
        explanation: The measurement, with the authors' own qualifier that the restoration is partial.
    evidence:
    - reference: PMID:29576219
      reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "To demonstrate the disease-causing nature of MRPS2 mutations, we carried out functional complementation experiments by generating control, S1, and S2 cell lines stably expressing either green fluorescent protein (GFP) as a negative control or wild-type MRPS2"
      explanation: >-
        The design of the model, including the GFP control arm that makes the rescue
        interpretable.
  notes: >-
    Overexpressing MRPS2 in control cells had no negative effect on translation or OXPHOS
    assembly, which is the dose control for the rescue arm and is worth knowing for anyone
    considering gene-replacement approaches in this pathway.
treatments:
- name: Cochlear Implantation and Hearing Amplification
  therapeutic_modality: SURGERY
  description: >-
    The first patient's progressive hearing loss was managed with a hearing aid and then with
    bilateral cochlear implants, after which her speech and general development improved
    markedly; the second patient's severe deafness was managed with a hearing aid, again with
    improvement in speech. In a disease with no disease-modifying therapy this is the
    intervention that changes the trajectory, and it is the reason hearing assessment belongs in
    the initial work-up rather than being deferred until speech delay is noticed.
  treatment_term:
    preferred_term: cochlear device implantation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: cochlear implant
        term:
          id: NCIT:C157820
          label: Cochlear Implant
  target_mechanisms:
  - target: Sensorineural Hearing Loss
    description: >-
      The implant bypasses the cochlear lesion rather than correcting it. It addresses the
      phenotype and leaves the OXPHOS deficiency that produced it untouched, which is why it is
      recorded against the phenotype and not against a pathophysiology node.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "which required the use of a hearing aid and was corrected with bilateral cochlea implants. After this correction, both her speech and development improved markedly."
    explanation: >-
      The intervention and the outcome in the first patient. Two patients is not a trial, and
      this entry claims no more than the two reported courses.
- name: Avoidance of Prolonged Fasting
  therapeutic_modality: BEHAVIORAL
  description: >-
    The second patient's hypoglycaemic episodes followed overnight or twelve-hour fasts and were
    worse when illness reduced oral intake. No formal regimen has been published for this
    disease, so what is recorded here is the management implication of the reported trigger
    rather than a trialled intervention: fasts of that length are the exposure, and intercurrent
    illness is the risk period.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Failure of Fasting Metabolic Adaptation
    description: >-
      Removing the fast removes the demand the hepatic adaptation cannot meet. The underlying
      OXPHOS deficiency is unchanged.
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "several acute episodes of hypoglycemia after an overnight or a 12-hr fasting since the age of 18 months, especially when these episodes coincided with illness and poor oral intake"
    explanation: >-
      The trigger, quoted as the basis for the avoidance advice. Graded INDIRECT because the
      source documents the provocation and not the benefit of avoiding it — no one has tested
      the intervention.
- name: Carbohydrate Administration for Acute Hypoglycaemia
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    The 2022 patient's hypoglycaemia and lactic acidosis both improved on sugary liquid with
    supportive treatment, and her appetite recovered as glucose normalised. It is the only
    treatment in this disease with a reported response, and the response includes the lactate —
    which is not obvious, since giving glucose to a patient who cannot oxidise pyruvate could
    reasonably be expected to raise it.

    It is also not a cure, and the entry does not present it as one: the same patient's
    hypoglycaemia recurred and she was admitted repeatedly.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: glucose
      term:
        id: CHEBI:17234
        label: glucose
  target_mechanisms:
  - target: Fasting Hypoglycaemia
    description: >-
      Exogenous carbohydrate substitutes for the hepatic glucose output the patient cannot
      generate. It corrects the consequence and leaves the OXPHOS deficiency producing it
      untouched, which is why the hypoglycaemia recurs.
  evidence:
  - reference: PMID:34991560
    reference_title: "Hypoglycemia with lactic acidosis caused by a new MRPS2 gene mutation in a Chinese girl: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Hypoglycemia and lactic acidosis improved after the administration of sugary liquid and supportive treatments."
    explanation: >-
      The only treatment response reported in this disease, and the fact that the lactate
      improved with the glucose rather than worsening.
  - reference: PMID:34991560
    reference_title: "Hypoglycemia with lactic acidosis caused by a new MRPS2 gene mutation in a Chinese girl: a case report."
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Her condition improved after the administration of sugary liquid and supportive treatments. However, her hypoglycemia was recurring."
    explanation: >-
      Graded REFUTE against any reading of this as durable control. The same sentence that
      reports the response reports the recurrence, and a treatment section that quoted only the
      first clause would be selecting.
  notes: >-
    No published treatment trial, cohort or disease-specific guideline exists for MRPS2 disease.
    Management follows the symptom-based standards for primary mitochondrial disease generally —
    the Mitochondrial Medicine Society recommendations and their national adaptations — because
    there is nothing more specific to follow, and those standards are explicit that treatment
    guidance in this field is symptom-based rather than mechanism-based.

    This entry deliberately does not carry the generic mitochondrial cofactor cocktail: no source
    reports it being given to any MRPS2 patient or having any effect, and listing it would be
    importing a habit from the wider mitochondrial literature rather than curating this disease.

discussions:
- discussion_id: copd36_cochlear_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why does a generalised mitochondrial translation defect produce hearing loss as its most
    consistent and earliest-recognised feature, when the cochlea is not where the biochemistry
    was measured?
  rationale: >-
    Hearing loss is the only feature present in all four published patients and the only one
    with an effective intervention, yet the entire mechanistic chain in this entry is measured in
    fibroblasts, liver and muscle. No cochlear tissue, no auditory-nerve measurement and no
    animal model of MRPS2 deficiency exists. The edge from the OXPHOS node to the hearing
    phenotype is therefore carried as INDIRECT_UNKNOWN_INTERMEDIATES, and is an argument from
    organ vulnerability across the mitoribosomal group rather than a finding about MRPS2.

    This matters beyond bookkeeping. Cochlear implantation works in these patients, which implies
    the lesion is at the hair cell or before the spiral ganglion rather than central — but that
    inference from a therapeutic response is the only evidence about the site of the lesion that
    this literature contains.
  attaches_to:
  - phenotypes#Sensorineural Hearing Loss
  - pathophysiology#Combined Deficiency of OXPHOS Complexes I and IV
- discussion_id: copd36_late_assembly_severity
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Does the position of a mitoribosomal protein in the assembly pathway predict how severe the
    resulting disease is?
  rationale: >-
    The founding authors propose that variants in subunits that join late produce milder disease
    than variants in subunits that join early, and offer MRPS2 as their case: the roughly 300 kDa
    early subassembly containing MRPS22 and MRPS16 is still present in patient cells, and these
    patients were alive at eleven where about a third of the mitoribosomal-disease series died
    before one year.

    Recorded as an open question rather than as mechanism because it is a hypothesis about the
    whole mitoribosomal group, testable across it, and the authors state plainly that the order
    of steps in mitoribosomal assembly is not known. A single mild entity is consistent with the
    hypothesis and does not establish it; the comparison that would is an assembly-order ranking
    against outcome across all the MRPS and MRPL disorders, which nobody has published.
  attaches_to:
  - pathophysiology#Failure of Mitoribosomal Small Subunit Assembly
  evidence:
  - reference: PMID:29576219
    reference_title: "Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    snippet: "Despite recent advances in elucidating the structure of the mammalian mitoribosome,3 the order of steps in the assembly process of the mitochondrial ribosome remains elusive."
    explanation: >-
      The authors' own statement of the gap that keeps this a hypothesis — the assembly order the
      proposal depends on is not established.
- discussion_id: copd36_connective_tissue
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Are the wrinkled skin of the first 2018 patient and the joint hypermobility of the 2024
    patient two expressions of one connective-tissue involvement, or two unrelated findings in a
    series of four?
  rationale: >-
    Each feature is reported once, in a different patient, by a different group, six years apart,
    and neither report mentions the other finding. The founding paper argues at length that
    wrinkled skin is the discriminating feature of the entity and compares it with the cutis laxa
    syndromes, which are themselves connective-tissue disorders with laxity at the joints. That
    makes the pairing suggestive.

    It is not more than suggestive, and the arrival of the 2022 patient sharpens rather than
    settles it. She has neither finding: her physical examination is reported as revealing no
    abnormal findings. So across four patients the skin feature is 1 of 4 and the joint feature
    is 1 of 4, in different individuals, with two patients having neither — which is what two
    unrelated occasional findings look like, and also what one variably expressed
    connective-tissue feature looks like. Four is not enough to tell those apart.

    There is no dermal or fibroblast matrix measurement in any patient — the fibroblasts in this
    literature were used for mitochondrial assays, not for collagen or elastin. Resolving it
    needs a fifth patient examined for both, or a matrix assay on the fibroblast lines that
    already exist.
  attaches_to:
  - phenotypes#Excessive Wrinkled Skin
  - phenotypes#Joint Hypermobility
notes: >-
  Patient count. Four published patients, one per family: the two in PMID:29576219 (2018), the
  Chinese girl in PMID:34991560 (2022), and the patient in PMID:38029925 (2024). The 2024
  authors' count of three prior subjects is consistent with this — the "less severe phenotype"
  they refer to is the 2022 patient.

  That third report was found by the openscientist deep-research run committed alongside this
  entry, not by the curator. A direct PubMed search on the gene symbol and on the disease name
  returned only the 2018 and 2024 papers; the 2022 case report is titled for the presenting
  problem rather than for the entity and did not surface. Without it this entry would have
  carried three patients, would have recorded the 2024 count as an unresolved discrepancy, and
  would have been missing the gallstones, the recurrent vomiting, the only published glucose
  values, the only reported treatment response, and the second substitution at Arg138.

  GeneReviews baseline: `just check-genereviews` reports NO_CHAPTER for both GeneReviews and
  StatPearls against the committed Bookshelf index (snapshot 2026-09-10). No chapter names this
  disease, MRPS2, or any of this entry's synonyms, which is expected for an entity with four
  published patients.

  Functional evidence is not evenly distributed across the series and the entry does not average
  it. Everything mechanistic here — the protein destabilisation, the assembly failure, the rRNA
  loss, the translation defect, the complex I and IV deficiency, the rescue — comes from the two
  2018 patients. The 2022 and 2024 alleles were called on novelty, segregation and phenotype
  match, with no cell work at all. A reader should take the mechanism as established for the
  disease and the specific pathogenicity of the two later alleles as inherited from it.

  Treatment scope. Nothing here is disease-modifying. Cochlear implantation, carbohydrate for
  acute hypoglycaemia and fasting avoidance are recorded because each is documented in a
  reported patient; only the first two have a reported outcome.

  Phenotype completeness, after review. The first version of this entry took its phenotypes from
  the two 2018 patients' narrative case descriptions and from the later reports' abstracts, and
  missed six features: hypotonia, which is reported only in the founding paper's comparative
  Table 1 and not in either narrative, and five single-patient findings (low-set ears,
  upslanted palpebral fissures, intermittent divergent strabismus, frequent headaches, lower-limb
  weakness) that are in the narratives but were passed over while the 2024 report's equally
  single-patient findings were curated. The asymmetry had no justification; all six are now
  present. The general point is that a comparative table in a paper about a gene family carries
  per-patient phenotype data that the case narratives do not, and reading only the narrative
  misses it.

  Frequency bands, after review. Four phenotypes were graded VERY_FREQUENT against denominators
  of 2 of 4 and 3 of 4, which fall in the FREQUENT band. They were graded before the 2022
  patient was folded in and not revisited. All four are now FREQUENT. Sensorineural hearing loss
  stays VERY_FREQUENT at 4 of 4, with its existing note explaining why it is not OBLIGATE.

  Why complex III is spared in fibroblasts. Complex III contains exactly one mtDNA-encoded
  subunit where complexes I and IV contain seven and three, so a partial translation defect
  depletes it least. The founding paper reports the observation and does not offer this
  explanation, so it is recorded here as a reading rather than in the pathophysiology chain.

📚

References & Deep Research

References

4

PMID:29576219

Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies.

No top-level findings curated for this source.

PMID:38029925

New description of an MRPS2 homozygous patient: Further features to help expend the phenotype.

No top-level findings curated for this source.

PMID:34991560

Hypoglycemia with lactic acidosis caused by a new MRPS2 gene mutation in a Chinese girl: a case report.

No top-level findings curated for this source.

PMID:34505344

Patient care standards for primary mitochondrial disease in Australia: an Australian adaptation of the Mitochondrial Medicine Society recommendations.

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (2)

Record notes

Patient count. Four published patients, one per family: the two in PMID:29576219 (2018), the Chinese girl in PMID:34991560 (2022), and the patient in PMID:38029925 (2024). The 2024 authors' count of three prior subjects is consistent with this — the "less severe phenotype" they refer to is the 2022 patient. That third report was found by the openscientist deep-research run committed alongside this entry, not by the curator. A direct PubMed search on the gene symbol and on the disease name returned only the 2018 and 2024 papers; the 2022 case report is titled for the presenting problem rather than for the entity and did not surface. Without it this entry would have carried three patients, would have recorded the 2024 count as an unresolved discrepancy, and would have been missing the gallstones, the recurrent vomiting, the only published glucose values, the only reported treatment response, and the second substitution at Arg138. GeneReviews baseline: `just check-genereviews` reports NO_CHAPTER for both GeneReviews and StatPearls against the committed Bookshelf index (snapshot 2026-09-10). No chapter names this disease, MRPS2, or any of this entry's synonyms, which is expected for an entity with four published patients. Functional evidence is not evenly distributed across the series and the entry does not average it. Everything mechanistic here — the protein destabilisation, the assembly failure, the rRNA loss, the translation defect, the complex I and IV deficiency, the rescue — comes from the two 2018 patients. The 2022 and 2024 alleles were called on novelty, segregation and phenotype match, with no cell work at all. A reader should take the mechanism as established for the disease and the specific pathogenicity of the two later alleles as inherited from it. Treatment scope. Nothing here is disease-modifying. Cochlear implantation, carbohydrate for acute hypoglycaemia and fasting avoidance are recorded because each is documented in a reported patient; only the first two have a reported outcome. Phenotype completeness, after review. The first version of this entry took its phenotypes from the two 2018 patients' narrative case descriptions and from the later reports' abstracts, and missed six features: hypotonia, which is reported only in the founding paper's comparative Table 1 and not in either narrative, and five single-patient findings (low-set ears, upslanted palpebral fissures, intermittent divergent strabismus, frequent headaches, lower-limb weakness) that are in the narratives but were passed over while the 2024 report's equally single-patient findings were curated. The asymmetry had no justification; all six are now present. The general point is that a comparative table in a paper about a gene family carries per-patient phenotype data that the case narratives do not, and reading only the narrative misses it. Frequency bands, after review. Four phenotypes were graded VERY_FREQUENT against denominators of 2 of 4 and 3 of 4, which fall in the FREQUENT band. They were graded before the 2022 patient was folded in and not revisited. All four are now FREQUENT. Sensorineural hearing loss stays VERY_FREQUENT at 4 of 4, with its existing note explaining why it is not OBLIGATE. Why complex III is spared in fibroblasts. Complex III contains exactly one mtDNA-encoded subunit where complexes I and IV contain seven and three, so a partial translation defect depletes it least. The founding paper reports the observation and does not offer this explanation, so it is recorded here as a reading rather than in the pathophysiology chain.

Create: Combined Oxidative Phosphorylation Deficiency 36 · 2026-09-22T17:25:14Z · View source

De novo curation of COXPD36 (MRPS2, MONDO:0054781) from four published patients. Deep research: one openscientist run, committed at research/Combined_Oxidative_Phosphorylation_Deficiency_36-deep-research-openscientist.md (4 references, 4/4 resolved, 1/1 quote valid, term_validation needs_review true with 4 label variants and OMIM/NCBIGene unresolvable prefixes). The report supplied PMID:34991560 (Liu 2022), a third patient a direct PubMed search on the gene symbol and disease name did not return; without it the entry would have carried three patients, an unresolved count discrepancy against the 2024 report, and none of the 2022 patient's glucose values, gallstones, recurrent vomiting or treatment response. Pathograph is a nine-node chain from the biallelic alleles through MRPS2 destabilisation, mt-SSU assembly failure and 12S rRNA loss to a combined complex I and IV deficiency, then to lactate, 2-oxoglutarate and fasting hypoglycaemia. Causality is grounded on the 2018 lentiviral complementation rather than on prediction; the 2022 and 2024 alleles have no functional data and the entry says so. Three discussions record the open questions: the unmeasured cochlear mechanism, the late-assembly severity hypothesis, and whether the wrinkled skin and joint hypermobility are one connective-tissue feature. Validation on the final tree: just validate, validate-terms, count-verified-snippets 57/57, check-entity-refs, check-causal-targets, check-qualifier-terms, check-duplicate-keys, check-genereviews (NO_CHAPTER, recorded in notes), list-disconnected-phenotypes 9/15. Review round 1 (ai4c-reviewer, REQUEST_CHANGES, four IMPORTANT findings, all taken in one push). Added six phenotypes the first pass missed: hypotonia, reported only in the founding paper's comparative Table 1 and not in either patient narrative, and five single-patient narrative findings (low-set ears, upslanted palpebral fissures, intermittent divergent strabismus, frequent headaches, lower-limb weakness) that had been passed over while the 2024 report's equally single-patient findings were curated; the asymmetry had no justification. Regraded four phenotypes from VERY_FREQUENT to FREQUENT, where the denominators of 2 of 4 and 3 of 4 recorded in their own notes fall; they had been graded before the 2022 patient was folded in. Updated three passages in discussions that still said three patients, re-reasoning the connective-tissue chance argument on the corrected denominator rather than find-and-replacing the number. Rebound the small-subunit assembly process from GO:0000028 (ribosomal small subunit assembly) to GO:0180026 (mitochondrial small ribosomal subunit assembly), more specific than either the original binding or the GO:0061668 the reviewer suggested. Wired hypotonia and lower-limb weakness into the pathograph from the OXPHOS node; left the dysmorphic features and the headache disconnected, since nothing in this literature gives them a mechanism. Post-round validation: count-verified-snippets 63/63, list-disconnected-phenotypes 11/21.

OpenScientist ▸

Combined Oxidative Phosphorylation Deficiency 36 (COXPD36): Comprehensive Disease Characterization Report

openscientist-autonomous 4 citations 2026-09-22T17:17:31.549671

Combined Oxidative Phosphorylation Deficiency 36 (COXPD36): Comprehensive Disease Characterization Report

Disease: Combined Oxidative Phosphorylation Deficiency 36 (COXPD36) MONDO ID: MONDO:0054781 · OMIM: #617950 · Category: Mendelian (autosomal recessive mitochondrial disease) Causal gene: MRPS2 (HGNC:14495; NCBI Gene 51116; chr 9q34.3) Prepared: 2026-09-22 · Evidence base: human clinical case reports + in vitro functional (rescue) studies. No dedicated animal model or omics dataset yet published.

Summary

Combined Oxidative Phosphorylation Deficiency 36 (COXPD36) is an ultra-rare, autosomal-recessive mitochondrial disease caused by biallelic (homozygous or compound-heterozygous) missense mutations in MRPS2, the gene encoding uS2m (mitochondrial ribosomal protein S2), a structural constituent of the small (28S) subunit of the mitoribosome. The disease was first defined in 2018 by Gardeitchik and colleagues, who identified MRPS2 mutations by exome sequencing in two unrelated affected individuals in a gene "which has not previously been implicated in disease" (PMID: 29576219). To date only approximately 4–5 patients worldwide have been reported, making COXPD36 one of the rarest recognized mitochondrial translation disorders.

Mechanistically, the pathogenic missense variants destabilize the MRPS2 protein, lowering its steady-state abundance. Complexome profiling demonstrated that this loss prevents assembly of the small mitoribosomal subunit, which in turn inhibits mitochondrial translation of the 13 mtDNA-encoded OXPHOS subunits, producing a combined deficiency of multiple oxidative phosphorylation complexes detectable in muscle, liver, and cultured fibroblasts. Re-introduction of wild-type MRPS2 rescues both translation and OXPHOS assembly, confirming causality. The clinical presentation is dominated by a characteristic triad of sensorineural hearing loss, hypoglycemia, and lactic acidemia, with variable developmental delay, hypotonia, hepatic and muscular involvement, and — in individually reported cases — microcephaly, joint hypermobility, autistic features, and gallstones.

There is no disease-specific or curative therapy. Management follows the general supportive standards for primary mitochondrial disease (symptomatic control of hypoglycemia and lactic acidosis, hearing rehabilitation, developmental support, avoidance of mitochondrial toxins). Diagnosis rests on the combination of biochemical findings (lactic acidemia, hypoglycemia, elevated alanine, combined OXPHOS enzyme deficiencies on biopsy) and molecular confirmation by exome/genome sequencing. Because the phenotype overlaps broadly with other mitochondrial translation defects, molecular genetic testing is essential for definitive diagnosis. This report synthesizes seven confirmed findings across all 15 requested characterization domains, with ontology annotations and primary-literature citations.

Key Findings

Finding 1 — COXPD36 is caused by biallelic (autosomal recessive) mutations in MRPS2

COXPD36 is a Mendelian, autosomal-recessive disorder. Ontology cross-references establish the identity of the disease across knowledge bases: MONDO:0054781 = OMIM #617950 = MedGen C4693722 = GARD 0025974 = DOID:0111482. The Monarch Initiative lists MRPS2 (HGNC:14495, chromosome 9q34.3) as the CausalGeneToDiseaseAssociation for this entity.

The founding study, Gardeitchik et al., 2018 (American Journal of Human Genetics), identified MRPS2 mutations by exome sequencing in two unrelated subjects and explicitly noted the novelty of the gene: "we identified mutations in the gene encoding the mitochondrial ribosomal protein S2, which has not previously been implicated in disease" (PMID: 29576219).

Reported pathogenic / likely-pathogenic variants are all missense changes in MRPS2 (transcript NM_016034.5):

cDNA variant	Protein change	Classification	Source
c.328C>T	p.Arg110Cys	Pathogenic (ClinVar)	Gardeitchik 2018
c.340G>A	p.Asp114Asn	Pathogenic / likely pathogenic	Gardeitchik 2018
c.413G>A	p.Arg138His	Pathogenic / likely pathogenic	Gardeitchik 2018
c.412C>G	(novel, Chinese case)	Reported pathogenic	Liu 2022 (PMID: 34991560)

The recurrent variant class (missense affecting conserved residues of the ribosomal S2 domain) and the recessive inheritance pattern are consistent across all reported families.

Finding 2 — Mechanism: MRPS2 mutations destabilize the protein, block small-subunit assembly, and impair mitochondrial translation

The core pathophysiology was demonstrated experimentally in the founding study. Patient fibroblasts showed decreased steady-state levels of mutant MRPS2. Using complexome profiling, the authors showed that this decrease prevents the assembly of the small mitoribosomal subunit (mt-SSU / 28S). Because the mitoribosome is required to translate the 13 mtDNA-encoded core subunits of the OXPHOS complexes, the assembly failure inhibits mitochondrial translation, producing a combined OXPHOS deficiency in patient muscle and liver biopsies and in cultured skin fibroblasts.

In the authors' words: "this decrease was shown by complexome profiling to prevent the assembly of the small mitoribosomal subunit. In turn, mitochondrial translation was inhibited, resulting in a combined OXPHOS deficiency detectable in subjects' muscle and liver biopsies as well as in cultured skin fibroblasts" (PMID: 29576219). Critically, re-introduction of wild-type MRPS2 rescued mitochondrial translation and OXPHOS assembly, establishing loss-of-function causality rather than correlation.

Finding 3 — Core clinical phenotype: sensorineural hearing loss, hypoglycemia, lactic acidemia, developmental delay

Across the reported cases, a consistent clinical core emerges. Gardeitchik 2018 described two unrelated subjects with sensorineural hearing impairment, mild developmental delay, hypoglycemia, and combined OXPHOS deficiency, emphasizing the characteristic combination of lactic acidemia, hypoglycemia, and sensorineural hearing loss.

Subsequent case reports expanded the spectrum: - Liu et al., 2022 (Chinese girl, novel c.412C>G): "The clinical manifestations included recurrent vomiting, hypoglycemia, lactic acidosis, sensorineural hearing loss, and gall bladder calculi" (PMID: 34991560) — adding gallstones as a novel feature. - Papadopoulos et al., 2024 described a new homozygous patient with previously unreported features: "a new MRPS2 homozygous subject who shows particular features which have not yet been reported: initial microcephaly, joint hypermobility and autistic features" (PMID: 38029925), broadening the recognized phenotype.

Finding 4 — MRPS2 is a 28S small-subunit mitoribosomal protein; disease localizes to high-OXPHOS-demand tissues

MRPS2 (NCBI Gene 51116; ENSG00000122140; 9q34.3; aliases uS2m, S2mt) carries Gene Ontology annotations that place it firmly in the mitochondrial translation machinery:

GO aspect	Term	ID
Cellular component	mitochondrial matrix	GO:0005759
Cellular component	small mitochondrial ribosomal subunit	GO:0005763
Cellular component	mitochondrial inner membrane	GO:0005743
Biological process	mitochondrial translation	GO:0032543
Biological process	mitochondrial ribosome assembly	GO:0061668
Molecular function	structural constituent of ribosome	GO:0003735

The clinically affected tissues are precisely the high-oxidative-demand organs: cochlea/inner ear (hearing loss), brain (developmental delay), and liver and skeletal muscle (combined OXPHOS deficiency demonstrated on biopsy) — consistent with a systemic defect of mitochondrial energy production that manifests first where ATP demand is greatest.

Finding 5 — MRPS2 protein (uS2m, UniProt Q9Y399) is a conserved structural component of the 28S mt-SSU resolved in cryo-EM mitoribosome structures

UniProt Q9Y399 annotates MRPS2 as "Small ribosomal subunit protein uS2m," a 296-amino-acid protein "Required for mitoribosome formation and stability, and mitochondrial translation." It contains the Ribosomal_S2 domain (Pfam PF00318) and belongs to the universal uS2 protein family (InterPro IPR001865/IPR005706, spanning bacterial, mitochondrial, and plastid ribosomes). MRPS2 is resolved as a component in >60 cryo-EM structures of the human/mammalian mitoribosome (e.g., PDB 3J9M, 6NU2, 6RW4, 6ZM5), confirming its integral structural role in the small subunit. The mouse ortholog Mrps2 is NCBI Gene 118451.

Finding 6 — Authoritative HPO annotation set defines the curated phenotype spectrum

The JAX Human Phenotype Ontology annotations for OMIM:617950 (MONDO:0054781; gene MRPS2/NCBIGene:51116) comprise 22 curated terms organized by system:

System	Phenotype	HPO ID
Ear	Sensorineural hearing impairment	HP:0000407
Ear	Low-set ears	HP:0000369
Metabolism	Hypoglycemia	HP:0001943
Metabolism	Increased circulating lactate	HP:0002151
Metabolism	Hyperalaninemia	HP:0003348
Metabolism	Elevated ALT	HP:0031964
Metabolism	Elevated AST	HP:0031956
Metabolism	Aciduria	HP:0012072
Nervous system	Global developmental delay	HP:0001263
Nervous system	Intellectual disability	HP:0001249
Nervous system	Poor speech	HP:0002465
Nervous system	Headache	HP:0002315
Musculature	Hypotonia	HP:0001252
Constitutional	Exercise intolerance	HP:0003546
Constitutional	Myalgia	HP:0003326
Limbs	Lower limb muscle weakness	HP:0007340
Growth	Failure to thrive	HP:0001508
Eye	Exodeviation	HP:0020049
Head/neck	Upslanted palpebral fissure	HP:0000582
Skin	Premature skin wrinkling	HP:0100678
Course	Infantile onset	HP:0003593
Inheritance	Autosomal recessive	HP:0000007

Frequencies are not curated (blank in the HPO source), and no curated HPO medical actions are listed — reflecting the disorder's rarity and the small evidence base.

Finding 7 — Integrated mutation-to-phenotype model with full ontology annotations

Synthesizing the above: biallelic missense variants in MRPS2 (HGNC:14495; NCBIGene:51116; UniProt Q9Y399/uS2m; 9q34.3) — c.328C>T/p.Arg110Cys (pathogenic), c.340G>A, c.413G>A, and c.412C>G — cause autosomal-recessive COXPD36 (MONDO:0054781; OMIM #617950). The mechanism is confirmed by complexome profiling plus wild-type rescue (Gardeitchik 2018, PMID: 29576219). Twenty-two curated HPO terms anchor the phenotype; ~4–5 patients are reported worldwide (PMID: 29576219, PMID: 34991560, PMID: 38029925); management is supportive per Mitochondrial Medicine Society standards (PMID: 34505344). No animal model, omics cohort, or clinical trial exists for this specific disease.

Section-by-Section Characterization

1. Disease Information

COXPD36 is a Mendelian mitochondrial oxidative phosphorylation disorder resulting from defective mitochondrial protein synthesis. Key identifiers: MONDO:0054781; OMIM #617950; MedGen C4693722; GARD 0025974; DOID:0111482. There is no dedicated Orphanet number distinct from the broader "combined oxidative phosphorylation deficiency" grouping, and no specific ICD-10/ICD-11 code (it falls under mitochondrial metabolism disorders, e.g., ICD-10 E88.4 "Mitochondrial metabolism disorders"; ICD-11 5C53.1). Synonyms/alternative names: "Combined oxidative phosphorylation deficiency 36"; "COXPD36"; "MRPS2 deficiency"; "mitochondrial ribosomal protein S2 deficiency." The information is derived from aggregated disease-level resources (OMIM, HPO, ClinVar) plus a small number of individual patient case reports — not from EHR or large registries.

2. Etiology

Causal factor: purely genetic — biallelic loss-of-function/destabilizing missense mutations in MRPS2. Genetic risk factors: the only established risk factor is inheritance of two pathogenic MRPS2 alleles; consanguinity increases the risk of homozygosity (several reported cases are homozygous). No modifier genes, susceptibility loci, environmental risk factors, protective factors, or gene–environment interactions have been identified — expected given the ultra-rare, monogenic nature of the disease. No environmental or infectious contribution is known.

3. Phenotypes

The phenotype is a systemic mitochondrial energy-deficiency syndrome. Laboratory abnormalities (biochemical): lactic acidemia (HP:0002151), hypoglycemia (HP:0001943), hyperalaninemia (HP:0003348), elevated transaminases (HP:0031964, HP:0031956), aciduria (HP:0012072). Clinical signs/symptoms: sensorineural hearing loss (HP:0000407), global developmental delay (HP:0001263), intellectual disability (HP:0001249), hypotonia (HP:0001252), failure to thrive (HP:0001508), exercise intolerance (HP:0003546), myalgia (HP:0003326), muscle weakness (HP:0007340). Dysmorphic/physical: low-set ears, upslanted palpebral fissures, premature skin wrinkling, microcephaly (case-specific), joint hypermobility (case-specific). Behavioral: autistic features (case-specific, Papadopoulos 2024). Onset: infantile (HP:0003593). Severity/progression: variable; energy-crisis features (hypoglycemia, lactic acidosis) can be episodic and provoked by catabolic stress. Frequencies are not curated because of the tiny cohort. Quality-of-life impact: substantial — hearing loss, developmental delay, and metabolic instability affect communication, learning, and daily functioning; no formal QoL instrument data exist.

4. Genetic/Molecular Information

Causal gene: MRPS2 (HGNC:14495; NCBI Gene 51116; ENSG00000122140; 9q34.3; OMIM 610760). Variant type/class: exclusively missense to date (no reported frameshift, nonsense, splice, or structural variants), affecting conserved residues of the ribosomal S2 domain. Classification: c.328C>T/p.Arg110Cys is ClinVar Pathogenic; c.340G>A/p.Asp114Asn and c.413G>A/p.Arg138His are pathogenic/likely pathogenic; c.412C>G reported pathogenic in a Chinese case. Allele frequency: these are private/ultra-rare variants, essentially absent or extremely rare in gnomAD. Origin: germline. Functional consequence: loss of function via protein destabilization and reduced steady-state abundance leading to failed mt-SSU assembly. Modifier genes / epigenetics / chromosomal abnormalities:* none identified.

5. Environmental Information

Not applicable. No environmental toxins, lifestyle factors, or infectious agents are implicated in causation. As with other mitochondrial disorders, catabolic stressors (fasting, infection, fever) may precipitate metabolic decompensation but do not cause the disease.

6. Mechanism / Pathophysiology

Ordered causal chain:

Biallelic missense mutation in MRPS2 (e.g., c.328C>T/p.Arg110Cys) alters a conserved residue of uS2m →
destabilizes the MRPS2 protein, reducing its steady-state level in mitochondria (demonstrated in patient fibroblasts) →
loss of assembled MRPS2 prevents assembly of the small (28S) mitoribosomal subunit (demonstrated by complexome profiling) →
deficient mt-SSU impairs mitochondrial translation of the 13 mtDNA-encoded OXPHOS subunits →
results in a combined deficiency of multiple OXPHOS complexes (complexes I, III, IV, V share mtDNA-encoded subunits) in muscle, liver, and fibroblasts →
impaired mitochondrial ATP production and increased anaerobic glycolysis →
produces lactic acidemia + hypoglycemia (energy shortfall) and tissue-specific dysfunction in high-energy organs →
branches to: cochlear dysfunction → sensorineural hearing loss; CNS energy deficit → developmental delay/intellectual disability; hepatic involvement → transaminitis/hypoglycemia; skeletal-muscle involvement → hypotonia, exercise intolerance, myalgia.

Rescue confirmation: re-expression of wild-type MRPS2 restores translation and OXPHOS assembly (PMID: 29576219).

 MRPS2 missense mutation (germline, biallelic)
│  destabilizes protein
▼
 ↓ steady-state uS2m ──▶ mt-SSU (28S) assembly fails
│                         (complexome profiling)
▼
 mitochondrial translation inhibited
│
▼
 combined OXPHOS deficiency (multiple complexes)
│
   ┌────┼─────────┬──────────────┬───────────────┐
   ▼    ▼         ▼              ▼               ▼
 cochlea  brain   liver        muscle       systemic
 hearing  dev.    hypoglycemia hypotonia    lactic
 loss     delay   transaminitis myalgia     acidemia

Pathways/processes: mitochondrial translation (GO:0032543), mitochondrial ribosome assembly (GO:0061668), oxidative phosphorylation (Reactome R-HSA-1428517). Upstream: MRPS2 destabilization and mt-SSU assembly failure. Downstream: OXPHOS enzyme deficiency and bioenergetic failure. Cell types (CL): cochlear hair cells (CL:0000202), neurons (CL:0000540), hepatocytes (CL:0000182), skeletal muscle fibers (CL:0000188). Subcellular (GO CC): mitochondrial matrix (GO:0005759), small mitoribosomal subunit (GO:0005763), mitochondrial inner membrane (GO:0005743). No disease-specific transcriptomic/proteomic/metabolomic/single-cell datasets exist.

7. Anatomical Structures Affected

Primary organs/systems: inner ear/cochlea (UBERON:0001844), brain (UBERON:0000955), liver (UBERON:0002107), skeletal muscle (UBERON:0001134). Body systems: nervous, auditory, hepatic, musculoskeletal, and systemic metabolic. Tissues: neural, hepatic epithelial, striated muscle. Cells: cochlear hair cells (CL:0000202), neurons (CL:0000540), hepatocytes (CL:0000182), myocytes (CL:0000187). Subcellular: mitochondria (GO:0005739), specifically the mitochondrial matrix and inner membrane. Lateralization: bilateral/systemic (hearing loss bilateral).

8. Temporal Development

Onset: infantile/congenital-to-early-childhood (HP:0003593). Pattern: typically chronic with superimposed episodic metabolic crises (hypoglycemia, lactic acidosis) triggered by catabolic stress. Progression: variable; developmental delay is persistent, hearing loss is stable-to-progressive. Duration: chronic, lifelong. Critical periods: neonatal/infantile metabolic decompensations are windows of vulnerability; early hearing rehabilitation and metabolic management are opportunities for intervention. No natural-history study exists given the tiny cohort.

9. Inheritance and Population

Inheritance: autosomal recessive (HP:0000007). Epidemiology: ultra-rare — only ~4–5 patients reported worldwide; true prevalence/incidence unknown (well below Orphanet's <1/1,000,000 ultra-rare threshold). Penetrance: presumed complete in biallelic carriers (too few cases to quantify). Expressivity: variable (e.g., microcephaly, autistic features, gallstones in individual cases). Consanguinity: relevant — homozygous cases reported. Founder effects/carrier frequency: none established; variants are private. Anticipation/germline mosaicism: not reported/not applicable. Populations: reported in European and Chinese individuals; no ethnic predilection established. Sex ratio: no established skew (both sexes reported).

10. Diagnostics

Biochemical/laboratory: elevated blood lactate, hypoglycemia, hyperalaninemia, elevated ALT/AST, organic aciduria; enzymatic assay of respiratory-chain complexes in muscle/liver/fibroblasts showing combined (multiple-complex) OXPHOS deficiency. Biopsy: muscle and liver biopsies demonstrate combined OXPHOS enzyme deficiency (Gardeitchik 2018). Genetic testing (definitive): exome or genome sequencing identifying biallelic MRPS2 variants; single-gene testing or mitochondrial/nuclear gene panels covering MRPS2 are alternatives. WES/WGS is the practical route because the phenotype is nonspecific. Functional confirmation (research): complexome profiling of mt-SSU assembly, mitochondrial translation assays, wild-type rescue. Clinical criteria: no disease-specific diagnostic criteria; diagnosis follows general mitochondrial-disease frameworks plus molecular confirmation. Differential diagnosis: other combined OXPHOS deficiencies and mitochondrial translation defects (other MRPS/MRPL genes, aminoacyl-tRNA synthetases such as EARS2/AARS2), MELAS and other mtDNA disorders — distinguished by gene-specific testing. Screening: no newborn screening; cascade carrier testing possible within affected families.

11. Outcome / Prognosis

Prognosis is guarded and variable given the small evidence base. Reported patients survived infancy with chronic disability; outcomes depend on severity of metabolic instability and CNS involvement. Morbidity includes permanent sensorineural hearing loss, developmental delay/intellectual disability, and risk of metabolic decompensation. No survival statistics, life-expectancy data, or validated prognostic biomarkers exist. Lactate and glucose stability, and the degree of neurodevelopmental involvement, are reasonable clinical prognostic indicators. Complications: recurrent hypoglycemia/lactic acidosis, failure to thrive, and (case-specific) gallstones.

12. Treatment

No disease-specific or curative therapy exists. Management is supportive, following primary mitochondrial-disease standards (PMID: 34505344): prevention/treatment of hypoglycemia (avoid fasting, provide carbohydrate support during illness), management of lactic acidosis, nutritional support for failure to thrive, hearing rehabilitation (hearing aids/cochlear implants), developmental/educational support, and physical/occupational therapy. "Mitochondrial cocktail" supplements (e.g., coenzyme Q10, riboflavin, thiamine, L-carnitine) are often used empirically in mitochondrial disease but have no proven efficacy specifically for COXPD36. Pharmacogenomics/gene/cell/RNA/targeted/immunotherapies: none developed for this disease. Experimental trials: no COXPD36-specific clinical trials (NCT) exist. NCIT annotations: supportive care (NCIT:C133421), symptomatic treatment.

13. Prevention

Primary prevention is genetic: genetic counseling for at-risk families, carrier testing of relatives, and reproductive options including prenatal diagnosis or preimplantation genetic testing (PGT-M) once the familial MRPS2 variants are known. Avoidance of consanguineous partnerships reduces recessive-disease risk at the population level. Secondary/tertiary prevention: early recognition and aggressive management of metabolic crises, avoidance of mitochondrial-toxic drugs, and prompt hearing/developmental intervention to limit complications. No vaccine, public-health, or environmental prevention applies.

14. Other Species / Natural Disease

No naturally occurring animal disease equivalent to COXPD36 has been documented (OMIA lists no MRPS2 entry for this phenotype). Orthologs: mouse Mrps2 (NCBI Gene 118451); the uS2 protein family is universally conserved across bacteria, mitochondria, and plastids (InterPro IPR001865/IPR005706), underscoring deep evolutionary conservation of the mitoribosomal small-subunit function. No zoonotic or cross-species transmission is relevant (non-infectious genetic disease).

15. Model Organisms

No published Mrps2 animal model of COXPD36 exists. The disease mechanism has been studied only in patient-derived cultured skin fibroblasts and via in vitro complexome/translation assays with wild-type rescue (PMID: 29576219). A conditional or knock-in mouse (Mrps2, Gene 118451) would be expected to be embryonic-lethal if null (as for other essential mitoribosomal proteins), so a hypomorphic/knock-in strategy modeling patient missense alleles would be required. Yeast and other model systems are informative for general mitoribosome biology but not disease-specific. This is a clear resource gap (see Follow-up).

Evidence Base

PMID	Title (abbrev.)	Role in this report
29576219	Bi-allelic Mutations in MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies (Gardeitchik et al., AJHG 2018)	Foundational. Identifies MRPS2 as causal gene; establishes mechanism (protein destabilization → mt-SSU assembly failure → translation inhibition → combined OXPHOS deficiency) with complexome profiling and wild-type rescue; defines core phenotype.
34991560	Hypoglycemia with lactic acidosis caused by a new MRPS2 gene mutation in a Chinese girl (Liu et al., 2022)	Third patient; novel variant c.412C>G; adds gallstones; confirms core triad (recurrent vomiting, hypoglycemia, lactic acidosis, sensorineural hearing loss).
38029925	New description of an MRPS2 homozygous patient (Papadopoulos et al., 2024)	Expands phenotype with newly reported features: initial microcephaly, joint hypermobility, autistic features.
34505344	Patient care standards for primary mitochondrial disease (Australian adaptation of Mitochondrial Medicine Society recommendations)	Supports the supportive-care management framework in the absence of disease-specific therapy.

Supporting ontology/database evidence (non-PMID): OMIM #617950; MONDO:0054781; HPO annotations for OMIM:617950 (22 terms); UniProt Q9Y399; GO annotations for MRPS2; Pfam PF00318 / InterPro IPR001865; PDB mitoribosome structures (3J9M, 6NU2, 6RW4, 6ZM5); ClinVar variant classifications.

Other papers surfaced during literature searches (e.g., SIRM metabolomics reviews, MELAS case reports, the Friedreich's ataxia NAD⁺/exercise trial) provide contextual background on mitochondrial disease biology and general supportive/experimental approaches but do not address COXPD36 or MRPS2 directly, and are not used to support disease-specific claims.

Mechanistic Model / Interpretation

COXPD36 is best understood as a mitochondrial translation disorder — a subclass of combined OXPHOS deficiencies in which the primary lesion is not in an OXPHOS structural gene but in the machinery that synthesizes OXPHOS subunits. Because the mitoribosome translates all 13 mtDNA-encoded OXPHOS core subunits, a small-subunit assembly defect produces a generalized, multi-complex ("combined") deficiency, distinguishing it from isolated single-complex deficiencies. The tissue distribution of disease (cochlea, brain, liver, muscle) reflects relative bioenergetic dependence: neurons and cochlear hair cells are exquisitely ATP-dependent, and hepatic/muscle metabolism is destabilized during catabolic stress, explaining the episodic hypoglycemia and lactic acidosis.

The evidence chain is unusually clean for an ultra-rare disorder because the founding study coupled human genetics with a functional rescue experiment: identification of biallelic missense variants, demonstration of reduced mutant protein, complexome evidence of mt-SSU assembly failure, and restoration of function by wild-type MRPS2. This satisfies causality criteria (association + mechanism + rescue) and anchors confidence in the gene–disease relationship. The variant spectrum (all missense, all affecting conserved S2-domain residues) is consistent with destabilizing hypomorphic alleles rather than complete nulls — biologically plausible because complete loss of an essential mitoribosomal protein would likely be embryonic-lethal.

Supported and Refuted Hypotheses

No formal hypotheses were tested statistically in this investigation; the work was a structured literature/knowledge-base synthesis. The central mechanistic model — MRPS2 destabilization → mt-SSU assembly failure → mitochondrial translation defect → combined OXPHOS deficiency → clinical triad — is supported by direct experimental evidence including a wild-type rescue experiment (PMID: 29576219). No competing causal model was found in the literature.

Limitations and Knowledge Gaps

Tiny cohort (~4–5 patients): frequencies, penetrance, expressivity, natural history, and prognosis cannot be quantified; HPO frequencies are uncurated.
No animal or cellular disease model beyond patient fibroblasts: limits mechanistic dissection and therapeutic testing.
No omics cohort: no disease-specific transcriptomic, proteomic, or metabolomic signatures; no biomarkers beyond generic mitochondrial markers (lactate, alanine).
No therapeutics pipeline: no trials, no targeted therapy, and no evidence base for the "mitochondrial cocktail" in this specific disorder.
Narrow variant spectrum: only missense variants reported; the pathogenicity landscape (e.g., LoF, structural variants) is uncharacterized.
Genotype–phenotype correlations unknown: drivers of variable features (microcephaly, autism, gallstones) are unexplained.
No formal QoL or disability data.

Proposed Follow-up Experiments / Actions

Establish an international patient registry / GeneMatcher outreach to aggregate additional MRPS2 cases, enabling frequency, penetrance, and natural-history estimates.
Generate a knock-in mouse or zebrafish model carrying a patient missense allele (e.g., p.Arg110Cys) — a conditional/hypomorphic strategy to avoid lethality — to characterize tissue-specific pathology and test interventions.
Deep functional characterization of each reported variant (steady-state protein, mt-SSU assembly, translation rate, OXPHOS assembly) in isogenic cell lines to build a variant-pathogenicity map for clinical interpretation.
Multi-omics profiling (transcriptomics, proteomics, metabolomics) of patient fibroblasts and iPSC-derived neurons/hepatocytes to identify candidate biomarkers and therapeutic targets.
iPSC-derived cochlear organoids and cortical neurons to model the two most disabling phenotypes (hearing loss, developmental delay) and screen candidate compounds.
Systematic evaluation of "mitochondrial cocktail" components and NAD⁺ precursors in patient-derived models before any empiric clinical use.
Standardized clinical data collection (audiology, developmental assessment, metabolic-crisis frequency, QoL instruments) to define prognostic factors.

Consensus Answer

Combined Oxidative Phosphorylation Deficiency 36 (COXPD36; MONDO:0054781, OMIM #617950) is an ultra-rare autosomal-recessive mitochondrial disease caused by biallelic missense mutations in MRPS2, which encodes uS2m, a structural protein of the small (28S) subunit of the mitoribosome; the mutations destabilize MRPS2 and block small-subunit assembly, impairing mitochondrial translation and causing a combined deficiency of multiple OXPHOS complexes. It presents in infancy with a characteristic triad of sensorineural hearing loss, hypoglycemia, and lactic acidemia, alongside variable developmental delay and hepatic/muscular involvement; only ~4–5 patients have been reported worldwide, and management is supportive with no disease-specific therapy.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	4
Resolved	4
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	1
Quoted claims found in source	1
Quoted claims not found in source	0
References weighed for topical relevance	4
On topic	3
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	44
Resolved	41
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	3
Terms whose name was checked	28
Terms named correctly	24
Terms named as a different term	0
Terms whose name is worth a second look	4

Terms whose name is worth a second look

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

HP:0002151 (2 mentions) - the report calls it "Increased circulating lactate"; HP calls it Increased circulating lactate concentration
HP:0031964 (2 mentions) - the report calls it "Elevated ALT"; HP calls it Elevated circulating alanine aminotransferase concentration, and lists "Elevated serum ALT" among its other names
HP:0031956 (2 mentions) - the report calls it "Elevated AST"; HP calls it Elevated circulating aspartate aminotransferase concentration, and lists "Elevated serum AST" among its other names
HP:0000007 (2 mentions) - the report calls it "Autosomal recessive"; HP calls it Autosomal recessive inheritance, and lists "Autosomal recessive" among its other names

Prefixes with no resolver

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

41 of 44 terms resolved to a current term; the rest could not be looked up either way.

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Combined Oxidative Phosphorylation Deficiency 36 (COXPD36): Comprehensive Disease Characterization Report

Summary

Key Findings

Finding 1 — COXPD36 is caused by biallelic (autosomal recessive) mutations in MRPS2

Finding 2 — Mechanism: MRPS2 mutations destabilize the protein, block small-subunit assembly, and impair mitochondrial translation

Finding 3 — Core clinical phenotype: sensorineural hearing loss, hypoglycemia, lactic acidemia, developmental delay

Finding 4 — MRPS2 is a 28S small-subunit mitoribosomal protein; disease localizes to high-OXPHOS-demand tissues

Finding 5 — MRPS2 protein (uS2m, UniProt Q9Y399) is a conserved structural component of the 28S mt-SSU resolved in cryo-EM mitoribosome structures

Finding 6 — Authoritative HPO annotation set defines the curated phenotype spectrum

Finding 7 — Integrated mutation-to-phenotype model with full ontology annotations

Section-by-Section Characterization

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Evidence Base

Mechanistic Model / Interpretation

Supported and Refuted Hypotheses

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Consensus Answer

Artifacts

Reference Validation

Term Validation

Terms whose name is worth a second look

Prefixes with no resolver