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Classifications

ICIMD (Inherited Metabolic Disorders)

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Subtypes

3

Vitamin B12-responsive methylmalonic acidemia

MMUT hgnc:7526 MMAA hgnc:18871 MMAB hgnc:19331 MMADHC hgnc:25221

Partial biochemical response to hydroxocobalamin in cblA, cblB, and some mut- genetic forms. Associated with generally better prognosis.

Show evidence (4 references)

PMID:20301409 SUPPORT Human Clinical

"Isolated MMA is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut– enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, 5-deoxy-adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the..."

GeneReviews names the genotype groups of isolated MMA, including cblD-MMA among the adenosylcobalamin cofactor defects, which is the set this row's gene list is drawn from.

CGGV:assertion_52b61ff5-afba-4ff7-adbc-51de6a837db7-2022-07-13T160000.000Z SUPPORT Other

"While patients with MMA due to variants in MMAA (type CblA) are responsive to Vitamin B12, only rare individuals with type CblB are responsive to treatment with Vitamin B12"

ClinGen contrasts cblA responsiveness with the rarity of cblB responsiveness, supporting MMAA as the core responsive genotype and MMAB as a rare one.

PMID:25205257 SUPPORT Human Clinical

"Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine."

Directly supports existence of vitamin B12-responsive MMA forms with better outcomes.

+ 1 more reference

Vitamin B12-unresponsive methylmalonic acidemia

MMUT hgnc:7526 MMAB hgnc:19331

Severe mut0/mut- forms without meaningful cobalamin response. Associated with higher mortality and worse long-term outcomes.

Show evidence (2 references)

PMID:20301409 SUPPORT Human Clinical

"Infantile/non-B12-responsive form (mut0 enzymatic subtype, cblB), the most common phenotype"

GeneReviews assigns the non-B12-responsive infantile phenotype to the mut0 and cblB genotypes, which is what this row's gene list records.

PMID:25205257 SUPPORT Human Clinical

"Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine."

Supports that non-responsive MMA forms have poorer outcomes.

Transcobalamin receptor (CD320) defect MONDO:0013341

CD320 hgnc:16692 Autosomal recessive inheritance

Biallelic CD320 loss of function, most commonly homozygosity for the in-frame p.Glu88del deletion, restricts cellular uptake of cobalamin-loaded transcobalamin and raises propionylcarnitine (C3) and methylmalonic acid enough to produce a positive newborn screen for propionic/methylmalonic aciduria. It is set apart from the mutase and cofactor forms by its course rather than by its biochemistry. The elevations correct on oral cobalamin, and ClinGen records that p.Glu88del homozygotes have typically had no major health or developmental concerns and that the condition is probably benign, while still grading the gene-disease relationship Definitive; one consanguineous case with bilateral retinal artery occlusions at seven weeks is the reported exception. It is kept as a subtype row here, and not promoted to its own entry, because GeneReviews does not count CD320 among the genes whose biallelic variants establish a diagnosis of isolated MMA and the mechanism is fully captured by the cobalamin-uptake node in this entry.

Show evidence (2 references)

CGGV:assertion_d98515f5-4296-4d41-95a9-adac90c00349-2022-09-23T160000.000Z SUPPORT Other

ClinGen classifies the CD320 gene-disease relationship as definitive with autosomal recessive inheritance, against the MONDO term bound here.

PMID:29663633 SUPPORT Human Clinical

"To date, both patients remain asymptomatic with normal neurodevelopment more than 6 years."

The long-term outcome on which this row's description of a benign course rests.

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Pathophysiology

10

MMUT/AdoCbl pathway molecular function deficiency

Pathogenic variants affecting MMUT and adenosylcobalamin-handling genes reduce catalytic conversion capacity for methylmalonyl-CoA utilization. MMUT encodes the mutase apoenzyme itself; MMAA (cblA) and MMAB (cblB) supply and deliver its adenosylcobalamin cofactor, and MMADHC (cblD) sits at the branch point of intracellular cobalamin trafficking that partitions cobalamin between mitochondrial adenosylcobalamin and cytosolic methylcobalamin, so cblD variants that impair the mitochondrial arm present as isolated methylmalonic aciduria.

hepatocyte CL:0000182

MMUT hgnc:7526 MMAA hgnc:18871 MMAB hgnc:19331 MMADHC hgnc:25221

methylmalonyl-CoA mutase activity GO:0004494 ↓ DECREASED

mitochondrion GO:0005739

Downstream

Impaired methylmalonyl-CoA metabolism Defective MMUT/AdoCbl function blocks conversion of methylmalonyl-CoA to succinyl-CoA.

Show evidence (3 references)

PMID:25205257 SUPPORT Human Clinical

"Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC)."

Supports proximal enzyme/cofactor molecular defects as the initiating mechanism in MMA.

CGGV:assertion_40ec59af-a143-4424-9218-7fd75deb6a61-2021-05-12T182739.747Z SUPPORT Other

"MMADHC is involved in the intracellular conversion of cobalamin to its two coenzymes, adenosylcobalamin (AdoCbl) in mitochondria and methylcobalamin (MeCbl) in the cytoplasm"

Places MMADHC at this node, on the adenosylcobalamin arm of intracellular cobalamin handling alongside MMAA and MMAB.

PMID:20301409 SUPPORT Human Clinical

"The diagnosis of isolated MMA is established in a proband by identification of biallelic pathogenic variants in MCEE, MMAA, MMAB, MMADHC, or MMUT"

The GeneReviews baseline names all five genes whose biallelic variants establish a diagnosis of isolated MMA.

Methylmalonyl-CoA epimerase deficiency

A separate enzymatic step from the mutase and its cofactor. MCEE interconverts D- and L-methylmalonyl-CoA, the racemization that must happen before methylmalonyl-CoA mutase can act, so biallelic MCEE loss of function blocks the propionyl-CoA to succinyl-CoA route one step earlier than MMUT does and produces methylmalonic aciduria. The clinical consequence is variable, from no symptoms to severe metabolic acidosis, and ClinGen notes that the range of reported phenotypes leaves causation of anything beyond the methylmalonic aciduria itself uncertain.

MCEE hgnc:16732

methylmalonyl-CoA epimerase activity GO:0004493 ↓ DECREASED

Downstream

Impaired methylmalonyl-CoA metabolism Loss of epimerase activity starves the mutase of its L-methylmalonyl-CoA substrate, blocking the same propionyl-CoA to succinyl-CoA conversion.

Show evidence (3 references)

PMID:30682498 SUPPORT Human Clinical

"We investigated a cohort of 150 individuals suffering from MMAuria of unknown origin, identifying ten new patients with pathogenic variations in MCEE."

A cohort screen attributing methylmalonic aciduria of previously unknown cause to biallelic MCEE variants in ten further patients.

PMID:30682498 SUPPORT BACKGROUND Other

"Human methylmalonyl-CoA epimerase (MCEE) catalyzes the interconversion of d-methylmalonyl-CoA and l-methylmalonyl-CoA in propionate catabolism."

States the reaction this node places at the racemization step, upstream of the mutase.

CGGV:assertion_b8546531-fe3d-48fd-8103-f5f84fd04514-2020-07-09T160000.000Z SUPPORT Other

"The mechanism for disease is biallelic loss of function, with defective protein activity causing a blockage in the propionyl-CoA to succinyl-CoA pathway in human cells and a resulting buildup of methylmalonic acid."

ClinGen states the loss-of-function mechanism and the pathway block this node models.

Impaired cellular cobalamin uptake

The most upstream step modeled here, and the mildest. CD320 encodes the transcobalamin receptor, which takes cobalamin-loaded transcobalamin into the cell; biallelic loss of function therefore limits the cobalamin available for both coenzymes, and the mitochondrial arm shows up as elevated propionylcarnitine on the newborn screen and elevated methylmalonic acid on its workup. Unlike the mutase and cofactor defects the biochemical abnormality is correctable with oral cobalamin and the reported homozygotes have typically had no major health or developmental concerns, so this node is modeled as a cobalamin-availability constraint on the mutase step rather than as a route to the decompensation and organ injury nodes.

CD320 hgnc:16692

cobalamin transport GO:0015889 ↓ DECREASED

Downstream

MMUT/AdoCbl pathway molecular function deficiency Restricted cobalamin entry reduces the adenosylcobalamin available to methylmalonyl-CoA mutase, inhibiting the mutase step.

Show evidence (2 references)

CGGV:assertion_d98515f5-4296-4d41-95a9-adac90c00349-2022-09-23T160000.000Z SUPPORT Other

"CD320 encodes the transcobalamin receptor, which mediates the cellular uptake of vitamin B12 (cobalamin, Cbl)."

States the transport function whose loss this node models.

PMID:32898552 SUPPORT BACKGROUND Other

"Cellular uptake of vitamin B12 (cobalamin, Cbl) is mediated by a cell surface receptor (TCblR/CD320) that binds transcobalamin (TC) saturated with Cbl."

Independent statement that CD320 is the receptor for cellular uptake of transcobalamin-bound cobalamin.

Impaired methylmalonyl-CoA metabolism

Defects in methylmalonyl-CoA mutase or cobalamin-dependent cofactor pathways block conversion of methylmalonyl-CoA to succinyl-CoA, disrupting mitochondrial anaplerosis and the TCA cycle.

methylmalonyl-CoA metabolic process GO:0046491 ↓ DECREASED propionate catabolic process GO:0019543 ↓ DECREASED tricarboxylic acid cycle GO:0006099 ↓ DECREASED

Downstream

Methylmalonic acid Blocked methylmalonyl-CoA mutase activity causes methylmalonic acid accumulation.

Propionylcarnitine (C3) Propionate-pathway flux produces elevated plasma propionylcarnitine during MMA diagnosis and monitoring.

2-Methylcitric acid Propionyl-CoA overflow generates methylcitric acid, a disease-specific organic acid marker.

3-Hydroxypropionate Propionyl-CoA is diverted through beta-oxidation to urinary 3-hydroxypropionate.

Acute organic acid decompensation Accumulating organic acids and anaplerotic failure create episodic metabolic crises under catabolic stress.

Mitochondrial energy metabolism dysfunction Accumulated metabolites and reduced succinyl-CoA input impair the TCA cycle and oxidative phosphorylation.

Aberrant mitochondrial protein methylmalonylation Enlarged methylmalonyl-CoA and related acyl-CoA pools drive mitochondrial protein hyperacylation.

Lysosomal-autophagy system dysfunction MUT deficiency perturbs lysosomal and autophagy regulation in cellular MMA models.

Pancreatitis Pancreatitis is a reported complication of MMA and other branched-chain organic acidemias; the intervening mechanism is not resolved in the cited evidence.

Reduced bone mineral density Low bone density is a chronic complication in MMA/PA, but the intervening mechanism is incompletely defined.

Osteoporosis Osteoporosis is a chronic skeletal complication in MMA/PA, with unresolved causal intermediates.

Show evidence (2 references)

PMID:25205257 SUPPORT Human Clinical

"Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC)."

Supports blocked methylmalonyl-CoA handling and downstream metabolite accumulation.

PMID:38030482 SUPPORT Other

"MMA is normally present at low levels in the body, but increased levels can come from different sources, such as vitamin B12 deficiency, genetic mutations in enzymes related to the propionate pathway"

Opinion/review source providing supportive context for propionate-pathway genetic etiologies.

Acute organic acid decompensation

Catabolic stress in MMA precipitates acute metabolic decompensation with organic acid and ketoacid accumulation, metabolic acidosis, secondary hyperammonemia, vomiting, feeding intolerance, and altered mental status.

Downstream

Metabolic acidosis Organic acid and ketoacid accumulation during decompensation produces high-anion-gap metabolic acidosis.

Hyperammonemia Propionyl-CoA and methylmalonyl-CoA interfere with urea-cycle activation, causing secondary hyperammonemia.

Ammonia Urea-cycle inhibition raises circulating ammonia during decompensation.

Vomiting Acute decompensation commonly presents with nausea and vomiting.

Lethargy Decompensation produces altered mental status and lethargy.

Show evidence (2 references)

PMID:27653704 SUPPORT Other

"With intercurrent illness, PA and MMA patients typically present with nausea and vomiting, worsening anorexia, and encephalopathy, with laboratory studies demonstrating metabolic acidosis, ketonuria, hyperammonemia, pancytopenia, and electrolyte disturbances"

Review text summarizes the clinical and biochemical acute decompensation pattern.

PMID:27653704 SUPPORT Other

"Accumulation of propionyl-CoA, and to some extent methylmalonyl-CoA, results in secondary inhibition of N-acetylglutamate synthase (NAGS), causing secondary hyperammonemia in these patients"

Review text provides the urea-cycle mechanism for secondary hyperammonemia.

Mitochondrial energy metabolism dysfunction

Accumulating primary and secondary organic acid metabolites plus deficient succinyl-CoA input disrupt the TCA cycle, oxidative phosphorylation, and fatty-acid-derived energy generation, creating energetic vulnerability in high-demand organs.

mitochondrial electron transport, NADH to ubiquinone GO:0006120 ↓ DECREASED oxidative phosphorylation GO:0006119 ↓ DECREASED

mitochondrial inner membrane GO:0005743

Downstream

Neurometabolic brain injury Mitochondrial energy failure and metabolite toxicity injure the high-energy CNS compartment.

Poor growth Chronic metabolic energy stress and dietary fragility contribute to poor growth.

Dilated cardiomyopathy Cardiac energy vulnerability and organic-acidemia complications contribute to dilated cardiomyopathy in a subset of MMA patients.

Prolonged QT interval Organic-acidemia cardiac involvement can include acquired long QT syndrome.

Optic neuropathy High-energy ocular tissue vulnerability contributes to optic neuropathy and vision loss in classical MMA.

GDF15 Circulating GDF15 is used as a mitochondrial dysfunction biomarker in isolated MMA.

Show evidence (2 references)

PMID:27653704 SUPPORT Other

"End-organ injury occurs due to both primary toxicity of both the accumulating primary and secondary metabolites and deficiency of succinyl-CoA resulting in Kreb cycle and oxidative phosphorylation dysfunction."

Review text directly supports metabolite-driven TCA cycle and oxidative phosphorylation dysfunction.

PMID:37169781 SUPPORT In Vitro

"Changes in tricarboxylic acid cycle metabolites and impaired energy generation from fatty acid oxidation were detected."

Renal epithelial cell model supports impaired mitochondrial energy metabolism under MMA stress.

Neurometabolic brain injury

Accumulated methylmalonic acid and related metabolites, secondary mitochondrial energy failure, and acute metabolic crises injure brain tissue, particularly basal ganglia circuits, producing developmental delay, cognitive impairment, epilepsy, and metabolic stroke-like injury.

brain UBERON:0000955

Downstream

Global developmental delay Neurometabolic injury slows developmental trajectory in children with isolated MMA.

Intellectual disability Brain tissue damage and neuropsychological deficits manifest as cognitive impairment.

Seizures Chronic brain injury and acute metabolic crises can manifest as epilepsy or seizures.

Basal ganglia injury MMA-associated metabolic brain injury targets basal ganglia regions and can present as metabolic stroke.

Movement disorder Metabolic brain injury and metabolic stroke sequelae can manifest as movement disorders.

Spasticity Metabolic stroke sequelae can include spastic quadri- or paraparesis.

Show evidence (2 references)

PMID:27653704 SUPPORT Other

"Patients with organic acidopathies suffer metabolic brain injury that targets specific regions of the basal ganglia in a distinctive pattern"

Review text supports basal ganglia-targeted metabolic brain injury in organic acidopathies.

PMID:36777632 SUPPORT Other

"The accumulation of methylmalonic acid and other metabolites in the body of patients causes brain tissue damage, which can manifest as various degrees of intellectual disability and severe neurological dysfunction."

Neuroimaging review connects metabolite accumulation to brain tissue damage and neurological dysfunction.

Aberrant mitochondrial protein methylmalonylation

Excess methylmalonyl-CoA, propionyl-CoA, and malonyl-CoA drive widespread lysine hyperacylation of mitochondrial proteins across TCA cycle, beta-oxidation, amino acid metabolism, urea cycle, and oxidative stress pathways. Reduced levels of mitochondrial sirtuins SIRT3/4/5, particularly SIRT5 which can remove methylmalonylation, amplify dysfunction.

protein acylation GO:0043543 ↑ INCREASED

mitochondrial matrix GO:0005759

Downstream

Lipodystrophy Abnormal adipose methylmalonylation and acyl-CoA accretion are associated with the MMA lipodystrophy phenotype.

FGF21 FGF21 tracks mitochondrial/adipose stress associated with acyl-CoA accretion and methylmalonylation.

Show evidence (1 reference)

PMID:37078237 SUPPORT Other

"new observations have revealed that aberrant acylation, specifically methylmalonylation, is a characteristic feature of MMA. The mitochondrial sirtuin enzyme SIRT5 is capable of recognizing and removing this PTM, however, reduced protein levels of SIRT5 along with other mitochondrial SIRTs 3 and 4 in MMA"

Directly supports hyperacylation/methylmalonylation and reduced sirtuin deacylation as key pathomechanism.

Lysosomal-autophagy system dysfunction

MUT deficiency directly perturbs the lysosome-autophagy system, causing enlarged lysosomes with reduced acidity and degradative capacity, impaired autophagosome-lysosome fusion, and severely reduced autophagic flux. These defects are pharmacologically reversible with anti-propionigenic compounds.

autophagy GO:0006914 ↓ DECREASED lysosome organization GO:0007040 ⚠ ABNORMAL

lysosome GO:0005764

Downstream

Renal mitochondrial stress and impaired mitophagy Lysosomal-autophagy failure impairs clearance of damaged mitochondria and contributes to renal mitochondrial stress.

Show evidence (1 reference)

PMID:38760822 SUPPORT In Vitro

"Lysosomes of MMA cells present as enlarged vacuoles with low degradative capabilities. Notwithstanding, treatment with an anti-propionigenic drug is capable of totally rescuing lysosomal morphology and functional activity in MUT-deficient cells."

Demonstrates lysosomal-autophagy dysfunction and pharmacological reversibility in MMA cellular models.

Renal mitochondrial stress and impaired mitophagy

In renal epithelial cells from MMA patients, metabolic stressors cause impaired mitophagy (reduced PINK1), shifted mitochondrial dynamics toward fission (elevated DRP1, reduced OPA1), compromised antioxidant defenses, and lowered glutathione ratios, contributing to progressive chronic kidney disease.

epithelial cell of proximal tubule CL:0002306

mitophagy GO:0000422 ↓ DECREASED mitochondrial fission GO:0000266 ↑ INCREASED antioxidant defence capacity GO:0098869 ↓ DECREASED

kidney UBERON:0002113

Downstream

Chronic kidney disease Renal epithelial mitochondrial stress and impaired mitophagy contribute to progressive CKD in MMA.

Lipocalin-2 (LCN2) Renal injury from MMA is tracked by LCN2 as a circulating kidney injury biomarker.

Show evidence (2 references)

PMID:37169781 SUPPORT In Vitro

"Mitophagy was disabled in MMA-uria cells, while autophagy was highly active particularly under HP and I/V conditions. Mitochondrial dynamics were shifted towards fission."

Directly demonstrates impaired mitophagy and fission shift in renal MMA cells.

PMID:37169781 SUPPORT In Vitro

"Creatinine levels were increased and antioxidant stress defense was severely comprised in MMA-uria cells."

Supports compromised antioxidant defense in renal MMA cells.

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Pathograph

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

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Phenotypes

19

Cardiovascular 2

Dilated cardiomyopathy HP:0001644

Show evidence (2 references)

PMID:38132258 SUPPORT Human Clinical

"Cardiac anomalies were found in 23/60 OA patients, all with PA or MMA, represented by DCM (17/23 patients)"

Quantifies DCM as the predominant cardiac phenotype in OA patients including MMA.

PMID:38132258 SUPPORT Human Clinical

"35% in MMA with cardiomyopathy"

Quantifies 5-year MACE rate in MMA patients with cardiomyopathy.

Prolonged QT interval HP:0001657

Show evidence (1 reference)

PMID:38132258 SUPPORT Human Clinical

"Cardiac anomalies were found in 23/60 OA patients, all with PA or MMA, represented by DCM (17/23 patients) and/or acquired long QT syndrome (3/23 patients)."

Directly reports acquired long QT syndrome in OA patients including MMA.

Digestive 2

Vomiting HP:0002013

Show evidence (1 reference)

PMID:27653704 SUPPORT Other

"With intercurrent illness, PA and MMA patients typically present with nausea and vomiting, worsening anorexia, and encephalopathy"

Review text directly supports vomiting during acute decompensation.

Pancreatitis HP:0001733

Show evidence (2 references)

PMID:8301430 SUPPORT Human Clinical

"Five had methylmalonic acidemia, three had isovaleric acidemia, and one had maple syrup urine disease."

Case series directly reports pancreatitis in patients with methylmalonic acidemia.

PMID:8301430 SUPPORT Human Clinical

"Acute or chronic pancreatitis may complicate branched-chain organic acidemias and must be considered in the assessment of patients with these disorders who have acute clinical deterioration and vomiting, abdominal pain, encephalopathy or shock, or milder symptoms."

Case-series conclusion supports pancreatitis as an organic-acidemia complication.

Eye 1

Optic neuropathy HP:0001138

Show evidence (2 references)

PMID:31269850 SUPPORT Human Clinical

"Eleven (52.4%) patients had optic neuropathy."

Classical MMA cohort directly supports optic neuropathy.

PMID:27653704 SUPPORT Other

"not entirely prevent brain injury or the development of optic neuropathy and cardiac disease"

Management review supports optic neuropathy as an MMA/PA end-organ complication.

Genitourinary 1

Chronic kidney disease HP:0012622

Show evidence (2 references)

PMID:37243446 SUPPORT Human Clinical

"It is characterized by life-threatening episodes of ketoacidosis, chronic kidney disease, and other multiorgan complications."

Directly identifies CKD as a characteristic complication of MMA.

PMID:37169781 SUPPORT In Vitro

"Chronic kidney disease (CKD) is a well-known long-term complication."

Confirms CKD as an established long-term complication.

Metabolism 2

Metabolic acidosis HP:0001942

Show evidence (1 reference)

PMID:25205257 SUPPORT Human Clinical

"Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia"

Directly supports metabolic acidosis as a presenting feature.

Hyperammonemia HP:0001987

Show evidence (2 references)

PMID:25205257 SUPPORT Human Clinical

"Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia"

Directly supports hyperammonemia during decompensation.

PMID:27653704 SUPPORT Other

"Accumulation of propionyl-CoA, and to some extent methylmalonyl-CoA, results in secondary inhibition of N-acetylglutamate synthase (NAGS), causing secondary hyperammonemia in these patients"

Review text supports the biochemical mechanism for secondary hyperammonemia.

Musculoskeletal 4

Spasticity HP:0001257

Show evidence (2 references)

PMID:27653704 SUPPORT Other

"Chronic complications include poor growth, movement disorders, progressive spastic quadraparesis, epilepsy, cardiac dysfunction (PA>MMA), progressive renal disease (MMA), osteopenia/osteoporosis, vision loss (MMA>PA), and functional immunodeficiency"

Review text lists progressive spastic quadriparesis among chronic organic-acidemia complications.

PMID:27653704 SUPPORT Other

"Movement disorders or spastic quadra- or paraparesis, potential sequelae of metabolic strokes, should be managed in collaboration with a neurologist and/or physiatrist"

Review text supports spastic paresis as a potential metabolic-stroke sequela.

Reduced bone mineral density HP:0004349

Show evidence (2 references)

PMID:27653704 SUPPORT Other

"Although the specific mechanisms associated with bone health in OAs remain incompletely investigated, patients with PA and MMA are at significantly increased risk for osteopenia or osteoporosis that their age-matched peers, with and without renal disease"

Review text supports increased risk for osteopenia/reduced bone density in MMA/PA.

PMID:27653704 SUPPORT Other

"Various pathologies including vertebral fusion anomalies, vertebral compression and fractures, as well as generalized osteopenia, have been observed."

Review text reports generalized osteopenia among observed skeletal pathologies.

Osteoporosis HP:0000939

Show evidence (2 references)

PMID:27653704 SUPPORT Other

"Although the specific mechanisms associated with bone health in OAs remain incompletely investigated, patients with PA and MMA are at significantly increased risk for osteopenia or osteoporosis that their age-matched peers, with and without renal disease"

Review text directly supports osteoporosis risk in MMA/PA.

PMID:27653704 SUPPORT Other

"If pathological fractures or significant osteopenia/osteoporosis are detected on screening, more robust monitoring for bone density and response to interventions are indicated."

Review text supports osteoporosis surveillance and management as part of MMA/PA care.

Lipodystrophy HP:0009125

Show evidence (1 reference)

PMID:38271099 SUPPORT Human Clinical

"A distinct adipose tissue distribution pattern was observed in patients with methylmalonyl-CoA mutase deficiency, an inborn error of branched-chain amino acid (BCAA) metabolism, characterized by centripetal obesity with proximal upper and lower extremity fat deposition and paucity of visceral fat"

Directly identifies a novel lipodystrophy phenotype in MMA patients.

Nervous System 6

Lethargy HP:0001254

Show evidence (1 reference)

PMID:27653704 SUPPORT Other

"These decompensation events typically present with decreased oral intake or enteral feeding intolerance, vomiting, and altered mental status or lethargy."

Review text directly supports lethargy during decompensation.

Global developmental delay HP:0001263

Show evidence (2 references)

PMID:35348993 SUPPORT Human Clinical

"Children with this disorder still are at risk for developmental delay, cognitive difficulties and progressive declines in functioning."

Directly supports developmental delay risk in MMA.

PMID:35348993 SUPPORT Human Clinical

"Mean IQ for all types apart from cblA defect enzymatic subtype is rarely above 85"

Quantifies intellectual impairment severity by MMA subtype.

Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:35348993 SUPPORT Human Clinical

"Children with this disorder still are at risk for developmental delay, cognitive difficulties and progressive declines in functioning."

Supports cognitive difficulties as a key feature of MMA.

Seizures HP:0001250

Show evidence (1 reference)

PMID:27653704 SUPPORT Other

"Chronic complications include poor growth, movement disorders, progressive spastic quadraparesis, epilepsy, cardiac dysfunction (PA>MMA), progressive renal disease (MMA), osteopenia/osteoporosis, vision loss (MMA>PA), and functional immunodeficiency"

Review text lists epilepsy among chronic organic-acidemia complications; this supports seizure involvement.

Basal ganglia injury Abnormal basal ganglia morphology HP:0002134

Show evidence (1 reference)

PMID:27653704 SUPPORT Other

"Patients with organic acidopathies suffer metabolic brain injury that targets specific regions of the basal ganglia in a distinctive pattern"

Review text directly supports basal ganglia-targeted metabolic brain injury.

Movement disorder Abnormality of movement HP:0100022

Show evidence (2 references)

PMID:27653704 SUPPORT Other

"Chronic complications include poor growth, movement disorders, progressive spastic quadraparesis, epilepsy, cardiac dysfunction (PA>MMA), progressive renal disease (MMA), osteopenia/osteoporosis, vision loss (MMA>PA), and functional immunodeficiency"

Review text lists movement disorders among chronic organic-acidemia complications.

PMID:27653704 SUPPORT Other

"Movement disorders or spastic quadra- or paraparesis, potential sequelae of metabolic strokes, should be managed in collaboration with a neurologist and/or physiatrist"

Review text supports movement disorders as potential metabolic-stroke sequelae.

Growth 1

Poor growth Growth delay HP:0001510

Show evidence (1 reference)

PMID:27653704 SUPPORT Other

"Chronic complications include poor growth, movement disorders, progressive spastic quadraparesis, epilepsy, cardiac dysfunction (PA>MMA), progressive renal disease (MMA), osteopenia/osteoporosis, vision loss (MMA>PA), and functional immunodeficiency"

Review text directly supports chronic poor growth in MMA/PA.

🧬

Genetic Associations

6

MMUT (methylmalonyl-CoA mutase)

Gene: MMUT hgnc:7526 relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (1 reference)

CGGV:assertion_3c5301da-0dad-417a-8257-5b1c6155e8fa-2019-05-09T160000.000Z SUPPORT Other

ClinGen classifies the MMUT gene-disease relationship as definitive with autosomal recessive inheritance.

Variants (2)

mut0 (complete deficiency)

Complete loss of methylmalonyl-CoA mutase activity. Non-B12 responsive. Associated with the most severe phenotype and worst neuropsychological outcomes.

mut- (partial deficiency)

Partial residual methylmalonyl-CoA mutase activity. Some forms show partial response to hydroxocobalamin.

MMAA (cblA complementation group)

Gene: MMAA hgnc:18871 gene page relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (2 references)

PMID:35348993 SUPPORT Human Clinical

"These other disorders include enzymatic subtypes related to cobalamin A defect (cblA) (OMIM #25,110), cobalamin B defect (cblB) (OMIM #251,110) and related conditions."

Identifies cblA as a defined enzymatic subtype of MMA.

CGGV:assertion_5b81bb9e-5f71-47bf-b187-5eef83d91d57-2022-07-13T160000.000Z SUPPORT Other

ClinGen classifies the MMAA gene-disease relationship as definitive with autosomal recessive inheritance.

MMAB (cblB complementation group)

Gene: MMAB hgnc:19331 gene page relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (3 references)

PMID:37243446 SUPPORT Human Clinical

"Data are presented from a US natural history protocol that evaluated subjects with different types of MMA including mut-type (N = 91), cblB-type (15), and cblA-type MMA (17)"

Identifies cblB as a defined subtype with distinct severity profile.

CGGV:assertion_52b61ff5-afba-4ff7-adbc-51de6a837db7-2022-07-13T160000.000Z SUPPORT Other

ClinGen classifies the MMAB gene-disease relationship as definitive with autosomal recessive inheritance.

CGGV:assertion_52b61ff5-afba-4ff7-adbc-51de6a837db7-2022-07-13T160000.000Z SUPPORT Other

"While patients with MMA due to variants in MMAA (type CblA) are responsive to Vitamin B12, only rare individuals with type CblB are responsive to treatment with Vitamin B12"

Supports assigning cblB predominantly to the vitamin B12-unresponsive subtype and cblA to the responsive one.

MMADHC (cblD complementation group)

Gene: MMADHC hgnc:25221 gene page relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (4 references)

PMID:18385497 SUPPORT In Vitro

"The cblD gene was localized to human chromosome 2q23.2, and a candidate gene, designated MMADHC (methylmalonic aciduria, cblD type, and homocystinuria), was identified in this region."

The identification of MMADHC as the cblD gene, by mapping plus rescue of the cellular phenotype in patient fibroblasts.

PMID:18385497 SUPPORT Human Clinical

"One of these defects, the cblD defect, can cause isolated methylmalonic aciduria, isolated homocystinuria, or both."

Establishes that isolated methylmalonic aciduria is one of the three cblD presentations, which is the one this entry covers.

PMID:22156578 SUPPORT In Vitro

"Expression of 10 mutant alleles from 15 cblD patients confirmed that the nature and location of the mutations correlate with the biochemical phenotype."

Transfection of patient alleles into cblD fibroblasts shows the variant's position determines whether the MMA-only, HC-only or combined phenotype results.

+ 1 more reference

MCEE (methylmalonyl-CoA epimerase)

Gene: MCEE hgnc:16732 gene page relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (2 references)

PMID:20301409 SUPPORT Human Clinical

"The diagnosis of isolated MMA is established in a proband by identification of biallelic pathogenic variants in MCEE, MMAA, MMAB, MMADHC, or MMUT"

GeneReviews counts MCEE among the five genes whose biallelic variants establish a diagnosis of isolated MMA.

CGGV:assertion_b8546531-fe3d-48fd-8103-f5f84fd04514-2020-07-09T160000.000Z SUPPORT Other

ClinGen classifies the MCEE gene-disease relationship as definitive with autosomal recessive inheritance.

CD320 (transcobalamin receptor defect)

Gene: CD320 hgnc:16692 relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (4 references)

CGGV:assertion_d98515f5-4296-4d41-95a9-adac90c00349-2022-09-23T160000.000Z SUPPORT Other

"Data indicates that about 85% of these individuals may not be identified, and that the condition is probably benign, although further studies are needed to assess any longterm health effects"

ClinGen's own caveat that the transcobalamin receptor defect is probably a benign biochemical phenotype, which is why it is kept distinct from the mutase and cofactor forms.

PMID:29663633 SUPPORT Human Clinical

"Two asymptomatic cases were identified through a positive newborn screening for propionic/methylmalonic aciduria."

The route by which this form presents, and the basis for treating it as a newborn-screening differential rather than a clinical organic acidemia.

PMID:29663633 SUPPORT Human Clinical

"To date, both patients remain asymptomatic with normal neurodevelopment more than 6 years."

Long-term follow-up supporting the benign course recorded in this entry's description of the subtype.

+ 1 more reference

💊

Medical Actions

7

Protein-restricted diet

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

Platform: Behavioral / lifestyle

Dietary restriction of propiogenic amino acids (valine, isoleucine, threonine, methionine) with specialized metabolic formula support is the cornerstone of chronic MMA management.

Show evidence (1 reference)

PMID:25205257 SUPPORT Human Clinical

"Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine."

Directly supports low-protein dietary therapy for MMA management.

Hydroxocobalamin therapy

Action: Pharmacotherapy NCIT:C15986

Agent: hydroxocobalamin CHEBI:27786

Pharmacologic hydroxocobalamin supplementation for genotypes with demonstrated B12 responsiveness, particularly cblA and some cblB and mut- forms. B12 responsiveness is a key prognostic factor.

Show evidence (2 references)

PMID:25205257 SUPPORT Human Clinical

"Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine."

Supports genotype-dependent cobalamin responsiveness in MMA management.

PMID:39075538 SUPPORT Human Clinical

"NBS-detected patients showed younger age at diagnosis, less incidence of disease onset, better responsiveness of vitamin B12"

B12 responsiveness identified as a key factor in NBS-detected MMA outcomes.

Carnitine supplementation

Action: carnitine supplementation Ontology label: Nutritional Support NCIT:C15433

L-carnitine supplementation to support organic acid detoxification and excretion via propionylcarnitine formation, and to prevent secondary carnitine deficiency.

Show evidence (1 reference)

PMID:25205257 SUPPORT Human Clinical

"Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine."

Directly supports carnitine supplementation in MMA management.

Acute decompensation management

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

Emergency supportive care during metabolic crisis, including high glucose infusion to reverse catabolism, complete cessation of protein intake, correction of metabolic acidosis with bicarbonate, and management of hyperammonemia.

Show evidence (1 reference)

PMID:25205257 SUPPORT Human Clinical

"Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia"

Supports need for urgent supportive crisis management during acute decompensation.

Liver or combined liver-kidney transplantation

Action: organ transplantation Ontology label: Organ Transplantation NCIT:C15289

Platform: Surgery

Liver or combined liver-kidney transplantation for severe MMA with recurrent metabolic crises. Meta-analysis shows pooled patient survival of 99.9% and graft survival of 98.5%. CKD remission is more promising after combined liver-kidney transplantation (70.3% vs 37.6% LT only). Transplantation also stabilizes cardiac function in patients with cardiac impairment.

Show evidence (3 references)

PMID:33422927 SUPPORT Human Clinical

"Liver transplantation (LT) and combined liver and kidney transplantation (CLKT) have been proposed as enzyme replacement therapies for methylmalonic aciduria (MMA)."

Directly supports transplantation as an established therapeutic strategy.

PMID:33422927 SUPPORT Human Clinical

"The pooled estimate rates were 99.9% (95% CI 95.3-100.0) for patient survival, 98.5% (95% CI 91.5-100.0) for graft survival after LT/CLKT."

Quantifies favorable survival outcomes after transplantation.

PMID:38132258 SUPPORT Human Clinical

"Liver transplantation was performed in seven patients (12%), all with PA or MMA, due to worsening cardiac impairment, and led to the stabilization of metabolic status and cardiac function."

Supports liver transplantation for metabolic and cardiac stabilization.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Genetic counseling for affected families, including discussion of autosomal recessive inheritance, recurrence risk, carrier testing, and prenatal diagnostic options.

Show evidence (1 reference)

PMID:25205257 SUPPORT Human Clinical

"MMA has an estimated incidence of ~ 1: 50,000"

Genetic etiology and defined inheritance pattern support the role of genetic counseling.

mRNA therapy (investigational)

Action: gene therapy Ontology label: Gene Therapy NCIT:C15238

Platform: Gene therapy

mRNA-3705 (Moderna) is an intravenous mRNA replacement therapy encoding human methylmalonyl-CoA mutase, currently in Phase 1/2 clinical trials (NCT04899310, NCT05295433) for isolated MMA due to MUT deficiency. Primary endpoints include safety and percent change in plasma MMA.

Show evidence (4 references)

clinicaltrials:NCT04899310 SUPPORT Human Clinical

"This is a study of mRNA-3705 in participants with isolated elevated methylmalonic acid (MMA) due to methylmalonyl-coenzyme A (CoA) mutase (MUT) deficiency."

Directly supports active interventional testing of mRNA-3705 in MUT-deficient isolated MMA.

clinicaltrials:NCT05295433 SUPPORT Human Clinical

"The primary objective of this study is to evaluate the long-term safety and clinical activity of mRNA-3705 administered to participants with isolated methylmalonic acidemia (MMA) due to methylmalonyl-coenzyme A mutase (MUT) deficiency who have previously participated in other clinical studies of..."

Supports long-term extension evaluation of mRNA-3705 in the same MMA population.

PMID:37243446 SUPPORT Human Clinical

"Liver transplantation can improve patient stability and survival and thus provides clinical and biochemical benchmarks for the development of hepatocyte-targeted genomic therapies."

Supports the rationale for hepatocyte-targeted therapies including mRNA replacement.

+ 1 more reference

🔬

Biochemical Markers

8

Methylmalonic acid (INCREASED)

Context: The hallmark metabolite of MMA. Massively elevated in blood and urine. Normal blood levels are less than 270 nmol/L; MMA patients have supraphysiologic elevations.

Pathograph Readouts

Readout Of Impaired methylmalonyl-CoA metabolism Positive Diagnostic

Increased serum or urinary methylmalonic acid reports the blocked methylmalonyl-CoA mutase/cofactor pathway.

Show evidence (1 reference)

PMID:37243446 SUPPORT Human Clinical

"Canonical metabolic markers, such as serum methylmalonic acid and propionylcarnitine, are variable and affected by dietary intake and renal function."

Patient biomarker study identifies serum methylmalonic acid as a canonical MMA metabolic marker.

Show evidence (2 references)

PMID:37243446 SUPPORT Human Clinical

"Canonical metabolic markers, such as serum methylmalonic acid and propionylcarnitine, are variable and affected by dietary intake and renal function."

Identifies serum methylmalonic acid as a canonical metabolic marker in MMA.

PMID:38030482 SUPPORT Other

"MMA is normally present at low levels in the body, but increased levels can come from different sources, such as vitamin B12 deficiency, genetic mutations in enzymes related to the propionate pathway"

Opinion/review source providing contextual support for MMA elevation mechanisms.

Propionylcarnitine (C3) (INCREASED)

Context: Elevated C3-acylcarnitine is the primary newborn screening marker for MMA. Also used for clinical monitoring during follow-up.

Pathograph Readouts

Readout Of Impaired methylmalonyl-CoA metabolism Positive Diagnostic

Elevated propionylcarnitine reports propionate-pathway metabolite accumulation used for MMA diagnosis and newborn screening.

Show evidence (1 reference)

PMID:27653704 SUPPORT Other

"In MMA, elevations of plasma propionylcarnitine, glycine, and alanine coupled with elevation of urinary methylmalonic, 3-OH-propionic, and methylcitric acids provide the diagnosis"

Review evidence directly supports propionylcarnitine as a positive diagnostic readout of MMA metabolite burden.

Show evidence (3 references)

PMID:37243446 SUPPORT Human Clinical

"Canonical metabolic markers, such as serum methylmalonic acid and propionylcarnitine, are variable and affected by dietary intake and renal function."

Directly identifies propionylcarnitine as a canonical metabolic marker.

PMID:39075538 SUPPORT Human Clinical

"NBS-detected patients showed younger age at diagnosis, less incidence of disease onset, better responsiveness of vitamin B12, younger age at start of treatment, lower levels of biochemical features before and after treatment"

Supports biochemical marker reduction after newborn-screening detection and treatment.

PMID:27653704 SUPPORT Other

"Diagnosis is based on clinical presentation and laboratory analysis, metabolic acidosis, ketoacidosis, lactic acidosis, hyperammonemia, hypoglycemia, pancytopenia, and elevated C3 acylcarnitines and organic acids in the urine."

Review text directly supports elevated C3 acylcarnitines as a diagnostic biochemical abnormality.

2-Methylcitric acid (INCREASED)

Context: A characteristic metabolite formed by condensation of propionyl-CoA with oxaloacetate via citrate synthase. Methylcitrate-to-citrate ratio is used in clinical monitoring. Potentially toxic metabolite contributing to TCA cycle disruption.

Pathograph Readouts

Readout Of Impaired methylmalonyl-CoA metabolism Positive Diagnostic

Increased methylcitric acid reports propionyl-CoA overflow into disease-specific organic-acid metabolites.

Show evidence (1 reference)

PMID:27653704 SUPPORT Other

"In MMA, elevations of plasma propionylcarnitine, glycine, and alanine coupled with elevation of urinary methylmalonic, 3-OH-propionic, and methylcitric acids provide the diagnosis"

Review evidence supports methylcitric acid as a positive diagnostic readout of MMA metabolite burden.

Readout Of Renal mitochondrial stress and impaired mitophagy Positive Monitoring

Increased methylcitrate under renal epithelial metabolic stress reports a potentially toxic, disease-specific metabolite branch relevant to kidney injury models.

Show evidence (1 reference)

PMID:37169781 SUPPORT In Vitro

"Methylcitrate as potentially toxic, disease-specific metabolite was increased by HP and I/V load."

Renal epithelial cell model evidence supports methylcitrate as a stress-responsive toxic MMA metabolite.

Show evidence (1 reference)

PMID:37169781 SUPPORT In Vitro

"Methylcitrate as potentially toxic, disease-specific metabolite was increased by HP and I/V load."

Identifies methylcitrate as a toxic, disease-specific metabolite elevated in MMA.

3-Hydroxypropionate (INCREASED)

Context: Urinary organic acid marker elevated in MMA, reflecting propionate pathway overflow.

Pathograph Readouts

Readout Of Impaired methylmalonyl-CoA metabolism Positive Diagnostic

Urinary 3-hydroxypropionate reports propionyl-CoA diversion through beta-oxidation during MMA.

Show evidence (1 reference)

PMID:4507604 SUPPORT Human Clinical

"[l-(14)C]Propionate administered intravenously was metabolized to methylmalonate, to 3-hydroxypropionate, and to methylcitrate in the urine of a patient with methylmalonic acidemia."

Patient isotope-tracing evidence directly supports 3-hydroxypropionate as a positive readout of MMA propionate-pathway overflow.

Show evidence (2 references)

PMID:4507604 SUPPORT Human Clinical

"[l-(14)C]Propionate administered intravenously was metabolized to methylmalonate, to 3-hydroxypropionate, and to methylcitrate in the urine of a patient with methylmalonic acidemia."

Patient isotope tracing directly supports urinary 3-hydroxypropionate formation in methylmalonic acidemia.

PMID:27653704 SUPPORT Other

"In MMA, elevations of plasma propionylcarnitine, glycine, and alanine coupled with elevation of urinary methylmalonic, 3-OH-propionic, and methylcitric acids provide the diagnosis"

Review text includes urinary 3-OH-propionic acid in the diagnostic biochemical pattern.

FGF21 (INCREASED)

Context: Fibroblast growth factor 21 is a mitochondrial stress biomarker elevated in MMA. Correlates with disease severity and complications attributed to mitochondrial dysfunction. Responds to liver-targeted therapies and transplantation.

Pathograph Readouts

Readout Of Mitochondrial energy metabolism dysfunction Positive Monitoring

Increased FGF21 reports mitochondrial dysfunction and multisystem disease burden in isolated MMA.

Show evidence (1 reference)

PMID:37243446 SUPPORT Human Clinical

"We have therefore explored the use of the 1-13 C-propionate oxidation breath test (POBT) to measure metabolic capacity and the changes in circulating proteins to assess mitochondrial dysfunction (fibroblast growth factor 21 FGF21 and growth differentiation factor 15 GDF15) and kidney injury..."

Clinical biomarker study identifies FGF21 as a circulating protein marker used to assess mitochondrial dysfunction.

Correlates With Aberrant mitochondrial protein methylmalonylation Positive Monitoring

FGF21 levels correlate with acyl-CoA accretion and aberrant adipose methylmalonylation in MMA.

Show evidence (1 reference)

PMID:38271099 SUPPORT Human Clinical

"Fibroblast growth factor 21 levels were associated with acyl-CoA accretion, aberrant methylmalonylation in adipose tissue, and an attenuated inflammatory cytokine profile."

Human cohort evidence supports FGF21 as a positive correlate of acyl-CoA accretion and aberrant methylmalonylation.

Show evidence (2 references)

PMID:38271099 SUPPORT Human Clinical

"Fibroblast growth factor 21 levels were associated with acyl-CoA accretion, aberrant methylmalonylation in adipose tissue, and an attenuated inflammatory cytokine profile."

Links FGF21 levels to aberrant methylmalonylation in MMA patients.

PMID:37243446 SUPPORT Human Clinical

"Biomarker concentrations are higher in patients with the severe mut0 -type and cblB-type MMA"

Supports increased biomarker concentrations in severe MMA subtypes after FGF21/GDF15/LCN2 are introduced as biomarker targets.

GDF15 (INCREASED)

Context: Growth differentiation factor 15 is a mitochondrial stress biomarker elevated in MMA, used alongside FGF21 to assess disease severity.

Pathograph Readouts

Readout Of Mitochondrial energy metabolism dysfunction Positive Monitoring

Increased GDF15 reports mitochondrial dysfunction and multisystem disease burden in isolated MMA.

Show evidence (1 reference)

PMID:37243446 SUPPORT Human Clinical

"We have therefore explored the use of the 1-13 C-propionate oxidation breath test (POBT) to measure metabolic capacity and the changes in circulating proteins to assess mitochondrial dysfunction (fibroblast growth factor 21 FGF21 and growth differentiation factor 15 GDF15) and kidney injury..."

Clinical biomarker study identifies GDF15 as a circulating protein marker used to assess mitochondrial dysfunction.

Correlates With MMUT/AdoCbl pathway molecular function deficiency Positive Prognostic

Higher biomarker concentrations are associated with severe mut0 and cblB MMA subtypes and reduced propionate oxidation capacity.

Show evidence (1 reference)

PMID:37243446 SUPPORT Human Clinical

"Biomarker concentrations are higher in patients with the severe mut0 -type and cblB-type MMA, correlate with a decreased POBT, and show a significant response postliver transplant."

Patient biomarker evidence supports GDF15/FGF21/LCN2 concentrations as positive severity correlates in severe MMA subtypes.

Show evidence (2 references)

PMID:37243446 SUPPORT Human Clinical

"We have therefore explored the use of the 1-13 C-propionate oxidation breath test (POBT) to measure metabolic capacity and the changes in circulating proteins to assess mitochondrial dysfunction (fibroblast growth factor 21 FGF21 and growth differentiation factor 15 GDF15) and kidney injury..."

Identifies GDF15 as a circulating mitochondrial dysfunction biomarker evaluated in isolated MMA cohorts.

PMID:37243446 SUPPORT Human Clinical

"Biomarker concentrations are higher in patients with the severe mut0 -type and cblB-type MMA"

Provides cohort context that biomarker elevations are strongest in severe MMA subtypes.

Lipocalin-2 (LCN2) (INCREASED)

Context: A kidney injury biomarker elevated in MMA, tied to proximal tubule mitochondrial dysfunction and oxidative stress. May be more sensitive than creatinine for early detection of renal injury.

Pathograph Readouts

Readout Of Renal mitochondrial stress and impaired mitophagy Positive Monitoring

Increased LCN2 reports kidney injury downstream of renal mitochondrial stress and toxic organic-acid exposure.

Show evidence (1 reference)

PMID:37243446 SUPPORT Human Clinical

"We have therefore explored the use of the 1-13 C-propionate oxidation breath test (POBT) to measure metabolic capacity and the changes in circulating proteins to assess mitochondrial dysfunction (fibroblast growth factor 21 FGF21 and growth differentiation factor 15 GDF15) and kidney injury..."

Clinical biomarker study identifies LCN2 as a kidney-injury marker in isolated MMA.

Show evidence (1 reference)

PMID:37243446 SUPPORT Human Clinical

"We have therefore explored the use of the 1-13 C-propionate oxidation breath test (POBT) to measure metabolic capacity and the changes in circulating proteins to assess mitochondrial dysfunction (fibroblast growth factor 21 FGF21 and growth differentiation factor 15 GDF15) and kidney injury..."

Identifies LCN2 as a kidney injury biomarker in MMA.

Ammonia (INCREASED)

Context: Secondary hyperammonemia occurs during acute decompensation due to inhibition of N-acetylglutamate synthase by propionyl-CoA, impairing the urea cycle.

Pathograph Readouts

Readout Of Acute organic acid decompensation Positive Diagnostic

Increased ammonia reports secondary urea-cycle inhibition during acute organic-acid decompensation.

Show evidence (1 reference)

PMID:27653704 SUPPORT Other

"Accumulation of propionyl-CoA, and to some extent methylmalonyl-CoA, results in secondary inhibition of N-acetylglutamate synthase (NAGS), causing secondary hyperammonemia in these patients"

Review evidence supports increased ammonia as a positive readout of secondary hyperammonemia during decompensation.

Readout Of Hyperammonemia Positive Diagnostic

Increased circulating ammonia is the biochemical readout of the hyperammonemia phenotype.

Show evidence (1 reference)

PMID:25205257 SUPPORT Human Clinical

"Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia"

Guideline evidence supports hyperammonemia as a presenting biochemical abnormality in MMA.

Show evidence (2 references)

PMID:25205257 SUPPORT Human Clinical

"Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia"

Directly supports hyperammonemia as a presenting feature of MMA.

PMID:27653704 SUPPORT Other

"Accumulation of propionyl-CoA, and to some extent methylmalonyl-CoA, results in secondary inhibition of N-acetylglutamate synthase (NAGS), causing secondary hyperammonemia in these patients"

Review text supports the urea-cycle mechanism that raises ammonia.

🔬

Diagnosis

1

Newborn screening

Detection of MMA via tandem mass spectrometry using elevated propionylcarnitine (C3) as the primary marker. A multicenter Chinese study demonstrated NBS-detected mut-type MMA patients had significantly lower mortality (12.5% vs 32.7%) and better outcomes (normal outcome 51.8% vs 15.7%) compared to clinically diagnosed patients.

newborn screening NCIT:C81178

propionylcarnitine (C3), DBS LOINC:53160-8 propionylcarnitine/acetylcarnitine (C3/C2) molar ratio, DBS LOINC:53163-2 methylmalonic acid, DBS (second tier) LOINC:82385-6 2-methylcitric acid, DBS (second tier) LOINC:82386-4

Reference Ranges

Propionylcarnitine (C3) [Moles/volume] in DBS (healthy newborns, Serbia (n=1,771); cut-offs proposed for a programme that did not yet screen organic acidemias)

Screen negative (< 5.73 umol/L) Screen positive (≥ 5.73 umol/L)

Screen positive: An elevated C3 is shared with propionic acidemia, the cobalamin disorders and maternal vitamin B12 deficiency; recall for second-tier methylmalonic acid and 2-methylcitric acid or confirmatory plasma acylcarnitines and urine organic acids.

A proposed cut-off, derived from the distribution in healthy newborns and offered as the starting point for a future Serbian programme, not a value an operating programme applied. It is stated as ">5.73", so exactly 5.73 is negative there; the half-open band places exactly 5.73 in the positive band. The source states one cut-off for methylmalonic acidemia or propionic acidemia, because the analyte does not separate them; the same range is recorded on the Propionic_Acidemia entry. An operating programme's absolute C3 cut-off could not be found stated in a PubMed abstract: the search propionylcarnitine[tiab] AND newborn screening[tiab] AND (cutoff[tiab] OR cut-off[tiab]) returned the Ontario programme's confirmation that it screens on C3 and C3/C2 but not its numeric value.

Show evidence (2 references)

PMID:35254746 SUPPORT Human Clinical

"The cut-offs for methylmalonic acidemia (MMA) or propionic acidemia (PA) were C3>5.73 μmol/L, C3/C2>0.23, and C3/C16>2.36."

States the proposed dried-blood-spot propionylcarnitine cut-off, and that one value serves methylmalonic and propionic acidemia.

PMID:35254746 SUPPORT Human Clinical

"Therefore, the proposed cut-offs represent a reliable starting point for the future development of the OA NBS."

Records that the value is a proposal for a programme not yet screening, which is why the population names no operating programme.

Propionylcarnitine (C3)/Acetylcarnitine (C2) [Molar ratio] in DBS (healthy newborns, Serbia (n=1,771); cut-offs proposed for a programme that did not yet screen organic acidemias)

Screen negative (< 0.23 {ratio}) Screen positive (≥ 0.23 {ratio})

Screen positive: The ratio corrects C3 for total acylcarnitine load and is read alongside the absolute C3 value.

Same source and status as the C3 range above: a proposed value, stated as ">0.23", so exactly 0.23 is negative there and the half-open band places it in the positive band. Operating programmes use the ratio with C3 (Newborn Screening Ontario screens on "C3 and C3/C2 ratio"), but the cited Ontario abstract does not state its numeric ratio cut-off. In the Chinese mut-type cohort cited on this row, the blood C3/C2 ratio was also a prognostic factor, which is a different use of the same measurement.

Show evidence (1 reference)

PMID:35254746 SUPPORT Human Clinical

"The cut-offs for methylmalonic acidemia (MMA) or propionic acidemia (PA) were C3>5.73 μmol/L, C3/C2>0.23, and C3/C16>2.36."

States the proposed C3/C2 ratio cut-off.

Methylmalonate [Moles/volume] in DBS (second-tier LC-MS/MS on dried blood spots, Zhejiang (China) programme; cut-offs set in 1,998 healthy infants and applied to 804 suspected positives from 381,399 screened newborns)

Second tier negative (< 2.12 umol/L) Second tier positive (≥ 2.12 umol/L)

Second tier positive: Referral for confirmatory testing of a methylmalonic acidemia.

A second-tier cut-off applied to spots already positive on the C3 screen. The abstract states the value without saying whether it is inclusive, so the half-open band convention is applied as written and the boundary case is unresolved by the source. Methylmalonic acid on the spot is what separates the methylmalonic acidemias from propionic acidemia within the shared C3 screen, which is why this analyte is recorded here and not on the Propionic_Acidemia entry.

Show evidence (1 reference)

PMID:32615850 SUPPORT Human Clinical

"Cutoff values for methylmalonic acid, 2-methylcitric acid, and total homocysteine were 2.12, 0.70, and 10.05 µmol/l, respectively."

States the Zhejiang second-tier dried-blood-spot methylmalonic acid cut-off of 2.12 µmol/l.

2-Methylcitrate [Moles/volume] in DBS (second-tier LC-MS/MS on dried blood spots, Zhejiang (China) programme; cut-offs set in 1,998 healthy infants and applied to 804 suspected positives from 381,399 screened newborns)

Second tier negative (< 0.7 umol/L) Second tier positive (≥ 0.7 umol/L)

Same source and inclusivity caveat as the methylmalonic acid range above. 2-Methylcitric acid is raised in both the methylmalonic and the propionic acidemias, so this range is also recorded on the Propionic_Acidemia entry.

Show evidence (1 reference)

PMID:32615850 SUPPORT Human Clinical

"Cutoff values for methylmalonic acid, 2-methylcitric acid, and total homocysteine were 2.12, 0.70, and 10.05 µmol/l, respectively."

States the Zhejiang second-tier dried-blood-spot 2-methylcitric acid cut-off of 0.70 µmol/l.

2-Methylcitrate [Moles/volume] in DBS (second-tier testing of C3/C3-C2 screen-positive dried blood spots, Newborn Screening Ontario, July 2011-December 2012)

Second tier negative (< 1.0 umol/L) Second tier positive (≥ 1.0 umol/L)

A second-tier cut-off applied only to spots already positive on C3 and C3/C2. The source says samples "exceeded" 1.0 µmol/l, so exactly 1.0 is negative there; the half-open band places exactly 1.0 in the positive band. The Ontario true positives included one cobalamin A case, an isolated methylmalonic acidemia within this entry's scope. The paper also reports a 2-methylcitric acid reference range of 0.04-0.36 µmol/l, which is a population interval and is not recorded as disease content.

Show evidence (1 reference)

PMID:27216769 SUPPORT Human Clinical

"Only 14 samples exceeded the set 2-methylcitric acid cut-off of 1.0 µmol/l, including the samples from all nine true positives."

States the Ontario second-tier 2-methylcitric acid cut-off and that every true positive exceeded it.

Measurements bind the method-less quantitative DBS codes; the specimen is intrinsic to a newborn screen, so the DBS code is the test's identity here. The first-tier screen is shared with propionic acidemia and the cobalamin disorders, so the C3 and C3/C2 rows say "methylmalonic or propionic acidemia" as their source does, and those two cut-offs are a published proposal rather than an operating programme's rule; the second-tier methylmalonic acid and 2-methylcitric acid cut-offs come from operating programmes. Total homocysteine, measured on the same second-tier spot to separate the combined cobalamin disorders, is out of this entry's scope and is not bound.

Show evidence (5 references)

PMID:39075538 SUPPORT Human Clinical

"This research highly demonstrated NBS could prevent major disease-related events and allow an earlier treatment initiation."

Directly supports NBS as beneficial for improving survival in MMA.

PMID:39075538 SUPPORT Human Clinical

"By comparison of the clinically-diagnosed patients, NBS-detected patients showed younger age at diagnosis, less incidence of disease onset, better responsiveness of vitamin B12, younger age at start of treatment, lower levels of biochemical features before and after treatment, and better..."

Quantifies multiple improved outcome measures with NBS detection.

PMID:27216769 SUPPORT Human Clinical

"Of 222,420 samples screened, 103 were positive for methylmalonic acidurias or propionic acidemia using C3 and C3/C2 ratio as markers."

Documents C3 together with the C3/C2 ratio as the first-tier markers of an operating programme, and that one screen serves both disorders.

+ 2 more references

📊

Prevalence

2

Worldwide newborn screening cohorts

Birth Prevalence 1.14 per 100,000 1–9 per 100,000 (births)

Meta-analysis of 111 studies estimated a pooled worldwide newborn prevalence of about 1 in 87,700, with higher pooled prevalence in Asia and Africa than in other regions.

Show evidence (1 reference)

PMID:34847798 SUPPORT Human Clinical

"The pooled prevalence of MMA worldwide was 1.14 per 100,000 newborns (1516/190,229,777 newborns, 95% CI: 0.99-1.29)"

Meta-analysis provides the strongest pooled newborn prevalence estimate for methylmalonic acidemia.

Conventional clinical estimates

Point Prevalence 2.0 per 100,000 1–9 per 100,000

Clinical reviews still commonly cite an incidence around 1 in 50,000, reflecting longstanding clinically ascertained estimates for MMA.

Show evidence (1 reference)

PMID:25205257 SUPPORT Human Clinical

"MMA has an estimated incidence of ~ 1: 50,000 and PA of ~ 1:100'000 -150,000."

This review captures the conventional incidence estimate widely cited in clinical literature.

🔬

Clinical Trials

2

NCT04899310 PHASE_II ACTIVE_NOT_RECRUITING

Global Phase 1/2 study evaluating safety, pharmacodynamics, and pharmacokinetics of IV mRNA-3705 in isolated MMA due to MUT deficiency.

Target Phenotypes: Metabolic acidosis HP:0001942 Hyperammonemia HP:0001987

Show evidence (2 references)

clinicaltrials:NCT04899310 SUPPORT Human Clinical

"This is a study of mRNA-3705 in participants with isolated elevated methylmalonic acid (MMA) due to methylmalonyl-coenzyme A (CoA) mutase (MUT) deficiency."

Confirms target population and intervention in isolated MUT-deficient MMA.

clinicaltrials:NCT04899310 SUPPORT Human Clinical

"The main goal of the study is to assess safety, efficacy, pharmacokinetics, and pharmacodynamics of intravenously (IV)-infused mRNA-3705."

Defines the trial objectives and primary clinical development intent.

NCT05295433 PHASE_II NOT_RECRUITING

Global open-label extension study evaluating long-term safety and clinical activity of mRNA-3705 in participants previously enrolled in mRNA-3705 clinical studies.

Target Phenotypes: Metabolic acidosis HP:0001942 Chronic kidney disease HP:0012622

Show evidence (1 reference)

clinicaltrials:NCT05295433 SUPPORT Human Clinical

"The primary objective of this study is to evaluate the long-term safety and clinical activity of mRNA-3705 administered to participants with isolated methylmalonic acidemia (MMA) due to methylmalonyl-coenzyme A mutase (MUT) deficiency who have previously participated in other clinical studies of..."

Confirms open-label extension focus on long-term safety and activity in the same MMA target group.

{ }

Source YAML

click to show

name: Methylmalonic Acidemia
category: Mendelian
creation_date: '2026-02-23T22:58:40Z'
synonyms:
- Methylmalonic aciduria
- MMA
- Methylmalonyl-CoA mutase deficiency
- Isolated methylmalonic acidemia
description: 'Methylmalonic acidemia (MMA) is an autosomal recessive inborn error of propionate metabolism caused by deficiency of methylmalonyl-CoA mutase (MMUT) or defects in intracellular adenosylcobalamin (AdoCbl) cofactor synthesis and handling (cblA/MMAA, cblB/MMAB). Impaired conversion of methylmalonyl-CoA to succinyl-CoA leads to systemic accumulation of methylmalonic acid, propionyl-CoA, 2-methylcitrate, and related metabolites, disrupting mitochondrial anaplerosis, respiratory chain function, and protein acylation homeostasis. The disease manifests with recurrent metabolic decompensation, progressive chronic kidney disease, neurological injury including basal ganglia injury, cardiomyopathy, and a distinctive lipodystrophy-like phenotype. Estimated incidence is approximately 1:50,000 live births. Newborn screening via elevated propionylcarnitine (C3) allows pre-symptomatic detection and significantly improves outcomes.

  '
classifications:
  icimd_category:
  - classification_value: organic_acidurias
    notes: >-
      ICIMD (Ferreira et al. 2021, PMID:33340416): group "Organic acidurias"
      under category "Disorders of amino acid metabolism". MMA is an organic
      aciduria of propionate/methylmalonyl-CoA metabolism.
disease_term:
  preferred_term: methylmalonic acidemia
  term:
    id: MONDO:0002012
    label: methylmalonic acidemia
parents:
- Organic Acidemia
- Inborn error of metabolism
prevalence:
- population: Worldwide newborn screening cohorts
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.14
  percentage: 1.14 per 100,000 newborns
  notes: >-
    Meta-analysis of 111 studies estimated a pooled worldwide newborn
    prevalence of about 1 in 87,700, with higher pooled prevalence in Asia and
    Africa than in other regions.
  evidence:
  - reference: PMID:34847798
    reference_title: "Prevalence of methylmalonic acidemia among newborns and the clinical-suspected population: a meta-analyse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pooled prevalence of MMA worldwide was 1.14 per 100,000 newborns (1516/190,229,777 newborns, 95% CI: 0.99-1.29)"
    explanation: Meta-analysis provides the strongest pooled newborn prevalence estimate for methylmalonic acidemia.
- population: Conventional clinical estimates
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 2.0
  percentage: ~1 in 50,000
  notes: >-
    Clinical reviews still commonly cite an incidence around 1 in 50,000,
    reflecting longstanding clinically ascertained estimates for MMA.
  evidence:
  - reference: PMID:25205257
    reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MMA has an estimated incidence of ~ 1: 50,000 and PA of ~ 1:100'000 -150,000."
    explanation: This review captures the conventional incidence estimate widely cited in clinical literature.
has_subtypes:
- name: Vitamin B12-responsive methylmalonic acidemia
  description: 'Partial biochemical response to hydroxocobalamin in cblA, cblB, and some mut- genetic forms. Associated with generally better prognosis.

    '
  review_notes: >-
    GeneReviews groups the partially deficient or B12-responsive phenotypes as
    the mut– enzymatic subtype, cblA, cblB (rare) and cblD-MMA (PMID:20301409),
    which is the basis for this row's four-gene list. That sentence is not used
    as the snippet because the reference validator strips its bracketed "[rare]"
    qualifier and the remainder then fails to match the source, so the
    bracket-free genotype sentence from the same abstract is quoted instead.
  genes:
  - preferred_term: MMUT
    term:
      id: hgnc:7526
      label: MMUT
  - preferred_term: MMAA
    term:
      id: hgnc:18871
      label: MMAA
  - preferred_term: MMAB
    term:
      id: hgnc:19331
      label: MMAB
  - preferred_term: MMADHC
    term:
      id: hgnc:25221
      label: MMADHC
  evidence:
  - reference: PMID:20301409
    reference_title: "Isolated Methylmalonic Acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Isolated MMA is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut– enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, 5-deoxy-adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase."
    explanation: >-
      GeneReviews names the genotype groups of isolated MMA, including cblD-MMA
      among the adenosylcobalamin cofactor defects, which is the set this row's
      gene list is drawn from.
  - reference: CGGV:assertion_52b61ff5-afba-4ff7-adbc-51de6a837db7-2022-07-13T160000.000Z
    reference_title: "MMAB / methylmalonic aciduria, cblB type (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "While patients with MMA due to variants in MMAA (type CblA) are responsive to Vitamin B12, only rare individuals with type CblB are responsive to treatment with Vitamin B12"
    explanation: ClinGen contrasts cblA responsiveness with the rarity of cblB responsiveness, supporting MMAA as the core responsive genotype and MMAB as a rare one.
  - reference: PMID:25205257
    reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine.
    explanation: Directly supports existence of vitamin B12-responsive MMA forms with better outcomes.
  - reference: PMID:39075538
    reference_title: "Clinical outcomes of patients with mut-type methylmalonic acidemia identified through expanded newborn screening in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: NBS-detected patients showed younger age at diagnosis, less incidence of disease onset, better responsiveness of vitamin B12
    explanation: Supports that B12 responsiveness is a key prognostic factor in MMA.
- name: Vitamin B12-unresponsive methylmalonic acidemia
  description: 'Severe mut0/mut- forms without meaningful cobalamin response. Associated with higher mortality and worse long-term outcomes.

    '
  genes:
  - preferred_term: MMUT
    term:
      id: hgnc:7526
      label: MMUT
  - preferred_term: MMAB
    term:
      id: hgnc:19331
      label: MMAB
  evidence:
  - reference: PMID:20301409
    reference_title: "Isolated Methylmalonic Acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infantile/non-B12-responsive form (mut0 enzymatic subtype, cblB), the most common phenotype"
    explanation: GeneReviews assigns the non-B12-responsive infantile phenotype to the mut0 and cblB genotypes, which is what this row's gene list records.
  - reference: PMID:25205257
    reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine.
    explanation: Supports that non-responsive MMA forms have poorer outcomes.
- name: TCblR defect
  display_name: Transcobalamin receptor (CD320) defect
  description: >-
    Biallelic CD320 loss of function, most commonly homozygosity for the in-frame
    p.Glu88del deletion, restricts cellular uptake of cobalamin-loaded
    transcobalamin and raises propionylcarnitine (C3) and methylmalonic acid
    enough to produce a positive newborn screen for propionic/methylmalonic
    aciduria. It is set apart from the mutase and cofactor forms by its course
    rather than by its biochemistry. The elevations correct on oral cobalamin,
    and ClinGen records that p.Glu88del homozygotes have typically had no major
    health or developmental concerns and that the condition is probably benign,
    while still grading the gene-disease relationship Definitive; one
    consanguineous case with bilateral retinal artery occlusions at seven weeks
    is the reported exception. It is kept as a subtype row here, and not promoted
    to its own entry, because GeneReviews does not count CD320 among the genes
    whose biallelic variants establish a diagnosis of isolated MMA and the
    mechanism is fully captured by the cobalamin-uptake node in this entry.
  subtype_term:
    preferred_term: methylmalonic acidemia due to transcobalamin receptor defect
    term:
      id: MONDO:0013341
      label: methylmalonic acidemia due to transcobalamin receptor defect
  genes:
  - preferred_term: CD320
    term:
      id: hgnc:16692
      label: CD320
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: CGGV:assertion_d98515f5-4296-4d41-95a9-adac90c00349-2022-09-23T160000.000Z
    reference_title: "CD320 / methylmalonic acidemia due to transcobalamin receptor defect (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CD320 | HGNC:16692 | methylmalonic acidemia due to transcobalamin receptor defect | MONDO:0013341 | AR | Definitive"
    explanation: ClinGen classifies the CD320 gene-disease relationship as definitive with autosomal recessive inheritance, against the MONDO term bound here.
  - reference: PMID:29663633
    reference_title: "Transcobalamin receptor defect: Identification of two new cases through positive newborn screening for propionic/methylmalonic aciduria and long-term outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, both patients remain asymptomatic with normal neurodevelopment more than 6 years."
    explanation: The long-term outcome on which this row's description of a benign course rests.
pathophysiology:
- name: MMUT/AdoCbl pathway molecular function deficiency
  description: >-
    Pathogenic variants affecting MMUT and adenosylcobalamin-handling genes
    reduce catalytic conversion capacity for methylmalonyl-CoA utilization. MMUT
    encodes the mutase apoenzyme itself; MMAA (cblA) and MMAB (cblB) supply and
    deliver its adenosylcobalamin cofactor, and MMADHC (cblD) sits at the
    branch point of intracellular cobalamin trafficking that partitions
    cobalamin between mitochondrial adenosylcobalamin and cytosolic
    methylcobalamin, so cblD variants that impair the mitochondrial arm present
    as isolated methylmalonic aciduria.
  genes:
  - preferred_term: MMUT
    term:
      id: hgnc:7526
      label: MMUT
  - preferred_term: MMAA
    term:
      id: hgnc:18871
      label: MMAA
  - preferred_term: MMAB
    term:
      id: hgnc:19331
      label: MMAB
  - preferred_term: MMADHC
    term:
      id: hgnc:25221
      label: MMADHC
  molecular_functions:
  - preferred_term: methylmalonyl-CoA mutase activity
    term:
      id: GO:0004494
      label: methylmalonyl-CoA mutase activity
    modifier: DECREASED
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:25205257
    reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC).
    explanation: Supports proximal enzyme/cofactor molecular defects as the initiating mechanism in MMA.
  - reference: CGGV:assertion_40ec59af-a143-4424-9218-7fd75deb6a61-2021-05-12T182739.747Z
    reference_title: "MMADHC / inborn disorder of cobalamin metabolism and transport (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MMADHC is involved in the intracellular conversion of cobalamin to its two coenzymes, adenosylcobalamin (AdoCbl) in mitochondria and methylcobalamin (MeCbl) in the cytoplasm"
    explanation: Places MMADHC at this node, on the adenosylcobalamin arm of intracellular cobalamin handling alongside MMAA and MMAB.
  - reference: PMID:20301409
    reference_title: "Isolated Methylmalonic Acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of isolated MMA is established in a proband by identification of biallelic pathogenic variants in MCEE, MMAA, MMAB, MMADHC, or MMUT"
    explanation: The GeneReviews baseline names all five genes whose biallelic variants establish a diagnosis of isolated MMA.
  downstream:
  - target: Impaired methylmalonyl-CoA metabolism
    description: Defective MMUT/AdoCbl function blocks conversion of methylmalonyl-CoA to succinyl-CoA.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27653704
      reference_title: "Methylmalonic and propionic acidemias: clinical management update."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Isolated MMA is caused by mutations in the MUT gene encoding methylmalonyl-CoA mutase (mut) or the genes encoding the enzymes responsible for the generation of 5-deoxyadenosylcobalamin (AdoCbl) cofactor of Mut (MMAA and MMAB)
      explanation: Review text directly links MUT/MMAA/MMAB defects to isolated MMA at the first pathway step.
- name: Methylmalonyl-CoA epimerase deficiency
  genes:
  - preferred_term: MCEE
    term:
      id: hgnc:16732
      label: MCEE
  description: >-
    A separate enzymatic step from the mutase and its cofactor. MCEE
    interconverts D- and L-methylmalonyl-CoA, the racemization that must happen
    before methylmalonyl-CoA mutase can act, so biallelic MCEE loss of function
    blocks the propionyl-CoA to succinyl-CoA route one step earlier than MMUT
    does and produces methylmalonic aciduria. The clinical consequence is
    variable, from no symptoms to severe metabolic acidosis, and ClinGen notes
    that the range of reported phenotypes leaves causation of anything beyond
    the methylmalonic aciduria itself uncertain.
  molecular_functions:
  - preferred_term: methylmalonyl-CoA epimerase activity
    modifier: DECREASED
    term:
      id: GO:0004493
      label: methylmalonyl-CoA epimerase activity
  evidence:
  - reference: PMID:30682498
    reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated a cohort of 150 individuals suffering from MMAuria of unknown origin, identifying ten new patients with pathogenic variations in MCEE."
    explanation: A cohort screen attributing methylmalonic aciduria of previously unknown cause to biallelic MCEE variants in ten further patients.
  - reference: PMID:30682498
    reference_title: "Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Human methylmalonyl-CoA epimerase (MCEE) catalyzes the interconversion of d-methylmalonyl-CoA and l-methylmalonyl-CoA in propionate catabolism."
    explanation: States the reaction this node places at the racemization step, upstream of the mutase.
  - reference: CGGV:assertion_b8546531-fe3d-48fd-8103-f5f84fd04514-2020-07-09T160000.000Z
    reference_title: "MCEE / methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism for disease is biallelic loss of function, with defective protein activity causing a blockage in the propionyl-CoA to succinyl-CoA pathway in human cells and a resulting buildup of methylmalonic acid."
    explanation: ClinGen states the loss-of-function mechanism and the pathway block this node models.
  downstream:
  - target: Impaired methylmalonyl-CoA metabolism
    causal_link_type: DIRECT
    description: >-
      Loss of epimerase activity starves the mutase of its L-methylmalonyl-CoA
      substrate, blocking the same propionyl-CoA to succinyl-CoA conversion.
    evidence:
    - reference: PMID:20301409
      reference_title: "Isolated Methylmalonic Acidemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Methylmalonyl-CoA epimerase deficiency, in which findings range from complete absence of symptoms to severe metabolic acidosis."
      explanation: GeneReviews counts methylmalonyl-CoA epimerase deficiency among the isolated MMA phenotypes arising from this pathway block.
- name: Impaired cellular cobalamin uptake
  genes:
  - preferred_term: CD320
    term:
      id: hgnc:16692
      label: CD320
  description: >-
    The most upstream step modeled here, and the mildest. CD320 encodes the
    transcobalamin receptor, which takes cobalamin-loaded transcobalamin into
    the cell; biallelic loss of function therefore limits the cobalamin
    available for both coenzymes, and the mitochondrial arm shows up as elevated
    propionylcarnitine on the newborn screen and elevated methylmalonic acid on
    its workup. Unlike the mutase and cofactor defects the biochemical
    abnormality is correctable with oral cobalamin and the reported homozygotes
    have typically had no major health or developmental concerns, so this node is
    modeled as a cobalamin-availability constraint on the mutase step rather than
    as a route to the decompensation and organ injury nodes.
  biological_processes:
  - preferred_term: cobalamin transport
    modifier: DECREASED
    term:
      id: GO:0015889
      label: cobalamin transport
  evidence:
  - reference: CGGV:assertion_d98515f5-4296-4d41-95a9-adac90c00349-2022-09-23T160000.000Z
    reference_title: "CD320 / methylmalonic acidemia due to transcobalamin receptor defect (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CD320 encodes the transcobalamin receptor, which mediates the cellular uptake of vitamin B12 (cobalamin, Cbl)."
    explanation: States the transport function whose loss this node models.
  - reference: PMID:32898552
    reference_title: "Cellular uptake of vitamin B(12): Role and fate of TCblR/CD320, the transcobalamin receptor."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Cellular uptake of vitamin B12 (cobalamin, Cbl) is mediated by a cell surface receptor (TCblR/CD320) that binds transcobalamin (TC) saturated with Cbl."
    explanation: Independent statement that CD320 is the receptor for cellular uptake of transcobalamin-bound cobalamin.
  downstream:
  - target: MMUT/AdoCbl pathway molecular function deficiency
    causal_link_type: DIRECT
    description: >-
      Restricted cobalamin entry reduces the adenosylcobalamin available to
      methylmalonyl-CoA mutase, inhibiting the mutase step.
    evidence:
    - reference: CGGV:assertion_d98515f5-4296-4d41-95a9-adac90c00349-2022-09-23T160000.000Z
      reference_title: "CD320 / methylmalonic acidemia due to transcobalamin receptor defect (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Cbl deficiency, due to various defects in Cbl transport and metabolism, can result in homocysteinemia due to inhibition of the methionine synthase pathway, and methylmalonic acidemia (MMA) due to inhibition of the mutase pathway."
      explanation: ClinGen states that a cobalamin transport defect produces methylmalonic acidemia by inhibiting the mutase pathway, which is the edge drawn here.
- name: Impaired methylmalonyl-CoA metabolism
  description: 'Defects in methylmalonyl-CoA mutase or cobalamin-dependent cofactor pathways block conversion of methylmalonyl-CoA to succinyl-CoA, disrupting mitochondrial anaplerosis and the TCA cycle.

    '
  biological_processes:
  - preferred_term: methylmalonyl-CoA metabolic process
    term:
      id: GO:0046491
      label: L-methylmalonyl-CoA metabolic process
    modifier: DECREASED
  - preferred_term: propionate catabolic process
    term:
      id: GO:0019543
      label: propionate catabolic process
    modifier: DECREASED
  - preferred_term: tricarboxylic acid cycle
    term:
      id: GO:0006099
      label: tricarboxylic acid cycle
    modifier: DECREASED
  chemical_entities:
  - preferred_term: methylmalonyl-CoA
    term:
      id: CHEBI:16625
      label: methylmalonyl-CoA
    modifier: INCREASED
  - preferred_term: succinyl-CoA
    term:
      id: CHEBI:15380
      label: succinyl-CoA
    modifier: DECREASED
  - preferred_term: methylmalonic acid
    term:
      id: CHEBI:30860
      label: methylmalonic acid
    modifier: INCREASED
  - preferred_term: propionyl-CoA
    term:
      id: CHEBI:15539
      label: propionyl-CoA
    modifier: INCREASED
  - preferred_term: propionylcarnitine
    term:
      id: CHEBI:17387
      label: O-acylcarnitine
    modifier: INCREASED
  - preferred_term: 2-methylcitric acid
    term:
      id: CHEBI:30835
      label: 2-methylcitric acid
    modifier: INCREASED
  - preferred_term: 3-hydroxypropionate
    term:
      id: CHEBI:16510
      label: 3-hydroxypropionate
    modifier: INCREASED
  evidence:
  - reference: PMID:25205257
    reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC).
    explanation: Supports blocked methylmalonyl-CoA handling and downstream metabolite accumulation.
  - reference: PMID:38030482
    reference_title: "Methylmalonic acid in aging and disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: MMA is normally present at low levels in the body, but increased levels can come from different sources, such as vitamin B12 deficiency, genetic mutations in enzymes related to the propionate pathway
    explanation: Opinion/review source providing supportive context for propionate-pathway genetic etiologies.
  downstream:
  - target: Methylmalonic acid
    description: Blocked methylmalonyl-CoA mutase activity causes methylmalonic acid accumulation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25205257
      reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC).
      explanation: Guideline abstract supports methylmalonic acid accumulation downstream of MUT deficiency.
  - target: Propionylcarnitine (C3)
    description: Propionate-pathway flux produces elevated plasma propionylcarnitine during MMA diagnosis and monitoring.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Propionyl-CoA accumulation is buffered by carnitine conjugation.
    evidence:
    - reference: PMID:27653704
      reference_title: "Methylmalonic and propionic acidemias: clinical management update."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: In MMA, elevations of plasma propionylcarnitine, glycine, and alanine coupled with elevation of urinary methylmalonic, 3-OH-propionic, and methylcitric acids provide the diagnosis
      explanation: Review text directly identifies propionylcarnitine as elevated in MMA.
  - target: 2-Methylcitric acid
    description: Propionyl-CoA overflow generates methylcitric acid, a disease-specific organic acid marker.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Propionyl-CoA condenses with oxaloacetate to form methylcitrate.
    evidence:
    - reference: PMID:27653704
      reference_title: "Methylmalonic and propionic acidemias: clinical management update."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: In MMA, elevations of plasma propionylcarnitine, glycine, and alanine coupled with elevation of urinary methylmalonic, 3-OH-propionic, and methylcitric acids provide the diagnosis
      explanation: Review text supports methylcitric acid elevation as part of the diagnostic biochemical pattern.
  - target: 3-Hydroxypropionate
    description: Propionyl-CoA is diverted through beta-oxidation to urinary 3-hydroxypropionate.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Propionyl-CoA beta-oxidation through acryloyl-CoA produces 3-hydroxypropionate.
    evidence:
    - reference: PMID:4507604
      reference_title: "3-hydroxypropionate: significance of -oxidation of propionate in patients with propionic acidemia and methylmalonic acidemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The appearance of radioactive 3-hydroxypropionate in the urine after the administration of these compounds indicates that beta-oxidation of propionyl-CoA through acryloyl-CoA was functioning in these patients.
      explanation: Patient isotope tracing supports propionyl-CoA diversion to urinary 3-hydroxypropionate.
  - target: Acute organic acid decompensation
    description: Accumulating organic acids and anaplerotic failure create episodic metabolic crises under catabolic stress.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Organic acid accumulation
    - Ketoacidosis
    - Secondary mitochondrial dysfunction
    evidence:
    - reference: PMID:27653704
      reference_title: "Methylmalonic and propionic acidemias: clinical management update."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: During decompensation, acidosis in these patients occurs due to accumulation of organic acids and ketoacids, while lactic acidosis also occurs, particularly in severe decompensation or with severe secondary mitochondrial dysfunction
      explanation: Review text explains the metabolic intermediates that connect the enzymatic block to acute decompensation.
  - target: Mitochondrial energy metabolism dysfunction
    description: Accumulated metabolites and reduced succinyl-CoA input impair the TCA cycle and oxidative phosphorylation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Accumulating primary and secondary organic acid metabolites
    - Succinyl-CoA deficiency
    evidence:
    - reference: PMID:27653704
      reference_title: "Methylmalonic and propionic acidemias: clinical management update."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: End-organ injury occurs due to both primary toxicity of both the accumulating primary and secondary metabolites and deficiency of succinyl-CoA resulting in Kreb cycle and oxidative phosphorylation dysfunction.
      explanation: Review text ties metabolite toxicity and succinyl-CoA deficiency to TCA and oxidative phosphorylation dysfunction.
  - target: Aberrant mitochondrial protein methylmalonylation
    description: Enlarged methylmalonyl-CoA and related acyl-CoA pools drive mitochondrial protein hyperacylation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37078237
      reference_title: "New insights into the pathophysiology of methylmalonic acidemia."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: new observations have revealed that aberrant acylation, specifically methylmalonylation, is a characteristic feature of MMA.
      explanation: Review abstract identifies methylmalonylation as a characteristic feature downstream of MMA metabolism.
  - target: Lysosomal-autophagy system dysfunction
    description: MUT deficiency perturbs lysosomal and autophagy regulation in cellular MMA models.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - MUT-deficient cellular proteome dysregulation
    evidence:
    - reference: PMID:38760822
      reference_title: "Methylmalonic acidemia triggers lysosomal-autophagy dysfunctions."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: These results indicate a strict connection between MUT deficiency and lysosomal-autophagy dysfunction, providing promising therapeutic perspectives for MMA.
      explanation: Cellular evidence connects MUT deficiency to lysosomal-autophagy dysfunction.
  - target: Pancreatitis
    description: Pancreatitis is a reported complication of MMA and other branched-chain organic acidemias; the intervening mechanism is not resolved in the cited evidence.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:8301430
      reference_title: "Pancreatitis in patients with organic acidemias."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Five had methylmalonic acidemia, three had isovaleric acidemia, and one had maple syrup urine disease.
      explanation: Case series directly reports pancreatitis in patients with methylmalonic acidemia.
    - reference: PMID:8301430
      reference_title: "Pancreatitis in patients with organic acidemias."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Acute or chronic pancreatitis may complicate branched-chain organic acidemias and must be considered in the assessment of patients with these disorders who have acute clinical deterioration and vomiting, abdominal pain, encephalopathy or shock, or milder symptoms.
      explanation: Case-series conclusion supports pancreatitis as an organic-acidemia complication while leaving the causal intermediates unresolved.
  - target: Reduced bone mineral density
    description: Low bone density is a chronic complication in MMA/PA, but the intervening mechanism is incompletely defined.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27653704
      reference_title: "Methylmalonic and propionic acidemias: clinical management update."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Although the specific mechanisms associated with bone health in OAs remain incompletely investigated, patients with PA and MMA are at significantly increased risk for osteopenia or osteoporosis that their age-matched peers, with and without renal disease
      explanation: Review text supports reduced bone density risk in MMA/PA while stating that mechanisms remain incompletely investigated.
  - target: Osteoporosis
    description: Osteoporosis is a chronic skeletal complication in MMA/PA, with unresolved causal intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27653704
      reference_title: "Methylmalonic and propionic acidemias: clinical management update."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Although the specific mechanisms associated with bone health in OAs remain incompletely investigated, patients with PA and MMA are at significantly increased risk for osteopenia or osteoporosis that their age-matched peers, with and without renal disease
      explanation: Review text supports osteoporosis risk in MMA/PA while stating that mechanisms remain incompletely investigated.
- name: Acute organic acid decompensation
  conforms_to: "metabolic_intoxication_decompensation#Acute Metabolic Decompensation"
  description: 'Catabolic stress in MMA precipitates acute metabolic decompensation with organic acid and ketoacid accumulation, metabolic acidosis, secondary hyperammonemia, vomiting, feeding intolerance, and altered mental status.

    '
  chemical_entities:
  - preferred_term: ammonia
    term:
      id: CHEBI:16134
      label: ammonia
    modifier: INCREASED
  evidence:
  - reference: PMID:27653704
    reference_title: "Methylmalonic and propionic acidemias: clinical management update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: With intercurrent illness, PA and MMA patients typically present with nausea and vomiting, worsening anorexia, and encephalopathy, with laboratory studies demonstrating metabolic acidosis, ketonuria, hyperammonemia, pancytopenia, and electrolyte disturbances
    explanation: Review text summarizes the clinical and biochemical acute decompensation pattern.
  - reference: PMID:27653704
    reference_title: "Methylmalonic and propionic acidemias: clinical management update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Accumulation of propionyl-CoA, and to some extent methylmalonyl-CoA, results in secondary inhibition of N-acetylglutamate synthase (NAGS), causing secondary hyperammonemia in these patients
    explanation: Review text provides the urea-cycle mechanism for secondary hyperammonemia.
  downstream:
  - target: Metabolic acidosis
    description: Organic acid and ketoacid accumulation during decompensation produces high-anion-gap metabolic acidosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27653704
      reference_title: "Methylmalonic and propionic acidemias: clinical management update."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: During decompensation, acidosis in these patients occurs due to accumulation of organic acids and ketoacids, while lactic acidosis also occurs, particularly in severe decompensation or with severe secondary mitochondrial dysfunction
      explanation: Review text directly explains acidosis during decompensation.
  - target: Hyperammonemia
    description: Propionyl-CoA and methylmalonyl-CoA interfere with urea-cycle activation, causing secondary hyperammonemia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - N-acetylglutamate synthase inhibition
    evidence:
    - reference: PMID:27653704
      reference_title: "Methylmalonic and propionic acidemias: clinical management update."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Accumulation of propionyl-CoA, and to some extent methylmalonyl-CoA, results in secondary inhibition of N-acetylglutamate synthase (NAGS), causing secondary hyperammonemia in these patients
      explanation: Review text directly supports the hyperammonemia mechanism.
  - target: Ammonia
    description: Urea-cycle inhibition raises circulating ammonia during decompensation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - N-acetylglutamate synthase inhibition
    evidence:
    - reference: PMID:27653704
      reference_title: "Methylmalonic and propionic acidemias: clinical management update."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Accumulation of propionyl-CoA, and to some extent methylmalonyl-CoA, results in secondary inhibition of N-acetylglutamate synthase (NAGS), causing secondary hyperammonemia in these patients
      explanation: Hyperammonemia entails increased ammonia as the biochemical abnormality.
  - target: Vomiting
    description: Acute decompensation commonly presents with nausea and vomiting.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27653704
      reference_title: "Methylmalonic and propionic acidemias: clinical management update."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: With intercurrent illness, PA and MMA patients typically present with nausea and vomiting, worsening anorexia, and encephalopathy
      explanation: Review text directly supports vomiting during acute decompensation.
  - target: Lethargy
    description: Decompensation produces altered mental status and lethargy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27653704
      reference_title: "Methylmalonic and propionic acidemias: clinical management update."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: These decompensation events typically present with decreased oral intake or enteral feeding intolerance, vomiting, and altered mental status or lethargy.
      explanation: Review text directly supports lethargy during decompensation.
- name: Mitochondrial energy metabolism dysfunction
  description: 'Accumulating primary and secondary organic acid metabolites plus deficient succinyl-CoA input disrupt the TCA cycle, oxidative phosphorylation, and fatty-acid-derived energy generation, creating energetic vulnerability in high-demand organs.

    '
  biological_processes:
  - preferred_term: mitochondrial electron transport, NADH to ubiquinone
    term:
      id: GO:0006120
      label: mitochondrial electron transport, NADH to ubiquinone
    modifier: DECREASED
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
  locations:
  - preferred_term: mitochondrial inner membrane
    term:
      id: GO:0005743
      label: mitochondrial inner membrane
  evidence:
  - reference: PMID:27653704
    reference_title: "Methylmalonic and propionic acidemias: clinical management update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: End-organ injury occurs due to both primary toxicity of both the accumulating primary and secondary metabolites and deficiency of succinyl-CoA resulting in Kreb cycle and oxidative phosphorylation dysfunction.
    explanation: Review text directly supports metabolite-driven TCA cycle and oxidative phosphorylation dysfunction.
  - reference: PMID:37169781
    reference_title: "The impact of metabolic stressors on mitochondrial homeostasis in a renal epithelial cell model of methylmalonic aciduria."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Changes in tricarboxylic acid cycle metabolites and impaired energy generation from fatty acid oxidation were detected.
    explanation: Renal epithelial cell model supports impaired mitochondrial energy metabolism under MMA stress.
  downstream:
  - target: Neurometabolic brain injury
    description: Mitochondrial energy failure and metabolite toxicity injure the high-energy CNS compartment.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Accumulating primary and secondary metabolites
    - Deficient succinyl-CoA input to the TCA cycle
    evidence:
    - reference: PMID:27653704
      reference_title: "Methylmalonic and propionic acidemias: clinical management update."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Because normal mitochondrial function requires sufficient energy production through the citric acid cycle and oxidative phosphorylation, MMA and PA result in multi-systemic chronic disease, particularly in the highly energetic organs such as brain, heart, kidney, and eye.
      explanation: Review text connects mitochondrial energy failure to injury of the brain and other high-energy organs.
  - target: Poor growth
    description: Chronic metabolic energy stress and dietary fragility contribute to poor growth.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27653704
      reference_title: "Methylmalonic and propionic acidemias: clinical management update."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Chronic complications include poor growth, movement disorders, progressive spastic quadraparesis, epilepsy, cardiac dysfunction (PA>MMA), progressive renal disease (MMA), osteopenia/osteoporosis, vision loss (MMA>PA), and functional immunodeficiency
      explanation: Review text supports poor growth as a chronic organic-acidemia complication.
  - target: Dilated cardiomyopathy
    description: Cardiac energy vulnerability and organic-acidemia complications contribute to dilated cardiomyopathy in a subset of MMA patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38132258
      reference_title: "Cardiac Involvement in Classical Organic Acidurias: Clinical Profile and Outcome in a Pediatric Cohort."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Cardiac anomalies were found in 23/60 OA patients, all with PA or MMA, represented by DCM (17/23 patients) and/or acquired long QT syndrome (3/23 patients).
      explanation: Pediatric cohort directly links organic acidurias including MMA to DCM.
  - target: Prolonged QT interval
    description: Organic-acidemia cardiac involvement can include acquired long QT syndrome.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38132258
      reference_title: "Cardiac Involvement in Classical Organic Acidurias: Clinical Profile and Outcome in a Pediatric Cohort."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Cardiac anomalies were found in 23/60 OA patients, all with PA or MMA, represented by DCM (17/23 patients) and/or acquired long QT syndrome (3/23 patients).
      explanation: Pediatric cohort directly reports acquired long QT syndrome in OA patients including MMA.
  - target: Optic neuropathy
    description: High-energy ocular tissue vulnerability contributes to optic neuropathy and vision loss in classical MMA.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31269850
      reference_title: "Optic neuropathy in classical methylmalonic acidemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Eleven (52.4%) patients had optic neuropathy.
      explanation: Classical MMA cohort supports optic neuropathy as a frequent ocular complication.
  - target: GDF15
    description: Circulating GDF15 is used as a mitochondrial dysfunction biomarker in isolated MMA.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Mitochondrial stress signaling
    evidence:
    - reference: PMID:37243446
      reference_title: "Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: growth differentiation factor 15
      explanation: Clinical biomarker study identifies GDF15 as a circulating marker of mitochondrial dysfunction in MMA.
- name: Neurometabolic brain injury
  conforms_to: "metabolic_intoxication_decompensation#Neurological Injury and Multiorgan Crisis"
  description: 'Accumulated methylmalonic acid and related metabolites, secondary mitochondrial energy failure, and acute metabolic crises injure brain tissue, particularly basal ganglia circuits, producing developmental delay, cognitive impairment, epilepsy, and metabolic stroke-like injury.

    '
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:27653704
    reference_title: "Methylmalonic and propionic acidemias: clinical management update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Patients with organic acidopathies suffer metabolic brain injury that targets specific regions of the basal ganglia in a distinctive pattern
    explanation: Review text supports basal ganglia-targeted metabolic brain injury in organic acidopathies.
  - reference: PMID:36777632
    reference_title: "Methylmalonic acidemia: Neurodevelopment and neuroimaging."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The accumulation of methylmalonic acid and other metabolites in the body of patients causes brain tissue damage, which can manifest as various degrees of intellectual disability and severe neurological dysfunction.
    explanation: Neuroimaging review connects metabolite accumulation to brain tissue damage and neurological dysfunction.
  downstream:
  - target: Global developmental delay
    description: Neurometabolic injury slows developmental trajectory in children with isolated MMA.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35348993
      reference_title: "Review of neuropsychological outcomes in isolated methylmalonic acidemia: recommendations for assessing impact of treatments."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Children with this disorder still are at risk for developmental delay, cognitive difficulties and progressive declines in functioning.
      explanation: Neuropsychology review directly supports developmental delay downstream of isolated MMA brain involvement.
  - target: Intellectual disability
    description: Brain tissue damage and neuropsychological deficits manifest as cognitive impairment.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36777632
      reference_title: "Methylmalonic acidemia: Neurodevelopment and neuroimaging."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The accumulation of methylmalonic acid and other metabolites in the body of patients causes brain tissue damage, which can manifest as various degrees of intellectual disability and severe neurological dysfunction.
      explanation: Review text directly connects MMA metabolite accumulation and brain damage to intellectual disability.
  - target: Seizures
    description: Chronic brain injury and acute metabolic crises can manifest as epilepsy or seizures.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Metabolic brain injury
    - Encephalopathy
    evidence:
    - reference: PMID:27653704
      reference_title: "Methylmalonic and propionic acidemias: clinical management update."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Chronic complications include poor growth, movement disorders, progressive spastic quadraparesis, epilepsy, cardiac dysfunction (PA>MMA), progressive renal disease (MMA), osteopenia/osteoporosis, vision loss (MMA>PA), and functional immunodeficiency
      explanation: Review text lists epilepsy among chronic organic-acidemia complications.
  - target: Basal ganglia injury
    description: MMA-associated metabolic brain injury targets basal ganglia regions and can present as metabolic stroke.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27653704
      reference_title: "Methylmalonic and propionic acidemias: clinical management update."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Patients with organic acidopathies suffer metabolic brain injury that targets specific regions of the basal ganglia in a distinctive pattern
      explanation: Review text directly supports basal ganglia-targeted brain injury.
  - target: Movement disorder
    description: Metabolic brain injury and metabolic stroke sequelae can manifest as movement disorders.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27653704
      reference_title: "Methylmalonic and propionic acidemias: clinical management update."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Movement disorders or spastic quadra- or paraparesis, potential sequelae of metabolic strokes, should be managed in collaboration with a neurologist and/or physiatrist
      explanation: Review text identifies movement disorders as potential sequelae of metabolic strokes in organic acidopathies.
  - target: Spasticity
    description: Metabolic stroke sequelae can include spastic quadri- or paraparesis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27653704
      reference_title: "Methylmalonic and propionic acidemias: clinical management update."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Movement disorders or spastic quadra- or paraparesis, potential sequelae of metabolic strokes, should be managed in collaboration with a neurologist and/or physiatrist
      explanation: Review text supports spastic paresis as a potential sequela of metabolic strokes.
- name: Aberrant mitochondrial protein methylmalonylation
  description: 'Excess methylmalonyl-CoA, propionyl-CoA, and malonyl-CoA drive widespread lysine hyperacylation of mitochondrial proteins across TCA cycle, beta-oxidation, amino acid metabolism, urea cycle, and oxidative stress pathways. Reduced levels of mitochondrial sirtuins SIRT3/4/5, particularly SIRT5 which can remove methylmalonylation, amplify dysfunction.

    '
  biological_processes:
  - preferred_term: protein acylation
    term:
      id: GO:0043543
      label: protein acylation
    modifier: INCREASED
  locations:
  - preferred_term: mitochondrial matrix
    term:
      id: GO:0005759
      label: mitochondrial matrix
  evidence:
  - reference: PMID:37078237
    reference_title: "New insights into the pathophysiology of methylmalonic acidemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: new observations have revealed that aberrant acylation, specifically methylmalonylation, is a characteristic feature of MMA. The mitochondrial sirtuin enzyme SIRT5 is capable of recognizing and removing this PTM, however, reduced protein levels of SIRT5 along with other mitochondrial SIRTs 3 and 4 in MMA
    explanation: Directly supports hyperacylation/methylmalonylation and reduced sirtuin deacylation as key pathomechanism.
  downstream:
  - target: Lipodystrophy
    description: Abnormal adipose methylmalonylation and acyl-CoA accretion are associated with the MMA lipodystrophy phenotype.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Acyl-CoA accretion in adipose tissue
    - Altered adipose inflammatory and thermogenic signaling
    evidence:
    - reference: PMID:38271099
      reference_title: "Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Fibroblast growth factor 21 levels were associated with acyl-CoA accretion, aberrant methylmalonylation in adipose tissue, and an attenuated inflammatory cytokine profile.
      explanation: Human cohort study links adipose methylmalonylation and acyl-CoA accretion to the lipodystrophy phenotype context.
    - reference: PMID:38271099
      reference_title: "Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: A distinct adipose tissue distribution pattern was observed in patients with methylmalonyl-CoA mutase deficiency, an inborn error of branched-chain amino acid (BCAA) metabolism, characterized by centripetal obesity with proximal upper and lower extremity fat deposition and paucity of visceral fat
      explanation: Human cohort study directly supports the downstream adipose distribution phenotype.
  - target: FGF21
    description: FGF21 tracks mitochondrial/adipose stress associated with acyl-CoA accretion and methylmalonylation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Adipose methylmalonylation
    - Mitochondrial stress signaling
    evidence:
    - reference: PMID:38271099
      reference_title: "Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Fibroblast growth factor 21 levels were associated with acyl-CoA accretion, aberrant methylmalonylation in adipose tissue, and an attenuated inflammatory cytokine profile.
      explanation: Study abstract supports FGF21 association with acyl-CoA accretion and methylmalonylation.
- name: Lysosomal-autophagy system dysfunction
  description: 'MUT deficiency directly perturbs the lysosome-autophagy system, causing enlarged lysosomes with reduced acidity and degradative capacity, impaired autophagosome-lysosome fusion, and severely reduced autophagic flux. These defects are pharmacologically reversible with anti-propionigenic compounds.

    '
  biological_processes:
  - preferred_term: autophagy
    term:
      id: GO:0006914
      label: autophagy
    modifier: DECREASED
  - preferred_term: lysosome organization
    term:
      id: GO:0007040
      label: lysosome organization
    modifier: ABNORMAL
  locations:
  - preferred_term: lysosome
    term:
      id: GO:0005764
      label: lysosome
  evidence:
  - reference: PMID:38760822
    reference_title: "Methylmalonic acidemia triggers lysosomal-autophagy dysfunctions."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Lysosomes of MMA cells present as enlarged vacuoles with low degradative capabilities. Notwithstanding, treatment with an anti-propionigenic drug is capable of totally rescuing lysosomal morphology and functional activity in MUT-deficient cells.
    explanation: Demonstrates lysosomal-autophagy dysfunction and pharmacological reversibility in MMA cellular models.
  downstream:
  - target: Renal mitochondrial stress and impaired mitophagy
    description: Lysosomal-autophagy failure impairs clearance of damaged mitochondria and contributes to renal mitochondrial stress.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Impaired autophagosome-lysosome fusion
    - Reduced lysosomal activity
    evidence:
    - reference: PMID:38760822
      reference_title: "Methylmalonic acidemia triggers lysosomal-autophagy dysfunctions."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Our data prove that MMA triggers such dysfunctions impacting on autophagosome-lysosome fusion and lysosomal activity.
      explanation: Cellular evidence supports the autophagy-lysosome failure that would impair mitochondrial quality control.
- name: Renal mitochondrial stress and impaired mitophagy
  description: 'In renal epithelial cells from MMA patients, metabolic stressors cause impaired mitophagy (reduced PINK1), shifted mitochondrial dynamics toward fission (elevated DRP1, reduced OPA1), compromised antioxidant defenses, and lowered glutathione ratios, contributing to progressive chronic kidney disease.

    '
  biological_processes:
  - preferred_term: mitophagy
    term:
      id: GO:0000422
      label: autophagy of mitochondrion
    modifier: DECREASED
  - preferred_term: mitochondrial fission
    term:
      id: GO:0000266
      label: mitochondrial fission
    modifier: INCREASED
  - preferred_term: antioxidant defence capacity
    term:
      id: GO:0098869
      label: cellular oxidant detoxification
    modifier: DECREASED
  cell_types:
  - preferred_term: epithelial cell of proximal tubule
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:37169781
    reference_title: "The impact of metabolic stressors on mitochondrial homeostasis in a renal epithelial cell model of methylmalonic aciduria."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Mitophagy was disabled in MMA-uria cells, while autophagy was highly active particularly under HP and I/V conditions. Mitochondrial dynamics were shifted towards fission.
    explanation: Directly demonstrates impaired mitophagy and fission shift in renal MMA cells.
  - reference: PMID:37169781
    reference_title: "The impact of metabolic stressors on mitochondrial homeostasis in a renal epithelial cell model of methylmalonic aciduria."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Creatinine levels were increased and antioxidant stress defense was severely comprised in MMA-uria cells.
    explanation: Supports compromised antioxidant defense in renal MMA cells.
  downstream:
  - target: Chronic kidney disease
    description: Renal epithelial mitochondrial stress and impaired mitophagy contribute to progressive CKD in MMA.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Impaired mitophagy
    - Antioxidant stress defense compromise
    evidence:
    - reference: PMID:37169781
      reference_title: "The impact of metabolic stressors on mitochondrial homeostasis in a renal epithelial cell model of methylmalonic aciduria."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The results point to protein toxicity in MMA-uria and lead to a better understanding, how the accumulating, potentially toxic organic acids might trigger CKD.
      explanation: Renal epithelial model links toxic organic acids and mitochondrial homeostasis changes to CKD.
  - target: Lipocalin-2 (LCN2)
    description: Renal injury from MMA is tracked by LCN2 as a circulating kidney injury biomarker.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Proximal tubular injury
    - Kidney injury biomarker response
    evidence:
    - reference: PMID:37243446
      reference_title: "Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: kidney injury (lipocalin-2
      explanation: Clinical biomarker study identifies LCN2 as a kidney injury marker in isolated MMA.
phenotypes:
- name: Metabolic acidosis
  description: Recurrent high-anion-gap metabolic acidosis, often presenting in the neonatal period.
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:25205257
    reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia
    explanation: Directly supports metabolic acidosis as a presenting feature.
- name: Hyperammonemia
  description: 'Secondary hyperammonemia during acute metabolic decompensation, related to inhibition of N-acetylglutamate synthase by propionyl-CoA.

    '
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:25205257
    reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia
    explanation: Directly supports hyperammonemia during decompensation.
  - reference: PMID:27653704
    reference_title: "Methylmalonic and propionic acidemias: clinical management update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Accumulation of propionyl-CoA, and to some extent methylmalonyl-CoA, results in secondary inhibition of N-acetylglutamate synthase (NAGS), causing secondary hyperammonemia in these patients
    explanation: Review text supports the biochemical mechanism for secondary hyperammonemia.
- name: Vomiting
  description: Recurrent emesis during catabolic stress and metabolic decompensation episodes.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:27653704
    reference_title: "Methylmalonic and propionic acidemias: clinical management update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: With intercurrent illness, PA and MMA patients typically present with nausea and vomiting, worsening anorexia, and encephalopathy
    explanation: Review text directly supports vomiting during acute decompensation.
- name: Lethargy
  description: Reduced alertness during metabolic decompensation episodes.
  phenotype_term:
    preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
  evidence:
  - reference: PMID:27653704
    reference_title: "Methylmalonic and propionic acidemias: clinical management update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: These decompensation events typically present with decreased oral intake or enteral feeding intolerance, vomiting, and altered mental status or lethargy.
    explanation: Review text directly supports lethargy during decompensation.
- name: Poor growth
  description: Chronic growth impairment due to metabolic instability, dietary restrictions, and feeding intolerance.
  phenotype_term:
    preferred_term: Poor growth
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:27653704
    reference_title: "Methylmalonic and propionic acidemias: clinical management update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Chronic complications include poor growth, movement disorders, progressive spastic quadraparesis, epilepsy, cardiac dysfunction (PA>MMA), progressive renal disease (MMA), osteopenia/osteoporosis, vision loss (MMA>PA), and functional immunodeficiency
    explanation: Review text directly supports chronic poor growth in MMA/PA.
- name: Global developmental delay
  description: 'Delayed developmental trajectory, particularly in severe mut0 forms. Mean IQ for mut0 enzymatic subtype is rarely above 85.

    '
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:35348993
    reference_title: "Review of neuropsychological outcomes in isolated methylmalonic acidemia: recommendations for assessing impact of treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Children with this disorder still are at risk for developmental delay, cognitive difficulties and progressive declines in functioning.
    explanation: Directly supports developmental delay risk in MMA.
  - reference: PMID:35348993
    reference_title: "Review of neuropsychological outcomes in isolated methylmalonic acidemia: recommendations for assessing impact of treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mean IQ for all types apart from cblA defect enzymatic subtype is rarely above 85
    explanation: Quantifies intellectual impairment severity by MMA subtype.
- name: Intellectual disability
  description: 'Cognitive impairment is common in severe MMA subtypes, with processing speed, working memory, language, and attention particularly affected.

    '
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:35348993
    reference_title: "Review of neuropsychological outcomes in isolated methylmalonic acidemia: recommendations for assessing impact of treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Children with this disorder still are at risk for developmental delay, cognitive difficulties and progressive declines in functioning.
    explanation: Supports cognitive difficulties as a key feature of MMA.
- name: Seizures
  description: 'Seizures may occur particularly in the context of metabolic decompensation and basal ganglia injury.

    '
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:27653704
    reference_title: "Methylmalonic and propionic acidemias: clinical management update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Chronic complications include poor growth, movement disorders, progressive spastic quadraparesis, epilepsy, cardiac dysfunction (PA>MMA), progressive renal disease (MMA), osteopenia/osteoporosis, vision loss (MMA>PA), and functional immunodeficiency
    explanation: Review text lists epilepsy among chronic organic-acidemia complications; this supports seizure involvement.
- name: Basal ganglia injury
  description: 'Basal ganglia injury (metabolic stroke-like injury), particularly involving basal ganglia regions, is a recognized neurological complication during acute metabolic crises.

    '
  phenotype_term:
    preferred_term: Basal ganglia injury
    term:
      id: HP:0002134
      label: Abnormal basal ganglia morphology
  evidence:
  - reference: PMID:27653704
    reference_title: "Methylmalonic and propionic acidemias: clinical management update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Patients with organic acidopathies suffer metabolic brain injury that targets specific regions of the basal ganglia in a distinctive pattern
    explanation: Review text directly supports basal ganglia-targeted metabolic brain injury.
- name: Movement disorder
  description: Movement disorders can occur as chronic complications and as sequelae of metabolic strokes in MMA/PA.
  phenotype_term:
    preferred_term: Movement disorder
    term:
      id: HP:0100022
      label: Abnormality of movement
  evidence:
  - reference: PMID:27653704
    reference_title: "Methylmalonic and propionic acidemias: clinical management update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Chronic complications include poor growth, movement disorders, progressive spastic quadraparesis, epilepsy, cardiac dysfunction (PA>MMA), progressive renal disease (MMA), osteopenia/osteoporosis, vision loss (MMA>PA), and functional immunodeficiency
    explanation: Review text lists movement disorders among chronic organic-acidemia complications.
  - reference: PMID:27653704
    reference_title: "Methylmalonic and propionic acidemias: clinical management update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Movement disorders or spastic quadra- or paraparesis, potential sequelae of metabolic strokes, should be managed in collaboration with a neurologist and/or physiatrist
    explanation: Review text supports movement disorders as potential metabolic-stroke sequelae.
- name: Spasticity
  description: Spastic quadri- or paraparesis is reported as a chronic complication and potential metabolic-stroke sequela in MMA/PA.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:27653704
    reference_title: "Methylmalonic and propionic acidemias: clinical management update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Chronic complications include poor growth, movement disorders, progressive spastic quadraparesis, epilepsy, cardiac dysfunction (PA>MMA), progressive renal disease (MMA), osteopenia/osteoporosis, vision loss (MMA>PA), and functional immunodeficiency
    explanation: Review text lists progressive spastic quadriparesis among chronic organic-acidemia complications.
  - reference: PMID:27653704
    reference_title: "Methylmalonic and propionic acidemias: clinical management update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Movement disorders or spastic quadra- or paraparesis, potential sequelae of metabolic strokes, should be managed in collaboration with a neurologist and/or physiatrist
    explanation: Review text supports spastic paresis as a potential metabolic-stroke sequela.
- name: Chronic kidney disease
  description: 'Progressive chronic kidney disease is a major long-term complication of MMA, mechanistically linked to proximal tubular mitochondrial dysfunction, oxidative stress, and impaired mitophagy.

    '
  phenotype_term:
    preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
  evidence:
  - reference: PMID:37243446
    reference_title: "Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: It is characterized by life-threatening episodes of ketoacidosis, chronic kidney disease, and other multiorgan complications.
    explanation: Directly identifies CKD as a characteristic complication of MMA.
  - reference: PMID:37169781
    reference_title: "The impact of metabolic stressors on mitochondrial homeostasis in a renal epithelial cell model of methylmalonic aciduria."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Chronic kidney disease (CKD) is a well-known long-term complication.
    explanation: Confirms CKD as an established long-term complication.
- name: Dilated cardiomyopathy
  description: 'Dilated cardiomyopathy occurs in a subset of MMA patients. In a 2000-2022 pediatric cohort, cardiac involvement occurred in approximately 38% of PA/MMA patients, with DCM predominant.

    '
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:38132258
    reference_title: "Cardiac Involvement in Classical Organic Acidurias: Clinical Profile and Outcome in a Pediatric Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cardiac anomalies were found in 23/60 OA patients, all with PA or MMA, represented by DCM (17/23 patients)
    explanation: Quantifies DCM as the predominant cardiac phenotype in OA patients including MMA.
  - reference: PMID:38132258
    reference_title: "Cardiac Involvement in Classical Organic Acidurias: Clinical Profile and Outcome in a Pediatric Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 35% in MMA with cardiomyopathy
    explanation: Quantifies 5-year MACE rate in MMA patients with cardiomyopathy.
- name: Prolonged QT interval
  description: 'Acquired long QT syndrome is a recognized arrhythmia risk in MMA, associated with metabolic decompensation and chronic disease.

    '
  phenotype_term:
    preferred_term: Prolonged QT interval
    term:
      id: HP:0001657
      label: Prolonged QT interval
  evidence:
  - reference: PMID:38132258
    reference_title: "Cardiac Involvement in Classical Organic Acidurias: Clinical Profile and Outcome in a Pediatric Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cardiac anomalies were found in 23/60 OA patients, all with PA or MMA, represented by DCM (17/23 patients) and/or acquired long QT syndrome (3/23 patients).
    explanation: Directly reports acquired long QT syndrome in OA patients including MMA.
- name: Pancreatitis
  description: 'Acute pancreatitis is a recognized complication, occurring during or independent of metabolic decompensation episodes.

    '
  phenotype_term:
    preferred_term: Pancreatitis
    term:
      id: HP:0001733
      label: Pancreatitis
  evidence:
  - reference: PMID:8301430
    reference_title: "Pancreatitis in patients with organic acidemias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Five had methylmalonic acidemia, three had isovaleric acidemia, and one had maple syrup urine disease.
    explanation: Case series directly reports pancreatitis in patients with methylmalonic acidemia.
  - reference: PMID:8301430
    reference_title: "Pancreatitis in patients with organic acidemias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Acute or chronic pancreatitis may complicate branched-chain organic acidemias and must be considered in the assessment of patients with these disorders who have acute clinical deterioration and vomiting, abdominal pain, encephalopathy or shock, or milder symptoms.
    explanation: Case-series conclusion supports pancreatitis as an organic-acidemia complication.
- name: Reduced bone mineral density
  description: Osteopenia or reduced bone mineral density is a chronic skeletal complication in MMA/PA; the mechanism is not fully established.
  phenotype_term:
    preferred_term: Reduced bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  evidence:
  - reference: PMID:27653704
    reference_title: "Methylmalonic and propionic acidemias: clinical management update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Although the specific mechanisms associated with bone health in OAs remain incompletely investigated, patients with PA and MMA are at significantly increased risk for osteopenia or osteoporosis that their age-matched peers, with and without renal disease
    explanation: Review text supports increased risk for osteopenia/reduced bone density in MMA/PA.
  - reference: PMID:27653704
    reference_title: "Methylmalonic and propionic acidemias: clinical management update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Various pathologies including vertebral fusion anomalies, vertebral compression and fractures, as well as generalized osteopenia, have been observed.
    explanation: Review text reports generalized osteopenia among observed skeletal pathologies.
- name: Osteoporosis
  description: Osteoporosis is reported as a chronic skeletal complication in MMA/PA, requiring bone-density surveillance.
  phenotype_term:
    preferred_term: Osteoporosis
    term:
      id: HP:0000939
      label: Osteoporosis
  evidence:
  - reference: PMID:27653704
    reference_title: "Methylmalonic and propionic acidemias: clinical management update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Although the specific mechanisms associated with bone health in OAs remain incompletely investigated, patients with PA and MMA are at significantly increased risk for osteopenia or osteoporosis that their age-matched peers, with and without renal disease
    explanation: Review text directly supports osteoporosis risk in MMA/PA.
  - reference: PMID:27653704
    reference_title: "Methylmalonic and propionic acidemias: clinical management update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: If pathological fractures or significant osteopenia/osteoporosis are detected on screening, more robust monitoring for bone density and response to interventions are indicated.
    explanation: Review text supports osteoporosis surveillance and management as part of MMA/PA care.
- name: Optic neuropathy
  description: 'Optic neuropathy has been reported as a long-term complication, attributed to mitochondrial dysfunction in the optic nerve.

    '
  phenotype_term:
    preferred_term: Optic neuropathy
    term:
      id: HP:0001138
      label: Optic neuropathy
  evidence:
  - reference: PMID:31269850
    reference_title: "Optic neuropathy in classical methylmalonic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Eleven (52.4%) patients had optic neuropathy.
    explanation: Classical MMA cohort directly supports optic neuropathy.
  - reference: PMID:27653704
    reference_title: "Methylmalonic and propionic acidemias: clinical management update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: not entirely prevent brain injury or the development of optic neuropathy and cardiac disease
    explanation: Management review supports optic neuropathy as an MMA/PA end-organ complication.
- name: Lipodystrophy
  description: 'A distinct adipose tissue distribution pattern resembling familial multiple lipomatosis, with centripetal obesity, proximal extremity fat deposition, and paucity of visceral fat. Associated with elevated FGF21 and aberrant methylmalonylation in adipose tissue.

    '
  phenotype_term:
    preferred_term: Lipodystrophy
    term:
      id: HP:0009125
      label: Lipodystrophy
  evidence:
  - reference: PMID:38271099
    reference_title: "Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A distinct adipose tissue distribution pattern was observed in patients with methylmalonyl-CoA mutase deficiency, an inborn error of branched-chain amino acid (BCAA) metabolism, characterized by centripetal obesity with proximal upper and lower extremity fat deposition and paucity of visceral fat
    explanation: Directly identifies a novel lipodystrophy phenotype in MMA patients.
biochemical:
- name: Methylmalonic acid
  presence: INCREASED
  context: 'The hallmark metabolite of MMA. Massively elevated in blood and urine. Normal blood levels are less than 270 nmol/L; MMA patients have supraphysiologic elevations.

    '
  loinc_term:
    id: LOINC:LP15735-1
    label: Methylmalonate
  notes: >-
    Described in blood and urine, so loinc_term binds the specimen-agnostic
    LOINC Part; the dried-blood-spot second-tier code and its cut-off sit on
    the newborn-screening diagnosis row.
  biomarker_term:
    preferred_term: methylmalonic acid
    term:
      id: CHEBI:30860
      label: methylmalonic acid
  readouts:
  - target: Impaired methylmalonyl-CoA metabolism
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Increased serum or urinary methylmalonic acid reports the blocked
      methylmalonyl-CoA mutase/cofactor pathway.
    evidence:
    - reference: PMID:37243446
      reference_title: "Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Canonical metabolic markers, such as serum methylmalonic acid and propionylcarnitine, are variable and affected by dietary intake and renal function.
      explanation: Patient biomarker study identifies serum methylmalonic acid as a canonical MMA metabolic marker.
  evidence:
  - reference: PMID:37243446
    reference_title: "Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Canonical metabolic markers, such as serum methylmalonic acid and propionylcarnitine, are variable and affected by dietary intake and renal function.
    explanation: Identifies serum methylmalonic acid as a canonical metabolic marker in MMA.
  - reference: PMID:38030482
    reference_title: "Methylmalonic acid in aging and disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: MMA is normally present at low levels in the body, but increased levels can come from different sources, such as vitamin B12 deficiency, genetic mutations in enzymes related to the propionate pathway
    explanation: Opinion/review source providing contextual support for MMA elevation mechanisms.
- name: Propionylcarnitine (C3)
  presence: INCREASED
  context: 'Elevated C3-acylcarnitine is the primary newborn screening marker for MMA. Also used for clinical monitoring during follow-up.

    '
  loinc_term:
    id: LOINC:LP19303-4
    label: Propionylcarnitine (C3)
  notes: >-
    Described in the newborn-screening dried blood spot and in follow-up
    plasma monitoring, so loinc_term binds the specimen-agnostic LOINC Part;
    the DBS quantitative code and its cut-offs sit on the newborn-screening
    diagnosis row.
  biomarker_term:
    preferred_term: propionylcarnitine
    term:
      id: CHEBI:17387
      label: O-acylcarnitine
  readouts:
  - target: Impaired methylmalonyl-CoA metabolism
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated propionylcarnitine reports propionate-pathway metabolite
      accumulation used for MMA diagnosis and newborn screening.
    evidence:
    - reference: PMID:27653704
      reference_title: "Methylmalonic and propionic acidemias: clinical management update."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: In MMA, elevations of plasma propionylcarnitine, glycine, and alanine coupled with elevation of urinary methylmalonic, 3-OH-propionic, and methylcitric acids provide the diagnosis
      explanation: Review evidence directly supports propionylcarnitine as a positive diagnostic readout of MMA metabolite burden.
  evidence:
  - reference: PMID:37243446
    reference_title: "Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Canonical metabolic markers, such as serum methylmalonic acid and propionylcarnitine, are variable and affected by dietary intake and renal function.
    explanation: Directly identifies propionylcarnitine as a canonical metabolic marker.
  - reference: PMID:39075538
    reference_title: "Clinical outcomes of patients with mut-type methylmalonic acidemia identified through expanded newborn screening in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: NBS-detected patients showed younger age at diagnosis, less incidence of disease onset, better responsiveness of vitamin B12, younger age at start of treatment, lower levels of biochemical features before and after treatment
    explanation: Supports biochemical marker reduction after newborn-screening detection and treatment.
  - reference: PMID:27653704
    reference_title: "Methylmalonic and propionic acidemias: clinical management update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Diagnosis is based on clinical presentation and laboratory analysis, metabolic acidosis, ketoacidosis, lactic acidosis, hyperammonemia, hypoglycemia, pancytopenia, and elevated C3 acylcarnitines and organic acids in the urine.
    explanation: Review text directly supports elevated C3 acylcarnitines as a diagnostic biochemical abnormality.
- name: 2-Methylcitric acid
  presence: INCREASED
  context: 'A characteristic metabolite formed by condensation of propionyl-CoA with oxaloacetate via citrate synthase. Methylcitrate-to-citrate ratio is used in clinical monitoring. Potentially toxic metabolite contributing to TCA cycle disruption.

    '
  loinc_term:
    id: LOINC:LP18136-9
    label: 2-Methylcitrate
  notes: >-
    Described as a metabolite across body fluids, so loinc_term binds the LOINC
    Part; the dried-blood-spot second-tier code and its cut-offs sit on the
    newborn-screening diagnosis row.
  biomarker_term:
    preferred_term: 2-methylcitric acid
    term:
      id: CHEBI:30835
      label: 2-methylcitric acid
  readouts:
  - target: Impaired methylmalonyl-CoA metabolism
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Increased methylcitric acid reports propionyl-CoA overflow into
      disease-specific organic-acid metabolites.
    evidence:
    - reference: PMID:27653704
      reference_title: "Methylmalonic and propionic acidemias: clinical management update."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: In MMA, elevations of plasma propionylcarnitine, glycine, and alanine coupled with elevation of urinary methylmalonic, 3-OH-propionic, and methylcitric acids provide the diagnosis
      explanation: Review evidence supports methylcitric acid as a positive diagnostic readout of MMA metabolite burden.
  - target: Renal mitochondrial stress and impaired mitophagy
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: >-
      Increased methylcitrate under renal epithelial metabolic stress reports a
      potentially toxic, disease-specific metabolite branch relevant to kidney
      injury models.
    evidence:
    - reference: PMID:37169781
      reference_title: "The impact of metabolic stressors on mitochondrial homeostasis in a renal epithelial cell model of methylmalonic aciduria."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Methylcitrate as potentially toxic, disease-specific metabolite was increased by HP and I/V load.
      explanation: Renal epithelial cell model evidence supports methylcitrate as a stress-responsive toxic MMA metabolite.
  evidence:
  - reference: PMID:37169781
    reference_title: "The impact of metabolic stressors on mitochondrial homeostasis in a renal epithelial cell model of methylmalonic aciduria."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Methylcitrate as potentially toxic, disease-specific metabolite was increased by HP and I/V load.
    explanation: Identifies methylcitrate as a toxic, disease-specific metabolite elevated in MMA.
- name: 3-Hydroxypropionate
  presence: INCREASED
  context: 'Urinary organic acid marker elevated in MMA, reflecting propionate pathway overflow.

    '
  biomarker_term:
    preferred_term: 3-hydroxypropionate
    term:
      id: CHEBI:16510
      label: 3-hydroxypropionate
  readouts:
  - target: Impaired methylmalonyl-CoA metabolism
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Urinary 3-hydroxypropionate reports propionyl-CoA diversion through
      beta-oxidation during MMA.
    evidence:
    - reference: PMID:4507604
      reference_title: "3-hydroxypropionate: significance of -oxidation of propionate in patients with propionic acidemia and methylmalonic acidemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: '[l-(14)C]Propionate administered intravenously was metabolized to methylmalonate, to 3-hydroxypropionate, and to methylcitrate in the urine of a patient with methylmalonic acidemia.'
      explanation: Patient isotope-tracing evidence directly supports 3-hydroxypropionate as a positive readout of MMA propionate-pathway overflow.
  evidence:
  - reference: PMID:4507604
    reference_title: "3-hydroxypropionate: significance of -oxidation of propionate in patients with propionic acidemia and methylmalonic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '[l-(14)C]Propionate administered intravenously was metabolized to methylmalonate, to 3-hydroxypropionate, and to methylcitrate in the urine of a patient with methylmalonic acidemia.'
    explanation: Patient isotope tracing directly supports urinary 3-hydroxypropionate formation in methylmalonic acidemia.
  - reference: PMID:27653704
    reference_title: "Methylmalonic and propionic acidemias: clinical management update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In MMA, elevations of plasma propionylcarnitine, glycine, and alanine coupled with elevation of urinary methylmalonic, 3-OH-propionic, and methylcitric acids provide the diagnosis
    explanation: Review text includes urinary 3-OH-propionic acid in the diagnostic biochemical pattern.
- name: FGF21
  presence: INCREASED
  context: 'Fibroblast growth factor 21 is a mitochondrial stress biomarker elevated in MMA. Correlates with disease severity and complications attributed to mitochondrial dysfunction. Responds to liver-targeted therapies and transplantation.

    '
  biomarker_term:
    preferred_term: fibroblast growth factor 21 measurement
    term:
      id: NCIT:C112280
      label: Fibroblast Growth Factor 21 Measurement
  readouts:
  - target: Mitochondrial energy metabolism dysfunction
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: >-
      Increased FGF21 reports mitochondrial dysfunction and multisystem disease
      burden in isolated MMA.
    evidence:
    - reference: PMID:37243446
      reference_title: "Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We have therefore explored the use of the 1-13 C-propionate oxidation breath test (POBT) to measure metabolic capacity and the changes in circulating proteins to assess mitochondrial dysfunction (fibroblast growth factor 21 FGF21 and growth differentiation factor 15 GDF15) and kidney injury (lipocalin-2 LCN2)."
      explanation: Clinical biomarker study identifies FGF21 as a circulating protein marker used to assess mitochondrial dysfunction.
  - target: Aberrant mitochondrial protein methylmalonylation
    relationship: CORRELATES_WITH
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: >-
      FGF21 levels correlate with acyl-CoA accretion and aberrant adipose
      methylmalonylation in MMA.
    evidence:
    - reference: PMID:38271099
      reference_title: "Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Fibroblast growth factor 21 levels were associated with acyl-CoA accretion, aberrant methylmalonylation in adipose tissue, and an attenuated inflammatory cytokine profile.
      explanation: Human cohort evidence supports FGF21 as a positive correlate of acyl-CoA accretion and aberrant methylmalonylation.
  evidence:
  - reference: PMID:38271099
    reference_title: "Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Fibroblast growth factor 21 levels were associated with acyl-CoA accretion, aberrant methylmalonylation in adipose tissue, and an attenuated inflammatory cytokine profile.
    explanation: Links FGF21 levels to aberrant methylmalonylation in MMA patients.
  - reference: PMID:37243446
    reference_title: "Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Biomarker concentrations are higher in patients with the severe mut0 -type and cblB-type MMA
    explanation: Supports increased biomarker concentrations in severe MMA subtypes after FGF21/GDF15/LCN2 are introduced as biomarker targets.
- name: GDF15
  presence: INCREASED
  context: 'Growth differentiation factor 15 is a mitochondrial stress biomarker elevated in MMA, used alongside FGF21 to assess disease severity.

    '
  biomarker_term:
    preferred_term: growth differentiation factor 15 measurement
    term:
      id: NCIT:C181406
      label: Growth Differentiation Factor 15 Measurement
  readouts:
  - target: Mitochondrial energy metabolism dysfunction
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: >-
      Increased GDF15 reports mitochondrial dysfunction and multisystem disease
      burden in isolated MMA.
    evidence:
    - reference: PMID:37243446
      reference_title: "Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We have therefore explored the use of the 1-13 C-propionate oxidation breath test (POBT) to measure metabolic capacity and the changes in circulating proteins to assess mitochondrial dysfunction (fibroblast growth factor 21 FGF21 and growth differentiation factor 15 GDF15) and kidney injury (lipocalin-2 LCN2)."
      explanation: Clinical biomarker study identifies GDF15 as a circulating protein marker used to assess mitochondrial dysfunction.
  - target: MMUT/AdoCbl pathway molecular function deficiency
    relationship: CORRELATES_WITH
    direction: POSITIVE
    endpoint_context: PROGNOSTIC
    interpretation: >-
      Higher biomarker concentrations are associated with severe mut0 and cblB
      MMA subtypes and reduced propionate oxidation capacity.
    evidence:
    - reference: PMID:37243446
      reference_title: "Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Biomarker concentrations are higher in patients with the severe mut0 -type and cblB-type MMA, correlate with a decreased POBT, and show a significant response postliver transplant.
      explanation: Patient biomarker evidence supports GDF15/FGF21/LCN2 concentrations as positive severity correlates in severe MMA subtypes.
  evidence:
  - reference: PMID:37243446
    reference_title: "Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have therefore explored the use of the 1-13 C-propionate oxidation breath test (POBT) to measure metabolic capacity and the changes in circulating proteins to assess mitochondrial dysfunction (fibroblast growth factor 21 FGF21 and growth differentiation factor 15 GDF15) and kidney injury (lipocalin-2 LCN2)."
    explanation: Identifies GDF15 as a circulating mitochondrial dysfunction biomarker evaluated in isolated MMA cohorts.
  - reference: PMID:37243446
    reference_title: "Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Biomarker concentrations are higher in patients with the severe mut0 -type and cblB-type MMA
    explanation: Provides cohort context that biomarker elevations are strongest in severe MMA subtypes.
- name: Lipocalin-2 (LCN2)
  presence: INCREASED
  context: 'A kidney injury biomarker elevated in MMA, tied to proximal tubule mitochondrial dysfunction and oxidative stress. May be more sensitive than creatinine for early detection of renal injury.

    '
  biomarker_term:
    preferred_term: lipocalin-2 measurement
    term:
      id: NCIT:C106539
      label: Lipocalin-2 Measurement
  readouts:
  - target: Renal mitochondrial stress and impaired mitophagy
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: >-
      Increased LCN2 reports kidney injury downstream of renal mitochondrial
      stress and toxic organic-acid exposure.
    evidence:
    - reference: PMID:37243446
      reference_title: "Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We have therefore explored the use of the 1-13 C-propionate oxidation breath test (POBT) to measure metabolic capacity and the changes in circulating proteins to assess mitochondrial dysfunction (fibroblast growth factor 21 FGF21 and growth differentiation factor 15 GDF15) and kidney injury (lipocalin-2 LCN2)."
      explanation: Clinical biomarker study identifies LCN2 as a kidney-injury marker in isolated MMA.
  evidence:
  - reference: PMID:37243446
    reference_title: "Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have therefore explored the use of the 1-13 C-propionate oxidation breath test (POBT) to measure metabolic capacity and the changes in circulating proteins to assess mitochondrial dysfunction (fibroblast growth factor 21 FGF21 and growth differentiation factor 15 GDF15) and kidney injury (lipocalin-2 LCN2)."
    explanation: Identifies LCN2 as a kidney injury biomarker in MMA.
- name: Ammonia
  presence: INCREASED
  context: 'Secondary hyperammonemia occurs during acute decompensation due to inhibition of N-acetylglutamate synthase by propionyl-CoA, impairing the urea cycle.

    '
  biomarker_term:
    preferred_term: ammonia
    term:
      id: CHEBI:16134
      label: ammonia
  readouts:
  - target: Acute organic acid decompensation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Increased ammonia reports secondary urea-cycle inhibition during acute
      organic-acid decompensation.
    evidence:
    - reference: PMID:27653704
      reference_title: "Methylmalonic and propionic acidemias: clinical management update."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Accumulation of propionyl-CoA, and to some extent methylmalonyl-CoA, results in secondary inhibition of N-acetylglutamate synthase (NAGS), causing secondary hyperammonemia in these patients
      explanation: Review evidence supports increased ammonia as a positive readout of secondary hyperammonemia during decompensation.
  - target: Hyperammonemia
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Increased circulating ammonia is the biochemical readout of the
      hyperammonemia phenotype.
    evidence:
    - reference: PMID:25205257
      reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia
      explanation: Guideline evidence supports hyperammonemia as a presenting biochemical abnormality in MMA.
  evidence:
  - reference: PMID:25205257
    reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia
    explanation: Directly supports hyperammonemia as a presenting feature of MMA.
  - reference: PMID:27653704
    reference_title: "Methylmalonic and propionic acidemias: clinical management update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Accumulation of propionyl-CoA, and to some extent methylmalonyl-CoA, results in secondary inhibition of N-acetylglutamate synthase (NAGS), causing secondary hyperammonemia in these patients
    explanation: Review text supports the urea-cycle mechanism that raises ammonia.
genetic:
- name: MMUT (methylmalonyl-CoA mutase)
  gene_term:
    preferred_term: MMUT
    term:
      id: hgnc:7526
      label: MMUT
  relationship_type: CAUSATIVE
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:35348993
      reference_title: "Review of neuropsychological outcomes in isolated methylmalonic acidemia: recommendations for assessing impact of treatments."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Methylmalonic acidemia (MMA) due to methylmalonyl-CoA mutase deficiency (OMIM #251,000) is an autosomal recessive disorder of organic acid metabolism'
      explanation: Directly supports autosomal recessive inheritance.
  variants:
  - name: mut0 (complete deficiency)
    description: 'Complete loss of methylmalonyl-CoA mutase activity. Non-B12 responsive. Associated with the most severe phenotype and worst neuropsychological outcomes.

      '
  - name: mut- (partial deficiency)
    description: 'Partial residual methylmalonyl-CoA mutase activity. Some forms show partial response to hydroxocobalamin.

      '
  features: 'MMUT encodes the mitochondrial enzyme methylmalonyl-CoA mutase that catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA using adenosylcobalamin as cofactor. Biallelic pathogenic variants produce mut0 (complete deficiency, non-B12 responsive) and mut- (partial deficiency, sometimes B12 responsive) phenotypes.

    '
  evidence:
  - reference: CGGV:assertion_3c5301da-0dad-417a-8257-5b1c6155e8fa-2019-05-09T160000.000Z
    reference_title: "MMUT / methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MMUT | HGNC:7526 | methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency | MONDO:0009612 | AR | Definitive"
    explanation: ClinGen classifies the MMUT gene-disease relationship as definitive with autosomal recessive inheritance.
- name: MMAA (cblA complementation group)
  gene_term:
    preferred_term: MMAA
    term:
      id: hgnc:18871
      label: MMAA
  relationship_type: CAUSATIVE
  subtype: Vitamin B12-responsive methylmalonic acidemia
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:35348993
      reference_title: "Review of neuropsychological outcomes in isolated methylmalonic acidemia: recommendations for assessing impact of treatments."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'These other disorders include enzymatic subtypes related to cobalamin A defect (cblA) (OMIM #25,110), cobalamin B defect (cblB) (OMIM #251,110) and related conditions.'
      explanation: Explicitly names cblA as an isolated MMA subtype; inheritance is inferred from the shared disease class.
  features: 'MMAA encodes a mitochondrial protein required for adenosylcobalamin cofactor delivery to MMUT. cblA-type MMA is generally associated with better B12 responsiveness and milder phenotype.

    '
  evidence:
  - reference: PMID:35348993
    reference_title: "Review of neuropsychological outcomes in isolated methylmalonic acidemia: recommendations for assessing impact of treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'These other disorders include enzymatic subtypes related to cobalamin A defect (cblA) (OMIM #25,110), cobalamin B defect (cblB) (OMIM #251,110) and related conditions.'
    explanation: Identifies cblA as a defined enzymatic subtype of MMA.
  - reference: CGGV:assertion_5b81bb9e-5f71-47bf-b187-5eef83d91d57-2022-07-13T160000.000Z
    reference_title: "MMAA / methylmalonic aciduria, cblA type (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MMAA | HGNC:18871 | methylmalonic aciduria, cblA type | MONDO:0009613 | AR | Definitive"
    explanation: ClinGen classifies the MMAA gene-disease relationship as definitive with autosomal recessive inheritance.
- name: MMAB (cblB complementation group)
  gene_term:
    preferred_term: MMAB
    term:
      id: hgnc:19331
      label: MMAB
  relationship_type: CAUSATIVE
  subtype: Vitamin B12-unresponsive methylmalonic acidemia
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:35348993
      reference_title: "Review of neuropsychological outcomes in isolated methylmalonic acidemia: recommendations for assessing impact of treatments."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'These other disorders include enzymatic subtypes related to cobalamin A defect (cblA) (OMIM #25,110), cobalamin B defect (cblB) (OMIM #251,110) and related conditions.'
      explanation: Explicitly names cblB as an isolated MMA subtype; inheritance is inferred from the shared disease class.
  features: 'MMAB encodes cob(I)alamin adenosyltransferase required for adenosylcobalamin synthesis. cblB-type MMA tends to be more severe than cblA-type with higher biomarker levels.

    '
  evidence:
  - reference: PMID:37243446
    reference_title: "Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Data are presented from a US natural history protocol that evaluated subjects with different types of MMA including mut-type (N = 91), cblB-type (15), and cblA-type MMA (17)
    explanation: Identifies cblB as a defined subtype with distinct severity profile.
  - reference: CGGV:assertion_52b61ff5-afba-4ff7-adbc-51de6a837db7-2022-07-13T160000.000Z
    reference_title: "MMAB / methylmalonic aciduria, cblB type (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MMAB | HGNC:19331 | methylmalonic aciduria, cblB type | MONDO:0009614 | AR | Definitive"
    explanation: ClinGen classifies the MMAB gene-disease relationship as definitive with autosomal recessive inheritance.
  - reference: CGGV:assertion_52b61ff5-afba-4ff7-adbc-51de6a837db7-2022-07-13T160000.000Z
    reference_title: "MMAB / methylmalonic aciduria, cblB type (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "While patients with MMA due to variants in MMAA (type CblA) are responsive to Vitamin B12, only rare individuals with type CblB are responsive to treatment with Vitamin B12"
    explanation: Supports assigning cblB predominantly to the vitamin B12-unresponsive subtype and cblA to the responsive one.
- name: MMADHC (cblD complementation group)
  gene_term:
    preferred_term: MMADHC
    term:
      id: hgnc:25221
      label: MMADHC
  relationship_type: CAUSATIVE
  subtype: Vitamin B12-responsive methylmalonic acidemia
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:20301409
      reference_title: "Isolated Methylmalonic Acidemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All forms of isolated MMA are inherited in an autosomal recessive manner."
      explanation: GeneReviews states autosomal recessive inheritance for every form of isolated MMA, cblD-MMA included.
  features: >-
    MMADHC (formerly C2orf25) is the cblD gene. Its product acts at the branch
    point of intracellular cobalamin trafficking, so which of the two coenzymes
    is lost depends on where in the protein the variant falls. Variants that
    spare the cytosolic methylcobalamin arm but not the mitochondrial
    adenosylcobalamin arm give isolated methylmalonic aciduria (cblD-MMA), and
    it is that form which belongs to this entry; cblD-HC and combined cblD-MMA/HC
    are curated separately.
  evidence:
  - reference: PMID:18385497
    reference_title: "Gene identification for the cblD defect of vitamin B12 metabolism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The cblD gene was localized to human chromosome 2q23.2, and a candidate gene, designated MMADHC (methylmalonic aciduria, cblD type, and homocystinuria), was identified in this region."
    explanation: The identification of MMADHC as the cblD gene, by mapping plus rescue of the cellular phenotype in patient fibroblasts.
  - reference: PMID:18385497
    reference_title: "Gene identification for the cblD defect of vitamin B12 metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One of these defects, the cblD defect, can cause isolated methylmalonic aciduria, isolated homocystinuria, or both."
    explanation: Establishes that isolated methylmalonic aciduria is one of the three cblD presentations, which is the one this entry covers.
  - reference: PMID:22156578
    reference_title: "Molecular mechanisms leading to three different phenotypes in the cblD defect of intracellular cobalamin metabolism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Expression of 10 mutant alleles from 15 cblD patients confirmed that the nature and location of the mutations correlate with the biochemical phenotype."
    explanation: Transfection of patient alleles into cblD fibroblasts shows the variant's position determines whether the MMA-only, HC-only or combined phenotype results.
  - reference: CGGV:assertion_40ec59af-a143-4424-9218-7fd75deb6a61-2021-05-12T182739.747Z
    reference_title: "MMADHC / inborn disorder of cobalamin metabolism and transport (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MMADHC | HGNC:25221 | inborn disorder of cobalamin metabolism and transport | MONDO:0019220 | AR | Definitive"
    explanation: ClinGen classifies MMADHC as definitive, curated at the lumped cobalamin-disorder level rather than separately for the cblD-MMA presentation.
- name: MCEE (methylmalonyl-CoA epimerase)
  gene_term:
    preferred_term: MCEE
    term:
      id: hgnc:16732
      label: MCEE
  relationship_type: CAUSATIVE
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:20301409
      reference_title: "Isolated Methylmalonic Acidemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All forms of isolated MMA are inherited in an autosomal recessive manner."
      explanation: GeneReviews states autosomal recessive inheritance for every form of isolated MMA, epimerase deficiency included.
  features: >-
    MCEE acts one step before the mutase, racemizing D-methylmalonyl-CoA to the
    L isomer that methylmalonyl-CoA mutase requires. Fewer than twenty probands
    have been reported and the founder nonsense allele p.Arg47* accounts for the
    predominance of cases. The gene has its own dismech entry
    (Methylmalonyl-CoA_Epimerase_Deficiency), bound to MONDO:0009615; it is
    listed here because GeneReviews counts it among the genes whose biallelic
    variants establish a diagnosis of isolated MMA.
  evidence:
  - reference: PMID:20301409
    reference_title: "Isolated Methylmalonic Acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of isolated MMA is established in a proband by identification of biallelic pathogenic variants in MCEE, MMAA, MMAB, MMADHC, or MMUT"
    explanation: GeneReviews counts MCEE among the five genes whose biallelic variants establish a diagnosis of isolated MMA.
  - reference: CGGV:assertion_b8546531-fe3d-48fd-8103-f5f84fd04514-2020-07-09T160000.000Z
    reference_title: "MCEE / methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MCEE | HGNC:16732 | methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency | MONDO:0009615 | AR | Definitive"
    explanation: ClinGen classifies the MCEE gene-disease relationship as definitive with autosomal recessive inheritance.
- name: CD320 (transcobalamin receptor defect)
  gene_term:
    preferred_term: CD320
    term:
      id: hgnc:16692
      label: CD320
  relationship_type: CAUSATIVE
  subtype: TCblR defect
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_d98515f5-4296-4d41-95a9-adac90c00349-2022-09-23T160000.000Z
      reference_title: "CD320 / methylmalonic acidemia due to transcobalamin receptor defect (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "CD320 | HGNC:16692 | methylmalonic acidemia due to transcobalamin receptor defect | MONDO:0013341 | AR | Definitive"
      explanation: ClinGen records autosomal recessive inheritance for the transcobalamin receptor defect.
  features: >-
    CD320 encodes the transcobalamin receptor (TCblR), which brings
    cobalamin-loaded transcobalamin into the cell. The defect is picked up almost
    exclusively through newborn screening for propionic/methylmalonic aciduria,
    and it is separated from the mutase and cofactor forms by its course rather
    than by its biochemistry, in that the elevations correct on oral cobalamin
    and ClinGen records that p.Glu88del homozygotes have typically had no major
    health or developmental concerns. ClinGen grades the gene-disease
    relationship Definitive while recording that the condition is probably
    benign.
  evidence:
  - reference: CGGV:assertion_d98515f5-4296-4d41-95a9-adac90c00349-2022-09-23T160000.000Z
    reference_title: "CD320 / methylmalonic acidemia due to transcobalamin receptor defect (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Data indicates that about 85% of these individuals may not be identified, and that the condition is probably benign, although further studies are needed to assess any longterm health effects"
    explanation: ClinGen's own caveat that the transcobalamin receptor defect is probably a benign biochemical phenotype, which is why it is kept distinct from the mutase and cofactor forms.
  - reference: PMID:29663633
    reference_title: "Transcobalamin receptor defect: Identification of two new cases through positive newborn screening for propionic/methylmalonic aciduria and long-term outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two asymptomatic cases were identified through a positive newborn screening for propionic/methylmalonic aciduria."
    explanation: The route by which this form presents, and the basis for treating it as a newborn-screening differential rather than a clinical organic acidemia.
  - reference: PMID:29663633
    reference_title: "Transcobalamin receptor defect: Identification of two new cases through positive newborn screening for propionic/methylmalonic aciduria and long-term outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, both patients remain asymptomatic with normal neurodevelopment more than 6 years."
    explanation: Long-term follow-up supporting the benign course recorded in this entry's description of the subtype.
  - reference: CGGV:assertion_d98515f5-4296-4d41-95a9-adac90c00349-2022-09-23T160000.000Z
    reference_title: "CD320 / methylmalonic acidemia due to transcobalamin receptor defect (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Except for one individual from a consanguineous family who presented with bilateral retinal artery occlusions at 7 weeks of age"
    explanation: The one reported symptomatic exception to the otherwise asymptomatic course, recorded so the benign characterization is not read as absolute.
diagnosis:
- name: Newborn screening
  description: 'Detection of MMA via tandem mass spectrometry using elevated propionylcarnitine (C3) as the primary marker. A multicenter Chinese study demonstrated NBS-detected mut-type MMA patients had significantly lower mortality (12.5% vs 32.7%) and better outcomes (normal outcome 51.8% vs 15.7%) compared to clinically diagnosed patients.

    '
  diagnosis_term:
    preferred_term: newborn screening
    term:
      id: NCIT:C81178
      label: Newborn Screening
  measurements:
  - preferred_term: propionylcarnitine (C3), DBS
    term:
      id: LOINC:53160-8
      label: Propionylcarnitine (C3) [Moles/volume] in DBS
  - preferred_term: propionylcarnitine/acetylcarnitine (C3/C2) molar ratio, DBS
    term:
      id: LOINC:53163-2
      label: Propionylcarnitine (C3)/Acetylcarnitine (C2) [Molar ratio] in DBS
  - preferred_term: methylmalonic acid, DBS (second tier)
    term:
      id: LOINC:82385-6
      label: Methylmalonate [Moles/volume] in DBS
  - preferred_term: 2-methylcitric acid, DBS (second tier)
    term:
      id: LOINC:82386-4
      label: 2-Methylcitrate [Moles/volume] in DBS
  reference_ranges:
  - loinc_term:
      id: LOINC:53160-8
      label: Propionylcarnitine (C3) [Moles/volume] in DBS
    unit: umol/L
    population: >-
      healthy newborns, Serbia (n=1,771); cut-offs proposed for a programme
      that did not yet screen organic acidemias
    notes: >-
      A proposed cut-off, derived from the distribution in healthy newborns and
      offered as the starting point for a future Serbian programme, not a value
      an operating programme applied. It is stated as ">5.73", so exactly 5.73
      is negative there; the half-open band places exactly 5.73 in the positive
      band. The source states one cut-off for methylmalonic acidemia or
      propionic acidemia, because the analyte does not separate them; the same
      range is recorded on the Propionic_Acidemia entry. An operating
      programme's absolute C3 cut-off could not be found stated in a PubMed
      abstract: the search propionylcarnitine[tiab] AND newborn screening[tiab]
      AND (cutoff[tiab] OR cut-off[tiab]) returned the Ontario programme's
      confirmation that it screens on C3 and C3/C2 but not its numeric value.
    evidence:
    - reference: PMID:35254746
      reference_title: "The markers of the organic acidemias and their ratios in healthy neonates in Serbian population."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The cut-offs for methylmalonic acidemia (MMA) or propionic acidemia (PA) were C3>5.73 μmol/L, C3/C2>0.23, and C3/C16>2.36."
      explanation: States the proposed dried-blood-spot propionylcarnitine cut-off, and that one value serves methylmalonic and propionic acidemia.
    - reference: PMID:35254746
      reference_title: "The markers of the organic acidemias and their ratios in healthy neonates in Serbian population."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Therefore, the proposed cut-offs represent a reliable starting point for the future development of the OA NBS."
      explanation: Records that the value is a proposal for a programme not yet screening, which is why the population names no operating programme.
    interpretation_bands:
    - name: Screen negative
      upper_bound: 5.73
      unit: umol/L
      abnormal_flag: NORMAL
    - name: Screen positive
      lower_bound: 5.73
      unit: umol/L
      abnormal_flag: HIGH
      interpretation: >-
        An elevated C3 is shared with propionic acidemia, the cobalamin
        disorders and maternal vitamin B12 deficiency; recall for second-tier
        methylmalonic acid and 2-methylcitric acid or confirmatory plasma
        acylcarnitines and urine organic acids.
  - loinc_term:
      id: LOINC:53163-2
      label: Propionylcarnitine (C3)/Acetylcarnitine (C2) [Molar ratio] in DBS
    unit: '{ratio}'
    population: >-
      healthy newborns, Serbia (n=1,771); cut-offs proposed for a programme
      that did not yet screen organic acidemias
    notes: >-
      Same source and status as the C3 range above: a proposed value, stated
      as ">0.23", so exactly 0.23 is negative there and the half-open band
      places it in the positive band. Operating programmes use the ratio with
      C3 (Newborn Screening Ontario screens on "C3 and C3/C2 ratio"), but the
      cited Ontario abstract does not state its numeric ratio cut-off. In the
      Chinese mut-type cohort cited on this row, the blood C3/C2 ratio was also
      a prognostic factor, which is a different use of the same measurement.
    evidence:
    - reference: PMID:35254746
      reference_title: "The markers of the organic acidemias and their ratios in healthy neonates in Serbian population."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The cut-offs for methylmalonic acidemia (MMA) or propionic acidemia (PA) were C3>5.73 μmol/L, C3/C2>0.23, and C3/C16>2.36."
      explanation: States the proposed C3/C2 ratio cut-off.
    interpretation_bands:
    - name: Screen negative
      upper_bound: 0.23
      unit: '{ratio}'
      abnormal_flag: NORMAL
    - name: Screen positive
      lower_bound: 0.23
      unit: '{ratio}'
      abnormal_flag: HIGH
      interpretation: >-
        The ratio corrects C3 for total acylcarnitine load and is read
        alongside the absolute C3 value.
  - loinc_term:
      id: LOINC:82385-6
      label: Methylmalonate [Moles/volume] in DBS
    unit: umol/L
    population: >-
      second-tier LC-MS/MS on dried blood spots, Zhejiang (China) programme;
      cut-offs set in 1,998 healthy infants and applied to 804 suspected
      positives from 381,399 screened newborns
    notes: >-
      A second-tier cut-off applied to spots already positive on the C3 screen.
      The abstract states the value without saying whether it is inclusive, so
      the half-open band convention is applied as written and the boundary
      case is unresolved by the source. Methylmalonic acid on the spot is what
      separates the methylmalonic acidemias from propionic acidemia within the
      shared C3 screen, which is why this analyte is recorded here and not on
      the Propionic_Acidemia entry.
    evidence:
    - reference: PMID:32615850
      reference_title: "Determination of methylmalonic acid, 2-methylcitric acid, and total homocysteine in dried blood spots by liquid chromatography-tandem mass spectrometry: A reliable follow-up method for propionylcarnitine-related disorders in newborn screening."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cutoff values for methylmalonic acid, 2-methylcitric acid, and total homocysteine were 2.12, 0.70, and 10.05 µmol/l, respectively."
      explanation: States the Zhejiang second-tier dried-blood-spot methylmalonic acid cut-off of 2.12 µmol/l.
    interpretation_bands:
    - name: Second tier negative
      upper_bound: 2.12
      unit: umol/L
      abnormal_flag: NORMAL
    - name: Second tier positive
      lower_bound: 2.12
      unit: umol/L
      abnormal_flag: HIGH
      interpretation: Referral for confirmatory testing of a methylmalonic acidemia.
  - loinc_term:
      id: LOINC:82386-4
      label: 2-Methylcitrate [Moles/volume] in DBS
    unit: umol/L
    population: >-
      second-tier LC-MS/MS on dried blood spots, Zhejiang (China) programme;
      cut-offs set in 1,998 healthy infants and applied to 804 suspected
      positives from 381,399 screened newborns
    notes: >-
      Same source and inclusivity caveat as the methylmalonic acid range above.
      2-Methylcitric acid is raised in both the methylmalonic and the
      propionic acidemias, so this range is also recorded on the
      Propionic_Acidemia entry.
    evidence:
    - reference: PMID:32615850
      reference_title: "Determination of methylmalonic acid, 2-methylcitric acid, and total homocysteine in dried blood spots by liquid chromatography-tandem mass spectrometry: A reliable follow-up method for propionylcarnitine-related disorders in newborn screening."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cutoff values for methylmalonic acid, 2-methylcitric acid, and total homocysteine were 2.12, 0.70, and 10.05 µmol/l, respectively."
      explanation: States the Zhejiang second-tier dried-blood-spot 2-methylcitric acid cut-off of 0.70 µmol/l.
    interpretation_bands:
    - name: Second tier negative
      upper_bound: 0.7
      unit: umol/L
      abnormal_flag: NORMAL
    - name: Second tier positive
      lower_bound: 0.7
      unit: umol/L
      abnormal_flag: HIGH
  - loinc_term:
      id: LOINC:82386-4
      label: 2-Methylcitrate [Moles/volume] in DBS
    unit: umol/L
    population: >-
      second-tier testing of C3/C3-C2 screen-positive dried blood spots,
      Newborn Screening Ontario, July 2011-December 2012
    notes: >-
      A second-tier cut-off applied only to spots already positive on C3 and
      C3/C2. The source says samples "exceeded" 1.0 µmol/l, so exactly 1.0 is
      negative there; the half-open band places exactly 1.0 in the positive
      band. The Ontario true positives included one cobalamin A case, an
      isolated methylmalonic acidemia within this entry's scope. The paper also
      reports a 2-methylcitric acid reference range of 0.04-0.36 µmol/l, which
      is a population interval and is not recorded as disease content.
    evidence:
    - reference: PMID:27216769
      reference_title: "Quantification of 2-methylcitric acid in dried blood spots improves newborn screening for propionic and methylmalonic acidemias."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Only 14 samples exceeded the set 2-methylcitric acid cut-off of 1.0 µmol/l, including the samples from all nine true positives."
      explanation: States the Ontario second-tier 2-methylcitric acid cut-off and that every true positive exceeded it.
    interpretation_bands:
    - name: Second tier negative
      upper_bound: 1.0
      unit: umol/L
      abnormal_flag: NORMAL
    - name: Second tier positive
      lower_bound: 1.0
      unit: umol/L
      abnormal_flag: HIGH
  notes: >-
    Measurements bind the method-less quantitative DBS codes; the specimen is
    intrinsic to a newborn screen, so the DBS code is the test's identity here.
    The first-tier screen is shared with propionic acidemia and the cobalamin
    disorders, so the C3 and C3/C2 rows say "methylmalonic or propionic
    acidemia" as their source does, and those two cut-offs are a published
    proposal rather than an operating programme's rule; the second-tier
    methylmalonic acid and 2-methylcitric acid cut-offs come from operating
    programmes. Total homocysteine, measured on the same second-tier spot to
    separate the combined cobalamin disorders, is out of this entry's scope and
    is not bound.
  evidence:
  - reference: PMID:39075538
    reference_title: "Clinical outcomes of patients with mut-type methylmalonic acidemia identified through expanded newborn screening in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This research highly demonstrated NBS could prevent major disease-related events and allow an earlier treatment initiation.
    explanation: Directly supports NBS as beneficial for improving survival in MMA.
  - reference: PMID:39075538
    reference_title: "Clinical outcomes of patients with mut-type methylmalonic acidemia identified through expanded newborn screening in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: By comparison of the clinically-diagnosed patients, NBS-detected patients showed younger age at diagnosis, less incidence of disease onset, better responsiveness of vitamin B12, younger age at start of treatment, lower levels of biochemical features before and after treatment, and better long-term prognosis
    explanation: Quantifies multiple improved outcome measures with NBS detection.
  - reference: PMID:27216769
    reference_title: "Quantification of 2-methylcitric acid in dried blood spots improves newborn screening for propionic and methylmalonic acidemias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of 222,420 samples screened, 103 were positive for methylmalonic acidurias or propionic acidemia using C3 and C3/C2 ratio as markers."
    explanation: Documents C3 together with the C3/C2 ratio as the first-tier markers of an operating programme, and that one screen serves both disorders.
  - reference: PMID:27216769
    reference_title: "Quantification of 2-methylcitric acid in dried blood spots improves newborn screening for propionic and methylmalonic acidemias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among false positives there were 72 neonates not affected, 20 with maternal B12 deficiency, and two incidental finding (transcobalamin II and unclassified Cbl defect)."
    explanation: Shows why a C3 result is not specific to methylmalonic acidemia, since the same elevation reports maternal B12 deficiency and cobalamin defects.
  - reference: PMID:32615850
    reference_title: "Determination of methylmalonic acid, 2-methylcitric acid, and total homocysteine in dried blood spots by liquid chromatography-tandem mass spectrometry: A reliable follow-up method for propionylcarnitine-related disorders in newborn screening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 75 of 804 cases were screened positive by combined tandem mass spectrometry and liquid chromatography-tandem mass spectrometry, thus eliminating 90% of the false positives without compromising sensitivity."
    explanation: Supports the second-tier dried-blood-spot methylmalonic acid and 2-methylcitric acid measurement as part of the screening algorithm.
treatments:
- name: Protein-restricted diet
  description: 'Dietary restriction of propiogenic amino acids (valine, isoleucine, threonine, methionine) with specialized metabolic formula support is the cornerstone of chronic MMA management.

    '
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  evidence:
  - reference: PMID:25205257
    reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine.
    explanation: Directly supports low-protein dietary therapy for MMA management.
- name: Hydroxocobalamin therapy
  description: 'Pharmacologic hydroxocobalamin supplementation for genotypes with demonstrated B12 responsiveness, particularly cblA and some cblB and mut- forms. B12 responsiveness is a key prognostic factor.

    '
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: hydroxocobalamin
      term:
        id: CHEBI:27786
        label: hydroxocobalamin
  evidence:
  - reference: PMID:25205257
    reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine.
    explanation: Supports genotype-dependent cobalamin responsiveness in MMA management.
  - reference: PMID:39075538
    reference_title: "Clinical outcomes of patients with mut-type methylmalonic acidemia identified through expanded newborn screening in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: NBS-detected patients showed younger age at diagnosis, less incidence of disease onset, better responsiveness of vitamin B12
    explanation: B12 responsiveness identified as a key factor in NBS-detected MMA outcomes.
- name: Carnitine supplementation
  description: 'L-carnitine supplementation to support organic acid detoxification and excretion via propionylcarnitine formation, and to prevent secondary carnitine deficiency.

    '
  treatment_term:
    preferred_term: carnitine supplementation
    term:
      id: NCIT:C15433
      label: Nutritional Support
  evidence:
  - reference: PMID:25205257
    reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine.
    explanation: Directly supports carnitine supplementation in MMA management.
- name: Acute decompensation management
  description: 'Emergency supportive care during metabolic crisis, including high glucose infusion to reverse catabolism, complete cessation of protein intake, correction of metabolic acidosis with bicarbonate, and management of hyperammonemia.

    '
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:25205257
    reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia
    explanation: Supports need for urgent supportive crisis management during acute decompensation.
- name: Liver or combined liver-kidney transplantation
  description: 'Liver or combined liver-kidney transplantation for severe MMA with recurrent metabolic crises. Meta-analysis shows pooled patient survival of 99.9% and graft survival of 98.5%. CKD remission is more promising after combined liver-kidney transplantation (70.3% vs 37.6% LT only). Transplantation also stabilizes cardiac function in patients with cardiac impairment.

    '
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  evidence:
  - reference: PMID:33422927
    reference_title: "Safety and efficacy of liver transplantation for methylmalonic acidemia: A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Liver transplantation (LT) and combined liver and kidney transplantation (CLKT) have been proposed as enzyme replacement therapies for methylmalonic aciduria (MMA).
    explanation: Directly supports transplantation as an established therapeutic strategy.
  - reference: PMID:33422927
    reference_title: "Safety and efficacy of liver transplantation for methylmalonic acidemia: A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The pooled estimate rates were 99.9% (95% CI 95.3-100.0) for patient survival, 98.5% (95% CI 91.5-100.0) for graft survival after LT/CLKT.
    explanation: Quantifies favorable survival outcomes after transplantation.
  - reference: PMID:38132258
    reference_title: "Cardiac Involvement in Classical Organic Acidurias: Clinical Profile and Outcome in a Pediatric Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Liver transplantation was performed in seven patients (12%), all with PA or MMA, due to worsening cardiac impairment, and led to the stabilization of metabolic status and cardiac function.
    explanation: Supports liver transplantation for metabolic and cardiac stabilization.
- name: Genetic counseling
  description: 'Genetic counseling for affected families, including discussion of autosomal recessive inheritance, recurrence risk, carrier testing, and prenatal diagnostic options.

    '
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:25205257
    reference_title: "Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'MMA has an estimated incidence of ~ 1: 50,000'
    explanation: Genetic etiology and defined inheritance pattern support the role of genetic counseling.
- name: mRNA therapy (investigational)
  description: 'mRNA-3705 (Moderna) is an intravenous mRNA replacement therapy encoding human methylmalonyl-CoA mutase, currently in Phase 1/2 clinical trials (NCT04899310, NCT05295433) for isolated MMA due to MUT deficiency. Primary endpoints include safety and percent change in plasma MMA.

    '
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  notes: 'Investigational therapy. NCT04899310 is active, not recruiting (n=74). NCT05295433 is an open-label extension (n=56).

    '
  evidence:
  - reference: clinicaltrials:NCT04899310
    reference_title: "A Global Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of mRNA-3705 in Participants With Isolated Methylmalonic Acidemia Due to Methylmalonyl-CoA Mutase Deficiency"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This is a study of mRNA-3705 in participants with isolated elevated methylmalonic acid (MMA) due to methylmalonyl-coenzyme A (CoA) mutase (MUT) deficiency.
    explanation: Directly supports active interventional testing of mRNA-3705 in MUT-deficient isolated MMA.
  - reference: clinicaltrials:NCT05295433
    reference_title: "A Phase 1/2, Global, Open-Label, Extension Study to Evaluate the Long-Term Safety and Clinical Activity of mRNA-3705 in Participants Previously Enrolled in Other Clinical Studies of mRNA-3705"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The primary objective of this study is to evaluate the long-term safety and clinical activity of mRNA-3705 administered to participants with isolated methylmalonic acidemia (MMA) due to methylmalonyl-coenzyme A mutase (MUT) deficiency who have previously participated in other clinical studies of mRNA-3705.
    explanation: Supports long-term extension evaluation of mRNA-3705 in the same MMA population.
  - reference: PMID:37243446
    reference_title: "Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Liver transplantation can improve patient stability and survival and thus provides clinical and biochemical benchmarks for the development of hepatocyte-targeted genomic therapies.
    explanation: Supports the rationale for hepatocyte-targeted therapies including mRNA replacement.
  - reference: PMID:37243446
    reference_title: "Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A combination of biomarkers reflecting disease severity and multisystem involvement will be needed to help stratify patients for clinical trials and assess the efficacy of new therapies for MMA.
    explanation: Supports biomarker-based clinical trial design for emerging MMA therapies.
clinical_trials:
- name: NCT04899310
  phase: PHASE_II
  status: ACTIVE_NOT_RECRUITING
  description: Global Phase 1/2 study evaluating safety, pharmacodynamics, and pharmacokinetics of IV mRNA-3705 in isolated MMA due to MUT deficiency.
  target_phenotypes:
  - preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  - preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: clinicaltrials:NCT04899310
    reference_title: "A Global Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of mRNA-3705 in Participants With Isolated Methylmalonic Acidemia Due to Methylmalonyl-CoA Mutase Deficiency"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This is a study of mRNA-3705 in participants with isolated elevated methylmalonic acid (MMA) due to methylmalonyl-coenzyme A (CoA) mutase (MUT) deficiency.
    explanation: Confirms target population and intervention in isolated MUT-deficient MMA.
  - reference: clinicaltrials:NCT04899310
    reference_title: "A Global Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of mRNA-3705 in Participants With Isolated Methylmalonic Acidemia Due to Methylmalonyl-CoA Mutase Deficiency"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The main goal of the study is to assess safety, efficacy, pharmacokinetics, and pharmacodynamics of intravenously (IV)-infused mRNA-3705.
    explanation: Defines the trial objectives and primary clinical development intent.
- name: NCT05295433
  phase: PHASE_II
  status: NOT_RECRUITING
  description: Global open-label extension study evaluating long-term safety and clinical activity of mRNA-3705 in participants previously enrolled in mRNA-3705 clinical studies.
  target_phenotypes:
  - preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  - preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
  evidence:
  - reference: clinicaltrials:NCT05295433
    reference_title: "A Phase 1/2, Global, Open-Label, Extension Study to Evaluate the Long-Term Safety and Clinical Activity of mRNA-3705 in Participants Previously Enrolled in Other Clinical Studies of mRNA-3705"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The primary objective of this study is to evaluate the long-term safety and clinical activity of mRNA-3705 administered to participants with isolated methylmalonic acidemia (MMA) due to methylmalonyl-coenzyme A mutase (MUT) deficiency who have previously participated in other clinical studies of mRNA-3705.
    explanation: Confirms open-label extension focus on long-term safety and activity in the same MMA target group.
references:
- reference: PMID:20301409
  title: Isolated Methylmalonic Acidemia.
  tags:
  - GeneReviews
  findings: []
notes: 'Key PMIDs for this entry: 25205257 (MMA/PA guidelines), 27653704 (management update), 35348993 (neuropsych review), 37078237 (pathophysiology/methylmalonylation), 37243446 (biomarkers), 38760822 (lysosomal-autophagy), 38030482 (MMA in aging/disease), 37169781 (renal mitochondrial), 38271099 (lipodystrophy/FGF21), 39075538 (NBS China outcomes), 38132258 (cardiac OA cohort), 33422927 (transplant meta-analysis), 4507604 (3-hydroxypropionate), 31269850 (optic neuropathy), 36777632 (neurodevelopment/neuroimaging), and 8301430 (pancreatitis). The 2023-2024 literature supports a multi-hit pathophysiology model integrating metabolite accumulation, mitochondrial energy metabolism dysfunction, protein hyperacylation/methylmalonylation with impaired sirtuin deacylation, and organelle quality-control failure (mitophagy plus lysosome/autophagy dysfunction). Emerging therapies include mRNA replacement (mRNA-3705) and gene therapy approaches, with FGF21/GDF15/LCN2 as biomarkers for clinical trial endpoints. The gene list follows the GeneReviews "Isolated Methylmalonic Acidemia" chapter, which establishes the diagnosis on biallelic variants in MCEE, MMAA, MMAB, MMADHC or MMUT. All five are also represented outside this entry, which is the umbrella rather than a replacement for them. Methylmalonyl-CoA_Epimerase_Deficiency covers MONDO:0009615 (MCEE) and Methylmalonic_Aciduria_cblA_Type covers MONDO:0009613 (MMAA), while MONDO:0009612 (MMUT, mut type) and MONDO:0009614 (MMAB, cblB type) have curation stubs and no entry yet. The cblD forms are split across MMADHC-related_Disorder_of_Cobalamin_Metabolism_cblD_Type, whose disease_term is the cblD homocystinuria class MONDO:0700297 and whose cblD-MMA subtype row carries MONDO:0700298 isolated methylmalonic aciduria cblD type. Combined methylmalonic aciduria with homocystinuria is out of scope here and has its own entries per complementation group (cblC, cblE, cblG, cblJ, cblL).

  '

📚

References & Deep Research

References

1

PMID:20301409

Isolated Methylmalonic Acidemia.

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.

Falcon ▸

Disease Pathophysiology Research Template

Edison Scientific Literature 44 citations 2026-02-23T23:19:25.769499

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

Disease Name: Methylmalonic Acidemia
MONDO ID: (if available)
Category: Genetic

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Methylmalonic Acidemia. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

What are the primary pathophysiological mechanisms?
What molecular pathways are dysregulated?
What cellular processes are affected?

2. Key Molecular Players

Genes/Proteins: Which genes are causally involved or implicated?
Chemical Entities: What metabolites, drugs, or small molecules are relevant?
Cell Types: Which cell types are primarily affected?
Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

What biological processes (GO terms) are disrupted?
Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

Where in the cell do key processes occur?
Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

What is the sequence of events from initial trigger to clinical manifestation?
Are there distinct stages or phases?

6. Phenotypic Manifestations

What are the key clinical phenotypes?
How do they relate to the underlying mechanisms?

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic claims
Prioritize recent reviews and landmark papers
Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Title: Pathophysiology of Methylmalonic Acidemia (Isolated MMA / Methylmalonic Aciduria)

Disease definition and core concepts (current understanding)

Methylmalonic acidemia (MMA) is an inborn error of propionate metabolism in which impaired conversion of methylmalonyl‑CoA to succinyl‑CoA disrupts mitochondrial anaplerosis and leads to systemic accumulation of methylmalonic acid (MMA) and related metabolites. The canonical biochemical lesion is methylmalonyl‑CoA mutase (MMUT/MUT) deficiency, but isolated MMA can also arise from defects in adenosylcobalamin (AdoCbl) cofactor synthesis/handling (cblA/cblB) and other related genes depending on classification scheme. (head2023newinsightsinto pages 1-3, manoli2023biomarkerstopredict pages 15-16, tejero2024methylmalonicacidin pages 3-4)

A concise systems-level schematic of dysregulated pathways in MMA—MMUT block, metabolite accumulation, downstream TCA/ETC/urea-cycle effects, and aberrant acylation regulated by mitochondrial sirtuins—is provided in Figure 5 of Head et al. 2023. (head2023newinsightsinto media 2be035c5)

Scope note: This report focuses on isolated MMA (mut/MMUT; cblA/MMAA; cblB/MMAB) but includes mechanistic insights that overlap with related cobalamin and mitochondrial disorders when explicitly supported by the retrieved sources.

Core pathophysiology: dysregulated pathways and affected cellular processes

2.1 Metabolite accumulation and mitochondrial energetic failure

Primary accumulated/toxic metabolites reported across recent reviews include: MMA, methylmalonyl‑CoA, propionyl‑CoA, 2‑methylcitrate, 3‑hydroxypropionate, propionyl‑carnitine (C3), and ammonia; these occur together with reduced succinyl‑CoA production (loss of anaplerotic input into the TCA cycle). (tejero2024methylmalonicacidin pages 3-4, head2023newinsightsinto pages 3-4, manoli2023biomarkerstopredict pages 17-21)

Mechanistically, multiple sources emphasize direct and indirect inhibition of mitochondrial enzymes/respiratory chain components by MMA and related metabolites. Head et al. (2023) describe inhibition of succinate dehydrogenase (SDH/Complex II) and respiratory complexes including Complex I and Complex II+III, along with inhibition of β‑hydroxybutyrate dehydrogenase (HBDH), mitochondrial creatine kinase, and lactate dehydrogenase—collectively consistent with impaired oxidative metabolism and ATP depletion. (head2023newinsightsinto pages 3-4, head2023newinsightsinto pages 12-13)

Tejero et al. (2024) further summarize that MMA competitively inhibits SDH (Complex II) and also inhibits Complex I, and report reduced abundance of multiple TCA enzymes (e.g., 2‑oxoglutarate dehydrogenase, fumarate hydratase, malate dehydrogenase) in disease models, supporting broad mitochondrial/TCA dysfunction. (tejero2024methylmalonicacidin pages 3-4)

2.2 Hyperammonemia via urea-cycle disruption

A key mechanistic connection between propionate-pathway dysfunction and hyperammonemia is inhibition of N‑acetylglutamate synthetase (NAGS) by propionyl‑CoA, which reduces activation of the urea cycle. Head et al. (2023) also link 2‑methylcitrate exposure to ammonium accumulation and report cerebral ammonium accumulation in brain-specific Mut−/− models. (head2023newinsightsinto pages 12-13)

2.3 Aberrant mitochondrial protein acylation/methylmalonylation (a recent conceptual advance)

A major 2023 mechanistic theme is that MMA is not only a “metabolite toxicity” disorder but also a disorder of mitochondrial protein hyperacylation. Head et al. (2023) describe increased pools of malonyl‑, propionyl‑, and methylmalonyl‑CoA driving widespread malonylation/propionylation/methylmalonylation of mitochondrial proteins across pathways including TCA cycle, β‑oxidation, amino acid metabolism, urea cycle, glutathione/oxidative-stress pathways, and mitochondrial DNA maintenance. (head2023newinsightsinto pages 7-9)

This conceptual framework also highlights reduced levels of mitochondrial sirtuins (SIRT3/4/5) in MMA tissues and the role of SIRT5 as a demalonylase/desuccinylase that can also remove methylmalonylation, suggesting that impaired deacylation may amplify dysfunction. (head2023newinsightsinto pages 7-9)

2.4 Mitochondrial quality control failure (mitophagy), and lysosome/autophagy dysfunction

Mitochondrial dysfunction in MMA is increasingly linked to impaired mitochondrial quality control.

Renal epithelial models (2023): In patient-derived renal epithelial cells, Schumann et al. (2023) report mitophagy impairment (PINK1 down to ~0.7-fold at baseline and further suppressed under metabolic stress), a shift toward mitochondrial fission (DRP1 up to 4.3-fold under high-protein load; OPA1 down to 0.2-fold under high-protein load), and increased bulk autophagy marker SQSTM1, consistent with altered mitochondrial turnover and stress vulnerability. (schumann2023theimpactof pages 4-5, schumann2023theimpactof pages 8-8)

Fibroblast and engineered models (2024): Costanzo et al. (2024) provide direct evidence that MUT deficiency causes lysosomal/autophagy dysfunction, including enlarged LAMP1+ lysosomes, reduced autophagosome–lysosome fusion, reduced lysosomal acidity and degradative function, and severely reduced autophagic flux. They explicitly state: “Lysosomes of MMA cells present as enlarged vacuoles with low degradative capabilities.” (costanzo2024methylmalonicacidemiatriggers pages 1-2)

Quantitatively, Costanzo et al. report autophagic flux (J) of 0.96 in controls versus J < 0.1 in MUT-deficient lines, impaired LysoTracker signal (reduced lysosomal acidity), and impaired EGFR degradation kinetics. (costanzo2024methylmalonicacidemiatriggers pages 7-10)

Importantly, these lysosomal defects were pharmacologically reversible: treatment with 2,2-dimethylbutanoic acid (DMBA; also referred to as an anti-propionigenic approach related to HST5040 development) rescued lysosomal morphology and function and improved degradative capacity in MUT-deficient cells. (costanzo2024methylmalonicacidemiatriggers pages 12-14, costanzo2024methylmalonicacidemiatriggers pages 10-12)

2.5 Oxidative stress and redox imbalance

Multiple sources connect MMA to oxidative stress. Head et al. (2023) discuss free-radical generation and oxidative stress–linked neurotoxicity (e.g., glial activation, seizures) in experimental systems. (head2023newinsightsinto pages 3-4, head2023newinsightsinto pages 12-13)

In kidney models, Schumann et al. (2023) report compromised antioxidant defenses and a lowered reduced:oxidized glutathione ratio under high-protein or isoleucine/valine exposure, consistent with increased oxidative stress under metabolic stressors relevant to MMA. (schumann2023theimpactof pages 5-6, schumann2023theimpactof pages 6-8)

2.6 ER stress, Ca2+ dysregulation, and impaired selective autophagy (hepatocyte evidence)

A hepatocyte model reported in a 2023 preprint (Research Square) links high MMA exposure to ER stress (IRE1α–XBP1 activation), disrupted Ca2+ handling, inhibited ER-phagy (via downregulation of FAM134B), and inhibited mitophagy (mt‑Keima evidence of reduced mitochondria entering lysosomes), providing a mechanistic hypothesis for hepatocyte injury that integrates ER stress and mitochondrial quality control defects. (zhang2023transcriptomeanalysisreveals pages 7-10)

Key molecular players (genes/proteins, chemicals, cells, anatomy)

3.1 Genes/proteins (HGNC-style entities)

Causal/primary genes for isolated MMA in recent reviews:

• MMUT (MUT; methylmalonyl‑CoA mutase): defines mut0 (non–B12 responsive) and mut− (partial/B12 responsive) phenotypes. (tejero2024methylmalonicacidin pages 3-4) • MMAA (cblA) and MMAB (cblB): genes required for AdoCbl cofactor formation/handling for MUT activity; Manoli et al. (2023) explicitly link cblA to MMAA and cblB to MMAB. (manoli2023biomarkerstopredict pages 15-16)

Additional genes listed in a 2024 expert review as implicated in MMAemia phenotypes (may include broader/related MMA biology and specific subclasses): MMADHC, MCEE, SUCLG1, SUCLA2. (tejero2024methylmalonicacidin pages 3-4)

Mitochondrial protein deacylation/quality control regulators implicated:

• SIRT3, SIRT4, SIRT5: reduced protein levels in MMA tissues; SIRT5 can remove methylmalonylation and other negatively charged acylations. (head2023newinsightsinto pages 7-9) • PINK1 (mitophagy priming) and DRP1/OPA1 (fission/fusion) in renal epithelial MMA models. (schumann2023theimpactof pages 4-5) • LAMP1/LAMP2 (lysosomal membrane proteins), TFEB (lysosomal biogenesis regulator), LC3 and p62/SQSTM1 (autophagy markers) in MUT-deficient cells. (costanzo2024methylmalonicacidemiatriggers pages 5-7, costanzo2024methylmalonicacidemiatriggers pages 10-12)

3.2 Chemical entities / metabolites (CHEBI-style entities)

Key metabolites and biomarkers reported across sources:

• Methylmalonic acid; methylmalonyl‑CoA; propionyl‑CoA; 2‑methylcitrate; 3‑hydroxypropionate; propionyl‑carnitine (C3); ammonia. (tejero2024methylmalonicacidin pages 3-4, manoli2023biomarkerstopredict pages 17-21, head2023newinsightsinto pages 12-13) • Methylcitrate-to-citrate ratio and methylcitrate as biomarkers in blood spots/clinical monitoring contexts. (head2023newinsightsinto pages 12-13) • Mitochondrial stress/organ injury biomarkers: FGF21, GDF15 (mitochondrial stress), LCN2 (kidney injury marker). (manoli2023biomarkerstopredict pages 9-10, manoli2023biomarkerstopredict pages 10-12)

Reference-level statistic: normal blood MMA levels are reported as <270 nmol/L (general clinical reference, not MMAemia-specific); this is relevant for conceptualizing “supraphysiologic” elevations in disease. (tejero2024methylmalonicacidin pages 3-4)

3.3 Cell types (CL-style) and anatomy (UBERON-style)

Organ systems and cell types repeatedly implicated:

• Liver/hepatocytes: central to propionate metabolism and targeted for liver-directed therapies; hepatomegaly/steatosis and mitochondrial ultrastructural abnormalities are described in clinical biomarker reviews. (manoli2023biomarkerstopredict pages 10-12, manoli2023biomarkerstopredict pages 12-13) • Kidney/renal proximal tubular epithelial cells: chronic kidney disease is a key long-term complication; proximal tubular mitochondrial dysfunction, oxidative stress, and mitophagy defects are implicated. (manoli2023biomarkerstopredict pages 10-12, schumann2023theimpactof pages 4-5) • Brain/CNS (neurons and glia; basal ganglia/striatum): neurotoxicity with oxidative stress, glial activation, and seizures described in metabolite exposure and model systems. (head2023newinsightsinto pages 12-13) • Heart/cardiomyocytes: cardiomyopathy and QT prolongation occur in a subset of organic aciduria patients (including MMA). (passantino2023cardiacinvolvementin pages 1-2, passantino2023cardiacinvolvementin pages 6-8) • Adipose tissue (white and brown adipocytes): a 2024 JCI Insight study describes a distinct adipose distribution and “beiging” phenotype with metabolic stress markers and methylmalonylation in adipose. (manoli2024lipodystrophyinmethylmalonic pages 2-4, manoli2024lipodystrophyinmethylmalonic pages 10-11)

Biological processes and cellular components (GO-oriented annotation candidates)

The following GO Biological Process (BP) candidates are directly motivated by mechanisms described in the cited sources:

• Propionate metabolic process / methylmalonyl‑CoA metabolic process (MMUT block; MMAA/MMAB involvement). (tejero2024methylmalonicacidin pages 3-4, manoli2023biomarkerstopredict pages 15-16) • Tricarboxylic acid cycle and anaplerotic processes (loss of succinyl‑CoA; TCA rewiring; reduced TCA enzyme abundance). (tejero2024methylmalonicacidin pages 3-4, head2023newinsightsinto pages 12-13) • Mitochondrial electron transport / oxidative phosphorylation (Complex I/II inhibition; respiratory chain impairment). (head2023newinsightsinto pages 3-4, tejero2024methylmalonicacidin pages 3-4) • Urea cycle and ammonia detoxification (NAGS inhibition; ammonia accumulation). (head2023newinsightsinto pages 12-13) • Protein acylation (including lysine methylmalonylation/malonylation/propionylation) and protein deacylation (sirtuin-regulated). (head2023newinsightsinto pages 7-9) • Mitophagy and macroautophagy, including autophagosome–lysosome fusion and lysosomal acidification/degradative function. (costanzo2024methylmalonicacidemiatriggers pages 7-10, schumann2023theimpactof pages 4-5) • Cellular oxidant detoxification / glutathione metabolism and oxidative stress response. (schumann2023theimpactof pages 6-8, head2023newinsightsinto pages 3-4) • Endoplasmic reticulum stress / unfolded protein response (IRE1α–XBP1) and selective ER-phagy (hepatocyte model evidence). (zhang2023transcriptomeanalysisreveals pages 7-10)

GO Cellular Component (CC) candidates:

• Mitochondrial matrix and mitochondrial inner membrane (MMUT, TCA enzymes, ETC complexes; sirtuins; respiratory chain inhibition). (tejero2024methylmalonicacidin pages 3-4, head2023newinsightsinto pages 7-9) • Lysosome and autophagosome (LAMP1/2 changes; LC3/p62 accumulation; reduced fusion and acidity). (costanzo2024methylmalonicacidemiatriggers pages 12-14, costanzo2024methylmalonicacidemiatriggers pages 5-7) • Endoplasmic reticulum (ER stress and ER-phagy findings in hepatocyte model). (zhang2023transcriptomeanalysisreveals pages 7-10)

Disease progression model (sequence of events)

A mechanistic sequence consistent with current evidence:

(1) Genetic lesion (MMUT; MMAA; MMAB; other listed genes) → impaired conversion of methylmalonyl‑CoA to succinyl‑CoA. (tejero2024methylmalonicacidin pages 3-4, manoli2023biomarkerstopredict pages 15-16)

(2) Metabolite accumulation (MMA, methylmalonyl‑CoA, propionyl‑CoA, methylcitrate, etc.) plus anaplerotic deficit (low succinyl‑CoA input). (tejero2024methylmalonicacidin pages 3-4, head2023newinsightsinto pages 3-4)

(3) Mitochondrial dysfunction via (i) direct inhibition of respiratory/TCA enzymes and (ii) widespread hyperacylation/methylmalonylation of mitochondrial proteins, with reduced sirtuin deacylation capacity, leading to multi-pathway enzymatic impairment. (head2023newinsightsinto pages 3-4, head2023newinsightsinto pages 7-9)

(4) Secondary stress responses (oxidative stress; hyperammonemia; metabolic inflexibility), and failure of mitochondrial quality control (impaired mitophagy; altered fission/fusion). (head2023newinsightsinto pages 12-13, schumann2023theimpactof pages 4-5)

(5) Downstream organelle homeostasis failure: lysosomal/autophagy system dysfunction (reduced autophagic flux, reduced lysosomal acidity/degradation, impaired autophagosome–lysosome fusion), which can further amplify mitochondrial dysfunction by preventing clearance of damaged organelles. (costanzo2024methylmalonicacidemiatriggers pages 7-10, costanzo2024methylmalonicacidemiatriggers pages 12-14)

(6) Organ-specific injury phenotypes emerge over time (CKD, cardiomyopathy/QT issues, neurodevelopmental injury, adipose remodeling), influenced by metabolic stressors and disease severity. (manoli2023biomarkerstopredict pages 9-10, passantino2023cardiacinvolvementin pages 1-2, manoli2024lipodystrophyinmethylmalonic pages 2-4)

Phenotypic manifestations and mechanistic links (HP-style concepts)

Kidney disease: Chronic kidney disease is a major long-term complication and is mechanistically linked to proximal tubular mitochondrial dysfunction, oxidative stress, and altered mitophagy/dynamics. LCN2 (lipocalin-2) is highlighted as a kidney injury biomarker linked to proximal tubule mitochondrial dysfunction and oxidative stress in MMA models. (manoli2023biomarkerstopredict pages 10-12, schumann2023theimpactof pages 4-5)

Neurologic injury: Experimental evidence links methylmalonate and methylcitrate exposure to oxidative stress, inflammation, glial activation, and seizure-related phenotypes; ammonia may potentiate oxidative damage and seizures. (head2023newinsightsinto pages 12-13)

Cardiac involvement: In a 2000–2022 pediatric cohort of classical organic acidurias (including MMA; combined MMA with homocystinuria excluded), cardiac involvement occurred in 23/60 (~38%) and was confined to PA and MMA; dilated cardiomyopathy was predominant and long-QT was observed in a subset. Five-year MACE rates were 35% for MMA with cardiomyopathy and 23% for MMA without cardiomyopathy. (passantino2023cardiacinvolvementin pages 1-2)

Adipose/lipodystrophy-like phenotype: A distinct pattern of subcutaneous fat distribution and beiging markers is reported in MMA and associated with elevated FGF21 and abnormal adipose methylmalonylation. In 46 MMA patients vs 99 controls, subtotal fat mass % was higher (30.9% ± 10.5% vs 26.5% ± 9.8%, P=0.0147). (manoli2024lipodystrophyinmethylmalonic pages 2-4)

Recent developments (2023–2024) and real-world implementations

7.1 Newborn screening and prognosis (2024, large real-world cohort)

A 2024 multicenter Chinese cohort compared mut-type MMA detected by newborn screening (NBS) (n=168) vs clinically diagnosed after symptom onset (n=210). Key outcome statistics:

• Mortality: 12.5% (21/168) in NBS-detected vs 32.7% (69/210) in clinically diagnosed. (ling2024clinicaloutcomesof pages 5-6, ling2024clinicaloutcomesof pages 4-5) • Outcomes: normal outcome 51.79% (87/168) in NBS vs 15.71% (33/210) clinically; poor outcomes 43.45% vs 78.57%. (ling2024clinicaloutcomesof pages 5-6) • Biochemistry (examples): baseline blood C3 median 7.88 vs 11.49 μmol/L; baseline C3/C2 0.58 vs 0.72; urinary MMA 160.9 vs 366 mmol/mol Cr (NBS vs clinical). (ling2024clinicaloutcomesof pages 5-6) • Vitamin B12 responsiveness: 54.76% (92/168) in NBS vs 33.33% (70/210) clinical. (ling2024clinicaloutcomesof pages 5-6)

This supports NBS as an implementation that can shift disease course by enabling earlier therapy and reducing metabolic crises and mortality. (ling2024clinicaloutcomesof pages 6-8, ling2024clinicaloutcomesof pages 5-6)

7.2 Biomarkers for severity and therapeutic monitoring (2023)

Manoli et al. (2023) emphasize FGF21 and GDF15 as mitochondrial stress biomarkers in MMA, with FGF21 correlating with disease severity and complications attributed to mitochondrial dysfunction (e.g., renal failure, optic neuropathy, cardiomyopathy) and responding to liver-targeted therapies/transplantation. (manoli2023biomarkerstopredict pages 9-10)

The same review highlights LCN2 as a renal injury biomarker tied to proximal tubule mitochondrial dysfunction and oxidative stress, with preclinical evidence that Lcn2 can rise earlier and be more sensitive than creatinine or serum MMA in therapeutic contexts. (manoli2023biomarkerstopredict pages 10-12)

7.3 Therapeutic development and clinical trial landscape (ClinicalTrials.gov; accessed via retrieved records)

mRNA replacement therapy (mRNA‑3705, Moderna) for MUT deficiency:

• NCT04899310 (posted record year 2021): Phase 1/2; status ACTIVE_NOT_RECRUITING; estimated enrollment 74. Intervention is IV infusion of a modified mRNA encoding human methylmalonyl‑CoA mutase, dosed Q2W or Q3W in Part 1 for up to 10 doses. Primary endpoints include safety (TEAEs/AESIs/SAEs) for Parts 1 and 3 and % change in plasma MMA at Month 3 for Part 2. (NCT04899310 chunk 1) • NCT05295433: Phase 1/2 open-label extension; status RECRUITING; estimated enrollment 56. Secondary endpoints include % change in plasma MMA and 2‑methylcitric acid (2‑MC), annualized metabolic decompensation event rates, and healthcare utilization, among others. (NCT05295433 chunk 1)

Liver-targeted AAV genome integration approach (hLB‑001; LK03 capsid; SUNRISE study):

• NCT04581785: Phase 1/2 open-label; status TERMINATED; actual enrollment 4; termination reason “Due to low likelihood of clinical benefit in treated participants.” The intervention is an IV infusion of a liver-targeted engineered rAAV (LK03 capsid) designed to integrate human MMUT at the albumin locus. Primary outcomes are safety-focused (TEAEs; infusion toxicities) through Week 52. (NCT04581785 chunk 1)

Anti-propionigenic/small-molecule approach (HST5040):

• NCT04732429: Phase 2; status TERMINATED; actual enrollment 26; termination due to sponsor business considerations. Primary endpoint: change in plasma 2‑methylcitric acid (MCA) over 6 months. Secondary endpoints include changes in C3, C3:C2 ratio, 3‑OH propionate, MMA (in MMA subjects), ammonia, and acute metabolic decompensation frequency, among others. (NCT04732429 chunk 1)

Mechanistic bridge to lysosomal rescue: In MUT-deficient cells, DMBA (2,2-dimethylbutanoic acid) rescued lysosomal morphology, acidity (LysoTracker), and degradative function, providing a mechanistic rationale for targeting downstream cellular homeostasis in addition to metabolite lowering. (costanzo2024methylmalonicacidemiatriggers pages 12-14)

7.4 Adjunct mitochondrial/metabolic modulation (2024 mechanistic phenotype study)

A 2024 JCI Insight study identifies a lipodystrophy-like phenotype in MMA and links it to elevated FGF21, acyl-CoA accretion, and aberrant methylmalonylation in adipose tissue. In a liver-rescued MMA mouse model, bezafibrate treatment increased Ucp1 expression, improved survival (P=0.009), and partially rescued GFR (42.14% ± 3.35% → 61.29% ± 7.24%, P=0.02), suggesting that modulating mitochondrial/adipose programs can alter systemic phenotypes in MMA models. (manoli2024lipodystrophyinmethylmalonic pages 10-11)

Expert synthesis and analysis (authoritative interpretations anchored to cited sources)

The 2023–2024 literature supports a “multi-hit” pathophysiology in which (i) anaplerotic deficit and metabolite accumulation, (ii) mitochondrial enzyme/ETC inhibition, (iii) mitochondrial protein hyperacylation/methylmalonylation with impaired deacylation, and (iv) organelle quality-control failure (mitophagy plus lysosome/autophagy dysfunction) together drive progressive multiorgan pathology. This integrated view is explicitly emphasized in the 2023 JIMD review, which reframes MMA around aberrant post-translational modifications and mitochondrial sirtuin biology as potentially actionable mechanisms. (head2023newinsightsinto pages 7-9)

In parallel, the 2024 Cell & Bioscience study adds a new mechanistic layer by showing that MUT deficiency directly perturbs the lysosome–autophagy system and that these defects are pharmacologically reversible, strengthening the hypothesis that “downstream” cell-biological dysfunctions contribute materially to disease progression beyond metabolite accumulation alone. (costanzo2024methylmalonicacidemiatriggers pages 12-14, costanzo2024methylmalonicacidemiatriggers pages 7-10)

Finally, biomarker-focused 2023 work supports the view that mitochondrial stress readouts (FGF21/GDF15) and kidney injury markers (LCN2) can serve as nearer-term pharmacodynamic endpoints than classic metabolites alone, which are confounded by diet and renal function, and are therefore central to trial design and precision stratification in emerging therapies. (manoli2023biomarkerstopredict pages 9-10, manoli2023biomarkerstopredict pages 10-12)

Knowledge-base style annotation blocks

9.1 Pathophysiology (narrative)

Isolated MMA arises from defects in mitochondrial MMUT or its AdoCbl cofactor synthesis/handling (MMAA/MMAB), causing accumulation of MMA-related metabolites and loss of succinyl‑CoA production. Accumulated MMA/methylcitrate/propionyl-CoA disrupt mitochondrial metabolism via inhibition of respiratory chain complexes (Complex I; Complex II/SDH) and multiple dehydrogenases, and by driving widespread mitochondrial protein lysine hyperacylation/methylmalonylation. Reduced mitochondrial sirtuins (SIRT3/4/5) and impaired deacylation capacity may amplify dysfunction. Mitochondrial quality control is impaired (reduced PINK1-dependent priming; altered fission/fusion), and new evidence demonstrates lysosomal/autophagy system failure (reduced lysosomal acidity, reduced autophagosome–lysosome fusion, low autophagic flux) that is reversible by an anti-propionigenic small molecule (DMBA). These combined mechanisms produce multi-organ disease dominated by renal proximal tubule injury/CKD, neurologic injury (oxidative stress/glial activation and metabolic stroke risk), cardiac involvement (cardiomyopathy/QT issues), and systemic metabolic stress phenotypes including altered adipose remodeling. (tejero2024methylmalonicacidin pages 3-4, head2023newinsightsinto pages 3-4, head2023newinsightsinto pages 7-9, schumann2023theimpactof pages 4-5, costanzo2024methylmalonicacidemiatriggers pages 12-14)

9.2 Gene/protein annotations (examples)

• MMUT (methylmalonyl‑CoA mutase): mitochondrial anaplerotic enzyme; loss causes mut0/mut− isolated MMA. (tejero2024methylmalonicacidin pages 3-4) • MMAA (cblA): AdoCbl cofactor handling for MMUT. (manoli2023biomarkerstopredict pages 15-16) • MMAB (cblB): cob(I)alamin adenosyltransferase activity; AdoCbl formation. (manoli2023biomarkerstopredict pages 15-16) • SIRT5 (mitochondrial deacylase): removes methylmalonylation; reduced protein levels in MMA liver; implicated in hyperacylation state. (head2023newinsightsinto pages 7-9) • PINK1 / DRP1 / OPA1 (mitochondrial quality control and dynamics): altered in renal epithelial MMA models under metabolic stress. (schumann2023theimpactof pages 4-5)

9.3 Phenotype associations (HP-style concepts; examples)

• Metabolic acidosis/metabolic decompensation crises; hyperammonemia (urea-cycle impairment). (head2023newinsightsinto pages 12-13) • Chronic kidney disease / proximal tubular dysfunction. (manoli2023biomarkerstopredict pages 10-12, schumann2023theimpactof pages 4-5) • Dilated cardiomyopathy; acquired long QT. (passantino2023cardiacinvolvementin pages 1-2, passantino2023cardiacinvolvementin pages 6-8) • Neurodevelopmental impairment, seizures/metabolic stroke risk (mechanistically linked to oxidative stress and ammonia). (head2023newinsightsinto pages 12-13) • Abnormal adipose distribution / lipodystrophy-like phenotype; altered thermogenesis and “beiging.” (manoli2024lipodystrophyinmethylmalonic pages 2-4, manoli2024lipodystrophyinmethylmalonic pages 10-11)

9.4 Cell types and anatomical locations (CL/UBERON-style; examples)

• Hepatocyte / liver: central metabolic organ and therapeutic target. (manoli2023biomarkerstopredict pages 10-12) • Renal proximal tubule epithelial cell / kidney cortex: CKD driver; mitochondrial stress and mitophagy defects. (manoli2023biomarkerstopredict pages 10-12, schumann2023theimpactof pages 4-5) • Neuron and glial cell / basal ganglia (striatum, globus pallidus as referenced by review): vulnerable to metabolite/ammonia-driven oxidative injury. (head2023newinsightsinto pages 12-13) • Cardiomyocyte / heart ventricle: cardiomyopathy phenotype in OA cohorts. (passantino2023cardiacinvolvementin pages 1-2) • White and brown adipocyte / subcutaneous adipose tissue and BAT depots: beiging and thermogenic dysfunction. (manoli2024lipodystrophyinmethylmalonic pages 10-11, manoli2024lipodystrophyinmethylmalonic pages 2-4)

9.5 Cellular components (subcellular localization)

• Mitochondrial matrix and inner membrane (MMUT; TCA/ETC; sirtuins; respiratory chain targets). (tejero2024methylmalonicacidin pages 3-4, head2023newinsightsinto pages 7-9) • Lysosome and autophagosome (LAMP1/2, LC3/p62; fusion; acidification). (costanzo2024methylmalonicacidemiatriggers pages 12-14, costanzo2024methylmalonicacidemiatriggers pages 7-10) • Endoplasmic reticulum (ER stress/UPR; ER-phagy evidence in hepatocyte model). (zhang2023transcriptomeanalysisreveals pages 7-10)

Evidence items (PMID/URL notes)

The retrieved texts provide stable DOIs/URLs and ClinicalTrials.gov identifiers; PubMed IDs (PMIDs) were not present in the extracted evidence snippets and therefore are not asserted here.

Key peer-reviewed sources (publication date; URL):

• Head et al. “New insights into the pathophysiology of methylmalonic acidemia.” Journal of Inherited Metabolic Disease. May 2023. https://doi.org/10.1002/jimd.12617 (head2023newinsightsinto pages 1-3, head2023newinsightsinto pages 3-4) • Manoli et al. “Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia.” Journal of Inherited Metabolic Disease. Jun 2023. https://doi.org/10.1002/jimd.12636 (manoli2023biomarkerstopredict pages 9-10, manoli2023biomarkerstopredict pages 10-12) • Costanzo et al. “Methylmalonic acidemia triggers lysosomal-autophagy dysfunctions.” Cell & Bioscience. May 2024. https://doi.org/10.1186/s13578-024-01245-1 (costanzo2024methylmalonicacidemiatriggers pages 7-10, costanzo2024methylmalonicacidemiatriggers pages 1-2) • Tejero et al. “Methylmalonic acid in aging and disease.” Trends in Endocrinology & Metabolism. Mar 2024. https://doi.org/10.1016/j.tem.2023.11.001 (tejero2024methylmalonicacidin pages 3-4) • Schumann et al. “The impact of metabolic stressors on mitochondrial homeostasis in a renal epithelial cell model of methylmalonic aciduria.” Scientific Reports. May 2023. https://doi.org/10.1038/s41598-023-34373-8 (schumann2023theimpactof pages 4-5, schumann2023theimpactof pages 6-8) • Manoli et al. “Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation.” JCI Insight. Feb 2024. https://doi.org/10.1172/jci.insight.174097 (manoli2024lipodystrophyinmethylmalonic pages 2-4, manoli2024lipodystrophyinmethylmalonic pages 10-11) • Ling et al. “Clinical outcomes of patients with mut-type methylmalonic acidemia identified through expanded newborn screening in China.” Human Genomics. Jul 2024. https://doi.org/10.1186/s40246-024-00646-0 (ling2024clinicaloutcomesof pages 5-6, ling2024clinicaloutcomesof pages 4-5) • Passantino et al. “Cardiac involvement in classical organic acidurias: clinical profile and outcome in a pediatric cohort.” Diagnostics. Dec 2023. https://doi.org/10.3390/diagnostics13243674 (passantino2023cardiacinvolvementin pages 1-2, passantino2023cardiacinvolvementin pages 6-8)

Selected ClinicalTrials.gov records:

• NCT04899310 (mRNA‑3705). Phase 1/2. ACTIVE_NOT_RECRUITING. Estimated enrollment 74. (NCT04899310 chunk 1) • NCT05295433 (mRNA‑3705 extension). Phase 1/2. RECRUITING. Estimated enrollment 56. (NCT05295433 chunk 1) • NCT04581785 (hLB‑001 AAV LK03 albumin-locus integration). Phase 1/2. TERMINATED. Enrollment 4. (NCT04581785 chunk 1) • NCT04732429 (HST5040). Phase 2. TERMINATED. Enrollment 26. (NCT04732429 chunk 1)

End of report.

References

(head2023newinsightsinto pages 1-3): PamelaSara E. Head, Jordan L. Meier, and Charles P. Venditti. New insights into the pathophysiology of methylmalonic acidemia. Journal of Inherited Metabolic Disease, 46:436-449, May 2023. URL: https://doi.org/10.1002/jimd.12617, doi:10.1002/jimd.12617. This article has 38 citations and is from a peer-reviewed journal.
(manoli2023biomarkerstopredict pages 15-16): Irini Manoli, Abigael Gebremariam, Samantha McCoy, Alexandra R. Pass, Jack Gagné, Camryn Hall, Susan Ferry, Carol Van Ryzin, Jennifer L. Sloan, Elisa Sacchetti, Giulio Catesini, Cristiano Rizzo, Diego Martinelli, Marco Spada, Carlo Dionisi‐Vici, and Charles P. Venditti. Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia. Journal of Inherited Metabolic Disease, 46:554-572, Jun 2023. URL: https://doi.org/10.1002/jimd.12636, doi:10.1002/jimd.12636. This article has 28 citations and is from a peer-reviewed journal.
(tejero2024methylmalonicacidin pages 3-4): Joanne D Tejero, Felicia Lazure, and Ana P Gomes. Methylmalonic acid in aging and disease. Trends in Endocrinology & Metabolism, 35:188-200, Mar 2024. URL: https://doi.org/10.1016/j.tem.2023.11.001, doi:10.1016/j.tem.2023.11.001. This article has 43 citations and is from a domain leading peer-reviewed journal.
(head2023newinsightsinto media 2be035c5): PamelaSara E. Head, Jordan L. Meier, and Charles P. Venditti. New insights into the pathophysiology of methylmalonic acidemia. Journal of Inherited Metabolic Disease, 46:436-449, May 2023. URL: https://doi.org/10.1002/jimd.12617, doi:10.1002/jimd.12617. This article has 38 citations and is from a peer-reviewed journal.
(head2023newinsightsinto pages 3-4): PamelaSara E. Head, Jordan L. Meier, and Charles P. Venditti. New insights into the pathophysiology of methylmalonic acidemia. Journal of Inherited Metabolic Disease, 46:436-449, May 2023. URL: https://doi.org/10.1002/jimd.12617, doi:10.1002/jimd.12617. This article has 38 citations and is from a peer-reviewed journal.
(manoli2023biomarkerstopredict pages 17-21): Irini Manoli, Abigael Gebremariam, Samantha McCoy, Alexandra R. Pass, Jack Gagné, Camryn Hall, Susan Ferry, Carol Van Ryzin, Jennifer L. Sloan, Elisa Sacchetti, Giulio Catesini, Cristiano Rizzo, Diego Martinelli, Marco Spada, Carlo Dionisi‐Vici, and Charles P. Venditti. Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia. Journal of Inherited Metabolic Disease, 46:554-572, Jun 2023. URL: https://doi.org/10.1002/jimd.12636, doi:10.1002/jimd.12636. This article has 28 citations and is from a peer-reviewed journal.
(head2023newinsightsinto pages 12-13): PamelaSara E. Head, Jordan L. Meier, and Charles P. Venditti. New insights into the pathophysiology of methylmalonic acidemia. Journal of Inherited Metabolic Disease, 46:436-449, May 2023. URL: https://doi.org/10.1002/jimd.12617, doi:10.1002/jimd.12617. This article has 38 citations and is from a peer-reviewed journal.
(head2023newinsightsinto pages 7-9): PamelaSara E. Head, Jordan L. Meier, and Charles P. Venditti. New insights into the pathophysiology of methylmalonic acidemia. Journal of Inherited Metabolic Disease, 46:436-449, May 2023. URL: https://doi.org/10.1002/jimd.12617, doi:10.1002/jimd.12617. This article has 38 citations and is from a peer-reviewed journal.
(schumann2023theimpactof pages 4-5): Anke Schumann, Marion Brutsche, Monique Havermans, Sarah C. Grünert, Stefan Kölker, Olaf Groß, Luciana Hannibal, and Ute Spiekerkoetter. The impact of metabolic stressors on mitochondrial homeostasis in a renal epithelial cell model of methylmalonic aciduria. Scientific Reports, May 2023. URL: https://doi.org/10.1038/s41598-023-34373-8, doi:10.1038/s41598-023-34373-8. This article has 11 citations and is from a peer-reviewed journal.
(schumann2023theimpactof pages 8-8): Anke Schumann, Marion Brutsche, Monique Havermans, Sarah C. Grünert, Stefan Kölker, Olaf Groß, Luciana Hannibal, and Ute Spiekerkoetter. The impact of metabolic stressors on mitochondrial homeostasis in a renal epithelial cell model of methylmalonic aciduria. Scientific Reports, May 2023. URL: https://doi.org/10.1038/s41598-023-34373-8, doi:10.1038/s41598-023-34373-8. This article has 11 citations and is from a peer-reviewed journal.
(costanzo2024methylmalonicacidemiatriggers pages 1-2): Michele Costanzo, Armando Cevenini, Laxmikanth Kollipara, Marianna Caterino, Sabrina Bianco, Francesca Pirozzi, Gianluca Scerra, Massimo D’Agostino, Luigi Michele Pavone, Albert Sickmann, and Margherita Ruoppolo. Methylmalonic acidemia triggers lysosomal-autophagy dysfunctions. Cell & Bioscience, May 2024. URL: https://doi.org/10.1186/s13578-024-01245-1, doi:10.1186/s13578-024-01245-1. This article has 16 citations and is from a peer-reviewed journal.
(costanzo2024methylmalonicacidemiatriggers pages 7-10): Michele Costanzo, Armando Cevenini, Laxmikanth Kollipara, Marianna Caterino, Sabrina Bianco, Francesca Pirozzi, Gianluca Scerra, Massimo D’Agostino, Luigi Michele Pavone, Albert Sickmann, and Margherita Ruoppolo. Methylmalonic acidemia triggers lysosomal-autophagy dysfunctions. Cell & Bioscience, May 2024. URL: https://doi.org/10.1186/s13578-024-01245-1, doi:10.1186/s13578-024-01245-1. This article has 16 citations and is from a peer-reviewed journal.
(costanzo2024methylmalonicacidemiatriggers pages 12-14): Michele Costanzo, Armando Cevenini, Laxmikanth Kollipara, Marianna Caterino, Sabrina Bianco, Francesca Pirozzi, Gianluca Scerra, Massimo D’Agostino, Luigi Michele Pavone, Albert Sickmann, and Margherita Ruoppolo. Methylmalonic acidemia triggers lysosomal-autophagy dysfunctions. Cell & Bioscience, May 2024. URL: https://doi.org/10.1186/s13578-024-01245-1, doi:10.1186/s13578-024-01245-1. This article has 16 citations and is from a peer-reviewed journal.
(costanzo2024methylmalonicacidemiatriggers pages 10-12): Michele Costanzo, Armando Cevenini, Laxmikanth Kollipara, Marianna Caterino, Sabrina Bianco, Francesca Pirozzi, Gianluca Scerra, Massimo D’Agostino, Luigi Michele Pavone, Albert Sickmann, and Margherita Ruoppolo. Methylmalonic acidemia triggers lysosomal-autophagy dysfunctions. Cell & Bioscience, May 2024. URL: https://doi.org/10.1186/s13578-024-01245-1, doi:10.1186/s13578-024-01245-1. This article has 16 citations and is from a peer-reviewed journal.
(schumann2023theimpactof pages 5-6): Anke Schumann, Marion Brutsche, Monique Havermans, Sarah C. Grünert, Stefan Kölker, Olaf Groß, Luciana Hannibal, and Ute Spiekerkoetter. The impact of metabolic stressors on mitochondrial homeostasis in a renal epithelial cell model of methylmalonic aciduria. Scientific Reports, May 2023. URL: https://doi.org/10.1038/s41598-023-34373-8, doi:10.1038/s41598-023-34373-8. This article has 11 citations and is from a peer-reviewed journal.
(schumann2023theimpactof pages 6-8): Anke Schumann, Marion Brutsche, Monique Havermans, Sarah C. Grünert, Stefan Kölker, Olaf Groß, Luciana Hannibal, and Ute Spiekerkoetter. The impact of metabolic stressors on mitochondrial homeostasis in a renal epithelial cell model of methylmalonic aciduria. Scientific Reports, May 2023. URL: https://doi.org/10.1038/s41598-023-34373-8, doi:10.1038/s41598-023-34373-8. This article has 11 citations and is from a peer-reviewed journal.
(zhang2023transcriptomeanalysisreveals pages 7-10): Zhilei Zhang, Xin Wang, Yanyun Wang, Yahong Li, Peiying Yang, Yun Sun, and jiang tao. Transcriptome analysis reveals a new insights toward molecular mechanisms of methylmalonic acidemia in hepatocytes. Unknown journal, Dec 2023. URL: https://doi.org/10.21203/rs.3.rs-3691276/v1, doi:10.21203/rs.3.rs-3691276/v1.
(costanzo2024methylmalonicacidemiatriggers pages 5-7): Michele Costanzo, Armando Cevenini, Laxmikanth Kollipara, Marianna Caterino, Sabrina Bianco, Francesca Pirozzi, Gianluca Scerra, Massimo D’Agostino, Luigi Michele Pavone, Albert Sickmann, and Margherita Ruoppolo. Methylmalonic acidemia triggers lysosomal-autophagy dysfunctions. Cell & Bioscience, May 2024. URL: https://doi.org/10.1186/s13578-024-01245-1, doi:10.1186/s13578-024-01245-1. This article has 16 citations and is from a peer-reviewed journal.
(manoli2023biomarkerstopredict pages 9-10): Irini Manoli, Abigael Gebremariam, Samantha McCoy, Alexandra R. Pass, Jack Gagné, Camryn Hall, Susan Ferry, Carol Van Ryzin, Jennifer L. Sloan, Elisa Sacchetti, Giulio Catesini, Cristiano Rizzo, Diego Martinelli, Marco Spada, Carlo Dionisi‐Vici, and Charles P. Venditti. Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia. Journal of Inherited Metabolic Disease, 46:554-572, Jun 2023. URL: https://doi.org/10.1002/jimd.12636, doi:10.1002/jimd.12636. This article has 28 citations and is from a peer-reviewed journal.
(manoli2023biomarkerstopredict pages 10-12): Irini Manoli, Abigael Gebremariam, Samantha McCoy, Alexandra R. Pass, Jack Gagné, Camryn Hall, Susan Ferry, Carol Van Ryzin, Jennifer L. Sloan, Elisa Sacchetti, Giulio Catesini, Cristiano Rizzo, Diego Martinelli, Marco Spada, Carlo Dionisi‐Vici, and Charles P. Venditti. Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia. Journal of Inherited Metabolic Disease, 46:554-572, Jun 2023. URL: https://doi.org/10.1002/jimd.12636, doi:10.1002/jimd.12636. This article has 28 citations and is from a peer-reviewed journal.
(manoli2023biomarkerstopredict pages 12-13): Irini Manoli, Abigael Gebremariam, Samantha McCoy, Alexandra R. Pass, Jack Gagné, Camryn Hall, Susan Ferry, Carol Van Ryzin, Jennifer L. Sloan, Elisa Sacchetti, Giulio Catesini, Cristiano Rizzo, Diego Martinelli, Marco Spada, Carlo Dionisi‐Vici, and Charles P. Venditti. Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia. Journal of Inherited Metabolic Disease, 46:554-572, Jun 2023. URL: https://doi.org/10.1002/jimd.12636, doi:10.1002/jimd.12636. This article has 28 citations and is from a peer-reviewed journal.
(passantino2023cardiacinvolvementin pages 1-2): Silvia Passantino, Serena Chiellino, Francesca Girolami, Mattia Zampieri, Giovanni Calabri, Gaia Spaziani, Elena Bennati, Giulio Porcedda, Elena Procopio, Iacopo Olivotto, and Silvia Favilli. Cardiac involvement in classical organic acidurias: clinical profile and outcome in a pediatric cohort. Diagnostics, 13:3674, Dec 2023. URL: https://doi.org/10.3390/diagnostics13243674, doi:10.3390/diagnostics13243674. This article has 1 citations.
(passantino2023cardiacinvolvementin pages 6-8): Silvia Passantino, Serena Chiellino, Francesca Girolami, Mattia Zampieri, Giovanni Calabri, Gaia Spaziani, Elena Bennati, Giulio Porcedda, Elena Procopio, Iacopo Olivotto, and Silvia Favilli. Cardiac involvement in classical organic acidurias: clinical profile and outcome in a pediatric cohort. Diagnostics, 13:3674, Dec 2023. URL: https://doi.org/10.3390/diagnostics13243674, doi:10.3390/diagnostics13243674. This article has 1 citations.
(manoli2024lipodystrophyinmethylmalonic pages 2-4): Irini Manoli, Justin R. Sysol, PamelaSara E. Head, Madeline W. Epping, Oksana Gavrilova, Melissa K. Crocker, Jennifer L. Sloan, Stefanos A. Koutsoukos, Cindy Wang, Yiouli P. Ktena, Sophia Mendelson, Alexandra R. Pass, Patricia M. Zerfas, Victoria Hoffmann, Hilary J. Vernon, Laura A. Fletcher, James C. Reynolds, Maria G. Tsokos, Constantine A. Stratakis, Stephan D. Voss, Kong Y. Chen, Rebecca J. Brown, Ada Hamosh, Gerard T. Berry, Xiaoyuan Shawn Chen, Jack A. Yanovski, and Charles P. Venditti. Lipodystrophy in methylmalonic acidemia associated with elevated fgf21 and abnormal methylmalonylation. JCI Insight, Feb 2024. URL: https://doi.org/10.1172/jci.insight.174097, doi:10.1172/jci.insight.174097. This article has 3 citations and is from a domain leading peer-reviewed journal.
(manoli2024lipodystrophyinmethylmalonic pages 10-11): Irini Manoli, Justin R. Sysol, PamelaSara E. Head, Madeline W. Epping, Oksana Gavrilova, Melissa K. Crocker, Jennifer L. Sloan, Stefanos A. Koutsoukos, Cindy Wang, Yiouli P. Ktena, Sophia Mendelson, Alexandra R. Pass, Patricia M. Zerfas, Victoria Hoffmann, Hilary J. Vernon, Laura A. Fletcher, James C. Reynolds, Maria G. Tsokos, Constantine A. Stratakis, Stephan D. Voss, Kong Y. Chen, Rebecca J. Brown, Ada Hamosh, Gerard T. Berry, Xiaoyuan Shawn Chen, Jack A. Yanovski, and Charles P. Venditti. Lipodystrophy in methylmalonic acidemia associated with elevated fgf21 and abnormal methylmalonylation. JCI Insight, Feb 2024. URL: https://doi.org/10.1172/jci.insight.174097, doi:10.1172/jci.insight.174097. This article has 3 citations and is from a domain leading peer-reviewed journal.
(ling2024clinicaloutcomesof pages 5-6): Shiying Ling, Shengnan Wu, Ruixue Shuai, Yue Yu, Wenjuan Qiu, Haiyan Wei, Chiju Yang, Peng Xu, Hui Zou, Jizhen Feng, Tingting Niu, Haili Hu, Huiwen Zhang, Lili Liang, Yu Wang, Ting Chen, Feng Xu, Xuefan Gu, and Lianshu Han. Clinical outcomes of patients with mut-type methylmalonic acidemia identified through expanded newborn screening in china. Human Genomics, Jul 2024. URL: https://doi.org/10.1186/s40246-024-00646-0, doi:10.1186/s40246-024-00646-0. This article has 3 citations and is from a peer-reviewed journal.
(ling2024clinicaloutcomesof pages 4-5): Shiying Ling, Shengnan Wu, Ruixue Shuai, Yue Yu, Wenjuan Qiu, Haiyan Wei, Chiju Yang, Peng Xu, Hui Zou, Jizhen Feng, Tingting Niu, Haili Hu, Huiwen Zhang, Lili Liang, Yu Wang, Ting Chen, Feng Xu, Xuefan Gu, and Lianshu Han. Clinical outcomes of patients with mut-type methylmalonic acidemia identified through expanded newborn screening in china. Human Genomics, Jul 2024. URL: https://doi.org/10.1186/s40246-024-00646-0, doi:10.1186/s40246-024-00646-0. This article has 3 citations and is from a peer-reviewed journal.
(ling2024clinicaloutcomesof pages 6-8): Shiying Ling, Shengnan Wu, Ruixue Shuai, Yue Yu, Wenjuan Qiu, Haiyan Wei, Chiju Yang, Peng Xu, Hui Zou, Jizhen Feng, Tingting Niu, Haili Hu, Huiwen Zhang, Lili Liang, Yu Wang, Ting Chen, Feng Xu, Xuefan Gu, and Lianshu Han. Clinical outcomes of patients with mut-type methylmalonic acidemia identified through expanded newborn screening in china. Human Genomics, Jul 2024. URL: https://doi.org/10.1186/s40246-024-00646-0, doi:10.1186/s40246-024-00646-0. This article has 3 citations and is from a peer-reviewed journal.
(NCT04899310 chunk 1): A Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of mRNA-3705 in Participants With Isolated Methylmalonic Acidemia. ModernaTX, Inc.. 2021. ClinicalTrials.gov Identifier: NCT04899310
(NCT05295433 chunk 1): An Extension Study to Evaluate the Long-Term Safety and Clinical Activity of mRNA-3705 in Participants Previously Enrolled in Other Clinical Studies of mRNA-3705. ModernaTX, Inc.. 2022. ClinicalTrials.gov Identifier: NCT05295433
(NCT04581785 chunk 1): Gene Therapy With hLB-001 in Pediatric Patients With Severe Methylmalonic Acidemia. LogicBio Therapeutics, Inc. 2021. ClinicalTrials.gov Identifier: NCT04581785
(NCT04732429 chunk 1): Study of HST5040 in Subjects With Propionic or Methylmalonic Acidemia. HemoShear Therapeutics. 2021. ClinicalTrials.gov Identifier: NCT04732429

Methylmalonic Acidemia

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