🏷

Classifications

ICIMD (Inherited Metabolic Disorders)

👪

Inheritance

1

Autosomal recessive HP:0000007

Biallelic MMAA variants. The majority of reported cblA alleles are premature termination codons, with a single nonsense allele accounting for a large share of the mutant chromosomes.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:20301409 SUPPORT Other

"All forms of isolated MMA are inherited in an autosomal recessive manner."

GeneReviews states the inheritance mode for the isolated MMA group, of which cblA is a member.

PMID:17957493 SUPPORT Human Clinical

"Most of the cblA patients carried premature termination codons (PTC) in both alleles."

Documents the biallelic, predominantly truncating allele architecture in the cblA subgroup of this cohort.

?

Discussions and Knowledge Gaps

7

Is there an animal model of cblA that reproduces the human disease, and what would it take to establish one?

KNOWLEDGE GAP cbla_no_published_animal_model

Attached to

pathophysiology#Reduced Methylmalonyl-CoA Mutase Holoenzyme Activity

This entry curates no animal models because no published study characterises an Mmaa-deficient animal as a model of cblA methylmalonic aciduria. That is a statement about the literature, not about the reagents. A constitutive null allele does exist, Mmaa em1(IMPC)J, MGI:5825155, produced by the International Mouse Phenotyping Consortium, and MGI records abnormal phenotype annotations for it across adipose, cardiovascular, growth, haematopoietic, homeostasis and skeletal systems. MGI attaches no human disease model assertion to that allele, no publication describes its metabolic phenotype, and consortium phenotype annotations are not a citable quoted finding of the kind this knowledge base requires for an evidence item, so the allele is recorded here rather than curated as a model. The published rodent work on Mmaa is a developmental expression survey of Mmaa, Mmab and Mut during mouse organogenesis rather than a disease model, and the established mouse models of methylmalonic acidemia are mutase-deficient. The gap matters because the two arms of MMAA function that human biochemistry has separated, cofactor gating and cofactor repair, cannot be separated pharmacologically in patients, and an animal in which they could be dissociated is the obvious way to ask which one sets the residual mutase activity that determines cobalamin responsiveness.

Why does chronic kidney disease still develop in cblA patients whose methylmalonate is well controlled on cobalamin?

KNOWLEDGE GAP cbla_residual_renal_disease_on_treatment

Attached to

pathophysiology#Renal Tubulointerstitial Injury

Renal mitochondrial dysfunction is represented as a hypothesis, with a causal path to tubulointerstitial injury and CKD. cblA-specific mediation remains unproven: incomplete metabolite control, damage before treatment and tissue mitochondrial dysfunction may contribute. The adult series was retrospective and included variable initial treatment; the Polish series used cystatin C to identify CKD. Neither cohort establishes why renal disease persists in a particular well-controlled patient. The full 2022 severe-case biopsy account localizes disease to the tubulointerstitium with glomerulosclerosis, without specifying proximal epithelial cells; the accessible 2013 biopsy abstract likewise reports nonspecific interstitial inflammation. A later biomarker study found no elevated urinary markers in five genetically confirmed cblA patients sampled while well, all with normal cystatin C. That small, preserved-function subgroup neither demonstrates proximal-cell injury nor excludes it in cblA patients with CKD.

Show evidence (4 references)

PMID:35618652 SUPPORT INDIRECT Other

"This is also in line with the pathophysiological hypotheses suggesting that chronic kidney disease is more directly linked to MMA toxicity, while brain involvement seems to be more complex and related partially to acute decompensation and energy deficit, and partially to de novo synthesis and..."

The cblA cohort discussion proposes organ-injury routes; these are hypotheses, not measured causal mediation.

url:https://www.ncbi.nlm.nih.gov/books/NBK1231/ SUPPORT INDIRECT Other

"Secondary mitochondrial dysfunction rather than direct nephrotoxicity of methylmalonic acid is hypothesized as the cause for renal disease"

GeneReviews presents a mechanistic hypothesis across isolated MMA; subtype-specific renal confirmation is lacking.

PMID:35618652 SUPPORT Human Clinical

"A renal biopsy was performed at the age of 14 years, and showed tubulo‐interstitial nephropathy with glomerulosclerosis compatible with MMA."

The severe homozygous MMAA p.Ala196* case had this tissue lesion; the report does not identify the injured nephron segment or a proximal epithelial-cell mechanism.

+ 1 more reference

Which mechanisms account for these cblA findings in the reported patients?

KNOWLEDGE GAP cbla_neurologic_attribution

Attached to

phenotypes#Hypotonia phenotypes#Seizure phenotypes#Ataxia phenotypes#Developmental regression phenotypes#Spasticity phenotypes#Diminished ability to concentrate

The reviewed sources establish these findings in cblA, but do not establish a finding-specific path from the modeled brain or basal-ganglia injury in the reported individuals. Acute toxicity, chronic brain metabolism, prior injury and other contributors may differ; the severe-case co-occurrence alone does not determine mediation. Basal-ganglia causation is represented for extrapyramidal movement disorders where the source explicitly supports it.

Show evidence (1 reference)

PMID:35618652 SUPPORT INDIRECT Other

"This is also in line with the pathophysiological hypotheses suggesting that chronic kidney disease is more directly linked to MMA toxicity, while brain involvement seems to be more complex and related partially to acute decompensation and energy deficit, and partially to de novo synthesis and..."

The cblA cohort discussion proposes organ-injury routes; these are hypotheses, not measured causal mediation.

Which mechanisms account for these cblA findings in the reported patients?

KNOWLEDGE GAP cbla_optic_and_imaging_mechanisms

Attached to

phenotypes#Optic atrophy phenotypes#Cerebral atrophy phenotypes#Ventriculomegaly

Optic atrophy causes visual impairment in the reported cblA patient, but the liver OXPHOS defect does not establish an optic-nerve mechanism. Cerebral atrophy and ventricular dilatation co-occur in the Polish cohort; ex-vacuo ventricular enlargement is plausible but not demonstrated. The predominantly normal or nonspecific adult imaging and absent lesion-outcome correlation preclude assigning every image to a single causal route.

Show evidence (2 references)

PMID:19277894 SUPPORT Human Clinical

"An adult patient with methylmalonic aciduria due to defective cobalamin synthesis (CblA) responsive to vitamin B(12) presented suddenly with severe visual impairment ascribed to optic atrophy followed by a fatal multiorgan failure and lactic acidosis but low methylmalonic acid in plasma and urine."

The case establishes optic atrophy with visual loss despite low contemporaneous MMA. The reported OXPHOS defect was in liver, so it does not establish the upstream optic-nerve lesion.

PMID:35618652 SUPPORT Human Clinical

"Two patients showed basal ganglia signal changes, but these did not correlate with their neurological examination, which was normal, or with cognitive function, normal as well."

The cblA cohort illustrates limitations of attributing clinical deficits to imaging abnormalities.

Which mechanisms account for these cblA findings in the reported patients?

KNOWLEDGE GAP cbla_systemic_attribution

Attached to

phenotypes#Feeding difficulties phenotypes#Hyperuricemia phenotypes#Dehydration phenotypes#Hypothermia phenotypes#Hyperglycemia phenotypes#Ketonuria phenotypes#Elevated circulating hepatic transaminase concentration phenotypes#Osteopenia phenotypes#Vomiting

Vomiting, feeding problems and constitutional or laboratory abnormalities are observed during cblA illness, but the available sources often establish association rather than a specific causal route. Hyperuricemia and osteopenia may reflect kidney disease or other factors; hyperglycemia, ketonuria and transaminase elevations were not mechanistically characterized. A direct liver OXPHOS result in a different cblA case does not establish the cause of the Polish cohort’s transaminase elevations. The represented nutritional growth, osteoporosis and renal-anemia pathways retain alternative contributors; the remaining gaps concern causal attribution rather than an absence of these biological hypotheses.

Show evidence (3 references)

PMID:31921599 SUPPORT Human Clinical

"In addition, more than half of the patients had anemia, hyperglycemia and ketonuria."

Observed at diagnosis in the five-patient cblA cohort; exact individual counts are not supplied in this sentence.

PMID:34915869 SUPPORT Human Clinical

"On the fourth postnatal day, she developed apathy, hypothermia, and dehydration with metabolic acidosis and hyperammonaemia (1,601 μmol/L)."

The clinical history is patient 2 with homozygous MMAA p.Leu89Pro.

PMID:35618652 SUPPORT Human Clinical

"Bone densitometry was performed in 9 patients and was abnormal in 5 of them with osteoporosis (n = 2) or osteopenia (n = 3)."

The denominator is nine tested adults, not all 23; selection for densitometry may affect the proportion.

What caused conduction and repolarization abnormalities in the severe cblA case?

KNOWLEDGE GAP cbla_cardiac_conduction_attribution

Attached to

phenotypes#Atrioventricular block phenotypes#Prolonged QT interval

Renal disease, electrolyte imbalance and myocardial dysfunction could contribute, but the historical case lacks the data needed to assign a particular mechanism. The source explicitly proposes a renal contribution to hypertrophy, which is represented; it does not make an equivalent causal attribution for the block or QT prolongation.

Show evidence (1 reference)

PMID:35618652 SUPPORT Human Clinical

"He developed intellectual disability, ataxia, epilepsy, and renal insufficiency (since the age of 11 years) with arterial hypertension, cardiac left hypertrophy and cardiac rhythm anomalies (atrioventricular block, long QT at the age of 15 years)."

The severe homozygous MMAA p.Ala196* case had these cardiac rhythm abnormalities; neither the degree of block nor a corrected QT interval was specified.

How much of the adult-onset constitutional presentation was attributable to MMAA deficiency versus concurrent low vitamin B12?

KNOWLEDGE GAP cbla_adult_constitutional_symptom_scope

Attached to

pathophysiology#Reduced Methylmalonyl-CoA Mutase Holoenzyme Activity

One molecularly and functionally confirmed adult had fatigue, myalgia, exercise intolerance, headache and nausea after a flu-like illness, with concurrent low serum B12. Symptoms resolved after intensive B12 while MMA remained elevated. These observations support a possible attenuated presentation but do not separate MMAA-dependent symptoms from acquired B12 deficiency or another contributor; they are not generalized as characteristic cblA phenotypes.

Show evidence (1 reference)

PMID:35618652 SUPPORT Human Clinical

"After treatment with B12 up to 1 mg IM daily her chronic symptoms completely disappeared; plasma B12 level normalized although MMA remained elevated (8 μmol/L)."

Clinical response in the described adult cblA patient, whose pretreatment serum B12 was also low.

⚙

Pathophysiology

13

Biallelic MMAA Loss of Function

Two damaged copies of MMAA, on chromosome 4q31, remove or cripple the mitochondrial G-protein that chaperones adenosylcobalamin onto methylmalonyl-CoA mutase. Most reported alleles are premature termination codons; the remainder are missense changes at conserved residues, and roughly a third of those destabilise the protein in expression systems.

MMAA hgnc:18871

mitochondrion GO:0005739

Downstream

Loss of MMAA-Mutase Functional Interaction MMAA alleles can reduce protein stability or disrupt productive cofactor-handling interactions with MMUT. Physical binding and residual biochemical activity vary by allele; loss of productive function does not require complete loss of binding.

Show evidence (2 references)

PMID:12438653 SUPPORT Human Clinical

"These data confirm that the identified gene, MMAA, corresponds to the cblA complementation group."

Establishes MMAA as the gene defective in the cblA complementation group.

PMID:15523652 SUPPORT Human Clinical

"A total of 13 mutations result in premature stop codons; three are splice site defects; and six are missense mutations that occur at highly conserved residues."

Describes the allele classes underlying loss of MMAA function in cblA patients.

Loss of MMAA-Mutase Functional Interaction

MMAA variants can disrupt its functional interaction with MMUT and impair cofactor loading and repair. The 2017 series found reduced MMUT-stimulated GTPase activity in all 15 tested mutant proteins, with physical binding lost in nine. This is not universal across alleles: a 2023 study found enhanced MMUT-stimulated activity for R98G but defective gating and cofactor repair.

mutase-stimulated MMAA GTPase activity GO:0003924

Downstream

Failure of Adenosylcobalamin Gating onto Methylmalonyl-CoA Mutase Disruption of productive MMAA-MMUT interaction impairs nucleotide-gated cofactor transfer. The measured defect need not abolish physical binding or all loading.

Failure of Holoenzyme Cofactor Protection and Reactivation MMAA-MMUT interaction also supports cofactor protection and exchange. Disease variants can impair these functions along with gating, with the degree and combination of defects depending on the allele.

Show evidence (6 references)

PMID:28497574 SUPPORT In Vitro

"However, all mutations strongly decreased functional association with MUT by reducing GTPase activity stimulation upon incubation with MUT, while nine mutant proteins additionally lost the ability to physically bind MUT."

All 15 purified mutants had reduced functional association in this assay; only nine additionally lost physical binding, so the two defects are distinguished.

PMID:28497574 SUPPORT In Vitro

"All 15 purified mutant proteins demonstrated wild-type like intrinsic GTPase activity and only one (p.Asp292Val), where the mutation is in the GTP binding domain, revealed decreased GTP binding."

Establishes that intrinsic catalytic activity is retained, so the lesion is in the interaction rather than in the GTPase chemistry itself.

PMID:20876572 SUPPORT In Vitro

"The physiological importance of this interaction is highlighted by a recently identified homoallelic patient mutation of MMAA, G188R, which, we show, retains basal GTPase activity but has abrogated interaction."

An independent patient allele shows the same dissociation of preserved GTPase activity from abolished complex formation.

+ 3 more references

Failure of Adenosylcobalamin Gating onto Methylmalonyl-CoA Mutase

In health, MMAA favours complex formation with the apo-mutase, licenses transfer of adenosylcobalamin from the adenosyltransferase MMAB, and then releases the loaded holoenzyme in a GTP-dependent cycle. In cblA, defective gating disrupts controlled cofactor loading despite intact MMAB-dependent synthesis; it does not imply that every allele abolishes all cofactor transfer or residual holoenzyme activity.

mitochondrial adenosylcobalamin handling GO:0009235 ↓ DECREASED

cobalamin binding by the mutase holoenzyme GO:0031419 ↓ DECREASED

Downstream

Reduced Methylmalonyl-CoA Mutase Holoenzyme Activity Impaired productive cofactor loading reduces the active holoenzyme pool even when intact mutase protein is present; residual loading and activity can persist.

Show evidence (3 references)

PMID:20876572 SUPPORT In Vitro

"Together, our data point to a gatekeeping role for MMAA by favoring complex formation with MUT apoenzyme for AdoCbl assembly and releasing the AdoCbl-loaded holoenzyme from the complex, in a GTP-dependent manner."

States the gatekeeping model for adenosylcobalamin assembly onto the mutase that this node describes.

PMID:28497574 SUPPORT In Vitro

"Finally, all mutations interfered with gating the transfer of AdoCbl from MMAB to MUT."

Every tested patient missense allele disrupts the gating step, which is the specific failure asserted here.

PMID:19955418 SUPPORT In Vitro

"While the GTP-binding energy is needed for the editing function; that is, to discriminate between active and inactive cofactor forms, the chemical energy of GTP hydrolysis is required for gating cofactor transfer."

Separates the two nucleotide requirements of the gating cycle. This was established in the bacterial MeaB orthologue rather than in human MMAA, so it is cited for the mechanism of gating and not as a cblA genotype result.

Failure of Holoenzyme Cofactor Protection and Reactivation

Adenosylcobalamin is destroyed slowly during normal mutase turnover, accumulating as the oxidised hydroxocobalamin form and inactivating the enzyme. MMAA both slows that oxidation while in complex with the mutase and, once inactivation has occurred, removes the damaged cofactor through GTP hydrolysis so a fresh one can be installed. Impaired MMAA protection or repair can therefore reduce sustained mutase activity; the residual function depends on the allele and experimental context.

Downstream

Reduced Methylmalonyl-CoA Mutase Holoenzyme Activity Impaired repair allows inactive cofactor to accumulate and can compound defective loading, reducing sustained holoenzyme activity.

Show evidence (4 references)

PMID:28943303 SUPPORT In Vitro

"the formation and accumulation of OH2Cbl, the oxidized form of the AdoCbl cofactor formed during catalysis, is the cause of hMCM inactivation"

Identifies oxidative cofactor damage during catalysis as the process MMAA counteracts.

PMID:28943303 SUPPORT In Vitro

"Moreover, an inactive model of hMCM was used to demonstrate that hMMAA is able to remove the damaged cofactor through GTP hydrolysis."

Demonstrates the cofactor-exchange repair function whose loss this node asserts.

PMID:21138732 SUPPORT In Vitro

"When it was added at the beginning of the reaction, it prevents inactivation by guarding MCM. After 60 min of reaction, when MCM is inactive, the addition of MMAA increases the enzymatic activity through GTP hydrolysis, indicating reactivation of MCM by exchange of the damaged cofactor."

Establishes the dual protective and reactivating roles of MMAA on the mutase in a purified system.

+ 1 more reference

Reduced Methylmalonyl-CoA Mutase Holoenzyme Activity

Insufficient effective MMUT holoenzyme activity reduces propionate-pathway flux in intact cells. This is a cofactor-handling defect: MMUT activity measured in extracts with excess adenosylcobalamin can be normal, while cellular propionate incorporation is low and improves with hydroxocobalamin.

propionate catabolic process GO:0019543 ↓ DECREASED

methylmalonyl-CoA mutase activity GO:0004494 ↓ DECREASED

mitochondrial matrix GO:0005759

Downstream

Methylmalonic Acid and Propionyl-CoA Accumulation Methylmalonyl-CoA that cannot be isomerised to succinyl-CoA is hydrolysed to methylmalonic acid, and propionyl-CoA backs up behind it.

Show evidence (1 reference)

PMID:35618652 SUPPORT In Vitro

"Enzymatic studies of her fibroblasts showed a deficit in propionate incorporation (1.61 nmol/mg prot/16 h vs. 6.08 nmol/mg prot/16 h in the experimental control; range in controls 3.5–24.4) with a clear increase after B12 supplementation (11.7 nmol/mg prot/16 h vs. 7.79 nmol/mg prot/16 h in the..."

Diagnostic cell studies in an MMAA-confirmed adult show impaired pathway flux with intact cofactor-supplemented apoenzyme activity.

Methylmalonic Acid and Propionyl-CoA Accumulation

The MMUT functional block causes accumulation of methylmalonic acid and upstream acyl-CoA metabolites. Urine and plasma MMA were lower in treated cblA than in mut patients in the registry comparison; this does not establish a uniformly partial genetic defect or an individual threshold for organ toxicity.

Downstream

Acute Metabolic Decompensation The metabolite burden can precipitate acidosis and secondary hyperammonemia during catabolic stress.

Episodic metabolic acidosis Accumulating organic acids contribute to high-anion-gap acidosis during decompensation.

Secondary impairment of ureagenesis Propionyl-CoA can inhibit N-acetylglutamate synthesis. Transfer of this biochemical mechanism to cblA is provisional; it is not the only proposed cause of hyperammonemia.

Secondary renal mitochondrial dysfunction A proposed route from the metabolic block to renal injury; direct methylmalonate nephrotoxicity and secondary mitochondrial effects are not resolved in cblA.

Neurologic Injury Chronic metabolite production and trapping in brain, together with energy deficit, are proposed contributors to neurological injury in cblA.

Show evidence (2 references)

PMID:32754920 SUPPORT Human Clinical

"Methylmalonic acidemia (MMA) levels in urine and plasma were significantly lower in cblA."

Quantifies the lower metabolite burden in cblA relative to mut-type disease in a registry comparison of 28 cblA and 95 mut patients.

PMID:31921599 SUPPORT Human Clinical

"Significant excretion of methylmalonic acid in urine and metabolic acidosis traits with significantly increased anionic gap were observed in all patients."

Documents methylmalonate accumulation in every patient of a purely MMAA-genotyped series.

Acute Metabolic Decompensation

Episodic metabolic crisis with ketoacidosis, vomiting and encephalopathy, precipitated by catabolic stress such as intercurrent illness, fasting or protein load. This is the usual route to diagnosis in cblA as in mutase deficiency.

Downstream

Neurologic Injury Acute decompensation and energy deficit can contribute to brain injury, but severe initial crisis does not determine the final cognitive outcome.

Basal ganglia injury Acute metabolic crisis can injure the basal ganglia, including the globus pallidus. This route applies to some affected infants, not all movement findings.

Reduced consciousness Acute acid-base and ammonia disturbances can impair alertness during a cblA crisis; the individual contribution of each disturbance is unresolved.

Lethargy Acute acid-base and ammonia disturbances can impair alertness during a cblA crisis; the individual contribution of each disturbance is unresolved.

Show evidence (2 references)

PMID:32754920 SUPPORT Human Clinical

"Metabolic crisis is the predominant symptom leading to diagnosis in both groups."

Establishes metabolic crisis as the dominant presenting event in the cblA arm of this registry study.

PMID:35618652 SUPPORT Human Clinical

"Disease onset was mostly pediatric (78% < 1 year, median = 4 months) with acute neurologic deterioration (65%)."

Characterises the acute presentation and its timing in an entirely cblA case series.

Renal Tubulointerstitial Injury

Tubulointerstitial injury can impair renal function in cblA. Chronic interstitial inflammation has been documented on biopsy, and another severe cblA case had tubulointerstitial nephropathy with glomerulosclerosis. Renal involvement is variable, and early hydroxocobalamin benefit remains supported by observational evidence.

kidney UBERON:0002113

Downstream

Chronic kidney disease Loss of renal tubular and interstitial integrity contributes to progressive renal dysfunction.

Show evidence (2 references)

PMID:24095221 SUPPORT Human Clinical

"Kidney biopsies showed non-specific manifestations of chronic interstitial inflammation."

Histological confirmation of interstitial renal disease in a molecularly confirmed cblA patient.

PMID:32754920 SUPPORT Human Clinical

"Glomerular filtration rate was significantly higher in cblA; and as a consequence, chronic renal failure and related complications were significantly less frequent and renal function could be preserved even in older patients."

Establishes that renal involvement occurs in cblA but is less severe than in mut-type disease.

Neurologic Injury

Neurological injury in cblA may involve acute decompensation and energy deficit, as well as chronic production and trapping of toxic metabolites in the brain. These routes are incompletely resolved. Developmental and cognitive outcomes vary, and the adult treatment comparison cannot exclude benefit from earlier diagnosis and management.

brain UBERON:0000955

Downstream

Global developmental delay Brain injury can impair development and cognition. The relative contributions of acute energy failure and chronic metabolite toxicity are unresolved in cblA.

Intellectual disability Brain injury can impair development and cognition. The relative contributions of acute energy failure and chronic metabolite toxicity are unresolved in cblA.

Show evidence (3 references)

PMID:35618652 SUPPORT Human Clinical

"The main long-term problems were intellectual disability (39%) and renal failure (30%)."

Quantifies the neurological and renal long-term burden in an entirely cblA cohort.

PMID:32754920 SUPPORT Human Clinical

"Neurological complications were predominantly found in the mut subgroup."

Bounds the claim by showing neurological complications are less characteristic of cblA than of mut-type disease in direct comparison.

PMID:35618652 SUPPORT INDIRECT Other

"This is also in line with the pathophysiological hypotheses suggesting that chronic kidney disease is more directly linked to MMA toxicity, while brain involvement seems to be more complex and related partially to acute decompensation and energy deficit, and partially to de novo synthesis and..."

The cblA cohort discussion proposes organ-injury routes; these are hypotheses, not measured causal mediation.

Secondary impairment of ureagenesis

Mechanism confidence: Provisional

Propionyl-CoA inhibition of N-acetylglutamate synthase can reduce the N-acetylglutamate required to activate carbamoyl-phosphate synthetase I. Rat liver extract experiments support this candidate route to hyperammonemia in organic acidemias. Its quantitative contribution in MMAA deficiency is unmeasured, and other mechanisms of urea-cycle impairment may contribute.

Downstream

Hyperammonemia Reduced urea-cycle ammonia clearance is a plausible contributor to secondary hyperammonemia in cblA.

Show evidence (1 reference)

PMID:500823 SUPPORT INDIRECT In Vitro

"A decreased level of N-acetylglutamate in liver mitochondria that would follow inhibition of N-acetylglutamate synthetase by propionyl-CoA would be expected to lead to hyperammonemia."

The authors infer reduced ammonia clearance from their rat mitochondrial biochemical results.

Secondary renal mitochondrial dysfunction

Mechanism confidence: Hypothetical

Secondary mitochondrial dysfunction is proposed to mediate renal damage in isolated MMA. Its specific causal contribution in cblA has not been established, and a liver OXPHOS defect in one cblA patient does not establish the renal mechanism.

Downstream

Renal Tubulointerstitial Injury Provisional mitochondrial route to tubulointerstitial damage, rather than an established cblA-specific renal experiment.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK1231/ SUPPORT INDIRECT Other

"Secondary mitochondrial dysfunction rather than direct nephrotoxicity of methylmalonic acid is hypothesized as the cause for renal disease"

GeneReviews presents a mechanistic hypothesis across isolated MMA; subtype-specific renal confirmation is lacking.

Basal ganglia injury

Acute metabolic crises can produce basal-ganglia injury and a subsequent movement disorder in cblA. A normal examination despite basal-ganglia MRI signal changes in two adults shows that an imaging abnormality alone does not determine clinical impairment.

basal ganglion UBERON:0002420

Downstream

Abnormality of extrapyramidal motor function Basal-ganglia injury can produce extrapyramidal motor dysfunction after metabolic crisis. This route does not assign the adult cohort’s probably neuroleptic-related signs to cblA.

Dystonia Dystonia is a possible expression of the basal-ganglia movement disorder after metabolic injury. Applying this route to the Polish cblA patients is an inference across sources; their individual lesion-to-dystonia correlation was not established.

Choreoathetosis Choreoathetosis may arise as part of the movement disorder following basal-ganglia injury. The Polish cblA observations establish choreoathetosis, but do not individually demonstrate this route or exclude other contributors.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK1231/ SUPPORT Other

"Some individuals develop a "metabolic stroke" or bilateral lacunar infarction of the basal ganglia during acute metabolic decompensation, which can produce an incapacitating movement disorder."

GeneReviews describes the causal crisis–basal-ganglia injury–movement disorder route. Its preceding B12-responsive phenotype section explicitly names cblA and mut– infants as susceptible.

Chronic illness and inadequate nutritional intake

Mechanism confidence: Provisional

Chronic disease burden, feeding problems and relative protein malnutrition can impair growth in isolated MMA. Renal dysfunction can aggravate this process. The nutritional contribution to growth and bone findings in specific cblA patients is not measured.

Downstream

Short stature Chronic illness and inadequate intake can impair linear growth or weight gain. This is a multifactorial isolated-MMA mechanism, not proof that all cblA growth problems are dietary.

Failure to thrive Chronic illness and inadequate intake can impair linear growth or weight gain. This is a multifactorial isolated-MMA mechanism, not proof that all cblA growth problems are dietary.

Osteoporosis Low-protein intake is a proposed contributor to osteoporosis in the cblA cohort.

Decreased body weight Chronic illness and relative nutritional insufficiency can lower body weight, with renal disease as a possible contributor. The relative contributions in individual cblA patients are unresolved.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/books/NBK1231/ SUPPORT INDIRECT Other

"It is the result of severe chronic illness and perhaps relative protein malnutrition that is complicated further by chronic renal failure."

The preceding GeneReviews sentence identifies growth failure as the subject. This is a proposed multifactorial route across isolated MMA, including cblA.

PMID:35618652 SUPPORT INDIRECT Other

"In the long‐term, patients with cblA deficiency can also present osteoporosis, likely related to low‐protein diet, and hypertension and cardiac hypertrophy, likely related to chronic kidney disease."

The authors propose these secondary relationships in cblA; the qualifiers are preserved.

⬡

Pathograph

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

●

Phenotypes

41

Blood 1

Anemia HP:0001903

Show evidence (1 reference)

PMID:31921599 SUPPORT Human Clinical

"In addition, more than half of the patients had anemia, hyperglycemia and ketonuria."

Observed at diagnosis in the five-patient cblA cohort; exact individual counts are not supplied in this sentence.

Cardiovascular 4

Hypertension HP:0000822

Show evidence (1 reference)

PMID:31921599 SUPPORT Human Clinical

"Three patients have renal failure and pharmacologically treated arterial hypertension."

The entire five-person cohort had MMAA-associated cblA.

Left ventricular hypertrophy HP:0001712

Show evidence (1 reference)

PMID:35618652 SUPPORT Human Clinical

"He developed intellectual disability, ataxia, epilepsy, and renal insufficiency (since the age of 11 years) with arterial hypertension, cardiac left hypertrophy and cardiac rhythm anomalies (atrioventricular block, long QT at the age of 15 years)."

The detailed case had homozygous MMAA p.Ala196*; the broader discussion attributes cardiac hypertrophy provisionally to kidney disease.

Atrioventricular block HP:0001678

Show evidence (1 reference)

PMID:35618652 SUPPORT Human Clinical

"He developed intellectual disability, ataxia, epilepsy, and renal insufficiency (since the age of 11 years) with arterial hypertension, cardiac left hypertrophy and cardiac rhythm anomalies (atrioventricular block, long QT at the age of 15 years)."

The severe homozygous MMAA p.Ala196* case had these cardiac rhythm abnormalities; neither the degree of block nor a corrected QT interval was specified.

Prolonged QT interval HP:0001657

Show evidence (1 reference)

PMID:35618652 SUPPORT Human Clinical

"He developed intellectual disability, ataxia, epilepsy, and renal insufficiency (since the age of 11 years) with arterial hypertension, cardiac left hypertrophy and cardiac rhythm anomalies (atrioventricular block, long QT at the age of 15 years)."

The severe homozygous MMAA p.Ala196* case had these cardiac rhythm abnormalities; neither the degree of block nor a corrected QT interval was specified.

Digestive 2

Vomiting HP:0002013

Temporal: RECURRENT

Show evidence (1 reference)

PMID:31921599 SUPPORT Human Clinical

"At the time of diagnosis the median of age was 18.8 months, but the symptoms had already appeared since infancy, as recurrent vomiting and delayed psychomotor development."

Names recurrent vomiting as a presenting symptom from infancy in this cblA series.

Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:20301409 SUPPORT Other

"symptoms occur in the first few months or years of life and are characterized by feeding problems, failure to thrive, hypotonia, and developmental delay marked by episodes of metabolic decompensation."

The preceding subject is the partially deficient or B12-responsive group, explicitly including cblA; this is clinical synthesis rather than a cblA cohort frequency.

Eye 2

Optic atrophy HP:0000648

Sequelae: Visual impairment

Show evidence (1 reference)

PMID:19277894 SUPPORT Human Clinical

"An adult patient with methylmalonic aciduria due to defective cobalamin synthesis (CblA) responsive to vitamin B(12) presented suddenly with severe visual impairment ascribed to optic atrophy followed by a fatal multiorgan failure and lactic acidosis but low methylmalonic acid in plasma and urine."

One B12-responsive adult with cblA had optic atrophy despite low plasma and urinary MMA at the time; this case does not estimate disease frequency.

Visual impairment HP:0000505

Show evidence (1 reference)

PMID:19277894 SUPPORT Human Clinical

"An adult patient with methylmalonic aciduria due to defective cobalamin synthesis (CblA) responsive to vitamin B(12) presented suddenly with severe visual impairment ascribed to optic atrophy followed by a fatal multiorgan failure and lactic acidosis but low methylmalonic acid in plasma and urine."

Sudden severe visual impairment was observed in the adult cblA patient before fatal multiorgan failure; no visual-outcome frequency is inferred.

Genitourinary 4

Methylmalonic aciduria VERY_FREQUENT HP:0012120

Show evidence (1 reference)

PMID:31921599 SUPPORT Human Clinical

"Significant excretion of methylmalonic acid in urine and metabolic acidosis traits with significantly increased anionic gap were observed in all patients."

Methylmalonic aciduria was present in every patient of this MMAA-genotyped series.

Chronic kidney disease FREQUENT HP:0012622

Course: PROGRESSIVE

Sequelae: Hypertension Left ventricular hypertrophy Chronic illness and inadequate nutritional intake Anemia

Show evidence (2 references)

PMID:35618652 SUPPORT Human Clinical

"Chronic renal failure (CRF), defined as a glomerular filtration rate less than 60 ml/min/1.73 m2, was present in 7/23 patients (30%) and was moderate in three and severe in four cases (one requiring renal transplantation)."

Specifies the adult cohort denominator and renal-function threshold behind the frequency band.

PMID:31921599 SUPPORT Human Clinical

"Three patients have renal failure and pharmacologically treated arterial hypertension."

Independent confirmation of renal failure in a majority of a small genotyped cblA series.

Tubulointerstitial nephritis HP:0001970

Temporal: CHRONIC

Show evidence (1 reference)

PMID:24095221 SUPPORT Human Clinical

"Kidney biopsies showed non-specific manifestations of chronic interstitial inflammation."

Direct biopsy evidence of the interstitial lesion in a cblA patient followed for 42 years.

Ketonuria HP:0002919

Show evidence (1 reference)

PMID:31921599 SUPPORT Human Clinical

"In addition, more than half of the patients had anemia, hyperglycemia and ketonuria."

Observed at diagnosis in the five-patient cblA cohort; exact individual counts are not supplied in this sentence.

Metabolism 8

Decreased methylmalonyl-CoA mutase activity HP:0003210

Show evidence (1 reference)

PMID:35618652 SUPPORT In Vitro

"Enzymatic studies of her fibroblasts showed a deficit in propionate incorporation (1.61 nmol/mg prot/16 h vs. 6.08 nmol/mg prot/16 h in the experimental control; range in controls 3.5–24.4) with a clear increase after B12 supplementation (11.7 nmol/mg prot/16 h vs. 7.79 nmol/mg prot/16 h in the..."

Diagnostic cell studies in an MMAA-confirmed adult show impaired pathway flux with intact cofactor-supplemented apoenzyme activity.

Episodic metabolic acidosis HP:0004911

Show evidence (2 references)

PMID:31921599 SUPPORT Human Clinical

"Significant excretion of methylmalonic acid in urine and metabolic acidosis traits with significantly increased anionic gap were observed in all patients."

Records metabolic acidosis with increased anion gap in all five MMAA patients.

PMID:34915869 SUPPORT Human Clinical

"Metabolic decompensations occurred rarely (3-times during the 8-years of follow-up), and they were always provoked by an acute infection, accompanied by mild metabolic acidosis, mild hyperammonaemia, and a higher concentration of methylmalonic acid in urine."

Patient 2 had homozygous MMAA p.Leu89Pro; the sentence documents recurrent episodic acidosis in cblA.

Hyperuricemia OCCASIONAL HP:0002149

Show evidence (1 reference)

PMID:35618652 SUPPORT Human Clinical

"Hyperuricemia was present in 5/23 patients (22%), three of whom were treated with allopurinol."

Gives both the frequency in an adult cblA-only cohort and the fact that it prompted treatment.

Hyperammonemia HP:0001987

Show evidence (3 references)

PMID:35618652 SUPPORT Human Clinical

"This patient presented at 9 days of life with a severe acute decompensation with ketoacidosis and hyperammonia (up to 500 micromol/l) requiring hemofiltration"

A molecularly confirmed cblA patient (homozygous MMAA c.586C>T) with severe neonatal hyperammonemia, which is why this phenotype is not restricted to the mild form. It is a single narrated patient in a 23-patient cohort rather than a reported cohort frequency.

PMID:31921599 SUPPORT Human Clinical

"In all patients, at the moment of diagnosis, the features of unbalanced metabolic acidosis with significantly increased anionic gap were found, but only in two patients the concentration of ammonia was mild increased."

Reports mild elevations in 2/5 patients at diagnosis; this is not a disease-wide frequency estimate.

PMID:34915869 SUPPORT Human Clinical

"On the fourth postnatal day, she developed apathy, hypothermia, and dehydration with metabolic acidosis and hyperammonaemia (1,601 μmol/L)."

This is patient 2, subsequently confirmed homozygous for MMAA p.Leu89Pro, not the MMAB patient 1.

Dehydration HP:0001944

Show evidence (1 reference)

PMID:34915869 SUPPORT Human Clinical

"On the fourth postnatal day, she developed apathy, hypothermia, and dehydration with metabolic acidosis and hyperammonaemia (1,601 μmol/L)."

The clinical history is patient 2 with homozygous MMAA p.Leu89Pro.

Hypothermia HP:0002045

Show evidence (1 reference)

PMID:34915869 SUPPORT Human Clinical

"On the fourth postnatal day, she developed apathy, hypothermia, and dehydration with metabolic acidosis and hyperammonaemia (1,601 μmol/L)."

The clinical history is patient 2 with homozygous MMAA p.Leu89Pro.

Hyperglycemia HP:0003074

Show evidence (1 reference)

PMID:31921599 SUPPORT Human Clinical

"In addition, more than half of the patients had anemia, hyperglycemia and ketonuria."

Observed at diagnosis in the five-patient cblA cohort; exact individual counts are not supplied in this sentence.

Elevated circulating hepatic transaminase concentration HP:0002910

Show evidence (1 reference)

PMID:31921599 SUPPORT Human Clinical

"In 3/5 there was detected an increased activity of aminotransferases."

Direct biochemical observation in the MMAA-confirmed cohort.

Musculoskeletal 4

Hypotonia HP:0001252

Show evidence (1 reference)

PMID:20301409 SUPPORT Other

"symptoms occur in the first few months or years of life and are characterized by feeding problems, failure to thrive, hypotonia, and developmental delay marked by episodes of metabolic decompensation."

The preceding subject is the partially deficient or B12-responsive group, explicitly including cblA; this is clinical synthesis rather than a cblA cohort frequency.

Spasticity HP:0001257

Show evidence (1 reference)

PMID:31921599 SUPPORT Human Clinical

"All patients have a diagnosed intellectual disability; in addition, two patients present features of pyramidal extrapyramidal syndrome (spastic limb paresis, dystonic movements and choreatetosis)."

The two affected patients among five had these specific motor abnormalities; no generalized severity or frequency is assigned.

Osteoporosis HP:0000939

Show evidence (1 reference)

PMID:35618652 SUPPORT Human Clinical

"Bone densitometry was performed in 9 patients and was abnormal in 5 of them with osteoporosis (n = 2) or osteopenia (n = 3)."

The denominator is nine tested adults, not all 23; selection for densitometry may affect the proportion.

Osteopenia HP:0000938

Show evidence (1 reference)

PMID:35618652 SUPPORT Human Clinical

"Bone densitometry was performed in 9 patients and was abnormal in 5 of them with osteoporosis (n = 2) or osteopenia (n = 3)."

The denominator is nine tested adults, not all 23; selection for densitometry may affect the proportion.

Nervous System 13

Global developmental delay HP:0001263

Show evidence (2 references)

PMID:31921599 SUPPORT Human Clinical

"At the time of diagnosis the median of age was 18.8 months, but the symptoms had already appeared since infancy, as recurrent vomiting and delayed psychomotor development."

The clinical presentation includes psychomotor delay; Table 1 records delay in four of five patients.

PMID:34915869 SUPPORT Human Clinical

"Currently, the child has an age-appropriate mental development with occasional attention deficit and concentration difficulty at school and is without renal complications."

Patient 2 is the MMAA-confirmed child; this bounds the claim of universal persistent delay.

Intellectual disability FREQUENT HP:0001249

Show evidence (2 references)

PMID:35618652 SUPPORT Human Clinical

"The main long-term problems were intellectual disability (39%) and renal failure (30%)."

Gives the frequency of intellectual disability in an adult cblA-only case series.

PMID:35618652 SUPPORT Human Clinical

"Intellectual disability was equally distributed among the initial treatment groups, while renal failure (moderate and beginning at the age of 38 years) was present in only one out of seven patients initially treated with B12."

Small retrospective initial-treatment groups had similar cognitive outcomes; the authors explicitly could not exclude effects of delayed diagnosis and treatment.

Abnormality of extrapyramidal motor function HP:0002071

Show evidence (1 reference)

PMID:35618652 SUPPORT Human Clinical

"Neurological examination was normal in 17/23 patients (74%): only five patients had mild extrapyramidal features, such as bradykinesia or involuntary movements, and in at least one patient (patient 1/Lon01) this was probably secondary to long standing neuroleptic treatments; one patient had..."

Includes the medication confound and normal-examination denominator.

Seizure OCCASIONAL HP:0001250

Show evidence (1 reference)

PMID:35618652 SUPPORT Human Clinical

"one patient had ataxia; three patients had seizures."

Three of 23 adult cblA patients had seizures, which sets the OCCASIONAL band.

Cerebral atrophy HP:0002059

Show evidence (1 reference)

PMID:31921599 SUPPORT Human Clinical

"At the time of diagnosis, 4/5 of the patients had cortical and subcortical atrophy and ventricular dilatation in neuroimaging studies."

Reports cerebral atrophy on imaging at diagnosis in four of five MMAA-genotyped patients.

Ventriculomegaly HP:0002119

Show evidence (1 reference)

PMID:31921599 SUPPORT Human Clinical

"At the time of diagnosis, 4/5 of the patients had cortical and subcortical atrophy and ventricular dilatation in neuroimaging studies."

The same imaging finding reports ventricular dilatation alongside the atrophy.

Dystonia HP:0001332

Show evidence (1 reference)

PMID:31921599 SUPPORT Human Clinical

"All patients have a diagnosed intellectual disability; in addition, two patients present features of pyramidal extrapyramidal syndrome (spastic limb paresis, dystonic movements and choreatetosis)."

The two affected patients among five had these specific motor abnormalities; no generalized severity or frequency is assigned.

Choreoathetosis HP:0001266

Show evidence (1 reference)

PMID:31921599 SUPPORT Human Clinical

"All patients have a diagnosed intellectual disability; in addition, two patients present features of pyramidal extrapyramidal syndrome (spastic limb paresis, dystonic movements and choreatetosis)."

The two affected patients among five had these specific motor abnormalities; no generalized severity or frequency is assigned.

Ataxia HP:0001251

Show evidence (1 reference)

PMID:35618652 SUPPORT Human Clinical

"one patient had ataxia; three patients had seizures."

Reports ataxia in one adult; this is not a disease-wide frequency.

Developmental regression HP:0002376

Show evidence (1 reference)

PMID:35618652 SUPPORT Human Clinical

"early onset failure to thrive (patient 13/Lyo01); and early onset failure to thrive with psychomotor regression (patient 21/Neck05; patient 23/Mont01)."

Specific chronic presentations include regression.

Reduced consciousness HP:0004372

Show evidence (1 reference)

PMID:31921599 SUPPORT Human Clinical

"Three children were in a severe general state with disturbances of consciousness, and one patient had convulsions."

Direct clinical observation; the source does not establish coma in all three.

Lethargy HP:0001254

Show evidence (1 reference)

PMID:12438653 SUPPORT Human Clinical

"WG3080 is from a white female who presented at 7 days with lethargy, poor feeding, and seizures."

Clinical history of a cblA patient cell-line donor; it is not a cultured-cell phenotype.

Diminished ability to concentrate HP:0031987

Show evidence (1 reference)

PMID:34915869 SUPPORT Human Clinical

"Currently, the child has an age-appropriate mental development with occasional attention deficit and concentration difficulty at school and is without renal complications."

Patient 2 is the MMAA-confirmed child.

Growth 3

Short stature HP:0004322

Show evidence (1 reference)

PMID:31921599 SUPPORT Human Clinical

"Three patients have weight and height deficiency (<3 percentile for age and gender according to WHO centile grids)."

Direct observation of short stature in 3/5 patients supports the more specific HPO term.

Failure to thrive HP:0001508

Show evidence (2 references)

PMID:20301409 SUPPORT Other

"symptoms occur in the first few months or years of life and are characterized by feeding problems, failure to thrive, hypotonia, and developmental delay marked by episodes of metabolic decompensation."

The preceding subject is the partially deficient or B12-responsive group, explicitly including cblA; this is clinical synthesis rather than a cblA cohort frequency.

PMID:35618652 SUPPORT Human Clinical

"early onset failure to thrive (patient 13/Lyo01); and early onset failure to thrive with psychomotor regression (patient 21/Neck05; patient 23/Mont01)."

Direct cblA observations establish failure to thrive and accompanying regression.

Decreased body weight HP:0004325

Show evidence (1 reference)

PMID:31921599 SUPPORT Human Clinical

"Three patients have weight and height deficiency (<3 percentile for age and gender according to WHO centile grids)."

Direct anthropometric observation of low weight and height in three of five patients.

🧬

Genetic Associations

1

MMAA

Gene: MMAA hgnc:18871 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:12438653 SUPPORT Human Clinical

"It is located on chromosome 4q31.1-2 and encodes a predicted protein of 418 aa."

Establishes the locus and product size of MMAA.

PMID:28497574 SUPPORT Human Clinical

"Here, we present 67 new patients with cblA-type MMA, identifying 19 novel mutations."

Establishes the size of the reported patient and allele series for this gene.

Variants (2)

c.433C>T (p.Arg145Ter)

Recurrent nonsense allele on a common haplotype, reported as 43% of pathogenic alleles in the founding mutation survey and seen in the homozygous state in long-followed patients.

Show evidence (2 references)

PMID:15523652 SUPPORT Human Clinical

"One mutation, c.433C>T (R145X), represents 43% of pathogenic alleles and a common haplotype was identified."

Quantifies the recurrence of this allele among cblA pathogenic alleles.

PMID:24095221 SUPPORT Human Clinical

"We report on a patient with a vitamin B12-responsive cobalamin A type (cblA) MMA-uria caused by a homozygous stop mutation (p.R145X) in the cobalamin A gene (MMAA)."

Documents the same allele in the homozygous state in a molecularly confirmed cblA patient.

Missense alleles at conserved residues

A minority allele class that is mechanistically the most informative. The protein is made and retains intrinsic GTPase activity, but cannot engage the mutase or gate cofactor transfer, and about a third of these alleles additionally destabilise the protein.

Show evidence (1 reference)

PMID:28497574 SUPPORT In Vitro

"About a third confer instability to the recombinant protein in bacterial and human expression systems."

Quantifies the destabilising fraction among patient missense alleles tested in expression systems.

🗃️

External Assertions

1

Orphanet nosology record for cblA

Orphanet structured subtype record ORPHA:79310

Orphanet classifies cblA as a clinical subtype rather than a disorder in its own right, and its cross-reference table is the authority for the identity of this entity across MONDO, OMIM and the ICD systems. Two things in that table are worth recording. The MONDO and OMIM mappings are exact, which confirms the disease_term binding used here. The ICD-10 and ICD-11 mappings are both Narrower, meaning cblA sits beneath a broader code rather than carrying one of its own, so there is no cblA-specific ICD code to record. That is the coding-level counterpart of the under-recognition problem described in this entry.

Generated with `just structured-rebuild-orphanet --id 79310`. The cached record carries the nosology and cross-reference sections only, without the definition, phenotype or epidemiology sections, because `just refresh-orphadata` aborted on a checksum mismatch after downloading en_product1.xml and before fetching the en_product4, en_product6 and en_product9_prev bulk files that supply those sections. No Orphanet prevalence class was therefore available for this entity.

Show evidence (2 references)

ORPHA:79310 SUPPORT Other

"MONDO:0009613 | Exact"

Orphanet asserts an exact mapping between ORPHA:79310 and the MONDO term bound as this entry's disease_term.

ORPHA:79310 SUPPORT Other

"ICD-10:E71.1 | Narrower"

The ICD-10 mapping is narrower rather than exact, which is the basis for stating that cblA has no ICD code of its own.

💊

Medical Actions

7

Parenteral hydroxocobalamin

Action: Pharmacotherapy NCIT:C15986

Agent: hydroxocobalamin CHEBI:27786

Platform: Small molecule

Parenteral hydroxocobalamin is the principal cblA treatment. Responsiveness was reported in 27/28 registry patients, but historical clinical response assessments sometimes misclassified patients. Pharmacologic cobalamin can improve cofactor availability and cellular pathway flux; a mass-action bypass of one specific MMAA step is not established for every genotype.

Mechanism Target:

Failure of Adenosylcobalamin Gating onto Methylmalonyl-CoA Mutase — Improving cobalamin availability can restore deficient adenosylcobalamin-dependent function despite the MMAA defect; the exact rescue route is not established for each allele.

Show evidence (1 reference)

PMID:27858373 SUPPORT Other

"Hydroxocobalamin (OHCbl) is the cornerstone of cblA treatment because vitamin B12 may completely restore AdoCbl deficiency."

States the mechanism by which hydroxocobalamin acts on the adenosylcobalamin supply defect in cblA.

Show evidence (4 references)

PMID:32754920 SUPPORT Human Clinical

"27/28 cblA patients were reported to be responsive to cobalamin, only 86% of cblA patients were treated with i.m. hydroxocobalamin."

Quantifies cobalamin responsiveness in the cblA arm of the registry and shows a treatment gap against it.

PMID:35618652 SUPPORT In Vitro

"Most of the patients (61%) were initially classified as vitamin B12-unresponsive methylmalonic aciduria (MMA); in vitro B12 responsiveness was subsequently found in all the tested patients (n = 13)."

Thirteen tested fibroblast lines were responsive in vitro, including patients previously classified clinically as unresponsive; in vitro responsiveness does not invariably predict clinical response.

PMID:27858373 SUPPORT Other

"Parenteral administration, intravenous, subcutaneous or intramuscular, is generally required to achieve effect."

Establishes the route requirement for effective cobalamin therapy in cblA.

+ 1 more reference

Early cobalamin replacement for renal protection

Action: Pharmacotherapy NCIT:C15986

Agent: hydroxocobalamin CHEBI:27786

Platform: Small molecule

Early B12 treatment was associated with less severe renal disease in a retrospective series of adults. The initial-treatment comparison included 22 childhood-onset patients; 1/7 initially treated with B12 developed late moderate renal failure. Small groups, historical treatment variability and survivor selection prevent a causal estimate or exclusion of neurodevelopmental benefit.

Mechanism Target:

Renal Tubulointerstitial Injury — Lowering the lifetime methylmalonate burden is the proposed route by which early replacement slows progression of tubulointerstitial disease.

Show evidence (1 reference)

PMID:35618652 SUPPORT Human Clinical

"Intellectual disability was equally distributed among the initial treatment groups, while renal failure (moderate and beginning at the age of 38 years) was present in only one out of seven patients initially treated with B12."

Observational comparison among initial-treatment groups; similar cognitive outcomes do not establish absence of neurological benefit.

Show evidence (2 references)

PMID:35618652 SUPPORT Human Clinical

"Early B12 supplementation seems to protect from severe renal insufficiency."

The authors' own hedged statement of the renal-protection effect, quoted with its hedge intact.

PMID:24095221 SUPPORT Human Clinical

"Further investigation will be necessary to prove the protective effect of hydroxocobalamin in the kidney in vitamin B12-responsive patients."

An explicit statement that the renal protective effect is not yet proven, recorded here so the claim is not overstated.

Natural protein restriction with propiogenic precursor limitation

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

Platform: Behavioral / lifestyle

Restriction of natural protein, particularly the propiogenic amino acid precursors, on a high-calorie diet. Used in about three-quarters of cblA patients, notably less than in mut-type disease, reflecting the lesser metabolite burden.

Mechanism Target:

Methylmalonic Acid and Propionyl-CoA Accumulation — Limiting propiogenic substrate entry reduces the flux that the residual mutase capacity must handle.

Show evidence (1 reference)

PMID:20301409 SUPPORT Other

"restrict natural protein, particularly of propiogenic amino acid precursors, while maintaining a high-calorie diet"

States the dietary principle in propiogenic precursor terms.

Show evidence (1 reference)

PMID:32754920 SUPPORT Human Clinical

"In total, 73% of cblA and 98% of mut patients followed a calculated diet with amino acid supplements in 27% (cblA) and 69% (mut)."

Quantifies dietary treatment uptake specifically in the cblA arm against the mut arm.

Emergency management of acute decompensation

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

Anticatabolic emergency treatment during metabolic crisis, aimed at averting catabolism and limiting central nervous system injury, together with avoidance of the fasting, stress and protein-load precipitants. This applies to cblA as to the other isolated methylmalonic acidemias, since metabolic crisis remains the dominant presenting event.

Mechanism Target:

Acute Metabolic Decompensation — Reversing the catabolic state removes the substrate load that precipitated the crisis.

Show evidence (1 reference)

PMID:20301409 SUPPORT Other

"provide emergency treatment during episodes of acute decompensation with the goal of averting catabolism and minimizing central nervous system injury."

States the goal of emergency management in terms of the decompensation mechanism it targets.

Show evidence (1 reference)

PMID:20301409 SUPPORT Other

"Agents/circumstances to avoid: Fasting, stress, increased dietary protein,"

Lists the precipitants to avoid, which is the preventive half of decompensation management.

L-carnitine supplementation

Action: Pharmacotherapy NCIT:C15986

Agent: L-carnitine CHEBI:16347

Platform: Small molecule

Carnitine supplementation supports excretion of acyl groups and replaces deficient free carnitine. All five Polish patients received it; treatment is monitored using serum concentrations.

Mechanism Target:

Methylmalonic Acid and Propionyl-CoA Accumulation — Conjugation of the accumulated propionyl-CoA to an excretable acylcarnitine drains the pool that builds up behind the mutase block.

Show evidence (1 reference)

PMID:20301409 SUPPORT Other

"provide supplemental carnitine to those with carnitine deficiency"

GeneReviews states the indication for carnitine supplementation in isolated methylmalonic acidemia.

Show evidence (2 references)

PMID:31921599 SUPPORT Other

"It is also recommended to supplement l-carnitine under control of its serum concentration"

States that carnitine is given under serum-level control, in a paper whose entire cohort is MMAA-genotyped.

PMID:35618652 SUPPORT Human Clinical

"Additional medications included L‐ carnitine, neomycin and metronidazole."

Records carnitine among the medications actually used in an adult cblA-only cohort.

Gut decontamination to reduce propionate production

Action: Pharmacotherapy NCIT:C15986

Agent: metronidazole CHEBI:6909 neomycin CHEBI:7507

Platform: Small molecule

Intermittent antibiotic decontamination of the gut, typically with metronidazole or neomycin, to suppress the anaerobic flora that produce propionate. This targets a substrate source that dietary protein restriction does not reach.

Mechanism Target:

Methylmalonic Acid and Propionyl-CoA Accumulation — Gut flora are a substrate source independent of dietary intake, so suppressing them lowers the propiogenic load reaching the blocked pathway.

Show evidence (1 reference)

PMID:20301409 SUPPORT Other

"reduce propionate production from gut flora"

States the mechanism by which gut decontamination acts on the substrate load.

Show evidence (1 reference)

PMID:35618652 SUPPORT Human Clinical

"Additional medications included L‐ carnitine, neomycin and metronidazole."

Names the two decontamination antibiotics actually used in an adult cblA-only cohort.

Liver or kidney transplantation

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

Platform: Surgery

Liver and/or kidney transplantation may be considered in isolated MMA with severe metabolic instability or renal failure. cblA-specific reports document kidney transplantation, including one patient transplanted at age 35 and followed for six years under continued hydroxocobalamin. These observations do not establish a cblA-specific liver-transplant benefit.

Mechanism Target:

Renal Tubulointerstitial Injury — Kidney transplantation replaces the failing organ without correcting MMAA deficiency elsewhere. Preserved graft function under continued B12 in one case does not prove that B12 alone protected the graft.

Show evidence (1 reference)

PMID:24095221 SUPPORT Human Clinical

"The patient received a renal transplant at age 35 years."

Documents renal transplantation in a molecularly confirmed cblA patient.

Show evidence (2 references)

PMID:20301409 SUPPORT Other

"In those with significant metabolic instability and/or renal failure, liver and/or renal transplantation may be considered."

States the indication for transplantation in isolated methylmalonic acidemia.

PMID:24095221 SUPPORT Human Clinical

"Under continuous treatment with hydroxocobalamin there is no evidence of kidney damage due to MMA-uria until the last follow-up 6 years after transplantation."

Shows the graft outcome under continued cobalamin therapy, which is the reason the metabolic treatment is not stopped after transplantation.

🔬

Biochemical Markers

3

Methylmalonic acid (Increased)

Context: The defining analyte. Plasma and urine concentrations are elevated but significantly lower in cblA than in mutase-deficient disease, and fall substantially on hydroxocobalamin, which makes it both the diagnostic marker and the treatment monitor.

Pathograph Readouts

Readout Of Methylmalonic Acid and Propionyl-CoA Accumulation Positive Diagnostic

Reports the systemic methylmalonate burden produced by the residual mutase block.

Show evidence (1 reference)

PMID:32754920 SUPPORT Human Clinical

"Methylmalonic acidemia (MMA) levels in urine and plasma were significantly lower in cblA."

Establishes the direction and the cblA-versus-mut contrast for this analyte.

Show evidence (1 reference)

PMID:24095221 SUPPORT Human Clinical

"Following re-evaluation, the patient received vitamin B12 (hydroxocobalamin) treatment, resulting in a significant decrease in the concentration of methylmalonic acid (MMA) in urine and plasma."

Shows the analyte responds to cobalamin, which is what makes it the treatment-monitoring marker in cblA.

Propionylcarnitine (C3) (Increased)

Context: The newborn-screening analyte. Raised C3 on a dried blood spot is what flags isolated methylmalonic acidemia before the subtype is known; it does not distinguish cblA from the other forms, which is why molecular testing follows.

Pathograph Readouts

Readout Of Methylmalonic Acid and Propionyl-CoA Accumulation Positive Diagnostic

Reports the propionyl-CoA pool that backs up behind the mutase block.

Show evidence (1 reference)

PMID:31921599 SUPPORT Human Clinical

"elevated levels of propionylcarnitine (C3-carnitine) and/or methylmalonylcarnitine (C4DC-carnitine) are found"

Names the acylcarnitine species raised in methylmalonic acidemia on tandem mass spectrometry.

2-Methylcitric acid (Increased)

Context: A confirmatory urinary organic acid, formed when accumulated propionyl-CoA condenses with oxaloacetate. Measured alongside methylmalonic acid on the organic acid profile.

Pathograph Readouts

Readout Of Methylmalonic Acid and Propionyl-CoA Accumulation Positive Diagnostic

Second-line marker of the same propionyl-CoA accumulation, independent of methylmalonate itself.

Show evidence (1 reference)

PMID:31921599 SUPPORT Human Clinical

"methylmalonic acid, methylcytric acid, 3-hydroxypropionic acid are primarily detected"

Lists the urinary organic acids detected in methylmalonic acidemia, quoted verbatim including the source's spelling of methylcitric acid.

🔬

Diagnosis

2

Molecular confirmation in MMAA

Identification of biallelic pathogenic MMAA variants. Molecular testing has largely displaced complementation and enzymatic assays for establishing the cblA diagnosis, although historically the group was defined by somatic cell complementation.

genetic testing NCIT:C15709

Show evidence (1 reference)

PMID:20301409 SUPPORT Other

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

GeneReviews states that biallelic MMAA variants establish the diagnosis of isolated methylmalonic acidemia.

Plasma and urine methylmalonic acid

Plasma and urine methylmalonic acid support diagnosis and monitoring. A chronic, nonacute presentation occurred in 8/23 adults, whereas 4/23 never had an acute decompensation. Unexplained renal, developmental or growth findings can therefore warrant MMA testing outside a metabolic crisis.

laboratory procedure NCIT:C25294

Show evidence (3 references)

PMID:35618652 SUPPORT Human Clinical

"We confirm that about 35% of the patients do not present acutely, underlining the importance of measuring MMA in any case of unexplained chronic renal failure, intellectual disability, or growth delay."

States the indication for measuring methylmalonic acid outside the acute setting in cblA.

PMID:35618652 SUPPORT Human Clinical

"In most of the patients the symptom leading to diagnosis was acute neurologic deterioration (15/23, 65%). The other patients (8/23, 35%) presented with chronic problems:"

The presentation analysis explicitly separates eight chronic presentations from fifteen acute presentations among 23 adults; it does not measure lifetime freedom from crisis.

PMID:35618652 SUPPORT Human Clinical

"no more decompensations after the initial presentation in nine patients (39%); four patients (17%) had a sub‐acute presentation and never experienced an acute decompensation."

The longitudinal analysis identifies four of 23 patients who never decompensated, separately from nine with no further crisis after their initial presentation. This is distinct from the eight patients whose presenting problems were chronic.

📊

Prevalence

1

Published cblA case literature, worldwide

Cases In Literature

The 2020 paper reported fewer than 200 published cblA patients. This historical literature count is not a population prevalence estimate and does not establish a prevalence band. Mixed-MMA incidence estimates are not cblA-specific.

Show evidence (1 reference)

PMID:31921599 SUPPORT Other

"So far, <200 patients with phenotype of cblA-type MMA have been described in the literature"

Historical count summarized in the introduction, not an incidence or population prevalence calculation.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Methylmalonic Aciduria, cblA Type:

Methylmalonyl-CoA mutase deficiency (mut-type isolated methylmalonic acidemia) MONDO:0002012

Overlapping Features The other, and commoner, cause of isolated methylmalonic acidemia, curated as `kb/disorders/Methylmalonic_Acidemia.yaml`. The biochemical presentation at first crisis is essentially the same and the age at diagnosis is similar, so the two are separated by genotype and by cobalamin responsiveness rather than at the bedside.

Distinguishing Features

Near-universal cobalamin responsiveness in cblA, against a much lower rate in mut-type disease and none in mut0.
Significantly lower plasma and urine methylmalonic acid in cblA.
Better preserved glomerular filtration rate and less frequent chronic renal failure in cblA.
Neurological complications predominate in the mut subgroup on direct comparison.
The lesion in cblA is in cofactor delivery to a structurally intact mutase, whereas in mut-type disease the mutase apoenzyme itself is deficient.

Show evidence (1 reference)

PMID:32754920 SUPPORT Human Clinical

"Although similar at first, cblA patients respond to hydroxocobalamin treatment, subsequently show significantly lower levels of MMA and a milder course than mut patients."

The registry study's own summary of how the two entities diverge after presentation.

cblB type methylmalonic aciduria (MMAB deficiency)

Overlapping Features The other adenosylcobalamin-synthesis defect causing isolated methylmalonic acidemia, caused by biallelic MMAB variants and covered within `kb/disorders/Methylmalonic_Acidemia.yaml`. cblB affects the adenosyltransferase that makes adenosylcobalamin, whereas cblA affects the G-protein that delivers and maintains it, and the clinical courses differ sharply despite the shared pathway.

Distinguishing Features

cblB patients have an earlier onset, more complications and deaths, and higher urinary methylmalonic acid than cblA patients.
Chronic renal failure is common in cblB and relatively spared in cblA.
Cobalamin responsiveness is the rule in cblA and only occasional in cblB.
MONDO keeps the two as separate terms with separate OMIM anchors and separate causal genes, MMAA with OMIM:251100 for cblA and MMAB with OMIM:251110 for cblB.

Show evidence (2 references)

PMID:17597648 SUPPORT Human Clinical

"Overall, patients with mut0 and cblB defects had an earlier onset of symptoms, a higher frequency of complications and deaths, and a more pronounced urinary excretion of MMA than those with mut- and cblA defects."

The four-way comparison that places cblB with mut0 at the severe end and cblA at the attenuated end. This is a mixed cohort of 83 patients of which only 20 were cblA, so the statement is a between-group contrast and not a cblA-specific rate.

PMID:17597648 SUPPORT Human Clinical

"Chronic renal failure (CRF) was found most frequently in mut0 (61%) and cblB patients (66%), and was predicted by the urinary excretion of methylmalonic acid (MMA) before CRF."

The renal-failure percentages quoted here belong to the mut0 and cblB subgroups, not to cblA. They are recorded to bound the renal claim rather than to describe cblA.

cblD-MMA (MMADHC deficiency, methylmalonic aciduria form)

Overlapping Features MMADHC defects can cause isolated MMA (cblD-MMA) or combined methylmalonic aciduria and homocystinuria. MMAA deficiency affects the adenosylcobalamin pathway; an elevated homocysteine result warrants investigation for a combined disorder or a secondary cause and is not by itself a genotype exclusion.

Distinguishing Features

Distinguished by gene, MMADHC versus MMAA, since the isolated-MMA biochemical phenotype is shared.
MMADHC variants elsewhere in the gene give isolated homocystinuria or combined disease, a positional allelic spectrum that MMAA does not show.
cblA has no homocysteine arm at all, so any hyperhomocysteinemia excludes it.

Show evidence (1 reference)

PMID:20301409 SUPPORT Other

"synthesis of its cofactor, 5-deoxy-adenosyl-cobalamin (cblA, cblB, or cblD-MMA),"

Groups cblA, cblB and cblD-MMA as the cofactor-side causes of isolated methylmalonic acidemia that must be distinguished from one another.

cblH

Overlapping Features A complementation class defined out of the cblA cohort itself. A patient with the clinical and biochemical phenotype of cblA whose fibroblasts complemented all cblA lines was assigned to a new class, cblH, before MMAA was cloned. The episode is why a cblA-like biochemical phenotype is not by itself a cblA diagnosis.

Distinguishing Features

Defined by somatic cell complementation rather than by biochemistry, which cannot separate it from cblA.
Requires molecular testing to resolve, since MMAA sequencing is normal.

Show evidence (1 reference)

PMID:10882753 SUPPORT In Vitro

"These results strongly suggest that the cblA variant represents a novel complementation class, which we have designated cblH and which represents a mutation at a distinct gene."

Documents that a patient meeting the clinical and biochemical definition of cblA carried a defect at a different locus.

{ }

Source YAML

click to show

name: Methylmalonic Aciduria, cblA Type
creation_date: "2026-08-31T10:30:00Z"
category: Mendelian
description: >-
  Biallelic pathogenic MMAA variants cause an adenosylcobalamin-handling defect that reduces
  effective methylmalonyl-CoA mutase (MMUT) activity. MMAA is a mitochondrial GTPase chaperone
  involved in cofactor loading, protection and repair. Recombinant patient-variant studies identify
  impaired functional interaction with MMUT and, for some alleles, protein instability. These
  mechanisms differ from the primary MMUT apoenzyme defect and from MMAB-associated cblB disease.


  The resulting isolated methylmalonic aciduria can present with severe neonatal or infantile
  metabolic decompensation, or with chronic developmental, growth or renal problems. Hydroxocobalamin
  responsiveness was reported in 27/28 cblA patients in a registry comparison with 95 mut patients,
  with lower methylmalonate concentrations and milder subsequent disease in cblA. Responsiveness
  does not exclude severe onset or later complications. The precise biochemical route of pharmacologic
  rescue is not established for every MMAA genotype.


  In a separate retrospective series of 23 adults, 8/23 presented with chronic symptoms, but
  only 4/23 never experienced acute decompensation. Intellectual disability and chronic renal
  failure occurred in 9/23 and 7/23, respectively. These historical adult-survivor data should
  not be treated as untreated or contemporary birth-cohort risks. Early B12 treatment was associated
  with less severe renal disease; the small, nonrandomized comparison cannot establish renal
  protection or exclude neurodevelopmental benefit.
disease_term:
  preferred_term: methylmalonic aciduria, cblA type
  term:
    id: MONDO:0009613
    label: methylmalonic aciduria, cblA type
synonyms:
- cblA
- cblA-type methylmalonic aciduria
- cobalamin A deficiency
- MMAA deficiency
- methylmalonic acidemia, cblA type
- vitamin B12-responsive methylmalonic aciduria type cblA
parents:
- Inborn Disorder of Cobalamin Metabolism and Transport
- Methylmalonic Acidemia
classifications:
  icimd_category:
  - classification_value: cobalamin_metabolism
    notes: >-
      ICIMD Disorders of cobalamin (vitamin B12) metabolism: MMAA is a GTPase chaperone involved
      in mitochondrial cofactor handling. The resulting functional MMUT deficit differs from
      primary MMUT apoenzyme deficiency.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic MMAA variants. The majority of reported cblA alleles are premature
    termination codons, with a single nonsense allele accounting for a large share of the
    mutant chromosomes.
  evidence:
  - reference: PMID:20301409
    reference_title: Isolated Methylmalonic Acidemia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: All forms of isolated MMA are inherited in an autosomal recessive manner.
    explanation: GeneReviews states the inheritance mode for the isolated MMA group, of which cblA is a member.
  - reference: PMID:17957493
    reference_title: "Methylmalonic acidaemia: examination of genotype and biochemical data in 32 patients belonging to mut, cblA or cblB complementation group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of the cblA patients carried premature termination codons (PTC) in both alleles."
    explanation: Documents the biallelic, predominantly truncating allele architecture in the cblA subgroup of this cohort.
prevalence:
- population: Published cblA case literature, worldwide
  measure_type: CASES_IN_LITERATURE
  notes: >-
    The 2020 paper reported fewer than 200 published cblA patients. This historical literature
    count is not a population prevalence estimate and does not establish a prevalence band.
    Mixed-MMA incidence estimates are not cblA-specific.
  evidence:
  - reference: PMID:31921599
    reference_title: Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related to MMAA mutations.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "So far, <200 patients with phenotype of cblA-type MMA have been described in the literature"
    explanation: Historical count summarized in the introduction, not an incidence or population
      prevalence calculation.
pathophysiology:
- name: Biallelic MMAA Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Two damaged copies of MMAA, on chromosome 4q31, remove or cripple the mitochondrial
    G-protein that chaperones adenosylcobalamin onto methylmalonyl-CoA mutase. Most
    reported alleles are premature termination codons; the remainder are missense changes
    at conserved residues, and roughly a third of those destabilise the protein in
    expression systems.
  genes:
  - preferred_term: MMAA
    term:
      id: hgnc:18871
      label: MMAA
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  downstream:
  - target: Loss of MMAA-Mutase Functional Interaction
    causal_link_type: DIRECT
    description: >-
      MMAA alleles can reduce protein stability or disrupt productive cofactor-handling
      interactions with MMUT. Physical binding and residual biochemical activity vary
      by allele; loss of productive function does not require complete loss of binding.
  evidence:
  - reference: PMID:12438653
    reference_title: Identification of the gene responsible for the cblA complementation group of vitamin B12-responsive methylmalonic acidemia based on analysis of prokaryotic gene arrangements.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data confirm that the identified gene, MMAA, corresponds to the cblA complementation group."
    explanation: Establishes MMAA as the gene defective in the cblA complementation group.
  - reference: PMID:15523652
    reference_title: Mutations in the MMAA gene in patients with the cblA disorder of vitamin B12 metabolism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 13 mutations result in premature stop codons; three are splice site defects; and six are missense mutations that occur at highly conserved residues."
    explanation: Describes the allele classes underlying loss of MMAA function in cblA patients.
- name: Loss of MMAA-Mutase Functional Interaction
  biological_scale: MOLECULAR
  description: >-
    MMAA variants can disrupt its functional interaction with MMUT and impair cofactor loading
    and repair. The 2017 series found reduced MMUT-stimulated GTPase activity in all 15 tested
    mutant proteins, with physical binding lost in nine. This is not universal across alleles:
    a 2023 study found enhanced MMUT-stimulated activity for R98G but defective gating and cofactor
    repair.
  molecular_functions:
  - preferred_term: mutase-stimulated MMAA GTPase activity
    term:
      id: GO:0003924
      label: GTPase activity
  notes: >-
    No modifier is set on the GTPase descriptor because the biochemical effects are
    allele-dependent. All 15 purified mutants in the 2017 series retained wild-type-like
    intrinsic GTPase activity but had reduced MMUT stimulation; nine also lost physical
    binding. The p.Asp292Val exception concerned GTP binding, not basal GTPase activity.
    R98G showed enhanced MMUT stimulation in the 2023 study despite defective gating and
    repair. A uniform DECREASED annotation would obscure these distinctions.
  downstream:
  - target: Failure of Adenosylcobalamin Gating onto Methylmalonyl-CoA Mutase
    causal_link_type: DIRECT
    description: >-
      Disruption of productive MMAA-MMUT interaction impairs nucleotide-gated cofactor
      transfer. The measured defect need not abolish physical binding or all loading.
  - target: Failure of Holoenzyme Cofactor Protection and Reactivation
    causal_link_type: DIRECT
    description: >-
      MMAA-MMUT interaction also supports cofactor protection and exchange. Disease
      variants can impair these functions along with gating, with the degree and
      combination of defects depending on the allele.
  evidence:
  - reference: PMID:28497574
    reference_title: Protein destabilization and loss of protein-protein interaction are fundamental mechanisms in cblA-type methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "However, all mutations strongly decreased functional association with MUT by reducing GTPase activity stimulation upon incubation with MUT, while nine mutant proteins additionally lost the ability to physically bind MUT."
    explanation: All 15 purified mutants had reduced functional association in this assay;
      only nine additionally lost physical binding, so the two defects are distinguished.
  - reference: PMID:28497574
    reference_title: Protein destabilization and loss of protein-protein interaction are fundamental mechanisms in cblA-type methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "All 15 purified mutant proteins demonstrated wild-type like intrinsic GTPase activity and only one (p.Asp292Val), where the mutation is in the GTP binding domain, revealed decreased GTP binding."
    explanation: Establishes that intrinsic catalytic activity is retained, so the lesion is in the interaction rather than in the GTPase chemistry itself.
  - reference: PMID:20876572
    reference_title: Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA mutase and insight into their complex formation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The physiological importance of this interaction is highlighted by a recently identified homoallelic patient mutation of MMAA, G188R, which, we show, retains basal GTPase activity but has abrogated interaction."
    explanation: An independent patient allele shows the same dissociation of preserved GTPase activity from abolished complex formation.
  - reference: PMID:37468522
    reference_title: Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B(12) delivery and repair.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The complex, stabilized by MMAA wedging between two MMUT domains, leads to ordering of the switch I and III loops, revealing the molecular basis of mutase-dependent GTPase activation."
    explanation: The human co-crystal structure shows how MMAA engages the mutase and why that engagement is what activates its GTPase, which is the interaction this node reports as lost.
  - reference: PMID:37468522
    reference_title: Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B(12) delivery and repair.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The structure explains the biochemical penalties incurred by methylmalonic aciduria-causing mutations that reside at the MMAA-MMUT interfaces we identify here."
    explanation: Places the disease-causing alleles at the MMAA-mutase interface itself, which is the structural counterpart of the biochemical interaction loss.
  - reference: PMID:37468522
    reference_title: Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly
      for B(12) delivery and repair.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      While neither mutation affects the intrinsic GTPase activity, GAP activation by MMUT is
      either enhanced 2-fold (R98G) or lost (R209S)
    explanation: >-
      The two MMAA variants in the 2023 human-protein experiments show allele-dependent MMUT
      stimulation; both nevertheless impaired cofactor gating and repair.
- name: Failure of Adenosylcobalamin Gating onto Methylmalonyl-CoA Mutase
  biological_scale: MOLECULAR
  description: >-
    In health, MMAA favours complex formation with the apo-mutase, licenses transfer of
    adenosylcobalamin from the adenosyltransferase MMAB, and then releases the loaded
    holoenzyme in a GTP-dependent cycle. In cblA, defective gating disrupts controlled
    cofactor loading despite intact MMAB-dependent synthesis; it does not imply that
    every allele abolishes all cofactor transfer or residual holoenzyme activity.
  biological_processes:
  - preferred_term: mitochondrial adenosylcobalamin handling
    term:
      id: GO:0009235
      label: cobalamin metabolic process
    modifier: DECREASED
  molecular_functions:
  - preferred_term: cobalamin binding by the mutase holoenzyme
    term:
      id: GO:0031419
      label: cobalamin binding
    modifier: DECREASED
  downstream:
  - target: Reduced Methylmalonyl-CoA Mutase Holoenzyme Activity
    causal_link_type: DIRECT
    description: >-
      Impaired productive cofactor loading reduces the active holoenzyme pool even when
      intact mutase protein is present; residual loading and activity can persist.
  evidence:
  - reference: PMID:20876572
    reference_title: Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA mutase and insight into their complex formation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Together, our data point to a gatekeeping role for MMAA by favoring complex formation with MUT apoenzyme for AdoCbl assembly and releasing the AdoCbl-loaded holoenzyme from the complex, in a GTP-dependent manner."
    explanation: States the gatekeeping model for adenosylcobalamin assembly onto the mutase that this node describes.
  - reference: PMID:28497574
    reference_title: Protein destabilization and loss of protein-protein interaction are fundamental mechanisms in cblA-type methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Finally, all mutations interfered with gating the transfer of AdoCbl from MMAB to MUT."
    explanation: Every tested patient missense allele disrupts the gating step, which is the specific failure asserted here.
  - reference: PMID:19955418
    reference_title: A G-protein editor gates coenzyme B12 loading and is corrupted in methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "While the GTP-binding energy is needed for the editing function; that is, to discriminate between active and inactive cofactor forms, the chemical energy of GTP hydrolysis is required for gating cofactor transfer."
    explanation: Separates the two nucleotide requirements of the gating cycle. This was established in the bacterial MeaB orthologue rather than in human MMAA, so it is cited for the mechanism of gating and not as a cblA genotype result.
- name: Failure of Holoenzyme Cofactor Protection and Reactivation
  biological_scale: MOLECULAR
  description: >-
    Adenosylcobalamin is destroyed slowly during normal mutase turnover, accumulating as
    the oxidised hydroxocobalamin form and inactivating the enzyme. MMAA both slows that
    oxidation while in complex with the mutase and, once inactivation has occurred,
    removes the damaged cofactor through GTP hydrolysis so a fresh one can be installed.
    Impaired MMAA protection or repair can therefore reduce sustained mutase activity;
    the residual function depends on the allele and experimental context.
  downstream:
  - target: Reduced Methylmalonyl-CoA Mutase Holoenzyme Activity
    causal_link_type: DIRECT
    description: >-
      Impaired repair allows inactive cofactor to accumulate and can compound defective
      loading, reducing sustained holoenzyme activity.
  evidence:
  - reference: PMID:28943303
    reference_title: Human MMAA induces the release of inactive cofactor and restores methylmalonyl-CoA mutase activity through their complex formation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the formation and accumulation of OH2Cbl, the oxidized form of the AdoCbl cofactor formed during catalysis, is the cause of hMCM inactivation"
    explanation: Identifies oxidative cofactor damage during catalysis as the process MMAA counteracts.
  - reference: PMID:28943303
    reference_title: Human MMAA induces the release of inactive cofactor and restores methylmalonyl-CoA mutase activity through their complex formation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Moreover, an inactive model of hMCM was used to demonstrate that hMMAA is able to remove the damaged cofactor through GTP hydrolysis."
    explanation: Demonstrates the cofactor-exchange repair function whose loss this node asserts.
  - reference: PMID:21138732
    reference_title: Protection and reactivation of human methylmalonyl-CoA mutase by MMAA protein.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "When it was added at the beginning of the reaction, it prevents inactivation by guarding MCM. After 60 min of reaction, when MCM is inactive, the addition of MMAA increases the enzymatic activity through GTP hydrolysis, indicating reactivation of MCM by exchange of the damaged cofactor."
    explanation: Establishes the dual protective and reactivating roles of MMAA on the mutase in a purified system.
  - reference: PMID:19955418
    reference_title: A G-protein editor gates coenzyme B12 loading and is corrupted in methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The G protein chaperone also exerts its editing function during turnover by using the binding energy of GTP to elicit release of inactive cofactor that is occasionally formed during the catalytic cycle of MCM."
    explanation: States the during-turnover editing function whose loss this node asserts. Established in the bacterial MeaB orthologue, so it is cited for the conserved mechanism rather than as a human cblA measurement.
- name: Reduced Methylmalonyl-CoA Mutase Holoenzyme Activity
  biological_scale: CELLULAR
  description: >-
    Insufficient effective MMUT holoenzyme activity reduces propionate-pathway flux in intact
    cells. This is a cofactor-handling defect: MMUT activity measured in extracts with excess
    adenosylcobalamin can be normal, while cellular propionate incorporation is low and improves
    with hydroxocobalamin.
  molecular_functions:
  - preferred_term: methylmalonyl-CoA mutase activity
    term:
      id: GO:0004494
      label: methylmalonyl-CoA mutase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: propionate catabolic process
    term:
      id: GO:0019543
      label: propionate catabolic process
    modifier: DECREASED
  cellular_components:
  - preferred_term: mitochondrial matrix
    term:
      id: GO:0005759
      label: mitochondrial matrix
  downstream:
  - target: Methylmalonic Acid and Propionyl-CoA Accumulation
    causal_link_type: DIRECT
    description: >-
      Methylmalonyl-CoA that cannot be isomerised to succinyl-CoA is hydrolysed to
      methylmalonic acid, and propionyl-CoA backs up behind it.
  evidence:
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Enzymatic studies of her fibroblasts showed a deficit in propionate incorporation (1.61
      nmol/mg prot/16 h vs. 6.08 nmol/mg prot/16 h in the experimental control; range in controls
      3.5–24.4) with a clear increase after B12 supplementation (11.7 nmol/mg prot/16 h vs.
      7.79 nmol/mg prot/16 h in the experimental control; range in controls 4.33–28.9), and
      normal MCM activity (measured with excess of AdoCbl), indicating a B12‐responsive defect
      of AdoCbl synthesis.
    explanation: >-
      Diagnostic cell studies in an MMAA-confirmed adult show impaired pathway flux with intact
      cofactor-supplemented apoenzyme activity.
- name: Methylmalonic Acid and Propionyl-CoA Accumulation
  biological_scale: ORGANISM
  description: >-
    The MMUT functional block causes accumulation of methylmalonic acid and upstream acyl-CoA
    metabolites. Urine and plasma MMA were lower in treated cblA than in mut patients in the
    registry comparison; this does not establish a uniformly partial genetic defect or an individual
    threshold for organ toxicity.
  chemical_entities:
  - 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
  downstream:
  - target: Acute Metabolic Decompensation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - organic-acid accumulation and secondary metabolic disturbances during increased catabolic
      flux
    description: The metabolite burden can precipitate acidosis and secondary hyperammonemia
      during catabolic stress.
    evidence:
    - reference: PMID:34915869
      reference_title: >-
        Genetic testing is necessary for correct diagnosis and treatment in patients with isolated
        methylmalonic aciduria: a case report.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Organic acids, particularly methylmalonate and methylcitrate, are formed from MMCoA
        in an alternative metabolic pathway and can cause metabolic acidosis, carnitine deficiency,
        and secondary hyperammonaemia.
      explanation: >-
        The introduction describes the shared downstream chemistry of isolated MMA, including
        cblA; it is not a cblA-specific experimental measurement.
  - target: Episodic metabolic acidosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Accumulating organic acids contribute to high-anion-gap acidosis during decompensation.
    evidence:
    - reference: PMID:34915869
      reference_title: >-
        Genetic testing is necessary for correct diagnosis and treatment in patients with isolated
        methylmalonic aciduria: a case report.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Organic acids, particularly methylmalonate and methylcitrate, are formed from MMCoA
        in an alternative metabolic pathway and can cause metabolic acidosis, carnitine deficiency,
        and secondary hyperammonaemia.
      explanation: >-
        The introduction describes the shared downstream chemistry of isolated MMA, including
        cblA; it is not a cblA-specific experimental measurement.
  - target: Secondary impairment of ureagenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Propionyl-CoA can inhibit N-acetylglutamate synthesis. Transfer of this biochemical mechanism
      to cblA is provisional; it is not the only proposed cause of hyperammonemia.
    evidence:
    - reference: PMID:500823
      reference_title: >-
        Inhibition by propionyl-coenzyme A of N-acetylglutamate synthetase in rat liver mitochondria.
        A possible explanation for hyperammonemia in propionic and methylmalonic acidemia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In the search for the mechanism by which hyperammonemia complicates propionic and methylmalonic
        acidemia the effects of a series of acyl-coenzyme A (CoA) derivatives were studied on
        the activity of N-acetylglutamate synthetase in rat liver mitochondria using acetyl-CoA
        as substrate. Propionyl-CoA was found to be a competitive inhibitor.
      explanation: >-
        Rat liver mitochondrial extracts demonstrate competitive inhibition; no MMAA-deficient
        patient liver was tested.
      directness: INDIRECT
  - target: Secondary renal mitochondrial dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A proposed route from the metabolic block to renal injury; direct methylmalonate nephrotoxicity
      and secondary mitochondrial effects are not resolved in cblA.
    evidence:
    - reference: PMID:35618652
      reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        This is also in line with the pathophysiological hypotheses suggesting that chronic
        kidney disease is more directly linked to MMA toxicity, while brain involvement seems
        to be more complex and related partially to acute decompensation and energy deficit,
        and partially to de novo synthesis and trapping of toxic metabolites in brain tissue.
      explanation: >-
        The cblA cohort discussion proposes organ-injury routes; these are hypotheses, not measured
        causal mediation.
      directness: INDIRECT
  - target: Neurologic Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Chronic metabolite production and trapping in brain, together with energy deficit, are
      proposed contributors to neurological injury in cblA.
    evidence:
    - reference: PMID:35618652
      reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        This is also in line with the pathophysiological hypotheses suggesting that chronic
        kidney disease is more directly linked to MMA toxicity, while brain involvement seems
        to be more complex and related partially to acute decompensation and energy deficit,
        and partially to de novo synthesis and trapping of toxic metabolites in brain tissue.
      explanation: >-
        The cblA cohort discussion proposes organ-injury routes; these are hypotheses, not measured
        causal mediation.
      directness: INDIRECT
  evidence:
  - reference: PMID:32754920
    reference_title: "Delineating the clinical spectrum of isolated methylmalonic acidurias: cblA and mut."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Methylmalonic acidemia (MMA) levels in urine and plasma were significantly lower in cblA."
    explanation: Quantifies the lower metabolite burden in cblA relative to mut-type disease in a registry comparison of 28 cblA and 95 mut patients.
  - reference: PMID:31921599
    reference_title: Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related to MMAA mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Significant excretion of methylmalonic acid in urine and metabolic acidosis traits with significantly increased anionic gap were observed in all patients."
    explanation: Documents methylmalonate accumulation in every patient of a purely MMAA-genotyped series.
- name: Acute Metabolic Decompensation
  biological_scale: ORGANISM
  description: >-
    Episodic metabolic crisis with ketoacidosis, vomiting and encephalopathy, precipitated
    by catabolic stress such as intercurrent illness, fasting or protein load. This is the
    usual route to diagnosis in cblA as in mutase deficiency.
  downstream:
  - target: Neurologic Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Acute decompensation and energy deficit can contribute to brain injury, but severe initial
      crisis does not determine the final cognitive outcome.
    evidence:
    - reference: PMID:35618652
      reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        This is also in line with the pathophysiological hypotheses suggesting that chronic
        kidney disease is more directly linked to MMA toxicity, while brain involvement seems
        to be more complex and related partially to acute decompensation and energy deficit,
        and partially to de novo synthesis and trapping of toxic metabolites in brain tissue.
      explanation: >-
        The cblA cohort discussion proposes organ-injury routes; these are hypotheses, not measured
        causal mediation.
      directness: INDIRECT
  - target: Basal ganglia injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Acute metabolic crisis can injure the basal ganglia, including the globus pallidus. This
      route applies to some affected infants, not all movement findings.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1231/
      reference_title: Isolated Methylmalonic Acidemia - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Some individuals develop a "metabolic stroke" or bilateral lacunar infarction of the
        basal ganglia during acute metabolic decompensation, which can produce an incapacitating
        movement disorder.
      explanation: >-
        GeneReviews describes the causal crisis–basal-ganglia injury–movement disorder route.
        Its preceding B12-responsive phenotype section explicitly names cblA and mut– infants
        as susceptible.
  - target: Reduced consciousness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Acute acid-base and ammonia disturbances can impair alertness during a cblA crisis; the
      individual contribution of each disturbance is unresolved.
    evidence:
    - reference: PMID:34915869
      reference_title: >-
        Genetic testing is necessary for correct diagnosis and treatment in patients with isolated
        methylmalonic aciduria: a case report.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We describe two patients who presented in the first week of life with rapid neurological
        deterioration caused by metabolic acidosis with severe hyperammonaemia requiring extracorporeal
        elimination in addition to protein restriction, energy support, carnitine, and vitamin
        B12 treatment.
      explanation: >-
        The paper attributes acute neurological deterioration to metabolic acidosis and hyperammonemia
        in both patients; patient 2 is MMAA-confirmed cblA. This does not assign the MMAB patient’s
        other findings to cblA.
  - target: Lethargy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Acute acid-base and ammonia disturbances can impair alertness during a cblA crisis; the
      individual contribution of each disturbance is unresolved.
    evidence:
    - reference: PMID:34915869
      reference_title: >-
        Genetic testing is necessary for correct diagnosis and treatment in patients with isolated
        methylmalonic aciduria: a case report.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We describe two patients who presented in the first week of life with rapid neurological
        deterioration caused by metabolic acidosis with severe hyperammonaemia requiring extracorporeal
        elimination in addition to protein restriction, energy support, carnitine, and vitamin
        B12 treatment.
      explanation: >-
        The paper attributes acute neurological deterioration to metabolic acidosis and hyperammonemia
        in both patients; patient 2 is MMAA-confirmed cblA. This does not assign the MMAB patient’s
        other findings to cblA.
  evidence:
  - reference: PMID:32754920
    reference_title: "Delineating the clinical spectrum of isolated methylmalonic acidurias: cblA and mut."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Metabolic crisis is the predominant symptom leading to diagnosis in both groups."
    explanation: Establishes metabolic crisis as the dominant presenting event in the cblA arm of this registry study.
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disease onset was mostly pediatric (78% < 1 year, median = 4 months) with acute neurologic deterioration (65%)."
    explanation: Characterises the acute presentation and its timing in an entirely cblA case series.
- name: Renal Tubulointerstitial Injury
  biological_scale: TISSUE
  description: >-
    Tubulointerstitial injury can impair renal function in cblA. Chronic interstitial inflammation
    has been documented on biopsy, and another severe cblA case had tubulointerstitial nephropathy
    with glomerulosclerosis. Renal involvement is variable, and early hydroxocobalamin benefit
    remains supported by observational evidence.
  notes: >-
    The cblA biopsy evidence establishes a tubulointerstitial lesion without resolving its
    proximal-tubule epithelial-cell localization. CL:0002306 is therefore not assigned to
    this tissue node. Proximal-tubule mitochondrial mechanisms from other MMA subtypes remain
    candidates for cblA, not a demonstrated cellular lesion in these patients.
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:24095221
    reference_title: "Renal involvement in a patient with cobalamin A type (cblA) methylmalonic aciduria: a 42-year follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kidney biopsies showed non-specific manifestations of chronic interstitial inflammation."
    explanation: Histological confirmation of interstitial renal disease in a molecularly confirmed cblA patient.
  - reference: PMID:32754920
    reference_title: "Delineating the clinical spectrum of isolated methylmalonic acidurias: cblA and mut."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Glomerular filtration rate was significantly higher in cblA; and as a consequence, chronic renal failure and related complications were significantly less frequent and renal function could be preserved even in older patients."
    explanation: Establishes that renal involvement occurs in cblA but is less severe than in mut-type disease.
  downstream:
  - target: Chronic kidney disease
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Loss of renal tubular and interstitial integrity contributes to progressive
      renal dysfunction.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1231/
      reference_title: Isolated Methylmalonic Acidemia - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Tubulointerstitial nephritis with progressive impairment of renal function.
      explanation: >-
        GeneReviews identifies the renal lesion and its functional consequence across isolated
        MMA, including cblA.
- name: Neurologic Injury
  biological_scale: TISSUE
  description: >-
    Neurological injury in cblA may involve acute decompensation and energy deficit, as well
    as chronic production and trapping of toxic metabolites in the brain. These routes are incompletely
    resolved. Developmental and cognitive outcomes vary, and the adult treatment comparison
    cannot exclude benefit from earlier diagnosis and management.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main long-term problems were intellectual disability (39%) and renal failure (30%)."
    explanation: Quantifies the neurological and renal long-term burden in an entirely cblA cohort.
  - reference: PMID:32754920
    reference_title: "Delineating the clinical spectrum of isolated methylmalonic acidurias: cblA and mut."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological complications were predominantly found in the mut subgroup."
    explanation: Bounds the claim by showing neurological complications are less characteristic of cblA than of mut-type disease in direct comparison.
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This is also in line with the pathophysiological hypotheses suggesting that chronic kidney
      disease is more directly linked to MMA toxicity, while brain involvement seems to be more
      complex and related partially to acute decompensation and energy deficit, and partially
      to de novo synthesis and trapping of toxic metabolites in brain tissue.
    explanation: >-
      The cblA cohort discussion proposes organ-injury routes; these are hypotheses, not measured
      causal mediation.
    directness: INDIRECT
  downstream:
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Brain injury can impair development and cognition. The relative contributions of acute
      energy failure and chronic metabolite toxicity are unresolved in cblA.
    evidence:
    - reference: PMID:35618652
      reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        This is also in line with the pathophysiological hypotheses suggesting that chronic
        kidney disease is more directly linked to MMA toxicity, while brain involvement seems
        to be more complex and related partially to acute decompensation and energy deficit,
        and partially to de novo synthesis and trapping of toxic metabolites in brain tissue.
      explanation: >-
        The cblA cohort discussion proposes organ-injury routes; these are hypotheses, not measured
        causal mediation.
      directness: INDIRECT
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Brain injury can impair development and cognition. The relative contributions of acute
      energy failure and chronic metabolite toxicity are unresolved in cblA.
    evidence:
    - reference: PMID:35618652
      reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        This is also in line with the pathophysiological hypotheses suggesting that chronic
        kidney disease is more directly linked to MMA toxicity, while brain involvement seems
        to be more complex and related partially to acute decompensation and energy deficit,
        and partially to de novo synthesis and trapping of toxic metabolites in brain tissue.
      explanation: >-
        The cblA cohort discussion proposes organ-injury routes; these are hypotheses, not measured
        causal mediation.
      directness: INDIRECT
- name: Secondary impairment of ureagenesis
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Propionyl-CoA inhibition of N-acetylglutamate synthase can reduce the N-acetylglutamate
    required to activate carbamoyl-phosphate synthetase I. Rat liver extract experiments support
    this candidate route to hyperammonemia in organic acidemias. Its quantitative contribution
    in MMAA deficiency is unmeasured, and other mechanisms of urea-cycle impairment may contribute.
  evidence:
  - reference: PMID:500823
    reference_title: >-
      Inhibition by propionyl-coenzyme A of N-acetylglutamate synthetase in rat liver mitochondria.
      A possible explanation for hyperammonemia in propionic and methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      A decreased level of N-acetylglutamate in liver mitochondria that would follow inhibition
      of N-acetylglutamate synthetase by propionyl-CoA would be expected to lead to hyperammonemia.
    explanation: The authors infer reduced ammonia clearance from their rat mitochondrial biochemical
      results.
    directness: INDIRECT
  downstream:
  - target: Hyperammonemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Reduced urea-cycle ammonia clearance is a plausible contributor to secondary
      hyperammonemia in cblA.
    intermediate_mechanisms:
    - reduced N-acetylglutamate activation of carbamoyl-phosphate synthetase I
    - reduced urea-cycle ammonia disposal
    evidence:
    - reference: PMID:500823
      reference_title: >-
        Inhibition by propionyl-coenzyme A of N-acetylglutamate synthetase in rat liver mitochondria.
        A possible explanation for hyperammonemia in propionic and methylmalonic acidemia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        A decreased level of N-acetylglutamate in liver mitochondria that would follow inhibition
        of N-acetylglutamate synthetase by propionyl-CoA would be expected to lead to hyperammonemia.
      explanation: The authors infer reduced ammonia clearance from their rat mitochondrial
        biochemical results.
      directness: INDIRECT
- name: Secondary renal mitochondrial dysfunction
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Secondary mitochondrial dysfunction is proposed to mediate renal damage in isolated MMA.
    Its specific causal contribution in cblA has not been established, and a liver OXPHOS defect
    in one cblA patient does not establish the renal mechanism.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1231/
    reference_title: Isolated Methylmalonic Acidemia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Secondary mitochondrial dysfunction rather than direct nephrotoxicity of methylmalonic
      acid is hypothesized as the cause for renal disease
    explanation: >-
      GeneReviews presents a mechanistic hypothesis across isolated MMA; subtype-specific renal
      confirmation is lacking.
    directness: INDIRECT
  downstream:
  - target: Renal Tubulointerstitial Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Provisional mitochondrial route to tubulointerstitial damage, rather than an established
      cblA-specific renal experiment.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1231/
      reference_title: Isolated Methylmalonic Acidemia - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Secondary mitochondrial dysfunction rather than direct nephrotoxicity of methylmalonic
        acid is hypothesized as the cause for renal disease
      explanation: >-
        GeneReviews presents a mechanistic hypothesis across isolated MMA; subtype-specific
        renal confirmation is lacking.
      directness: INDIRECT
- name: Basal ganglia injury
  biological_scale: TISSUE
  locations:
  - preferred_term: basal ganglion
    term:
      id: UBERON:0002420
      label: basal ganglion
  description: >-
    Acute metabolic crises can produce basal-ganglia injury and a subsequent movement disorder
    in cblA. A normal examination despite basal-ganglia MRI signal changes in two adults shows
    that an imaging abnormality alone does not determine clinical impairment.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1231/
    reference_title: Isolated Methylmalonic Acidemia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Some individuals develop a "metabolic stroke" or bilateral lacunar infarction of the basal
      ganglia during acute metabolic decompensation, which can produce an incapacitating movement
      disorder.
    explanation: >-
      GeneReviews describes the causal crisis–basal-ganglia injury–movement disorder route.
      Its preceding B12-responsive phenotype section explicitly names cblA and mut– infants
      as susceptible.
  downstream:
  - target: Abnormality of extrapyramidal motor function
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Basal-ganglia injury can produce extrapyramidal motor dysfunction after metabolic crisis.
      This route does not assign the adult cohort’s probably neuroleptic-related signs to cblA.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1231/
      reference_title: Isolated Methylmalonic Acidemia - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Some individuals develop a "metabolic stroke" or bilateral lacunar infarction of the
        basal ganglia during acute metabolic decompensation, which can produce an incapacitating
        movement disorder.
      explanation: >-
        GeneReviews supports basal-ganglia injury as a cause of a movement disorder, with cblA
        included in its B12-responsive clinical scope. This supports the general extrapyramidal
        consequence, not attribution of every abnormal adult examination to metabolic injury.
  - target: Dystonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Dystonia is a possible expression of the basal-ganglia movement disorder after metabolic
      injury. Applying this route to the Polish cblA patients is an inference across sources;
      their individual lesion-to-dystonia correlation was not established.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1231/
      reference_title: Isolated Methylmalonic Acidemia - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Some individuals develop a "metabolic stroke" or bilateral lacunar infarction of the
        basal ganglia during acute metabolic decompensation, which can produce an incapacitating
        movement disorder.
      explanation: >-
        GeneReviews supports a causal movement-disorder route and separately lists dystonia
        among isolated-MMA motor findings. Dystonia is observed in the Polish cblA cohort
        (PMID:31921599), but applying the shared route to those patients remains an inference
        without an individual lesion-outcome correlation.
  - target: Choreoathetosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Choreoathetosis may arise as part of the movement disorder following basal-ganglia injury.
      The Polish cblA observations establish choreoathetosis, but do not individually demonstrate
      this route or exclude other contributors.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1231/
      reference_title: Isolated Methylmalonic Acidemia - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Some individuals develop a "metabolic stroke" or bilateral lacunar infarction of the
        basal ganglia during acute metabolic decompensation, which can produce an incapacitating
        movement disorder.
      explanation: >-
        GeneReviews supports the basal-ganglia injury–movement disorder relationship and lists
        choreoathetosis among isolated-MMA motor findings. The Polish cblA cohort (PMID:31921599)
        establishes the specific clinical sign; the causal attribution to basal-ganglia injury
        is a qualified synthesis rather than a demonstrated mechanism in each patient.
- name: Chronic illness and inadequate nutritional intake
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  description: >-
    Chronic disease burden, feeding problems and relative protein malnutrition can impair growth
    in isolated MMA. Renal dysfunction can aggravate this process. The nutritional contribution
    to growth and bone findings in specific cblA patients is not measured.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1231/
    reference_title: Isolated Methylmalonic Acidemia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It is the result of severe chronic illness and perhaps relative protein malnutrition that
      is complicated further by chronic renal failure.
    explanation: >-
      The preceding GeneReviews sentence identifies growth failure as the subject. This is a
      proposed multifactorial route across isolated MMA, including cblA.
    directness: INDIRECT
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In the long‐term, patients with cblA deficiency can also present osteoporosis, likely
      related to low‐protein diet, and hypertension and cardiac hypertrophy, likely related
      to chronic kidney disease.
    explanation: The authors propose these secondary relationships in cblA; the qualifiers are
      preserved.
    directness: INDIRECT
  downstream:
  - target: Short stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Chronic illness and inadequate intake can impair linear growth or weight gain. This is
      a multifactorial isolated-MMA mechanism, not proof that all cblA growth problems are dietary.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1231/
      reference_title: Isolated Methylmalonic Acidemia - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        It is the result of severe chronic illness and perhaps relative protein malnutrition
        that is complicated further by chronic renal failure.
      explanation: >-
        The preceding GeneReviews sentence identifies growth failure as the subject. This is
        a proposed multifactorial route across isolated MMA, including cblA.
      directness: INDIRECT
  - target: Failure to thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Chronic illness and inadequate intake can impair linear growth or weight gain. This is
      a multifactorial isolated-MMA mechanism, not proof that all cblA growth problems are dietary.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1231/
      reference_title: Isolated Methylmalonic Acidemia - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        It is the result of severe chronic illness and perhaps relative protein malnutrition
        that is complicated further by chronic renal failure.
      explanation: >-
        The preceding GeneReviews sentence identifies growth failure as the subject. This is
        a proposed multifactorial route across isolated MMA, including cblA.
      directness: INDIRECT
  - target: Osteoporosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Low-protein intake is a proposed contributor to osteoporosis in the cblA cohort.
    evidence:
    - reference: PMID:35618652
      reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        In the long‐term, patients with cblA deficiency can also present osteoporosis, likely
        related to low‐protein diet, and hypertension and cardiac hypertrophy, likely related
        to chronic kidney disease.
      explanation: The authors propose these secondary relationships in cblA; the qualifiers
        are preserved.
      directness: INDIRECT
  - target: Decreased body weight
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Chronic illness and relative nutritional insufficiency can lower body weight, with renal
      disease as a possible contributor. The relative contributions in individual cblA patients
      are unresolved.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1231/
      reference_title: Isolated Methylmalonic Acidemia - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        It is the result of severe chronic illness and perhaps relative protein malnutrition
        that is complicated further by chronic renal failure.
      explanation: >-
        The preceding GeneReviews sentence identifies growth failure as the subject. This is
        a proposed multifactorial route across isolated MMA, including cblA.
      directness: INDIRECT
phenotypes:
- name: Methylmalonic aciduria
  category: Biochemical
  description: >-
    Elevated urinary methylmalonic acid is the defining biochemical finding, present in all
    five patients at diagnosis in the Polish MMAA-confirmed series. Levels depend on treatment
    and renal function; normalization can occur with treatment.
  phenotype_term:
    preferred_term: Methylmalonic aciduria
    term:
      id: HP:0012120
      label: Methylmalonic aciduria
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:31921599
    reference_title: Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related to MMAA mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Significant excretion of methylmalonic acid in urine and metabolic acidosis traits with significantly increased anionic gap were observed in all patients."
    explanation: Methylmalonic aciduria was present in every patient of this MMAA-genotyped series.
  reports_on:
  - target: Methylmalonic Acid and Propionyl-CoA Accumulation
    relationship: READOUT_OF
    interpretation: >-
      Urinary MMA measures metabolite accumulation; it is not an additional causal consequence
      distinct from that accumulation.
- name: Decreased methylmalonyl-CoA mutase activity
  category: Biochemical
  description: >-
    Reduced effective cellular mutase-pathway activity is reflected by low propionate incorporation
    that improves with hydroxocobalamin. This does not imply deficient cofactor-saturated MMUT
    apoenzyme activity: the latter was normal in the tested adult cblA patient.
  phenotype_term:
    preferred_term: Decreased methylmalonyl-CoA mutase activity
    term:
      id: HP:0003210
      label: Decreased methylmalonyl-CoA mutase activity
  evidence:
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Enzymatic studies of her fibroblasts showed a deficit in propionate incorporation (1.61
      nmol/mg prot/16 h vs. 6.08 nmol/mg prot/16 h in the experimental control; range in controls
      3.5–24.4) with a clear increase after B12 supplementation (11.7 nmol/mg prot/16 h vs.
      7.79 nmol/mg prot/16 h in the experimental control; range in controls 4.33–28.9), and
      normal MCM activity (measured with excess of AdoCbl), indicating a B12‐responsive defect
      of AdoCbl synthesis.
    explanation: >-
      Diagnostic cell studies in an MMAA-confirmed adult show impaired pathway flux with intact
      cofactor-supplemented apoenzyme activity.
  reports_on:
  - target: Reduced Methylmalonyl-CoA Mutase Holoenzyme Activity
    relationship: READOUT_OF
    interpretation: >-
      Functional assay readout of cofactor-dependent pathway impairment; assay conditions and
      exogenous cofactor matter.
- name: Episodic metabolic acidosis
  category: Biochemical
  description: >-
    High-anion-gap acidosis occurred at diagnosis in all five Polish cblA patients, while none
    had acidosis at follow-up under treatment. Recurrent infection-triggered episodes were also
    documented in an MMAA-confirmed child. This is not a claim of persistent acidosis between
    crises.
  phenotype_term:
    preferred_term: Episodic high-anion-gap metabolic acidosis
    term:
      id: HP:0004911
      label: Episodic metabolic acidosis
  evidence:
  - reference: PMID:31921599
    reference_title: Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related to MMAA mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Significant excretion of methylmalonic acid in urine and metabolic acidosis traits with significantly increased anionic gap were observed in all patients."
    explanation: Records metabolic acidosis with increased anion gap in all five MMAA patients.
  - reference: PMID:34915869
    reference_title: >-
      Genetic testing is necessary for correct diagnosis and treatment in patients with isolated
      methylmalonic aciduria: a case report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Metabolic decompensations occurred rarely (3-times during the 8-years of follow-up), and
      they were always provoked by an acute infection, accompanied by mild metabolic acidosis,
      mild hyperammonaemia, and a higher concentration of methylmalonic acid in urine.
    explanation: Patient 2 had homozygous MMAA p.Leu89Pro; the sentence documents recurrent
      episodic acidosis in cblA.
- name: Vomiting
  category: Gastrointestinal
  description: Recurrent vomiting began in infancy and was present in all five Polish patients
    at diagnosis.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
    temporality: RECURRENT
  evidence:
  - reference: PMID:31921599
    reference_title: Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related to MMAA mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the time of diagnosis the median of age was 18.8 months, but the symptoms had already appeared since infancy, as recurrent vomiting and delayed psychomotor development."
    explanation: Names recurrent vomiting as a presenting symptom from infancy in this cblA series.
- name: Global developmental delay
  category: Neurologic
  description: >-
    Delayed psychomotor development was present at diagnosis in four of five Polish patients.
    Outcomes vary: an early-treated MMAA p.Leu89Pro child had age-appropriate mental development
    at follow-up.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:31921599
    reference_title: Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related to MMAA mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the time of diagnosis the median of age was 18.8 months, but the symptoms had already
      appeared since infancy, as recurrent vomiting and delayed psychomotor development.
    explanation: The clinical presentation includes psychomotor delay; Table 1 records delay
      in four of five patients.
  - reference: PMID:34915869
    reference_title: >-
      Genetic testing is necessary for correct diagnosis and treatment in patients with isolated
      methylmalonic aciduria: a case report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Currently, the child has an age-appropriate mental development with occasional attention
      deficit and concentration difficulty at school and is without renal complications.
    explanation: Patient 2 is the MMAA-confirmed child; this bounds the claim of universal persistent
      delay.
- name: Intellectual disability
  category: Neurologic
  description: >-
    Intellectual disability affected 9/23 adults in a retrospective cblA series. Similar proportions
    across small initial-treatment groups do not exclude a benefit of early diagnosis or B12
    therapy; historical treatment and adult-survivor selection limit interpretation.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: FREQUENT
  evidence:
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main long-term problems were intellectual disability (39%) and renal failure (30%)."
    explanation: Gives the frequency of intellectual disability in an adult cblA-only case series.
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intellectual disability was equally distributed among the initial treatment groups, while renal failure (moderate and beginning at the age of 38 years) was present in only one out of seven patients initially treated with B12."
    explanation: >-
      Small retrospective initial-treatment groups had similar cognitive outcomes; the authors
      explicitly could not exclude effects of delayed diagnosis and treatment.
- name: Chronic kidney disease
  category: Renal
  description: >-
    Chronic renal failure, defined as GFR below 60 mL/min/1.73 m2, affected 7/23 adults in a
    retrospective cblA series. The frequency reflects that historical adult cohort. The Polish
    series identified CKD in 3/5 using cystatin C, although creatinine was normal at follow-up
    and only one had estimated GFR below 75. Renal disease may present chronically and can progress
    despite treatment.
  phenotype_term:
    preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
    clinical_course: PROGRESSIVE
  frequency: FREQUENT
  evidence:
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chronic renal failure (CRF), defined as a glomerular filtration rate less than 60 ml/min/1.73
      m2, was present in 7/23 patients (30%) and was moderate in three and severe in four cases
      (one requiring renal transplantation).
    explanation: Specifies the adult cohort denominator and renal-function threshold behind
      the frequency band.
  - reference: PMID:31921599
    reference_title: Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related to MMAA mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients have renal failure and pharmacologically treated arterial hypertension."
    explanation: Independent confirmation of renal failure in a majority of a small genotyped cblA series.
  sequelae:
  - target: Hypertension
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The cblA cohort authors consider this a likely secondary complication of kidney disease;
      patient-specific mediation was not tested.
    evidence:
    - reference: PMID:35618652
      reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        In the long‐term, patients with cblA deficiency can also present osteoporosis, likely
        related to low‐protein diet, and hypertension and cardiac hypertrophy, likely related
        to chronic kidney disease.
      explanation: The authors propose these secondary relationships in cblA; the qualifiers
        are preserved.
      directness: INDIRECT
  - target: Left ventricular hypertrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The cblA cohort authors consider this a likely secondary complication of kidney disease;
      patient-specific mediation was not tested.
    evidence:
    - reference: PMID:35618652
      reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        In the long‐term, patients with cblA deficiency can also present osteoporosis, likely
        related to low‐protein diet, and hypertension and cardiac hypertrophy, likely related
        to chronic kidney disease.
      explanation: The authors propose these secondary relationships in cblA; the qualifiers
        are preserved.
      directness: INDIRECT
  - target: Chronic illness and inadequate nutritional intake
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Chronic renal failure can worsen the illness and nutritional burden affecting
      growth.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1231/
      reference_title: Isolated Methylmalonic Acidemia - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        It is the result of severe chronic illness and perhaps relative protein malnutrition
        that is complicated further by chronic renal failure.
      explanation: >-
        The preceding GeneReviews sentence identifies growth failure as the subject. This is
        a proposed multifactorial route across isolated MMA, including cblA.
      directness: INDIRECT
  - target: Anemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired erythropoietic support in chronic renal disease
    description: >-
      Renal dysfunction can contribute to anemia. Nutritional and acute metabolic causes remain
      possible, particularly before substantial CKD develops.
    evidence:
    - reference: PMID:31921599
      reference_title: >-
        Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related
        to MMAA mutations.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Complications resulting from chronic kidney disease (hypertension, anemia, renal osteodystrophy
        and hyperparathyroidism) aggravate the basic disease
      explanation: >-
        The discussion identifies anemia as a possible CKD consequence in MMA; it does not attribute
        every anemic child to this route.
- name: Tubulointerstitial nephritis
  category: Renal
  description: >-
    Biopsy-documented chronic interstitial inflammation in a cblA patient. Another severe MMAA-confirmed
    case had tubulointerstitial nephropathy with glomerulosclerosis, so concomitant glomerular
    pathology is not excluded.
  phenotype_term:
    preferred_term: Tubulointerstitial nephritis
    term:
      id: HP:0001970
      label: Tubulointerstitial nephritis
    temporality: CHRONIC
  evidence:
  - reference: PMID:24095221
    reference_title: "Renal involvement in a patient with cobalamin A type (cblA) methylmalonic aciduria: a 42-year follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kidney biopsies showed non-specific manifestations of chronic interstitial inflammation."
    explanation: Direct biopsy evidence of the interstitial lesion in a cblA patient followed for 42 years.
  reports_on:
  - target: Renal Tubulointerstitial Injury
    relationship: READOUT_OF
    interpretation: >-
      Biopsy phenotype reports the tissue lesion itself; an identity arrow from the identically
      scoped injury would not add a causal explanation.
- name: Short stature
  category: Growth
  description: >-
    Height below the third percentile was documented in three of five Polish cblA patients at
    follow-up. This is a measured stature phenotype rather than a diagnostic recommendation
    to investigate unexplained growth delay.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:31921599
    reference_title: >-
      Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related
      to MMAA mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients have weight and height deficiency (<3 percentile for age and gender according
      to WHO centile grids).
    explanation: Direct observation of short stature in 3/5 patients supports the more specific
      HPO term.
- name: Optic atrophy
  category: Ophthalmologic
  description: >-
    Optic atrophy is a recognised late complication of vitamin B12-responsive
    methylmalonic aciduria and has been reported in cblA specifically, in a patient whose
    metabolite levels were low at the time.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:19277894
    reference_title: Multiple OXPHOS deficiency in the liver of a patient with CblA methylmalonic aciduria sensitive to vitamin B(12).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An adult patient with methylmalonic aciduria due to defective cobalamin synthesis (CblA)
      responsive to vitamin B(12) presented suddenly with severe visual impairment ascribed
      to optic atrophy followed by a fatal multiorgan failure and lactic acidosis but low methylmalonic
      acid in plasma and urine.
    explanation: One B12-responsive adult with cblA had optic atrophy despite low plasma and urinary MMA at the time; this case does not estimate disease frequency.
  sequelae:
  - target: Visual impairment
    causal_link_type: DIRECT
    description: Optic nerve atrophy caused the visual impairment in the reported adult cblA
      case.
    evidence:
    - reference: PMID:19277894
      reference_title: >-
        Multiple OXPHOS deficiency in the liver of a patient with CblA methylmalonic aciduria
        sensitive to vitamin B(12).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        An adult patient with methylmalonic aciduria due to defective cobalamin synthesis (CblA)
        responsive to vitamin B(12) presented suddenly with severe visual impairment ascribed
        to optic atrophy followed by a fatal multiorgan failure and lactic acidosis but low
        methylmalonic acid in plasma and urine.
      explanation: >-
        The authors explicitly ascribe this adult cblA patient’s severe visual impairment to optic atrophy, supporting the case-specific causal relationship.
- name: Hyperuricemia
  category: Metabolic
  description: >-
    Hyperuricemia occurred in 5/23 adults (22%) in the retrospective cblA cohort; three received
    allopurinol. This frequency is cohort-specific.
  phenotype_term:
    preferred_term: Hyperuricemia
    term:
      id: HP:0002149
      label: Hyperuricemia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hyperuricemia was present in 5/23 patients (22%), three of whom were treated with allopurinol."
    explanation: Gives both the frequency in an adult cblA-only cohort and the fact that it prompted treatment.
- name: Abnormality of extrapyramidal motor function
  category: Neurologic
  description: >-
    Five of 23 adults had mild extrapyramidal signs; at least one was probably neuroleptic-related.
    Two of five Polish patients had more disabling pyramidal-extrapyramidal syndromes. The adult
    mild-sign count is not a disease-attributable prevalence estimate.
  phenotype_term:
    preferred_term: Extrapyramidal motor abnormalities
    term:
      id: HP:0002071
      label: Abnormality of extrapyramidal motor function
  evidence:
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurological examination was normal in 17/23 patients (74%): only five patients had mild
      extrapyramidal features, such as bradykinesia or involuntary movements, and in at least
      one patient (patient 1/Lon01) this was probably secondary to long standing neuroleptic
      treatments; one patient had ataxia; three patients had seizures.
    explanation: Includes the medication confound and normal-examination denominator.
- name: Seizure
  category: Neurologic
  description: >-
    Seizures were reported in 3/23 adults in the retrospective cblA cohort and in one of five
    Polish patients at diagnosis. The frequency is based on the adult cohort; seizure type and
    recurrence are not established for every affected person.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "one patient had ataxia; three patients had seizures."
    explanation: Three of 23 adult cblA patients had seizures, which sets the OCCASIONAL band.
- name: Hypotonia
  category: Neurologic
  description: >-
    Hypotonia in the first months to years of life, part of the presenting picture of the
    B12-responsive phenotypes that GeneReviews names cblA among.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:20301409
    reference_title: Isolated Methylmalonic Acidemia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      symptoms occur in the first few months or years of life and are characterized by feeding
      problems, failure to thrive, hypotonia, and developmental delay marked by episodes of
      metabolic decompensation.
    explanation: >-
      The preceding subject is the partially deficient or B12-responsive group, explicitly including
      cblA; this is clinical synthesis rather than a cblA cohort frequency.
- name: Feeding difficulties
  category: Gastrointestinal
  description: >-
    Feeding problems in early life, listed by GeneReviews alongside failure to thrive and
    hypotonia for the B12-responsive group that includes cblA.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:20301409
    reference_title: Isolated Methylmalonic Acidemia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      symptoms occur in the first few months or years of life and are characterized by feeding
      problems, failure to thrive, hypotonia, and developmental delay marked by episodes of
      metabolic decompensation.
    explanation: >-
      The preceding subject is the partially deficient or B12-responsive group, explicitly including
      cblA; this is clinical synthesis rather than a cblA cohort frequency.
- name: Failure to thrive
  category: Growth
  description: >-
    Poor weight gain can present in infancy or as a chronic feature before diagnosis. It is
    distinct from measured short stature, and may have nutritional, metabolic and renal contributors.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:20301409
    reference_title: Isolated Methylmalonic Acidemia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      symptoms occur in the first few months or years of life and are characterized by feeding
      problems, failure to thrive, hypotonia, and developmental delay marked by episodes of
      metabolic decompensation.
    explanation: >-
      The preceding subject is the partially deficient or B12-responsive group, explicitly including
      cblA; this is clinical synthesis rather than a cblA cohort frequency.
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      early onset failure to thrive (patient 13/Lyo01); and early onset failure to thrive with
      psychomotor regression (patient 21/Neck05; patient 23/Mont01).
    explanation: Direct cblA observations establish failure to thrive and accompanying regression.
- name: Hyperammonemia
  category: Biochemical
  description: >-
    Secondary hyperammonemia ranges from mild elevations to severe neonatal crises. Two of five
    Polish patients had mild elevation at diagnosis; an MMAA p.Ala196* patient reached 500 micromol/L,
    and an MMAA p.Leu89Pro neonate reached 1,601 micromol/L. Absence of a cohort-wide ammonia
    count in other reports cannot establish an OCCASIONAL frequency.
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This patient presented at 9 days of life with a severe acute decompensation with ketoacidosis and hyperammonia (up to 500 micromol/l) requiring hemofiltration"
    explanation: A molecularly confirmed cblA patient (homozygous MMAA c.586C>T) with severe neonatal hyperammonemia, which is why this phenotype is not restricted to the mild form. It is a single narrated patient in a 23-patient cohort rather than a reported cohort frequency.
  - reference: PMID:31921599
    reference_title: Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related to MMAA mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In all patients, at the moment of diagnosis, the features of unbalanced metabolic acidosis
      with significantly increased anionic gap were found, but only in two patients the concentration
      of ammonia was mild increased.
    explanation: Reports mild elevations in 2/5 patients at diagnosis; this is not a disease-wide
      frequency estimate.
  - reference: PMID:34915869
    reference_title: >-
      Genetic testing is necessary for correct diagnosis and treatment in patients with isolated
      methylmalonic aciduria: a case report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On the fourth postnatal day, she developed apathy, hypothermia, and dehydration with metabolic
      acidosis and hyperammonaemia (1,601 μmol/L).
    explanation: This is patient 2, subsequently confirmed homozygous for MMAA p.Leu89Pro, not
      the MMAB patient 1.
- name: Cerebral atrophy
  category: Neurologic
  description: >-
    Cortical and subcortical atrophy on neuroimaging. Note the two cblA series disagree in
    emphasis: it was present in four of five patients in a paediatric-onset series, while
    imaging in the adult cohort was mostly normal or showed only non-specific findings.
  phenotype_term:
    preferred_term: Cortical and subcortical atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:31921599
    reference_title: Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related to MMAA mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the time of diagnosis, 4/5 of the patients had cortical and subcortical atrophy and ventricular dilatation in neuroimaging studies."
    explanation: Reports cerebral atrophy on imaging at diagnosis in four of five MMAA-genotyped patients.
- name: Ventriculomegaly
  category: Neurologic
  description: >-
    Ventricular dilatation accompanying the cortical and subcortical atrophy, reported in
    the same patients and subject to the same caveat about the contrasting adult cohort.
  phenotype_term:
    preferred_term: Ventricular dilatation
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:31921599
    reference_title: Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related to MMAA mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the time of diagnosis, 4/5 of the patients had cortical and subcortical atrophy and ventricular dilatation in neuroimaging studies."
    explanation: The same imaging finding reports ventricular dilatation alongside the atrophy.
- name: Dystonia
  category: Neurologic
  description: Reported as part of pyramidal-extrapyramidal syndromes in two of five Polish
    MMAA-confirmed patients.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:31921599
    reference_title: >-
      Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related
      to MMAA mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients have a diagnosed intellectual disability; in addition, two patients present
      features of pyramidal extrapyramidal syndrome (spastic limb paresis, dystonic movements
      and choreatetosis).
    explanation: >-
      The two affected patients among five had these specific motor abnormalities; no generalized
      severity or frequency is assigned.
- name: Choreoathetosis
  category: Neurologic
  description: Reported as part of pyramidal-extrapyramidal syndromes in two of five Polish
    MMAA-confirmed patients.
  phenotype_term:
    preferred_term: Choreoathetosis
    term:
      id: HP:0001266
      label: Choreoathetosis
  evidence:
  - reference: PMID:31921599
    reference_title: >-
      Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related
      to MMAA mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients have a diagnosed intellectual disability; in addition, two patients present
      features of pyramidal extrapyramidal syndrome (spastic limb paresis, dystonic movements
      and choreatetosis).
    explanation: >-
      The two affected patients among five had these specific motor abnormalities; no generalized
      severity or frequency is assigned.
- name: Spasticity
  category: Neurologic
  description: Reported as part of pyramidal-extrapyramidal syndromes in two of five Polish
    MMAA-confirmed patients.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:31921599
    reference_title: >-
      Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related
      to MMAA mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients have a diagnosed intellectual disability; in addition, two patients present
      features of pyramidal extrapyramidal syndrome (spastic limb paresis, dystonic movements
      and choreatetosis).
    explanation: >-
      The two affected patients among five had these specific motor abnormalities; no generalized
      severity or frequency is assigned.
- name: Ataxia
  category: Neurologic
  description: >-
    One adult in the 23-person cblA series had ataxia; the severe-case narrative also records
    epilepsy and renal disease.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: one patient had ataxia; three patients had seizures.
    explanation: Reports ataxia in one adult; this is not a disease-wide frequency.
- name: Developmental regression
  category: Neurologic
  description: >-
    Psychomotor regression accompanied early failure to thrive in two patients with a chronic
    presentation in the adult cblA series.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      early onset failure to thrive (patient 13/Lyo01); and early onset failure to thrive with
      psychomotor regression (patient 21/Neck05; patient 23/Mont01).
    explanation: Specific chronic presentations include regression.
- name: Hypertension
  category: Cardiovascular
  description: Pharmacologically treated arterial hypertension occurred in 3/5 Polish patients,
    all with renal disease.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:31921599
    reference_title: >-
      Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related
      to MMAA mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Three patients have renal failure and pharmacologically treated arterial hypertension.
    explanation: The entire five-person cohort had MMAA-associated cblA.
- name: Left ventricular hypertrophy
  category: Cardiovascular
  description: >-
    Left cardiac hypertrophy was reported in a severe cblA patient with renal insufficiency
    and arterial hypertension. This does not establish primary hypertrophic cardiomyopathy.
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  evidence:
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He developed intellectual disability, ataxia, epilepsy, and renal insufficiency (since
      the age of 11 years) with arterial hypertension, cardiac left hypertrophy and cardiac
      rhythm anomalies (atrioventricular block, long QT at the age of 15 years).
    explanation: >-
      The detailed case had homozygous MMAA p.Ala196*; the broader discussion attributes cardiac
      hypertrophy provisionally to kidney disease.
- name: Visual impairment
  category: Ophthalmologic
  description: >-
    Severe sudden visual impairment was ascribed to optic atrophy in an adult cblA patient,
    before multiorgan failure.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: PMID:19277894
    reference_title: >-
      Multiple OXPHOS deficiency in the liver of a patient with CblA methylmalonic aciduria
      sensitive to vitamin B(12).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An adult patient with methylmalonic aciduria due to defective cobalamin synthesis (CblA)
      responsive to vitamin B(12) presented suddenly with severe visual impairment ascribed
      to optic atrophy followed by a fatal multiorgan failure and lactic acidosis but low methylmalonic
      acid in plasma and urine.
    explanation: >-
      Sudden severe visual impairment was observed in the adult cblA patient before fatal multiorgan failure; no visual-outcome frequency is inferred.
- name: Reduced consciousness
  category: Neurologic
  description: Disturbances of consciousness occurred in three of five Polish cblA patients
    at diagnosis.
  phenotype_term:
    preferred_term: Reduced consciousness
    term:
      id: HP:0004372
      label: Reduced consciousness
  evidence:
  - reference: PMID:31921599
    reference_title: >-
      Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related
      to MMAA mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three children were in a severe general state with disturbances of consciousness, and
      one patient had convulsions.
    explanation: Direct clinical observation; the source does not establish coma in all three.
- name: Lethargy
  category: Neurologic
  description: >-
    Lethargy was documented in several patient histories used to identify MMAA, including an
    infant with poor feeding and seizures.
  phenotype_term:
    preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
  evidence:
  - reference: PMID:12438653
    reference_title: >-
      Identification of the gene responsible for the cblA complementation group of vitamin B12-responsive
      methylmalonic acidemia based on analysis of prokaryotic gene arrangements.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: WG3080 is from a white female who presented at 7 days with lethargy, poor feeding,
      and seizures.
    explanation: Clinical history of a cblA patient cell-line donor; it is not a cultured-cell
      phenotype.
- name: Dehydration
  category: Constitutional
  description: Present during the severe neonatal crisis of the MMAA p.Leu89Pro patient.
  phenotype_term:
    preferred_term: Dehydration
    term:
      id: HP:0001944
      label: Dehydration
  evidence:
  - reference: PMID:34915869
    reference_title: >-
      Genetic testing is necessary for correct diagnosis and treatment in patients with isolated
      methylmalonic aciduria: a case report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On the fourth postnatal day, she developed apathy, hypothermia, and dehydration with metabolic
      acidosis and hyperammonaemia (1,601 μmol/L).
    explanation: The clinical history is patient 2 with homozygous MMAA p.Leu89Pro.
- name: Hypothermia
  category: Constitutional
  description: Present during the severe neonatal crisis of the MMAA p.Leu89Pro patient.
  phenotype_term:
    preferred_term: Hypothermia
    term:
      id: HP:0002045
      label: Hypothermia
  evidence:
  - reference: PMID:34915869
    reference_title: >-
      Genetic testing is necessary for correct diagnosis and treatment in patients with isolated
      methylmalonic aciduria: a case report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On the fourth postnatal day, she developed apathy, hypothermia, and dehydration with metabolic
      acidosis and hyperammonaemia (1,601 μmol/L).
    explanation: The clinical history is patient 2 with homozygous MMAA p.Leu89Pro.
- name: Anemia
  category: Hematologic
  description: >-
    Reported in more than half of the five Polish patients at diagnosis; mechanism and persistence
    were not individually characterized.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:31921599
    reference_title: >-
      Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related
      to MMAA mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, more than half of the patients had anemia, hyperglycemia and ketonuria.
    explanation: >-
      Observed at diagnosis in the five-patient cblA cohort; exact individual counts are not
      supplied in this sentence.
- name: Hyperglycemia
  category: Biochemical
  description: >-
    Reported in more than half of the five Polish patients at diagnosis; mechanism and persistence
    were not individually characterized.
  phenotype_term:
    preferred_term: Hyperglycemia
    term:
      id: HP:0003074
      label: Hyperglycemia
  evidence:
  - reference: PMID:31921599
    reference_title: >-
      Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related
      to MMAA mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, more than half of the patients had anemia, hyperglycemia and ketonuria.
    explanation: >-
      Observed at diagnosis in the five-patient cblA cohort; exact individual counts are not
      supplied in this sentence.
- name: Ketonuria
  category: Biochemical
  description: >-
    Reported in more than half of the five Polish patients at diagnosis; mechanism and persistence
    were not individually characterized.
  phenotype_term:
    preferred_term: Ketonuria
    term:
      id: HP:0002919
      label: Ketonuria
  evidence:
  - reference: PMID:31921599
    reference_title: >-
      Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related
      to MMAA mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, more than half of the patients had anemia, hyperglycemia and ketonuria.
    explanation: >-
      Observed at diagnosis in the five-patient cblA cohort; exact individual counts are not
      supplied in this sentence.
- name: Elevated circulating hepatic transaminase concentration
  category: Biochemical
  description: >-
    Aminotransferases were elevated in 3/5 Polish patients at diagnosis; this does not establish
    chronic hepatopathy or hepatic failure.
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:31921599
    reference_title: >-
      Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related
      to MMAA mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In 3/5 there was detected an increased activity of aminotransferases.
    explanation: Direct biochemical observation in the MMAA-confirmed cohort.
- name: Osteoporosis
  category: Skeletal
  description: >-
    Densitometry classified 2/9 tested adults as having osteoporosis; the study proposes a contribution
    from protein restriction.
  phenotype_term:
    preferred_term: Osteoporosis
    term:
      id: HP:0000939
      label: Osteoporosis
  evidence:
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bone densitometry was performed in 9 patients and was abnormal in 5 of them with osteoporosis
      (n = 2) or osteopenia (n = 3).
    explanation: The denominator is nine tested adults, not all 23; selection for densitometry
      may affect the proportion.
- name: Osteopenia
  category: Skeletal
  description: >-
    Densitometry classified 3/9 tested adults as having osteopenia. Renal disease, nutrition
    and other factors may contribute.
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  evidence:
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bone densitometry was performed in 9 patients and was abnormal in 5 of them with osteoporosis
      (n = 2) or osteopenia (n = 3).
    explanation: The denominator is nine tested adults, not all 23; selection for densitometry
      may affect the proportion.
- name: Diminished ability to concentrate
  category: Behavioral
  description: >-
    Occasional school concentration difficulties occurred in the early-treated MMAA p.Leu89Pro
    child with otherwise age-appropriate mental development. This does not establish ADHD.
  phenotype_term:
    preferred_term: Diminished ability to concentrate
    term:
      id: HP:0031987
      label: Diminished ability to concentrate
  evidence:
  - reference: PMID:34915869
    reference_title: >-
      Genetic testing is necessary for correct diagnosis and treatment in patients with isolated
      methylmalonic aciduria: a case report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Currently, the child has an age-appropriate mental development with occasional attention
      deficit and concentration difficulty at school and is without renal complications.
    explanation: Patient 2 is the MMAA-confirmed child.
- name: Atrioventricular block
  category: Cardiovascular
  description: >-
    Reported at age 15 in a severe cblA case with chronic renal insufficiency, hypertension
    and cardiac hypertrophy. The contribution of electrolyte disturbances or primary myocardial
    dysfunction was not established.
  phenotype_term:
    preferred_term: Atrioventricular block
    term:
      id: HP:0001678
      label: Atrioventricular block
  evidence:
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He developed intellectual disability, ataxia, epilepsy, and renal insufficiency (since
      the age of 11 years) with arterial hypertension, cardiac left hypertrophy and cardiac
      rhythm anomalies (atrioventricular block, long QT at the age of 15 years).
    explanation: >-
      The severe homozygous MMAA p.Ala196* case had these cardiac rhythm abnormalities; neither
      the degree of block nor a corrected QT interval was specified.
- name: Prolonged QT interval
  category: Cardiovascular
  description: >-
    Reported at age 15 in a severe cblA case with chronic renal insufficiency, hypertension
    and cardiac hypertrophy. The contribution of electrolyte disturbances or primary myocardial
    dysfunction was not established.
  phenotype_term:
    preferred_term: Prolonged QT interval
    term:
      id: HP:0001657
      label: Prolonged QT interval
  evidence:
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He developed intellectual disability, ataxia, epilepsy, and renal insufficiency (since
      the age of 11 years) with arterial hypertension, cardiac left hypertrophy and cardiac
      rhythm anomalies (atrioventricular block, long QT at the age of 15 years).
    explanation: >-
      The severe homozygous MMAA p.Ala196* case had these cardiac rhythm abnormalities; neither
      the degree of block nor a corrected QT interval was specified.
- name: Decreased body weight
  category: Growth
  description: >-
    Weight below the third percentile was documented in three of five Polish cblA patients at
    follow-up. This measured low-weight finding is distinct from a history of failure to thrive.
  phenotype_term:
    preferred_term: Decreased body weight
    term:
      id: HP:0004325
      label: Decreased body weight
  evidence:
  - reference: PMID:31921599
    reference_title: >-
      Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related
      to MMAA mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients have weight and height deficiency (<3 percentile for age and gender according
      to WHO centile grids).
    explanation: Direct anthropometric observation of low weight and height in three of five
      patients.
genetic:
- name: MMAA
  relationship_type: CAUSATIVE
  features: >-
    MMAA encodes a 418-residue mitochondrial G-protein that chaperones adenosylcobalamin
    onto methylmalonyl-CoA mutase. Biallelic loss-of-function variants define the cblA
    complementation group. The allele spectrum is dominated by premature termination
    codons, and one nonsense allele, c.433C>T (p.Arg145Ter), accounts for a large fraction
    of mutant chromosomes.
  gene_term:
    preferred_term: MMAA
    term:
      id: hgnc:18871
      label: MMAA
  frequency: approximately 20% of isolated methylmalonic acidemia
  case_fractions:
  - population: Isolated methylmalonic acidemia, literature estimate
    case_fraction_percent: 20.0
    notes: >-
      Share of isolated methylmalonic acidemia attributable to cblA, quoted as an
      approximate literature figure rather than derived from a single genotyped cohort.
    evidence:
    - reference: PMID:31921599
      reference_title: Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related to MMAA mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "is responsible for approx. 20% of causes of isolated MMA (OMIM #251100)."
      explanation: States the proportion of isolated methylmalonic acidemia caused by cblA.
  variants:
  - name: c.433C>T (p.Arg145Ter)
    description: >-
      Recurrent nonsense allele on a common haplotype, reported as 43% of pathogenic
      alleles in the founding mutation survey and seen in the homozygous state in
      long-followed patients.
    evidence:
    - reference: PMID:15523652
      reference_title: Mutations in the MMAA gene in patients with the cblA disorder of vitamin B12 metabolism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "One mutation, c.433C>T (R145X), represents 43% of pathogenic alleles and a common haplotype was identified."
      explanation: Quantifies the recurrence of this allele among cblA pathogenic alleles.
    - reference: PMID:24095221
      reference_title: "Renal involvement in a patient with cobalamin A type (cblA) methylmalonic aciduria: a 42-year follow-up."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We report on a patient with a vitamin B12-responsive cobalamin A type (cblA) MMA-uria caused by a homozygous stop mutation (p.R145X) in the cobalamin A gene (MMAA)."
      explanation: Documents the same allele in the homozygous state in a molecularly confirmed cblA patient.
  - name: Missense alleles at conserved residues
    description: >-
      A minority allele class that is mechanistically the most informative. The protein is
      made and retains intrinsic GTPase activity, but cannot engage the mutase or gate
      cofactor transfer, and about a third of these alleles additionally destabilise the
      protein.
    evidence:
    - reference: PMID:28497574
      reference_title: Protein destabilization and loss of protein-protein interaction are fundamental mechanisms in cblA-type methylmalonic aciduria.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "About a third confer instability to the recombinant protein in bacterial and human expression systems."
      explanation: Quantifies the destabilising fraction among patient missense alleles tested in expression systems.
  evidence:
  - reference: PMID:12438653
    reference_title: Identification of the gene responsible for the cblA complementation group of vitamin B12-responsive methylmalonic acidemia based on analysis of prokaryotic gene arrangements.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is located on chromosome 4q31.1-2 and encodes a predicted protein of 418 aa."
    explanation: Establishes the locus and product size of MMAA.
  - reference: PMID:28497574
    reference_title: Protein destabilization and loss of protein-protein interaction are fundamental mechanisms in cblA-type methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we present 67 new patients with cblA-type MMA, identifying 19 novel mutations."
    explanation: Establishes the size of the reported patient and allele series for this gene.
biochemical:
- name: Methylmalonic acid
  presence: Increased
  context: >-
    The defining analyte. Plasma and urine concentrations are elevated but significantly
    lower in cblA than in mutase-deficient disease, and fall substantially on
    hydroxocobalamin, which makes it both the diagnostic marker and the treatment monitor.
  biomarker_term:
    preferred_term: methylmalonic acid
    term:
      id: CHEBI:30860
      label: methylmalonic acid
  readouts:
  - target: Methylmalonic Acid and Propionyl-CoA Accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Reports the systemic methylmalonate burden produced by the residual mutase block.
    evidence:
    - reference: PMID:32754920
      reference_title: "Delineating the clinical spectrum of isolated methylmalonic acidurias: cblA and mut."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Methylmalonic acidemia (MMA) levels in urine and plasma were significantly lower in cblA."
      explanation: Establishes the direction and the cblA-versus-mut contrast for this analyte.
  evidence:
  - reference: PMID:24095221
    reference_title: "Renal involvement in a patient with cobalamin A type (cblA) methylmalonic aciduria: a 42-year follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following re-evaluation, the patient received vitamin B12 (hydroxocobalamin) treatment, resulting in a significant decrease in the concentration of methylmalonic acid (MMA) in urine and plasma."
    explanation: Shows the analyte responds to cobalamin, which is what makes it the treatment-monitoring marker in cblA.
- name: Propionylcarnitine (C3)
  presence: Increased
  context: >-
    The newborn-screening analyte. Raised C3 on a dried blood spot is what flags isolated
    methylmalonic acidemia before the subtype is known; it does not distinguish cblA from
    the other forms, which is why molecular testing follows.
  biomarker_term:
    preferred_term: propionylcarnitine
    term:
      id: CHEBI:53210
      label: O-propanoyl-L-carnitine
  readouts:
  - target: Methylmalonic Acid and Propionyl-CoA Accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Reports the propionyl-CoA pool that backs up behind the mutase block.
    evidence:
    - reference: PMID:31921599
      reference_title: Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related to MMAA mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "elevated levels of propionylcarnitine (C3-carnitine) and/or methylmalonylcarnitine (C4DC-carnitine) are found"
      explanation: Names the acylcarnitine species raised in methylmalonic acidemia on tandem mass spectrometry.
- name: 2-Methylcitric acid
  presence: Increased
  context: >-
    A confirmatory urinary organic acid, formed when accumulated propionyl-CoA condenses
    with oxaloacetate. Measured alongside methylmalonic acid on the organic acid profile.
  biomarker_term:
    preferred_term: methylcitric acid
    term:
      id: CHEBI:30835
      label: 2-methylcitric acid
  readouts:
  - target: Methylmalonic Acid and Propionyl-CoA Accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Second-line marker of the same propionyl-CoA accumulation, independent of methylmalonate itself.
    evidence:
    - reference: PMID:31921599
      reference_title: Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related to MMAA mutations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "methylmalonic acid, methylcytric acid, 3-hydroxypropionic acid are primarily detected"
      explanation: Lists the urinary organic acids detected in methylmalonic acidemia, quoted verbatim including the source's spelling of methylcitric acid.
diagnosis:
- name: Molecular confirmation in MMAA
  description: >-
    Identification of biallelic pathogenic MMAA variants. Molecular testing has largely
    displaced complementation and enzymatic assays for establishing the cblA diagnosis,
    although historically the group was defined by somatic cell complementation.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:20301409
    reference_title: Isolated Methylmalonic Acidemia.
    supports: SUPPORT
    evidence_source: OTHER
    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 states that biallelic MMAA variants establish the diagnosis of isolated methylmalonic acidemia.
- name: Plasma and urine methylmalonic acid
  description: >-
    Plasma and urine methylmalonic acid support diagnosis and monitoring. A chronic, nonacute
    presentation occurred in 8/23 adults, whereas 4/23 never had an acute decompensation. Unexplained
    renal, developmental or growth findings can therefore warrant MMA testing outside a metabolic
    crisis.
  diagnosis_term:
    preferred_term: laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We confirm that about 35% of the patients do not present acutely, underlining the importance of measuring MMA in any case of unexplained chronic renal failure, intellectual disability, or growth delay."
    explanation: States the indication for measuring methylmalonic acid outside the acute setting in cblA.
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In most of the patients the symptom leading to diagnosis was acute neurologic deterioration
      (15/23, 65%). The other patients (8/23, 35%) presented with chronic problems:
    explanation: >-
      The presentation analysis explicitly separates eight chronic presentations from fifteen
      acute presentations among 23 adults; it does not measure lifetime freedom from crisis.
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      no more decompensations after the initial presentation in nine patients (39%); four patients
      (17%) had a sub‐acute presentation and never experienced an acute decompensation.
    explanation: >-
      The longitudinal analysis identifies four of 23 patients who never decompensated, separately
      from nine with no further crisis after their initial presentation. This is distinct from
      the eight patients whose presenting problems were chronic.
treatments:
- name: Parenteral hydroxocobalamin
  description: >-
    Parenteral hydroxocobalamin is the principal cblA treatment. Responsiveness was reported
    in 27/28 registry patients, but historical clinical response assessments sometimes misclassified
    patients. Pharmacologic cobalamin can improve cofactor availability and cellular pathway
    flux; a mass-action bypass of one specific MMAA step is not established for every genotype.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: hydroxocobalamin
      term:
        id: CHEBI:27786
        label: hydroxocobalamin
  target_mechanisms:
  - target: Failure of Adenosylcobalamin Gating onto Methylmalonyl-CoA Mutase
    description: >-
      Improving cobalamin availability can restore deficient adenosylcobalamin-dependent function
      despite the MMAA defect; the exact rescue route is not established for each allele.
    evidence:
    - reference: PMID:27858373
      reference_title: Vitamin B(12) Administration by Subcutaneous Catheter Device in a Cobalamin A (cblA) Patient.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Hydroxocobalamin (OHCbl) is the cornerstone of cblA treatment because vitamin B12 may completely restore AdoCbl deficiency."
      explanation: States the mechanism by which hydroxocobalamin acts on the adenosylcobalamin supply defect in cblA.
  evidence:
  - reference: PMID:32754920
    reference_title: "Delineating the clinical spectrum of isolated methylmalonic acidurias: cblA and mut."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "27/28 cblA patients were reported to be responsive to cobalamin, only 86% of cblA patients were treated with i.m. hydroxocobalamin."
    explanation: Quantifies cobalamin responsiveness in the cblA arm of the registry and shows a treatment gap against it.
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Most of the patients (61%) were initially classified as vitamin B12-unresponsive methylmalonic aciduria (MMA); in vitro B12 responsiveness was subsequently found in all the tested patients (n = 13)."
    explanation: >-
      Thirteen tested fibroblast lines were responsive in vitro, including patients previously
      classified clinically as unresponsive; in vitro responsiveness does not invariably predict
      clinical response.
  - reference: PMID:27858373
    reference_title: Vitamin B(12) Administration by Subcutaneous Catheter Device in a Cobalamin A (cblA) Patient.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Parenteral administration, intravenous, subcutaneous or intramuscular, is generally required to achieve effect."
    explanation: Establishes the route requirement for effective cobalamin therapy in cblA.
  - reference: PMID:31921599
    reference_title: Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related to MMAA mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with a mutation in the MMAA gene are sensitive to treatment with hydroxocobalamine, but the inclusion of appropriate treatment does not protect against neurodevelopmental disorders and chronic kidney disease."
    explanation: >-
      All five patients were responsive but had cognitive impairment and three had CKD. This
      uncontrolled cohort demonstrates residual morbidity, not absence of treatment benefit.
- name: Early cobalamin replacement for renal protection
  description: >-
    Early B12 treatment was associated with less severe renal disease in a retrospective series
    of adults. The initial-treatment comparison included 22 childhood-onset patients; 1/7 initially
    treated with B12 developed late moderate renal failure. Small groups, historical treatment
    variability and survivor selection prevent a causal estimate or exclusion of neurodevelopmental
    benefit.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: hydroxocobalamin
      term:
        id: CHEBI:27786
        label: hydroxocobalamin
  target_mechanisms:
  - target: Renal Tubulointerstitial Injury
    description: >-
      Lowering the lifetime methylmalonate burden is the proposed route by which early
      replacement slows progression of tubulointerstitial disease.
    evidence:
    - reference: PMID:35618652
      reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Intellectual disability was equally distributed among the initial treatment groups, while renal failure (moderate and beginning at the age of 38 years) was present in only one out of seven patients initially treated with B12."
      explanation: >-
        Observational comparison among initial-treatment groups; similar cognitive outcomes
        do not establish absence of neurological benefit.
  evidence:
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early B12 supplementation seems to protect from severe renal insufficiency."
    explanation: The authors' own hedged statement of the renal-protection effect, quoted with its hedge intact.
  - reference: PMID:24095221
    reference_title: "Renal involvement in a patient with cobalamin A type (cblA) methylmalonic aciduria: a 42-year follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further investigation will be necessary to prove the protective effect of hydroxocobalamin in the kidney in vitamin B12-responsive patients."
    explanation: An explicit statement that the renal protective effect is not yet proven, recorded here so the claim is not overstated.
- name: Natural protein restriction with propiogenic precursor limitation
  description: >-
    Restriction of natural protein, particularly the propiogenic amino acid precursors, on
    a high-calorie diet. Used in about three-quarters of cblA patients, notably less than
    in mut-type disease, reflecting the lesser metabolite burden.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Methylmalonic Acid and Propionyl-CoA Accumulation
    description: >-
      Limiting propiogenic substrate entry reduces the flux that the residual mutase
      capacity must handle.
    evidence:
    - reference: PMID:20301409
      reference_title: Isolated Methylmalonic Acidemia.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        restrict natural protein, particularly of propiogenic amino acid precursors, while maintaining
        a high-calorie diet
      explanation: States the dietary principle in propiogenic precursor terms.
  evidence:
  - reference: PMID:32754920
    reference_title: "Delineating the clinical spectrum of isolated methylmalonic acidurias: cblA and mut."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In total, 73% of cblA and 98% of mut patients followed a calculated diet with amino acid supplements in 27% (cblA) and 69% (mut)."
    explanation: Quantifies dietary treatment uptake specifically in the cblA arm against the mut arm.
- name: Emergency management of acute decompensation
  description: >-
    Anticatabolic emergency treatment during metabolic crisis, aimed at averting catabolism
    and limiting central nervous system injury, together with avoidance of the fasting,
    stress and protein-load precipitants. This applies to cblA as to the other isolated
    methylmalonic acidemias, since metabolic crisis remains the dominant presenting event.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Acute Metabolic Decompensation
    description: >-
      Reversing the catabolic state removes the substrate load that precipitated the
      crisis.
    evidence:
    - reference: PMID:20301409
      reference_title: Isolated Methylmalonic Acidemia.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        provide emergency treatment during episodes of acute decompensation with the goal of
        averting catabolism and minimizing central nervous system injury.
      explanation: States the goal of emergency management in terms of the decompensation mechanism it targets.
  evidence:
  - reference: PMID:20301409
    reference_title: Isolated Methylmalonic Acidemia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Agents/circumstances to avoid: Fasting, stress, increased dietary protein,"
    explanation: Lists the precipitants to avoid, which is the preventive half of decompensation management.
- name: L-carnitine supplementation
  description: >-
    Carnitine supplementation supports excretion of acyl groups and replaces deficient free
    carnitine. All five Polish patients received it; treatment is monitored using serum concentrations.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: L-carnitine
      term:
        id: CHEBI:16347
        label: (R)-carnitine
  target_mechanisms:
  - target: Methylmalonic Acid and Propionyl-CoA Accumulation
    description: >-
      Conjugation of the accumulated propionyl-CoA to an excretable acylcarnitine drains
      the pool that builds up behind the mutase block.
    evidence:
    - reference: PMID:20301409
      reference_title: Isolated Methylmalonic Acidemia.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "provide supplemental carnitine to those with\ncarnitine deficiency"
      explanation: GeneReviews states the indication for carnitine supplementation in isolated methylmalonic acidemia.
  evidence:
  - reference: PMID:31921599
    reference_title: Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related to MMAA mutations.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It is also recommended to supplement l-carnitine under control of its serum concentration"
    explanation: States that carnitine is given under serum-level control, in a paper whose entire cohort is MMAA-genotyped.
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional medications included L‐ carnitine, neomycin and metronidazole."
    explanation: Records carnitine among the medications actually used in an adult cblA-only cohort.
- name: Gut decontamination to reduce propionate production
  description: >-
    Intermittent antibiotic decontamination of the gut, typically with metronidazole or
    neomycin, to suppress the anaerobic flora that produce propionate. This targets a
    substrate source that dietary protein restriction does not reach.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: metronidazole
      term:
        id: CHEBI:6909
        label: metronidazole
    - preferred_term: neomycin
      term:
        id: CHEBI:7507
        label: neomycin
  target_mechanisms:
  - target: Methylmalonic Acid and Propionyl-CoA Accumulation
    description: >-
      Gut flora are a substrate source independent of dietary intake, so suppressing them
      lowers the propiogenic load reaching the blocked pathway.
    evidence:
    - reference: PMID:20301409
      reference_title: Isolated Methylmalonic Acidemia.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "reduce propionate production from gut flora"
      explanation: States the mechanism by which gut decontamination acts on the substrate load.
  evidence:
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional medications included L‐ carnitine, neomycin and metronidazole."
    explanation: Names the two decontamination antibiotics actually used in an adult cblA-only cohort.
- name: Liver or kidney transplantation
  description: >-
    Liver and/or kidney transplantation may be considered in isolated MMA with severe metabolic
    instability or renal failure. cblA-specific reports document kidney transplantation, including
    one patient transplanted at age 35 and followed for six years under continued hydroxocobalamin.
    These observations do not establish a cblA-specific liver-transplant benefit.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  target_mechanisms:
  - target: Renal Tubulointerstitial Injury
    description: >-
      Kidney transplantation replaces the failing organ without correcting MMAA deficiency elsewhere.
      Preserved graft function under continued B12 in one case does not prove that B12 alone
      protected the graft.
    evidence:
    - reference: PMID:24095221
      reference_title: "Renal involvement in a patient with cobalamin A type (cblA) methylmalonic aciduria: a 42-year follow-up."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The patient received a renal transplant at age 35 years."
      explanation: Documents renal transplantation in a molecularly confirmed cblA patient.
  evidence:
  - reference: PMID:20301409
    reference_title: Isolated Methylmalonic Acidemia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In those with\nsignificant metabolic instability and/or renal failure, liver and/or renal\ntransplantation may be considered."
    explanation: States the indication for transplantation in isolated methylmalonic acidemia.
  - reference: PMID:24095221
    reference_title: "Renal involvement in a patient with cobalamin A type (cblA) methylmalonic aciduria: a 42-year follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Under continuous treatment with hydroxocobalamin there is no evidence of kidney damage due to MMA-uria until the last follow-up 6 years after transplantation."
    explanation: Shows the graft outcome under continued cobalamin therapy, which is the reason the metabolic treatment is not stopped after transplantation.
differential_diagnoses:
- name: Methylmalonyl-CoA mutase deficiency (mut-type isolated methylmalonic acidemia)
  disease_term:
    preferred_term: methylmalonic acidemia
    term:
      id: MONDO:0002012
      label: methylmalonic acidemia
  description: >-
    The other, and commoner, cause of isolated methylmalonic acidemia, curated as
    `kb/disorders/Methylmalonic_Acidemia.yaml`. The biochemical presentation at first
    crisis is essentially the same and the age at diagnosis is similar, so the two are
    separated by genotype and by cobalamin responsiveness rather than at the bedside.
  distinguishing_features:
  - Near-universal cobalamin responsiveness in cblA, against a much lower rate in mut-type disease and none in mut0.
  - Significantly lower plasma and urine methylmalonic acid in cblA.
  - Better preserved glomerular filtration rate and less frequent chronic renal failure in cblA.
  - Neurological complications predominate in the mut subgroup on direct comparison.
  - The lesion in cblA is in cofactor delivery to a structurally intact mutase, whereas in mut-type disease the mutase apoenzyme itself is deficient.
  evidence:
  - reference: PMID:32754920
    reference_title: "Delineating the clinical spectrum of isolated methylmalonic acidurias: cblA and mut."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although similar at first, cblA patients respond to hydroxocobalamin treatment, subsequently show significantly lower levels of MMA and a milder course than mut patients."
    explanation: The registry study's own summary of how the two entities diverge after presentation.
- name: cblB type methylmalonic aciduria (MMAB deficiency)
  description: >-
    The other adenosylcobalamin-synthesis defect causing isolated methylmalonic acidemia,
    caused by biallelic MMAB variants and covered within
    `kb/disorders/Methylmalonic_Acidemia.yaml`. cblB affects the adenosyltransferase that
    makes adenosylcobalamin, whereas cblA affects the G-protein that delivers and
    maintains it, and the clinical courses differ sharply despite the shared pathway.
  distinguishing_features:
  - cblB patients have an earlier onset, more complications and deaths, and higher urinary methylmalonic acid than cblA patients.
  - Chronic renal failure is common in cblB and relatively spared in cblA.
  - Cobalamin responsiveness is the rule in cblA and only occasional in cblB.
  - MONDO keeps the two as separate terms with separate OMIM anchors and separate causal genes, MMAA with OMIM:251100 for cblA and MMAB with OMIM:251110 for cblB.
  evidence:
  - reference: PMID:17597648
    reference_title: "Long-term outcome in methylmalonic acidurias is influenced by the underlying defect (mut0, mut-, cblA, cblB)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, patients with mut0 and cblB defects had an earlier onset of symptoms, a higher frequency of complications and deaths, and a more pronounced urinary excretion of MMA than those with mut- and cblA defects."
    explanation: The four-way comparison that places cblB with mut0 at the severe end and cblA at the attenuated end. This is a mixed cohort of 83 patients of which only 20 were cblA, so the statement is a between-group contrast and not a cblA-specific rate.
  - reference: PMID:17597648
    reference_title: "Long-term outcome in methylmalonic acidurias is influenced by the underlying defect (mut0, mut-, cblA, cblB)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chronic renal failure (CRF) was found most frequently in mut0 (61%) and cblB patients (66%), and was predicted by the urinary excretion of methylmalonic acid (MMA) before CRF."
    explanation: The renal-failure percentages quoted here belong to the mut0 and cblB subgroups, not to cblA. They are recorded to bound the renal claim rather than to describe cblA.
- name: cblD-MMA (MMADHC deficiency, methylmalonic aciduria form)
  description: >-
    MMADHC defects can cause isolated MMA (cblD-MMA) or combined methylmalonic aciduria and
    homocystinuria. MMAA deficiency affects the adenosylcobalamin pathway; an elevated homocysteine
    result warrants investigation for a combined disorder or a secondary cause and is not by
    itself a genotype exclusion.
  distinguishing_features:
  - Distinguished by gene, MMADHC versus MMAA, since the isolated-MMA biochemical phenotype is shared.
  - MMADHC variants elsewhere in the gene give isolated homocystinuria or combined disease, a positional allelic spectrum that MMAA does not show.
  - cblA has no homocysteine arm at all, so any hyperhomocysteinemia excludes it.
  evidence:
  - reference: PMID:20301409
    reference_title: Isolated Methylmalonic Acidemia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "synthesis of its cofactor, 5-deoxy-adenosyl-cobalamin (cblA, cblB, or cblD-MMA),"
    explanation: Groups cblA, cblB and cblD-MMA as the cofactor-side causes of isolated methylmalonic acidemia that must be distinguished from one another.
- name: cblH
  description: >-
    A complementation class defined out of the cblA cohort itself. A patient with the
    clinical and biochemical phenotype of cblA whose fibroblasts complemented all cblA
    lines was assigned to a new class, cblH, before MMAA was cloned. The episode is why a
    cblA-like biochemical phenotype is not by itself a cblA diagnosis.
  distinguishing_features:
  - Defined by somatic cell complementation rather than by biochemistry, which cannot separate it from cblA.
  - Requires molecular testing to resolve, since MMAA sequencing is normal.
  evidence:
  - reference: PMID:10882753
    reference_title: "Complementation studies in the cblA class of inborn error of cobalamin metabolism: evidence for interallelic complementation and for a new complementation class (cblH)."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These results strongly suggest that the cblA variant represents a novel complementation class, which we have designated cblH and which represents a mutation at a distinct gene."
    explanation: Documents that a patient meeting the clinical and biochemical definition of cblA carried a defect at a different locus.
external_assertions:
- name: Orphanet nosology record for cblA
  source: Orphanet
  assertion_type: structured_subtype_record
  external_id: ORPHA:79310
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=79310
  description: >-
    Orphanet classifies cblA as a clinical subtype rather than a disorder in its own
    right, and its cross-reference table is the authority for the identity of this entity
    across MONDO, OMIM and the ICD systems. Two things in that table are worth recording.
    The MONDO and OMIM mappings are exact, which confirms the disease_term binding used
    here. The ICD-10 and ICD-11 mappings are both Narrower, meaning cblA sits beneath a
    broader code rather than carrying one of its own, so there is no cblA-specific ICD
    code to record. That is the coding-level counterpart of the under-recognition problem
    described in this entry.
  evidence:
  - reference: ORPHA:79310
    reference_title: Vitamin B12-responsive methylmalonic acidemia type cblA
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0009613 | Exact"
    explanation: Orphanet asserts an exact mapping between ORPHA:79310 and the MONDO term bound as this entry's disease_term.
  - reference: ORPHA:79310
    reference_title: Vitamin B12-responsive methylmalonic acidemia type cblA
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ICD-10:E71.1 | Narrower"
    explanation: The ICD-10 mapping is narrower rather than exact, which is the basis for stating that cblA has no ICD code of its own.
  notes: >-
    Generated with `just structured-rebuild-orphanet --id 79310`. The cached record
    carries the nosology and cross-reference sections only, without the definition,
    phenotype or epidemiology sections, because `just refresh-orphadata` aborted on a
    checksum mismatch after downloading en_product1.xml and before fetching the
    en_product4, en_product6 and en_product9_prev bulk files that supply those sections.
    No Orphanet prevalence class was therefore available for this entity.
discussions:
- discussion_id: cbla_no_published_animal_model
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is there an animal model of cblA that reproduces the human disease, and what would it
    take to establish one?
  attaches_to:
  - pathophysiology#Reduced Methylmalonyl-CoA Mutase Holoenzyme Activity
  rationale: >-
    This entry curates no animal models because no published study characterises an
    Mmaa-deficient animal as a model of cblA methylmalonic aciduria. That is a statement
    about the literature, not about the reagents. A constitutive null allele does exist,
    Mmaa em1(IMPC)J, MGI:5825155, produced by the International Mouse Phenotyping
    Consortium, and MGI records abnormal phenotype annotations for it across adipose,
    cardiovascular, growth, haematopoietic, homeostasis and skeletal systems. MGI attaches
    no human disease model assertion to that allele, no publication describes its
    metabolic phenotype, and consortium phenotype annotations are not a citable quoted
    finding of the kind this knowledge base requires for an evidence item, so the allele
    is recorded here rather than curated as a model. The published rodent work on Mmaa is
    a developmental expression survey of Mmaa, Mmab and Mut during mouse organogenesis
    rather than a disease model, and the established mouse models of methylmalonic
    acidemia are mutase-deficient. The gap matters because the two arms of MMAA function
    that human biochemistry has separated, cofactor gating and cofactor repair, cannot be
    separated pharmacologically in patients, and an animal in which they could be
    dissociated is the obvious way to ask which one sets the residual mutase activity that
    determines cobalamin responsiveness.
- discussion_id: cbla_residual_renal_disease_on_treatment
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why does chronic kidney disease still develop in cblA patients whose methylmalonate is
    well controlled on cobalamin?
  attaches_to:
  - pathophysiology#Renal Tubulointerstitial Injury
  rationale: >-
    Renal mitochondrial dysfunction is represented as a hypothesis, with a causal path to tubulointerstitial
    injury and CKD. cblA-specific mediation remains unproven: incomplete metabolite control,
    damage before treatment and tissue mitochondrial dysfunction may contribute. The adult series
    was retrospective and included variable initial treatment; the Polish series used cystatin
    C to identify CKD. Neither cohort establishes why renal disease persists in a particular
    well-controlled patient. The full 2022 severe-case biopsy account localizes disease to the
    tubulointerstitium with glomerulosclerosis, without specifying proximal epithelial cells;
    the accessible 2013 biopsy abstract likewise reports nonspecific interstitial inflammation.
    A later biomarker study found no elevated urinary markers in five genetically confirmed
    cblA patients sampled while well, all with normal cystatin C. That small, preserved-function
    subgroup neither demonstrates proximal-cell injury nor excludes it in cblA patients with CKD.
  evidence:
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This is also in line with the pathophysiological hypotheses suggesting that chronic kidney
      disease is more directly linked to MMA toxicity, while brain involvement seems to be more
      complex and related partially to acute decompensation and energy deficit, and partially
      to de novo synthesis and trapping of toxic metabolites in brain tissue.
    explanation: >-
      The cblA cohort discussion proposes organ-injury routes; these are hypotheses, not measured
      causal mediation.
    directness: INDIRECT
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1231/
    reference_title: Isolated Methylmalonic Acidemia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Secondary mitochondrial dysfunction rather than direct nephrotoxicity of methylmalonic
      acid is hypothesized as the cause for renal disease
    explanation: >-
      GeneReviews presents a mechanistic hypothesis across isolated MMA; subtype-specific renal
      confirmation is lacking.
    directness: INDIRECT
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A renal biopsy was performed at the age of 14 years, and showed tubulo‐interstitial
      nephropathy with glomerulosclerosis compatible with MMA.
    explanation: >-
      The severe homozygous MMAA p.Ala196* case had this tissue lesion; the report does not
      identify the injured nephron segment or a proximal epithelial-cell mechanism.
  - reference: PMID:37603032
    reference_title: Kidney urinary biomarkers in patients with branched-chain amino acid and cobalamin metabolism defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      B2MG, was elevated in all three diseases, and correlated with DKK-3 in Mut0/CblA and with
      eGFR(CysC) and KIM-1 in PA patients, respectively. None of the markers were elevated in
      CblA patients.
    explanation: >-
      The abstract contrasts cblA with Mut0, PA and cblC. The full study included five genetically
      confirmed cblA patients sampled in well-state, all with normal cystatin C; the absence
      of elevated markers in this small subgroup cannot exclude proximal injury in cblA with CKD.
- discussion_id: cbla_neurologic_attribution
  kind: KNOWLEDGE_GAP
  prompt: Which mechanisms account for these cblA findings in the reported patients?
  attaches_to:
  - phenotypes#Hypotonia
  - phenotypes#Seizure
  - phenotypes#Ataxia
  - phenotypes#Developmental regression
  - phenotypes#Spasticity
  - phenotypes#Diminished ability to concentrate
  rationale: >-
    The reviewed sources establish these findings in cblA, but do not establish a finding-specific
    path from the modeled brain or basal-ganglia injury in the reported individuals. Acute toxicity,
    chronic brain metabolism, prior injury and other contributors may differ; the severe-case
    co-occurrence alone does not determine mediation. Basal-ganglia causation is represented
    for extrapyramidal movement disorders where the source explicitly supports it.
  evidence:
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This is also in line with the pathophysiological hypotheses suggesting that chronic kidney
      disease is more directly linked to MMA toxicity, while brain involvement seems to be more
      complex and related partially to acute decompensation and energy deficit, and partially
      to de novo synthesis and trapping of toxic metabolites in brain tissue.
    explanation: >-
      The cblA cohort discussion proposes organ-injury routes; these are hypotheses, not measured
      causal mediation.
    directness: INDIRECT
- discussion_id: cbla_optic_and_imaging_mechanisms
  kind: KNOWLEDGE_GAP
  prompt: Which mechanisms account for these cblA findings in the reported patients?
  attaches_to:
  - phenotypes#Optic atrophy
  - phenotypes#Cerebral atrophy
  - phenotypes#Ventriculomegaly
  rationale: >-
    Optic atrophy causes visual impairment in the reported cblA patient, but the liver OXPHOS
    defect does not establish an optic-nerve mechanism. Cerebral atrophy and ventricular dilatation
    co-occur in the Polish cohort; ex-vacuo ventricular enlargement is plausible but not demonstrated.
    The predominantly normal or nonspecific adult imaging and absent lesion-outcome correlation
    preclude assigning every image to a single causal route.
  evidence:
  - reference: PMID:19277894
    reference_title: >-
      Multiple OXPHOS deficiency in the liver of a patient with CblA methylmalonic aciduria
      sensitive to vitamin B(12).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An adult patient with methylmalonic aciduria due to defective cobalamin synthesis (CblA)
      responsive to vitamin B(12) presented suddenly with severe visual impairment ascribed
      to optic atrophy followed by a fatal multiorgan failure and lactic acidosis but low methylmalonic
      acid in plasma and urine.
    explanation: >-
      The case establishes optic atrophy with visual loss despite low contemporaneous MMA. The reported OXPHOS defect was in liver, so it does not establish the upstream optic-nerve lesion.
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two patients showed basal ganglia signal changes, but these did not correlate with their
      neurological examination, which was normal, or with cognitive function, normal as well.
    explanation: The cblA cohort illustrates limitations of attributing clinical deficits to
      imaging abnormalities.
- discussion_id: cbla_systemic_attribution
  kind: KNOWLEDGE_GAP
  prompt: Which mechanisms account for these cblA findings in the reported patients?
  attaches_to:
  - phenotypes#Feeding difficulties
  - phenotypes#Hyperuricemia
  - phenotypes#Dehydration
  - phenotypes#Hypothermia
  - phenotypes#Hyperglycemia
  - phenotypes#Ketonuria
  - phenotypes#Elevated circulating hepatic transaminase concentration
  - phenotypes#Osteopenia
  - phenotypes#Vomiting
  rationale: >-
    Vomiting, feeding problems and constitutional or laboratory abnormalities are observed during
    cblA illness, but the available sources often establish association rather than a specific
    causal route. Hyperuricemia and osteopenia may reflect kidney disease or other factors;
    hyperglycemia, ketonuria and transaminase elevations were not mechanistically characterized.
    A direct liver OXPHOS result in a different cblA case does not establish the cause of the
    Polish cohort’s transaminase elevations. The represented nutritional growth, osteoporosis
    and renal-anemia pathways retain alternative contributors; the remaining gaps concern causal
    attribution rather than an absence of these biological hypotheses.
  evidence:
  - reference: PMID:31921599
    reference_title: >-
      Clinical picture and treatment effects in 5 patients with Methylmalonic aciduria related
      to MMAA mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, more than half of the patients had anemia, hyperglycemia and ketonuria.
    explanation: >-
      Observed at diagnosis in the five-patient cblA cohort; exact individual counts are not
      supplied in this sentence.
  - reference: PMID:34915869
    reference_title: >-
      Genetic testing is necessary for correct diagnosis and treatment in patients with isolated
      methylmalonic aciduria: a case report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On the fourth postnatal day, she developed apathy, hypothermia, and dehydration with metabolic
      acidosis and hyperammonaemia (1,601 μmol/L).
    explanation: The clinical history is patient 2 with homozygous MMAA p.Leu89Pro.
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bone densitometry was performed in 9 patients and was abnormal in 5 of them with osteoporosis
      (n = 2) or osteopenia (n = 3).
    explanation: The denominator is nine tested adults, not all 23; selection for densitometry
      may affect the proportion.
- discussion_id: cbla_cardiac_conduction_attribution
  kind: KNOWLEDGE_GAP
  prompt: What caused conduction and repolarization abnormalities in the severe cblA case?
  attaches_to:
  - phenotypes#Atrioventricular block
  - phenotypes#Prolonged QT interval
  rationale: >-
    Renal disease, electrolyte imbalance and myocardial dysfunction could contribute, but the
    historical case lacks the data needed to assign a particular mechanism. The source explicitly
    proposes a renal contribution to hypertrophy, which is represented; it does not make an
    equivalent causal attribution for the block or QT prolongation.
  evidence:
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He developed intellectual disability, ataxia, epilepsy, and renal insufficiency (since
      the age of 11 years) with arterial hypertension, cardiac left hypertrophy and cardiac
      rhythm anomalies (atrioventricular block, long QT at the age of 15 years).
    explanation: >-
      The severe homozygous MMAA p.Ala196* case had these cardiac rhythm abnormalities; neither
      the degree of block nor a corrected QT interval was specified.
- discussion_id: cbla_adult_constitutional_symptom_scope
  kind: KNOWLEDGE_GAP
  prompt: >-
    How much of the adult-onset constitutional presentation was attributable to MMAA deficiency
    versus concurrent low vitamin B12?
  attaches_to:
  - pathophysiology#Reduced Methylmalonyl-CoA Mutase Holoenzyme Activity
  rationale: >-
    One molecularly and functionally confirmed adult had fatigue, myalgia, exercise intolerance,
    headache and nausea after a flu-like illness, with concurrent low serum B12. Symptoms resolved
    after intensive B12 while MMA remained elevated. These observations support a possible attenuated
    presentation but do not separate MMAA-dependent symptoms from acquired B12 deficiency or
    another contributor; they are not generalized as characteristic cblA phenotypes.
  evidence:
  - reference: PMID:35618652
    reference_title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After treatment with B12 up to 1 mg IM daily her chronic symptoms completely disappeared;
      plasma B12 level normalized although MMA remained elevated (8 μmol/L).
    explanation: Clinical response in the described adult cblA patient, whose pretreatment serum
      B12 was also low.
notes: >-
  Entity verification. MONDO:0009613 was resolved with OAK before this entry was written.
  Its definition is "An autosomal recessive form of methylmalonic aciduria, caused by
  mutation(s) in the MMAA gene, encoding MMAA protein", it carries the relationship
  RO:0004003 HGNC:18871 MMAA, its single superclass is MONDO:0017214 (vitamin
  B12-responsive methylmalonic acidemia), and it xrefs OMIM:251100, Orphanet:79310,
  DOID:0060742, MEDGEN:344422 and NCIT:C142171. This matches the gene recorded in
  stubs/Methylmalonic_Aciduria_cblA_Type.yaml.

  One MONDO synonym on this term is wrong and has deliberately not been copied into the
  synonyms list. MONDO:0009613 carries "cobalamin B disease" as an EXACT synonym.
  Cobalamin B disease is cblB, the MMAB disorder, which is a different complementation
  group with a different gene and a different OMIM anchor, OMIM:251110. The curation stub
  inherited the same error as "cblB - cobalamin locus b". Propagating it into this entry
  would defeat the entity separation the entry exists to make, so the synonym list here
  carries only cblA designations. This is worth reporting upstream to MONDO but is not
  fixed by this pull request.

  Scope, and the relationship to the two entries that already mention cblA. cblA was
  listed in two places in this knowledge base before this entry and curated in neither.
  kb/disorders/Methylmalonic_Acidemia.yaml carries a genetic record "MMAA (cblA
  complementation group)" with two sentences of features prose and evidence consisting of
  a single review sentence that merely names cblA. It has no cblA pathophysiology node, no
  MMAA mechanism, and its two has_subtypes entries are biochemical response classes
  spanning three genotypes rather than complementation groups.
  kb/disorders/Inborn_Disorder_of_Cobalamin_Metabolism_and_Transport.yaml carries a
  has_subtypes entry "cblA" with a three-line description, no bound disease term and no
  evidence. Neither file carries MONDO:0009613. Both were read and neither was modified by
  this pull request, exactly as the cblD entry left the same two files alone when it was
  created. That cblD precedent establishes that a complementation group may be listed as a
  has_subtypes line on the group umbrella and simultaneously carry its own Disease entry.

  Named Entity Confusion preflight. The risk for this entity is not that the literature is
  about a different gene but that it is about a different methylmalonic acidemia. Two
  further hazards are specific to the string cblA, which is also the name of a Burkholderia
  cepacia cable-pilus adhesin gene (PMID:11896764, PMID:12427939) and an unrelated
  engineering acronym (PMID:34710427, PMID:39182974). None of these were used. Every
  clinical source cited here was checked for the composition of its study population.
  PMID:32754920, PMID:35618652 and PMID:31921599 are cblA-specific or report cblA as a
  separately analysed arm, and are the backbone of the clinical claims. PMID:17597648 and
  PMID:17957493 are mixed cohorts spanning mut0, mut-, cblA and cblB. They are cited only
  for between-group contrasts, and where a percentage in the quoted sentence belongs to a
  non-cblA subgroup the explanation says so explicitly rather than letting the number read
  as a cblA rate. No cohort-wide statistic from a mixed series has been attributed to cblA
  anywhere in this entry.

  Evidence-source grading convention, applied consistently throughout this file.
  Measurements made on patients or patient material and reported as findings about those
  patients, including diagnostic enzymology and biopsy histology, are graded
  HUMAN_CLINICAL. Experiments performed on cultured cells or purified proteins to test a
  mechanism, including somatic cell complementation, recombinant protein biochemistry,
  crystallography and transcript-stability assays, are graded IN_VITRO. Papers that report
  both, notably PMID:28497574 and PMID:17957493, have their evidence split into separate
  items so each carries a single grade. GeneReviews is graded OTHER, matching the
  treatment of the sibling GeneReviews chapter in
  kb/disorders/MMADHC-related_Disorder_of_Cobalamin_Metabolism_cblD_Type.yaml.

  Not curated, and why. The Orphanet record ORPHA:79310 is cited under
  external_assertions, but only partially. just refresh-orphadata aborts on a checksum
  mismatch: the upstream en_product1.xml no longer matches the sha256 pinned in
  data/orphadata/MANIFEST.yaml. It downloads that file before failing, which is enough
  for just structured-rebuild-orphanet --id 79310 to generate a valid nosology and
  cross-reference record, and that is what is committed here. It is not enough for the
  definition, phenotype and epidemiology sections, which come from the en_product4,
  en_product6 and en_product9_prev bulk files that the aborted run never fetched. So no
  Orphanet prevalence class or HPO frequency table was available. Repinning the manifest
  would rewrite every committed ORPHA cache file and does not belong in a curation pull
  request; the stale pin is reported instead. Note also that just fetch-reference
  ORPHA:79310 does not work and reports "No source found for reference type" -
  structured-rebuild-orphanet is the path for this prefix. No animal models are curated,
  for the reasons set out in the first knowledge gap. No prevalence rate is recorded
  because none specific to cblA has been published.
references:
- reference: PMID:20301409
  title: Isolated Methylmalonic Acidemia.
  tags:
  - GeneReviews
- reference: PMID:12438653
  title: Identification of the gene responsible for the cblA complementation group of vitamin B12-responsive methylmalonic acidemia based on analysis of prokaryotic gene arrangements.
- reference: PMID:28497574
  title: Protein destabilization and loss of protein-protein interaction are fundamental mechanisms in cblA-type methylmalonic aciduria.
- reference: PMID:32754920
  title: "Delineating the clinical spectrum of isolated methylmalonic acidurias: cblA and mut."
- reference: PMID:35618652
  title: Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.
- reference: PMID:19955418
  title: A G-protein editor gates coenzyme B12 loading and is corrupted in methylmalonic aciduria.
- reference: PMID:37468522
  title: Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B(12) delivery and repair.
- reference: ORPHA:79310
  title: Vitamin B12-responsive methylmalonic acidemia type cblA
- reference: PMID:34915869
  title: >-
    Genetic testing is necessary for correct diagnosis and treatment in patients with isolated
    methylmalonic aciduria: a case report.
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1231/
  title: Isolated Methylmalonic Acidemia - GeneReviews® - NCBI Bookshelf
- reference: PMID:500823
  title: >-
    Inhibition by propionyl-coenzyme A of N-acetylglutamate synthetase in rat liver mitochondria.
    A possible explanation for hyperammonemia in propionic and methylmalonic acidemia.
- reference: PMID:37603032
  title: Kidney urinary biomarkers in patients with branched-chain amino acid and cobalamin metabolism defects.

📚

References & Deep Research

References

12

PMID:20301409

Isolated Methylmalonic Acidemia.

No top-level findings curated for this source.

PMID:12438653

Identification of the gene responsible for the cblA complementation group of vitamin B12-responsive methylmalonic acidemia based on analysis of prokaryotic gene arrangements.

No top-level findings curated for this source.

PMID:28497574

Protein destabilization and loss of protein-protein interaction are fundamental mechanisms in cblA-type methylmalonic aciduria.

No top-level findings curated for this source.

PMID:32754920

Delineating the clinical spectrum of isolated methylmalonic acidurias: cblA and mut.

No top-level findings curated for this source.

PMID:35618652

Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.

No top-level findings curated for this source.

PMID:19955418

A G-protein editor gates coenzyme B12 loading and is corrupted in methylmalonic aciduria.

No top-level findings curated for this source.

PMID:37468522

Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B(12) delivery and repair.

No top-level findings curated for this source.

ORPHA:79310

Vitamin B12-responsive methylmalonic acidemia type cblA

No top-level findings curated for this source.

PMID:34915869

Genetic testing is necessary for correct diagnosis and treatment in patients with isolated methylmalonic aciduria: a case report.

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/books/NBK1231/

Isolated Methylmalonic Acidemia - GeneReviews® - NCBI Bookshelf

No top-level findings curated for this source.

PMID:500823

Inhibition by propionyl-coenzyme A of N-acetylglutamate synthetase in rat liver mitochondria. A possible explanation for hyperammonemia in propionic and methylmalonic acidemia.

No top-level findings curated for this source.

PMID:37603032

Kidney urinary biomarkers in patients with branched-chain amino acid and cobalamin metabolism defects.

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 Characteristics Research Template

Edison Scientific Literature 34 citations 2026-08-31T10:25:04.238337

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

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

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

Disease Characteristics Research Template

Target Disease

Disease Name: Methylmalonic Aciduria, cblA Type
MONDO ID: MONDO:0009613 (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Methylmalonic Aciduria, cblA Type covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive research report: Methylmalonic aciduria, cblA type

Executive summary and scope

Methylmalonic aciduria, cblA type is an autosomal-recessive, usually hydroxocobalamin-responsive form of isolated methylmalonic acidemia/aciduria caused by biallelic pathogenic variants in MMAA. A critical nomenclature point is that MMAA causes cblA, whereas MMAB causes cblB; the latter should not be assigned to MONDO:0009613. The best subtype-specific natural-history evidence is a multinational registry cohort of 28 cblA patients. It found 27/28 to be cobalamin responsive, relatively preserved neurologic and renal function, and survival of all 28 during observation. Nevertheless, neonatal metabolic crises, severe acidosis, and hyperammonemia can occur, so early diagnosis and sustained parenteral hydroxocobalamin remain important. (horster2021delineatingtheclinical pages 1-2, brennerova2021genetictestingis pages 1-2)

The compact knowledge-base summary below precedes the detailed report.

Topic	Compact knowledge-base entry
Identity	Methylmalonic aciduria, cblA type is an isolated methylmalonic aciduria/acidemia due to defective intracellular cobalamin handling for mitochondrial methylmalonyl-CoA mutase function. Important correction: MMAA causes cblA, whereas MMAB causes cblB. Suggested ontology: MONDO:0009613; Orphanet:79310; HPO parent phenotype Methylmalonic aciduria HP:0012120. Evidence is from aggregated disease resources and patient cohorts, not EHR-only datasets. (OpenTargets Search: methylmalonic aciduria cblA type-MMAB, horster2021delineatingtheclinical pages 1-2, brennerova2021genetictestingis pages 1-2)
Causal gene	MMAA (methylmalonic aciduria type A gene); disease is caused by biallelic germline pathogenic variants in MMAA, located on chromosome 4q31.21. Common reported cblA alleles in the 28-patient registry study were *c.433C>T (p.Arg145) and c.592_595delACTG (p.Thr198Serfs6); four novel variants were also reported there. MMAB is not the cblA gene. Suggested gene/protein annotation: GO process terms related to cobalamin cofactor metabolic process* and methylmalonyl-CoA mutase activity regulation may be used cautiously. (horster2021delineatingtheclinical pages 1-2, horster2021delineatingtheclinical pages 2-4, abdrabo2019nextgenerationsequencing pages 31-37)
Inheritance	Autosomal recessive. No convincing evidence retrieved here for somatic causation, chromosomal abnormalities, anticipation, or established modifier genes specific to cblA. Variable expressivity is supported clinically; penetrance was not quantified in the retrieved cblA-specific sources. (horster2021delineatingtheclinical pages 1-2, brennerova2021genetictestingis pages 1-2)
Mechanism	MMAA encodes a mitochondrial G3E-family P-loop GTPase that interacts with MMUT and helps protect, load/gate, and reactivate adenosylcobalamin (AdoCbl)-dependent mutase function. Loss of MMAA function impairs effective AdoCbl handling for MMUT, reducing conversion of methylmalonyl-CoA to succinyl-CoA, which leads to accumulation of methylmalonic acid and related toxic metabolites. Demonstrated components: MMAA/MMUT interaction, GTP-dependent protectase/reactivase roles, and variant-associated protein instability for some alleles; downstream organ injury is supported clinically but remains partly inferred mechanistically. Suggested ontology: GO mitochondrial matrix; UBERON mitochondrion not applicable—use GO CC for subcellular annotation. (takahashiiniguez2012roleofvitamin pages 11-12, froese2009geneticsandbiochemistry pages 32-37, brennerova2021genetictestingis pages 1-2)
Biochemical signature	Hallmark findings are marked methylmalonic acid elevation in urine/plasma, often with elevated propionylcarnitine (C3) and methylcitrate; homocysteine is typically not elevated in isolated MMA/cblA, helping distinguish cblA from proximal cobalamin/remethylation disorders. During crises, patients may develop metabolic acidosis, secondary hyperammonemia, and low free carnitine. Suggested HPO/lab terms: Metabolic acidosis, Hyperammonemia, Increased urinary methylmalonic acid. (forny2021guidelinesforthe pages 6-8, brennerova2021genetictestingis pages 1-2, schnabel2023combinednewbornscreening pages 10-11)
Onset	Often neonatal or early infancy, but variable. In the cblA registry subset with symptomatic data, metabolic crisis was the leading presentation; among 21 cblA patients, 43% had first crisis in the neonatal period, 33% after the neonatal period, and 24% had no metabolic crisis; median age at first symptoms was 24.5 days. Suggested HPO: Infantile onset / Neonatal onset where appropriate. (horster2021delineatingtheclinical pages 6-7, horster2021delineatingtheclinical pages 5-6)
Major cblA cohort statistics	In the European registry study, 28 cblA patients were analyzed. 27/28 had reported cobalamin responsiveness. Among symptomatic cblA patients, 16/21 (76%) presented with metabolic crisis. Neurologic/functional outcomes were relatively favorable: 0/27 seizures, 1/27 (4%) movement disorder, 14/18 (78%) attended regular school. Renal outcomes were substantially milder than mut disease: chronic renal failure in about 2/23 (9%); 1/22 (5%) had arterial hypertension. Nutritional support burden was lower: 1/27 PEG, 3/27 NG feeding. All 28 cblA patients survived during the study interval. (horster2021delineatingtheclinical pages 1-2, horster2021delineatingtheclinical pages 15-17, horster2021delineatingtheclinical pages 17-19)
Diagnosis	Diagnostic workflow: newborn screening or symptomatic workup showing elevated C3/C3:C2, then confirmation with urine organic acids and/or plasma/DBS methylmalonic acid ± methylcitrate, while checking that homocysteine is not elevated for isolated MMA. Definitive subtype assignment requires molecular testing of MMAA (single gene, panel, WES/WGS depending context). A standardized hydroxocobalamin responsiveness test is recommended in MMA: baseline MMA measurement, 1 mg intramuscular hydroxocobalamin on 3 consecutive days, repeat sampling over ~10 days, with >50% MMA reduction indicating significant response. NBS can detect attenuated B12-responsive cases, including cblA. (forny2021guidelinesforthe pages 8-9, forny2021guidelinesforthe pages 6-8, forny2021guidelinesforthe pages 12-14, schnabel2023combinednewbornscreening pages 1-2, brennerova2021genetictestingis pages 1-2)
Core treatment	Genotype-guided and response-guided long-term therapy centers on parenteral hydroxocobalamin, especially in cblA, which “will mostly improve” with cobalamin therapy in guidelines. Common adjuncts in isolated MMA include protein management, levocarnitine ~100 mg/kg/day, and metronidazole 10–20 mg/kg/day to reduce gut propionate production. In acute decompensation, guidelines support stop/reduce protein, provide high-calorie glucose ± lipids, and treat hyperammonemia/acidosis per emergency protocols. Suggested NCIT intervention terms inline: hydroxocobalamin, levocarnitine, metronidazole, dietary management. (forny2021guidelinesforthe pages 11-12, forny2021guidelinesforthe pages 12-14, brennerova2021genetictestingis pages 1-2, brennerova2021genetictestingis pages 4-7)
Prognosis	Compared with mut MMA, cblA has a significantly milder long-term course with better preservation of renal and neurologic function and better survival, particularly under hydroxocobalamin treatment. Newborn screening plus specialized metabolic care appears beneficial to some extent in cobalamin-responsive MMA, but less so for cbl-nonresponsive MMA overall. Prognosis can still be serious if treatment is delayed or underestimated. (horster2021delineatingtheclinical pages 1-2, reischl‐hajiabadi2024outcomesafternewborn pages 1-2, brennerova2021genetictestingis pages 1-2)
Evidence gaps	No robust cblA-specific evidence was retrieved for: formal prevalence/incidence specific to cblA, validated QoL instruments, modifier genes, epigenetic changes, single-cell/spatial transcriptomics, multi-omics signatures, dedicated Mmaa animal model, or cblA-specific interventional clinical trials. Available recent screening/outcome studies usually pool cblA with other isolated MMA forms; careful subtype separation is required. (reischl‐hajiabadi2024outcomesafternewborn pages 1-2, liu2024theutilityof pages 1-2, OpenTargets Search: methylmalonic aciduria cblA type-MMAB)

Table: This table summarizes the core disease-knowledge elements for methylmalonic aciduria, cblA type, emphasizing the correct causal gene assignment to MMAA and the clinically important distinction from MMAB-associated cblB disease.

1. Disease information

Definition

cblA disease is an inborn error of intracellular cobalamin metabolism in which deficient MMAA function compromises the delivery, protection, and reactivation of adenosylcobalamin-dependent methylmalonyl-CoA mutase (MMUT). The resulting biochemical phenotype is isolated methylmalonic aciduria—methylmalonate elevation without the marked hyperhomocysteinemia characteristic of combined cobalamin disorders. (forny2021guidelinesforthe pages 6-8, brennerova2021genetictestingis pages 1-2, takahashiiniguez2012roleofvitamin pages 11-12)

Identifiers and synonyms

MONDO: MONDO:0009613.
Orphanet: ORPHA:79310, “Vitamin B12-responsive methylmalonic acidemia type cblA.”
OMIM phenotype: 251100 in the strongest subtype-specific registry source. One secondary excerpt gave 251000; this conflict should be resolved in favor of the current OMIM record before automated ingestion. (OpenTargets Search: methylmalonic aciduria cblA type-MMAB, liu2010constructionofaa pages 21-26, horster2021delineatingtheclinical pages 1-2)
Gene: MMAA, chromosome 4q31.21; the clinical case-report source gives MIM 607481 for the gene. (brennerova2021genetictestingis pages 1-2, horster2021delineatingtheclinical pages 1-2)
Common names: methylmalonic acidemia/aciduria cblA type; cobalamin A deficiency; vitamin B12-responsive methylmalonic acidemia, cblA; isolated MMA, cblA complementation class.
ICD: no cblA-specific ICD-10 code was established in the retrieved evidence. It is generally subsumed under disorders of amino-acid/organic-acid metabolism. A local ICD-10/ICD-11 terminology service should be queried before coding.
MeSH: usually indexed under methylmalonic acidemia rather than a dedicated cblA descriptor.

The evidence is primarily aggregated disease-level information and consented registry/cohort data, supplemented by individual case reports and biochemical experiments—not routine EHR-derived population data. The principal cblA cohort comprised 28 patients from a 123-person isolated-MMA registry sample spanning 17 countries. (horster2021delineatingtheclinical pages 1-2, horster2021delineatingtheclinical pages 2-4)

2. Etiology, risk, protective factors, and gene–environment interaction

Causal factor

The necessary cause is biallelic germline loss-of-function or function-impairing variants in MMAA. The resulting defect is recessive and impairs mitochondrial AdoCbl handling rather than dietary B12 absorption. (brennerova2021genetictestingis pages 1-2, horster2021delineatingtheclinical pages 1-2)

Genetic risk

Risk is highest for siblings of an affected person: under standard autosomal-recessive assumptions, each pregnancy of two confirmed carriers has a 25% affected, 50% carrier, and 25% unaffected/non-carrier probability. The most frequent alleles in the registry were c.433C>T, p.(Arg145), and c.592_595delACTG, p.(Thr198Serfs6). Four additional variants reported there were c.1098G>A, c.589A>G, c.662_664delCAA, and c.593_596delCTGA. The p.(Arg145*) allele has been reported to account for approximately half of disease alleles in some European-ancestry series, suggesting a population enrichment, although a formal founder analysis was not retrieved. (abdrabo2019nextgenerationsequencing pages 31-37, horster2021delineatingtheclinical pages 2-4)

No validated susceptibility loci, modifier genes, protective alleles, anticipation, or quantified incomplete penetrance were identified. Expressivity is variable: presentation ranges from asymptomatic screening detection to severe neonatal decompensation. Large deletions should be considered if sequencing finds only one allele, but recurrent cblA-specific chromosomal rearrangements are not established.

Environmental and protective factors

There is no environmental cause, infectious agent, toxin, smoking, alcohol, sex, or occupational exposure known to generate cblA disease. Environment instead modifies decompensation risk:

fasting, fever, infection, surgery, vomiting, and excessive protein catabolism increase endogenous propionate production and can precipitate crisis;
adequate energy during illness, avoidance of prolonged fasting, prompt treatment of infection, an emergency regimen, and sustained hydroxocobalamin reduce risk;
dietary precursor load from valine, isoleucine, methionine, threonine, odd-chain fatty acids, and gut microbial propionate interacts with residual pathway capacity. The normal pathway degrades these substrates through methylmalonyl-CoA to succinyl-CoA. (takahashiiniguez2012roleofvitamin pages 4-6, forny2021guidelinesforthe pages 11-12)

These are gene–environment interactions affecting severity, not disease acquisition. Routine vaccination is indirectly protective by reducing infection-triggered catabolism.

3. Phenotypes

The most reliable cblA frequencies come from the 28-patient registry; denominators vary because of missing data. (horster2021delineatingtheclinical pages 1-2, horster2021delineatingtheclinical pages 5-6, horster2021delineatingtheclinical pages 15-17)

Phenotype	Character and frequency	Suggested HPO annotation
Methylmalonic aciduria	Defining laboratory abnormality; persistent but usually lower than in mut-type MMA	HP:0012120
Metabolic crisis	Leading diagnostic manifestation, 16/21 symptomatic patients (76%); episodic	Metabolic acidosis; Acute metabolic decompensation
Neonatal/infantile onset	Median first symptoms 24.5 days; 43% had neonatal first crisis, 33% later, 24% no crisis	Neonatal onset; Infantile onset
High-anion-gap metabolic acidosis	Potentially severe during crisis	HP:0001942
Hyperammonemia	Secondary; case-level values of 1,600 µmol/L reported in severe neonatal cblA	HP:0001987
Vomiting, poor feeding, lethargy/dehydration	Typical crisis manifestations; cblA-specific percentages unavailable	HP:0002013; HP:0011968; HP:0001254; HP:0001944
Hypotonia/encephalopathy	Acute neurologic manifestations; frequencies unavailable	HP:0001252; HP:0001298
Movement disorder	1/27 (4%)	HP:0100022
Seizures	0/27 in the registry, although possible in severe MMA generally	HP:0001250
Chronic kidney disease/renal failure	2/23, approximately 9%; substantially less common than mut-type MMA	HP:0012622 / HP:0000083
Hypertension	1/22 (5%)	HP:0000822
Feeding support	NG tube 3/27 (11%); PEG 1/27 (4%)	HP:0011968; Feeding difficulties
Pancreatitis	0 reported in the cblA cohort	HP:0001733, if present individually
Growth impairment	Less marked than in mut disease; exact cblA prevalence unavailable	HP:0004322 / HP:0001510 when documented

Functional outcomes were comparatively favorable: 14/18 (78%) attended regular school, and all four adult cblA participants lived independently. These are useful proxies for cognitive and daily function, but no cblA-specific EQ-5D, SF-36, PROMIS, caregiver-burden, or disease-specific quality-of-life study was retrieved. Intramuscular injections and restrictive diets plausibly burden daily life, but that impact was not quantitatively measured. (horster2021delineatingtheclinical pages 15-17, horster2021delineatingtheclinical pages 17-19)

4. Genetic and molecular information

Gene and variant classes

MMAA encodes a 418-amino-acid mitochondrial protein in the G3E family of P-loop GTPases. Disease alleles include nonsense, frameshift/deletion, and missense variants. They are constitutionally inherited; somatic cblA disease is not recognized. (takahashiiniguez2012roleofvitamin pages 11-12, liu2010constructionofaa pages 21-26, horster2021delineatingtheclinical pages 1-2)

p.(Arg145*): truncating, recurrent, expected loss of function.
p.(Thr198Serfs*6): frameshift/truncating and recurrent.
p.(Leu89Pro): missense; experimental/structural analyses support severe protein destabilization and it can produce neonatal disease despite cobalamin responsiveness.
Other experimentally discussed substitutions—R145Q, R359Q, Y209C, G147E, and G218E—can impair stability, secondary structure, or conformational flexibility. (brennerova2021genetictestingis pages 4-7, takahashiiniguez2012roleofvitamin pages 11-12, horster2021delineatingtheclinical pages 2-4)

Clinical classification must be assigned variant by variant using current ClinVar/ACMG evidence. Population allele frequencies and ClinVar review status were not present in the retrieved full texts and should not be inferred. Most disease alleles are expected to be extremely rare because the disorder is recessive and ultra-rare.

No established modifier gene, methylation signature, histone abnormality, recurrent copy-number syndrome, aneuploidy, or structural chromosome lesion specific to cblA was found. CMA, karyotyping, and FISH therefore are not first-line tests unless an independent syndromic indication exists.

5. Environmental information

No toxin, radiation exposure, pollutant, pathogen, or lifestyle behavior causes cblA. Relevant exposures are metabolic stressors—fasting, infection, fever, surgery, dehydration, and inadequate caloric intake—which drive proteolysis and precursor flux. Diet is therapeutic rather than preventive of genotype. Gut bacteria contribute propionate; this is the rationale for intermittent antimicrobial therapy in selected MMA patients. (takahashiiniguez2012roleofvitamin pages 4-6, forny2021guidelinesforthe pages 11-12)

6. Mechanism and pathophysiology

Ordered causal chain

Biallelic pathogenic MMAA variants lead to absent, unstable, or functionally impaired mitochondrial MMAA protein.
Defective MMAA GTPase/chaperone activity leads to impaired protection, gating/loading, and reactivation of AdoCbl-dependent MMUT; the protein interaction and protectase/reactivase functions are experimentally demonstrated, while their exact relative contribution in every human allele remains partly inferred. (takahashiiniguez2012roleofvitamin pages 11-12, froese2009geneticsandbiochemistry pages 32-37)
Impaired active MMUT formation leads to reduced conversion of L-methylmalonyl-CoA into succinyl-CoA in the mitochondrial matrix.
The metabolic block leads to accumulation of methylmalonyl-CoA and diversion into methylmalonic acid and methylcitrate, with elevated C3 and depletion of free carnitine/CoA. (forny2021guidelinesforthe pages 6-8, brennerova2021genetictestingis pages 1-2)
During fasting, infection, or other catabolism, increased precursor flux leads to abrupt organic-acid accumulation, high-anion-gap acidosis, ketosis, secondary hyperammonemia, and mitochondrial energetic stress.
Acute biochemical toxicity and energetic failure lead to vomiting, lethargy, dehydration, hypotonia, encephalopathy, and potentially coma or death.
Branch A—recurrent/chronic metabolite exposure leads to renal tubular/interstitial and neurologic injury; the tissue-level route is incompletely demonstrated in cblA specifically.
Branch B—residual MMAA function plus pharmacologic hydroxocobalamin leads to greater effective AdoCbl/MMUT activity, lower methylmalonate, fewer crises, and the characteristically milder cblA course. (horster2021delineatingtheclinical pages 1-2, brennerova2021genetictestingis pages 4-7)

Molecular and cellular detail

MMAA has a mitochondrial targeting sequence and physically associates with MMUT. Biochemical work supports nucleotide-dependent protection of MMUT from oxidative inactivation and GTP-hydrolysis-dependent reactivation by exchanging inactive cofactor; one system recovered approximately 70% mutase activity. (takahashiiniguez2012roleofvitamin pages 11-12)

Relevant ontology suggestions include:

GO biological process: cobalamin metabolic process; propionyl-CoA catabolic process; cellular response to oxidative stress; mitochondrial organization.
GO molecular function: GTP binding; GTPase activity; protein-folding chaperone activity/regulation of methylmalonyl-CoA mutase.
GO cellular component: mitochondrial matrix.
Cell Ontology: hepatocyte (CL:0000182), renal proximal-tubule epithelial cell, neuron, astrocyte, skeletal-muscle cell, and cardiomyocyte are biologically relevant, although cblA-specific cell-resolution injury maps are unavailable.

No cblA-specific single-cell atlas, spatial transcriptomic study, lipidomic signature, validated epigenomic signature, or multi-omics integration was retrieved. Recent biomarker work in pooled isolated MMA emphasizes FGF21, GDF15, LCN2, propionate oxidation, methylmalonate, and C3, but subtype-specific cblA performance remains insufficiently established.

7. Anatomical structures affected

Primary biochemical compartment: mitochondrial matrix, especially in liver, kidney, brain, skeletal muscle, and other high-energy tissues.
Primary organs clinically affected: central nervous system and kidney; gastrointestinal/nutritional function during crisis.
Possible secondary involvement: heart, pancreas, optic pathways, and bone marrow are recognized in broader MMA, but were uncommon or insufficiently characterized in the cblA cohort. ECG abnormalities occurred in 1/5 tested and echocardiographic abnormalities in 1/8, with inadequate data to define a cblA cardiac phenotype. (horster2021delineatingtheclinical pages 15-17)
Laterality: systemic and generally bilateral/non-lateralized.

Suggested anatomy: UBERON liver, kidney, brain, basal ganglion, skeletal muscle, heart, and pancreas; GO: mitochondrial matrix. Exact UBERON identifiers should be resolved through an ontology service rather than assigned from memory.

8. Temporal development

cblA is congenital genetically but may be clinically silent at birth. Among 21 evaluable cblA patients, first crisis was neonatal in 43%, post-neonatal in 33%, and absent in 24%; median age at first symptoms was 24.5 days. Severe neonatal onset does not exclude cblA or B12 responsiveness. (horster2021delineatingtheclinical pages 6-7, brennerova2021genetictestingis pages 1-2)

The course is lifelong, with episodic catabolic crises superimposed on chronic biochemical disease. Effective hydroxocobalamin can yield prolonged stability, but biochemical normalization is not guaranteed. Critical windows are the newborn period, intercurrent illness, surgery, fasting, and any delay in recognizing B12 responsiveness. There is no established spontaneous remission; apparent remission is treatment-induced metabolic stability.

9. Inheritance and population

Inheritance is autosomal recessive with no expected sex bias; the registry included 17 males and 11 females, compatible with equal susceptibility. Its mean age was 11.9 years. (horster2021delineatingtheclinical pages 2-4, horster2021delineatingtheclinical pages 1-2)

A robust cblA-specific birth prevalence or incidence was not identified. Estimates of all MMA, such as 1:48,000–1:250,000, pool genetically distinct subtypes and must not be entered as cblA prevalence. (brennerova2021genetictestingis pages 1-2)

Recent screening context illustrates rarity but not subtype-specific incidence: in 548,707 newborns, a German multiple-tier program confirmed five methylmalonic acidurias among 166 total confirmed findings; the study highlighted two cofactor-responsive MMA cases. (schnabel2023combinednewbornscreening pages 1-2)

Consanguinity increases the probability that both parents carry the same rare allele. The c.433C>T, p.(Arg145*) enrichment in European ancestry is the best available population-specific signal, but carrier frequency and a proven founder haplotype were not established. Penetrance has not been formally quantified; expressivity is variable. Germline mosaicism is theoretically possible but not documented as a recurrent cblA feature.

10. Diagnostics

Biochemical and clinical workflow

Newborn screening: increased propionylcarnitine (C3), C3/C2, and related ratios. Single-tier C3 has a high false-positive rate, so second-tier methylmalonate/methylcitrate testing improves specificity. (forny2021guidelinesforthe pages 8-9, schnabel2023combinednewbornscreening pages 1-2)
Confirmatory testing: quantitative plasma or urine methylmalonic acid and urine organic-acid analysis; C3 and methylcitrate are commonly increased.
Subtype discrimination: total homocysteine and methionine. cblA produces isolated MMA with no substantial hyperhomocysteinemia; combined cblC and related disorders elevate homocysteine. Serum B12 should be checked to exclude acquired deficiency. (forny2021guidelinesforthe pages 6-8, brennerova2021genetictestingis pages 1-2)
Acute severity tests: blood gas, electrolytes/anion gap, glucose, lactate, ketones, ammonia, CBC, liver tests, creatinine/cystatin C, urinalysis, and carnitine profile.
Definitive diagnosis: biallelic pathogenic/likely pathogenic MMAA variants, using a targeted isolated-MMA/cobalamin panel or single-gene analysis. WES/WGS is useful for unresolved or atypical cases; deletion/duplication analysis is appropriate if only one allele is found. CMA, karyotype, FISH, mtDNA, and repeat-expansion testing are not routine.
Functional confirmation where needed: fibroblast propionate incorporation, AdoCbl synthesis, complementation analysis, or RNA studies for uncertain splice variants.

Cobalamin-response test

Guidelines recommend assessing every MMA patient. Measure urine or plasma MMA on separate baseline days, administer 1 mg intramuscular hydroxocobalamin on three consecutive days, and repeat MMA measurements over approximately ten days; a reduction exceeding 50% supports response. Testing should be performed when metabolically stable because dialysis, infusions, or crisis resolution can confound it. Genotyping is still essential because poorly standardized in-vivo testing can misclassify patients. (brennerova2021genetictestingis pages 1-2, brennerova2021genetictestingis pages 4-7, forny2021guidelinesforthe pages 12-14)

Imaging and ancillary tests

MRI brain, EEG, ECG/echocardiography, ophthalmologic examination, neuropsychology, hearing testing, and renal imaging are complication-directed rather than diagnostic. Biopsy is generally unnecessary.

Differential diagnosis

MMUT deficiency: often more severe and less B12 responsive.
cblB: biallelic MMAB; impaired adenosyltransferase, often less responsive.
cblD variant 2: MMADHC with isolated MMA.
MCEE deficiency: generally milder isolated MMA.
cblC and other combined cobalamin defects: methylmalonate plus hyperhomocysteinemia/low methionine.
Propionic acidemia: elevated C3/methylcitrate without marked methylmalonate.
Maternal/neonatal nutritional B12 deficiency: biochemical mimic resolved by nutritional evaluation.

A 2024 LC–MS/MS study of 140 controls and 228 patients reported DBS reference intervals of 0.04–1.02 µmol/L for methylmalonate and 0.02–0.27 µmol/L for methylcitrate. DBS methylmalonate correlated with urine MMA at r=0.849, while DBS methylcitrate correlated with urine methylcitrate at r=0.693; this is promising for follow-up but was not cblA-specific. (liu2024theutilityof pages 1-2)

11. Outcome and prognosis

The treated cblA prognosis is substantially better than mut-type MMA. In the 28-person registry, all cblA participants survived, compared with six deaths among 95 mut patients. Chronic renal failure occurred in about 2/23 (9%), seizures in 0/27, and movement disorder in 1/27. Preserved schooling and independent adult living suggest relatively favorable function. (horster2021delineatingtheclinical pages 15-17, horster2021delineatingtheclinical pages 17-19)

No validated 5- or 10-year survival rate or life-expectancy estimate exists specifically for cblA. Prognostic factors include residual MMAA function, response and adherence to hydroxocobalamin, age/severity at first decompensation, crisis frequency, renal function, and access to specialist care. Canonical MMA and C3 levels are influenced by diet and renal clearance, so trends and multisystem biomarkers are preferable to isolated measurements.

The 2024 German screening follow-up—six MMA cases within a mixed 27-patient IMD cohort, median follow-up 3.6 years—concluded that screening and specialist care benefited cobalamin-responsive MMA “to some extent,” while cobalamin-nonresponsive MMA retained high early risk. These pooled results support early cblA detection but cannot supply a cblA-specific effect size. (reischl‐hajiabadi2024outcomesafternewborn pages 1-2)

12. Treatment

Maintenance therapy

Hydroxocobalamin: cornerstone, preferably parenteral/intramuscular. The cblA cohort had 27/28 reported responders; among patients with route data, 86% received intramuscular treatment. Dose and frequency are individualized by biochemical response and adherence. A severe p.(Leu89Pro) case became stable on 1 mg IM weekly, with urine MMA approximately 799–1,291 µmol/mmol creatinine. (horster2021delineatingtheclinical pages 1-2, horster2021delineatingtheclinical pages 5-6, brennerova2021genetictestingis pages 4-7)
Protein/nutrition: avoid excessive propiogenic amino-acid intake while supplying enough natural protein for normal growth. In the registry, 19/26 (73.1%) followed a calculated diet and 7/26 (27%) received precursor-free amino-acid supplements. Over-restriction risks malnutrition. (horster2021delineatingtheclinical pages 5-6)
Levocarnitine: guideline starting framework approximately 100 mg/kg/day, titrated to free carnitine and clinical status.
Metronidazole: approximately 10–20 mg/kg/day, often intermittently, to reduce intestinal propionate production; monitor neurologic toxicity and antimicrobial stewardship.
Rehabilitation/support: PT, OT, speech/feeding therapy, educational support, renal and neuropsychological surveillance as indicated. (forny2021guidelinesforthe pages 11-12)

Suggested NCIt concepts are Hydroxocobalamin, Levocarnitine, Metronidazole, Medical Nutrition Therapy, Hemodialysis, Liver Transplantation, and Kidney Transplantation; exact NCIt identifiers should be terminology-service validated.

Acute decompensation

Emergency care aims to reverse catabolism: temporarily stop or reduce protein, deliver high-calorie IV glucose with or without lipid, give carnitine, continue/initiate hydroxocobalamin, correct fluids/electrolytes/acidosis, identify infection, and monitor ammonia and neurologic status closely. Severe hyperammonemia or refractory acidosis may require extracorporeal clearance. The neonatal cblA case literature demonstrates that ammonia can exceed 1,000 µmol/L and require extracorporeal elimination. (brennerova2021genetictestingis pages 1-2, forny2021guidelinesforthe pages 11-12)

Transplantation and advanced therapy

Liver or combined liver–kidney transplantation is considered in MMA with frequent severe decompensations or advanced renal disease; it improves stability but does not cure systemic disease, and lifelong metabolic follow-up remains necessary. Because most cblA patients respond well to hydroxocobalamin and have milder outcomes, transplantation is uncommon and evidence is largely extrapolated from severe MMUT/cblB disease. (forny2021guidelinesforthe pages 12-14)

No approved cblA gene, mRNA, RNAi, ASO, CRISPR, or cell therapy was identified. The retrieved trial landscape contained broad MMA natural-history and gene-therapy studies, but none demonstrated a cblA-specific interventional program; MMUT-directed gene therapy should not be represented as MMAA replacement.

13. Prevention

Primary prevention of genotype: unavailable after conception. Carrier testing, reproductive counseling, prenatal diagnosis, and preimplantation genetic testing are possible once familial variants are known.
Secondary prevention: newborn screening, rapid confirmatory metabolite testing, molecular subtyping, and immediate response testing/treatment. The 2023 pilot found 161/166 confirmed newborns asymptomatic at first report and demonstrated feasibility of a multiple-tier algorithm. (schnabel2023combinednewbornscreening pages 1-2)
Tertiary prevention: hydroxocobalamin adherence, avoidance of fasting, written sick-day protocols, adequate calories during illness, carnitine and dietary management, vaccination, prompt infection treatment, and periodic renal, neurologic, nutritional, ophthalmologic, and cardiac surveillance.
Cascade screening: test siblings and at-risk relatives; offer biochemical testing promptly to newborn siblings while molecular results are pending.

No disease-specific vaccine or environmental public-health intervention applies.

14. Other species and natural disease

No well-validated naturally occurring veterinary counterpart caused by orthologous MMAA variants was identified in the retrieved literature. There is no zoonotic potential or cross-species transmission because cblA is inherited, not infectious. MMAA/MeaB conservation across species is mechanistically important: bacterial MeaB is the experimentally tractable ortholog that established GTP-dependent mutase protection and reactivation. However, bacterial biochemistry is not equivalent to naturally occurring cblA disease. (takahashiiniguez2012roleofvitamin pages 9-11, takahashiiniguez2012roleofvitamin pages 11-12)

Suggested taxa for comparative work include Homo sapiens (NCBI Taxon 9606), Mus musculus (10090), and commonly used bacterial MeaB systems, but no breed ontology annotation is applicable.

15. Model organisms and experimental systems

Disease-specific systems

Patient dermal fibroblasts: principal cblA cellular model. Assays include propionate incorporation, AdoCbl synthesis after exogenous cobalamin, complementation, and hydroxocobalamin rescue.
Recombinant MMAA/MMUT proteins: define GTPase activity, protein interaction, stability, protectase/reactivase function, and structural effects of missense variants.
Bacterial MeaB–MCM systems: useful for conserved chaperone mechanism and nucleotide-dependent cofactor exchange. (takahashiiniguez2012roleofvitamin pages 9-11, takahashiiniguez2012roleofvitamin pages 11-12)

Limitations and gaps

No dedicated, well-characterized Mmaa knockout/knock-in mouse, zebrafish cblA model, cblA iPSC-derived organoid, or cblA-specific CRISPR screen was established in the retrieved evidence. Published Mmut models represent mut-type MMA, while Mmachc models represent cblC disease; neither should be annotated as a cblA model. Fibroblasts are excellent for biochemical classification but do not reproduce organ-level renal, cerebral, or systemic catabolic physiology.

Recent developments and expert interpretation

2023 multiple-tier screening: 548,707 newborns were screened; five methylmalonic acidurias were confirmed, and cofactor-responsive cases could be detected before major symptoms. Published 28 July 2023, DOI: https://doi.org/10.3390/nu15153355. Its abstract states that the method “allows the identification of attenuated and severe disease courses.” (schnabel2023combinednewbornscreening pages 1-2)
2024 screening outcomes: median 3.6-year follow-up supported meaningful but incomplete benefit for cobalamin-responsive MMA. Published online after acceptance on 7 March 2024, DOI: https://doi.org/10.1002/jimd.12731. (reischl‐hajiabadi2024outcomesafternewborn pages 1-2)
2024 DBS monitoring: simultaneous MMA, methylcitrate, and homocysteine measurement offers a less invasive monitoring approach, with strong correlation between DBS and urine MMA. Published 20 June 2024, DOI: https://doi.org/10.3389/fnut.2024.1414681. Subtype-specific validation remains needed. (liu2024theutilityof pages 1-2)
Expert consensus: the 2021 international guideline recommends molecular subtyping and testing B12 responsiveness in every MMA patient; cblA patients “will mostly improve” with parenteral cobalamin. DOI: https://doi.org/10.1002/jimd.12370. (forny2021guidelinesforthe pages 11-12, forny2021guidelinesforthe pages 12-14)
Natural-history interpretation: the principal registry study concluded that cblA and mut disease can initially present similarly, but treated cblA has lower MMA, fewer renal and neurologic complications, and superior survival. DOI: https://doi.org/10.1002/jimd.12297. (horster2021delineatingtheclinical pages 1-2, horster2021delineatingtheclinical pages 17-19)

Evidence limitations

cblA is ultra-rare, and much MMA literature pools MMAA, MMAB, and MMUT disease. Accordingly, broad MMA statistics, transplant outcomes, biomarkers, and experimental therapies cannot automatically be assigned to cblA. PMID metadata were not consistently exposed in the retrieved full-text records; DOI URLs and publication dates are therefore supplied where verified rather than risking incorrect PMID assignment. The clearest unmet needs are a larger genotype-resolved longitudinal cohort, cblA-specific patient-reported outcomes, standardized hydroxocobalamin dosing/response criteria, contemporary allele-frequency analysis, and dedicated organismal and advanced human-cell models.

References

(horster2021delineatingtheclinical pages 1-2): Friederike Hörster, Ali Tunç Tuncel, Florian Gleich, Tanja Plessl, Sean D. Froese, Sven F. Garbade, Stefan Kölker, and Matthias R. Baumgartner. Delineating the clinical spectrum of isolated methylmalonic acidurias: cbla and mut. Sep 2021. URL: https://doi.org/10.1002/jimd.12297, doi:10.1002/jimd.12297. This article has 43 citations and is from a peer-reviewed journal.
(brennerova2021genetictestingis pages 1-2): Katarína Brennerová, Martina Škopková, Mária Ostrožlíková, Jana Šaligová, Juraj Staník, Vladimír Bzdúch, and Daniela Gašperíková. Genetic testing is necessary for correct diagnosis and treatment in patients with isolated methylmalonic aciduria: a case report. BMC Pediatrics, Dec 2021. URL: https://doi.org/10.1186/s12887-021-03067-3, doi:10.1186/s12887-021-03067-3. This article has 4 citations and is from a peer-reviewed journal.
(OpenTargets Search: methylmalonic aciduria cblA type-MMAB): Open Targets Query (methylmalonic aciduria cblA type-MMAB, 2 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(horster2021delineatingtheclinical pages 2-4): Friederike Hörster, Ali Tunç Tuncel, Florian Gleich, Tanja Plessl, Sean D. Froese, Sven F. Garbade, Stefan Kölker, and Matthias R. Baumgartner. Delineating the clinical spectrum of isolated methylmalonic acidurias: cbla and mut. Sep 2021. URL: https://doi.org/10.1002/jimd.12297, doi:10.1002/jimd.12297. This article has 43 citations and is from a peer-reviewed journal.
(abdrabo2019nextgenerationsequencing pages 31-37): LS Abdrabo. Next generation sequencing to identify genes underlying methylmalonic aciduria. Unknown journal, 2019.
(takahashiiniguez2012roleofvitamin pages 11-12): Tóshiko Takahashi-Iñiguez, Enrique García-Hernandez, Roberto Arreguín-Espinosa, and María Elena Flores. Role of vitamin b12 on methylmalonyl-coa mutase activity. Journal of Zhejiang University SCIENCE B, 13:423-437, Jun 2012. URL: https://doi.org/10.1631/jzus.b1100329, doi:10.1631/jzus.b1100329. This article has 199 citations.
(froese2009geneticsandbiochemistry pages 32-37): Darren Sean Froese. Genetics and biochemistry of cobalamin disorders. Jan 2009. URL: https://doi.org/10.11575/prism/16795, doi:10.11575/prism/16795. This article has 0 citations.
(forny2021guidelinesforthe pages 6-8): Patrick Forny, Friederike Hörster, Diana Ballhausen, Anupam Chakrapani, Kimberly A. Chapman, Carlo Dionisi‐Vici, Marjorie Dixon, Sarah C. Grünert, Stephanie Grunewald, Goknur Haliloglu, Michel Hochuli, Tomas Honzik, Daniela Karall, Diego Martinelli, Femke Molema, Jörn Oliver Sass, Sabine Scholl‐Bürgi, Galit Tal, Monique Williams, Martina Huemer, and Matthias R. Baumgartner. Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: first revision. Mar 2021. URL: https://doi.org/10.1002/jimd.12370, doi:10.1002/jimd.12370. This article has 337 citations and is from a peer-reviewed journal.
(schnabel2023combinednewbornscreening pages 10-11): Elena Schnabel, Stefan Kölker, Florian Gleich, Patrik Feyh, Friederike Hörster, Dorothea Haas, Junmin Fang-Hoffmann, Marina Morath, Gwendolyn Gramer, Wulf Röschinger, Sven F. Garbade, Georg F. Hoffmann, Jürgen G. Okun, and Ulrike Mütze. Combined newborn screening allows comprehensive identification also of attenuated phenotypes for methylmalonic acidurias and homocystinuria. Nutrients, 15:3355, Jul 2023. URL: https://doi.org/10.3390/nu15153355, doi:10.3390/nu15153355. This article has 25 citations.
(horster2021delineatingtheclinical pages 6-7): Friederike Hörster, Ali Tunç Tuncel, Florian Gleich, Tanja Plessl, Sean D. Froese, Sven F. Garbade, Stefan Kölker, and Matthias R. Baumgartner. Delineating the clinical spectrum of isolated methylmalonic acidurias: cbla and mut. Sep 2021. URL: https://doi.org/10.1002/jimd.12297, doi:10.1002/jimd.12297. This article has 43 citations and is from a peer-reviewed journal.
(horster2021delineatingtheclinical pages 5-6): Friederike Hörster, Ali Tunç Tuncel, Florian Gleich, Tanja Plessl, Sean D. Froese, Sven F. Garbade, Stefan Kölker, and Matthias R. Baumgartner. Delineating the clinical spectrum of isolated methylmalonic acidurias: cbla and mut. Sep 2021. URL: https://doi.org/10.1002/jimd.12297, doi:10.1002/jimd.12297. This article has 43 citations and is from a peer-reviewed journal.
(horster2021delineatingtheclinical pages 15-17): Friederike Hörster, Ali Tunç Tuncel, Florian Gleich, Tanja Plessl, Sean D. Froese, Sven F. Garbade, Stefan Kölker, and Matthias R. Baumgartner. Delineating the clinical spectrum of isolated methylmalonic acidurias: cbla and mut. Sep 2021. URL: https://doi.org/10.1002/jimd.12297, doi:10.1002/jimd.12297. This article has 43 citations and is from a peer-reviewed journal.
(horster2021delineatingtheclinical pages 17-19): Friederike Hörster, Ali Tunç Tuncel, Florian Gleich, Tanja Plessl, Sean D. Froese, Sven F. Garbade, Stefan Kölker, and Matthias R. Baumgartner. Delineating the clinical spectrum of isolated methylmalonic acidurias: cbla and mut. Sep 2021. URL: https://doi.org/10.1002/jimd.12297, doi:10.1002/jimd.12297. This article has 43 citations and is from a peer-reviewed journal.
(forny2021guidelinesforthe pages 8-9): Patrick Forny, Friederike Hörster, Diana Ballhausen, Anupam Chakrapani, Kimberly A. Chapman, Carlo Dionisi‐Vici, Marjorie Dixon, Sarah C. Grünert, Stephanie Grunewald, Goknur Haliloglu, Michel Hochuli, Tomas Honzik, Daniela Karall, Diego Martinelli, Femke Molema, Jörn Oliver Sass, Sabine Scholl‐Bürgi, Galit Tal, Monique Williams, Martina Huemer, and Matthias R. Baumgartner. Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: first revision. Mar 2021. URL: https://doi.org/10.1002/jimd.12370, doi:10.1002/jimd.12370. This article has 337 citations and is from a peer-reviewed journal.
(forny2021guidelinesforthe pages 12-14): Patrick Forny, Friederike Hörster, Diana Ballhausen, Anupam Chakrapani, Kimberly A. Chapman, Carlo Dionisi‐Vici, Marjorie Dixon, Sarah C. Grünert, Stephanie Grunewald, Goknur Haliloglu, Michel Hochuli, Tomas Honzik, Daniela Karall, Diego Martinelli, Femke Molema, Jörn Oliver Sass, Sabine Scholl‐Bürgi, Galit Tal, Monique Williams, Martina Huemer, and Matthias R. Baumgartner. Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: first revision. Mar 2021. URL: https://doi.org/10.1002/jimd.12370, doi:10.1002/jimd.12370. This article has 337 citations and is from a peer-reviewed journal.
(schnabel2023combinednewbornscreening pages 1-2): Elena Schnabel, Stefan Kölker, Florian Gleich, Patrik Feyh, Friederike Hörster, Dorothea Haas, Junmin Fang-Hoffmann, Marina Morath, Gwendolyn Gramer, Wulf Röschinger, Sven F. Garbade, Georg F. Hoffmann, Jürgen G. Okun, and Ulrike Mütze. Combined newborn screening allows comprehensive identification also of attenuated phenotypes for methylmalonic acidurias and homocystinuria. Nutrients, 15:3355, Jul 2023. URL: https://doi.org/10.3390/nu15153355, doi:10.3390/nu15153355. This article has 25 citations.
(forny2021guidelinesforthe pages 11-12): Patrick Forny, Friederike Hörster, Diana Ballhausen, Anupam Chakrapani, Kimberly A. Chapman, Carlo Dionisi‐Vici, Marjorie Dixon, Sarah C. Grünert, Stephanie Grunewald, Goknur Haliloglu, Michel Hochuli, Tomas Honzik, Daniela Karall, Diego Martinelli, Femke Molema, Jörn Oliver Sass, Sabine Scholl‐Bürgi, Galit Tal, Monique Williams, Martina Huemer, and Matthias R. Baumgartner. Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: first revision. Mar 2021. URL: https://doi.org/10.1002/jimd.12370, doi:10.1002/jimd.12370. This article has 337 citations and is from a peer-reviewed journal.
(brennerova2021genetictestingis pages 4-7): Katarína Brennerová, Martina Škopková, Mária Ostrožlíková, Jana Šaligová, Juraj Staník, Vladimír Bzdúch, and Daniela Gašperíková. Genetic testing is necessary for correct diagnosis and treatment in patients with isolated methylmalonic aciduria: a case report. BMC Pediatrics, Dec 2021. URL: https://doi.org/10.1186/s12887-021-03067-3, doi:10.1186/s12887-021-03067-3. This article has 4 citations and is from a peer-reviewed journal.
(reischl‐hajiabadi2024outcomesafternewborn pages 1-2): Anna T. Reischl‐Hajiabadi, Elena Schnabel, Florian Gleich, Katharina Mengler, Martin Lindner, Peter Burgard, Roland Posset, Svenja Lommer‐Steinhoff, Sarah C. Grünert, Eva Thimm, Peter Freisinger, Julia B. Hennermann, Johannes Krämer, Gwendolyn Gramer, Dominic Lenz, Stine Christ, Friederike Hörster, Georg F. Hoffmann, Sven F. Garbade, Stefan Kölker, and Ulrike Mütze. Outcomes after newborn screening for propionic and methylmalonic acidemia and homocystinurias. Journal of Inherited Metabolic Disease, 47:674-689, Apr 2024. URL: https://doi.org/10.1002/jimd.12731, doi:10.1002/jimd.12731. This article has 20 citations and is from a peer-reviewed journal.
(liu2024theutilityof pages 1-2): Yi Liu, Xue Ma, Lulu Kang, Ying Jin, Mengqiu Li, Jin-qing Song, Haixia Li, Yongtong Cao, and Yanling Yang. The utility of methylmalonic acid, methylcitrate acid, and homocysteine in dried blood spots for therapeutic monitoring of three inherited metabolic diseases. Frontiers in Nutrition, Jun 2024. URL: https://doi.org/10.3389/fnut.2024.1414681, doi:10.3389/fnut.2024.1414681. This article has 5 citations.
(liu2010constructionofaa pages 21-26): JH Liu. Construction of a knockout mouse model for combined methylmalonic aciduria and homocystinuria,«cblc» type («mmachc»). Unknown journal, 2010.
(takahashiiniguez2012roleofvitamin pages 4-6): Tóshiko Takahashi-Iñiguez, Enrique García-Hernandez, Roberto Arreguín-Espinosa, and María Elena Flores. Role of vitamin b12 on methylmalonyl-coa mutase activity. Journal of Zhejiang University SCIENCE B, 13:423-437, Jun 2012. URL: https://doi.org/10.1631/jzus.b1100329, doi:10.1631/jzus.b1100329. This article has 199 citations.
(takahashiiniguez2012roleofvitamin pages 9-11): Tóshiko Takahashi-Iñiguez, Enrique García-Hernandez, Roberto Arreguín-Espinosa, and María Elena Flores. Role of vitamin b12 on methylmalonyl-coa mutase activity. Journal of Zhejiang University SCIENCE B, 13:423-437, Jun 2012. URL: https://doi.org/10.1631/jzus.b1100329, doi:10.1631/jzus.b1100329. This article has 199 citations.

Artifacts

Edison artifact artifact-00

Ask OpenScientist

OpenScientist Report

Classifications

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

External Assertions

Medical Actions

Biochemical Markers

Diagnosis

Prevalence

Differential Diagnoses

Source YAML

References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Comprehensive research report: Methylmalonic aciduria, cblA type

Executive summary and scope

1. Disease information

Definition

Identifiers and synonyms

2. Etiology, risk, protective factors, and gene–environment interaction

Causal factor

Genetic risk

Environmental and protective factors

3. Phenotypes

4. Genetic and molecular information

Gene and variant classes

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

Molecular and cellular detail

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Biochemical and clinical workflow

Cobalamin-response test

Imaging and ancillary tests

Differential diagnosis

11. Outcome and prognosis

12. Treatment

Maintenance therapy

Acute decompensation

Transplantation and advanced therapy

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Disease-specific systems

Limitations and gaps

Recent developments and expert interpretation

Evidence limitations

Artifacts