| 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. (pqac-00000000, pqac-00000027, pqac-00000017) |
| 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.Thr198Serfs\*6)**; 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. (pqac-00000027, pqac-00000028, pqac-00000025) |
| 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. (pqac-00000027, pqac-00000017) |
| 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. (pqac-00000021, pqac-00000022, pqac-00000017) |
| 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**. (pqac-00000010, pqac-00000017, pqac-00000008) |
| 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. (pqac-00000005, pqac-00000003) |
| 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. (pqac-00000001, pqac-00000006, pqac-00000007) |
| 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. (pqac-00000009, pqac-00000010, pqac-00000020, pqac-00000011, pqac-00000017) |
| 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. (pqac-00000019, pqac-00000020, pqac-00000017, pqac-00000018) |
| 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. (pqac-00000001, pqac-00000012, pqac-00000017) |
| 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. (pqac-00000012, pqac-00000016, pqac-00000000) |


*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.*