IEMbase 0316: MMADHC-related methylmalonic aciduria and homocystinuria, cblD type
Scope
| Field | Value |
|---|---|
| IEMbase ID | 316 |
| Nosology | 21.9.11.03 |
| Gene | MMADHC |
| External IDs | OMIM:277410; ORPHA:79283 |
| Generated mapping | UNMAPPED |
| Candidate DisMech targets | Manual target Inborn_Disorder_of_Cobalamin_Metabolism_and_Transport.yaml#cblD |
| Review date | 2026-07-07 |
IEMbase phenotype signal
IEMbase represents this as the combined MMADHC/cblD form with methylmalonic aciduria and homocystinuria. Characteristic rows include megaloblastic anemia, failure to thrive, life-threatening illness, neurologic dysfunction, and impaired vision.
Additional clinical rows include cardiomyopathy, cerebral atrophy, dementia, developmental delay, dysmorphic features, extrapyramidal signs, feeding difficulties, hematuria, hemolytic uremic syndrome, hypotonia, liver dysfunction, low weight, maculopathy, myelopathy, hypersegmented neutrophils, nystagmus, psychiatric disturbance, retinopathy, and seizures.
The biochemical pattern spans both MMA and remethylation branches: elevated urine and plasma homocysteine, low-to-normal plasma methionine, elevated C3 propionylcarnitine in blood and plasma, elevated urinary 3-hydroxypropionic and methylcitric acids, elevated methylmalonic acid in plasma and urine, and decreased S-adenosylmethionine in CSF and plasma. Treatment rows are hydroxycobalamin, betaine, and carnitine.
DisMech phenotype coverage
The generated UNMAPPED status is a false negative. The best local target is
Inborn_Disorder_of_Cobalamin_Metabolism_and_Transport.yaml#cblD.
DisMech already has a cblD subtype for MMADHC deficiency and states that MMADHC defects can produce isolated methylmalonic acidemia, isolated homocystinuria, or combined disease. The same file covers methylmalonic aciduria, homocystinuria, hyperhomocysteinemia, hypomethioninemia, megaloblastic anemia, intellectual disability, seizures, hypotonia, global developmental delay, encephalopathy, failure to thrive, renal thrombotic microangiopathy, and hydroxocobalamin, betaine, and L-carnitine treatment.
Prior notes for IEMbase 88 and 89 already identify the isolated cblD-MMA and cblD-HC records as false negatives to the same local cblD subtype. This record is the combined branch of the same MMADHC spectrum.
Concordance and completeness
Judgement: false-negative mapping with high umbrella-level local coverage.
Concordance is high for MMADHC/cblD identity, combined methylmalonic aciduria and homocystinuria, megaloblastic anemia, developmental and neurologic involvement, renal thrombotic microangiopathy or HUS-like disease, and hydroxocobalamin, betaine, and carnitine therapy.
The main gap is subtype granularity. DisMech has one cblD subtype rather than separate cblD-MMA, cblD-HC, and combined cblD-MMA/HC branches. IEMbase also adds detailed biomarker compartment prompts for C3 propionylcarnitine, 3-hydroxypropionic acid, methylcitric acid, methylmalonic acid, homocysteine, methionine, and S-adenosylmethionine.
Curation actions
- Update the mapping logic or manual crosswalk to resolve this record to
Inborn_Disorder_of_Cobalamin_Metabolism_and_Transport.yaml#cblD. - Consider splitting cblD into isolated MMA, isolated HC, and combined forms if subtype granularity becomes important.
- Preserve the combined biochemical signal when curating: MMA markers, homocysteine elevation, low-to-normal methionine, and low S-adenosylmethionine.