Conditions · Metabolism: amino acids and the urea cycle
Methylmalonic acidaemia !
In methylmalonic acidaemia some amino acids and fats are not broken down well; methylmalonic acid builds up, with acidosis crises and kidney damage.
Updated 2026-11-01
Structures involved
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In biochemistry
- Propionyl-CoA to succinyl-CoA: Step 3 · Methylmalonyl-CoA mutase (MMUT), B12-dependent
- Homocysteine
- Branched-chain α-keto acid dehydrogenase (BCKDH)
- Methionine synthase
- One-carbon metabolism (folate, B12 and SAM)
- Glucogenic and ketogenic amino acids
What it is
An inherited organic acidaemia from lack of methylmalonyl-CoA mutase or of the synthesis of its cofactor, adenosylcobalamin (B12).
Who gets it
It is estimated at 1 in 50,000 to 100,000 people.
Causes
- Variants of MMUT (about 60 % of cases)
- Defects of cobalamin synthesis: MMAA, MMAB, MMADHC
- Autosomal recessive inheritance
Risk factors
- Carrier parents
- Infections, fasting or surgery (trigger crises)
Pathophysiology
Valine, isoleucine, methionine, threonine, odd-chain fatty acids and cholesterol give propionyl-CoA and then methylmalonyl-CoA. Without the mutase, this does not become succinyl-CoA: methylmalonic and propionic acids build up, causing high anion gap acidosis, inhibiting the urea cycle (hyperammonaemia) and damaging the kidney and basal ganglia.
Classification
- mut⁰: no activity, no B12 response
- mut⁻: residual activity
- Cobalamin defects, often B12-responsive
- Combined forms with homocystinuria (cblC and others)
Symptoms and signs
- Vomiting, lethargy and hypotonia in the first days
- Fast, deep breathing from acidosis
- Poor growth and development
- Repeated crises with infections
Diagnosis
- Clinical
- An infant with acidosis crises and encephalopathy; many cases are found by expanded newborn screening.
- Tests
- Very high methylmalonic acid in urine and plasma; high propionylcarnitine (C3); ammonia, gases, lactate and ketones; B12 and homocysteine to separate the forms; genetic testing.
- Imaging
- Brain MRI: globus pallidus lesions after crises; renal ultrasound.
Treatment
- Acute
- In a crisis: stop protein, give glucose and lipids, correct acidosis and treat hyperammonaemia; dialysis if severe
- Lifestyle
- Low-protein diet with a formula free of the precursor amino acids
- Medical
- Hydroxocobalamin in B12-responsive forms, carnitine, and metronidazole to cut bacterial propionate
- Surgical
- Liver or combined liver–kidney transplant in selected cases
Complications
- Chronic kidney disease
- Basal ganglia injury («metabolic stroke»)
- Pancreatitis
- Intellectual disability
Prognosis
Variable: better in B12-responsive forms; forms with no activity have crises and progressive kidney damage.
Test yourself
Think of the answer, then tap the question to see it.
Which enzyme fails, and which cofactor does it use?
Methylmalonyl-CoA mutase, which uses adenosylcobalamin (B12) to turn methylmalonyl-CoA into succinyl-CoA.
Which precursors give methylmalonyl-CoA?
Valine, isoleucine, methionine, threonine, odd-chain fatty acids and the cholesterol side chain.
Why can an organic acidaemia cause hyperammonaemia?
Accumulated acyl-CoAs slow N-acetylglutamate synthesis and so CPS-I of the urea cycle.
Related conditions
- Propionic acidaemia
- Hyperammonaemia
- Homocystinuria
- Chronic kidney disease
- Acute pancreatitis
- Heart failure
Educational information, not medical advice. For any symptom, see a health professional.
Sources: Methylmalonic acidemia: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); MMUT gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Propionyl-CoA catabolism (Reactome, 2026).
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