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# 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

Tap one to see what it is and open it in 3D.

- [Kidneys](https://durgical.com/en/anatomy/kidney/)
- [Globus pallidus](https://durgical.com/en/anatomy/globus-pallidus/)
- [Pancreas](https://durgical.com/en/anatomy/pancreas/)
- [Liver](https://durgical.com/en/anatomy/liver/)

## In biochemistry

- [Propionyl-CoA to succinyl-CoA: Step 3 · Methylmalonyl-CoA mutase (MMUT), B12-dependent](https://durgical.com/en/biochemistry/pathways/propionyl-coa-to-succinyl-coa/#paso-3)
- [Homocysteine](https://durgical.com/en/biochemistry/molecules/homocysteine/)
- [Branched-chain α-keto acid dehydrogenase (BCKDH)](https://durgical.com/en/biochemistry/enzymes/branched-chain-keto-acid-dehydrogenase/)
- [Methionine synthase](https://durgical.com/en/biochemistry/enzymes/methionine-synthase/)
- [One-carbon metabolism (folate, B12 and SAM)](https://durgical.com/en/biochemistry/topics/one-carbon-metabolism/)
- [Glucogenic and ketogenic amino acids](https://durgical.com/en/biochemistry/topics/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

## Red flags

- Severe metabolic acidosis with ketones in an infant
- Hyperammonaemia
- Falling urine output or acute neurological decline

## 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](https://durgical.com/en/anatomy/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](https://durgical.com/en/anatomy/liver/) or combined liver– [kidney](https://durgical.com/en/anatomy/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.

[Add to my cards (3)](https://durgical.app/estudiar/?add=/en/conditions/methylmalonic-acidaemia/)

## Related conditions

- [Propionic acidaemia](https://durgical.com/en/conditions/propionic-acidaemia/)
- [Hyperammonaemia](https://durgical.com/en/conditions/hyperammonaemia/)
- [Homocystinuria](https://durgical.com/en/conditions/homocystinuria/)
- [Chronic kidney disease](https://durgical.com/en/conditions/chronic-kidney-disease/)
- [Acute pancreatitis](https://durgical.com/en/conditions/acute-pancreatitis/)
- [Heart failure](https://durgical.com/en/conditions/heart-failure/)

Educational information, not medical advice. For any symptom, see a health professional.

Sources: [Methylmalonic acidemia: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/methylmalonic-acidemia/) (MedlinePlus, US National Library of Medicine, 2026); [MMUT gene: MedlinePlus Genetics](https://medlineplus.gov/genetics/gene/mmut/) (MedlinePlus, US National Library of Medicine, 2026); [Propionyl-CoA catabolism](https://reactome.org/PathwayBrowser/#/R-HSA-71032) (Reactome, 2026).

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Source: https://durgical.com/en/conditions/methylmalonic-acidaemia/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/conditions/methylmalonic-acidaemia/