Conditions · Metabolism (biochemistry)
Fumarase deficiency !
Fumarase deficiency is a very rare genetic disease of the Krebs cycle that causes severe brain damage from birth.
Updated 2026-10-31
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In biochemistry
What it is
Lack of fumarate hydratase (FH gene) from variants in both copies of the gene: fumarate does not become malate and is lost in the urine.
Who gets it
Very rare; only a few dozen cases have been described worldwide.
Causes
- Autosomal recessive inheritance, FH gene
- A single altered copy does not cause this picture but hereditary leiomyomatosis and renal cell cancer (HLRCC)
Risk factors
- Carrier or related parents
Pathophysiology
Without fumarase the Krebs cycle is cut and the developing brain does not get enough energy; neuronal migration and brain growth are disturbed. Stored fumarate modifies proteins and the hypoxia signal.
Symptoms and signs
- Low muscle tone and poor feeding from birth
- Seizures
- Severe developmental delay
- Distinctive facial features and a large or small head
Diagnosis
- Clinical
- Newborn encephalopathy with brain malformations and mild acidosis.
- Tests
- Urine organic acids with very high fumarate; fumarase activity in fibroblasts or lymphocytes; FH gene testing.
- Imaging
- MRI: large ventricles, polymicrogyria, a small or absent corpus callosum.
Treatment
- Medical
- Supportive care: seizure control and nutrition
- Rehabilitation
- Rehabilitation therapies
- Follow-up
- Genetic counselling for the family; carriers (one copy) need kidney and skin surveillance for HLRCC
Complications
- Hard-to-control epilepsy
- Severe disability
Test yourself
Think of the answer, then tap the question to see it.
Which metabolite is very high in the urine?
Fumarate.
What does a single altered FH copy cause?
Hereditary leiomyomatosis and renal cell cancer (HLRCC).
Which step of the cycle fails?
Step 7: fumarate + water → malate.
Related conditions
Educational information, not medical advice. For any symptom, see a health professional.
Sources: Fumarase deficiency: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); FH gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Hereditary leiomyomatosis and renal cell cancer: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026).
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