What else is it called?
- Fumarate hydratase deficiency
- Fumaric aciduria
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What causes it?
This disorder is caused by a problem in the FH (fumarate hydratase) gene. This gene produces the fumarase enzyme (sometimes also known as the fumarate hydratase enzyme), which helps in the process that allows cells to use oxygen in order to produce energy. This process is needed to give energy to your brain and other neurological systems whilst they are developing.
If you have a problem in the FH gene, you will not produce enough of the fumarase enzyme. Therefore, you will be unable to produce enough energy for the cells in your brain and your nervous system to work to their full potential, and this will cause ongoing issues with your intellectual and neurological development.
How common is it?
Fumarase Deficiency is a very rare disorder, and only around 100 cases have been reported. Although the disorder appears to affect people from many different countries and ethnicities, an unusually high prevalence was found in an isolated religious community in southwestern USA. It has been suggested that this particular surge in cases may be the result of children born from interrelated marriages.
What are the signs and symptoms?
Many people with Fumarase Deficiency begin to show symptoms soon after birth. There are a wide range of symptoms and they vary depending on the severity of the person’s condition. Symptoms and signs can include:
- An abnormally small head size (microcephaly)
- Abnormal brain structure
- Severe developmental delay
- Weak muscle tone (hypotonia)
- Failure to gain weight and grow at the expected rate (failure to thrive)
- Seizures that can be severe and have been known to cause strokes
- Enlarged liver and spleen (hepatosplenomegaly)
Some people may also experience:
- An excess of red blood cells (polycythaemia)
- Recurrent vomiting
If you have Fumarase Deficiency, you are likely to have distinctive facial features, which can include an unusually prominent forehead (frontal bossing), low-set ears, a small jaw (micrognathia), a squashed nasal bridge, and widely spaced eyes.
Life expectancy is short, and most children do not live beyond early childhood. In a small number of cases where the symptoms are particularly mild, there have been reports of people living into adulthood.
How is it diagnosed?
To diagnose Fumarase Deficiency, your medical team may use specialised blood and urine tests. They may also carry out an MRI scan of the brain in order to determine the seriousness of the disorder. This may also help to identify the neurological symptoms that you are likely to have.
Sometimes, due to its rarity, the disorder is first diagnosed as a more common disorder, such as Polymicrogyria or Leigh Syndrome, before the correct diagnosis is identified.
Can it be treated?
Treatment for Fumarase Deficiency can only support you and help reduce the severity of some symptoms. There is currently no cure for this disorder.
You may be offered treatments such as medication to reduce seizures. Your medical team may also insert a feeding tube to ensure that the body is receiving the right nutrients.
In the long term, you may require support from occupational therapists, speech and language therapists, and physical therapists in order to develop social, language, and motor skills. This will be discussed with your medical team to ensure that any specific needs are met.
Due to the complex nature of Fumarase Deficiency, prognosis is poor and many children with the disorder don’t make it past early childhood although there have been reports of some people with relatively mild symptoms living into adulthood.
Do my family need to be tested?
Fumarase Deficiency is inherited from both parents in an autosomal recessive inheritance pattern. This means that both parents are carriers of the disorder through their genes.
All genes come in pairs. Carriers of Fumarase Deficiency have one working FH gene and one faulty gene. Children inherit one gene from each parent to make their pair. Whether you have Fumarase Deficiency depends on the genes you inherit:
- There is a 50% chance that the child will inherit one faulty and one working gene, which means they will also be a carrier.
- There is a 25% chance that the child will inherit two working genes and not inherit or carry the faulty gene.
- There is a 25% chance that the child will inherit two faulty genes, which means they will have Fumarase Deficiency.
Carriers of Fumarase Deficiency are likely to develop benign tumours. This is different to carriers of other disorders inherited in an autosomal recessive pattern, who typically do not show signs of having the faulty gene. Tumours are usually located in the skin and also, for females, in the uterus. There is also an increased risk of developing kidney cancer, so people who believe they may be a carrier should speak to their medical team as you may require regular check-ups.
If you think somebody in your family may have Fumarase Deficiency, or that you may be a carrier, contact your medical team who may refer you for genetic testing.