Fumarase Deficiency (& 6 ways to manage it)


In this blog we will discuss Fumarase Deficiency in terms of the signs and symptoms it can be spotted through, its underlying causes, what lines of treatment are followed, and its prevalence.. 

Fumarase Deficiency, also known as fumaric aciduria or fumarate hydratase deficiency, is a chronic and degenerative disorder of the nervous system, especially targeting that brain, which is caused due to an abnormally low amount of fumarase in the cells.This disorder is characterised by a deficiency of the enzyme fumarate hydratase, leading to a deficiency of malate. It can manifest in form of neurological difficulties, like intellectual disabilities, epileptic seizures, and brain malformations. 

Signs and symptoms

Fumarase Deficiency, or fumaric aciduria, is an autosomal recessive disorder of the nervous system, specially affecting the brain. It can be first identified on prenatal ultrasound, with the presentation of excessive amniotic fluid in the amniotic sac (a condition termed as polyhydramnios). Neonates who are affected usually have the following signs:

  • Abnormally small head, or microcephaly
  • Hypotonia, or a weak muscle tone
  • Failure of gain weight
  • Inability to thrive or grow at expected rate
  • Severe developmental delays
  • Abnormal or atypical brain structure

Associated features of the disorder may also include: 

  • Intellectual impairment or disabilities
  • Epileptic seizures
  • Unusual facial features, like frontal bossing, small jaw, low set ears, depressed nasal bridge, and widely spaced eyes
  • Poor feeding
  • Enlarged liver and spleen
  • Excess of RBCs, i.e., red blood cells (also called polythemia)
  • Leukopenia, or deficiency of the WBCs or white blood cells

Thus, the affected tissues of areas largely include the brain, face (eyes and nasal bridge), and the liver, with a severe global developmental delay [2].

Causes/ etiology

It is caused  by the Fumarate Hydratase (FH) gene in humans, which has an autosomal recessive pattern of inheritance. This gene encodes the enzyme that is used to convert fumarate (or fumaric acid), into malate (or malic acid), in the mitochondria of the human body cells [3].  

Fumarase deficiency is a deficiency of the Krebs cycle or the tricarboxylic acid cycle (which is the cycle used by all aerobic organisms to release stored energy through a series of chemical pathways/ reactions. 

Fumarase is thus, very important for the process of cellular metabolism, which may be compromised in individuals suffering from fumarase deficiency, leading to the inability to thrive, or grow at expected rates, and the global developmental delays. 

It is fairly common in individuals born to parents who were the first cousins of individuals born with fumarase deficiency. Fumarase deficiency is characterised by elevated levels of fumaric acid in the urine, early-onset hypotonia (weak muscle tone), profound psychomotor delays, and neurological or brain related abnormalities.  


Very few individuals with the fumarase deficiency disorder survive past childhood, and most individuals suffering from this disorder don’t make it past middle adulthood. 

Unfortunately, no effective treatment currently exists for fumarase deficiency. The goal is to manage the symptoms , prevent complications, and ultimately increase the quality of life of those who suffer from fumarase deficiency. The standard management options include:

  • Feeding tube in case of poor feeding to prevent malnutrition
  • Help with activities of fairly living in case of severe intellectual impairment
  • In case of mild intellectual impairment, teaching ways of coping or adapting
  • Anticonvulsant medication to treat epileptic seizures 
  • Speech training in case of linguistic difficulties
  • Psychomotor intervention for psychomotor issues

The goal is to teach those who suffer from fumarase deficiency, and those around them, to teach with the disorder. 


It is an extremely rare disease, with around 100 reported cases worldwide (as of 2017) [1]. Thus, prevalence: <1/1000000 (worldwide) [4]. The age of onset is since conception, and the age of death is usually early. 


In this article we looked at fumarase deficiency, its signs and symptoms, its etiology or underlying causes, its prevalence, and understood the means of treatment, or in this case management of the disease. 

Frequently Asked Questions (FAQs): Fumarase deficiency

What enzyme is affected by Fumarase deficiency?

It affects the enzyme fumarate hydratase, and is thus also called fumarate hydratase disorder. It causes a buildup of fumaric acid in the urine, and a buildup of malate enzyme, which leads to inability of the mitochondria to oxidize energy. 

What is the function of Fumarase?

Fumarase is an enzyme that aids the Krebs cycle to convert fumarate to malate in the mitochondria. This process is important for the process of metabolism.

What type of enzyme is Fumarase?

It is a well- known tricarboxylic-acid-cycle enzyme, which belongs to the family of lyases, particularly the hydro-lyases, which break down the carbon-oxygen bonds.

Why is citric acid cycle important?

The citric acid cycle or the Krebs cycle, or the tricarboxylic-acid-cycle is at the center of cellular metabolism, and plays a significant role in energy production and the process of biosynthesis. 

Fumarase Disease typically affects what part of the  body most?

Fumarase Disease is a degenerative disease of the nervous system, especially the brain. Other tissues that are affected include the liver, spleen, anf facial features like the eyes and the nasal bridge. 

What do you mean by autosomal recessive inheritance?

It means that both the parents need to pass on their recessive gene containing fumarase deficiency , for the offspring to inherit this disorder. 


[1]. Fumarase deficiency. Genetics Home Reference. September, 2017; http://ghr.nlm.nih.gov/condition/fumarase-deficiency.

[2]. Fumarase Deficiency (2018) Genetic and Rare Diseased Information Center. NIH.

[3]. Fumarase deficiency (2020) Wikipedia Foundation, Inc. 

[4]. Fumarase Deficiency. Mala Cards. Human Disease Database.