Fumarase Deficiency: Understanding the Metabolic Disorder Report

This report provides a detailed overview of Fumarase Deficiency, an inborn error of metabolism. It begins with an executive summary and table of contents, followed by an overview of the disorder, including its genetic basis and clinical manifestations. The report delves into recent research findings, diagnostic methods (biochemical and molecular), and available treatment options, including dietary interventions and genetic counseling. It also discusses relevant policies, such as newborn bloodspot screening in Australia. The report emphasizes the rarity of the condition, the diverse clinical phenotypes, and the challenges associated with diagnosis and treatment. Overall, the report aims to provide a comprehensive understanding of Fumarase Deficiency, covering its various aspects from the underlying genetic defect to the clinical management of affected individuals.

Running head: FUMARASE DEFICIENCEY
FUMARASE DEFICIENCY
Name of the Student
Name of the University
Author Note

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Executive Summary
The report briefly describes about fumarase or fumarate hydratase deficiency disorder which
is classified as an inborn error metabolic disorder. Recent researches, diagnosis, treatment
and different policies regarding fumarase deficiency are also been described in detail in this
report.

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Table of Contents
Overview....................................................................................................................................3
Research.....................................................................................................................................4
Diagnosis....................................................................................................................................5
Biochemical and molecular diagnosis....................................................................................5
Treatment...................................................................................................................................6
Policy..........................................................................................................................................6
References..................................................................................................................................7

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Overview
Inborn errors of metabolism (IEM) is cluster of rare genetic disorders characterized by
a single gene defect that in turn causes an enzyme defect in biochemical pathways. Thus,
affecting proteins, fats, carbohydrates metabolism. This report briefly describes about the
fumarate hydratase or fumarase deficiency disorder which is an inborn error metabolic
disorder. The inheritance pattern of this metabolic disorder is autosomal recessive. Fumarase
or Fumarate hydratase (FH) (EC 4.2.1.2) is a member of the class II fumarase enzymes that
helps in the reversible inter-conversion of fumarate and malate in tricarboxylic acid cycle.
Generally, there are two different types of fumarase isoenzymes. These enzymes are present
in the cytosol and mitochondria of every cell. The fumarate hydratase present in mitochondria
catalytically converts fumarate into malate during TCA cycle. On the other hand, the
fumarase present in the cytosol of a cell involves in fumarate metabolism which is connected
to the urea cycle. The mutant alleles of the FH gene are situated on human chromosome 1 at
position 1q42.1 (1).
FH deficiency shows a diverse clinical phenotype along with deadly outcome within
the first 2 years of life. FH deficiency also shows a sub-acute encephalopathy and different
types of brain developmental disorders. Due to FH deficiency some sensitive metabolic crises
arises in our body. Some sensitive metabolic crises include ketosis, hypoglycaemia and
acidosis. Antenatal symptoms of FH deficiency include intrauterine growth retardation,
internal & external hydrocephalus and other brain abnormalities (2).

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Research
(a) (b)
(a) Schematic of different steps in TCA cycle; (b) Inactivity of fumarase in TCA cycle
Source: (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122040/)
Fumarase deficiency is exceptional. So far, less than 100 fumarase deficiency cases
have been seen across the world. This metabolic disorder is predominantly seen in individuals
of diverse cultural backgrounds. Fumarate hydratase deficiency may give rise to acute
neonatal and infantile encephalopathy. Fumarase deficiency is considered by deprived
hypotonia, difficulty in normal feeding, stupor, and seizures. There are various dysmorphic
facial appearances are seen in a fumarase deficient patient. Dysmorphic facial appearances
include frontal bossing, uneven nasal bridge as well as broadly spaced eyes. Individuals
affected with fumarate hydratase deficiency are always microcephalic (2). A wide variety of
brain deformities are observed on brain magnetic resonance imaging (MRI). Developmental
brain disorders are commonly seen such as bilateral polymicrogyria, multiple sclerosis and
thinning of the corpus callosum. Due to the absence of corpus callosum cross-talk between
the two hemispheres (Right hemisphere and left hemisphere of brain) are severely affected.
Thus, most of the individuals affected with fumarate hydratase deficiency are non-verbal (3).

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ERK signalling pathway has been severely affected in the individuals with fumarate
hydratase deficiency. Due to the severe affection in ERK pathway, abnormal accumulation of
short hairpin RNA (shRNA) is observed in tissues like kidney, liver and prostate. Recent
researches have focused the role of fumarase as a contributor in the response to DNA double
strand breaks (DSBs) in the nucleus. Recently, it has been found that the cytosolic fumarate
hydtatase and its enzymatic activity are necessary for the cellular DNA damage response
(DDR) to double-strand breaks (4).
Diagnosis
Biochemical and molecular diagnosis
To diagnose a genetic disease precisely, several sophisticated biochemical tests are
needed. To diagnose fumarate hydratase deficiency precisely and accurately healthcare
experts specifically observe a person’s therapeutic history, physical exam, symptoms and
pathological reports. The Genetic Testing Registry (GTR) delivers statistics about the genetic
tests for this particular disorder. Analysing the rapid rise in the concentration of fumaric acid
in urine is significantly recommended in order to diagnose fumarate hydratase deficiency. An
increased level of fumaric acid in urine occurs due to metabolic stress. Diagnosis of this
disease is discovered by identification of reduced activity of fumarate hydratase enzyme in
lymphoblasts and fibroblasts by molecular genetic testing of FH. MRI of a fumarate
hydratase deficient patients’ brain discloses different types of brain anomalies such as
macrocephaly, inflated extra-axial cerebral spinal fluid (CSF) spaces, multiple sclerosis,
cerebral atrophy, delayed myelination, thinning of the corpus callosum (1).
Treatment
No such proper therapeutic techniques are available to prevent the abnormalities
occurred due to fumarate hydratase deficiency. Various progressive treatments are available

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to prevent the abnormalities related with deficiency of fumarate hydratase. Progressive
treatments may comprise regular treatments that are helpful to manage seizures occur during
epilepsy; gastrostomy treatment to improve nutrition as well as to hinder aspiration;
orthopedic therapy to diminish contractures and scoliosis. In order to treat fumarate hydratase
deficiency particular commendations are recommended to know about each patient's
individual necessities. Specific recommendations may include an annual assessments by
pediatric neurology and general neuro-medicine. Treatment of fumarate hydratase deficiency
also may include episodic assessments by genetics and orthopedic surgery. The ketogenic
diet is known to be the most effective treatment for treating epileptic seizures which are
commonly seen in the patients of fumarate hydratase deficiency. Genetic counselling is also
considered to be the most effective treatment for the fumarase deficiency (5).
Policy
In Australia, for the proper screening of neonatal and infantile metabolic disorders
newborn bloodspot screening (NBS) policy has been introduced by Australian Government.
The purpose of NBS is to recognize rare genetic as well as non-genetic disorders in children.
This, in turn, develops different therapies to prevent the progressive, irreversible and rare
disabilities at the very beginning (6).

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References
1. Ewbank C, Kerrigan JF, Aleck K. Fumarate hydratase deficiency.
InGeneReviews®[Internet] 2013 Apr 4. University of Washington, Seattle.
2. Chaturvedi S, Singh AK, Keshari AK, Maity S, Sarkar S, Saha S. Human metabolic
enzymes deficiency: a genetic mutation based approach. Scientifica. 2016;2016.
3. Ryder B, Moore F, Mitchell A, Thompson S, Christodoulou J, Balasubramaniam S.
Fumarase deficiency: A safe and potentially disease modifying effect of high fat/low
carbohydrate diet. InJIMD Reports, Volume 40 2017 (pp. 77-83). Springer, Berlin,
Heidelberg.
4. Leshets M, Silas YB, Lehming N, Pines O. Fumarase: From the TCA cycle to DNA
damage response and tumor suppression. Frontiers in molecular biosciences. 2018;5:68.
5. Linehan WM, Rouault TA. Molecular pathways: fumarate hydratase-deficient kidney
cancer—targeting the Warburg effect in cancer. Clinical cancer research. 2013 Jul
1;19(13):3345-52.
6. Therrell BL, Padilla CD, Loeber JG, Kneisser I, Saadallah A, Borrajo GJ, Adams J.
Current status of newborn screening worldwide: 2015. InSeminars in Perinatology 2015 Apr
1 (Vol. 39, No. 3, pp. 171-187). WB Saunders.