Tyrosinemia

Submitted By : Tirth A Patel (20SC02030)

Submitted To : Dr. Saroj Shekhawat
B.Sc Biotechnology ( 3rd sem )
GSFC University, Vadodara
 Introduction
• Tyrosinemia type I is a rare autosomal recessive metabolic
disorder caused by a lack of the enzyme fumarylacetoacetate
hydrolase (FAH), which is essential for the amino acid tyrosine's
ultimate breakdown.
• Inadequate tyrosine breakdown leads to an abnormal
accumulation of tyrosine and its metabolites in the liver, which
can cause significant liver damage. Tyrosine can also accumulate
in the kidneys and central nervous system.
• Tyrosinemia type I may progress to more serious complications
such as severe liver disease, cirrhosis, and hepatocarcinoma if left
untreated. 
• As a result, we may conclude that those suffering from this
ailment require adequate care and medicine.

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 Genetic Inheritance Pattern
• Tyrosinemia type I is a hereditary autosomal recessive disorder. The gene's mutant alleles are passed down from both parents.
The fumarylacetoacetate hydrolase (FAH) enzyme gene, which is found on chromosome 15, has a genetic mutation. IVS12+5(G-
>A) and IVS6-1(G-T) mutations are the most prevalent. This mutation leads in an enzyme that is no longer functioning.
• Tyrosinemia type 1 is inherited as an autosomal recessive trait.
• To be impacted by an autosomal recessive condition, two copies of the gene must be mutated. Unaffected parents, who each have
a single copy of the mutant gene and are referred to be genetic carriers, are common among affected people.
• Normally, neither parent with a faulty gene exhibits symptoms. With each pregnancy, two unaffected people who each possess
one copy of the mutant gene have a 25% chance of conceiving a kid with the condition.

• For instance this figure shows the genetic inheritance pattern for tyrosinemia.
• Here, both the parents are carrier for this disease.
• So, out of 4 offspring 2 will be carrier of this disorder, 1 will receives non mutated alleles from each parents and 1 will receives
mutated alleles from both the parents. 3
 Responsible Factors For This Mutation
 Mutagens are the agents either physical, chemical or biological that causes
mutations by altering the nucleotide sequence of gene which results in genetic
abnormality.
1. Biological Mutagens : Viruses, bacteria and transposon (non-coding DNA
sequence) are biological mutagens.
2. Physical Mutagens : Physical mutagens include electromagnetic radiation, such
as gamma rays, X rays, and UV light, and particle radiation, such as fast and
thermal neutrons, beta and alpha particles.
3. Chemical Mutagens : Most chemical mutagens are alkylating agents and azides

• 95 mutations in FAH enzyme gene.

• Among the known HT1 alleles causing
mutations, 45 are missense mutations, 23 are
splicing mutations, 13 are nonsense mutations,
10 are deletions and 4 are frameshift.

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 Biochemical Pathway
• Fumarylacetoacetate hydrolase catalyzes the final step in the degradation
of tyrosine - fumarylacetoacetate to fumarate and acetoacetate.
• The increase in fumarylacetoacetate inhibits previous steps in tyrosine
degradation leading to an accumulation of tyrosine in the body.

Tyrosine metabolic pathway

• FAH enzyme mutations result in nonfunctional FAH in all cells expressing this gene, impairing tyrosine metabolism.
• When FAH is depleted, upstream chemicals in the catabolic pathway accumulate. Maleylacetoacetate (MAA) and fumarylacetoacetate are two
of them (FAA). Succinylacetoacetate (SAA) is formed from MAA and FAA, which is subsequently catabolized to succinylacetone (SA).
• The buildup of MAA, FAA, and SA in cells prevents thiol compounds from being broken down, resulting in post-translational changes to the
antioxidant glutathione. This reduces glutathione's antioxidant action, causing reactive oxygen species (ROS) to damage cell components.
• The buildup of hazardous metabolic intermediates and high amounts of reactive oxygen species (ROS) in liver and kidney cells causes
apoptosis, which leads to organ failure. SA builds up in the liver and kidney cells, which causes it to be released into the circulation, causing
secondary consequences.The enzyme 5-ALA dehydratase, which converts aminolevulinic acid (5-ALA) to porphobilinogen, a precursor to
porphyrin, is inhibited by SA. As a result, porphyrin deposits accumulate in the circulation, causing neuropathic pain and the severe
neurological crises that some patients suffer. Additionally. SA has the ability to impair renal tubular function, heme production, and immune
system.
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• Deficient catabolism can result in a buildup of unprocessed tyrosine in the bloodstream, which can affect hormonal
signalling and neurotransmission. 
• Tyrosine is a precursor molecule for various neurotransmitters and hormones, including dopamine, norepinephrine, and
thryoxine. 
• Increased tyrosine levels cause excessive production of these molecules, which can impede physical growth, motor
function, and speech development.

Overview of Tyrosine Metabolic Pathway 6

 Symptoms
• Symptoms include failure to gain weight and grow at the expected rate (failure to thrive),
• fever, diarrhea,
• vomiting,
• an abnormally enlarged liver (hepatomegaly)
• yellowing of the skin and the whites of the eyes (jaundice).
• accumulation of fluid (edema) in the abdomen (ascites).
• liver failure and blood clotting abnormalities (coagulopathy).

Diagnosis
•  The definitive criterion for diagnostic assessment of Tyrosinemia Type I is elevated succinylacetone (SA) in blood
and urine.
• Molecular genetic testing for FAH gene mutations is available to confirm the diagnosis.
• Succinylacetone can be measured on the newborn blood spot by tandem mass spectroscopy. 
• Next Generation DNA sequencing techniques, like exome sequencing, whole genome sequencing (WGS) can help in
identifying the mutations responsible for the disease.
• Prenatal diagnosis is also possible by detection of succinylacetone and DNA analysis in amniotic fluid.

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 Treatment
• There is currently no cure for tyrosinemia type 1. Individuals with this condition need to be on a special diet restricted
in two amino acids, tyrosine and phenylalanine, throughout life.

1. Diet :
• The prescribed diet for treatment of HT1 is low in protein.
• Patients received amino acid supplements lacking tyrosine and phenylalanine in order to acquire sufficient protein.
•  The ideology behind maintaining low tyrosine levels is two-fold. Firstly, it prevents the toxic metabolic intermediates
from accumulating
• Secondly, the mechanism of action of nitisinone is prevention of any tyrosine metabolism, thus it is important to
prevent tyrosine from accumulating.

2. Medication :
• Nitisinone is prescribed ultimately to reduce the accumulation of toxic metabolic intermediates.
• It is recommended that nitisinone treatment begins immediately following a confirmed or suspected case of HT1
• Patient responsiveness to nitisinone is assessed by measuring blood
coagulation activity and SA levels in blood and urine. 

Nitisinone 8
 Predicted Future Treatment
• As we've already stated, there is currently no medication that promises to prevent or cure these disorders. But, to the
best of my knowledge, we can prevent this disease by having both parents take a test before planning for the baby. So, if
one or both parents are carriers or suffer from certain disorders, we can learn about the baby's genotype.
• Because this is an autosomal recessive illness, there is no possibility of the disease being passed down to the kid unless
both parents have the disease or are carriers for it.
• When both parents have illnesses or are carriers of a disease and yet wish to have a child, gene editing at an early
embryonic stage is one feasible answer, in my opinion.
• Because the FAH gene is located on the austosomal chromosome, there are no ethical concerns with executing this sort
of editing.
• So, based on my study and understanding, gene editing may be an appropriate treatment for this illness.

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THANK
YOU