Tyrosinemia type I is a
genetic disorder
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorde ...
that disrupts the
metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...
of the amino acid
tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
, resulting in damage primarily to the
liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...
along with the
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; bloo ...
s and
peripheral nerves
The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain an ...
.
The inability of cells to
process
A process is a series or set of activities that interact to produce a result; it may occur once-only or be recurrent or periodic.
Things called a process include:
Business and management
*Business process, activities that produce a specific se ...
tyrosine can lead to
chronic liver damage ending in
liver failure, as well as
renal disease
Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can b ...
and
rickets
Rickets is a condition that results in weak or soft bones in children, and is caused by either dietary deficiency or genetic causes. Symptoms include bowed legs, stunted growth, bone pain, large forehead, and trouble sleeping. Complications ma ...
. Symptoms such as
poor growth and
enlarged liver
Hepatomegaly is the condition of having an enlarged liver. It is a non-specific medical sign having many causes, which can broadly be broken down into infection, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdomi ...
are associated with the clinical presentation of the disease.
Clinical manifestation of disease occurs typically within the first two years of life. The severity of the disease is correlated with the timing of onset of symptoms, earlier being more severe.
Tyrosinemia type I is an
autosomal recessive
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and ...
disorder caused by
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
s in both copies of the
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
encoding the
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
fumarylacetoacetate hydrolase (FAH). FAH is a metabolic enzyme that catalyzes the conversion of
fumarylacetoacetate
Fumarylacetoacetic acid (fumarylacetoacetate) is an intermediate in the metabolism of tyrosine. It is formed through the conversion of maleylacetoacetate into fumarylacetoacetate by the enzyme maleylacetoacetate isomerase.
See also
* Fumarylace ...
to
fumarate
Fumaric acid is an organic compound with the formula HO2CCH=CHCO2H. A white solid, fumaric acid occurs widely in nature. It has a fruit-like taste and has been used as a food additive. Its E number is E297.
The salts and esters are known as f ...
and
acetoacetate
Acetoacetic acid (also acetoacetate and diacetic acid) is the organic compound with the formula CHCOCHCOOH. It is the simplest beta-keto acid, and like other members of this class, it is unstable. The methyl and ethyl esters, which are quite stab ...
. It is expressed primarily in the liver and kidney. Loss of FAH activity results in the accumulation of certain
metabolic intermediate
Metabolic intermediates are molecules that are the precursors or metabolites of biologically significant molecules.
Although these intermediates are of relatively minor direct importance to cellular function, they can play important roles in the a ...
s in the tyrosine
catabolic pathway
Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipids, ...
.
These compounds are toxic to cells and lead to
differential gene expression and
apoptosis in high concentrations.
HT1 is diagnosed when elevated levels of
succinylacetone (SA), one of the metabolites in this pathway, is detected in
blood
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in th ...
and
urine samples
A urine test is any medical test performed on a urine specimen. The analysis of urine is a valuable diagnostic tool because its composition reflects the functioning of many body systems, particularly the kidneys and urinary system, and specimens a ...
.
While there is no cure for tyrosinemia type I, management of the disease is possible utilizing
dietary restrictions and
medication
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field an ...
s. A diet low in tyrosine and
phenylalanine
Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...
is utilized indefinitely once a diagnosis is suspected or confirmed. Additionally, the drug
nitisinone
Nitisinone, sold under the brand name Orfadin among others, is a medication used to slow the effects of hereditary tyrosinemia type 1 (HT-1).
Uses
Nitisinone is used to treat hereditary tyrosinemia type 1 (HT-1) in patients from all ages, in com ...
(brand name
Orfadin
Nitisinone, sold under the brand name Orfadin among others, is a medication used to slow the effects of hereditary tyrosinemia type 1 (HT-1).
Uses
Nitisinone is used to treat hereditary tyrosinemia type 1 (HT-1) in patients from all ages, in co ...
) is prescribed and continued indefinitely in order to combat liver and kidney damage, promoting normal function of these organs.
Prior to the development of nitisinone, dietary restrictions and liver transplantation were the only forms of treatment for HT1.
Tyrosinemia type I is especially prevalent in the
Saguenay-Lac Saint-Jean region of
Quebec
Quebec ( ; )According to the Government of Canada, Canadian government, ''Québec'' (with the acute accent) is the official name in Canadian French and ''Quebec'' (without the accent) is the province's official name in Canadian English is ...
, where the prevalence is 1 in 1,850 births. It is most common among those with
French-Canadian ancestry and this frequency of infliction has been attributed to the
founder effect
In population genetics, the founder effect is the loss of genetic variation that occurs when a new population is established by a very small number of individuals from a larger population. It was first fully outlined by Ernst Mayr in 1942, usi ...
. There are five other known types of tyrosinemia, all of which derange the metabolism of tyrosine in the human body. They are distinguished by their symptoms and genetic cause.
Signs and symptoms
Type 1 tyrosinemia typically presents in infancy as failure to thrive and
hepatomegaly
Hepatomegaly is the condition of having an enlarged liver. It is a non-specific medical sign having many causes, which can broadly be broken down into infection, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an ab ...
. The primary effects are progressive liver and kidney dysfunction. The liver disease causes cirrhosis, conjugated hyperbilirubinemia, elevated AFP, hypoglycemia and coagulation abnormalities. This can lead to
jaundice
Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme met ...
,
ascites
Ascites is the abnormal build-up of fluid in the abdomen. Technically, it is more than 25 ml of fluid in the peritoneal cavity, although volumes greater than one liter may occur. Symptoms may include increased abdominal size, increased weight, a ...
and hemorrhage. There is also an increased risk of
hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide.
It occurs in th ...
.The kidney dysfunction presents as
Fanconi syndrome
Fanconi syndrome or Fanconi's syndrome (, ) is a syndrome of inadequate reabsorption in the proximal renal tubules of the kidney. The syndrome can be caused by various underlying congenital or acquired diseases, by toxicity (for example, from toxi ...
: Renal tubular acidosis, hypophosphatemia and aminoaciduria. Cardiomyopathy, neurologic and dermatologic manifestations are also possible. The urine has an odor of cabbage or rancid butter.
The presentation of symptoms of tyrosinemia type 1 in terms of timing is broken into three categories: acute, sub-acute, and chronic.
The acute classification typically is presented clinically between birth and 6 months of age. The common presentation in an acute case is
synthetic liver failure, marked by the lack of formation of
coagulation factors
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanis ...
in
blood
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in th ...
. Patients are prone to infections at this stage accompanied by
fever
Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...
,
vomiting
Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.
Vomiting can be the result of ailments like food poisoning, gastroenteri ...
, increased tendency to
bleed, and
diarrhea
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin ...
along with
bloody feces as manifestations of
sepsis
Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is foll ...
. Other symptoms include
enlarged liver
Hepatomegaly is the condition of having an enlarged liver. It is a non-specific medical sign having many causes, which can broadly be broken down into infection, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdomi ...
,
jaundice
Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme met ...
, and
excess abdominal fluid.
Sub-acute cases present between 6 months and the first year of life and the severity of
liver disease
Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.
Signs and symptoms
Some of the s ...
is lessened to an extent. Again, synthetic function of the liver in terms of blood coagulation factors is impaired in addition to
enlargement of the liver and spleen. The infant may also display a
failure to thrive
Failure to thrive (FTT), also known as weight faltering or faltering growth, indicates insufficient weight gain or absence of appropriate physical growth in children. FTT is usually defined in terms of weight, and can be evaluated either by a low ...
as their growth is limited by the disease. This growth impairment can manifest itself in
rickets
Rickets is a condition that results in weak or soft bones in children, and is caused by either dietary deficiency or genetic causes. Symptoms include bowed legs, stunted growth, bone pain, large forehead, and trouble sleeping. Complications ma ...
, which is the softening of bones.
The final classification, chronic HT1, is detected with presentations occurring after one year of life. The course of the disease up to this point can lead to different ailments affecting the liver.
Cirrhosis
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...
,
liver failure, or
cancer of the liver may present as a result of chronic liver disease. Additional symptoms common in this classification include
cardiomyopathy
Cardiomyopathy is a group of diseases that affect the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. ...
,
renal disease
Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can b ...
, and
acute neurological crises.
Liver
The liver is the organ affected most by Tyrosinemia Type I due to the high level of expression of the gene for fumarylacetoacetate hydrolase (FAH) in liver cells. The production of blood coagulation factors by the liver is disrupted, causing
hemophiliac-like symptoms. Acute liver failure is common, especially in early life. Additionally, the synthesis of
albumin
Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...
in the liver may be defective, therefore leading to
hypoalbuminemia
Hypoalbuminemia (or hypoalbuminaemia) is a medical sign in which the level of albumin in the blood is low. This can be due to decreased production in the liver, increased loss in the gastrointestinal tract or kidneys, increased use in the body, or ...
. As the disease progresses,
cirrhosis
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...
is common. This can lead to a
fatty liver
Fatty liver disease (FLD), also known as hepatic steatosis, is a condition where excess fat builds up in the liver. Often there are no or few symptoms. Occasionally there may be tiredness or pain in the upper right side of the abdomen. Complic ...
and the
development of tumors in areas affected by this scarring of liver tissue. These scars are known as nodules.
There is a 37% chance of developing a
hepatocellular carcinoma (HCC) for untreated patients.
Renal and neurological manifestations
Many patients display impaired kidney function and neurological symptoms. In addition to liver cells, kidney cell expression involves expression of the gene for FAH. Kidney failure is a potential result of impaired kidney function, but the most common symptom associated with renal dysfunction is
hypophosphatemic rickets
X-linked hypophosphatemia (XLH) is an X-linked dominant form of rickets (or osteomalacia) that differs from most cases of dietary deficiency rickets in that vitamin D supplementation does not cure it. It can cause bone deformity including short st ...
.
Neurological manifestations are characterized by acute neurological crises due to overaccumulation of
porphyrin
Porphyrins ( ) are a group of heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH−). The parent of porphyrin is porphine, a rare chemical ...
. These crises are characterized by
porphyria
Porphyria is a group of liver disorders in which substances called porphyrins build up in the body, negatively affecting the skin or nervous system. The types that affect the nervous system are also known as acute porphyria, as symptoms are ra ...
. They typically follow an infection. Patients can present with a variety of varied symptoms including
paresthesia
Paresthesia is an abnormal sensation of the skin (tingling, pricking, chilling, burning, numbness) with no apparent physical cause. Paresthesia may be transient or chronic, and may have any of dozens of possible underlying causes. Paresthesias ar ...
s,
abdominal pain
Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues.
Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a m ...
,
pain-induced seizures, and can result in
self-mutilation
Self-harm is intentional behavior that is considered harmful to oneself. This is most commonly regarded as direct injury of one's own skin tissues usually without a suicidal intention. Other terms such as cutting, self-injury and self-mutilatio ...
in response to this pain. Episodes can last for 1–7 days and can lead to
neuropathy
Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...
.
Genetics

Tyrosinemia type I is an
autosomal recessive inherited condition. Mutant
allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
s in the
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
are inherited from both parents. The genetic mutation occurs to the fumarylacetoacetate hydrolase (FAH) enzyme gene, located on
chromosome 15
Chromosome 15 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 15 spans about 102 million base pairs (the building material of DNA) and represents between 3% and 3.5% of the total DNA ...
. The most common mutation is IVS12+5(G->A) which is a mutation in the
splice site consensus sequence of
intron
An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene ...
12, therefore affecting
exon
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequenc ...
12. A second allele is the IVS6-1(G-T) mutation. This mutation results in a nonfunctional enzyme.
Type 1 tyrosinemia is inherited in an autosomal recessive pattern.
Pathophysiology
Fumarylacetoacetate hydrolase catalyzes the final step in the degradation of
tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
- fumarylacetoacetate to fumarate, acetoacetate and succinate. Fumarylacetoacetate accumulates in
hepatocytes
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, bi ...
and proximal renal tubal cells and causes oxidative damage and DNA damage leading to cell death and dysfunctional gene expression which alters metabolic processes like protein synthesis and
gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non- carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verteb ...
. The increase in fumarylacetoacetate inhibits previous steps in tyrosine degradation leading to an accumulation of tyrosine in the body. Tyrosine is not directly toxic to the liver or kidneys but causes dermatologic and neurodevelopmental problems.
Tyrosine metabolic pathway

Fumarylacetoacetate hydrolase (FAH) is the final enzyme in the tyrosine metabolic pathway.
The mutation of FAH enzyme results in nonfunctional FAH in all cells expressing this gene and thus metabolizing tyrosine is impaired. FAH catalyzes the conversion of
fumarylacetoacetate
Fumarylacetoacetic acid (fumarylacetoacetate) is an intermediate in the metabolism of tyrosine. It is formed through the conversion of maleylacetoacetate into fumarylacetoacetate by the enzyme maleylacetoacetate isomerase.
See also
* Fumarylace ...
to
fumarate
Fumaric acid is an organic compound with the formula HO2CCH=CHCO2H. A white solid, fumaric acid occurs widely in nature. It has a fruit-like taste and has been used as a food additive. Its E number is E297.
The salts and esters are known as f ...
and
acetoacetate
Acetoacetic acid (also acetoacetate and diacetic acid) is the organic compound with the formula CHCOCHCOOH. It is the simplest beta-keto acid, and like other members of this class, it is unstable. The methyl and ethyl esters, which are quite stab ...
. Loss of FAH results in the accumulation of upstream compounds in the catabolic pathway. These include
maleylacetoacetate (MAA) and
fumarylacetoacetate (FAA). MAA and FAA are converted to
succinylacetoacetate (SAA) which is then catabolized to
succinylacetone (SA).
The accumulation of MAA, FAA, and SA in cells inhibits the breakdown of
thiol derivatives, leading to post-translational modifications to the
antioxidant
Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricants ...
glutathione
Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pe ...
. This inhibits the antioxidant activity of glutathione, leading to
reactive oxygen species (ROS)
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () ...
damaging cell components. Over time, the combined effect of accumulation of toxic metabolic intermediates and elevated ROS levels in liver and kidney cells leads to
apoptosis in these tissues which ultimately results in organ failure.
Accumulated SA in liver and kidney cells results in its release into the bloodstream, which leads to secondary effects. SA inhibits the enzyme
5-ALA dehydratase which converts
aminolevulinic acid (5-ALA) into
porphobilinogen
Porphobilinogen (PBG) is an organic compound that occurs in living organisms as an intermediate in the biosynthesis of porphyrins, which include critical substances like hemoglobin and chlorophyll.
The structure of the molecule can be described a ...
, a precursor to
porphyrin
Porphyrins ( ) are a group of heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH−). The parent of porphyrin is porphine, a rare chemical ...
. Consequently, porphyrin deposits form in the bloodstream and cause
neuropathic pain
Neuropathic pain is pain caused by damage or disease affecting the somatosensory system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli ( allodynia). It may have continuo ...
, leading to the acute neurological crises experienced by some patients. Additionally. SA can function to inhibit
renal tubular function, the
synthesis of heme, and the
immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as Tumor immunology, cancer cells and objects such ...
.
The accumulation of unprocessed
tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
itself in the blood stream as a consequence of deficient catabolism can also lead to disruption of
hormonal signaling and
neurotransmission
Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron), ...
. Tyrosine is a precursor molecule required for synthesis of several neurotransmitters and hormones, mainly
Dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 8 ...
,
norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad ...
, and
thryoxine. Excessive synthesis of these molecules due to elevated tyrosine levels can impair physical growth,
motor function
Motor control is the regulation of movement in organisms that possess a nervous system. Motor control includes reflexes as well as directed movement.
To control movement, the nervous system must integrate multimodal sensory information (both ...
, and speech development.
Diagnosis

Beyond the identification of physical clinical symptoms outlined above, the definitive criterion for diagnostic assessment of Tyrosinemia Type I is elevated succinylacetone (SA) in
blood
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in th ...
and
urine
Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra.
Cellular ...
. Elevated SA levels are not associated with any other known medical condition, so there is minimal risk of misdiagnosis.
Quantitation of tyrosine levels is also used as a diagnostic but is less reliable due to high false positive and false negative rates.
Newborns are not generally screened for HT1 due to rarity of the condition and lack of apparent symptoms at time of birth.
However, prompt assessment upon the manifestation of physical symptoms such as
fever
Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...
,
vomiting
Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.
Vomiting can be the result of ailments like food poisoning, gastroenteri ...
, increased tendency to
bleed,
diarrhea
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin ...
along with
bloody feces, and
jaundice
Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme met ...
is critical for improving long term prognosis.
Management
The primary treatment for type 1 tyrosinemia is
nitisinone
Nitisinone, sold under the brand name Orfadin among others, is a medication used to slow the effects of hereditary tyrosinemia type 1 (HT-1).
Uses
Nitisinone is used to treat hereditary tyrosinemia type 1 (HT-1) in patients from all ages, in com ...
and restriction of tyrosine in the diet.
Nitisinone inhibits the conversion of 4-OH phenylpyruvate to homogentisic acid by
4-Hydroxyphenylpyruvate dioxygenase
4-Hydroxyphenylpyruvate dioxygenase (HPPD), also known as α-ketoisocaproate dioxygenase (KIC dioxygenase), is an Fe(II)-containing non-heme oxygenase that catalyzes the second reaction in the catabolism of tyrosine - the conversion of 4-hydroxy ...
, the second step in tyrosine degradation. By inhibiting this enzyme, the accumulation of the fumarylacetoacetate is prevented. Previously, liver transplantation was the primary treatment option and is still used in patients in whom nitisinone fails.
Clinical treatment of HT1 relies on medications and strict
regulation of diet. Nitisinone and dietary restrictions that decrease the amount of
tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
and
phenylalaine absorbed from the
GI tract
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans an ...
during protein
digestion
Digestion is the breakdown of large insoluble food molecules into small water-soluble food molecules so that they can be absorbed into the watery blood plasma. In certain organisms, these smaller substances are absorbed through the small intest ...
are used in combination as therapeutic measures that control the disease state if they are continued indefinitely. If not, there is a lack of control over the disease, resulting in continued liver and kidney damage, contributing to
organ failure
Organ dysfunction is a condition where an organ does not perform its expected function. Organ failure is organ dysfunction to such a degree that normal homeostasis cannot be maintained without external clinical intervention.
It is not a diagnosi ...
and
death
Death is the irreversible cessation of all biological functions that sustain an organism. For organisms with a brain, death can also be defined as the irreversible cessation of functioning of the whole brain, including brainstem, and brain ...
. In this case, a liver transplant may be required.
Levels of SA are monitored throughout treatment in order to assess treatment effectiveness.
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. It is recommended that tyrosine levels remain below 500 μmol/L.
Phenylalnine is the precursor to tyrosine. The ideology behind maintaining low tyrosine levels is two-fold. Firstly, it prevents the toxic metabolic intermediates from accumulating as a result of the dysfunctional tyrosine metabolic pathway. Prior to the introduction of nitisinone, this was the main treatment measure. Secondly, the mechanism of action of nitisinone is prevention of any tyrosine metabolism, thus it is important to prevent tyrosine from accumulating. Dietary protein consumption while taking nitisinone can also lead to side effects affecting the ocular system, which are easily reversed by removing protein from the diet.
Medication
Nitisinone
Nitisinone, sold under the brand name Orfadin among others, is a medication used to slow the effects of hereditary tyrosinemia type 1 (HT-1).
Uses
Nitisinone is used to treat hereditary tyrosinemia type 1 (HT-1) in patients from all ages, in com ...
is prescribed ultimately to reduce the accumulation of toxic metabolic intermediates, such as succinylacetate, which are toxic to cells. It modifies the function of
4-hydrooxyphenylpyruvate dioxygenase by acting as a
competitive inhibitor
Competitive inhibition is interruption of a chemical pathway owing to one chemical substance inhibiting the effect of another by competing with it for binding or bonding. Any metabolic or chemical messenger system can potentially be affected b ...
. 4-hydrooxyphenylpyruvate dioxygenase functions to convert
4-hydroxyphenylpyruvate
4-Hydroxyphenylpyruvic acid (4-HPPA) is an intermediate in the metabolism of the amino acid phenylalanine. The aromatic side chain of phenylalanine is hydroxylated by the enzyme phenylalanine hydroxylase to form tyrosine. The conversion from tyr ...
to
homogentisate
Homogentisic acid (2,5-dihydroxyphenylacetic acid) is a phenolic acid usually found in '' Arbutus unedo'' (strawberry-tree) honey. It is also present in the bacterial plant pathogen ''Xanthomonas campestris'' pv. ''phaseoli'' as well as in the ...
as the second enzymatic reaction in the tyrosine catabolic pathway. This prevents the further catabolism of tyrosine.
It is recommended that nitisinone treatment begins immediately following a confirmed or suspected case of HT1.
It is supplied orally as a
capsule or
suspension
Suspension or suspended may refer to:
Science and engineering
* Suspension (topology), in mathematics
* Suspension (dynamical systems), in mathematics
* Suspension of a ring, in mathematics
* Suspension (chemistry), small solid particles suspen ...
in dose increments of 2 mg, 5 mg, 10 mg, or 20 mg or 4 mg/mL respectively.
The starting dose is 1 mg/kg one time daily or 2 mg/kg one time daily for 48 hours if the patient is experiencing acute liver failure. Patient responsiveness to nitisinone is assessed by measuring
blood coagulation activity and SA levels in blood and urine. Patients should display a
positive response within 24–48 hours of first dose. Establishment of the long-term dosage will vary from patient to patient. It is recommended that nitisinone levels be maintained at 30-50 μM in the blood stream.
Prognosis
Prior to the development of nitisinone, dietary restrictions and liver transplantation were the only forms of treatment for HT1.
A study regarding the efficacy of treatment with nitisinone and dietary restrictions found that 93% of people survived at two years, four years, and six years indicating the prognosis of stabilizing the HT1 disease state is positive.
Epidemiology
Tyrosinemia type I affects males and females in equal numbers. Its prevalence has been estimated to be 1 in 100,000 to 120,000 births worldwide. HT1 is especially prevalent in the
Saguenay-Lac Saint-Jean region of
Quebec
Quebec ( ; )According to the Government of Canada, Canadian government, ''Québec'' (with the acute accent) is the official name in Canadian French and ''Quebec'' (without the accent) is the province's official name in Canadian English is ...
is one in 1,850 births. The elevated frequency of this disorder within individuals of
French-Canadian ancestry in Quebec is believed to be due to reduced genetic heterogeneity within the original founder population for the Saguenay-Lac Saint-Jean region. The initial settlement of Saguenay Lac-Saint-Jean (SLSJ) occurred between 1838 and 1911. From a total of 28,656 settlers, 75 percent originated from the neighboring
Charlevoix
Charlevoix ( , ) is a cultural and natural region in Quebec, on the north shore of the Saint Lawrence River as well as in the Laurentian Mountains area of the Canadian Shield. This dramatic landscape includes rolling terrain, fjords, headlan ...
region. The settling of the Charlevoix region itself started in 1675 when 599 founders of mostly French descent moved to this region from the Quebec City area.
Worldwide, type I tyrosinemia affects about 1 person in 100,000. This type of tyrosinemia is much more common in Quebec, Canada. The overall incidence in
Quebec
Quebec ( ; )According to the Government of Canada, Canadian government, ''Québec'' (with the acute accent) is the official name in Canadian French and ''Quebec'' (without the accent) is the province's official name in Canadian English is ...
is about 1 in 16,000 individuals. In the
Saguenay-Lac-Saint-Jean region of Quebec, type 1 tyrosinemia affects 1 person in 1,846. The
carrier
Carrier may refer to:
Entertainment
* ''Carrier'' (album), a 2013 album by The Dodos
* ''Carrier'' (board game), a South Pacific World War II board game
* ''Carrier'' (TV series), a ten-part documentary miniseries that aired on PBS in April 20 ...
rate has been estimated to be between 1 in 20 and 1 in 31.
History
Nitisinone was first used to clinically treat tyrosinemia type I in 1991. Nitisinone was approved by the European Medicine Agency (EMA) under exceptional circumstances in 2005. Originally, nitisinone was developed as a weed-killer by Zeneca Agrochemicals. It was epidemiologically observed that the growth of plants and weeds was inhibited under the bottlebrush plant (Callistemon citrinus). It became clear that neither the shade nor the litterfall of these plants was responsible for the suppression of plant and weed growth. Rather, a substance – which was identified as leptospermone – in the soil under the bottlebrush plant was shown to have bleaching activity on the emerging plants. The allelochemical leptospermone was extracted from the bottlebrush plant and chemically characterized. Leptospermone belongs to the triketone family and inhibits chloroplast development due to a lack of plastoquinone secondary to hepatic 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibition; thus, it served as a blueprint for the synthesis of nitisinone.
In 1932,
Grace Medes
Grace Medes (November 9, 1886 – December 31, 1967) was an American biochemist, who discovered tyrosinosis—a metabolic disorder today known as tyrosinemia—and studied fatty acid metabolism. She was awarded the Garvan-Olin Medal in 1955 for ...
first described "a new disorder of tyrosine metabolism," She coined the condition "tyrosinosis" after observing 4-hydroxyphenylpyruvate in the urine of a 49-year-old man with myasthenia gravis. She proposed that the metabolic defect in this patient was a deficiency of 4-hydroxyphenylpyruvate dioxygenase, but her case remains puzzling and has since been assigned a separate OMIM number. The first typical patient with hepatorenal tyrosinemia was described in 1956 by Margaret D Baber at Edgware General Hospital in Middlesex, England. Starting the following year, Kiyoshi Sakai and colleagues, at the Jikei University School of Medicine in Tokyo, published 3 reports describing the clinical, biochemical, and pathological findings of a 2-year-old boy with hepatorenal tyrosinemia who was then thought to have an "atypical" case of tyrosinosis. Between 1963 and 1965, Swedish pediatrician Rolf Zetterström and colleagues at the Karolinska Institute in Sweden published the first detailed clinical account of hepatorenal tyrosinemia and its variants. Shortly thereafter, a Canadian group also described the clinical and laboratory findings of hepatorenal tyrosinemia. Both the Scandinavian and Canadian groups suggested that the Japanese patients described earlier by Sakai and colleagues had the same disorder, ie, hepatorenal tyrosinemia. In 1965, doubts emerged that the underlying biochemical cause of hepatorenal tyrosinemia was a defective form of the 4-hydroxyphenylpyruvate dioxygenase enzyme. In 1977, Bengt Lindblad and colleagues at the University of Gothenburg in Sweden demonstrated that the actual defect in causing hepatorenal tyrosinemia involved the fumarylacetoacetate hydrolase enzyme. This was subsequently confirmed using direct enzyme assays.
Research directions
As of April 2020, two new clinical trials, are underway in the USA for a Mass Spectrometry-based biomarker for the early and sensitive diagnosis of Tyrosinemia type 1 from blood plasma.
References
External links
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{{Amino acid metabolic pathology
Amino acid metabolism disorders
Autosomal recessive disorders
Rare diseases