Tyrosinemia type I is a genetic disorder that disrupts the metabolism of the amino acid tyrosine, resulting in damage primarily to the liver along with the kidneys and peripheral nerves.

[2] If not detected via newborn screening and management not begun before symptoms appear, clinical manifestation of disease occurs typically within the first two years of life.

[1] If diagnosed through newborn screening prior to clinical manifestation, and well managed with diet and medication, normal growth and development is possible.

Tyrosinemia type I is an autosomal recessive disorder caused by mutations in both copies of the gene encoding the enzyme fumarylacetoacetate hydrolase (FAH).

Additionally, the drug nitisinone (brand name Orfadin) is prescribed and continued indefinitely in order to combat liver and kidney damage, promoting normal function of these organs.

[citation needed]The kidney dysfunction presents as Fanconi syndrome: Renal tubular acidosis, hypophosphatemia and aminoaciduria.

The common presentation in an acute case is synthetic liver failure, marked by the lack of formation of coagulation factors in blood.

Patients are prone to infections at this stage accompanied by fever, vomiting, increased tendency to bleed, and diarrhea along with bloody feces as manifestations of sepsis.

[1][2] Sub-acute cases present between 6 months and the first year of life and the severity of liver disease is lessened to an extent.

[2] The accumulation of MAA, FAA, and SA in cells inhibits the breakdown of thiol derivatives, leading to post-translational modifications to the antioxidant glutathione.

This inhibits the antioxidant activity of glutathione, leading to reactive oxygen species (ROS) 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.

Consequently, porphyrin deposits form in the bloodstream and cause neuropathic pain, leading to the acute neurological crises experienced by some patients.

[2] The accumulation of unprocessed tyrosine itself in the blood stream as a consequence of deficient catabolism can also lead to disruption of hormonal signaling and neurotransmission.

Tyrosine is a precursor molecule required for synthesis of several neurotransmitters and hormones, mainly Dopamine, norepinephrine, and thryoxine.

Excessive synthesis of these molecules due to elevated tyrosine levels can impair physical growth, motor function, and speech development.

[7][8] 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 and urine.

[1] However, prompt assessment upon the manifestation of physical symptoms such as fever, vomiting, increased tendency to bleed, diarrhea along with bloody feces, and jaundice is critical for improving long term prognosis.

Nitisinone and dietary restrictions that decrease the amount of tyrosine and phenylalaine absorbed from the GI tract during protein digestion 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 and death.

Patients received amino acid supplements lacking tyrosine and phenylalanine, most often by drinking a specially engineered formula, in order to acquire sufficient protein.

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.

[9] In 1932, Grace Medes 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.

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 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.

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.