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 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.
This can lead to a fatty liver 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. Neurological manifestations are characterized by acute neurological crises due to overaccumulation of porphyrin. These crises are characterized by porphyria. They typically follow an infection. Patients can present with a variety of varied symptoms including paresthesias, abdominal pain, pain-induced seizures, and can result in self-mutilation in response to this pain. Episodes can last for 1–7 days and can lead to neuropathy. Genetics
Tyrosinemia type I is an autosomal recessive inherited condition. Mutant alleles in the gene are inherited from both parents. The genetic mutation occurs to the fumarylacetoacetate hydrolase (FAH) enzyme gene, located on chromosome 15. The most common mutation is IVS12+5(G->A) which is a mutation in the splice site consensus sequence of intron 12, therefore affecting exon 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 - fumarylacetoacetate to fumarate, acetoacetate and succinate.