Hereditary Tyrosinemia Type-1

The American biochemist Grace Medes (09/11/1886-31/12/1967) coins the term Tyrosinosis meanwhile describing the first biochemical findings in a 49-year-old man with myasthenia gravis. The paper entitled “A new error of tyrosine metabolism: Tyrosinosis” disclosed an unusual reducing substance in the urine of this patient which was identified as 4-hydroxyphenylpyruvate (4-HPP), assigning the defect in tyrosinosis to a deficiency of 4-hydroxyphenylpyruvate dioxygenase (4-HPPD). This condition was assigned the Mendelian Inheritance in Man code 76800.

Grace Medes wins the Garvan Medal, a prize that recognizes distinguished services to chemistry by women chemists.

Sakai and Kitagawa report the case of a two-year-old boy with marked hepatosplenomegaly having difficulties to thrive. Analysis of his urine revealed a large amount of 4-hydroxyphenyllactate (4-HPL) and a small amount of 4-HPP, 4-hydroxyphenylacetate (4-HPA) and tyrosine. The physical findings and biochemical observations led the authors to thinking that the patient presented a different inborn error of tyrosine metabolism from that reported a quarter of century before by Medes. They published their first paper on this case presenting it as “An atypical case of tyrosinosis”.

Third paper from Sakai, Kitagawa and Yoshioka, describing the pathological and biochemical observations of the organ tissues of this patient.

Prof. Sverre Halvorsen (24/07/1925-08/08/2012) and Leiv R. Gjessing disclose for the first time the upmost importance of a diet low in phenylalanine and tyrosine in the pathogenesis of the renal tubular lesions in a 2-year-old girl.

A symposium on tyrosinosis is organized in honour of Grace Medes by Prof. Sverre Halvorsen and Leiv R. Gjessing. It is of note that, Dr. Asbjorn Fölling, Professor Emeritus of the University of Oslo, who described the first case of phenylketonuria in 1934 attended the conference.

Dr. Jean Larochelle proposes to name the disease Hereditary Tyrosinemia.

Fumaryacetoacetate hydrolase (FAH) enzyme is identified as being the defective enzyme leading to HT-1. FAH is the last enzyme in the catabolic pathway of tyrosine.

Dr. Richard Gagné describes a method of detection of HT-1 as early as of 16 weeks of pregnancy by measuring the level of succinylacetone in the amniotic fluid.

The triketone herbicide Nitisinone, derived from leptospermone produced by the bottlebrush plant, is discovered by Zeneca Agrochemicals. Nitisinone is a 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor. HPPD is the second enzyme out of five, involved in the catabolic pathway of tyrosine, Fah being the last one. It is of note that, four of the five enzymes are associated with Inborn Errors of Metabolism (tyrosinemia type 2 and 3, hawkinsinuria, alkaptonuria and hyperphenylalaninemia due to dehydratase deficiency)

OMIM 276700 is assigned to tyrosinemia, type 1 (HT-1).

A critically ill 2-month-old baby becomes the first patient successfully treated with nitisinone for HT-1, after approval of a clinical trial in February by the Swedish Medical Agency. Then, more HT-1 patients were treated with nitisinone on a compassionate-use basis.

Sven Lindstedt (1927-2015) and Prof Elisabeth Holmes (1947-2015) describe that the use of nitisinone together with a proper diet correct and prevent neurological crisis deriving from HT-1. This discovery opened new hopes in patients who otherwise would have had to be transplanted.

Orfadin®, first treatment against HT-1 is approved by FDA in USA having nitisinone as active ingredient. Because of its instability at room temperature, Orfadin® has to be stored between 2-8°C.

Orfadin® is approved by EMA in Europe.

A working group from specialists in HT-1 chosen from Europe and Canada publishes the first recommendations for the management of HT-1.

The generic version Nitisinone Dipharma is approved in Europe, the first Nitisinone capsule formulation stable at room temperature.