Rare diseases
Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder caused by pathogenic variants in the homogentisate 1,2-dioxygenase (HGD) gene. This leads to a deficient HGD enzyme with the consequent accumulation of homogentisic acid (HGA) in different tissues causing complications in various organs, particularly in joints, heart valves and kidneys.
History of the disease and its pharmacological treatment
Alkaptonuria
Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder caused by pathogenic variants in the homogentisate 1,2-dioxygenase (HGD) gene. This leads to a deficient HGD enzyme with the consequent accumulation of homogentisic acid (HGA) in different tissues causing complications in various organs, particularly in joints, heart valves and kidneys.
History of the disease and its pharmacological treatment
Doctor Garrod published a paper entitled The Incidence of Alkaptonuria: A Study of Chemical Individuality wherein, applying the new Mendel’s concept, he describes the disease as to be conform to the principles of mendelian autosomal recessive inheritance
Doctor Garrod coins the expression “inborn error of metabolism” and hypothesized that alkaptonuria derived from a deficient enzyme involved in the degradation pathway of homogentisic acid.
Dr. Bert N. La Du demonstrates biochemically that a single missing enzyme is responsible of the disease
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)
Martin R. Pollack maps the homogentisate 1,2-dioxygenase (HGD) gene responsible of Alkaptonuria on chromosome 3q21-q23 and demonstrates its autosomal recessive nature
Nitisinone is first proposed as potential treatment of Alkaptonuria to prevent the production of homogentisic acid believed to cause the signs and symptoms of alkaptonuria
Orfadin® (Nitisinone) is approved by FDA for the treatment of HT-1
AKU Society is founded in UK (https://akusociety.org/)
The European DevelopAKUre project aiming at developing nitisinone for the treatment of Alkaptonuria is funded by an European Consortium
The results of the SONIA 2 study are presented, showing the effectiveness of nitisinone treatment in reducing urine and serum HGA in patients with alkaptonuria and slowing disease progression
Orfadin® (Nitisinone) is approved by EMA for the treatment of Alkaptonuria
Room Temperature stable formulation capsules of Nitisinone Dipharma for HT-1 treatment is approved in some European countries for the treatment of Alkaptonuria
Symptoms
The three major features of Alkaptonuria are the presence of dark urine, ochronosis (a buildup of dark pigment in connective tissues such as cartilage and skin), and arthritis of the spine and larger joints. Other features of this condition can include heart problems, kidney stones, prostate stones and vision impairment.
Incidence
The incidence of alkaptonuria is 1 in 250,000 to 1 in 1,000,000 live births.
Treatment in Europe
Nitisinone is the sole treatment authorized for AKU patients. AKU patients should also follow a diet restricted in tyrosine and phenylalanine.
