Ochronosis is one of three clinical types in the spectrum of alterations originated by Alcaptonuria (AKU), an inborn error of metabolism. This spectrum is a continuum of modifications based on the deficiency of the enzyme homogentisate 1,2 dioxygenase (HGD), which is responsible for the cleansing of homogentisic acid (HGA), an intermediate metabolite of phenylalanine and tyrosine amino acids metabolism in the liver.
HGA, which is a brownish pigment, accumulates in the intracellular and extracellular environment of the connective tissues and is excreted by the kidneys, making a urine dark overtime, which characterizes the Homogentisic Aciduria, the first of the AKU clinical types, often mistaken as AKU itself.
Oxidation of HGA in benzoquinone acetate (BQA) makes polymers that accumulate as ochronotic pigment1 in connective tissues, preferably in the dermis, hyaline cartilage, and tendons. This type of manifestation characterizes the second clinical type of AKU, which is Ochronosis itself.
Fig. 2: Phenylalanine and Tyrosine metabolism with homogentisic acid and benzoquinone acetate formation. Adapted from Ranganath RL et al. (2019) Ochronotic pigmentation is caused by homogentisic acid and is the key event in alkaptonuria leading to the destructive consequences of the disease – a review. J Inherit Metab Dis. 42:776–792.
More rarely, HGA may condense in the renal pelvis, cardiac fibrocartilage, and glands. In this type of manifestation, the HGA can aggregate to create urinary or even biliary stones 2,3,11.
Over the years, exaggerated pigmentation by ochronotic pigment causes serious problems, particularly in the hyaline and cardiac fibrous cartilages, often developing osteoarthritis, osteopenia, and spontaneous fractures. Less commonly can progress to valvulopathies too. These are the third clinical type of AKU, the Ochronotic Arthropathy2.
Table 1: Tissue localization of ochronotic pigment in affected joint components. Adapted from Mistry JB, et al. (2013) Alkaptonuria. Rare Dis. 1:e 27475.
Eighteen mutations were described in the autosomal recessive gene which transcribes the HGD, located at gene locus 1 in arm q of chromosome 3, all leading to Ochronosis manifestations. It has a Mendelian inheritance genetic pattern4.
Although ancient Egypt mummies already showed typical signs of Ochronosis5, this condition was first described in Germany region in the 16th century by Wilhelm Adolf Scribonius, who observed the urine of a boy become “dark as ink” overtime2. A few centuries later in the same region, with the advent of microscopy, Rudolf Virchow, in 1866, could observe the ocher color of HGA deposits in bearers of this condition6, calling it "Ochronosis". At the same time, AKU was named by Friederich Boedeker in 1859, due to the alkaline properties of a patient's urine2. But only in 1908 in London, these conditions began to be publicized scientifically, thanks to Archibald Edward Garrod, who created the concept of inborn errors of metabolism based on AKU7.
Nowadays it is estimated there are about one to four cases of AKU for every million people in the United States. Worldwide, the highest prevalence occurs in Slovakia, Germany, and the Dominican Republic, where this proportion may be a case for every 19,000 people. AKU makes no distinction between genders or ethnicities 8.
