Ocular Manifestations of Alkaptonuria

Alkaptonuria is a rare autosomal recessive disorder that arises from a mutation of the homogentisate 1,2-dioxygenase () gene, resulting in a deficiency of the enzyme HGD. This enzyme plays a role in the phenylalanine and tyrosine degradation pathways by catabolizing the tyrosine intermediate metabolite homogentisic acid (HGA) into maleylacetoacetic acid (Figure 1). Deficiency of the HGD enzyme results in the abnormal accumulation of upstream precursors HGA, tyrosine, and phenylalanine. In particular, the buildup and deposition of HGA is the major contributor to the classic manifestations and consequences of the disease, including homogentisic aciduria, ochronosis, and ochronotic osteoarthropathy. Alkaptonuria leads to dysfunctions in various tissues throughout the body; this article will broadly cover the prominent presentations and focus on ocular manifestations of the disorder in particular. Early identification and diagnosis of the disorder are imperative for management and treatment as complications can be sight-threatening, including astigmatism, central vein occlusion, glaucoma, and blindness. The first case of alkaptonuria is believed to have presented in 1500 BC as found in the Egyptian mummy . Biopsy of the body’s hip cartilage and intervertebral discs in 1979 demonstrated extensive calcification and HGA pigmentation consistent with the process of ochronosis.  Cases of the disease reported in the 16 century centered around the observation of dark urine, which continued to be the identifying feature and namesake of the “black urine disease” through the 19 century. In 1859, Dr. Carl Boedeker found that adding alkali to these patients’ urine produced the appearance of dark discoloration (later discovered to be due to HGA’s reducing power). He subsequently named the disease “alkaptonuria” in reference to “alkali” in Arabic, meaning “alkali,” “alkali” in Greek, meaning “to suck up oxygen greedily in alkali,” and “alkapton” in German, meaning “a reducing compound.” Alkaptonuria is a disease that occupies a noteworthy place in the histories of biochemistry, genetics, and medicine. In 1902, it was the first medical disorder reported to adhere to the Mendelian principles of autosomal recessive inheritance by Sir Archibald Garrod. Garrod deduced that all cases of alkaptonuria reported at the time required certain genetic contributions from both parents. In other words, the spectrum of outward manifestations could all be traced back to a specific underlying genetic trait, emphasizing the impact of science and genetics on the human constitution. At the time, many debilitating diseases were already noted to be more prevalent in consanguineous marriages, but few reports addressed consanguinity from a strictly scientific perspective. By connecting alkaptonuria to a genetic basis and referring to the similar gametes passed on by consanguineous parents, Garrod provided scientific evidence for some deleterious effects of consanguineous unions.  In his 1908 Croonian Lecture to the Royal College of Physicians, Garrod also later used alkaptonuria as an example to demonstrate his concept of “the inborn error of metabolism,” now a widely used term applied to genetic disorders of innate metabolic pathways such as alkaptonuria.