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The Application of Clinical Genetics 2020The last 15 years have been the most fruitful in the history of research on the metabolic disorder alkaptonuria (AKU). AKU is caused by a deficiency of homogentisate... (Review)
Review
The last 15 years have been the most fruitful in the history of research on the metabolic disorder alkaptonuria (AKU). AKU is caused by a deficiency of homogentisate dioxygenase (HGD), the enzyme involved in metabolism of tyrosine, and is characterized by the presence of dark ochronotic pigment in the connective tissue that is formed, due to high levels of circulating homogentisic acid. Almost 120 years ago, Sir Archibald Garrod used AKU to illustrate the concept of Mendelian inheritance in man. In January 2019, the phase III clinical study SONIA 2 was completed, which tested the effectiveness and safety of nitisinone in the treatment of AKU. Results were positive, and they will serve as the basis for the application for registration of nitisinone for treatment of AKU at the European Medicines Agency. Therefore, AKU might become a rare disease for which a cure will be found by 2020. We understand the natural history of the disease and the process of ochronosis much more, but at the same time there are still unanswered questions. One of them is the issue of the factors influencing the varying severity of the disease, since our recent genotype-phenotype study did not show that differences in residual homogentisic acid activity caused by the different mutations was responsible. Although nitisinone has proved to arrest the process of ochronosis, it has some unwanted effects and does not cure the disease completely. As such, enzyme replacement or gene therapy might become a new focus of AKU research, for which a novel suitable mouse model of AKU is available already. We believe that the story of AKU is also a story of effective collaboration between scientists and patients that might serve as an example for other rare diseases.
PubMed: 32158253
DOI: 10.2147/TACG.S186773 -
Cureus Aug 2023We report a case of minocycline-induced ocular ochronosis with scleral, retinal, and cutaneous manifestations. A 65-year-old male who had taken minocycline for four...
We report a case of minocycline-induced ocular ochronosis with scleral, retinal, and cutaneous manifestations. A 65-year-old male who had taken minocycline for four years to treat hidradenitis suppurativa, an inflammatory skin condition affecting the apocrine sweat glands and hair follicles, presented for evaluation of discoloration of bilateral sclera, nail beds, and gingiva. Ophthalmic evaluation revealed intact visual acuity, diffuse blue-gray hyperpigmentation of the sclera, more pronounced overlying insertions of the horizontal muscles, without any scleral thinning. Macular optical coherence tomography and fundus exam revealed a blue hue to the underlying choroid with dark deposits in the retinal pigment epithelium. Despite drug discontinuation, after six years the discoloration persisted. Management was directed towards patient tolerability.
PubMed: 37700983
DOI: 10.7759/cureus.43307 -
European Journal of Human Genetics :... Feb 2022Alkaptonuria is characterized by the accumulation of homogentisic acid (HGA), part of which is excreted in the urine but the excess HGA forms a dark brown ochronotic...
Alkaptonuria is characterized by the accumulation of homogentisic acid (HGA), part of which is excreted in the urine but the excess HGA forms a dark brown ochronotic pigment that deposits in the connective tissue (ochronosis), eventually leading to early-onset severe arthropathy. We analyzed a cohort of 48 Russian AKU families by sequencing all 14 exons (including flanking intronic sequences) of the homogentisate 1,2-dioxygenase gene (HGD) and Multiplex Ligation-dependent Probe Amplification (MLPA) analysis. Nine novel likely pathogenic HGD variants were identified, which have not been reported previously in any other country. Recently, Bychkov et al. [1] reported on the variant spectrum in another cohort of 49 Russian AKU patients. Here we summarize complete data from both cohorts that include 82 Russian AKU families. Taken together, 31 different HGD variants were found in these patients, of which 14 are novel and found only in Russia. The most common variant was c.481G>A (p.(Gly161Arg)), present in almost 54% of all AKU alleles.
Topics: Alkaptonuria; Exons; Homogentisate 1,2-Dioxygenase; Homogentisic Acid; Humans; Joint Diseases; Ochronosis
PubMed: 34504318
DOI: 10.1038/s41431-021-00955-1 -
Clinical Case Reports Apr 2022Blue discoloration of the skin and cartilage, or ochronosis, is a rare physical examination finding. We present two cases of childhood onset ochronosis, one exogenous...
Blue discoloration of the skin and cartilage, or ochronosis, is a rare physical examination finding. We present two cases of childhood onset ochronosis, one exogenous and one endogenous in etiology. The first was caused by minocycline use for severe acne, and the second was caused by congenital alkaptonuria.
PubMed: 35441025
DOI: 10.1002/ccr3.5717 -
Rheumatology and Immunology Research Jun 2022
PubMed: 36465319
DOI: 10.2478/rir-2022-0009