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Medical Journal, Armed Forces India Oct 2018
PubMed: 30449931
DOI: 10.1016/j.mjafi.2017.06.006 -
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 -
Rare Diseases (Austin, Tex.) 2013Alkaptonuria (AKU) is a rare disorder of autosomal recessive inheritance. It is caused by a mutation in a gene that results in the accumulation of homogentisic acid... (Review)
Review
Alkaptonuria (AKU) is a rare disorder of autosomal recessive inheritance. It is caused by a mutation in a gene that results in the accumulation of homogentisic acid (HGA). Characteristically, the excess HGA means sufferers pass dark urine, which upon standing turns black. This is a feature present from birth. Over time patients develop other manifestations of AKU, due to deposition of HGA in collagenous tissues, namely ochronosis and ochronotic osteoarthropathy. Although this condition does not reduce life expectancy, it significantly affects quality of life. The natural history of this condition is becoming better understood, despite gaps in knowledge. Clinical assessment of the condition has also improved along with the development of a potentially disease-modifying therapy. Furthermore, recent developments in AKU research have led to new understanding of the disease, and further study of the AKU arthropathy has the potential to influence therapy in the management of osteoarthritis.
PubMed: 25003018
DOI: 10.4161/rdis.27475 -
Indian Journal of Dermatology Mar 2011A case of alkaptonuria, a rare disorder with autosomal recessive inheritance, is reported here. The patient had palmar pigmentation in addition to the usual features of...
A case of alkaptonuria, a rare disorder with autosomal recessive inheritance, is reported here. The patient had palmar pigmentation in addition to the usual features of alkaptonuria.
PubMed: 21716546
DOI: 10.4103/0019-5154.80415 -
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 -
Indian Journal of Dermatology 2015Exogenous ochronosis (EO) is a cutaneous disorder characterized by blue-black pigmentation resulting as a complication of long-term application of skin-lightening creams... (Review)
Review
Exogenous ochronosis (EO) is a cutaneous disorder characterized by blue-black pigmentation resulting as a complication of long-term application of skin-lightening creams containing hydroquinone but may also occur due to topical contact with phenol or resorcinol in dark-skinned individuals. It can also occur following the use of systemic antimalarials such as quinine. EO is clinically and histologically similar to its endogenous counterpart viz., alkaptonuria, which, however, exhibits systemic effects and is an inherited disorder. Dermoscopy and in vivo skin reflectance confocal microscopy are noninvasive in vivo diagnostic tools. It is very difficult to treat EO, a cosmetically disfiguring and troubling disorder with disappointing treatment options.
PubMed: 26677264
DOI: 10.4103/0019-5154.169122