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Molecular Genetics and Metabolism Apr 2002Research on alkaptonuria (AKU; OMIM # 230500) in Slovakia started in 1968 by the Research Laboratory (later on the Institute) for Clinical Genetics at Martin. Its first... (Review)
Review
Research on alkaptonuria (AKU; OMIM # 230500) in Slovakia started in 1968 by the Research Laboratory (later on the Institute) for Clinical Genetics at Martin. Its first stage was focused on clinical, biochemical, genetic and epidemiologic questions and on the reasons for the high prevalence of AKU in Slovakia. Based on a screening programme of now over 611,000 inhabitants (509,000 newborns) the world-wide highest incidence of AKU (1 in 19,000) was recorded, and a total of 208 patients (110 children) were registered. Extensive genealogical studies (sometimes over two centuries) resulted in the fusion of several "unrelated" nuclear families into larger pedigrees and enabled tracing most AKU ancestors to their original geographic localities, predominantly in remote mountain areas. A likely founder effect was detected among the shepherd population of the so-called Valachian colonization that resulted in a high degree of inbreeding and persisting genetic isolation. These epidemiologic data formed the basis for molecular studies in collaboration with the Würzburg group. The AKU locus was mapped to human chromosome 3q2 by orthology to the mouse locus aku. Following the cloning of the homogentisate-1,2 dioxygenase (HGD) genes from human and mouse, nine different mutations were identified in 21 AKU index patients. These include 4 missense, 2 splice-site, 2 single-base insertion and 1 deletion mutation. The most frequent mutations among the 42 AKU chromosomes of the index cases are c.648G > A (Gly161Arg; 42.9%), and c.1278insC (Pro370fs; 19.1%). To date, the genotypes of 29 patients and of 74 gene carriers from 21 families have been established. The highest prevalence and allelic heterogeneity were observed in the Kysuce district with five different mutations. Molecular epidemiology studies by haplotyping were carried out to uncover the original geographic localities of all AKU index chromosomes. This strongly suggests that several founders have contributed to the HGD gene mutation pool. While there is no straightforward explanation for the clustering of independent mutations, the genetic isolation in the past is likely to be responsible for the high prevalence of AKU in Slovakia.
Topics: Alkaptonuria; Dioxygenases; Genotype; Homogentisate 1,2-Dioxygenase; Humans; Incidence; Molecular Epidemiology; Mutation; Oxygenases; Phenotype; Prevalence; Research; Slovakia
PubMed: 12051967
DOI: 10.1016/S1096-7192(02)00002-1 -
American Journal of Human Genetics Apr 1998
Review
Topics: Alkaptonuria; Dioxygenases; Genetic Therapy; Homogentisate 1,2-Dioxygenase; Humans; Oxygenases; Point Mutation
PubMed: 9529368
DOI: 10.1086/301810 -
The Johns Hopkins Medical Journal Dec 1979Alkaptonuria is found relatively frequently in Slovakia, Eastern Czechoslovakia (1 in 25,000 inhabitants). Reported herein are the clinical, radiographic, and...
Alkaptonuria is found relatively frequently in Slovakia, Eastern Czechoslovakia (1 in 25,000 inhabitants). Reported herein are the clinical, radiographic, and biochemical aspects and genetics of 126 patients with alkaptonuria. Forty-seven were diagnosed in childhood; the sequential appearance of each manifestation is documented by decade. A simple screening method for this disorder is described. Pedigree analyses confirm recessive inheritance. Possible genetic and sociologic factors responsible for this high frequency of alkaptonuria are discussed.
Topics: Adolescent; Adult; Aged; Alkaptonuria; Child; Child, Preschool; Czechoslovakia; Female; Homogentisic Acid; Humans; Male; Middle Aged; Ochronosis; Pedigree; Pigmentation Disorders
PubMed: 513428
DOI: No ID Found -
Endocrine Regulations Jan 2023Alkaptonuria (AKU, OMIM, No. 203500) is a rare, slow-progressing, irreversible, multisystemic disease resulting from a deficiency of the homogentisate 1,2-dioxygenase...
Alkaptonuria (AKU, OMIM, No. 203500) is a rare, slow-progressing, irreversible, multisystemic disease resulting from a deficiency of the homogentisate 1,2-dioxygenase enzyme, which leads to the accumulation of homogentisic acid (HGA) and subsequent deposition as pigment in connective tissues called ochronosis. As a result, severe arthropathy of large joints and spondyloarthropathy with frequent fractures, ligament ruptures, and osteoporosis develops in AKU patients. Since 2020, the first-time treatment with nitisinone has become available in the European Union. Nitisinone significantly reduces HGA production and arrests ochronosis in AKU patients. However, blocking of the tyrosine metabolic pathway by the drug leads to tyrosine plasma and tissue concentrations increase. The nitisinone-induced hypertyrosinemia can lead to the development of corneal keratopathy, and once it develops, the treatment needs to be interrupted. A decrease in overall protein intake reduces the risk of the keratopathy during nitisinone-induced hypertyrosinemia in AKU patients. The low-protein diet is not only poorly tolerated by patients, but over longer periods, leads to a severe muscle loss and weight gain due to increased energy intake from carbohydrates and fats. Therefore, the development of novel nutritional approaches is required to prevent the adverse events due to nitisinone-induced hypertyrosinemia and the negative impact on skeletal muscle metabolism in AKU patients.
Topics: Humans; Alkaptonuria; Ochronosis; Tyrosinemias; Tyrosine; Homogentisic Acid
PubMed: 36966367
DOI: 10.2478/enr-2023-0008 -
General Thoracic and Cardiovascular... Mar 2021Alkaptonuria is an inherited metabolic disease caused by a genetic deficiency of homogentisate 1,2-dioxygenase and characterized by dark-brown connective tissue related... (Review)
Review
Alkaptonuria is an inherited metabolic disease caused by a genetic deficiency of homogentisate 1,2-dioxygenase and characterized by dark-brown connective tissue related to the deposition of oxidized homogentisic acid. Pigment deposition is also observed in the cardiovascular system, such as in the coronary arteries, cardiac valves, and aorta. Because aortic stenosis may develop secondary to pigment deposition-related calcification at the aortic valve, aortic valve replacement may be necessary for severe aortic valve disease. We report the case of a 75 year-old man with alkaptonuria-associated severe aortic stenosis who was successfully treated with minimally invasive endoscopic aortic valve replacement via right anterior minithoracotomy. The tricuspid aortic valve was severely calcified and both the valve and the aortic intima were ochronotic. No perioperative complications were observed and the postoperative course was uneventful.
Topics: Aged; Alkaptonuria; Aortic Valve; Aortic Valve Stenosis; Heart Valve Prosthesis; Humans; Male; Ochronosis
PubMed: 32970271
DOI: 10.1007/s11748-020-01492-2 -
Review of Czechoslovak Medicine 1956
Topics: Alkaptonuria; Humans
PubMed: 13420633
DOI: No ID Found -
Guy's Hospital Reports 1970
Topics: Alkaptonuria; Chromatography, Thin Layer
PubMed: 5498826
DOI: No ID Found -
Rheumatology (Oxford, England) Feb 2007
Topics: Alkaptonuria; Genetics, Medical; History, 19th Century; History, 20th Century; Humans; Hyperpigmentation; London; Lumbar Vertebrae; Radiography; Spinal Osteophytosis
PubMed: 17116657
DOI: 10.1093/rheumatology/kel345 -
The Ceylon Medical Journal Sep 1984
Topics: Alkaptonuria; Calcinosis; Female; Humans; Intervertebral Disc; Middle Aged; Spinal Diseases
PubMed: 6534535
DOI: No ID Found -
Journal of the Indian Medical... Jan 1983
Topics: Alkaptonuria; Dietary Proteins; Humans; Male; Middle Aged; Phenylalanine; Tyrosine
PubMed: 6863950
DOI: No ID Found