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Nature Reviews. Disease Primers Mar 2024Alkaptonuria is a rare inborn error of metabolism caused by the deficiency of homogentisate 1,2-dioxygenase activity. The consequent homogentisic acid (HGA) accumulation... (Review)
Review
Alkaptonuria is a rare inborn error of metabolism caused by the deficiency of homogentisate 1,2-dioxygenase activity. The consequent homogentisic acid (HGA) accumulation in body fluids and tissues leads to a multisystemic and highly debilitating disease whose main features are dark urine, ochronosis (HGA-derived pigment in collagen-rich connective tissues), and a painful and severe form of osteoarthropathy. Other clinical manifestations are extremely variable and include kidney and prostate stones, aortic stenosis, bone fractures, and tendon, ligament and/or muscle ruptures. As an autosomal recessive disorder, alkaptonuria affects men and women equally. Debilitating symptoms appear around the third decade of life, but a proper and timely diagnosis is often delayed due to their non-specific nature and a lack of knowledge among physicians. In later stages, patients' quality of life might be seriously compromised and further complicated by comorbidities. Thus, appropriate management of alkaptonuria requires a multidisciplinary approach, and periodic clinical evaluation is advised to monitor disease progression, complications and/or comorbidities, and to enable prompt intervention. Treatment options are patient-tailored and include a combination of medications, physical therapy and surgery. Current basic and clinical research focuses on improving patient management and developing innovative therapies and implementing precision medicine strategies.
Topics: Male; Humans; Female; Alkaptonuria; Quality of Life; Ochronosis; Kidney; Homogentisic Acid
PubMed: 38453957
DOI: 10.1038/s41572-024-00498-x -
Advances in Clinical Chemistry 2023Alkaptonuria (AKU) is an ultra-rare inherited inborn error of metabolism that afflicts the tyrosine metabolic pathway, resulting in the accumulation of homogentisic acid... (Review)
Review
Alkaptonuria (AKU) is an ultra-rare inherited inborn error of metabolism that afflicts the tyrosine metabolic pathway, resulting in the accumulation of homogentisic acid (HGA) in the circulation, and significant excretion in urine. Clinical manifestations, typically observed from the third decade of life, are lifelong and significantly affect the quality of life. This review provides a comprehensive overview of the natural history of AKU, including clinical, biochemical and genetic perspectives. An update on the major advances on studies in murine models and human subjects, providing mechanistic insight into the molecular and biochemical processes that underlie pathophysiology and its response to treatment are presented. The impact of treatment with nitisinone is also presented with a specific emphasis on hypertyrosinemia, as uncertainty on this topic remains. Future perspectives are explored, such as novel approaches to treat hypertyrosinemia including the use of binding agents and amino acid transporter inhibitors, as well as advanced potentially curative gene and cell therapy initiatives.
Topics: Humans; Animals; Mice; Alkaptonuria; Quality of Life; Tyrosinemias; Homogentisic Acid; Tyrosine
PubMed: 37268334
DOI: 10.1016/bs.acc.2023.02.005 -
Wiadomosci Lekarskie (Warsaw, Poland :... 2009Alkaptonuria is a hereditary disease resulted from accumulation of homogentisic acid within the body due to deficiency of homogentisic acid oxidase. The main clinical... (Review)
Review
Alkaptonuria is a hereditary disease resulted from accumulation of homogentisic acid within the body due to deficiency of homogentisic acid oxidase. The main clinical feature is dark brown color of urine caused by high urinary output of homogentisic acid. There are no other symptoms or signs of the disease until the fourth decade of life when ochronosis is developed. Life-long accumulation of abnormal metabolites becomes overt in form of severe spondylosis, peripheral arthropathy, tendon rupture, bone osteoporosis as well as aortic valve stenosis and skin pigmentation. The features of the disease are associated with affinity of homogentisic acid to the connective tissue and its effect on collagen structure. Only symptomatic treatment is applied in case of alkaptonuria and ochronosis.
Topics: Adult; Alkaptonuria; Cartilage; Child; Disease Progression; Humans; Islets of Langerhans; Joint Diseases; Kidney Tubules; Skin; Spondylosis
PubMed: 20229718
DOI: No ID Found -
MMW Fortschritte Der Medizin Feb 2022
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Journal of Inherited Metabolic Disease Sep 2015Alkaptonuria (AKU) is an ultra-rare inborn error of metabolism developed from the lack of homogentisic acid oxidase activity, causing homogentisic acid (HGA)... (Review)
Review
Alkaptonuria (AKU) is an ultra-rare inborn error of metabolism developed from the lack of homogentisic acid oxidase activity, causing homogentisic acid (HGA) accumulation that produces an HGA-melanin ochronotic pigment, of hitherto unknown composition. Besides the accumulation of HGA, the potential role and presence of unidentified proteins has been hypothesized as additional causal factors involved in ochronotic pigment deposition. Evidence has been provided on the presence of serum amyloid A (SAA) in several AKU tissues, which allowed classifying AKU as a novel secondary amyloidosis. In this paper, we will briefly review all direct and indirect lines of evidence related to the presence of amyloidosis in AKU. We also report the first data on abnormal SAA serum levels in a cohort of AKU patients.
Topics: Alkaptonuria; Amyloidosis; Cartilage; Humans; Inflammation; Ochronosis; Oxidative Stress; Staining and Labeling
PubMed: 25868666
DOI: 10.1007/s10545-015-9842-8 -
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 -
The Lancet. Diabetes & Endocrinology Sep 2020
Review
Topics: Alkaptonuria; Cyclohexanones; Enzyme Inhibitors; Humans; Nitrobenzoates
PubMed: 32822593
DOI: 10.1016/S2213-8587(20)30222-9 -
Annals of Clinical Biochemistry Mar 2020
Review
Topics: Alkaptonuria; Animals; Cyclohexanones; Disease Models, Animal; Enzyme Inhibitors; Homogentisic Acid; Humans; Mice; Nitrobenzoates; Tyrosine
PubMed: 31529982
DOI: 10.1177/0004563219879957 -
QJM : Monthly Journal of the... Jun 2022
Topics: Adult; Alkaptonuria; Homogentisic Acid; Humans; Male; Urine
PubMed: 35394539
DOI: 10.1093/qjmed/hcac098 -
Orthopedics Jul 2016A 50-year-old woman with a chronic polyarthropathy was seen by her orthopedist for long-standing back and shoulder and worsening hip pain. A lateral labral tear and...
A 50-year-old woman with a chronic polyarthropathy was seen by her orthopedist for long-standing back and shoulder and worsening hip pain. A lateral labral tear and chronic trochanteric bursitis were diagnosed on hip magnetic resonance imaging, which was otherwise unremarkable. Hip arthroscopy was performed revealing an unusual bluish-tinged femoral head articular surface. Computed tomography scans of the spine were also obtained.
Topics: Alkaptonuria; Arthralgia; Arthroscopy; Female; Humans; Joint Diseases; Magnetic Resonance Imaging; Middle Aged; Tomography, X-Ray Computed
PubMed: 27158826
DOI: 10.3928/01477447-20160503-03