Alkaptonuria

Mistry, Jemma; Bukhari, Marwan; Taylor, Adam Michael

doi:10.4161/rdis.27475

Cited by 100 publications

(120 citation statements)

References 54 publications

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“…Alkaptonuria (AKU) is a rare autosomal recessive condition which results from a single-enzyme deficiency on the tyrosine metabolic pathway (Mistry et al 2013). This enzyme, homogentisate 1,2-dioxygenase (HGD), is responsible for cleaving the benzene ring of homogentisic acid (HGA).…”

Section: Introductionmentioning

confidence: 99%

Analysis of Melanin-like Pigment Synthesized from Homogentisic Acid, with or without Tyrosine, and Its Implications in Alkaptonuria

Taylor

Vercruysse

2016

JIMD Reports

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Alkaptonuria is an iconic disease used by Archibald Garrod to demonstrate the theory of "inborn errors of metabolism". AKU knowledge has advanced in recent years: development of an in vitro model, discovery of murine models and advances in understanding bone and cartilage phenotypes and arthropathy in AKU. These discoveries have aided in a new clinical trial into nitisinone. However, there are still knowledge gaps surrounding the pigment in AKU and the pigmentation process. We demonstrate an advance in the understanding in the kinetics and chemistry of the polymerisation of homogentisic acid (HGA) into its pigment using size-exclusion chromatography and IR spectroscopy. We compared the properties of HGA-based pigments that were freshly prepared to those stored in solution for 2 years. Our results demonstrate the importance of pH in the polymerisation process and that colour change seen in solution (analogous to AKU patient urine) is not initially due to presence of ochronotic pigment but the quinone intermediary. In addition, we observed that pigment formation from HGA can occur in the presence of tyrosine, without the inclusion of this tyrosine into the pigment. These observations have positive implications for patients with alkaptonuria; an increased understanding of the pigment polymer chemistry, the presence of an intermediary and their kinetics present more therapeutic opportunities for treating the condition, including preventing the pigment from forming, binding or reversing established pigmentation. AKU patients treated with nitisinone show elevated tyrosine levels causing side effects such as corneal opacities; our data demonstrates that elevated tyrosine levels should not contribute or add to the ochronotic pigment burden in these patients.

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Section: Introductionmentioning

confidence: 99%

Analysis of Melanin-like Pigment Synthesized from Homogentisic Acid, with or without Tyrosine, and Its Implications in Alkaptonuria

Taylor

Vercruysse

2016

JIMD Reports

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“…Alkaptonuria is a very rare inborn error of amino acid metabolism due to deficient homogentisic acid (HGA) oxidase enzyme leading to accumulation of HGA in plasma, cartilage, other tissues of human body and its excretion in urine 13,14 . It has both systemic and peripheral signs and symptoms.…”

Section: Discussionmentioning

confidence: 99%

Misdiagnosis of alkaptonuria in an elderly patient

Tseliou¹,

Giannelou²,

Boulios³

et al. 2018

JRPMS

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“…The observation that a high proportion of families with HGD alterations from South Tyrol may harbour a founder mutation has significant impact in health community policies, since a role for heterozygous mutations of HGD as one of the liability genetic determinants in complex traits of rheumatologic interest has been envisaged (Mistry et al 2013;Gallagher et al 2015). Biochemical screening could be undertaken as a first step before direct molecular analysis for G360R, at least in individuals of ascertained South Tyrolean ancestry.…”

Section: Discussionmentioning

confidence: 99%

A Founder Effect for the HGD G360R Mutation in Italy: Implications for a Regional Screening of Alkaptonuria

et al. 2016

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We sought to establish rapid and specific genotyping methods for G360R mutation and for seven tightly linked markers in the homogentisate dioxygenase gene to address the question of whether G360R is a mutational hot spot or the result of a founder effect, as it has been repeatedly found in alkaptonuric patients from a geographic isolate in Italy.For G360R and single nucleotide polymorphism genotyping, high-resolution melting analysis was performed. Microsatellites were analysed by multiplex PCR and capillary electrophoresis. To investigate the natural history of the G360R mutation, we genotyped markers in 52 controls and in 8 unrelated patients from the UK and USA, who also segregated the G360R mutation, and calculated its age using DMLE+2.3 software.A distinct G360R-bearing haplotype was identified in all patients of Caucasian descent. Estimated mutation age was 545 generations (95% credible set, 402-854), suggesting that G360R arose in an ancestor who lived 8,000-10,000 years BC. Archaeological, historical and demographic data support that a G360R carrier has settled the remote valley where present-day population might have a heterozygote frequency of at least 6%.Given the late health-threatening complications of alkaptonuria and a cure within reach, inhabitants of this isolate would benefit from screening and genetic counselling.

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Alkaptonuria

Cited by 100 publications

References 54 publications

Analysis of Melanin-like Pigment Synthesized from Homogentisic Acid, with or without Tyrosine, and Its Implications in Alkaptonuria

Analysis of Melanin-like Pigment Synthesized from Homogentisic Acid, with or without Tyrosine, and Its Implications in Alkaptonuria

Misdiagnosis of alkaptonuria in an elderly patient

A Founder Effect for the HGD G360R Mutation in Italy: Implications for a Regional Screening of Alkaptonuria

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