ApreciseKUre: an approach of Precision Medicine in a Rare Disease

Spiga, Ottavia; Cicaloni, Vittoria; Bernini, Andrea; Zaťková, Andrea; Santucci, Annalisa

doi:10.1186/s12911-017-0438-0

Cited by 27 publications

(21 citation statements)

References 15 publications

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“…This is also relevant in view of the recent in vitro reports indicating that even nearly physiological HGA concentrations might enhance the aggregation of SAA 62 . Importantly, all the data obtained within this work could be used to populate an AKU database integrating biomarker levels, demographics, patient's quality of life, environmental and life-style data, and clinical outcomes 82 . Such a database could represent an optimal tool with potential relapses for the study of AKU mechanisms and the development of a precision medicine approach for AKU and other more common rheumatic disorders.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory and oxidative stress biomarkers in alkaptonuria: data from the DevelopAKUre project

Braconi

Giustarini

Marzocchi

et al. 2018

Osteoarthritis and Cartilage

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Section: Discussionmentioning

confidence: 99%

Inflammatory and oxidative stress biomarkers in alkaptonuria: data from the DevelopAKUre project

Braconi

Giustarini

Marzocchi

et al. 2018

Osteoarthritis and Cartilage

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“…The Subclinical Ochronotic Features In Alkaptonuria (SOFIA) study evaluates at what age ochronosis starts and whether it presents before the onset of clinical symptoms of AKU, such as joint pain. In addition, we have established a novel ApreciseKUre database that facilitates collection and analysis of clinical and biochemical patient data shared among registered researchers [20].…”

Section: Introductionmentioning

confidence: 99%

Homogentisate 1,2-dioxygenase (HGD) gene variants, their analysis and genotype–phenotype correlations in the largest cohort of patients with AKU

et al. 2019

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Alkaptonuria (AKU) is a rare metabolic disorder caused by a deficient enzyme in the tyrosine degradation pathway, homogentisate 1,2-dioxygenase (HGD). In 172 AKU patients from 39 countries, we identified 28 novel variants of the HGD gene, which include three larger genomic deletions within this gene discovered via self-designed multiplex ligationdependent probe amplification (MLPA) probes. In addition, using a reporter minigene assay, we provide evidence that three of eight tested variants potentially affecting splicing cause exon skipping or cryptic splice-site activation. Extensive bioinformatics analysis of novel missense variants, and of the entire HGD monomer, confirmed mCSM as an effective computational tool for evaluating possible enzyme inactivation mechanisms. For the first time for AKU, a genotypephenotype correlation study was performed for the three most frequent HGD variants identified in the Suitability Of Nitisinone in Alkaptonuria 2 (SONIA2) study. We found a small but statistically significant difference in urinary homogentisic acid (HGA) excretion, corrected for dietary protein intake, between variants leading to 1% or >30% residual HGD activity. There was, interestingly, no difference in serum levels or absolute urinary excretion of HGA, or clinical symptoms, indicating that protein intake is more important than differences in HGD variants for the amounts of HGA that accumulate in the body of AKU patients.

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“…In addition to AKU-causing mutations, the ApreciseKUre database (http://www.bio.unisi.it/aku-db) facilitates collection and analysis of clinical and biochemical patients' data, with an aim to share the results among registered users. 22 The protomer of HGD is composed of 445 amino acids (NP_000178.2) and expressed mainly in kidneys and liver, 2 but some expression has also been reported in the prostate, small intestine, colon, 2 chondrocytes, synoviocytes, osteoblasts, 23 and brain. 24 However, recent detailed analysis in a new mouse model confirmed expression only in the liver and kidney cortex.…”

Section: Genetics Of Aku and The Hgd Mutation Databasementioning

confidence: 99%

<p>Alkaptonuria: Current Perspectives</p>

Zaťková

Ranganath

Kádaši

2020

TACG

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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.

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ApreciseKUre: an approach of Precision Medicine in a Rare Disease

Cited by 27 publications

References 15 publications

Inflammatory and oxidative stress biomarkers in alkaptonuria: data from the DevelopAKUre project

Inflammatory and oxidative stress biomarkers in alkaptonuria: data from the DevelopAKUre project

Homogentisate 1,2-dioxygenase (HGD) gene variants, their analysis and genotype–phenotype correlations in the largest cohort of patients with AKU

<p>Alkaptonuria: Current Perspectives</p>

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