Alkaptonuria Severity Score Index Revisited: Analysing the AKUSSI and Its Subcomponent Features

Langford, B.; Besford, Megan; Hall, A.; Eddowes, LA; Timmis, Oliver; Gallagher, James A.; Ranganath, L.

doi:10.1007/8904_2018_98

Cited by 10 publications

(9 citation statements)

References 10 publications

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“…As AKU research has gathered traction and more patients have become involved in research, the AKUSSI has clearly demonstrated the effect of nitisinone on the various parameters of the index. It shows how effective the therapy is, adding further validation to its use in AKU, it reduces HGA but also demonstrates numerous secondary important features of monitoring patients and their tissues which become symptomatic during the course of the disease [77,78]. The efficacy of nitisinone is clearer seen in longitudinal studies spanning 3 years examining multiple patients with AKU, not only reducing HGA, but also arresting ocular and auricular ochronosis [59].…”

Section: Effectiveness Of Nitisinone In Akumentioning

confidence: 87%

The potential of nitisinone for the treatment of alkaptonuria

Taylor

Shepherd

2019

Expert Opinion on Orphan Drugs

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Introduction: Alkaptonuria is an iconic disease, dating back to the Egyptians and has continued to prove a valuable teaching tool to many medics as an example of an inborn error of metabolism. In recent years, much progress has been made on understanding the condition and its symptoms; the single defective gene has been identified and cloned. In humans novel phenotypic presentations of the condition have been documented, and in vitro models developed to understand the disease. Furthermore, a mouse model has studied and most recently clinical trials into the effectiveness of nitisinone have been undertaken. Nitisinone has been on a miraculous journey from its discovery as a weed killer to its effective treatment in hereditary tyrosinaemia type-1. Areas covered: The authors describe research into nitisinone and its application in model and human systems in both hereditary tyrosinaemia type 1 (HTT-1) and Alkaptonuria. The published literature was searched for outputs relating to "Alkaptonuria", "ochronosis", "nitisinone", "hereditary tyrosinaemia type 1". Any paper not in English or had no translation were excluded. Expert opinion: Now nitisinone is being studied for use in Alkaptonuria and this paper documents the journey of AKU and the promising potential of nitisinone in the treatment of Alkaptonuria.

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Section: Effectiveness Of Nitisinone In Akumentioning

confidence: 87%

The potential of nitisinone for the treatment of alkaptonuria

Taylor

Shepherd

2019

Expert Opinion on Orphan Drugs

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“…Further, our analyses were performed using a larger and more geographically dispersed sample than previous assessments of the cAKUSSI, and included both nitisinone‐treated and untreated patients, allowing assessment of how well alternative AKUSSI versions captured treatment response. 9 …”

Section: Discussionmentioning

confidence: 99%

“…Authors' expert opinion was also used to validate measurements suggested for removal by the statistical methods described below. (2) Principal component analysis (PCA) was used to analyse the contribution of each measurement to the variation in cAKUSSI score data, and therefore its ability to distinguish between patients of different disease severities, as per Langford et al 9 PCA was performed separately at each timepoint and results were compared to determine consistency over time. Relative weights from the first four principal components were used to identify which cAKUSSI components contributed most to the variation in the data.…”

Section: Methodsmentioning

confidence: 99%

“… 6 , 7 The clinical evaluation AKUSSI (cAKUSSI) has been used in recent research and consists of many components, including spine and joint manifestations along with other non‐rheumatological features of AKU (Table S1 ). 7 , 8 , 9 However, some measurements for components of the cAKUSSI assess similar features of AKU or may be difficult to measure reliably, potentially introducing noise to the cAKUSSI. Further, some measurements cannot be performed in resource‐limited environments, where equipment or specialist clinical expertise may not be available or where waiting lists are long.…”

Section: Introductionmentioning

confidence: 99%

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Improving the clinical accuracy and flexibility of the Alkaptonuria severity score index

Cant

Chatzidaki

Olsson³

et al. 2022

JIMD Reports

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Alkaptonuria (AKU) is a rare genetic disorder where oxidised homogentisic acid accumulates in connective tissues, leading to multisystem disease. The clinical evaluation Alkaptonuria Severity Score Index (cAKUSSI) is a composite score that assesses the extent of AKU disease. However, some components assess similar disease features, are difficult to measure reliably or cannot be measured in resource-limited environments. cAKUSSI data from the 4-year SONIA 2 randomised controlled trial, which investigated nitisinone treatment in adults with AKU, were analysed (N = 125). Potentially biased or lowinformation cAKUSSI measurements were identified using clinical and statistical input to create a revised AKUSSI for use in AKU research (cAKUSSI 2.0).Additionally, resource-intensive measurements were removed to explore a flexible AKUSSI (flex-AKUSSI) for use in low-resource environments. Revised scores were compared to cAKUSSI in terms of correlation and how they capture disease progression and treatment response. Eight measurements were removed from the cAKUSSI to create the cAKUSSI 2.0, which performed comparably to the cAKUSSI in measuring disease extent, progression and treatment response. When removing resource-intensive measurements except for osteoarticular disease, the flex-AKUSSI was highly correlated with the cAKUSSI, indicating that they quantified disease extent similarly. However, when osteoarticular disease (measured using scans) was removed, the corresponding flex-AKUSSI underestimated disease progression and overestimated treatment response compared to the cAKUSSI. Clinicians may use the cAKUSSI 2.0 to reduce time, effort and patient burden. Clinicians in resource-limited environments may find value in computing a flex-AKUSSI score, offering potential for future global registries to expand knowledge about AKU.Birgitta Olsson and Mattias Rudebeck were affiliated with Swedish Orphan Biovitrum (Sobi), Stockholm, Sweden at the initiation of the research.

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“…Detailed evaluation and comparison of clinical and genomic data of sibling patient pairs can be a key to understanding its variability. A disease severity index for AKU 32 (AKUSSI) and other clinical and biochemical features can serve for careful monitoring of disease status, and the influence of non-AKU genes can be evaluated, including those responsible for aging and osteoarthritis susceptibility.…”

Section: Genotype-phenotype Correlationsmentioning

confidence: 99%

<p>Alkaptonuria: Current Perspectives</p>

Zaťková

Ranganath

Kádaši

2020

TACG

Self Cite

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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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Alkaptonuria Severity Score Index Revisited: Analysing the AKUSSI and Its Subcomponent Features

Abstract: PCA and redundancy analysis supported the AKUSSI as a robust AKU disease severity measure, although some AKUSSI features could be removed for simplicity. For small patient populations and rare diseases, PCA and redundancy analysis together can aid validation of disease severity metrics.

Cited by 10 publications

References 10 publications

The potential of nitisinone for the treatment of alkaptonuria

The potential of nitisinone for the treatment of alkaptonuria

Improving the clinical accuracy and flexibility of the Alkaptonuria severity score index

<p>Alkaptonuria: Current Perspectives</p>

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