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L R Ranganath - One of the best experts on this subject based on the ideXlab platform.
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evaluating the aortic stenosis phenotype before and after the effect of homogentisic acid lowering therapy analysis of a large cohort of eighty one alkaptonuria patients
Molecular Genetics and Metabolism, 2021Co-Authors: L R Ranganath, Milad Khedr, T Heseltine, Michael FisherAbstract:Abstract Aims A large alkaptonuria (AKU) cohort was studied to better characterise the poorly understood phenotype of aortic stenosis of rare disease AKU. Methods and results Eighty-one patients attended the National Alkaptonuria Centre (NAC) between 2007 and 2020. Nine only attended once. Fifty-one attended more than once and received nitisinone 2 mg daily. Twenty-one attended at least twice without receiving nitisinone. Assessments included questionnaire analysis, standard transthoracic echocardiography, as well as photographs of ochronotic pigment in eyes and ears at baseline when 2 mg nitisinone was commenced, and yearly thereafter. Blood and urine samples were collected for chemical measurement. The prevalence of aortic stenosis and aortic valve replacement were 22.2 and 6.2% in the current group. Aortic maximum velocity (Vmax) was directly related to varying degrees to age (R = 0.58, p Conclusion Aortic valve disease is highly prevalent in this NAC cohort, and strongly associated with Ochronosis and disease severity. Nitisinone decreases Ochronosis and had a similar significant effect on Vmax.
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characterizing the alkaptonuria joint and spine phenotype and assessing the effect of homogentisic acid lowering therapy in a large cohort of 87 patients
Journal of Inherited Metabolic Disease, 2021Co-Authors: L R Ranganath, Milad Khedr, Sobhan Vinjamuri, J A GallagherAbstract:A large alkaptonuria (AKU) cohort was studied to better characterize the poorly understood spondyloarthropathy of rare disease AKU. Eighty-seven patients attended the National Alkaptonuria Centre (NAC) between 2007 and 2020. Seven only attended once. Fifty-seven attended more than once and received nitisinone 2 mg daily. Twenty-three attended at least twice without receiving nitisinone. Assessments included questionnaire analysis, 18F Positron emission tomography computerised tomography (PETCT), as well as photographs of ochronotic pigment in eyes and ears at baseline when 2 mg nitisinone was commenced and yearly thereafter. Blood and urine samples were collected for chemical measurement. The prevalence of Ochronosis, as well as pain, PETCT and combined pain and PETCT scores, was greatly increased at 90.5%, 85.7%, 100%, and 100%, respectively. Joint pain scores were greatest in proximal joints in upper and lower limbs. PETCT joint scores were higher in proximal joints in upper limb but higher in distal joints in the lower limb. Spine pain scores were highest in lumbar, followed by cervical, thoracic, and cervical regions at 77.4%, 59.5%, 46.4%, and 25%, respectively. PETCT spine scores were highest in thoracic followed by lumbar, cervical, and sacroiliac regions at 74.4%, 70.7%, 64.6%, and 47.8% respectively; Ochronosis associated closely with spondyloarthropathy scores (R = .65; P < .0001). Nitisinone reversed Ochronosis significantly, with a similar pattern of decreased joint and spine disease. Spondyloarthropathy is a highly prevalent feature in this NAC cohort. Ochronosis appears to be associated with spondyloarthropathy. Nitisinone decreases Ochronosis and had a similar nonsignificant effect pattern on spondyloarthropathy.
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characterising the arthroplasty in spondyloarthropathy in a large cohort of eighty seven patients with alkaptonuria
Journal of Inherited Metabolic Disease, 2020Co-Authors: J A Gallagher, L R Ranganath, John S Davidson, Sobhan VinjamuriAbstract:Arthroplasty in the spondyloarthropathy (SPOND) of alkaptonuria (AKU) in incompletely characterised. The aim was to improve the understanding of arthroplasty in AKU through a study of patients attending the National Alkaptonuria Centre (NAC). Eighty-seven patients attended the NAC between 2007 and 2020. Seven only attended once. Fifty-seven attended more than once and received nitisinone 2 mg daily. Twenty-three attended at least twice without receiving nitisinone. Assessments including questionnaire analysis eliciting details of arthroplasty and other surgical treatments for SPOND, 18 FPETCT and CT densitometry at the neck of hip and lumbar spine, as well as photographs of the eyes and ears were acquired from patients attending the National Alkaptonuria Centre (NAC) at baseline when 2 mg nitisinone was commenced, and yearly thereafter. Photographs were scored to derive Ochronosis scores. Blood and urine samples were collected for chemical analyses. The prevalence of arthroplasty was 36.8%, similar in males and females, occurring especially in the knees, hips and shoulders. Multiple arthroplasties were found in 29 patients (33.3%) in this cohort. Incident arthroplasty was 6.5% in the nitisinone group and 7.1% in the no-nitisinone group. Incident arthroplasty was 11.3% in the group with baseline arthroplasty and 3.51% in the group without. A strong association of arthroplasty with SPOND (R = 0.5; P << .0001) and Ochronosis (R = 0.54; P < .0001) was seen. Nitisinone had no significant effect on incident arthroplasty. Arthroplasty due to Ochronosis and SPOND is common in AKU. Nitisinone decreased Ochronosis but had no effect on arthroplasty in this cohort.
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reversal of ochronotic pigmentation in alkaptonuria following nitisinone therapy analysis of data from the united kingdom national alkaptonuria centre
JIMD reports, 2020Co-Authors: L R Ranganath, Andrew T. Hughes, Andrew S Davison, Milad Khedr, Anna M. Milan, Peter Wilson, Elizabeth West, J P Dillon, J A GallagherAbstract:Background Increased homogentisic acid (HGA) causes Ochronosis. Nitisinone decreases HGA. The aim was to study the effect of nitisinone on the Ochronosis progression. Methods Photographs of the eyes and ears were acquired from patients attending the National Alkaptonuria Centre (NAC) at V-1 (pre-baseline visit), V0 (baseline visit when 2 mg nitisinone was commenced), and yearly at V1, V2, and V3 visits. Photographs were inspected for evolution of ochronotic pigment and also scored categorically to derive eye, ear, and combined Ochronosis scores. An ear cartilage biopsy was also carried out at V0 and one year after V3 (V4) and ochronotic pigment was assessed and quantitated. Visits were compared for changes in pigment. Fasting blood and 24-hour urine samples were collected for measurement of HGA. Results There were 80 AKU patients at V0, and 52, 47, and 40 at V1, V2, and V3 in the group with variable numbers (VAR Group) respectively; 23 patients attended once before V0, in the V-1 visit. Photographs of patients show increase in eye pigment between V-1 and V0, followed by decrease post-nitisinone at V1, V2, and V3. Ear and combined Ochronosis semiquantitative scoring showed an increase between V-1 and V0 (P < .01), followed by a decrease at V1, V2, and V3, in the VAR group (P < .01). Ochronotic pigment in ear biopsy between V0 and V4 showed a 19.1% decrease (P < .05). Conclusions Nitisinone decreases HGA and partially reverses Ochronosis.
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ochronotic pigmentation is caused by homogentisic acid and is the key event in alkaptonuria leading to the destructive consequences of the disease a review
Journal of Inherited Metabolic Disease, 2019Co-Authors: Brendan P Norman, L R Ranganath, J A GallagherAbstract:Ochronosis is the process in alkaptonuria (AKU) that causes all the debilitating morbidity. The process involves selective deposition of homogentisic acid (HGA)-derived pigment in tissues altering the properties of these tissues, leading to their failure. Some tissues like cartilage are more easily affected by Ochronosis while others such as the liver and brain are unaffected for reasons that are still not understood. In vitro and mouse models of Ochronosis have confirmed the dose relationships between HGA and Ochronosis and also their modulation by p-hydroxyphenylpyruvate dioxygenase inhibition. Ochronosis cannot be fully reversed and is a key factor in influencing treatment decisions. Earlier detection of Ochronosis preferably by noninvasive means is desirable. A cause-effect relationship between HGA and Ochronosis is discussed. The similarity in AKU and familial hypercholesterolaemia is explored and lessons learnt. More research is needed to more fully understand the crucial nature of Ochronosis.
J A Gallagher - One of the best experts on this subject based on the ideXlab platform.
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characterizing the alkaptonuria joint and spine phenotype and assessing the effect of homogentisic acid lowering therapy in a large cohort of 87 patients
Journal of Inherited Metabolic Disease, 2021Co-Authors: L R Ranganath, Milad Khedr, Sobhan Vinjamuri, J A GallagherAbstract:A large alkaptonuria (AKU) cohort was studied to better characterize the poorly understood spondyloarthropathy of rare disease AKU. Eighty-seven patients attended the National Alkaptonuria Centre (NAC) between 2007 and 2020. Seven only attended once. Fifty-seven attended more than once and received nitisinone 2 mg daily. Twenty-three attended at least twice without receiving nitisinone. Assessments included questionnaire analysis, 18F Positron emission tomography computerised tomography (PETCT), as well as photographs of ochronotic pigment in eyes and ears at baseline when 2 mg nitisinone was commenced and yearly thereafter. Blood and urine samples were collected for chemical measurement. The prevalence of Ochronosis, as well as pain, PETCT and combined pain and PETCT scores, was greatly increased at 90.5%, 85.7%, 100%, and 100%, respectively. Joint pain scores were greatest in proximal joints in upper and lower limbs. PETCT joint scores were higher in proximal joints in upper limb but higher in distal joints in the lower limb. Spine pain scores were highest in lumbar, followed by cervical, thoracic, and cervical regions at 77.4%, 59.5%, 46.4%, and 25%, respectively. PETCT spine scores were highest in thoracic followed by lumbar, cervical, and sacroiliac regions at 74.4%, 70.7%, 64.6%, and 47.8% respectively; Ochronosis associated closely with spondyloarthropathy scores (R = .65; P < .0001). Nitisinone reversed Ochronosis significantly, with a similar pattern of decreased joint and spine disease. Spondyloarthropathy is a highly prevalent feature in this NAC cohort. Ochronosis appears to be associated with spondyloarthropathy. Nitisinone decreases Ochronosis and had a similar nonsignificant effect pattern on spondyloarthropathy.
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characterising the arthroplasty in spondyloarthropathy in a large cohort of eighty seven patients with alkaptonuria
Journal of Inherited Metabolic Disease, 2020Co-Authors: J A Gallagher, L R Ranganath, John S Davidson, Sobhan VinjamuriAbstract:Arthroplasty in the spondyloarthropathy (SPOND) of alkaptonuria (AKU) in incompletely characterised. The aim was to improve the understanding of arthroplasty in AKU through a study of patients attending the National Alkaptonuria Centre (NAC). Eighty-seven patients attended the NAC between 2007 and 2020. Seven only attended once. Fifty-seven attended more than once and received nitisinone 2 mg daily. Twenty-three attended at least twice without receiving nitisinone. Assessments including questionnaire analysis eliciting details of arthroplasty and other surgical treatments for SPOND, 18 FPETCT and CT densitometry at the neck of hip and lumbar spine, as well as photographs of the eyes and ears were acquired from patients attending the National Alkaptonuria Centre (NAC) at baseline when 2 mg nitisinone was commenced, and yearly thereafter. Photographs were scored to derive Ochronosis scores. Blood and urine samples were collected for chemical analyses. The prevalence of arthroplasty was 36.8%, similar in males and females, occurring especially in the knees, hips and shoulders. Multiple arthroplasties were found in 29 patients (33.3%) in this cohort. Incident arthroplasty was 6.5% in the nitisinone group and 7.1% in the no-nitisinone group. Incident arthroplasty was 11.3% in the group with baseline arthroplasty and 3.51% in the group without. A strong association of arthroplasty with SPOND (R = 0.5; P << .0001) and Ochronosis (R = 0.54; P < .0001) was seen. Nitisinone had no significant effect on incident arthroplasty. Arthroplasty due to Ochronosis and SPOND is common in AKU. Nitisinone decreased Ochronosis but had no effect on arthroplasty in this cohort.
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reversal of ochronotic pigmentation in alkaptonuria following nitisinone therapy analysis of data from the united kingdom national alkaptonuria centre
JIMD reports, 2020Co-Authors: L R Ranganath, Andrew T. Hughes, Andrew S Davison, Milad Khedr, Anna M. Milan, Peter Wilson, Elizabeth West, J P Dillon, J A GallagherAbstract:Background Increased homogentisic acid (HGA) causes Ochronosis. Nitisinone decreases HGA. The aim was to study the effect of nitisinone on the Ochronosis progression. Methods Photographs of the eyes and ears were acquired from patients attending the National Alkaptonuria Centre (NAC) at V-1 (pre-baseline visit), V0 (baseline visit when 2 mg nitisinone was commenced), and yearly at V1, V2, and V3 visits. Photographs were inspected for evolution of ochronotic pigment and also scored categorically to derive eye, ear, and combined Ochronosis scores. An ear cartilage biopsy was also carried out at V0 and one year after V3 (V4) and ochronotic pigment was assessed and quantitated. Visits were compared for changes in pigment. Fasting blood and 24-hour urine samples were collected for measurement of HGA. Results There were 80 AKU patients at V0, and 52, 47, and 40 at V1, V2, and V3 in the group with variable numbers (VAR Group) respectively; 23 patients attended once before V0, in the V-1 visit. Photographs of patients show increase in eye pigment between V-1 and V0, followed by decrease post-nitisinone at V1, V2, and V3. Ear and combined Ochronosis semiquantitative scoring showed an increase between V-1 and V0 (P < .01), followed by a decrease at V1, V2, and V3, in the VAR group (P < .01). Ochronotic pigment in ear biopsy between V0 and V4 showed a 19.1% decrease (P < .05). Conclusions Nitisinone decreases HGA and partially reverses Ochronosis.
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pigmentation chemistry and radical based collagen degradation in alkaptonuria and osteoarthritic cartilage
Angewandte Chemie, 2020Co-Authors: Wing Ying Chow, Brendan P Norman, Lakshminarayan R Ranganath, Christian Teutloff, Robert Bittl, J A Gallagher, Melinda J Duer, N B Roberts, Hartmut OschkinatAbstract:Alkaptonuria (AKU) is a rare disease characterized by high levels of homogentisic acid (HGA); patients suffer from tissue Ochronosis: dark brown pigmentation, especially of joint cartilage, leading to severe early osteoarthropathy. No molecular mechanism links elevated HGA to Ochronosis; the pigment's chemical identity is still not known, nor how it induces joint cartilage degradation. Here we give key insight on HGA-derived pigment composition and collagen disruption in AKU cartilage. Synthetic pigment and pigmented human cartilage tissue both showed hydroquinone-resembling NMR signals. EPR spectroscopy showed that the synthetic pigment contains radicals. Moreover, we observed intrastrand disruption of collagen triple helix in pigmented AKU human cartilage, and in cartilage from patients with osteoarthritis. We propose that collagen degradation can occur via transient glycyl radicals, the formation of which is enhanced in AKU due to the redox environment generated by pigmentation.
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ochronotic pigmentation is caused by homogentisic acid and is the key event in alkaptonuria leading to the destructive consequences of the disease a review
Journal of Inherited Metabolic Disease, 2019Co-Authors: Brendan P Norman, L R Ranganath, J A GallagherAbstract:Ochronosis is the process in alkaptonuria (AKU) that causes all the debilitating morbidity. The process involves selective deposition of homogentisic acid (HGA)-derived pigment in tissues altering the properties of these tissues, leading to their failure. Some tissues like cartilage are more easily affected by Ochronosis while others such as the liver and brain are unaffected for reasons that are still not understood. In vitro and mouse models of Ochronosis have confirmed the dose relationships between HGA and Ochronosis and also their modulation by p-hydroxyphenylpyruvate dioxygenase inhibition. Ochronosis cannot be fully reversed and is a key factor in influencing treatment decisions. Earlier detection of Ochronosis preferably by noninvasive means is desirable. A cause-effect relationship between HGA and Ochronosis is discussed. The similarity in AKU and familial hypercholesterolaemia is explored and lessons learnt. More research is needed to more fully understand the crucial nature of Ochronosis.
Milad Khedr - One of the best experts on this subject based on the ideXlab platform.
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evaluating the aortic stenosis phenotype before and after the effect of homogentisic acid lowering therapy analysis of a large cohort of eighty one alkaptonuria patients
Molecular Genetics and Metabolism, 2021Co-Authors: L R Ranganath, Milad Khedr, T Heseltine, Michael FisherAbstract:Abstract Aims A large alkaptonuria (AKU) cohort was studied to better characterise the poorly understood phenotype of aortic stenosis of rare disease AKU. Methods and results Eighty-one patients attended the National Alkaptonuria Centre (NAC) between 2007 and 2020. Nine only attended once. Fifty-one attended more than once and received nitisinone 2 mg daily. Twenty-one attended at least twice without receiving nitisinone. Assessments included questionnaire analysis, standard transthoracic echocardiography, as well as photographs of ochronotic pigment in eyes and ears at baseline when 2 mg nitisinone was commenced, and yearly thereafter. Blood and urine samples were collected for chemical measurement. The prevalence of aortic stenosis and aortic valve replacement were 22.2 and 6.2% in the current group. Aortic maximum velocity (Vmax) was directly related to varying degrees to age (R = 0.58, p Conclusion Aortic valve disease is highly prevalent in this NAC cohort, and strongly associated with Ochronosis and disease severity. Nitisinone decreases Ochronosis and had a similar significant effect on Vmax.
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characterizing the alkaptonuria joint and spine phenotype and assessing the effect of homogentisic acid lowering therapy in a large cohort of 87 patients
Journal of Inherited Metabolic Disease, 2021Co-Authors: L R Ranganath, Milad Khedr, Sobhan Vinjamuri, J A GallagherAbstract:A large alkaptonuria (AKU) cohort was studied to better characterize the poorly understood spondyloarthropathy of rare disease AKU. Eighty-seven patients attended the National Alkaptonuria Centre (NAC) between 2007 and 2020. Seven only attended once. Fifty-seven attended more than once and received nitisinone 2 mg daily. Twenty-three attended at least twice without receiving nitisinone. Assessments included questionnaire analysis, 18F Positron emission tomography computerised tomography (PETCT), as well as photographs of ochronotic pigment in eyes and ears at baseline when 2 mg nitisinone was commenced and yearly thereafter. Blood and urine samples were collected for chemical measurement. The prevalence of Ochronosis, as well as pain, PETCT and combined pain and PETCT scores, was greatly increased at 90.5%, 85.7%, 100%, and 100%, respectively. Joint pain scores were greatest in proximal joints in upper and lower limbs. PETCT joint scores were higher in proximal joints in upper limb but higher in distal joints in the lower limb. Spine pain scores were highest in lumbar, followed by cervical, thoracic, and cervical regions at 77.4%, 59.5%, 46.4%, and 25%, respectively. PETCT spine scores were highest in thoracic followed by lumbar, cervical, and sacroiliac regions at 74.4%, 70.7%, 64.6%, and 47.8% respectively; Ochronosis associated closely with spondyloarthropathy scores (R = .65; P < .0001). Nitisinone reversed Ochronosis significantly, with a similar pattern of decreased joint and spine disease. Spondyloarthropathy is a highly prevalent feature in this NAC cohort. Ochronosis appears to be associated with spondyloarthropathy. Nitisinone decreases Ochronosis and had a similar nonsignificant effect pattern on spondyloarthropathy.
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reversal of ochronotic pigmentation in alkaptonuria following nitisinone therapy analysis of data from the united kingdom national alkaptonuria centre
JIMD reports, 2020Co-Authors: L R Ranganath, Andrew T. Hughes, Andrew S Davison, Milad Khedr, Anna M. Milan, Peter Wilson, Elizabeth West, J P Dillon, J A GallagherAbstract:Background Increased homogentisic acid (HGA) causes Ochronosis. Nitisinone decreases HGA. The aim was to study the effect of nitisinone on the Ochronosis progression. Methods Photographs of the eyes and ears were acquired from patients attending the National Alkaptonuria Centre (NAC) at V-1 (pre-baseline visit), V0 (baseline visit when 2 mg nitisinone was commenced), and yearly at V1, V2, and V3 visits. Photographs were inspected for evolution of ochronotic pigment and also scored categorically to derive eye, ear, and combined Ochronosis scores. An ear cartilage biopsy was also carried out at V0 and one year after V3 (V4) and ochronotic pigment was assessed and quantitated. Visits were compared for changes in pigment. Fasting blood and 24-hour urine samples were collected for measurement of HGA. Results There were 80 AKU patients at V0, and 52, 47, and 40 at V1, V2, and V3 in the group with variable numbers (VAR Group) respectively; 23 patients attended once before V0, in the V-1 visit. Photographs of patients show increase in eye pigment between V-1 and V0, followed by decrease post-nitisinone at V1, V2, and V3. Ear and combined Ochronosis semiquantitative scoring showed an increase between V-1 and V0 (P < .01), followed by a decrease at V1, V2, and V3, in the VAR group (P < .01). Ochronotic pigment in ear biopsy between V0 and V4 showed a 19.1% decrease (P < .05). Conclusions Nitisinone decreases HGA and partially reverses Ochronosis.
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Data on items of AKUSSI in Alkaptonuria collected over three years from the United Kingdom National Alkaptonuria Centre and the impact of nitisinone.
Data in brief, 2018Co-Authors: R. Griffin, Andrew T. Hughes, Andrew S Davison, Milad Khedr, Anna M. Milan, Eftychia E. Psarelli, Trevor Cox, J.l. Usher, Sophie Taylor, N. LoftusAbstract:Alkaptonuria is a rare genetic disorder characterized by a high level of circulating (and urine) homogentisic acid (HGA), which contributes to Ochronosis when it is deposited in connective tissue as a pigmented polymer. In an observational study carried out by National AKU Centre (NAC) in Liverpool, a total of thirty-nine AKU patients attended yearly visits in varying numbers. At each visit a mixture of clinical, joint and spinal assessments were carried out and the results calculated to yield an AKUSSI (Alkaptonuria Severity Score Index), see "Nitisinone arrests Ochronosis and decreases rate of progression of Alkaptonuria: evaluation of the effect of nitisinone in the United Kingdom National Alkaptonuria Centre" (Ranganath at el., 2018). The aim of this data article is to produce visual representation of the change in the components of AKUSSI over 3 years, through radar charts. The metabolic effect of nitisinone is shown through box plots.
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nitisinone arrests Ochronosis and decreases rate of progression of alkaptonuria evaluation of the effect of nitisinone in the united kingdom national alkaptonuria centre
Molecular Genetics and Metabolism, 2018Co-Authors: L R Ranganath, Andrew T. Hughes, Andrew S Davison, Milad Khedr, Anna M. Milan, J.l. Usher, Sophie Taylor, N. Loftus, Anna Daroszewska, Elizabeth WestAbstract:QUESTION: Does Nitisinone prevent the clinical progression of the Alkaptonuria? FINDINGS: In this observational study on 39 patients, 2 mg of daily nitisinone inhibited Ochronosis and significantly slowed the progression of AKU over a three-year period. MEANING: Nitisinone is a beneficial therapy in Alkaptonuria. BACKGROUND: Nitisinone decreases homogentisic acid (HGA), but has not been shown to modify progression of Alkaptonuria (AKU). METHODS: Thirty-nine AKU patients attended the National AKU Centre (NAC) in Liverpool for assessments and treatment. Nitisinone was commenced at V1 or baseline. Thirty nine, 34 and 22 AKU patients completed 1, 2 and 3 years of monitoring respectively (V2, V3 and V4) in the VAR group. Seventeen patients also attended a pre-baseline visit (V0) in the VAR group. Within the 39 patients, a subgroup of the same ten patients attended V0, V1, V2, V3 and V4 visits constituting the SAME Group. Severity of AKU was assessed by calculation of the AKU Severity Score Index (AKUSSI) allowing comparison between the pre-nitisinone and the nitisinone treatment phases. RESULTS: The ALL (sum of clinical, joint and spine AKUSSI features) AKUSSI rate of change of scores/patient/month, in the SAME group, was significantly lower at two (0.32 ± 0.19) and three (0.15 ± 0.13) years post-nitisinone when compared to pre-nitisinone (0.65 ± 0.15) (p < .01 for both comparisons). Similarly, the ALL AKUSSI rate of change of scores/patient/month, in the VAR group, was significantly lower at one (0.16 ± 0.08) and three (0.19 ± 0.06) years post-nitisinone when compared to pre-nitisinone (0.59 ± 0.13) (p < .01 for both comparisons). Combined ear and ocular Ochronosis rate of change of scores/patient/month was significantly lower at one, two and three year's post-nitisinone in both VAR and SAME groups compared with pre-nitisinone (p < .05). CONCLUSION: This is the first indication that a 2 mg dose of nitisinone slows down the clinical progression of AKU. Combined ocular and ear Ochronosis progression was arrested by nitisinone.
Trevor Cox - One of the best experts on this subject based on the ideXlab platform.
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subclinical Ochronosis features in alkaptonuria a cross sectional study
BMJ Innovations, 2019Co-Authors: Trevor Cox, Daniela Braconi, Eftychia E. Psarelli, Sophie Taylor, Federica Genovese, H Shepherd, Mark A Robinson, Gabor Barton, Alpesh Mistry, Daniela GiustariniAbstract:Background Alkaptonuria (AKU) is present from birth, yet clinical effects are considered to appear later in life. Morbidity of AKU, considered irreversible, is secondary to Ochronosis. Age of Ochronosis onset is not clearly known. Nitisinone profoundly lowers homogentisic acid (HGA), the metabolic defect in AKU. Nitisinone also arrests Ochronosis and slows progression of AKU. However, tyrosinaemia post-nitisinone has been associated with corneal keratopathy, rash and cognitive impairment in HT 1. The optimal time to start nitisinone in AKU is unknown. Methods In an open, cross-sectional, single-site study, 32 patients with AKU were to be recruited. The primary outcome was presence of Ochronosis in an ear biopsy. Secondary outcomes included analysis of photographs of eyes/ears, serum/urine HGA, markers of tissue damage/inflammation/oxidation, MRI imaging, gait, quality of life and Alkaptonuria Severity Score Index (qAKUSSI). Results Thirty patients, with mean age (SD) 38 (14) years, were recruited. Percentage pigmentation within ear biopsies increased with age. Ear pigmentation was detected in a 20-year-old woman implying Ochronosis can start in patients before the age of 20. Gait and qAKUSSI were outside the normal range in all the patients with AKU. Conclusions Ochronosis can be present before age 20 years.
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Data on items of AKUSSI in Alkaptonuria collected over three years from the United Kingdom National Alkaptonuria Centre and the impact of nitisinone.
Data in brief, 2018Co-Authors: R. Griffin, Andrew T. Hughes, Andrew S Davison, Milad Khedr, Anna M. Milan, Eftychia E. Psarelli, Trevor Cox, J.l. Usher, Sophie Taylor, N. LoftusAbstract:Alkaptonuria is a rare genetic disorder characterized by a high level of circulating (and urine) homogentisic acid (HGA), which contributes to Ochronosis when it is deposited in connective tissue as a pigmented polymer. In an observational study carried out by National AKU Centre (NAC) in Liverpool, a total of thirty-nine AKU patients attended yearly visits in varying numbers. At each visit a mixture of clinical, joint and spinal assessments were carried out and the results calculated to yield an AKUSSI (Alkaptonuria Severity Score Index), see "Nitisinone arrests Ochronosis and decreases rate of progression of Alkaptonuria: evaluation of the effect of nitisinone in the United Kingdom National Alkaptonuria Centre" (Ranganath at el., 2018). The aim of this data article is to produce visual representation of the change in the components of AKUSSI over 3 years, through radar charts. The metabolic effect of nitisinone is shown through box plots.
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clinical development of nitisinone for alkaptonuria developakure a rare disease clinical trials design
Trials, 2013Co-Authors: Eftychia E. Psarelli, Trevor Cox, L R RanganathAbstract:Alkaptonuria (AKU) is an orphan inherited homogentisate dioxygenase enzyme deficiency resulting in accumulation of homogentisic acid (HGA). HGA is converted to a black pigment polymer known as Ochronosis that causes tissue damage affecting many tissues including joints and heart, with significant poor quality of life. The DevelopAKUre project is a Europe-wide collaboration to study the efficacy and safety of nitisinone as a potential treatment in three clinical studies. The first is a phase 2 dose-response study (SONIA 1) which will determine the optimal dose of nitisinone that decreases HGA levels. The second is a phase III efficacy study (SONIA 2) based on the optimal dose and the third is a cross-sectional study (SOFIA) that will define the age that treatment should begin after determining the onset of Ochronosis. Details and rationale of the SONIA 2 design will be described, with special attention to issues arising from the rarity of the disease.
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natural history of alkaptonuria revisited analyses based on scoring systems
Journal of Inherited Metabolic Disease, 2011Co-Authors: L R Ranganath, Trevor CoxAbstract:Increased circulating homogentisic acid in body fluids occurs in alkaptonuria (AKU) due to lack of enzyme homogentisate dioxygenase leading in turn to conversion of HGA to a pigmented melanin-like polymer, known as Ochronosis. The tissue damage in AKU is due to Ochronosis. A potential treatment, a drug called nitisinone, to decrease formation of HGA is available. However, deploying nitisinone effectively requires its administration at the most optimal time in the natural history. AKU has a long apparent latent period before overt Ochronosis develops. The rate of change of Ochronosis and its consequences over time following its recognition has not been fully described in any quantitative manner. Two potential tools are described that were used to quantitate disease burden in AKU. One tool describes scoring the clinical features that includes clinical assessments, investigations and questionnaires in 15 patients with AKU. The second tool describes a scoring system that only includes items obtained from questionnaires in 44 people with AKU. Analysis of the data reveals distinct phases of the disease, a pre-ochronotic phase and an ochronotic phase. The ochronotic phase appears to demonstrate an earlier slower progression followed by a rapidly progressive phase. The rate of change of the disease will have implications for monitoring the course of the disease as well as decide on the most appropriate time that treatment should be started for it to be effective either in prevention or arrest of the disease.
Daniela Braconi - One of the best experts on this subject based on the ideXlab platform.
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subclinical Ochronosis features in alkaptonuria a cross sectional study
BMJ Innovations, 2019Co-Authors: Trevor Cox, Daniela Braconi, Eftychia E. Psarelli, Sophie Taylor, Federica Genovese, H Shepherd, Mark A Robinson, Gabor Barton, Alpesh Mistry, Daniela GiustariniAbstract:Background Alkaptonuria (AKU) is present from birth, yet clinical effects are considered to appear later in life. Morbidity of AKU, considered irreversible, is secondary to Ochronosis. Age of Ochronosis onset is not clearly known. Nitisinone profoundly lowers homogentisic acid (HGA), the metabolic defect in AKU. Nitisinone also arrests Ochronosis and slows progression of AKU. However, tyrosinaemia post-nitisinone has been associated with corneal keratopathy, rash and cognitive impairment in HT 1. The optimal time to start nitisinone in AKU is unknown. Methods In an open, cross-sectional, single-site study, 32 patients with AKU were to be recruited. The primary outcome was presence of Ochronosis in an ear biopsy. Secondary outcomes included analysis of photographs of eyes/ears, serum/urine HGA, markers of tissue damage/inflammation/oxidation, MRI imaging, gait, quality of life and Alkaptonuria Severity Score Index (qAKUSSI). Results Thirty patients, with mean age (SD) 38 (14) years, were recruited. Percentage pigmentation within ear biopsies increased with age. Ear pigmentation was detected in a 20-year-old woman implying Ochronosis can start in patients before the age of 20. Gait and qAKUSSI were outside the normal range in all the patients with AKU. Conclusions Ochronosis can be present before age 20 years.
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Redox-proteomics of the effects of homogentisic acid in an in vitro human serum model of alkaptonuric Ochronosis
Journal of Inherited Metabolic Disease, 2011Co-Authors: Daniela Braconi, Giulia Bernardini, Marcella Laschi, Lia Millucci, Adriano Spreafico, Claretta Bianchini, Annalisa SantucciAbstract:Alkaptonuria (AKU) is a rare inborn error of metabolism associated with a deficient activity of homogentisate 1,2-dioxygenase (HGO), an enzyme involved in tyrosine and phenylalanine metabolism. Such a deficiency leads to the accumulation of homogentisic acid (HGA) and its oxidized/polymerized products in connective tissues, where melanin-like pigments accumulate (Ochronosis). Ochronosis involves especially joints, where an ochronotic arthropathy develops. Little is known on the molecular mechanisms leading to Ochronosis and ochronotic arthropathy in AKU. Previous works of ours showed that HGA in vitro propagates oxidative stress through its conversion into benzoquinone acetate (BQA). We hence used an in vitro model consisting of human serum treated with HGA and evaluated the activities of glutathione related anti-oxidant enzymes and levels of compounds indexes of oxidative stress. Proteomics and redox-proteomics were used to identify oxidized proteins and proteins more likely able to bind BQA. Overall, we found that the production of ochronotic pigment in HGA-treated serum is accompanied by lipid peroxidation, decreased activity of the enzyme glutathione peroxidase and massive depletion of thiol groups, together with increased protein carbonylation and thiol oxidation. We also found that BQA was likely to bind carrier proteins and naturally abundant serum proteins, eventually altering their chemico-physical properties. Concluding, our work points towards a critical importance of thiol compounds in counteracting HGA- and BQA- mediated stress in AKU, so that future research for disease biomarkers and pharmacological treatments for AKU and Ochronosis will be more easily addressed.
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proteomic and redox proteomic evaluation of homogentisic acid and ascorbic acid effects on human articular chondrocytes
Journal of Cellular Biochemistry, 2010Co-Authors: Daniela Braconi, J A Gallagher, Giulia Bernardini, Marcella Laschi, Laura Tinti, Adam Michael Taylor, Adriano Spreafico, Annalisa SantucciAbstract:Alkaptonuria (AKU) is a rare genetic disease associated with the accumulation of homogentisic acid (HGA) and its oxidized/polymerized products in connective tissues up to the deposition of melanin-like pigments (Ochronosis). Since little is known on the effects of HGA and its metabolites on articular cells, we carried out a proteomic and redox-proteomic analysis to investigate how HGA and ascorbic acid (ASC) affect the human chondrocytic protein repertoire. We settled up an in vitro model using a human chondrocytic cell line to evaluate the effects of 0.33 mM HGA, alone or combined with ASC. We found that HGA and ASC significantly affect the levels of proteins with specific functions in protein folding, cell organization and, notably, stress response and cell defense. Increased protein carbonyls levels were found either in HGA or ASC treated cells, and evidences produced in this paper support the hypothesis that HGA-induced stress might be mediated by protein oxidation. Our finding can lay the basis towards the settling up of more sophisticated models to study AKU and Ochronosis.