Nitisinone arrests ochronosis and decreases rate of progression of Alkaptonuria: Evaluation of the effect of nitisinone in the United Kingdom National Alkaptonuria Centre

Ranganath, L.R.; Khedr, Milad; Milan, Anna M.; Davison, Andrew S.; Hughes, Andrew T.; Usher, J.; Taylor, Sophie; Loftus, Nadia; Daroszewska, Anna; West, Elizabeth A.; Jones, A. S.; Briggs, Michael; Fisher, Michael; McCormick, M; Judd, Shirley; Vinjamuri, Sobhan; Griffin, Rebecca; Psarelli, EE; Cox, TF; Sireau, Nicolas; Dillon, J.P.; Devine, J.; Hughes, Georgina; Harrold, Joanne A.; Barton, Gábor; Jarvis, JC; Gallagher, J.A.

doi:10.1016/j.ymgme.2018.07.011

Cited by 98 publications

(127 citation statements)

References 18 publications

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“…Recent data suggest partial reversibility of external ochronosis by HPPD inhibition, while data from imaging studies have shown a similar partial reversal of atherosclerosis by reducing cholesterol . A study has been reported showing a slower progression of AKU using HPPD inhibition, similar to statin trials on CVD progression . However it is worth noting differences in the inheritance of AKU and FH; AKU is autosomal recessive with prevalence of 1:250 000 worldwide, whereas FH is autosomal dominant and relatively more common with estimated worldwide prevalence of 1:200 to 300 .…”

Section: Lessons For Aku From the Role Of Cholesterol In Atheroscleromentioning

confidence: 96%

“…It is currently believed that the OP process is not fully reversible, although there are indications of some reversal of pigment; the mechanism of such reversal is currently unknown . It is not known if the OP process is dynamic, that is, formation and removal co‐existing, although macrophages with pigment has been described in case reports …”

Section: Formation Of Ochronotic Pigmentmentioning

confidence: 99%

“…Gross ochronosis is easily visible as blue‐black pigment in tissues such as the cartilage of the ears and sclera of the eyes. Photographs of the eyes and ears have been used to follow the OP process, both in terms of understanding the natural history as well as to study the effect of reducing HGA concentrations on OP using HPPD inhibitors, and may be the most efficacious way to follow pigment change …”

Section: Detection Of Ochronosismentioning

confidence: 99%

“…The colocalization of amyloid with shards of OP suggests a close association with ochronosis, although the clinical significance of amyloidosis in AKU remains unknown. In addition, the observation that OP can reverse is difficult to explain on the basis of amyloid being the major component of pigment.…”

Section: Op and Amyloidmentioning

confidence: 99%

“…The use of HPPD inhibition employing nitisinone to decrease flux in the tyrosine pathway has revolutionized the treatment of hereditary tyrosinemia . Nitisinone was first suggested as a treatment for HGA in AKU in 1998, and is now shown to be highly effective in reducing HGA despite not being approved in AKU . Nitisinone not only decreases HGA but also arrests ochronosis in mice .…”

Section: Therapy and Ochronosismentioning

confidence: 99%

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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

Ranganath

Norman

Gallagher

2019

J of Inher Metab Disea

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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.

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Section: Lessons For Aku From the Role Of Cholesterol In Atheroscleromentioning

confidence: 96%

Section: Formation Of Ochronotic Pigmentmentioning

confidence: 99%

Section: Detection Of Ochronosismentioning

confidence: 99%

Section: Op and Amyloidmentioning

confidence: 99%

Section: Therapy and Ochronosismentioning

confidence: 99%

See 3 more Smart Citations

Ochronotic pigmentation is caused by homogentisic acid and is the key event in alkaptonuria leading to the destructive consequences of the disease—A review

Ranganath

Norman

Gallagher

2019

J of Inher Metab Disea

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Pigmentierungschemie und radikalbasierter Kollagenabbau bei Alkaptonurie und Arthrose

Chow

Norman²,

Roberts³

et al. 2020

Angewandte Chemie

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Alkaptonurie (AKU) ist eine seltene Krankheit, die durch einen hohen Gehalt an Homogentisinsäure (HGA) im Körper gekennzeichnet ist. Patienten leiden an Gewebe‐Ochronose: eine dunkelbraune Verfärbung, insbesondere des Gelenkknorpels, die zu schwerer früher Osteoarthropathie führt. Kein molekularer Mechanismus verbindet erhöhten HGA‐Gehalt mit Ochronose; weder die chemische Identität des Pigments ist bekannt, noch wie es den Abbau des Gelenkknorpels induziert. Hier geben wir wichtige Einblicke in die mit HGA verbundene Pigmentzusammensetzung und die Kollagenstörung im AKU‐Knorpel. Synthetisches Pigment und pigmentiertes menschliches Knorpelgewebe zeigten beide Hydrochinon‐ähnliche NMR‐Signalmuster. EPR‐Spektroskopie zeigte, dass das synthetische Pigment Radikale enthält. Darüber hinaus beobachteten wir eine strukturelle Störung der Kollagen‐Tripelhelix im pigmentierten menschlichen AKU‐Knorpel und im Knorpel von Patienten mit Arthrose. Wir schlagen vor, dass der Kollagenabbau über transiente Glycylradikale erfolgen kann, die bei AKU aufgrund der durch Pigmentierung erzeugten Redoxumgebung verstärkt gebildet werden.

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Pigmentation Chemistry and Radical‐Based Collagen Degradation in Alkaptonuria and Osteoarthritic Cartilage

et al. 2020

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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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Nitisinone arrests ochronosis and decreases rate of progression of Alkaptonuria: Evaluation of the effect of nitisinone in the United Kingdom National Alkaptonuria Centre

Cited by 98 publications

References 18 publications

Ochronotic pigmentation is caused by homogentisic acid and is the key event in alkaptonuria leading to the destructive consequences of the disease—A review

Ochronotic pigmentation is caused by homogentisic acid and is the key event in alkaptonuria leading to the destructive consequences of the disease—A review

Pigmentierungschemie und radikalbasierter Kollagenabbau bei Alkaptonurie und Arthrose

Pigmentation Chemistry and Radical‐Based Collagen Degradation in Alkaptonuria and Osteoarthritic Cartilage

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