Patient-reported outcomes and functional assessments of patients with Alkaptonuria in a 3-year Nitisinone treatment trial

Patient-reported outcomes and functional assessments of patients with Alkaptonuria in a 3-year Nitisinone treatment trial

Alkaptonuria is a rare disorder of tyrosine catabolism caused by deficiency of homogentisate 1,2-dioxygenase that leads to accumulation of homogentisic acid (HGA). Deposition of HGA-derived polymers in connective tissue causes progressive arthropathy of the spine and large joints, cardiac valvular d...

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Bibliographic Details
Published in:Molecular genetics and metabolism Vol. 143; no. 1-2; p. 108562
Main Authors: Spears, Kathryn R., Rossignol, Francis, Perry, Monique B., Kayser, Michael A., Suwannarat, Pim, O'Brien, Kevin E., Bryant, Joy C., Greenwood, Wendy F., Fuller, Steve, Gahl, William A., Introne, Wendy J.
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01-09-2024
Subjects:
4-Hydroxyphenylpyruvate Dioxygenase - antagonists & inhibitors
Adult
Aged
Alkaptonuria
Alkaptonuria - drug therapy
Cyclohexanones - therapeutic use
Female
Homogentisate 1,2-Dioxygenase - genetics
Homogentisic acid
Homogentisic Acid - metabolism
Homogentisic Acid - urine
Humans
Male
Middle Aged
Nitisinone
Nitrobenzoates - therapeutic use
Patient Reported Outcome Measures
Patient-reported outcomes
Quality of Life
Treatment Outcome
EF
GH
HGA
RLEP
Alkaptonuria
6MWT
SF-36
P
Homogentisic acid
EW
AAS
SF
RLPH
HAP
PF
Patient-reported outcomes
MAS
Nitisinone
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Summary:Alkaptonuria is a rare disorder of tyrosine catabolism caused by deficiency of homogentisate 1,2-dioxygenase that leads to accumulation of homogentisic acid (HGA). Deposition of HGA-derived polymers in connective tissue causes progressive arthropathy of the spine and large joints, cardiac valvular disease, and genitourinary stones beginning in the fourth decade of life. Nitisinone, a potent inhibitor of the upstream enzyme, 4-hydroxyphenylpyruvate dioxygenase, dramatically reduces HGA production. As such, nitisinone is a proposed treatment for alkaptonuria. A randomized clinical trial of nitisinone in alkaptonuria confirmed the biochemical efficacy and tolerability of nitisinone for patients with alkaptonuria but the selected primary outcome did not demonstrate significant clinical benefit. Given that alkaptonuria is a rare disease with slow progression and variable presentation, identifying outcome parameters that can detect significant change during a time-limited clinical trial is challenging. To gain insight into patient-perceived improvements in quality of life and corresponding changes in physical function associated with nitisinone use, we conducted a post-hoc per protocol analysis of patient-reported outcomes and a functional assessment. Analysis revealed that nitisinone-treated patients showed significant improvements in complementary domains of the 36-Item Short-Form Survey (SF-36) and 6-min walk test (6MWT). Together, these findings suggest that nitisinone improves both quality of life and function of patients with alkaptonuria. The observed trends support nitisinone as a therapy for alkaptonuria. •Nitisinone benefits quality of life and function of patients with alkaptonuria•Nitisinone-treated patients report gains in physical functioning and activity•6-minute walk improvements support reported gains in nitisinone-treated patients•Patient-reported outcomes offer novel insight into clinical benefit of nitisinone
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ISSN:1096-7192
1096-7206
1096-7206
DOI:10.1016/j.ymgme.2024.108562