A 3-year randomized therapeutic trial of nitisinone in alkaptonuria.
Author(s): Introne WJ, Perry MB, Troendle J, Tsilou E, Kayser MA, Suwannarat P, O'Brien KE,
Bryant J, Sachdev V, Reynolds JC, Moylan E, Bernardini I, Gahl WA.
Affiliation(s): Office of the Clinical Director, National Human Genome Research Institute,
National Institutes of Health, Bethesda, MD 20892, USA. wintrone@mail.nih.gov
Publication date & source: 2011, Mol Genet Metab. , 103(4):307-14
Alkaptonuria is a rare, autosomal recessive disorder of tyrosine degradation due
to deficiency of the third enzyme in the catabolic pathway. As a result,
homogentisic acid (HGA) accumulates and is excreted in gram quantities in the
urine, which turns dark upon alkalization. The first symptoms, occurring in early
adulthood, involve a painful, progressively debilitating arthritis of the spine
and large joints. Cardiac valvular disease and renal and prostate stones occur
later. Previously suggested therapies have failed to show benefit, and management
remains symptomatic. Nitisinone, a potent inhibitor of the second enzyme in the
tyrosine catabolic pathway, is considered a potential therapy; proof-of-principle
studies showed 95% reduction in urinary HGA. Based on those findings, a
prospective, randomized clinical trial was initiated in 2005 to evaluate 40
patients over a 36-month period. The primary outcome parameter was hip total
range of motion with measures of musculoskeletal function serving as secondary
parameters. Biochemically, this study consistently demonstrated 95% reduction of
HGA in urine and plasma over the course of 3 years. Clinically, primary and
secondary parameters did not prove benefit from the medication. Side effects were
infrequent. This trial illustrates the remarkable tolerability of nitisinone, its
biochemical efficacy, and the need to investigate its use in younger individuals
prior to development of debilitating arthritis.
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