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Nitisinone-Induced Keratopathy in Alkaptonuria: A Challenging Diagnosis Despite Clinical Suspicion.

ABSTRACT: Alkaptonuria is a rare disorder of amino acid metabolism that causes premature large joint and spine arthropathy and cardiac valvular disease. It is characterised by elevated levels of homogentisic acid. Nitisinone (NTBC) is a benzoylcyclohexane-1,3-dione that reversibly inhibits the activity of the enzymatic step immediately prior to homogentisate dioxygenase, hence reducing the production of homogentisic acid. Thus it is thought that nitisinone might be a treatment for alkaptonuria. A side effect of NTBC therapy is elevation of plasma tyrosine levels in a manner analogous to tyrosinemia type 2, another related condition which causes a painful palmoplantar hyperkeratosis and eye pathology described as conjunctivitis and herpetic-like corneal ulceration. There are only two previous reports of NTBC causing eye symptoms in patients with alkaptonuria. Here we provide further evidence of this side effect of treatment and its resolution with cessation of NTBC. Repeat challenges with NTBC provoked symptoms, but introducing a low protein diet with low dose NTBC was successful in controlling plasma tyrosine levels and the patient remained free of symptoms when levels were below 600 ?mol/L. Our patient was remarkable for the low dose of NTBC that precipitated symptoms (as little as 0.5 mg daily), and for the difficulty in proving its causation despite clinical suspicion.

SUBMITTER: White A

PROVIDER: S-EPMC6122027 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Nitisinone-Induced Keratopathy in Alkaptonuria: A Challenging Diagnosis Despite Clinical Suspicion.

White Andrew A C Tchan Michel M

JIMD reports 20170907

Alkaptonuria is a rare disorder of amino acid metabolism that causes premature large joint and spine arthropathy and cardiac valvular disease. It is characterised by elevated levels of homogentisic acid. Nitisinone (NTBC) is a benzoylcyclohexane-1,3-dione that reversibly inhibits the activity of the enzymatic step immediately prior to homogentisate dioxygenase, hence reducing the production of homogentisic acid. Thus it is thought that nitisinone might be a treatment for alkaptonuria. A side eff ...[more]

PMID: 28879639

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Project description:Alkaptonuria (AKU) is caused by homogentisate 1,2-dioxygenase deficiency that leads to homogentisic acid (HGA) accumulation, ochronosis and severe osteoarthropathy. Recently, nitisinone treatment, which blocks HGA formation, has been effective in AKU patients. However, a consequence of nitisinone is elevated tyrosine that can cause keratopathy. The effect of tyrosine and phenylalanine dietary restriction was investigated in nitisinone-treated AKU mice, and in an observational study of dietary intervention in AKU patients. Nitisinone-treated AKU mice were fed tyrosine/phenylalanine-free and phenylalanine-free diets with phenylalanine supplementation in drinking water. Tyrosine metabolites were measured pre-nitisinone, post-nitisinone, and after dietary restriction. Subsequently an observational study was undertaken in 10 patients attending the National Alkaptonuria Centre (NAC), with tyrosine >700??mol/L who had been advised to restrict dietary protein intake and where necessary, to use tyrosine/phenylalanine-free amino acid supplements. Elevated tyrosine (813??mol/L) was significantly reduced in nitisinone-treated AKU mice fed a tyrosine/phenylalanine-free diet in a dose responsive manner. At 3?days of restriction, tyrosine was 389.3, 274.8, and 144.3 ?mol/L with decreasing phenylalanine doses. In contrast, tyrosine was not effectively reduced in mice by a phenylalanine-free diet; at 3?days tyrosine was 757.3, 530.2, and 656.2 ?mol/L, with no dose response to phenylalanine supplementation. In NAC patients, tyrosine was significantly reduced (P =?.002) when restricting dietary protein alone, and when combined with tyrosine/phenylalanine-free amino acid supplementation; 4 out of 10 patients achieved tyrosine <700??mol/L. Tyrosine/phenylalanine dietary restriction significantly reduced nitisinone-induced tyrosinemia in mice, with phenylalanine restriction alone proving ineffective. Similarly, protein restriction significantly reduced circulating tyrosine in AKU patients.

Dataset Information

Nitisinone-Induced Keratopathy in Alkaptonuria: A Challenging Diagnosis Despite Clinical Suspicion.

Publications

Nitisinone-Induced Keratopathy in Alkaptonuria: A Challenging Diagnosis Despite Clinical Suspicion.

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