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

摘要

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 μmol/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.