Rare diseases Xagena

Xagena Mappa
Xagena Newsletter

Alkaptonuria: reversible keratopathy due to hypertyrosinaemia with use of intermittent low-dose Nitisinone

Alkaptonuria ( AKU ) is a rare inherited metabolic disorder with severe premature spondyloarthropathy as a major manifestation.
Although joint disease is a major feature, virtually all connective tissues are affected leading to a variety of clinical features and complications.

A promising new agent, called Nitisinone ( Orfadin ), is available for the treatment of alkaptonuria. Early Nitisinone therapy is likely to prevent morbidity but may only slow or arrest disease progression if started later.

Alkaptonuria is a rare inborn error of metabolism characterized by high circulating homogentisic acid ( HGA ) due to a genetic defect in the enzyme homogentisate dioxygenase ( HGD ).
The main pathophysiological event is conversion of HGA to a polymeric melanin-like pigment and binding of this pigment to connective tissue, especially cartilage. This process takes many years and is known as ochronosis.
The damaging effects of ochronosis include arthritis ( especially in the spine and large weight bearing joints ), stones ( renal, prostatic, gall bladder and salivary ), cardiac valve disease especially aortic, ruptures ( muscle, tendons and ligaments ), osteopenia and fractures.
Virtually all connective tissue is affected.

Nitisinone inhibits p-hydroxyphenyl pyruvate dioxygenase, the enzyme leading to the formation of HGA. In keeping with the mode of action of Nitisinone, circulating tyrosine increases.
The tyrosinaemia that occurs during Nitisinone treatment resembles hereditary tyrosinaemia type 3. Adverse effects known to be associated with tyrosinaemia include corneal and dermal toxicity. Therefore, skin rash and dendritic keratopathy might be expected in some patients with a Nitisinone-induced tyrosinaemia.

Nitisinone at a dose of 1–2 mg/kg/day has been widely used for more than 20 years in the treatment of a life-threatening condition called hereditary tyrosinaemia type 1 ( HT-1 ).

Corneal involvement is not part of the natural history in HT-1. Corneal lesions in medically managed HT-1 are reported as being rare with less than 7.4% frequency in one large series of 176 HT-1 patients treated with Nitisinone.

Another report on 46 HT-1 patients noted 8.7% prevalence of keratitis with Nitisinone treatment.

A smaller series reported no eye symptoms or keratopathy in 11 HT-1 patients treated with Nitisinone despite seeing high circulating tyrosine concentrations in several patients.

In contrast to the quantities of Nitisinone employed in HT-1 to prevent hepatic and renal pathology, the dose of Nitisinone that decreases homogentisic acid in alkaptonuria by greater than 95% is only 2 mg daily, or approximately 5% of the dose used in HT-1. This is based on the experience of using Nitisinone in the National Institutes of Health, USA.
However, one patient in the clinical trial of Nitisinone in alkaptonuria developed corneal keratopathy that resolved fully with discontinuation of Nitisinone. ( Xagena )

Stewart RMK et al, JIMD Rep 2014; 17: 1–6