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
HELIOS-A study: Vutrisiran has reversed polyneuropathy manifestations with improvements in neuropathy, quality of life, and gait speed
Full positive results from the HELIOS-A phase 3 study of Vutrisiran, an investigational RNAi therapeutic in development for the treatment...
Pulmonary hypertension: aortic and/or mitral valve surgery performed via a minimally invasive approach
Pulmonary hypertension ( PH ) in the setting of left-sided valvular heart disease is common, and significantly increases the risk...
The FDA ( Food and Drug Administration ) has expanded the approved use of the CoreValve System to treat certain...
Transcatheter aortic valve replacement patients who are unable to undergo surgery: CoreValve System has obtained early FDA approval
The FDA ( Food and Drug Administration ) has approved of the self-expanding transcatheter CoreValve System for severe aortic stenosis...
Patients with bicuspid aortic valve without Marfan syndrome: identification of fibrillin 1 gene mutations
Bicuspid aortic valve ( BAV ) is the most frequent congenital heart disease with frequent involvement in thoracic aortic dilatation,...
Pallister-Killian syndrome ( PKS ) is a sporadic multisystem genetic diagnosis characterized by facial dysmorphia, variable developmental delay and intellectual...
A newly identified genetic variant doubles the risk of calcium buildup in the heart’s aortic valve. Calcium buildup is the...
Alkaptonuria is caused by deficiency of homogentisate 1,2-dioxygenase, an enzyme that converts homogentisic acid ( HGA ) to maleylacetoacetic acid...
The SEAS ( Simvastatin and Ezetimibe in Aortic Stenosis ) study has investigated the effects of intensive cholesterol lowering with...