Increased prevalence of Parkinson's disease in alkaptonuria

Abstract

Amongst a cohort of 88 alkaptonuria (AKU) patients attending the United Kingdom National Alkaptonuria Centre (NAC), four unrelated patients had co-existing Parkinson's disease (PD). Two of the NAC patients developed PD before receiving nitisinone (NIT) while the other two developed overt PD during NIT therapy. NIT lowers redox-active homogentisic acid (HGA) and profoundly increases tyrosine (TYR). A further unpublished case of a Dutch patient with AKU and PD on deep brain stimulation is included in this report. A Pubmed search revealed a further five AKU patients with PD, all without NIT usage. The prevalence of PD in AKU in the NAC appears to be nearly 20-times higher than in the non-AKU population (p < 0.001) even when adjusted for age. We propose that life-long exposure to redox-active HGA may account for the higher prevalence of PD in AKU. Furthermore, the appearance of PD in AKU patients during NIT therapy may be due to unmasking dopamine deficiency in susceptible individuals, as a result of the tyrosinaemia during NIT therapy inhibiting the rate-limiting brain tyrosine hydroxylase.

Keywords: Parkinson's disease; alkaptonuria; homogentisic acid; nitisinone; oxidative stress; tyrosine.

FIGURE 1

Pathway showing synthesis of DA from TYR as well as the degradation of TYR to fumarate and acetoacetate. Metabolites are shown in black. Enzymes are shown in blue. NIT is shown in red and HGA in brown. DA, dopamine; TYR, tyrosine.

FIGURE 2

The relationships between NIT‐induced tyrosinaemia and HGA and oxidative stress‐mediated pathophysiology of Parkinson's disease is shown. Autooxidation of homogentisic acid and DA cause oxidative stress which in turn leads to death of substantia nigra neurons, mitochondrial dysfunction and Lewy body formation resulting in Parkinson's disease. Nitisinone‐induced tyrosinaemia leads to oxidative stress as well as inhibits rate‐limiting enzyme tyrosine hydroxylase involved in conversion of TYR to L‐DOPA and subsequently DA. DA, dopamine; DOPA, dihydroxyphenylacetic acid; TYR, tyrosine.

FIGURE 3

The pathways of formation of DA from TYR are shown including the enzymes catalysing the reactions. The main pathway is through conversion of TYR to L‐DOPA and then DA effected by rate‐limiting tyrosine hydroxylase and amino acid decarboxylase sequentially. The alternative pathway involves conversion to tyramine and then DA effected by amino acid decarboxylase and oxidoreductase CYP2DS sequentially. The minor pathway may adapt during decreased tyrosine hydroxylase activity. DA, dopamine; DOPA, dihydroxyphenylacetic acid; TYR, tyrosine.

FIGURE 4

NIT‐induced tyrosinaemia and effect on LAT 1 (SLC 7A5). Markedly increased circulating TYR competes with L‐DOPA and other essential and non‐essential amino acids for transport from the blood into the brain, decreasing their transport into the brain (shown as yellow lines from TYR label). During tyrosinaemia consequent to increase in brain TYR, tyrosine hydroxylase is inhibited (shown as red cross) preventing conversion of brain TYR (directly transported as well as derived from PHE) to L‐DOPA and therefore to DA. Tyrosinaemia therefore decreases formation of DA in the brain from TYR, as well as decreases transport of L‐DOPA into the brain, attesting to multiple defects in Parkinson's disease of AKU during nitisinone therapy. DA, dopamine; DOPA, dihydroxyphenylacetic acid; TYR, tyrosine.