Long-term low dose nitisinone therapy in adults with alkaptonuria shows no cognitive decline or increased severity of depression.

Little is documented on whether nitisinone-induced hypertyrosinaemia alters cognitive functioning or leads to worsening depression in alkaptonuria (AKU). Wechsler Adult Intelligence Scale-IV (WAIS-IV) and Beck Depression Inventory-II (BDI-II) assessments were performed before and annually following treatment with nitisinone 2 mg daily to assess the impact on cognitive functioning and severity of depression. Serum tyrosine concentrations were also measured annually. 63 patients (27 females/36 males: mean age[years] [±standard deviation, range] 55.7[13.7, 26-79]; 60.3[9.6, 19-75]) were included at baseline for assessment of: verbal comprehension (VC), perceptual reasoning (PR), working memory (WM), and processing speed (PS) using separate indices. Over the 6-year period studied 43, 39, 36, 29, 26 and 15 patients had annual assessments. Using a longitudinal model (age and sex adjusted) no significant differences were observed in any of the indices over this period, apart from VC which showed a significant increase after adjustment for sex ( < 0.05). 74 patients (32 females/42 males: mean age[years] [±standard deviation, range] 56.1[13.2, 26-79]; 42 males, 51.5[16.3, 19-70]) were included at baseline. Over the 7-year period studied 48, 47, 38, 34, 32, 24 and 12 patients had annual assessments. No significant differences in BDI-II scores were observed when compared to baseline. Hypertyrosinaemia was observed in all patients following treatment with nitisinone ( < 0.001, at all annual visits). Serum tyrosine was not correlated with WAIS-IV sub-test indices or BDI-II scores pre- or post-nitisinone therapy. These findings suggest that treatment with nitisinone does not affect cognitive functioning and or lead to increased severity of depression.