Neurocognitive Outcome in Hepatorenal Tyrosinemia

Background/Purpose: Hepatorenal tyrosinemia (HT1, MIM #276700) severely damages liver and kidney if untreated. It is frequently associated with peripheral neuropathy and central demyelination, attributed to increased 5-aminolevulinic acid levels. Introduction of nitisinone (NTBC, Orfadin®) revolutionized outcome, stabilizing liver and kidney function. Acute neuropathy can be avoided. However, negative long-term effects on neurocognitive function have been postulated.

Methods: Five patients with HT1 were tested at ages of 3 – 19 years with either Bayley-III Scales of Infant Development (BSID) or Wechsler Intelligence Scale for Children (WISC IV).

Results: In all patients, succinylacetone was not detectable in blood or urine. Mean concentration of tyrosine in plasma was 419 µmol/L (315–636), mean NTBC dosage was 0.53 mg/kg/d (0.13–1), and mean NTBC blood level 13.7 µmol/L (8.5–25.7). Cognitive deficits were found in four of five patients. In patients > 6 years, these affected especially the perceptual reasoning and processing speed scores. With increasing age, cognitive function decreased (r = 0.82; p = 0.04). There was no correlation between cognitive function and average NTBC dose or NTBC levels (in dried blood spots), age at onset of therapy or average plasma tyrosine level in patients.

Conclusion: In spite of good dietary compliance, cognitive function of patients with HT1 apparently may decline over time. This might be caused by increased tyrosine levels (not affected by NTBC treatment), low phenylalanine levels or drug toxicity. Finally, cognitive deficits may be part of the natural course of HT1.