Evolution of tyrosinemia type 1 disease in patients treated with nitisinone in Spain

Abstract

Treatment with nitisinone (NTBC) has brought about a drastic improvement in the treatment and prognosis of hereditary tyrosinemia type I (HT1). We conducted a retrospective observational multicentric study in Spanish HT1 patients treated with NTBC to assess clinical and biochemical long-term evolution.We evaluated 52 patients, 7 adults and 45 children, treated with NTBC considering: age at diagnosis, diagnosis by clinical symptoms, or by newborn screening (NBS); phenotype (acute/subacute/chronic), mutational analysis; symptoms at diagnosis and clinical course; biochemical markers; doses of NTBC; treatment adherence; anthropometric evolution; and neurocognitive outcome.The average follow-up period was 6.1 ± 4.9 and 10.6 ± 5.4 years in patients with early and late diagnosis respectively. All patients received NTBC from diagnosis with an average dose of 0.82 mg/kg/d. All NBS-patients (n = 8) were asymptomatic at diagnosis except 1 case with acute liver failure, and all remain free of liver and renal disease in follow-up. Liver and renal affectation was markedly more frequent at diagnosis in patients with late diagnosis (P < .001 and .03, respectively), with ulterior positive hepatic and renal course in 86.4% and 93.2% of no-NBS patients, although 1 patient with good metabolic control developed hepatocarcinoma.Despite a satisfactory global nutritional evolution, 46.1% of patients showed overweight/obesity. Interestingly lower body mass index was observed in patients with good dietary adherence (20.40 ± 4.43 vs 24.30 ± 6.10; P = .08) and those with good pharmacological adherence (21.19 ± 4.68 vs 28.58 ± 213.79).intellectual quotient was ≥85 in all NBS- and 68.75% of late diagnosis cases evaluated, 15% of which need pedagogical support, and 6.8% (3/44) showed school failure.Among the 12 variants identified in fumarylacetoacetate hydrolase gene, 1 of them novel (H63D), the most prevalent in Spanish population is c.554–1 G>T.After NTBC treatment a reduction in tyrosine and alpha-fetoprotein levels was observed in all the study groups, significant for alpha-fetoprotein in no NBS-group (P = .03), especially in subacute/chronic forms (P = .018).This series confirms that NTBC treatment had clearly improved the prognosis and quality of life of HT1 patients, but it also shows frequent cognitive dysfunctions and learning difficulties in medium-term follow-up, and, in a novel way, a high percentage of overweight/obesity.

Type 1 tyrosinemia in Finland: a nationwide study

“…Comparable gradual improvement in renal ndings has also been reported by a British group [25] whereas clinically important data about the disappearance of the other ndings or signi cance of their perseverance has been limited. Persistent liver abnormalities have been reported in 19-57% of patients, but the follow-up times have been shorter than in the present study [6,16,17,19,23,29]. Here the nonresponsive ndings and reappearance of splenomegaly were major warning signs for subsequent hepatic transplantation.…”

“…These previously unreported ndings should be kept in mind as possible early signs of TT1 in high-prevalence areas. Inexplicably, we found no cases with frequently described [16,19,22,29] cardiomyopathy and neurological crises. Of note, although according to laboratory parameters most of the patients had deep coagulopathy typical for TT1 [22,24,29], severe bleeding was rare.…”

“…The number of screen-detected patients was low, but their milder phenotype compared with those detected clinically was evident. Moreover, in line with earlier short-term studies [6,13,22,29], early detection seemed to improve the prognosis; all subjects needing transplantation despite nitisinone had late diagnosis. As regards the bene ts of NBS, the current evidence is again based mainly on short-term reports [6,17,29], an exception being a Canadian study which found none of the NBS patients to have signi cant liver problems after 5-10 years [16].…”

“…Moreover, in line with earlier short-term studies [6,13,22,29], early detection seemed to improve the prognosis; all subjects needing transplantation despite nitisinone had late diagnosis. As regards the bene ts of NBS, the current evidence is again based mainly on short-term reports [6,17,29], an exception being a Canadian study which found none of the NBS patients to have signi cant liver problems after 5-10 years [16]. However, like some other groups [6,17,29]we observed signs of hepatic dysfunction which, together with the aforesaid neonatal symptoms, suggests disease progression already in utero [17,30].…”

“…As regards the bene ts of NBS, the current evidence is again based mainly on short-term reports [6,17,29], an exception being a Canadian study which found none of the NBS patients to have signi cant liver problems after 5-10 years [16]. However, like some other groups [6,17,29]we observed signs of hepatic dysfunction which, together with the aforesaid neonatal symptoms, suggests disease progression already in utero [17,30]. The frequency of neonatal hypoglycaemia was also surprisingly high.…”