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Type 1 tyrosinemia in Finland: a nationwide study



Introduction of nitisinone and newborn screening (NBS) have transformed the treatment of type 1 tyrosinemia, but the effects of these changes on the long-term outcomes remain obscure. Also, the predictors for later complications, the significance of drug levels and the normalization of laboratory and imaging findings are poorly known. We investigated these issues in a nationwide study.


Type 1 tyrosinemia was diagnosed in 22 children in 1978–2019 in Finland. Incidence was 1/90,102, with a significant enrichment in South Ostrobothnia (1/9990). Median age at diagnosis was 5 (range 0.5–36) months, 55% were girls and 13 had homozygotic Trp262X mutation. Four patients were detected through screening and 18 clinically, their main findings being liver failure (50% vs. 100%, respectively, p = 0.026), ascites (0% vs. 53%, p = 0.104), renal tubulopathy (0% vs. 65%, p = 0.035), rickets (25% vs. 65%, p = 0.272), growth failure (0% vs. 66%, p = 0.029), thrombocytopenia (25% vs. 88%, p = 0.028) and anaemia (0% vs. 47%, p = 0.131). One patient was treated with diet, seven with transplantation and 14 with nitisinone. Three late-diagnosed (6–33 months) nitisinone treated patients needed transplantation later. Kidney dysfunction (86% vs. 7%, p = 0.001), hypertension (57% vs. 7%, p = 0.025) and osteopenia/osteoporosis (71% vs. 14%, p = 0.017) were more frequent in transplanted than nitisinone-treated patients. Blood/serum alpha-fetoprotein decreased rapidly on nitisinone in all but one patient, who later developed intrahepatic hepatocellular carcinoma. Liver values normalized in 31 months and other laboratory values except thrombocytopenia within 18 months. Imaging findings normalized in 3–56 months excluding five patients with liver or splenic abnormalities. Low mean nitisinone concentration was associated with higher risk of severe complications (r = 0.758, p = 0.003) despite undetectable urine succinylacetone.


Prognosis of type 1 tyrosinemia has improved in the era of nitisinone, and NBS seems to provide further benefits. Nevertheless, the long-term risk for complications remains, particularly in the case of late diagnosis and/or insufficient nitisinone levels.


Tyrosinemia is an autosomal recessively inherited metabolic disease presenting with three clinically distinct subtypes. The majority of patients have type I tyrosinemia (TT1, OMIM 276,700), types II and III being extremely rare [1,2,3]. The global incidence is ~ 1/100,000–1/200,000, but TT1 has enriched in certain areas, particularly in Northern Europe and Canada [4,5,6,7]. The disease is caused by a homozygous or compound heterozygous mutation in the gene on chromosome 15q25, leading to a lack of fumarylacetoacetate hydrolase (EC and an ensuing accumulation of blood tyrosine, succinylacetoacetate and succinylacetone (SA) [6, 8, 9]. Typical presentation includes liver failure and kidney tubular dysfunction, other reported findings being, for example, growth failure, rickets and pseudo-porphyric crises [6, 9,10,11,12]. Untreated TT1 increases the risk for liver carcinoma [12, 13].

Liver transplantation was the only cure for TT1 until the discovery of nitisinone [14]. Although the drug is effective in preventing the production of toxic metabolites, the accumulation of tyrosine must be prevented by protein restriction [11]. Furthermore, although data is scarce, nitisinone-treated patients may also develop complications [6, 15, 16], particularly in the case of delayed diagnosis or persistently high tyrosine levels [6]. However, optimal long-term concentrations of plasma nitisinone and tyrosine are unclear. Newborn screening (NBS) has improved the short-term outcomes of TT1 patients [16, 17], but long-term results are still lacking [12]. Altogether, natural history studies of TT1 in the era of nitisinone and NBS are scant and have concentrated on a few geographical areas [16].

In Finland, the treatment of TT1 is centralized, with systematically maintained medical records and NBS programmes launched in 2014. This has enabled us to evaluate the incidence, changing features and long-term outcomes of TT1 in a nationwide setting.


Incidence, family background and genetics

Twenty-one patients were diagnosed in the period 1987–2018, and one in 1978. Additional search resulted in > 2000 metabolic/liver patients, none of whom had TT1. Incidence was 1/90,102 with significant enrichment in South Ostrobothnia (Fig. 1a), the area from which most patients originated (Fig. 1b). Two patients were of non-Finnish origin, and one of these had consanguineous parents. Three families had a history of TT1. Thirteen patients had a homozygous Finnish type c.786G > A, (p.Trp262X) mutation. Four patients had a compound heterozygous mutation, including Trp262X + c.1062 + 5G > A (p.?), Trp262X + unidentified other mutation, c.205del (p.Ser69fs) + c.554-1G > T (p.?) and c.191delA (p.Gln64fs) + c.191delA (p.Gln64fs). The latter two patients were originally from Kosovo and Iraq.

Fig. 1
figure 1

Incidence of type 1 tyrosinemia in 19 Finnish provinces (a) and the family origins of the patients (b)

Pregnancy and neonatal data

No pregnancy complications were reported. Median births weight was 0.1 (− 1.4 to 2.2) SD, length 0.4 (range − 1.3 to 3.8) SD, and head circumference 0.1 (− 1.3 to 1.8) SD. Of note, glucose value was measured in 20 out of the 22 newborns, and 45% of them needed intensified surveillance due to hypoglycaemia and 30% due to transient hypotonia. Five hypoglycaemic patients needed oral glucose supplementation and four intravenous infusion for a few days. Three of those with hypoglycaemia received TT1 diagnosis by NBS. Glucose value is measured frequently from Finnish newborns before discharging them from hospital.

Characteristics at diagnosis

Twelve (55%) patients were girls and the median age was 5 (range 0.5–36) months. Eighteen patients were found clinically, the main findings including acute abdomen (n = 8), septicaemia (n = 4), ascites (n = 3), rickets (n = 2) and intestinal bleeding (n = 1). Three were found by NBS and one by family screening. They had fewer clinical (Table 1), laboratory (Table 2) and imaging abnormalities (Table 3) and higher calcium and prothrombin time (PT) and lower conjugated bilirubin levels (Table 2) than those detected clinically. One patient had kidney dysfunction (increased plasma creatinine and urea, oliguria) while 11 had tubulopathy (acidosis and abnormal urine protein and/or glucose and/or microglobulin). Median height was − 1.3 (− 1.8 to 0.1) SD in screened and − 1.7 (− 3.1 to 0.7) SD in clinically-detected patients (p > 0.05) respectively. Three clinically-detected children had bilateral and two unilateral inguinal hernia and two also scrotum hernia; they all had ascites.

Table 1 Clinical findings at diagnosis in clinically-detected and screen-detected patients with type 1 tyrosinemia
Table 2 Laboratory findings at diagnosis in clinically-detected and screen-detected patients with type 1 tyrosinemia
Table 3 Radiological findings at diagnosis in clinically-detected and screen-detected patients with type 1 tyrosinemia

Initial treatment and short-term outcomes

One patient was treated with diet and seven with transplantation. One explant contained hepatocellular carcinoma, six cirrhosis and four cell atypia. Fourteen patients started nitisinone (median 1.0, range 0.9 –1.3 mg/kg/day). Eleven of them had dietary challenges and two needed temporary gastrostomy. Median hospitalization time, including the time before and after diagnosis and during liver transplantation, was 150 (range 78–195) days for children before the nitisinone era and 17 (2–45) days for children on nitisinone (p < 0.001).

Long-term outcomes

Median follow-up time of all patients was 16 (range 3–32) years and 12 (3–24) years on nitisinone. One patient died (at the age of 7 years) before the era of transplantation, one (29 years) with transplant due to unknown cause and one (15 years) later transplanted patient for intracerebral haemorrhage. Median age of the surviving patients was 12 (3–24) years on nitisinone and 30 (29–32) with initial liver transplant.

Kidney dysfunction, hypertension and reduced bone mineral density were more common in transplanted than among nitisinone-treated patients, but not after adjusting for current age (Table 4). Four patients needed liver re-transplant(s) and one kidney transplant due to severe kidney dysfunction after liver transplantation, and four patients had surgical complications. Three late-diagnosed (6–33 months) patients on nitisinone also needed transplant due to elevation of alpha-fetoprotein (AFP) and new/persisting nodules in imaging studies raising suspicion of intrahepatic malignancy. One of them had non-metastatic hepatocellular carcinoma and two had cirrhosis. One nitisinone-treated patient had pseudo-porphyric crisis while having undetectable urine SA but low serum nitisinone (13 µmol/l). None had eye complications. Three screen-detected patients also had subsequent health problems (developmental delay, learning difficulties, osteopenia). Median adult height was − 1.4 (− 0.5 to − 3.9) SD in nitisinone-treated and − 1.5 (0.2 to − 2.0) SD in transplanted patients (p = 0.639).

Table 4 Long-term complications in tyrosinemia patients treated primarily either with liver transplantation or with nitisinone medication

Predictors for long-term complications

Males had more often ≥ 2 complications (100% vs. 50%, p = 0.015), whereas there was no association between complications and age or clinical presentation at diagnosis. Those with multiple complications had lower median calcium (r = −0.447, p = 0.055) and higher creatinine (r = 0.496, p = 0.036), alkaline phosphatase (ALP, r = 0.483, p = 0.027) and gamma-glutamyl transferase (γ-GT, r = 0.547, p = 0.019) levels at diagnosis, and lower nitisinone levels during follow-up (r = −0.758, p = 0.003). Growth delay at diagnosis also predicted later growth disturbances (p = 0.045).

Normalization of the laboratory and imaging results

Serum AFP decreased steadily on nitisinone except in one patient with later malignancy (Fig. 2a), while tyrosine and nitisinone levels varied markedly (Fig. 2b, c). In transplanted patients, AFP persisted (Fig. 2a) and tyrosine was kept low until operation (Fig. 2b). Conjugated bilirubin normalized in 10–550 days, albumin in 58–60 days, and haemoglobin in 3–90 days on nitisinone. Thrombocytopenia normalized in 3–90 days, except in three patients, of whom two were later transplanted. All three had persistent or reappearing splenomegaly. Acidosis and tubulopathy disappeared within three months and urine SA within one month. Normalization of the other values is presented in Figs. 3 and 4.

Fig. 2
figure 2

Individual blood alpha-fetoprotein (a), tyrosine (b) and nitisinone (c) values of the study patients. Black lines denote nitisinone-treated patients and red lines the values of the liver transplanted patients from diagnosis until the transplantation (star). Grey area denotes the recommended target range

Fig. 3
figure 3

Changes in individual prothrombin time (a) and phosphate (b), total bilirubin (c) and ammonium ion (d) values in nitisinone-treated study patients

Fig. 4
figure 4

Changes in individual alanine aminotransferase (a) and gamma-glutamyl transferase (b) values in nitisinone-treated study patients. Red star shows the time of liver transplantation eventually required in one subject

Liver imaging abnormalities persisted until transplantation. On nitisinone, they normalized in 10/13 patients within 56 months; two of the three with persistent findings were later transplanted. Splenomegaly normalized within 56 months except in two transplanted patients and one (diagnosed at 8 months) nitisinone-treated patient. It also appeared later in two transplanted and three nitisinone-treated (diagnosis 5–33 months) patients of whom four developed liver complications. Kidney, central nervous system (CNS) and cardiac findings and rickets normalized within 56 months. However, 5/6 transplanted and 1/6 nitisinone-treated patients with rickets later developed osteopenia/osteoporosis. None of the NBS patients had persistent laboratory or imaging abnormalities and thus none needed transplantation.

Long-term nitisinone treatment, tyrosine levels and protein intake

The median nitisinone dose (n = 13) was 1.00 (range 0.69–1.83) mg/kg/day and the mean serum level of 212 measurements 56 (12–97) µmol/l. There was no correlation between the levels and dosing or taking the drug once (n = 3) or twice a day (n = 10). Urine SA remained constantly negative even with low nitisinone. Median protein intake during nitisinone was 2.2 (1.0–3.0) and 2.0 (1.3–3.0) mg/kg/day before and after one year of age respectively, and the ratio between natural and tyrosine/phenylalanine-free protein 0.7 (0.2–1.1) and 0.8 (0.3–2.0). Higher natural and modified protein ratio increased the likelihood of later transplantation (p = 0.007).

Low serum nitisinone was associated with later complications, these being present in six patients with mean value ≤ 54 µmol/l and none with > 54 µmol/l (AUC 0.85 [0.63–1.00]; p = 0.040). This was seen particularly with growth failure (0.93 [0.78–1.00], p = 0.028) and later transplantation (0.93 [0.78–1.00], p = 0.028). Also, low minimum nitisinone was associated with learning difficulties (0.86 [0.64−1.00], p = 0.045); three out of four children with minimum ≤ 24 µmol/l and 1/9 of those with > 24 µmol/l). Neither the type nor the number of complications was associated with tyrosine levels or variability of those levels.


We found the incidence of TT1 to be 1/90,102 in Finland, with a significant enrichment (1/9,990) in South Ostrobothnia. The latter is likely due to the homogenous population and overrepresentation of inherited diseases in this area [18]. In central Europe the corresponding figure is ~ 1/100,000–200,000 [6, 19], in Norway 1/74,800 [7] and in Quebec (Canada) up to 1/16,000 [4], whereas in Japan TT1 is exceptional [1]. As a further supporting founder effect, most patients living in South Ostrobothnia had homozygotic “Finnish type” Trp262X mutation [5] and their ancestors also originated from there. The other mutations were c.1062 + 5G > , which is common in Quebec [16, 20], c.191delA common in Turkey [21] and “Mediterranean” c.554-1G > T [20]. Of note, one patient had a previously unreported c.205del (p.Ser69fs) mutation [20].

Clinical presentations were mostly in line with earlier reports [6, 16, 17, 19, 22,23,24,25,26,27], the main findings including e.g. liver failure, poor growth and rickets. Pregnancies had also been uneventful [17, 23], but quite many had temporary hypoglycaemia or hypotonia after birth and five presented with inguinal/scrotum hernias, likely due to ascites [28]. These previously unreported findings 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 benefits 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 significant 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. Although this could be due in part to the sensitive screening performed frequently on Finnish newborns, it may also be TT1-related, and further studies on this interesting issue are needed. Risk of later health problems emphasizes the need for careful follow-up also for screen-detected patients [6].

Basic laboratory values and liver function tests normalized rapidly in most cases, while this took longer in case of transaminases and biliary parameters. This is mostly in line with earlier reports [17, 19, 23, 25], although the follow-up time has usually been shorter. Transaminase levels were higher and normalized more slowly than described before [16, 23], but this did not predict later complications. Some children also presented with high ammonium ion (NH4 +), this being feared to predict early need for transplantation [11], but the values decreased promptly on nitisinone. Slow decline of AFP is a physiological phenomenon in infancy [30, 31], but our findings confirm that nondecreasing or rerising values predict malignancy [16, 19, 22, 32]. Of note, persistent thrombocytopenia, which was associated with splenomegaly and is a classical sign of a chronic liver disease, was also a strong predictor of subsequent need for transplantation.

The kidney, CNS, cardiac and bone imaging findings normalized within a few years, but some patients had persistent liver abnormalities and/or splenomegaly. Comparable gradual improvement in renal findings has also been reported by a British group [25] whereas clinically important data about the disappearance of the other findings or significance 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 findings and reappearance of splenomegaly were major warning signs for subsequent hepatic transplantation.

Long-term complications of TT1 were mostly analogous with those reported in the literature [15,16,17, 19, 25, 29, 33, 34]. Neurological problems and poor growth were more common here, but the follow-up times of these earlier studies may have been too short to detect these late-appearing issues. The former have been suggested to be partially attributable to the side effects of nitisinone [34, 35], but this is debatable [33, 36] and here low levels seemed more harmful. However, early disease onset seems to increase the risk for neurological complications [6], again supporting the idea of in utero progression of TT1. Poor growth has been sparsely reported28, but the possible risk for short stature observed here calls for further studies. The association observed between low mean nitisinone and growth failure may be due to inadequate treatment and ongoing liver disease. Then again, these same patients needed liver transplant despite nitisinone use, and hence the role of transplantation must also be considered. There is also limited and inconsistent data about the prevalence and appropriate follow-up of bone issues in TT1 [12, 16], but our results suggest that surveillance at least for cases with rickets at diagnosis is warranted. In contrast, as in prior short-term studies [17, 19, 23, 25, 29], persistent renal involvement seems to be rare.

We found no significant association between long-term complications and tyrosine levels, but low serum nitisinone, even with negative urine SA, was associated with learning difficulties, growth delay and a need for transplantation. The reported nitisinone target range has varied 20–80 µmol/l [6, 11, 37] and the dosing usually aims to achieve negative urine SA [6, 24]. Optimal levels remain somewhat unclear, but frequent monitoring of the levels with a target of 40–60 µmol/l has been recommended [12]. Interestingly, recent studies have reported increased blood SA with nitisinone concentrations < 44.3 µmol/l [38] and positive urine SA with nitisinone < 40 µmol/l, respectively [39]. Thus, there may in theory have been intermittent SA secretion in our patients with low mean nitisinone levels even without detectable urine SA at follow-up visits. Urine SA varies depending on urine concentration and blood measurement may be more stable and replicable indicator of ongoing SA production [40]. Thus, the latter in combination with the nitisinone level could thus be preferable as a follow-up marker [38,39,40]. Interpretation of the markedly fluctuating nitisinone values can be difficult, but our results underline the importance of sufficient levels, which may be even higher than previously suggested. Of note, the increased ratio of natural to modified protein was also associated with subsequent need for liver transplantation in nitisinone-treated patients. This may be related to generally higher tyrosine levels, although we found no statistically significant association between tyrosine levels and complications.

The main strengths of the present study were the nationwide coverage and availability of comprehensive medical data. Detailed registers also provided information on long-term outcomes and enabled us to assess risk factors for later complications, although weaknesses in the retrospective design remain. As a further limitation, an intensified register search was conducted in only one district, which in theory could have led to a few earlier cases being missed. Some patients may also have died before the transplantation era and were thus lost since medical records are deleted 12 years posthumously.


The overall prognosis of TT1 has improved in the nitisinone era and NBS seems to provide further benefits. However, clinicians should realize that a risk of complications persist even among screen-detected patients. Intensified surveillance is warranted, especially in patients with delayed diagnosis and persistent laboratory or imaging abnormalities. In addition, maintaining sufficient nitisinone levels is important.


Study design and patients

Treatment of metabolic disorders in Finland is centralized in the university hospitals of Tampere (TAYS), Helsinki, Turku, Oulu and Kuopio. Patients with TT1 were searched from these centres by contacting the physicians responsible and by applying International Classification of Diseases code E70.2. In addition, since TAYS was known to diagnose most of the TT1 patients due its location near South Ostrobothnia, an intensified search among children with metabolic disease or liver failure diagnosed since 1960 was conducted there. Some follow-up visits took place in the central hospitals of Seinäjoki and Satakunta, and this data was also obtained. After patient identification, comprehensive medical data on each case was collected from birth until Sept. 2019.

Clinical characteristics and family background

The date of diagnosis was defined as the first positive urine SA, also in the case of NBS performed initially from dried blood spot. TT1 became part of the Finnish NBS programme in 2014 and currently 97% of newborns are tested. Positive blood spot screening result is confirmed by urinary SA measurement. If SA is negative, false positive NBS is confirmed by measuring plasma amino acids and urine organic acids [12, 41]. The collected data comprised a diagnostic approach (clinical suspicion vs. screening), demographic data, symptoms and clinical findings, developmental stage and growth parameters [42, 43] and relevant data about pregnancy and delivery. In addition, the origins of patients’ grandparents or the birthplace of the patient, presence of other TT1 cases in the family and possible consanguinity were documented.

Laboratory and imaging findings

The collected blood values included alanine aminotransferase (ALT), albumin, ALP, AFP, NH4+, blood count, calcium, γ-GT, glucose, PT and total (TBil) and conjugated bilirubin. The presence of liver or kidney dysfunction, kidney tubulopathy, anaemia, thrombocytopenia and hypoglycaemia [11, 26, 44,45,46] were also recorded. Liver dysfunction was diagnosed by the clinician based on the presence of characteristic findings (e.g. coagulopathy, hypoglycaemia, hypoalbuminemia, low cholesterol, increased NH4+). Kidney tubulopathy was based on the presence of acidosis and abnormal urine protein and/or glucose and/or microglobulin. During nitisinone treatment, the above-mentioned laboratory values, blood tyrosine and nitisinone levels and urine SA were monitored until current date. In transplanted patients, AFP and tyrosine values were monitored until transplantation.

The presence of ascites, abnormalities of liver, spleen, kidney, heart and CNS and the presence of rickets and osteopenia/osteoporosis were evaluated using X-rays, ultrasound, computer tomography, magnetic resonance and bone densitometry. Besides diagnostic imaging, at least annual abdominal surveillance was conducted in all patients. The disappearance of the abnormalities and the appearance of new findings were also documented.


Possible treatment modalities included sole dietary restriction, liver transplantation and nitisinone. Histology of the explants and possible transplantation complications were recorded, as were the compliance to and dosing (mg/kg/day) of nitisinone.

Long-term outcomes

Possible later complications were categorized to surgical complications, need for retransplant or transplantation despite nitisinone, kidney dysfunction, hypertension, pseudo-porphyric crises [11, 12, 47], osteopenia/osteoporosis, cardiac and ophthalmologic complications, delayed growth and neurological problems [11]. Kidney dysfunction was defined as decreased glomerular filtration rate. Cause of death were also noted.

Statistical analysis

Categorical variables are reported as numbers and percentages, and numerical data as medians with quartiles or ranges. Comparisons were made with Mann–Whitney test, Chi-square or Fisher’s exact test as appropriate. Associations between diagnostic findings and later complications were analysed with Spearman’s correlation and binary logistic regression, which was used for age adjustments, and those between nitisinone and tyrosine levels and complications with ROC [48] and crosstabulation. The possible association between low minimum nitisinone level (the lowest level of an individual patient during treatment) and later complications was also tested for each patient. Levels measured at the beginning of treatment while still adjusting the dosage were excluded. Similarly, the association between mean nitisinone and tyrosine levels (all values measured during follow-up visits) and risk for later complications was assessed. Specifically, ROC curve and crosstabulation were used to find the nitisinone and tyrosine levels at which the risk of later complications started to increase. Incidence was the number of TT1 patients divided with all live births. General birth data was provided by Statistics Finland [49]. Coefficient of variation (SD/mean) illustrated variability of blood tyrosine and nitisinone concentrations in each patient. Delayed diagnosis was considered to be a delay longer than the median of the study patients. Significance was defined as P value < 0.05. Analyses were performed using SPSS Statistics 25.0. (IBM Corp Armonk, NY).

Availability of data and materials

All data generated or analysed during this study are included in this published article.





Alanine aminotransferase


Alkaline phosphatase


Area under the curve


Central nervous system


Gamma-glutamyl transferase


Newborn screen

NH4+ :

Ammonium ion


Prothrombin time




Standard deviation


Tampere University Hospital


Total bilirubin


Type 1 tyrosinemia


  1. Nakamura K, Matsumoto S, Mitsubuchi H, Endo F. Diagnosis and treatment of hereditary tyrosinemia in Japan. Pediatr Int. 2015;57:37–40.

    Article  CAS  PubMed  Google Scholar 

  2. Tomoeda K, Awata H, Matsuura T, Matsuda I, Ploechl E, Milovac T, et al. Mutations in the 4-hydroxyphenylpyruvic acid dioxygenase gene are responsible for tyrosinemia type III and hawkinsinuria. Mol Genet Metab. 2000;71:506–10.

    Article  CAS  PubMed  Google Scholar 

  3. Meissner T, Betz RC, Pasternack SM, Eigelshoven S, Ruzicka T, Kruse R, et al. Richner-Hanhart syndrome detected by expanded newborn screening. Pediatr Dermatol. 2008;25:378–80.

    Article  PubMed  Google Scholar 

  4. De Braekeleer M, Larochelle J. Genetic epidemiology of hereditary tyrosinemia in Quebec and in Saguenay-Lac-St-Jean. Am J Hum Genet. 1990;47:302–7.

    PubMed  PubMed Central  Google Scholar 

  5. St-Louis M, Leclerc B, Laine J, Salo MK, Holmberg C, Tanguay RM. Identification of a stop mutation in five Finnish patients suffering from hereditary tyrosinemia type I. Hum Mol Genet. 1994;3:69–72.

    Article  CAS  PubMed  Google Scholar 

  6. Mayorandan S, Meyer U, Gokcay G, Segarra NG, De Baulny HO, Van Spronsen F, et al. Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice. Orphanet J Rare Dis. 2014;9:107.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bliksrud YT, Brodtkorb E, Backe PH, Woldseth B, Rootwelt H. Hereditary tyrosinaemia type I in Norway: incidence and three novel small deletions in the fumarylacetoacetase gene. Scand J Clin Lab Invest. 2012;72:369–73.

    Article  CAS  PubMed  Google Scholar 

  8. Phaneuf D, Labelle Y, Bérubé D, Arden K, Cavenee W, Gagné R, et al. Cloning and expression of the cDNA encoding human fumarylacetoacetate hydrolase, the enzyme deficient in hereditary tyrosinemia: assignment of the gene to chromosome 15. Am J Hum Genet. 1991;48:525–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Lindblad B, Lindstedt S, Steen G. On the enzymic defects in hereditary tyrosinemia. Proc Natl Acad Sci U S A. 1977;74:4641–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Larochelle J, Mortezai A, Belanger M, Tremblay M, Claveau JC, Aubin G. Experience with 37 infants with tyrosinemia. Can Med Assoc J. 1967;97:1051–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. de Laet C, Dionisi-Vici C, Leonard JV, McKiernan P, Mitchell G, Monti L, et al. Recommendations for the management of tyrosinaemia type 1. Orphanet J Rare Dis. 2013;8:8.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Chinsky JM, Singh R, Ficicioglu C, van Karnebeek CDM, Grompe M, Mitchell G, et al. Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations. Genet Med. 2017;19:20.

    Article  Google Scholar 

  13. van Spronsen FJ, Bijleveld CM, van Maldegem BT, Wijburg FA. Hepatocellular carcinoma in hereditary tyrosinemia type I despite 2-(2 nitro-4-3 trifluoro- methylbenzoyl)-1, 3-cyclohexanedione treatment. J Pediatr Gastroenterol Nutr. 2005;40:90–3.

    Article  PubMed  Google Scholar 

  14. Lindstedt S, Holme E, Lock EA, Hjalmarson O, Strandvik B. Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. Lancet. 1992;340:813–7.

    Article  CAS  PubMed  Google Scholar 

  15. van Ginkel WG, Jahja R, Huijbregts SC, Daly A, MacDonald A, De LC, et al. Neurocognitive outcome in tyrosinemia type 1 patients compared to healthy controls. Orphanet J Rare Dis. 2016;11:85–7.

    Article  Google Scholar 

  16. Larochelle J, Alvarez F, Bussieres JF, Chevalier I, Dallaire L, Dubois J, et al. Effect of nitisinone (NTBC) treatment on the clinical course of hepatorenal tyrosinemia in Quebec. Mol Genet Metab. 2012;107:49–544.

    Article  CAS  PubMed  Google Scholar 

  17. McKiernan PJ, Preece MA, Chakrapani A. Outcome of children with hereditary tyrosinaemia following newborn screening. Arch Dis Child. 2015;100:738–41.

    Article  CAS  PubMed  Google Scholar 

  18. Tienari PJ, Sumelahti ML, Rantamäki T, Wikström J. Multiple sclerosis in western Finland: evidence for a founder effect. Clin Neurol Neurosurg. 2004;106:175–9.

    Article  PubMed  Google Scholar 

  19. Masurel-Paulet A, Poggi-Bach J, Rolland MO, Bernard O, Guffon N, Dobbelaere D, et al. NTBC treatment in tyrosinaemia type I: long-term outcome in French patients. J Inherit Metab Dis. 2008;31:81–7.

    Article  CAS  PubMed  Google Scholar 

  20. Angileri F, Bergeron A, Morrow G, Lettre F, Gray G, Hutchin T, et al. Geographical and ethnic distribution of mutations of the fumarylacetoacetate hydrolase gene in hereditary tyrosinemia type 1. JIMD reports. 2015;19:43–58.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Dursun A, Özgül RK, Sivri S, Tokatlı A, Güzel A, Mesci L, et al. Mutation spectrum of fumarylacetoacetase gene and clinical aspects of tyrosinemia type I disease. JIMD Rep. 2011;1:17–211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bartlett DC, Lloyd C, McKiernan PJ, Newsome PN. Early nitisinone treatment reduces the need for liver transplantation in children with tyrosinaemia type 1 and improves post-transplant renal function. J Inherit Metab Dis. 2014;37:745–52.

    Article  CAS  PubMed  Google Scholar 

  23. Gokay S, Ustkoyuncu PS, Kardas F, Kendirci M. The outcome of seven patients with hereditary tyrosinemia type 1. J Pediatr Endocrinol Metab. 2016;29:1151–7.

    Article  CAS  PubMed  Google Scholar 

  24. El-Karaksy H, Fahmy M, El-Raziky M, El-Koofy N, El-Sayed R, Rashed MS, et al. Hereditary tyrosinemia type 1 from a single center in Egypt: Clinical study of 22 cases. World J Pediatr. 2011;7:224–31.

    Article  CAS  PubMed  Google Scholar 

  25. Santra S, Preece MA, Hulton SA, McKiernan PJ. Renal tubular function in children with tyrosinaemia type I treated with nitisinone. J Inherit Metab Dis. 2008;31:399–402.

    Article  CAS  PubMed  Google Scholar 

  26. Forget S, Patriquin HB, Dubois J, Lafortune M, Merouani A, Paradis K, et al. The kidney in children with tyrosinemia: Sonographic, CT and biochemical findings. Pediatr Radiol. 1999;29:104–8.

    Article  CAS  PubMed  Google Scholar 

  27. Maiorana A, Malamisura M, Emma F, Boenzi S, Di CVM, Dionisi-Vici C. Early effect of NTBC on renal tubular dysfunction in hereditary tyrosinemia type 1. Mol Genet Metab. 2014;113:188–93.

    Article  CAS  PubMed  Google Scholar 

  28. Zeitler MR and Wouk N. Incarcerated inguinal hernia as a complication of new-onset ascites. BMJ Case Rep. 2017;bcr2017219613.

  29. Couce ML, Sánchez-Pintos P, Aldámiz-Echevarría L, Vitoria I, Navas V, Martín-Hernández E, et al. Evolution of tyrosinemia type 1 disease in patients treated with nitisinone in Spain. Med. 2019;98:e17303.

    Article  CAS  Google Scholar 

  30. Hostetter MK, Levy HL, Winter HS, Knight GJ, Haddow JE. Evidence for liver disease preceding amino acid abnormalities in hereditary tyrosinemia. N Engl J Med. 1983;308:1265–7.

    Article  CAS  PubMed  Google Scholar 

  31. Lahdenne P, Kuusela P, Siimes MA, Kai Rönnholm AR, Salmenperä L, Heikinheimo M. Biphasic reduction and concanavalin A binding properties of serum alpha-fetoprotein in preterm and term infants. J Pediatr. 1991;118:272–6.

    Article  CAS  PubMed  Google Scholar 

  32. Koelink CJL, Van Hasselt P, der Ploeg V, Van den Heuvel-Eibrink MM, Wijburg FA, Bijlefeld CM, et al. Tyrosinemia type I treated by NTBC: How does AFP predict liver cancer? Mol Genet Metab. 2006;89:310–5.

    Article  CAS  PubMed  Google Scholar 

  33. Bendadi F, De Koning TJ, Visser G, Prinsen HCMT, De Sain MGM, Verhoeven-Duif N, et al. Impaired cognitive functioning in patients with tyrosinemia type i receiving nitisinone. J Pediatr. 2014;164:398–401.

    Article  PubMed  Google Scholar 

  34. Walker H, Pitkanen M, Rahman Y, Barrington SF. Three cases of hereditary tyrosinaemia type 1: neuropsychiatric outcomes and brain imaging following treatment with NTBC. JIMD Rep. 2018;40:97–103.

    Article  PubMed  Google Scholar 

  35. Van Vliet K, Van Ginkel WG, Jahja R, Daly A, MacDonald A, De Laet C, et al. Emotional and behavioral problems, quality of life and metabolic control in NTBC-treated Tyrosinemia type 1 patients. Orphanet J Rare Dis. 2019;14:285.

    Article  PubMed  PubMed Central  Google Scholar 

  36. De Laet C, Terrones Munoz V, Jaeken J, François B, Carton D, Sokal EM, et al. Neuropsychological outcome of NTBC-treated patients with tyrosinaemia type 1. Dev Med Child Neurol. 2011;53:962–4.

    Article  PubMed  Google Scholar 

  37. Scott CR. The genetic tyrosinemias. Am J Med Genet C Semin Med Genet. 2006;142C:121–6.

    Article  CAS  PubMed  Google Scholar 

  38. Kienstra N, van Reemst HE, van Ginkel WG, Daly A, van Dam E, MacDonald A, et al. Daily variation of NTBC and its relation to succinylacetone in tyrosinemia type 1 patients comparing a single dose to two doses a day. J Inherit Metab Dis. 2018;41:181–6.

    Article  CAS  PubMed  Google Scholar 

  39. Jack RM, Scott CR. Validation of a therapeutic range for nitisinone in patients treated for tyrosinemia type 1 based on reduction of succinylacetone excretion. JIMD Rep. 2019;46:75–8.

    PubMed  PubMed Central  Google Scholar 

  40. Holme E, Lindstedt S. Tyrosinaemia type I and NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione). J Inherit Metab Dis. 1998;21:507–17.

    Article  CAS  PubMed  Google Scholar 

  41. Autti-Rämö I, Mäkelä M, Sintonen H, Koskinen H, Laajalahti L, Halila R, et al. Expanding screening for rare metabolic disease in the newborn: An analysis of costs, effect and ethical consequences for decision-making in Finland. Acta Paediatr Int J Paediatr. 2005;94:1126–36.

    Article  Google Scholar 

  42. Nurminen S, Kivelä L, Taavela J, Huhtala H, Mäki M, Kaukinen K, et al. Factors associated with growth disturbance at celiac disease diagnosis in children: a retrospective cohort study. BMC Gastroenterol. 2015;15:124–5.

    Article  CAS  Google Scholar 

  43. Saari A, Sankilampi U, Hannila ML, Kiviniemi V, Kesseli K, Dunkel L. New Finnish growth references for children and adolescents aged 0 to 20 years: Length/height-for-age, weight-for-length/height, and body mass index-for-age. Ann Med. 2011;43:235–48.

    Article  PubMed  Google Scholar 

  44. Demirbilek H, Hussain K. Congenital hyperinsulinism: diagnosis and treatment update. J Clin Res Pediatr Endocrinol. 2017;9:69–87.

    PubMed  PubMed Central  Google Scholar 

  45. Repo M, Rajalahti T, Hiltunen P, Sotka A, Kivelä L, Huhtala H, et al. Diagnostic findings and long-term prognosis in children with anemia undergoing GI endoscopies. Gastrointest Endosc. 2020;91:1272–81.

    Article  PubMed  Google Scholar 

  46. Neunert C, Lim W, Crowther M, Cohen A, Solberg L, Crowther MA. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117:4190–207.

    Article  CAS  PubMed  Google Scholar 

  47. Mitchell G, Larochelle J, Lambert M, de Weerd AW, Gianella-Borradori A, Michaud J, et al. Neurologic crises in hereditary tyrosinemia. N Engl J Med. 1990;322:432–7.

    Article  CAS  PubMed  Google Scholar 

  48. Caetano SJ, Sonpavde G, Pond GR. C-statistic: A brief explanation of its construction, interpretation and limitations. Eur J Cancer. 2018;90:130–2.

    Article  CAS  PubMed  Google Scholar 

  49. Official Statistics of Finland (OSF): Births [e-publication]. ISSN=1798-2413. Helsinki: Statistics Finland. Accessed 9 Sept 2019.

  50. Research Ethics at the University of Turku. Accessed 31 May 2020.

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We want to thank Dr. Liisa Viitasalo for helping with genetic issues, as well as the university hospitals of Helsinki, Turku and Oulu and central hospitals of Satakunta and Seinäjoki for helping with the data collection.


The authors have received grants from Orion Research Foundation and the Päivikki and Sakari Sohlberg Foundation, the Foundation for Pediatric Research, the Competitive State Research Financing of the Expert Area of Tampere University Hospital, the Maire Rossi Foundation, the Maud Kuistila Foundation, the Mary and Georg Ehrnrooth Foundation, the Paulo Foundation, the Emil Aaltonen Foundation, the Finnish-Norwegian Medical Foundation, the Finnish Celiac Society and the Sigrid Jusélius Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or in the preparation of the present manuscript.

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LÄ: study design, data collection and analysis, drafting of the manuscript; PH and TS: study design, data collection and critical revision of the manuscript; MH, NV, PIN and LK: study design and critical revision of the manuscript; HH: study design, data analysis and critical revision of the manuscript; KK: study design and supervision, manuscript drafting and critical revision of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Kalle Kurppa.

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The study was conducted in accordance with the Helsinki Declaration of 1975 and its 2000 revision. Obtaining medical records was approved by the hospital districts of Pirkanmaa, Southwest Finland, Northern Ostrobothnia and Uusimaa, by the university hospitals of Tampere, Oulu, Turku and Helsinki, and by the central hospitals of Seinäjoki and Satakunta. According our national guidelines, no further ethical approval or informed consent was needed for this retrospective registry-based study [50].

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Äärelä, L., Hiltunen, P., Soini, T. et al. Type 1 tyrosinemia in Finland: a nationwide study. Orphanet J Rare Dis 15, 281 (2020).

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