Tyrosinaemia Type 1

Fumarylacetoacetate hydrolase deficiency — FAH-related hereditary hepatorenal tyrosinaemia.

Literature and regulatory information updated: 4 October 2026.

0. Initial Reference Table

1. Introduction

In tyrosinaemia type 1, an inborn error of metabolism, the disease name may distract from the principal mechanism. Elevated tyrosine is an indirect and variable sign; organ injury results mainly from compounds accumulating downstream when fumarylacetoacetate hydrolase is deficient. This distinction explains why a neonate with normal tyrosine may have TT1, why diet alone does not prevent hepatic progression, and why nitisinone protects the liver despite increasing tyrosine. The disease combines a treatable metabolic emergency with an acquired predisposition to malignant transformation in a liver exposed to toxic metabolites [1, 2].

Historical descriptions of “tyrosinosis” did not all correspond to the molecularly defined condition recognised today. The Atlas highlights Sakai and Kitagawa's 1957 work on hepatorenal disease with abnormalities of tyrosine metabolism. In 1977, Lindblad, Lindstedt and Steen identified the terminal enzyme deficiency and linked succinylacetone to the block in haem metabolism, establishing the biochemical explanation that distinguishes TT1 from other tyrosinaemias. Lindstedt and colleagues' 1992 publication introduced inhibition of 4-hydroxyphenylpyruvate dioxygenase by nitisinone: an upstream pharmacological block reduces formation of intermediates that deficient FAH cannot metabolise [1, 10, 11].

Before this intervention, dietary restriction could improve biochemical parameters but did not eliminate the risk of liver failure, neurological crisis or hepatocellular carcinoma. Transplantation became an alternative for children who would otherwise have progressive disease. With SA-based newborn screening and immediate treatment, the aim became preventing these complications from developing. Age at treatment initiation is therefore a prognostic variable that must accompany any comparison of outcomes: a child treated in the first month and an adolescent with pre-existing cirrhosis do not have the same residual risk [2, 3].

The 2013 guidance and the 2017 North American consensus continue to underpin diagnosis and care organisation. The 2025 consensus updates practical decisions, while the November GeneReviews revision that year integrates diagnosis, genetics and follow-up. These sources do not agree on every biochemical target or on post-transplant management. The article identifies these differences rather than merging distinct reference ranges into a single unsupported recommendation [3, 6–8]. The PNDS (French National Diagnosis and Care Protocol) published by the Haute Autorité de Santé (HAS) in October 2022, drafted by the French metabolic diseases network G2M, adds the operational perspective of a national system: the newborn screening pathway based on SA, the emergency card, pregnancy and contraception, an age-based surveillance schedule and the social organisation of care, with its own biochemical targets that do not always coincide with those of the other recommendations [5].

2. Molecular Genetics and Pathophysiology

2.1. The tyrosine pathway and mechanism of injury

Phenylalanine is converted to tyrosine by phenylalanine hydroxylase. Tyrosine degradation proceeds through transamination to 4-hydroxyphenylpyruvate, conversion to homogentisate, opening of the aromatic ring to form maleylacetoacetate, isomerisation to fumarylacetoacetate and final hydrolysis to fumarate and acetoacetate. These products connect amino acid metabolism with the tricarboxylic acid cycle and energy metabolism. FAH is expressed mainly in the liver and kidney, helping explain the distribution of injury [2].

The table summarises the metabolic sequence and related diagnoses described in the textbooks; abnormalities in genes within the same pathway do not make these conditions allelic forms of TT1 [1, 2].

Fumarylacetoacetate and maleylacetoacetate are reactive compounds produced within cells that interact with sulphydryl groups and form glutathione adducts. Depletion of antioxidant defences increases vulnerability to free radicals. These intermediates also modify proteins and nucleic acids; interference with DNA repair mechanisms, including base excision repair, contributes to genomic instability. Persistent exposure promotes dysplasia, clonal expansion and hepatocellular carcinoma. Resistance to cell death in hepatocyte subpopulations helps explain the coexistence of synthetic failure with only moderately elevated aminotransferases [2, 3].

SA circulates and can be measured in blood and urine, unlike the reactive intermediates whose effects are predominantly intracellular. It inhibits δ-aminolevulinate dehydratase, also called porphobilinogen synthase, reducing conversion of δ-aminolevulinic acid (ALA) to porphobilinogen. Increased ALA and impaired haem synthesis explain neurovisceral crises. The inhibited enzyme is a dehydratase, not a dehydrogenase; distinguishing these names prevents confusion with other metabolic steps. Secondary dysfunction of HPD and methionine adenosyltransferase contributes to hypertyrosinaemia and hypermethioninaemia, although these elevations are not disease-specific [2, 3, 10].

2.2. FAH, variant classes and genotype–phenotype correlation

FAH has 14 exons and encodes the terminal enzyme of the pathway. Missense, nonsense and splicing variants, small insertions/deletions and, less frequently, copy number changes may impair activity. The mechanism is biallelic loss of function. Molecular classification should distinguish pathogenic, likely pathogenic, uncertain significance, likely benign and benign variants. Computational predictions of damage or variant rarity alone do not establish causality [3].

Genotype–phenotype correlation is insufficient to predict the age of liver failure, carcinoma risk or renal disease severity in an individual child. Marked differences exist between relatives with the same genotype. Residual activity, metabolic exposure, timing of diagnosis and modifying factors influence expression; early treatment now alters the phenotype in ways more useful for clinical decisions than assigning severity solely from genotype [2, 3].

The table designations use MANE Select transcript NM_000137.4 and protein NP_000128.1, according to the ClinVar records consulted. Deletion c.744del is also called c.744delG in historical literature. A diagnostic report should include transcript and version, HGVS, zygosity, classification, phase when known and method limitations; population data in the table derive from the GeneReviews synthesis [3, 12].

The French allelic distribution, summarised in the 2022 PNDS (French National Diagnosis and Care Protocol), shows how the composition of a population alters the molecular strategy. In France, c.554-1G>T accounts for 51% of identified variants, in relation to the southern European and North African ancestry of many families, and c.1062+5G>A for only 7%, compared with 86% in Canada. The remaining 42% are private variants: 29% missense, 10% infrequent nonsense or splicing variants and 1% deletions of one or more exons. More than a hundred variants, in homozygous or compound heterozygous state, have been described in the gene. The existence of exonic deletions justifies complementing sequencing with copy-number analysis when only one allele is found. The PNDS also stresses that acute and chronic forms may coexist within the same sibship, another argument against predicting the clinical course from the genotype [5].

2.3. Pseudodeficiency, attenuated forms and revertant mosaicism

The p.Arg341Trp allele may produce low assay activity without causing the classic phenotype in homozygotes. When combined with another allele, biochemical results may require specialist interpretation. This illustrates why reduced enzyme activity, a rare variant and clinical disease are not interchangeable concepts. Attenuated presentations with very low or undetectable SA have also been described; a negative SA investigation strongly reduces the probability of classic TT1 but does not end investigation of suggestive liver disease with concordant genetic evidence [2, 3].

The PNDS specifies the behaviour of this allele: individuals carrying p.Arg341Trp in trans with a pathogenic variant excrete SA at moderate concentration and remain asymptomatic without treatment. In newborn screening, the corresponding profile is mild hypersuccinylacetonaemia, with SA three to five times above normal and normal liver function at birth, which requires surveillance without treatment once clarified by genetic testing. The same document mentions a single published case of “silent” TT1, without SA or the other characteristic metabolites, and atypical late-presenting forms that escape newborn screening because they do not excrete SA. When there is strong clinical, biochemical or imaging suspicion with negative SA, the PNDS recommends genetic testing of FAH [5].

Hepatic nodules may develop with somatic restoration of FAH function through reversion or compensatory changes. These hepatocytes have a selective advantage over deficient cells and may expand. Revertant mosaicism does not correct the constitutional variant or reproductive risk, and sampling a region with restored activity may yield a misleading enzyme assay. This heterogeneity limits the ability of a small hepatic sample to represent the whole organ [1, 2].

No second germline FAH-related multitumour predisposition syndrome independent of the metabolic disease has been established. TT1 cancer risk is concentrated in the injured liver; heterozygotes should not receive a cancer surveillance programme designed for patients with biallelic variants. Tyrosinaemias types 2 and 3 and GSTZ1 deficiency involve other genes and are considered in the differential diagnosis [2, 3].

3. Clinical Spectrum and Manifestations by System

3.1. Age at onset and forms of presentation

Classification into acute, subacute and chronic forms describes natural history rather than three distinct molecular diseases. The acute form presents before six months, rarely in the first two weeks, usually with liver failure. Subacute presentation, between six and twelve months, combines liver disease, growth delay and bone disease; chronic disease presents after the first year and may first appear in adolescence or adulthood. None of these presentations need occur in a patient detected by screening and treated immediately [2].

Manifestation frequencies in untreated series compiled in GeneReviews place hepatic involvement at 80–90%, renal involvement at 60–80%, growth abnormalities/rickets at 40–70% and neurological manifestations at 20–40%. These ranges derive from heterogeneous cohorts and depend on age and selection; they do not describe expected incidence in children treated from the neonatal period [3].

The French PNDS (French National Diagnosis and Care Protocol) adopts another delineation, adapted from Morrow and Tanguay. The acute form presents after the first 15 days of life and before 12 months, being more severe when it begins before two months; there is no symptomatic form before 15 days. The subacute form, presenting after six months, combines more moderate liver disease, failure to thrive, hepatosplenomegaly, coagulopathy, hypophosphataemic rickets and pseudoporphyric crises. The chronic form, also presenting after six months, progresses slowly and presents with cirrhosis that is often already established, tubulopathy and neurological crises; some patients develop cirrhosis and tubulopathy insidiously until the end of adolescence, and diagnosis in adulthood is exceptional [5].

The PNDS age limits overlap with those of Saudubray (acute <6 months, subacute 6–12 months, chronic >1 year) without coinciding with them. The criterion that actually separates the forms is the speed of progression; the survival figures refer to the era before nitisinone and transplantation [2, 5].

3.2. Liver and neoplastic risk

Loss of synthetic function is frequently disproportionate to cytolysis. Prothrombin and activated partial thromboplastin times may be markedly prolonged without adequate correction by vitamin K. Bilirubin may be normal or only slightly elevated despite liver failure. Hypoglycaemia, hypoalbuminaemia and oedema provide further evidence of functional impairment. A cooked-cabbage-like odour may occur because of altered methionine metabolism, but its absence does not exclude the diagnosis [1, 3].

The PNDS adds details of diagnostic value. As coagulation factors fall, factor V is the last to decrease. Markedly raised alkaline phosphatase contrasts with a normal or slightly raised gamma-glutamyltransferase and mainly reflects tubulopathy and rickets. Thrombocytopenia and anaemia complete the picture, the latter attributed to inhibition of haem synthesis. Hyperbilirubinaemia may be absent at first and worsen later, so its absence does not exclude TT1; conversely, moderate liver failure with rapidly progressive jaundice makes the diagnosis less likely. Clinical signs of hepatic encephalopathy are hard to detect in infants, and hypoglycaemia may result from liver failure, associated hyperinsulinism or both. On ultrasound, the liver is heterogeneous, with hyperechoic areas of steatosis and a multinodular appearance that may be mistaken for a tumour, and there may be signs of portal hypertension already at diagnosis; outside the liver, nephromegaly, nephrocalcinosis, hyperechoic renal cortex and hypertrophy or hyperechogenicity of the pancreas are observed. Histologically, cirrhosis begins as micronodular and evolves to macronodular [5].

Alpha-fetoprotein (AFP) is frequently markedly elevated, sometimes around 100,000–400,000 ng/mL in classic descriptions. In infants, interpretation must account for age and, especially, the trajectory after treatment. A single high value does not establish carcinoma, and normalisation does not exclude malignant transformation. Regeneration, dysplasia and multiple nodules complicate imaging distinction between benign and malignant lesions. Cirrhosis may be both micronodular and macronodular and be accompanied by splenomegaly, varices, gastrointestinal bleeding and ascites [1, 2].

Hepatocellular carcinoma risk is higher in people exposed longer to metabolites before starting nitisinone. Historical proportions of 17–37% in untreated series should not be converted into a universal lifetime risk. Carcinoma may occur in childhood, and risk may persist even with metabolite control. A series published in 2022 described three patients requiring transplantation for carcinoma despite nitisinone and AFP normalisation, reinforcing the need for continued imaging [3, 13].

3.3. Kidney and bone

Proximal tubulopathy causes loss of amino acids, glucose, phosphate and bicarbonate: generalised aminoaciduria, glycosuria without hyperglycaemia, tubular acidosis and hypophosphataemia. Renal phosphate loss leads to rickets, limb deformities, bone pain and motor delay. Nephromegaly, hypercalciuria, nephrocalcinosis and reduced glomerular filtration may accompany the presentation. Creatinine alone is insufficient to exclude tubular disease, particularly in a child with low muscle mass [1, 2].

In a series of 32 patients summarised in the Atlas, aminoaciduria was reported in 82%, hypercalciuria in 67%, tubular acidosis in 59%, reduced filtration in 48%, nephromegaly and increased echogenicity in 47% each, and nephrocalcinosis in 16%. Saudubray reports nephrocalcinosis in approximately 40% in other pre-nitisinone series. These different figures reflect different populations and observation times rather than a single estimate applicable to current follow-up [1, 2].

Tubular function may normalise in the first treatment year, particularly without established nephrocalcinosis, but established chronic disease or post-transplant nephrotoxicity may prevent complete normalisation. Rickets should be treated by correcting the metabolic cause and documented deficiencies; vitamin D alone does not address the mechanism if phosphate loss is unrecognised [2, 3].

According to the PNDS, hyperechoic nephromegaly appears mainly after six months and may be discovered because of abdominal pain, discomfort or distension, constipation, a palpable mass or an ultrasound performed for another reason; the tubulopathy of subacute and chronic forms may present with bone deformity, failure to thrive or episodes of dehydration. In addition to the losses already described, the Fanconi syndrome of TT1 includes hypokalaemia, hypocalcaemia and low-grade tubular or mixed proteinuria. Rickets occurs with non-deficient 25-hydroxyvitamin D, which is why the PNDS recommends looking for TT1 in any hypophosphataemic rickets. On nitisinone, tubulopathy usually regresses within the first three months, and nephromegaly and nephrocalcinosis within four to five years, depending on initial severity. With late treatment, recovery may be incomplete and progress to chronic kidney disease through glomerulosclerosis, interstitial fibrosis with tubular atrophy, dilated tubules, cystic lesions or nephrocalcinosis; arterial hypertension is rare and occurs mainly during neurological crises, associated with hyponatraemia. Reappearance of signs of proximal tubulopathy during a pregnancy has been described [5].

3.4. Nervous system and development

Neurovisceral crises include abdominal or limb pain, vomiting, constipation or ileus, tachycardia, hypertension and progressive motor neuropathy. They may progress to ascending weakness, respiratory paralysis, hyponatraemia and seizures. In classic descriptions, the active phase lasts one to seven days and recovery may take months. Consciousness may remain intact even with severe paralysis, although altered mental status also occurs. Infection, anorexia and interruption of nitisinone are relevant settings [1, 2].

The PNDS places these crises in untreated children older than six months, frequently triggered by infection and lasting up to one week. They include abdominal and neuropathic pain, opisthotonus, confusion, seizures and acute ascending peripheral neuropathy resembling a rapidly evolving Guillain–Barré syndrome, which may progress to flaccid tetraparesis with diaphragmatic paralysis and need for ventilation; they were rarely fatal. They now occur only in patients who interrupt nitisinone for more than one week. The G2M network emergency card describes an insidious initial phase, weeks after interruption and often precipitated by a trivial infection — asthenia, agitation or psychotic symptoms, anorexia, vomiting, abdominal pain with hyponatraemia, sometimes self-harm, hypertension and tachycardia — followed by painful paraesthesiae and ascending motor polyneuropathy with hyperextension; without treatment, respiratory paralysis may lead to death by asphyxia, and the manifestations regress within a few weeks of resuming nitisinone. In chronic forms, hypotonia attributed to peripheral neuropathy has also been described [5].

Learning difficulties are a separate problem from acute crises. They may affect attention, executive function, processing speed and school performance even in metabolically treated patients. A single cause has not been demonstrated: the underlying disease, previous injury, elevated tyrosine exposure, persistently low phenylalanine and other factors are considered. Hepatic normalisation does not justify assuming normal neuropsychological development; assessment should precede persistent school failure [2, 3, 14].

In García and colleagues' Chilean series of 12 individuals, the Bayley mental development index showed delayed performance in 29–38% of those assessed at different ages. Mean full-scale IQ was 88 ± 16 at preschool age and 79 ± 18 at school age; the groups assessed at each stage were small and not identical. Four of eight individuals with repeated measurements showed decline. These are clinical cohort findings, not an individual prediction for every treated neonate [14].

The literature synthesis in the PNDS points in the same direction. In children screened in the neonatal period, psychomotor developmental milestones are usually achieved without delay in the first three years; among those not screened, 20% show delayed acquisitions. In a French series, 35% of patients had learning difficulties, and several studies describe a low intelligence quotient or one that declines with age, predominantly in the verbal component, as well as deficits in attention, working memory and executive functions. The causal hypotheses — raised tyrosine, excessively low phenylalanine or an intrinsic effect of nitisinone — have not been demonstrated; keeping tyrosine and phenylalanine within target is the measure that might limit these complications. Behavioural and relational disorders, anxiety and depression have been described in some patients, with repercussions on family quality of life [5].

3.5. Other manifestations

Cardiomyopathy, frequently hypertrophic, is occasional and may improve with metabolic treatment. Pancreatic islet cell hypertrophy may cause hyperinsulinism and hypoglycaemia, whose mechanism should not automatically be attributed solely to liver failure. Macrosomia and macroglossia have been described in some presentations. Conversely, keratopathy, photophobia and palmoplantar lesions during nitisinone treatment should raise the possibility of hypertyrosinaemia related to treatment and dietary control rather than immediately being interpreted as hepatorenal progression [1–3].

The PNDS sets at 600 µmol/L the plasma tyrosine concentration above which keratitis — pain, photophobia, lacrimation and hyperaemia — may appear, regressing when tyrosine falls; keratitis does not occur in untreated TT1 and is a consequence of nitisinone-induced hypertyrosinaemia. The document recommends a baseline ophthalmological examination. The hypertrophic cardiomyopathy described in TT1 predominantly affects the septum, is asymptomatic in most cases and resolves with nitisinone and diet or after liver transplantation [5].

4. Clinical Recognition and Warning Signs

The combination of marked coagulopathy, elevated AFP and relatively modest aminotransferases in an infant warrants urgent SA measurement. The association of liver disease with proximal tubulopathy or hypophosphataemic rickets strengthens suspicion. These manifestations need not all coexist: waiting for the complete triad may delay treatment until cirrhosis develops [1, 2].

A “normal” newborn screen based solely on tyrosine, a negative family history or examination without dysmorphic features does not exclude TT1. Most parents are healthy and unaware of a family history. For a previously diagnosed adult, the emergency letter should explicitly identify neurological crisis risk: the generic label “liver disease” may lead to paralysis being investigated only as Guillain–Barré syndrome [3, 15].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Biochemical and molecular confirmation

No validated clinical score replaces biochemical and molecular diagnosis. Elevated SA in a compatible setting is the central biochemical finding. It must be requested explicitly: conventional urinary organic acid analysis may not adequately measure low SA concentrations or may omit it from the report. Tyrosine, methionine and other aromatic metabolites help characterise metabolic status but lack sufficient specificity to establish TT1 [2, 3].

Whenever possible, diagnostic samples are collected before the first nitisinone dose because SA may fall rapidly. Sampling must not delay treatment of a child with liver failure and well-founded suspicion. Once medication has started, undetectable SA may demonstrate pharmacological efficacy rather than absence of disease. Dose information and the time of the last administration should accompany the request [3, 7].

The PNDS (French National Diagnosis and Care Protocol) describes the biochemical work-up based on plasma amino acids and urinary organic acids collected before any treatment, which can normalise the parameters within a few hours. Plasma amino acids generally show marked elevation of tyrosine, methionine and phenylalanine, reflecting liver injury, and any increase in plasma tyrosine justifies looking for SA among the organic acids. These reveal massive excretion of 4-hydroxyphenyllactic, 4-hydroxyphenylpyruvic and 4-hydroxyphenylacetic acids, N-acetyltyrosine and N-lactyltyrosine, and detect SA without quantifying it; SA must then be quantified in urine by mass spectrometry after chromatographic separation (GC-MS or LC-MS/MS). Aminoaciduria reflects the tubulopathy. The urinary increase in ALA accompanies SA accumulation and pseudoporphyric crises, but is not specific and should not be measured in isolation. Measurement of FAH activity in liver, fibroblasts or lymphocytes is no longer performed in France. To measure nitisinone, 3 mL of blood is collected in lithium heparin, centrifuged, the plasma separated into two aliquots and frozen at −20 °C, recording the time of the last dose, the dose and the time of sampling; for SA and ALA, a 12-hour urine collection or a 10 mL sample frozen at −20 °C [5].

Identification of two pathogenic or likely pathogenic FAH variants in trans confirms the molecular basis. In conventional analysis, sequencing identifies more than 95% of described pathogenic variants and deletion/duplication analysis a fraction below 5%, according to GeneReviews. These method-specific proportions do not represent universal 100% clinical sensitivity. Inadequate coverage, deep intronic changes, structural variants and interpretive difficulties may leave cases unresolved [3].

A variant of uncertain significance (VUS) on each allele, or a pathogenic variant accompanied by a VUS, does not automatically constitute molecular confirmation. Parental segregation, RNA or functional data, biochemistry and reassessment of classification may resolve uncertainty. Conversely, incomplete genetic investigation should not lead to treatment withdrawal in a patient with convincing biochemical diagnosis [3].

5.2. Clinical algorithm and assessment of disease extent

With clinical suspicion or a positive screen, the first step is quantitative SA measurement and immediate assessment of hepatic, renal and metabolic status. Concordant TT1 evidence justifies starting nitisinone and dietary intervention with a specialist team while investigating FAH. If SA is only mildly elevated, repeat measurement and organ assessment and consider GSTZ1; if normal but suspicion persists, review previous treatment, analytical quality and attenuated forms. At any stage, signs of liver failure require parallel discussion with a transplant centre [2, 3].

Initial assessment includes full blood count, prothrombin time/INR, activated partial thromboplastin time, albumin, bilirubin, aminotransferases, gamma-glutamyltransferase, AFP, glucose and, depending on severity, ammonia and blood gases. Renal assessment should measure creatinine, electrolytes, bicarbonate, calcium and phosphate, alongside urine testing for glucose, protein and tubular losses. Alkaline phosphatase, vitamin D and targeted radiological assessment characterise rickets. Hepatic and renal ultrasound establishes an anatomical baseline; magnetic resonance imaging (MRI) clarifies nodules or suspicious findings. Growth, intake, development, neurological examination and cardiac signs are assessed [2, 3].

The PNDS details the initial renal assessment, to be carried out on the same day, and adds family genetic testing and the ophthalmological examination.

The diagnosis is disclosed in stages, first at suspicion and then at confirmation by urinary SA. The PNDS recommends emphasising that the disease is treatable and explaining from the outset the low risk of no immediate response to nitisinone requiring urgent transplantation, the possibility of transplantation in the medium or long term if nodules appear with a renewed rise in AFP, and the late complications, in particular neuropsychological difficulties [5].

Liver biopsy is unnecessary to establish TT1 when biochemistry and genetics are concordant. Although the Atlas discusses biopsy in historical nodule investigation, the 2025 consensus advises against it because of tumour dissemination risk. A suspicious lesion should be discussed by hepatology, radiology and transplantation specialists rather than automatically prompting needle biopsy [1, 8].

5.3. Newborn screening: performance and false negatives

SA should be the primary marker; requiring elevated tyrosine before measuring it may miss patients. In the Dutch programme between 2018 and 2021, 693,821 neonates yielded 23 referrals and two confirmed diagnoses: positive predictive value was approximately 9% and specificity 99.997%. The observed sensitivity of 100% during that period is constrained by the small case number and identification of false negatives; it does not guarantee freedom from future failures. The same study analyses a false negative from an earlier period and the possibility of improving algorithms with combined markers [16].

British laboratory guidance updated in January 2026 recognises attenuated variants and intrauterine nitisinone exposure as potential causes of false-negative results. If the mother receives nitisinone, the laboratory must be informed and the neonate assessed through a specific pathway accounting for its transient pharmacological effect. In TT1 families, early targeted testing must not be replaced by waiting for routine screening; the British handbook updated in September 2026 specifies an additional sample at 24–48 hours for a family history [17, 18].

Programme sensitivity and specificity depend on the method, threshold, sampling age and follow-up of negative cases. No single value is transferable to every programme. A positive result warrants urgent confirmation rather than an irrevocable disease diagnosis, and a negative result must not prevent subsequent clinical investigation when hepatorenal signs develop [3, 16].

In France, the HAS recommended in 2020 the inclusion of TT1 in the newborn screening panel, with implementation planned for 2023, because the disease meets most of the Wilson and Jungner criteria: severity, known natural history, an acceptable and inexpensive test, a diagnostic test and, above all, effective treatment if started in the first month. The 2022 PNDS describes the pathway. SA is measured by tandem mass spectrometry, with a method common to all French laboratories, in the same dried blood spot used for amino acids and acylcarnitines, with its own extraction, internal standard and derivatisation of SA into a hydrazone. Tyrosinaemia types 2 and 3 are not detected, because they do not raise SA, and atypical forms of TT1 without SA excretion may escape screening [5].

According to the PNDS, all screen-positive newborns had coagulopathy at the time of confirmation. During the initial admission, in addition to treatment, abdominal ultrasound is performed, samples are taken for FAH from the newborn and parents, urinary SA is tested in siblings, the ophthalmological examination is scheduled within the first month, the family is trained in preparing nitisinone and in the diet, ALD 17 recognition and social support are requested, and the contacts of patient associations are provided. Annex 10 gives an incidence of 1:125,000 in Europe and 7–10 cases per year in France [5].

When a newborn is suspected because of an index case in the family, without prenatal diagnosis, the PNDS proposes urgent SA measurement in the first urine and molecular testing on cord blood or a sample on day three, maintaining normal feeding (breast milk or formula) during the first 48–72 hours while awaiting the result. The analysis is repeated 24–48 hours later, whatever the first result, and population screening is not awaited, as its result only arrives around day 10. The SA of an affected fetus is detectable in amniotic fluid and is raised in cord blood [5].

6. Differential Diagnosis

The first axis distinguishes hypertyrosinaemia from TT1: elevated tyrosine may result from neonatal immaturity, protein loading, parenteral nutrition or liver injury of multiple causes. The second separates causes of elevated SA. The third considers disorders reproducing liver failure, Fanconi syndrome or neuropathy without affecting the same pathway. This approach prevents a single laboratory abnormality from becoming a definitive diagnostic label [2, 3].

Distinctions between types 1, 2 and 3 and transient tyrosinaemia follow Saudubray chapters 17.1–17.5 and the GeneReviews synthesis; other differentials should be selected by phenotype rather than requested indiscriminately as a biochemical panel without a clinical hypothesis [2, 3].

The PNDS (French National Diagnosis and Care Protocol) places TT1 within the epidemiology of acute liver failure in the newborn and infant, in which metabolic diseases predominate. In the series cited, metabolic causes account for about a quarter of cases, non-metabolic causes for a third, neonatal haemochromatosis for 10% and indeterminate causes for a quarter. Among the metabolic causes, galactosaemia accounts for 24%, mitochondrial respiratory chain deficiencies for 23%, tyrosinaemias for 14%, urea cycle disorders for 6%, and fatty acid oxidation disorders and Niemann–Pick disease type C for 3%. Among the non-metabolic causes, infections (herpes simplex 1/2, enterovirus) total 44%, ischaemia 26%, immuno-haematological causes (lymphohistiocytosis, leukaemia) 14%, toxic causes such as paracetamol 10%, and other causes (adrenal insufficiency, autoimmunity, vascular disease, recurrent acute liver failure due to NBAS) 7%. These proportions describe hospital series from reference centres and serve to order the urgent work-up, not to estimate probabilities in an individual patient [5].

GSTZ1 deficiency merits additional attention. The first six cases described in the textbook were detected by screening, without abnormalities of liver function, coagulation or AFP, and remained asymptomatic during follow-up lasting up to 13 years. In 2025, Barretta and colleagues added two individuals: in one, treatment initially instituted for suspected TT1 was discontinued after molecular clarification; in the other, biochemical confirmation no longer showed elevated SA. These findings establish a real differential diagnosis, but the small sample cannot guarantee lifelong benignity for every GSTZ1 variant [2, 19].

7. Treatments and Risk Management Strategies

7.1. Principles and treatment initiation

Standard treatment combines continuous nitisinone, a tyrosine- and phenylalanine-controlled diet, and surveillance for organ injury. Nitisinone inhibits HPD, reducing formation of fumarylacetoacetate, maleylacetoacetate and SA. It neither replaces FAH nor corrects the genetic variant. Diet limits hypertyrosinaemia caused by the pharmacological block. The two interventions have complementary functions: withdrawing medication to lower tyrosine restores toxic metabolite production; continuing nitisinone without nutritional control may cause toxicity from elevated tyrosine [2, 3].

Treatment should start as soon as sufficient TT1 evidence exists, without awaiting molecular confirmation in a child with a compatible biochemical diagnosis and clinical condition. Transplant assessment proceeds simultaneously in severe liver failure. The initial phase may require weekly or fortnightly tests before stable follow-up intervals are adopted [8]. Coagulation may improve rapidly, but AFP, structural abnormalities and tubular recovery follow different timelines. Failure of immediate normalisation should not always be classified as nitisinone failure, and SA disappearance should not be interpreted as resolution of established cirrhosis [2, 7].

The PNDS (French National Diagnosis and Care Protocol) describes the expected chronology of response. Urinary SA usually normalises in less than 24 hours; liver function, measured by factor V, improves on average within one week, with normalisation of synthetic functions between three weeks and one month. Correction of metabolic acidosis, hypophosphataemia and hyperaminoaciduria takes several weeks, and normalisation of AFP several months, given its half-life of about three weeks. Nitisinone prevents and treats renal, bone and neurological complications and, almost always, hepatocellular failure, but may not prevent carcinoma, particularly in late-diagnosed forms [5].

7.2. Nitisinone: doses, formulations and labels

The following doses refer to TT1. The alkaptonuria indication and its regimens must not be transferred to this disease. Dose is adjusted to weight and SA suppression, with verification of adherence, preparation, administration and drug concentration. Increasing the dose without investigating interrupted supply or incorrect preparation may not resolve the problem [3].

Distinguishing mg/kg per dose from mg/kg per day is essential to prevent doubling. The initial US regimen of 0.5 mg/kg twice daily equals a total of 1 mg/kg/day; titration proceeds through 0.75 mg/kg twice daily (1.5 mg/kg/day), with a total maximum of 2 mg/kg/day, the same maximum as in the European SmPC, at all ages and weights. Metabolic suppression must be confirmed after any change in frequency or formulation [3, 20, 21].

The sources diverge on three dosing points. First, in acute liver failure, Saudubray proposes starting with 2 mg/kg/day, whereas the PNDS starts with 1 mg/kg/day and only increases to 2 mg/kg/day, the maximum common to all sources, after one week without improvement; the European SmPC provides for the intermediate increase to 1.5 mg/kg/day only if SA persists after one month. The French guideline is the reference for the stepwise approach, but an unstable child should be discussed with the transplant team from the outset, without waiting for the end of that period. Second, regarding frequency, the PNDS and the European SmPC divide the dose into two administrations below 20 kg and allow a single daily dose above that weight, whereas the US labels start from twice-daily dosing and only allow once-daily dosing from five years of age with stable control. The PNDS justifies once-daily dosing in adolescents by the half-life of about 52 hours, which maintains stable concentrations, and by better adherence; Saudubray gives about 54 hours, a difference without practical relevance. Third, for maintenance, the PNDS keeps 1 mg/kg/day in children and recommends reducing in adolescents and adults to the lowest effective dose, guided by SA and plasma concentration, whereas the labels do not describe reduction below the starting dose [2, 5, 20, 21].

In the screened newborn, the PNDS indicates 1 mg/kg/day in two doses (maximum 2 mg/kg/day if SA does not become negative in the following days), preferably with the 4 mg/mL oral suspension, given with the graduated syringe, alone or with a little milk; failing this, 2 mg capsules are opened and the contents dispersed in water or milk, which requires multiples of 2 mg (for example, 2 mg twice daily for 3.5 kg). The medicine must be stocked in the hospital pharmacies of reference and competence centres. Checks are performed at 48 hours and on day seven (coagulation, urinary SA, plasma amino acids), and the plasma nitisinone concentration is measured one week after each dose change. Orfadin® capsules (2, 5, 10 and 20 mg, bottles of 60) are stored in the refrigerator at 2–8 °C before opening, and may then be kept below 25 °C for two months (2 mg) to three months (5, 10 and 20 mg). The suspension (90 mL bottle, with adapter and 1, 3 and 5 mL syringes) is stored upright in the refrigerator, must be shaken vigorously before the first dose, because the particles form a solid sediment, and once opened is kept below 25 °C for a maximum of two months [5].

Food instructions depend on the formulation. In the USA, Orfadin capsules are administered at least one hour before or two hours after a meal; the suspension may be taken irrespective of food. In the EU, suspension should be taken with food, and if capsules are started with food, that consistency should be maintained. US Nityr permits administration with or without food. Families need instructions matching the dispensed container, including initial preparation, shaking and an appropriate suspension syringe [20–22].

7.3. Nutritional treatment and biochemical targets

Diet reduces natural protein to control tyrosine and its precursor phenylalanine while maintaining sufficient energy, protein equivalent, vitamins and minerals for growth and tissue repair. Amino acid mixtures formulated for tyrosinaemia, without tyrosine and phenylalanine, are combined with measured amounts of natural protein. A phenylketonuria formula may contain tyrosine and should not automatically replace the disease-specific formula. Prescription depends on age, growth, tolerance, tests and actual intake; no fixed amount of natural protein suits everyone [2, 3].

Phenylalanine is essential. Excessive restriction, particularly when tyrosine remains high, may create deficiency without proportionately improving metabolic control. Persistently low values require review of meal distribution, natural protein intake and the need for targeted supplementation. Insufficient energy promotes catabolism and mobilisation of endogenous protein. In infants, breast milk or standard formula may be incorporated in calculated quantities with the specific mixture; this is not feeding without any natural protein [3, 7].

The table presents targets from different sources to make their divergence explicit. The selected therapeutic range should be documented by the team and applied consistently to the measured matrix. Joint assessment of SA, amino acids and drug exposure is more informative than any isolated value [2, 3, 8, 21]. The PNDS is the most restrictive of the guidelines regarding tyrosine: it maintains ≤400 µmol/L throughout life and rejects the relaxation from 12 years of age practised by some teams, as that relaxation is not based on prospective studies; its nitisinone range (35–60 µmol/L) lies between that of GeneReviews and that of the 2025 consensus. The unit of the creatinine-indexed SA target appears in the PNDS sometimes as mol/mmol and sometimes as µmol/mmol; the form consistent with the concentration of <0.1 µmol/L is µmol/mmol [3, 5, 8].

The PNDS defines each patient's tyrosine tolerance as the maximum daily amount of natural protein that can be eaten while keeping tyrosine within target. The diet has three objectives: to limit natural protein, the source of tyrosine and phenylalanine; to complete protein requirements with an amino acid mixture free of these two amino acids, which generally contains vitamins, minerals and trace elements; and to ensure sufficient energy to maintain anabolism, adapted to age, weight, activity and clinical situation. The sum of natural protein and the protein equivalent of the mixture must cover at least the EFSA dietary reference values for age, and the mixture is divided into three to four doses, taken with meals. The tolerated natural protein is also distributed throughout the day, ideally with about half of animal origin, of better nutritional quality. Manufactured low-protein foods contain less than 10% of the protein of the equivalent natural food, are rich in carbohydrates and lipids and poor in micronutrients; in France and in the European Union, mixtures and low-protein foods are foods for special medical purposes, regulated by Delegated Regulation (EU) 2016/128, applicable since 22 February 2019. Complete vitamin, mineral and trace-element formulas for metabolic diseases are essential when the amino acid mixture is not taken, and any documented deficiency is specifically supplemented [5].

In practice, three food lists are organised. Prohibited foods, because they are rich in protein, include meat, fish, eggs, milk, soft or hard cheeses with more than 10 g of protein/100 g, dairy products with more than 4 g of protein per unit, wheat and its derivatives, dried pulses, nuts and oilseeds, sweet products with more than 1% protein, gelatine sweets, chocolate and drinks containing aspartame. Controlled foods, weighed, provide the protein tolerance: infant milk, processed cheese with less than 2 g of protein per unit and, later, dairy products with less than 4 g, vegetables, potatoes, rice and fruit. Free foods (≤0.5 g of protein/100 g) include fats, sugar, jams, juices and sweetened drinks without aspartame, together with low-protein foods. Aspartame (E951) is prohibited in young children and discouraged in older ones, but its presence in an indispensable medicine is not a formal contraindication. Calculation is done in exchanges of 1 or 2 g of protein, depending on the centre, or in exchanges of 20 mg of phenylalanine, with the tools used in phenylketonuria; in adolescence, counting in grams of protein becomes simpler. Weaning, between four and six months, reduces the quantity of milk so as not to exceed tolerance; prohibited foods must never be offered as a taste. In adolescence, household measures may replace weighing; in adulthood the diet is maintained for life, without relaxation, with a divided amino acid mixture and portable low-protein foods for eating away from home. The PNDS considers it unnecessary to restrict phenylalanine during infections [5].

The examples illustrate orders of magnitude from a French protocol and do not replace individual prescription, which depends on measured tolerance and plasma tyrosine [5].

In the acute phase, the PNDS initially institutes a low-protein diet, because of hepatocellular failure, and reintroduces natural protein in steps soon after nitisinone is started, through breast milk or infant formula, under tyrosine monitoring, adding the amino acid mixture until age-appropriate requirements are covered. Breastfeeding an affected infant is possible and even recommended, alternating with or supplemented by bottles of the mixture. In the screened and treated newborn, natural protein is withheld for 48 hours, with the phenylalanine- and tyrosine-free mixture at 2 g/kg/day, and then 200 mg of phenylalanine per day (about 4 g of natural protein) is reintroduced with 1–1.5 g/kg/day of mixture, in eight to nine feeds, for a fluid intake of 90 mL/kg/day in the first days rising to 130–150 mL/kg/day; the breastfeeding mother is supported to maintain lactation during the pause. The same regimen, without the initial pause, applies from birth to the newborn with a prenatal diagnosis, who receives nitisinone at 1 mg/kg/day. Phenylalanine adjustments follow amino acids at 48 hours, at the first week, weekly in the first month and monthly in the first year. If hypoglycaemia persists after liver failure has been corrected, probably due to hyperinsulinism, feeds are enriched with dextrin-maltose and fasting periods are shortened [5].

Nitisinone has a half-life of approximately 54 hours, but this does not make planned interruptions safe. Phenylalanine varies throughout the day; sampling at consistent times and under consistent conditions facilitates interpretation without imposing prolonged fasting on infants [2].

Home dried blood spot collection may facilitate frequent monitoring but requires training in volume, paper saturation, drying, storage and posting. The relationship between plasma and whole-blood concentrations depends on the analyte and method and must not be treated as a universal conversion. Available results must prompt a clinical response: repeatedly recording high tyrosine without reviewing intake and adherence barriers does not constitute therapeutic control [3].

7.4. Safety, interactions and adverse effect management

Principal problems include hypertyrosinaemia, ocular manifestations, skin abnormalities and cytopenias. Photophobia, red eyes, pain or visual changes require ophthalmological assessment and tyrosine control. Keratopathy from tyrosine deposits may regress with dietary improvement. GeneReviews describes transient thrombocytopenia and neutropenia; the US label quantifies leucopenia and thrombocytopenia at approximately 3% each in the observations presented. Causality and severity must be assessed in a patient who may also have hypersplenism or liver disease [3, 21].

Ocular examination guidance is not entirely concordant: the US label specifies slit-lamp examination before treatment and regularly thereafter, whereas some clinical recommendations focus assessment on symptoms. In practice, the plan should comply with the applicable label and ensure urgent access when manifestations arise. Nitisinone must not be reduced or discontinued solely to correct elevated tyrosine, because its control depends mainly on diet and withdrawal may precipitate a crisis [3, 21].

Nitisinone affects CYP2C9; narrow therapeutic index drugs metabolised by this pathway, such as warfarin or phenytoin, require monitoring when nitisinone is started, changed or discontinued. Potential interactions with renal transporters also exist. The full medication list should be reviewed, including emergency treatments. Excipients vary by formulation: glycerol and sodium benzoate in the European suspension have specific warnings, particularly relevant to high volumes and neonates. A formulation change is more than a change of packaging [20].

The emergency card annexed to the PNDS summarises the rules for hospital admissions and intercurrent illnesses. Treated TT1 does not carry a risk of coma or acute metabolic decompensation, and an isolated dietary error or a missed meal carries no immediate risk; if the prescribed meal is unavailable during an admission, a protein-free meal (low-protein pasta or bread with butter and jam) or a bottle of carbohydrate-lipid module (one scoop per 30 mL of water, about 0.7 kcal/mL) is given. The only acute risk is interruption of nitisinone, which must never be stopped, including during preoperative fasting; it exists only for oral use, with no intravenous form, and adherence is confirmed by measuring nitisinone and urinary SA and ALA. Acetylsalicylic acid and non-steroidal anti-inflammatory drugs are contraindicated; other medicines may be given. All vaccines are recommended. Surgery requires no specific precautions and there is no contraindication to anaesthetics, except during a pseudoporphyric crisis [5].

7.5. Evidence of efficacy and limitations

Evidence combines open-label studies, historical comparisons and cohorts because disease rarity and severity limited placebo trials. Findings consistently support early initiation, but percentages from different studies should not be compared as if populations, outcomes and durations were identical [3, 7].

In the Quebec cohort, no hospitalisations for acute complications occurred during 5,731 months of nitisinone exposure, compared with 184 hospitalisations over 1,312 untreated months. None of the children treated before one month had detectable liver disease after more than five years in the report. These findings support screening and presymptomatic treatment but do not remove the need for follow-up for late events [24].

7.6. Acute decompensation and supportive treatment

Liver failure, neurological crisis or inability to maintain feeding and medication require hospital assessment. The plan must ensure nitisinone, sufficient energy to limit catabolism, blood glucose monitoring and targeted correction of fluid, electrolyte and acid–base disturbances. Intravenous glucose is used when oral intake is insufficient; concentration and rate depend on age, blood glucose, circulatory status and fluid restriction. A general supportive care reference cannot safely be converted into a fixed prescription for every age [2, 3].

In a neurovisceral crisis, strength, swallowing and respiratory function are assessed repeatedly, together with blood pressure, heart rate, sodium and renal function. Analgesia, treatment of hypertension and careful correction of hyponatraemia accompany urgent resumption of metabolic blockade. Vomiting or ileus requires planning a reliable route of administration. Haem arginate has been used in selected reports, but does not replace nitisinone and has no evidence supporting a universal regimen for TT1 [3, 15]. The Portuguese SmPC of Normosang® (human hemin), authorised for acute attacks of hepatic porphyria, indicates 3 mg/kg once daily for four days by intravenous infusion over at least 30 minutes, not exceeding 250 mg/day, and states that limited experience in tyrosinaemia suggests that, in children, it is safe not to exceed 3 mg/kg/day for four days; this is the reference dose, extrapolated from porphyria [27]. The US label of Panhematin® (hemin), indicated only for recurrent attacks of acute intermittent porphyria related to the menstrual cycle, provides for 1–4 mg/kg/day for 3–14 days, not exceeding 6 mg/kg in 24 hours; in the USA, use in TT1 is off-label [28].

The PNDS treats the pseudoporphyric crisis with rapid resumption of nitisinone at high dose (2 mg/kg/day, the maximum dose), a low-protein diet with optimised caloric intake and symptomatic treatment in intermediate care. The emergency card lists assisted ventilation, morphine analgesia, correction of hyponatraemia, glucose infusion, beta-blockers, clonazepam and diazepam, and recommends considering hemin (Normosang®) in contact with the French reference centre for porphyrias. The indications for hemin described are hyperalgesic forms resistant to symptomatic treatment, forms with central neurological, sensorimotor or psychiatric symptoms, and hyponatraemia. Recovery takes several weeks and may be incomplete [5].

For acute hepatocellular failure, the PNDS uses the definition of the North American Pediatric Acute Liver Failure (PALF) group: INR ≥1.5 (prothrombin time ≥15 seconds, prothrombin ratio <50%) not corrected by parenteral vitamin K1 in the presence of encephalopathy, or INR ≥2 (≥20 seconds, <30%) with or without encephalopathy, with abnormal liver tests and no known pre-existing liver disease. Without specific treatment or transplantation, mortality exceeds 70%. Encephalopathy may be absent, appear within hours or weeks, be limited to a change in behaviour in infants and become lethal within a few hours; it is graded in four clinical and five electroencephalographic stages of prognostic value. The child is transferred to intensive care when the prothrombin ratio and factor V fall below 50%, with hourly clinical monitoring, liver tests and coagulation every six hours and an electroencephalogram on admission, early contact with a transplant team and transfer to that centre if there is deterioration [5].

For tubulopathy, the PNDS replaces sodium, potassium, phosphate and bicarbonate to normal values and institutes, as soon as the liver situation allows, hyperhydration, preferably oral and adjusted to weight, age and losses, for weeks to months, to limit nephrocalcinosis; replacements are reduced progressively according to electrolyte measurements, until stopped when possible [5].

For rickets and tubulopathy, replacement of phosphate, bicarbonate, potassium and vitamin D is guided by losses and tests, with attention to hypercalciuria and nephrocalcinosis. Requirements may decrease after disease control. Recurrent hypoglycaemia requires distinction between hepatic synthetic failure and hyperinsulinism. Infections, bleeding and other complications are treated according to clinical status; correction of coagulation tests should consider bleeding and procedures without replacing assessment of liver failure [2, 3].

7.7. Transplantation, nodules and hepatocellular carcinoma

Transplantation is indicated when liver failure persists despite adequate treatment, in advanced chronic liver disease or in carcinoma eligible for this approach. The textbook recommends early reassessment if coagulation does not improve in the first week and immediate discussion with encephalopathy or deterioration. One week is not a mandatory waiting period in an unstable child. Indication integrates metabolic response, synthetic function, clinical course, imaging and centre capacity [2].

Transplantation replaces the deficient hepatic compartment and generally permits liberalisation of the disease-specific diet but does not eliminate constitutional variants or all extrahepatic SA production. Immunosuppression introduces other risks, including infection and nephrotoxicity. Renal disease requires its own follow-up, particularly if injury preceded transplantation [1, 2].

The PNDS reserves transplantation for acute liver failure that does not recover with nitisinone and for suspected or confirmed carcinoma in a patient already treated. It notes that survival of infants treated with nitisinone and diet is higher than that of transplanted infants and cites the UNOS registry analysis: 125 patients transplanted for TT1 between 1987 and 2008, with a mean age of 2.5 years at transplantation and 90% survival at five years. After transplantation, factor V exceeds 50% by the end of the first week if there are no surgical complications, AFP normalises within three months, tyrosine normalises, rickets disappears within six months and renal function normalises in the great majority of cases, without diet. SA decreases without disappearing, probably owing to renal production, and porphobilinogen synthase activity remains at the lower limit of normal; the long-term consequences are unknown and could include tubulopathy or hypertension. The PNDS therefore recommends annual metabolic assessment and screening for renal complications in transplant recipients, taking into account the nephrotoxicity of ciclosporin and tacrolimus, and recognises that maintaining low-dose nitisinone has neither proof nor consensus, a position close to that of Saudubray and the 2025 consensus [2, 5, 8].

Faced with a suspicious liver lesion, the PNDS does not recommend biopsy when the radiological appearance is typical in a cirrhotic liver. If the lesion remains indeterminate, contrast imaging techniques are repeated and varied and a targeted biopsy is discussed, ideally accompanied by a biopsy of the non-suspicious parenchyma to assess the degree of dysplasia; surgical excision of an accessible nodule, with oncological margins, may also confirm the diagnosis. Hepatoblastoma, exceptional in TT1, and mixed tumours follow their own protocols. In children, transplantation is the treatment of choice for carcinoma, whatever the size or number of lesions; the adult Milan criteria do not apply, and chemotherapy and interventional radiology (radiofrequency ablation, embolisation, chemoembolisation) have not shown efficacy. The position differs in degree from that of the 2025 consensus, which advises against biopsy because of the risk of dissemination: both sources avoid biopsying typical lesions, but the PNDS allows targeted biopsy of indeterminate ones [5, 8].

A divergence requires explicit recognition: GeneReviews describes the possibility of low-dose nitisinone after transplantation, citing persistent SA; Saudubray and the 2025 consensus do not recommend routine post-transplant use. Detection of residual kidney-derived SA alone does not demonstrate clinical benefit from continued treatment. Decisions are individualised with metabolic and transplant centres, without presenting either strategy as a universal consensus [2, 3, 8].

7.8. Children, pregnancy, breastfeeding and adult life

In children, doses follow weight gain and amino acid requirements change with growth. Preparation of small doses and complete medication intake must be demonstrated to families. Absence of crises does not justify indefinitely extending monitoring intervals because nutritional and developmental changes may be silent [3].

Pregnancy in a woman with TT1 requires joint metabolic and obstetric planning, with tyrosine and phenylalanine control, adequate energy intake and review of hepatic/renal function. Textbooks recommend continuing nitisinone when pregnancy occurs; interruption may cause maternal disease. However, fetal safety data come from few reports and cannot establish absence of risk. Zöggeler and colleagues described two pregnancies and breastfeeding exposure with favourable childhood outcomes, useful evidence but insufficient to establish population-level safety [2, 29].

The PNDS brings together what is known. Sexuality, fertility, contraception, heredity, pregnancy and breastfeeding should be addressed in adolescence, and any pregnancy plan discussed before conception with the specialist team. Only five pregnancies in women with TT1 had been described, with nitisinone continued in all, and the PNDS adds other cases known to the authors. There is no fertility problem attributed to the disease or its treatment, nor any known impact on obstetric comorbidities, mode of delivery or delivery complications. In rabbits, doses 2.5 times the maximum human dose (2 mg/kg/day) caused malformations (umbilical hernia, gastroschisis), and in rats doses 25 to 125 times higher reduced the weight of suckling pups and caused corneal lesions. In humans, nitisinone and tyrosine cross the placenta: at birth, the newborn's nitisinone is comparable to the mother's and tyrosine about double. By analogy with tyrosinaemia type 2, in which pregnancies with maternal tyrosine of 1,300–1,650 µmol/L resulted in intrauterine growth restriction, microcephaly or psychomotor delay and pregnancies with tyrosine <232 µmol/L in normal children, fetal toxicity of hypertyrosinaemia without a known threshold is assumed. In pregnancies with TT1, maternal tyrosine was often above 400 µmol/L but below 1,000 µmol/L; there were several moderately preterm deliveries, weight and head circumference between the 3rd and 25th centiles, one agenesis of the cerebellar vermis and one pelvicalyceal dilatation. Long-term development has been described in only two children: one with attention deficit hyperactivity disorder at seven years and another, whose mother kept tyrosine between 200 and 400 µmol/L, with an intelligence quotient of 111 at five years. The increase in protein tolerance in the third trimester known in phenylketonuria and maple syrup urine disease was not observed, perhaps because transplacental nitisinone prevents fetal clearance of tyrosine [5].

The PNDS contraindicates, as a precaution, breastfeeding in women treated with nitisinone, although it allows it when the newborn itself is affected; maternal tyrosinaemia in itself does not contraindicate it, and there are no human data on the passage of nitisinone into milk. The newborn of a mother with TT1 should be examined to exclude malformations. Cord and early-day tyrosine may exceed 1,000 µmol/L and regresses within a few weeks without the need for diet; the newborn's nitisinone, close to the maternal level at birth, falls rapidly and becomes undetectable after one month. To establish the child's status, urinary SA and nitisinone are measured weekly during the first month — SA is initially negative owing to the effect of maternal nitisinone — and FAH is studied. Biometric follow-up, especially of head circumference, and neurodevelopmental follow-up at 2, 4, 8 and 14 years are recommended [5].

Regarding contraception, there are no specific data in TT1, and the PNDS considers the risks to be comparable to those of the general population, with no known excess of thromboembolism, cholestasis, focal nodular hyperplasia or haemangioma. The precautions for chronic liver disease apply: progestogen-only methods, oral or implant, are preferred, and the low-dose combined oestrogen–progestogen pill is reserved for intolerance of progestogens; copper or levonorgestrel intrauterine devices and barrier methods are alternatives. Hepatocellular adenoma, rare and associated with the duration and dose of oestrogens, carries haemorrhage in 20% and malignant transformation in 5–10% of cases, and requires stopping combined hormonal contraception [5].

The European SmPC contraindicates breastfeeding during nitisinone treatment. The US label provides for weighing the benefits of breastfeeding against therapeutic needs given insufficient human data. This difference should be explained before delivery and resolved according to jurisdiction and the responsible team; a favourable report does not override a regulatory contraindication. The neonatal team must be aware of intrauterine exposure, given the possible effect on newborn screening [17, 20, 21]. The PNDS aligns with the European SmPC in contraindicating breastfeeding on nitisinone, whereas the Zöggeler report describes breastfeeding without adverse effects in the children; in the newborn of a treated mother, the PNDS considers diet unnecessary for transient hypertyrosinaemia [5, 29].

Vaccination follows the national schedule; TT1 does not require its suspension. Cardiac symptoms warrant targeted assessment, without mandatory serial echocardiography for every asymptomatic patient, according to the 2025 consensus [8].

In adults, the priority is continuity of supply, a feasible dietary plan and hepatic follow-up even after years without symptoms. University, shift work, travel, relocation abroad and service transition may interrupt medication. Once-daily options, when authorised and metabolically appropriate, may facilitate adherence but do not remove the need for laboratory confirmation after switching [3, 26].

The PNDS stresses that the course of treated TT1 in adulthood is poorly described, with no published cohorts. It recommends applying the childhood objectives to adults, with consultations at least every six months, hepatic and metabolic assessment, an annual nutritional review and emphasis on adherence: no acute liver failure has been described after discontinuation, but hepatic deterioration in the short or medium term is feared, in addition to the risk of neurological crisis. As it is unknown whether nitisinone prevents or merely delays liver disease, it anticipates that transplantation for liver failure or carcinoma will become a problem specific to adulthood [5].

7.9. Regulatory status and access

US dates appear in the FDA's 2025 paediatric pharmacovigilance review and European dates in the respective EPAR reports. The indication includes TT1 with dietary restriction; once-daily criteria and administration instructions must be checked for the specific product [23, 30, 31].

In Brazil, Anvisa included Nitikabs® (nitisinone) among the medicines approved for rare diseases in its 2019 review, for TT1 at all ages in combination with diet. Marketing authorisation, hospital procurement and incorporation into the Unified Health System (SUS) are distinct processes. In Portugal, centralised European authorisation likewise does not, by itself, demonstrate immediate availability or a particular funding arrangement. Care planning must ensure the medicine and metabolic formula without supply gaps [31, 32]. In France, the PNDS refers to Orfadin® and generic nitisinone medicines with European authorisation for all ages, mandatory availability in the hospital pharmacies of reference and competence centres for urgent initiation, an annual list of amino acid mixtures reimbursed by health insurance and full coverage as ALD 17 [5].

7.10. Updates and research through October 2026

The 2025 European survey collected responses from 32 centres in 16 countries caring for 305 patients and documented variation in practice and a need for harmonisation. This is a practice survey by the MetabERN professional collaboration rather than an already implemented new European guideline. The 2026 British updates add operational details on screening and maternal nitisinone exposure, directly affecting neonatal result interpretation [9, 17].

The selective advantage of hepatocytes with functional FAH makes TT1 a research model for cell transplantation, genetic correction and genome editing. A 2026 study used fluorinated lipid nanoparticles to deliver base editor messenger RNA and correct a Fah abnormality in mice, restoring protein expression and disease parameters. This is preclinical evidence; it does not demonstrate efficacy, safety or availability in humans [33].

Historical records identified include nitisinone dosing frequency and bioequivalence studies, such as NCT02323529 and NCT02750345. A formulation study in healthy volunteers must not be presented as a genetic cure trial. The targeted search performed up to the date of this article identified no human phase 2/3 TT1 gene editing programme with clinical results changing established treatment. This describes the search scope rather than proving the absence of every experimental initiative [26, 34].

8. Reproductive Options and Family Counselling

TT1 is autosomal recessive. When both parents are heterozygous for disease-causing variants, each pregnancy has a 25% probability of an affected child, 50% of a heterozygote and 25% of a child inheriting neither familial variant. These probabilities apply anew at each conception and are independent of sex. Among proven unaffected siblings born to two carriers, the conditional probability of heterozygosity is two thirds before molecular testing [3].

Parental segregation of variants identified in the proband should be confirmed. Apparent homozygosity may require exclusion of deletion of the other allele or rarer mechanisms such as uniparental disomy. If a variant is not found in the expected parent, Mendelian risk estimates should not automatically be retained without clarification. Family analysis also helps establish whether two variants are in trans [3].

Carrier diagnosis relies on genetics because SA, tyrosine and enzyme activity are unsuitable for excluding heterozygosity. Inclusion of FAH in the carrier screening proposed by ACMG in 2021, cited in GeneReviews, also allows identification of couples without a family history. In adults at risk, targeted familial variant testing enables reproductive counselling; in the partner, analysis with appropriate FAH coverage should be considered rather than looking only for the other partner's variant. Consanguinity and founder ancestry may increase pre-test risk but do not replace individual analysis [3].

The PNDS (French National Diagnosis and Care Protocol) quantifies the risk for an affected woman whose partner is unrelated and of unknown carrier status: about 1/350 per pregnancy, which amounts to assuming a carrier probability of about 1/175 in the partner, multiplied by the 1/2 probability of transmitting the allele. With a consanguineous partner the risk is higher, and if both parents have TT1 all children will be affected. A genetics clinic referral should be offered systematically before a pregnancy plan, and testing of the index case's siblings is essential to treat an affected sibling early [5].

When the familial variants are established, molecular prenatal diagnosis on a sample obtained by chorionic villus sampling or amniocentesis, and preimplantation genetic testing for monogenic disease (PGT-M) combined with in vitro fertilisation, may be discussed. The laboratory process, technical limits, the possibility of inconclusive results and the legally available options should be explained. Usual non-invasive prenatal tests for aneuploidies do not diagnose TT1 [3]. The PNDS considers prenatal diagnosis debatable since nitisinone improved the prognosis: it requires prior genetics consultation with the index case and both parents and a case-by-case decision with the family, in a multidisciplinary prenatal diagnosis centre, by chorionic villus sampling or amniocentesis; preimplantation genetic diagnosis may also be offered to at-risk couples [5].

Enzyme or SA assays in fetal material have historical interest or use in selected situations, but pseudodeficiency and low enzyme expression in some tissues complicate interpretation. Molecular analysis is preferred when the familial genotype is known. Invasive procedures follow current obstetric timing; historical descriptions of very early amniocentesis must not be reproduced as recommendations [2, 3].

Reproductive decisions should account for the disease being treatable while requiring ongoing care, medication access and complication surveillance. Counselling should be non-directive. After an at-risk child's birth, SA and targeted familial testing are obtained promptly rather than waiting for clinical manifestations. Transplanted women retain the same genetic transmission and additionally need obstetric counselling concerning graft function and immunosuppression [2, 3].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency and founder effects

Global estimates place birth frequency approximately between 1:90,000 and 1:120,000 in regions without systematic screening, but distribution is heterogeneous. Birth frequency, prevalence among living people, heterozygote frequency and founder allele proportions are different measures. Improved survival may increase adult prevalence without changing birth frequency [3].

International estimates and founder effects are compiled in GeneReviews; Portuguese numbers derive directly from the 18-year analysis of the National Newborn Screening Programme [3, 35].

In southern Europe, c.554-1G>T accounts for approximately 60% of alleles in Mediterranean series cited in Saudubray. This is not an estimate for all Portuguese or Brazilian patients. Likewise, the proportion above 90% attributed to the French Canadian founder allele in some historical series differs from the 87% in GeneReviews because the patient sets are not identical [2, 3].

9.2. Portugal, Brazil and Latin America

Specific published Portuguese data exist: Gonçalves and colleagues analysed screening of 1,764,830 neonates between 2004 and 2022 and identified six TT1 cases. Declaring an absence of Portuguese data is incorrect. The small numerator and programme characteristics limit direct comparisons with founder populations; observed frequency is not an estimate of national prevalence among all living people with TT1 [35].

In Brazil, Seda Neto and colleagues studied 16 children transplanted between 1993 and 2012 without previous nitisinone exposure. All explants showed cirrhosis and 12/16 had hepatocellular carcinoma, three with microvascular invasion. Reported survival was 86% after a median of 6.6 years. This 75% carcinoma proportion belongs to a transplant-selected series and does not estimate risk in Brazilian children diagnosed through screening and treated early [36].

Brazilian research also includes a 2025 study of inflammatory and oxidative injury markers in nitisinone-treated patients. Such work helps explore residual injury mechanisms but does not validate a new cancer surveillance biomarker or demonstrate clinical benefit from antioxidant supplements. The absence of a representative national estimate in the consulted sources should be distinguished from the existence of clinical series and local research [37].

In Latin America, late diagnosis and irregular treatment access reports demonstrate care problems but do not justify transferring Quebec incidence to the region. Screening organisation, SA confirmation and access to formulas and nitisinone vary across health systems. The patient-relevant outcome is time from sampling to treatment, not merely inclusion of the disease on a screening list [7, 38].

9.3. Care networks and equity

The relevant European network is MetabERN, particularly its amino acid and organic acid disorders area. The 2025 multicentre study demonstrates this collaboration's role in comparing practices and developing recommendations. Metabolic centres, hepatology, nephrology, nutrition, genetics, psychology and transplantation should share the care plan; division of responsibilities must not leave gaps in prescribing or surveillance [3, 9].

In France, according to the PNDS, care is coordinated by the reference and competence centres for inherited metabolic diseases of the G2M network, in liaison with the rare liver diseases network and, depending on the centre, with paediatric hepatologists. The coordinating reference centre is in Marseille (Hôpital de la Timone), with constituent centres in Lyon, Lille, Nancy, Paris (Necker and Pitié-Salpêtrière), Toulouse and Tours and about twenty competence centres. The team includes metabolic specialists, specialist dietitians, intensivists, paediatric and adult hepatologists, nephrologists and neurologists, ophthalmologists, biochemists, radiologists, geneticists, pharmacists, obstetricians, psychologists and neuropsychologists, the transplant team, general practitioners and school doctors, maternal and child protection services, nursing, speech and language therapy, occupational therapy, psychomotor therapy and social services. The diagnosis always leads to an application for recognition as ALD 17 and to contact with social services for disability or parental presence allowances. The specific associations indicated are Ensemble contre la Tyrosinémie and, for metabolic diseases requiring diet, Les Enfants du Jardin and Les Feux Follets; Orphanet maintains the European directory of associations [5].

Adherence should be assessed alongside medication availability, formula tolerability, literacy, distance from the centre, and work and school circumstances. Before attributing elevated SA to “non-adherence”, it is necessary to establish whether the family received medication and understood preparation. Adapted education, contact between visits, home sampling and documentation for travel and emergencies are components of crisis prevention [3].

In Portugal, the Portuguese Association for Phenylketonuria and Other Metabolic Disorders (APOFEN) provides a specific tyrosinaemia type 1 leaflet. GeneReviews also identifies the Tyrosinemia Society and Metabolic Support UK as support resources. These materials complement consultations and may facilitate communication with relatives and schools [3, 39].

10. Illustrative Clinical Case

10.1. Neurological crisis in an adult after intermittent adherence

Dawson and colleagues described six adults from three British centres with neurological crises after nitisinone interruption or irregular dosing. A 26-year-old man presented with confusion, agitation and hallucinations while travelling, followed by abdominal pain, anorexia and vomiting. He progressed to generalised motor weakness, peripheral neuropathy and respiratory failure requiring intubation; Guillain–Barré syndrome was considered in the differential diagnosis. Recovery required prolonged hospitalisation and rehabilitation, with residual weakness resolving approximately one year later. No single hospitalisation duration is assigned because the article text and table give different timelines [15].

The case shows that previous hepatic control does not protect against reopening of the metabolic pathway when medication is interrupted. The temporal association with missed nitisinone, neurovisceral pain, dysautonomia and weakness should prompt urgent metabolic and respiratory assessment. Preparation for adult care transition and travel therefore serves a concrete clinical purpose [2, 3].

10.2. Childhood diagnosis and difficulties maintaining treatment continuity

In 2025, Vallejo and colleagues reported a child from Bogotá, born at 34 weeks and assessed at ten months for hepatomegaly and coagulation abnormalities. Investigation found SA and multiple hepatic nodules, with lesions up to 11 mm. During follow-up, ocular episodes and nitisinone interruptions complicated treatment continuity; the authors described adjustments and a stable course at six years, without new adverse events in the final two years reported. Figure 1, liver MRI, and figure 3, clinical timeline, are identified in the original article [38].

The protocol termed “desensitisation” by the authors remains an individual report; it neither demonstrates immunologically mediated allergy nor validates nitisinone reduction as a general response to hypertyrosinaemia. Practice should follow SA suppression, ophthalmological assessment and nutritional adjustment. The biopsy performed in the report should likewise not be generalised to current nodule recommendations [3, 8].

The two cases illustrate distinct problems: loss of metabolic protection following interruption in adulthood and difficulty sustaining demanding treatment after a late childhood diagnosis. They do not replace newborn screening cohort findings, where intervention precedes organ injury [24].

11. Prognosis and Long-Term Follow-Up

11.1. Natural history and prognosis with treatment

In the natural history compiled in the Atlas, one-year mortality was approximately 60% when symptoms began before two months, 20% between two and six months and 4% after six months. These figures describe the era before current treatment and must not be used to counsel a family whose neonate has started nitisinone. In Saudubray, more than 90% of acute presentations respond clinically to treatment, although the non-responsive minority requires urgent transplant assessment [1, 2].

The PNDS (French National Diagnosis and Care Protocol) summarises the same historical evolution with other figures. Before transplantation and nitisinone, TT1 presenting with liver failure and treated with diet alone caused the death of more than 60% of children before one year, mainly from liver failure (67% of deaths) and pseudoporphyric neurological crises (10%); in survivors, hepatocellular carcinoma affected 18–37% from the second year of evolution. From the 1980s, liver transplantation became the main treatment, with survival above 92% in the Quebec series. With nitisinone and diet, survival is about 90%, and about 10% of children with acute liver failure do not respond and require transplantation [5].

Age at nitisinone initiation also relates to cancer risk. The following table reproduces denominators and assessment periods from the textbook synthesis, preserving the distinction between observed proportion and lifetime risk [2].

The table does not estimate an isolated unconfounded age effect: groups differ in exposure duration before treatment, established injury and observation time. In the compiled cohorts, no carcinomas were observed among those treated in the first month, but lifelong risk remains unknown. Transplant-free survival, carcinoma prevention, renal function and cognitive performance are distinct outcomes and should be communicated separately [2, 25].

According to the PNDS synthesis, the risk of carcinoma in the era of diet alone exceeded 37%, with a peak incidence between four and five years of age, and is much higher than that of other causes of cirrhosis in children or adults. With nitisinone started before one month of life, it is estimated at about 1%; with later initiation, the risk increases with age at initiation and is multiplied by 2 to 12 depending on associated factors. Whatever the form, clinically diagnosed patients have a cirrhotic or pre-cirrhotic liver at diagnosis. In adults, the risk is high when treatment began after two years of age and in the absence of adherence to nitisinone; carcinoma may arise with or without cirrhosis, and established cirrhosis, with good adherence, rarely progresses to liver failure or portal hypertension. Today, almost all carcinomas are discovered during surveillance, and not because of abdominal symptoms and cachexia; they are usually well differentiated, with hepatoblastoma or mixed tumours being exceptional [5].

11.2. Metabolic and organ surveillance

Follow-up is more frequent initially and after changes in dose, diet, growth or adherence. GeneReviews proposes monthly amino acids and SA in the first year, every three months until age five after stabilisation, and every six months thereafter, with clinical adaptations. These are not rigid minimum intervals for an unstable person. Nitisinone concentration must be interpreted with dose, frequency and sampling time [3].

Table intervals are explicitly attributed to sources, which differ mainly in hepatic surveillance intensity. The 2025 consensus allows AFP and imaging surveillance every six to twelve months depending on context, while the Saudubray schedule is more frequent. Established liver disease or suspicious findings require a more intensive individual programme; no routine schedule justifies waiting until the next visit when a warning sign develops [2, 3, 8].

The PNDS proposes an age-based schedule, applicable after diagnosis by screening or clinical diagnosis, with intensification in the event of metabolic imbalance, AFP change or an imaging finding [5].

This table is the most intensive of the cited guidelines for liver surveillance: AFP is every three months until five years and every six months in adults, ultrasound every three months in the first year and MRI annual at all ages, whereas the 2025 consensus allows intervals of six to twelve months and GeneReviews allows annual imaging. The PNDS itself is not homogeneous: the synthesis for the general practitioner indicates six-monthly AFP and ultrasound and annual MRI when the situation is stable, the biological follow-up chapter proposes AFP at least monthly in the first year, every three months thereafter and every six months from five years, and the ages for densitometry vary between sections. For the eye examination, the PNDS allows a systematic annual examination or one reserved for symptomatic patients with raised tyrosine, whereas the US label provides for regular examination; for the heart, it agrees with the 2025 consensus in dispensing with systematic surveillance [3, 5, 8, 21].

In interpreting AFP, the PNDS describes, after nitisinone is started, an exponential decline to values <10 ng/mL by the end of one year. An excessively slow decline, a plateau above 10 ng/mL or a renewed rise suggests carcinoma; in adults, an AFP above normal that plateaus or rises requires cross-sectional imaging even with a normal ultrasound, so as not to miss a diffuse infiltrative form. Unlike cirrhosis due to alcohol, viruses or steatohepatitis, AFP has significant predictive value in TT1 and always accompanies ultrasound. The sensitivity of MRI for malignant nodules ranges between 89% and 100% in studies, higher than that of ultrasound, but detection and characterisation are difficult in nodules <1–2 cm in a highly remodelled parenchyma; on ultrasound, nodules of about 1 cm correspond to carcinoma in less than half of cases. The typical appearance is spontaneous T2 hyperintensity, restricted diffusion and intense arterial enhancement with early washout in the portal phase after gadolinium, with the same semiology on iodinated contrast-enhanced computed tomography and contrast-enhanced ultrasound; the latter, little studied in children, assesses the kinetics of a target nodule but not the whole liver in a single injection [5].

Ultrasound is operator-dependent and limited in a nodular liver. MRI improves lesion characterisation, but decisions must consider examination quality, sedation requirements, renal function and availability. Normal AFP does not remove the need for imaging; an isolated elevated AFP does not establish carcinoma. The combined trajectory is more useful than decisions based on a single result [3, 13].

11.3. Development, quality of life and transition

Neuropsychological review should include attention, executive functions, learning and school participation alongside a global intelligence measure. A low result does not prove nitisinone toxicity; it requires review of clinical history, metabolic control, nutrition, hearing/vision and educational factors. Early intervention and school adaptations should address identified difficulties without waiting for a definitive causal explanation [2, 14].

Transition to adult care should transfer information on genotype, SA method, amino acid targets, formulation, doses, previous liver injury, imaging and the emergency plan. Young people need to understand that medication remains necessary even when they feel well, how to obtain replacement before supplies run out, and whom to contact if unable to take a dose. Assessment of quality of life and family burden complements laboratory tests; no SA value alone describes the daily impact of a permanent diet [3].

The PNDS proposes neuropsychological assessment for all patients at the main stages of schooling — before the 1st, 6th and 10th years — to detect even mild difficulties early and organise speech and language therapy, psychomotor therapy, psychotherapy, a school assistant or curricular adaptation. The assessment includes intellectual efficiency using the age-appropriate Wechsler scales (WPPSI, WISC, WAIS), tests of executive functions and the BRIEF questionnaire, with the Conners questionnaire for screening for attention deficit hyperactivity disorder. Psychological support is desirable for patients and relatives, given the difficulty of social integration associated with the diet; in young children, the impact may be greater on the family than on the patient, and family acceptance influences the child's quality of life. In adolescence, the lack of short-term symptoms makes adherence difficult, and psychological support is offered when tyrosine leaves the target range [5].

Therapeutic education, according to the PNDS, begins with parents and carers and passes progressively to the patient, with self-care and adaptation skills. It covers pathophysiology, the principles of the diet and the method of counting protein or phenylalanine, the preparation of nitisinone and the rule of never interrupting it, the emergency card and management of intercurrent illnesses and neurological crises, management of prescriptions and home stock of dietary products, complications and surveillance tests, school and occupational integration, genetics and planning of future pregnancies, contraception and enhanced surveillance of pregnancy, and judicious use of information on the internet. Dietetic consultations assess intake, prevent malnutrition, monitor growth, renew prescriptions and prepare for travel and school trips; adjustments between consultations are made by telephone or email, which requires team availability [5].

In the French context, the child benefits at school from an individualised reception plan describing the diet, generally with meals brought from home, and an adult with neurological repercussions may apply for the disabled adult allowance, which gives access to sheltered employment. For travel, the patient informs the team and carries an updated medical certificate in French and translated, a card with the disease, the principles of treatment, the team's contacts and the management of a pseudoporphyric crisis, and sufficient dietary products and nitisinone for the whole stay; the team contacts in advance the reference centre near the destination, and a procedure allows more than one month of treatment to be dispensed for prolonged stays abroad. Holiday camps are assessed with the team, according to age and the kitchen and nursing arrangements [5].

Transition to adult care should be planned, anticipated, explained and multidisciplinary, during a period of metabolic stability, ideally with a joint consultation with the paediatrician, the adult physician, the dietitian, the psychologist and the social worker, followed by consultations in the adult service. It is a time of high risk of loss of adherence and loss to follow-up, aggravated by the difficulty of finding adult counterparts (hepatology, nephrology, neurology, dietetics, metabolism) for a disease treated with nitisinone only since the 1990s. As the long-term prognosis remains poorly characterised, the PNDS recommends supervision by a specialist centre throughout life [5].

12. Summary and Final Considerations

TT1 should be investigated in hepatic synthetic failure disproportionate to cytolysis, liver disease with tubulopathy or rickets, and neurovisceral crises in a compatible context. SA is the priority marker and FAH genetics clarifies cause and family risk; tyrosine alone and a negative newborn screen do not replace clinical interpretation [2, 3].

Presymptomatic nitisinone and diet change prognosis but do not remove the need for nutritional, renal, cognitive and cancer surveillance. Residual risk depends on pretreatment exposure and established injury. Doses, formulations and instructions must follow the product used, recognising regulatory differences and divergent recommendations [3, 24, 25].

Follow-up must prevent both interruption of metabolic blockade and excessive nutritional restriction. The availability of Portuguese data, Brazilian cohorts and recent studies allows the disease to be contextualised without extrapolating selected series to whole populations. Genetic research remains distinct from the clinical treatment available, and the gains of screening are only realised when confirmation and therapeutic access are rapid and continuous [33, 35, 36]. The French PNDS (French National Diagnosis and Care Protocol) shows how these principles translate into a national pathway, with admission within 24 hours of a positive screen, tyrosine targets of ≤400 µmol/L for life, an emergency card and liver surveillance more intensive than that of other recommendations [5].

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