RARE DISEASE
Tyrosinemia type 1
Tyrosinemia type 1
Tyrosinemia type 1
Synonyms: FAH deficiency, Fumarylacetoacetase deficiency, Fumarylacetoacetate hydrolase deficiency, Hepatorenal tyrosinemia, Tyrosinemia type I
Synonyms: FAH deficiency, Fumarylacetoacetase deficiency, Fumarylacetoacetate hydrolase deficiency, Hepatorenal tyrosinemia, Tyrosinemia type I
Synonyms: FAH deficiency, Fumarylacetoacetase deficiency, Fumarylacetoacetate hydrolase deficiency, Hepatorenal tyrosinemia, Tyrosinemia type I
Drug discovery
2
drugs
With orphan designations
Overview
Tyrosinemia Type 1 (HT-1) is an autosomal recessive disorder caused by deficient fumarylacetoacetate hydrolase (FAH), leading to toxic accumulation of succinylacetone and tyrosine metabolites. This results in acute/chronic liver failure, renal tubular dysfunction, hypophosphatemic rickets, and porphyria-like neurological crises. Untreated, it carries a high risk of hepatocellular carcinoma. Primary treatment combines nitisinone (NTBC) to inhibit tyrosine catabolism and a tyrosine/phenylalanine-restricted diet. Newborn screening via succinylacetone detection enables early intervention, drastically improving survival [1][2][5].
Therapies
Nitisinone (NTBC): Inhibits 4-hydroxyphenylpyruvate dioxygenase, reducing toxic metabolites [1][3][5].
Dietary management: Protein-restricted diet with medical formulas to limit tyrosine/phenylalanine [5][14][16].
Liver transplantation: Reserved for NTBC non-responders or hepatocellular carcinoma [5][14][17].
Categories: rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare neoplastic diseases, rare neurological diseases, rare renal diseases, rare transplant-related disorders
Research Papers
448 drug discovery papers about Tyrosinemia type 1, with 3 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
448 drug discovery papers about Tyrosinemia type 1, with 3 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-06-10 | De novo Crohn's Disease Treated with Ustekinumab in a Pediatric Liver Transplant Recipient with Tyrosinemia: A Case Report.
De novo inflammatory bowel disease (IBD) is more frequent in transplant recipients than in the general population and should be considered in the differential diagnosis of chronic diarrhea. In pediatric liver transplant recipients, an incidence of 206 vs. 20 cases per 100,000 patient-years has been reported, suggesting an underrecognized complication of immunosuppression. We report an 11-year-old girl with tyrosinemia type 1 who underwent liver transplantation and later developed de novo Crohn's disease. Despite maintenance therapy with tacrolimus, methylprednisolone, and everolimus, she presented with chronic diarrhea, weight loss, and elevated inflammatory markers after several episodes of Clostridioides difficile infection treated with oral vancomycin and only transient improvement. Initial inflammatory markers were only mildly elevated but showed a progressive rise over 18 months despite antibiotic therapy, alongside positive ASCA IgG and ASCA IgA with negative pANCA at the time of formal evaluation. Colonoscopy showed patchy aphthous and serpiginous ulcers with a cobblestone appearance, and histology revealed cryptitis and a mixed lymphoplasmacytic infiltrate without granulomas. Magnetic resonance enterography demonstrated ileocolic inflammation with wall thickening and mesenteric vessel engorgement. Infectious and drug-induced colitis and Epstein-Barr virus-related disease were excluded, and de novo ileocolic Crohn's disease (Paris A1b L3 B1 G1) was diagnosed. Ustekinumab (260 mg intravenously, then 90 mg subcutaneously every 4 weeks) was added to baseline immunosuppression, inducing clinical remission with normalization of C-reactive protein and a decrease in fecal calprotectin to 10 µg/g by week 20, sustained at 18 months with preserved graft function. This case illustrates the diagnostic challenges of de novo Crohn's disease in pediatric liver transplant recipients with metabolic liver disease and supports ustekinumab as a safe and effective option when other biologics are limited by prior infectious or lymphoproliferative.
2026-06-02 | An optimized engineered bacterium for tyrosinemia type 1 therapy: A multi-species preclinical study.
Hereditary tyrosinemia type 1 (HT1) is a life-threatening metabolic disorder caused by the toxic accumulation of tyrosine and its metabolites. While treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) combined with a strict dietary regimen has improved outcomes, it imposes a significant lifelong burden and is associated with debilitating side effects and incomplete protection. Here, we developed an engineered probiotic with an optimized design, e-EcN-HT, and demonstrated its comprehensive efficacy and safety in HT1 across multiple animal models, including fumarylacetoacetate hydrolase (FAH)-/- mice, FAH-/- rabbits, and Bama minipigs. Our findings indicate that e-EcN-HT not only mitigates multifaceted acute manifestations of FAH-/- mice, including neonatal death and acute liver injury, but also improves chronic liver lesions when combined with NTBC. The therapeutic effect translated successfully to the FAH-/- rabbit model. Moreover, e-EcN-HT administration led to rapid metabolism of orally administered 13C-tyrosine, confirming robust and active tyrosine consumption in pigs. Comprehensive safety assessments across murine and porcine models showed that e-EcN-HT was well tolerated, with no significant adverse effects, systemic dissemination, or detrimental disruption to the resident gut microbiota. Collectively, our multi-species preclinical data underscore the potential of engineered bacteria as a viable therapeutic strategy for HT1 and possibly other metabolic disorders.
2026-05-12 | Rational Design of Small-Molecule Stabilizers of Human Fumarylacetoacetate Hydrolase for the Treatment of Tyrosinemia Type I.
Hereditary tyrosinemia type 1 (HT1) stems from the loss of fumarylacetoacetate hydrolase (FAH) activity, causing severe liver-kidney disease. Nitisinone does not restore FAH function and carries metabolic and dietary burdens. Here, we used an integrated workflow guided by X-ray structures of human FAH to obtain small-molecule pharmacological chaperones that bind with low-μM affinity and stabilize FAH. Hits were validated by NMR and isothermal titration calorimetry. Protein stabilization was assessed by DOSY-NMR and circular dichroism; functional effects were tested in FAH activity assays, a CRISPR-engineered cellular model, and testing in an animal model of HT1. Compounds shifted the G337S pathological variant toward the active dimer and slowed unfolding/aggregation, resulting in dose-dependent enhancement of FAH activity and partial rescue of FAH homeostasis in cells and the liver tissue of a mouse model of HT1. These molecules support a therapeutic approach that could complement nitisinone in HT1.
2026-04-03 | Toward Next-Gen Cell Therapy for Pediatric Patients: Neonatal Hepatocytes Tolerate Electroporation-Mediated Gene Editing and Engraft in the Liver.
Hepatocyte transplantation (HTx) offers a safer, less invasive alternative to orthotopic liver transplantation for inherited metabolic liver diseases, especially in high-risk pediatric patients. Combining HTx with ex vivo gene editing is a promising autologous therapeutic strategy using the patient's cells. We investigated the feasibility of this approach by applying CRISPR-Cas9 gene knock-out to neonatal mouse hepatocytes and comparing their engraftment potential with that of mature adult cells in the Fah-/- mouse model of hereditary tyrosinemia type I (HT1). Electroporation-mediated gene editing did not significantly impair the ability of neonatal hepatocytes to engraft in vivo. Quantitative histological analysis revealed comparable liver repopulation levels between recipients of gene-edited neonatal cells and adult cells after hepatoxicity-mediated selection, providing a benchmark for electroporation-mediated gene editing in neonatal hepatocytes, and supporting the development of genetically corrected neonatal hepatocyte products as a crucial long-term or bridge-to-transplant therapeutic strategy for pediatric liver disease.
2026-03-07 | Pediatric liver transplantation for inherited metabolic disease-Current challenges.
Liver transplantation (LT) was first introduced in the early 1960s, with early paediatric experience marked by significant technical challenges and high risk. Advances in surgical techniques and immunosuppressive therapy in the late 1970s led to successful paediatric LT outcomes, while continued improvements throughout the 1980s and 1990s have enhanced survival and reduced complications. Current 10-year graft and patient survival rates for elective paediatric indications exceed 90%. Over the past two decades, LT has increasingly been used to treat inherited metabolic diseases (IMDs), which now account for 25-30% of paediatric LT. Initially recommended for tyrosinaemia type 1 in 1978 and later for urea cycle disorders such as ornithine transcarbamylase deficiency, LT can be curative when the metabolic defect is confined to the liver and partially corrective in conditions with extrahepatic involvement. As indications expand and earlier intervention is emphasized, this review examines the role of LT in IMDs, highlighting current concepts, challenges, and controversies.
2026-06-10 | De novo Crohn's Disease Treated with Ustekinumab in a Pediatric Liver Transplant Recipient with Tyrosinemia: A Case Report.
De novo inflammatory bowel disease (IBD) is more frequent in transplant recipients than in the general population and should be considered in the differential diagnosis of chronic diarrhea. In pediatric liver transplant recipients, an incidence of 206 vs. 20 cases per 100,000 patient-years has been reported, suggesting an underrecognized complication of immunosuppression. We report an 11-year-old girl with tyrosinemia type 1 who underwent liver transplantation and later developed de novo Crohn's disease. Despite maintenance therapy with tacrolimus, methylprednisolone, and everolimus, she presented with chronic diarrhea, weight loss, and elevated inflammatory markers after several episodes of Clostridioides difficile infection treated with oral vancomycin and only transient improvement. Initial inflammatory markers were only mildly elevated but showed a progressive rise over 18 months despite antibiotic therapy, alongside positive ASCA IgG and ASCA IgA with negative pANCA at the time of formal evaluation. Colonoscopy showed patchy aphthous and serpiginous ulcers with a cobblestone appearance, and histology revealed cryptitis and a mixed lymphoplasmacytic infiltrate without granulomas. Magnetic resonance enterography demonstrated ileocolic inflammation with wall thickening and mesenteric vessel engorgement. Infectious and drug-induced colitis and Epstein-Barr virus-related disease were excluded, and de novo ileocolic Crohn's disease (Paris A1b L3 B1 G1) was diagnosed. Ustekinumab (260 mg intravenously, then 90 mg subcutaneously every 4 weeks) was added to baseline immunosuppression, inducing clinical remission with normalization of C-reactive protein and a decrease in fecal calprotectin to 10 µg/g by week 20, sustained at 18 months with preserved graft function. This case illustrates the diagnostic challenges of de novo Crohn's disease in pediatric liver transplant recipients with metabolic liver disease and supports ustekinumab as a safe and effective option when other biologics are limited by prior infectious or lymphoproliferative.
2026-06-02 | An optimized engineered bacterium for tyrosinemia type 1 therapy: A multi-species preclinical study.
Hereditary tyrosinemia type 1 (HT1) is a life-threatening metabolic disorder caused by the toxic accumulation of tyrosine and its metabolites. While treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) combined with a strict dietary regimen has improved outcomes, it imposes a significant lifelong burden and is associated with debilitating side effects and incomplete protection. Here, we developed an engineered probiotic with an optimized design, e-EcN-HT, and demonstrated its comprehensive efficacy and safety in HT1 across multiple animal models, including fumarylacetoacetate hydrolase (FAH)-/- mice, FAH-/- rabbits, and Bama minipigs. Our findings indicate that e-EcN-HT not only mitigates multifaceted acute manifestations of FAH-/- mice, including neonatal death and acute liver injury, but also improves chronic liver lesions when combined with NTBC. The therapeutic effect translated successfully to the FAH-/- rabbit model. Moreover, e-EcN-HT administration led to rapid metabolism of orally administered 13C-tyrosine, confirming robust and active tyrosine consumption in pigs. Comprehensive safety assessments across murine and porcine models showed that e-EcN-HT was well tolerated, with no significant adverse effects, systemic dissemination, or detrimental disruption to the resident gut microbiota. Collectively, our multi-species preclinical data underscore the potential of engineered bacteria as a viable therapeutic strategy for HT1 and possibly other metabolic disorders.
2026-05-12 | Rational Design of Small-Molecule Stabilizers of Human Fumarylacetoacetate Hydrolase for the Treatment of Tyrosinemia Type I.
Hereditary tyrosinemia type 1 (HT1) stems from the loss of fumarylacetoacetate hydrolase (FAH) activity, causing severe liver-kidney disease. Nitisinone does not restore FAH function and carries metabolic and dietary burdens. Here, we used an integrated workflow guided by X-ray structures of human FAH to obtain small-molecule pharmacological chaperones that bind with low-μM affinity and stabilize FAH. Hits were validated by NMR and isothermal titration calorimetry. Protein stabilization was assessed by DOSY-NMR and circular dichroism; functional effects were tested in FAH activity assays, a CRISPR-engineered cellular model, and testing in an animal model of HT1. Compounds shifted the G337S pathological variant toward the active dimer and slowed unfolding/aggregation, resulting in dose-dependent enhancement of FAH activity and partial rescue of FAH homeostasis in cells and the liver tissue of a mouse model of HT1. These molecules support a therapeutic approach that could complement nitisinone in HT1.
2026-04-03 | Toward Next-Gen Cell Therapy for Pediatric Patients: Neonatal Hepatocytes Tolerate Electroporation-Mediated Gene Editing and Engraft in the Liver.
Hepatocyte transplantation (HTx) offers a safer, less invasive alternative to orthotopic liver transplantation for inherited metabolic liver diseases, especially in high-risk pediatric patients. Combining HTx with ex vivo gene editing is a promising autologous therapeutic strategy using the patient's cells. We investigated the feasibility of this approach by applying CRISPR-Cas9 gene knock-out to neonatal mouse hepatocytes and comparing their engraftment potential with that of mature adult cells in the Fah-/- mouse model of hereditary tyrosinemia type I (HT1). Electroporation-mediated gene editing did not significantly impair the ability of neonatal hepatocytes to engraft in vivo. Quantitative histological analysis revealed comparable liver repopulation levels between recipients of gene-edited neonatal cells and adult cells after hepatoxicity-mediated selection, providing a benchmark for electroporation-mediated gene editing in neonatal hepatocytes, and supporting the development of genetically corrected neonatal hepatocyte products as a crucial long-term or bridge-to-transplant therapeutic strategy for pediatric liver disease.
2026-03-07 | Pediatric liver transplantation for inherited metabolic disease-Current challenges.
Liver transplantation (LT) was first introduced in the early 1960s, with early paediatric experience marked by significant technical challenges and high risk. Advances in surgical techniques and immunosuppressive therapy in the late 1970s led to successful paediatric LT outcomes, while continued improvements throughout the 1980s and 1990s have enhanced survival and reduced complications. Current 10-year graft and patient survival rates for elective paediatric indications exceed 90%. Over the past two decades, LT has increasingly been used to treat inherited metabolic diseases (IMDs), which now account for 25-30% of paediatric LT. Initially recommended for tyrosinaemia type 1 in 1978 and later for urea cycle disorders such as ornithine transcarbamylase deficiency, LT can be curative when the metabolic defect is confined to the liver and partially corrective in conditions with extrahepatic involvement. As indications expand and earlier intervention is emphasized, this review examines the role of LT in IMDs, highlighting current concepts, challenges, and controversies.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for Tyrosinemia type 1, including 1 approved therapy.
2 orphan drug designations for Tyrosinemia type 1, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Lentiviral vector expressing human fumarylacetoacetate hydrolase | gene therapies | FDA | 2019-08-08 | — | Castle Creek Biosciences, LLC |
Nitisinone [Orfadin] | small molecules | FDA | 1995-05-16 | 2002-01-18 | Swedish Orphan Biovitrum AB (publ) |
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