What is Tyrosinemia?
 

Hereditary Tyrosinemia is a group of inherited metabolic disorders caused by deficiencies of specific enzymes in the tyrosine metabolic pathway. Based on the deficient enzyme, it is clinically classified into three main subtypes: Type I (HT1), Type II (TAT deficiency), and Type III (HPD deficiency).
 

Among these, Hereditary Tyrosinemia Type I (HT1) is the most common and severe form within this group. It is caused by a deficiency or defect in fumarylacetoacetate hydrolase (FAH), the key enzyme in the final step of tyrosine catabolism. Its global incidence is approximately 1 in 100,000.
 

The disease can be primarily divided into acute and chronic clinical types. The acute type often presents in early infancy with rapid progression, typically manifesting as severe liver damage, coagulation disorders, jaundice, and hypermethioninemia, which can rapidly lead to liver failure and be life-threatening. The chronic type has a later onset, commonly in late infancy or childhood, and is primarily characterized by progressive liver fibrosis or cirrhosis, renal tubular dysfunction (presenting as Fanconi syndrome), and a significantly increased risk of hepatocellular carcinoma.
 

Pathogenesis
 

Hereditary Tyrosinemia Type I (HT1) is caused by mutations in the FAHgene leading to a deficiency in fumarylacetoacetate hydrolase (FAH). In normal metabolism, tyrosine is sequentially broken down into fumarate and acetoacetate through a series of enzymatic reactions (TAT, HPD, HGD, MAI, FAH), entering the tricarboxylic acid cycle or participating in energy metabolism. When the FAH enzyme is inactivated, its substrate, fumarylacetoacetate, cannot be normally degraded and accumulates in liver and kidney cells. It is partially converted to succinylacetoacetate, which in turn generates succinylacetone, a characteristic toxic metabolite of HT-1.
 

These accumulated toxic metabolites induce typical clinical manifestations through multiple mechanisms: Succinylacetone potently inhibits δ-aminolevulinic acid dehydratase, blocking the heme synthesis pathway and leading to the accumulation of δ-aminolevulinic acid, thereby causing neurological and abdominal crises similar to acute intermittent porphyria. Concurrently, succinylacetone and fumarylacetoacetate cause abnormal urinary loss of substances like glucose, amino acids, and phosphate, presenting as Fanconi syndrome, by altering the fluidity of renal tubular epithelial cell membranes and interfering with their reabsorption function. In the liver, these toxic substances directly induce hepatocyte damage, necrosis, and apoptosis, persistently disrupting energy metabolism and inducing oxidative stress, ultimately leading to liver failure, cirrhosis, and significantly increasing the risk of hepatocellular carcinoma.
 

Image source: Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations

Mouse Models
 

FAH Knockout Mice:​ The FAHgene is knocked out in mice, modeling the pathological state of human HT1, including acute liver failure, renal tubular damage, and a high incidence of hepatocellular carcinoma. Long-term surviving FAH⁻/⁻ mice serve as a unique model for studying hepatocellular carcinogenesis driven by chronic liver injury, inflammation, and regeneration.
 

Supporting Gene Therapy
 

Gene therapy offers hope for rare diseases, but its development and validation rely heavily on animal model support. MingCeler Biotech, leveraging its self-developed TurboMice™ technology, has developed multiple rare disease mouse models. TurboMice™ technology overcomes the technical challenges of long mouse model generation cycles and low success rates for complex models, enabling editing at almost any target gene locus. It can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as two months.
 

MingCeler Biotech​ can customize various HT1 mouse models according to client needs, such as FAH knockout mice. Inquiries are welcome.
 

References
 

1.https://www.ncbi.nlm.nih.gov/books/NBK1515/

2.Chinsky JM, Singh R, Ficicioglu C, van Karnebeek CDM, Grompe M, Mitchell G, Waisbren SE, Gucsavas-Calikoglu M, Wasserstein MP, Coakley K, Scott CR. Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations. Genet Med. 2017 Dec;19(12). doi: 10.1038/gim.2017.101. Epub 2017 Aug 3. PMID: 28771246; PMCID: PMC5729346.

3.Anne Bergeron, Myreille D'Astous, David E. Timm, Robert M.Tanguay, Structural and Functional Analysis of Missense Mutations in Fumarylacetoacetate Hydrolase, the Gene Deficient in Hereditary Tyrosinemia Type 1*, Journal of Biological Chemistry, Volume 276, Issue 18, 2001, Pages 15225-15231, ISSN 0021-9258, https://doi.org/10.1074/jbc.M009341200.

4.Tang Y, Kong Y. Hereditary tyrosinemia type Ⅰ: newborn screening, diagnosis and treatment. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2021 Aug 25;50(4):514-523. English. doi: 10.3724/zdxbyxb-2021-0255. PMID: 34704422; PMCID: PMC8777462.