Chapter 40 - Hepatorenal Tyrosinemia

Abstract

Hereditary tyrosinemia type I (HTI), also referred to as hepatorenal tyrosinemia, is the most severe metabolic disorder of the tyrosine degradation pathway. HTI is caused by a deficiency in fumarylacetoacetate hydrolase (FAH), the last enzyme of the pathway, which catalyzes the conversion of fumarylacetoacetate (FAA) in fumarate and acetoacetate. HTI presents into two main clinical types, acute and chronic. The acute form, with early onset at birth or soon after, is mainly characterized by severe liver failure associated with cirrhosis, hepato- and splenomegaly, abnormal blood coagulation and hypoglycemia leading to death in the first months of life. Renal tubular dysfunctions such as Fanconi syndrome and rickets have also been considered signs of HTI. In the chronic form, onset is insidious and progress is less aggressive. However, renal manifestations, mainly proximal tubulopathy, are prominent. Patients show impaired renal tubular reabsorptive function leading to Fanconi syndrome characterized by renal tubular acidosis, generalized aminoaciduria, hypophosphatemic vitamin D-resistant rickets and growth retardation. In vivo reversion of inherited somatic mutations has been reported in a number of inherited diseases, such as adenosine deaminase deficient severe combined immuno deficiency, Wiskott-Aldrich and Bloom syndromes, epidermolysis bullosa, Fanconi anemia, and HTI. It is in HTI, however, that reversion has been shown to occur most frequently. A mosaic pattern of FAH expression was observed in hepatic regenerative nodules of ›85% of studied patients. DNA analysis performed on FAH immunopositive liver nodules showed correction of the HTI-causing mutation in one allele. The treatment currently used in HTI patients is administration of the drug (2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3 cyclohexanedione) (NTBC) combined with a low-protein diet.