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The tyrosine degradation pathway consists of 5 enzymes, and inherited disorders have been described for 4 of these. Importantly, not all defects are characterized by hypertyrosinemia, and disease pathologies are not all caused by elevated tyrosine levels. Furthermore, hypertyrosinemia is not specific for disorders of the tyrosine degradation pathway. It can also be found in other conditions such as transient tyrosinemia of the preterm newborn, scurvy, and many diseases that cause hepatocellular injury.



Hereditary tyrosinemia type 1 (HT1) is the most severe disorder of the pathway and causes early hepatic failure as well as renal injury. Symptoms are not present at birth, and early therapy can completely prevent severe disease manifestations. In untreated patients, liver failure may begin early in infancy and result in vomiting, jaundice, hypoglycemia, ascites, and bleeding. In later onset cases, the manifestations include failure to thrive, hepatosplenomegaly, a tendency to bleed, and hypophosphatemic rickets due to renal tubular dysfunction of the Fanconi type. Intellectual disability is not a primary feature. Acute attacks of peripheral neuropathy, resembling acute porphyria, with severe abdominal pain, vomiting, and paralysis, may occur. The risk of cirrhosis and hepatocellular carcinoma is significantly elevated in this disorder, and late-presenting individuals have a high risk of cancer.

Metabolic Derangement and Pathophysiology

Deficiency of the last enzyme in tyrosine catabolism, fumarylacetoacetate hydrolase (FAH), leads to the accumulation of fumarylacetoacetate, a metabolite that causes hepatic and renal cellular damage (Fig. 131-1). Fumarylacetoacetate can be reduced to succinylacetoacetate, which is decarboxylated to succinylacetone, the pathognomonic hallmark metabolite of this disorder. Secondary inhibition of 4-hydroxyphenylpyruvate dioxygenase (HPD) leads to elevated concentrations of tyrosine, and accumulating tyrosine metabolites such as 4-hydroxyphenylpyruvate, -lactate, and -acetate are excreted in urine, a phenomenon known as tyrosyluria. Succinylacetone is a potent inhibitor of porphobilinogen synthase and thus causes secondary acute intermittent porphyria (see Chapter 162). Complete absence of FAH leads to early infantile disease, but milder cases with much later onset can exist even within the same sibship.

Figure 131-1

Phenylalanine-tyrosine catabolic pathway.


Tyrosinemia type 1 (MIM no. 276700) is inherited in an autosomal recessive manner. The FAH gene is located at chromosome 15q23-q25. More than 100 mutations have been reported, the most common of which is IVS12,G-A,+5, which is found in one-quarter of all alleles in the United States. Due to a founder effect, this mutation has a very high carrier frequency and disease incidence in the French Canadian population. A clear genotype-phenotype correlation has not been established. Antenatal testing can be accomplished by molecular methods. Somatic reversion and self-induced mutation correction occur in over 50% of cases. Rare hepatocytes revert the mutation, reacquire FAH activity, and then ...

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