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The five known inherited disorders in the metabolism of the nonessential amino acid tyrosine are each very rare and present in different ways. Four of them share a degree of hypertyrosinemia, but this sign is not specific and can also be found in other conditions such as transient tyrosinemia of the preterm newborn, which results from delayed maturation of tyrosine-metabolizing enzymes; in scurvy; and in many forms of general liver disease.

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Clinical Presentation

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Symptoms may begin early in infancy due to rapidly progressive liver failure and may include vomiting, diarrhea, jaundice, hypoglycemia, edema, ascites, and especially bleeding. The symptoms may also progress slowly over many years and may include failure to thrive, hepatosplenomegaly, tendency to bleed, and hypophosphatemic rickets due to renal tubular dysfunction of the Fanconi type. Mental retardation is not a feature. Acute attacks of peripheral neuropathy, resembling acute porphyria, with severe abdominal pain, vomiting, paralytic ileus, extensor hypertonus, and muscular weakness may occur. Late-presenting individuals can remain undiagnosed, but all types of tyrosinemia type 1 have a high risk for developing hepatocellular carcinoma.1

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Metabolic Derangement,Pathophysiology

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Deficiency of the last enzyme in tyrosine catabolism, fumarylacetoacetate hydrolase (FAH), leads to the accumulation of fumarylacetoacetate and possibly maleylacetoacetate, two cellular toxins that cause hepatic and renal cellular damage (see Fig. 135-1). 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. Fumarylacetoacetate can be reduced to succinylacetoacetate, which is decarboxylated to succinylacetone. The latter is a strong inhibitor of porphobilinogen synthase and thus causes secondary acute intermittent porphyria2 (see Chapter 167). Complete absence of FAH leads to early infantile disease, whereas late-presenting cases usually have some residual activity.3

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Genetics

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Tyrosinemia type 1 (OMIM No. 276700) is inherited in an autosomal-recessive manner. The FAH gene is located at chromosome 15q23-q25. More than 40 mutations have been reported, the most common of which is IVS12,G-A,+5. This is found in one quarter of all alleles.4,5 The same mutation is responsible for most of the cases in the French Canadian population, where a founder effect led to a tenfold increased incidence of 1:8400 for this disease. A clear genotype-phenotype correlation has not been established yet. Some of the clinical variability can be attributed to spontaneous mutation reversion to heterozygosity leading to liver mosaicism for FAH activity. Antenatal testing can be accomplished by stable isotope dilution–based quantification of succinylacetone in amniotic fluid or enzyme activity measurement in fetal cells.2 Mutation analysis helps prevent false-positive diagnoses caused by pseudodeficiency of FAH in carriers of the Arg341Trp amino acid substitution.

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Diagnostic Tests, Differential Diagnoses

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Some cases may be accidentally diagnosed by newborn screening programs using elevated tyrosine levels in blood. This is, however, neither ...

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