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