Rudolph's Pediatrics, 22nd Ed.

CHAPTER 136. Disorders of Tyrosine Metabolism

Bernd Christian Schwahn

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 tyrosinemetabolizing 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

Metabolic Derangement, Pathophysiology

Deficiency of the last enzyme in tyrosine catabolism, fumarylacetoacetate hydrolase (FAH), leads to the accumulation of fumarylacetoace-tate 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.


Some cases may be accidentally diagnosed by newborn screening programs using elevated tyrosine levels in blood. This is, however, neither a specific nor sensitive parameter. Screening for succinylacetone in dried blood or urine seems to be highly specific and sensitive6 but has yet to be introduced into mass screening programs. Highly elevated concentrations of α-fetoprotein (AFP) and coagulopathy are usually seen, even before the elevation in tyrosine. Plasma methionine is often elevated. Delta-aminolevulinic acid (a neurotoxic intermediate of porphyrin biosynthesis) can be found in urine, and porphobilinogen synthase activity in red blood cells is decreased. However, all biochemical abnormalities apart from elevated succinylacetone are not specific and can be found in other liver diseases. Secondary porphyria can occur in lead poisoning. Children with suspected tyrosinemia should have their blood or urine evaluated for an elevation of succinylacetone, which is diagnostic. The diagnosis should then be confirmed by enzyme activity measurements in lymphocytes or fibroblasts or by mutation analysis.2


The drug 2(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) can effectively treat the liver failure and renal Fanconi syndrome of hepatorenal tyrosinemia in at least 90% of affected infants. This drug inhibits the second step of tyrosine catabolism, 4-OH phenylpyruvic dioxygenase (HPD) and thus prevents the accumulation of toxic metabolites (see Fig. 135-1). The inhibition of HPD with NTBC leads to iatrogenic tyrosinemia type 3 with tyrosine accumulation. Drug therapy needs to be combined with a diet low in phenylalanine and tyrosine to keep plasma tyrosine below 800 μmol/L to prevent keratitis and hyperkeratosis; plasma tyrosine should probably be kept even lower to prevent possible cognitive decline.2,7,8



The characteristic features of this disease are bilateral corneal ulcers or dendritic keratitis, presenting with photophobia, pain, and lacrimation, and erythematous papular or hyper-keratotic painful lesions on pressure areas of the palms and soles. About 60% of patients display mental retardation. Symptoms usually start in infancy but may occur at any age and in any combination.2,10,11


Oculocutaneous tyrosinemia responds to a diet low in phenylalanine and tyrosine.


In 1902, Garrod21 was the first to suggest that this disorder results from an inherited absence of the liver enzyme that catalyzes the oxidation of homogentisic acid (see Fig. 135-1) .22 This hypothesis gave rise to the one-gene, one-enzyme hypothesis and the field of biochemical genetics.


Persons with alkaptonuria are usually asymptomatic in childhood. After the third decade, deposition of brownish or bluish pigment is seen, particularly in the ears and sclerae. This pigmentation may be extensive in fibrous tissues, including heart valves, and is referred to as ochronosis. Ochronotic arthritis, which occurs later, produces symptoms resembling rheumatoid arthritis or osteoarthritis, with limitation of motion; complete ankylosis is common.23

Table 136-1. Other Rare Disorders of Tyrosine Metabolism


Treatment of alkaptonuria has not been successful so far2,25 (see Table 136-1).