Chapter 136. Disorders of Tyrosine Metabolism

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.

Clinical Presentation

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 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

Genetics

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 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

Treatment, Prognosis, and Long-Term Outcome

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 Liver function tests and AFP levels must be monitored, and regular ultrasounds are recommended to detect early signs of liver hyperregeneration, which may lead to adenoma or carcinoma. Liver transplantation is the only other therapeutic option if NTBC therapy fails or if hepatocellular carcinoma develops. The latter has been observed in only a few patients, mostly in those with preexistent significant liver damage. Prognosis of patients with hepatorenal tyrosinemia in general has vastly improved with NTBC therapy.9

Clinical Presentation

The characteristic features of this disease are bilateral corneal ulcers or dendritic keratitis, presenting with photophobia, pain, and lacrimation, and erythematous papular or hyperkeratotic 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

Metabolic Derangement, Including Pathophysiology

Cytosolic tyrosine aminotransferase (TAT), the first enzyme in tyrosine degradation, is deficient in oculocutaneous tyrosinemia. Tyrosine itself is not toxic to the liver or the kidney. Plasma concentrations of tyrosine are higher than in other forms of tyrosinemia, and the urine contains large amounts of tyrosine metabolites that stem from either direct deamination of tyrosine in the kidneys or of mitochondrial aspartate aminotransferase activity. The lesions on the palms and soles and in the eyes are believed to result from local crystallization of tyrosine. How high tyrosine levels lead to mental retardation has not been elucidated yet.

Genetics

Tyrosinemia type 2 (OMIM No. 276600) is inherited in an autosomal recessive manner. The TAT gene is located at chromosome 16q22.1-q22.3. More than 15 mutations have been identified.12,13

Diagnostic Tests, Including Differential Diagnoses

Newborn screening programs may detect the illness by using tyrosine as a screening parameter. In symptomatic cases, plasma amino acid analysis reveals tyrosine concentrations that usually exceed 1200 μmol/l. In less pronounced hypertyrosinemia, a diagnosis of tyrosinemia type 3 should be considered. The enzymatic defect can be confirmed only in liver tissue, but a liver biopsy for differentiation is usually not justified. Mutation analysis can confirm the diagnosis.

Treatment, Prognosis, and Long-Term Outcome

Oculocutaneous tyrosinemia responds to a diet low in phenylalanine and tyrosine. This diet is similar to the diet for severe hyperphenylalaninemia and needs to be supplemented with a commercially available phenylalanine- and tyrosine-free protein substitute, with micronutrients, and with special low-protein staple food. Treatment aims to keep plasma tyrosine below 800 μmol/l to prevent oculocutaneous manifestations. Safe tyrosine concentrations to prevent brain damage have not been defined and may be lower. Maternal tyrosinemia has an adverse effect on the developing fetus in women with tyrosinemia type 2, indicating the need for strict dietary control during pregnancy.14

Clinical Presentation

Several patients with this disorder have been identified, and most suffer from neurological symptoms such as mild to severe psychomotor retardation and, less frequently, seizures. No other organ systems are involved.

Metabolic Derangement, Including Pathophysiology

Tyrosinemia type 3 is caused by a deficiency of 4-hydroxyphenylpyruvate dioxygenase (HPD) that catalyzes the second step in tyrosine catabolism. Tyrosine levels are elevated but usually not to levels that cause corneal ulcers or hyperkeratosis.15

Genetics

Deficiency of 4-hydroxyphenylpyruvate dioxygenase (OMIM No. 276710) is inherited in an autosomal recessive manner. The HPD gene is located at chromosome 12q24-qter, and a few mutations have been identified.16,17

Diagnostic Tests, Including Differential Diagnoses

Plasma tyrosine concentrations of 500 to 1200 μmol/l suggest tyrosinemia type 3. Tyrosyluria is usually observed, and the diagnosis can be confirmed by enzyme activity measurement in liver or kidney tissue or by mutational analysis.2

Treatment, Prognosis, and Long-Term Outcome

Treatment similar to that of oculocutaneous tyrosinemia is recommended, although the benefit of dietary treatment has not been demonstrated.

Clinical Presentation

The few patients who have been identified with this disorder suffer from failure to thrive and metabolic acidosis during infancy, which seems to be precipitated by weaning from breast-feeding. Further development seems to be normal and asymptomatic individuals have been described.18–20

Metabolic Derangement, Including Pathophysiology

Hawkinsuria is believed to be caused by an abnormal function of 4-hydroxyphenylpyruvate dioxygenase (HPD, EC 1.13.11.27), which leads to the formation of two unusual metabolites of 4-hydroxy-phenylpyruvate, hawkinsin, and 4-hydroxycyclohexylacetate.19 This process is thought to lead to a depletion of glutathione, which is associated with 5-oxoprolinuria and metabolic acidosis. However, the pathophysiology of this condition is not completely understood.

Genetics

Hawkinsinuria (OMIM No. 140350) is allelic to tyrosinemia type 316 and is being transmitted as an autosomal dominant trait with variable penetrance.20 Several mutations have been described within the HPD gene.

Diagnostic Tests, Including Differential Diagnoses

The identification of hawkinsin and 4-hydroxycyclohexylacetate in urine by gas chromatography-mass spectrometry allows a diagnosis. Moderate tyrosinemia, tyrosyluria, and 5-oxoprolinuria have been observed during infancy.

Treatment, Prognosis, and Long-Term Outcome

Treatment consists of mild dietary phenylalanine and tyrosine restriction. Symptomatic infants have developed normally.

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), which was later confirmed.22 This hypothesis gave rise to the one-gene, one-enzyme hypothesis and the field of biochemical genetics.

Clinical Presentation

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

Metabolic Derangement, Including Pathophysiology

Alkaptonuria results from defective activity of the enzyme homogentisate 1,2 dioxygenase (HGD), the third enzyme in tyrosine degradation. The disorder is characterized by the excretion of dark-colored urine containing large amounts of homogentisic acid, which causes a positive test result for reducing substances. Fresh urine appears normal, but on standing and particularly after alkalinization, oxidation of homogentisic acid to benzoquinone proceeds, and a dark brown or black pigment appears; this is believed to act as a chemical irritant and can damage the cartilage. Blood tyrosine levels are not elevated.

Genetics

Alkaptonuria (OMIM No. 203500) is inherited in an autosomal-recessive manner. A few hundred patients have been reported. The HGD gene is located on chromosome 13q21-q23, and several mutations have been described.24

Diagnostic Tests, Including Differential Diagnoses

Homogentisic acid can be measured in urine by gas chromatography-mass spectrometry once the condition is suspected. The diagnosis is usually first made in adult life during routine urinalysis or during investigation of arthritis.

Treatment, Prognosis, and Long-Term Outcome

Treatment of alkaptonuria has not been successful so far2,25 Strict dietary restriction of phenylalanine and tyrosine is usually not accepted by adults. Moderate doses of NTBC could help to reduce the accumulation of homogentisic acid but needs to be combined with dietary restriction. Ascorbic acid may alleviate some of the toxic effects, but no long-term research is available. Therapy cannot reverse the symptoms related to ankylosing arthritis or aortic or mitral valvulitis (see Table 136-1).