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Tyrosine Metabolism Disorders

By Lee M. Sanders, MD, MPH

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Tyrosine is an amino acid that is a precursor of several neurotransmitters (eg, dopamine, norepinephrine, epinephrine), hormones (eg, thyroxine), and melanin; deficiencies of enzymes involved in its metabolism lead to a variety of syndromes.

There are numerous disorders of phenylalanine and tyrosine metabolism (see Table). Also see Approach to the Patient With a Suspected Inherited Disorder of Metabolism and testing for suspected inherited disorders of metabolism.

Phenylalanine and Tyrosine Metabolism Disorders

Disease (OMIM Number)

Defective Proteins or Enzymes

Defective Gene or Genes (Chromosomal Location)

Comments

Phenylketonuria (PKU), with classic and mild forms (261600)

Phenylalanine hydroxylase

PAH (12q24.1)*

Biochemical profile: Elevated plasma phenylalanine

Clinical features: Intellectual disability, behavioral problems

Treatment: Dietary phenylalanine restriction, tyrosine supplementation

Dihydropteridine reductase deficiency (261630)

Dihydropteridine reductase

QDPR (4p15.31)*

Biochemical profile: Elevated plasma phenylalanine, high urine biopterin, low plasma biopterin

Clinical features: Similar to mild PKU, but if neurotransmitter deficiency is unrecognized, development of intellectual disability, seizures, and dystonia

Treatment: Dietary phenylalanine restriction, tyrosine supplementation, folinic acid, neurotransmitter replacement

Pterin-4α-carbinolamine dehydratase deficiency (264070)

Pterin-4α-carbinolamine dehydratase

PCBD (10q22)*

Biochemical profile: Elevated plasma phenylalanine, high urine neopterin and primapterin, low plasma biopterin

Clinical features: Similar to mild PKU, but if neurotransmitter deficiency is unrecognized, development of intellectual disability, seizures, and dystonia

Treatment: Dietary phenylalanine restriction, tyrosine supplementation, neurotransmitter replacement

Biopterin synthesis deficiency

GTP-cyclohydrolase (233910)

GCH1 (14q22)*

Biochemical profile: Elevated plasma phenylalanine, low urine biopterin, low (GCH) or high (PTS and SPR) urine neopterin

Clinical features: Similar to mild PKU, but if neurotransmitter deficiency is unrecognized, development of intellectual disability, seizures, and dystonia

Treatment: Tetrahydrobiopterin and neurotransmitter supplementation

6-Pyruvoyl-tetrahydropterin synthase (261640)

PTS (11q22-q23)*

Sepiapterin reductase (182125)

SPR (2p14-p12)*

Tyrosinemia type I (hepatorenal; 276700)

Fumarylacetoacetate hydrolase

FAH (15q23-q25)*

Biochemical profile: Elevated plasma tyrosine, elevated plasma and urinary succinylacetone

Clinical features: Cirrhosis, acute liver failure, peripheral neuropathy, Fanconi syndrome

Treatment: Dietary phenylalanine, tyrosine, and methionine restriction; nitisinone; liver transplantation

Tyrosinemia type II (oculocutaneous; 276600)

Tyrosine aminotransferase

TAT (16q22.1-q22.3)*

Biochemical profile: Elevated plasma tyrosine and phenylalanine

Clinical features: Intellectual disability, palmoplantar hyperkeratitis, corneal ulcers

Treatment: Dietary phenylalanine and tyrosine restriction

Tyrosinemia type III (276710)

4-Hydroxyphenylpyruvate dioxygenase

HPD (12q24-qter)*

Biochemical profile: Elevated plasma tyrosine, elevated urinary 4-hydroxyphenyl derivatives

Clinical features: Developmental delay, seizures, ataxia

Treatment: Dietary phenylalanine and tyrosine restriction, ascorbate supplementation

4-Hydroxyphenylpyruvate dioxygenase

Not genetic

Biochemical profile: Elevated plasma phenylalanine and tyrosine

Clinical features: Usually occurring in premature infants; mostly asymptomatic

Occasionally poor feeding and lethargy

Treatment: Tyrosine restriction and ascorbate supplementation for symptomatic patients only

Hawkinsinuria (140350)

4-Hydroxyphenylpyruvate dioxygenase complex

HPD (12q24-qter)*

Biochemical profile: Mild hypertyrosinemia, elevated urinary hawkinsin

Clinical features: Failure to thrive, ketotic metabolic acidosis

Treatment: Dietary phenylalanine and tyrosine restriction, ascorbate supplementation

Alkaptonuria (203500)

Homogentisate oxidase

HGD (3q21-q23)*

Biochemical profile: Elevated urine homogentisic acid

Clinical features: Dark urine, ochronosis, arthritis

Treatment: None; ascorbate supplementation to reduce pigmentation

Oculocutaneous albinism type I (A and B; 203100)

Tyrosinase

TYR (11q21)*

Biochemical profile: No abnormality in plasma and urine amino acids, absent (IA) or decreased (IB) tyrosinase

Clinical features: Absent (IA) or decreased (IB) pigment in skin, hair, iris, and retina; nystagmus; blindness; skin cancer

Treatment: Protection of skin and eyes from actinic radiation

*Gene has been identified, and molecular basis has been elucidated.

OMIM = online mendelian inheritance in man (see the OMIM database ).

Transient tyrosinemia of the newborn

Transient immaturity of metabolic enzymes, particularly 4-hydroxyphenylpyruvic acid dioxygenase, sometimes leads to elevated plasma tyrosine levels (usually in premature infants, particularly those receiving high-protein diets); metabolites may show up on routine neonatal screening for phenylketonuria (PKU).

Most infants are asymptomatic, but some have lethargy and poor feeding.

Tyrosinemia is distinguished from PKU by elevated plasma tyrosine levels.

Most cases resolve spontaneously. Symptomatic patients should have dietary tyrosine restriction (2 g/kg/day) and be given vitamin C 200 to 400 mg po once/day.

Tyrosinemia type I

This disorder is an autosomal recessive trait caused by deficiency of fumarylacetoacetate hydroxylase, an enzyme important for tyrosine metabolism.

Disease may manifest as fulminant liver failure in the neonatal period or as indolent subclinical hepatitis, painful peripheral neuropathy, and renal tubular disorders (eg, normal anion gap metabolic acidosis, hypophosphatemia, vitamin D–resistant rickets) in older infants and children. Children who do not die of associated liver failure in infancy have a significant risk of developing liver cancer.

Diagnosis of tyrosinemia type I is suggested by elevated plasma levels of tyrosine; it is confirmed by a high level of succinylacetone in plasma or urine and by low fumarylacetoacetate hydroxylase activity in blood cells or liver biopsy specimens. Treatment with nitisinone is effective in acute episodes and slows progression.

A diet low in phenylalanine and tyrosine is recommended. Liver transplantation is effective.

Tyrosinemia type II

This rare autosomal recessive disorder is caused by tyrosine transaminase deficiency.

Accumulation of tyrosine causes cutaneous and corneal ulcers. Secondary elevation of phenylalanine, though mild, may cause neuropsychiatric abnormalities if not treated.

Diagnosis of tyrosinemia type II is by elevation of tyrosine in plasma, absence of succinylacetone in plasma or urine, and measurement of decreased enzyme activity in liver biopsy.

This disorder is easily treated with mild to moderate restriction of dietary phenylalanine and tyrosine.

Alkaptonuria

This rare autosomal recessive disorder is caused by homogentisic acid oxidase deficiency; homogentisic acid oxidation products accumulate in and darken skin, and crystals precipitate in joints.

The condition is usually diagnosed in adults and causes dark skin pigmentation (ochronosis) and arthritis. Urine turns dark when exposed to air because of oxidation products of homogentisic acid. Diagnosis of alkaptonuria is by finding elevated urinary levels of homogentisic acid (> 4 to 8 g/24 h).

There is no effective treatment for alkaptonuria, but ascorbic acid 1 g po once/day may diminish pigment deposition by increasing renal excretion of homogentisic acid.

Oculocutaneous albinism

Tyrosinase deficiency results in absence of skin and retinal pigmentation, causing a much increased risk of skin cancer and considerable vision loss. Nystagmus is often present, and photophobia is common.

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