There are numerous disorders of phenylalanine and tyrosine metabolism (see the table). See also 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 |
Comments |
|
Phenylketonuria (PKU), with classic and mild forms (261600*) |
Phenylalanine hydroxylase |
Biochemical profile: Elevated plasma phenylalanine Clinical features: Intellectual disability, behavioral problems Treatment: Dietary phenylalanine restriction, tyrosine supplementation |
|
Dihydropteridine reductase deficiency (261630*) |
Dihydropteridine reductase |
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-4alpha-carbinolamine dehydratase deficiency (264070*) |
Pterin-4alpha-carbinolamine dehydratase |
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) |
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) |
||
|
Sepiapterin reductase (182125) |
||
|
Tyrosinemia type I (hepatorenal; 276700*) |
Fumarylacetoacetate hydrolase |
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 (NTBC); liver transplantation |
|
Tyrosinemia type II (oculocutaneous; 276600*) |
Tyrosine aminotransferase |
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 |
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 |
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 |
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 |
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 |
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 |
|
* For complete gene, molecular, and chromosomal location information, see the Online Mendelian Inheritance in Man® (OMIM®) database. |
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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 orally once a 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 genetic testing or 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 (NTBC) 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 genetic testing; measurement of decreased enzyme activity in liver biopsy is usually not needed.
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 hours).
There is no effective treatment for alkaptonuria, but ascorbic acid 1 g orally once a day may diminish pigment deposition by increasing renal excretion of homogentisic acid.
Oculocutaneous albinism
Drugs Mentioned In This Article
| Drug Name | Select Trade |
|---|---|
norepinephrine |
LEVOPHED |
epinephrine |
ADRENALIN |
dopamine |
No US brand name |
