Genetic defects in phenylalanine metabolism can result in disease. The symptoms are often useful diagnostic indicators of the underlying genetic defect. Here are some cases that present typical symptoms of various metabolic diseases connected with phenylalanine.
Infant, male.
Guthrie test positive: given 10 days after birth, in pediatrician's office. Called back for further testing.
Family history: Northern European ancestry on both sides; grand-maternal sib with PKU: retarded, stunted growth, pale complexion, died young; no other relatives known with overt disease
Physical symptoms: none for newborn
HPLC analysis of serum (after 10 days): [Phe] > 1200 micromol/L
1. What is the Guthrie test, and how does it work?
2. What is the significance of the patient being of Northern European ancestry? What about the family history of the maternal sibling?
3. Explain the significance of the HPLC analysis of the serum for phenylalanine.
4. What connection is there between PKU and aberrantly low levels of serotonin in the serum and urine?
5. What therapy would you recommend?
1. The Guthrie test is a bacterial assay for the presence of high levels of phenylalanine.
2. The incidence of PKU is higher among people of Northern European ancestry. The maternal sibling likely had an undiagnosed case of classical PKU.
3. A serum level of Phe of 1200 micromoles per liter (which is very high) is typical of classical PKU.
4. High concentrations of phenylalanine can inhibit the enzyme that decarboxylates 5-hydroxytryptophan to form serotonin. This leads to abnormally low levels of serotonin overall, hence low levels in the serum and urine.
5. Therapy:
restricted diet, low Phe, supplement for Tyr; monitor serum levels of Phe closely.
Referral to parent support group.
7yr old female; mental retardation; infrequent episodes of seizures. Adopted from former Soviet Union. No available family history.
Born outside US. Did not undergo screening for congenital disorders.
Child is blond with blue eyes. Peculiar body smell. Mentally retarded; functions at about the level of a child at 20 months. No gross pathology.
Serum [Phe] at 29 mg/dL
Urinary Pterin analysis: normal
1. What is the significance of the child being adopted from the former Soviet Union?
2. What do the lab results tell you about Phe metabolism in this child?
3. What might be causing the peculiar body smell of this child?
1. With the disruption of social services there, screening for PKU was neglected. This blond, blue-eyed child might well have ancestors from northern Europe, where the incidence of PKU is significantly higher than in the general population.
2. The high level of Phe in the serum indicates PKU; the normal urinary Pterin levels (neopterin, biopterin) indicate no defect in biopterin metabolism. Together, these indicate a classical case of PKU.
3. The peculiar odor is probably due to phenylacetate, a metabolite of phenylalanine that normally does not accumulate appreciably.
Diagnosis: Classical PKU. Deficiency in phenylalanine hydroxylase. Not detected earlier since child was born where neonatal screening was not in effect.
Treatment: Restrict intake of Phe; supplement diet with Tyr. Referral to parent support group.
16 yr old male; mental retardation; episodic seizures.
Born in rural US at home. Did not undergo screening for congenital disorders.
Youth is mentally retarded; functions at about the level of a 5 year old child.
Analysis of serum samples gave the following results:
Serum [Phe] : 1600 micromol/L
Serum [Tyr]: 180 micromol/L
Dopamine, serotonin levels abnormally low
HPLC of urine gave the following results:
Biopterin as BH2: abnormally high
Biopterin as BH4: abnormally low
Liver biopsy for enzyme activity gave the following results:
PAH activity: normal activity
DHPR activity: absent
1. What is the significance of the youth having been born at home in a rural area?
2. Is there a block in phenylalanine hydroxylase? What about DHPR? Interpret the levels of the biopterin forms.
3. Why are there low levels of the neurotransmitter dopamine and serotonin here?
4. Why the episodes of seizures?
5. What therapy would you recommend?
1. He did not undergo the usual screening for PKU that is done at birth, hence his case went undiagnosed.
2. Not classical PKU, but many symptoms in common. Lab tests needed to carefully distinguish between them. Block is not in conversion of Phe to Tyr, since PAH activity (by biopsy) is normal. Abnormal pterin profile (low BH4 and high BH2), along with absence of DHPR activity, indicates a problem in the synthesis of the reduced form of the biopterin cofactor.
3. Tetrahydrobiopterin is needed for the biosynthesis of these neurotransmitters. This patient has a defect in the synthesis of tetrahydrobiopterin, hence the neurotransmitters are present only in abnormally low levels.
4. The blockage in neurotransmitter synthesis may be responsible here.
5. Restrict dietary intake of phenylalanine, supplement with tyrosine. However, this is insufficient in a case like this. Supplementation with tetrahydrobiopterin may possibly be helpful, but since BH4 does not cross the blood-brain barrier, this will probably not result in sufficient levels of the neurotransmitters. Supplementation with L-dopa and 5-hydroxytryptophan (which do cross the blood-brain barrier, and are precursors to the neurotransmitters) would be preferred here.
1. What is the incidence of phenylketonuria in newborns?
2. PKU is a genetic disease. Is the classic form of PKU autosomal or sex-linked?
3. Describe the most common enzyme defect of PKU. List other enzyme defects that might raise levels of Phe.
4. Why are there higher levels of phenylpyruvate, and phenyllactate in PKU? Describe a likely reaction scheme leading to higher levels of phenylpyruvate.
5. In treating PKU,
why must one restrict the dietary intake of Phe? Why should the diet be
supplemented with Tyr?
Links to
Genetics
of PKU
Phe
metabolic pathway
Biopterin
reduction reactions
Essential vs. nonessential
amino acids
Transamination
of aminoacids to alpha-keto acids
Explain in detail how a defect in biopterin synthesis would lead to excess Phe levels.
Rationalize the mental retardation effect with PKU causes - how might excess Phe cause retardation?
Explain the pale complexion of the grandmaternal sibling with PKU in Case 1.
In suspected cases of PKU, why analyze the urine for branched-chain amino acids? Why analyze for neurotransmitters like serotonin?
An old test for PKU used ferric chloride added to urine. A positive result was signified by a developing green color. The color was due to chelation of the ferric ions by aromatic carboxylates. What metabolite is likely chelating the iron in a positive PKU test here? Would this assay work for mild PKU cases? Discuss how false positives could arise here, also the possibility of masking of the green color by other compounds in urine.
Links to
References
Biopterin
metabolism
Inhibition
of enzymes by Phe