Phenylketonuria

General description of the disease

 Phenylketonuria (PKU) is an autosomal recessive metabolic genetic disorder characterized by a mutation in the
gene for the hepatic enzyme phenylalanine hydroxylase (PAH), rendering it nonfunctional.
 This enzyme is necessary to metabolize the amino acid phenylalanine(Phe) to the amino acid tyrosine.When PAH
activity is reduced, phenylalanine accumulates and is converted into phenylpyruvate (also known as
phenylketone), which can be detected in the urine.

 The enzyme phenylalanine hydroxylase (in the presence of co-factor tetrahydrobiopterin bh4) ormally converts the
amino acid phenylalanine into the amino acid tyrosine.

o If this reaction does not take place, phenylalanine accumulates and tyrosine is deficient

o excessive phenylalanine can be metabolized into phenylketones through the minor route, a transaminase pathway with glutamate.

Metabolites and diagnostic criteria

 Metabolites include phenylacetate, phenylpyruvate and phenethylamine.

 Elevated levels of phenylalanine in the blood and detection of phenylketones inthe urine is diagnostic, however most patients are
diagnosed via newborn screening.

PKU and Brain disability

 Phenylalanine is a large, neutral amino acid .

 LNAAs compete for transport across the blood– brain barrier via the large neutral amino acid transporter . If phenylalanine is in excess in
the blood, it will saturate the transporter. Excessive levels of phenylalanine tend to decrease the levels of other LNAAs in the brain.
However, as these amino acids are necessary for protein and neurotransmitter synthesis, Phe buildup hinders the development of the
brain, causing intellectual disability.

Normal (a&b) and abnormal (c) metabolism in phenylketonuric subjects

Levels of blood
phenylalanine

 A normal blood phenylalanine level is about 1mg/dl.

 In cases of pku, levels may range from 6- 80mg/dl, but are usually greater than 30mg/dl.

Symptoms

 Chronically, high levels of phenylalanine and some of its breakdown products can cause

o Significant brain problems.

o There are other disorders of hyperphenylalaninemia, but classic PKU is the most common
cause of high levels of Phenylalanine in the blood

o Phenylalanine accumulates, causing rashes, seizures, hyperactivity, and mental retardation, if

untreated.

o Prominent cheek and jaw bones

o widely spaced teeth

o Poor development of tooth enamel.

 o It is important to remember that some phenylalanine is needed to maintain normal body function.

o Insufficient phenylalanine intake may cause mental and physical sluggishness, loss of appetite, anemia, rashes, and diarrhea.

Heredity

 A single mutant recessive allele of the Phenylalanine Hydroxylase (PAH)gene

 Location : Long arm of Chromosome 1 2 -locus 22.

 PAH only allow a tolerance of 20 mg/kg/day.

 Missense mutations and deletions.

 Dietary excess of plant proteins which results in the exhaustion of a protein cofactor
Tetrahydrobiopterin BH4 needed by the enzyme.

o Two people who conceive a child must both be the carriers of the defective gene
inorderfortheirchildtohavethe disorder.

o The “carrier” for pku does not have the symptoms.

Pregnancy and PKU

 It is recommended that women with PKU who are of child bearing age, closely adhere to the
low-phenylalanine levels before conception and throughout pregnancy. The risk of
miscarriage, mental retardation, microcephaly, and congenital heart disease in the child is high if the mother’s blood phenylalanine is
poorly controlled.

Screening test
GUTHERIA
 Usually a few drops of blood are obtained by a small prick on the heel, placed on
a card and then sent for measurement.

 Newborn screening allows early identification and early implementation of

treatment.

 All babies are screened for pku by heel- prick test. Blood tested for excess
phenylalanine.

 Blood placed on agar plate with bacteria that need phenylalanine to grow.

 Healthy babies’ blood doesn’t have extra phenylalanine, so bacteria can’t grow.
Babies with PKU have extra phenylalanine, so bacteria grow.

 Ferric chloride +urine of new born baby Green colour in the presence of
ketone bodies.

 Astrictly controlled phenylalanine free diet upto the age of about 14 years old

 Phenylalanine is itself an essential amino acid small doses must besupplied.

 After 14 years, the growth and development of the brain is not affected by high levels of phenylalanine in the body.

Treatment

 Individuals with PKU must be alert for food sweetened with aspartame - artificial sweetener made from amino acids phenylalanine and
aspartic acid.

 If PKU goes untreated or undetected, severe brain problems occur such as seizures and mental retardation.

 More frequent Dr visits

 Required dietary restrictions that may impact day today activities

 Permanent monitoring of blood phenylalanine levels

 Cystinuria
General description of the disease

 Cystinuria is an autosomal-recessive defect in reabsorptive transport of cystine and the dibasic amino acids ornithine, arginine, and
lysine from the luminal fluid of the renal proximal tubule and small intestine. The only phenotypic manifestation of cystinuria is cystine
urolithiasis (kidney stones90

o 1 in 7000 births
Presentation
o 1-2% of all stone formers
Presentation is similar to that of other types of
renal calculi and includes renal colic, chronic
o Up to 5% in pediatric stone formers
urinary tract infections in a young person with a
family history of renal stones, passage of stones
Pathophysiology or gravel, hematuria, and dysuria.

Renal transport of cystine

o Amino acids filtered undergo nearly complete reabsorption by proximal tubular cells.
o Only 0.4% of the filtered cystine appears in the urine.

Intestinal transport of cystine

 The high-affinity transporter is present in the apical brush-border membrane of the jejunum and is responsible for absorption of cystine
and dibasic amino acids.
 Normally, cystine and the other dibasic amino acids (ie, ornithine, lysine, arginine) are filtered at the glomerulus and reabsorbed in the
proximal convoluted tubule
 Defects in this channel cause elevated levels of dibasic amino acid secretion in the urine.
 Whereas ornithine, lysine, and arginine are completely soluble, cystine is relatively insoluble at physiologic urine pH levels of 5-7

Diagnosis

 Positive family history of cystinuria

 Stone analysis showing cystine

 Identification of pathognomonic hexagonal cystine crystals on urinalysis

 A positive cyanide-nitroprusside screen indicates a urinary cystine concentration >75 mg/L

 Quantitative 24-h urinary cystine excretion more than 30 mg/day are considered abnormal

Treatment

 The aim of medical therapy is to maintain the cystine concentration in the

urine below its solubility level
  Solubility of cystine in urine from 175 to 360 mg/L ≈ about 243 mg/L  avoiding cystine crystallisation is to maintain urine pH
between 7.5. and 8.5

 High fluid intake

Sodium and protein restriction

 Urinary alkalinization

Surgical procedures

 Large calculi that are unlikely to dissolve

 Obstructing or otherwise symptomatic calculi.

 The ultimate goal of surgery is to make the patient free of stones. While the risk of recurrence is unchanged