Phenylketonuria Lecture 4

Norwegian doctor Asbjørn Følling discovered PKU in 1934. Only 1 in about 15,000 babies are born with PKU, which means PKU is very rare. Caused by deficiency of phenylalanine hydroxylase Accumulation of phenylalanine and deficiency of Tyrosine

Classical PKU Phe is high in tissue, plasma and urine Phenyllactate, phenylacetate and phenylpyruvate give characteristic musty (mousy odor) to urine. CNS symptoms (appear after the age of 1 yr, IQ below 50) Mental retardation failure to walk or talk, Seizures Hyperactivity Tremor Microcephaly failure to grow

Hypopigmentation Fair hair Light skin color Blue eyes (The hydroxylation of tyrosine by tyrosinase first step in the formation of the pigment melanin, is competitively inhibited by the high levels of phenylalanine present in PKU)

Neonatal screening and diagnosis Early diagnosis is mandatory as it is treatable disease In infants levels are normal as mother clears elevated levels by placenta Levels rise after 24-48 hours of the exposure to diet. After positive screening test you have to do quantitive test for phenylalanine levels

Test Ferric chloride + urine of new born baby Green colour in the presence of ketone bodies © 2008 Paul Billiet ODWS

Phenylketonuria, also known as PKU, is a genetic disorder that affects a person’s ability to process an important part of protein called phenylalanine or phe. from the food we eat, and it helps our bodies grow, learn, and feel healthy

Soon after birth, babies born in the United States are checked for PKU and other medical conditions. This is called newborn screening. If children and adults with PKU eat too much phe, it will actually hurt them.

Children and adults with PKU have to eat such small amounts of phe so cannot eat meats, dairy, eggs, beans or nuts. Someone with PKU cannot eat pizza, birthday cake, regular bread, yogurt, cheese, ice cream, chocolate, hot dogs, hamburgers, or turkey.

Children and adults with PKU eat fruits, vegetables, and special foods very low in protein. Some cereals and crackers are okay in small amounts. Phe must be calculated using a gram scale, measuring cups or by counting how many pieces, all day, every day.

Treatment The earlier treatment is started, the more completely neurologic damage can be prevented (within first 7-10 days. over zealous treatment that results in blood phenylalanine levels below normal is avoided because this can lead to poor growth and neurologic symptoms. tyrosine cannot be synthesized from phenylalanine and, therefore, it becomes an essential amino acid and so must be supplied in the diet. Discontinuance of the phenyalanine-restricted diet before 8 years of age is associated with poor performance on IQ tests. Adult PKU patients show deterioration of IQ scores after discontinuation of the diet

Individuals with PKU are advised to avoid aspartame, an artificial sweetener that contains phenylalanine. Maternal PKU If women with PKU who are not on a low-phenyl -alanine diet become pregnant, the offspring are affected with “maternal PKU syndrome.” High blood phenylalanine levels in the mother cause microcephaly, mental retardation, and congenital heart abnormalities in the fetus—phenlyalanine is a teratogen.

Some of these developmental responses to high phenylalanine occur during the first months of pregnancy. Thus, dietary control of blood phenylalanine must begin prior to conception, and must be maintained throughout the pregnancy

Cystic fibrosis This is the most common lethal genetic disease in Caucasians of Northern European ancestry, and has a prevalence of about 1:3,000 births. This autosomal recessive disorder is caused by mutations on to the gene for the CF transmembrane conductance regulator (CFTR) protein chromosome 7 that functions as a chloride channel on epithelium. Defective CFTR results in decreased secretion of chloride and increased reabsorption of sodium and water. 1:25 are carriers

deletion of three nucleotides from the coding region of a gene, resulting in the loss of phenylalanine at the 508th position (ΔF508) in the protein encoded by that gene. This ΔF508 mutation prevents normal folding of the CF transmembrane conductance regulator (CFTR) protein, leading to its destruction by the proteasome The name cystic fibrosis refers to the characteristic scarring (fibrosis) and cyst formation within the pancreas, first recognized in the 1930s.

Defective CFTR results in decreased secretion of chloride and increased reabsorption of sodium and water. In the pancreas, the decreased hydration results in thickened secretions such that pancreatic enzymes are not able to reach the intestine, leading to pancreatic insufficiency. Treatment includes replacement of these enzymes and supplementation with fat-soluble vitamins CF also causes chronic lung infections with progressive pulmonary disease.

Prenatal diagnosis and carrier detection of cystic fibrosis Sweat test Concentration greater than 45 mmol/l for sodium is suggestive of cystic fibrosis. Usually it is 100 mmol/L PCR a PCR test can distinguish between homozygous normal, heterozygous (carriers), and homozygous mutant (affected) individuals.