215 Diseases and Disorders of the Metabolism
Phenylketonuria (PKU)
Phenylketonuria (PKU) is an autosomal recessive metabolic genetic disorder due to a mutation in the phenylalanine hydroxylasegene gene.
Learning Objectives
Describe the factors involved in phenylketonuria (PKU)
Key Takeaways
Key Points
- PKU is an autosomal recessive genetic disorder that occurs due to a mutation in phenylalanine hydroxylase gene, which makes this enzyme non-functional.
- Phenylalanine hydroxylase is the enzyme that is necessary for the conversion of the amino acid phenylalanine (Phe) to the amino acid tyrosine.
- Phenylalanine is a large, neutral amino acid (LNAA), which can compete for transport across the blood – brain barrier (BBB) via the large neutral amino acid transporter (LNAAT).
- Untreated PKU can lead to mental retardation, seizures, and other serious medical problems. Therefore, PKU is commonly included in the newborn screening panel of most countries, with varied detection techniques.
- The mainstream treatment for classic PKU patients is a strict PHE-restricted diet supplemented by a medical formula containing amino acids and other nutrients.
- PKU is an autosomal recessive genetic disorder.
Key Terms
- autosomal recessive: A mode of inheritance of genetic traits located on the allosomes (the sex determining chromosomes).
- Phenylketonuria: An autosomal recessive metabolic genetic disorder characterized by a mutation in the gene for the hepatic enzyme phenylalanine hydroxylase, rendering it nonfunctional.
- phenylalanine: An essential amino acid C9H11NO2 found in most animal proteins; it is essential for growth; the inability to metabolize it leads to phenylketonuria; it is a constituent of aspartame.
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. Other non-PAH mutations can also cause PKU. This is an example of non-allelic genetic heterogeneity. The PAH gene is located on chromosome 12 in the bands 12q22-q24.1. More than 400 disease-causing mutations have been found in the PAH gene. PAH deficiency causes a spectrum of disorders, including classic phenylketonuria and hyperphenylalaninemia (a less severe accumulation of phenylalanine). Because PKU is an autosomal recessive genetic disorder, both parents must have at least one mutated allele of the PAH gene. The child must inherit both mutated alleles, one from each parent. Therefore, it is possible for a parent with the disease to have a child without it if the other parent possesses one functional allele of the gene for PAH. Yet, a child from two parents with PKU will inherit two mutated alleles every time, and therefore will also inherit the disease.
Inheritance of PKU: Phenylketonuria is inherited in an autosomal recessive fashion.
PAH enzyme is necessary for the metabolism of the amino acid phenylalanine (Phe) to the amino acid tyrosine. When PAH activity is reduced, phenylalanine accumulates. Excessive phenylalanine can be metabolized into phenylketones through the minor route, a transaminase pathway with glutamate. Metabolites include phenylacetate, phenylpyruvate, and phenethylamine. Elevated levels of phenylalanine in the blood and detection of phenylketones in the urine is diagnostic.
Phenylalanine is a large, neutral amino acid (LNAA). LNAAs compete for transport across the blood–brain barrier (BBB) via the large neutral amino acid transporter (LNAAT). 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 mental retardation.
Treatment
The mainstream treatment for classic PKU patients is a strict PHE-restricted diet supplemented by a medical formula containing amino acids and other nutrients. In the United States, the current recommendation is that the PKU diet should be maintained for life. Patients who are diagnosed early and maintain a strict diet can have a normal life span with normal mental development. However, recent research suggests that neurocognitive, psychosocial, quality of life, growth, nutrition, and bone pathology are slightly suboptimal.
Detection
PKU is commonly included in the newborn screening panel of most countries, with varied detection techniques. Most babies in developed countries are screened for PKU soon after birth. Screening for PKU is done with bacterial inhibition assay (Guthrie test), immunoassays using fluorometric or photometric detection, or amino acid measurement using tandem mass spectrometry (MS/MS). Measurements done using MS/MS determine the concentration of Phe and the ratio of Phe to tyrosine, both of which will be elevated in PKU.
Incidence
A rarer form of hyperphenylalaninemia occurs when PAH is normal, but there is a defect in the biosynthesis or recycling of the cofactor tetrahydrobiopterin (BH4) by the patient. This cofactor is necessary for proper activity of the enzyme. The coenzyme (called biopterin) can be supplemented as treatment. Those who suffer from PKU must be supplemented with tyrosine to account for PAH deficiency in converting phenylalanine to tyrosine sufficiently. Dihydrobiopterin reductase activity is to replenish quinonoid-dihydrobiopterin back into its tetrahydrobiopterin form, which is an important cofactor in many metabolic reactions in amino acid metabolism. Those with this deficiency may produce sufficient levels of PAH, but since tetrahydrobiopterin is a cofactor for PAH activity, deficient dihydrobiopterin reductase renders any PAH enzyme non-functional. Tetrahydrobiopterin is also a cofactor in the production of L-DOPA from tyrosine and 5-hydroxy-l-tryptophan from tryptophan, which must also be supplemented as treatment in addition to the supplements for classical PKU. Levels of dopamine can be used to distinguish between these two types. Low levels of dopamine lead to high levels of prolactin. By contrast, in classic PKU, prolactin levels would be relatively normal. Tetrahydrobiopterin deficiency can be caused by defects in four different genes.
The mean incidence of PKU varies widely in different human populations. Caucasians are affected at a rate of 1 in 10,000. Turkey has the highest documented rate in the world, with 1 in 2,600 births, while countries such as Finland and Japan have extremely low rates with fewer than one case of PKU in 100,000 births.
Galactosemia and Glycogen Storage Disease
Galactosemia and GSD are two diseases that are caused by improper carbohydrate metabolism.
Learning Objectives
Differentiate between galactosemia and glycogen storage disease
Key Takeaways
Key Points
- Galactosemia follows is a rare genetic metabolic disorder that affects an individual’s ability to metabolize the sugar galactose properly.
- Infants affected by galactosemia typically present with symptoms of lethargy, vomiting, diarrhea, failure to thrive, and jaundice.
- A galactosemia test is a blood test (from the heel of the infant) or urine test that checks for three enzymes that are needed to change galactose sugar that is found in milk and milk products into glucose, a sugar that your body uses for energy.
- The only treatment for classic galactosemia is eliminating lactose and galactose from the diet.
- Glycogen storage disease (GSD, also glycogenosis and dextrinosis) is the result of defects in the processing of glycogen synthesis or breakdown within muscles, liver, and other cell types.
- The only treatment for classic galactosemia is eliminating lactose and galactose from the diet.
- There are eleven (11) distinct diseases that are commonly considered to be glycogen storage diseases.
Key Terms
- enzyme: A globular protein that catalyses a biological chemical reaction.
- glycogen: A polysaccharide that is the main form of carbohydrate storage in animals; converted to glucose as needed.
Galactosemia (British Galactosaemia) is a rare genetic metabolic disorder that affects an individual’s ability to metabolize the sugar galactose properly. Although the sugar and lactose metabolizes to galactose, galactosemia is not related to and should not be confused with lactose intolerance. Galactosemia follows an autosomal recessive mode of inheritance that confers a deficiency in an enzyme responsible for adequate galactose degradation. Its incidence is about one per 60,000 births for Caucasians. In other populations the incidence rate differs.
Galactose: Galactosemia is caused by the inability to metabolize galactose, shown here.
Lactose in food (such as dairy products) is broken down by the enzyme lactase into glucose and galactose. In individuals with galactosemia, the enzymes needed for further metabolism of galactose are severely diminished or missing entirely, leading to toxic levels of galactose 1-phosphate in various tissues as in the case of classic galactosemia, resulting in hepatomegaly (an enlarged liver), cirrhosis, renal failure, cataracts, brain damage, and ovarian failure. Without treatment, mortality in infants with galactosemia is about 75%.
Diagnosis
Infants are routinely screened for galactosemia in the United States. Infants affected by galactosemia typically present with symptoms of lethargy, vomiting, diarrhea, failure to thrive, and jaundice. If the family of the baby has a history of galactosemia, doctors can test prior to birth by taking a sample of fluid from around the fetus or from the placenta.
Detection of the disorder through newborn screening (NBS) does not depend on protein or lactose ingestion, and, therefore, it should be identified on the first specimen unless the infant has been transfused. A specimen should be taken prior to transfusion. The enzyme is prone to damage if analysis of the sample is delayed or exposed to high temperatures.
Treatment
The only treatment for classic galactosemia is eliminating lactose and galactose from the diet. Even with an early diagnosis and a restricted diet, however, some individuals with galactosemia experience long-term complications such as speech difficulties, learning disabilities, neurological impairment (e.g., tremors, etc.), and ovarian failure in females. Infants with classic galactosemia cannot be breast-fed due to lactose in human breast milk and are usually fed a soy-based formula.
Galactosemia is sometimes confused with lactose intolerance, but galactosemia is a more serious condition. Lactose intolerant individuals have an acquired or inherited shortage of the enzyme lactase, and experience abdominal pains after ingesting dairy products, but no long-term effects. In contrast, a galactosemic individual who consumes galactose can cause permanent damage to their bodies.
Glycogen Storage Disease
Glycogen storage disease (GSD, also glycogenosis and dextrinosis) is the result of defects in the processing of glycogen synthesis or breakdown within muscles, liver, and other cell types. GSD has two classes of cause: genetic and acquired. Genetic GSD is caused by any inborn error of metabolism (genetically defective enzymes) involved in these processes. In livestock, acquired GSD is caused by intoxication with the alkaloid castanospermine. Overall, according to a study in British Columbia, approximately 2.3 children per 100,000 births (one in 43,000) have some form of glycogen storage disease. In the United States, they are estimated to occur in one per 20,000–25,000 births. A Dutch study estimated it to be one in 40,000.
There are 11 distinct diseases that are commonly considered to be glycogen storage diseases (some previously thought to be distinct have been reclassified).
