L32: Biochemical Basis of Metabolic Disease Flashcards
Why are enzymopathies almost always recessive?
Most enzymes are produced in quantities significantly in excess of minimal biochemical requirements, so that heterozygotes with about 50% of residual activity are clinically normal. In fact, many enzymes may maintain normal substrate and product levels with activities of less than 10% of control.
What are the two pathophysiological consequences of enzymopathis?
Because the function of an enzyme is to convert a substrate to a product, all of the pathophysiological consequences of enzymopathies can be attributed either to the accumulation of the substrate, to the deficiency of the product, or to some combination of the two.
significance of diffusible versus macromolecular substrates determining tissue pathology
The pathology of the macromolecular diseases is confined to the tissues in which the substrate (e.g. mucopolysaccharide) accumulates, whereas the site of the disease in the small molecule disorder is often unpredictable because the unmetabolized substrate (e.g. phenylalanine), or its derivatives, can move freely throughout the body, damaging cells that may normally have no relationship to the affected enzyme.
Hereditary Fructose Intolerance (fructose poisoning)
Primary cause, inheritance pattern and biochemical steps that are affected.
Primary cause: mutations in the hepatic aldolase B gene. Inheritance: autosome recessive.
1. Metabolic block results in a hepatic accumulation of fructose 1-phosphate, which is osmotically active, resulting in liver damage.
2. Decreased cellular inorganic phosphate levels because Pi is tied up to F-1-P.
-Decreased Pi results in a decrease in hepatic liver
glycogenolysis.
-Decreased Pi results in a decrease in ATP synthesis. (both leading to SEVERE HYPOGLYCEMIA!)
Hereditary Fructose Intolerance (fructose poisoning)
Clinical Presentations and Therapy
Presentations:
1. Severe hypoglycemia
-decreased glycogenolysis due to low levels of Pi, which is a substrate for glycogen phosphorylase
-decreased gluconeogenesis due to low ATP
2. Jaundice due to liver damage.
3. Hepatic failure due to liver damage
Therapy: avoid dietary fructose & sucrose intake.
Why are cataracts not a clinical presentation in Hereditary Fructose Intolerance?
because fructose is not an aldose sugar, and therefore not a substrate for aldose reductase in the lens.
Classic galactosemia
inheritance pattern, primary cause and biochemical steps that are affected
Primary cause: mutations in the hepatic galactose-1-p uridyltransferase gene. inheritance: autosomal recessive.
Biochem steps that are affected:
1. Metabolic block results in a hepatic accumulation of galactose 1-phosphate, which is osmotically active, resulting in liver damage.
2. Accumulation of galactose, an upstream substrate in the liver and in other tissues.
3. Galactose in the cell (either in the liver or in the extrahepatic tissues) is converted to galactitol (a substrate derivative) by aldose reductase enzyme.
Classic galactosemia
Clinical Presentations and Therapy
Presentations:
1. Galactosemia (galactose in the blood.
2. Galactosuria (galactose in the urine)
3. Liver damage due to accumulation of galactose 1P and galactitol
4. Extrahepatic tissue damage:
-Cataracts due to galactitol accumulation in the lens: galactitol leads to an
increased cellular osmolarity, causing other cellular proteins to denature such as
lens crystallins, resulting in cataracts. Aldose reductase has a high Km for
galactose, and is usually insignificant in physiological galactose concentration.
-Kidney damage due to galactitol
-Nerve tissues damage due to galactitol, which result in severe mental retardation
Therapy: remove all dietary galactose, e.g. lactose‐containing foods or compounds
containing galactose.
Why is it justified to perform population screening of newborns for Galactosemia?
In short, if not recognized, galactosemia causes severe mental retardation and is often fatal. Infants with galactosemia are usually normal at birth but begin to develop gastrointestinal problems, liver cirrhosis and cataracts in the weeks after they are given milk. Complete removal of galactose-containing compounds such as lactose (found in milk and dairy products) can protect against most of the harmful consequences. However, as with PKU, learning disabilities are now recognized to be common even in well‐treated galactosemia patients. Newborn screening for galactosemia is required in all 50 states of the U.S.
Without any dietary galactose intake, will an individual with this enzyme deficiency suffer from galactose deficiency?
No. It is because endogenous galactose pool (in form of UDPgalactose) can be derived from its C4 epimer glucose. This conversion is mediated through UDP‐Gal‐C4‐epimerase.
Classic Phenylketonuria
Primary cause, inheritance pattern, biochemical steps that are affected
primary cause: mutations in the hepatic phenylalanine hydroxylase (PAH) gene (recessive)
Biochemical steps that are affected:
The PAH deficiency leads to an accumulation of phenylalanine (substrate) and phenylpyruvic acid (derivative via an alternate reaction) and a reduced tyrosine (product) and its derivatives.
Classic Phenylketonuria
Presentations and therapy
Presentations:
-Hyperphenylalaninemia: patients with PKU accumulate phenylalanine (diffusible molecule) in body fluids.
-Irreversible central nervous system damage/mental retardation caused by phenylalanine and phenylpyruvic acid, typically happens 4 weeks post natal.
Therapy: the management of PKU is a paradigm of the treatment of many metabolic diseases whose outcome can be improved by preventing accumulation of an enzyme substrate and its derivatives.
What are the substrates and product and it’s downstream products of Phenylalanine hydroxylase (PAH)?
substrate: phenylalanine
product: tyorsine
Given the fact that PKU is a relatively rare condition in the U.S. (average prevalence in the U.S. and Europe is about 1 in 10,000), why does it make sense to perform population screening of newborns for PKU?
If detected within a few weeks of birth, the mental and physical degeneration can be prevented and easily treated by dietary modifications such as phenylalanine intake restriction (not elimination, though) and tyrosine supplementation.
The screening test, Guthrie test, is inexpensive and simple, which measures plasma phenylalanine levels.
Why is it crucial to advise a female with PKU at childbearing age to continue on the low phenylalanine diet if she becomes pregnant?
Most women with PKU at childbearing age have abandoned the diet therapy by their early teens. This termination of diet therapy seems to have limited ill effects on the women themselves, but can cause irreparable harm to the developing fetus. High levels of phenylalanine can diffuse
across the placenta, causing brain damage of the
developing fetus. Therefore, even though the fetus is heterozygous for the mutated PAH and is born without classic PKU disease, the infant can exhibit severe mental retardation, a condition termed maternal PKU.
