2. Missense mutation: altered DNA codes for a different •
amino acid, which changes the phenotypic effect.
In both sickle cell trait and sickle cell disease, a missense mutation occurs when adenine replaces thymidine, causing valine to replace glutamic acid in the sixth position of the 3-globin chain. As a result, red blood cells spontaneously sickle in the peripheral blood if the amount of sickle hemoglobin is greater
than 60%. •
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3. Nonsense mutation: altered DNA codes for a stop codon that causes premature termination of protein synthesis.
In p-thalassemia major, a nonsense mutation pro- duces a stop codon that causes premature termina- tion of DNA transcription of the P-globin chain.
Consequently, there is a marked decrease in the synthesis of hemoglobin A (a2(32), resulting in a microcytic anemia.
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Chapter 5 Genetic and Developmental Disorders 45
A
7 II A 0
Normal Affected Heterozygous Normal Affected Heterozygous male male male female female female
Figure 5-1 Pedigree of an autosomal recessive disorder Both parents must have the mutant gene to transmit the disorder to their children On average, 25% of the children of heterozygous parents are normal, 50% are asymptomatic heterozygous carriers, and 25%
have the disorder
C. Frameshift mutation
1. Insertion or deletion of one or more nucleotides shifts the reading frame of the DNA strand.
2. Example: in Tay-Sachs disease, a four-base insertion results in the synthesis of a defective lysosomal enzyme (hexosaminidase).
D. Trinucleotide repeat disorders
1. Errors in DNA replication cause amplification of a se- quence of three nucleotides (e.g., CAG), which disrupts gene function.
2. Anticipation is the increasing severity of clinical disease in each successive generation.
a. Anticipation is caused by the addition of more tri- nucleotide sequences during gametogenesis.
b. Female carriers may be symptomatic if they have more paternally (than maternally) derived X chromo- somes with trinucleotide repeats.
3. Examples: fragile X syndrome, Huntington's disease, Friedreich's ataxia, myotonic dystrophy
II. Mendelian Disorders
• Usually single-gene mutations A. Autosomal recessive disorders
1. Inheritance pattern (Figure 5-1)
a. Individuals must be homozygous for the mutant recessive gene (aa) to express the disorder; they are symptomatic early in life.
b. Heterozygous individuals (Aa) are asymptomatic carriers; the dominant gene (A) overrides the mutant recessive gene (a).
c. Both parents must be heterozygous to transmit the disorder.
Most common type of mendelian dis- order: autosomal recessive
46 Pathology
TABLE 5-1 Protein Defects Associated With Some Mendelian Disorders Protein Type Specific Protein Disorder Inheritance Pattern Enzyme
Structural
Cl esterase inhibitor deficiency
Glucose-6-phosphate dehydrogenase Sickle hemoglobin Spectrin
Dystrophin
Hereditary angio- edema
Glucose-6-phosphate dehydrogenase deficiency Sickle cell disease Congenital sphero-
cytosis
Duchenne's muscular dystrophy
Cystic fibrosis
Familial hypercholes- terolemia
Neurofibromatosis Hemophilia A
Autosomal dominant X-linked recessive
Autosomal recessive Autosomal dominant X-linked recessive Autosomal recessive
Autosomal dominant Autosomal dominant X-linked recessive Transport Cystic fibrosis trans-
membrane regu- lator
Receptor Low-density lipopro- tein receptor Growth Neurofibromin
regulating
Hemostasis Factor VIII
Example: Aa x Aa ---> AA, Aa, Aa, as (25% without disorder; 50% asymptomatic carriers; 25% with disorder)
Cystic fibrosis (CF) is an autosomal recessive disease with a carrier rate of 1/25. To calculate the prevalence of CF in the population, the number of couples at risk of having a child with CF (1/25 x 1/25, or 1/625) is multiplied by the chance of having a child with CF (1/4).
Prevalence of CF = 1/625 x 1/4, or 1/2500 2. Protein defects (Table 5-1)
3. Inborn errors of metabolism (Table 5-2): metabolic dis- orders characterized by an enzyme deficiency
a. These disorders involve the metabolism of amino acids (e.g., phenylketonuria, PKU); carbohydrates (e.g., galactosemia); ammonia (arginase deficiency);
or organic acids (e.g., pyruvate dehydrogenase deficiency).
(1) Substrate and intermediates proximal to the enzyme block increase.
(2) Intermediates and the end-product distal to the enzyme block decrease.
Most autosomal re- cessive disorders involve enzyme deficiencies.
Chapter 5 Genetic and Developmental Disorders 47 TABLE 5-2 Some Inborn Errors of Metabolism
Error Deficient Enzyme
Accumulated
Substrate(s) Comments
Alkaptonuria Homogentisate oxidase Homogentisate Black urine and cartilage, degen- erative arthritis
Galactosemia GALT Galactose 1-phosphate Mental retardation, cirrhosis, hypoglycemia
Avoid dairy products Hereditary fructose
intolerance
Aldolase B Fructose 1-phosphate Cirrhosis, hypoglycemia, renal disease
Avoid fructose and sucrose Homocystinuria Cystathionine synthase Homocysteine and
methionine
Mental retardation, vessel thrombosis
McArdle's disease Muscle phosphorylase Glycogen Glycogenosis, muscle fatigue; no increase in lactic acid with exercise
Maple syrup urine disease
Branched chain a-ketoacid
Leucine, valine, isoleu- cine, and their
Mental retardation, seizures, feeding problems, sweet-
dehydrogenase ketoacids smelling urine
Phenylketonuria (PKUI
Phenylalanine hydroxylase
Phenylalanine Mental retardation, microcephaly, decreased tyrosine
Restrict phenylalanine; avoid arti- ficial sweeteners containing phenylalanine
Pompe's disease a-1,4-Glucosidase (lyso- somal enzyme)
Glycogen Glycogenosis, cardiomegaly with early death
Von Gierke's disease Glucose-6-phosphatase (gluconeogenic enzyme)
Glucose 6-phosphate Glycogenosis, enlarged liver and kidneys, hypoglycemia (no response to glucagon) GALT, galactose-1-phosphate-uridyl transferase.
PKU is characterized by a deficiency of phenylalanine hydroxylase, causing an increase in the substrate phenylalanine and a decrease in the product tyrosine. In indi- viduals with PKU, phenylalanine is further metabolized into neurotoxic phenylke- tones and acids that produce mental retar- dation and urine with a musty odor.
Glycogenoses: glycogen storage diseases
(1) Associated with an increase in glycogen syn- thesis (e.g., von Gierke's disease) or inhibition of glycogenolysis (e.g., debranching enzyme deficiency)
(2) Associated with an increase in normal or struc- turally abnormal glycogen in different tissues;
organ dysfunction depends on the site of glycogen accumulation (e.g., muscle, kidneys, heart).
b.
48 Pathology
TABLE 5-3 Some Lysosomal Storage Disorders Accumulated
Disorder Deficient Enzyme Substrate Clinical Findings Gaucher's disease Glucocerebrosidase Glucocerebroside Hepatosplenomegaly;
(adult type) fibrillar appearing
macrophages in liver, spleen, and bone marrow
Hurler's syndrome a-L-Iduronidase
Niemann-Pick Sphingomyelinase disease
Tay-Sachs disease Hexosaminidase
Dermatan and heparan sulfate
Sphingomyelin
GM 2 ganglioside
Mental retardation, coarse facial features, corneal clouding, coronary artery disease
X-linked recessive form (Hunter's syndrome) is milder
Mental retardation, hepatosplenomegaly, foamy macrophages Mental retardation,
muscle weakness, cherry-red macula, blindness
(3) Fasting hypoglycemia may result from inter- ference with gluconeogenesis (e.g., glucose 6-phosphatase deficiency) or liver glycogenoly- sis (e.g., liver phosphorylase deficiency).
c. Lysosomal storage diseases (Table 5-3)
(1) Enzyme deficiencies lead to accumulation of undigested substrates (e.g., glycosaminoglycans, sphingolipids) in lysosomes.
(2) Metabolites accumulate where the substrate is most active (e.g., sphingomyelin in brain; glu- cocerebrosides in macrophages in liver, bone marrow, and spleen).
4. Other autosomal recessive disorders: cc,-antitrypsin de- ficiency, 21-hydroxylase deficiency, Wilson's disease B. Autosomal dominant disorders
1. Inheritance pattern
a. One dominant mutant gene (A) is required to express the disorder.
(1) Heterozygotes (Aa) express the disorder.
(2) Homozygotes (AA) are often spontaneously aborted.
(3) Example: Aa x aa —> Aa, Aa, aa, aa (50% with disorder; 50% without disorder)
b. Some disorders arise by new mutations involving either an egg or a sperm.
2. Protein defects (see Table 5-1); enzyme deficiencies are relatively uncommon.
Most common autosomal reces- sive disorder:
hemochromatosis
Chapter 5 Genetic and Developmental Disorders 49 A
4
n b 6 a
B
0 6 q 0 0
a
Normal Affected Normal Affected
ti male male female female ,
Figure 5-2 Pedigrees showing complete and reduced penetrance in an autosomal dominant disorder. Complete penetrance (A) means that all individuals with the mutant gene express the disorder. Reduced penetrance (8) means that an individual has the mutant gene but does not express the disorder (arrow) The unaffected father has transmitted the disorder to his son