Genetic and Developmental Disorders

Chapter 5 Genetic and Developmental Disorders

I. Mutations

• Mutations are a permanent change in DNA.

A. Point mutations

• Mutation involving a change in a single nucleotide base within a gene

1. Silent mutation (Fig. 5-1A)

• Altered DNA codes for the same amino acid without changing the phenotypic effect

5-1: Point mutations: silent mutation (A), missense mutation (B), nonsense mutation (C). See text for discussion.

(From Pelley JW, Goljan E: Rapid Review Biochemistry, 2nd ed. St. Louis, Mosby Elsevier, 2007, p 190, Fig. 10-11.)

Missense mutation: sickle cell disease/trait

2. Missense mutation (Fig. 5-1B)

• 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 β-globin chain. As a result, RBCs spontaneously sickle in the peripheral blood if the amount of sickle hemoglobin is greater than 60%.

3. Nonsense mutation (Fig. 5-1C)

• Altered DNA codes for a stop codon that causes premature termination of protein synthesis

In β-thalassemia major, a nonsense mutation produces a stop codon that causes premature termination of DNA transcription of the β-globin chain. Consequently, there is no synthesis of hemoglobin A (α₂β₂), resulting in a microcytic anemia.

β-Thalassemia major: nonsense mutation with stop codon

B. Frameshift mutation

1. Insertion or deletion of one or more nucleotides shifts the reading frame of the DNA strand

Frameshift mutation: Tay-Sachs disease

2. Example—in Tay-Sachs disease, a four-base insertion results in an altered DNA code leading to formation of a stop codon leading to decreased synthesis of hexosaminidase (Fig. 5-2).

C. Trinucleotide repeat disorders

1. Errors in DNA replication

• Cause amplification of a sequence of three nucleotides (e.g., CAG), which disrupts gene function

5-2: Frameshift mutation. See text for discussion.

Anticipation: additional trinucleotide repeats increase disease severity in future generations

2. Associated with anticipation

a. Increasing severity of clinical disease in each successive generation

b. Caused by the addition of more trinucleotide sequences during gametogenesis

c. Female carriers may be symptomatic

• Occurs if they have more paternally (than maternally) derived X chromosomes with trinucleotide repeats

d. Examples—fragile X syndrome, Huntington’s disease, Friedreich’s ataxia, myotonic dystrophy

II. Mendelian Disorders

• Usually single-gene mutations

Most common type of mendelian disorder: autosomal recessive

A. Autosomal recessive (AR) disorders

1. Inheritance pattern (Fig. 5-3)

a. Individuals must be homozygous for the mutant recessive gene (aa) to express the disorder.

b. Homozygotes are symptomatic early in life.

c. Heterozygous individuals (Aa) are asymptomatic carriers.

• The dominant gene (A) overrides the mutant recessive gene (a).

d. Both parents must be heterozygous to transmit the disorder.

• Example—Aa × Aa → AA, Aa, Aa, aa (25% without disorder; 50% asymptomatic carriers; 25% with disorder)

5-3: 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.

AR inheritance: both parents must have mutant gene.

Cystic fibrosis (CF) is an AR disorder 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 × 1/25, or 1/625) is multiplied by the chance of having a child with CF (1/4). Prevalence of CF = 1/625 × 1/4, or 1/2500. Note how it is possible to calculate the carrier rate if given the prevalence of the disease by dividing 1/2500 by 4 to get the number of couples at risk and then taking the square root of 1/625 to get the carrier rate of 1/25.

2. AR protein defects (Table 5-1)

3. Inborn errors of metabolism (Figs. 5-4 to 5-7 and Table 5-2)

a. Most metabolic disorders are due to an enzyme deficiency.

Table 5-1 Protein Defects Associated With Selected Mendelian Disorders

5-5: Galactosemia: See Table 5-2 for information. GALT, galactose-1-phosphate uridyltransferase; P, phosphate; UDP, uridine diphosphate.

(From Pelley JW, Goljan E: Rapid Review Biochemistry, 2nd ed. St. Louis, Mosby Elsevier, 2007, p 104, Fig. 6-10.)

5-6: Hereditary fructose intolerance. See Table 5-2 for information. DHAP, dihydroxyacetone phosphate; P, phosphate.

(From Pelley JW, Goljan E: Rapid Review Biochemistry, 2nd ed. St. Louis, Mosby Elsevier, 2007, p 104, Fig. 6-11.)

5-7: Homocystinuria. See text for discussion. CH₃, methyl group.

(From Pelley JW, Goljan E: Rapid Review Biochemistry, 2nd ed. St. Louis, Mosby Elsevier, 2007, p 143, Fig. 8-5.)

Table 5-2 Selected Inborn Errors Of Metabolism

Most AR disorders involve enzyme deficiencies.

b. Substrate and intermediates proximal to the enzyme block increase.

c. Intermediates and the end-product distal to the enzyme block decrease.

Phenylketonuria (PKU, see Fig. 5-4) is characterized by a deficiency of phenylalanine hydroxylase, causing an increase in the substrate phenylalanine and a decrease in the product tyrosine. In individuals with PKU, phenylalanine is further metabolized into neurotoxic phenylketones and acids that produce mental retardation and urine with a musty odor.

5-4: Alkaptonuria. In alkaptonuria, there is a deficiency of homogentisic oxidase with proximal accumulation of homogentisic acid, which turns black upon oxidation.

(From Pelley JW, Goljan E: Rapid Review Biochemistry, 2nd ed. St. Louis, Mosby Elsevier, 2007, p 139, Fig. 8-4.)

PKU: ↑ phenylalanine, ↓ tyrosine

d. Glycogenoses

(1) Pathogenesis

Von Gierke’s disease: glucose-6-phosphatase deficiency (gluconeogenic enzyme); fasting hypoglycemia, hepatorenomegaly

(a) Increase in glycogen synthesis (e.g., von Gierke’s disease)

(b) Inhibition of glycogenolysis (e.g., debranching enzyme deficiency)

(c) Increase in normal or structurally abnormal glycogen

(2) Clinical findings

(a) Organ dysfunction (e.g., restrictive heart disease, Pompe’s disease).

(b) Fasting hypoglycemia

• Decrease in gluconeogenesis (e.g., glucose-6-phosphatase deficiency, von Gierke’s disease) or liver glycogenolysis (e.g., liver phosphorylase deficiency)

e. Lysosomal storage diseases (Table 5-3 and Figs. 5-8 and 5-9)

• Enzyme deficiencies lead to accumulation of undigested substrates (e.g., glycosaminoglycans, sphingolipids) in lysosomes

Table 5-3 Selected Lysosomal Storage Disorders

5-8: Sphingolipid degeneration. See Table 5-3 for discussion of selected sphingolipidoses.

(From Pelley JW, Goljan E: Rapid Review Biochemistry, 2nd ed. St. Louis, Mosby Elsevier, 2007, p 104, Fig. 6-11.)

5-9: Hurler syndrome. Note the coarse facial features and short neck.

(From Seidel HM, Ball JW, Danis JE, Benedict GW: Mosby’s Guide to Physical Examination, 6th ed. St. Louis, Mosby Elsevier, 2006, p 273, Fig. 10-26.)

Most common AR disorder: hemochromatosis

4. Other AR disorders

• Hematochromatosis, 21-hydroxylase deficiency, Wilson’s disease, thalassemia

B. Autosomal dominant (AD) disorders

1. Inheritance pattern

a. One dominant mutant gene (A) is required to express the disorder.

AD inheritance: heterozygotes with dominant mutant gene express disease

(1) Heterozygotes (Aa) express the disorder.

(2) Homozygotes (AA) are often spontaneously aborted.

(3) Example—Aa × 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. AD protein defects (see Table 5-1)

• Enzyme deficiencies are relatively uncommon.

3. Characteristics

a. Delayed manifestations of disease

(1) Symptoms and signs may not occur early in life.

(2) Example—in adult polycystic kidney disease, cysts are not present at birth.

(1) Complete penetrance (Fig. 5-10A)

• All individuals with the mutant gene express the disorder (e.g., familial polyposis).

(2) Reduced penetrance (Fig. 5-10B)

5-10: 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 (B) 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.

Reduced penetrance: individual with mutant gene does not express the disease; transmits to children

(a) Individuals with the mutant gene are phenotypically normal.

(b) They transmit the disorder to their offspring (e.g., Marfan syndrome; see Fig. 9-6A).

c. Variable expressivity

• All individuals with the mutant gene express the disorder but at different levels of severity.

4. Other AD disorders

Most common AD disorder: von Willebrand disease

• Huntington’s disease, osteogenesis imperfecta, achondroplasia, tuberous sclerosis

C. X-linked recessive (XR) disorders

1. Inheritance pattern (Fig. 5-11)

a. Males must have the mutant recessive gene on the X chromosome to express the disorder.

b. Affected males (XY) transmit the mutant gene to all of their daughters.

(1) Males are homozygous for the mutant gene.

(2) Example—XY × XX → XX, XX, XY, XY

(3) Daughters (XX) are usually asymptomatic carriers.

c. Asymptomatic female carriers (X mutant gene) transmit the disorder to 50% of their male offspring.

• Example—XX × XY → XX, XX, XY, XY

5-11: Pedigree of an X-linked recessive disorder. The affected male transmits the mutant gene on the X chromosome to both of his daughters and none of his sons. Both daughters are asymptomatic heterozygous carriers of the mutant gene. The daughter with four children has transmitted the mutant gene to 50% of her sons.

XR inheritance: asymptomatic female carrier transmits mutant gene to 50% of sons

d. In rare cases, female carriers can be symptomatic.

(1) Maternally derived X chromosomes (without the mutant gene) are preferentially inactivated.

• Only paternally derived X chromosomes with the mutant gene remain.

(2) Offspring of a symptomatic male and asymptomatic female carrier

• Example—XX × XY → XX, XX, XY, XY

e. Some XR disorders may arise as new mutations.

2. XR protein defects (see Table 5-1)

• Enzymes are the most common type of protein affected in XR disorders.

3. Fragile X syndrome

a. Trinucleotide repeat disorder

b. Clinical findings

(1) Mental retardation

(a) Most common mendelian disorder that causes mental retardation

Most common X-linked disorder: fragile X syndrome

(b) 50% of female carriers may develop mental retardation.

(2) Phenotypic changes

• Long face, large mandible, everted ears

(3) Macro-orchidism (enlarged testes) at puberty

(a) DNA analysis to identify trinucleotide repeats (best test)

(b) Fragile X chromosome study

4. Lesch-Nyhan syndrome

a. Deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT)

• Normally involved in salvaging the purines hypoxanthine and guanine

b. Clinical findings

• Mental retardation, hyperuricemia, self-mutilation

5. Other XR disorders

• Testicular feminization, chronic granulomatous disease, Bruton’s agammaglobulinemia

D. X-linked dominant (XD) disorders

1. Inheritance pattern

• Same as XR except the dominant mutant gene causes disease in males and females (Fig. 5-12)

5-12: Pedigree of an X-linked dominant disorder. In these rare disorders, female carriers and males with the mutant dominant gene express the disorder. The distribution is similar to that of X-linked recessive disorders, except that carrier females are symptomatic.

XD inheritance: female carriers are symptomatic

2. Vitamin D–resistant rickets

a. Defect in renal and gastrointestinal reabsorption of phosphate

b. Causes defective bone mineralization (i.e., osteomalacia)

3. Alport’s syndrome

• Hereditary glomerulonephritis with nerve deafness

III. Chromosomal Disorders

A. General considerations

1. Most human cells are diploid (46 chromosomes).

a. Autosomes: 22 pairs

b. Sex chromosomes (XX in females and XY in males): 1 pair

2. Gametes, the products of meiosis, are haploid (23 chromosomes).

Barr body: inactivated X chromosome

3. Lyon hypothesis

a. In females, one of the two X chromosomes is randomly inactivated.

• Inactivation occurs in the embryonic period of development.

b. The inactivated X chromosome is called a Barr body.

Barr body: attached to nuclear membrane

(1) The Barr body is attached to the nuclear membrane of cells.

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Tags: Rapid Review Pathology Revised Reprint

Jun 25, 2017 | Posted by admin in PATHOLOGY & LABORATORY MEDICINE | Comments Off

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