Chapter 5: Genetic & Congenital Disorders

Question 1

Congenital Defects (Birth Defects)

Answer 1

abnormalities of body structure, function, or metabolism that are present at birth
leading cause of infant death

Question 2

Gene mutation

Answer 2

a biochemical event that produces a new allele for a particular gene
a single mutant gene may be expressed in many different areas of the body (i.e. Marfan syndrome)

Question 3

Single Gene Disorders

Answer 3

defect of a mutant allele at a single gene locus

follow a Mendelian pattern of inheritance

Question 4

Mendelian Patterns of Inheritance

Answer 4

depend on:
whether phenotype is dominant or recessive
whether gene is an autosomal or sex chromosome

Question 5

Types of Single Gene Disorders

Answer 5

Autosomal Dominant
Autosomal Recessive
X-Linked Disorders

Question 6

Autosomal Dominant Disorders

Answer 6

single mutant allele from affected parent = 50% change of passing gene to offspring regardless of sex
Examples:
Marfan Syndrome
Neurofibromatosis 1 and 2 (NF-1 and NF-2)
Huntington chorea

Question 7

Penetrance

Answer 7

chance that a person who inherited the defective gene will express it (a percentage)

Question 8

Variable Expressivity

Answer 8

extent of variation in phenotype (mild to severe)

Question 9

Co-dominant Genes

Answer 9

alleles are different but both genes are expressed (i.e. AB blood type)

Question 10

MARFAN SYNDROME

Autosomal Dominant Disorder

Answer 10

inherited disorder of the connective tissue, mutations on chromosome 15 that codes for Fibrillin I (component of connective tissue)
average lifespan 30-40 years

Question 11

Clinical Manifestations of MARFAN SYNDROME

Answer 11

tall, thin, long extremities with joint hypermobility
arachnodactyly
cataracts, lens dislocation, retinal detachments, myopia
valvular abnormalities (MVP, aortic regurg)
spontaneous pneumothorax

Question 12

Arachnodactyly

Answer 12

“spider-like” appearance of fingers and toes; seen in someone with Marfan Syndrome

Question 13

NEUROFIBROMATOSIS 1 (von Recklinghausen disease)
(Autosomal Dominant Disorder)

Answer 13

most common autosomal dominant disorder caused by a genetic defect in the tumor suppressor gene (NF-1) located on chromosome 17
100% penetrance - variable expressivity

Question 14

Clinical Manifestations of NF-1

Answer 14

Neurofibromas
Cafe-au-lait spots
Benign pigmented nodules on iris (Lisch nodules)
learning and speech disabilities - ADD - seizures

Question 15

Neurofibromas

NF-1

Answer 15

benign peripheral tumors of the nerves
Cutaneous: soft, pedunculated lesions projecting from the skin
Subcutaneous: firm, round, painful
vary in number

Question 16

Lisch nodules

NF-1

Answer 16

benign pigmented nodules on iris

present after age 6 years

Question 17

NEUROFIBROMATOSIS 2 (Acoustic NF)
(Autosomal Dominant Disorder)

Answer 17

characterized by tumors of the acoustic nerve (CN VIII) - gene is located on chromosome 22
asymptomatic first 15 years of life

Question 18

Clinical Symptoms of NF-2

Answer 18

headaches, hearing loss, tinnitus
worsens with pregnancy and oral contraceptives
severe disorientation may occur during diving or swimming underwater (drowning may result)

Question 19

HUNTINGTON CHOREA

Autosomal Dominant Disorder

Answer 19

neurodegenerative disorder where basal ganglia are destroyed caused by mutation on chromosome 4
age-dependent penetrance (between 30 and 50 years)
100% penetrance

Question 20

Clinical Manifestations of HUNTINGTON CHOREA

Answer 20

cognitive decline
mood swings
involuntary movements
hallucinations
speech difficulties
behavioral and personality changes

Question 21

Autosomal Recessive Disorders

Answer 21

manifested only when BOTH genes are affected (homozygous)
occurence risks: 25% affected, 50% carriers, 25% unaffected
“loss of function” mutation - includes most inborn errors of metabolism
Examples: PKU, Tay-Sachs disease, sickle cell disease, cystic fibrosis

Question 22

PHENYLKETONURIA (PKU)

Autosomal Recessive Disorder

Answer 22

inborn error of metabolism of the amino acid phenylalanine - lack activity of phenylalanine hydroxylase
results in cerebral damage and intellectual disability
irreversible damage usually complete by age 2 or 3 years
more common in Caucasians and Native Americans

Question 23

Phenylalanine hydroxylase

Answer 23

liver enzyme that converts phenylalanine to tyrosine

lacking in PKU, causing phenylalanine accumulation in blood and urine leading to cerebral damage

Question 24

Clinical Manifestations of PKU

Answer 24

symptoms are gradual and difficult to assess - screen ALL infants
mental retardation
personality and behavior disturbance (antisocial or uncontrolled temper)
seizures - hyperactivity, irritability, repetitive motions
microcephaly - slowed growth
eczematous skin lesions or rough skin
musty odor from skin and urine

Question 25

TAY-SACHS DISEASE | Autosomal Recessive Disorder

Answer 25

results from a congenital enzyme deficiency (hexosaminidase A) causing lipids to accumulate in organs and demyelinate and destroy CNS cells progressive mental and motor deterioration fatal before age 5 more common in those of Jewish ancestry

Question 26

Hexosaminidase A

Answer 26

enzyme necessary for metabolism of GM2 (glycolipids found in tissues of the CNS) deficiency in Tay-Sachs disease causes GM2 to accumulate in the lysosomes

Question 27

Clinical Manifestations of TAY-SACHS DISEASE | 6 to 12 months

Answer 27

``` appearance of symptoms - progressive weakness of all muscles unable to sit up or lift head trouble turning over cannot grasp objects vision loss progressing to blindness ```

Question 28

Clinical Manifestations of TAY-SACHS DISEASE | by age 18 months

Answer 28

Seizures generalized paralysis and spasticity decerebrate rigidity and complete vegetative state follows

Question 29

Clinical Manifestations of TAY-SACHS DISEASE | age 2+ years

Answer 29

vegetative state recurrent bronchopneumonia treatment is supportive usually fatal by age 5 years

Question 30

SICKLE CELL DISEASE | Autosomal Recessive Disorder

Answer 30

disease of the beta subunit of hemoglobin (HbS) - mutation of gene on chromosome 11 hemoglobin does not form correctly and RBCs become rigid and die early more common in African Americans (1 in 365)

Question 31

Clinical Manifestations of SICKLE CELL DISEASE

Answer 31

"sickled" RBCs can cause obstruction and reduced perfusion/ischemia impaired oxygenation pain

Question 32

X-Linked Dominant Disorders

Answer 32

lethal in embryonic males or the homozygous mutant females heterozygous affected females transmit disorder to 50% of offspring (regardless of sex) affected males will have 100% affected daughters or 100% normal sons Example: Fragile X Syndrome

Question 33

FRAGILE X SYNDROME | X-Linked Dominant Disorder

Answer 33

most common form of inherited intellectual disability mapped to the long arm (q) of the X chromosome (Xq27) designated as the Fragile X Mental Retardation 1 (FMR-I) site affects males > females

Question 34

Characteristics of FRAGILE X SYNDROME

Answer 34

``` intellectually disabled long face with large mandible large ears/high arched palate hyperextensible joints mitral valve prolapse large testes ```

Question 35

X-Linked Recessive Disorders

Answer 35

Most X-linked disorders are recessive Each son of affected mother has 50% chance of being affected Daughters have 50% chance of being carriers 100% of daughters of affected males will be carriers Example: Hemophilia A

Question 36

HEMOPHILIA A | X-Linked Recessive Disorder

Answer 36

bleeding disorder inherited from mother due to factor VIII deficiency - mutation on F8 gene on X long arm (q) treatment with replacement therapy affected males will transmit the gene to all of their daughters and none to their sons

Question 37

Multifactorial Disorders

Answer 37

caused by multiple genetic mutations and environmental factors and teratogens can be congenital or expressed later in life

Question 38

Multifactorial Congenital Disorders

Answer 38

Cleft lip and cleft palate Clubfoot/congenital dislocation of the hip Pyloric stenosis Congenital heart disease

Question 39

Multifactorial Disorders Occurring Later in Life

Answer 39

CAD HTN DM Cancer

Question 40

CLEFT LIP and CLEFT PALATE | Multifactorial Congenital Disorders

Answer 40

``` cleft lip (with or without) cleft palate it one of the most common birth defects originates around 35th day of gestation; results in distorted facial appearance nutritional intake speech are affected commonly have hearing problems from middle ear damage/infections ```

Question 41

Treatment of CLEFT LIP/CLEFT PALATE

Answer 41

special bottle/nipples for feeding (palate) surgery: lip by 3 months of age, palate before 1 year speech therapy

Question 42

Chromosomal Disorders

Answer 42

described according to the description of the karyotype result in large proportions of early miscarriages, congenital malformations, and intellectual disability Examples: Down Syndrome (Trisomy 21), Turner's Syndrome (monosomy, XO), Klinefelter's Syndrome (Trisomy, XXY)

Question 43

Trisomy 13, 18, and 21

Answer 43

the only chromosomal trisomies that can result in term pregnancy trisomy on any other chromosome result in death or spontaneous abortion

Question 44

``` DOWN SYNDROME (Trisomy 21) (Chromosomal Disorder) ```

Answer 44

chromosomal aberration in which chromosome 21 has 3 copies vs. 2; most commonly caused by nondisjunction most common chromosomal disorder that produces intellectual disability, characteristic facial features, and distinctive physical abnormalities extra chromosome originates in mother in 90% of cases (risk increases with maternal age)

Question 45

Physical Signs of Down Syndrome | apparent at birth

Answer 45

small, square head with flattened face and small nose small open mouth and protruding tongue low-set ears, upward slanted eyes with epicanthal folds short fingers w/ transverse crease on palm Brushfield's spots and cataracts

Question 46

TURNER'S SYNDROME (45, XO) | Sex Chromosome Disorders

Answer 46

most frequently occuring genetic disorder in females | absence of all or part of the X chromosome (less feminine)

Question 47

Characteristics of TURNER'S SYNDROME (45, XO)

Answer 47

short stature and underdeveloped breasts no secondary sex characteristics treated with growth hormone and estrogen therapy

Question 48

KLINEFELTER'S SYNDROME (47, XXY) | Sex Chromosome Disorder

Answer 48

presence of >1 X chromosome in excess of the normal male XY complement results from nondisjunction extra X (extra feminine)

Question 49

Characteristics of KLINEFELTER'S SYNDROME (47, XXY)

Answer 49

enlarged breasts small testes and inability to produce sperm sparse body hair tall stature feminine distribution of SQ fat treatment through PT/SLP; androgen therapy

Question 50

Period of vulnerability

Answer 50

day 15 to day 60 after conception embryo's development is most easily disturbed during the period when differentiation and development of the organs (organogenesis) is taking place

Question 51

Teratogens

Answer 51

a substance, organism, physical agent, or deficiency state present during gestation capable of causing adverse effects

Question 52

Fetal Alcohol Syndrome

Answer 52

group of physical, behavioral, and cognitive abnormalities caused by harmful effects of alcohol throughout pregnancy effects vary widely commonly see growth retardation, neurologic abnormalities (behavioral, developmental) small palpebral fissures and smooth philtrum (upper lip)

Question 53

Infectious Teratogens: TORCH

Answer 53

``` T = Toxoplasmosis O = Others (syphilis, parvovirus B19, varicella) R = Rubella C = Cytomegalovirus H = Herpes simplex 2, HIV, Hep B & C ```

Question 54

Folic Acid Deficiency

Answer 54

implicated in the development of neural tube defects | recommended all women of childbearing age receive 400mcg (0.4 mg) of folic acid daily