Lecture 17: Genetic and Developmental Disorders Flashcards
Study of Heridity
- transmitted through genes in gametes (eggs or ova and sperm)
- genetic make-up is determined at fertilization
- in nucleus of each gamete are structures called chromosomes
- each chromosome contains a strand of DNA (made up of genes)
Counting Chromosomes
-ovum and sperm each contain 23 chromosomes and, when united, they pair up
-the fertilized cell has 23 pairs or 46 chromosomes and undergoes cell division (mitosis): each of the 46 chromosomes produces an exact duplicate, cell then divides and each new cell receives one set of the 46 chromosomes…this repeats itself over and over, so, each cell in a person’s body contains 46 identical
chromosomes…except the ova and sperm
-each person receives one set of chromosomes and genes from each parent-so, there are 2 genes for each trait that person inherits and one gene may be more influential (dominant) than the other (recessive) in
developing a specific trait
-locus=location of a gene on a chromosome very specific and does not vary from person to person
-of the 23 pairs, 22 pairs are not involved in controlling a person’s gender called autosomes, 2 sex chromosomes of the 23rd pair determine gender
-gene mutations may be transmitted during reproduction and may cause serious or deadly disorders
Alleles
- variation of a gene and the trait it controls (brown, green or blue eye color) is called an allele
- when 2 different alleles are inherited=heterozygous
- when 2 identical alleles are inherited=homozygous
- if an allele is dominant, only 1 copy may be necessary for trait expression (may be expressed in both homozygous and heterozygous states)
- recessive allele is incapable of expression unless recessive alleles are carried by both chromosomes in a pair
Single-Gene Disorders: Autosomal Dominant
- disorders are inherited in clearly identifiable patterns
- male and female offspring affected equally
- one of the parents also usually affected
- if one parent is affected, the children have a 50% chance of being affected
- if both parents are affected, all of the children will be affected
Single-Gene Disorders: Autosomal Recessive
- male and female offspring affected equally
- if both parents unaffected, but heterozygous for the trait (carriers), each of the children has a 1 in 4 chance of being affected
- if both parents affected, all children affected
- one parent is affected and the other is not a carrier, all of the children will be unaffected, but will carry the altered gene
- one parent is affected and the other is a carrier, all of the children will have a 1 in 2 chance of being affected and a 1 in 2 chance of being a carrier
- certain autosomal recessive conditions are more common in specific ethnic groups (cystic fibrosis in white people and sickle cell anemia in black people)
Single-Gene Disorders: Sex-Linked Inheritance
- disorders caused by genes located on the sex chromosomes (usually refers to X-linked disorders
- males are more commonly affected by X-linked disorders, since they have only one X chromosome
- in comparison, females need two copies of the diseased gene to be affected
Single-Gene Disorders: Sex-Linked Inheritance- X-Linked Dominant
- person with the abnormal trait will typically have 1 affected parent
- father has an X-linked dominant disorder, all of his daughters and none of this sons will be affected (can only pass Y, no X
- mother has an X-linked dominant disorder, there is a 50% chance that each child will be affected
d. Evidence of the inherited trait most commonly appears in the family history - X-linked dominant disorders are commonly lethal in males (prenatal or neonatal deaths): family history may show miscarriages or predominance of female offspring
Single-Gene Disorders: Sex-Linked Inheritance-X-Linked Recessive
- most cases, affected people are males with unaffected parents
- all of the daughters of an affected male will be carriers
- sons of an affected male are unaffected (unaffected sons can’t transmit the disorder)
- unaffected male children of a female carrier don’t transmit the disorder
Chromosomal Disorders
- disorders caused by chromosomal aberrations
- nondisjunction: normally there is a separation of chromosomes during cell division, but if distribution is unequal between two cells it’s called nondisjunction
- monosomy: cell that’s missing a chromosome (Turner Syndrome)
- trisomy: a cell that contains an extra chromosome (Down Syndrome)
- incidence increases with parental age
- translocation: two different chromosomes break and rejoin in abnormal arrangement (abnormalities may present in 2nd generation)
Multifactorial Disorders
- disorders caused by both genetic and environmental factors
- ex: cleft lip, cleft palate, myelomeningocele
Cleft Lip and Cleft Palate
- malformations occur in ~1/800 births
- cleft lip with or without cleft palate is more common in males and cleft palate alone is more common in females
- multifactorial genetic disorder and originates in the 2nd month of gestation
- malformations fall into 4 categories: cleft lip, unilateral cleft lip and cleft palate, bilateral cleft lip and cleft palate, cleft palate
- malformations may range from a simple notch to a complete cleft, structural changes can permanently affect speech
- dx: may be detected prenatally using US
- tx: combo of speech therapy and sx
Cystic Fibrosis
- inherited autosomal recessive trait disorder of ion transport (Na+ and Cl-) affecting the hepatic, digestive, male reproductive, and respiratory systems
- incidence is highest in Whites of Northern Europe (1/3,300) and less common in black people, Native Americans, and asians people
- mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene located on chromosome 7
- patho: mutation results in a protein that doesn’t function properly (lacks phenylalanine…an essential amino acid)
- lack of an essential amino acid leads to dehydration and mucosal thickening
- salt accumulates in the cells lining the lungs and digestive tissues, making the surrounding mucus abnormally thick and sticky
- CM: abnormally high sodium and calcium concentrations in sweat; gastrointestinal: prevents essential pancreatic enzymes from reaching the duodenum, thus impairing digestion and absorption of nutrients; poor nutrition and weight loss as a result of malabsorption, inadequate oral intake, early satiety, and ↑’d utilization of calories; diabetes and pancreatitis may result; hepatic failure and cholecystitis
- pulmonary: chronic cough and purulent sputum production, unable to expectorate mucus because of increased viscosity, increased risk for infection, frequent bouts of pneumonia, dyspnea
- genitourinary: infertility is universal in me (azoospermia-no sperm in semen), thick mucus in cervical canal prevents conception (mucus plug)
- musculoskeletal: decreased bone mineral density and bone mineral content are common
- predisposes one to chronic bacterial airway infections leading to obstructive lung disease and progression can result in loss of pulmonary function
SIFTT for Cystic Fibrosis
- chest PT: several times a day but not before or immediately after meals
- nutrition: malnutrition and deterioration of lung function are closely interrelated and interdependent in child with CF
- exercise: supervised exercise programs enhance fitness, increases sputum clearance, delay onset of dyspnea, delay declines in pulmonary function
- athletes with CF: eat 1.5 times of protein and calories of an athlete who does not have CF in order to maintain weight, individuals who have portal HTN with significant enlargement of the spleen and liver should be advised against contact sports
Down Syndrome
-trisomy 21, characterized by muscle hypotonia, cognitive delay, abnormal facial features, heart defects, and other congenital disorders
-most common inherited chromosome disorder, 1/800-1000 live births
-incidence rises with maternal age: before maternal age 30 the incidence is 1 in 2000 births; 1 in 50 for
mothers aged 35-39, and 1 in 12-20 in mothers over 40; women over age 35 bear 20% of all children with Down syndrome
-produces 3 copies of chromosome 21 instead of the normal 2 because of faulty meiosis (cell division by which reproductive cells are formed) of the ovum or sometimes the sperm
-can also occur after fertilization leading to only a portion of cells being affected with a milder clinical picture
-incidence of nondisjunction ↑’s with maternal age with the extra chromosome originating from the mother more than 90% of the time: 5-10% of Down’s syndrome is correlated to paternal age
-overall reduction in brain weight
-CM: flattened nasal bridges, almond eye shape, short limbs, short broad hands/feet and mild to moderate hypotonia
-many other associated clinical manifestations may also be present: flat occiput, joint hyperextensibility, epicanthal folds, high arched palate; protruding, fissured tongue, CHD, simian line (transverse
palmar crease)
-variety of musculoskeletal or orthopaedic problems believed to be acquired secondary to soft tissue laxity and muscle hypotonia
-common findings include recurrent patellar dislocation, excessive foot pronation, scoliosis, slipped capital femoral epiphyses, late hip dislocation (after 2 years)
-atlantoaxial instability (AAI) of the c/spine (subluxation between C1 and C2) odontoid process can slide back into spinal column leading to death
-feeding difficulties and delayed acquisition of motor skills: these skills, however, improve with age, these children present with slower reaction times and slower postural reactions
-gait abnormalities
-secondary disorders develop after age 30 or 35
-obesity, DM, cardiovascular disease
-dx: triple screen (screen for alpha fetal protein AFP) allows detection of an estimated 60-70% of fetuses with down syndrome; prenatal diagnosis may be made during 2nd trimester
-prognosis: presence of congenital malformations, especially of heart, GI tract, can result in high mortality rates in affected population; mobility and eating skills are also predictors of early death
-SIFTT: because AAI is a problem, radiographs should be considered before any type of event that could result in a direct downward force on the cervical area (need to be sure odontoid is at risk of sliding backward in any act that involves movement)
Hemophilia
-x-linked recessive genetic disorder