Genetic Disorders Flashcards
what is genetic disease?
the price humankind pays for the tendency of genes to change
congenital disorder
present/manifest at birth
is congenital disorder genetic?
may be genetic or non-genetic (trauma, infection)
when does a genetic disorder manifest?
the moment the egg is fertilized (picked the wrong parents ;))
when can genetic disorders manifest?
may or may not manifest at birth
examples of genetic diseases that result from post-fertilization somatic mutations
can’t be inherited
McCune-Albright syndrome (rare)
Neoplasms (“acquired” genetic disease, common)
hereditary disease
“genetic disease” except those you can’t trust
familial disease
“diseases that cluster within families”
examples of familial disease
genetic diseases polygenic disease nutritional stuff environmental stuff (lead poisoning) behavioral stuff (child abuse, obesity)
vertical transmission
parent to child (genetic disease)
horizontal transmission
within cells of single person (tumors)
what are chromosomal disorders?
cytogenic disorders
what causes a chromosomal disorder?
wrong number of copies of a chromosome or alterations of one or more chromosomes
what percentage of newborns have a chromosomal disorder?
1%
what percentage of chromosomal disorders result in spontaneous abortions?
50%
how are chromosomal disorders described?
as total chromosomes, sex chromosomes, abnormality
i.e. 47 XY +21; 47 XXY
haploid
number of chromosomes in sex cell
diploid
exactly twice haploid (i.e. somatic cells)
euploid
exact multiples of haploid (2x, 4x, etc.)
aneuploid
any other number (45, 47, etc.)
what does aneuploid usually result from?
nondisjunction
what is nondisjunction?
failure of duplicated chromosomes to separate in meiosis 1
OR
failure of chromatids to separate in meiosis II
what does nondisjunction result in?
gametes carrying 2 copies of a chromosome or none
what can also causes nondisjunction?
anaphase lag
sister chromatids do not properly separate from each other
what can DNA breaks result from?
radiation
chemicals
viral infections
chromosomal disorders mechanisms of action
deletion/substitution
inversion
translocation
deletion/substitution
terminal or interstitial piece of chromosome deleted/duplicated
inversion
broken chromosome segment replaced “backwards”
translocation
2 chromosomal breaks with exchange of segments
balanced translocation
even exchange of genetic material, no extra or missing DNA
unbalanced translocation
unequal exchange, extra or missing genes
robertsonian translocation
one large and one extremely small (usually lost) chromosome result
what type of autosomal disorders can cause abortion?
autosomal monosomy or no X chromosome causes early abortion
what do trisomies normally produce?
infants who will usually die during the first few months of life
exception trisomy that is viable
trisomy 21
what can cause autosomal disorders to recur?
parent carries a balanced translocation
advanced parental age
what is trisomy 21 also known as?
down syndrome
how do you express down syndrome?
47XX (or XY) + 21
how does trisomy 21 commonly occur?
maternal nondisjunction of 21
what causes maternal nondisjunction of 21?
advanced maternal age
what is the most common aneuploidy to reach birth?
trisomy 21
what markers indicate trisomy 21?
a-fetoprotein
pregnancy-associated protein A
human chorionic gonadotropin
clinical features of trisomy 21
lack of muscle tone at birth ("floppy")
flat face, open, big tongue
slanted eyes and epicanthic folds ("mongolism")
low-set, funny-looking ears
single palmar crease ("simian")
heart defects (40%)
brushfield's spots on iristrisomy 21 future problems
mental retardation hypothyroidism conductive hearing loss various leukemias Alzheimer's disease
when do you recognize trisomy 21?
usually recognizable at birth
lifespan trisomy 21
most die before 30s
what is trisomy 18 known as?
edward’s syndrome
how to express edward’s syndrome
47XX (or XY) + 18
prevalence edward’s syndrome
second most common trisomy to reach term
what causes edward’s syndrome
maternal nondisjunction during meiosis II
trisomy 18 prognosis
most stillborn or die within first month
trisomy 18 clinical features
growth retardation prominent occiput micrognathia overlapping fingers rocker-bottom feet choroid plexus cysts (prenatal US)
sex chromosome disorders-y chromsome
necessary and sufficient for phenotypic maleness, assuming the body can also make and use testosterone
sex chromosomal disorders x chromosome characteristics
the more X chromosomes, the more abnormal the person
sex chromosomal disoders
diagnosis usually missed at birth
what are sex chromosomal disorders better tolerated than?
autosomal aneuploidy
example of klinefelter syndrome
47XXY, 48XXXY, etc.
what causes klinefelter syndrome
maternal (or paternal) (or both) nondisjunction
what slightly increases risk of klinefelter’s
advanced maternal age
when is klinefelter syndrome detected?
usually detected at puberty
symptoms of klinefelter’s
small testes and penis long limbs diminished body hair, rarely go bald "female" hips gynecomastia
hormone levels klinefelter’s
low plasma testosterone, high estrogen
reproductive ability klinefelter’s
almost all are sterile
infertility
IQ klinefelter’s
slightly lower IQ’s than XY dudes
what are people with klinefelter’s prone to?
osteoporosis
do people with klinefelter’s have a propensity for violent crimes?
no!
what can help klinefelter’s?
androgen replacement
what is turner syndrome?
monosomy of Xp, 45X0
percentage of spontaneous abortions turner syndrome
99% spontaneously abort
turner syndrome prevalence
most frequent genetic disorder in females (1 in 2000)
when is turner syndrome detected and why?
usually detected at puberty, lack feminization
symptoms of turner syndrome
nonfunctional ovaries primary amenorrhea lack of breast development no pubic hair "menopause occurs before menarche"
turner physical features
short stature multiple pigmented nevi webbed neck shield-shaped chest valgus deformity of elbows (turned out) coarctation of aorta infertile
what can help turner’s syndrome?
hGH and estrogen therapy help
how is genetic (chromosomal) sex determined?
presence/absence of Y chromosome
what actually determines intersex states?
SRY genes (sex determining region on Y)
what happens when dudes have SRY on X?
46XX
what is gonadal sex determined by?
histology of gonads
what indicates gonadal sex?
follicles vs. tubules vs. both (hermaphrodites) vs. neither (Turner)
what determines phenotypic (genital) sex
external genitalia
what indicates phenotypic sex?
vulva vs. penis vs. can’t tell
what do true hermaphrodites have?
ovaries and testes
how to express true hermaphrodites?
46XX with translocation of Y to another chromosome-very rare
what do pseudohermaphrodites have disparity between?
gonadal and phenotypic sex
female pseudohermaphrodites
penis and ovaries
“penis” is really an enlarged clitoris
what causes female pseudohermaphrodites?
usually due to error of metabolism
Adrenogenital syndrome
male pseudohermaphrodites
vulva and testes
what causes male pseudohermaphrodites?
problems with testosterone synthesis and responsiveness
“testicular feminization”
autosomal dominant disorders
single gene of a pair affected
what do autosomal dominant disorders result in?
defective or decreased amounts of protein product
what is variable in autosomal dominant disorders?
variable penetrance and expressivity
when do autosomal dominant disorder manifest?
later in life (after carrier has had chance to reproduce)
what chance of passing on autosomal dominant disorders?
affected parents have 50% chance of passing to offspring regardless of gender
mechanisms of autosomal dominant disorders
problems with the quantity or arrangement of structural proteins
problems with regulator proteins or receptors
deficiency in proteins that are in short supply even in health
anti-oncogene deletion syndromes
the mutant gene makes a harmful protein (“gain of function”)
anti-oncogene deletion syndromes
a “second hit” on the normal allele turns it to a tumor cell
autosomal dominant disorders-structural proteins
Marfan’s syndrome (connective tissue proteins)
Ehlers-Danios (connective tissue proteins)
Hereditary spherocytosis (red cell membrane)
Familial hypertrophic cardiomyopathy (heart muscle proteins)
Familial psoriasis
Achondroplastic dwarfism (fibroblast growth factor receptors)
Hereditary hemorrhagic telangiectasia (several)
Osteogenesis imperfecta (collagen)
autosomal dominant disorders-connective tissue proteins
Marfan’s syndrome
Ehlers-Danlos
autosomal dominant disorders-receptors
Familial hypercholesterolemia (LDL receptor) Benign familial tremor Ion channel problems
example of ion channel problems autosomal dominant
malignant hyperthermia susceptibility syndromes
autosomal dominant disorders-short supply proteins
von Willebrand’s disease (vWF)
Maturity onset diabetes of the young (glucokinase)
Acute intermittent porphyria
autosomal dominant disorders-tumor genes
retinoblastoma neurofibromatosis I and II familial polyposis coli lynch's hereditary non-polyposis colon cancer multiple endocrine neoplasia syndrome I, Ila, Ilb Li-fraumeni cancer syndrome Tuberous sclerosis Von Hippel-Lindau disease Peutz-Jegher's syndrome Adult polycystic kidney disease
autosomal dominant disorders-harmful proteins
prion diseases
Huntington’s disease (“Huntington’s chorea”)
familial dysplastic nevus syndrome (melanin generates rather than protects from free radicals)
the common thrombophilias (hypercoagulability)
examples of the common thrombophillias (hypercoagulability)
Antithrombin III deficiency
Protein S deficiency
Protein C deficiency
Factor V Leiden
what is Marfan syndrome?
heterogenous group of disorders affecting connective tissue matrix
Marfan-mutations
many different mutations known, many unknown
what does Marfan syndrome usually involve?
fibrillin I
15q21
associates with elastin fibers
what types of manifestations in Marfan syndrome?
ocular, cardiovascular and musculoskeletal manifestations
Marfan syndrome symptoms
tall, long extremities long "spider" fingers hyperextensible "loose" joints chest wall deformities -pectus excavatum or carinatum spinal curvatures -kyphosis, scoliosis funny-looking face
Marfan syndrome eye symptoms
ectopia lentis -lax suspensory ligaments -virtually pathognomonic elongated globe, cornea loses convexity -severe myopia
Marfan syndrome heart sx
lax aortic valve ring -aortic insufficiency -severe heart failure "cystic medial necrosis" of thoracic aorta -aortic dissections 1/3 of Marfan deaths
familial hypercholesterolemia
most common mendelian disorder
1 in 500 (or less)
many mutations known, usually 19p13
what is family hypercholesterolemia characterized by?
deficiency or defect in apoprotein B-100 (“LDL”) receptors
-the “bad” serum cholesterol
basic mechanism familial hypercholesterolemia
decreased liver clearance of LDL from the plasma with high plasma LDL levels
increased receptor-independent uptake of LDL by macrophages
chaotic uptake of LDL by macrophages leads to manifestations
familial hypercholesterolemia lab results
high serum cholesterol levels 300-500mg/dL
xanthomas
masses of lipid-stuffed macrophages
familial hypercholesterolemia induced precocious atherosclerosis leads to
heart attacks
strokes
how is familial hypercholesterolemia treated?
statins
familial hypercholesterolemia homozygotes
die in teens
autosomal recessive disorders
both genes of pair affected
what do autosomal recessive disorders result in?
absence or lack of function of gene product
autosomal recessive penetrance
usually complete penetrance
when do autosomal recessive disorders manifest?
early in life
how are autosomal recessive disorders passed on?
affected parents always pass gene to offspring regardless of gender
what increases risk of autosomal recessive disorders?
consanguineous mating increases risk (don’t kiss your cousin)
what are autosomal recessive disorders?
deficiencies or defects in highly specialized proteins
-enzymes, membrane transport proteins
what are autosomal recessive disorders characterized by?
hemoglobinopathies
what are most inborn errors of metabolism?
autosomal recessive
what can common disorders often confer?
survival advantage to heterozygous carriers
examples of survival advantages autosomal recessive disorders
- sickle cell carriers can resist malaria
- hemochromatosis carriers maintain body iron stores easier
- cystic fibrosis carriers are resistant to gram-negative intestinal infections
autosomal recessive disorders-specialized proteins
albinism
cystic fibrosis
phenylketonuria
galactosemia
maple syrup urine disease
a-1 protease ("antitrypsin") inhibitor deficiency
Wilson's disease
most glycogen storage diseases
most lysosomal storage diseasesautosomal recessive disorders-hemoglobinopathies
sickle cell anemia
hemoglobin C disease
B-thalassemia major
a-thalassemia syndromes
albinism
inability to synthesize melanin
how many autosomal loci known for albinism?
at least 12
what deficiency from albinism most common?
deficiency of tyrosinase
what body parts are affected by albinism?
skin, eyes, hair affected
light sensitivity-albinism
highly photosensitive
what are albinos predisposed to?
skin and eye cancers
what is phenylketonuria a deficiency of?
phenylalanine hydroxylase
what does an accumulation of phenylalanine cause?
CNS toxicity
phenylketonuria sx
mental retardation
microcephaly
delayed speech development
hypopigmentation
phenylketonuria screening
all US infants screened at birth
what can prevent brain damage with phenylketonuria?
dietary restrictions
what are lysosomal storage diseases?
failure to catabolize large molecules within lysosomes
how many lysosomal storage diseases are known?
lots
what is the prototype lysosomal storage disease?
tay-sachs “amaurotic family idiocy”
what is tay-sachs a deficiency of?
hexosaminidase
what builds up in tay-sachs?
buildup of GM2 ganglioside (cell membrane component) within lysosomes
what is mostly affected in tay-sachs?
CNS and retinal neurons
what population is tay-sachs common in?
Ashkenazic Jews (1 in 30 is a carrier)
tay-sachs infants
normal at birth
what do tay-sach infants develop?
mental retardation, blindness, incoordination
tay-sachs brain and head sx
enlargement of brain and head
-lipid accumulation within neurons
tay-sachs macula
cherry red spots on macula
surrounding yellow indicates lipid accumulation
tay-sachs prognosis
death occurs within years
no cure
sex-linked disorders
little to no homology between X and Y
how do defects on one X work sex-linked disorders?
defects on one X are overridden by normal allele on other X
-no true x-linked dominant disorders
allele requirement sex-linked disorders
males (Y) require one abnormal allele (hemizygous), females require two (homozygous)
usual genders affected by sex-linked disorders
females are carriers
males manifest disease (usually)
sex-linked disorders how many males with the gene are affected?
all males with the gene are affected
when will sex-linked disorders affect a woman?
she has two affected x-chromosomes
she suffers from really unfortunate lyonization
disease is expressed when individually lyonized cells are affected (G6PD deficiency)
she has turner’s syndrome (XO) or testicular feminization (XY)
are sex-linked disorders transmitted from father to son?
never
sex-linked daughters of affected males
all carriers
sex-linked disorders
hemophilia A (factor VIII deficiency)
hemophilia B (factor IX deficiency)
G6PD deficiency ("favism")
Lesh-Nyhan syndrome
Duchenne's muscular dystrophy (Jerry's kids)
Emery-Dreifuss muscular dystrophy
Fragile X syndrome
Fabry's disease
Red-green color-blindness
testicular feminization (common type)
nephrogenic diabetes insipidus
Bruton's agammaglubulinemia
"David the Bubble Boy's" immunodeficiencyLesch-Nyhan Syndrome
deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
needed for purine synthesis (salvage pathway)
leads to buildup of uric acid (gout)
intellectual disability
writhing movements
self-mutilating behaviors
polygenic disorders
disorders in which heredity plays a dominant role but there is no single gene
what do most cases of polygenic disorders involve?
environmental factors
polygenic disorders inheritance
do not follow clear-cut rules of inheritance
how can polygenic disorders represent?
congenital or later in life
polygenic disorders index patient
the sicker the index patient, the greater the risk to close relatives
polygenic disorders-siblings
the more sibs that are affected, the greater the risk to the next child
polygenic disorders-what is tricky to distinguish between?
single-gene diseases with incomplete penetrance
genetic diseases modified by environment
genetic heterogeneity
polygenic disorders examples
alcoholism asthma atherosclerosis attention-deficit disorder/hyperactivity baldness and hirsutism breast cancer risk cleft palate diabetes mellitus (type I, type II) hypertension pyloric stenosis schizophrenia obesity (appetite out-of-sync with bodyweight)
acquired genetic disorders
a fertilized egg with the disease is non-viable
a post-zygotic mutation involving only some cells occurs
expression acquired genetic disorders
expression variable depending on what/where affected cells are
McCune-Albright syndrome
Proteus syndrome
what is the great acquired genetic disease?
neoplasms
