Sex linked disorders Flashcards
inheritance of genes located on sex chromosomes
sex linked inheritance
males and sex chromosomes
receive their only X from mom
x-linked mutation will be present in any male with disease
females and sex chromosomes
X chromosomes from both parents
may not express the disease if mutation exists (x inactivation)
x linked recessive
phenotype is not expressed in females, exclusively men
all daughters of affected males are carriers
no male to male transmission
x linked dominant
phenotype is consistently expressed in female
females > males
all daughters of affected males are affected but not sons
Men usually die in uterine
y linked
affects only males
affected males always have affected fathers
x linked recessive probability
affected men born from carrier mothers have 50% risk of disease
no male to male transmission
affected male can only pass disease onto daughter (she will be a carrier)
x linked dominant probability
child of an affected female has 50% risk of disease
y linked transmission
affected dad CANNOT give to his daughter
affected dad CAN give to his son
mitochondrial traits transmission
appear in every generation
can affect males and females
fathers do not pass mitochondrial traits, only ovum contributes mitochondria to offspring
x inactivation
ability of second X chromosome to compensate for a mutant or defective gene on other X chromosome
occurs in every female, during development. Randomly, so that females are essentially mosaics
incomplete, so some regions remain active in all copies
x chromosome
X is much larger than Y so it codes for many proteins
females have twice the dosage of X than males
calico cats
example of X inactivation
alternating black and orange spots show the mosaicism in female cats
one contains X with active orange allele and one with black allele
X linked recessive disorders discussed in this class
hemophilia
Duchenne muscular dystrophy
Becker muscular dystrophy
hemophilia A and B are distinguished by
aPTT test
tests intrinsic pathway, both will have elevated aPTT
factor 8 and 9, involved in intrinsic pathway, are elevated
other than this test, hemophilia A and B are indistinguishable
hemophilia
sex linked recessive
severe bleeding disorder
85% are A and 15% are B
aPTT test distinguishes
prolonged or severe bleeding from wounds and hemorrhage in joints and muscles causes hemearthroses and intracranial disorder
genetic abnormality:
hemophilia A
long arm q of X chromosome (F8C gene)
protein affected:
hemophilia A
deficiency or defect in factor 8
clotting factor, therefore causes excessive bleeding
treatment for hemophilia A and B
- monoclonal purified, plasma derived factor VIII (can cause infection)
- recombinant Factor VIII (non human, made in lab so safer)
hemophilia B
aka christmas disease
caused by mutation on F9 of X, coding for Factor 9 Leyden
severe hemophilia during childhood, spontaneous resolution during puberty
most common and most severe form of muscular dystrophy
Duchenne muscular dystrophy
characterized by progressive weakness and loss of muscle
genetic abnormality
Duchenne muscular dystrophy
Xp21
deletion or duplication producing FRAMESHIFT mutation
more common in males
Duchenne muscular dystrophy
protein affected
dystrophin
results in ABSENCE of protein, most likely responsible for maintaining structural integrity of cytoskeleton
Duchenne muscular dystrophy
pathophysiology
lack of dystrophin causes muscle cells to die as they are stressed by muscular contractions
muscle death causes release of creation kinase, CK, into the blood stream
Duchenne muscular dystrophy
clinical manifestations
progressive weakness and loss of muscle
cardiomyopathy in all affected after 18, few live beyond 30
respiratory problems and DMC as MC cause of death
proximal weakness, waddling gait, difficulty climbing
pseudo hypertrophy of calves
Duchenne muscular dystrophy
expression pattern
symptoms seen before age 5
female heterozygote carriers often show some symptoms
DMD is rapidly progressive, children in wheel chair by age 12
Gowers maneuver to ID
Duchenne muscular dystrophy
treatment
mandage cardiomyopathy
prednisone to improve strength, function
Becker muscular dystrophy
genetic abnormality
Xp21, dystrophin gene
IN-FRAME mutation
Becker muscular dystrophy
protein affected
dystrophin
DECREASED LEVELS
10% from spontaneous mutation
Becker muscular dystrophy
clinical manifestations
slower progression, less severe than DMD
never lose ability to walk
later onset skeletal muscle weakness
DMC is MC cause of mortality
Becker muscular dystrophy
expression pattern
11 years of age
most common inherited cause od mental retardation
Fragile X syndrome
only need one mutation to cause disease (both males and females) MORE MEN
Fragile X syndrome
genetic abnormality
FMR1 gene, Xq28
expansion of CGG repeat
Fragile X syndrome
penetrance levels
normal CGG length is 6-54
normal, transmitting males = 60-200
affected individuals = 200-thousands of CGGs
anticipation is seen with Fragile X (# increases w/generation and severity)
anticipation Fragile X syndrome in men
permutation is passed thru men then it doesn’t significantly increase in size
dad can give to daughter, not son
anticipation Fragile X syndrome in women
CGG expansion is unstable, high risk of it expanding to full mutation in children
mom can give to daughter (50%) and son as well
Fragile X syndrome
protein affected
FMRP or FMR-1
protein is necessary for normal brain development and function
Fragile X syndrome
pathophys
when repeats expand over 200, the gene is turned off = full mutation
this causes decrease in protein product which causes manifestations
Fragile X syndrome
clinical manifestations
distance facial appearance (lg. head, long face, lg. ears, macroorchidism)
moderate to severe mental retardation
physical features distinct after puberty
normal life expectancy
Fragile X syndrome
expression pattern
depends on number of repeats
females there is variability in phenotype expression due to effect of x-inactivation
Fragile X syndrome
penetrance
reduced pentrance
Rhett syndrome
x-linked dominant
disorder of brain development
occurs exclusively in females
rhett syndrome
genetic abnormality
MECP2 gene on X chromosome (Xq28)
Rhett syndrome
protein affected
MECP2
regulates other genes in brain by switching them off
binds a MeCP2 protein to methylated cells to prevent access to DNA transcriptions
Rhett syndrome
pathophys
MECP2 mutations disrupt normal functioning of nerve cells
normal brain development until 6-18 months
why do symptoms of Rhett syndrome not appear until 6-18 months?
by 6 months new neuronal cells are maturing and certain proteins become active and MeCP2 must interact with them to promote new and existing brain cell development
Rhett syndrome
clinical manifestations
disruption of neurotransmitters causes excessive anxiety (withdrawn and anxious)
autistic like behaviors, acquire specific symptoms like teeth grinding and hand wringing
MECP2 and anxiety
normally controls activity of CRH
this mutations results in overabundance of CRH in brain
therefore Rhett syndrome results in excessive anxiety and stress
Rhett syndrome
expression pattern
x-inactivation
50% of mutant gene and 50% of normal gene causes Rhett to develop (50:50)
if majority of x cells turn off chromosome that includes mutant MECP2 gene then mild disorders develop and patients don’t show the pattern
Rhett syndrome
penetrance pattern
not all children with MECP2 mutations will develop classic Rhett syndrome
Rhett syndrome treatment
gene therapy is being developed
x-linked dominant disorders discussed in this class
Rhett syndrome
Fragile X syndrome
Y-linked disorders genetic transmission
dad cannot give it to his daughter but CAN give to his son
y chromosome
plays a crucial house keeping role into cell
referred to as pseudoautosomal
Y-linked genes
SRY gene - specifies male fathers and maleness
hypertrichosis pinnae auris – hairy ears, gene found on Y chromosome
Mitochondrial disorders
appear in every generation of a family
affect both males and females
fathers DO NOT pass mitochondrial traits to children, only mothers
mitochondria
have their own DNA
found in tale of sperm, falls off when fertilization occurs
therefore only ovum contributes to mitochondria in offspring
heteroplasmy
fraction of molecule in mtDNA that carry a mutation
phenotype of a cell depends on percentage of mutated DNA it contains
severity of condition correlates with extent of heteroplasmy
mitochondrial disorders in this class
Leber Hereditary Optic Neuropathy (LHON)
Myoclonic Epilepsy with Ragged Red Fiber Syndrome (MERRF)
Pearson Syndrome
LHON
bilateral loss of central vision caused by atrophy of optic never
vision disappears within a few weeks
appears in second or third decade of life and affects more men than women (classic)`
Myoclonic Epilepsy with Ragged Red Fiber Syndrome
MERRF
characterized by myoclonic epilepsy
generalized convulsions of myopathy with presence of ragged red fibers
clumps of diseased mitochondria that accumulate and aggregate in individual muscle fivers
LHON is caused by mutations
mtDNA
component of the elevon transport chain
specific inability to generate ATP
MERRF is caused by mutations
mtDNA
caused by mutations of mitochondrial tRNA (tRNALys)
caused by a general defect in mitochondrial protein synthesis
Pearson Syndrome
first year of life
children usually die before three years of life
affects hematopoiesis and endocrine pancreatic function
anemia with vacuolization of bone marrow precursors, manifested with microcytic anemia, thrombocytopenia, neutropenia
mitochondrial genomes reading assignment
mitochondria contain multiple genomes, every cell contains multiple mitochondria
req. for energy production vary from one tissue to another
mutations in mitochondrial DNA affect only a fraction of mitochondrial genomes within a given individual
