Genetic Disorders II Flashcards
Tx for lysosomal storage
enzyme replacement
substrate reduction
molecular chaperones
tay sachs disease
Gm2 - gangliosidoses storage disease
common in jews of European descent
motor and mental problems - 6 months of age
blindness and death by age 2-3
progressive neuronal destruction
cherry red spot in macula
Gm2 gangliosidose
tay sachs
hexosaminidase alpha-subunit deficiency
tay sachs
sphingomyelinase deficiency
nieman pick A and B
accumulation in sphingomyelin
common in ashrkenazic jews
type B - organomegaly - no CNS involvement - survive until adulthood
type A niemann pick
more common
- manifest at birth
- death within 3 years
protuberant abdomen (hepatosplenomegaly), failure to thrive, vomiting, fever, lymphadenpaothy, psychomotor dysfunction
Dx of nieman pickmann type A
liver or bone marrow Bx
-look for sphingomyelinase activity
niemann pick type C
mutation in NPC1 or NPC2
-cholesterol transport
cholesterol and gangliosides Gm1 and Gm2 accumulation
hydrops fetalis, neonatal hepatitis
-progressive neuro degeneration beginning in childhood with ataxia, dystonia, psychomotor regression
NPC1
mutated in nieman pick C
gaucher disease
autosomal recessive
mutation in glucocerebrosidase
accumulation of glucocerebroside
type I more common - non-neuronopathic - some enzyme
type II - neuronopathic - NO enzyme - death at early age
type III - intermediated
glucocerebrosidase
mutated in gaucher disease
type I gaucher disease
in european jews
- non-neuronopathic
- splenomegaly and lymphadenopathy
mucopolysaccharidoses
deficient enzyme that degrade glycosaminoglycans
coarse facial features, hepatosplenomegaly, corneal clouding, valve thickening, joint stiffness, mental retardation
hurler syndrome
MPS 1-H
deficient alpha-1 iduronidase
onset 6-24 months
death age 6-10 (cardiovascular)
hunter syndrome
MPS II
lacking corneal clouding - less severe than hurler
von gierke disease
glycogen storage disease
deficient glucose 6 phosphatase
-hepatic enlargement and hypoglycemia
hepatic type - treatable - but with late complications
mcardle disease
glycogen storage disease
muscle cramps after exercise, low lactate after exercise
deficient muscle phosphorylase
pompe disease
glycogen storage disease
deficient acid maltase
-cardiac involvement prominent (cardiomegaly)
alkaptonuria
ochronosis - blue black pigment of ears, nose, cheeks
-autosomal recessive
deficient homogentistic oxidase
blocks phenylalanine metabolism
homogentistic acid accumulation
-black color in urine
clinically evident - age 30s
giemsa stain
G-banding
-to determine karyotype
G-band organization
arm (p,q)
region
band
sub-band
Xp21.2
chromosome X, p arm, region 2, band 1, sub band 2
aneuploidy
not an exact multiple of 3
caused by nondisjunction
and anaphase lag
roberstonian translocation
results in one large and one small chromosome
balanced reciprocal tanslocation
results in no net gain or loss of genetic material
isochromose
one arm lost, remaining arm duplicated
trisomy 21
down syndrome
common 47, XY, +21
influenced in maternal age
Dx: flat facies oblique palpebral fissure, epicanthic folds, simian hand creases
mental retardation
heart disease
risk for acute leukemia
live to age 47
trisomy 18
edwards syndrome severe malformations, die within first year of life prominent occiput overlap fingers limited hip abduction
trisomy 13
patau syndrome
severe malformations, die within first year of life
microcephaly
umbilical hernia
cleft palate and lip
chromosome 22q11.2 deletion syndrome
digeorge syndrome -T cell deficiency and hypocalcemia
velicardiofacial syndrome - heart defect, facial dysmorphism, palate abnormalities,
lyons hypothesis
only one X chromosome is active
Y gene
has SRY
-determines testicle formation
klinefelter syndrome
47XXY
male hypogonadism
-elongated body
-reduced spermatogenesis - infertility
nondisjunction during meiosis
turner syndrome
monosomy of X -hypogonadism in females 45X neck webbing heart disease failure to develop secondary sex characteristics
short stature and amennorhea
true hermaphrodite
both testicular and ovarian tissue
most 46XX
female pseudohermaphrodites
46, XX
normal ovaries and internal genitalia
ambiguous external genitalia
steroid exposure during gestation
male pseudohermaphrotdites
gonads are testes
-external genitalia are female or ambiguous
due to androgen insensitivity
complete testicular feminization
fragile X syndrome
trinucleotide repeat mutation
familial mental retardation
FMR-1 gene
mental retardation and enlarged testicles elongated face, large mandible
FMR -1 gene
fragile X syndrome
47XXY
klinefelter
monosomy X
turner
edwards
trisomy 18
patau
trisomy 13
leber hereditary optic neuropathy
bilateral loss of central vision
- age 15-35
- eventual blindness
mutation in mitochondrial gene
-from mother
maternal imprinting
silencing of the maternal allele
paternal imprinting
silencing of the paternal allele
prader willi
deletion of q12 on chromosome 15 paternal allele
short, hypotonia, hyperphagia, obesity, small hands and feet, hypogonadism
angelman syndrome
deletion of q12 on chromosome 15 of maternal allele
retarded, ataxic gait, seizures, inappropriate laughter
-happy puppets
gonadal mosaicism
results from mutations that affect cells that form gonads
-offspring manifest the disease
indications for genetic analysis in mothers
over age 35 previous problems ultrasound deformities abnormal triple test (AFP, betaHCG, estriol) carrier of X-linked disease
indications for postnatal genetic analysis
congenital anomalies
mental retardation unexplained
suspected chromosomal abnormalities
analysis of acquired genetic alterations
Dx and management of malignancy and infectious disease
direct recombinant DNA
sequence gene
indirect recombinant DNA
association with markers
SNP
single nucleotide polymorphism
repeat length polymorphisms
microsatellites - 2-6 bp, 1 kb length
minisatellite - 15-70 bp, 1-3kb length
epigenetic alterations
heritable genetic changes without change in DNA sequence
RNA analysis
for RNA virus
chromosomal translocation analysis
