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genetic regulation of oculogenesis
5x
PAX 6 gene
11p13, transcription factor
the main oculogenesis regulator
- initially is in the head ectoderm, later is in the optic vesicle and lens vesicles
mutation of PAX6 gene
aniridia
peters anomaly, congentital cataract
hereditary keretitis
isolated macular hypoplasia
isolated pupil dislocation
mutiple eye defect without aniridia
homozygotic PAX6 mutation
congenital anophthalmia
11p13 microdeletion
WAGR syndrome
aniridia
always bilateral, PAX6 gnen mutation, AD inheritance
clinical classification of aniridia
1. total, low VA, macular hypoplasia and nystagmus
2. partial with normal VA
3. ataxia and MR - AR, very rare
4. with WIlm tumor, genitourinary system defect and MR (WAGR syndrome, Miller's syndrome) 11p13 microdeletion or AD
5. with other eye defect
6. with other systemic effect
prevention of aniridia
75% has glaucoma - early surgical intervention
regular US of kidney
karyotype analysis - to exclude microdeletion
Oculogenes genes
PAX6
EYA1
PAX2
PAX3
SIX3
SIX6
CHX10
PITX2
EYA1 mutation
brachio-oto-renal syndrome
SIX3 mutation
holoprosencephaly and severe eye defect ( microphthalmia, hypotelorismus, cyclopia)
SIX6 mutation
microphthalmia and congenital cataract
PAX2 mutation
optic nerve head defect
colobmas with kidney defect (papillo-renal syndrome)
PAX3 mutation
Waardenburg syndrome
CHX10 mutation
complex microphthalmia
PITX2 mutation
Axenfeld-Reiger syndrome
Axenfeld- Reiger syndrome
AD, PITX2 mutation, effect the development of teeth, eye and abdomen region
posterior embryotoxon
eye-
peripheral iris streaks
iris defect - pseudopolycoria, hypotrophy
glaucoma - 50-60%
hypotelorism
teeth-
malar hypoplasia
abdomen-
umbilical hernia

also empty saddle syndrome
diagnosis of Axenfeld-Reiger syndrome
physical and clinical appearance
genetic analysis of the PITX2 gene mutation
prenatal diagnosis - CVS, amniocentesis, preimplantation genetic diagnosis
Waardenburg syndrome
AD, PAX3 and MITF gene
neurosensory deafness
uveal hypopigmentation
white forelock
local skin discoloaration
tumor supressor gene in ophthamology
retinoblastoma - RB1, 13q14
Von hippel-Lindau disease - VHL - 3p26
neurofibromatosis type 1 - NF1 - 17q11
neurofibromatosis type 2 - NF2 - 22q12
tuberous sclerosis - TSC1 - 9q24, TSC2 - 16p13
malignant meloma - CDKN2/p16
polypous colon cancer - APC - 5q21
retinoblastoma
rapidly developing cancer which develops in the cells of retina
malignant embryonic neoplasm of retina, children < 5 years
- leukocoria
- persistent unilateral strabismus
- eye/orbit inflammatory reaction
- secondary glaucoma

2 hit theory
neurofibromatosis type 1
AD, NF1 gene
Lisch nodules on iris
multiple skin neurofibromas
Cafe-au-lait skin spots
optic nerve glioma
other CNS tumor, pheochromocytoma
arterial hypertention, epilepsy
tuberous sclerosis
AD, TSC1, TSC2
facial fibroangioma - adenoma sebacum
retinal astrocytoma
skin discoloration spots
shagreen skin
enamel defect
intracranial calcification
eplipesy, MR, kidney tumor, heart myomas
Von hippel-Lindau disease
AD, VHL gene
retinal hemangioma
embryonic hemangiomas of cerebellum, spinal cord and brainstem
renal cancer
pheochromocytoma
renal, pancreatic, hepatic and epidydymic cyst
Sturge-Weber syndrome
usually sporatic
facial hemangioma, port-wine stain
ipsilateral soft meninges hemangioma
sometimes epilepsy, paresis, MR
secondary glaucoma
hereditary optic nerve neuropathies
LHON - leber hereditary optic nerve neuropathy, Mt
ADOA - Kjer hereditary optic nerve neuropathy, AD
simple, recessive optic nerve neuropath, AR
hereditary XR optic nerve nuropathy - OPA2 gene
complex Behr optic nerve neuropathy - AR
LHOH leber hereditary optic nerve neuropathy
mitochondrial inheritence
degeneration of retinal ganglion cells and their axons - subacute loss of central vision
evolve to very severe optic atrophy and permanent decrease of visual acuity
heteroplasmy
heteroplasmy
presence of both normal and mutated mtDNA in one person, result in variable expression in mitochondrial inherited disease
kjer optic nerve neuropathy ADOA
AD, OPA1,3,4 gene mutate
<10yrs, blue color vision defect
mitochondrial dysfunction mediating the death of optic nerve fibers
better visual prognosis
peripapillar telangeictatic microangiopathy (acute LHON)
recessive optic nerve neuropathy
AR, rare, <5yrs
very pale optic head with retinal vessel narrowing (like retinal dystrophy)
Behr syndrome
Behr syndrome
complex optic nerve neuropathy with cerebellar ataxia, spasticity, muscular hypertonia, MR
hereditary hypopigmentation
melanin production defect - 3
melanocyte migration defect - 3
Oculo cutaneous albinism
OCA1- tyrosinase
OCA2 - P gene
OCA3 - TRP1 gene
chediak- Higashi syndrome
AR, decrease in phagocytosis
recurrent pyogenic infections, partial albinism and peripheral neuropathy
partial OCA,
hepatomegaly
lymphadenopathy
lymphomas in youth
Hermansky-Pudlak syndrome
AR, classical or partial OCA
blood platets dysfuntion
subcutaneous hemorrhages
pulm fibrosis
enterocolitis
Ocular albinism
nettleship-fall type - XR
Aland island type - XR
autosomal recessive tyep - very rare
retinal dystrophies
macular dystrophies - central
peripheral retinal dystrophyies
hereditary vitroretinopathies
chroidal dystrophy
stationary photoreceptor dystrophy
macular dystrophy
stargardt disease
Leber congenital amaurosis
Best vitelliform macular dystrophy
cone-rod dystrophy
juvenile retinoschisis
pattern macular dystrophy
sorsby pseudo-inflammatory dystrophy
famililal macular drusen
cystic macular dystrophy
Stargadt disease
inherited juvenile macular degeneration
progressive vision loss usually to the point of legal blindness
opthalmoscopy -
initially normal
then yellow granules in macula
and then typical maculopathy

fluroescein angiograhy FA - mask choriodea

family history negative

AR,ABCR gene molecular analysis

genetics - 3x

no ERG response
Leber congenital amaurosis (LCA)
AR, adult are usually blind

nystagmus, photophobia, eye-finger symptom, no pupil light reaction,

hyperopia, very low VA

0-6 yrs - normal eye funds
then - leopard skin appearance

molecular analysis of caustive gene
Cone-rod dystrophy
AD, rare XR
photophobia
nystagmus (not always)
decrease VA
color vision defect
ophthalmoscopy and FA - bull eye muculopathy
ERG - photopic response reduction
Alstrom syndrome
AR, cone-rod dystrophy, ALMS1 gene, multiorgan dysfunction
obesity, hypogonadism
diabetes, asthma
hypothyriodism
cardiomyopathy, hypertension
sensorineural hearing loss
Juvenile retinochisis
1st symptom <10yrs
XR - RS1 gene - retinoschisin
diagnosis -
- opthamoscopy - bicycle wheel maculopathy
- FA - normal
- ERG - elective B wave reduction
- family history, gene molecular analysis
Best vitelliform macular dystrophy
AD, BEST1 (VMD2) gene, bestrophin
electrive exrpession in cell membrane of RPE and form a chlorine channel
typical, atypical and adult form

initially - decrease VA and metamorphopsia
vitelliform changes in macular after birth with later onset

Diagnosis
- VA, Amsler test
- ophthalmoscopy
-ERG - normal
- EOG - atypical
no increase in light (arden factor<1,5)
pattern macular dystrophy
AD, RDS gene - peripherin - structural proten of photoreceptor outer segment discs

butterfly shape, reticular, foveo-macular and other
mild course

Diagnosis
- ophthalmoscopy
- FA
- ERG, EOG - normal
peripheral retinal dystrophy
- retinitis pigmentosa
- juvenile retinoschisis
- Leber congenital amaurosis
- fundus falvimaculatus
- fundus albipunctatus
renitis pigmentosa
more than 40 diff gene
- phototransduction protein
- rod outer segments protein
- retinol metabolism protein
- other protein

molecular analysis

ophthalmoscopy - typical triad of symptom
visual field - concentric narrowing, tunnel vision
night blindness - first sign
ERG - scotopic response
Usher syndrome
AR, several types
retinitis pigmentosa
congenital sensorineural deafness
sometimes labyrinthine dysfunction and psychotic symptom
Bardet- Biedl syndrome
AR
atypical retinitis pigmentosa with maculopathy
obesity and hypogonadism
polydactly, renal defect
sensorineural deafness
sometimes MR
Kearns-Sayre syndrome
mitochondrial inheritance, atypical RP
external ophthalmoplegia.
cardiac conduction defects, Sensorineural hearing loss
ataxia, myopathy, diabetes, hypogonadism, hypothyrodism, deafness
cohen syndrome
..
hereditary vitreoretinopathies
8x
choroidal dystrophy
4x
stationary phtoreceptor dystrophy
2x
alarming eye symptom in infant
8x
Kabuki make-up syndrome
dup 8p23, Niikawa- kuroki syndrome

facial -
inverted later lower eyelid
large prominent earlobe
broad depressed nasal tip

skeletal-
sciolosis, fingerpad
joint hyperextensibility, short statue

Mental retardation
Microdeletion
Kabuki Make-up syndrome
Beckwith-Wiedemann syndrome
WAGR syndrome
Langer Giedion syndrome
Rubinstein Taybi syndrome
Smith Magenis Dysndrome
22q11 deletion
William syndrome
Angelman and PWS
Wolf-Hirschhorn Syndrome
Miller-Dieker Syndrome
Alagille Syndrome
Beckwith-Wiedemann syndrome
dup 11p15
EMG - Exomphalos + Macroglossia + gigiantism
aniridia, ear lobe crease, neonatal hypoglycemia
midline abdominal defect - hernia, omphocele
Alagille syndrome -
del 20p12 - JAG1
defect of liver and heart
Jaudice, chronic cholestasis
WAGR syndrome
del 11p13
W - Wilm tumor
A - aniridia
G - genitourinary anomalies
R - retardation

loss of both allels of WT1 gene
Wolf-Hirsshorn syndrome
del 4p

microcephaly, micrognathia
hypertelorism, broad nasal bridge
periauricular tag
severe MR and physical retardation
hypotonia an seisure
cleft lip and palate
William syndrome
Del 7q11, elastin gene
vascular and connective tissue damage
supravavular aortic stenosis
elfian face
hypocalcemia (increase sensitivity to Vit D)
MR
microdontia, enamel hypoplasia
Smith Magenis syndrome
Del 17q

short, sleep disturbance, self-insertion of the things to orificies, square face

MR, chaplin gait, Tics
Miller Dieker syndrome
Del 17p13 - LISI gene

lissencephaly (smooth brain, absense of gyris and sulci)
MR, eplipsy
short
tall prominent forehead, vertical furrowing
bitemporal narrowing, short nose with antevert nares
heart, kidney and limb defect
rubinstein taybi syndrome
Del 16p13

Broad thumb and toes
short
peak nose, with long septum extending below nasal alae and short columella
MR, microcephaly

congenital heart, kidney and genitalia defect
Langer Giedion syndrome
Del 8q24, TRP1 and TRP2

TRP1 - trochorhinophalangeal syndrome
pear nose
short stature
slow growth of sparse hair
bent finger with cone-shaped epiphysis

TRP 2
MR
many bone exotoses
hypermobility of joints
hyperelasticity of skin
22q11 deletion
Cardiac defect
Anomalieof face
Thymic hypoplasia
Cleft palate
Hypocalcemia
22

Digeorge, Velo-cardio-facial syndrome, Shprintzen
PWS and angelman syndrome
genetic imprinting
chromosome 15 del
FISH
triploidy
maternal triploidy - digynic
paternal triploidy - diandric
uniparental disomy UPD
offspring receive 2 copies of chromosome from 1 parent and no copies from the other

isodiosomy - 2 identical homolgues are inherited
heterodisomy - non identical
microdeletion diagnosis
FISH

HRBT - high resolution banding technique
karotype of the skin fibroblast
molecular karyotyping (FISH, CGH, MLPA)
Indication for karyotyping
6x
types of genetic disorder
chromosomal
microdeletion
single gene disorder
definition of mental retardation
3x
diagnostic tool for MR
FISH - fluorescent in sity hybridization
MLPA - multiplex ligation dependent probe amplication
array CGH - comparative genomic hybridization
the cause of MR
prenatal - genetic, acquired, unknown
perinatal
postnatal
unknown moment of injury to CNS
sex chromosome disorer
Klinefelter syndrome 47XXY
Turner's syndrome 45X
Double Y male - XYY47
Klinefelter syndrome
Testicular atrophy
tall, long extremties
gynecomastia
female hair districbution
may have development delay
presence of inactivated X chromosome (barr body)
hypogonadism and infertility
increase FSH, LH and estrogen

Mild MR, specific learning difficulties- dyslexia, dysgraphia, attention and memory deficit
behavorial abnormality
Turner's syndrome
short stature (premature fusing of the epiphyseal plate)
ovarian dysgenesis (streak ovary)
shield chest
bicuspid aortic valve
webbing neck, cystic hygroma
preductal coarctation
most common cause of amenorrhea
No barr body
decrease estrogen and increase LH and FSH
When is FISH used
confirmation of some clinical diagnosis of chromosomal disorder
use in chromosomal aberration in low mosaic state

fluorescent DNA or RNA probe binds to specific gene site of interest

used for specific localization of gene
direct visualization of anomalies (microdeletion) at the molecular level (when deletion is too small to be visualized in karyotype)
sotos
cerebral gigiantism
high birthweight
advance bone age
macrocephaly,
large front...
fragile x syndrome
martin-bell syndrome
chromosomal breakages impair DNA repair process
xeroderma pigmentosum
ataxia teleangiectasia (louis-bar syndrome)
nijmegen breakage syndrome
prenatal diagnosis
..
infertility
chromosomal cause
molecular cause
multifactorial cause
reccurrent miscarriage
karotype both partner in every case of 2 spontaneous abortions or 1 stillbirth
management of couples with reproductive failure
..
when is pre-implantation genetic diagnosis used?
HD, CF, SMA, FraX, DMD
hemophilia,
robersonian translocation
balanced translocation
inversion deletion
genetic defect types
monogenic
chromosomal aberration
multifactoral
inidication of genetic counselling
..
method use in genetic counselling
cytogenic analysis (chromosome analysis)
molecular genetic analysis
metabolic testing
imaging
problems in genetic counselling
..
types of congenital anomalies, examples
malformation
deformation
dysfunction
dysplasia
types of multiple congenital defects
sequence
complex (development field defects)
association
syndrome
minor anomalies
CNS defects, examples, and causes
,,
neural tube defect, types, epidemiology, etiology, risk, prophylaxism and supplements
..
Congenital heart disease examples, causes,
3-8wks
congenital renal and urinary tract, examples
4-7wkes
congenital of GI
3-8wks, intestinal loop returns around 12th wk
congenital defect of skeletal
4-7 wks
Features suggesting an inherited cancer predisposition
..
clinical criteria for breast/ ovarian cancer diagnosis, definitive and suspected
..
prophylatic breast/ ovarian caner
..
Lynch syndrome, amersterdam criteria, and suspected criteria
..
genomic imprinting
phenotypic expression of the disease can depend whether the mutation is of maternal or paternal origin
uniparental disomy
isodisomy
heterodisomy
pleiotropy
1 gene has >1 effect
loss of herterozygosity
..
locus heterogeneity
..