Ch 5 Flashcards
Genetics: What is ‘variable expressivity’
All individuals who have the mutant gene express it differently
____ of function mutations are commonly associated with autosomal dominant disorders.
Loss of function
What are characteristics of autosomal recessive disorders?
- Can occur due to consanguinity
- 1 in 4 chance of having trait
- Does not usually affect parents, but siblings may have it
Marfan syndrome is associated with ____ gene mutation.
Fibrillin-1
Ghents criteria is used to diagnose (condition)
Marfan syndrome
What are the 2 autosomal recessive ehler danlos conditions?
- Kyphoscoliosis Type VI
- Dermatopraxis Type VIIc
What enzyme is deficient in EDS kyphoscoliosis type VI?
Lysyl hydroxylase
What enzyme is deficient in EDS dermatopraxis type VIIc?
N peptidase
Familial hypercholesterolemia gene mutations 3
- Mutations in LDL-R
- Apo B gene mutations
- Activating mutations PCSK9 gene
What is an example of codominant pattern of inheritance?
AB blood group, HLA genes
What is a point mutation?
Replacement of one nucleotide with another in a sequence
Example of a disease with point mutation?
Sickle cell anemia
What are the types of point mutations 3
- Silent
- Missense
- Nonsense
What is a silent mutation?
Replacement of nucleotide and still codes for same protein
Eg GAA —> glu
GAG —> glu
What is a nonsense mutation?
Replacement of nucleotide leads to stop
Eg GAA –> glu
UAA–> stop
What is a missense mutation?
Replacement of nucleotide that gives another protein
Eg GAA –> Glu
GAC–> Asp
What are the stop codons? 3
UAA
UAG
UGA
What is a frame shift mutation?
Caused by addition or deletion of nucleotide
A codon is made of (number) nucleosides
3
What are the type of frame shift mutations? 3
- Wild type
- Base pair deletion
- Three nucleoside insertion/deletion
Y linked disorders are also known as ___(name)
Holandric inheritance
What is penetrance?
How often someone with the genotype shows the corresponding phenotype
What are the characteristics of autosomal recessive disorders?
- Narrow expressivity (no variability)
- Childhood onset
- Complete penetrance
Any disease that ends with ‘uria’ is ____ inheritance.
Autosomal recessive
Autosomal recessive conditions examples
Anything than ends with ‘uria’
ABCDEF
Albinism
Beta thalassemia/Sickle cell
Cystic fibrosis/Congenital adrenal hyperplasia
Friedrich’s ataxia/Fanconi
Glycogen/lysosomal storage disease
Haemochromatosis
Wilson disease
Haemochromatosis
Which protein is negatively affected in Marfan syndrome?
Elastin
Marfan syndrome causes elevation of ____ (growth factor)
TGF-B
Which way does the lens dislocate in Marfan syndrome?
Superotemporal dislocation
Inferonasal dislocation of lens is associated with ___(condition)
Homocytinuria
Neurofibromatosis type 1 is caused by mutation in which chromasome?
17
Neurofibromatosis type 2 is caused by mutation in which chromasome?
22
Cafe au late spots are seen in which types of neurofibromatosis?
Type 1 and 2
Neurofibromatosis 1 has defect in which protein?
Neurofibromin
Neurofibromatosis 2 has defect in which protein?
Merlin
Leisch nodules are seen in (neurofibromatosis)
Type 1 only
Ependymoma, acoustic schwanoma and meningioma are seen in which neurofibromatosis type?
2
Classic cells seen in meningioma
Psamomma bodies
Drop metastasis is associated with ____ (condition)
Ependymoma
All metabolic diseases
All inborn errors of metabolism are autosomal recessive except 2
- Fabrys
- Hunters
Both are X linked recessive
What enzyme is deficient in phenylketonuria?
Phenylalanine hydroxylase
What is the enzyme deficient in Alkaptonuria?
Homogenisticnacid oxidase
Onion skin lysosome is associated with which lysosome disease?
Tay Sachs
Ochronosis is associated with which disease?
Alkaptonuria
Tay Sachs disease is cause by (enzyme deficiency)
Hexomidase A deficiency
What is Tay Sachs disease?
Neurodegenerative disease (accumulation of GM2 gangliosides in lysosomes of neurons)
Which conditions would you see Cherry Red spots in eye?
Cherry Trees Never Grow Tall
Central retinal artery occlusion
Tay Sachs
Nieman Pick
Gauchers disease
Trauma (Berlints oedema)
What is the deficiency in Nieman Pick?
Spholingomyelinase
Zebra bodies are seen in which conditions? 4
Nieman pick
Hunters
Harley
Fabry
Askanazi Jews are associated with development of which lysosomal condition?
Nieman pick
Which lysosomal condition has foam cells in spleen and liver?
Nieman pick
Glucocerebrosidase deficiency is which disease?
Gauchers disease
Bone pain and hepatosplenomegaly is associated with which lysosomal disorder?
Gaucher
Crumpled tissue paper appearance is associated with which lysosomal disorder?
Gaucher
Which condition has gout, intellectual disability and self-mutilating behaviour?
Leisch nyhan syndrome (X linked)
Which conditions are X linked recessive but manifest in females?
- Turners 45XO
- Lyonization (X becomes inactive)
- Carrier mother
What are X linked recessive disorders?
ABCDEFGH
A Haemophilia A/B
B Burton’s abetaglobulinema
C colour blindness (red-green), CJD (chronic granulomatous disease)
D Duchenne/BMD
E Leisch Nyhan
F Fabry disease, Fragile X
G G6PD deficiency
H Hunters
What are the disorders that are non Mendelian? 4
- Mitochondrial disorders
- Genomic imprinting
- Gonadal mosaicism
4.trinucleotide repeat disorders
Mitochondrial gene disorders characteristics of inheritance
- Inherited from mother only
- Affected mother spreads disease to all children
- Affected father does not spread it
What are the mitochondrial disorders? 6 examples
- MELAS: Mitochondrial encephalopathic lactic acidosis
- CPEO: Chronic progressive ophthalmoplegia
- MERRF: Myoclonic epilepsy red ragged fibers
- NARP: neurogenic ataxia retinitis pigmentosa
- LHON: Lebers hereditary optic neuropathy
- Leigh syndrome
What is a classic feature of CPEO?
Bilateral ptosis
What are 2 key features of MELAS?
Tonic clinic seizures
Muscle weakness
What are 3 features of MERRF?
Dementia
Cerebellar ataxia
Generalised seizure
Mitochondrial cristae that look like ‘phonographic records’ and/or ‘car park’ appearance is suggestive of
MERRF
What mitochondrial disorder presents with sudden vision loss?
Labors hereditary optic neuropathy
How does Labors neuropathy cause vision loss?
Complex 1 dysfunction–> death optic nerve
What is the dysfunction in Leigh syndrome?
1.SuRF-1 (80%)
2.MT-ATP6 (20%)
Both lead to complex 1 dysfunction
What are the 2 main features of Leigh syndrome?
Hypertrophic cardiomyopathy
Nystagmus
What trinucleotide repeat is seen in Huntington ataxia?
CAG
What trinucleotide repeat is seen in fragile X syndrome?
CGG
What trinucleotide repeat is seen in Friedrich ataxia?
GAA
What is the gene mutation in fragile X syndrome?
FMR-1 (Familial mental retardation)
Carrier females of fragile X syndrome are at risk of developing (condition)
Premature ovarian failure
What are the clinical features of fragile X syndrome?
- Long face/ears/mandible
- Mitral valve prolapse
- Normal nose
Fragile X syndrome: how many repeats of its sequence will lead to this?
> 200 trinucleotide repeats
What is the mutation in prader-willi syndrome?
SNORP gene inactivation
- Paternal ch 15 deletion
Or - Maternal Ch 15 x2
What are the clinical features of Down syndrome?
- Macroglossia
- Mental retardation
- Upslanting palpebral fissures
- Flat nasal bridge
- Bushfield spots
- Saddle toe
- Single Palmar fissure
What are the complications seen in Down Syndrome?
- Alzheimer’s by 40
- Hirschprungs/dueodenal atresia
- Transient abnormal mylopoisis
- Endocardial cushion defects
What is the most common cancers that patients with Down syndrome get <3 years of age?
Acute megakaryoblastic leukemia
What is the most common cancer the Down patients get >5 years age?
ALL
What are the markers for Down syndrome (lab)?
- B HCG (high)
- PAPP A (High) - only for dual testing
- Estriol (Low)
- AFP (low)
- Inhibin A (high) - quadruple test
Turner Syndrome: which chromosome is missing (45XO)
Paternal (80%)
Deletion of which amino acid causes cystic fibrosis?
F508 (Phenylalanine)
What is the most common form of EDS (Ehler Danlos)?
Kyphoscoliosis (Type VI)
Von Gierke disease, what enzyme is deficient?
Glucose 6 phosphatase (excessive glycogen storage in liver)
What type of point mutation is Nieman-Pick Type A?
Missense
Which storage disorder has fibrillary cytoplasm?
Gauchers
PAS staining positive is associated with which storage disorder?
Gaucher
Main cause of death in mucopolysaccharidoses (MPS)?
MI (balloon cells: accumulate in coronary arteries)
What are the affected areas (ochronosis of Alkaptonuria)
Cartilage (ears, nose, joints - big joints)
Androgen insensitivity syndrome inheritance?
X linked
Androgen insensitivity syndrome: what is the mechanism?
Defective androgen receptor: does not respond to DHT but responds to estradiol
How is fragile X syndrome detected in fetus?
PCR or western blot amniotic fluid
Fragile X syndrome: when do the trinucleotide repeats occur (fertile cell cycle, parent)
Oogenesis in mum
What is the difference btw Nieman Pick and Tay Sachs in presentation?
Tay Sachs has NO hepatosplenomegaly
What is the deficiency in MC Ardle disease?
Glycogen phosphorylase - muscle cannot use glycogen, pee myoglobin after severe excercise
What is the deficiency in Hurler disease?
Iduronidase
Hurler disease inheritance?
Autosomal recessive
What metabolites accumulate in Hurler’s and Hunter’s disease? 4
Dermatan sulfate
heparin sulfate
Keratin sulfate
Chondroitin sulfate
What is the difference in presentation btw Hurler’s and Hunter’s?
Hunter has no Corneal clouding
What is the chromosome of Kleinfelters?
47 XXY
What is the inheritance of Hunters?
X linked recessive
What is the deficiency in Pompe disease?
Acid maltase (lysosomal glucosidase)
What is cause of death in Pompe disease?
Glycogen gets stored in myocardium (cardiomegaly and heart failure)
What is patau syndrome?
Trisomy 13
Cleft lip
Microcephaly
Polydactly
Monosomy (is 45 X) has which classic presentation?
Short 4th metacarpal
Trisomy 18 (Edwards) has which classic hand presentation?
Overlapping digits (2 over 3, 5 over 4)
What are the types of Gaucher disease?
- Type 1: 99% of cases. NO neurologic SX. Has large macrophages.
- Type 2: CNS affected, lethal.
- Type 3: CNS affected, less severe.
Macrophages: Nieman pick vs Gauchers
Nieman pick has multiple vacuoles within macrophages
Which chromosomal abnormality is likely to be carried to term?
Mosaicism
Trisomy 18: features
Growth retardation
VSD
Horseshoe kidney
Omphalocele
Which 2 conditions have hygroma?
Turners
Downs (+VSD)
What is a Northern blot?
To detect RNA of interest in a sample
What is an alternative to nitrocellulose blotting?
Diazobenzyloxymethyl paper - can bind single standard DNA, RNA and proteins by linking to diazonium group
What is a western blot?
Similar to northern plot, but detects protein of interest (eg AIDS)
Which direction does RNA move in a Northern blot membrane?
Negative end to positive
What gel is used in western blot?
SDS PAGE gel
What membrane is used in western blot?
PVDF membrane
What is an ELIZA?
Colorimetric test that uses antibodies and colour change to identify a substance
What is an indirect ELIZA?
Detect an antibody against a known antigen
What is a Sandwich Eliza?
Detect antigen of interest
What is competitive Eliza?
Detects how much antigen is in patient sample
Competitive Eliza: faint or no colour change means
Lots of antigen present