Genetic Disorders Part 1 Flashcards
what is genetics
- study of heredity
- study of function and composition of a single gene
what is genomics
study of ALL GENES and their relationships to identify their combined influence on and development of the organism
what are hereditary disorders
derived from the parents = familial
define congenital
-present at birth
does congenital imply heredity
no!
nature of genetic abnormalities contributing to human disease
- mutations in protein-coding genes
2. alterations in protein-coding genes other than mutations
what are mutations
permanent change in DNA
mutations of germ cells are transmitted to who
progeny
mutations of germ cells may give rise to what type of diseases
inherited disease
are mutations of somatic cells transmitted to progeny
no!
mutations of somatic cells cause
- cancer
- congenital malformations
what mutations can occur in protein-coding genes
- point mutations
- frameshift mutations
- trinucleotide repeat mutations
name 2 point mutations
- missence mutations
- nonsense mutations
what are missence mutations
change in SINGLE nucleotide base
example of a missence mutation
sickle cell disease
A–>T
what are nonsense mutations
termination codon; interrupt translation
what are the termination codons
UAA
UAG
UGA
what are frameshift mutations
- deletion and insertion
- one or 2 base pairs
- reading frame is altered
what are trinucleotide repeat mutations
-amplification sequence of 3 nucleotides
example of trinucleotide repeat mutations
Fragile X syndrome
CGG amplification
what are other alternations in protein-coding genes oter than mutations
- polymorphisms
- epigenetic changes
- alternations in non-coding RNAs
what are 2 most common types of polymorphism
- single nucleotide polymorphism (SNP)
- copy number variation (CNV)
what are single nucleotide polymorphism (SNP)
- variation at a single nucleotide position
- anywhere in the genome
1% of SNP occurs in
coding regions therefore alters gene product
are SNPs inherited
coinherited with a disease
what are copy number variations (CNVs)
large stretches of DNA
what % of CNSs are involved with gene-coding sequences
50%
CNVs contribute to
human phenotypic diversity
CNVs affect
CNS and immune system! (EXAM)
what are epigenetic changes
- modulation of gene
- absence of mutation
how can epigenetic changes occur
- methylation of gene promoter
- silencing of tumor suppressor gene
- acetylation of histone
what is imprinting
physiologic epigenetic silencing (gene in that particular chromosome is silent or not expressed)
name 2 alternations in non-coding RNAs
- microRNA
2. long non-coding RNA
what do long non-coding RNA do
- do not encode protein
- inhibit translation
what are the 3 major categories of genetic disorders
- mendelian disorders: disease caused by single-gene defects
- complex multigenic disorders
- cytogenetic disorders
what are the transmission patterns of single gene Mendelian disorders
- autosomal dominant
- autosomal recessive
- X-linked
what are the characteristics of an autosomal dominant gene
- heterozygous state
- at least 1 parent is affected
- M an F are affected
- 1 chance in 2 (50%) **
- delayed age at onset
example of an autosomal dominant disease
Huntington disease (mutation at birth, but doesn’t manifest until adult)
do autosomal dominant genes encode enzymes
NO!
autosomal dominant genes are involved in
- regulation of metabolic pathways (eg. Familial Hypercholesterolemia)
- structural proteins (eg. collagen), cytoskeletal components (eg. ankyrin)
clinical features of autosomal dominant inheritance are affected by
- variable expressivity
- reduced penetrance
what type of disease is Familial Hypercholesterolemia
an autosomal dominant inheritance
1 in 500 affected
what does Familial Hypercholesterolemia effect
intracellular transport of LDL
catabolism of LDL
where is the mutation in Familial Hypercholesterolemia
in LDL receptor
what class of Familial Hypercholesterolemia is most common
class II
what is class II Familial Hypercholesterolemia
defective folding of protein
- receptor is present
- impaired transport of LDL
what are the clinical manifestations of Familial Hypercholesterolemia
- atherosclerosis
- coronary artery disease
- xanthoma
what type of disease is Marfan syndrome
autosomal dominant
Marfan syndrome affects what gene
FBN1 gene
characteristics of marfan syndrome
- affects structural protein fibrins
- skeletal abnormalities
- ecotopia lentis
- CHF
what is the most common cause of death in Marfan syndrome
aortic rupture
Marfan syndrome results in a loss of
microfibrils
- excessive activation of TGF-beta
- affects vascular smooth muscle
what drugs are used to treat Marfan syndrome
-angiotension receptor blockers (ARBs) may improve cardiac function in MFS
what tyep of disease is Ehlers-Danlos syndrome
autosomal dominant
what are the 3 types of Ehlers-Danlos Syndrome
- Classic EDS
- Vascular EDS
- Kyphoscoliotic EDS
what is the mutation in classic EDS
-COL5A1 and COL5A2 (type V collagen defect)
what is the mutation in vascular EDS
-COL3A1 gene (type III collagen defect)
what is the mutation in Kyphoscoliotic EDS
- deficient enzyme: Lysyl hydroxylase
- type I and III colagen
EDS causes the skin to be
hyperextensible
- vulnerable to trauma
- poor wound healing
EDS also affects
- cornea
- blood vessels
- colon may rupture
characteristics of autosomal recessive inheritance disorders
- both alleles are mutant
- trait does not affect parents
- 25% recurrence risk
- low frequency mutant gene = strong likelihood of consagunitiy (related by blood)
- uniform expression
- complete penetrance
- early in life
- new mutations rarely detected
do autosomal recessive disorders affect enzymes
yes! enzyme proteins are affected
what is the mutation in cystic fibrosis
mutation in CFTR (cystic fibrosis transmembrane conductance regulator gene)
what is the most common cystic fibrosis mutation
change in F508
what are complications of CF in pancreas
- pancreatitis
- hyperglycemia
- biliary atresia
- neonatal obstructive jaundice
- cholelithiasis
- Vit. deficiency
- Meconium Ileus
complication os CF in lungs
- pneumonia
- bronchiectasis
- lung abscess (S. aureus, P.aeru, H.influ_
- Sinusitis
- mucoid impaction
- nasal polyps
- respiratory failure
what are other complications of CF
- congenital bilateral atrophy of vas deferens (CBAVD)
- infertility
- strictures in the colon
how can CF be diagnosed
- quantitive sweat test
- CFTR mutation lab evidence
what factors can give a false positive or negative sweat test
false positive: eczema, Klftr
false negative: hyponatremia, malnutrition
how is CF treatment managed
- team approach
- supportive
who does Phenylketonuria affect
Scandinavian
what is phenylketonuria
phenylalanine hydroxylase deficiency
what is hyperphenylalainemia
- normal levels at birth
- few weeks: plasma levels increase
- 6mo: mental retardation
- seizures, eczema
what are maternal PKU syndrome
- heterozygous infant
- microcephaly
- mental retardation
- congential heart disease
what type of disease is galactosemia
an autosome recessive
galactosemia affects what gene
galactose -1-phosphate uridyl transferase (GALT)
galactosemia affects what part of the body
- brain
- eyes
- liver
- spleen
- kidneys
in newborns, galactosemia causes
- vomiting
- diarrhea
- jaundice
- hepatomegaly
what type of disease is a lysosomal storage disease
autosomal recessive
who does lysosomal storage affect
infants, children
what is mutated in lysosomal storage disease
- gene that codes for specific enzymes
- therefore lack of specific enzymes
- mononuclear phagocytes
Tay-Sachs disease affects
Ashkenazi Jews
tay-sachs disease is deficient in
hexosaminidase A
describe the progression of Tay-Sachs disease
at birth: normal
3-6 mo: motor weakness
2-3 yrs: progressive disease; death
Tay-Sachs disease affects
brain, spinal cord, retina
under a microscop Tay-Sachs is characterized by
- neuron, with lipid vacuolation
- lysosomes with whorled configuration
Tay-sachs disease has a mutation in what gene
HEXA
how can you diagnose the mutation in HEXA gene
- plasma levels or WBS
- prenatal Dx: CV sampling, amnioscentesis
- carriers: genotyping
what is characteristic of a mutation in HEXA gene
retina: cherry red spot
Niemann-pick disease (NPD) affects
Ashkenazi Jews
NPD is deficient in what
acid sphingomyelinase
what is type A NPD
neurodegenerative
- results in organomegaly
- fatal in 3 yrs
what is type B NPD
no CNS involvement
+ organomegaly
survival to adulthood
what microscopic features are characteristic of NPD
vacuolated hepatocytes and Kupffer cells with accumulated sphingomyelin
what genes are affected in type C NPD
NPC1 and NPC2
type C NPD is defective in
intracellular cholesterol/lipid transport
type C NPD causes
ataxia, dystonia
-vertical supranuclear gaze palsy
what type of disease is Gaucher disease
autosomal recessive
what enzyme is Gaucher disease deficient in
glucocerebrosidase
what type of Gaucher Disease is most comon
type 1
what does Gaucher disease affect
Ashkenazi Jews
what symptoms does Gaucher disease cause
- osteopenia (radiographic bone disease; Erhlenmyer flask deformity)
- hepatosplenomegaly
is Gaucher disease neuronopathic
no; no CNS manifestation
what is type II Gaucher disease
acute infantile
- cause seizures
- incompatible with life
what is type III Gaucher disease
- chronic neuronopathic
- causes mental retardation
- seizures
what is the pathogenesis of Gaucher disease
- senescent RBC release glycosphingolipids
- degraded in spleen liver, bone marrow
function of glucocerebrosidase
cleaves glucose from ceramide
what happens in a glucocerebrosidase deficiency
-glycosphingolipids accumulate
what cytokines are activated in glucocerebrosidase deficiency
IL-1, IL-6, TNF
what microscopic features are characteristic of Gaucher disease
- lipid laded Gaucher cells in bone marrow
- Gaucher cell with distended lysosome
what therapy is given for Gaucher disease
- IV recombinant glucocerebrosidase for life
- oral drugs that inhibit glucocerebroside synthase
- gene therapy - normal gene transfected autologous hematopoietic stem cells (HPC)
what accumulates of Mucopolysaccharidoses (MPS)
- dermatan
- heparan
- keratan
- chondroitin sulfate
what are the symptoms of mucopolysaccharidoses
- skeletal abnormalities
- hepatomegaly
- cardiovascular disease
what is Hurler Syndrome
MPS Type 1
MPS type 1 is deficinet in
L-iduronidase
what is the life expectancy of MPS type 1
6-10yrs
what enzymes build up in MPS type 1
- dermatan
- heparan
what are the effects of MPS type 1
- mental retardation
- affects vascular endothelium, neurons, cornea
what is Hunter syndrome
MPS type II
what type of disease is MPS type II
X-linked!
all other MPS = autosomal recessive
what enzyme is deficient in MPS type II
L-iduronate sulfatase
what is the clinical corse of MPS type II
MILD
what is affects is absent in MPS type II
corneal clouding
what type of disease is glycogen storage disease (glycogenoses)
autosomal recessive inheritance
what are the 3 forms of glycogen storage disease
hepatic, myopathic, miscellaneous
describe the hepatic form of glycogen storage disease
- organomegaly
- hypoglycemia
- Von Gierke = type 1
- glucose 6 phosphatase
describe the myopathic form of glycogen storage disease
McArdle disease =Type V Muscle phosporylase Skeletal muscle only Painful cramps Myoglobinuria Onset: 20 y.o.
describe the miscellaneous glycogen storage disease
Pompe disease = Type II
Generalized glycogenosis
Lysosomal glucosidase
(acid maltase)
Hepatomegaly: mild
Massive CARDIOMEGALYall sex linked disorders are
x-linked
what are the characteristics of x-linked disorders
- heterozygous female carriers transmit only to sons
- rarely express phenotypic change
- sons: 1 chance in 2 of receiving mutant gene from heterozygous mother
- son manifest the disease
in x-linked disorders affect males do not transmit disorder to
- sons
- all daughters are carriers
what are the 3 most common X-linked recessive inheritance
- hemophilia A
- Duchenne/Becker muscular dystrophy
- Fragile X syndrome
what type of disease is hemophilia A
x-linked
what gene is mutation in hemophilia A
F8 gene
-results in inversion of 22 sequence (40%)
