Biochemistry-Genetics Flashcards
What is codominance?
both alleles contribute to the phenotype of the heterozygote (e.g. blood groups A, B, AB)
What is variable expressivity?
phenotype varies among individuals with the same genotype (2 pts. with neurofibromatosis type I (NF1) may have varying disease severity)
What is incomplete penetrance?
not all individuals with a mutant genotype show the mutant phenotype (e.g. BRCA gene mutations do not always result in breast or ovarian cancer)
What is pleiotropy?
when one gene contributes to multiple phenotypic effects (e.g. untreated PKU manifests with light skin, intellectual disability, and musty body odor)
What is anticipation?
increased severity or earlier onset of disease in succeeding generation (.e.g Huntington disease)
Describe loss of heterozygosity
if a pt inherits or develops a mutation in a tumor supressor gene, the complementary allele must be deleted/mutated before cancer develops. THis is not true of oncogenes (i.e. two hit theory)
What are dominant negative mutations?
exerts a dominant effect. A heterozygote produces a nonfunctional altered protein that also prevents the normal gnee product from functioning
What is linkage disequilibrium?
tendency for certain alleles at 2 linked loci to occur together more or less often than expected by change. Measured in a population, not in a family, and often varies in different populations
What is heteroplasmy?
presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrially inherited disease
What is allelic heterogeneity?
different mutations in the same locus produce the same phenotype (i.e. B-thalassemia)
What is locus heterogeneity?
different mutations in the same locus produce the same phenotype (i.e. albinism)
What is mosaicism?
presence of genetically distinct cell lines in the same individual
Somatic mosaicism- mutation arises from mitotic errors after fertilization and prpagates through mutliple tissues or organs
Gonadal mosaicism- mutation only in egg or sperm cells
What is McCune-Albright Syndrome?
due to mutations affecting G-protein signaling. Presents with unilatera cafe-au-lait spots, polyostotic fibrous dysplasia, precocious puberty, and multiple endocrine abnormalities
lethal if mutation occurs before fertilization (affecting all cells), but survivable in pts with mosaicism
What is uniparental disomy?
When an offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent.
Heterodisomy (heterozygote) indicates a meiosis I error
Isodisomy (homozygous) indicates a meiosis II error or postzygotic chromosomal duplication of one of a pair of chromosomes, and the loss of the other of the original pair
Example of uniparental disomy
Uniparental is eUploid (correct number of chromosomes), not aneuploid. Most occurences of UPD leads to normal phenotypes. Consider UDP in an individual manifesting in a recessive disorder when only one parent is a carrier
If a population is in Hardy-Weinberg equilbrium and if p and q are the frequencies of seperate alleles, then: p2 + 2pq + q2= 1 and p+q=1 which implies that:
p2= frequency of homozygosity for allele p
q2= frequency of homozygosity for allele q
2qp= frequency of heteroxygote
In Hardy-Weinberg equilbrium, the frequency of an X-linked recessive disease in males=
q, and in females = q2
Hardy- Weinberg law assumptions:
No mutation occuring at the locus
Natural selecction is occurring
Completely random mating
No net migration
What is imprinting?
At some loci, only one allele is active; the other is inactive (imprinted/inactivated by methylation). With one allele inactivated, deletion of the active allele causes disease
E.g. both Prader-Willi and Angelman syndromes are due to mutation or deletion of genes on chromosome 15
What is Prader Willi syndrome?
maternal imprinting disease where the gene from mom is normally silent and the paternal gene is deleted/mutated resulting in:
hyperphagia, obesity, intellectual disability, hypogonadism, and hypotonia
25% of Prader Willi syndrome cases are due to what?
maternal uniparental disomy (two maternally imprinted genes are recieved; no paternal genes received)
What is Angelman syndrome?
paternal imprinting disease when the gene from dad is normally silent and the maternal gene is deleted/mutated resulting in:
inappropriate laughter (“happy puppet”)
seizures
ataxia
and severe intellectual disability
What inheritance pattern is shown below?
AD- often due to defects in structural genes; often pleiotropic (multiple apparently unrelated effects) and variably expressed
AR recessive pattern
Often due to enzymes deficiencies (usually seen in only 1 generation and skips); commonly more severe than dominant disorders and pts often present in childhood
Increased risk in consanguineous families
What inehritance pattern is this?
X-linked recessive (sons of heterozygote mothers have a 50% chance of having phenotypic disease); no male to male transmission; skips generations
females must be homozygous to be infected
X-linked dominant pattern
Transmitted via both parents; mothers transmit to 50% of sons AND daughters and fathers thansmit to all daughter but no sons
What disease famously has X-linked dominant transmission?
Hypophosphatemic rickets (aka vitD resistant rickets)
Results in increased phosphate wasting at the proximal tubules with rickets like presentation
Describe mitochondrial inheritance
Transmitted only through the mother and ALL offspring of affected females may show signs of disease
Mitochondrial myopathies often present with what symptoms/signs?
myopathy, lactic acidosis, and CNS disase. Secondary to oxidative phosphorylation
muscle biopsy often show ragged red fibers
What are some major AD diseases?
ADPKD
Familial adenomatous polyposis
Familial hypercholesterolemia
Hereditary hemorrhagic telangiectasia
Hereditary spherocytosis
Huntington disease
Describe ADPKD
Bilateral enlargement of the kidneys due to multiple large cysts that result from mutation of PKD1 (chromosome 16; 16 letters in polycystic kidney) or some in PKD2 (chromosome 4)
Describe familial adenomatous polyposis
colon becomes covered with adenomatous polyps after puberty and progresses to colon cancer unless the colon is resected
due to mutation of APC gene on chromosome 5 (5 letters in polyp)
Describe familial hypercholesterolemia and its presentation
Elevated LDL due to defective or absent LDL receptor that leads to sever atherosclerotic disease early in life, corneal arcus (below), tendon xanthomas (common on the achilles tendon)
Describe familial hereditary hemorrhagic telangiectasia (aka Osler-Weber-Rendu syndrome) and its presentation
Inherited disorder of blood vessles with findings of branching skin lesions (telangiectasias), arteriovenous malformations (AVMs), GI bleeding, and hematuria
Describe hereditary spherocytosis
the development of spheroid erthryocytes (below) due to spectrin or ankyrin defects in the RBC membrane
tx with splenectomy
What are the NTM findings of Huntington disease?
increased dopamine
decreased GABA and ACh in the brain
What are the findings of Huntington disease?
depression, and the onset of chorea progressing to rigid Parkinson like symptoms (caudate atrophy seen)
What causes Huntington disease?
CAG trinulceotide repeat on chromosome 4
What are some other AD diseases?
Li-Fraumeni syndrome
Marfan syndrome
MEN syndromes (1, 2A, and 2B)
Neuofibromatosis type I (von Recklinghausen disease)
Neurofibromatosis type 2
Tuberous sclerosis
von-Hippel Lindau disease
Describe Li-Fraumeni syndrome
abnormalities in TP53 gene cause the occurrence of multiple malignancies at an early age. AKA SBLA cancer syndrome (sarcoma, breast, leukemia, and adrenal gland)
What causes Marfan syndrome?
FBN1 mutation on chromosome 15 leading to defective fibrin (scaffold for elastin) which produces a CT disorder affecting skeleton, heart, and eyes.
What are the findings of Marfan syndrome?
tall with long extremities, pectus ecavatum, hypermobile jointsm and long, tapering fingers and toes (arachnodactyly)
can also cause cystic medial necrosis of the aorta resulting in aortic incompetence and dissecting aneurysms or a floppy mitral valve, as well as subluxation of the lens, typically upward and temporarily
What causes MEN1? MEN2A/B?
MEN1- MEN1 gene mutation
MEN2A/B- RET gene mutation
How does NFM type I present?
neurocutaneous disorder characterized by cafe-au-lait spots (below), cutaneous neurofibromas, optic gliomas, pheos, and Lisch nodules (pigmented iris hamartomas)
Note that there is 100% penetrance but very variable expression
NFM type 1- cutaneous neurofibromas
NFM type 1- optic gliomas
NFM type 1- Lisch nodules
Lisch nodules
What causes NFM type 1?
caused by mutation of NF1 gene on chromosome 17 (17 letters in von Recklinghausen)
What are the findings of NFM type 2? Cause?
bilateral acoustic schwannomas, juvenile cataracts, meningiomas, and ependymomas
NF2 gene on chromosome 22
Describe tuberous sclerosis
neurocutaneous disorder with multi-organ system involvement, characterized by numerous benign hamartomas (incomplete penetrance, and variable expression)
Describe VHL disorder
disorder characterized by the development of numerous tumors, both benign and malignant.
Caused by deletion of the VHL gene on chromosome 3 (3 letters)
What are some AR diseases?
Albinism
ARPKD
cystic fibrosis
glycogen storages diseases
hemochromatosis, Wilson disease
Kartagener syndrome
What are some more AR diseases?
mucopolysaccharidoses (except Hunter syndrome)
PKU
Sickle cell anemia
sphingolipidoses (except Fabry disease)
thalassemias
What causes cystic fibrosis?
AR disease caused by a defect in the CFTR gene on chromosome 7 (most commonly a deletion of Phe508)- most common lethal genetic disease in Caucasians
What is the pathophysiology of Cystic Fibrosis?
CTFR encodes an ATP-gated Cl- channel that secretes Cl- in the lungs and GI tract, and resorbs Cl- in sweat glands. In CF, the protein is misfolded and retained in the RER causing decreased Cl- (and water) secretion.
Increased intracellular chloride results in compensatory Na+ reabsorption via ENaC channels causing increased water reabsorption, which produces abnormally thick mucus secreted into the lungs and GI tract
How is Cystic Fibrosis diagnosed?
elevated Cl- (60+mEq/mL) in sweat is diagnostic
can present with contraction alkalosis and hypokalemia
elevated immunoreative trypsinogen
What are the major complications of Cystic Fibrosis?
recurrent pulmonary infections (e.g. Pseudomonas),
chronic bronchitis and bronchiectasis causing a reticulonodular pattern on CXR (below)
pancreatic insufficiency and malabsoprtion with steatorrhea
nasal polyps
Other signs of cystic fibrosis?
meconium ileus in newborns
bilateral agensis of vas deferens and subfertilty in females (amenorrhea, and thick cervical mucus)
fat soluble (ADEK) vitamin deficiencies
How is cystic fibrosis tx?
N-acetylcysteine to loosen mucus plugs (cleaves disulfide bonds within mucus glycoproteins)
dornase alfa (DNAse)
What are some X-linked recessive disorders?
Bruton agammaglobulinemia
Wiskott Aldrich syndrome
Fabry disease
G6PD deficiency
Ocular ablinism
Lesch-Nyhan syndrome
What are some more X-linked recessive disorders?
Duchenne and Becker muscular dystrophy
Hunter syndrome
Hemophilia A and B
Ornithine transcarbamylase deficiency
Mnemonic for X-linked recessive disorders
Be Wise, Fool’s GOLD Heeds Silly HOpe
Remember: female carries can be variably affected depending on the percentage inactivation of the X chromosome carrying the mutant vs normal gene
What causes Duchenne muscular dystrophy?
X-linked disorder typically due to frameshift (deletions, duplications, or nonsense) mutations causing a truncated dystrophin protein that results inhibited muscle regeneration
How does Duchenne muscular dystrophy present?
onset around 5 yo
weakness starts in the pelvic girdle muscles and progresses superiorly
pseudohypertrophy of the calf muscles due to fibrofatty replacement of muscle (below)
gower manuver (pts use upper extermities to stand up)
waddling gait
What is the most common cause of death with Duchenne muscular dystrophy?
dilated cardiomyopathy
What is dystrophin?
the largest protein-coding human gene. Dystrophin helps anchor muscle fibers, primarily in skeletal and cardiac muscle. it connects the intracellular cytoskeleton (actin) to the transmembrane proteins a- and B-dystroglycan, which are conected to the ECM
loss of dystrophin results in myonecrosis
How is Duchenne diagnosed?
elevated CPK and aldolase are seen
Western blot and muscle biopsy confirm the diagnosis
What causes Becker dystrophy?
X-linked disorder due to non-frameshift insertions into the dystrophin gene (partially functioning instead of truncated). Thus, similar but less severe than Duchenne (onset is in adolescence or early adulthood)
What causes myotonic type I dystrophy?
AD disease caused by a CTG trinucleotide repeat expansion in the DMPK gene leading to abnormal expression of myotonin protein kinase
How does myotonic type I dystrophy present?
myotonia
muscle wasting
cataracts
testicular atrophy
frontal balding
arrhythmias
My tonia, My testicles, My Toupee, and My ticker
What causes Fragile X syndrome?
X-linked defect affecting the methylation and expression of the FMR1 gene (trinucleotide repeat of CGG) (2nd most common cause of genetic intellectual disability (after Down syndrome))
How does Fragile X syndrome present?
post-pubertal macroorchisism (enlarged testes)
long face with a large jaw
large everted ears
autism
mitral valve prolapse
What are some trinucleotide repeat expansion disorders?
Huntington disease
myotonic dystrophy
Friedrich ataxia
Fragile X syndrome
Mnemonic for remembering the trinucleotide expansions of these disorders
X-Girlfriend’s First Aid Helped Ace My Test
Fragile X: CGG
Friedreich Ataxia: GAA
Huntington: CAG
Myotonic dystrophy: CTG
Remember that these show genetic anticipation (worse disease and earlier age of onset in successive generations)
What are the main Autosomal trisomies?
Down syndrome (trisomy 21)
Edwards syndrome (trisomy 18)
Patau syndrome (trisomy 13)
How does Down syndrome present?
intellectual disability
flat facies, prominent epicanthal folds, single palmar crease
gap between 1st 2 toes
duodenal atresia
Hirschsprung disease
congenital heart disease (atrial septal defects ASDs)
Brushfield spots (below)
Associations of Down syndrome
early-onset Alzheimer disease (chromosome 21 encodes for amyloid precursor proteins)
icnreased risk of ALL and AML
95% of Down syndrome cases are due to what:
meiotic nondisjunction (associated with advanced maternal age)
4% due to Robertsonian translocation and 1% due mosaicism (post-fertilization mitotic error)
Diagnosis of Down syndrome in utero
first-trimester ultrasound commonly shows increased nuchal translucency and hypoplastic nasal bone; serum PAPP-A is low and free B-HCG is elevated
2nd trimester quad screen shows decreased a-fetoprotein and inhibin A, and elevated B-HCG and estriol
How does Edwards syndrome present?
severe intellectual disbaility
rocker-bottom feet
micrognathia (small jaw)
low-set ears
clenched ears with overlapping fingers
prominent occiput
congenital heart disease
What is the prognosis for Edwards syndrome?
death within 1 yr common
What are some serum markers for diagnosing Edwards syndrome?
Decreased PAPP-A and free B-hCG in the first trimester
quad screen shows decreased a-fetoprotein, B-hCG, estriol, and inhibin A
How does Patau syndrome present?
intellectual disability
rocker-bottom feet
micropthalamia (small eyes)
microcephaly
cleft lip/palate
holoprosecenphaly
congenital heart disease (death within 1 yr)
How is Patau syndrome diagnosed?
first-trimester pregnancy screen shows decreased free B-hCG, decreased PAPP-A, and icnreased nuchal translucency
Mutation of chromosome 3, think:
vHL disease and renal cell carcinoma
Mutation of chromosome 4, think:
ADPKD with PKD2 defect, Huntington disease
Mutation of chromosome 5, think:
cri-du-chat syndrome, familial adenomatous polyposis
Mutation of chromosome 7, think:
Williams syndrome, cystic fibrosis
Mutation of chromosome 9, think:
Friedrich ataxia
Mutation of chromosome 11, think:
Wilm’s tumor
Mutation of chromosome 13, think:
Patau syndrome, Wilson disease
Mutation of chromosome 15, think:
Prader-Willi syndrome, Angelman syndrome
Mutation of chromosome 16, think:
ADPKD, with PKD1 mutation
Mutation of chromosome 18, think:
Edwards syndrome
Mutation of chromosome 21, think:
Down syndrome
What is a Robertonian translocation?
chromosomal translocation that commonly involves chromosome pairs 13-15, 21, and 22.
Occurs when the long arms of 2 acrocentric chromsomes (chromosomes with centromeres near their ends) fuse at the centromere and the 2 short arms are lost (balanced translocations normally dont cause any abnormaly phenotype, but unbalanced translocations can result in micarriage, stillbirth, and chromosomal imbalances (e.g. Down syndrome, Patau)
What is cri-du-chat (aka cry of the cat) syndrome?
Congenital microdeletion of the short arm of chromosome 5 producing findings of:
microcephaly
moderate to severe intellectual diability
high-pitched crying/mewing
epicanthal folds
VSDs (heart)
What is Williams syndrome?
congenital microdeletion of the long arm of chromosome 7 (deleted region includes the elastin gene) resulting in:
distinctive ‘elfin’ facies
intellectual disability
hypercalcemia (sensitivity to vitD)
well-developed verbal skills
extreme friendliness with strangers
CV problems
What are the 22q11 deletion syndromes?
DiGeorge syndrome and Velocardiofacial syndrome
What does microdeletion at 22q11 cause?
variable presentations including;
Cleft palate, Abnormal facies,
Thymic aplasia (T cell deficiency)
Cardiac defects
Hypocalcemia secondary to PTH aplasia
CATCH-22
What causes 22q11 microdeletion?
aberrant development of the 3rd and 4th branchial pouches
