Random Genetic Diseases Flashcards
Kartagener Syndrome (what is it?, what does it cause? how is it inherited?)
Dynein arm defect -> immotile cilia
Causes: dec. fertility (sperm/fallopian tube dysfunction), inc. risk ectopic pregnancy, bronchiectasis, recurrent sinusitis, chronic ear infections, hearing loss, situs inversus
Autosomal recessive
Primary ciliary dyskinesia (what is it?)
Group of disorders similar to Kartagener WITHOUT situs inversus
Osteogenesis Imperfecta: what is it? what causes it?
Brittle bone disorder
Genetic bone disorder due to variety of gene defects: most commonly COL1A1 and COL1A2
Common type is AD: decreased production of Type I collagen (collagen is normal)
Osteogenesis Imperfecta: How does it present?
- Multiple fractures with minimal trauma (could happen during birth)
- BLUE sclerae (translucent CT over choroidal veins)
- Tooth abnormalities: opalescent teeth that wear easily bc they lack dentin (supports enamel)
- Progressive Hearing loss
“Patients can’t BITE”: Bones I(eye) Teeth Ear
Ehlers-Danlos Syndrome: what is it? How is it inherited? How does it present?
Faulty collagen synthesis -> hyperextensible skin, easy bleeding/bruising, hypermobile joints
Different types, different inheritance patterns
Ehlers-Danlos possible complications
Joint dislocation, berry/aortic aneurysms, organ rupture
Types of Ehlers-Danlos
- Hypermobility type: most common, joint instability
- Classical type: type V collagen mutation COL5A1/COL5A2, joint and skin Sx
- Vascular type: deficient type III collagen, vascular/organ rupture
Collagen Type I
most common: bone, skin, tendon, dentin, fascia, cornear, late wound repair
osteogenesis imperfecta
“bONE”
Collagen Type II
Cartilage, vitreous body, nucleus pulposis
“carTWOlage”
Collagen Type III
Reticuluin - skin, blood vessels, uterus, fetal tissue, granulation tissue
Ehlers-Danlos vascular type
Collagen Type IV
Basement membrane, basal lamina, lens
Alport Syndrome, Goodpasture syndrome
“type 4 under the floor (basement)”
Menke’s Syndrome (what is it?, how it is inherited?, how does it present?)
X-linked recessive
CT disease due to impaired Cu absorption/transport due to defective Menkes protein: leads to decreased lysyl oxidase activity (needs Cu as a cofactor, responsible for cross-linking collagen/elastin)
Presentation: brittle kinky hair, hypotonia, growth retardation
Marfan Syndrome: what causes it/how is it inherited?
Autosomal Dominant
CT disorder due to mutation of chromosome 15 which results in a defective fibrillin protein
Marfan Syndrome: Presentation
- tall w long extremities
- pectus carinatum (pigeon chest)/excavatum (chest sinks in)
- hypermobile joints
- arachnodactyly: long tapering fingers/toes (spider fingers)
- Heart problems: cystic medial necrosis of aorta, aortic incompetence, aortic dissection, floppy mitral valve
- Subluxation of lens: upward/temporally
Fibrillin
Forms a sheath around elastin
alpha1-antitrypsin deficiency
a1-at normally inhibits elastase: deficiency leads to inc breakdown of elastin
LINKED WITH EMPHYSEMA
McCune-Albright Syndrome: what is it? how is it inherited?
Mutation with G protein signaling
Mosaicism! otherwise it would be lethal
McCune-Albright Syndrome: presentation
Unilateral cafe-au-lait spots with ragged edges, at least 1 endocrinopathy (ex. precocious puberty), polyostotic fibrous dysplasia (when normal bone marrow is replaced with fibrous tissue making it weak/prone to expansion, can lead to fx/deformity/pain)
Prader-Willi syndrome: how is it inherited?
Maternal imprinting on chromosome 15
aka mom’s gene is silent, and Paternal gene is mutated/deleted
25% of cases due to maternal uniparental disomy: aka you get 2 silent mom copies, no paternal copies of gene
Prader-Willi syndrome: presentation
Hyperphagia (polyphagia), obesity, intellectual disability, hypogonadism, hypotonia
Angelman syndrome: how is it inherited?
Paternal imprinting on chromosome 15
aka dad’s gene is silent and Maternal gene is mutated/deleted
5% cases due to paternal uniparental disomy: aka you get 2 silent dad copies, no maternal copies of gene
Angelman syndrome: presentation
Inappropriate laughter, seizures, ataxia, severe intellectual disabilities
“happy puppet”
Hypophosphatemic rickets
Vitamin-D resistant rickets is other name.
X-linked dominant disorder causing increased phosphate wasting at proximal tubule: FGF-23 expression is increased and this promotes phosphaturia
Results in rickets-like presentation
Cystic fibrosis: mutation/inheritance
Autosomal recessive, defect in CFTR gene on chromosome 7
commonly a deletion of Phe508
Cystic fibrosis: pathophysiology
CFTR codes for ATP-gated Cl channel that secretes Cl in lungs/gut and reabsorbs Cl from sweat gland
Common mutation results in CFTR protein misfolding so you lose that channel: you can’t secrete Cl so it remains in the cells -> increased Na reabsorption into cells to balance charge -> increased H2O reabsorption -> abnormally thick mucus secreted in lungs and GI tract that is hard to clear
Cystic fibrosis: diagnosis
Cl concentration greater than 60 in the sweat is diagnostic
Can present like contraction alkalosis and hypokalemia bc of the ECF H2O and Na loss
In newborn screenings: can look at increased immunoreactive trypsinogen
Cystic fibrosis: complications
Recurrent pulmonary infections (Staph auerus in early infancy, pseduomonas in adolescence), chronic broncitis, bronchiectasis
Pancreatic insufficiency, malabsorption with steatorrhea, fat-soluble vitamin deficiencies, biliary cirrhosis, liver disease
Meconium ileus in children
Infertility in men, subfertility in women (amenorrhea due to super thick cervical mucus)
Nasal polyps
Clubbing of nails
Cystic fibrosis: treatment
for mucus clearance: chest physiotherapy, albuterol, aerosolized dornase alfa DNAse, hypertonic saline
Anti-inflammatory: Azithromycin
Pancreatic enzymes
Ibuprofen slows disease progression
Duchenne Muscular Dystrophy: how is it inherited?
X linked disorder due to FRAMESHIFT/nonsense mutations that lead to truncated/absent dystrophin protein
Becker Muscular Dystrophy: how is it inherited?
X linked disorder due to NON-FRAMESHIFT deletions in the dystrophin gene
Dystrophin
Gene is largest protein-coding human gene so increased risk for mutations.
Helps to anchor muscle fibers (actin in the cytoskeleton) to the ECM
Loss = myonecrosis
Duchenne Muscular Dystrophy: presentation, onset, how is it diagnosed?
Myofiber damage. Weakness starts in pelvic girdle muscles and progresses superiorly
Pseudohypertrophy of calf muscles due to fibrofatty replacement of the muscle
Waddling gait
Dilated cardiomyopathy
Onset before age 5, diagnosed via genetic testing, will also have elevated CK and aldolase
Becker Muscular Dystrophy: presentation, onset
Less severe than DMD, onset adolescence
Myotonic Type 1 Muscular Dystrophy: inheritance
Autosomal dominant, CTG trinucleotide expansion repeat in DMPK gene leading to abnormal expression of myotonin protein kinase
Myotonic Type 1 Muscular Dystrophy: presentation
Myotonic, muscle wasting, cataracts, testicular atrophy, frontal balding, arrhythmia
Cataracts Toupee Gonadal atrophy (CTG repeats)
Gower sign
When pt uses upper extremities to help stand up, seen in DMD and other muscular dystrophies and inflammatory myopathies
Fragile X syndrome: inheritance
X-linked dominant, trinucleotide repeat in FMR1 gene leads to hypermethylation and decreased expression
CGG repeat
Fragile X Syndrome: presentation
Most common cause inherited intellectual disability/autism
Post-pubertal macroorchidism (enlarged testes), long face, large jaw, everted ears, mitral valve prolapse
Chin, Giant Gonads (CGG repeat)
22q11 deletion syndromes: what are they, how do they typically present?
Microdeletions at chr 22q11, have variable presentations
CATCH 22: Cleft palate Abnormal facies Thymic aplasia Cardiac defects Hypocalcemia due to parathyroid aplasia
DiGeorge Syndrome: what is it? how does it present?
22q11 deletion syndrome
Thymic, parathyroid, cardiac defects
Velocardiofacial syndrome: what is it? how does it present?
22q11 deletion syndrome
Palate, facial, cardiac defects
Williams Syndrome: what is it? how does it present?
Deletion of long arm of chr 7 that includes the elastin gene
Presentation: elfin face, intellectual disability, extreme friendliness with strangers, CV problems, hypercalcemia due to increased Vitamin D sensitivity, well developed verbal skills
Cri-du-chat syndrome: what is it? how does it present?
Deletion of sort arm of chr 5
Presentation: microcephaly, intellectual disability, high-pitched crying/meowing, epicanthal folds, VSD cardiac problem
Patau syndrome: what is it?
Trisomy 13
Patau syndrome: pregnancy screen
First trimester screen shows decreased free BHCG, decreased PAPP-A
PAPP-A
Pregnancy-associated plasma protein A
Protease, main substrates are insulin-like growth factor binding proteins
Patau syndrome: presentation
- Intellectual disability
- Rocker bottom feet
- Microphtlamia
- Microcephaly
- Cleft lip/palate
- Polydactyly
- Cutis aplasia (hole on top of head thing)
- Congenital heart defects
- Holoprosencephaly: embryo fails to develop 2 hemispheres
Patau syndrome: prognosis
Death by age 1
Edwards syndrome: what is it?
Trisomy 18
Edwards syndrome: presentation
- Prominent occiput
- Rocker bottom feet
- Intellectual disability
- Nondisjunction
- Clenched fists with overlapping fingers
- Low-set ears
- Micrognathia, Small jaw
- congenital heart disease
Edwards syndrome: prognosis
Death by age 1
Edwards syndrome: screening
First trimester: PAPP-A and BHCG are decreased
Quad screen: decreased BHCG, estriol, alpha-fetoprotein, inhibin A (could be normal)
Type of collagen in scars, define keloid and hypertrophic scar
Initially Type III and then gets replaced by type I
Keloid: disorganized Type I and III
Hypertrophic scar: Type III in parallel
Lesch-Nyhan Syndrome: how is it inherited?
X-linked recessive
Lesch-Nyhan Syndrome: what is the pathophys?
Lack of HGPRT enzyme which is used in the purine salvage pathway (recycles guanine to GMP and hypoxanthine to IMP)
You end up with excess uric acid production
Lesch-Nyhan syndrome: how does it present?
Hyperuricemia
Gout
Pissed off: aggressive behavior, lip biting, self mutilation
Retardation: intellectual disability
T: dysTonia, choreoathetosis (writing movement)
Lesch-Nyhan syndrome: how do you treat it?
Allopurinol, Febuxostat: you want to decrease amt of uric acid
Doesn’t treat the neuro sx though
Adenosine deaminase deficiency: what is it?
you lack ADA enzyme which is needed for degradation of adenosine
Adenosine deaminase deficiency: what is it a cause of?
Autosomal recessive SCID!
Xeroderma pigmentosum: what is it?
defect in nucleotide excision repair so you can’t remove pyrimidine dimers that are formed due to UV light exposure
Xeroderma pigmentosum: how does it present?
Increased risk for skin cancer: melanoma, basal cell skin CA, squamous cell skin CA
Lynch syndrome: what is the defect in?
Nucleotide mismatch repair
Lynch syndrome: what is another name for it?
Hereditary nonpolyposis colorectal cancer
Lynch syndrome: sequelae
Colon CA, endometrial CA
Ataxia telangiectasia: what is it?
Defect in non-homologous end joining in DNA repair
Ataxia telangiectasia: how does it present?
IgA deficiency, cerebellar ataxia, poor smooth pursuit with eyes, elevated AFP at 8 months, sensitivity to XR radiation
I-cell disease: what is it
Inherited lysosomal storage disease where the Golgi is unable to phosphorylate mannose residues on glycoproteins
This means that these proteins are NOT targeted for the lysosome but are instead secreted extracellularly
I-cell disease: how does it present?
Coarse facial features, cloudy corneas, restricted joint movement, high levels of lysosomal enzymes in plasma
Often fatal
Down’s Syndrome: what is it
Trisomy 21
Most common viable chromosomal disorder, most common cause of intellectual disability
Down’s Syndrome: how does it present?
- Intellectual disability
- Flat facies
- Prominent epicanthal folds
- Single palmar crease
- Gap btw 1st and 2nd toe
- Duodenal atresia
- Hirschsprung disease
- ASD/other congenital heart defects
- Brushfield spots (white spots in periphery of iris)
Early onset Alzheimers, Increased risk ALL/AML
Down’s Syndrome: what causes it
95% of cases due to meiotic nondisjunction which increases with maternal age
4% of cases due to unbalanced Robertsonian translocation btw chr 14 and 21
1% of cases due to mosaicism
Down’s Syndrome: what will the first trimester US show?
Increased nuchal translucency, hypoplastic nasal bone
Decreased serum PAPP-A, increased free BHCG
Down’s Syndrome: what will the second trimester quad screen show?
dec AFP, inc BHCG, dec estriol, inc inhibin A
