Conditions Flashcards
Neurofibromatosis, type 1 (NF1)
AD, NF1 LOSS OF FUNCTION. neurofibromas, Lisch nodules on the iris, cafe au lait spots, axillary freckles. Optic glioma, osseous lesions. Shows variable expressivity and has a pleiotrophic phenotype and age-dependent penetrance
congenital disorder
a disorder present at birth
Congenital adrenal hyperplasia
Autosomal recessive. Cortisol synthesis blocked but increased synthesis of androgens. ACTH secretion increased, adrenals produce more androgens–>ambiguous genitalia, masculinization in females
Duchenne Muscular dystrophy
X linked. frameshift. Loss of function mutation, deletion of dystrophin gene–>accelerated muscle breakdown.
- pseudohypertrophy of the calf
- Gower’s maneuver to stand
- weakness starts in pelvic girdle, progresses superiorly
- cardiac myopathy**
Hereditary retinoblastoma
Rb gene mutation, loss of function mutation. Loss of tumor suppressor function
Osteogenesis imperfecta type I
Autosomal dominant bone disorder. Nonsense mutation=premature termination of Col1A1. Reduced collagen=brittle bones, fractures, blue sclera, can be confused with child abuse
Hemoglobin Kempsey
missesnse mutation of Beta hemoglobin gene. Gain of function mutation. Hemoglobin has higher affinity for oxygen, does not unload oxygen effectively in tissues.
Achondroplasia
AD. FGFR3 mutation increases the normal signaling though intracellular tyrosine kinase domain (receptor always in the ‘turned-on’ state).
- Rhizomelic limb shortening, short fingers, trident hands, midface retrustion, frontal bossing, small foramen magnum, craniocervical instability
- associated with advanced paternal age
Alzheimer disease
Multifactorial or Autosomal Dominant. Gain of function mutation. in Trisomy 21, extra copy of chromosome = 3 copies of the APP gene. increased production of APP protein which contributes to early-onset Alzheimer
Charcot-Marie-Tooth
Autosomal Dominant. PMP22(duplication) Gain of function mutation. increases amount of PMP22 protein. degenerative nerve disorder that affects peripheral nerves and myelin sheaths.
Sickle cell anemia
Autosomal recessive, novel property mutation. Glu6Val mutation of the beta globin gene= Hb that transports oxygen essentially normally. In low O2, the Val residue leads to polymerization of hemoglobin into long protein-fibers which deform and restrict RBCs
Huntington disease
Autosomal dominant. Novel property mutation. triplet repeat disorder -expansion of CAG repeats in the gene increases number of glutamine residues. Above threshold = a novel toxic effect on the huntington protein
Tay Sachs
AR. HEXA mutation=defective hexosaminidaseA, can’t degrade ganglioside=progressive CNS destruction.
Achondroplasia
Autosomal Dominant. Mutation in FGFR3. Rhizomelic limb shortening, short fingers, genu varum, trident hands, large head/frontal bossing, midface retrusion, crainocervical instability
What is an example of full penetrance?
Achondroplasia
What are 3 examples of reduced penetrance?
Retinoblastoma, BRCA, Huntington’s
What are two examples of variable expressivity?
neurofibromatosis Type 1, Van der Woude
What are some of the variable expressivity traits of neurofibromatosis type 1?
cafe au lait spots, neurofibromas, axillary/inguinal freckles, optic glioma, lisch nodules, osseous lesions
What causes neurofibromatosis?
Loss of function mutation of NF1 (neurofibromin-tumor suppressor gene)
Marfan’s
Autosomal dominant, mutation in FBN1-reduces amount
Symptoms of Marfans
connective tissue: occular, skeletal, cardiovascular. Aortic root enlargement, ectopia lentis, tall stature
Autosomal Dominant Polycystic Kidney disease
Autosomal dominant, PKD1 and PKD2 mutations produce truncated polycystin 1 and 2. large renal cysts
Familial hypercholesterolemia
Autosomal Dominant. LDLR mutation, high cholesterol and LDL, xanthomas, premature artery disease and death
Huntington disease
Autosomal Dominant. Mutation of HTT protein with trinucleotide expansion of glutamine. Penetrance depends on the number of repeats. Anticipation common from generation to generation. Paternal transmission bias
Duchenne Muscular Dystrophy
X linked recessive. DMD mutates, absence of dystrophin. Calf hypertrophy, muscular weakness proximal>distal, cardiomyopathy. Onset before 5, wheelchair bound by 13, death in 30s. Gower’s maneuver
Hemophilia A
X linked recessive, F8 mutation, Factor 8 deficiency. Spontaneous bleeds, bruising, delayed wound healing. 10% of females affected. Treat with giving factor VIII
Fragile X
Trinucleotide repeat (CGG) FMR1, silenced=failure to produce protein=mental retardation.located in 5’UTR** 1/3 females affected. dysmorphic features, autistic behaviors (biting/flapping), aggression
syndromic deafness with retinitis pigmentosum suggests:
Usher (AR)
syndromic deafness with thyroid goiter suggests
Pendred (AR)
syndromic deafness with arrhythmia or sudden death suggests
Jervell and Lange-Nielson (AR)
syndromic deafness with White forelock
Waardenburg type 1 (AD)
syndromic deafness with 8th nerve schwannomas
neurofibromatosis type 2
Androgen insensitivity
X linked recessive, loss of function. Mutation in androgen receptor causes feminization
Becker Muscular dystrophy
X linked. exon deletion (but in frame unlike DMD), loss of function-too little dystrophin, onset later than Duchenne’s, death in 40s
HNPP
AD. PMP 22 (deletion) Loss of function. focal pressure neuropathies
Osteogenesis Imperfecta type II, III, IV
AD. Novel property. COL1A2. Makes malformed collagen, more severe than Type 1
Fragile X ataxia
X linked. Trinucleotide repeat in 5’UTR. Too much FMRP Parkinson symptoms, ataxia/tremor
Frederich ataxia
Trinucleotide repeat ** loss of function in intron
Myotonic dystrophy 2
AD. Trinucleotide Repeat novel property,in intron
PKU
AR mutation in phenylalanine hydroxilase mutation. Mental retardation, hyperactivity, microcephaly. Can treat with diet and BH4 cofactor
A1-antitrypsin deficiency (ATD)
AR. a1-AT mutation. Too little ADT cannot inhibit elastase effectively. emphysema and liver cirrhosis Z allele (severe): misfolded protein S allele (less severe) unstable protein doesn't get stuck in liver
Sandhoff
AR. HEXB. mutated hexoaminaseB, cannot break down globoside
Marfan
AD. FBN1 mutation, loss of function-conenctive tissue disorder: tall, aortic root enlargement, ectopia lentis,
Cooley’s anemia (_____ ______)
(Thalassemia major)dense skull, bone marrow, ostopenia, enlarged splen, iron overload
Fabry disease
X linked. Deficiency of a-galactosidase A. Clinical: neuropathy, nephropathy, cardiomyopathy, need renal dialysis or transplantation or treat with recombinant (intracellular fairy) alpha-gal
Pompe
AR, deficiency in acid a-glucosidase. progressive muscle failure unless given ERT
Progeria
aging disease from lamin protein mutation. Treat with Farnesyl Transferase Inhibitor
Nonsyndromic deafness
Both AD or AR (allelic heterogeneity but GJB2 is most common AR) 3/4 of hearing loss in non syndromic. conductive and neural hearing loss
Premature ovarian failure
X linked triplet repeat expansion. Women only
ADA deficiency
Metabolic disorder, treat with replacing intracellular protein
