Autosomal Dominant Flashcards
HNPP (Hereditary Neuropathy with Liability to Pressure Palsies)
Temporary (usually reversible) neuropathy when pressure is applied to various nerves; limbs can ‘go to sleep’ for longer periods of time (hours, days, to months)
First attack in 20-30 yrs old (usually recovery is complete, there is mild disability if not)
Loss of Function:
Deletion of PMP22 gene due to unequal crossing over (PMP22 is integral glycoprotein in nerves)
Osteogenesis Imperfecta Type 1
Brittle bones, increased fractures, blue sclerae, normal stature, progressive hearing loss in adults
Loss of Function: nonsense frameshift in COL1A1
Causes unstable mRNA that’s degraded, reducing COL1A1, which is important for collagen strength
Charcot-Marie-Tooth Type 1A
Demyelinating motor and sensory neuropathy; lower extremity weakness and muscle atrophy and mild sensory loss; foot deformity known as hammertoes
Note: all versions of CMT affect peripheral nervous system, type 1A is dominant
Gain of Function: duplication of of PMP22 gene, 17p11.2
(PMP22 is integral glycoprotein in nerves)
Osteogenesis Imperfecta Types II, III, IV
Brittle bones, increased fractures, blue sclerae (Type II much more severe, usually lethal in perinatal period)
Novel Property Mutation: the COL1A2 protein has new property due to new/different folding, forming collagen trimers (much worse than Type I)
Classified as problem of assembly of monomers into homodimer
Huntington’s Disease
Progressive neurodegenerative disorder with adult onset; chorea (child-like dance movement); death within 15 yrs of onset; Gene anticipation (earlier onset in offspring and subsequent generations) most commonly occurs with paternal repeats
Polyglutamate disease; increased CAG repeats (>40 penetrant, <27 is normal, some traits in between) in huntingtin gene (number of repeats correlates with disease onset and severity) due to slipped mispairing
Parental transmission bias—trinucleotide expansion more likely to come from father
Larger the repeat number, the greater the clinical severity in terms of age-of-onset and progression
Myotonic Dystrophy 1
Droopy eyes, intellectual difficulty, hypotonia
Increased CTG repeats (in 3’ UTR) of DMPK gene
Achondroplasia
Short stature, rhizomelic limb shortening (proximal limb shorter than distal limbs), large head with frontal bossing (prominent forehead); megalencephaly; “trident” hand; spinal cord compression (small cranial foramina); between 3-7% die suddenly in during first year
Gain of Function:Gly380Arg mutation in FGFR3 Gene (hot spot for mutation)
Receptor normally inhibits bone growth; defective receptor always on, causing shortening of limbs
De novo mutations occur almost exclusively in father’s germline and increase with paternal age
Homozygous state is lethal! Only see phenotype in heterozygotes (this is incomplete dominance)
Neurofibromatosis Type 1
Cafe au Lait spots, axillary and inguinal freckling; multiple neurofibromas; Lisch nodules (spots/bumbs on eye)
100% penetrance, variable expressivity
Mutation on chr. 17 on NF1 gene (codes for neurofibroma protein)
Marfan Syndrome
Connective tissue disorder; ocular, skeletal and cardiovascular manifestations; risk of aortic aneurysm; appear tall and skinny (long-limbed); hypermobile joint, pectus excatum/carnatum
Mutation in FBN1 mutations (codes for fibrillin)
AD Polycystic Kidney Disease
Enlarged kidneys with multiple cysts, end stage renal disease, extra-renal cysts (i.e. in pancreas), intracranial aneurysms
Mutation in ADPKD-1 (85%; chr. 16) or ADPKD-1 (14.5%; chr. 4); Locus heterogeneity (mutation in more than one locus can the same clinical condition)
Tuberous Sclerosis
Angiofibromas, cortical dysplasias, cardiac rhabomyoma, renal problems, ungual fibroma, dental enamel pits
LOTS OF TUMORS
Loss of function: mutation in TSC1, TSC2 (Chrs 9 and 16) that encode proteins monitoring cell growth/proliferation (hamartin, tuberin)
