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209 Cards in this Set
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penetrance
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percentage of individuals carrying and autosomal dominant gene and expressing the trait
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what does it mean if disease has 100% penetrance
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if you carry gene you will have disease
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what does it mean if disease has less than 100% penetrance
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you carry it but may not have disease
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variable expressivity
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showing a variety of problmes from patient to patient with same autsomal dominant disease
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what is an example of a disease with variable expressivity
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myotonic dystrophy
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pleiotropism
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multiple effects of a single mutant gene
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what is an example of a pleiotropic disease
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marfans syndrome
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what is an example of the pleiotrophy of marfans syndrome
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skeletal, ocular, and cardiovascular problems all arising from single mutant fibrillin gene
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genetic heterogeneity
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production of a given trait by different mutations
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what is an example of a disease with genetic heterogeneity
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charcot marie tooth disease
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what are mutations affecting in autosomal dominant disorders
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structural or regulatory proteins
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what percent of offspring will inherit autosomal dominant disorders
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50%
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when is the onset of clinical features with autosomal dominant
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may occur later than autosomal recessive
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marfans syndrome
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disorder of the connective tissues of the body
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where are the pricipal manefestation of marfans syndrome
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skeleton, eyes, and cardiovascular system
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what is the prevelance of marfans
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1 in 5000
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what percent of cases of marfans are familial
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70-85%
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marfans is a defect in what
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fibrillin-1
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what is fibrillin-1
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extracellular glycoprotein
major component of microfibrils found in extracellular matrix |
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fibrillin-1 acts as what
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scaffold on which topoelastin is deposited formin elastic fibers
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what are the majority of mutations in marfans syndrome
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missense mutations
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what is the less common mutation of marfans syndrome
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mutations of fibrillin-2
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what does mutation of fibrillin-2 cause
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congenital contractural arachnodactyly
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what are the skeletal abnormalities seen in marfans
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tall w/long extremities
ratio of upper body to lower is significantly longer than normal lax ligaments kyphosis, scoliosis, pectus excavatum, pigeon-breast deformity |
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what are the ocular changes seen in marfans
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bilateral subluxation or dislocation of the lens
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what are the cardiovascular changes seen in marfans
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mitral valve prolapse
aneurysm of ascending aorta |
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aortic aneurysm in marfans may become what
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dissecting
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aoric aneurysm in marfans may also cause what
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may involve aortic ring causing incompentence of aortic valve
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what should you look for in diagnosis of marfans
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ocular, skeletal, and cardiovascular changes, and family history
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what is the cause of death with marfans
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30-45% dissecting aortic aneurysm with rupture through wall
cardiac failure |
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achonodroplasia
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short limbed dwarfism with large head size
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80% of achonodroplasia are what
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new mutation
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huningtons disease
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progressive dementia and choreic movements
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when is typical onset of huningtons disease
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typically in 40's
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what is the gene loci on split hand split foot disorders
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7q21.3-q22.1
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how many loci are implicated in split hand split foot
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at least 5 distinct loci
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what gentic principals are important in split hand split foot
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reduced penetrance and variable expressivity
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acrocephalosyndactyly has what
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zero fitness and therefore 100% are new mutations
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acrocephalosyndactyly is associated with what
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syndactyly of the hands and feet
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what are common characteristics of acrocephalosyndactyly
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mental deficiency
craniosynostosis hypertelorism |
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what do we see fusion of in aperts syndrome
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2 fingers or 2 toes or a tab of skin representing an extra digit
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premature closer of what in aperts syndrome
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cranial sutures
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mutations of what in ruperts syndrome
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fibroblast growth factor receptor-2
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chromosomes involved in tuberous sclerosis
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9 or 16
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tuberous sclerosis characterized by what
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seizures
mental retardation sebaceous adenomas |
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what are the cutaneous lesions of tuberous sclerosis
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angiofibromas
leathery thickening in localized patches hypopigmented areas subungal fibromas |
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kidney problems of tubereous sclerosis
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angiomyolipoma
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autosomal dominant disorders
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marfans syndrome
achondroplasia huningtons disease split hand split foot aperts syndrome tuberous sclerosis |
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single largest category of mendelian disorders
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autosomal recessive
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onset of autosomal recessive disorders
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early
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protiens effected by autosomal recessive disorders
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enzyme protiens
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alleles effected by autosomal recessive disorders
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both alleles are mutations
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kind of penetrance with autosomal recessive
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complete penetrance
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expression in autosomal recessive tends to be what
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more uniform
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phenylketouria
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deficency in phenylalanine hydroxylase
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what does phenylketouria lead to
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hyperphenylalninemia
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what is the onset of phenylketouria
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normal at birth within weeks dvlp rising levels in plasma
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what is the result of phenylketouria
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impaired brain dvlpmnt and mental retardation
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what is the treatment for phenylketouria
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strict diet from birth
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what is the diagnosis of phenylketouria
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routine screening in postnatal period
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what are the categories of lysosomal storage disorders
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spingolipidoses
mucopolysaccharidesoses mucolipidoses |
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characteristics of lysosomal storgae diseases
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inherited lack of functional lysosomal enzymes or proteins exxential for function
lysosomes become filled with undigested macromolecules normal cell function is inhibited |
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what two conditions are typical in lysosomal storage disorders
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hepatomegaly and splenomegaly
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spingolipidoses
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tay-sachs disease
sandoff disease neimann pick disease gauchers disease krabbes disease |
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other names for tay-sachs
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GM2 gangliosidosis, hesosaminidase alpha subunit deficiency
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tay sachs has a deficiency in what
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hexosaminidase A
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what accumulates in tay sachs
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GM2 ganglioside
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where does GM2 gangioside accumulate in tay sachs
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neurons in central and autonomic nervous system and retina
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tay sachs most common in what population
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jews of eastern european origin
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gene location for tay sachs
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chromosome 15
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characteristics of tay-sachs
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motor/mental deterioration at 6 months
death by 2-3 yrs blindness cherry red spot on retina |
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characteristics of neurons in tay sachs
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ballooning of neurons with cytoplasmic vacuoles which stain positive for lipids
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what are the vacuoles in the neurons of tay-sachs
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distended lysosomes filled with gangliosides
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what does tay sachs look like under EM
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whorled configuration within lysosomes
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sandoff disease
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deficiency of hexosaminidase B
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what is the gene location of sandoff disease
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chromosome 5
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types of neimann-pick disease
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A, B, C
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neimann-pick disease
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deficiency of sphingomyelinase
acculumation of sphingomyelin |
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Type A neimann-pick
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infantile form with sever neurologic involvement and marked visceral accumulations
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what is life expectancy with type A neimann-pick
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within 1st 3 yrs of life
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Type B neimann-pick
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organomegaly without CNS involvement
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Type C neimann-pick
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defects in intracellular exterification of cholesterol
accumulation of cholesterol |
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most common lysosomal storage disorder
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gauchers disease
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gauchers disease
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lack of glucocerbroside
accumulation of glucocerbroside |
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how many clinical subtypes of gauchers are there
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three
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characteristics of type 1 gauchers disease
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adulthood
splenic and skeletal involvement pathologic fractures massive splenomegaly somewhat shortened lifespan |
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characteristics of type 2 gauchers disease
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acute neuroneopathic infantile
no glucocerebroside activity progressive CNS involvement with early death |
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characteristics of type 3 gauchers disease
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intermediate between type 1 and 2
jevenile presentation progressive CNS involvement life span shortened |
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morphology of gauchers
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accumulation of glucocerebrosides in phagocytic cells
cytoplasm has fibrillary apperance |
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apperance of cytoplasm in gauchers
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crumpled tissue paper apperance
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inborn errors of metabolism affecting the CNS
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Krabbes disease
metachromatic leukodystrophy adrenoleukodystrophy |
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krabbes disease
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deficiency of galactosylceramidase
accumulation of glactocerebroside |
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function of galactosylceramidase
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catabolism of galactocerebroside to ceramide and galactose
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what is the toxic element in krabbes disease
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psychosine
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what is the course of krabbe disease
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rapidly progressive course
onset btwn 3 and 6 mo survival beyond age 2 uncommon |
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presentation of krabbe disease
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stiffness, weakness, problems feeding (failure to thrive)
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morphology of krabbe disease
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loss of myelin and oligodendrocytes, macrophages filled with cerebroside
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metachromatic leukodystrophy
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deficiency of arylsulfatae A
accumulation of sulfitides especially glactosyl sulfatide |
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adrenoleukodystophy
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accumulate high levels of saturated very long chain fatty acids in the brain and adrenal cortex
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characterisitcs of adrenoleukodystrophy
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progressive disease with symptoms due to myelin loss in the CNS and PNS and adrenal insufficiency
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most common form of ALD
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x-linked
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general characteristics of mucopolysaccharidoses
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coarse facial features
clouding of the cornea joint stiffness mental retardation |
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mucupolysaccharidoses
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hurler syndrome
scheie disease hunter syndrome sanfilippo disease morquio disease |
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mucopolysaccharidoses effect what enzymes
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enzymes that are responsible for the degradation of mucopolysaccharides
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all mucopolysaccharidoses are what except what
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all are AR except hunters which is X linked
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morphology of mucopolysaccharidoses
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accumulated muchopolysaccharides are usually found in mononuclear phagocytic cells, endothelial cells, smooth muscle cells, and fibroblasts
hepatosplenomegaly, skeletal deformities, valvular lesions, and subendothelial arterial deposits are common |
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hurlers syndrome
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deficiency of alpah L iduronidase
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severe forms of hurlers syndrome
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dwarfism
gargoyle faces other |
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course of hurlers syndrome
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normal at birth
dvlp hepatosplenomegaly by age 6-24 mo. |
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hunters syndrome mode of inheritance
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x-linked recessive
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hunters syndrome
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deficiency of L iduronate sulfate
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glycogen storage disease defects
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defects in the synthesis or catabolism of glycogen
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von gierkes disease
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deficiency of G6P
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conditions seen in patient with von gierkes disease
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hypoglycemia
hepatomegaly |
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mcardles syndrome
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glycogen stores in the muscle increase
muscular weakness |
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clinical signs of mcardles syndrome
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muscle cramping after exercise and failure of exercise induced lacic acidosis
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pompe disease
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deficiency in alpha glucosidase
lack of branching enzyme |
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alkaptonuria
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deficiency of homogentisic acid oxidase
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alkaptonura blocks what
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metabolism of phenylalanine
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what are signs of alkaptonuria
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black urine
ochronosis-blue/black pigmentation pigmented cartilage is readily eroded |
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marjority of X-linked disorders
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X-linked recessive
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X-linked recessive are expressed
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fully in males
paritally in heterozygous females but are carriers |
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lyon hypothesis
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random inactivation of either parternally or maternally inherited X chromosome occurs in each cell of females
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due to lyon hypotheis normal females are
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mosaics
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X inactivation is regulated by
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XIST gene (Xq13)
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inactivated X gene is reactivated when
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in germ cells
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X linked dominant disorders
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rett syndrome
vitamin D resistant ricketts |
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signs of rett syndrome
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mental retardation
females are infertile prenatally lethal in males |
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vitamin D resistant rickets
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renal tubular loss of phosphate
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vitamin D resistant rickets interferes with what
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skeletal muscle ossification
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lesch-nyhan syndrome
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complete lack of HGPRT
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what is HGPRT involved in
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salvage pathway for purine synthesis salvages purine bases from the breakdown of nucleic acids
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what happens in the absence of HGPRT
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increased purine synthesis de novo and increased production of uric acid
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signs of lesch-nyhan syndrome
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normal at birth
high uric acid levels self mutilation, mental retardation, spasticity gout |
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lack of what type of terminals in lesch-nyhan syndrome
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dopaminergic terminals
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multifactorial inheritance
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combined action of environment and two or more mutant genes
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in multifactorial inheritance the risk of expressing gene is based on
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the number of mutant genes inherited
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the rate of recurrence of mulitfactorial inheritance is
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the same for all first degree relatives
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examples of multifactorial inheritance
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congenital heart disease
diabetes mellitus cleft lip or palate hypertension gout |
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cytogenic disorders
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alterations in the number or structure of chromosomes
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euploid
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exact multiple of 23
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aneuploidy
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not exact multiple of 23
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causes of aneuploidy
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nondisjunction
anaphase lag |
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what happens to gamete with nondisjunction
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either have one extra chromosome or one less
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what does monosome of a autsome usually result in
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loss of too much genetic material to have a live birth
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monosomy or trisomy of sex chromosomes are what
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compatible with life but demonstrate phenotypic abnormalities
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mosaicism
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mitotic errors in early development give rise to two or more populations of cells in the same individual
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where is mosaicism common
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more common on sex chromosomes less common on autosomal choromosomes
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translocation
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one segment of a chromosome is transferred to another
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balances reciprocal translocation
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single break in two chromosomes with exchange of material
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robertsonian translocation
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translocation between two acrocentric chromosomes
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inversions
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a rearrangement that involves two breaks within a single chromosome with inverted reinsertion of the segment
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ring chromosome
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terminal ends of the chromosome are lost and remaining chromosome circularizes
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isochromosomes
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chromosomes in which one arm is missing and the other arm is duplicated
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most common chromosomal disorder
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trisomy 21
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is is the chromosome count in trisomy 21
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47 in 95%
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those with trisomy 21 but not 47 chromosomes have what
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normal numbers of chromosomes but extra chromosomal material is present as a translocation
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cause of trisomy 21
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meiotic nondisjunction 95%
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4% cause of trisomy 21
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robertsonian translocation
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1% cause of trisomy 21
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mosaics
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parent are what with trisomy 21 children
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normal karotype
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what is a strong influence on trisomy 21
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maternal age
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clinical presentation of trisomy 21
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flat face with palpebral fissures and epicanthic folds
mental retardation congenital heart disease increased risk for leukemia abnormal immune response simian crease |
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common trait of trisomy 21 patients over 40
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neuropathic changes characterisitc of alzheimers disease
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medial age for death with trisomy 21
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47
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trisomy 13
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patau's syndrome
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cause of trisomy 13
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nondisjunction
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trisomy 13 high association with
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maternal age
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clinical presentation of trisomy 13
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severe mental retardation
microcephaly cleft lip and palate microphthalmia rocker bottom feet polydactyly |
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trisomy 18
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edwards syndrome
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clinical presentation of trisomy 18
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mental retardation
rocker bottom feet low set ears congenital heart defects |
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cri-du-chat syndrome
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deletion of 5p
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clinical symptoms of cri-du-chat syndrome
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severe mental retardation
catlike cry congenital heart disease hypertelorism epicanthus retrognathia |
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most frequent genetic disease involving sex chromosomes
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klinefelters syndrome
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klinefelters syndrome
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male hypogonadism
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when does klinefelters syndrome occur
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occurs when there are two or more X chromosomes and at least one or more Y chromosomes
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what is the prinicipal cause of reduced spermatogenesis and male infertility
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klinefelters syndrome
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this is uncommon in klinefelters
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mental retardation
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what hormones are consistent finding in klinefelters
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high FSH and estrogen, low testoterone
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clinical presentation of klinefelters
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long limbs
gynecomastia tall, thin small genitalia eunochoid body habitus |
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klinefelters has increased risk of what
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breast cancer
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XXY syndrome
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tall
phenotypically normal |
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Turners syndrome
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complete or partial monosomy of the X chromosome
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what is turners syndrome characterized by
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hypogonadism in phentypic females
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what percent of turners lacks entire X chromosome
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57%
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1/3 of turners lack what
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a portion of X
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2/3 of turners are what
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mosaics
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clinical presentation of turners syndrome
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peripheral lymphedema at birth
congenital heart disease webbed neck short stature broad chest and widely spaced nipples |
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congential heart defects with turners
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preductal coarctation of aorta
bicuspid aortic valve |
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sign of turners in adolescents and adults
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failure to dvlp normal secondary sex characteristics
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turners syndrome has increased risk for
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dvlping autoantibodies to thyroid gland
glucose intolerance insulin resistance |
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what do you see in women with turners
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primary amenorrhea
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ehlers danlos syndromes
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defect in the synthesis of fibrillar collagen
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modes of inheritance of ehlers danlos
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all three patterns of mendelian
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what tissue are usually effected by ehlers danlos
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skin and joints
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genotype of androgen insensitivity syndrome
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46XY
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phenotype of androgen insensitivity syndrome
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female
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clinical finding in androgen insensitivity syndrome
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mutation of androgen receptor gene
no ovaries or uterus testes within abdomen or inguinal canal |
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mode of transmission for androgen insensitivity syndrome
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x-linked
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Fragile X syndrome
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multiple repeats of CGG
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normal CGG repeats
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29
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CGG premutation level
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50-200
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CGG mutations
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>200
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clinical signs of fragile X syndrome
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severe MR
enlarged testes elongated face large everted ears |
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most common inherited cause of MR
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fragile X syndrome
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2nd most common cause of MR
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fragile X syndrome
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Differences from typical X-linked disorders to fragile X
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carrier males
affected females |
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risk of phenotypic effects of fragile X
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depends upon position of individual pedigree
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anticipation of fragil X
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clinical features worssen with each successive generation
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