Introduction to Medical Genetics Flashcards
medical genetics
the study of human genetic variation of medical significance
-vs human-study of heredity in man
subunits of medical genetics
- clinical genetics-diagnosis
- genetic counseling- info
- molecular genetics, biochemical, cytogenetics-lab
mutation
- permanent, heritable change in the sequence of genomic DNA
- can occur at either the molecular or cytogenetic level
- may give rise to new alleles
- important mechanism of population variation
- neutral mutation-blue eyes
- pos-sickle cell trait
- neg-sickle cell disease
patterns of inheritance
- dominant vs recessive
- autosomal vs x linked
inherited gene complement
- mutations may be transmitted from one or both parents
- typically called the constitutional genome
acquired gene complement
-subset of cells in an individual that arose by clonal propagation from a single mutation in one cell
syndrome
- set of characteristics which occur together and are assumed to have a common basis
- not all characters occur in all affected individuals
- range of variability within a population
- VCFS-250 features, no single person has all of them
biochemical genetics
-subspecialty of genetics that deals with the diagnosis, treatment and research of inborn errors of metabolism
inborn errors of met
- genetically determined biochemical disorder in which a specific enzyme defect produces a metabolic block
- accumulation of substrate
- deficiency of products
- first reported in 1908-alcaptonuria, cystonuria, pentosuria, albinism
alkaptonuria
-accumulation of homogentisic acid in the blood, damage to cartilage, heart, kidney
pathways
- depending on what enzyme is gone, substrates will accumulate
- different color kitties-tyrosine oxidase leads to white kitty
enzyme defects
- secondary pathways may show increases in activity if primary can’t work
- salvage pathways
shared enzymes
-both products decrease and both precursors accumulate
inborn errors 2
- single enzyme defect
- recessive
- many recognized disorders
- challenge to detect the particular substance and pathway involved
- use of knowledge and biochem of genetics to make diagnosis
general clinical features of metabolic disorders
- poor growth
- mental retardation
- problems in general metabolism
- neurological problems
- patient evaluation- clinical picture- onset of MR over time
- family history- other affected siblings, unexplained infant deaths
biochemical genetic diseases
- aminoacidopathies
- organic acidemias
- FA oxidation disorders
- urea cycle disorders
- carb metabolism disorders
- glycogen storage disease
- lysosomal storage diseases
hyperphenylalaninemias
- PKU, variant PKU
- defects in BH4 metabolism
- phenylalanine hydroxylase
PKU
- phenylalanine hydroxylase to tyrosine
- build up and phenylpyruvic acid
- AR
- 1/ 10,000 live births
- treat by diet modification- early in life and in pregnancy
- low Phe diet
variant PKU and non PKU-hyperphenylalaninemia
- non PKU- 10 fold increase in Phe levels, less damaging, may be benign, may not require diet
- variant PKU- b/n extremes- requires a diet but not as restrictive
- clinical heterogeneity-different phenotypes from mutation of a single gene
BH4
- used with phenylalanine hydroxylase
- if deficient, can have PKU
- defect of BH4 metabolism, not the PAH
- locus heterogeneity- mutations in different genes leading to same disease, dont completely respond to diet
- also cofactor for other reactions-deficit of dopamine and serotonin
- give BH4 and nts
lysosomal storage diseases
- recessive
- mutation of a lysosomal hydrolytic enzyme leads to failure of degradation and the accumulation of macromolecules in lysosomes
- over 50 known
- clinically heterogeneous
- common presentation: progressive degeneration
lysosomal storage diseases 2
- cystinosis
- fabry
- gaucher
- i cell disease
- krabbe
- metachromatic leukodystrophy
- mucopolysaccharidosis
- niemann pick
- pompe
- sulfatase def
- tay sachs
GM2 gangliosidoses
- three different genes produce 3 different proteins that function together
- mutation in any one can result in abnormality
tay sachs
- AR
- rare except for ashkenazi jews
- onset 3-6 months, death 2-4 years
- deficiency of hexosaminidase A
- inability to degrade GM2 ganglioside
- no known trt
- carrier rate 1/27
- accumulation in brain
- cherry red macula
mucopolysaccharideoses
- group of heterogeneous disorders
- absence of specific enzyme involved in degradation of glycosaminoglycans
- accumulation of macromolecules in the lysosomes
- pernament progressive damage
- short stature, delay, skeletal abnormalities and joint stiffness, thickened skin, heart, liver or spleen damage
hunter
-iduronate sulfatase (enzyme)
-build up of dermatan sulfate and heparan sulfate
X linked recessive
hurler
- a-L-iduronidase
- dermatan and heparan sulfate
Scheie
- a-L-iduronidase
- dermatan and heparan sulfate
sanfilippo
- 4 enzymes
- heparan sulfate
morquio a
- gal-6-sulfatase
- keratan sulfate
morquio b
- b galactosidase
- keratan sulfate
maroteaux-lamy
- arysulfatase B
- dermatan sulfate
sly
- b glucuronidase
- dermatan and heparan sulfate
treatment for mucopolysaccharidoses
- bone marrow transplantation
- enzyme replacement therapy
- gene therapy
CT disorders: collagen
- procollagen/collagen
- collagen fibril
- mineralization in bone
OI
- mutations in type 1 collagen with either reduced production or defective collagen
- 4 classes
- AD
- brittle bones and skeletal deformities
- reduced production is mildest class, produced in half normal quantity
- type II is perinatal lethal
- type IV is mild to moderate bone deformity and fracturing, class III is intermediate
ehler-danlos
- error in post translational modification of collagen
- multiple subtypes
- AD, AR, x linked recessive
- skin fragility
- joint hypermobility
- skin hyperextensibility
- COL5A or COL3A
- shunned/freaks/circus
Marfan
- CT- fibrillin gene
- skeleton, eyes, heart
- tall and thin with long fingers
- joint laxity and scoliosis
- lung-pneumothorax
- dislocation of lens, cataracts, glaucoma, retinal detachment
- mitral valve prolapse, dilatation and dissection of aorta (athletes)
