Path Genetic Disorders

Front 1

point mutation missense/nonsense

Back 1

Point mutations – single nucleotide change, missense causes a different amino acid to be coded for, nonsense causes a stop codon to be coded for

Front 2

Pleiotropy

Back 2

– a single gene mutation may lead to many phenotypic effects

Front 3

Genetic heterogeneity

Back 3

the same disease may be caused by several different mutations

Front 4

Autosomal dominant disorders
- kids/parents
- penetrance/expressivity
- what kind of genes do they encode

Back 4

- 1 parent has the disease
- if there is 1 affected parent, each kid has a ½ chance of getting the disease
- if neither parent is affected, a new mutation could have arisen in index case, in which case no siblings have increased risk of developing disease
- have have reduced penetrance – some people w/ trait may not show the diease
- may have variable expressivity – people that have the trait may have different phenotypes
- usually delayed age of onset
- dominant traits do not usually encode enzymes, usually encode parts of metabolic pathways, like the receptors or transport proteins, or structural proteins like collagen

Front 5

Autosomal recessive disorders
- kids/parents
- penetrance/expressivity
- what kind of genes do they encode

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- both of the alleles at a gene locus are mutants
- usually, neither parents are affected (both heterozygote carriers), and siblings have a ¼ chance of getting disease
- usually have complete penetrance and uniform expression
- onset is usually early in life
- new mutations are rarely found because they form a heterozygote carrier, no clinical s/x
- usually encode enzyme proteins

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X linked disorders
- male /female parent/kid

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- all the daughters of an affected male are carriers
- ½ of sons of a carrier mother are infected
- carrier women are rarely affected, but may be due to x inactivation

Front 7

Marfan’s syndrome
- mutated gene
- pattern of inheritance
- clinical features

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- autosomal dominant, 1/20,000
- fibrillin makes up microfibrils which are integral components of elastic fibers
- FBN1 encodes fibrillin, mutation here = marfan’s; deficiency of fibrillin is also seen w/ ⇑ TGFbeta production, which regulates connective tissue growth
- Clinical: slender, elongated, long arms, legs, fingers, hyperextensible joints, chest deformities, ocular changes; aortic dissection or rupture are possible due to fragmented elastic and is the most common form of death

Front 8

Ehlers-Danlos Syndromes
- what kind of gene is mutated (3 possible defects)
- complications
- clinical features

Back 8

- collagen defect
o can be due to enzyme deficiency of enzyme lysyl hydroxylase – causes interference w/ normal cross linking of collagen, autosomal recessive
o can have defect in type III collagen gene – COL3A1 (type III collagen found in colon, blood vessels), dominant
o can have defective type I collagen COL1A1 and COL1A2 genes
- skin – hyperextensible, fragile, vulnerable due to lack of tensile strength
- joints – hypermobile
- serious complications: rupture of colon, arteries, ocular problems, diaphragm hernia

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Familial Hypercholesterolemia
- type of mutation
- epi
- what happens

Back 9

- defect in LDL receptor, which can transport both LDL and IDL, very common 1/500
- in liver, LDL receptor uptakes IDL to produce VLDL, but if IDL is not taken up by liver, it is transformed into to LDL
- in other cells, LDL binds receptor, which is internalized into cell, LDL is degraded in lysosome into free cholesterol which ⇓ cholesterol synthesis
- in familial hypercholesteremia, cells can’t uptake and degrade cholesterol, liver can’t up take IDL, so there is ⇑ synthesis of LDL
- excess cholesterol enters monocytes and blood vessel walls via the scavenger receptor, causes skin xanthomas (deposits of cholesterol in skin) and premature atherosclerosis
- many mutations can cause LDL receptor deficiency: receptor can’t be synthesized, if synthesized, not transported from ER to golgi, can’t bind LDL, can’t internalize into the cell, get’s trapped in lysosome

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Phenylketouria (PKU)
- what the mutation is
- what this leads to/ how it causes clinical s/xs
-t/x

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- 1/12,000, recessive
- mutation in the enzyme phenylalanine hydroxylase, which converts phenylalanine to tyrosine
- → ⇑⇑ phenylalanine, impairs brain dvmt → mental retardation, seizures
- →⇓ tyrosine, needed for melanin formation → ⇓ pigment in hair/skin
- t/x: restrict dietary phenylalanine until brain dvmt is complete
- maternal PKU – if mom has PKU and has ⇑⇑ phenylalanine in circulation, it can cross the placenta and cause the developing fetus to be retarded and have abnormalities
- other enzymes can cause PKU, impt to know because they can’t be t/x w/ dietary restriction of phenylalanine
Galactosemia

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Galactosemia
- epi - how common
- where the mutation is
- clinical s/xs

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- galactose is converted by galactose-1-phostphate uridyl transferase, this enzyme is deficient in galactosemia; not common disase
- accumulation of galactose -1-phosphate, and galactitol (from another metabolic pathway) can accumulate in organs
- liver damage is common – cirrhosis like scarring
- lens of eye absorbs h20 and galactitol → cataracts
- CNS damage
- t/x w/ removal of galactose from diet for the 1st 2 yrs

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Lysosomal Storage Diseases
- define
-list

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= cause the accumulation of partially degraded metabolites in lysosome; often cause hepatospleomegaly since protein intermediates are in monocytes, often CNS involvement

Tay Sachs Disease, Neimann pick, gaucher's disease, mucopolysaccharidoses

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Tay Sachs Disease
- who it affects/ how commonly
- what is deficient
- what the deficiency causes
- clinical progression

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- 1 in 30 Ashkenazi jews are carriers
- deficiency of hexosaminidase A which degrades ganglioside GM2
- GM2 accumulates in neurons and glial cells, mutant protein can cause apoptosies
- Clinical progression: motor weakness @ 3-6 months, mental retardation, blindness, neuro probs – death w/in 2-3 years

Front 14

Niemann pick disease A and B
- what is deficient
- what the deficiency causes
- difference btw A and B

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- deficiency of acid sphingomyelinase which results in accumulation of sphinomyelin
- accumulates in macrophages (which look foamy), organs w/ lots of macrophages like the spleen, liver, bone marrow, lymph nodes and lungs are more affected
- in type A, CNS is also affected w/ severe neurological deterioration
- in type B, organomegaly but no CNS probs

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Neimann pick type C
what accumulates
what is deficient

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, primary defect in lipid transport, affected cells accumulate cholesterol and gangliosides

Front 16

Gauchers Disease
- deficiency
- type I/ II/III

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- RBCs are broken down to glucosylceramide
- In gaucher’s disease, glucosylcerimidase is deficient, can’t remove glucose from ceramide
- Glucosylceramide is in blood as macromolecule, engulfed by phagocytic macrophages in liver, spleen, bone marrow → hepatosplenomegaly
- Activated macrophages release IL2, 5, TNF – damaging
- Type I – no CNS involvement, hepatosplenomegaly, bone involvment (due to cytokines from macrophages); seen in jews, good prognosis
- Type II and III have CNS involvement, w/ II being more severe

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Mucopolysaccharidoses
- clinical features
- different types

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- defective degredation of mucopolysaccharieds, progressive disorders involving liver, spleen, heart, BVs
- course facial features, clouding of cornea, joint stiffness, mental retardation
- type I – recessive, hurler syndrome, deficiency of alpha l idurnidase, short life expectancy, death due to mucopolysaccharides in coronary arteries and valves, accumulation in neurons cause retardation
- type II hunter syndrome – x linked, milder clinical course

Front 18

Glycogen Storage Diseases

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- excessive accumulation of glycogen, recessive
- hepatic type, ex Gierke disease – deficiency of liver enzyme involved in glycogen metabolism; hepatomegaly due to glycogen storage, hypoclycemia due to failure of glucose prodction
- myopathic type, ex McArdle disease – enzymes involved in muscle glycolysis are deficient, glycogen in stored in muscles; muscle cramps after exercise, myoglobinuria, failure of exercise to induce increased lactic acid since glycolysis is blocked
- pompe disease – lysosomal storage disease of glycogen

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Trisomy 21
- clinical
- genes

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Karyotypes: trisomy 21 (due to meiotic nondisjunction), translocation of the long arm of 21 (usually when a parent has a robertsonian translocation), mosaics
Epidemiology: most common, 1/700
Genes: NFAT (nuclear factorof activated T cells), pleiotropic transcription factor – regulates many genes in development
Clinical: epicanthic fold, flat profile, mental retardation, cardiac malformations, infections, infections

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DiGeorge syndrome/ velocardiofacial syndrome
- chromosomal
- clinical
- gene

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Deletion 22q11.2 DiGeorge syndrome/ velocardiofacial syndrome
Genes: TBX1
Clinical: facial dysmorphism, heart disease developmental delay, thymic hypoplasia cuasing impaired T cell immunity, parathyroid hypoplasia causing hypocalcemia

Front 21

Kleinfelter Syndrome

Back 21

Karyotype: at least 2xs and at least 1 Y, cuased by nondisjunction of sex chromosomes
Clinical: male hypogonadism, ⇑ length btw soles and pubic bone, ⇓ facial/body/pubic hair, sterility, possibly mild rediuction in intelligence

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Turner Syndrome
- karyotype
- clinical

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Karyotype: X, may be missing entire X chromosome or have deletions from the short arm of the X chromsomes, may have moscaicism → karyotypic variation causes phenotypic variation
Clinical: short stature, 1° ammenhorea, webbing of neck, broad cehst, infertility, lymphedema at birth, coarction of aorta , hypothyroidism, normal mental dvmpt
Epi: 1/3000 femalres
Genes: short stature homeobox (SHOX) – remains on in both copies of X chromosomes (not inactivated), responsible for vertical growth

Front 23

Trisomy 18 – Edward’s syndrome

Back 23

- heart and renal defect/malformations
- rocker bottom feet
- prominent occiput
- overlapping fingers
- small jaw

Front 24

Trisomy 13 – Patau sydrome

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- cleft lip
- micrcephaly
- polydactyly
- heart and renal malformations
- rocker bottom feet

Front 25

Fragile X syndrome
- inheritance
- gene
- clinical features
- premutation clinical

Back 25

Triplet repeat mutations: Fragile X syndrome
Amplification of CGG repeats within the FMR1 gene on the X chromosome; normal people ~ 29 repeats, premutation ~ 52-200 repeats, full mutation >200 repeats
Hypermethylated CGG repeats results in the silencing of the FMR1 gene, the product of which is impt in brain and testes
Can ⇑⇑ # of repeats during oogenesis
Clinical: mental retardation, large testicles. large mandible
Permutation – premature ovarian failure, progressuve neurodegenerative syndrom in males (w/ intention tremor, may progress to parkinsons)

Front 26

Mitochondrial genes

Back 26

transmitted thru maternal inheritance, each person has their mothers mito DNA, and mom passes her mito DNA to all offspring; encodes enzymes involved in ox phos, so if affected, causes diseases in the organs most dependent on ox phos – skeletal muscle, heart, brain

Front 27

Angelman’s syndrome

Back 27

An area of chromosome 15q is inactivated in paternal imprinting and the maternal gene is active in offspring, if there is a mutation in this region of the normally active maternal gene, the child gets Angelman syndrome – mental retardation, ataxic gait, seizures, inappropriate laughter

Front 28

Prader Willi

Back 28

Another area in the same region of chromosome 15q is inactivated in maternal imprinting and the active form is the paternal gene, a deletion in the normally active paternal gene causes Prader willi syndrom in which there is retardation, short stature, hypotonia, obesity, small hands and feet, hypogonadism