M2M Unit 2 Flashcards
CYP3A
Substrates: Cyclosporine mechanism: genetically less important than other drug metabolism genes b/c activity continuous and unimodal Inhibitors: Ketoconazole, grapefruit juice inducers: Rifampin
CYP2D6
Substrates: Tricyclic antidepressants and codeine (activates codeine->morphine) Inhibitors: Quinidine, Fluoxetine, Paroxetine Whites poor metabolizers
CYP2C9
Substrates: Warfarin use VKORC1 as marker to approx. target dose underdose-> clot; overdose-> bleed 20% Whites need lower dose–> poor metabolizers
NAT
Drugs: Isoniazid for TB mechanism: rate of acetylation determined by genetic polymorphism comments: Important in Phase II pathway -Modifies risk of cancers though differences in acetylation of carcinogens
TMPT
Drugs: 6-mercaptopurine, 6-thioguanine 5% of kids with ALL (leukemia) poor metabolizers (absent activity)–> will KILL child (immunosuppression) if don’t test for it (functional assay) Solution: give lower dose
G6PD
Substrates: Sulfonamide antibiotics, dapsone Mechanism: X-linked enzyme -Deficient individuals susceptible to hemolytic anemia after sulfa or dapsone drug exposures
VKORC1
Drug: Warfarin Mechanism: reduces vit. K; single nucleotide polymorphism –Warfarin is a ‘blood thinner” one of the most commonly prescribed meds given to >20,000,000 pts. in the US/year
Trisomy 21
Down syndrome
45, X
Short, webbed neck, borad chest, infertility
Turner syndrome
tall, hypogonadism, sterility, lang. impairment, gynecomastia
Klinefelter syndrome
47, XXY
Klinefelter syndrome (tall, hypogonadism, sterility, lang. impairment, gynecomastia)
47, XXY look like normal males increased behavioral and educational problems
XXY syndrome
characteristic facies, CNS ab., Facial cleft, polydactyly, Congenital heart disease, etc.
Patau Syndrome
47, XX, +13
Patau Syndrome (characteristic facies, CNS ab., Facial cleft, polydactyly, Congenital heart disease, etc.)
growth retardation, Hypertonicity, Seizures, ID severe
Edwards syndrome
47, XX, +18
Edwards syndrome (growth retardation, Hypertonicity, Seizures, ID severe)
46, XX, t(9;22) (q34;q11.2)
Cronic Myelogenous leukemia (reciprocal translocation) anemia
46, XX, der(14;21)(q10;q10), +21
Down syndrome (robertsonian translocation)
46, XY, del(5)(p15)
cri-du-chat syndrome (deletion)
46, XX, i(21)(21q21q)
Down syndrome (Isochromosomes)
weakness in legs, lower extremity muscle atrophy, foot deformity, some loss of sensation in feet
Charcot-marie-tooth disease duplication of gene for peripheral myelin protein-22
46, XX, dup(17p11.2)
Charcot-marie-tooth disease duplication of gene for peripheral myelin protein-22 (contiguous gene syndromes/ “genetic” disorders)
46, XX, del(17p11.2)
Hereditary neuropathy with liability to pressure palsies -deletion of the gene encoding peripheral myelin protein-22 (contiguous gene syndromes/”genetic” disorders)
25yo with foot drop, loss of sensation in legs for days to months.
Hereditary neuropathy with liability to pressure palsies -deletion of the gene encoding peripheral myelin protein-22 (AD)
Cleft palate, septal defects
Velocardiofacial syndrome
del 22q11
Velocardiofacial syndrome (cleft palate, septal defects)
del 22q11
neural crest, cranchial pouches, great vessels, outflow tract defects in heart
DiGeorge Syndrome
Initially not eating well on own now 3 yo is obese and will eat all the time. behavioral issues and a little slow to learn in school
Prader-Willi
del(15)(q11-13) paternal
Prader-Willi
developmentally delayed, tremulous movement of limbs, language impairment, hand flapping, happy demeanor, seizures when <3yo, misaligned eyes (strabismus)
Angelman syndrome
del(15)(q11-q13) maternal
Angelman syndrome
Interstitial duplication on chr 15
autism/ hypotonia/seizures/ID
Marker chr-inverted duplicaiton on chr 15
autism/hypotonia/seizures (supernumery marker chr)
t(15;17)(q22;q21)
Acute Myeloid Leukemia (fusion of PML-RARalpha)
t(8;22)(q34;q11)
Acute Myeloid Leukemia (fusion of Abl1;BCR)
t(9;22)(q34;q11.2)
Chronic myeloid leukemia (night sweats, fatigue, weight loss, anemia) treatment: GLEEVEC
46, XY Phenotypes range from mild under-virilization to full sex reversal
Androgen Insensitivity Syndrome (AIS)
46, XY Phenotype shows undervirilized male with increased virilization at the time of puberty
5-Alpha Reductase Deficiency
46, XY Deletion or absence of SRY
sex reversal and a phenotypically normal female
46, XX Ectopic presence of the SRY gene
individual results in a phenotypically normal male
46, XY mutation in WT1 gene
Denys-Drash & Frasier Syndrome sex reversal, chronic kidney disease
Ambiguous genitalia and salt wasting in first few weeks of life in 46, XX
Congenital Adrenal Hyperplasia
tall, female, seizures, LD, delayed speech, variable expressivity
Triple X syndrome
47 XXX
Triple X syndrome (tall, female, seizures, LD, delayed speech)
Male, LD, behavioral issues, tall, developmental delays, autism
Jacobs Syndrome, 47 XYY
47, XYY
Jacobs Syndrome (Male, LD, behavioral issues, tall, developmental delays, autism)
Turner syndrome
45, XO (short, webbed neck, broad chest)
Klinefelter syndrome
47, XXY (tall, hypogonadism, sterility, lang. impairment, gynecomastia)
XXY syndrome
47, XXY look like normal males increased behavioral and educational problems
Patau Syndrome
46, XX, +13 (characteristic facies, CNS ab., Facial cleft, polydactyly, Congenital heart disease, etc.)
Edwards syndrome
46, XX, +18 (growth retardation, Hypertonicity, Seizures, ID severe)
Cronic Myelogenous leukemia
46, XX, t(9;22) (q34;q11.2)
cri-du-chat syndrome
46, XY, del(5)(p15)
Charcot-marie-tooth disease
46, XX, dup(17p11.2) duplication of gene for peripheral myelin protein-22 (contiguous gene syndromes/ “genetic” disorders)
Hereditary neuropathy with liability to pressure palsies
46, XX, del(17p11.2) -deletion of the gene encoding peripheral myelin protein-22 (contiguous gene syndromes/”genetic” disorders)
Velocardiofacial syndrome
del 22q11 (cleft palate, septal defects)
DiGeorge Syndrome
del 22q11 (neural crest, cranchial pouches, great vessels, outflow tract defects in heart)
Prader-Willi
del(15)(q11-13) paternal
Angleman Syndrome
del(15)(q11-13) maternal
Acute Myeloid Leukemia
t(15;17)(q22;q21) or t(8;22)(q34;q11)
Chronic myeloid leukemia
t(9;22)(q34;q11.2) (night sweats, fatigue, weight loss, anemia) treatment: GLEEVEC
Androgen Insensitivity Syndrome (AIS)
46, XY Phenotypes range from mild under-virilization to full sex reversal
mutation of androgen receptor
5-Alpha Reductase Deficiency
46, XY Phenotype shows undervirilized male with increased virilization at the time of puberty
Denys-Drash & Frasier Syndrome
46, XY mutation in WT1 gene sex reversal, chronic kidney disease
Congenital Adrenal Hyperplasia
Ambiguous genitalia in 46, XX (Complicated by salt wasting in the first few weeks of life)
Triple X syndrome
47 XXX (tall, seizures, LD, delayed speech)
Jacobs Syndrome
47 XYY (LD, behavioral issues, tall, developmental delays, autism)
Skeletal dysplasia, Rhizomelic limb shortening, small stature, trident hands, short fingers, large head/frontal bossing
Achodroplasia
Mutation: FGFR3 (fibroblast growth factor receptor 3) Amino acid substitution GtoA Mutation increases activity of the protein interfering with skeletal devo. Paternal age effect
Achodroplasia
Complete penetrance, AD De novo mutations
Clinical: Skeletal dysplasia, Rhizomelic limb shortening, small stature, trident hands, short fingers, large head/frontal bossing
AA=lethal
Mutation: FGFR3 (fibroblast growth factor receptor 3) Amino acid substitution GtoA Mutation increases activity of the protein interfering with skeletal devo. Paternal age effect
Diseases with reduced penetrance
Retinoblastoma
BRCA mutation
Huntington disease
Retinoblastoma
Reduced penetrance, AD
Clinical: malignant tumor of retina
Mutation: RB1 on chr. 13 protein regulates cell cycle 90% penetrance
Disease with variable expressivity
Neurofibromatosis Type 1
Osteogenesis Imperfecta Type 1
Neurofibromatosis Type 1
Variable expressivity, AD
need two or more criteria:
>6 cafe-au-lait spots
>2 neurofibromas plexiform
neuro fibroma
optic glioma
>2 lisch nodules
affected 1st degree relative
Mutation: NF1 tumor supressor gene LOF must have mut. in both genes to show phenotype even though considered AD
Osteogenesis Imperfecta Type 1
variable expressivity, AD
Clinical: multiple fracture Blue sclera, mild short stature, adult onset hearing loss.
Mutation: COL1A1 (collagen type 1 alpha 1) reduced production of pro alpha 1 chains–> reduce type 1 collagen production
Marfan Syndrome
AD Clinical: systemic disorder of connective tissue in eye, skeletal, cardio Diagnosis: aortic root enlargement, ectopia lentis, systemic score >7 Mutation: FBN1 (fibrillin extracellular matrix protein) dominant negative activity mut. reduce # of microfibrils
Bilateral renal cysts cysts in other organs vascular abnormalities End stage renal disease 50% of 60yo
Autosomal Dominant Polycystic Kidney Disease
AD, Locus heterogeneity
Mutation: PKD1 (chr 16p13.3) PKD2 (chr 4q22.1) polycystin 1 and 2 Truncated protein
Autosomal Dominant Polycystic Kidney Disease
AD, Locus heterogeneity Clinical: Bilateral renal cysts cysts in other organs vascular abnormalities End stage renal disease 50% of 60yo Mutation: PKD1 (chr 16p13.3) PKD2 (chr 4q22.1) polycystin 1 and 2 Truncated protein
High cholesterol and LDL levels, Xanthomas (fat build up under skin), premature coronary artery disease and death
Familial Hypercholesterolemia
AD, Locus heterogeneity
Mutation: 3 genes LDLK (highest rate), APOB, PCSK9
Familial Hypercholesterolemia
AD, Locus heterogeneity
Clinical: High cholesterol and LDL levels Xanthomas premature coronary artery disease and death Mutation: 3 genes LDLK (highest rate), APOB, PCSK9
neuronal degeneration onset at 35-44 yo death ~15 yrs after onset, jerking movements, halucinations, father died young, irritability, paranoia and later on confusion and memory loss.
Huntington Disease
AD, Trinucleotide repeat disorder (CAG) Anticipation, paternal transmission
Mutation: HTT (huntingtin) Chr 4p16.3 expansion of the CAG can cause altered structure of protein
Huntington Disease
AD, Trinucleotide repeat disorder (CAG) Anticipation, paternal transmission
Clinical: neuronal degeneration onset at 35-44 yo death ~15 yrs after onset
Mutation: HTT (huntingtin) Chr 4p16.3 expansion of the CAG can cause altered structure of protein
muscular dystrophy, progressive muscle wasting and weakness, myotonia, cataracts
Myotonic Dystrophy Type 1
AD, Trinucleotide repeat disorder (CTG) located in 3’ UTR
anticipation, maternal transmission
Mutation: DMPK (myotonic dystrophy protein kinase) plays important roll in muscle, heart and brain cells.
Myotonic Dystrophy Type 1
AD, Trinucleotide repeat disorder (CTG) located in 3’ UTR
anticipation, maternal transmission
Clinical: muscular dystrophy progressive muscle wasting and weakness, myotonia, cataracts
Mutation: DMPK (myotonic dystrophy protein kinase) plays important roll in muscle, heart and brain cells.
autism/ hypotonia/seizures/ID
Interstitial duplication on chr 15
autism/hypotonia/seizures (supernumery marker chr)
Marker chr-inverted duplicaiton on chr 15
malignant tumor of retina
Retinoblastoma
Reduced penetrance, AD
Mutation: RB1 on chr. 13 protein regulates cell cycle 90% penetrance
multiple cafe-au-lait spots, neurofibromas plexiform, optic glioma, multiple lisch nodules
Neurofibromatosis Type 1
Variable expressivity, AD
Mutation: NF1 tumor supressor gene LOF must have mut. in both genes to show phenotype even though considered AD
multiple fractures, Blue sclera, mild short stature, adult onset hearing loss.
Osteogenesis Imperfecta Type 1
variable expressivity, AD
Mutation: COL1A1 (collagen type 1 alpha 1) reduced production of pro alpha 1 chains–> reduce type 1 collagen production
systemic disorder of connective tissue in eye, skeletal, cardio, aortic root enlargement, ectopia lentis, systemic score >7
Marfan Syndrome
Mutation: FBN1 (fibrillin extracellular matrix protein) dominant negative activity mut. reduce # of microfibrils
X-linked Dominant Disorders
Hypophosphatemic Rickets Fragile X Syndrome Charcot Marie Tooth Incontinentia pigmenti rett syndrome Orofacicodigital syndrome focal dermal hypoplasia
Hypophosphatemic Rickets
X-linked Dominant PHEX, regulates fibroblast GF inhibits the kidneys ability to reabsorb phosphate into blood
Hypophosphatemia, short stature, bone deformity
Hypophosphatemic Rickets X-linked Dominant Mutation: PHEX, regulates fibroblast GF inhibits the kidneys ability to reabsorb phosphate into blood
Fragile X Syndrome
X-linked dominant Trinucleotide repeat disorder CGG (in 5’UTR region) Anticipation, Maternal transmission Clinical: ID, dysmorphic features (large ears, long face, macroorchidism), Autism, Social anxiety, hand flapping/biting, aggression Mutation: FMR1 (protein essential for normal cognitive devo and female repo. function increase trinucleotide repeat number methylate gene–> LOF
ID, dysmorphic features (large ears, long face, macroorchidism), Autism, Social anxiety, hand flapping/biting, aggression
Fragile X Syndrome X-linked dominant Trinucleotide repeat disorder CGG (in 5’UTR region) Mutation: FMR1 (protein essential for normal cognitive devo and female repo. function increase trinucleotide repeat number methylate gene–> LOF
Rett Syndrome
X-linked Dominant Clinical: Loss of normal movement and coordination, loss of communication skills, failure to thrive, Seizures, abnormal hand movements Mutation: MECP2 (methyl CpG binding protein) essential for the normal function of nerve cells
Loss of normal movement and coordination, loss of communication skills, failure to thrive, Seizures, abnormal hand movements
Rett Syndrome X-linked Dominant Mutation: MECP2 (methyl CpG binding protein) essential for the normal function of nerve cells
X-linked Recessive Disorders
Lesch-Nyhan Syndrome Dystrophinopathies Hunter’s Disease Menaces Disease Glucose 6 phosphate dehydrogenase deficiency Hemophilia A and B Wiscott Aldrich Syndrome Colorblindness
Lesch-Nyhan Syndrome
X-linked recessive Clinical: Neurological and behavioral abnormalities, overproduction of uric acid, self injury Mutation: HPRT1 recycling of purines
Neurological and behavioral abnormalities, overproduction of uric acid, self injury
Lesch-Nyhan Syndrome X-linked recessive Mutation: HPRT1 recycling of purines
Dystrophinopathies
X-linked recessive spectrum of muscle disease from mild to severe: Duchenne Muscular Dystrophy (most severe) Becker Muscular Dystrophy DMD-associated dilated cardiomyopathy mutation: DMD (dystrophin) Xp21-21.1
Duchenne Muscular Dystrophy
X-linked recessive Clinical: Progressive muscular weakness (proximal to distal), calf hypertrophy, dilated cardiomyopathy, High CK levels, onset before age 5, wheelchair before age 13, death in 30s No dystrophin Mutation: DMD
15 yo, wheelchair bound since age 13, muscle weakness, calf hypertrophy, dilated cardiomyopathy, CK levels x10
Duchenne Muscular Dystrophy X-linked recessive
Becker Muscular Dystrophy
X-linked recessive Clinical: Progressive muscular weakness (proximal to distal), dilated cardiomyopathy, CK levels 5x, onset later than duchenne muscular dystrophy, wheelchair bound after 16yo, death in 40s abnormal quantity or quality of Dystrophin Mutation: DMD
20 yo, wheelchair bound since age 16, muscle weakness that developed over time, dilated cardiomyopathy, CK levels 5x
Becker Muscular Dystrophy X-linked recessive
DMD-associated DCM
X-linked recessive Clinical: dilated cardiomyopathy presenting between 20-40 yo, early death, no skeletal muscle involved no dystrophin in myocardium Mutation: DMD
Died around 55 after presenting with dilated cardiomyopathy at age 30
DMD-associated DCM
Hemophilia A
X-linked recessive Clinical: Spontaneous bleeds into joints, muscles or intracranial. excessive bruising, prolonged bleeding after injury, delayed wound healing Mutation: F8 deficiency of factor VIII, chr. Xq28
Spontaneous bleeds into joints, muscles or intracranial. excessive bruising, prolonged bleeding after injury, delayed wound healing
Hemophilia A X-linked recessive Mutation: F8 deficiency of factor VIII, chr. Xq28
mycrocephaly and mental retardation, seizures, gait disorders, tremors
Phenylketonuria (PKU)
AR
Mutation: PAH mutation–> high levels of Phe because not converted to Tyr
Phenylketonuria (PKU)
mycrocephaly and mental retardation, seizures, gait disorders, tremors
AR
Mutation: PAH mutation–> high levels of Phe because not converted to Tyr
alpha1- Antitrypsin Deficiency (ATD)
increased risk of developing emphysema, late onset, increased risk of liver cirrhosis and liver cancer worse in smokers
AR
Mutation: two alleles Z and S
Z/Z= 10-15% normal activity, S/S 50-60% normal activity (no symptoms)
Biological: SERPINA1 (serine protease inhibitor) targets elastase–> neutrophils in lung
Molecular: Z allele–> misfolded protein aggragated in liver, S allele–> unstable protein less effective
increased risk of developing emphysema, late onset, increased risk of liver cirrhosis and liver cancer worse in smokers
alpha1- Antitrypsin Deficiency (ATD)
Tay-Sachs disease
infants appear normal until 3-6 months then get muscle weakness, decreased attentiveness, increase startle response. later get nurodegeneration–seizures, vison and hearing loss, diminished mental function, paralysis
AR (ashkenazic jews higher risk)
Biological: lysosomal storage disorder, inability to degrade Gm2 ganglioside–> accumulation in neurons of CNS.
Mutation : defective Hex A
infants appear normal until 3-6 months then get muscle weakness, decreased attentiveness, increase startle response. later get nurodegeneration–seizures, vison and hearing loss, diminished mental function, paralysis
Tay-Sachs disease
AR (ashkenazic jews higher risk)
Biological: lysosomal storage disorder, inability to degrade Gm2 ganglioside–> accumulation in neurons of CNS.
Mutation : defective Hex A
Sandhoff disease
Same syptoms as Tay-Sachs: muscle weakness, neurodegeneration (seizures, vision and hearing loss, diminishing mental function, “cherry-red spot” in the eyes.
AR
Mutation: Mutation of HEXB (insertion)
Biological: Dysfunctional beta subunit –> build up of Gm2 ganglioside
AB-variant of Tay-Sachs
Rare
Both HexA and HexB functional but Gm2 accumulates dues to defective Gm2 activator protein
