genetics diseases premidterm

Question 0

Huntington disease

Answer 0

Autosomal dominant. Gain of function mutation. Triplet repeat expansion in father - CAG (codes for glutamine) in exon 1 of Huntington gene = polyglutamine expansion in protein. Late onset - manifests at approx 40 yrs of age. Progressive dementia, loss of motor control. Degeneration of neurons in cerebral cortex, chorea caused by degeneration of basal ganglia, cognitive and language design. Dx via RFLP for probe G8, closely linked to dz

Question 1

Familial hypercholesterolemia (LDL rec deficiency)

Answer 1

Autosomal dominant. Haplo-insufficiency

Question 2

Myotonic dystrophy

Answer 2

Autosomal dominant. Triplet repeat expansion in mother - CTG at 3’ end of DMPK gene. Most pleiotropic phenotype of all unstable repeat disorders. Wasting of mm, cataracts, heart conduction defects, endocrine changes, developmental delay, and myotonia. DM1 worse than DM2 (DM2 = muscle pain, stiffness, fatigue, wkness in extremities)

Question 3

Marfan syndrome

Answer 3

Autosomal dominant. Dominant-negative mutation in fibrillin gene. Skeletal abnormalities (long limbs, pectus excavatum, arachnodactyly), hypermobile joints, ocular abnormalities (myopia, lens dislocation), cardiovascular disease (mitral valve prolapse, aortic aneurysm)

Question 4

Osteogenesis imperfecta

Answer 4

Autosomal dominant. Dominant negative model - mutation in one allele of collagen alpha 1 gene. Association of triple helical molecules w/at least one mutant alpha 1 results in the degradation of collagen (75% of the collagen is degraded, only have 25% normal collagen). Easily fractured bones, blue sclerae

Question 5

Achondroplasia

Answer 5

Autosomal dominant. Gain of function mutation in gene for FGFR3 (fibroblast growth factor rec) involved in differentiation of chondrocytes into osteoblasts, differentiation of cartilage to bone. Severe stunting of growth w/normal mental development

Question 6

Neurofibromatosis (NF1) type I

Answer 6

Autosomal dominant. Mutation in neurofibromin 1 (NF1) gene that codes for tumor suppressor protein. Caused by different mutations in NF-1 gene (allelic heterogeneity). High penetrance (generally all patients express at least some signs of disorder) but variable expression. Cafe au lait spots, Lisch nodules on iris, neurofibromas on skin, bone deformities, learning disabilities

Question 7

Acute intermittent porphyria

Answer 7

Autosomal dominant

Question 8

Cystic fibrosis

Answer 8

Autosomal recessive. Mutant CFTR channels

Question 9

Sickle cell anemia

Answer 9

Autosomal recessive. Allelic heterogeneity.

Question 10

Phenylketonuria

Answer 10

Autosomal recessive

Question 11

Tay-Sachs disease (hexosaminidase A)

Answer 11

Autosomal recessive

Question 12

Congenital deafness

Answer 12

Autosomal recessive. Don’t have to be homozygous recessive for two alleles -> homozygous recessive for one allele is enough to be deaf

Question 13

Hemochromatosis

Answer 13

Autosomal recessive. More severe in males. C282Y mutation (most common mutation of HFE gene). Also exhibits allelic heterogeneity (other known mutations of HFE gene are H63D and S65C). Delayed age of onset of sx’s

Question 14

Xeroderma pigmentosum

Answer 14

Autosomal recessive. More severe in individuals exposed more frequently to UV radiation

Question 15

Duchenne muscular dystrophy

Answer 15

X-linked recessive. Due to mutation on dystrophin gene. Very little to no production of normal dystrophin. SEVERE - lethal before the age of 30, low reproductive fitness. Muscle wasting

Question 16

Becker muscular dystrophy

Answer 16

X-linked recessive. Due to mutation on dystrophin gene

Question 17

Glucose 6 phosphate dehydrogenase (G6PD) deficiency

Answer 17

X-linked recessive. Hemolytic anemia when taking drugs such as primaquine, sulfa drugs

Question 18

Hemophilia A and B

Answer 18

X-linked recessive. Most of severe mutations due to inversion of intron sequence, but there’s also allelic heterogeneity. Deficiency of clotting factor VII -> increased tendency to bleed on minor trauma.

Question 19

Lesch-Nyhan syndrome (hypoxanthine guanine phosphoribosyl transferase (HGPRT))

Answer 19

X-linked recessive. Hyperuricemia and self-mutation

Question 20

Red-green color blindness

Answer 20

X-linked recessive

Question 21

Rett syndrome

Answer 21

X-linked. Due to mutation in x-linked gene MeCP2. Affects females more often than males. Males with mutant X gene usually die in utero or soon after birth UNLESS they have Klinefelter (XXY). Females may have skewed X chromosome inactivation that causes varying degrees of dzallows survival (normal cells rescues mutant cells), or may be due to germline mutation in mother.

Sx’s - develop normally until 6 to 18 months. Regression phases include loss of speech and acquired hand skills. Most get seizures, repetitive hand movements, irreg breathing, and motor control problems.

Question 22

Vitamin D-resistance Rickets (hypophosohatemic Rickets)

Answer 22

X-linked dominant disorder

Question 23

Incontinentia pigmenti

Answer 23

X-linked dominant. Due to mutation in IKBKG gene. Males with disorder die in utero. Females less severely affected bc of protection from other X - have skewed X-inactivation in favor of normal IKBKG gene. Rashes and blisters in early life. Later, patches of hyperpigmentation, “marble cake appearance” of skin - darker pigmentation where normal X has been inactivated (mutant X is active). Areas of normal pigmentation = normal X is active. Mental retardation and/or retinal detachment in some patients.

Question 24

Waardenburg syndrome

Answer 24

Autosomal dominant. Mutation in PAX3 gene. Sensorineural hearing loss, white forelock, heterochromia

Question 25

Fragile X syndrome/Martin Bell syndrome

Answer 25

X-linked dominant. Triplet repeat expansion in mother - CGG in promoter at 5’ end of FMR1 gene -> increased methylation of this region and silencing of FMR1 gene. Dx w/southern blot analysis of triplet repeats, or X chromosomes show breakage in folate-deficient medium (cytogenetic test) in pts with full mutation. Average age of dx is 8 years of age. Poor muscle tone, sunken chest, elongated head, difficulty learning, macroorchidism. Females less severely affected than makes. Mother’s X chromosome may have have germline mutation (???) 50-200 repeats represent the full mutation, 200 is full mutation

Question 26

Mitochondrial encephalopathy, lactic acidosis, stroke-like episodes (MELAS)

Answer 26

Mitochondrial inheritance

Question 27

Leber hereditary optic neuropathy

Answer 27

Mitochondrial inheritance. Manifests as progressive blindness around 20-30 yrs

Question 28

Myoclonic epilepsy with ragged red muscle fibers (MERRF)

Answer 28

Mitochondrial inheritance

Question 29

Angelman syndrome

Answer 29

Imprinting. Deletion of maternal 15q11-13 (absence of UBE3A), a region not normally methylated in mom’s chromosome or uniparental disomy via nondisjunction I and trisomy rescue of 15. Have 2 copies of SNRPN. Dx by FISH using specific probes against the region, methylation analysis (unmethylated DNA cleaved by enzyme). Happy puppet syndrome, severe metal retardation, seizures

Question 30

Turner’s syndrome

Answer 30

Phenotype X,O. Due to chromosomal non-disjunction after meiosis II ???

Question 31

Klinefelter’s syndrome

Answer 31

Genotype XXY. Due to chromosomal nondisjunction after meiosis I

Question 32

Trisomy 21

Answer 32

Due to chromosomal non-disjunction. Risk for disease increases if mother is over the age of 35

Question 33

Prader-Willi syndrome

Answer 33

Imprinting. Deletion of paternal 15q11-13 (absence of SNRPN), a region not normally methylated in dad’s chromosome or uniparental disomy via nondisjunction I and trisomy rescue of 15. Have 2 copies of UBE3A. Dx by FISH using specific probes against the region, methylation analysis (unmethylated DNA cleaved by enzyme). Obese bc of increased ghrelin, OCD behavior, mental and developmental delay, underdeveloped genitalia, hypotonia in infancy, failure to thrive

Question 34

Various mutations in SRY genes

Answer 34

Y-linked inheritance

Question 35

H-Y histocompatibility antigen

Answer 35

Y-linked inheritance

Question 36

Charcot Marie Tooth disease

Answer 36

Autosomal dominant or X-linked recessive. Neuropathy, little myelination of peripheral nerves

Question 37

Retinitis pigmentosa

Answer 37

Digenic disorder, result of mutation in two independent genetic loci (ROM1 and peripherin). Progressive visual disorder

Question 38

Friedrich ataxia

Answer 38

Autosomal recessive. Triplet repeat expansion disorder, possibly paternal anticipation - GAA in intron 1 of frataxin gene -> altered chromatin structure , formation of triplex DNA, and DNA methylation of bases and histone methylation -> transcrip repression of frataxin gene. Progressive neuro-degenerative disease. Ataxia and muscle weakness, vision and hearing impairment, scoliosis, diabetes, heart disorders. Typical onset between 5-15 years of age, sometimes between 20-35 years. First sx’s are difficulty walking and loss of LE DTRs

Question 39

New mutation diseases

Answer 39

OI, Marfan syndrome, achondroplasia, Duchenne muscular dystrophy, hemophilia

Question 40

Immunodeficiency-centromeric instability-facial anomalies syndrome (ICF)

Answer 40

Autosomal recessive. Due to mutation of Dnmt3b gene. Sx’s - facial dysmorphism, mental retardation, recurrent an prolonged infections, and variable immune deficiency with a constant decrease of IgA. Immunodeficiency associated w/centromere instability of chrmsms 1, 9, and 16

Question 41

Beckwith-Wiedemann syndrome (BWS)

Answer 41

Due to maternal chromosomal rearrangements of 11p15 (imprinted region). Paternal uniparental disomy. Abnormal methylation at 11p15. Children of IVF have 4-9 fold higher chance of BWS bc IVF causes abnormal methylation of 11p15

Sx’s - macroglossia, high birth weight and length, abdominal wall defects like umbilical hernia, ear creases/pits, neonatal hypoglycemia, increased risk of cancer

Question 42

Number of repeats in Huntington disease

Answer 42

• > 40 repeats - you will develop HD, children have 50% chance of HD
• 36-39 repeats - you may develop HD
• <35 repeats - you will not develop HD
• 29-39 repeats - children may or may not develop HD
• <29 repeats - children will not develop HD

Question 43

Proposed mechs for Huntington disease

Answer 43

1. Increase in polyglutamine tract length causes Huntington protein to aggregate, form inclusion bodies, and behave as a toxin
2. Abnormal Huntington protein interacts with different transcription factor proteins casing dysregulation of gene expression

Question 44

Spinocerebellar ataxia

Answer 44

Autosomal dominant, autosomal recessive, or X-linked. CAG repeat expansion in exons of at least 29 different genes, polyglutamine disorder (see mechs for Huntington dz). Progressive, degenerative disease. Sx’s - lack of muscle coordination and lack of coordination of hands, eyes, and speech.

Spinocerebellar ataxia 8 is unique bc it’s caused by CTG repeat expansion in 3’ terminal exon of non-protein coding RNA from SCA8 gene causing altered protein binding to the RNA

Question 45

Holoprosencephaly

Answer 45

Mutation in SHH or Six3 (regulator of SHH)

Question 46

Smith-Lemli-Opitz syndrome

Answer 46

Mutation in 7-dehydrocholesterol reductase. Microcephaly, mental retardation, malformation of mesodermal origin, syndactyly, and polydactyly

Question 47

Gorlin syndrome (Nevoid basal cell carcinoma)

Answer 47

Mutation in Ptc. Early basal cell carcinoma (<20 years). Rib defects

Question 48

Pallister-Hall syndrome

Answer 48

Mutation in Gli genes. Brain tumors, polydactyy

Question 49

Rubinstein-Taybi syndrome

Answer 49

Mutation in CREBBP. Broad thumbs and toes, mental disability, short stature, small head, facial features