Diseases

Question 1

Phenylketonuria

Answer 1

PKU
M: Phenyalanine Hydroxylase Deficiency (Can’t convert Phe to Tyr)
I: ARD
S: Developmental Delays/Intellectual Disability (CNS)
T: Synthetic Diet

Question 2

Gaucher Disease

Answer 2

M: Glucocerebrosidase Deficiency (Macrophages), LSD, Substrate Accumulation (GCs)
I: ARD
S: Hepato/splenomegaly, Bone Pain, Low CBC
T: Enzyme Replacement Therapy, Upstream Enzyme Inhibition, Need to modify proteins by exposing mannose tag for increased uptake into macrophages and lysosomes

Question 3

Classic Tay-Sachs Disease

Answer 3

M: Hex A Deficiency, Substrate Accumulation (GM2 - fatty acid in neurons), mutation in alpha-chain of Hex A dimer, LSD
I: ARD
S: Seizures, Deafness, Blindness, Hypotonia
Example of Allelic Heterogeneity

Question 4

Sandhoff Disease

Answer 4

M: Hex A & Hex B Deficiency due to mutation in beta-chain of both
I: ARD
S: Tay-Sachs PLUS

Question 5

Mucopolysaccharidosis I

Answer 5

M: Mutations in many genes can cause different enzyme deficiencies, Substrate Accumulation (GAGs), LSD
I: XLR for Hunter’s, ARD for all others
S: Visceromegaly, Spine Beaking, Joint Stiffness

Question 6

I-Cell Disease

Answer 6

M: Mutations in enzyme that creates mannose-6-P tag in Golgi results in many lysosomal hydroxylases being exocytosed
I: ARD
S: gargoylism, granulated fibroblasts
Multiple Enzyme Deficiencies from 1 mutation (and all enzymes are present in blood)

Question 7

Urea Cycle Deficiency

Answer 7

M: enzyme deficiency (most common - ornithine transcarbomoylase); Substrate Accumulation (ammonia - toxic)
I: ARD
S: brain swelling due to ammonia buildup & death
T: supplement with deficient product to keep cycle moving forward

Question 8

Propionic Acidemia

Answer 8

M: Propionyl CoA Carboxylase Deficiency; Activation of Alternate Pathways & Toxic Metabolites
I: ARD
S: Acidosis due to Propionyl CoA catabolizing into acids
T: Like MCD, treat by throwing biotin at it (not very effective)

Question 9

Multiple Carboxylase Deficiency

Answer 9

M: PCC, ACC, PC, MCC deficiencies caused by mutations in biotin cycle enzymes
Early Onset: Deficient Holocarboxylase Synthetase (can’t activate the carboxylases with biotin)
Late Onset: Deficient Biotinidase (can’t recycle biotin)
Caused by product deficiency & activation of alternate toxic metabolites
I: ARD
S: Acidosis +
T: Give biotin supplements (more effective for Late Onset)

Question 10

Galactosemia (Classical v. Non-Classical)

Answer 10

M: Enzyme Inhibition (Classical: GALT; Non-Classical: GALK); Classical causes substrate accumulation (Gal-1-P is toxic) and increase in galactitol (polyol pathway)
I: ARD
S: toxic to brain, liver, gut; cataracts in eye due to galactitol
T: reduce galactose in diet (hard because it is monomer in lactose - milk)

Question 11

Familial Hypercholesteremia

Answer 11

M: Haploinsufficiency; not enough LDL receptors to take up cholesterol
I: ADD
S: Fatty Deposits in Skin and Vessels
T: Statins to inhibit HMG CoA Reductase (reduce cholesterol synthesis and over-express LDL receptors

Question 12

Insulin Chicago

Answer 12

M: Dominant Negative; mutant insulin binds receptor without increasing glucose uptake
I: ADD
S: High blood sugar
T: Deliver additional insulin, monitor glucose levels

Question 13

Perinatal Lethal Osteogenesis Imperfecta (Mild v. Severe)

Answer 13

M: mutations in collagen genes - COLA1 & COLA2
Mild - Haploinsufficiency of collagen genes
Severe - Dominant Negative effects of collagen subunit assembly (protein suicide)
I: AD, but arises from de novo mutation or germ-line mosaicism
S: Blue Sclerae, In utero fractures (Mild - prone to more bone fractures)

Question 14

Classical Type Ehlers-Danlos Syndrome

Answer 14

M: Haploinsufficiency of Collagen Type V
I: AD
S: “Rubber Man”, hyperelastic tissue & joints

Question 15

Achondroplasia

Answer 15

M: Gain of Function - FGFR3 (activates inhibition of chondrocyte proliferation) becomes constitutively active
I: AD
S: Growth Deficiency, Disproportionate Proximal Limbs, most common form of dwarfism, spinal stenosis, normal intelligence
T: Protein Modification - add 2 AA onto N-terminus CNP (increases half-life/stabilizes protein) to bind NPR-B receptor to inhibit inhibition of chondrocyte proliferation

Question 16

Wolf-Hirschhorn Syndrome

Answer 16

M: Microdeletion of 4p (codes for FGFR3 and more)
I: Not inherited, de novo
S: Severe intellectual disability, growth deficiency, small chin, doesn’t survive to reproductive age

Question 17

Familial Male Precocious Puberty

Answer 17

M: Gain of Function - (LH receptor becomes constitutively active, causing increased testosterone)
I: AD, Sex Limited (only males express)
S: Advanced puberty in males at early age

Question 18

Down Syndrome

Answer 18

M: Trisomy 21 (95% NDJ, 5% Unbalanced Robertsonian Translocation)
Incidence: 1/700
RR: 1% if sibling has it, 15% if mom is carrier, 5% if dad is carrier (theoretical 33% if parent is carrier)
S: intellectual disability, epicanthal folds, round face, hypotonia, brashfield spots in eyes, cardiac defects, onset of dementia - decreased life expectancy
Most common viable trisomy

Question 19

Patau Syndrome

Answer 19

M: Trisomy 13
Incidence: 1/5000 (least likely trisomy)
S: severe mental deficiency, seizures, redundant skin on neck, multiple extra digits, cleft lip + cleft palate
Early mortality (82%)

Question 20

Edwards Syndrome

Answer 20

M: Trisomy 18
Incidence: 1/3000
S: small birth wait, underdeveloped, hypertonia, overlapping fingers, cardiac defects
highest early mortality (90%)

Question 21

Turner Syndrome

Answer 21

M: Monosomy X (only viable monosomy)
S: short stature, poor coordination, fused kidney, short 4th digit, steak ovaries (sterile)
T: Hormone Replacement Therapy, Daily GH Injections

Question 22

Williams-Bueren Syndrome

Answer 22

M: Microdeletion of 7q11.23
S: Loquacious Personality, intellectual disability, supravalvular aortic stenosis, big mouth

Question 23

Neurofibromatosis Type 1

Answer 23

M: mutation in NF-1 Gene (neurofibromin)
I: ADD, but 50% cases de novo due to long length
S: 6+ Cafe-au-lait spots, axillary/inguinal freckling, iris Lisch nodules, 2+ neurofibromas/1 plexiform NF, primary relative with NF, Osseous Lesion (tibial dysplasia), optic pathway tumor

Question 24

DiGeorge Syndrome

Answer 24

M: Microdeletion of 22q11.2
S: Cardiac anomaly, missing thymus, small chin

Question 25

Multiple Endocrine Neoplasia Type 2

Answer 25

M: mutation activating RET oncogene (heritable) S: thyroid tumors

Question 26

Retinoblastoma

Answer 26

M: mutation in Rb gene (cell cycle checkpoint in G1/S; needs to be phosphorylated to release E2F, allowing transcription of S genes) Mutation in tumor suppressor gene S: leukocoria (glow in pupil)

Question 27

Li Fraumeni Syndrome

Answer 27

M: mutation in p53 gene (cell cycle control, activated by ATM/ATR, can arrest cell cycle or start apoptosis due to DNA damage) Mutation in tumor suppressor gene S: multiple adenomas/tumors everywhere, not 100% penetrant

Question 28

Hereditary Breast and Ovarian Cancer Syndrome

Answer 28

M: mutation in BRCA1/2 (cell cycle control, DNA repair mechanisms, activated by CHEK 1/2 to activate p53) Mutation in tumor suppressor gene S: increased risk of developing breast/ovarian cancer T: increased surveillance with mammograms/breast MRIs at 25, consider prophylactic mastectomy/oopherectomy

Question 29

Familial Adenomatous Polyposis

Answer 29

M: mutation in APC (metaphase check point for chromosome alignment, MCC can inhibit APC, APC ubiquitinates cyclin B and securin) Mutation in tumor suppressor gene S: increased risk for developing colon cancer

Question 30

Ataxia Telangiectasia

Answer 30

M: causes chromosome instability, loss of function of ATM gene - poor DNA repair I: AR S: progressive ataxia

Question 31

Fanconi Anemia

Answer 31

M: mutation in complex that unwinds DNA for efficient repair and replication Chromosome Instability S: missing thumb, multiple cafe-au-lait spots, murmur

Question 32

Kabuki Syndrome

Answer 32

M: can't methylate 4th lysine residue, or can't demethylate 27th lysine residue = heterochromatin = decreased gene expression mutation in epigenetic machinery S: intellectual disability, growth deficiency, seizures, T: HDAC inhibitors (help keep DNA in euchromatin)

Question 33

Epileptic Encephalopathy

Answer 33

M: de novo mutation of CHD2 - can't properly unwind chromatin, problem with chromatin remodeling S: photosensitive seizures

Question 34

Fragile X Syndrome

Answer 34

M: extended trinucleotide repeat in 5' UTR causes hypermethylation of nearby CpG island resulting in more chromatin folding and decreased expression of FMR1 on X Chromosome I: more common in males, 50% penetrance in females due to X-inactivation, anticipation - grows in severity & frequency in later generations, XLR, the closer you are the more likely you will get it, pre-mutation only expands in oogenesis of females, mutation expands in meiosis & mitosis (can lead to mosaicism), gain of function effect in premutation carriers (Ataxia/Tremor) S: intellectual disability in males, seizure, long face

Question 35

Congenital Limb Malformations

Answer 35

M: mutations at TAD boundary affect expression of downstream genes S: Limb malformations

Question 36

Hypophosphatasia

Answer 36

M: alkaline phosphatase enzyme deficient, can't break down PPi into phosphate for bone mineralization S: poor bone mineralization, weak bones T: fusion protein, combine functional enzyme with Fc (stabilize in blood) and Deca-Aspartate sequence (increase uptake into bone) I: ARD

Question 37

Duchenne Muscular Dystrophy

Answer 37

M: Nonsense mutation causes premature stop of dystrophin translation I: XLR; 1/3 cases de novo S: most common form of muscular dystrophy T: Ataleuren "read-through" drug reads past stop codon or exon skipping over the exon containing stop codon; both treatments require the protein to still be functional with this mutation *female carriers at risk for cardiac anomalies later in life*

Question 38

Spinal Muscular Atrophy

Answer 38

M: mutation in SMN1 prevents proper gene product T: alternative splicing of pseudogene SMN2 to include exon 7

Question 39

MELAS, MERRF, NARP

Answer 39

M: point mutation in mitochondrial DNA S: affects cardiac muscle, skeletal muscle, CNS, ptosis I: mitochondrial (100% maternal transmission, 0% paternal) heteroplasmy results in same mutation causing varied expressivity

Question 40

Prader-Willi Syndrome

Answer 40

M: missing paternal chromosome 15 imprinting S: small at birth, hyperphagia and obesity I: deletion of paternal Ch 15, or maternal uniparental disomy

Question 41

Angelman Syndrome

Answer 41

M: missing maternal chromosome 15 imprinting S: inappropriate laughter, ataxia, joint stiffness, intellectual disability I: deletion of maternal Ch 15, or paternal uniparental disomy *Point deletion on UBE3A*

Question 42

Beckwith-Wiedemann Syndrome

Answer 42

M: Microdeletion of maternal Ch 11 (IC2) S: large at birth, large tonge, oomphalacele, ear crease

Question 43

Evolution of Colon Cancer through adenoma/carcinoma sequence

Answer 43

1. Mutation in APC 2. two-hit mutation in APC 3. Activation of RAS oncogene 4. Mutation in p53 5. mutations accumuluate/tumor becomes malignant

Question 44

Cleft Lip +/- Cleft Palate

Answer 44

Multifactorial trait Inheritance is more likely if more closely related Less affected sex is more likely to transmit Combination of genetic and environmental factors Use empiric data to estimate risk without solid model

Question 45

Myotonic Dystrophy

Answer 45

M: Expansion of 3' UTR S: can't relax muscles Gain of Function I: ADD

Question 46

Friedrich's Ataxia

Answer 46

M: Expansion of 1st intron of gene frataxin S: Ataxia I: ARD (needs expansion of both alleles)

Question 47

Spinal and Bulbar Muscular Atrophy (Kennedy's Disease)

Answer 47

M: Polyglutamine tract expansion in coding region of androgen receptor gene on X Chromosome I: XLD, Gain of Function affect (toxic to neurons) S: Dysfunctional motor neurons = weakness *Expansion more common in male meiosis*