Genetic Disorders

Question 1

Down Syndrome

Answer 1

Trisomy 21, often by nondisjunction at maternal meiosis I. Unbalanced translocation between 21 & another acrocentric chromosome. Mosaicism. Trisomy of APP (21q21) leads to Alzheimer’s. Short, moderate intellectual impairment, flattened middle faces, hypotonia, heart & gastrointestinal disease, chronic ear infection, early Alzheimer’s, opthalmologic problems

Question 2

Edwards Syndrome

Answer 2

Additional chromosome 18, Growth impairment, clenched hands, severe intellectual impairment, heart & renal diseases

Question 3

Patau Syndrome

Answer 3

Additional chromosome 13, Growth impairment, facial clefts, severe intellectual impairment, dermal defects (organs grow outside body), polydactyl, heart & renal diseases

Question 4

Klinefelter Syndrome

Answer 4

XXY chromosomal aneuploidy, Tall, hypogonadism, usually sterile, language & secondary sexual characteristics impairment

Question 5

Turner Syndrome

Answer 5

X chromosomal aneuploidy, Short, ptosis, webbed neck, edema of hands and feet, cubitus valgus, broad shield-like chest, narrow hips, infertile, bad at math & non-verbal comm, heart & skeletal problems, Rx GH.

Question 6

Mosaicism

Answer 6

Genetically different cells despite stemming from a single zygote, commonly due to early post-zygotic non-disjunction mitotic division, Typically more mild than full disease

Question 7

Prader-Willi Syndrome

Answer 7

Del(15q11-q13) or mistakenly silenced (methylation did not get erased) paternally. Maternal version is methylated/silenced. Obesity, excessive indiscriminate eating, short, small hands & feet, hypogonadism, intellectual disability, “floppy”/hypotonic at birth, opthalmologic problems.

Question 8

Angelman Syndrome

Answer 8

Del(15q11-q13) or mistakenly silenced (methylation did not get erased) maternally, defected expression of UBE3A. Paternal version is methylated/silenced. Seizures, intellectual disability, short, spasticity.

Question 9

B-cell Acute Lymphoblastic Leukemia (ALL)

Answer 9

Typically hypoploidy or hyperploidy, esp. trisomy 4, 10 & 17.

Question 10

Acute Myelogenous Leukemia (AML)

Answer 10

T(8;21), which causes a ETO/AML gene fusion

Question 11

Acute Promyelocytic Leukemia (APML)

Answer 11

Subtype of AML. Production of Auer rods. t(15;17), which causes a PML/RARA gene fusion inhibiting differentiation of myeloid hematopoetic precursors. Trans-retinoic acid.

Question 12

Chronic Myelogenous Leukemia (CML)

Answer 12

T(9;22), which causes a BRC/ABL gene fusion. Rx Gleevac.

Question 13

Duchenne Muscular Dystrophy

Answer 13

X-linked recessive. Xp21-21.1; Large deletion, frameshift, or nonsense. Insufficient dystrophin. More mild Becker variant if deletion is in-frame. Increased muscular contraction & weakness on limbs, abnormal gait, eventual progression from limbs to respiratory muscles. Calf hypertrophy.

Question 14

Charcot-Marie-Tooth Disease

Answer 14

Autosomal dominant, dup(17)(p11.2), which contains gene for peripheral myelin protein-22 (PMP-22). Hammertoes, weakness & muscular atrophy of foot & lower leg muscles & hands, neuropathy.

Question 15

Hereditary neuropathy w/ liability to pressure palsies (HNPP)

Answer 15

PMP22 deletion; autosomal dominant. Complete to partial recovery of acute pressurized neuropathy, foot drop

Question 16

Osteogenesis Imperfecta Type 1

Answer 16

Autosomal dominant. Normal procollagen triple helix has 2 pro-alpha1, 1 pro-alpha2 chain. Mutation in COL1A1 so only produces 1 pro-alpha1 & pro-alpha2 chain so has 50% less material to make triple helix and consequent Type 1 collagen. Brittle bones, blue sclera, early fractures in infant, progressive hearing loss.

Question 17

Hemoglobin Kempsey

Answer 17

Asp99Asn missense. Makes hemoglobin stay in Relaxed state longer so it binds O2 better but unable to release when needed. Opposite disease is Hemoglobin Kansas. Polycythemia (trigger more RBC production).

Question 18

Osteogenesis Imperfecta Type 2-4

Answer 18

Kink introduced in pro-alpha2 chain 50% of the time. WORST than Type 1 because it destablizes structure.

Question 19

Hereditary Persistence of fetal hemoglobin

Answer 19

Adult B-globins & d-globins genes are deleted so g-globins are expressed to compensate. Expression of fetal g-globins in adult life, which has higher O2 affinity.

Question 20

Huntington’s Disease

Answer 20

A repeat of more than 40 CAG (glutamine) repeats on mRNA exon, creating novel toxic effect on huntingtin protein. Autosomal dominant but expansion/slippage only occurs w/ paternal inheritance. Rapidly progressing neurodegeneration in motor, cognitive & psychiatric.

Question 21

Myotonic Dystrophy

Answer 21

A repeat of more than 34 CTG repeats on mRNA 3’ UTR, creating mutation in Myotonic Dystrophy Protein Kinase. Autosomal dominant but expansion/slippage only occurs w/ maternal inheritance. Cataracts, myotonia (hard to loosen grip), infantile hypotonia, intellectual disability, adult onset muscular dystrophy.

Question 22

Phenylketonuria (PKU)

Answer 22

Autosomal recessive, high allelic heterogeneneity. High blood phenylalanine & low tyrosine level usually due to defect in phenylalanine hydroxylase or BH4 cofactor. Hyperactivity, epilepsy, retardation, microcephaly. Low-phenylalanine diet, BH4 supplementation.

Question 23

a1-Antitrypsin Deficiency (ATD)

Answer 23

Autosomal recessive. Defective a1-antitrypsin, which is a suicide protease inhibitor that binds to elastase (which normally degrades elastin). Hyperactive elastase increases damage to lung connective tissue. Defective enzyme accumulates in liver (not transported to lung). Increased risk for emphysema, liver cirrhosis & cancer. Steroids, pulmonary O2 rehab, lung transplant.

Question 24

Tay-Sachs Disease (TS)

Answer 24

Autosomal recessive. Lysosomal storage disease; defective HEXA gene that encodes hexosaminidase A enzyme, which normally degrades Gm2 ganglioside. Sandhoff variant is defective HEXB gene. AB variant is defective GM2AP enzyme. Ashkenazi Jewish population has a high carrier rate for Sandhoff disease. Muscle weakness, seizure, retardation, loss of voluntary movement, cherry-red spot in eye.

Question 25

Androgen Insensitivity Syndrome (AIS)

Answer 25

X-linked recessive resulting in abnormal AR receptor. Under-virilization to full sex reversal. Surgical sexual reassignment, testosterone treatment possible but likely little response.

Question 26

5-Alpha Reductase Deficiency

Answer 26

X-linked recessive resulting in abnormal 5-Alpha Reductase (Testosterone&raquo_space; Dihydrotestosterone). Under-virilized male with increased virilization at the time of puberty.

Question 27

Denys-Drash Syndrome

Answer 27

Mutation in WT1 gene (TF for SRY). Chronic Kidney disease, risk for Wilms tumor.

Question 28

Frasier Syndrome

Answer 28

Mutation in WT1 gene (TF for SRY). Chronic kidney disease, risk for gonadoblastoma.

Question 29

Congenital Adrenal Hyperplasia

Answer 29

Autosomal recessive disorder, mutated 21-hydroxylase on chromosome 6. Salt wasting in first few weeks of life. Decreased sodium and chloride, increase potassium levels. Glucocorticoid supplementation.

Question 30

Gaucher Disease

Answer 30

Lysosomal storage disorder. Deficient glucocerebrosidase enzyme resulting in accumulation of glucocerebroside in macrophages as a byproduct of RBC breakdown. High carrier rate in Ashkenazi Jewish population. Hepatosplenomegaly, liver function, thromboccytopenia (decreased platelet levels), easily bruised, difficulty clotting. Enzyme replacement therapy (preferred) or Substrate reduction therapy.

Question 31

Sickle Cell anemia

Answer 31

Autosomal recessive. Glu->Val mutation in B-globin, which makes it more insoluble in Tense state. RBC polymerizes under low O2, easily lodged in capillaries. Shorter half-life.

Question 32

Hemoglobin C Disease

Answer 32

Autosomal recessive. Glu->Lys mutation in B-globin. Forms crystal outside RBC. Less soluble, easily lodged in capillaries.

Question 33

a-Thalassemia

Answer 33

Deletion of a-globin genes. B & g-globin excess and precipitates. Hemolysis, microcytosis (smaller cells), hypochromia (pale-colored), hydrops fetalis.

Question 34

b-Thalassemia

Answer 34

Deletion of b-globin or LCR genes. a-globin excess & precipitates. If both b-globin & d-globin are deleted, then it may be dB0-thalassemia variant or HPFH. Hemolysis, microcytosis, hypochromia, splenomegaly, marrow expansion, osteopenia, iron overload. Blood transfusion w/ iron chelation therapy, splenectomy, BM transplant.

Question 35

Achondroplasia

Answer 35

Autosomal dominant. High de novo mutation rate (increased by paternal effect: men > 40yo). Homozygotes are lethal. Fibroblast Growth Factor Receptor 3 mutation (Gly -> Arg) that impairs regulating bone formation from cartilage. Short, small foramen magnum, rhizomelic limb shortening, midfacial retrusion, trident hands.

Question 36

Retinoblastoma

Answer 36

Autosomal dominant. Mutation in RB1 gene, which is the protein regulating cell cycle. 90% penetrance. Malignant tumor of retina.

Question 37

Neurofibromatosis Type 1

Answer 37

Autosomal dominant. Symptoms worsen w/ age. Loss-of-fx mutation in NF1 neurofibromin gene (tumor suppressor). Neurofibromas, cafe-au-lait spots, optic glioma, Lish nodules in eyes.

Question 38

Marfan Syndrome

Answer 38

Autosomal dominant. Mutation in FBN1 fibrillin that reduces # of microfibrils, causing connective tissue to be easily stretched. Aortic, usually asc. aorta, root enlargement, ectopia lentis (lens displaced), systemic score > 7, tall w/ long arms.

Question 39

Autosomal Dominant Polycystic Kidney Disease

Answer 39

Mutation in PKD1 & PKD2 for polycystin proteins. Bilateral renal cysts, end-stage kidney disease.

Question 40

Hypophosphatemic Rickets

Answer 40

X-linked dominant. Mutation on PHEX gene, which normally regulates fibroblast growth factor, causing impaired kidney fx to reabsorb phosphate. Low phosphate, short, bone deformity.

Question 41

Fragile X Syndrome

Answer 41

X-linked dominant. >200 CGG repeats. Anticipation & maternal expansion bias. Increased methylation on FMR1 gene. Dev problems, intellectual impair, autistic behavior.

Question 42

Rett Syndrome

Answer 42

X-linked dominant. Mutation on MECP2 gene, which is methyl CpG binding protein. Usually lethal in male & sterile female. Dev problems. Impaired coordination, movement, communication. Seizures.

Question 43

Lesch-Nyhan

Answer 43

X-linked recessive. Mutation on HPRT1, inhibits recycling of purines. Dev problems, austistic, prone to self-injury, overproduction uric acid.

Question 44

Hemophilia A

Answer 44

X-linked recessive. Mutation on F8, deficiency of Factor VIII for clotting. Spontaneous bleeding into joints, prolonged bleeding, excessive bruising.

Question 45

Kearns-Sayre

Answer 45

Mitochondrial inheritance. Large > 12 genes deletion. Eye & kidney problems, ataxia, deaf.

Question 46

MELAS

Answer 46

Mitochondrial inheritance. Commonly mutation on MT-TL1. Muscle weakness, seizures, elevated lactic acid level, recurrent strokes.

Question 47

MERRF

Answer 47

Mitochondrial inheritance. MT-TK mutation. Muscle weakness, seizures, dementia, ragged-red fibers (impaired mitochondria cluster).