Diseases

Question 0

Cystic Fibrosis

Answer 0

CFTR, autosomal recessive
1 in 2000 - 2500 white children

progressive pulmonary disease, exocrine pancratic insufficiency, obstructie azoospermia, elevated sweat chloride concentration, growth failure, meconium ileus

Question 1

Neurofibromatosis

Answer 1

NF1, autosomal dominant
penetrance: 100% in adults; <50% in children

cafe au lait spots, neurofibromas; Lisch nodules (hamartomas) in the iris; mental retardation

Question 2

Turner syndrome

Answer 2

45, X

short stature, swelling, broad chest, webbed neck, low hairline, low-set ears
cognitive deficits: visuospatial, mathematical & memory
typically sterile, amenorrhea (non-working ovaries)

Question 3

Edwards syndrome

Answer 3

Trisomy 18

Intrauterine growth retardation
Hypertonicity - clenched hands, narrow hips
CNS abnormalities - posterior fossa anomalities, severe intellectual disabilities, seizures
Congenital heart disease

Question 4

Patau syndrome

Answer 4

Trisomy 13

Normal or deficient growth
CNS abnormalities - holoprosencephaly, severe intellectual disabilities
Facial clefts, polydactyly, renal dysplasia, congenital heart disease, omphalocele, dermal defects

Question 5

Klinefelter syndrome

Answer 5

47 XXY

Tall, hypogonadism, underdeveloped secondary sexual char., gynecomastia, usually in fertile, language impairment

1/1000 live births
50% of cases = patetnal meiosis I failure of recombination in pseudoautosomal regions

15% of cases = mosaicism (46, XY / 47, XXY)

Question 6

47 XYY syndrome

Answer 6

Indistinguishable physically / mentally from normal males

1/1000 live births
inc. risk of behavioral & educational problems; delayed speech / language

Question 7

Charcot-Marie-Tooth Disease

Answer 7

Duplication of 17p11.2 which contains the gene for peripheral myelin protein-22 (PMP-22)

weakness of the foot and lower leg muscles
foot deformities (hammer toes)
weakness & muscle atrophy of the hands (late in the disease course)
all forms of the disease affect peripreal nerves.

*of note, due to dosage differences, deletion in the same region of chr 17p leads to a different peripheral myelin disease HNLPP (p. 97)

Question 8

List the various mechanisms that lead to Down Syndrome.

Answer 8

1. Meiosis I nondisjunction
2. Robertsonian Translocation
3. Isochromosome
4. Mosaic Down Syndrome
5. Partial trisomy 21

Question 9

Velo-Cardio-Facial syndrome

Answer 9

del(22q11.2)

cleft palate, lateral nasal buildup, cardiac septal defects
“Contiguous Gene Syndrome”

Question 10

DiGeorge syndrome

Answer 10

del(22q11.2)

absent or hypoplastic thymus (T-cell abnormalities = a lot of infections) & parathyroids, congenital heart disease (outflow tract)

Question 11

List at least 4 contiguous gene syndromes (as discussed in class)

Answer 11

DiGeorge syndrome
Prader-Willi syndrome
Velo-Cardio-Facial syndrome
Angleman syndrome

Question 12

Chronic Myelogenous Leukemia

genotype…

Answer 12

46, XX t(9;22)(q34;q11.2) (95% of patients)

Reciprocal Translocation between chromosomes 9 and 22.
Philadelphia chromosome: BCR gene from chrom. 22 and the ABL gene from chrom. 9 fuse. BCR-ABL fusion gene is a tyrosine kinase.

Question 13

Chronic Myelogenous Leukemia

pathophys…

Answer 13

Cancer of the white blood cells
unregulated growth of myeloid cells in the bone marrow
accumulation of these cells in the blood

treated with tyrosine kinase inhibitors (imatinib, gleevec)

Question 14

For DiGeorge syndrome remember CATCH-22

Answer 14

Cardiac abnormality
Abnormal facies
Thymic aplasia
Cleft palate
Hypocalcemia/Hypoparathyroidism
Chromosome 22  del(22q11)

Question 15

Beckwith-Wiedmann syndrome

Answer 15

Uniparental Disomy for a portion of chr 11

large at birth, enlarged tongue, protrusion of the umbilicus
severe hypoglycemia, malignant neoplasms of kidney, adrenal and liver

see p. 79; also a focus of “ghost in your genes” video recommended by Dr. Johnson

Question 16

Huntington Disease - genetics

Answer 16

HD allele - expansion of a polyglutamine encoding repeat (CAG) in exon 1 of the HD gene
normal allele has 10-26 CAG repeats
mutant allele has >36 CAG repeats

Age at disease onset inversely proportional to # CAG repeats in HD gene
Reduced penetrance for 36-41 CAG repeats in HD gene
80% juvenile pts inherit from father
Mean age of onset is 35-44 years
Median survival after diagnosis is 15-18 years

Question 17

Huntington Disease - clinical presentation

Answer 17

Progressive motor, cognitive and psychiatric abnormaities
Motor: voluntary and involuntary movement disturbances; Chorea
Cognitive: language (later onset), behavioral social disinhibition, aggression, outbursts, apathy, sexual deviation, increased appetite
Psychiatric: personality changes, affective psychosis, schizophrenia

Question 18

Ellis-van Creveld syndrome

Answer 18

Autosomal recessive
Ex. of the Founder Effect in Old Order Amish populations

short-limbed dwarfism, polydactyly, abnormal nails & teeth, heart defects

Question 19

Type I Tyrosinemia

Answer 19

Autosomal recessive
Ex. of Founder Effect in French-Canadian region: Lac Saint Jean in Quebec

Hepatic failure, renal tubular dysfunction - deficiency in fumarylacetoacetase (enzyme in the degradation pathway of Tyrosine)
1/685 in Lac Saint Jean region of Quebec
1/100,000 in other parts of Quebec, Sweden and Norway

Question 20

Osteogenesis Imperfecta genetics…

Answer 20

Type-1 collagen deficiency (most common)
8 types in all from different genetic mutations
Most common mutations in COL1A1 or COL1A2 autosomal dominant; 60-100% de novo mutations
(some autosomal recessive versions exist)

1/20,000 live births

Question 21

Sickle Cell Anemia genetics…

Answer 21

SNP of Beta-globin gene Glu6Val
Beta-globin gene is located at 11q15.4

Confers Heterozygous Advantage against malaria
Common in regions with more malaria

*(E6V glutamic acid at position 6 changed to valine; GAG -> GTG; A to T mutation

Question 22

MODY-3

HNF1-alpha mutation

Answer 22

Mature Onset Diabetes of the Young - 3
most common (70%) of all MODY's
HNF1-alpha is a homeobox trxn factor (important for differentiaton of beta cells)
Different mutations within the HNF1-alpha gene lead to variable expressivity of onset age
is a considered a type 2 diabetes but insulin dependence eventually develops late (after many years with disease, beta cells deteriorate)

treat with sulfonylureas

Question 23

Duchene Muscular Dystrophy

Answer 23

X-linked recessive
Gower maneuver
giant calves
muscle wasting, extra connective tissue
progressive loss of respiratory function (diaphragm)

Question 24

Becker muscular dystrophy

Answer 24

less severe - point (in frame mutation)

same gene location (Xp) as duchenne m.d.

Question 25

Achondroplasia

Answer 25

autosomal dominant
chr. 4, fibroblast growth factor receptor
FGFRc - inhibits proliferation of chondrocytes
mutation leads to shortening of the long bones –> short stature
1 in 25,000