Mendelian Disorders

Question 1

Marfan Syndrome

Answer 1

AD
Mutation in FBN1 gene, fibrillin protein
Has pleiotropy (multiple phenotypes)
Most die of aortic aneurysm/rupture
Arachnodactyly, kyphoscoliosis, pectus excavatum, & ectopia lentis

Question 2

Ehlers-Danlos Syndrome

Answer 2

AD & AR subtypes
Lysyl hydroxylase deficiency interferes w/ collagen cross-links
Genetic heterogeneity - 6 variants lead to same phenotype
Hypermobile joints, hyperextensible skin, gaping wounds, & bowel rupture

Question 3

Familial Hypercholesterolemia

Answer 3

Most common Mendelian disorder!
Mutation in LDL receptor gene
AD
In homozygotes: 5-fold increase in hypercholesterolemia, xanthomas, premature atherosclerosis, MI by 20

Question 4

Cystic Fibrosis

Answer 4

Most common recessive disease in whites.
AR
CF gene mutations -> defective CFTR protein
Main mutation is delta F508; mannose-leptin mutation confers 3x risk of end-stage lung disease
Mutant CFTR doesn’t move Cl out of cells -> mucus builds up outside of cells
Bronchiectasis, pancreatic insufficiency, meconium ileus, bilateral absence of vas deferens, hepatic cirrhosis, nasal polyps, & cor pulmonale (end-stage lung disease)

Question 5

Phenylketonuria (PKU)

Answer 5

Most common inborn error of metabolism.
AR
Phenylalanine hydroxylase (PAH) deficiency -> hyperphenylalaninemia -> phenylketonuria
Mental retardation, seizures, decreased pigmentation, eczema, musty/mousy odor
PKU w/ dihydropterin reductase enzyme doesn’t respond to dietary restriction of PHE

Question 6

Maternal PKU

Answer 6

Babies born to mothers w/ hyperphenylalaninemia suffer TERATOGENIC EFFECTS of PHE
-Mental retardation, microcephaly, congenital heart disease

Question 7

Galactosemia

Answer 7

AR
Galactose-1-phosphate uridyltransferase (GALT) deficiency -> accumulation of galactose-1-phosphate -> toxicity
Hepatomegaly, cataracts, kidney failure, brain damage

Question 8

Tay-sachs

Answer 8

AR LSD
Hexosaminidase A deficiency -> GM2 ganliosidosis
Lethal, cherry red spot on retina, & severe neurologic deterioration by age 3

Question 9

Neimann-Pick

Answer 9

AR LSD
Lethal
Sphingomyelinase deficiency -> sphingomyelin accumulation
Type A - severe neurologic deterioration
Type A & B - zebra bodies & foamy macrophages

Type C1 - Defective NPC1 gene -> defect in lipid transport from lysosome to Golgi -> cholesterol accumulation
Ataxia, vertical gaze palsy, dysarthria, dystonia, & psychomotor regression

Question 10

Hurlers

Answer 10

AR LSD, MPS I
Iduronidase deficiency -> Accumulation of glycosaminoglycans (GAGs): dermatan & heparin sulfates
Coarse facial features, skeletal deformities, hepatosplenomegaly, early MIs, & corneal clouding

Question 11

Hunters

Answer 11

X-linked LSD, MPS II
Sulfatase deficiency -> Accumulation of glycosaminoglycans (GAGs): dermatan & heparin sulfates
Coarse facial features, skeletal deformities, hepatosplenomegaly, & early MIs

Question 12

Gaucher

Answer 12

AR LSD
Type I is most common, & non-lethal
Glucocerebrosidase deficiency -> glucocerebroside accumulation
Bone disease (erlenmayer flask bones), visceromegaly, & hematologic disease
Bone marrow has Gaucher cells - “wrinkled tissue” macrophages

Question 13

Pompe

Answer 13

AR LSD/GSD
Lysosomal acid maltase/glucocidase deficiency -> glycogenosis
Cardiac - cardiomegaly, cardiac failure

Question 14

von Gierkes

Answer 14

GSD
Glucose-6-phosphatase deficiency -> glycogenosis
Hepatic - hypoglycemia, hepatomegaly

Question 15

McArdle

Answer 15

GSD
Muscle phosphorylase deficiency -> glycogenosis
Myopathic - skeletal muscle cramps on exercising, myoglobinuria, failure of exercise induced lactic acid elevation