SM 259: Genetic Disease

Question 1

What are Ichthyoses?

Answer 1

Greek for scaly fish; a group of disorders grouped due to characteristic skin thickening and scaling

Question 2

Why does skin thickening and scaling occur in Ichthyoses?

Answer 2

Believed to be a compensatory mechanism to poor epidermal barrier formation

Question 3

What is the most common form of Ichythoses?

Answer 3

Ichythyoses Vulgaris

Question 4

How does Ichythyoses Vulgaris present?

Answer 4

Scaling on the lower legs, and mild thickening/hyperlinearity of the palms and soles

Question 5

What causes Ichythyoses Vulgaris?

Answer 5

A mutation in the gene encodes Filaggrin, leading to a decrease in the Stratum Granulosum of the Epidermis which normally contains Filaggrin granules

Question 6

Why is Ichythyoses Vulgaris “semidominant”?

Answer 6

Loss of 1 Fillagrin allele leads to a milder phenotype than if both alleles are effect (which is lethal)

Question 7

What is Recessive X-linked Ichthyosis?

Answer 7

A recessive X-linked Ichthyosis that only occurs in males, which effects the enzyme Steroid Sulfatase

Question 8

What enzyme is effected by Recessive X-linked Ichthyosis, and what does this cause?

Answer 8

Steroid Sulfatase; leading to an accumulation of Cholesterol Sulfate in the Epidermis and blood

Question 9

What is “collodion baby”?

Answer 9

A rare group of Ichthyosis which results in a baby with a shiny cellophan elike membrane due to a Autosomal Recessive conditions

Includes Lamellar Ichthyosis (TGM) and CIE

Eventually resolves and becomes a different Ichthyosis

Question 10

What gene is mutated in the AR Congenital Ichthyosis Lamellar Ichthyosis that causes Collodion baby?

Answer 10

Transglutainase 1, an enzyme needed for normal maturation of and shedding of epidermal cells, is lost, leading to large platelike scales and Collodion baby

Question 11

What is Congenital Ichthyosiform Erythroderma?

Answer 11

An AR Congenital Ichthyosis due to 10 potential mutations that causes fine scaling

Question 12

What group of Ichthyosis has blisters?

Answer 12

Epidermolytic Icthyosis - an Autosomal Dominant condition

Question 13

How does Epidermolytic Ichthyosis present?

Answer 13

A superficial blistering disorder at birth that later changes to thickening to compensate for the barrier abnormality

Question 14

What genes are mutated in Epidermolytic Ichthyosis?

Answer 14

Keratins 1 and 10, found above the basal areas of the epidermis, may be mutated, leading to blistering

Question 15

Which Keratins are mutated in blistering disorders, and where are they found?

Answer 15

Keratins 1 and 10, found in above basal layer of the epidermis, and mutations cause disorders like Epidermolytic Ichthyosis

Keratins 5 and 14, found in the basal layer of the epidermis, cause Epidermolytic Bullosa Simplex

Question 16

Which Keratin is found in palms and soles?

Answer 16

Keratin 9

Question 17

How could mutations in Keratin 1 and 10 manifest differently in the palm?

Answer 17

Keratin 1 + 9 form pairs in the palm; a mutation in Keratin 10 has only slightly thickened palms, while a mutation in Keratin 1 has severely thickened palms

Question 18

What Keratins are found in the proliferative basal layer of the Epidermis?

Answer 18

Keratins 5 and 14 are found in the proliferative basal layer

Keratins 1 and 10 are found above the proliferative basal layer

Question 19

What is Epidermolysis Bulbosa simplex?

Answer 19

A Keratinopathy due to mutations in Keratins 5 or 14, which presents with blistering without significant thickening

Question 20

What are Junctional Epidermolysis Bulbosa?

Answer 20

An AR group of disorders which result from the absence of Hemidesmosomes, leading to a loss of skin adhesion

Lethal

Question 21

What is Dystrophic EB?

Answer 21

A group of EB that results from mutations in Type VII Collagen, leading to mild scarring and blistering if 1 allele is lost and severe glistering as well as growth retardation and SCC if both alleles are lost

Question 22

What are the three tumor syndromes and what causes them?

Answer 22

Mutations that activate signaling pathways cause tumor syndromes, including: Neurofibromatosis, Basal Cell Nevus Syndrome, and Tuberous Sclerosis

Question 23

What is Neurofibromatosis?

Answer 23

An AD disorder that causes cafe au lait macules and lisch nodules, later leading to dermal neurofibromas and optic gliomas

Question 24

What causes Neurofibromatosis?

Answer 24

Mutations in Neurofibromin, a tumor suppressor gene that negatively regulates Ras, leading to loss of tumor suppression - a loss of heterozygosity

Question 25

What is Basal Cell Nevus Syndrome?

Answer 25

An AD tumor syndrome due to mutations in patched, which encodes part of the hedgehog signaling pathway that regulates growth, leading to multiple basal cell cancers in early life

Question 26

What is Tuberous Sclerosis?

Answer 26

An AD tumor syndrome that results from mutations in Tuberin and Hamartin, negative regulators of mTOR, leading to white patches on skin and seizures in infancy as well as tumors like: brain tumors, renal angiomyolipomas, and cardiac rhabdomyomas

Question 27

What class of drugs can read through genes?

Answer 27

Aminoglycosides

Question 28

What techniques can diagnose genetic disorders early?

Answer 28

Amniocentesis and Chorionic Villus sampling

Question 29

How can gene editing treat genetic disorders?

Answer 29

RNAi to block a broken gene, CRISPR/Cas9 to replace an abnormal gene