Genetic diseases

Question 1

describe Marfan Syndrome (MFS)

Answer 1

• autosomal dominant disorder
• characterized by involvement of ocular, skeletal, Cardio, pulmonary and skin
• MUTATION in FIBRILLIN-1 GENE disrupts microfibrils (component of elastic fibers)

Question 2

Dolichosternomelia

Answer 2

• unusually long and slender limbs

- sign of MFS

Question 3

Pectus carinatum

Answer 3

pigion chest

- sign of MFS

Question 4

Pectus excavatum

Answer 4

• hollow chest

- sign of MFS

Question 5

Myopia

Answer 5

• present in most patients of MFS

Question 6

Ectopia lentis

Answer 6

• displaced lens (near sightedness)

- occurs in 50% of MFS patients

Question 7

arachnodactylyl

Answer 7

• spider fingers
• denoting the characteristically long, slender fingers
• sign of MFS

Question 8

Joint hypermobility

Answer 8

• double jointedness

- sign of MFS

Question 9

Mitral valve prolapse

Answer 9

• mitral regurgitation

- sign of MFS

Question 10

describe the cardiovascular defects in marfan syndrome

Answer 10

• mitral valve prolapse
• dilation (widening) of ascending aorta leads to aortic valve incompetence may ensue and the aorta becomes susceptible to DISSECTION or rupture
• end result is congestive heart failure (How most patients die

Question 11

describe Ehlers-Danlos Syndrome (EDS)

Answer 11

• Heterogenous group of disorders caused by mutations that alter the structure or synthesis of fibrillar collagens
• characterized by joint hypermobility, cutaneous fragility (cigarette paper) skin, hyperextensiblity

Question 12

• Type I and II EDS

Answer 12

• Classical EDS
• characterized by mutations linked to loci that contain the COL5A1 or COL5A12 genes encoding the alpha-chains of type V collagen leading to defective type V collagen
• Type V collage = shapes and stabilizes type I collagen

Question 13

type IV EDS

Answer 13

• Vascular - thin skin, arterial or uterine rupture, bruising are all clinical findings
• characterized by decreased amount of type III collagen
• COL3A1 mutation
• very deadly

Question 14

type V and VI EDS

Answer 14

• are characterized by deficienceis in lysyl hydroxylase and lysyl oxidase, an important modifying enzyme in collagen biosynthesis

Question 15

type VII EDS

Answer 15

• has amino-terminal procollagen peptidase deficiency causing it to be unable to turn procollagen into collagen
• Congenital hip dislocation

Question 16

describe neurofibromatosis 1 (NF)

Answer 16

• Autosomal dominant disorder
• variable expressivity and 100% penetrance (if you get the disease you will have it)
• Caused by mutation of the NF-1 gene that resides on chromosome 17 and ENCODES NEUROFIBROMIN = tumor suppresor that inactivates the p21 Ras proto-oncogene (ras continues to signal and tumors develop)

Question 17

what are the characteristics of NF 1

Answer 17

• characterized by:
• -> neurofibromas, (benign peripheral nerve tumors
• ->hyperpigmented macules (cafe au lait spots),
• -> freckling of the armpits or groin area
• ->Lisch nodules (iris pigmented melanocyte hamartomas)

Question 18

describe cutaneous and subcutaneous neruofibromas in NF-1

Answer 18

• UNencapsulated benign tumors composed of SPINDLE CELLS = schwann cells, fibroblasts, perineurial cells
• appears as pedunculated masses and soft nodules along the course of peripheral nerves
• Plexiform neurofibromas infiltrate large nerves and cause severe disfigurement, and have potential for transformation into malignant schwannoma

Question 19

Describe Neurofibromatosis Type 2

Answer 19

• Autosomal dominant

- Caused by a mutation in NF-2 gene on chromosome 22 that ENCODES MERLIN(also called Schwannomin) (cytoskeletal protein)

Question 20

what is the characteristics of NF-2

Answer 20

• characterized by:
  –> bilateral 8th nerve schwannomas,
  –> multipe Meningiomas,
  –> gliomas,
  –> schwannosis ( nodular ingrowth of schwann cells into spinal cord)
  –> Meningioangiomatosis (aggregates of meningothelial cells and blood vessels within the brain or brainstem)
  –> cafe au lait macules, cutaneous neurofibromas, and juvenile cataracts are common
  (average age of death is 36)

Question 21

Compare and contrast NF-1 to NF-1

Answer 21

NF-1
- neurofibromin = GTPase activating protein that inactivates ras
- multiple benign neurofibromas, cafe au lait macules, iris hamartomas
NF-2
- Merlin = binds to actin and CD44
- bilateral vestibular schwannomas (acoustic neuromas) and hearing disturbances

Question 22

Fibrillin-1 mutation in Marfans syndrome causes…

Answer 22

• stiffening of aortic wall
• increased TGF-beta activity
• inflammation
• MMP upregulation
• Elastolysis/ Cell dessarray