Autosomal recessive disorders

Question 1

King Tut reading assignment

Answer 1

pictures showed him having gynecomastia

no gynecomastia, craniosynosteses or Marfan found

accumulation of malformations in his family is evident, consanguinity between mom and dad

avascular bone necrosis + malarial infection are cause of death

walking impairment and malarial disease is supported by discovery of canes in tomb

Question 2

Cystic fibrosis (general)

Answer 2

• most common fatal autosomal genetic disease in the white population
• affects the cells that produce mucus, sweat, saliva, and digestive juices.
  
  • Normally, these secretions are thin and slippery
  • In CF a defective gene causes the secretions to become thick and sticky
    
    • Instead of acting as a lubricant, the secretions plug up tubs, ducts and passageways, especially in the pancreas and lungs.

Question 3

CF genetic abnormality

Answer 3

q arm of chromosome 7

MC mutation is F508

3 base deletion which leads to absence of phenylalanine residue at postion 508 on CFTR position

Question 4

Protein affected CF

Answer 4

membrane associated protein, CFTR

transmembrane chloride channel protein that line passageways of lungs, liver, pancreas, etc.

transports Cl ions across membrane of cells in these areas

H₂O follows Cl

Question 5

CF pathophys

Answer 5

normal CFTR allows chloride, and therefore water and other fluids across various cells (keeping fluid secretions thin and slippery)

mutations here result in preventing usual flow of Cl and H₂O which makes thick and sticky mucus

mucus obstructs airways and glands– mucus is not cleared and lungs are highly susceptible to infection, pancreas ducts get clogged so malabsoprtion of nutrients and chronic malnutrition

Question 6

CF is pleotropic…

Answer 6

CF mutations result in complex multisystem effects:

• respiratory
• pancreas
• genital
• glands

Question 7

clinical manifestations of CF

Answer 7

respiratory failure is most dangerous

blockage of pancreatic secretions causes malabsorption of key vitamins

meconium ileus due to obstruction by viscid meconium (newborns)

Question 8

expression and penetrance patterns of CF

Answer 8

pulmonary dz and respiratory issues account for 90% of deaths in CF patients

lungs are histologically normal at birth

Question 9

HOw is CF diagnosed?

Answer 9

sweat test

high salt level in pts sweat glands indicates disease

high [Cl] in sweat confirms

Question 10

CF TREATMENT

Answer 10

focused on GI and pulmonary areas

mantain nutritional status, prevent airway obstruction and pancreatic enzyme replacement

bronchodilators, abx for infections

postural drainage to correct lung plugging

Question 11

lysosomal storage disorders

Answer 11

deficiency of lysosomal hydrolase causing lysosomal accumulation of sphingolipid substrate

causes an accumulation of whatever the lysozyme breaks down

inability to degrade glycosphinogolipids, essential component of cell membranes, results in accumulation and leads to neurodegenerative effects and organomegaly

Question 12

Tay-Sachs (general)

Answer 12

autosomal recessive metabolic lysosomal storage disorder

common among Ashkenazi Jews

three types: infantile, juvenile, adult

Question 13

Tay-Sachs

genetic abnormality

Answer 13

mutation of HEXA gene on chromsome 15

Question 14

tay-sachs

protein affeted

Answer 14

HEXA codes for alpha subunit of enxyme B-hexosaminidase A (in lysosomes)

Question 15

pathophys

Tay-Sachs

Answer 15

B-hex A degrades GM2 ganglioside

diminished enzyme - lysosomal accumulation of GM2 in CNS

after so much accumulation, these cells die causing neurodegeneration

Question 16

clinical manifestations of infantile tay sachs

Answer 16

showes up by 6 mo, characterized by blindness and presence of cherry red spot on macula

seizuers develop and neurodeneration is relentless

causes death by 2 years of age

Question 17

clinical manifestations of junvenile tay-sachs

Answer 17

slighly less neurodegenerative

shows up b/t 2-6 yrs and causes death by 10-15 yrs

Question 18

clinical manifestations of adult Tay-Sachs

Answer 18

varying symptoms in clinic

spinocerebellar and lower motor neuron dysfunciton

Question 19

main indicator of Tay-Sachs on exam

Answer 19

cherry red spot of macula

caused when ganglion cells degenerate

Question 20

expression and inheritance patterns of Tay-Sachs

Answer 20

earlier the age of onset= more severe

Question 21

Gaucher disesae

general

Answer 21

metabolic lysosomal storage disorder

doesnt affect nerve cells (unlike tay sachs)

depostiotion of glucocerebroside in cells of macrophage-monocyte system

Question 22

types of gaucher disease

Answer 22

• Type I: most common, treated with cerezyme
• Type II: rare and more severe

Question 23

genetic abnormality of gaucher disease

Answer 23

mutation on chromosome 1, GBA

Question 24

protein affected in Gaucher Disease

Answer 24

deficinecy of acid beta glucocerebrosidase

Question 25

glucocerebrosidase

Answer 25

breaks down a fat found in all cell membranes, glycocerebroside

when cells die they dont need glycocerebroside, so it is tagged to be picked up by macrophages or monocytes

macrophages will then phagocytize cell membrane and it is sent to lysosomes in macrophages for destruction

Question 26

Gaucher disease pathophys

Answer 26

macrophages produce defective or insufficient amounts of glucocerebrosidase

results in an inability to digest glucocerebroside and they then have excess that builds up in lysosome

causes appearence of Gaucher cell in liver, spleen, bone (where monocytes are produced)

Question 27

clinical manifestaitons of gaucher

Answer 27

organomegaly due to glycolipid storage

occasional pulmonary infiltration

classic symptom: massive hepatosplenomegaly

Question 28

Gaucher treatment

Answer 28

w.o treatment, liver expands 2-3x normal size, spleen 20x

type I: treated with cerozyme replacement theraphy

no treatment for type II