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Foundations 1 > Autosomal Recessive Disorders > Flashcards

Autosomal Recessive Disorders Flashcards

1
Q

What are the 3 general consequences of enzyme deficiency?

A
  • Substrate accumulation
  • Product deficiency
  • Upregulation of minor alternate pathway
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2
Q

What is the clinical course of Tay-Sachs?

A
  • Normal development for 3-5 months
  • Slowing of progress -> plateau -> loss of milestones
  • By 8-10 months: decrease in purposeful activity and lack of awareness of surroundings
  • Death by age 5
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3
Q

Symptoms of Tay-Sachs

A
  • Hyperacusis and easily startled
  • Progressive weakness and hypotonia
  • Decreased visual attentiveness and abnormal eye movements
  • Eventual deafness and blindness
  • Seizures
  • Vegetative state
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4
Q

What enzyme deficiency disorders are caused by accumulation of substrate?

A
  • Tay-Sachs
  • mucopolysaccharidoses
  • I-cell
  • glycogen storage diseases
  • urea cycle defects
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5
Q

What enzyme deficiency disorders are caused by product deficiency?

A
  • glycogen storage diseases

- biotinidase deficiency

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6
Q

What enzyme deficiency disorders are caused by toxic effects of abnormal metabolites?

A
  • Galactosemia
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7
Q

What is the incidence of Tay-Sachs disease and carriers?

A

Disease: 1/3500 Ashkenazi Jews and 1/300,000 non-Jews

Carrier: 1/25 Ashkenazi Jews and 1/300 non-Jews

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8
Q

What enzyme deficiency causes Tay-Sachs?

A

Hexosaminidase A (alpha subunit)

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9
Q

What is the function of hexosaminidase A?

A

Degradation of ganglioside GM2 in neuronal lysozymes

GM2 -> GM3 + galNAc

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10
Q

Allelic heteogeneity

A

Different alleles leading to very similar phenotypes

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11
Q

What mutation causes Tay-Sachs?

A

Multiple different mutations to HEXA:

  • insertion => frameshift
  • missense => defective splicing
  • deletion => no transcription
  • missense => defective processing
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12
Q

Tay-sachs brain histology

A

Neurons distended due to accumulation of fatty GM2 in lysosomes

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13
Q

What are the basic structural elements of GM2

A

cerebroside (3 carbon backbone) - glu - gal - NANA and galNAc

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14
Q

What elements are removed in the catabolism of GM1 -> GM2 -> GM3

A
  1. terminal galactose removed

2. N-acetylglucosamine removed

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15
Q

How does hexosaminidase activity compare in people +/- Tay-Sachs?

A

No difference

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16
Q

Compare the gene dosage of hexosaminidase A in normal, parents, and Tay-Sachs patients

A
  • normal
  • 1/2 (obligate heterozygotes)
  • negligable
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17
Q

What genes are involved in hexosaminidase A synthesis and how are the subunits assembled?

A

1 alpha chain (HEXA) + 1 beta chain (HEXB) + activation by activator (GM2A)

18
Q

What is the function of activator?

A

Used to bring fatty, hydrophobic GM2 to the water soluble proteins it needs to interact with in vivo

19
Q

What are symptoms of mucopolysaccharidosis I?

A
  • Joint contractures
  • Joint stiffness
  • Dysostosis multiplex = radiographic abnormalities (Gibbus abnormality, rounded hand x-ray, thicker ribs, thinner pelvis)
  • Visceromegaly = enlarged liver and spleen
  • Coarse facies
  • Corneal clouding
  • Metachromasia test of urine
20
Q

Which mucopolysaccharidosis is NOT autosomal recessive?

A

Hunter is X-linked

21
Q

Where do GAGs accumulate in patients with mucopolysaccharidoses?

A

Tissues and urine

22
Q

How were cross-corrective studies used in the study of mucopolysaccharidoses?

A
  • Cells from patients with different mucopolysaccharidoses cultured together with radioactive sulfate
  • Healthy cells should reach a steady state where incorporation and breakdown are constant
  • Diseased cells continue to accumulate sulfate as they can’t break down GAGs
  • If diseased cells cross-correct, must impact different enzymes
  • If diseased cells DON’t cross-correct, they must impact different enzymes
23
Q

Locus heterogeneity

A

Different genes (loci) => same phenotype

24
Q

Allelic heterogeneity

A

different mutations at the same locus => same phenotype

25
Q

What class of diseases do Tay-Sachs and mucopolysaccharidoses belong to and why?

A

Storage diseases because the buildup of the involved molecules is visible

26
Q

Why is there toxicity associated with defective urea cycle enzymes?

A

Ammonia buildup

27
Q

How are urea cycle enzyme defects treated?

A
  • Give product of defective enzyme reaction so cycle can continue
  • Any accumulated intermediate from before defective enzyme will be excreted in urine
28
Q

What is the clinical consequence of propionyl carboxylase deficiency?

A

Acidosis

29
Q

What products are generated from alternative pathways for propionyl CoA when propionyl CoA carboxylase is deficient?

A
  • propionic acid
  • 3-hydroxypropionante
  • methylcitrate
  • propionyl glycine
  • lactate
30
Q

What are the biotin dependent carboxylases?

A
  • Propionyl CoA carboxylase
  • Acetyl CoA carboxylase
  • Methylcrotonal carboxylase
  • Pyruvate carboxylase
31
Q

What is the function of holocarboxylase synthase?

A

Adds biotin to biotin-dependent carboxylase apoenzymes

32
Q

Apoenzyme

A

Inactive enzyme without cofactor

33
Q

Holoenzyme

A

Active enzyme with cofactor

34
Q

What enzyme is defective in early onset multiple carboxylase deficiency?

A

holocarboxylase deficiency

35
Q

What enzyme is defective in late onset multiple carboxylase deficiency? Why are the symptoms late onset?

A
  • Biotinidase
  • Apoenzymes can be biotinilated, but biotin cannot be recycled from degraded enzyme so eventually biotin will be depleted such that the biotin cycle cannot proceed
36
Q

What is the purpose of the biotin cycle?

A
  • Add biotin to biotin-dependent carboxylase apoenzymes

- Recycle biotin after proteolytic degradation of biotinilated proteins

37
Q

What is the function of biotinidase?

A

Removes biotin from lys residues after proteolytic degradation of a biotin-dependent carboxylase

38
Q

What intermediate causes the toxicity associated with galactosemia?

A

gal-1-p

39
Q

What alternative pathway for galactose is upregulated in galactosemia?

A

Reduction of galactose to galactitol via the polyol pathway

40
Q

What issue does galactitol cause in the lens?

A

Cataracts: galactitol is osmotically active, pulling water into the lens

Foundations 1 (26 decks)

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