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General Pathology > Exam #3: Genetic Disorders II > Flashcards

Exam #3: Genetic Disorders II Flashcards

1
Q

How do autosomal recessive disorders compare to the autosomal dominant?

A
  • More uniform expression
  • Complete penetrance
  • Onset early in life
  • Proteins show a loss of function
  • Skip generations & present in BOTH sexes
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2
Q

What is alkaptonuria?

A

Autosomal recessive inborn error of metabolism that presents as:

  • Blue-black pigment in the ears & nose
  • Urine that turns black
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3
Q

What causes alkaptonuria?

A

Deficiency of homogentisic acid oxidase leading to accumulation of homogentisic acid

*****This enzyme converts homogentisic acid to methylacetoacetic acid in the TYROSINE degradation pathway.

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4
Q

What are the effects of homogentisic acid on the MSK system?

A

“Precocious arthritis”

  • Homogentisic acid binding to collagen causes the bone & cartilage to turn brittle
  • Intervertebral discs involved first, then
  • knees
  • hips
  • shoulders

*****Note that the small joints are spared

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5
Q

How does alkaptonuria appear microscopically? How does alkaptonuria appear macroscopically?

A

Microscopically= yellow-brown pigment in articular cartilage

Macroscopically= “ochronosis” i.e. blue-black pigmentation of the ears, nose, & cheeks

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6
Q

What are lysosomal storage diseases?

A

Diseases caused by the inability of lysosomes to completely breakdown a product, due to an enzyme defect.

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7
Q

List the lysosomal storage diseases.

A

Tay-Sachs
Gaucher Disease
Niemann-Pick
Mucopolysaccharidoses

*****Note that all of these conditions are autosomal recessive.

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8
Q

What is the enzyme defect seen in Tay Sachs Disease? What is the major accumulating metabolite?

A

Enzyme= Hexosaminidase A

Product= Gm2 ganglioside

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9
Q

What is the enzyme defect seen in Gaucher Disease? What is the major accumulating metabolite?

A

Enzyme= glucocerebrosidase

Product= Glucocerebroside

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10
Q

What is the enzyme defect seen in Niemann Pick Disease? What is the major accumulating metabolite?

A

Enzyme= Sphingomyelinase

Product= Sphingomyelin

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11
Q

What is the enzyme defect seen in Mucopolusaccharidoses? What is the major accumulating metabolite?

A

Lysosomal enzymes involved in the degradation of mucopolysaccharides i.e. glycosaminoglycans

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12
Q

What are the three general treatment strategies for the lysosomal storage diseases?

A

1) Enzyme replacement therapy
2) Substrate reduction therapy
3) Molecular chaperone therapy to assist in proper folding of proteins

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13
Q

What is the specific mutation that causes Tay-Sachs Disease?

A
  • Frameshift mutation in HexA gene i.e. the alpha subunit locus
  • Located on chromosome 15
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14
Q

What are the symptoms of Tay-Sachs Disease?

A

~6 months of age, patients begin a rapid deterioration including:

1) Relentless motor & mental detioriation
2) Mental obtundation
3) Flaccidity, blindness, and increasing dementia

~1-2 years= vegetative state
~2-3 years= death

**At some point during the progression, “cherry red macula” appears

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15
Q

What is the Cherry Red Spot associated with Tay-Sachs Disease?

A

Retinal swelling at the margins of the macula due to Gm2 ganglioside accumulation that accentuates the color of the macular choroid (red?)

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16
Q

What are ballooned neurons? What disease are these associated with?

A

Histologic examination of neurons from Tay Sachs Disease shows “ballooned” neurons from the accumulation of cytoplasmic vacuoles containing distended lysosomes filled with gangliosides

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17
Q

What population is Tay-Sachs Disease associated with?

A

Ashkenazi Jew

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18
Q

What is the most common lysosomal storage disease?

A

Gaucher Disease

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19
Q

What is Gaucher Disease?

A

Autosomal recessive disease caused by a mutation in B-glucocerebrosidase causing glucocerebroside to accumulate in the lysosome

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20
Q

What would glucocerebrosidase normally cleave glucocerebroside into?

A

Ceramide & glucose

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21
Q

What is the hallmark feature of Gaucher Disease on microscopy?

A

“Gaucher cells” that are huge macrophages with a bloated cytoplasm that is “fibrillary” in nature vs. vacuolated & resembles crumpled tissue paper

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22
Q

What is the difference between Type II & Type III Gaucher Disease?

A

BOTH onset in childhood and are neuropathic; however,

  • Type II= more severe, rapidly progressive, and onsets in the first year of life
  • Type III= moderate disease that onsets in childhood/ adolescence & is progressive
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23
Q

What are the general symptoms of Gaucher Disease?

A
  • Hepatosplenomegaly

- Bone pain & pathologic fractures

24
Q

How does the bone marrow of patient’s with Gaucher Disease appear?

A

Filled with large eosinophilic macrophages

25
Q

What is the classic Gaucher cell?

A

Macrophage with “wrinkled tissue paper” cytoplasm

26
Q

How is Gaucher Disease treated?

A

Enzyme replacement therapy

27
Q

What is Type A Neimann Pick’s Disease?

A

This is the most severe/ infatile form of the disorder that is marked by:

  • Extensive neurologic involvement
  • Marked visceral accumulations
  • Progressive wasting
  • Death within 3 years
28
Q

What is Type B Neimann Pick’s Disease?

A

This is a less severe form of Neimann Picks disease characterized by:

  • Organomegaly esp. spleen & liver
  • NO CNS involvement
  • Patients survive into adulthood
29
Q

What are zebra bodies?

A

Characteristics appearance of Type A on EM

30
Q

What is Niemann-Pick Disease?

A

This is an autosomal recessive disease characterized by a defect in sphingomyelinase that leads to the accumulation of sphingomyelin

31
Q

What are the symptoms of Type C Neimann Picks?

A
  • Ataxia
  • Vertical supranuclear gaze palsy
  • Dystonia
  • Dysarthria
  • Psychomotor regression
32
Q

What is the hallmark of Niemann-Pick Disease?

A

Marked accumulation of “foamy” macrophages

33
Q

Which form of Neimann Pick’s Disease is most common?

A

Type C

34
Q

What is Type C Neimann Pick’s Disease?

A

This is a non-enzymatic defect in lipid transport that leads to accumulation of cholesterol & Gm gangliosides that cause neurological damage

35
Q

Describe the progression systemic and neurologic symptoms in Type C Neimann Picks Disease.

A
  • Neurologic symptoms get worse with time

- Systemic symptoms get better with time

36
Q

What are the four major diseases that are associated with a higher incidence in the Ashkenazi Jewish population?

A

1) Cystic Fibrosis
2) Gaucher Disease
3) Niemann Pick Disease
4) Tay-Sachs Disease

37
Q

What are the mucopolysaccharidoses?

A

Lysosomal storage diseases caused by defects in lysosomal enzymes that degrade mucopolysaccharides

38
Q

What are the two types of MPS?

A 
I= Hurler 
II= Hunter
39
Q

What is the cause of Hurler Syndrome?

A

Deficiency is a-L-iduronidase that is autosomal recessive

40
Q

What is the cause of Hunter Syndrome?

A

Deficiency in L-iduronidate sulfatase that is X-linked

41
Q

What are the symptoms of Hurler Syndrome?

A
  • Dwarfism
  • Protruding abdomen w/ umbilical hernia
  • Hepatosplenomegaly
  • Coarse facies
  • Joint contractures
  • Mental retardation
  • Corneal clouding

**Usually fatal by age 6-12 due to cardiac complications

42
Q

What are the symptoms of Hunter Syndrome?

A
  • Less severe dwarfism
  • Umbilical hernia
  • Hepatosplenomegaly
  • Intelligence may be normal
  • Life expectancy into adulthood

**Less severe than Hurler’s Syndrome

43
Q

Which is more severe, Hurler or Hunter Syndrome?

A

Hurler Sydrome (Type I)

44
Q

What are GAGs/ MPS?

A

Mucopolysaccharides are long-chain complex carbohydrates linked with proteins to form proteoglycans, also called glycosaminoglycans that include:

  • Dermatan sulfate
  • Heparan sulfate
  • Keratan sulfate
  • Chondroitin sulfate
45
Q

What are the Glycogen Storage Diseases?

A

Recessive diseases resulting in a defect in an enzyme involved in the synthesis or degradation of glycogen

46
Q

What are the three GSDs that we are responsible for?

A

Type I= von Gierke
Type II= Pompe
Type V= McArdle

47
Q

What is the enzyme defect seen in Type I GSD?

A

von Gierke= glucose 6-phosphatase

48
Q

What is the enzyme defect seen in Type II GSD?

A

Pompe= acid maltase

49
Q

What is the enzyme defect seen in Type V GSD?

A

McArdle= muscle phosphorylase

50
Q

What are the symptoms of Type II GSD?

A

Pompe=

  • Floppy baby
  • Big tongue
  • Cardiomegaly

Note that acid maltase is a lysosomal enzyme involved in the breakdown of glycogen; deficiency leads to accumulation of glycogen in all tissues, but most prominently the heart.

51
Q

Describe the microscopic appearance of Pompe Disease.

A

“Clear”

52
Q

What are the symptoms of von Gierke’s Disease?

A

Hepatomegaly
Hypoglycemia
Renomegaly

*****Note that defect in the hepatic enzyme in glycogen breakdown leads to hepatomegaly & reduction in blood glucose (hypoglycemia)

53
Q

What is the difference between Type I & Type V GSD?

A

Type I= von Gierke Disease
- hepatic form

Type V= McArdle
- myopathic form

54
Q

What are the symptoms of McArdle Disease?

A
  • Normal muscle strength
  • Muscle weakness & intolerance w/ exercise

*****Can lead to Rhabdomyolysis. Also, note that here glycogen cannot be utilized for its normal role in energy production in muscles

55
Q

How does von Gierke’s Disease appear microscopically?

A

Vacuolated

General Pathology (33 decks)

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