Exam #3: Genetic Disorders II

Question 1

How do autosomal recessive disorders compare to the autosomal dominant?

Answer 1

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

Question 2

What is alkaptonuria?

Answer 2

Autosomal recessive inborn error of metabolism that presents as:

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

Question 3

What causes alkaptonuria?

Answer 3

Deficiency of homogentisic acid oxidase leading to accumulation of homogentisic acid

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

Question 4

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

Answer 4

“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

Question 5

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

Answer 5

Microscopically= yellow-brown pigment in articular cartilage

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

Question 6

What are lysosomal storage diseases?

Answer 6

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

Question 7

List the lysosomal storage diseases.

Answer 7

Tay-Sachs
Gaucher Disease
Niemann-Pick
Mucopolysaccharidoses

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

Question 8

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

Answer 8

Enzyme= Hexosaminidase A

Product= Gm2 ganglioside

Question 9

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

Answer 9

Enzyme= glucocerebrosidase

Product= Glucocerebroside

Question 10

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

Answer 10

Enzyme= Sphingomyelinase

Product= Sphingomyelin

Question 11

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

Answer 11

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

Question 12

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

Answer 12

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

Question 13

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

Answer 13

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

Question 14

What are the symptoms of Tay-Sachs Disease?

Answer 14

~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

Question 15

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

Answer 15

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

Question 16

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

Answer 16

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

Question 17

What population is Tay-Sachs Disease associated with?

Answer 17

Ashkenazi Jew

Question 18

What is the most common lysosomal storage disease?

Answer 18

Gaucher Disease

Question 19

What is Gaucher Disease?

Answer 19

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

Question 20

What would glucocerebrosidase normally cleave glucocerebroside into?

Answer 20

Ceramide & glucose

Question 21

What is the hallmark feature of Gaucher Disease on microscopy?

Answer 21

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

Question 22

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

Answer 22

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

Question 23

What are the general symptoms of Gaucher Disease?

Answer 23

• Hepatosplenomegaly

- Bone pain & pathologic fractures

Question 24

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

Answer 24

Filled with large eosinophilic macrophages

Question 25

What is the classic Gaucher cell?

Answer 25

Macrophage with "wrinkled tissue paper" cytoplasm

Question 26

How is Gaucher Disease treated?

Answer 26

Enzyme replacement therapy

Question 27

What is Type A Neimann Pick's Disease?

Answer 27

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

Question 28

What is Type B Neimann Pick's Disease?

Answer 28

This is a less severe form of Neimann Picks disease characterized by: - Organomegaly esp. spleen & liver - NO CNS involvement - Patients survive into adulthood

Question 29

What are zebra bodies?

Answer 29

Characteristics appearance of Type A on EM

Question 30

What is Niemann-Pick Disease?

Answer 30

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

Question 31

What are the symptoms of Type C Neimann Picks?

Answer 31

- Ataxia - Vertical supranuclear gaze palsy - Dystonia - Dysarthria - Psychomotor regression

Question 32

What is the hallmark of Niemann-Pick Disease?

Answer 32

Marked accumulation of "foamy" macrophages

Question 33

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

Answer 33

Type C

Question 34

What is Type C Neimann Pick's Disease?

Answer 34

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

Question 35

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

Answer 35

- Neurologic symptoms get worse with time | - Systemic symptoms get better with time

Question 36

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

Answer 36

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

Question 37

What are the mucopolysaccharidoses?

Answer 37

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

Question 38

What are the two types of MPS?

Answer 38

``` I= Hurler II= Hunter ```

Question 39

What is the cause of Hurler Syndrome?

Answer 39

Deficiency is a-L-iduronidase that is autosomal recessive

Question 40

What is the cause of Hunter Syndrome?

Answer 40

Deficiency in L-iduronidate sulfatase that is X-linked

Question 41

What are the symptoms of Hurler Syndrome?

Answer 41

- 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

Question 42

What are the symptoms of Hunter Syndrome?

Answer 42

- Less severe dwarfism - Umbilical hernia - Hepatosplenomegaly - Intelligence may be normal - Life expectancy into adulthood ****Less severe than Hurler's Syndrome

Question 43

Which is more severe, Hurler or Hunter Syndrome?

Answer 43

Hurler Sydrome (Type I)

Question 44

What are GAGs/ MPS?

Answer 44

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

Question 45

What are the Glycogen Storage Diseases?

Answer 45

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

Question 46

What are the three GSDs that we are responsible for?

Answer 46

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

Question 47

What is the enzyme defect seen in Type I GSD?

Answer 47

von Gierke= glucose 6-phosphatase

Question 48

What is the enzyme defect seen in Type II GSD?

Answer 48

Pompe= acid maltase

Question 49

What is the enzyme defect seen in Type V GSD?

Answer 49

McArdle= muscle phosphorylase

Question 50

What are the symptoms of Type II GSD?

Answer 50

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.

Question 51

Describe the microscopic appearance of Pompe Disease.

Answer 51

"Clear"

Question 52

What are the symptoms of von Gierke's Disease?

Answer 52

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

Question 53

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

Answer 53

Type I= von Gierke Disease - hepatic form Type V= McArdle - myopathic form

Question 54

What are the symptoms of McArdle Disease?

Answer 54

- 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

Question 55

How does von Gierke's Disease appear microscopically?

Answer 55

Vacuolated