Exam #3: Genetic Disorders II Flashcards
How do autosomal recessive disorders compare to the autosomal dominant?
- More uniform expression
- Complete penetrance
- Onset early in life
- Proteins show a loss of function
- Skip generations & present in BOTH sexes
What is alkaptonuria?
Autosomal recessive inborn error of metabolism that presents as:
- Blue-black pigment in the ears & nose
- Urine that turns black
What causes alkaptonuria?
Deficiency of homogentisic acid oxidase leading to accumulation of homogentisic acid
*****This enzyme converts homogentisic acid to methylacetoacetic acid in the TYROSINE degradation pathway.
What are the effects of homogentisic acid on the MSK system?
“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
How does alkaptonuria appear microscopically? How does alkaptonuria appear macroscopically?
Microscopically= yellow-brown pigment in articular cartilage
Macroscopically= “ochronosis” i.e. blue-black pigmentation of the ears, nose, & cheeks
What are lysosomal storage diseases?
Diseases caused by the inability of lysosomes to completely breakdown a product, due to an enzyme defect.
List the lysosomal storage diseases.
Tay-Sachs
Gaucher Disease
Niemann-Pick
Mucopolysaccharidoses
*****Note that all of these conditions are autosomal recessive.
What is the enzyme defect seen in Tay Sachs Disease? What is the major accumulating metabolite?
Enzyme= Hexosaminidase A
Product= Gm2 ganglioside
What is the enzyme defect seen in Gaucher Disease? What is the major accumulating metabolite?
Enzyme= glucocerebrosidase
Product= Glucocerebroside
What is the enzyme defect seen in Niemann Pick Disease? What is the major accumulating metabolite?
Enzyme= Sphingomyelinase
Product= Sphingomyelin
What is the enzyme defect seen in Mucopolusaccharidoses? What is the major accumulating metabolite?
Lysosomal enzymes involved in the degradation of mucopolysaccharides i.e. glycosaminoglycans
What are the three general treatment strategies for the lysosomal storage diseases?
1) Enzyme replacement therapy
2) Substrate reduction therapy
3) Molecular chaperone therapy to assist in proper folding of proteins
What is the specific mutation that causes Tay-Sachs Disease?
- Frameshift mutation in HexA gene i.e. the alpha subunit locus
- Located on chromosome 15
What are the symptoms of Tay-Sachs Disease?
~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
What is the Cherry Red Spot associated with Tay-Sachs Disease?
Retinal swelling at the margins of the macula due to Gm2 ganglioside accumulation that accentuates the color of the macular choroid (red?)
What are ballooned neurons? What disease are these associated with?
Histologic examination of neurons from Tay Sachs Disease shows “ballooned” neurons from the accumulation of cytoplasmic vacuoles containing distended lysosomes filled with gangliosides
What population is Tay-Sachs Disease associated with?
Ashkenazi Jew
What is the most common lysosomal storage disease?
Gaucher Disease
What is Gaucher Disease?
Autosomal recessive disease caused by a mutation in B-glucocerebrosidase causing glucocerebroside to accumulate in the lysosome
What would glucocerebrosidase normally cleave glucocerebroside into?
Ceramide & glucose
What is the hallmark feature of Gaucher Disease on microscopy?
“Gaucher cells” that are huge macrophages with a bloated cytoplasm that is “fibrillary” in nature vs. vacuolated & resembles crumpled tissue paper
What is the difference between Type II & Type III Gaucher Disease?
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
What are the general symptoms of Gaucher Disease?
- Hepatosplenomegaly
- Bone pain & pathologic fractures
How does the bone marrow of patient’s with Gaucher Disease appear?
Filled with large eosinophilic macrophages
What is the classic Gaucher cell?
Macrophage with “wrinkled tissue paper” cytoplasm
How is Gaucher Disease treated?
Enzyme replacement therapy
What is Type A Neimann Pick’s Disease?
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
What is Type B Neimann Pick’s Disease?
This is a less severe form of Neimann Picks disease characterized by:
- Organomegaly esp. spleen & liver
- NO CNS involvement
- Patients survive into adulthood
What are zebra bodies?
Characteristics appearance of Type A on EM
What is Niemann-Pick Disease?
This is an autosomal recessive disease characterized by a defect in sphingomyelinase that leads to the accumulation of sphingomyelin
What are the symptoms of Type C Neimann Picks?
- Ataxia
- Vertical supranuclear gaze palsy
- Dystonia
- Dysarthria
- Psychomotor regression
What is the hallmark of Niemann-Pick Disease?
Marked accumulation of “foamy” macrophages
Which form of Neimann Pick’s Disease is most common?
Type C
What is Type C Neimann Pick’s Disease?
This is a non-enzymatic defect in lipid transport that leads to accumulation of cholesterol & Gm gangliosides that cause neurological damage
Describe the progression systemic and neurologic symptoms in Type C Neimann Picks Disease.
- Neurologic symptoms get worse with time
- Systemic symptoms get better with time
What are the four major diseases that are associated with a higher incidence in the Ashkenazi Jewish population?
1) Cystic Fibrosis
2) Gaucher Disease
3) Niemann Pick Disease
4) Tay-Sachs Disease
What are the mucopolysaccharidoses?
Lysosomal storage diseases caused by defects in lysosomal enzymes that degrade mucopolysaccharides
What are the two types of MPS?
I= Hurler II= Hunter
What is the cause of Hurler Syndrome?
Deficiency is a-L-iduronidase that is autosomal recessive
What is the cause of Hunter Syndrome?
Deficiency in L-iduronidate sulfatase that is X-linked
What are the symptoms of Hurler Syndrome?
- 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
What are the symptoms of Hunter Syndrome?
- Less severe dwarfism
- Umbilical hernia
- Hepatosplenomegaly
- Intelligence may be normal
- Life expectancy into adulthood
**Less severe than Hurler’s Syndrome
Which is more severe, Hurler or Hunter Syndrome?
Hurler Sydrome (Type I)
What are GAGs/ MPS?
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
What are the Glycogen Storage Diseases?
Recessive diseases resulting in a defect in an enzyme involved in the synthesis or degradation of glycogen
What are the three GSDs that we are responsible for?
Type I= von Gierke
Type II= Pompe
Type V= McArdle
What is the enzyme defect seen in Type I GSD?
von Gierke= glucose 6-phosphatase
What is the enzyme defect seen in Type II GSD?
Pompe= acid maltase
What is the enzyme defect seen in Type V GSD?
McArdle= muscle phosphorylase
What are the symptoms of Type II GSD?
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.
Describe the microscopic appearance of Pompe Disease.
“Clear”
What are the symptoms of von Gierke’s Disease?
Hepatomegaly
Hypoglycemia
Renomegaly
*****Note that defect in the hepatic enzyme in glycogen breakdown leads to hepatomegaly & reduction in blood glucose (hypoglycemia)
What is the difference between Type I & Type V GSD?
Type I= von Gierke Disease
- hepatic form
Type V= McArdle
- myopathic form
What are the symptoms of McArdle Disease?
- 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
How does von Gierke’s Disease appear microscopically?
Vacuolated
