Genetic diseases II Flashcards
True or false: AR diseases have much more uniform expression than AD
True
True or false: AR diseases often have complete penetrance
True
When do AR usually present, early, middle, or late in life?
Early
AR proteins usually show what mutation?
Loss of function
True or false: all inborn errors of metabolism are AR
True
Which are more common, AR or AD diseases?
AR
True or false: AD diseases usually skip generations
False-AR
Alkaptonuria is the result of a deficiency of what enzyme?
Homogentisic acid oxidase
What is the pathogenesis of alkaptonuria?
Homogentisic acid binds to cartilage, turning it blue-black
Urine that turns black upon standing = ?
alkaptonuria
What is the reaction that homogentisic acid oxidase catalyzes?
Homogentisic acid to maleyacetoacetic acid
What is the major symptom of alkaptonuria?
Early onset osteoarthritis d/t deposition of homogentisic acid in cartilage
What part of the body is susceptible to the osteoarthritis caused by alkaptonuria?
Vertebral discs
True or false: cartilage is the only place where homogentisic acid is deposited?
False–tendons as well
Black skin spots around the ears = ?
alkaptonuria
What is the general problem in lysosomal storage disease?
Lysosomes do not function correctly, thus causing a buildup of materials in a lysosome. This can cause cells death
What is the enzyme that is affected in Tay-sachs?
Hexosaminidase A
What is the enzyme that is affected in Gaucher’s disease?
Glucocerebrosidase
What is the enzyme that is affected in Niemann-pick disease?
Sphingomyelinase
What is the enzyme that is affected in mucopolysaccharidoses?
Induronidase
What is the major accumulating metabolite in Tay sachs?
CM2 ganglioside
What is the major accumulating metabolite in Gaucher’s disease?
glucocerebroside
What is the major accumulating metabolite in Niemann pick disease?
Sphingomyelin
What is the major accumulating metabolite in Hurler’s and hutner’s syndrome?
Dematan sulfate, heparan sulfate
What is the enzyme deficiency in Hunter’s syndrome? Hurlers?
Hulers = alpha-L-iduronidase Hunters = L-iduronosulfate sulfatase
What is the enzyme that is affected in Gaucher’s disease?
-Beta-Glucocerebrosidase
What is the therapeutic agent for Pompe’s disease?
Myozyme
What is the therapeutic agent for Hunter’s syndrome?
Elaprase
What is the therapeutic agent for Hurler’s syndrome?
Aldurazyme
Tay-Sach’s disease is caused by what mutation in what gene?
Frameshift mutation in the HexA gene
What are the symptoms of Tay-sachs? Pathogenesis?
MR and blindness after birth d/t accumulation of ganglioside accumulation
When does death occur in pts with Tay-sachs?
before age 4
What are the LM histological findings of Tay-sachs?
Swollen neurons
Membranous concentric bodies in neurons on EM = ?
Tay-sachs disease
Cherry red spot = what disease? Why?
Tay-sachs or Niemann Picks type A d/t increased deposition
What is the cherry red spot?
Enhanced macula d/t deposition of material around it. Seen in Tay-sachs and Niemann-Picks type A
What is the most common lysosomal storage disease?
Gaucher’s disease
What is the pathogenesis in Gaucher’s disease?
Accumulation of glucocerebrosides (ceramide + glucose) within lysosomes of macrophages
On what chromosome is the gene for glucocerebrosidase?
1q
What are Gaucher cells?
Macrophages with accumulation of glucoceramide
What are the histological findings of Gaucher’s disease?
Macrophages with wrinkled tissue paper appearance
Which type of Gaucher’s is most common (1, 2, or 3)? Which is most severe?
1 = most common 2 = most severe
Which type(s) of Gaucher’s have neuropathic involvement (1, 2, or 3)?
2 and 3
What are the symptoms of type 1 Gaucher’s? Pathogenesis?
Asymptomatic to skeletal deformities/hepatosplenomegaly d/t macrophage accumulations
What are the symptoms of type 2 Gaucher’s?
Type III +
Hydrops fetalis
Progressive neuro degeneration
What are the symptoms of type 3 Gaucher’s?
Parkinsonian
Eye movement disorders
Which type of Gaucher’s disease is seen in higher incidence amongst Ashkenazi jews?
Type I
What are the symptoms of type 1 Gaucher’s? Pathogenesis?
Asymptomatic to skeletal deformities/hepatosplenomegally d/t macrophage accumulations
What are the symptoms of type 2 Gaucher’s? Pathogenesis?
Type III +
Hydrops fetalis
Progressive neuro degeneration
What are the symptoms of type 3 Gaucher’s? Pathogenesis?
Parkinsonian
Eye movement disorders
What is the treatment for Gaucher’s disease?
Imiglucerase (cerezyme)
What is the mutation of type A and B Niemann-Pick’s disease? What is the gene affected?
Missense mutation in acid sphingomyelinase
What is the mutation of type C Niemann-Pick’s disease? What is the gene affected?
Deficiency in cholesterol transport–NOT an enzyme defect
What are the symptoms of type A Niemann-Picks disease?
Neurological defects
What are the symptoms of type B Niemann-Picks disease?
Hepatosplenomegaly
No CNS involvement
What is the mutation of type A and B Niemann-Pick’s disease?
Missense mutation in acid sphingomyelinase
What are the symptoms of type B Niemann-Picks disease?
Hepatosplenomegaly
No CNS involvement
In what cells does sphingomyelin accumulate in Niemann-Picks disease?
Macrophages
Zebra body macrophages = what disease?
Niemann-Picks
What is the mutation in type C Niemann-Picks disease? What does this cause? What is deposited in macrophages?
NPC1–defect in choleserol transport, causing increased deposition of GM1 and GM2
Which is most common Type A, B or C of Niemann-Picks disease?
Type C
What are the symptoms of type C Niemann-Picks disease?
Progressive neurological damage (ataxia, dystonia etc)
What is NP1 protein in Niemann picks type C?
G-coupled protein receptor to get cholesterol out of the lysosome
What is NP2 protein in Niemann picks type C?
Transporter of cholesterol
As pts with Niemann-Picks disease age, what happens to their neurological symptoms? Systemic symptoms?
Systemic go down
Neuro go up
What are the four major diseases that have an increased incidence in the Ashkenazi Jewish population?
- CF
- Gaucher’s disease
- Niemann-Pick
- Taysachs
What is the general problem with mucopolysaccharidoses?
Defect in lysosomal enzymes that degrade mucopolysaccharides, causing a buildup in lysosomes of muscle tissues
Which has a milder course: Hurler’s or Hunter’s syndrome?
Hunter
What are the histological characteristics of MPS?
cleared cytoplasm in cells
What is the inheritance pattern for Hunters syndrome? Hurlers?
Hunters = XLR Hurler's = AR
What are the symptoms of Hurler’s syndrome? (2)
Gargoyle children with EITHER progressive MR OR aortic valve problems
subendothelial arterial deposits in the coronary arteries
What are the symptoms of Hunter’s syndrome? (2)
mild hepatosplenomegaly
subendothelial arterial deposits in the coronary arteries
What symptom is common to Hurler’s and Hunter’s syndrome?
subendothelial arterial deposits in the coronary arteries
Which has corneal clouding: Hurler’s or Hunter’s syndrome?
Hurler’s
True or false: there is an enzyme replacement therapy for both Hurler’s and Hunter’s syndrome
True
What is the enzyme deficiency in von Gierke’s disease, (type I), and what does this cause (3)?
Glucose-6-phosphatase
Hepatomegaly, hypoglycemia, hyperlipidemia,
What is the enzyme deficiency in Pompe’s disease, (type III), and what does this cause (3)?
Acid maltase
Floppy baby, Cardiomegally, cardiorespiratory failure
What are the names of Type I, III, and V GSDs?
I = Von Gierke's disease V= McArdle's disease III = Pompe's disease
What is the enzyme deficiency in McArdle’s disease, (type V), and what does this cause (2)?
Muscle phosphorylase
Painful cramps with exercise +myoglobin uria
Floppy baby + glossomegaly + cardiomegaly = ?
Pompe’s disease (type III GSD)
What is the stain used to highlight carbs?
PAS
Hepatomegaly + Xanthomas + gout + hypoglycemia + hyperlipidemia + convulsion = what disease?
Type I GSD (von Gierke’s)
True or false: McArdle’s syndome have normal muscle strength
True